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(11) EP 2 478 895 A2

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 25.07.2012 Bulletin 2012/30 A61K 9/00 (2006.01) A61K 31/195 (2006.01) A61K 31/27 (2006.01) A61K 31/341 (2006.01) (2006.01) (2006.01) (21) Application number: 12164341.5 A61K 31/4164 A61K 31/4184 A61K 31/426 (2006.01) A61K 31/4439 (2006.01) (2006.01) (2006.01) (22) Date of filing: 21.12.2007 A61K 31/444 A61K 31/575 A61K 31/785 (2006.01) A61K 33/08 (2006.01) A61K 33/10 (2006.01) A61P 1/04 (2006.01) A61K 45/06 (2006.01)

(84) Designated Contracting States: (72) Inventor: Currie, Mark G AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Cambridge, MA 02141 (US) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR (74) Representative: Oldroyd, Richard Duncan Elkington and Fife LLP (30) Priority: 22.12.2006 US 871499 P Prospect House 8 Pembroke Road (62) Document number(s) of the earlier application(s) in Sevenoaks, Kent TN13 1XR (GB) accordance with Art. 76 EPC: 07869791.9 / 2 124 884 Remarks: This application was filed on 16-04-2012 as a (71) Applicant: Ironwood Pharmaceuticals, Inc. divisional application to the application mentioned Cambridge, MA 02142 (US) under INID code 62.

(54) Compositions for treating esophageal disorders

(57) Disclosed herein are novel compositions and bile acid sequestrant in combination with one or more methods for treating or preventing upper GI tract disor- agents chosen from, γ-aminobutyricacid-b (GABA-B) ag- ders. The methods generally include administering to a onists and prodrugs of GABA-B agonists. patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising at least one EP 2 478 895 A2

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 478 895 A2 2

Description spreads to the throat along with a sour taste in the mouth; nausea; vomiting bile; a cough; or hoarseness. BACKGROUND [0007] Bile and stomach acid reflux into the esophagus when the lower esophageal sphincter (LES), malfunc- [0001] The present application relates generally to 5 tions. The LES separates the esophagus and stomach. combinations of compounds and methods for treating up- Normally, it opens only to allow food to pass into the per gastrointestinal tract disorders. More particularly, the stomach and then closes tightly. But if the valve relaxes present application relates to the use of at least one bile abnormally or weakens, stomach acid and bile can wash acid sequestrant for treating esophageal disorders. back into the esophagus, causing heartburn and ongoing [0002] The esophagus carries food, liquids, and saliva 10 inflammation that may lead to serious complications. from the mouth to the stomach by coordinated contrac- [0008] A sticky mucous coating protects the stomach tions of its muscular lining. This process is automatic and from the corrosive effects of stomach acid, but the es- people are usually not aware of it. Many people have felt ophagus lacks this protection, which is why bile reflux their esophagus when they swallow something too large, and acid reflux can seriously damage esophageal tissue. try to eat too quickly, or drink very hot or very cold liquids. 15 And although bile reflux can injure the esophagus on its They then feel the movement of the food or drink down own - even when the pH of the reflux is neutral or alkaline the esophagus into the stomach, which may be an un- - the combination of bile and acid reflux seems to be comfortable sensation. particularly harmful, increasing the risk of complications, [0003] The muscular layers of the esophagus are nor- such as: Gastroesophageal reflux disease, or GERD; mally pinched together at both the upper and lower ends 20 Barrett’s esophagus; esophageal cancer, and gastritis. by muscles called sphincters. When a person swallows, [0009] GERD is a generic term encompassing diseas- the sphincters relax automatically to allow food or drink es with various digestive symptoms such as pyrosis, acid to pass from the mouth into the stomach. The muscles regurgitation, obstructed admiration, aphagia, pectoral- then close rapidly to prevent the swallowed food or drink gia, permeating feeling and the like sensibility caused by from leaking out of the stomach back into the esophagus 25 reflux in the esophagus and stagnation of gastric con- or into the mouth. These sphincters make it possible to tents, duodenal juice, pancreatic juice and the like. The swallow while lying down or even upside-down. When term covers both of reflux esophagitis in which erosion people belch to release swallowed air or gas from car- and ulcers are endoscopically observed, and esophageal bonated beverages, the sphincters relax and small regurgitation-type non-ulcer dyspepsia (NUD) in which amounts of food or drink may come back up briefly; this 30 no abnormality is endoscopically observed. GERD oc- condition is called reflux. The esophagus quickly squeez- curs when the LES does not close properly and stomach es the material back into the stomach. This amount of contents leak back, or reflux, into the esophagus. reflux and the reaction to it by the esophagus are con- [0010] A hiatal hernia may contribute to causing GERD sidered normal. and can happen in people of any age. Other factors that [0004] While most people are familiar with acid reflux 35 may contribute to GERD include, but are not limited to, - the backflow of caustic stomach acids into the esopha- alcohol use, overweight, pregnancy, smoking, Zollinger- gus - bile reflux, which occurs when bile - a digestive fluid Ellison syndrome, hypercalcemia, and scleroderma. Al- produced in the liver - flows upward (refluxes) from the so, certain foods can be associated with reflux events, small intestine into the stomach and esophagus, is less including, citrus fruits, chocolate, drinks with caffeine, fat- well known. Bile reflux often accompanies acid reflux, 40 ty and fried foods, garlic and onions, mint flavorings, spicy and together may lead to inflammation of the esophageal foods, and tomato- based foods, like spaghetti sauce, chi- lining and potentially increased risk of esophageal can- li, and pizza. cer. See AJG (1999) 94(12):3649-3650. Bile reflux also [0011] The inner mucosa of the esophagus is lined with affects the stomach, where it causes further inflamma- nonkeratinized stratified squamous epithelium arranged tion. 45 in longitudinal folds. Damage to the lining of the esopha- [0005] Unlike acid reflux, bile reflux usually can’t be gus causes the normal squamous cells that line the es- controlled by changes in diet or lifestyle. Instead, bile ophagus to turn into a type of cell not usually found in reflux is most often managed with certain medications humans, called specialized columnar cells. That conver- or, in severe cases, with surgery. Neither solution is uni- sion of cells in the esophagus by the acid reflux, is known formly effective, however, and some people continue to 50 as Barrett’s Esophagus. Although people who do not experience bile reflux even after treatment. have heartburn can have Barrett’s esophagus, it is found [0006] Bile reflux can be difficult to distinguish from about three to five times more often in people with this acid reflux - the signs and symptoms are similar, and the condition. Barrett’s esophagus does not cause symp- two conditions frequently occur at the same time. Unlike toms itself and is important only because it seems to pre- acid reflux, bile reflux inflames the stomach, often caus- 55 cede the development of a particular kind of cancer-es- ing a gnawing or burning pain in the upper abdomen. ophageal adenocarcinoma. The risk of developing ade- Other signs and symptoms may include: frequent heart- nocarcinoma is 30 to 125 times higher in people who burn, i.e., a burning sensation in the chest that sometimes have Barrett’s esophagus than in people who do not. This

2 3 EP 2 478 895 A2 4 type of cancer is increasing rapidly in white men. This nized challenge in gastroenterology and there is a need increase may be related to the rise in obesity and GERD. in the art to address and overcome upper GI tract disor- [0012] Barrett’s esophagus has no cure, short of sur- ders that are non- responsive to treatment by administra- gical removal of the esophagus, which is a serious op- tion of PPIs alone. eration. Surgery is recommended only for people who 5 [0017] Accordingly, the development of an effective have a high risk of developing cancer or who already treatment for pathologies in which inhibition of one or have it. Most physicians recommend treating GERD with both of gastric acid secretion and bile acid secretion is acid-blocking drugs, since this is sometimes associated required would be useful. with improvement in the extent of the Barrett’s tissue. However, this approach has not been proven to reduce 10 SUMMARY the risk of cancer. Treating reflux with a surgical proce- dure for GERD also does not seem to cure Barrett’s es- [0018] Briefly, the present application discloses a ophagus. Several different experimental approaches are treatment for upper gastrointestinal disorders in which under study. One attempts to see whether destroying the the inhibition of one or both of gastric acid secretion and Barrett’s tissue by heat or other means through an en- 15 bile acid secretion is desirable. doscope can eliminate the condition. This approach, [0019] In accordance with the above, the present ap- however, has potential risks and unknown effectiveness. plication discloses compositions and methods for treat- [0013] Esophageal cancer can occur almost anywhere ing or preventing upper GI tract disorders such as, for along the length of the esophagus, but it frequently starts example, gastroesophageal reflux disease (GERD), in the glandular cells closest to the stomach (adenocar- 20 heartburn, indigestion, dyspepsia, erosive esophagitis, cinoma). Because esophageal cancer may not be diag- peptic ulcer, gastric ulcer, NSAID- associated ulcers, du- nosed until it’s quite advanced, the outlook for people odenal ulcers, esophageal ulcers, esophagitis, laryngitis, with the disease is often poor. The risk of cancer of the ulcers arising from Meckel’s diverticulum, Barrett’s Es- esophagus is increased by long-term irritation of the es- ophagus, esophageal adenocarcinoma, pharyngitis, and ophagus, such as with smoking, heavy alcohol intake, 25 GERD-related pulmonary dysfunction (e.g., asthma and Barrett’s esophagitis. Thus, there is a link between and/or cough). esophageal cancer and bile reflux and acid reflux. In an- [0020] In a first aspect, compositions containing a ther- imal models, bile reflux alone has been shown to cause apeutically effective amount of at least one bile acid se- cancer of the esophagus. questrant, wherein the compositions are useful for treat- [0014] There are numerous medications available that 30 ing or preventing an upper GI tract disorder, or for pro- can effectively treat heartburn and indigestion. Presently, tecting the stratified squamous epithelium against injury the main therapies employed in the treatment of GERD by a noxious substance, are disclosed. and upper GI tract disorders include agents for reducing [0021] In certain embodiments, the bile acid seques- the stomach acidity, for example by using the histamine trant includes, but is not limited to, cholestyramine (i.e., 35 H2-receptor antagonists or proton pump inhibitors (PPIs). QUESTRAN®, QUESTRAN LIGHT®, CHOLYBAR®, H2 blockers are drugs that inhibit the production of acid CA registry no. 11041-12-6), colesevelam (i.e., WEL- in the stomach. Exemplary histamine H 2-receptor antag- CHOL®, CA registry nos. 182815-43-6 and onists include, for example, cimetidine (as sold under the 182815-44-7), ursodeoxycholic acid (i.e. CA registry no. brand-name TAGAMET HB ®), famotidine (as sold under 128-13-2), colestipol (i.e., COLESTID®, CA registry nos. the brand-name PEPCID AC ®), nizatidine (as sold under 40 50925-79-6 and 37296-80-3), sevelamer, dialkylami- the brand-name AXID AR ®), and ranitidine (as sold under noalkyl derivatives of a cross-linked dextran, LOC- the brand-name ZANTAC 75 ®). Both types of medication HOLEST®, DEAE-Sephadex (SECHOLEX®, POLI- are effective in treating heartburn and usually eliminate DEXIDE®), water soluble derivatives such as 3,3- ioene, symptoms within a short period of time. N-(cycloalkyl)alkylamines and poliglusam, insoluble [0015] PPIs act by inhibiting the parietal cell H +/K+ AT- 45 quaternized polystyrenes, saponins and mixtures there- Pase proton pumps responsible for acid secretion from of, those bile acid sequestrants disclosed in these cells. PPIs, such as omeprazole, and its pharma- WO97/11345, WO98/57652, US3692895, and ceutically acceptable salts are disclosed, for example, in US5703188, including pharmaceutically acceptable EP 05129, EP 124495 and U.S. Pat. No. 4,255,431. salts or mixtures thereof. Suitable inorganic cholesterol [0016] Despite their well-documented efficacy, PPIs 50 sequestrants include bismuth salicylate plus montmo- have notable limitations. These drugs exhibit substantial rillonite clay, aluminum hydroxide and carbonate inter-patient variability in pharmacokinetics and may . have significant interactions with other drugs. For exam- [0022] In other embodiments, the compositions con- ple, patients who are non-responsive to treatment with taining a therapeutically effective amount of at least one PPI inhibitor alone may be non- responsive because even 55 bile acid sequestrant can additionally include a therapeu- though the PPI is decreasing acid reflux from the stom- tically effective amount of at least one proton pump in- ach, bile acid from the duodenum is still present. Thus, hibitor. an improvement of PPI- mediated activity is a well- recog- [0023] In certain embodiments, the proton pump inhib-

3 5 EP 2 478 895 A2 6 itor includes, for example, any of the following com- trypsin and chymotrypsin inhibitors are known to those pounds: omeprazole (i.e., PRILOSEC®, ZEGERID®, skilled in the art and can be used in the methods de- LOSEC®, CA registry no. 73590-58-6), esomeprazole scribed herein. Such trypsin and chymotrypsin inhibitors (i.e., NEXIUM®, perprazole, s-omeprazole , can include tissue- factor-pathway inhibitor; α-2 antiplas- CA registry no. 161973-10-0), lansoprazole (i.e., PRE- 5 min; serpin α-1 antichymotrypsin family members; gelin; VACID®, ZOTON®, INHIBITOL®, CA registry no. hirustasin; eglins including eglin C; inhibitors from Bom- 103577-45-3), pantoprazole (i.e., PROTONIX®, PRO- byx mori (see; e.g.; JP 4013698 A2 and JP 04013697 TILTM®, SOMAC®, PANTOLOC®, CA registry no. A2; CA registry No. 142628-93-1); hirudin and variants 102625-70-7), rabeprazole (i.e., RABECID®, ACI- thereof; secretory leukocyte protease inhibitor (SLPI); α- PHEX®, PARIET®, habeprazole, pariprazole, CA regis- 10 1 anti-trypsin; Bowman-Birk protease inhibitors (BBIs); try nos. 117976-89-3 and 117976-90-6), tenatoprazole chymotrypsin inhibitors represented by CAS registry (i.e., benatoprazole, S-Tenatoprazole-Na STU-Na, CA Nos. 306762-66-3, 306762-67-4, 306762-68-5, registry no. 113712-98-4), leminoprazole (i.e., CA regis- 306762-69-6, 306762-70-9, 306762-71-0, 306762-72-1, try no. 104340-86-5), dontoprazole (i.e., CA registry no. 306762-73-2, 306762-74-3, 306762-75-4, 178330-92-2, 350507-35-6), ransoprazole (i.e., CA registry 15 no. 178330-93-3, 178330-94-4, 81459-62-3, 81459-79-2, 832103-67-0), or pharmaceutically acceptable salts or 81460-01-7, 85476-59-1, 85476-62-6, 85476-63-7, mixtures thereof. 85476-67-1, 85476-70-6, 85858-66-8, 85858-68-0, [0024] In other embodiments, the compositions de- 85858-69-1, 85858-70-4, 85858-71-5, 85858-72-6, scribed herein (whether prepared as a bile acid seques- 85858-73-7, 85858-75-9, 85858-77-1, 85858-79-3, trant alone or co-formulated with a proton pump inhibitor) 20 85858-81-7, 85858-83-9, 85858-84-0, 85858-85-1, can be further formulated to optionally include any one 85858-87-3, 85858-89-5, 85858-90-8, 85858-92-0, or a combination of the numerous commercially availa- 85879-03-4, 85879-05-6, 85879-06-7, 85879-08-9, ble, over-the-counter (OTC) medications for reducing the 85858-74-8, 90186-24-6, 90185-93-6, 89703-10-6, stomach acidity employed to treat GERD and other upper 138320-33-9 (YS3025), 94149-41-4 (MR889), GI tract disorders. Such commercially available OTC25 85858-76-0, 89703-10-6, 90185-92-5, 90185-96-9, medications include, but are not limited to, histamine 90185-98-1, 90186-00-8, 90186-01-9, 90186-05-3, H2-receptor antagonists and antacids. 90186-06-4, 90186-07-5, 90186-08-6, 90186-09-7, [0025] Exemplary histamine H2-receptor antagonists 90186-10-0, 90186-11-1, 90186-12-2, 90186-13-3, include, for example, cimetidine (as sold under the brand- 90186-14-4, 90186-22-4, 90186-23-5, 90186-24-6, name TAGAMET HB®), famotidine (as sold under the 30 90186-25-7, 90186-27-9, 90186-28-0, 90186-29-1, brand-name PEPCID AC ®), nizatidine (as sold under the 90186-31-5, 90186-35-9, 90186-43-9, 90209-88-4, brand-name AXID AR®), and ranitidine (as sold under 90209-89-5, 90209-92-0, 90209-94-2, 90209-96-4, the brand-name ZANTAC 75®). 90209-97-5, 90210-01-8, 90210-03-0, 90210-04-1, [0026] Exemplary antacids include, but are not limited 90210-25-6, 90210-26-7, 90210-28-9, 90230-84-5, to, insoluble inorganic salts such as , 35 90409-84-0, 95460-86-9, 95460-87-0, 95460-88-1, , calcium hydroxide, magnesium 95460-89-2, 95460-91-6, 114949-00-7, 114949-01-8, hydroxide, or aluminum hydroxide. Typical consumer 114949-02-9, 114949-03-0, 114949-04-1, 114949-05-2, products include, but are not limited to, TUMS®, 114949-06-3, 114949-18-7, 114949-19-8, 114964-69-1, MILK of MAGNESIA®, MAALOX PLUS®, ALKA-SELT- 114964-70-4, 9076-44-2 (chymostatin), 30827-99-7 (Pe- ZER®, MYLANTA®, PEPTO-BISMOL®, RIOPAN®, and 40 fabloc), 618-39-3 (benzamidine), 80449-31-6 (urinista- ROLAIDS®. tin), 130982-43-3, 197913-52-3, 179324-22-2, [0027] In still other embodiments, the compositions de- 274901-16-5, 792163-40-7, 339169-59-4, 243462-36-4, scribed herein (whether prepared as a bile acid seques- 654671-78-0, 55123-66-5 (leupeptin), 901-47-3, trant alone or co-formulated with a proton pump inhibitor 4272-74-6, 51050-59-0, 221051-66-7, 80449-31-6, and another agent) can be further formulatedto optionally 45 55-91-4, 60-32-2, 88070-98-8, 87928-05-0, 402-71-1 include any one or a combination of γ-aminobutyricacid- (benzenesulfonamide), 139466-47-0, 2A CI- (see b (GABA-B) agonists, prodrugs of GABA- B agonists, and US5167483),CI-2A (seebWO9205239), WCI- 3 (see Shi- protease inhibitors. bata et al. 1988 J Biochem (Tokyo) 104:537-43), WCI-2 [0028] Exemplary GABA-B agonists, include, for ex- (see Habu et al. 1992 J Biochem (Tokyo) 111:249-58), ample, baclofen. In an embodiment, the GABA- B agonist 50 and WCI-x (Habu et al., supra) and 178330-95-5; and is R-baclofen.. compounds with chymotrypsin inhibition activity de- [0029] Exemplary prodrugs of GABA-B agonists in- scribed in patent publications JP 56092217 A2, clude, for example, XP19986 (CAS Registry No.US4755383, US4755383, US4639435, US4620005, 847353-30-4). US4898876, and EP0128007. [0030] Exemplary protease inhibitors include, for ex- 55 [0031] In a second aspect, pharmaceutical composi- ample, aspartyl protease inhibitors, such as pepstatin tions for gastric retention of any of the compositions de- and other pepsin inhibitors (e.g., benzoate); and scribed herein are disclosed and provide sustained-re- chymotrypsin and trypsin inhibitors. A wide variety of lease of the active agents. In certain embodiments, the

4 7 EP 2 478 895 A2 8 pharmaceutical dosage form contains at least one bile quentially one or more agents chosen from an antacid, acid sequestrant and a gastric-retention vehicle compo- a histamine H2-receptor antagonist, a γ-aminobutyricac- sition that contains one or more hydrogels such that the id-b (GABA-B) agonist, a prodrug of a GABA-B agonist, dosage form expands upon contact with gastric fluid. and a protease inhibitor. [0032] In certain embodiments, the pharmaceutical 5 [0043] In other embodiments, the composition is in a dosage form is retained for a period of 6-24 hours (e.g., form suitable for oral administration. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, [0044] In another aspect, methods for protecting strat- 22, 23, or 24 hours), or longer. ified squamous epithelium against injury by a noxious [0033] In certain embodiments, the active agent com- substance byadministering to an individual in needthere- ponent can be in the form of a tablet and may additionally 10 of a therapeutically effective amount of a composition contain suitable diluents, glidants, lubricants, acidulants, comprising at least one bile acid sequestrant are dis- stabilizers, swelling agents and other pharmaceutically closed. acceptable excipients. [0045] In certain embodiments, the methods can in- [0034] Exemplary hydrogels include, for example, hy- clude administering simultaneously, separately, or se- droxypropyl methylcellulose, hydroxypropylcellulose,15 quentially, a therapeutically effective amount of one or sodium carboxymethylcellulose, agar, agarose, locust more proton pump inhibitors. bean gum, carageenan, alginic acid, konjac gum, guar [0046] In other embodiments, the methods can include gum, and xanthan gum. administering simultaneously, separately, or sequential- [0035] In other embodiments, the gastric- retention ve- ly one or more agents chosen from an antacid, a hista- 20 hicle composition can additionally include one or more mine H2-receptor antagonist, aγ -aminobutyricacid-b of a superdisintegrant, a binder, and a gas-generating (GABA-B) agonist, a prodrug of a GABA-B agonist, and agent. a protease inhibitor. [0036] Exemplary superdisintegrants include, for ex- [0047] In yet another aspect, kits for treating an upper ample, crospovidone, croscarmellose sodium, and sodi- GI tract disorder comprising, in one or more containers, um starch glycolate. 25 a therapeutically effective amount of the compositions [0037] Exemplary binders include, for example, as described in detail herein, and a label or packaging poloxamers, polyethylene glycols, insert containing instructions for use are disclosed. fatty acid esters, glyceryl palmitostearate, polyoxyethyl- [0048] These, and other objects, features and advan- ene alkyl ethers, glyceryl behenate, stearoyl - tages of this disclosure will become apparent from the 32-glyceride, polyoxyethylene derivatives,30 following detailed description of the various aspects of polyoxyethylene sorbitan fatty acid derivatives, polyox- the disclosure taken in conjunction with the accompany- yethylene stearates, polyoxyethylene-polyoxypropylene ing Examples. copolymers, starches, gelatin, sugars such as lactose, sucrose, glucose and molasses, natural and synthetic DETAILED DESCRIPTION gums such as acacia, sodium alginate, carboxymethyl- 35 cellulose, methylcellulose, polyvinylpyrrolidone, ethyl [0049] The present application discloses compositions cellulose and waxes. containing at least one bile acid sequestrant, alone or in [0038] Exemplary gas-generating agents include, for combination with other active agents, which are useful example, sodium hydrogen carbonate, sodium carbon- for treating or preventing a variety of upper gastrointes- ate, potassium carbonate, calcium carbonate, magnesi- 40 tinal (GI) tract disorders and associated conditions. um carbonate, and sodium glycine carbonate. [0050] The present application further discloses com- [0039] In a third aspect, methods for treating or pre- positions including at least one proton pump inhibitor and venting an upper gastrointestinal tract disorder by admin- at least one bile acid sequestrant which when adminis- istering to a patient in need thereof a composition con- tered to esophageal epithelial cell cultures, which are nor- taining a therapeutically effective amount of at least one 45 mally nonkeratinized, stratified squamous epithelium ar- bile acid sequestrant are disclosed. ranged in longitudinal folds, provide the benefit of inhib- [0040] In certain embodiments, the patient may be suf- iting transformation into specialized columnar cells (indi- fering from (or susceptible to developing) an upper GI cating premalignancy) at a greater efficacy than either tract disorder including, but not limited to, dyspepsia, agent alone. heartburn, erosive esophagitis GERD, peptic ulcer, es- 50 [0051] Accordingly, the compositions disclosed herein ophagitis, Barrett’s Esophagus, and esophageal adeno- are useful in methods for treating or preventing a variety carcinoma. of upper gastrointestinal (GI) tract disorders and associ- [0041] In other embodiments, the methods can include ated conditions such as, for example, gastroesophageal administering simultaneously, separately, or sequential- reflux disease (GERD) (including responsive non- ly, a therapeutically effective amount of one or more pro- 55 GERD), heartburn, indigestion, dyspepsia, erosive es- ton pump inhibitors. ophagitis, peptic ulcer, gastric ulcer, NSAID-associated [0042] In still other embodiments, the methods can in- ulcers, duodenal ulcers, esophageal ulcers, esophagitis, clude administering simultaneously, separately, or se- laryngitis, ulcers arising from Meckel’s diverticulum, Bar-

5 9 EP 2 478 895 A2 10 rett’s Esophagus, esophageal adenocarcinoma, and drug or agent that, when administered to a subject with pharyngitis. a disease or condition, will have the intended therapeutic [0052] The present application includes compositions effect, e.g., alleviation, amelioration, palliation or elimi- comprising therapeutically effective amounts of at least nation of one or more manifestations of the disease or one bile acid sequestrant, or pharmaceutically accepta- 5 condition in the subject. The full therapeutic effect does ble salts thereof, formulated alone or in combination with not necessarily occur by administration of one dose and a therapeutically effective amount of at least one proton may occur only after administration of a series of doses. pump inhibitor, or pharmaceutically acceptable salts Thus, a therapeutically effective amount may be admin- thereof. In an embodiment, the compositions disclosed istered in one or more administrations. herein can also include, or be administered in combina- 10 [0059] As used herein, a "prophylactically effective tion (either simultaneously, separately, or sequentially) amount" of a drug or pharmaceutical composition or for- with, one or more commercially available antacids, his- mulation, or agent, described herein is an amount of a tamine H2-receptor antagonists, γ-aminobutyricacid-b drug or agent that, when administered to a subj ect, will (GABA-B) agonists, prodrugs of GABA-B agonists, and have the intended prophylactic effect, e.g., preventing or protease inhibitors. 15 delaying the onset (or reoccurrence) of disease or symp- [0053] In certain embodiments, any of the composi- toms, or reducing the likelihood of the onset (or reoccur- tions disclosed herein can be provided as a sustained- rence) of disease or symptoms. The full prophylactic ef- release pharmaceutical dosage form that includes a ther- fect does not necessarily occur by administration of one apeutically effective amount of one of the compositions dose and may occur only after administration of a series described herein and a gastric-retention vehicle compo- 20 of doses. Thus, a prophylactically effective amount may sition that contains one or more hydrogels, such that the be administered in one or more administrations. dosage form expands upon contact with gastric fluid, [0060] As used herein, and as would be understood thereby retaining the dosage form in the user’s stomach by the person of skill in the art, the recitation of "a com- for a longer period of time. pound" or "a composition" is intended to include salts, [0054] The present application also includes methods 25 solvates and inclusion complexes of that compound as for treating or preventing an upper GI tract disorder by well as any stereoisomeric form, or a mixture of any such administering to a patient in need thereof a therapeuti- forms of that compound in any ratio. cally effective amount of a pharmaceutical composition [0061] The term "pharmaceutically acceptable salt" re- as disclosed and described in detail herein. fers to salts prepared from pharmaceutically acceptable [0055] Similarly, the present application also includes 30 non-toxic acids or bases including inorganic acids and methods for protecting stratified squamous epithelium bases and organic acids and bases. When the com- against injury by a noxious substance by administering pounds of the present disclosure are basic, salts may be to a patient in need thereof a therapeutically effective prepared from pharmaceutically acceptable non-toxic amount of a pharmaceutical composition as disclosed acids including inorganic and organic acids. Suitable and described in detail herein. 35 pharmaceutically acceptable acid addition salts for the [0056] As employed above and throughout the disclo- compounds of the present disclosure include acetic, ben- sure, the following terms are provided to assist the read- zenesulfonic (besylate), benzoic, camphorsulfonic, citric, er. Unless otherwise defined, all terms of art, notations ethenesulfonic, fumaric, gluconic, glutamic, hydrobro- and other scientific or medical terms or terminology used mic, hydrochloric, isethionic, lactic, maleic, malic, man- herein are intended to have the meanings commonly un- 40 delic, methanesulfonic, mucic, nitric, pamoic, pantothen- derstood by those of skill in the chemical and medical ic, phosphoric, succinic, sulfuric, tartaric acid, p-tolue- arts. In some cases, terms with commonly understood nesulfonic, and the like. When the compounds contain meanings are defined herein for clarity and/or for ready an acidic side chain, suitable pharmaceutically accepta- reference, and the inclusion of such definitions herein ble base addition salts for the compounds of the present should not necessarily be construed to represent a sub- 45 disclosure include metallic salts made from aluminum, stantial difference over the definition of the term as gen- calcium, lithium, magnesium, potassium, sodium and erally understood in the art unless otherwise indicated. zinc or organic salts made from lysine, N, N’-dibenzyleth- [0057] As used herein, "treating" or "treatment of’ a ylenediamine, chloroprocaine, choline, diethanolamine, condition or subject refers to taking steps to obtain ben- ethylenediamine, meglumine (N-methylglucamine) and eficial or desired results, including clinical results. For 50 procaine. purposes of this disclosure, beneficial or desired clinical [0062] Administration of any of the compositions or for- results include, but are not limited to, alleviation or amel- mulations described in detail herein includes parallel ad- ioration of one or more disease, symptom, or condition ministration (i.e., administration of elements of the for- related to lipid disorders, fatty liver disease, mulation to the subject over a period- of time), co-admin- hepatitis, or erectile dysfunction. 55 istration or sequential administration (in which elements [0058] As used herein, a "therapeutically effective of the formulation are administered at approximately the amount" of a drug or pharmaceutical composition or for- same time, e.g., within about a few seconds to a few mulation, or agent, described herein is an amount of a hours of one another), and simultaneous or co-formula-

6 11 EP 2 478 895 A2 12 tion (in which elements of the formulation are combined epithelium in vivo. Examples of such "noxious substanc- or compounded into a single dosage form suitable for es" include acids or other substances, including, but not oral or parenteral administration). limited to, gastric acid, HCl, N- acetylcysteine, pepsin, ac- [0063] Combination therapy can be achieved by ad- id-pepsin, or other irritant which contacts epithelial tissue. ministering two or more agents, e.g., a proton pump in- 5 [0069] The terms "gastric fluid" and "gastric juice" are hibitor and a bile acid sequestrant, each of which is for- used interchangeably throughout and refer to the endog- mulated and administered separately, or by administer- enous fluid medium of the stomach, including water and ing two or more agents in a single formulation. Other secretions. "Simulated gastric fluid" means any fluid that combinations are also encompassed by combination is generally recognized as providing a useful substitute therapy. For example, two agents can be formulated to- 10 for authentic gastric fluid in experiments designed to as- gether and administered in conjunction with a separate sess the chemical or biological behavior of substances formulation containing a third agent. While the two or in the stomach. One such simulated gastric fluid is aque- more agents in the combination therapy can be admin- ous 0.1 N HC1, pH 1.2. It will be understood that the term istered simultaneously, they need not be. For example, "gastric fluid" or "gastric juice" used throughout the dis- administration of a first agent (or combination of agents) 15 closure and claims means authentic (i.e. endogenous) can precede administration of a second agent (or com- gastric fluid or simulated gastric fluid. bination of agents) by minutes, hours, days, or weeks. [0070] The term "gastro-retentive form" or "gastric re- Thus, the two or more agents can be administered within tention vehicle" denotes dosage forms which effect sus- minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, tained release of the active ingredient in comparison with or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 20 conventional dosage forms, such as customary tablets 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, or capsules, while avoiding an undesirably high initial 8, 9, or 10 weeks of each other. In some cases even dose, the release being effected continuously over a rel- longer intervals are possible. While in many cases it is atively long period and controlled at a therapeutically ef- desirable that the two or more agents used in a combi- fective level by prolonged retention of the dosage form nation therapy be present in within the patient’s body at 25 in the stomach. the same time, this need not be so. [0071] This present disclosure provides, in various em- [0064] Combination therapy can also include two or bodiments, pharmaceutical combination kits and oral more administrations of one or more of the agents used drug dosage forms that contain at least one bile acid se- in the combination. For example, if agent X and agent Y questrant alone or in combination with at least one proton are used in a combination, one could administer them 30 pump inhibitor, optionally comprising one or more addi- sequentially in any combination one or more times, e.g., tional agents chosen from an antacid, a histamine H 2-re- in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc. ceptor antagonist, a γ-aminobutyricacid-b (GABA-B) ag- [0065] A "subject" or "patient" is a mammal, preferably onist, a prodrug of a GABA-B agonist, and a protease a human, but can also be an animal in need of veterinary inhibitor. These agents may be contained in the same treatment, e.g., companion animals ( e.g., dogs, cats, and 35 oral dosage form or in separate dosage forms that are the like), farm animals (e.g., cows, sheep, pigs, horses, administered sequentially or simultaneously. and the like) and laboratory animals e.g., ( rats, mice, [0072] The present disclosure also relates to a method guinea pigs, and the like). for treating or preventing an upper gastrointestinal tract [0066] A "susceptible individual" or "patient in need disorder, which is particularly useful as a first- line or initial thereof’ is an individual who suffers from, is suffering40 therapy, comprising administering to a patient in need from, or is likely to or predisposed to suffer from an upper thereof a combination therapeutic regimen as described GI tract disorder. In humans these conditions may in- in the kits and dosage forms provided and discussed clude, for example, gastroesophageal reflux disease herein. "First-line" or "initial" treatment refers to treatment (GERD), heartburn, indigestion, dyspepsia, erosive es- in the first instance after a new diagnosis of an upper ophagitis, peptic ulcer, gastric ulcer, NSAID-associated 45 gastrointestinal tract disorder, or after a relapse of an ulcers, duodenal ulcers, esophageal ulcers, esophagitis, upper gastrointestinal tract disorder following cessation laryngitis, Meckel’s diverticulum, Barrett’s Esophagus, of treatment. However, the treatment method can be use- esophageal adenocarcinoma, or pharyngitis. In animals ful in any upper gastrointestinal tract disorder patient who these conditions may include, for example, peptic ulcer is not responding to monotherapy with PPIs or bile acid of the forestomach. 50 sequestrants. [0067] As used herein "non-responsive GERD" refers [0073] PPI drugs are substituted benzimidazole com- to chronic reflux disorders that do not respond to current pounds that specifically inhibit gastric acid secretion by therapies used to treat such conditions. Such therapies affecting the H+/K+ ATPase enzyme system (the proton include, for example, administration of proton pump in- pump). These drugs, for example esomeprazole, are rap- 55 hibitors, H2 blockers, and various antacids that are well idly absorbed and have very short half-lives. However, known in the art. they exhibit prolonged binding to the H+/K+ ATPase en- [0068] A "noxious substance", as used herein, refers zyme. The anti-secretory effect reaches a maximum in to a substance which causes injury to stratified squamous about 4 days with once-daily dosing. Because of these

7 13 EP 2 478 895 A2 14 characteristics, patients beginning PPI therapy do not from about 0.1 mg to about 120 mg omeprazole. receive maximum benefit of the drug and healing may [0076] Lansoprazole is typically administered about not begin for up to 5 days after therapy begins when PPIs 15-30 mg/day; rabeprazole is typically administered 20 are used alone for initial therapy of upper GI tract disor- mg/day and pantoprazole is typically administered 40 ders. 5 mg/day. However, any therapeutic or sub-therapeutic [0074] Proton pump inhibitors (PPIs) are potent inhib- dose of these agents is considered within the scope of itors of gastric acid secretion, inhibiting H+/K+ ATPase, the present disclosure. the enzyme involved in the final step of hydrogen ion [0077] In certain embodiments, the proton pump inhib- production in the parietal cells. The term proton pump itor(s) included in the dosage forms of the present dis- inhibitor includes, but is not limited to, omeprazole (as 10 closure are protected from contact with acidic gastric sold under the brand-names PRILOSEC®, LOSEC®, or juice, and transferred without exposure to gastric fluid ZEGERID®), lansoprazole (as sold under the brand- until the dosage form reaches a part of the gastrointes- name PREVACID®, ZOTON®, or INHIBITOL®), rabe- tinal tract where the pH is near neutral and where rapid prazole (as sold under the brand- name RABECID®, ACI- absorption of omeprazole can occur. PHEX®, or PARIET®), pantoprazole (as sold under the 15 [0078] Bile acids are steroid acids found predominant- brand-name PROTONIX®, PROTILTM®, SOMAC®, or ly in the bile of mammals. They are produced in the liver PANTOLOC®), tenatoprazole (also referred to as ben- by the oxidation of cholesterol, and are stored in gallblad- atoprazole),and leminoprazole, including isomers, enan- der and secreted into the intestine in the form of salts. tiomers and tautomers thereof (e.g., esomeprazole (as They act as surfactants, emulsifying lipids and assisting sold under the brand-name NEXIUM®)), and alkaline 20 with the absorption and digestion of dietary fat and cho- salts thereof. The following patents describe various ben- lesterol. zimidazole compounds suitable for use in the disclosure [0079] Synthesis of bile acids is a major consumer of described herein: U.S. Pat. No. 4,045,563, U.S. Pat. No. cholesterol. The body synthesizes about 800 mg of cho- 4,255,431, U.S. Pat. No. 4,359,465, U.S. Pat. No. lesterol per day and about half of that is used for bile acid 4,472,409, U.S. Pat. No. 4,508,905, JP-A-59181277, 25 synthesis. In total about 20-30 grams of bile acids are U.S. Pat. No. 4,628,098, U.S. Pat. No. 4,738,975, U.S. secreted into the intestine daily; about 90% of excreted Pat. No. 5,045,321, U.S. Pat. No. 4,786,505, U.S. Pat. bile acids are reabsorbed (by active transport in the ile- No. 4,853,230, U.S. Pat. No. 5,045,552, EP-A-295603, um) and recycled. This is referred to as the enterohepatic U.S. Pat. No. 5,312,824, EP-A-166287, U.S. Pat. No. circulation. 5,877,192, EP-A-519365, EP5129, EP 174,726, EP30 [0080] Since bile acids are made from endogenous 166,287 and GB 2,163,747. All of the above patents are cholesterol, the enterohepatic circulation of bile acids hereby incorporated herein by reference. Thus, proton may be disrupted as a way to lower cholesterol. This is pump inhibitors and their pharmaceutically acceptable the usual therapeutic rationale for administering bile acid salts, which are used in accordance with the present dis- sequestrants. closure, are known compounds and can be produced by 35 [0081] The principal bile acids are: Cholic acid, Chen- known processes. In certain embodiments, the proton odeoxycholic acid, Deoxycholic acid, Taurocholic acid, pump inhibitor is omeprazole, either in racemic mixture and Glycocholic acid. The chemical distinctions between or only the (-)enantiomer of omeprazole (i.e. esomepra- different bile acids are minute, depending only on the zole), as set forth in U.S. Pat. No. 5,877,192, hereby in- presence or absence of hydroxyl groups on positions 3, corporated by reference. 40 7, and 12. In humans, the most important bile acids are [0075] Omeprazole is typically administered in a 20 cholic acid and chenodeoxycholic acid, and their conju- mg dose/day for active duodenal ulcer for 4-8 weeks; in gates with taurine and glycine (glycocholate and tauro- a 20 mg dose/day for gastro-esophageal reflux disease cholate). Some mammals synthesize predominantly de- (GERD) or severe erosive esophagitis for 4-8 weeks; in oxycholic acid. a 20 mg dose/twice a day for treatment of Helicobacter 45 [0082] As surfactants or detergents, bile acids are po- pylori (in combination with other agents); in a 60 mg tentially toxic to cells and their levels are tightly regulated. dose/day for active duodenal ulcer for 4-8 weeks and up They function directly as signaling molecules in the liver to 120 mg three times/day, and in a 40 mg dose/day for and the intestines by activating a nuclear hormone re- gastric ulcer for 4-8 weeks. Such dosages are contem- ceptor known as FXR and also NR1H4. This results in plated to be within the scope of the present disclosure. 50 inhibition of bile acid synthesis in the liver when bile acid Thus, in certain embodiments of the present disclosure, levels are too high. Emerging evidence associates FXR the amount of proton pump inhibitor which is included in activation with alterations in triglyceride metabolism, glu- the dosage form is an amount which is considered to be cose metabolism and liver growth. therapeutically effective, in accordance with the dosages [0083] Bile acid sequestrants bind bile acids in the set forth above for a variety of disease states. In other 55 small intestine and carry them out of the body. This caus- embodiments of the present disclosure, the dose of pro- es the body to use more cholesterol to make more bile ton pump inhibitor is sub-therapeutic. For example, when acids, which are secreted into the small intestine, bound the drug is omeprazole, the dosage form may contain to bile acid sequestrants, and carried out of the body.

8 15 EP 2 478 895 A2 16

The end result is lower cholesterol levels. Bile acid se- telenzepine, teprenone, trimoprostil, trithiozine, troxip- questrants also prevent absorption of some dietary cho- ide, zolimidine, baclofen, R-baclofen, XP19986 (CAS lesterol. Registry No. 847353-30-4), pepstatin and other pepsin [0084] Bile acid sequestrants currently approved for inhibitors (e.g., sodium benzoate); and chymotrypsin and human use are polymeric compounds which serve as ion 5 trypsin inhibitors. A wide variety of trypsin and chymot- exchange resins. Bile acid sequestrants exchange ani- rypsin inhibitors are known to those skilled in the art and ons such as chloride ions for bile acids. By doing so, they can be used in the methods described herein. Such bind bile acids and sequester them from enterohepatic trypsin and chymotrypsin inhibitors can include tissue- circulation. Since bile acid sequestrants are large poly- factor-pathway inhibitor; α-2 antiplasmin; serpin α-1 an- meric structures, they are not well- absorbed from the gut 10 tichymotrypsin family members; gelin; hirustasin; eglins into the bloodstream. Thus, bile acid sequestrants, along including eglin C; inhibitors from Bombyx mori (see; e.g.; with any bile acids bound to the drug, are excreted via JP 4013698 A2 and JP 04013697 A2; CA registry No. the feces after passage through the gastrointestinal tract. 142628-93-1); hirudin and variants thereof; secretory Exemplary bile acid sequestrants include, for example, leukocyte protease inhibitor (SLPI);α -1 anti-trypsin; cholestyramine (as sold under the name brand-15 Bowman-Birk protease inhibitors (BBIs); chymotrypsin QUESTRAN®), colesevelam (as sold under the brand- inhibitors represented by CAS registry Nos. name WELCHOL®), and colestipol (as sold under the 306762-66-3, 306762-67-4, 306762-68-5, 306762-69-6, brand-name COLESTID®), and pharmaceutically ac- 306762-70-9, 306762-71-0, 306762-72-1, 306762-73-2, ceptable salts thereof. 306762-74-3, 306762-75-4, 178330-92-2, 178330-93-3, [0085] The present disclosure is also directed to a dos- 20 178330-94-4, 81459-62-3, 81459-79-2, 81460-01-7, age form that provides for the release of at least one bile 85476-59-1, 85476-62-6, 85476-63-7, 85476-67-1, acid sequestrant to reduce bile acid reflux symptoms in 85476-70-6, 85858-66-8, 85858-68-0, 85858-69-1, a patient, as well as for the release of both at least one 85858-70-4, 85858-71-5, 85858-72-6, 85858-73-7, bile acid sequestrant and at least one proton pump in- 85858-75-9, 85858-77-1, 85858-79-3, 85858-81-7, hibitor to reduce both bile acid reflux and gastric acid25 85858-83-9, 85858-84-0, 85858-85-1, 85858-87-3, reflux symptoms in a patient. The dosage form can be 85858-89-5, 85858-90-8, 85858-92-0, 85879-03-4, prepared such that the active ingredients are for quick 85879-05-6, 85879-06-7, 85879-08-9, 85858-74-8, release or delayed release, or quick release of one active 90186-24-6, 90185-93-6, 89703-10-6, 138320-33-9 ingredient and delayed release of the other active ingre- (YS3025), 94149-41-4 (MR889), 85858-76-0, dient. 30 89703-10-6, 90185-92-5, 90185-96-9, 90185-98-1, [0086] The compositions comprising the active agents 90186-00-8, 90186-01-9, 90186-05-3, 90186-06-4, disclosed herein may also be formulated to include, or 90186-07-5, 90186-08-6, 90186-09-7, 90186-10-0, administered in conjunction with, other agents for treating 90186-11-1, 90186-12-2, 90186-13-3, 90186-14-4, the gastrointestinal tract, such as histamine H 2 receptor 90186-22-4, 90186-23-5, 90186-24-6, 90186-25-7, blockers, motility agents (gastroprokinetics), antacids, 35 90186-27-9, 90186-28-0, 90186-29-1, 90186-31-5, antiulcerative agents, γ-aminobutyricacid-b (GABA-B) 90186-35-9, 90186-43-9, 90209-88-4, 90209-89-5, agonists, prodrugs of GABA- B agonists, and/or protease 90209-92-0, 90209-94-2, 90209-96-4, 90209-97-5, inhibitors. Nonlimiting examples of these additional 90210-01-8, 90210-03-0, 90210-04-1, 90210-25-6, agents include those selected from the group consisting 90210-26-7, 90210-28-9, 90230-84-5, 90409-84-0, of cinitapride, cisapride, fedotozine, loxiglumide, alexitol 40 95460-86-9, 95460-87-0, 95460-88-1, 95460-89-2, sodium, , aluminum hydroxide, aluminum mag- 95460-91-6, 114949-00-7, 114949-01-8, 114949-02-9, nesium silicate, aluminum phosphate, azulene, basic 114949-03-0, 114949-04-1, 114949-05-2, 114949-06-3, aluminum carbonate gel, bismuth aluminate, bismuth 114949-18-7, 114949-19-8, 114964-69-1, 114964-70-4, phosphate, bismuth subgallate, bismuth subnitrate, cal- 9076-44-2 (chymostatin), 30827-99-7 (Pefabloc), cium carbonate, dihydroxyaluminum aminoacetate, di- 45 618-39-3 (benzamidine), 80449-31-6 (urinistatin), hydroxyaluminum sodium carbonate, ebimar,130982-43-3, 197913-52-3, 179324-22-2, 274901-16-5, , magnesium carbonate hydroxide, magnesi- 792163-40-7, 339169-59-4, 243462-36-4, 654671-78-0, um hydroxide, , magnesium , 55123-66-5 (leupeptin), 901-47-3, 4272-74-6, magnesium phosphate (tribasic), magnesium silicates, 51050-59-0, 221051-66-7, 80449-31-6, 55-91-4, potassium citrate, , aceglutamide50 60-32-2, 88070-98-8, 87928-05-0, 402-71-1 (benze- aluminum complex, acetoxolone, aldioxa, arbaprostil, nesulfonamide), 139466-47-0, CI-2A (see US5167483), benexate hydrochloride, carbenoxolone, cetraxate, ci- CI-2A (seebWO9205239), WCI-3 (see Shibata et al. metidine, colloidal bismuth subcitrate, ebrotidine,ecabet, 1988 J Biochem (Tokyo) 104:537-43), WCI- 2 (see Habu enprostil, esaprazole, famotidine, gefamate, guaiazu- et al. 1992 J Biochem (Tokyo) 111:249-58), and WCI-x lene, irsogladine, misoprostol, nizatidine, omoprostil, γ- 55 (Habu et al., supra) and 178330-95-5; and compounds Oryzanol, pifamine, pirenzepine, plaunotol, polaprezinc, with chymotrypsin inhibition activity described in patent ranitidine, rebamipide, rioprostil, rosaprostol, rotraxate, publications JP 56092217 A2, US4755383, US4755383, roxatidine acetate, sofalcone, spizofarone, sucralfate, US4639435, US4620005, US4898876, and EP0128007.

9 17 EP 2 478 895 A2 18

[0087] The active ingredients used in tablets, i.e., bile one or more of the following: methacrylic acid copoly- acid sequestrants alone or in combination with proton mers; shellac; hydroxypropylmethylcellulose phthalate; pump inhibitors, are well known in the art and many are polyvinyl acetate phthalate; hydroxypropylmethylcellu- commercially available. If desired, drugs can also be lose trimellitate; carboxymethylcellulose; cellulose ace- manufactured using methodology well known in the art. 5 tate phthalate; or other suitable enteric coating polymers. The pH at which the enteric coat will dissolve can be Formulation and Administration controlled by the polymer or combination of polymers se- lected and/or ratio of pendant groups. For example, dis- [0088] Making of Pharmaceutical Preparations: The solution characteristics of the coating can be altered by active agents used in the compositions of the present 10 the ratio of free carboxyl groups to ester groups. Enteric disclosure will typically be formulated in accordance with coating layers may also contain pharmaceutical plasti- methodsthat are standard in the art (see e.g., Remington: cizers such as: triethyl citrate; dibutyl phthalate; triacetin; the Science and Practice of Pharmacy 19th Ed. 1995 polyethylene glycols; polysorbates; etc. Additives such Mack Publishing Co. Easton Pa.). Drugs may be pre- as dispersants, colorants, anti-adhering and anti-foam- pared in admixture with conventional excipients, carriers, 15 ing agents may also be included. buffers, flavoring agents, etc. Typical carriers include, [0090] Making of Tablet Dosage Forms: Tablets can but are not limited to: water; salt solutions; alcohols; gum be made using standard technology well known in the arabic; vegetable oils; benzyl alcohols; polyethylene gly- art. Drugs used in the core or the outer coating may be cols; gelatin; carbohydrates, such as lactose, amylose granulated by methods such as slugging, low-shear or or starch; magnesium stearate; ; silicic acid; paraffin; 20 high-shear granulation, wet granulation, or fluidized bed perfume oil; fatty acid esters; hydroxymethylcellulose; granulation. Outer coatings may be formed by preparing polyvinyl pyrrolidone; etc. Pharmaceutical preparations a mixture containing appropriate polymers and a suffi- can be sterilized and, if desired, mixed with auxiliary cient amount of drug to produce a therapeutically effec- agents such as: lubricants; preservatives; disintegrants; tive dose. The solution may then be sprayed on pre- stabilizers such as cyclodextrans; wetting agents; emul- 25 formed, enterically-coated cores to produce the final tab- sifiers; salts; buffers; natural or artificial coloring agents; lets. If desired, a buffer layer or layer containing other natural or artificial flavoringagents; or aromaticsubstanc- agents may be interspersed between the enterically coat- es. Pharmaceutical preparations can also include one or ed core and the outer coating. more of the following: acetylated monoglyceride, aspar- [0091] In certain embodiments a pharmaceutical com- tame, beta carotene, calcium stearate, carnauba wax, 30 position is prepared by adding a pharmaceutically ac- cellulose acetate phthalate, citric acid, citric acid anhy- ceptable carrier to the aforementioned compound, a drous, colloidal silicon dioxide, confectioner’s sugar, pharmaceutically acceptable salt thereof, or a hydrate crospovidone, sodium, ethyl alcohol, ferric ox- thereof as an active ingredient of the medicament of the ide, fructose, gelatin, glycerine, glyceryl monostearate present disclosure. As the medicament of the present (e.g. glyceryl monostearate 40-50), glyceryl triacetate, 35 disclosure, a substance, per se, that is selected from the HPMC (hydroxypropyl methylcellulose), hydroxypropyl group consisting of the alkylenedioxybenzene derivative cellulose, hypromellose, iron oxide, isopropyl alcohol, and a pharmaceutically acceptable salt thereof, and a lactose monohydrate, low substituted hydroxypropyl cel- hydrate thereof and a solvate thereof may be adminis- lulose, magnesium carbonate, magnesium stearate, tered to a mammal including human. In certain embodi- maltol, , methacrylic acid, methacrylic acid co- 40 ments, pharmaceutical compositions comprising one or polymer (e.g. methacrylic acid copolymer type C), meth- more of the aforementioned substances as an active in- ylcellulose, microcrystalline cellulose, mono ammonium gredient and one or more of pharmaceutical additives glycyrrhizinate, n-butyl alcohol, paraffin, pectin propyl- are administered to a patient. ene glycol alginate, polyacrylate, polyethylene glycol [0092] A variety of administration routes can be used (e.g. polyethylene glycol 6000), polysorbate 80, polyvinyl 45 in accordance with the present disclosure. An effective pyrrolidone, povidone, propylene glycol, shellac, silicon amount of the peptide described herein can be adminis- dioxide, sodium carbonate, sodium citrate, sodium hy- tered parenterally, orally, by inhalation, nasally, buccally, droxide, sodium lauryl sulfate, sodium stearyl fumarate, or via an implanted reservoir. , starch, sucrose, sugar sphere, talc, titanium di- [0093] Examples of the pharmaceutical composition oxide, triethyl citrate, and xanthan gum. In certain em- 50 include formulations for oral administration such as tab- bodiments, buffers that can raise the pH of the stomach lets, capsules, subtilized granules, powders, pills, troch- are used. For example bicarbonate buffers may be in- es, sublingual tablets and liquid preparations, and formu- cluded in the outer coating or as a rapidly dissolving, lations for parenteral administration such as injections, separate layer immediately below the outer coating. suppositories, ointments, patches and the like. [0089] The enteric coating surrounding the core may 55 [0094] In certain embodiments, formulations including be applied using standard coating techniques. Materials those which slowly release the agent over time, such as used to form the enteric coating may be dissolved or dis- found in lozenges, gums, and buccal patches are used. persed in organic or aqueous solvents and may include In other embodiments, formulations including agents in

10 19 EP 2 478 895 A2 20 a bioadherent ingestible composition, such as those filler by repetitive mixing. Formulations for parenteral ad- found in U.S. Pat. Nos. 5,858,391 and 5,670,163 to Cuca, ministration are generally provided as unit dosage form et al. are used. The agent may also be formulated as a preparations containing the compound as the active in- liquid or as a tablet, pill, capsule or powder to be dissolved gredient and a sterilized medium. The solution for in a liquid, and is preferably slowly sipped by the patient. 5 parenteral administration may generally be prepared by [0095] The protective agents disclosed herein and dissolving the compound in a medium, subjecting the re- compositions comprising the agents may be adminis- sulting solution to filtration for sterilization, filling the so- tered by perfusion via a tube on to the surface of stratified lution in vials or ampoules, and sealing the vials or am- squamous epithelia, by oral ingestion, gum or lozenge poules. It is also possible to freeze the composition and (for treatment of oropharyngeal, rumen, forestomach and 10 fill the result in vials, and then eliminate the moisture in esophageal epithelium), by mouth rinse (for oropharyn- vacuo to improve stability. Parenteral suspensions can geal, tongue and buccal epithelium), by aerosol spray be prepared by substantially the same method as that (for oropharyngeal, buccal, tongue, laryngeal or vocal applied to solutions for parenteral administration; how- cord epithelium), or by other means. ever, the suspensions can preferably be manufactured [0096] Certain embodiments encompass where the 15 by suspending the active ingredient in a medium, and agent provides protection against damage by a noxious then subjecting the result to sterilization by using ethyl- substance to the epithelium after a short period of contact ene oxide or the like. Furthermore, surface active agents, with the epithelium. In certain embodiments the period moistening agents and so forth may also be added so of contact can be, for example, less than or equal to 1 that a uniform dispersion of the active ingredient can be hour, less than or equal to 30 minutes, less than or equal 20 obtained. to 15 minutes, less than or equal to 10 minutes, less than [0100] Combining two or moreactive ingredients insin- or equal to 5 minutes, less than or equal to 1 minute. In gle dosage form results in the possibility of chemical in- a preferred embodiment the epithelium is contacted with teractions between the active drug substances. For ex- or exposed to the agent for about 1 to 5 minutes. ample, acidic and basic active ingredients can react with [0097] Tablets and capsules for oral administration are 25 each other and acidic active ingredients can facilitate the usually provided in a unit dosage form, and can be pre- degradation of acid labile substances. Thus, in certain pared by adding ordinary pharmaceutical carriers such dosage forms, acidic and basic substances can be phys- as binders, fillers, diluents, compressing agents, lubri- ically separated as two distinct or isolated layers in a cants, disintegrating agents, coloring matters, flavoring compressed tablet, or in the core and shell of a press- agents, and moistening agents. Tablets may be coated 30 coated tablet. Additional agents that are compatible with according to a well known method, for example, by using acidic as well as basic substances, have the flexibility of an enteric coating agent. For example, fillers such as being placed in either layer. In certain multiple layer com- cellulose, mannitol and lactose; disintegrating agents positions at least one active ingredient can be enteric- such as starch, polyvinylpyrrolidone, starch derivatives coated. In certain embodiments thereof at least one ac- and sodium starchglycolate; lubricants such as magne- 35 tive ingredient can be presented in a controlled release sium stearate; moistening agents such as sodium laur- form. In certain embodiments where a combination of ylsulfate and the like may be used. three or more active substances are used, they can be [0098] Liquid preparations for oral administration can presented as physically isolated segments of a com- be provided in the forms of, for example, aqueous or oily pressed mutlilayer tablet, which can be optionally film suspensions, solutions, emulsions, syrups and elixirs, as 40 coated. well as dried formulations that is re-dissolvable before [0101] The therapeutic combinations described herein use by water or a suitable medium. Those liquid prepa- can be formulated as a tablet or capsule comprising a rations may contain ordinary additives, for example, sus- plurality of beads, granules, or pellets. All active ingredi- pending agents such as sorbitol, syrups, methylcellulose, ents including the vitamins of the combination are formu- gelatin, hydroxyethylcellulose, carboxymethylcellulose, 45 lated into granules or beads or pellets that are further aluminum stearate gel and hydrogenated edible fats; coated with a protective coat, an enteric coat, or a film emulsifiers such as lecitin, sorbitan monooleate and gum coat to avoid the possible chemical interactions. Granu- arabic; non-aqueous media including edible oils such as lation and coating of granules or beads is done using almond oil, rectified coconut oil, oily esters (e.g., esters techniques well known to a person skilled in the art. At of glycerin), propylene glycol and ethyl alcohol; preserv- 50 least one active ingredient can present in a controlled atives such as methyl ester, ethyl ester and propyl ester release form. Finally these coated granules or beads are of p-hydroxybenzoic acid and sorbic acid; and usual fla- filled into hard gelatin capsules or compressed to form voring agents and coloring matters as required. tablets. [0099] Formulations for oral administration can be [0102] The therapeutic combinations described herein manufactured according to a method well known in the 55 can be formulated as a capsule comprising microtablets art, for example, by mixing, filling, compressing and the or minitablets of all active ingredients. Microtablets of the like. In addition, it is also possible to disperse the active individual agents can be prepared using well known phar- ingredient in a formulation containing a large amount of maceutical procedures of tablet making like direct com-

11 21 EP 2 478 895 A2 22 pression, dry granulation or wet granulation. Individual ganisms. The pharmaceutical forms suitable for injection microtablets can be filled into hard gelatin capsules. A can include sterile aqueous or organic solutions or dis- final dosage form may comprise oneor moremicrotablets persions which include, e.g., water, an alcohol, an organ- of each individual component. The microtablets may be ic solvent, an oil or other solvent or dispersant (e.g., glyc- film coated or enteric coated. 5 erol, propylene glycol, polyethylene glycol, and vegeta- [0103] The therapeutic combinations described herein ble oils). The formulations may contain antioxidants, buff- can be formulated as a capsule comprising one or more ers, bacteriostats, and solutes that render the formulation microtablets and powder, or one or more microtablets isotonic with the blood of the intended recipient, and and granules or beads. In order to avoid interactions be- aqueous and non-aqueous sterile suspensions that can tween drugs, some active ingredients of a said combina- 10 include suspending agents, solubilizers, thickening tion can be formulated as microtablets and the others agents, stabilizers, and preservatives. Pharmaceutical filled into capsules as a powder, granules, or beads. The agents can be sterilized by filter sterilization or by other microtablets may befilm coated or entericcoated. At least suitable means one active ingredient can be presented in controlled re- [0108] Suitable pharmaceutical compositions in ac- lease form. 15 cordance with the invention will generally include an [0104] The therapeutic combinations described herein amount of the active compound(s) with an acceptable can be formulated wherein the active ingredients are dis- pharmaceutical diluent or excipient, such as a sterile tributed in the inner and outer phase of tablets. In an aqueous solution, to give a range of final concentrations, attempt to divide chemically incompatible components depending on the intended use. The techniques of prep- of proposed combination, few interacting components 20 aration are generally well known in the art, as exemplified are converted in granules or beads using well known by Remington’s Pharmaceutical Sciences, 19th Ed., pharmaceutical procedures in prior art. The prepared Mack Publishing Company, 1995. granulesor beads (inner phase) are then mixed with outer [0109] The agent can be in the form of a pharmaceu- phase comprising the remaining active ingredients and ticallyacceptable salt. Such salts are prepared from phar- at least one pharmaceutically acceptable excipient. The 25 maceutically acceptable non-toxic bases including inor- mixture thus comprising inner and outer phase is com- ganic bases and organic bases. Examples of salts de- pressed into tablets or molded into tablets. The granules rived from inorganic bases include aluminum, ammoni- or beads can be controlled release or immediate release um, calcium, copper, ferric, ferrous, lithium, magnesium, beads or granules, and can further be coated using an manganic salts, manganous, potassium, sodium, zinc, enteric polymer in an aqueous or non-aqueous system, 30 and the like. In some embodiments, the salt can be an using methods and materials that are known in the art. ammonium, calcium, magnesium, potassium, or sodium [0105] The therapeutic combinations described herein salt. Examples of salts derived from pharmaceutically ac- can be formulated as single dosage unit comprising suit- ceptable organicnon- toxic bases include salts of primary, able buffering agent. All powdered ingredients of said secondary, and tertiary amines, benethamine,N, combination are mixed and a suitable quantity of one or 35 N’-dibenzylethylenediamine, diethylamine, 2-diethylami- more buffering agents is added to the blend to minimize noethanol, 2-dimethylaminoethanol, diethanolamine, possible interactions. ethanolamine, ethylenediamine, N- ethylmorpholine, [0106] The agents described herein, alone or in com- N-ethylpiperidine, epolamine, glucamine, glucosamine, bination, can be combined with any pharmaceutically ac- histidine, hydrabamine, isopropylamine, lysine, methyl- ceptable carrier or medium. Thus, they can be combined 40 glucamine, meglumine, morpholine, piperazine, piperid- with materials that do not produce an adverse, allergic ine, polyamine resins, procaine, purines, theobromine, or otherwise unwanted reaction when administered to a triethylamine, trimethylamine, tripropylamine, and patient. The carriers or mediums used can include sol- trolamine, tromethamine. Examples of other salts include vents, dispersants, coatings, absorption promoting tris, arecoline, arginine, barium, betaine, bismuth, chlo- agents, controlled release agents, and one or more inert 45 roprocaine, choline, clemizole, deanol, imidazole, and excipients (which include starches, polyols, granulating morpholineethanol. agents, microcrystalline cellulose, diluents, lubricants, [0110] The agents ofthe inventioncan beadministered binders, disintegrating agents, and the like), etc. If de- orally, e.g., as a tablet or cachet containing a predeter- sired, tablet dosages of the disclosed compositions may mined amount of the active ingredient, pellet, gel, paste, be coated by standard aqueous or nonaqueous tech- 50 syrup, bolus, electuary, slurry, capsule; powder; gran- niques. The agents described herein, alone or in combi- ules; as a solution or a suspension in an aqueous liquid nation, can be formulated using Nanocrystal® technolo- or a non- aqueous liquid; asan oil- in-waterliquid emulsion gy (Elan Corporation, Dublin, Ireland). or a water-in-oil liquid emulsion, via a liposomal formu- [0107] The agents can be a free acid or base, or a lation (see, e.g., EP736299) or in some other form. Orally pharmacologically acceptable salt thereof. Solids can be 55 administered compositions can include binders, lubri- dissolved or dispersed immediately prior to administra- cants, inert diluents, lubricating, surface active or dis- tion or earlier. In some circumstances the preparations persing agents, flavoring agents, and humectants. Orally include a preservative to prevent the growth of microor- administered formulations such as tablets may optionally

12 23 EP 2 478 895 A2 24 be coated or scored and may be formulated so as to Active provide sustained, delayed or controlled release of the active ingredient therein. [0114] The active ingredient in the gastro-retentive dosage forms of the present invention includes any of Gastric-Retention Vehicles 5 the compositions described in detail and disclosed herein in an amount as contemplated and described below. [0111] A traditional oral sustained-release formulation [0115] The tablet component contains the active ingre- releases most of the drug at the colon. Thus, clinically dient (e.g., at least one bile acid sequestrant, alone or in acceptable sustained release dosage forms prepared combination with at least one proton pump inhibitor with conventional technology may not be successful10 and/or optionally one or more other agents) in a thera- where a particular drug has an absorption window in a peutically effective amount. Typically, the active ingredi- particular region of the gastrointestinal tract, such as the ent(s) is present in an amount from between 10% to about duodenum and upper jejunem segments. In such cases, 50% of the total tablet weight, preferably between about a gastroretentive drug delivery system can be employed 15% and about 40%. Other therapeutically effective dos- tohelp retain the active ingredient in the stomach, thereby 15 ages can be readily determined by one of skill in the phar- assisting in and improving the sustained delivery of the maceutical or medical arts. drug. [0112] Several approaches are currently used to pro- Binder long gastric retention time. These include floating drug delivery systems, also known as hydrodynamically bal- 20 [0116] The tablet component of the gastro-retentive anced systems, swelling and expanding systems, poly- dosage form comprises the active ingredient (for exam- meric bioadhesive systems, modified-shape systems, ple, at least one bile acid sequestrant or combinations of high-density systems, and other delayed gastric empty- at least one bile acid sequestrant and at least one proton ing systems. For example, Dave et al. AAPS Pharm- pump inhibitor), a gas-generating agent and a binder. SciTech 2004; 5 (2), 1-6, report on a gastroretentive drug 25 Binders (also called wetting agents) are agents used to delivery system of ranitidine hydrochloride using the prin- improve the cohesiveness of the tablet formulation, en- ciples of buoyant preparation, wherein guar gum, xan- suring that the tablet will remain intact after formation. than gum, and hydroxypropyl methylcellulose were eval- Suitable binders for use in the gastric-retention vehicle uated for gel-forming properties, sodium bicarbonate for use with the present invention include but are not lim- was used as a gas-generating agent, and the effects of 30 ited to poloxamers, polyethylene glycols (e.g., PEG citric acid and stearic acid on drug release profile and 3350), polyethylene glycol fatty acid esters (e.g., Myrj), floating properties were investigated. Similarly, Narendra glyceryl palmitostearate (e.g. Precirol AT05), polyoxyeth- et al. AAPS PharmSciTech 2006, 7(2), E1-7, reports on ylene alkyl ethers, glyceryl behenate (e.g., Compritol the development of an optimized gastric floating drug de- 888), stearoyl macrogol-32-glyceride (e.g., Gelucire), livery system containing metoprolol tartrate as a model 35 polyoxyethylene castor oil derivatives, polyoxyethylene drug, wherein the dosage form was prepared as a bilayer sorbitan fatty acid derivatives, polyoxyethylene stear- tablet comprising a drug- loading layer and a floating layer ates, polyoxyethylene-polyoxypropylene copolymers in a suitable ratio to provide a bulk density lower than (e.g. Lutrol or Pluronics), starches, gelatin, sugars such that of gastric fluids to remain buoyant on the stomach as lactose, sucrose, glucose and molasses, natural and contents. 40 synthetic gums such as acacia, sodium alginate, car- [0113] Other variations of gastric-retention vehicle boxymethylcellulose, methylcellulose, polyvinylpyrro- compositions are known to those skilled in the art and lidone, ethyl cellulose and waxes. Suitable binders also are suitable for use with the compositions and methods include Myrj 52 (particularly Myrj 52P or Myrj52FL), Lutrol described in detail and disclosed herein. For example, in F68, Compritol 888, Gelucire 50/13, PEG 3350, Precirol certain embodiments, the present invention provides45 AT05 methylcellulose and polyvinyl pyrrolidone. methods of making a gastro- retentive dosage form of any [0117] The binder is present in the tablet component of the compositions described herein, wherein said meth- in an amount effective to provide cohesion to the final od comprises (a) forming a tablet comprising any com- tablet form. The appropriate amount of binder can be position described herein, a binder and a pharmaceuti- readily determined by one of ordinary skill in the phar- cally-acceptable gas-generating agent, (b) surrounding 50 maceutical arts and will depend, inter alia, upon the par- the tablet with an expandable, hydrophilic, water- perme- ticular binder used and the method of preparation of the able and substantially gas-impermeable, membrane, tablet. The binder may be present in the tablet in an and (c) sealing the membrane to retard the escape of amount from between about 8% to about 15% of the total gas from within the sealed membrane. A further optional tablet weight. step comprises (d) encapulating the membrane-sealed 55 tablet within a covering that disintegrates without delay Gas-generating agent upon contact with gastric fluid. [0118] A gas-generating agent may be included in the

13 25 EP 2 478 895 A2 26 tablet component to generate the carbon dioxide gas that including preventing the adhesion of the tablet material results in the expansion of the membrane component to the surface of the dies and punches, reducing inter- upon contact with gastric juice. Suitable gas-generating particle friction, facilitating the ejection of the tablet from agents are, for example, solids that liberate this gas itself, the die cavity and in some instances, improving the rate for example under the action of body fluid or the hydrogen 5 of flow of the tablet granulation. Commonly used lubri- ions present therein. Such gas-generating agents are, cants include talc, magnesium stearate, calcium stear- for example, those capable of releasing carbon dioxide ate, zinc stearate, stearic acid, glyceryl monostearate, and include, but are not limited to, pharmaceutically ac- glyceryl palmitostearate, hydrogenated vegetable oils, ceptable mono- and di-basic salts of carbonic acid, for hydrogenated castor oil, light mineral oil, sodium ben- example alkali metal hydrogen carbonates or alkali metal 10 zoate, sodium stearyl fumarate and polyethylene glycol carbonates, alkaline earth metal carbonates or ammoni- (PEG). Any of the commonly used lubricants are suitable um carbonate. for use in the present invention. In one embodiment, mag- [0119] Such mono- or di-basic salts of carbonic acid nesium stearate is used as a lubricant. An acidulant may are especially sodium hydrogen carbonate (sodium bi- be added to increase the release of carbon dioxide from carbonate) or sodium carbonate, potassium carbonate, 15 this sodium hydrogen carbonate. Commonly used acid- calcium carbonate, magnesium carbonate, sodium gly- ulants include citric acid, fumaric acid, malic acid and cine carbonate, or mixtures thereof. In order to increase tartaric acid. It will be apparent from the foregoing that a the evolution of carbon dioxide, there may be added to single substance may serve more than one of the pur- the mentioned carbonates the acid component custom- poses described above. arily used in effervescent mixtures, for example sodium 20 dihydrogen phosphate or disodium hydrogen phosphate, Swelling Agents , sodium ascorbate or sodium citrate. Also suitable are yeasts which are likewise capable of gener- [0122] In addition to the afore-mentioned gas-gener- ating carbon dioxide gas. When yeasts, for example bak- ating agents, it is also possible for intensifying the action er’s yeast, are used, the necessary nutrients, for example 25 of the agent to use pharmaceutically acceptable hy- glucose, are added to the formulation. In certain embod- drophilic swelling agents, for example partially etherified iments, the gas-generating agent will be sodium hydro- cellulose derivatives, starches, water-soluble, aliphatic gen carbonate. or cyclic poly- N-vinylamides, polyvinyl alcohols, polyacr- [0120] The gas-generating agent may be present in ylates, polymethacrylates, polyethylene glycols or mix- the tablet component in an amount between about 30% 30 tures of these auxiliaries. In certain embodiments, the and about 82% of the total tablet weight. In certain em- hydrophilic swelling agent may also serve as a binder. bodiments, the gas-generating agent is present at about [0123] Hydrophilic, partially etherified cellulose deriv- 40% to about 82% of the total tablet weight. atives are, for example, lower alkyl ethers of cellulose having an average degree of molar substitution (MS) of Other Agents 35 more than 1 and less than 3 and an average degree of polymerisation of approximately 100-5000. [0121] In addition to the active ingredient, the binder [0124] The degree of substitution is a measure of the and the gas- generating agent, the tablet component may substitution of the hydroxy groups by lower alkoxy groups also include one or more of diluents, glidants, lubricants, per glucose unit. The average degree of molar substitu- acidulants, swelling agents, surfactants and other phar- 40 tion (MS) is a mean value and indicates the number of maceutically acceptable excipients. A diluent is a sub- lower alkoxy groups per glucose unit in the polymer. stance added to increase the bulk of a mixture to make [0125] The average degree of polymerisation (DP) is a tablet a practical size for granulation, compression or likewise a mean value and indicates the average number molding when only a small amount of active is present. of glucose units in the cellulose polymer. Suitable diluents include lactose, cellulose, dry starch, 45 [0126] Lower alkyl ethers of cellulose are, for example, powdered sugar, dicalcium phosphate, calcium sulfate, cellulose derivatives that are substituted at the hy- sodium chloride, kaolin, mannitol, sorbitol, sucrose, in- droxymethyl group (primary hydroxy group) of the glu- ositol. In certain embodiments, the diluent is lactose, cose unit forming the cellulose chains and optionally at sorbitol, mannitol, cellulose or starch. A glidant (or flow- the second and third secondary hydroxy group by C 1-C4 enhancing agent) is a substance that improves the flow 50 alkyl groups, especially methyl or ethyl, or by substituted characteristics of a powder mixture. Commonly used gli- C1-C4 alkyl groups, for example 2-hydroxyethyl, 3-hy- dants include colloidal silicon dioxide, magnesium trisil- droxy-n-propyl, carboxymethyl or 2-carboxyethyl. icate, powdered cellulose, starch, tribasic calcium phos- [0127] Suitable lower alkyl ethers of cellulose include phate and talc. Glidants useful in this invention include methylcellulose, ethylcellulose, methylhydroxyethylcel- these commonly used glidants. In certain embodiments, 55 lulose, methylhydroxypropylcellulose, ethylhydrox- the glidant is Aerosil 200, colloidal silicon dioxide. A lu- yethylcellulose, hydroxyethylcellulose, hydroxypropyl- bricant is a substance that has a number of functions in cellulose, carboxymethylcellulose (in salt form, for exam- the preparation of the tablet component of this invention, ple sodium salt form) or methylcarboxymethylcellulose

14 27 EP 2 478 895 A2 28

(likewise in salt form, for example sodium salt form). agar, or water-swellable polymers that can be produced [0128] A starch suitable for use as hydrophilic swelling by dispersion of a finely particulate copolymer of maleic agent is, for example, a mixture of approximately 15-20% acid anhydride and styrene, or tragacanth, gelatine or amylose (molar mass approximately 50,000 to 200,000) swellable ion exchange resins. and 80-85% amylopectin (molar mass approximately 5 [0135] Swellable ion exchangers are, for example, co- 100,000 to 1,000,000), for example rice, wheat or potato polymer resins having acidic groups, for example, sul- starch, and also starch derivatives, such as partially syn- fonic acid groups or salt forms thereof based on styren- thetic amylopectin, for example sodium carboxymethyl- edivinylbenzene. Such copolymer resins consist of amylopectin, and alginates of the alginic acid type. cross-linked styrene polymers which are obtained by co- [0129] Water-soluble, aliphatic or cyclic poly- N-vinyla- 10 polymerization of styrene with divinylbenzene as mides include, for example, poly-N-vinyl-methylaceta- crosslinking agent. Customary derivisation reactions, for mide, poly-N-vinylethylacetamide, poly-N-vinylmethyl- example sulfonation reactions, are used to incorporate propionamide, poly-N-vinylethylpropionamide, poly-N- acidic groups, such as sulfo groups, into the structure. vinylmethylisobutyramide, poly-N-vinyl-2-pyrrolidone, The preparation and the properties of these resins are poly-N-vinyl-2-piperidone, poly-N-vinyl-.epsilon.-caprol- 15 known. Reference is made to the article in Ullmanns En- actam, poly-N-vinyl-5-methyl-2-pyrrolidone or poly-N-vi- zyklopdie der Technischen Chemie, 4th Edition, Vol. 13, nyl-3-methyl-2-pyrrolidon- e, especially poly-N-vinylpyr- pp. 279 ff., and to Kirk- Othmer, Encyclopaedia of Chem- rolidone having a mean molar mass of approximately ical Technology, J. Wiley, Vol. 13, pp. 678 ff. , and to the 10,000-360,000, for example the polyvinylpyrrolidone numerous literature references cited therein. obtainable under the trade mark Kollidon® (BASF). 20 [0136] Preferred ion exchange resins are those having [0130] Suitable polyvinyl alcohols have a mean molar quaternary ammonium groups or sulfonic acid groups mass of approximately 15,000 to 250,000 and a degree based on styrenedivinylbenzene which are commercially of hydrolysis of approximately 70-99%. In certain embod- available and are acceptable for use in pharmaceutical iments, the polyvinyl alcohols have a degree of hydrolysis formulations, for example resins marketed by the firm of approximately 70-88% (partially hydrolysed polyvinyl 25 Rohm and Haas under the trade mark Amberlite® IRP- alcohol), for example the polyvinyl alcohol obtainable un- 69. der the trade name Mowiol® (Hoechst) denoted by MOWIOL 3-83, 4-80, 4-88, 5-88 or 8-88. Surfactants [0131] Hydrophilic polyacrylates that can be used as swelling agents have a mean molecular weight of ap- 30 [0137] The tablet component can also contain the cus- proximately 8.6X105 to 1.0X106. The polyacrylic acid tomary pharmaceutical formulation adjuncts that are chains carry a greater or smaller number of short side used at present for the manufacture of oral dosage forms, chains and so the individual commercial forms differ in such as tablets, for example surface-active substances, this respect, as well as in having different molecular for example so-called surfactants, for example anionic weights. In some embodiments, neutralised (for example 35 surfactants of the alkyl sulfate type, for example sodium, with dilute aqueous sodium hydroxide solution) poly- potassium or magnesium n- dodecyl sulfate, n- tetradecyl acrylic acid derivatives of the commercial form Car- sulfate, n-hexadecyl sulfate or n-octadecyl sulfate, alkyl bopol® (Goodrich), for example CARBOPOL 934 P or ether sulfate, for example sodium, potassium or magne- CARBOPOL 940, are used. sium n-dodecyloxyethyl sulfate, n-tetradecyloxyethyl sul- [0132] Suitable polymethacrylates are likewise swella- 40 fate, n-hexadecyloxyethyl sulfate or n-octadecyloxyethyl ble and have a mean molecular weight of more than sulfate, or alkanesulfonate, for example sodium, potas- 1.0X106. Commercial forms that can be used include the sium or magnesium n-dodecanesulfonate, n-tetrade- polymers of methacrylic acid and methacrylic acid esters canesulfonate, n-hexadecanesulfonate or n-octade- of the Eudragit® type, for example EUDRA-GIT L or canesulfonate. EUDRAGIT S (Rohm GmbH). 45 [0138] Suitable surfactants are also nonionic sur- [0133] Suitable polyethylene glycols have an average factants of the fatty acid/polyhydroxy alcohol ester type, molecular weight of approximately 4000 to 6000. Phar- such as orbitan monolaurate, monooleate, monostearate maceutical-quality commercial forms are preferred, for or monopalmitate, sorbitan tristearate or trioleate, poly- example polyethylene glycol such as Lutrol® (BASF), oxyethylene adducts of fatty acid/ polyhydroxy alcohol es- Polydiol®, Polywachs® (Huls), Polyglykol®, Lanogen® 50 ters, such as polyoxyethylene sorbitan monolaurate, mo- (Hoechst), Carbowax® (Union Carbide), Plurocol® nooleate, monostearate, monopalmitate, tristearate or (Wyandotte) or Tetronic® (Kuhlmann). trioleate, polyethylene glycol/fatty acid esters, such as [0134] Suitable hydrophilic swelling agents are also polyoxyethylene stearate, polyethylene glycol 400 stea- homopolymers, such as polyhydroxyalkyl methacrylate rate or polyethylene glycol 2000 stearate, especially eth- having a molecular weight from 5,000 to 5,000,000 ani- 55 ylene oxide/propylene oxide block copolymers of the onic or cationic hydrogels, mixtures of agar and car- Pluronics® (BWC) or Synperonic® (ICI) type, myristates boxymethylcellulose, swellable agents consisting of and their condensation products, or ethylene oxide methylcellulose in admixture with weakly cross-linked homopolymers having a degree of polymerisation of ap-

15 29 EP 2 478 895 A2 30 proximately 2,000 to 100,000, which are known, for ex- aqueous solution of polyvinyl alcohol, especially polyvi- ample, under the trade name Polyox® (Union Carbide). nyl alcohol having a degree of hydrolysis of more than 97%, and polyethylene glycol/fatty acid ester, for exam- Expandable Membrane ple polyethylene glycol 400 stearate or polyethylene gly- 5 col 2000 stearate, optionally with the addition of plasti- [0139] The hydrophilic membrane, which is expanda- cisers, such as glycerol, is distinguished by a high degree ble at the site of use and is permeable to body fluid, con- of extensibility. A film-like residue which can be obtained sists of a plastic or wax- like, pharmaceutically acceptable after evaporation of an aqueous solution containing ap- polymeric material that is substantially gas- impermeable proximately 40-85% polyvinyl alcohol, 0-40% polyethyl- to the gas generated by the gas-generating agent. By 10 ene glycol stearate and 10-30% glycerol has particularly "substantially gas-impermeable" is meant that the flow advantageous properties. This film is distinguished by of gas through the membrane is impeded sufficiently to particularly good extensibility. This film can be easily cut allow expansion of the membrane sachet or pouch upon and formed into pouches or sachets to accommodate the generation of gas from the gas- generating agent con- individual tablet components or used as a sheet to fold tained in the tablet component for a suitable period of 15 around the tablet component or several sheets of mem- time. Because of its hydrophilic properties, the mem- brane film can be used to sandwich the tablet compo- brane can absorb body fluid, such as gastric fluid, and nents. can effect retarded and continuous release of controlled amounts of the active ingredients contained in the tablet Optional Covering component by means of diffusion or optionally by the use 20 of osmosis. [0144] In certain embodiments, the gastro-retentive [0140] Suitable plastic or wax- like polymeric materials vehicle for use in accordance with the invention can be for the expandable hydrophilic membrane include for ex- provided with a covering which surrounds or contains the ample hydrophilic foils, for example foils of cellulose tablet component and the membrane component and ethers, such as methyl- or ethyl-cellulose, hydroxypro- 25 which disintegrates without delay under the action of pylcellulose, methyl-or ethyl-hydroxyethylcellulose, me- body fluid at the site of use and which consists of a film thyl- or ethyl-hydroxypropylcellulose carboxymethylcel- coating or, preferably, a covering in capsule form. lulose, polyvinyl alcohol, polyvinyl acetate, polyvinylpyr- [0145] Suitablefilm coatings delay the release of active rolidone, polyacrylonitrile, mixtures of polyvinylpyrro- ingredient only slightly or not at all. Water-soluble film lidone with polyvinyl alcohol, resins based on phthalic 30 coatings from approximately 20 Pm to approximately 150 acid anhydride/polyhydroxy alcohol, urethanes, polya- Pm in thickness are preferred. Suitable film coating ma- mides, shellac, etc. terials are especially hydrophilic cellulose derivatives, [0141] In certain embodiments, polyvinyl alcohols hav- such as cellulose ethers, for example methylcellulose, ing a degree of hydrolysis of more than 92% (fully hydro- hydroxypropylcellulose or especially hydroxypropyl- lysed polyvinyl alcohol), especially more than 97%, for 35 methylcellulose, mixtures of polyvinylpyrrolidone or of a example MOWIOL of the 98 series, for examplecopolymer of polyvinylpyrrolidone and polyvinyl acetate MOWIOL 4-98, 10-98, 20-98, 28-99, 56-98 and 66-100, with hydroxypropylmethylcellul- ose, mixtures of shellac PVAU228-08 are used. In other embodiments, MOWIOL with hydroxypropylmethylcellulose, polyvinyl acetate or 28-99 and PVAU228-08 are utilized. copolymers thereof with polyvinylpyrrolidone, or mixtures [0142] To these materials it is possible to add further 40 of water-soluble cellulose derivatives, such as adjuncts, for example plasticisers, which improve the hydroxypropylmethylcellulose- , and water-insoluble elasticity of the membrane, for example glycerol, poly- ethylcellulose. These coating agents can, if desired, be ethylene glycol/fatty acid esters, such as polyethylene used in admixture with other adjuncts, such as talc, wet- glycol 400 stearate or polyethylene glycol 2000 stearate, ting agents, for example polysorbates (for example to triethyl citrate, diethyl phthalate, diethyl sebacate, and 45 facilitate application), or pigments (for example for iden- the like. The amount of plasticiser added is approximately tification purposes). Depending upon the solubility of the from 0.01 to 60% by weight, based on the total weight of components, these coatings are applied in aqueous so- the dosage form. Glycerol at 10-30% w/w may be used lution or in organic solution (for example solutions of shel- as the plasticizer, for example, at 20%. lac or ethylcellulose in organic solvents). It is also possi- [0143] In one embodiment, the expandable membrane 50 ble to use mixtures of acrylates that are water-insoluble is produced by preparing a homogeneous mixture of pol- per se, for example the copolymer of ethyl acrylate and yvinyl alcohol and additives, such as plasticisers, for ex- methyl methacrylate, which are used in aqueous disper- ample glycerol and/or polyethylene glycol 400 stearate, sion, with water-soluble adjuncts, for example lactose, by dissolution in water, which is optionally heated, and polyvinylpyrrolidone, polyethylene glycol or evaporation to form layers of suitable thickness, for ex- 55 hydroxypropylmethylcellulose- . ample 100 mm, or by allowing a solution of polyvinyl al- [0146] Instead of using a film-like coating, the gastro- cohol in water (without additives) to evaporate. The film retentive vehicles for use in accordance with the inven- or the foil which is obtainable after evaporation of an tion can be provided with a covering in capsule form.

16 31 EP 2 478 895 A2 32

Hard gelatin capsules having high watersolubility and/or the tablet component. The sachet or pouch can be any swellability are preferred. Size 000, Size 00 and Size 0 convenient shape, typically will be rectangular or circular. dry-fill capsules such as by Capsugel are preferred, in Typically, the uninflated membrane sachet or pouch is order to accommodate the membrane enclosed tablets. about 20-25 mm in the longest dimension and may be [0147] When present, the covering is preferably a dry- 5 shorter, depending on the size of the tablet component fill capsule, more preferably a hard gelatindry- fill capsule. that must be accommodated. In some embodiments, the membrane film will not be preformed into pouches but Preparation of the Gastro-retentive Vehicles will be used as a film layer to surround the tablet com- ponent, either by sandwiching the tablet between two (or [0148] In an aspect, the present invention provides a 10 more) membrane layers or by folding a single layer over method of making a gastro-retentive dosage form of the the tablet. The membrane layers will be sealed on all compositions described in detail and disclosed herein, sides surrounding the tablet and cut along the seal to which method comprises: forming a tablet comprising produce the dosage form. Multiple dosage forms may be any of the compositions disclosed herein, a binder and produced simultaneously in this way by using a mem- a pharmaceutically-acceptable gas-generating agent, 15 brane layer large enough to accommodate multiple tab- surrounding the tablet with an expandable, hydrophilic, lets, sealing the membrane layers between the tablets water-permeable and substantially gas-impermeable and cutting at the sealed membrane to produce the dos- membrane, and sealing the membrane to retard the es- age forms. cape of gasfrom within the sealed membrane. Optionally, [0152] It is also possible for the tablet component to the method comprises the additional step of encapsulat- 20 be surrounded not by one but by several coverings of ing the sealed membrane within a covering that disinte- expansible permeable material. With such a multi-lay- grates without delay upon contact with gastric fluid. ered arrangement, it is also possible for a formulation of [0149] As described above, the tablet component can the compositions disclosed herein, or constituents of the be formed using any convenient tabletting method. Such formulation, for example the gas- generating agent, such methods are well known in the art and are described, for 25 as sodium hydrogen carbonate, to be located between example, in Remington: the Science and Practice of the individual layers. With a multi-layered arrangement Pharmacy 19th Ed. 1995 Mack Publishing Co. Easton it is possible to achieve an even longer dwell time of the Pa. dosage form at the site of action, for example in the stom- [0150] In one embodiment of the gastro- retentive dos- ach. In addition, the expansible membrane (b) may itself, age form of the present invention, the tablet component 30 contain physiologically active substances. will be surrounded by the expandable membrane com- [0153] In a one form of the process, the expandable ponent. The membrane surrounds the tablet on all sides membrane surrounding tablet component is produced and is sealed to retard the escape of gas generated by first, for example by preparing a homogeneous mixture the gas-generating agent contained in the tablet. This of polyvinyl alcohol and additives, such as plasticisers, surrounding can be accomplished in various ways. The 35 for example glycerol and/or polyethylene glycol 400 stea- membrane may be a preformed sachet or pouch that rate, by dissolution in water, which is optionally heated, contains an opening large enough for insertion of the and evaporation to form layers of suitable thickness, for tablet component. After insertion of the tablet, the open- example 100 mm, or by allowing a solution of polyvinyl ing is sealed by appropriate means, for example heat alcohol in water (without additives) to evaporate. The lay- and/or pressure. Alternatively, the membrane may be 40 ers are cut into strips of a suitable size and the active formed around the tablet, for example as a coating on ingredient formulation consisting of the tablet component the tablet that completely surrounds the tablet, or may is applied. This can be effected for example, by filling the be formed by sandwiching the tablet component between still open sachet, which is then closed completely, for two or more separate layers of membrane material, or example by sealing, for example with heat and/or pres- one membrane layer folded over the tablet, and sealing 45 sure. The sealed sachets can then be filled into dry-fill the membrane layers together around the tablet by heat capsules. and/or pressure. Typically, the membrane pouch sur- [0154] The gastro-retentive dosage form according to rounding the tablet component will be as small as possi- the invention can be of various shapes and may be, for ble consistent with the need to accommodate the tablet example, round, oval, oblong, tubular and so on, and may component and provide for sufficient expansion of the 50 be of various sizes depending upon the size and shape dosage form in the stomach. of the tablet component. In addition, the dosage form [0151] As mentioned, the hydrophilic membrane is typ- may be transparent, colourless or coloured in order to ically prepared in the form of a sachet or pouch into which impart to the product an individual appearance and the the tablet component can be inserted. Such a pouch or ability to be immediately recognised. sachet is readily prepared from the membrane film pre- 55 [0155] In some embodiments, the gastro-retentive pared as described herein. After insertion of the tablet, dosage form can be prepared using microparticulates or the pouch can be sealed around the tablet to retard the nanoparticulates comprising the active (i.e., bile acid se- escape of gas generated by the gas- generating agent in questrant or bile acid sequestrant:proton pump inhibitor

17 33 EP 2 478 895 A2 34 combinations) in lieu of a tablet. The microparticulates twice, three, or four times daily. Depending upon the de- or nanoparticulates will comprise the active ingredient, a sired therapeutic action, patient response and other fac- binder and a gas-generating agent, optionally other tors, the dosage form may be administered between agents as described herein, and other optional compo- meals, during meals, prior to a meal i.e.( , within 5, 10, nents as described for the tablets. The microparticulates 5 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes, 2 hours, or nanoparticulates are prepared using, for example, the 4 hours, 8 hours, or 12 hours prior to eating) or after a granulation techniques described herein or other well meal (i.e., within 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, known methods for preparing microparticulates and na- or 60 minutes, 2 hours, 4, hours, 8 hours, or 12 hours noparticulates. following a meal). [0156] Other gastro-retentive forms and methods of 10 A dosage unit (e.g. an oral dosage unit) can include from, making and using the same are known to those skilled for example, at least about or less than about 1 g to at in the art and are also suitable for use in accordance with least about or less than about 30 g (e.g. at least about the compositions described in detail and disclosed here- or less than about 1 g, at least about or less than about in, and include, for example, any of those described and 2 g, at least about or less than about 3 g, at least about disclosed in U.S. Pat. Nos. 4,996,058; 6,881,420;15 or less than about 4 g, at least about or less than about 6,776,999; 6,723,340; 6,685,962; 6,548,083; 5,972,389; 5 g, at least about or less than about 6 g, at least about 4,851,232; 4,735,804 and U.S. Published Application or less than about 7 g, at least about or less than about Nos. 20070269512; 20070196396; 20070190140; 8 g, at least about or less than about 9 g, at least about 20060013876; 20050202090; 20040180086;or less than about 10 g, at least about or less than about 20030104053; and 20030021845, each of which are in- 20 11 g, at least about or less than about 12 g, at least about corporated herein by reference in its entirety. or less than about 13 g, at least about or less than about 14 g, at least about or less than about 15 g, at least about Dosing and Regimen or less than about 16 g, at least about or less than about 17 g, at least about or less than about 18 g, at least about [0157] Doses of the aforementioned compound as the 25 or less than about 19 g, at least about or less than about active ingredient can be suitably decided depending on 20 g, at least about or less than about 21 g, at least about the purpose of administration, i.e., therapeutic or preven- or less than about 22 g, at least about or less than about tive treatment, nature of a disease to be treated or pre- 23 g, at least about or less than about 24 g, at least about vented, conditions, body weight, age, sexuality and the or less than about 25 g, at least about or less than about like of a patient. In the method for administering the phar- 30 26 g, at least about or less than about 27 g, at least about maceutical preparation according to the present disclo- or less than about 28 g, at least about or less than about sure, the proton pump inhibitor and/or other optional 29 g, at least about or less than about 30 g) of a bile acid agent may be administered simultaneously with the bile sequestrant (e.g., cholestyramine, colesevelam, cole- acid sequestrant or the agent (s) may be sequentially ad- sevelam-HCl, ursodeoxycholic acid). A dosage unit (e.g. ministered in an optional order. The practically desirable 35 an oral dosage unit) can include from, for example, at method and sequence for administration varies depend- least about or less than about 1 to at least about or less ing on the purpose of administration, i.e., therapeutic or than about 200 mg, at least about or less than about 5 preventive treatment, nature of a disease to be treated mg to at least about or less than about 100 mg, at least or prevented, conditions, body weight, age, sexuality and about or less than about 10 to at least about or less than the like of a patient. The optimum method and sequence 40 about 120 mg, at least about or less than about 20 to at for administration of the compounds described in detail least about or less than about 100 mg, at least about or herein under preset given conditions may be suitably se- less than about 40 mg to at least about or less than about lected by those skilled in the art with the aid of the routine 100 mg, at least about or less than about 5 to at least technique and the information contained in the present about or less than about 80 mg, at least about or less specification. 45 than about 10 to at least about or less than about 40 mg, [0158] Typically, an amount of about 2 g to 24 g of a at least about or less than about 10 mg to at least about bile acid sequestrant per day for an adult may be admin- or less than about 60 mg, at least about or less than about istered orally. Alternatively, an amount of about 10 mg 1 mg, at least about or less than about 2 mg, at least to 80 mg of a proton pump inhibitor and about 2 g to 24 about or less than about 3 mg, at least about or less than g of a bile acid sequestrant per day for an adult may be 50 about 4mg, at least about or less than about 5 mg, at administered orally. Such doses may be desirably ad- least about or less than about 10 mg, at least about or ministered once a day to several times a day as divided less than about 15 mg, at least about or less than about portions. For example, the compositions of the present 20 mg, at least about or less than about 25 mg, at least disclosure may be administered at least 1x, 2x, 3x, 4x, about or less than about 30 mg, at least about or less 5x, 6x, 8x, 10x or 20x. A preferred embodiment includes 55 than about , at least about or less than about 35 mg, at where the composition described herein is administered least about or less than about 40 mg, at least about or at least once a day for a period of days, weeks, months less than about 45 mg, at least about or less than about or years. The agent may be administered at least once, 50 mg, at least about or less than about 55 mg, at least

18 35 EP 2 478 895 A2 36 about or less than about 60 mg, at least about or less 5.6 g, at least about or less than about 5.8 g, at least than about 65 mg, at least about or less than about 70 about or less than about 6 g) of a bile acid sequestrant mg, at least about or less than about 75 mg, at least about (e.g., cholestyramine, colesevelam, colesevelam-HCl, or less than about 80 mg, at least about or less than about ursodeoxycholic acid). A dosage unit (e.g. an oral dosage 85 mg, at least about or less than about 90 mg, at least 5 unit) can include from, for example, at least about or less about or less than about 95 mg, at least about or less than about 1 to at least about or less than about 200 mg, than about 100 mg, at least about or less than about 105 at least about or less than about 5 mg to at least about mg, at least about or less than about 110 mg, at least or less than about 100 mg, at least about or less than about or less than about 115 mg, at least about or less about 10 to at least about or less than about 120 mg, at than about 120 mg of a proton pump inhibitor (e.g. ome- 10 least about or less than about 20 to at least about or less prazole, esomeprazole, lansoprazole, pantoprazole, than about 100 mg, at least about or less than about 40 rabeprazole, tenatoprazole, leminoprazole, dontopra- mg to at least about or less than about 100 mg, at least zole, and ransoprazole) and from at least about or less about or less than about 5 to at least about or less than than about 1 g to at least about or less than about 30 g about 80 mg, at least about or less than about 10 to at (e.g. at least about or less than about 1 g, at least about 15 least about or less than about 40 mg, at least about or or less than about 2 g, at least about or less than about less than about 10 mg to at least about or less than about 3 g, at least about or less than about 4 g, at least about 60 mg, at least about or less than about 1 mg, at least or less than about 5 g, at least about or less than about about or less than about 2 mg, at least about or less than 6 g, at least about or less than about 7 g, at least about about 3 mg, at least about or less than about 4mg, at or less than about 8 g, at least about or less than about 20 least about or less than about 5 mg, at least about or less 9 g, at least about or less than about 10 g, at least about than about 10 mg, at least about or less than about 15 or less than about 11 g, at least about or less than about mg, at least about or less than about 20 mg, at least about 12 g, at least about or less than about 13 g, at least about or less than about 25 mg, at least about or less than about or less than about 14 g, at least about or less than about 30 mg, at least about or less than about 35 mg, at least 15 g, at least about or less than about 16 g, at least about 25 about or less than about 35 mg, at least about or less or less than about 17 g, at least about or less than about than about 40 mg, at least about or less than about 45 18 g, at least about or less than about 19 g, at least about mg, at least about or less than about 50 mg, at least about or less than about 20 g, at least about or less than about or less than about 55 mg, at least about or less than about 21 g, at least about or less than about 22 g, at least about 60 mg, at least about or less than about 65 mg, at least or less than about 23 g, at least about or less than about 30 about or less than about 70 mg, at least about or less 24 g, at least about or less than about 25 g, at least about than about 75 mg, at least about or less than about 80 or less than about 26 g, at least about or less than about mg, at least about or less than about 85 mg, at least about 27 g, at least about or less than about 28 g, at least about or less than about 90 mg, at least about or less than about or less than about 29 g, at least about or less than about 95 mg, at least about or less than about 100 mg, at least 30 g) of a bile acid sequestrant (e.g., cholestyramine, 35 about or less than about 105 mg, at least about or less colesevelam, colesevelam-HCl, ursodeoxycholic acid). than about 110 mg, at least about or less than about 115 A dosage unit (e.g. an oral dosage unit) can include from, mg, at least about or less than about 120 mg of a proton for example, at least about or less than about 0.2 g to at pump inhibitor (e.g. omeprazole, esomeprazole, lanso- least about or less than about 6 g (e.g. at least about or prazole, pantoprazole, rabeprazole, tenatoprazole, lem- less than about 0.2 g, at least about or less than about 40 inoprazole, dontoprazole, and ransoprazole) and from at 0.4 g, at least about or less than about 0.6 g, at least least about or less than about 0.2 g to at least about or about or less than about 0.8 g, at least about or less than less than about 6 g (e.g. at least about or less than about about 1 g, at least about or less than about 1.2 g, at least 0.2 g, at least about or less than about 0.4 g, at least about or less than about 1.4 g, at least about or less than about or less than about 0.6 g, at least about or less than about 1.6 g, at least about or less than about 1.8 g, at 45 about 0.8 g, at least about or less than about 1 g, at least least about or less than about 2 g, at least about or less about or less than about 1.2 g, at least about or less than than about 2.2 g, at least about or less than about 2.4 g, about 1.4 g, at least about or less than about 1.6 g, at at least about or less than about 2.6 g, at least about or least about or less than about 1.8 g, at least about or less less than about 2.8 g, at least about or less than about than about 2 g, at least about or less than about 2.2 g, 3 g, at least about or less than about 3.2 g, at least about 50 at least about or less than about 2.4 g, at least about or or less than about 3.4 g, at least about or less than about less than about 2.6 g, at least about or less than about 3.6 g, at least about or less than about 3.8 g, at least 2.8 g, at least about or less than about 3 g, at least about about or less than about 4 g, at least about or less than or less than about 3.2 g, at least about or less than about about 4.2 g, at least about or less than about 4.4 g, at 3.4 g, at least about or less than about 3.6 g, at least least about or less than about 4.6 g, at least about or less 55 about or less than about 3.8 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 4 g, at least about or less than about 4.2 g, at least at least about or less than about 5.2 g, at least about or about or less than about 4.4 g, at least about or less than less than about 5.4 g, at least about or less than about about 4.6 g, at least about or less than about 4.8 g, at

19 37 EP 2 478 895 A2 38 least about or less than about 5 g, at least about or less mg, at least about or less than about 75 mg, at least about than about 5.2 g, at least about or less than about 5.4 g, or less than about 80 mg, at least about or less than about at least about or less than about 5.6 g, at least about or 85 mg, at least about or less than about 90 mg, at least less than about 5.8 g, at least about or less than about about or less than about 95 mg, at least about or less 6 g) of a bile acid sequestrant (e.g., cholestyramine, cole- 5 than about 100 mg, at least about or less than about 105 sevelam, colesevelam-HC1, ursodeoxycholic acid). mg, at least about or less than about 110 mg, at least [0159] A dosage unit (e.g. an oral dosage unit) can about or less than about 115 mg, at least about or less include from, for example, from at least about or less than than about 120 mg of a proton pump inhibitor (e.g. ome- about 0.1 g to at least about or less than about 3 g (e.g. prazole, esomeprazole, lansoprazole, pantoprazole, at least about or less than about 0.1 g, at least about or 10 rabeprazole, tenatoprazole, leminoprazole, dontopra- less than about 0.2 g, at least about or less than about zole, and ransoprazole) and from at least about or less 0.3 g, at least about or less than about 0.4 g, at least than about 0.1 g to at least about or less than about 3 g about or less than about 0.5 g, at least about or less than (e.g. at least about or less than about 0.1 g, at least about about 0.6 g, at least about or less than about 0.7 g, at or less than about 0.2 g, at least about or less than about least about or less than about 0.8 g, at least about or less 15 0.3 g, at least about or less than about 0.4 g, at least than about 0.9 g, at least about or less than about 1 g, about or less than about 0.5 g, at least about or less than at least about or less than about 1.1 g, at least about or about 0.6 g, at least about or less than about 0.7 g, at less than about 1.2 g, at least about or less than about least about or less than about 0.8 g, at least about or less 1.3 g, at least about or less than about 1.4 g, at least than about 0.9 g, at least about or less than about 1 g, about or less than about 1.5 g, at least about or less than 20 at least about or less than about 1.1 g, at least about or about 1.6 g, at least about or less than about 1.7 g, at less than about 1.2 g, at least about or less than about least about or less than about 1.8 g, at least about or less 1.3 g, at least about or less than about 1.4 g, at least than about 1.9 g, at least about or less than about 2 g, about or less than about 1.5 g, at least about or less than at least about or less than about 2.1 g, at least about or about 1.6 g, at least about or less than about 1.7 g, at less than about 2.2 g, at least about or less than about 25 least about or less than about 1.8 g, at least about or less 2.3 g, at least about or less than about 2.4 g, at least than about 1.9 g, at least about or less than about 2 g, about or less than about 2.5 g, at least about or less than at least about or less than about 2.1 g, at least about or about 2.6 g, at least about or less than about 2.7 g, at less than about 2.2 g, at least about or less than about least about or less than about 2.8 g, at least about or less 2.3 g, at least about or less than about 2.4 g, at least than about 2.9 g, at least about or less than about 3 g) 30 about or less than about 2.5 g, at least about or less than of a bile acid sequestrant (e.g., cholestyramine, cole- about 2.6 g, at least about or less than about 2.7 g, at sevelam, colesevelam-HCl, ursodeoxycholic acid). A least about or less than about 2.8 g, at least about or less dosage unit (e.g. an oral dosage unit) can include from, than about 2.9 g, at least about or less than about 3 g) for example, at least about or less than about 1 to at least of a bile acid sequestrant (e.g., cholestyramine, cole- about or less than about 200 mg, at least about or less 35 sevelam, colesevelam-HCl, ursodeoxycholic acid). than about 5 mg to at least about or less than about 100 [0160] A dosage unit (e.g. an oral dosage unit) can mg, at least about or less than about 10 to at least about include from, for example, from at least about or less than or less than about 120 mg, at least about or less than about 0.02 g to at least about or less than about 0.6 g about 20 to at least about or less than about 100 mg, at (e.g. at least about or less than about 0.02 g, at least least about or less than about 40 mg to at least about or 40 about or less than about 0.04 g, at least about or less less than about 100 mg, at least about or less than about than about 0.06 g, at least about or less than about 0.08 5 to at least about or less than about 80 mg, at least about g, at least about or less than about 0.1 g, at least about or less than about 10 to at least about or less than about or less than about 0.12 g, at least about or less than about 40 mg, at least about or less than about 10 mg to at least 0.14 g, at least about or less than about 0.16 g, at least about or less than about 60 mg, at least about or less 45 about or less than about 0.18 g, at least about or less than about 1 mg, at least about or less than about 2 mg, than about 0.2 g, at least about or less than about 0.22 at least about or less than about 3 mg, at least about or g, at least about or less than about 0.24 g, at least about less than about 4mg, at least about or less than about 5 or less than about 0.26 g, at least about or less than about mg, at least about or less than about 10 mg, at least about 0.28 g, at least about or less than about 0.3 g, at least or less than about 15 mg, at least about or less than about 50 about or less than about 0.32 g, at least about or less 20 mg, at least about or less than about 25 mg, at least than about 0.34 g, at least about or less than about 0.36 about or less than about 30 mg, at least about or less g, at least about or less than about 0.38 g, at least about than about 35 mg, at least about or less than about 35 or less than about 0.4 g, at least about or less than about mg, at least about or less than about 40 mg, at least about 0.42 g, at least about or less than about 0.44 g, at least or less than about 45 mg, at least about or less than about 55 about or less than about 0.46 g, at least about or less 50 mg, at least about or less than about 55 mg, at least than about 0.48 g, at least about or less than about 0.5 about or less than about 60 mg, at least about or less g, at least about or less than about 0.52 g, at least about than about 65 mg, at least about or less than about 70 or less than about 0.54 g, at least about or less than about

20 39 EP 2 478 895 A2 40

0.56 g, at least about or less than about 0.58 g, at least g, at least about or less than about 0.48 g, at least about about or less than about 0.6 g) of a bile acid sequestrant or less than about 0.5 g, at least about or less than about (e.g., cholestyramine, colesevelam, colesevelam-HCl, 0.52 g, at least about or less than about 0.54 g, at least ursodeoxycholic acid). A dosage unit (e.g. an oral dosage about or less than about 0.56 g, at least about or less unit) can include from, for example, at least about or less 5 than about 0.58 g, at least about or less than about 0.6 than about 1 to at least about or less than about 200 mg, g) of a bile acid sequestrant (e.g., cholestyramine, cole- at least about or less than about 5 mg to at least about sevelam, colesevelam-HCl, ursodeoxycholic acid). or less than about 100 mg, at least about or less than [0161] A dosage unit (e.g. an oral dosage unit) can about 10 to at least about or less than about 120 mg, at include from, for example, from at least about or less than least about or less than about 20 to at least about or less 10 about 0.01 g to at least about or less than about 0.3 g than about 100 mg, at least about or less than about 40 (e.g. at least about or less than about 0.01 g, at least mg to at least about or less than about 100 mg, at least about or less than about 0.02 g, at least about or less about or less than about 5 to at least about or less than than about 0.03 g, at least about or less than about 0.04 about 80 mg, at least about or less than about 10 to at g, at least about or less than about 0.05 g, at least about least about or less than about 40 mg, at least about or 15 or less than about 0.06 g, at least about or less than about less than about 10 mg to at least about or less than about 0.07 g, at least about or less than about 0.08 g, at least 60 mg, at least about or less than about 1 mg, at least about or less than about 0.09 g, at least about or less about or less than about 2 mg, at least about or less than than about 0.1 g, at least about or less than about 0.11 about 3 mg, at least about or less than about 4mg, at g, at least about or less than about 0.12 g, at least about least about or less than about 5 mg, at least about or less 20 or less than about 0.13 g, at least about or less than about than about 10 mg, at least about or less than about 15 0.14 g, at least about or less than about 0.15 g, at least mg, at least about or less than about 20 mg, at least about about or less than about 0.16 g, at least about or less or less than about 25 mg, at least about or less than about than about 0.17 g, at least about or less than about 0.18 30 mg, at least about or less than about 35 mg, at least g, at least about or less than about 0.19 g, at least about about or less than about 35 mg, at least about or less 25 or less than about 0.2 g, at least about or less than about than about 40 mg, at least about or less than about 45 0.21 g, at least about or less than about 0.22 g, at least mg, at least about or less than about 50 mg, at least about about or less than about 0.23 g, at least about or less or less than about 55 mg, at least about or less than about than about 0.24 g, at least about or less than about 0.25 60 mg, at least about or less than about 65 mg, at least g, at least about or less than about 0.26 g, at least about about or less than about 70 mg, at least about or less 30 or less than about 0.27 g, at least about or less than about than about 75 mg, at least about or less than about 80 0.28 g, at least about or less than about 0.29 g, at least mg, at least about or less than about 85 mg, at least about about or less than about 0.3 g) of a bile acid sequestrant or less than about 90 mg, at least about or less than about (e.g., cholestyramine, colesevelam, colesevelam-HCl, 95 mg, at least about or less than about 100 mg, at least ursodeoxycholic acid, sevelamer). A dosage unit (e.g. an about or less than about 105 mg, at least about or less 35 oral dosage unit) can include from, for example, at least than about 110 mg, at least about or less than about 115 about or less than about 1 to at least about or less than mg, at least about or less than about 120 mg of a proton about 200 mg, at least about or less than about 5 mg to pump inhibitor (e.g. omeprazole, esomeprazole, lanso- at least about or less than about 100 mg, at least about prazole, pantoprazole, rabeprazole, tenatoprazole, lem- or less than about 10 to at least about or less than about inoprazole, dontoprazole, and ransoprazole) and from at 40 120 mg, at least about or less than about 20 to at least least about or less than about 0.02 g to at least about or about or less than about 100 mg, at least about or less less than about 0.6 g (e.g. at least about or less than than about 40 mg to at least about or less than about 100 about 0.02 g, at least about or less than about 0.04 g, at mg, at least about or less than about 5 to at least about least about or less than about 0.06 g, at least about or or less than about 80 mg, at least about or less than about less than about 0.08 g, at least about or less than about 45 10 to at least about or less than about 40 mg, at least 0.1 g, at least about or less than about 0.12 g, at least about or less than about 10 mg to at least about or less about or less than about 0.14 g, at least about or less than about 60 mg, at least about or less than about 1 mg, than about 0.16 g, at least about or less than about 0.18 at least about or less than about 2 mg, at least about or g, at least about or less than about 0.2 g, at least about less than about 3 mg, at least about or less than about or less than about 0.22 g, at least about or less than about 50 4mg, at least about or less than about 5 mg, at least about 0.24 g, at least about or less than about 0.26 g, at least or less than about 10 mg, at least about or less than about about or less than about 0.28 g, at least about or less 15 mg, at least about or less than about 20 mg, at least than about 0.3 g, at least about or less than about 0.32 about or less than about 25 mg, at least about or less g, at least about or less than about 0.34 g, at least about than about 30 mg, at least about or less than about 35 or less than about 0.36 g, at least about or less than about 55 mg, at least about or less than about 35 mg, at least about 0.38 g, at least about or less than about 0.4 g, at least or less than about 40 mg, at least about or less than about about or less than about 0.42 g, at least about or less 45 mg, at least about or less than about 50 mg, at least than about 0.44 g, at least about or less than about 0.46 about or less than about 55 mg, at least about or less

21 41 EP 2 478 895 A2 42 than about 60 mg, at least about or less than about 65 least about or less than about 130 g, at least about or mg, at least about or less than about 70 mg, at least about less than about 135 g, at least about or less than about or less than about 75 mg, at least about or less than about 140 g, at least about or less than about 145 g, at least 80 mg, at least about or less than about 85 mg, at least about or less than about 150 g) of a bile acid sequestrant about or less than about 90 mg, at least about or less 5 (e.g., cholestyramine, colesevelam, colesevelam-HCl, than about 95 mg, at least about or less than about 100 ursodeoxycholic acid). A dosage unit (e.g. an oral dosage mg, at least about or less than about 105 mg, at least unit) can include from, for example, at least about or less about or less than about 110 mg, at least about or less than about 1 to 200 mg, at least about or less than about than about 115 mg, at least about or less than about 120 5 mg to at least about or less than about 100 mg, at least mg of a proton pump inhibitor (e.g. omeprazole, esome- 10 about or less than about 10 to at least about or less than prazole, lansoprazole, pantoprazole, rabeprazole, tenat- about 120 mg, at least about or less than about 20 to at oprazole, leminoprazole, dontoprazole, and ransopra- least about or less than about 100 mg, at least about or zole) and from at least about or less than about 0.01 g less than about 40 mg to at least about or less than about to at least about or less than about 0.3 g (e.g. at least 100 mg, at least about or less than about 5 to at least about or less than about 0.01 g, at least about or less 15 about or less than about 80 mg, at least about or less than about 0.02 g, at least about or less than about 0.03 than about 10 to at least about or less than about 40 mg, g, at least about or less than about 0.04 g, at least about at least about or less than about 10 mg to at least about or less than about 0.05 g, at least about or less than about or less than about 60 mg, at least about or less than about 0.06 g, at least about or less than about 0.07 g, at least 1 mg, at least about or less than about 2 mg, at least about or less than about 0.08 g, at least about or less 20 about or less than about 3 mg, at least about or less than than about 0.09 g, at least about or less than about 0.1 about 4mg, at least about or less than about 5 mg, at g, at least about or less than about 0.11 g, at least about least about or less than about 10 mg, at least about or or less than about 0.12 g, at least about or less than about less than about 15 mg, at least about or less than about 0.13 g, at least about or less than about 0.14 g, at least 20 mg, at least about or less than about 25 mg, at least about or less than about 0.15 g, at least about or less 25 about or less than about 30 mg, at least about or less than about 0.16 g, at least about or less than about 0.17 than about 35 mg, at least about or less than about 35 g, at least about or less than about 0.18 g, at least about mg, at least about or less than about 40 mg, at least about or less than about 0.19 g, at least about or less than about or less than about 45 mg, at least about or less than about 0.2 g, at least about or less than about 0.21 g, at least 50 mg, at least about or less than about 55 mg, at least about or less than about 0.22 g, at least about or less 30 about or less than about 60 mg, at least about or less than about 0.23 g, at least about or less than about 0.24 than about 65 mg, at least about or less than about 70 g, at least about or less than about 0.25 g, at least about mg, at least about or less than about 75 mg, at least about or less than about 0.26 g, at least about or less than about or less than about 80 mg, at least about or less than about 0.27 g, at least about or less than about 0.28 g, at least 85 mg, at least about or less than about 90 mg, at least about or less than about 0.29 g, at least about or less 35 about or less than about 95 mg, at least about or less than about 0.3 g) of a bile acid sequestrant (e.g., choles- than about 100 mg, at least about or less than about 105 tyramine, colesevelam, colesevelam-HCl, ursodeoxy- mg, at least about or less than about 110 mg, at least cholic acid, sevelamer). about or less than about 115 mg, at least about or less [0162] A dosage unit (e.g. an oral dosage unit) can than about 120 mg of a proton pump inhibitor (e.g. ome- include from, for example, from at least about or less than 40 prazole, esomeprazole, lansoprazole, pantoprazole, about 5 g to at least about or less than about 150 g (e.g. rabeprazole, tenatoprazole, leminoprazole, dontopra- at least about or less than about 5 g, at least about or zole, and ransoprazole) and from at least about or less less than about 10 g, at least about or less than about than about 5 g to at least about or less than about 150 g 15 g, at least about or less than about 20 g, at least about (e.g. at least about or less than about 5 g, at least about or less than about 25 g, at least about or less than about 45 or less than about 10 g, at least about or less than about 30 g, at least about or less than about 35 g, at least about 15 g, at least about or less than about 20 g, at least about or less than about 40 g, at least about or less than about or less than about 25 g, at least about or less than about 45 g, at least about or less than about 50 g, at least about 30 g, at least about or less than about 35 g, at least about or less than about 55 g, at least about or less than about or less than about 40 g, at least about or less than about 60 g, at least about or less than about 65 g, at least about 50 45 g, at least about or less than about 50 g, at least about or less than about 70 g, at least about or less than about or less than about 55 g, at least about or less than about 75 g, at least about or less than about 80 g, at least about 60 g, at least about or less than about 65 g, at least about or less than about 85 g, at least about or less than about or less than about 70 g, at least about or less than about 90 g, at least about or less than about 95 g, at least about 75 g, at least about or less than about 80 g, at least about or less than about 100 g, at least about or less than about 55 or less than about 85 g, at least about or less than about 105 g, at least about or less than about 110 g, at least 90 g, at least about or less than about 95 g, at least about about or less than about 115 g, at least about or less than or less than about 100 g, at least about or less than about about 120 g, at least about or less than about 125 g, at 105 g, at least about or less than about 110 g, at least

22 43 EP 2 478 895 A2 44 about or less than about 115 g, at least about or less than than about 65 mg, at least about or less than about 70 about 120 g, at least about or less than about 125 g, at mg, at least about or less than about 75 mg, at least about least about or less than about 130 g, at least about or or less than about 80 mg, at least about or less than about less than about 135 g, at least about or less than about 85 mg, at least about or less than about 90 mg, at least 140 g, at least about or less than about 145 g, at least 5 about or less than about 95 mg, at least about or less about or less than about 150 g) of a bile acid sequestrant than about 100 mg, at least about or less than about 105 (e.g., cholestyramine, colesevelam, colesevelam-HCl, mg, at least about or less than about 110 mg, at least ursodeoxycholic acid). about or less than about 115 mg, at least about or less [0163] A dosage unit (e.g. an oral dosage unit) can than about 120 mg of a proton pump inhibitor (e.g. ome- include from, for example, from at least about or less than 10 prazole, esomeprazole, lansoprazole, pantoprazole, about 2 g to at least about or less than about 60 g (e.g. rabeprazole, tenatoprazole, leminoprazole, dontopra- at least about or less than about 2 g, at least about or zole, and ransoprazole) and from at least about or less less than about 4 g, at least about or less than about 6 than about 2 g to at least about or less than about 60 g g, at least about or less than about 8 g, at least about or (e.g. at least about or less than about 2 g, at least about less than about 10 g, at least about or less than about 15 or less than about 4 g, at least about or less than about 12 g, at least about or less than about 14 g, at least about 6 g, at least about or less than about 8 g, at least about or less than about 16 g, at least about or less than about or less than about 10 g, at least about or less than about 18 g, at least about or less than about 20 g, at least about 12 g, at least about or less than about 14 g, at least about or less than about 22 g, at least about or less than about or less than about 16 g, at least about or less than about 24 g, at least about or less than about 26 g, at least about 20 18 g, at least about or less than about 20 g, at least about or less than about 28 g, at least about or less than about or less than about 22 g, at least about or less than about 30 g, at least about or less than about 32 g, at least about 24 g, at least about or less than about 26 g, at least about or less than about 34 g, at least about or less than about or less than about 28 g, at least about or less than about 36 g, at least about or less than about 38 g, at least about 30 g, at least about or less than about 32 g, at least about or less than about 40 g, at least about or less than about 25 or less than about 34 g, at least about or less than about 42 g, at least about or less than about 44 g, at least about 36 g, at least about or less than about 38 g, at least about or less than about 46 g, at least about or less than about or less than about 40 g, at least about or less than about 48 g, at least about or less than about 50 g, at least about 42 g, at least about or less than about 44 g, at least about or less than about 52 g, at least about or less than about or less than about 46 g, at least about or less than about 54 g, at least about or less than about 56 g, at least about 30 48 g, at least about or less than about 50 g, at least about or less than about 58 g, at least about or less than about or less than about 52 g, at least about or less than about 60 g) of a bile acid sequestrant (e.g., cholestyramine, 54 g, at least about or less than about 56 g, at least about colesevelam, colesevelam-HCl, ursodeoxycholic acid). or less than about 58 g, at least about or less than about A dosage unit (e.g. an oral dosage unit) can include from, 60 g) of a bile acid sequestrant (e.g., cholestyramine, for example, at least about or less than about 1 to at least 35 colesevelam, colesevelam-HCl, ursodeoxycholic acid). about or less than about 200 mg, at least about or less [0164] A dosage unit (e.g. an oral dosage unit) can than about 5 mg to at least about or less than about 100 include from, for example, from at least about or less than mg, at least about or less than about 10 to at least about about 10 g to at least about or less than about 300 g (e.g. or less than about 120 mg, at least about or less than at least about or less than about 10 g, at least about or about 20 to at least about or less than about 100 mg, at 40 less than about 20 g, at least about or less than about least about or less than about 40 mg to at least about or 30 g, at least about or less than about 40 g, at least about less than about 100 mg, at least about or less than about or less than about 50 g, at least about or less than about 5 to at least about or less than about 80 mg, at least about 60 g, at least about or less than about 70 g, at least about or less than about 10 to at least about or less than about or less than about 80 g, at least about or less than about 40 mg, at least about or less than about 10 mg to at least 45 90 g, at least about or less than about 100 g, at least about or less than about 60 mg, at least about or less about or less than about 110 g, at least about or less than than about 1 mg, at least about or less than about 2 mg, about 120 g, at least about or less than about 130 g, at at least about or less than about 3 mg, at least about or least about or less than about 140 g, at least about or less than about 4mg, at least about or less than about 5 less than about 150 g, at least about or less than about mg, at least about or less than about 10 mg, at least about 50 160 g, at least about or less than about 170 g, at least or less than about 15 mg, at least about or less than about about or less than about 180 g, at least about or less than 20 mg, at least about or less than about 25 mg, at least about 190 g, at least about or less than about 200 g, at about or less than about 30 mg, at least about or less least about or less than about 210 g, at least about or than about 35 mg, at least about or less than about 35 less than about 220 g, at least about or less than about mg, at least about or less than about 40 mg, at least about 55 230 g, at least about or less than about 240 g, at least or less than about 45 mg, at least about or less than about about or less than about 250 g, at least about or less than 50 mg, at least about or less than about 55 mg, at least about 260 g, at least about or less than about 270 g, at about or less than about 60 mg, at least about or less least about or less than about 280 g, at least about or

23 45 EP 2 478 895 A2 46 less than about 290 g, at least about or less than about least about or less than about 250 g, at least about or 300 g) of a bile acid sequestrant (e.g., cholestyramine, less than about 260 g, at least about or less than about colesevelam, colesevelam-HCl, ursodeoxycholic acid). 270 g, at least about or less than about 280 g, at least A dosage unit (e.g. an oral dosage unit) can include from, about or less than about 290 g, at least about or less than for example, at least about or less than about 1 to at least 5 about 300 g) of a bile acid sequestrant (e.g., cholesty- about or less than about 200 mg, at least about or less ramine, colesevelam, colesevelam-HCl, ursodeoxychol- than about 5 mg to at least about or less than about 100 ic acid). mg, at least about or less than about 10 to at least about [0165] In certain embodiments, the dosage unit com- or less than about 120 mg, at least about or less than prises at least about or less than about 5 mg of at least about 20 to at least about or less than about 100 mg, at 10 one proton pump inhibitor and at least about or less than least about or less than about 40 mg to at least about or about 1 g, at least about or less than about 2 g, at least less than about 100 mg, at least about or less than about about or less than about 3 g, at least about or less than 5 to at least about or less than about 80 mg, at least about about 4 g, at least about or less than about 5 g, at least or less than about 10 to at least about or less than about about or less than about 6 g, at least about or less than 40 mg, at least about or less than about 10 mg to at least 15 about 7 g, at least about or less than about 8 g, at least about or less than about 60 mg, at least about or less about or less than about 9 g, at least about or less than than about 1 mg, at least about or less than about 2 mg, about 10 g, at least about or less than about 11 g, at least at least about or less than about 3 mg, at least about or about or less than about 12 g, at least about or less than less than about 4mg, at least about or less than about 5 about 13 g, at least about or less than about 14 g, at least mg, at least about or less than about 10 mg, at least about 20 about or less than about 15 g, at least about or less than or less than about 15 mg, at least about or less than about about 16 g, at least about or less than about 17 g, at least 20 mg, at least about or less than about 25 mg, at least about or less than about 18 g, at least about or less than about or less than about 30 mg, at least about or less about 19 g, at least about or less than about 20 g, at least than about 35 mg, at least about or less than about 35 about or less than about 21 g, at least about or less than mg, at least about or less than about 40 mg, at least about 25 about 22 g, at least about or less than about 23 g, at least or less than about 45 mg, at least about or less than about about or less than about 24 g, at least about or less than 50 mg, at least about or less than about 55 mg, at least about 25 g, at least about or less than about 26 g, at least about or less than about 60 mg, at least about or less about or less than about 27 g, at least about or less than than about 65 mg, at least about or less than about 70 about 28 g, at least about or less than about 29 g, or at mg, at least about or less than about 75 mg, at least about 30 least about or less than about 30 g of at least one bile or less than about 80 mg, at least about or less than about acid sequestrant. In certain embodiments, the dosage 85 mg, at least about or less than about 90 mg, at least unit comprises at least about or less than about 10 mg about or less than about 95 mg, at least about or less of at least one proton pump inhibitor and at least about than about 100 mg, at least about or less than about 105 or less than about 1 g, at least about or less than about mg, at least about or less than about 110 mg, at least 35 2 g, at least about or less than about 3 g, at least about about or less than about 115 mg, at least about or less or less than about 4 g, at least about or less than about than about 120 mg of a proton pump inhibitor (e.g. ome- 5 g, at least about or less than about 6 g, at least about prazole, esomeprazole, lansoprazole, pantoprazole, or less than about 7 g, at least about or less than about rabeprazole, tenatoprazole, leminoprazole, dontopra- 8 g, at least about or less than about 9 g, at least about zole, and ransoprazole) and from at least about or less 40 or less than about 10 g, at least about or less than about than about 10 g to at least about or less than about 300 11 g, at least about or less than about 12 g, at least about g (e.g. at least about or less than about 10 g, at least or less than about 13 g, at least about or less than about about or less than about 20 g, at least about or less than 14 g, at least about or less than about 15 g, at least about about 30 g, at least about or less than about 40 g, at least or less than about 16 g, at least about or less than about about or less than about 50 g, at least about or less than 45 17 g, at least about or less than about 18 g, at least about about 60 g, at least about or less than about 70 g, at least or less than about 19 g, at least about or less than about about or less than about 80 g, at least about or less than 20 g, at least about or less than about 21 g, at least about about 90 g, at least about or less than about 100 g, at or less than about 22 g, at least about or less than about least about or less than about 110 g, at least about or 23 g, at least about or less than about 24 g, at least about less than about 120 g, at least about or less than about 50 or less than about 25 g, at least about or less than about 130 g, at least about or less than about 140 g, at least 26 g, at least about or less than about 27 g, at least about about or less than about 150 g, at least about or less than or less than about 28 g, at least about or less than about about 160 g, at least about or less than about 170 g, at 29 g, or at least about or less than about 30 g of at least least about or less than about 180 g, at least about or one bile acid sequestrant. In certain embodiments, the less than about 190 g, at least about or less than about 55 dosage unit comprises at least about or less than about 200 g, at least about or less than about 210 g, at least 15 mg of at least one proton pump inhibitor and at least about or less than about 220 g, at least about or less than about or less than about 1 g, at least about or less than about 230 g, at least about or less than about 240 g, at about 2 g, at least about or less than about 3 g, at least

24 47 EP 2 478 895 A2 48 about or less than about 4 g, at least about or less than about 21 g, at least about or less than about 22 g, at least about 5 g, at least about or less than about 6 g, at least about or less than about 23 g, at least about or less than about or less than about 7 g, at least about or less than about 24 g, at least about or less than about 25 g, at least about 8 g, at least about or less than about 9 g, at least about or less than about 26 g, at least about or less than about or less than about 10 g, at least about or less than 5 about 27 g, at least about or less than about 28 g, at least about 11 g, at least about or less than about 12 g, at least about or less than about 29 g, or at least about or less about or less than about 13 g, at least about or less than than about 30 g of at least one bile acid sequestrant. In about 14 g, at least about or less than about 15 g, at least certain embodiments, the dosage unit comprises at least about or less than about 16 g, at least about or less than about or less than about 30 mg of at least one proton about 17 g, at least about or less than about 18 g, at least 10 pump inhibitor and at least about or less than about 1 g, about or less than about 19 g, at least about or less than at least about or less than about 2 g, at least about or about 20 g, at least about or less than about 21 g, at least less than about 3 g, at least about or less than about 4 about or less than about 22 g, at least about or less than g, at least about or less than about 5 g, at least about or about 23 g, at least about or less than about 24 g, at least less than about 6 g, at least about or less than about 7 about or less than about 25 g, at least about or less than 15 g, at least about or less than about 8 g, at least about or about 26 g, at least about or less than about 27 g, at least less than about 9 g, at least about or less than about 10 about or less than about 28 g, at least about or less than g, at least about or less than about 11 g, at least about about 29 g, or at least about or less than about 30 g of or less than about 12 g, at least about or less than about at least one bile acid sequestrant. In certain embodi- 13 g, at least about or less than about 14 g, at least about ments, the dosage unit comprises at least about or less 20 or less than about 15 g, at least about or less than about than about 20 mg of at least one proton pump inhibitor 16 g, at least about or less than about 17 g, at least about and at least about or less than about 1 g, at least about or less than about 18 g, at least about or less than about or less than about 2 g, at least about or less than about 19 g, at least about or less than about 20 g, at least about 3 g, at least about or less than about 4 g, at least about or less than about 21 g, at least about or less than about or less than about 5 g, at least about or less than about 25 22 g, at least about or less than about 23 g, at least about 6 g, at least about or less than about 7 g, at least about or less than about 24 g, at least about or less than about or less than about 8 g, at least about or less than about 25 g, at least about or less than about 26 g, at least about 9 g, at least about or less than about 10 g, at least about or less than about 27 g, at least about or less than about or less than about 11 g, at least about or less than about 28 g, at least about or less than about 29 g, or at least 12 g, at least about or less than about 13 g, at least about 30 about or less than about 30 g of at least one bile acid or less than about 14 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 15 g, at least about or less than about 16 g, at least about comprises at least about or less than about 35 mg of at or less than about 17 g, at least about or less than about least one proton pump inhibitor and at least about or less 18 g, at least about or less than about 19 g, at least about than about 1 g, at least about or less than about 2 g, at or less than about 20 g, at least about or less than about 35 least about or less than about 3 g, at least about or less 21 g, at least about or less than about 22 g, at least about than about 4 g, at least about or less than about 5 g, at or less than about 23 g, at least about or less than about least about or less than about 6 g, at least about or less 24 g, at least about or less than about 25 g, at least about than about 7 g, at least about or less than about 8 g, at or less than about 26 g, at least about or less than about least about or less than about 9 g, at least about or less 27 g, at least about or less than about 28 g, at least about 40 than about 10 g, at least about or less than about 11 g, or less than about 29 g, or at least about or less than at least about or less than about 12 g, at least about or about 30 g of at least one bile acid sequestrant. In certain less than about 13 g, at least about or less than about embodiments, the dosage unit comprises at least about 14 g, at least about or less than about 15 g, at least about or less than about 25 mg of at least one proton pump or less than about 16 g, at least about or less than about inhibitor and at least about or less than about 1 g, at least 45 17 g, at least about or less than about 18 g, at least about about or less than about 2 g, at least about or less than or less than about 19 g, at least about or less than about about 3 g, at least about or less than about 4 g, at least 20 g, at least about or less than about 21 g, at least about about or less than about 5 g, at least about or less than or less than about 22 g, at least about or less than about about 6 g, at least about or less than about 7 g, at least 23 g, at least about or less than about 24 g, at least about about or less than about 8 g, at least about or less than 50 or less than about 25 g, at least about or less than about about 9 g, at least about or less than about 10 g, at least 26 g, at least about or less than about 27 g, at least about about or less than about 11 g, at least about or less than or less than about 28 g, at least about or less than about about 12 g, at least about or less than about 13 g, at least 29 g, or at least about or less than about 30 g of at least about or less than about 14 g, at least about or less than one bile acid sequestrant. In certain embodiments, the about 15 g, at least about or less than about 16 g, at least 55 dosage unit comprises at least about or less than about about or less than about 17 g, at least about or less than 40 mg of at least one proton pump inhibitor and at least about 18 g, at least about or less than about 19 g, at least about or less than about 1 g, at least about or less than about or less than about 20 g, at least about or less than about 2 g, at least about or less than about 3 g, at least

25 49 EP 2 478 895 A2 50 about or less than about 4 g, at least about or less than about 21 g, at least about or less than about 22 g, at least about 5 g, at least about or less than about 6 g, at least about or less than about 23 g, at least about or less than about or less than about 7 g, at least about or less than about 24 g, at least about or less than about 25 g, at least about 8 g, at least about or less than about 9 g, at least about or less than about 26 g, at least about or less than about or less than about 10 g, at least about or less than 5 about 27 g, at least about or less than about 28 g, at least about 11 g, at least about or less than about 12 g, at least about or less than about 29 g, or at least about or less about or less than about 13 g, at least about or less than than about 30 g of at least one bile acid sequestrant. In about 14 g, at least about or less than about 15 g, at least certain embodiments, the dosage unit comprises at least about or less than about 16 g, at least about or less than about or less than about 55 mg of at least one proton about 17 g, at least about or less than about 18 g, at least 10 pump inhibitor and at least about or less than about 1 g, about or less than about 19 g, at least about or less than at least about or less than about 2 g, at least about or about 20 g, at least about or less than about 21 g, at least less than about 3 g, at least about or less than about 4 about or less than about 22 g, at least about or less than g, at least about or less than about 5 g, at least about or about 23 g, at least about or less than about 24 g, at least less than about 6 g, at least about or less than about 7 about or less than about 25 g, at least about or less than 15 g, at least about or less than about 8 g, at least about or about 26 g, at least about or less than about 27 g, at least less than about 9 g, at least about or less than about 10 about or less than about 28 g, at least about or less than g, at least about or less than about 11 g, at least about about 29 g, or at least about or less than about 30 g of or less than about 12 g, at least about or less than about at least one bile acid sequestrant. In certain embodi- 13 g, at least about or less than about 14 g, at least about ments, the dosage unit comprises at least about or less 20 or less than about 15 g, at least about or less than about than about 45 mg of at least one proton pump inhibitor 16 g, at least about or less than about 17 g, at least about and at least about or less than about 1 g, at least about or less than about 18 g, at least about or less than about or less than about 2 g, at least about or less than about 19 g, at least about or less than about 20 g, at least about 3 g, at least about or less than about 4 g, at least about or less than about 21 g, at least about or less than about or less than about 5 g, at least about or less than about 25 22 g, at least about or less than about 23 g, at least about 6 g, at least about or less than about 7 g, at least about or less than about 24 g, at least about or less than about or less than about 8 g, at least about or less than about 25 g, at least about or less than about 26 g, at least about 9 g, at least about or less than about 10 g, at least about or less than about 27 g, at least about or less than about or less than about 11 g, at least about or less than about 28 g, at least about or less than about 29 g, or at least 12 g, at least about or less than about 13 g, at least about 30 about or less than about 30 g of at least one bile acid or less than about 14 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 15 g, at least about or less than about 16 g, at least about comprises at least about or less than about 60 mg of at or less than about 17 g, at least about or less than about least one proton pump inhibitor and at least about or less 18 g, at least about or less than about 19 g, at least about than about 1 g, at least about or less than about 2 g, at or less than about 20 g, at least about or less than about 35 least about or less than about 3 g, at least about or less 21 g, at least about or less than about 22 g, at least about than about 4 g, at least about or less than about 5 g, at or less than about 23 g, at least about or less than about least about or less than about 6 g, at least about or less 24 g, at least about or less than about 25 g, at least about than about 7 g, at least about or less than about 8 g, at or less than about 26 g, at least about or less than about least about or less than about 9 g, at least about or less 27 g, at least about or less than about 28 g, at least about 40 than about 10 g, at least about or less than about 11 g, or less than about 29 g, or at least about or less than at least about or less than about 12 g, at least about or about 30 g of at least one bile acid sequestrant. In certain less than about 13 g, at least about or less than about embodiments, the dosage unit comprises at least about 14 g, at least about or less than about 15 g, at least about or less than about 50 mg of at least one proton pump or less than about 16 g, at least about or less than about inhibitor and at least about or less than about 1 g, at least 45 17 g, at least about or less than about 18 g, at least about about or less than about 2 g, at least about or less than or less than about 19 g, at least about or less than about about 3 g, at least about or less than about 4 g, at least 20 g, at least about or less than about 21 g, at least about about or less than about 5 g, at least about or less than or less than about 22 g, at least about or less than about about 6 g, at least about or less than about 7 g, at least 23 g, at least about or less than about 24 g, at least about about or less than about 8 g, at least about or less than 50 or less than about 25 g, at least about or less than about about 9 g, at least about or less than about 10 g, at least 26 g, at least about or less than about 27 g, at least about about or less than about 11 g, at least about or less than or less than about 28 g, at least about or less than about about 12 g, at least about or less than about 13 g, at least 29 g, or at least about or less than about 30 g of at least about or less than about 14 g, at least about or less than one bile acid sequestrant. In certain embodiments, the about 15 g, at least about or less than about 16 g, at least 55 dosage unit comprises at least about or less than about about or less than about 17 g, at least about or less than 65 mg of at least one proton pump inhibitor and at least about 18 g, at least about or less than about 19 g, at least about or less than about 1 g, at least about or less than about or less than about 20 g, at least about or less than about 2 g, at least about or less than about 3 g, at least

26 51 EP 2 478 895 A2 52 about or less than about 4 g, at least about or less than about 21 g, at least about or less than about 22 g, at least about 5 g, at least about or less than about 6 g, at least about or less than about 23 g, at least about or less than about or less than about 7 g, at least about or less than about 24 g, at least about or less than about 25 g, at least about 8 g, at least about or less than about 9 g, at least about or less than about 26 g, at least about or less than about or less than about 10 g, at least about or less than 5 about 27 g, at least about or less than about 28 g, at least about 11 g, at least about or less than about 12 g, at least about or less than about 29 g, or at least about or less about or less than about 13 g, at least about or less than than about 30 g of at least one bile acid sequestrant. In about 14 g, at least about or less than about 15 g, at least certain embodiments, the dosage unit comprises at least about or less than about 16 g, at least about or less than about or less than about 80 mg of at least one proton about 17 g, at least about or less than about 18 g, at least 10 pump inhibitor and at least about or less than about 1 g, about or less than about 19 g, at least about or less than at least about or less than about 2 g, at least about or about 20 g, at least about or less than about 21 g, at least less than about 3 g, at least about or less than about 4 about or less than about 22 g, at least about or less than g, at least about or less than about 5 g, at least about or about 23 g, at least about or less than about 24 g, at least less than about 6 g, at least about or less than about 7 about or less than about 25 g, at least about or less than 15 g, at least about or less than about 8 g, at least about or about 26 g, at least about or less than about 27 g, at least less than about 9 g, at least about or less than about 10 about or less than about 28 g, at least about or less than g, at least about or less than about 11 g, at least about about 29 g, or at least about or less than about 30 g of or less than about 12 g, at least about or less than about at least one bile acid sequestrant. In certain embodi- 13 g, at least about or less than about 14 g, at least about ments, the dosage unit comprises at least about or less 20 or less than about 15 g, at least about or less than about than about 70 mg of at least one proton pump inhibitor 16 g, at least about or less than about 17 g, at least about and at least about or less than about 1 g, at least about or less than about 18 g, at least about or less than about or less than about 2 g, at least about or less than about 19 g, at least about or less than about 20 g, at least about 3 g, at least about or less than about 4 g, at least about or less than about 21 g, at least about or less than about or less than about 5 g, at least about or less than about 25 22 g, at least about or less than about 23 g, at least about 6 g, at least about or less than about 7 g, at least about or less than about 24 g, at least about or less than about or less than about 8 g, at least about or less than about 25 g, at least about or less than about 26 g, at least about 9 g, at least about or less than about 10 g, at least about or less than about 27 g, at least about or less than about or less than about 11 g, at least about or less than about 28 g, at least about or less than about 29 g, or at least 12 g, at least about or less than about 13 g, at least about 30 about or less than about 30 g of at least one bile acid or less than about 14 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 15 g, at least about or less than about 16 g, at least about comprises at least about or less than about 85 mg of at or less than about 17 g, at least about or less than about least one proton pump inhibitor and at least about or less 18 g, at least about or less than about 19 g, at least about than about 1 g, at least about or less than about 2 g, at or less than about 20 g, at least about or less than about 35 least about or less than about 3 g, at least about or less 21 g, at least about or less than about 22 g, at least about than about 4 g, at least about or less than about 5 g, at or less than about 23 g, at least about or less than about least about or less than about 6 g, at least about or less 24 g, at least about or less than about 25 g, at least about than about 7 g, at least about or less than about 8 g, at or less than about 26 g, at least about or less than about least about or less than about 9 g, at least about or less 27 g, at least about or less than about 28 g, at least about 40 than about 10 g, at least about or less than about 11 g, or less than about 29 g, or at least about or less than at least about or less than about 12 g, at least about or about 30 g of at least one bile acid sequestrant. In certain less than about 13 g, at least about or less than about embodiments, the dosage unit comprises at least about 14 g, at least about or less than about 15 g, at least about or less than about 75 mg of at least one proton pump or less than about 16 g, at least about or less than about inhibitor and at least about or less than about 1 g, at least 45 17 g, at least about or less than about 18 g, at least about about or less than about 2 g, at least about or less than or less than about 19 g, at least about or less than about about 3 g, at least about or less than about 4 g, at least 20 g, at least about or less than about 21 g, at least about about or less than about 5 g, at least about or less than or less than about 22 g, at least about or less than about about 6 g, at least about or less than about 7 g, at least 23 g, at least about or less than about 24 g, at least about about or less than about 8 g, at least about or less than 50 or less than about 25 g, at least about or less than about about 9 g, at least about or less than about 10 g, at least 26 g, at least about or less than about 27 g, at least about about or less than about 11 g, at least about or less than or less than about 28 g, at least about or less than about about 12 g, at least about or less than about 13 g, at least 29 g, or at least about or less than about 30 g of at least about or less than about 14 g, at least about or less than one bile acid sequestrant. In certain embodiments, the about 15 g, at least about or less than about 16 g, at least 55 dosage unit comprises at least about or less than about about or less than about 17 g, at least about or less than 90 mg of at least one proton pump inhibitor and at least about 18 g, at least about or less than about 19 g, at least about or less than about 1 g, at least about or less than about or less than about 20 g, at least about or less than about 2 g, at least about or less than about 3 g, at least

27 53 EP 2 478 895 A2 54 about or less than about 4 g, at least about or less than about 21 g, at least about or less than about 22 g, at least about 5 g, at least about or less than about 6 g, at least about or less than about 23 g, at least about or less than about or less than about 7 g, at least about or less than about 24 g, at least about or less than about 25 g, at least about 8 g, at least about or less than about 9 g, at least about or less than about 26 g, at least about or less than about or less than about 10 g, at least about or less than 5 about 27 g, at least about or less than about 28 g, at least about 11 g, at least about or less than about 12 g, at least about or less than about 29 g, or at least about or less about or less than about 13 g, at least about or less than than about 30 g of at least one bile acid sequestrant. In about 14 g, at least about or less than about 15 g, at least certain embodiments the at least one proton pump inhib- about or less than about 16 g, at least about or less than itor is omeprazole. In certain embodiments the at least about 17 g, at least about or less than about 18 g, at least 10 one proton pump inhibitor is esomeprazole. In certain about or less than about 19 g, at least about or less than embodiments the at least one proton pump inhibitor is about 20 g, at least about or less than about 21 g, at least lansoprazole. In certain embodiments the at least one about or less than about 22 g, at least about or less than proton pump inhibitor is pantoprazole. In certain embod- about 23 g, at least about or less than about 24 g, at least iments the at least one proton pump inhibitor is rabepra- about or less than about 25 g, at least about or less than 15 zole. In certain embodiments the at least one proton about 26 g, at least about or less than about 27 g, at least pump inhibitor is tenatoprazole. In certain embodiments about or less than about 28 g, at least about or less than the at least one bile acid sequestrant is cholestyramine. about 29 g, or at least about or less than about 30 g of In certain embodiments the at least one bile acid seques- at least one bile acid sequestrant. In certain embodi- trant is colesevelam. In certain embodiments the at least ments, the dosage unit comprises at least about or less 20 one bile acid sequestrant is colesevelam- HCl. In certain than about 95 mg of at least one proton pump inhibitor embodiments the at least one bile acid sequestrant is and at least about or less than about 1 g, at least about colestipol. In certain embodiments the at least one proton or less than about 2 g, at least about or less than about pump inhibitor is omeprazole and the at least one bile 3 g, at least about or less than about 4 g, at least about acid sequestrant is cholestyramine. In certain embodi- or less than about 5 g, at least about or less than about 25 ments the at least one proton pump inhibitor is omepra- 6 g, at least about or less than about 7 g, at least about zole and the at least one bile acid sequestrant is cole- or less than about 8 g, at least about or less than about sevelam. In certain embodiments the at least one proton 9 g, at least about or less than about 10 g, at least about pump inhibitor is omeprazole and the at least one bile or less than about 11 g, at least about or less than about acid sequestrant is colesevelam-HCl. In certain embod- 12 g, at least about or less than about 13 g, at least about 30 iments the at least one proton pump inhibitor is omepra- or less than about 14 g, at least about or less than about zole and the at least one bile acid sequestrant is 15 g, at least about or less than about 16 g, at least about colestipol. In certain embodiments the at least one proton or less than about 17 g, at least about or less than about pump inhibitor is esomeprazole and the at least one bile 18 g, at least about or less than about 19 g, at least about acid sequestrant is cholestyramine. In certain embodi- or less than about 20 g, at least about or less than about 35 ments the at least one proton pump inhibitor is esome- 21 g, at least about or less than about 22 g, at least about prazole and the at least one bile acid sequestrant is cole- or less than about 23 g, at least about or less than about sevelam. In certain embodiments the at least one proton 24 g, at least about or less than about 25 g, at least about pump inhibitor is esomeprazole and the at least one bile or less than about 26 g, at least about or less than about acid sequestrant is colesevelam-HCl. In certain embod- 27 g, at least about or less than about 28 g, at least about 40 iments the at least one proton pump inhibitor is esome- or less than about 29 g, or at least about or less than prazole and the at least one bile acid sequestrant is about 30 g of at least one bile acid sequestrant. In certain colestipol. In certain embodiments the at least one proton embodiments, the dosage unit comprises at least about pump inhibitor is lansoprazole and the at least one bile or less than about 100 mg of at least one proton pump acid sequestrant is cholestyramine. In certain embodi- inhibitor and at least about or less than about 1 g, at least 45 ments the at least one proton pump inhibitor is lansopra- about or less than about 2 g, at least about or less than zole and the at least one bile acid sequestrant is cole- about 3 g, at least about or less than about 4 g, at least sevelam. In certain embodiments the at least one proton about or less than about 5 g, at least about or less than pump inhibitor is lansoprazole and the at least one bile about 6 g, at least about or less than about 7 g, at least acid sequestrant is colesevelam-HCl. In certain embod- about or less than about 8 g, at least about or less than 50 iments the at least one proton pump inhibitor is lanso- about 9 g, at least about or less than about 10 g, at least prazole and the at least one bile acid sequestrant is about or less than about 11 g, at least about or less than colestipol. In certain embodiments the at least one proton about 12 g, at least about or less than about 13 g, at least pump inhibitor is pantoprazole and the at least one bile about or less than about 14 g, at least about or less than acid sequestrant is cholestyramine. In certain embodi- about 15 g, at least about or less than about 16 g, at least 55 ments the at least one proton pump inhibitor is pantopra- about or less than about 17 g, at least about or less than zole and the at least one bile acid sequestrant is cole- about 18 g, at least about or less than about 19 g, at least sevelam. In certain embodiments the at least one proton about or less than about 20 g, at least about or less than pump inhibitor is pantoprazole and the at least one bile

28 55 EP 2 478 895 A2 56 acid sequestrant is colesevelam-HCl. In certain embod- sequestrant. In certain embodiments, the dosage unit iments the at least one proton pump inhibitor is panto- comprises at least about or less than about 10 mg of at prazole and the at least one bile acid sequestrant is least one proton pump inhibitor and at least about or less colestipol. In certain embodiments the at least one proton than about 0.2 g, at least about or less than about 0.4 g, pump inhibitor is rabeprazole and the at least one bile 5 at least about or less than about 0.6 g, at least about or acid sequestrant is cholestyramine. In certain embodi- less than about 0.8 g, at least about or less than about ments the at least one proton pump inhibitor is rabepra- 1 g, at least about or less than about 1.2 g, at least about zole and the at least one bile acid sequestrant is cole- or less than about 1.4 g, at least about or less than about sevelam. In certain embodiments the at least one proton 1.6 g, at least about or less than about 1.8 g, at least pump inhibitor is rabeprazole and the at least one bile 10 about or less than about 2 g, at least about or less than acid sequestrant is colesevelam-HCl. In certain embod- about 2.2 g, at least about or less than about 2.4 g, at iments the at least one proton pump inhibitor is rabepra- least about or less than about 2.6 g, at least about or less zole and the at least one bile acid sequestrant isthan about 2.8 g, at least about or less than about 3 g, colestipol. In certain embodiments the at least one proton at least about or less than about 3.2 g, at least about or pump inhibitor is tenatoprazole and the at least one bile 15 less than about 3.4 g, at least about or less than about acid sequestrant is cholestyramine. In certain embodi- 3.6 g, at least about or less than about 3.8 g, at least ments the at least one proton pump inhibitor is tenato- about or less than about 4 g, at least about or less than prazole and the at least one bile acid sequestrant is cole- about 4.2 g, at least about or less than about 4.4 g, at sevelam. In certain embodiments the at least one proton least about or less than about 4.6 g, at least about or less pump inhibitor is tenatoprazole and the at least one bile 20 than about 4.8 g, at least about or less than about 5 g, acid sequestrant is colesevelam-HCl. In certain embod- at least about or less than about 5.2 g, at least about or iments the at least one proton pump inhibitor is tenato- less than about 5.4 g, at least about or less than about prazole and the at least one bile acid sequestrant is 5.6 g, at least about or less than about 5.8 g, or at least colestipol. In certain embodiments the dosage unit and about or less than about 6 g of at least one bile acid daily dose are equivalent. In various embodiments, the 25 sequestrant. In certain embodiments, the dosage unit dosage unit is administered with food at anytime of the comprises at least about or less than about 15 mg of at day, without food at anytime of the day, with food after least one proton pump inhibitor and at least about or less an overnight fast (e.g. with breakfast), at bedtime after a than about 0.2 g, at least about or less than about 0.4 g, low fat snack. In various embodiments, the dosage unit at least about or less than about 0.6 g, at least about or is administered once a day, twice a day, three times a 30 less than about 0.8 g, at least about or less than about day, four times a day. The dosage unit can optionally 1 g, at least about or less than about 1.2 g, at least about comprise other agents such as at least one antacid, at or less than about 1.4 g, at least about or less than about least one histamine H 2-receptor antagonist, or combina- 1.6 g, at least about or less than about 1.8 g, at least tions thereof. about or less than about 2 g, at least about or less than [0166] In certain embodiments, the dosage unit com- 35 about 2.2 g, at least about or less than about 2.4 g, at prises at least about or less than about 5 mg of at least least about or less than about 2.6 g, at least about or less one proton pump inhibitor and at least about or less than than about 2.8 g, at least about or less than about 3 g, about 0.2 g, at least about or less than about 0.4 g, at at least about or less than about 3.2 g, at least about or least about or less than about 0.6 g, at least about or less less than about 3.4 g, at least about or less than about than about 0.8 g, at least about or less than about 1 g, 40 3.6 g, at least about or less than about 3.8 g, at least at least about or less than about 1.2 g, at least about or about or less than about 4 g, at least about or less than less than about 1.4 g, at least about or less than about about 4.2 g, at least about or less than about 4.4 g, at 1.6 g, at least about or less than about 1.8 g, at least least about or less than about 4.6 g, at least about or less about or less than about 2 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 2.2 g, at least about or less than about 2.4 g, at 45 at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less less than about 5.4 g, at least about or less than about than about 2.8 g, at least about or less than about 3 g, 5.6 g, at least about or less than about 5.8 g, or at least at least about or less than about 3.2 g, at least about or about or less than about 6 g of at least one bile acid less than about 3.4 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 3.6 g, at least about or less than about 3.8 g, at least50 comprises at least about or less than about 20 mg of at about or less than about 4 g, at least about or less than least one proton pump inhibitor and at least about or less about 4.2 g, at least about or less than about 4.4 g, at than about 0.2 g, at least about or less than about 0.4 g, least about or less than about 4.6 g, at least about or less at least about or less than about 0.6 g, at least about or than about 4.8 g, at least about or less than about 5 g, less than about 0.8 g, at least about or less than about at least about or less than about 5.2 g, at least about or 55 1 g, at least about or less than about 1.2 g, at least about less than about 5.4 g, at least about or less than about or less than about 1.4 g, at least about or less than about 5.6 g, at least about or less than about 5.8 g, or at least 1.6 g, at least about or less than about 1.8 g, at least about or less than about 6 g of at least one bile acid about or less than about 2 g, at least about or less than

29 57 EP 2 478 895 A2 58 about 2.2 g, at least about or less than about 2.4 g, at at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less less than about 5.4 g, at least about or less than about than about 2.8 g, at least about or less than about 3 g, 5.6 g, at least about or less than about 5.8 g, or at least at least about or less than about 3.2 g, at least about or about or less than about 6 g of at least one bile acid less than about 3.4 g, at least about or less than about 5 sequestrant. In certain embodiments, the dosage unit 3.6 g, at least about or less than about 3.8 g, at least comprises at least about or less than about 35 mg of at about or less than about 4 g, at least about or less than least one proton pump inhibitor and at least about or less about 4.2 g, at least about or less than about 4.4 g, at than about 0.2 g, at least about or less than about 0.4 g, least about or less than about 4.6 g, at least about or less at least about or less than about 0.6 g, at least about or than about 4.8 g, at least about or less than about 5 g, 10 less than about 0.8 g, at least about or less than about at least about or less than about 5.2 g, at least about or 1 g, at least about or less than about 1.2 g, at least about less than about 5.4 g, at least about or less than about or less than about 1.4 g, at least about or less than about 5.6 g, at least about or less than about 5.8 g, or at least 1.6 g, at least about or less than about 1.8 g, at least about or less than about 6 g of at least one bile acid about or less than about 2 g, at least about or less than sequestrant. In certain embodiments, the dosage unit 15 about 2.2 g, at least about or less than about 2.4 g, at comprises at least about or less than about 25 mg of at least about or less than about 2.6 g, at least about or less least one proton pump inhibitor and at least about or less than about 2.8 g, at least about or less than about 3 g, than about 0.2 g, at least about or less than about 0.4 g, at least about or less than about 3.2 g, at least about or at least about or less than about 0.6 g, at least about or less than about 3.4 g, at least about or less than about less than about 0.8 g, at least about or less than about 20 3.6 g, at least about or less than about 3.8 g, at least 1 g, at least about or less than about 1.2 g, at least about about or less than about 4 g, at least about or less than or less than about 1.4 g, at least about or less than about about 4.2 g, at least about or less than about 4.4 g, at 1.6 g, at least about or less than about 1.8 g, at least least about or less than about 4.6 g, at least about or less about or less than about 2 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 2.2 g, at least about or less than about 2.4 g, at 25 at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less less than about 5.4 g, at least about or less than about than about 2.8 g, at least about or less than about 3 g, 5.6 g, at least about or less than about 5.8 g, or at least at least about or less than about 3.2 g, at least about or about or less than about 6 g of at least one bile acid less than about 3.4 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 3.6 g, at least about or less than about 3.8 g, at least30 comprises at least about or less than about 40 mg of at about or less than about 4 g, at least about or less than least one proton pump inhibitor and at least about or less about 4.2 g, at least about or less than about 4.4 g, at than about 0.2 g, at least about or less than about 0.4 g, least about or less than about 4.6 g, at least about or less at least about or less than about 0.6 g, at least about or than about 4.8 g, at least about or less than about 5 g, less than about 0.8 g, at least about or less than about at least about or less than about 5.2 g, at least about or 35 1 g, at least about or less than about 1.2 g, at least about less than about 5.4 g, at least about or less than about or less than about 1.4 g, at least about or less than about 5.6 g, at least about or less than about 5.8 g, or at least 1.6 g, at least about or less than about 1.8 g, at least about or less than about 6 g of at least one bile acid about or less than about 2 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 2.2 g, at least about or less than about 2.4 g, at comprises at least about or less than about 30 mg of at 40 least about or less than about 2.6 g, at least about or less least one proton pump inhibitor and at least about or less than about 2.8 g, at least about or less than about 3 g, than about 0.2 g, at least about or less than about 0.4 g, at least about or less than about 3.2 g, at least about or at least about or less than about 0.6 g, at least about or less than about 3.4 g, at least about or less than about less than about 0.8 g, at least about or less than about 3.6 g, at least about or less than about 3.8 g, at least 1 g, at least about or less than about 1.2 g, at least about 45 about or less than about 4 g, at least about or less than or less than about 1.4 g, at least about or less than about about 4.2 g, at least about or less than about 4.4 g, at 1.6 g, at least about or less than about 1.8 g, at least least about or less than about 4.6 g, at least about or less about or less than about 2 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 2.2 g, at least about or less than about 2.4 g, at at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less 50 less than about 5.4 g, at least about or less than about than about 2.8 g, at least about or less than about 3 g, 5.6 g, at least about or less than about 5.8 g, or at least at least about or less than about 3.2 g, at least about or about or less than about 6 g of at least one bile acid less than about 3.4 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 3.6 g, at least about or less than about 3.8 g, at least comprises at least about or less than about 45 mg of at about or less than about 4 g, at least about or less than 55 least one proton pump inhibitor and at least about or less about 4.2 g, at least about or less than about 4.4 g, at than about 0.2 g, at least about or less than about 0.4 g, least about or less than about 4.6 g, at least about or less at least about or less than about 0.6 g, at least about or than about 4.8 g, at least about or less than about 5 g, less than about 0.8 g, at least about or less than about

30 59 EP 2 478 895 A2 60

1 g, at least about or less than about 1.2 g, at least about about or less than about 4 g, at least about or less than or less than about 1.4 g, at least about or less than about about 4.2 g, at least about or less than about 4.4 g, at 1.6 g, at least about or less than about 1.8 g, at least least about or less than about 4.6 g, at least about or less about or less than about 2 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 2.2 g, at least about or less than about 2.4 g, at 5 at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less less than about 5.4 g, at least about or less than about than about 2.8 g, at least about or less than about 3 g, 5.6 g, at least about or less than about 5.8 g, or at least at least about or less than about 3.2 g, at least about or about or less than about 6 g of at least one bile acid less than about 3.4 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 3.6 g, at least about or less than about 3.8 g, at least10 comprises at least about or less than about 60 mg of at about or less than about 4 g, at least about or less than least one proton pump inhibitor and at least about or less about 4.2 g, at least about or less than about 4.4 g, at than about 0.2 g, at least about or less than about 0.4 g, least about or less than about 4.6 g, at least about or less at least about or less than about 0.6 g, at least about or than about 4.8 g, at least about or less than about 5 g, less than about 0.8 g, at least about or less than about at least about or less than about 5.2 g, at least about or 15 1 g, at least about or less than about 1.2 g, at least about less than about 5.4 g, at least about or less than about or less than about 1.4 g, at least about or less than about 5.6 g, at least about or less than about 5.8 g, or at least 1.6 g, at least about or less than about 1.8 g, at least about or less than about 6 g of at least one bile acid about or less than about 2 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 2.2 g, at least about or less than about 2.4 g, at comprises at least about or less than about 50 mg of at 20 least about or less than about 2.6 g, at least about or less least one proton pump inhibitor and at least about or less than about 2.8 g, at least about or less than about 3 g, than about 0.2 g, at least about or less than about 0.4 g, at least about or less than about 3.2 g, at least about or at least about or less than about 0.6 g, at least about or less than about 3.4 g, at least about or less than about less than about 0.8 g, at least about or less than about 3.6 g, at least about or less than about 3.8 g, at least 1 g, at least about or less than about 1.2 g, at least about 25 about or less than about 4 g, at least about or less than or less than about 1.4 g, at least about or less than about about 4.2 g, at least about or less than about 4.4 g, at 1.6 g, at least about or less than about 1.8 g, at least least about or less than about 4.6 g, at least about or less about or less than about 2 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 2.2 g, at least about or less than about 2.4 g, at at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less 30 less than about 5.4 g, at least about or less than about than about 2.8 g, at least about or less than about 3 g, 5.6 g, at least about or less than about 5.8 g, or at least at least about or less than about 3.2 g, at least about or about or less than about 6 g of at least one bile acid less than about 3.4 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 3.6 g, at least about or less than about 3.8 g, at least comprises at least about or less than about 65 mg of at about or less than about 4 g, at least about or less than 35 least one proton pump inhibitor and at least about or less about 4.2 g, at least about or less than about 4.4 g, at than about 0.2 g, at least about or less than about 0.4 g, least about or less than about 4.6 g, at least about or less at least about or less than about 0.6 g, at least about or than about 4.8 g, at least about or less than about 5 g, less than about 0.8 g, at least about or less than about at least about or less than about 5.2 g, at least about or 1 g, at least about or less than about 1.2 g, at least about less than about 5.4 g, at least about or less than about 40 or less than about 1.4 g, at least about or less than about 5.6 g, at least about or less than about 5.8 g, or at least 1.6 g, at least about or less than about 1.8 g, at least about or less than about 6 g of at least one bile acid about or less than about 2 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 2.2 g, at least about or less than about 2.4 g, at comprises at least about or less than about 55 mg of at least about or less than about 2.6 g, at least about or less least one proton pump inhibitor and at least about or less 45 than about 2.8 g, at least about or less than about 3 g, than about 0.2 g, at least about or less than about 0.4 g, at least about or less than about 3.2 g, at least about or at least about or less than about 0.6 g, at least about or less than about 3.4 g, at least about or less than about less than about 0.8 g, at least about or less than about 3.6 g, at least about or less than about 3.8 g, at least 1 g, at least about or less than about 1.2 g, at least about about or less than about 4 g, at least about or less than or less than about 1.4 g, at least about or less than about 50 about 4.2 g, at least about or less than about 4.4 g, at 1.6 g, at least about or less than about 1.8 g, at least least about or less than about 4.6 g, at least about or less about or less than about 2 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 2.2 g, at least about or less than about 2.4 g, at at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less less than about 5.4 g, at least about or less than about than about 2.8 g, at least about or less than about 3 g, 55 5.6 g, at least about or less than about 5.8 g, or at least at least about or less than about 3.2 g, at least about or about or less than about 6 g of at least one bile acid less than about 3.4 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 3.6 g, at least about or less than about 3.8 g, at least comprises at least about or less than about 70 mg of at

31 61 EP 2 478 895 A2 62 least one proton pump inhibitor and at least about or less than about 2.8 g, at least about or less than about 3 g, than about 0.2 g, at least about or less than about 0.4 g, at least about or less than about 3.2 g, at least about or at least about or less than about 0.6 g, at least about or less than about 3.4 g, at least about or less than about less than about 0.8 g, at least about or less than about 3.6 g, at least about or less than about 3.8 g, at least 1 g, at least about or less than about 1.2 g, at least about 5 about or less than about 4 g, at least about or less than or less than about 1.4 g, at least about or less than about about 4.2 g, at least about or less than about 4.4 g, at 1.6 g, at least about or less than about 1.8 g, at least least about or less than about 4.6 g, at least about or less about or less than about 2 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 2.2 g, at least about or less than about 2.4 g, at at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less 10 less than about 5.4 g, at least about or less than about than about 2.8 g, at least about or less than about 3 g, 5.6 g, at least about or less than about 5.8 g, or at least at least about or less than about 3.2 g, at least about or about or less than about 6 g of at least one bile acid less than about 3.4 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 3.6 g, at least about or less than about 3.8 g, at least comprises at least about or less than about 85 mg of at about or less than about 4 g, at least about or less than 15 least one proton pump inhibitor and at least about or less about 4.2 g, at least about or less than about 4.4 g, at than about 0.2 g, at least about or less than about 0.4 g, least about or less than about 4.6 g, at least about or less at least about or less than about 0.6 g, at least about or than about 4.8 g, at least about or less than about 5 g, less than about 0.8 g, at least about or less than about at least about or less than about 5.2 g, at least about or 1 g, at least about or less than about 1.2 g, at least about less than about 5.4 g, at least about or less than about 20 or less than about 1.4 g, at least about or less than about 5.6 g, at least about or less than about 5.8 g, or at least 1.6 g, at least about or less than about 1.8 g, at least about or less than about 6 g of at least one bile acid about or less than about 2 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 2.2 g, at least about or less than about 2.4 g, at comprises at least about or less than about 75 mg of at least about or less than about 2.6 g, at least about or less least one proton pump inhibitor and at least about or less 25 than about 2.8 g, at least about or less than about 3 g, than about 0.2 g, at least about or less than about 0.4 g, at least about or less than about 3.2 g, at least about or at least about or less than about 0.6 g, at least about or less than about 3.4 g, at least about or less than about less than about 0.8 g, at least about or less than about 3.6 g, at least about or less than about 3.8 g, at least 1 g, at least about or less than about 1.2 g, at least about about or less than about 4 g, at least about or less than or less than about 1.4 g, at least about or less than about 30 about 4.2 g, at least about or less than about 4.4 g, at 1.6 g, at least about or less than about 1.8 g, at least least about or less than about 4.6 g, at least about or less about or less than about 2 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 2.2 g, at least about or less than about 2.4 g, at at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less less than about 5.4 g, at least about or less than about than about 2.8 g, at least about or less than about 3 g, 35 5.6 g, at least about or less than about 5.8 g, or at least at least about or less than about 3.2 g, at least about or about or less than about 6 g of at least one bile acid less than about 3.4 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 3.6 g, at least about or less than about 3.8 g, at least comprises at least about or less than about 90 mg of at about or less than about 4 g, at least about or less than least one proton pump inhibitor and at least about or less about 4.2 g, at least about or less than about 4.4 g, at 40 than about 0.2 g, at least about or less than about 0.4 g, least about or less than about 4.6 g, at least about or less at least about or less than about 0.6 g, at least about or than about 4.8 g, at least about or less than about 5 g, less than about 0.8 g, at least about or less than about at least about or less than about 5.2 g, at least about or 1 g, at least about or less than about 1.2 g, at least about less than about 5.4 g, at least about or less than about or less than about 1.4 g, at least about or less than about 5.6 g, at least about or less than about 5.8 g, or at least 45 1.6 g, at least about or less than about 1.8 g, at least about or less than about 6 g of at least one bile acid about or less than about 2 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 2.2 g, at least about or less than about 2.4 g, at comprises at least about or less than about 80 mg of at least about or less than about 2.6 g, at least about or less least one proton pump inhibitor and at least about or less than about 2.8 g, at least about or less than about 3 g, than about 0.2 g, at least about or less than about 0.4 g, 50 at least about or less than about 3.2 g, at least about or at least about or less than about 0.6 g, at least about or less than about 3.4 g, at least about or less than about less than about 0.8 g, at least about or less than about 3.6 g, at least about or less than about 3.8 g, at least 1 g, at least about or less than about 1.2 g, at least about about or less than about 4 g, at least about or less than or less than about 1.4 g, at least about or less than about about 4.2 g, at least about or less than about 4.4 g, at 1.6 g, at least about or less than about 1.8 g, at least55 least about or less than about 4.6 g, at least about or less about or less than about 2 g, at least about or less than than about 4.8 g, at least about or less than about 5 g, about 2.2 g, at least about or less than about 2.4 g, at at least about or less than about 5.2 g, at least about or least about or less than about 2.6 g, at least about or less less than about 5.4 g, at least about or less than about

32 63 EP 2 478 895 A2 64

5.6 g, at least about or less than about 5.8 g, or at least ton pump inhibitor is tenatoprazole. In certain embodi- about or less than about 6 g of at least one bile acid ments the at least one bile acid sequestrant is cholesty- sequestrant. In certain embodiments, the dosage unit ramine. In certain embodiments the at least one bile acid comprises at least about or less than about 95 mg of at sequestrant is colesevelam. In certain embodiments the least one proton pump inhibitor and at least about or less 5 at least one bile acid sequestrant is colesevelam- HCl. In than about 0.2 g, at least about or less than about 0.4 g, certain embodiments the at least one bile acid seques- at least about or less than about 0.6 g, at least about or trant is colestipol. In certain embodiments the at least less than about 0.8 g, at least about or less than about one proton pump inhibitor is omeprazole and the at least 1 g, at least about or less than about 1.2 g, at least about one bile acid sequestrant is cholestyramine. In certain or less than about 1.4 g, at least about or less than about 10 embodiments the at least one proton pump inhibitor is 1.6 g, at least about or less than about 1.8 g, at least omeprazole and the at least one bile acid sequestrant is about or less than about 2 g, at least about or less than colesevelam. In certain embodiments the at least one about 2.2 g, at least about or less than about 2.4 g, at proton pump inhibitor is omeprazole and the at least one least about or less than about 2.6 g, at least about or less bile acid sequestrant is colesevelam-HCl. In certain em- than about 2.8 g, at least about or less than about 3 g, 15 bodiments the at least one proton pump inhibitor is ome- at least about or less than about 3.2 g, at least about or prazole and the at least one bile acid sequestrant is less than about 3.4 g, at least about or less than about colestipol. In certain embodiments the at least one proton 3.6 g, at least about or less than about 3.8 g, at least pump inhibitor is esomeprazole and the at least one bile about or less than about 4 g, at least about or less than acid sequestrant is cholestyramine. In certain embodi- about 4.2 g, at least about or less than about 4.4 g, at 20 ments the at least one proton pump inhibitor is esome- least about or less than about 4.6 g, at least about or less prazole and the at least one bile acid sequestrant is cole- than about 4.8 g, at least about or less than about 5 g, sevelam. In certain embodiments the at least one proton at least about or less than about 5.2 g, at least about or pump inhibitor is esomeprazole and the at least one bile less than about 5.4 g, at least about or less than about acid sequestrant is colesevelam-HCl. In certain embod- 5.6 g, at least about or less than about 5.8 g, or at least 25 iments the at least one proton pump inhibitor is esome- about or less than about 6 g of at least one bile acid prazole and the at least one bile acid sequestrant is sequestrant. In certain embodiments, the dosage unit colestipol. In certain embodiments the at least one proton comprises at least about or less than about 100 mg of at pump inhibitor is lansoprazole and the at least one bile least one proton pump inhibitor and at least about or less acid sequestrant is cholestyramine. In certain embodi- than about 0.2 g, at least about or less than about 0.4 g, 30 ments the at least one proton pump inhibitor is lansopra- at least about or less than about 0.6 g, at least about or zole and the at least one bile acid sequestrant is cole- less than about 0.8 g, at least about or less than about sevelam. In certain embodiments the at least one proton 1 g, at least about or less than about 1.2 g, at least about pump inhibitor is lansoprazole and the at least one bile or less than about 1.4 g, at least about or less than about acid sequestrant is colesevelam-HCl. In certain embod- 1.6 g, at least about or less than about 1.8 g, at least35 iments the at least one proton pump inhibitor is lanso- about or less than about 2 g, at least about or less than prazole and the at least one bile acid sequestrant is about 2.2 g, at least about or less than about 2.4 g, at colestipol. In certain embodiments the at least one proton least about or less than about 2.6 g, at least about or less pump inhibitor is pantoprazole and the at least one bile than about 2.8 g, at least about or less than about 3 g, acid sequestrant is cholestyramine. In certain embodi- at least about or less than about 3.2 g, at least about or 40 ments the at least one proton pump inhibitor is pantopra- less than about 3.4 g, at least about or less than about zole and the at least one bile acid sequestrant is cole- 3.6 g, at least about or less than about 3.8 g, at least sevelam. In certain embodiments the at least one proton about or less than about 4 g, at least about or less than pump inhibitor is pantoprazole and the at least one bile about 4.2 g, at least about or less than about 4.4 g, at acid sequestrant is colesevelam-HCl. In certain embod- least about or less than about 4.6 g, at least about or less 45 iments the at least one proton pump inhibitor is panto- than about 4.8 g, at least about or less than about 5 g, prazole and the at least one bile acid sequestrant is at least about or less than about 5.2 g, at least about or colestipol. In certain embodiments the at least one proton less than about 5.4 g, at least about or less than about pump inhibitor is rabeprazole and the at least one bile 5.6 g, at least about or less than about 5.8 g, or at least acid sequestrant is cholestyramine. In certain embodi- about or less than about 6 g of at least one bile acid50 ments the at least one proton pump inhibitor is rabepra- sequestrant. In certain embodiments the at least one pro- zole and the at least one bile acid sequestrant is cole- tonpump inhibitor is omeprazole. In certain embodiments sevelam. In certain embodiments the at least one proton the at least one proton pump inhibitor is esomeprazole. pump inhibitor is rabeprazole and the at least one bile In certain embodiments the at least one proton pump acid sequestrant is colesevelam-HCl. In certain embod- inhibitor is lansoprazole. In certain embodiments the at 55 iments the at least one proton pump inhibitor is rabepra- least one proton pump inhibitor is pantoprazole. In certain zole and the at least one bile acid sequestrant is embodiments the at least one proton pump inhibitor is colestipol. In certain embodiments the at least one proton rabeprazole. In certain embodiments the at least one pro- pump inhibitor is tenatoprazole and the at least one bile

33 65 EP 2 478 895 A2 66 acid sequestrant is cholestyramine. In certain embodi- about 1.8 g, at least about or less than about 1.9 g, at ments the at least one proton pump inhibitor is tenato- least about or less than about 2 g, at least about or less prazole and the at least one bile acid sequestrant is cole- than about 2.1 g, at least about or less than about 2.2 g, sevelam. In certain embodiments the at least one proton at least about or less than about 2.3 g, at least about or pump inhibitor is tenatoprazole and the at least one bile 5 less than about 2.4 g, at least about or less than about acid sequestrant is colesevelam-HCl. In certain embod- 2.5 g, at least about or less than about 2.6 g, at least iments the at least one proton pump inhibitor is tenato- about or less than about 2.7 g, at least about or less than prazole and the at least one bile acid sequestrant is about 2.8 g, at least about or less than about 2.9 g, or at colestipol. In certain embodiments the dosage unit and least about or less than about 3 g of at least one bile acid daily dose are equivalent. In various embodiments, the 10 sequestrant. In certain embodiments, the dosage unit dosage unit is administered with food at anytime of the comprises at least about or less than about 5 mg of at day, without food at anytime of the day, with food after least one proton pump inhibitor and at least about or less an overnight fast (e.g. with breakfast), at bedtime after a than about 0.1 g, at least about or less than about 0.2 g, low fat snack. In various embodiments, the dosage unit at least about or less than about 0.3 g, at least about or is administered once a day, twice a day, three times a 15 less than about 0.4 g, at least about or less than about day, four times a day. The dosage unit can optionally 0.5 g, at least about or less than about 0.6 g, at least comprise other agents such as at least one antacid, at about or less than about 0.7 g, at least about or less than least one histamine H 2-receptor antagonist, or combina- about 0.8 g, at least about or less than about 0.9 g, at tions thereof. least about or less than about 1 g, at least about or less [0167] In certain embodiments, the dosage unit com- 20 than about 1.1 g, at least about or less than about 1.2 g, prises at least about or less than about 5 mg of at least at least about or less than about 1.3 g, at least about or one proton pump inhibitor and at least about or less than less than about 1.4 g, at least about or less than about about 0.1 g, at least about or less than about 0.2 g, at 1.5 g, at least about or less than about 1.6 g, at least least about or less than about 0.3 g, at least about or less about or less than about 1.7 g, at least about or less than than about 0.4 g, at least about or less than about 0.5 g, 25 about 1.8 g, at least about or less than about 1.9 g, at at least about or less than about 0.6 g, at least about or least about or less than about 2 g, at least about or less less than about 0.7 g, at least about or less than about than about 2.1 g, at least about or less than about 2.2 g, 0.8 g, at least about or less than about 0.9 g, at least at least about or less than about 2.3 g, at least about or about or less than about 1 g, at least about or less than less than about 2.4 g, at least about or less than about about 1.1 g, at least about or less than about 1.2 g, at 30 2.5 g, at least about or less than about 2.6 g, at least least about or less than about 1.3 g, at least about or less about or less than about 2.7 g, at least about or less than than about 1.4 g, at least about or less than about 1.5 g, about 2.8 g, at least about or less than about 2.9 g, or at at least about or less than about 1.6 g, at least about or least about or less than about 3 g of at least one bile acid less than about 1.7 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 1.8 g, at least about or less than about 1.9 g, at least35 comprises at least about or less than about 15 mg of at about or less than about 2 g, at least about or less than least one proton pump inhibitor and at least about or less about 2.1 g, at least about or less than about 2.2 g, at than about 0.1 g, at least about or less than about 0.2 g, least about or less than about 2.3 g, at least about or less at least about or less than about 0.3 g, at least about or than about 2.4 g, at least about or less than about 2.5 g, less than about 0.4 g, at least about or less than about at least about or less than about 2.6 g, at least about or 40 0.5 g, at least about or less than about 0.6 g, at least less than about 2.7 g, at least about or less than about about or less than about 0.7 g, at least about or less than 2.8 g, at least about or less than about 2.9 g, or at least about 0.8 g, at least about or less than about 0.9 g, at about or less than about 3 g of at least one bile acid least about or less than about 1 g, at least about or less sequestrant. In certain embodiments, the dosage unit than about 1.1 g, at least about or less than about 1.2 g, comprises at least about or less than about 10 mg of at 45 at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less less than about 1.4 g, at least about or less than about than about 0.1 g, at least about or less than about 0.2 g, 1.5 g, at least about or less than about 1.6 g, at least at least about or less than about 0.3 g, at least about or about or less than about 1.7 g, at least about or less than less than about 0.4 g, at least about or less than about about 1.8 g, at least about or less than about 1.9 g, at 0.5 g, at least about or less than about 0.6 g, at least50 least about or less than about 2 g, at least about or less about or less than about 0.7 g, at least about or less than than about 2.1 g, at least about or less than about 2.2 g, about 0.8 g, at least about or less than about 0.9 g, at at least about or less than about 2.3 g, at least about or least about or less than about 1 g, at least about or less less than about 2.4 g, at least about or less than about than about 1.1 g, at least about or less than about 1.2 g, 2.5 g, at least about or less than about 2.6 g, at least at least about or less than about 1.3 g, at least about or 55 about or less than about 2.7 g, at least about or less than less than about 1.4 g, at least about or less than about about 2.8 g, at least about or less than about 2.9 g, or at 1.5 g, at least about or less than about 1.6 g, at least least about or less than about 3 g of at least one bile acid about or less than about 1.7 g, at least about or less than sequestrant. In certain embodiments, the dosage unit

34 67 EP 2 478 895 A2 68 comprises at least about or less than about 20 mg of at at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less less than about 1.4 g, at least about or less than about than about 0.1 g, at least about or less than about 0.2 g, 1.5 g, at least about or less than about 1.6 g, at least at least about or less than about 0.3 g, at least about or about or less than about 1.7 g, at least about or less than less than about 0.4 g, at least about or less than about 5 about 1.8 g, at least about or less than about 1.9 g, at 0.5 g, at least about or less than about 0.6 g, at least least about or less than about 2 g, at least about or less about or less than about 0.7 g, at least about or less than than about 2.1 g, at least about or less than about 2.2 g, about 0.8 g, at least about or less than about 0.9 g, at at least about or less than about 2.3 g, at least about or least about or less than about 1 g, at least about or less less than about 2.4 g, at least about or less than about than about 1.1 g, at least about or less than about 1.2 g, 10 2.5 g, at least about or less than about 2.6 g, at least at least about or less than about 1.3 g, at least about or about or less than about 2.7 g, at least about or less than less than about 1.4 g, at least about or less than about about 2.8 g, at least about or less than about 2.9 g, or at 1.5 g, at least about or less than about 1.6 g, at least least about or less than about 3 g of at least one bile acid about or less than about 1.7 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 1.8 g, at least about or less than about 1.9 g, at 15 comprises at least about or less than about 35 mg of at least about or less than about 2 g, at least about or less least one proton pump inhibitor and at least about or less than about 2.1 g, at least about or less than about 2.2 g, than about 0.1 g, at least about or less than about 0.2 g, at least about or less than about 2.3 g, at least about or at least about or less than about 0.3 g, at least about or less than about 2.4 g, at least about or less than about less than about 0.4 g, at least about or less than about 2.5 g, at least about or less than about 2.6 g, at least20 0.5 g, at least about or less than about 0.6 g, at least about or less than about 2.7 g, at least about or less than about or less than about 0.7 g, at least about or less than about 2.8 g, at least about or less than about 2.9 g, or at about 0.8 g, at least about or less than about 0.9 g, at least about or less than about 3 g of at least one bile acid least about or less than about 1 g, at least about or less sequestrant. In certain embodiments, the dosage unit than about 1.1 g, at least about or less than about 1.2 g, comprises at least about or less than about 25 mg of at 25 at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less less than about 1.4 g, at least about or less than about than about 0.1 g, at least about or less than about 0.2 g, 1.5 g, at least about or less than about 1.6 g, at least at least about or less than about 0.3 g, at least about or about or less than about 1.7 g, at least about or less than less than about 0.4 g, at least about or less than about about 1.8 g, at least about or less than about 1.9 g, at 0.5 g, at least about or less than about 0.6 g, at least30 least about or less than about 2 g, at least about or less about or less than about 0.7 g, at least about or less than than about 2.1 g, at least about or less than about 2.2 g, about 0.8 g, at least about or less than about 0.9 g, at at least about or less than about 2.3 g, at least about or least about or less than about 1 g, at least about or less less than about 2.4 g, at least about or less than about than about 1.1 g, at least about or less than about 1.2 g, 2.5 g, at least about or less than about 2.6 g, at least at least about or less than about 1.3 g, at least about or 35 about or less than about 2.7 g, at least about or less than less than about 1.4 g, at least about or less than about about 2.8 g, at least about or less than about 2.9 g, or at 1.5 g, at least about or less than about 1.6 g, at least least about or less than about 3 g of at least one bile acid about or less than about 1.7 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 1.8 g, at least about or less than about 1.9 g, at comprises at least about or less than about 40 mg of at least about or less than about 2 g, at least about or less 40 least one proton pump inhibitor and at least about or less than about 2.1 g, at least about or less than about 2.2 g, than about 0.1 g, at least about or less than about 0.2 g, at least about or less than about 2.3 g, at least about or at least about or less than about 0.3 g, at least about or less than about 2.4 g, at least about or less than about less than about 0.4 g, at least about or less than about 2.5 g, at least about or less than about 2.6 g, at least 0.5 g, at least about or less than about 0.6 g, at least about or less than about 2.7 g, at least about or less than 45 about or less than about 0.7 g, at least about or less than about 2.8 g, at least about or less than about 2.9 g, or at about 0.8 g, at least about or less than about 0.9 g, at least about or less than about 3 g of at least one bile acid least about or less than about 1 g, at least about or less sequestrant. In certain embodiments, the dosage unit than about 1.1 g, at least about or less than about 1.2 g, comprises at least about or less than about 30 mg of at at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less 50 less than about 1.4 g, at least about or less than about than about 0.1 g, at least about or less than about 0.2 g, 1.5 g, at least about or less than about 1.6 g, at least at least about or less than about 0.3 g, at least about or about or less than about 1.7 g, at least about or less than less than about 0.4 g, at least about or less than about about 1.8 g, at least about or less than about 1.9 g, at 0.5 g, at least about or less than about 0.6 g, at least least about or less than about 2 g, at least about or less about or less than about 0.7 g, at least about or less than 55 than about 2.1 g, at least about or less than about 2.2 g, about 0.8 g, at least about or less than about 0.9 g, at at least about or less than about 2.3 g, at least about or least about or less than about 1 g, at least about or less less than about 2.4 g, at least about or less than about than about 1.1 g, at least about or less than about 1.2 g, 2.5 g, at least about or less than about 2.6 g, at least

35 69 EP 2 478 895 A2 70 about or less than about 2.7 g, at least about or less than about or less than about 0.7 g, at least about or less than about 2.8 g, at least about or less than about 2.9 g, or at about 0.8 g, at least about or less than about 0.9 g, at least about or less than about 3 g of at least one bile acid least about or less than about 1 g, at least about or less sequestrant. In certain embodiments, the dosage unit than about 1.1 g, at least about or less than about 1.2 g, comprises at least about or less than about 45 mg of at 5 at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less less than about 1.4 g, at least about or less than about than about 0.1 g, at least about or less than about 0.2 g, 1.5 g, at least about or less than about 1.6 g, at least at least about or less than about 0.3 g, at least about or about or less than about 1.7 g, at least about or less than less than about 0.4 g, at least about or less than about about 1.8 g, at least about or less than about 1.9 g, at 0.5 g, at least about or less than about 0.6 g, at least10 least about or less than about 2 g, at least about or less about or less than about 0.7 g, at least about or less than than about 2.1 g, at least about or less than about 2.2 g, about 0.8 g, at least about or less than about 0.9 g, at at least about or less than about 2.3 g, at least about or least about or less than about 1 g, at least about or less less than about 2.4 g, at least about or less than about than about 1.1 g, at least about or less than about 1.2 g, 2.5 g, at least about or less than about 2.6 g, at least at least about or less than about 1.3 g, at least about or 15 about or less than about 2.7 g, at least about or less than less than about 1.4 g, at least about or less than about about 2.8 g, at least about or less than about 2.9 g, or at 1.5 g, at least about or less than about 1.6 g, at least least about or less than about 3 g of at least one bile acid about or less than about 1.7 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 1.8 g, at least about or less than about 1.9 g, at comprises at least about or less than about 60 mg of at least about or less than about 2 g, at least about or less 20 least one proton pump inhibitor and at least about or less than about 2.1 g, at least about or less than about 2.2 g, than about 0.1 g, at least about or less than about 0.2 g, at least about or less than about 2.3 g, at least about or at least about or less than about 0.3 g, at least about or less than about 2.4 g, at least about or less than about less than about 0.4 g, at least about or less than about 2.5 g, at least about or less than about 2.6 g, at least 0.5 g, at least about or less than about 0.6 g, at least about or less than about 2.7 g, at least about or less than 25 about or less than about 0.7 g, at least about or less than about 2.8 g, at least about or less than about 2.9 g, or at about 0.8 g, at least about or less than about 0.9 g, at least about or less than about 3 g of at least one bile acid least about or less than about 1 g, at least about or less sequestrant. In certain embodiments, the dosage unit than about 1.1 g, at least about or less than about 1.2 g, comprises at least about or less than about 50 mg of at at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less 30 less than about 1.4 g, at least about or less than about than about 0.1 g, at least about or less than about 0.2 g, 1.5 g, at least about or less than about 1.6 g, at least at least about or less than about 0.3 g, at least about or about or less than about 1.7 g, at least about or less than less than about 0.4 g, at least about or less than about about 1.8 g, at least about or less than about 1.9 g, at 0.5 g, at least about or less than about 0.6 g, at least least about or less than about 2 g, at least about or less about or less than about 0.7 g, at least about or less than 35 than about 2.1 g, at least about or less than about 2.2 g, about 0.8 g, at least about or less than about 0.9 g, at at least about or less than about 2.3 g, at least about or least about or less than about 1 g, at least about or less less than about 2.4 g, at least about or less than about than about 1.1 g, at least about or less than about 1.2 g, 2.5 g, at least about or less than about 2.6 g, at least at least about or less than about 1.3 g, at least about or about or less than about 2.7 g, at least about or less than less than about 1.4 g, at least about or less than about 40 about 2.8 g, at least about or less than about 2.9 g, or at 1.5 g, at least about or less than about 1.6 g, at least least about or less than about 3 g of at least one bile acid about or less than about 1.7 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 1.8 g, at least about or less than about 1.9 g, at comprises at least about or less than about 65 mg of at least about or less than about 2 g, at least about or less least one proton pump inhibitor and at least about or less than about 2.1 g, at least about or less than about 2.2 g, 45 than about 0.1 g, at least about or less than about 0.2 g, at least about or less than about 2.3 g, at least about or at least about or less than about 0.3 g, at least about or less than about 2.4 g, at least about or less than about less than about 0.4 g, at least about or less than about 2.5 g, at least about or less than about 2.6 g, at least 0.5 g, at least about or less than about 0.6 g, at least about or less than about 2.7 g, at least about or less than about or less than about 0.7 g, at least about or less than about 2.8 g, at least about or less than about 2.9 g, or at 50 about 0.8 g, at least about or less than about 0.9 g, at least about or less than about 3 g of at least one bile acid least about or less than about 1 g, at least about or less sequestrant. In certain embodiments, the dosage unit than about 1.1 g, at least about or less than about 1.2 g, comprises at least about or less than about 55 mg of at at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less less than about 1.4 g, at least about or less than about than about 0.1 g, at least about or less than about 0.2 g, 55 1.5 g, at least about or less than about 1.6 g, at least at least about or less than about 0.3 g, at least about or about or less than about 1.7 g, at least about or less than less than about 0.4 g, at least about or less than about about 1.8 g, at least about or less than about 1.9 g, at 0.5 g, at least about or less than about 0.6 g, at least least about or less than about 2 g, at least about or less

36 71 EP 2 478 895 A2 72 than about 2.1 g, at least about or less than about 2.2 g, than about 0.1 g, at least about or less than about 0.2 g, at least about or less than about 2.3 g, at least about or at least about or less than about 0.3 g, at least about or less than about 2.4 g, at least about or less than about less than about 0.4 g, at least about or less than about 2.5 g, at least about or less than about 2.6 g, at least 0.5 g, at least about or less than about 0.6 g, at least about or less than about 2.7 g, at least about or less than 5 about or less than about 0.7 g, at least about or less than about 2.8 g, at least about or less than about 2.9 g, or at about 0.8 g, at least about or less than about 0.9 g, at least about or less than about 3 g of at least one bile acid least about or less than about 1 g, at least about or less sequestrant. In certain embodiments, the dosage unit than about 1.1 g, at least about or less than about 1.2 g, comprises at least about or less than about 70 mg of at at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less 10 less than about 1.4 g, at least about or less than about than about 0.1 g, at least about or less than about 0.2 g, 1.5 g, at least about or less than about 1.6 g, at least at least about or less than about 0.3 g, at least about or about or less than about 1.7 g, at least about or less than less than about 0.4 g, at least about or less than about about 1.8 g, at least about or less than about 1.9 g, at 0.5 g, at least about or less than about 0.6 g, at least least about or less than about 2 g, at least about or less about or less than about 0.7 g, at least about or less than 15 than about 2.1 g, at least about or less than about 2.2 g, about 0.8 g, at least about or less than about 0.9 g, at at least about or less than about 2.3 g, at least about or least about or less than about 1 g, at least about or less less than about 2.4 g, at least about or less than about than about 1.1 g, at least about or less than about 1.2 g, 2.5 g, at least about or less than about 2.6 g, at least at least about or less than about 1.3 g, at least about or about or less than about 2.7 g, at least about or less than less than about 1.4 g, at least about or less than about 20 about 2.8 g, at least about or less than about 2.9 g, or at 1.5 g, at least about or less than about 1.6 g, at least least about or less than about 3 g of at least one bile acid about or less than about 1.7 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 1.8 g, at least about or less than about 1.9 g, at comprises at least about or less than about 85 mg of at least about or less than about 2 g, at least about or less least one proton pump inhibitor and at least about or less than about 2.1 g, at least about or less than about 2.2 g, 25 than about 0.1 g, at least about or less than about 0.2 g, at least about or less than about 2.3 g, at least about or at least about or less than about 0.3 g, at least about or less than about 2.4 g, at least about or less than about less than about 0.4 g, at least about or less than about 2.5 g, at least about or less than about 2.6 g, at least 0.5 g, at least about or less than about 0.6 g, at least about or less than about 2.7 g, at least about or less than about or less than about 0.7 g, at least about or less than about 2.8 g, at least about or less than about 2.9 g, or at 30 about 0.8 g, at least about or less than about 0.9 g, at least about or less than about 3 g of at least one bile acid least about or less than about 1 g, at least about or less sequestrant. In certain embodiments, the dosage unit than about 1.1 g, at least about or less than about 1.2 g, comprises at least about or less than about 75 mg of at at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less less than about 1.4 g, at least about or less than about than about 0.1 g, at least about or less than about 0.2 g, 35 1.5 g, at least about or less than about 1.6 g, at least at least about or less than about 0.3 g, at least about or about or less than about 1.7 g, at least about or less than less than about 0.4 g, at least about or less than about about 1.8 g, at least about or less than about 1.9 g, at 0.5 g, at least about or less than about 0.6 g, at least least about or less than about 2 g, at least about or less about or less than about 0.7 g, at least about or less than than about 2.1 g, at least about or less than about 2.2 g, about 0.8 g, at least about or less than about 0.9 g, at 40 at least about or less than about 2.3 g, at least about or least about or less than about 1 g, at least about or less less than about 2.4 g, at least about or less than about than about 1.1 g, at least about or less than about 1.2 g, 2.5 g, at least about or less than about 2.6 g, at least at least about or less than about 1.3 g, at least about or about or less than about 2.7 g, at least about or less than less than about 1.4 g, at least about or less than about about 2.8 g, at least about or less than about 2.9 g, or at 1.5 g, at least about or less than about 1.6 g, at least45 least about or less than about 3 g of at least one bile acid about or less than about 1.7 g, at least about or less than sequestrant. In certain embodiments, the dosage unit about 1.8 g, at least about or less than about 1.9 g, at comprises at least about or less than about 90 mg of at least about or less than about 2 g, at least about or less least one proton pump inhibitor and at least about or less than about 2.1 g, at least about or less than about 2.2 g, than about 0.1 g, at least about or less than about 0.2 g, at least about or less than about 2.3 g, at least about or 50 at least about or less than about 0.3 g, at least about or less than about 2.4 g, at least about or less than about less than about 0.4 g, at least about or less than about 2.5 g, at least about or less than about 2.6 g, at least 0.5 g, at least about or less than about 0.6 g, at least about or less than about 2.7 g, at least about or less than about or less than about 0.7 g, at least about or less than about 2.8 g, at least about or less than about 2.9 g, or at about 0.8 g, at least about or less than about 0.9 g, at least about or less than about 3 g of at least one bile acid 55 least about or less than about 1 g, at least about or less sequestrant. In certain embodiments, the dosage unit than about 1.1 g, at least about or less than about 1.2 g, comprises at least about or less than about 80 mg of at at least about or less than about 1.3 g, at least about or least one proton pump inhibitor and at least about or less less than about 1.4 g, at least about or less than about

37 73 EP 2 478 895 A2 74

1.5 g, at least about or less than about 1.6 g, at least least about or less than about 3 g of at least one bile acid about or less than about 1.7 g, at least about or less than sequestrant. In certain embodiments the at least one pro- about 1.8 g, at least about or less than about 1.9 g, at tonpump inhibitor is omeprazole. In certain embodiments least about or less than about 2 g, at least about or less the at least one proton pump inhibitor is esomeprazole. than about 2.1 g, at least about or less than about 2.2 g, 5 In certain embodiments the at least one proton pump at least about or less than about 2.3 g, at least about or inhibitor is lansoprazole. In certain embodiments the at less than about 2.4 g, at least about or less than about least one proton pump inhibitor is pantoprazole. In certain 2.5 g, at least about or less than about 2.6 g, at least embodiments the at least one proton pump inhibitor is about or less than about 2.7 g, at least about or less than rabeprazole. In certain embodiments the at least one pro- about 2.8 g, at least about or less than about 2.9 g, or at 10 ton pump inhibitor is tenatoprazole. In certain embodi- least about or less than about 3 g of at least one bile acid ments the at least one bile acid sequestrant is cholesty- sequestrant. In certain embodiments, the dosage unit ramine. In certain embodiments the at least one bile acid comprises at least about or less than about 95 mg of at sequestrant is colesevelam. In certain embodiments the least one proton pump inhibitor and at least about or less at least one bile acid sequestrant is colesevelam- HCl. In than about 0.1 g, at least about or less than about 0.2 g, 15 certain embodiments the at least one bile acid seques- at least about or less than about 0.3 g, at least about or trant is colestipol. In certain embodiments the at least less than about 0.4 g, at least about or less than about one proton pump inhibitor is omeprazole and the at least 0.5 g, at least about or less than about 0.6 g, at least one bile acid sequestrant is cholestyramine. In certain about or less than about 0.7 g, at least about or less than embodiments the at least one proton pump inhibitor is about 0.8 g, at least about or less than about 0.9 g, at 20 omeprazole and the at least one bile acid sequestrant is least about or less than about 1 g, at least about or less colesevelam. In certain embodiments the at least one than about 1.1 g, at least about or less than about 1.2 g, proton pump inhibitor is omeprazole and the at least one at least about or less than about 1.3 g, at least about or bile acid sequestrant is colesevelam-HCl. In certain em- less than about 1.4 g, at least about or less than about bodiments the at least one proton pump inhibitor is ome- 1.5 g, at least about or less than about 1.6 g, at least25 prazole and the at least one bile acid sequestrant is about or less than about 1.7 g, at least about or less than colestipol. In certain embodiments the at least one proton about 1.8 g, at least about or less than about 1.9 g, at pump inhibitor is esomeprazole and the at least one bile least about or less than about 2 g, at least about or less acid sequestrant is cholestyramine. In certain embodi- than about 2.1 g, at least about or less than about 2.2 g, ments the at least one proton pump inhibitor is esome- at least about or less than about 2.3 g, at least about or 30 prazole and the at least one bile acid sequestrant is cole- less than about 2.4 g, at least about or less than about sevelam. In certain embodiments the at least one proton 2.5 g, at least about or less than about 2.6 g, at least pump inhibitor is esomeprazole and the at least one bile about or less than about 2.7 g, at least about or less than acid sequestrant is colesevelam-HCl. In certain embod- about 2.8 g, at least about or less than about 2.9 g, or at iments the at least one proton pump inhibitor is esome- least about or less than about 3 g of at least one bile acid 35 prazole and the at least one bile acid sequestrant is sequestrant. In certain embodiments, the dosage unit colestipol. In certain embodiments the at least one proton comprises at least about or less than about 100 mg of at pump inhibitor is lansoprazole and the at least one bile least one proton pump inhibitor and at least about or less acid sequestrant is cholestyramine. In certain embodi- than about 0.1 g, at least about or less than about 0.2 g, ments the at least one proton pump inhibitor is lansopra- at least about or less than about 0.3 g, at least about or 40 zole and the at least one bile acid sequestrant is cole- less than about 0.4 g, at least about or less than about sevelam. In certain embodiments the at least one proton 0.5 g, at least about or less than about 0.6 g, at least pump inhibitor is lansoprazole and the at least one bile about or less than about 0.7 g, at least about or less than acid sequestrant is colesevelam-HCl. In certain embod- about 0.8 g, at least about or less than about 0.9 g, at iments the at least one proton pump inhibitor is lanso- least about or less than about 1 g, at least about or less 45 prazole and the at least one bile acid sequestrant is than about 1.1 g, at least about or less than about 1.2 g, colestipol. In certain embodiments the at least one proton at least about or less than about 1.3 g, at least about or pump inhibitor is pantoprazole and the at least one bile less than about 1.4 g, at least about or less than about acid sequestrant is cholestyramine. In certain embodi- 1.5 g, at least about or less than about 1.6 g, at least ments the at least one proton pump inhibitor is pantopra- about or less than about 1.7 g, at least about or less than 50 zole and the at least one bile acid sequestrant is cole- about 1.8 g, at least about or less than about 1.9 g, at sevelam. In certain embodiments the at least one proton least about or less than about 2 g, at least about or less pump inhibitor is pantoprazole and the at least one bile than about 2.1 g, at least about or less than about 2.2 g, acid sequestrant is colesevelam-HCl. In certain embod- at least about or less than about 2.3 g, at least about or iments the at least one proton pump inhibitor is panto- less than about 2.4 g, at least about or less than about 55 prazole and the at least one bile acid sequestrant is 2.5 g, at least about or less than about 2.6 g, at least colestipol. In certain embodiments the at least one proton about or less than about 2.7 g, at least about or less than pump inhibitor is rabeprazole and the at least one bile about 2.8 g, at least about or less than about 2.9 g, or at acid sequestrant is cholestyramine. In certain embodi-

38 75 EP 2 478 895 A2 76 ments the at least one proton pump inhibitor is rabepra- g, at least about or less than about 0.1 g, at least about zole and the at least one bile acid sequestrant is cole- or less than about 0.12 g, at least about or less than about sevelam. In certain embodiments the at least one proton 0.14 g, at least about or less than about 0.16 g, at least pump inhibitor is rabeprazole and the at least one bile about or less than about 0.18 g, at least about or less acid sequestrant is colesevelam-HCl. In certain embod- 5 than about 0.2 g, at least about or less than about 0.22 iments the at least one proton pump inhibitor is rabepra- g, at least about or less than about 0.24 g, at least about zole and the at least one bile acid sequestrant isor less than about 0.26 g, at least about or less than about colestipol. In certain embodiments the at least one proton 0.28 g, at least about or less than about 0.3 g, at least pump inhibitor is tenatoprazole and the at least one bile about or less than about 0.32 g, at least about or less acid sequestrant is cholestyramine. In certain embodi- 10 than about 0.34 g, at least about or less than about 0.36 ments the at least one proton pump inhibitor is tenato- g, at least about or less than about 0.38 g, at least about prazole and the at least one bile acid sequestrant is cole- or less than about 0.4 g, at least about or less than about sevelam. In certain embodiments the at least one proton 0.42 g, at least about or less than about 0.44 g, at least pump inhibitor is tenatoprazole and the at least one bile about or less than about 0.46 g, at least about or less acid sequestrant is colesevelam-HCl. In certain embod- 15 than about 0.48 g, at least about or less than about 0.5 iments the at least one proton pump inhibitor is tenato- g, at least about or less than about 0.52 g, at least about prazole and the at least one bile acid sequestrant is or less than about 0.54 g, at least about or less than about colestipol. In certain embodiments the dosage unit and 0.56 g, at least about or less than about 0.58 g, or at least daily dose are equivalent. In various embodiments, the about or less than about 0.6 g of at least one bile acid dosage unit is administered with food at anytime of the 20 sequestrant. In certain embodiments, the dosage unit day, without food at anytime of the day, with food after comprises at least about or less than about 15 mg of at an overnight fast (e.g. with breakfast), at bedtime after a least one proton pump inhibitor and at least about or less low fat snack. In various embodiments, the dosage unit than about 0.02 g, at least about or less than about 0.04 is administered once a day, twice a day, three times a g, at least about or less than about 0.06 g, at least about day, four times a day. The dosage unit can optionally 25 or less than about 0.08 g, at least about or less than about comprise other agents such as at least one antacid, at 0.1 g, at least about or less than about 0.12 g, at least least one histamine H 2-receptor antagonist, or combina- about or less than about 0.14 g, at least about or less tions thereof. than about 0.16 g, at least about or less than about 0.18 [0168] In certain embodiments, the dosage unit com- g, at least about or less than about 0.2 g, at least about prises at least about or less than about 5 mg of at least 30 or less than about 0.22 g, at least about or less than about one proton pump inhibitor and at least about or less than 0.24 g, at least about or less than about 0.26 g, at least about 0.02 g, at least about or less than about 0.04 g, at about or less than about 0.28 g, at least about or less least about or less than about 0.06 g, at least about or than about 0.3 g, at least about or less than about 0.32 less than about 0.08 g, at least about or less than about g, at least about or less than about 0.34 g, at least about 0.1 g, at least about or less than about 0.12 g, at least 35 or less than about 0.36 g, at least about or less than about about or less than about 0.14 g, at least about or less 0.38 g, at least about or less than about 0.4 g, at least than about 0.16 g, at least about or less than about 0.18 about or less than about 0.42 g, at least about or less g, at least about or less than about 0.2 g, at least about than about 0.44 g, at least about or less than about 0.46 or less than about 0.22 g, at least about or less than about g, at least about or less than about 0.48 g, at least about 0.24 g, at least about or less than about 0.26 g, at least 40 or less than about 0.5 g, at least about or less than about about or less than about 0.28 g, at least about or less 0.52 g, at least about or less than about 0.54 g, at least than about 0.3 g, at least about or less than about 0.32 about or less than about 0.56 g, at least about or less g, at least about or less than about 0.34 g, at least about than about 0.58 g, or at least about or less than about or less than about 0.36 g, at least about or less than about 0.6 g of at least one bile acid sequestrant. In certain em- 0.38 g, at least about or less than about 0.4 g, at least 45 bodiments, the dosage unit comprises at least about or about or less than about 0.42 g, at least about or less less than about 20 mg of at least one proton pump inhib- than about 0.44 g, at least about or less than about 0.46 itor and at least about or less than about 0.02 g, at least g, at least about or less than about 0.48 g, at least about about or less than about 0.04 g, at least about or less or less than about 0.5 g, at least about or less than about than about 0.06 g, at least about or less than about 0.08 0.52 g, at least about or less than about 0.54 g, at least 50 g, at least about or less than about 0.1 g, at least about about or less than about 0.56 g, at least about or less or less than about 0.12 g, at least about or less than about than about 0.58 g, or at least about or less than about 0.14 g, at least about or less than about 0.16 g, at least 0.6 g of at least one bile acid sequestrant. In certain em- about or less than about 0.18 g, at least about or less bodiments, the dosage unit comprises at least about or than about 0.2 g, at least about or less than about 0.22 less than about 10 mg of at least one proton pump inhib- 55 g, at least about or less than about 0.24 g, at least about itor and at least about or less than about 0.02 g, at least or less than about 0.26 g, at least about or less than about about or less than about 0.04 g, at least about or less 0.28 g, at least about or less than about 0.3 g, at least than about 0.06 g, at least about or less than about 0.08 about or less than about 0.32 g, at least about or less

39 77 EP 2 478 895 A2 78 than about 0.34 g, at least about or less than about 0.36 about or less than about 0.6 g of at least one bile acid g, at least about or less than about 0.38 g, at least about sequestrant. In certain embodiments, the dosage unit or less than about 0.4 g, at least about or less than about comprises at least about or less than about 35 mg of at 0.42 g, at least about or less than about 0.44 g, at least least one proton pump inhibitor and at least about or less about or less than about 0.46 g, at least about or less 5 than about 0.02 g, at least about or less than about 0.04 than about 0.48 g, at least about or less than about 0.5 g, at least about or less than about 0.06 g, at least about g, at least about or less than about 0.52 g, at least about or less than about 0.08 g, at least about or less than about or less than about 0.54 g, at least about or less than about 0.1 g, at least about or less than about 0.12 g, at least 0.56 g, at least about or less than about 0.58 g, or at least about or less than about 0.14 g, at least about or less about or less than about 0.6 g of at least one bile acid 10 than about 0.16 g, at least about or less than about 0.18 sequestrant. In certain embodiments, the dosage unit g, at least about or less than about 0.2 g, at least about comprises at least about or less than about 25 mg of at or less than about 0.22 g, at least about or less than about least one proton pump inhibitor and at least about or less 0.24 g, at least about or less than about 0.26 g, at least than about 0.02 g, at least about or less than about 0.04 about or less than about 0.28 g, at least about or less g, at least about or less than about 0.06 g, at least about 15 than about 0.3 g, at least about or less than about 0.32 or less than about 0.08 g, at least about or less than about g, at least about or less than about 0.34 g, at least about 0.1 g, at least about or less than about 0.12 g, at least or less than about 0.36 g, at least about or less than about about or less than about 0.14 g, at least about or less 0.38 g, at least about or less than about 0.4 g, at least than about 0.16 g, at least about or less than about 0.18 about or less than about 0.42 g, at least about or less g, at least about or less than about 0.2 g, at least about 20 than about 0.44 g, at least about or less than about 0.46 or less than about 0.22 g, at least about or less than about g, at least about or less than about 0.48 g, at least about 0.24 g, at least about or less than about 0.26 g, at least or less than about 0.5 g, at least about or less than about about or less than about 0.28 g, at least about or less 0.52 g, at least about or less than about 0.54 g, at least than about 0.3 g, at least about or less than about 0.32 about or less than about 0.56 g, at least about or less g, at least about or less than about 0.34 g, at least about 25 than about 0.58 g, or at least about or less than about or less than about 0.36 g, at least about or less than about 0.6 g of at least one bile acid sequestrant. In certain em- 0.38 g, at least about or less than about 0.4 g, at least bodiments, the dosage unit comprises at least about or about or less than about 0.42 g, at least about or less less than about 40 mg of at least one proton pump inhib- than about 0.44 g, at least about or less than about 0.46 itor and at least about or less than about 0.02 g, at least g, at least about or less than about 0.48 g, at least about 30 about or less than about 0.04 g, at least about or less or less than about 0.5 g, at least about or less than about than about 0.06 g, at least about or less than about 0.08 0.52 g, at least about or less than about 0.54 g, at least g, at least about or less than about 0.1 g, at least about about or less than about 0.56 g, at least about or less or less than about 0.12 g, at least about or less than about than about 0.58 g, or at least about or less than about 0.14 g, at least about or less than about 0.16 g, at least 0.6 g of at least one bile acid sequestrant. In certain em- 35 about or less than about 0.18 g, at least about or less bodiments, the dosage unit comprises at least about or than about 0.2 g, at least about or less than about 0.22 less than about 30 mg of at least one proton pump inhib- g, at least about or less than about 0.24 g, at least about itor and at least about or less than about 0.02 g, at least or less than about 0.26 g, at least about or less than about about or less than about 0.04 g, at least about or less 0.28 g, at least about or less than about 0.3 g, at least than about 0.06 g, at least about or less than about 0.08 40 about or less than about 0.32 g, at least about or less g, at least about or less than about 0.1 g, at least about than about 0.34 g, at least about or less than about 0.36 or less than about 0.12 g, at least about or less than about g, at least about or less than about 0.38 g, at least about 0.14 g, at least about or less than about 0.16 g, at least or less than about 0.4 g, at least about or less than about about or less than about 0.18 g, at least about or less 0.42 g, at least about or less than about 0.44 g, at least than about 0.2 g, at least about or less than about 0.22 45 about or less than about 0.46 g, at least about or less g, at least about or less than about 0.24 g, at least about than about 0.48 g, at least about or less than about 0.5 or less than about 0.26 g, at least about or less than about g, at least about or less than about 0.52 g, at least about 0.28 g, at least about or less than about 0.3 g, at least or less than about 0.54 g, at least about or less than about about or less than about 0.32 g, at least about or less 0.56 g, at least about or less than about 0.58 g, or at least than about 0.34 g, at least about or less than about 0.36 50 about or less than about 0.6 g of at least one bile acid g, at least about or less than about 0.38 g, at least about sequestrant. In certain embodiments, the dosage unit or less than about 0.4 g, at least about or less than about comprises at least about or less than about 45 mg of at 0.42 g, at least about or less than about 0.44 g, at least least one proton pump inhibitor and at least about or less about or less than about 0.46 g, at least about or less than about 0.02 g, at least about or less than about 0.04 than about 0.48 g, at least about or less than about 0.5 55 g, at least about or less than about 0.06 g, at least about g, at least about or less than about 0.52 g, at least about or less than about 0.08 g, at least about or less than about or less than about 0.54 g, at least about or less than about 0.1 g, at least about or less than about 0.12 g, at least 0.56 g, at least about or less than about 0.58 g, or at least about or less than about 0.14 g, at least about or less

40 79 EP 2 478 895 A2 80 than about 0.16 g, at least about or less than about 0.18 about or less than about 0.42 g, at least about or less g, at least about or less than about 0.2 g, at least about than about 0.44 g, at least about or less than about 0.46 or less than about 0.22 g, at least about or less than about g, at least about or less than about 0.48 g, at least about 0.24 g, at least about or less than about 0.26 g, at least or less than about 0.5 g, at least about or less than about about or less than about 0.28 g, at least about or less 5 0.52 g, at least about or less than about 0.54 g, at least than about 0.3 g, at least about or less than about 0.32 about or less than about 0.56 g, at least about or less g, at least about or less than about 0.34 g, at least about than about 0.58 g, or at least about or less than about or less than about 0.36 g, at least about or less than about 0.6 g of at least one bile acid sequestrant. In certain em- 0.38 g, at least about or less than about 0.4 g, at least bodiments, the dosage unit comprises at least about or about or less than about 0.42 g, at least about or less 10 less than about 60 mg of at least one proton pump inhib- than about 0.44 g, at least about or less than about 0.46 itor and at least about or less than about 0.02 g, at least g, at least about or less than about 0.48 g, at least about about or less than about 0.04 g, at least about or less or less than about 0.5 g, at least about or less than about than about 0.06 g, at least about or less than about 0.08 0.52 g, at least about or less than about 0.54 g, at least g, at least about or less than about 0.1 g, at least about about or less than about 0.56 g, at least about or less 15 or less than about 0.12 g, at least about or less than about than about 0.58 g, or at least about or less than about 0.14 g, at least about or less than about 0.16 g, at least 0.6 g of at least one bile acid sequestrant. In certain em- about or less than about 0.18 g, at least about or less bodiments, the dosage unit comprises at least about or than about 0.2 g, at least about or less than about 0.22 less than about 50 mg of at least one proton pump inhib- g, at least about or less than about 0.24 g, at least about itor and at least about or less than about 0.02 g, at least 20 or less than about 0.26 g, at least about or less than about about or less than about 0.04 g, at least about or less 0.28 g, at least about or less than about 0.3 g, at least than about 0.06 g, at least about or less than about 0.08 about or less than about 0.32 g, at least about or less g, at least about or less than about 0.1 g, at least about than about 0.34 g, at least about or less than about 0.36 or less than about 0.12 g, at least about or less than about g, at least about or less than about 0.38 g, at least about 0.14 g, at least about or less than about 0.16 g, at least 25 or less than about 0.4 g, at least about or less than about about or less than about 0.18 g, at least about or less 0.42 g, at least about or less than about 0.44 g, at least than about 0.2 g, at least about or less than about 0.22 about or less than about 0.46 g, at least about or less g, at least about or less than about 0.24 g, at least about than about 0.48 g, at least about or less than about 0.5 or less than about 0.26 g, at least about or less than about g, at least about or less than about 0.52 g, at least about 0.28 g, at least about or less than about 0.3 g, at least 30 or less than about 0.54 g, at least about or less than about about or less than about 0.32 g, at least about or less 0.56 g, at least about or less than about 0.58 g, or at least than about 0.34 g, at least about or less than about 0.36 about or less than about 0.6 g of at least one bile acid g, at least about or less than about 0.38 g, at least about sequestrant. In certain embodiments, the dosage unit or less than about 0.4 g, at least about or less than about comprises at least about or less than about 65 mg of at 0.42 g, at least about or less than about 0.44 g, at least 35 least one proton pump inhibitor and at least about or less about or less than about 0.46 g, at least about or less than about 0.02 g, at least about or less than about 0.04 than about 0.48 g, at least about or less than about 0.5 g, at least about or less than about 0.06 g, at least about g, at least about or less than about 0.52 g, at least about or less than about 0.08 g, at least about or less than about or less than about 0.54 g, at least about or less than about 0.1 g, at least about or less than about 0.12 g, at least 0.56 g, at least about or less than about 0.58 g, or at least 40 about or less than about 0.14 g, at least about or less about or less than about 0.6 g of at least one bile acid than about 0.16 g, at least about or less than about 0.18 sequestrant. In certain embodiments, the dosage unit g, at least about or less than about 0.2 g, at least about comprises at least about or less than about 55 mg of at or less than about 0.22 g, at least about or less than about least one proton pump inhibitor and at least about or less 0.24 g, at least about or less than about 0.26 g, at least than about 0.02 g, at least about or less than about 0.04 45 about or less than about 0.28 g, at least about or less g, at least about or less than about 0.06 g, at least about than about 0.3 g, at least about or less than about 0.32 or less than about 0.08 g, at least about or less than about g, at least about or less than about 0.34 g, at least about 0.1 g, at least about or less than about 0.12 g, at least or less than about 0.36 g, at least about or less than about about or less than about 0.14 g, at least about or less 0.38 g, at least about or less than about 0.4 g, at least than about 0.16 g, at least about or less than about 0.18 50 about or less than about 0.42 g, at least about or less g, at least about or less than about 0.2 g, at least about than about 0.44 g, at least about or less than about 0.46 or less than about 0.22 g, at least about or less than about g, at least about or less than about 0.48 g, at least about 0.24 g, at least about or less than about 0.26 g, at least or less than about 0.5 g, at least about or less than about about or less than about 0.28 g, at least about or less 0.52 g, at least about or less than about 0.54 g, at least than about 0.3 g, at least about or less than about 0.32 55 about or less than about 0.56 g, at least about or less g, at least about or less than about 0.34 g, at least about than about 0.58 g, or at least about or less than about or less than about 0.36 g, at least about or less than about 0.6 g of at least one bile acid sequestrant. In certain em- 0.38 g, at least about or less than about 0.4 g, at least bodiments, the dosage unit comprises at least about or

41 81 EP 2 478 895 A2 82 less than about 70 mg of at least one proton pump inhib- g, at least about or less than about 0.24 g, at least about itor and at least about or less than about 0.02 g, at least or less than about 0.26 g, at least about or less than about about or less than about 0.04 g, at least about or less 0.28 g, at least about or less than about 0.3 g, at least than about 0.06 g, at least about or less than about 0.08 about or less than about 0.32 g, at least about or less g, at least about or less than about 0.1 g, at least about 5 than about 0.34 g, at least about or less than about 0.36 or less than about 0.12 g, at least about or less than about g, at least about or less than about 0.38 g, at least about 0.14 g, at least about or less than about 0.16 g, at least or less than about 0.4 g, at least about or less than about about or less than about 0.18 g, at least about or less 0.42 g, at least about or less than about 0.44 g, at least than about 0.2 g, at least about or less than about 0.22 about or less than about 0.46 g, at least about or less g, at least about or less than about 0.24 g, at least about 10 than about 0.48 g, at least about or less than about 0.5 or less than about 0.26 g, at least about or less than about g, at least about or less than about 0.52 g, at least about 0.28 g, at least about or less than about 0.3 g, at least or less than about 0.54 g, at least about or less than about about or less than about 0.32 g, at least about or less 0.56 g, at least about or less than about 0.58 g, or at least than about 0.34 g, at least about or less than about 0.36 about or less than about 0.6 g of at least one bile acid g, at least about or less than about 0.38 g, at least about 15 sequestrant. In certain embodiments, the dosage unit or less than about 0.4 g, at least about or less than about comprises at least about or less than about 85 mg of at 0.42 g, at least about or less than about 0.44 g, at least least one proton pump inhibitor and at least about or less about or less than about 0.46 g, at least about or less than about 0.02 g, at least about or less than about 0.04 than about 0.48 g, at least about or less than about 0.5 g, at least about or less than about 0.06 g, at least about g, at least about or less than about 0.52 g, at least about 20 or less than about 0.08 g, at least about or less than about or less than about 0.54 g, at least about or less than about 0.1 g, at least about or less than about 0.12 g, at least 0.56 g, at least about or less than about 0.58 g, or at least about or less than about 0.14 g, at least about or less about or less than about 0.6 g of at least one bile acid than about 0.16 g, at least about or less than about 0.18 sequestrant. In certain embodiments, the dosage unit g, at least about or less than about 0.2 g, at least about comprises at least about or less than about 75 mg of at 25 or less than about 0.22 g, at least about or less than about least one proton pump inhibitor and at least about or less 0.24 g, at least about or less than about 0.26 g, at least than about 0.02 g, at least about or less than about 0.04 about or less than about 0.28 g, at least about or less g, at least about or less than about 0.06 g, at least about than about 0.3 g, at least about or less than about 0.32 or less than about 0.08 g, at least about or less than about g, at least about or less than about 0.34 g, at least about 0.1 g, at least about or less than about 0.12 g, at least 30 or less than about 0.36 g, at least about or less than about about or less than about 0.14 g, at least about or less 0.38 g, at least about or less than about 0.4 g, at least than about 0.16 g, at least about or less than about 0.18 about or less than about 0.42 g, at least about or less g, at least about or less than about 0.2 g, at least about than about 0.44 g, at least about or less than about 0.46 or less than about 0.22 g, at least about or less than about g, at least about or less than about 0.48 g, at least about 0.24 g, at least about or less than about 0.26 g, at least 35 or less than about 0.5 g, at least about or less than about about or less than about 0.28 g, at least about or less 0.52 g, at least about or less than about 0.54 g, at least than about 0.3 g, at least about or less than about 0.32 about or less than about 0.56 g, at least about or less g, at least about or less than about 0.34 g, at least about than about 0.58 g, or at least about or less than about or less than about 0.36 g, at least about or less than about 0.6 g of at least one bile acid sequestrant. In certain em- 0.38 g, at least about or less than about 0.4 g, at least 40 bodiments, the dosage unit comprises at least about or about or less than about 0.42 g, at least about or less less than about 90 mg of at least one proton pump inhib- than about 0.44 g, at least about or less than about 0.46 itor and at least about or less than about 0.02 g, at least g, at least about or less than about 0.48 g, at least about about or less than about 0.04 g, at least about or less or less than about 0.5 g, at least about or less than about than about 0.06 g, at least about or less than about 0.08 0.52 g, at least about or less than about 0.54 g, at least 45 g, at least about or less than about 0.1 g, at least about about or less than about 0.56 g, at least about or less or less than about 0.12 g, at least about or less than about than about 0.58 g, or at least about or less than about 0.14 g, at least about or less than about 0.16 g, at least 0.6 g of at least one bile acid sequestrant. In certain em- about or less than about 0.18 g, at least about or less bodiments, the dosage unit comprises at least about or than about 0.2 g, at least about or less than about 0.22 less than about 80 mg of at least one proton pump inhib- 50 g, at least about or less than about 0.24 g, at least about itor and at least about or less than about 0.02 g, at least or less than about 0.26 g, at least about or less than about about or less than about 0.04 g, at least about or less 0.28 g, at least about or less than about 0.3 g, at least than about 0.06 g, at least about or less than about 0.08 about or less than about 0.32 g, at least about or less g, at least about or less than about 0.1 g, at least about than about 0.34 g, at least about or less than about 0.36 or less than about 0.12 g, at least about or less than about 55 g, at least about or less than about 0.38 g, at least about 0.14 g, at least about or less than about 0.16 g, at least or less than about 0.4 g, at least about or less than about about or less than about 0.18 g, at least about or less 0.42 g, at least about or less than about 0.44 g, at least than about 0.2 g, at least about or less than about 0.22 about or less than about 0.46 g, at least about or less

42 83 EP 2 478 895 A2 84 than about 0.48 g, at least about or less than about 0.5 proton pump inhibitor is lansoprazole. In certain embod- g, at least about or less than about 0.52 g, at least about iments the at least one proton pump inhibitor is panto- or less than about 0.54 g, at least about or less than about prazole. In certain embodiments the at least one proton 0.56 g, at least about or less than about 0.58 g, or at least pump inhibitor is rabeprazole. In certain embodiments about or less than about 0.6 g of at least one bile acid 5 the at least one proton pump inhibitor is tenatoprazole. sequestrant. In certain embodiments, the dosage unit In certain embodiments the at least one bile acid seques- comprises at least about or less than about 95 mg of at trant is cholestyramine. In certain embodiments the at least one proton pump inhibitor and at least about or less least one bile acid sequestrant is colesevelam. In certain than about 0.02 g, at least about or less than about 0.04 embodiments the at least one bile acid sequestrant is g, at least about or less than about 0.06 g, at least about 10 colesevelam-HCl. In certain embodiments the at least or less than about 0.08 g, at least about or less than about one bile acid sequestrant is colestipol. In certain embod- 0.1 g, at least about or less than about 0.12 g, at least iments the at least one proton pump inhibitor is omepra- about or less than about 0.14 g, at least about or less zole and the at least one bile acid sequestrant is choles- than about 0.16 g, at least about or less than about 0.18 tyramine. In certain embodiments the at least one proton g, at least about or less than about 0.2 g, at least about 15 pump inhibitor is omeprazole and the at least one bile or less than about 0.22 g, at least about or less than about acid sequestrant is colesevelam. In certain embodiments 0.24 g, at least about or less than about 0.26 g, at least the at least one proton pump inhibitor is omeprazole and about or less than about 0.28 g, at least about or less the at least one bile acid sequestrant is colesevelam- HCl. than about 0.3 g, at least about or less than about 0.32 In certain embodiments the at least one proton pump g, at least about or less than about 0.34 g, at least about 20 inhibitor is omeprazole and the at least one bile acid se- or less than about 0.36 g, at least about or less than about questrant is colestipol. In certain embodiments the at 0.38 g, at least about or less than about 0.4 g, at least least one proton pump inhibitor is esomeprazole and the about or less than about 0.42 g, at least about or less at least one bile acid sequestrant is cholestyramine. In than about 0.44 g, at least about or less than about 0.46 certain embodiments the at least one proton pump inhib- g, at least about or less than about 0.48 g, at least about 25 itor is esomeprazole and the at least one bile acid se- or less than about 0.5 g, at least about or less than about questrant is colesevelam. In certain embodiments the at 0.52 g, at least about or less than about 0.54 g, at least least one proton pump inhibitor is esomeprazole and the about or less than about 0.56 g, at least about or less at least one bile acid sequestrant is colesevelam- HCl. In than about 0.58 g, or at least about or less than about certain embodiments the at least one proton pump inhib- 0.6 g of at least one bile acid sequestrant. In certain em- 30 itor is esomeprazole and the at least one bile acid se- bodiments, the dosage unit comprises at least about or questrant is colestipol. In certain embodiments the at less than about 100 mg of at least one proton pump in- least one proton pump inhibitor is lansoprazole and the hibitor and at least about or less than about 0.02 g, at at least one bile acid sequestrant is cholestyramine. In least about or less than about 0.04 g, at least about or certain embodiments the at least one proton pump inhib- less than about 0.06 g, at least about or less than about 35 itor is lansoprazole and the at least one bile acid seques- 0.08 g, at least about or less than about 0.1 g, at least trant is colesevelam. In certain embodiments the at least about or less than about 0.12 g, at least about or less one proton pump inhibitor is lansoprazole and the at least than about 0.14 g, at least about or less than about 0.16 one bile acid sequestrant is colesevelam- HCl. In certain g, at least about or less than about 0.18 g, at least about embodiments the at least one proton pump inhibitor is or less than about 0.2 g, at least about or less than about 40 lansoprazole and the at least one bile acid sequestrant 0.22 g, at least about or less than about 0.24 g, at least is colestipol. In certain embodiments the at least one pro- about or less than about 0.26 g, at least about or less ton pump inhibitor is pantoprazole and the at least one than about 0.28 g, at least about or less than about 0.3 bile acid sequestrant is cholestyramine. In certain em- g, at least about or less than about 0.32 g, at least about bodiments the at least one proton pump inhibitor is pan- or less than about 0.34 g, at least about or less than about 45 toprazole and the at least one bile acid sequestrant is 0.36 g, at least about or less than about 0.38 g, at least colesevelam. In certain embodiments the at least one about or less than about 0.4 g, at least about or less than proton pump inhibitor is pantoprazole and the at least about 0.42 g, at least about or less than about 0.44 g, at one bile acid sequestrant is colesevelam- HCl. In certain least about or less than about 0.46 g, at least about or embodiments the at least one proton pump inhibitor is less than about 0.48 g, at least about or less than about 50 pantoprazole and the at least one bile acid sequestrant 0.5 g, at least about or less than about 0.52 g, at least is colestipol. In certain embodiments the at least one pro- about or less than about 0.54 g, at least about or less ton pump inhibitor is rabeprazole and the at least one than about 0.56 g, at least about or less than about 0.58 bile acid sequestrant is cholestyramine. In certain em- g, or at least about or less than about 0.6 g of at least bodiments the at least one proton pump inhibitor is rab- one bile acid sequestrant. In certain embodiments the at 55 eprazole and the at least one bile acid sequestrant is least one proton pump inhibitor is omeprazole. In certain colesevelam. In certain embodiments the at least one embodiments the at least one proton pump inhibitor is proton pump inhibitor is rabeprazole and the at least one esomeprazole. In certain embodiments the at least one bile acid sequestrant is colesevelam-HCl. In certain em-

43 85 EP 2 478 895 A2 86 bodiments the at least one proton pump inhibitor is rab- g, at least about or less than about 0.12 g, at least about eprazole and the at least one bile acid sequestrant is or less than about 0.13 g, at least about or less than about colestipol. In certain embodiments the at least one proton 0.14 g, at least about or less than about 0.15 g, at least pump inhibitor is tenatoprazole and the at least one bile about or less than about 0.16 g, at least about or less acid sequestrant is cholestyramine. In certain embodi- 5 than about 0.17 g, at least about or less than about 0.18 ments the at least one proton pump inhibitor is tenato- g, at least about or less than about 0.19 g, at least about prazole and the at least one bile acid sequestrant is cole- or less than about 0.2 g, at least about or less than about sevelam. In certain embodiments the at least one proton 0.21 g, at least about or less than about 0.22 g, at least pump inhibitor is tenatoprazole and the at least one bile about or less than about 0.23 g, at least about or less acid sequestrant is colesevelam-HCl. In certain embod- 10 than about 0.24 g, at least about or less than about 0.25 iments the at least one proton pump inhibitor is tenato- g, at least about or less than about 0.26 g, at least about prazole and the at least one bile acid sequestrant is or less than about 0.27 g, at least about or less than about colestipol. In certain embodiments the dosage unit and 0.28 g, at least about or less than about 0.29 g, or at least daily dose are equivalent. In various embodiments, the about or less than about 0.3 g of at least one bile acid dosage unit is administered with food at anytime of the 15 sequestrant. In certain embodiments, the dosage unit day, without food at anytime of the day, with food after comprises at least about or less than about 15 mg of at an overnight fast (e.g. with breakfast), at bedtime after a least one proton pump inhibitor and at least about or less low fat snack. In various embodiments, the dosage unit than about 0.01 g, at least about or less than about 0.02 is administered once a day, twice a day, three times a g, at least about or less than about 0.03 g, at least about day, four times a day. The dosage unit can optionally 20 or less than about 0.04 g, at least about or less than about comprise other agents such as at least one antacid, at 0.05 g, at least about or less than about 0.06 g, at least least one histamine H 2-receptor antagonist, or combina- about or less than about 0.07 g, at least about or less tions thereof. than about 0.08 g, at least about or less than about 0.09 [0169] In certain embodiments, the dosage unit com- g, at least about or less than about 0.1 g, at least about prises at least about or less than about 5 mg of at least 25 or less than about 0.11 g, at least about or less than about one proton pump inhibitor and at least about or less than 0.12 g, at least about or less than about 0.13 g, at least about 0.01 g, at least about or less than about 0.02 g, at about or less than about 0.14 g, at least about or less least about or less than about 0.03 g, at least about or than about 0.15 g, at least about or less than about 0.16 less than about 0.04 g, at least about or less than about g, at least about or less than about 0.17 g, at least about 0.05 g, at least about or less than about 0.06 g, at least 30 or less than about 0.18 g, at least about or less than about about or less than about 0.07 g, at least about or less 0.19 g, at least about or less than about 0.2 g, at least than about 0.08 g, at least about or less than about 0.09 about or less than about 0.21 g, at least about or less g, at least about or less than about 0.1 g, at least about than about 0.22 g, at least about or less than about 0.23 or less than about 0.11 g, at least about or less than about g, at least about or less than about 0.24 g, at least about 0.12 g, at least about or less than about 0.13 g, at least 35 or less than about 0.25 g, at least about or less than about about or less than about 0.14 g, at least about or less 0.26 g, at least about or less than about 0.27 g, at least than about 0.15 g, at least about or less than about 0.16 about or less than about 0.28 g, at least about or less g, at least about or less than about 0.17 g, at least about than about 0.29 g, or at least about or less than about or less than about 0.18 g, at least about or less than about 0.3 g of at least one bile acid sequestrant. In certain em- 0.19 g, at least about or less than about 0.2 g, at least 40 bodiments, the dosage unit comprises at least about or about or less than about 0.21 g, at least about or less less than about 20 mg of at least one proton pump inhib- than about 0.22 g, at least about or less than about 0.23 itor and at least about or less than about 0.01 g, at least g, at least about or less than about 0.24 g, at least about about or less than about 0.02 g, at least about or less or less than about 0.25 g, at least about or less than about than about 0.03 g, at least about or less than about 0.04 0.26 g, at least about or less than about 0.27 g, at least 45 g, at least about or less than about 0.05 g, at least about about or less than about 0.28 g, at least about or less or less than about 0.06 g, at least about or less than about than about 0.29 g, or at least about or less than about 0.07 g, at least about or less than about 0.08 g, at least 0.3 g of at least one bile acid sequestrant. In certain em- about or less than about 0.09 g, at least about or less bodiments, the dosage unit comprises at least about or than about 0.1 g, at least about or less than about 0.11 less than about 10 mg of at least one proton pump inhib- 50 g, at least about or less than about 0.12 g, at least about itor and at least about or less than about 0.01 g, at least or less than about 0.13 g, at least about or less than about about or less than about 0.02 g, at least about or less 0.14 g, at least about or less than about 0.15 g, at least than about 0.03 g, at least about or less than about 0.04 about or less than about 0.16 g, at least about or less g, at least about or less than about 0.05 g, at least about than about 0.17 g, at least about or less than about 0.18 or less than about 0.06 g, at least about or less than about 55 g, at least about or less than about 0.19 g, at least about 0.07 g, at least about or less than about 0.08 g, at least or less than about 0.2 g, at least about or less than about about or less than about 0.09 g, at least about or less 0.21 g, at least about or less than about 0.22 g, at least than about 0.1 g, at least about or less than about 0.11 about or less than about 0.23 g, at least about or less

44 87 EP 2 478 895 A2 88 than about 0.24 g, at least about or less than about 0.25 g, at least about or less than about 0.03 g, at least about g, at least about or less than about 0.26 g, at least about or less than about 0.04 g, at least about or less than about or less than about 0.27 g, at least about or less than about 0.05 g, at least about or less than about 0.06 g, at least 0.28 g, at least about or less than about 0.29 g, or at least about or less than about 0.07 g, at least about or less about or less than about 0.3 g of at least one bile acid 5 than about 0.08 g, at least about or less than about 0.09 sequestrant. In certain embodiments, the dosage unit g, at least about or less than about 0.1 g, at least about comprises at least about or less than about 25 mg of at or less than about 0.11 g, at least about or less than about least one proton pump inhibitor and at least about or less 0.12 g, at least about or less than about 0.13 g, at least than about 0.01 g, at least about or less than about 0.02 about or less than about 0.14 g, at least about or less g, at least about or less than about 0.03 g, at least about 10 than about 0.15 g, at least about or less than about 0.16 or less than about 0.04 g, at least about or less than about g, at least about or less than about 0.17 g, at least about 0.05 g, at least about or less than about 0.06 g, at least or less than about 0.18 g, at least about or less than about about or less than about 0.07 g, at least about or less 0.19 g, at least about or less than about 0.2 g, at least than about 0.08 g, at least about or less than about 0.09 about or less than about 0.21 g, at least about or less g, at least about or less than about 0.1 g, at least about 15 than about 0.22 g, at least about or less than about 0.23 or less than about 0.11 g, at least about or less than about g, at least about or less than about 0.24 g, at least about 0.12 g, at least about or less than about 0.13 g, at least or less than about 0.25 g, at least about or less than about about or less than about 0.14 g, at least about or less 0.26 g, at least about or less than about 0.27 g, at least than about 0.15 g, at least about or less than about 0.16 about or less than about 0.28 g, at least about or less g, at least about or less than about 0.17 g, at least about 20 than about 0.29 g, or at least about or less than about or less than about 0.18 g, at least about or less than about 0.3 g of at least one bile acid sequestrant. In certain em- 0.19 g, at least about or less than about 0.2 g, at least bodiments, the dosage unit comprises at least about or about or less than about 0.21 g, at least about or less less than about 40 mg of at least one proton pump inhib- than about 0.22 g, at least about or less than about 0.23 itor and at least about or less than about 0.01 g, at least g, at least about or less than about 0.24 g, at least about 25 about or less than about 0.02 g, at least about or less or less than about 0.25 g, at least about or less than about than about 0.03 g, at least about or less than about 0.04 0.26 g, at least about or less than about 0.27 g, at least g, at least about or less than about 0.05 g, at least about about or less than about 0.28 g, at least about or less or less than about 0.06 g, at least about or less than about than about 0.29 g, or at least about or less than about 0.07 g, at least about or less than about 0.08 g, at least 0.3 g of at least one bile acid sequestrant. In certain em- 30 about or less than about 0.09 g, at least about or less bodiments, the dosage unit comprises at least about or than about 0.1 g, at least about or less than about 0.11 less than about 30 mg of at least one proton pump inhib- g, at least about or less than about 0.12 g, at least about itor and at least about or less than about 0.01 g, at least or less than about 0.13 g, at least about or less than about about or less than about 0.02 g, at least about or less 0.14 g, at least about or less than about 0.15 g, at least than about 0.03 g, at least about or less than about 0.04 35 about or less than about 0.16 g, at least about or less g, at least about or less than about 0.05 g, at least about than about 0.17 g, at least about or less than about 0.18 or less than about 0.06 g, at least about or less than about g, at least about or less than about 0.19 g, at least about 0.07 g, at least about or less than about 0.08 g, at least or less than about 0.2 g, at least about or less than about about or less than about 0.09 g, at least about or less 0.21 g, at least about or less than about 0.22 g, at least than about 0.1 g, at least about or less than about 0.11 40 about or less than about 0.23 g, at least about or less g, at least about or less than about 0.12 g, at least about than about 0.24 g, at least about or less than about 0.25 or less than about 0.13 g, at least about or less than about g, at least about or less than about 0.26 g, at least about 0.14 g, at least about or less than about 0.15 g, at least or less than about 0.27 g, at least about or less than about about or less than about 0.16 g, at least about or less 0.28 g, at least about or less than about 0.29 g, or at least than about 0.17 g, at least about or less than about 0.18 45 about or less than about 0.3 g of at least one bile acid g, at least about or less than about 0.19 g, at least about sequestrant. In certain embodiments, the dosage unit or less than about 0.2 g, at least about or less than about comprises at least about or less than about 45 mg of at 0.21 g, at least about or less than about 0.22 g, at least least one proton pump inhibitor and at least about or less about or less than about 0.23 g, at least about or less than about 0.01 g, at least about or less than about 0.02 than about 0.24 g, at least about or less than about 0.25 50 g, at least about or less than about 0.03 g, at least about g, at least about or less than about 0.26 g, at least about or less than about 0.04 g, at least about or less than about or less than about 0.27 g, at least about or less than about 0.05 g, at least about or less than about 0.06 g, at least 0.28 g, at least about or less than about 0.29 g, or at least about or less than about 0.07 g, at least about or less about or less than about 0.3 g of at least one bile acid than about 0.08 g, at least about or less than about 0.09 sequestrant. In certain embodiments, the dosage unit 55 g, at least about or less than about 0.1 g, at least about comprises at least about or less than about 35 mg of at or less than about 0.11 g, at least about or less than about least one proton pump inhibitor and at least about or less 0.12 g, at least about or less than about 0.13 g, at least than about 0.01 g, at least about or less than about 0.02 about or less than about 0.14 g, at least about or less

45 89 EP 2 478 895 A2 90 than about 0.15 g, at least about or less than about 0.16 about or less than about 0.28 g, at least about or less g, at least about or less than about 0.17 g, at least about than about 0.29 g, or at least about or less than about or less than about 0.18 g, at least about or less than about 0.3 g of at least one bile acid sequestrant. In certain em- 0.19 g, at least about or less than about 0.2 g, at least bodiments, the dosage unit comprises at least about or about or less than about 0.21 g, at least about or less 5 less than about 60 mg of at least one proton pump inhib- than about 0.22 g, at least about or less than about 0.23 itor and at least about or less than about 0.01 g, at least g, at least about or less than about 0.24 g, at least about about or less than about 0.02 g, at least about or less or less than about 0.25 g, at least about or less than about than about 0.03 g, at least about or less than about 0.04 0.26 g, at least about or less than about 0.27 g, at least g, at least about or less than about 0.05 g, at least about about or less than about 0.28 g, at least about or less 10 or less than about 0.06 g, at least about or less than about than about 0.29 g, or at least about or less than about 0.07 g, at least about or less than about 0.08 g, at least 0.3 g of at least one bile acid sequestrant. In certain em- about or less than about 0.09 g, at least about or less bodiments, the dosage unit comprises at least about or than about 0.1 g, at least about or less than about 0.11 less than about 50 mg of at least one proton pump inhib- g, at least about or less than about 0.12 g, at least about itor and at least about or less than about 0.01 g, at least 15 or less than about 0.13 g, at least about or less than about about or less than about 0.02 g, at least about or less 0.14 g, at least about or less than about 0.15 g, at least than about 0.03 g, at least about or less than about 0.04 about or less than about 0.16 g, at least about or less g, at least about or less than about 0.05 g, at least about than about 0.17 g, at least about or less than about 0.18 or less than about 0.06 g, at least about or less than about g, at least about or less than about 0.19 g, at least about 0.07 g, at least about or less than about 0.08 g, at least 20 or less than about 0.2 g, at least about or less than about about or less than about 0.09 g, at least about or less 0.21 g, at least about or less than about 0.22 g, at least than about 0.1 g, at least about or less than about 0.11 about or less than about 0.23 g, at least about or less g, at least about or less than about 0.12 g, at least about than about 0.24 g, at least about or less than about 0.25 or less than about 0.13 g, at least about or less than about g, at least about or less than about 0.26 g, at least about 0.14 g, at least about or less than about 0.15 g, at least 25 or less than about 0.27 g, at least about or less than about about or less than about 0.16 g, at least about or less 0.28 g, at least about or less than about 0.29 g, or at least than about 0.17 g, at least about or less than about 0.18 about or less than about 0.3 g of at least one bile acid g, at least about or less than about 0.19 g, at least about sequestrant. In certain embodiments, the dosage unit or less than about 0.2 g, at least about or less than about comprises at least about or less than about 65 mg of at 0.21 g, at least about or less than about 0.22 g, at least 30 least one proton pump inhibitor and at least about or less about or less than about 0.23 g, at least about or less than about 0.01 g, at least about or less than about 0.02 than about 0.24 g, at least about or less than about 0.25 g, at least about or less than about 0.03 g, at least about g, at least about or less than about 0.26 g, at least about or less than about 0.04 g, at least about or less than about or less than about 0.27 g, at least about or less than about 0.05 g, at least about or less than about 0.06 g, at least 0.28 g, at least about or less than about 0.29 g, or at least 35 about or less than about 0.07 g, at least about or less about or less than about 0.3 g of at least one bile acid than about 0.08 g, at least about or less than about 0.09 sequestrant. In certain embodiments, the dosage unit g, at least about or less than about 0.1 g, at least about comprises at least about or less than about 55 mg of at or less than about 0.11 g, at least about or less than about least one proton pump inhibitor and at least about or less 0.12 g, at least about or less than about 0.13 g, at least than about 0.01 g, at least about or less than about 0.02 40 about or less than about 0.14 g, at least about or less g, at least about or less than about 0.03 g, at least about than about 0.15 g, at least about or less than about 0.16 or less than about 0.04 g, at least about or less than about g, at least about or less than about 0.17 g, at least about 0.05 g, at least about or less than about 0.06 g, at least or less than about 0.18 g, at least about or less than about about or less than about 0.07 g, at least about or less 0.19 g, at least about or less than about 0.2 g, at least than about 0.08 g, at least about or less than about 0.09 45 about or less than about 0.21 g, at least about or less g, at least about or less than about 0.1 g, at least about than about 0.22 g, at least about or less than about 0.23 or less than about 0.11 g, at least about or less than about g, at least about or less than about 0.24 g, at least about 0.12 g, at least about or less than about 0.13 g, at least or less than about 0.25 g, at least about or less than about about or less than about 0.14 g, at least about or less 0.26 g, at least about or less than about 0.27 g, at least than about 0.15 g, at least about or less than about 0.16 50 about or less than about 0.28 g, at least about or less g, at least about or less than about 0.17 g, at least about than about 0.29 g, or at least about or less than about or less than about 0.18 g, at least about or less than about 0.3 g of at least one bile acid sequestrant. In certain em- 0.19 g, at least about or less than about 0.2 g, at least bodiments, the dosage unit comprises at least about or about or less than about 0.21 g, at least about or less less than about 70 mg of at least one proton pump inhib- than about 0.22 g, at least about or less than about 0.23 55 itor and at least about or less than about 0.01 g, at least g, at least about or less than about 0.24 g, at least about about or less than about 0.02 g, at least about or less or less than about 0.25 g, at least about or less than about than about 0.03 g, at least about or less than about 0.04 0.26 g, at least about or less than about 0.27 g, at least g, at least about or less than about 0.05 g, at least about

46 91 EP 2 478 895 A2 92 or less than about 0.06 g, at least about or less than about g, at least about or less than about 0.19 g, at least about 0.07 g, at least about or less than about 0.08 g, at least or less than about 0.2 g, at least about or less than about about or less than about 0.09 g, at least about or less 0.21 g, at least about or less than about 0.22 g, at least than about 0.1 g, at least about or less than about 0.11 about or less than about 0.23 g, at least about or less g, at least about or less than about 0.12 g, at least about 5 than about 0.24 g, at least about or less than about 0.25 or less than about 0.13 g, at least about or less than about g, at least about or less than about 0.26 g, at least about 0.14 g, at least about or less than about 0.15 g, at least or less than about 0.27 g, at least about or less than about about or less than about 0.16 g, at least about or less 0.28 g, at least about or less than about 0.29 g, or at least than about 0.17 g, at least about or less than about 0.18 about or less than about 0.3 g of at least one bile acid g, at least about or less than about 0.19 g, at least about 10 sequestrant. In certain embodiments, the dosage unit or less than about 0.2 g, at least about or less than about comprises at least about or less than about 85 mg of at 0.21 g, at least about or less than about 0.22 g, at least least one proton pump inhibitor and at least about or less about or less than about 0.23 g, at least about or less than about 0.01 g, at least about or less than about 0.02 than about 0.24 g, at least about or less than about 0.25 g, at least about or less than about 0.03 g, at least about g, at least about or less than about 0.26 g, at least about 15 or less than about 0.04 g, at least about or less than about or less than about 0.27 g, at least about or less than about 0.05 g, at least about or less than about 0.06 g, at least 0.28 g, at least about or less than about 0.29 g, or at least about or less than about 0.07 g, at least about or less about or less than about 0.3 g of at least one bile acid than about 0.08 g, at least about or less than about 0.09 sequestrant. In certain embodiments, the dosage unit g, at least about or less than about 0.1 g, at least about comprises at least about or less than about 75 mg of at 20 or less than about 0.11 g, at least about or less than about least one proton pump inhibitor and at least about or less 0.12 g, at least about or less than about 0.13 g, at least than about 0.01 g, at least about or less than about 0.02 about or less than about 0.14 g, at least about or less g, at least about or less than about 0.03 g, at least about than about 0.15 g, at least about or less than about 0.16 or less than about 0.04 g, at least about or less than about g, at least about or less than about 0.17 g, at least about 0.05 g, at least about or less than about 0.06 g, at least 25 or less than about 0.18 g, at least about or less than about about or less than about 0.07 g, at least about or less 0.19 g, at least about or less than about 0.2 g, at least than about 0.08 g, at least about or less than about 0.09 about or less than about 0.21 g, at least about or less g, at least about or less than about 0.1 g, at least about than about 0.22 g, at least about or less than about 0.23 or less than about 0.11 g, at least about or less than about g, at least about or less than about 0.24 g, at least about 0.12 g, at least about or less than about 0.13 g, at least 30 or less than about 0.25 g, at least about or less than about about or less than about 0.14 g, at least about or less 0.26 g, at least about or less than about 0.27 g, at least than about 0.15 g, at least about or less than about 0.16 about or less than about 0.28 g, at least about or less g, at least about or less than about 0.17 g, at least about than about 0.29 g, or at least about or less than about or less than about 0.18 g, at least about or less than about 0.3 g of at least one bile acid sequestrant. In certain em- 0.19 g, at least about or less than about 0.2 g, at least 35 bodiments, the dosage unit comprises at least about or about or less than about 0.21 g, at least about or less less than about 90 mg of at least one proton pump inhib- than about 0.22 g, at least about or less than about 0.23 itor and at least about or less than about 0.01 g, at least g, at least about or less than about 0.24 g, at least about about or less than about 0.02 g, at least about or less or less than about 0.25 g, at least about or less than about than about 0.03 g, at least about or less than about 0.04 0.26 g, at least about or less than about 0.27 g, at least 40 g, at least about or less than about 0.05 g, at least about about or less than about 0.28 g, at least about or less or less than about 0.06 g, at least about or less than about than about 0.29 g, or at least about or less than about 0.07 g, at least about or less than about 0.08 g, at least 0.3 g of at least one bile acid sequestrant. In certain em- about or less than about 0.09 g, at least about or less bodiments, the dosage unit comprises at least about or than about 0.1 g, at least about or less than about 0.11 less than about 80 mg of at least one proton pump inhib- 45 g, at least about or less than about 0.12 g, at least about itor and at least about or less than about 0.01 g, at least or less than about 0.13 g, at least about or less than about about or less than about 0.02 g, at least about or less 0.14 g, at least about or less than about 0.15 g, at least than about 0.03 g, at least about or less than about 0.04 about or less than about 0.16 g, at least about or less g, at least about or less than about 0.05 g, at least about than about 0.17 g, at least about or less than about 0.18 or less than about 0.06 g, at least about or less than about 50 g, at least about or less than about 0.19 g, at least about 0.07 g, at least about or less than about 0.08 g, at least or less than about 0.2 g, at least about or less than about about or less than about 0.09 g, at least about or less 0.21 g, at least about or less than about 0.22 g, at least than about 0.1 g, at least about or less than about 0.11 about or less than about 0.23 g, at least about or less g, at least about or less than about 0.12 g, at least about than about 0.24 g, at least about or less than about 0.25 or less than about 0.13 g, at least about or less than about 55 g, at least about or less than about 0.26 g, at least about 0.14 g, at least about or less than about 0.15 g, at least or less than about 0.27 g, at least about or less than about about or less than about 0.16 g, at least about or less 0.28 g, at least about or less than about 0.29 g, or at least than about 0.17 g, at least about or less than about 0.18 about or less than about 0.3 g of at least one bile acid

47 93 EP 2 478 895 A2 94 sequestrant. In certain embodiments, the dosage unit In certain embodiments the at least one bile acid seques- comprises at least about or less than about 95 mg of at trant is cholestyramine. In certain embodiments the at least one proton pump inhibitor and at least about or less least one bile acid sequestrant is colesevelam. In certain than about 0.01 g, at least about or less than about 0.02 embodiments the at least one bile acid sequestrant is g, at least about or less than about 0.03 g, at least about 5 colesevelam-HCl. In certain embodiments the at least or less than about 0.04 g, at least about or less than about one bile acid sequestrant is colestipol. In certain embod- 0.05 g, at least about or less than about 0.06 g, at least iments the at least one proton pump inhibitor is omepra- about or less than about 0.07 g, at least about or less zole and the at least one bile acid sequestrant is choles- than about 0.08 g, at least about or less than about 0.09 tyramine. In certain embodiments the at least one proton g, at least about or less than about 0.1 g, at least about 10 pump inhibitor is omeprazole and the at least one bile or less than about 0.11 g, at least about or less than about acid sequestrant is colesevelam. In certain embodiments 0.12 g, at least about or less than about 0.13 g, at least the at least one proton pump inhibitor is omeprazole and about or less than about 0.14 g, at least about or less the at least one bile acid sequestrant is colesevelam- HCl. than about 0.15 g, at least about or less than about 0.16 In certain embodiments the at least one proton pump g, at least about or less than about 0.17 g, at least about 15 inhibitor is omeprazole and the at least one bile acid se- or less than about 0.18 g, at least about or less than about questrant is colestipol. In certain embodiments the at 0.19 g, at least about or less than about 0.2 g, at least least one proton pump inhibitor is esomeprazole and the about or less than about 0.21 g, at least about or less at least one bile acid sequestrant is cholestyramine. In than about 0.22 g, at least about or less than about 0.23 certain embodiments the at least one proton pump inhib- g, at least about or less than about 0.24 g, at least about 20 itor is esomeprazole and the at least one bile acid se- or less than about 0.25 g, at least about or less than about questrant is colesevelam. In certain embodiments the at 0.26 g, at least about or less than about 0.27 g, at least least one proton pump inhibitor is esomeprazole and the about or less than about 0.28 g, at least about or less at least one bile acid sequestrant is colesevelam- HCl. In than about 0.29 g, or at least about or less than about certain embodiments the at least one proton pump inhib- 0.3 g of at least one bile acid sequestrant. In certain em- 25 itor is esomeprazole and the at least one bile acid se- bodiments, the dosage unit comprises at least about or questrant is colestipol. In certain embodiments the at less than about 100 mg of at least one proton pump in- least one proton pump inhibitor is lansoprazole and the hibitor and at least about or less than about 0.01 g, at at least one bile acid sequestrant is cholestyramine. In least about or less than about 0.02 g, at least about or certain embodiments the at least one proton pump inhib- less than about 0.03 g, at least about or less than about 30 itor is lansoprazole and the at least one bile acid seques- 0.04 g, at least about or less than about 0.05 g, at least trant is colesevelam. In certain embodiments the at least about or less than about 0.06 g, at least about or less one proton pump inhibitor is lansoprazole and the at least than about 0.07 g, at least about or less than about 0.08 one bile acid sequestrant is colesevelam- HCl. In certain g, at least about or less than about 0.09 g, at least about embodiments the at least one proton pump inhibitor is or less than about 0.1 g, at least about or less than about 35 lansoprazole and the at least one bile acid sequestrant 0.11 g, at least about or less than about 0.12 g, at least is colestipol. In certain embodiments the at least one pro- about or less than about 0.13 g, at least about or less ton pump inhibitor is pantoprazole and the at least one than about 0.14 g, at least about or less than about 0.15 bile acid sequestrant is cholestyramine. In certain em- g, at least about or less than about 0.16 g, at least about bodiments the at least one proton pump inhibitor is pan- or less than about 0.17 g, at least about or less than about 40 toprazole and the at least one bile acid sequestrant is 0.18 g, at least about or less than about 0.19 g, at least colesevelam. In certain embodiments the at least one about or less than about 0.2 g, at least about or less than proton pump inhibitor is pantoprazole and the at least about 0.21 g, at least about or less than about 0.22 g, at one bile acid sequestrant is colesevelam- HCl. In certain least about or less than about 0.23 g, at least about or embodiments the at least one proton pump inhibitor is less than about 0.24 g, at least about or less than about 45 pantoprazole and the at least one bile acid sequestrant 0.25 g, at least about or less than about 0.26 g, at least is colestipol. In certain embodiments the at least one pro- about or less than about 0.27 g, at least about or less ton pump inhibitor is rabeprazole and the at least one than about 0.28 g, at least about or less than about 0.29 bile acid sequestrant is cholestyramine. In certain em- g, or at least about or less than about 0.3 g of at least bodiments the at least one proton pump inhibitor is rab- one bile acid sequestrant. In certain embodiments the at 50 eprazole and the at least one bile acid sequestrant is least one proton pump inhibitor is omeprazole. In certain colesevelam. In certain embodiments the at least one embodiments the at least one proton pump inhibitor is proton pump inhibitor is rabeprazole and the at least one esomeprazole. In certain embodiments the at least one bile acid sequestrant is colesevelam-HCl. In certain em- proton pump inhibitor is lansoprazole. In certain embod- bodiments the at least one proton pump inhibitor is rab- iments the at least one proton pump inhibitor is panto- 55 eprazole and the at least one bile acid sequestrant is prazole. In certain embodiments the at least one proton colestipol. In certain embodiments the at least one proton pump inhibitor is rabeprazole. In certain embodiments pump inhibitor is tenatoprazole and the at least one bile the at least one proton pump inhibitor is tenatoprazole. acid sequestrant is cholestyramine. In certain embodi-

48 95 EP 2 478 895 A2 96 ments the at least one proton pump inhibitor is tenato- about 105 g, at least about or less than about 110 g, at prazole and the at least one bile acid sequestrant is cole- least about or less than about 115 g, at least about or sevelam. In certain embodiments the at least one proton less than about 120 g, at least about or less than about pump inhibitor is tenatoprazole and the at least one bile 125 g, at least about or less than about 130 g, at least acid sequestrant is colesevelam-HCl. In certain embod- 5 about or less than about 135 g, at least about or less than iments the at least one proton pump inhibitor is tenato- about 140 g, at least about or less than about 145 g, or prazole and the at least one bile acid sequestrant is at least about or less than about 150 g of at least one colestipol. In certain embodiments the dosage unit and bile acid sequestrant. In certain embodiments, the dos- daily dose are equivalent. In various embodiments, the age unit comprises at least about or less than about 15 dosage unit is administered with food at anytime of the 10 mg of at least one proton pump inhibitor and at least day, without food at anytime of the day, with food after about or less than about 5 g, at least about or less than an overnight fast (e.g. with breakfast), at bedtime after a about 10 g, at least about or less than about 15 g, at least low fat snack. In various embodiments, the dosage unit about or less than about 20 g, at least about or less than is administered once a day, twice a day, three times a about 25 g, at least about or less than about 30 g, at least day, four times a day. The dosage unit can optionally 15 about or less than about 35 g, at least about or less than comprise other agents such as at least one antacid, at about 40 g, at least about or less than about 45 g, at least least one histamine H 2-receptor antagonist, or combina- about or less than about 50 g, at least about or less than tions thereof. about 55 g, at least about or less than about 60 g, at least [0170] In certain embodiments, the dosage unit com- about or less than about 65 g, at least about or less than prises at least about or less than about 5 mg of at least 20 about 70 g, at least about or less than about 75 g, at least one proton pump inhibitor and at least about or less than about or less than about 80 g, at least about or less than about 5 g, at least about or less than about 10 g, at least about 85 g, at least about or less than about 90 g, at least about or less than about 15 g, at least about or less than about or less than about 95 g, at least about or less than about 20 g, at least about or less than about 25 g, at least about 100 g, at least about or less than about 105 g, at about or less than about 30 g, at least about or less than 25 least about or less than about 110 g, at least about or about 35 g, at least about or less than about 40 g, at least less than about 115 g, at least about or less than about about or less than about 45 g, at least about or less than 120 g, at least about or less than about 125 g, at least about 50 g, at least about or less than about 55 g, at least about or less than about 130 g, at least about or less than about or less than about 60 g, at least about or less than about 135 g, at least about or less than about 140 g, at about 65 g, at least about or less than about 70 g, at least 30 least about or less than about 145 g, or at least about or about or less than about 75 g, at least about or less than less than about 150 g of at least one bile acid sequestrant. about 80 g, at least about or less than about 85 g, at least In certain embodiments, the dosage unit comprises at about or less than about 90 g, at least about or less than least about or less than about 20 mg of at least one proton about 95 g, at least about or less than about 100 g, at pump inhibitor and at least about or less than about 5 g, least about or less than about 105 g, at least about or 35 at least about or less than about 10 g, at least about or less than about 110 g, at least about or less than about less than about 15 g, at least about or less than about 115 g, at least about or less than about 120 g, at least 20 g, at least about or less than about 25 g, at least about about or less than about 125 g, at least about or less than or less than about 30 g, at least about or less than about about 130 g, at least about or less than about 135 g, at 35 g, at least about or less than about 40 g, at least about least about or less than about 140 g, at least about or 40 or less than about 45 g, at least about or less than about less than about 145 g, or at least about or less than about 50 g, at least about or less than about 55 g, at least about 150 g of at least one bile acid sequestrant. In certain or less than about 60 g, at least about or less than about embodiments, the dosage unit comprises at least about 65 g, at least about or less than about 70 g, at least about or less than about 10 mg of at least one proton pump or less than about 75 g, at least about or less than about inhibitor and at least about or less than about 5 g, at least 45 80 g, at least about or less than about 85 g, at least about about or less than about 10 g, at least about or less than or less than about 90 g, at least about or less than about about 15 g, at least about or less than about 20 g, at least 95 g, at least about or less than about 100 g, at least about or less than about 25 g, at least about or less than about or less than about 105 g, at least about or less than about 30 g, at least about or less than about 35 g, at least about 110 g, at least about or less than about 115 g, at about or less than about 40 g, at least about or less than 50 least about or less than about 120 g, at least about or about 45 g, at least about or less than about 50 g, at least less than about 125 g, at least about or less than about about or less than about 55 g, at least about or less than 130 g, at least about or less than about 135 g, at least about 60 g, at least about or less than about 65 g, at least about or less than about 140 g, at least about or less than about or less than about 70 g, at least about or less than about 145 g, or at least about or less than about 150 g about 75 g, at least about or less than about 80 g, at least 55 of at least one bile acid sequestrant. In certain embodi- about or less than about 85 g, at least about or less than ments, the dosage unit comprises at least about or less about 90 g, at least about or less than about 95 g, at least than about 25 mg of at least one proton pump inhibitor about or less than about 100 g, at least about or less than and at least about or less than about 5 g, at least about

49 97 EP 2 478 895 A2 98 or less than about 10 g, at least about or less than about or less than about 90 g, at least about or less than about 15 g, at least about or less than about 20 g, at least about 95 g, at least about or less than about 100 g, at least or less than about 25 g, at least about or less than about about or less than about 105 g, at least about or less than 30 g, at least about or less than about 35 g, at least about about 110 g, at least about or less than about 115 g, at or less than about 40 g, at least about or less than about 5 least about or less than about 120 g, at least about or 45 g, at least about or less than about 50 g, at least about less than about 125 g, at least about or less than about or less than about 55 g, at least about or less than about 130 g, at least about or less than about 135 g, at least 60 g, at least about or less than about 65 g, at least about about or less than about 140 g, at least about or less than or less than about 70 g, at least about or less than about about 145 g, or at least about or less than about 150 g 75 g, at least about or less than about 80 g, at least about 10 of at least one bile acid sequestrant. In certain embodi- or less than about 85 g, at least about or less than about ments, the dosage unit comprises at least about or less 90 g, at least about or less than about 95 g, at least about than about 40 mg of at least one proton pump inhibitor or less than about 100 g, at least about or less than about and at least about or less than about 5 g, at least about 105 g, at least about or less than about 110 g, at least or less than about 10 g, at least about or less than about about or less than about 115 g, at least about or less than 15 15 g, at least about or less than about 20 g, at least about about 120 g, at least about or less than about 125 g, at or less than about 25 g, at least about or less than about least about or less than about 130 g, at least about or 30 g, at least about or less than about 35 g, at least about less than about 135 g, at least about or less than about or less than about 40 g, at least about or less than about 140 g, at least about or less than about 145 g, or at least 45 g, at least about or less than about 50 g, at least about about or less than about 150 g of at least one bile acid 20 or less than about 55 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 60 g, at least about or less than about 65 g, at least about comprises at least about or less than about 30 mg of at or less than about 70 g, at least about or less than about least one proton pump inhibitor and at least about or less 75 g, at least about or less than about 80 g, at least about than about 5 g, at least about or less than about 10 g, at or less than about 85 g, at least about or less than about least about or less than about 15 g, at least about or less 25 90 g, at least about or less than about 95 g, at least about than about 20 g, at least about or less than about 25 g, or less than about 100 g, at least about or less than about at least about or less than about 30 g, at least about or 105 g, at least about or less than about 110 g, at least less than about 35 g, at least about or less than about about or less than about 115 g, at least about or less than 40 g, at least about or less than about 45 g, at least about about 120 g, at least about or less than about 125 g, at or less than about 50 g, at least about or less than about 30 least about or less than about 130 g, at least about or 55 g, at least about or less than about 60 g, at least about less than about 135 g, at least about or less than about or less than about 65 g, at least about or less than about 140 g, at least about or less than about 145 g, or at least 70 g, at least about or less than about 75 g, at least about about or less than about 150 g of at least one bile acid or less than about 80 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 85 g, at least about or less than about 90 g, at least about 35 comprises at least about or less than about 45 mg of at or less than about 95 g, at least about or less than about least one proton pump inhibitor and at least about or less 100 g, at least about or less than about 105 g, at least than about 5 g, at least about or less than about 10 g, at about or less than about 110 g, at least about or less than least about or less than about 15 g, at least about or less about 115 g, at least about or less than about 120 g, at than about 20 g, at least about or less than about 25 g, least about or less than about 125 g, at least about or 40 at least about or less than about 30 g, at least about or less than about 130 g, at least about or less than about less than about 35 g, at least about or less than about 135 g, at least about or less than about 140 g, at least 40 g, at least about or less than about 45 g, at least about about or less than about 145 g, or at least about or less or less than about 50 g, at least about or less than about than about 150 g of at least one bile acid sequestrant. In 55 g, at least about or less than about 60 g, at least about certain embodiments, the dosage unit comprises at least 45 or less than about 65 g, at least about or less than about about or less than about 35 mg of at least one proton 70 g, at least about or less than about 75 g, at least about pump inhibitor and at least about or less than about 5 g, or less than about 80 g, at least about or less than about at least about or less than about 10 g, at least about or 85 g, at least about or less than about 90 g, at least about less than about 15 g, at least about or less than about or less than about 95 g, at least about or less than about 20 g, at least about or less than about 25 g, at least about 50 100 g, at least about or less than about 105 g, at least or less than about 30 g, at least about or less than about about or less than about 110 g, at least about or less than 35 g, at least about or less than about 40 g, at least about about 115 g, at least about or less than about 120 g, at or less than about 45 g, at least about or less than about least about or less than about 125 g, at least about or 50 g, at least about or less than about 55 g, at least about less than about 130 g, at least about or less than about or less than about 60 g, at least about or less than about 55 135 g, at least about or less than about 140 g, at least 65 g, at least about or less than about 70 g, at least about about or less than about 145 g, or at least about or less or less than about 75 g, at least about or less than about than about 150 g of at least one bile acid sequestrant. In 80 g, at least about or less than about 85 g, at least about certain embodiments, the dosage unit comprises at least

50 99 EP 2 478 895 A2 100 about or less than about 50 mg of at least one proton 70 g, at least about or less than about 75 g, at least about pump inhibitor and at least about or less than about 5 g, or less than about 80 g, at least about or less than about at least about or less than about 10 g, at least about or 85 g, at least about or less than about 90 g, at least about less than about 15 g, at least about or less than about or less than about 95 g, at least about or less than about 20 g, at least about or less than about 25 g, at least about 5 100 g, at least about or less than about 105 g, at least or less than about 30 g, at least about or less than about about or less than about 110 g, at least about or less than 35 g, at least about or less than about 40 g, at least about about 115 g, at least about or less than about 120 g, at or less than about 45 g, at least about or less than about least about or less than about 125 g, at least about or 50 g, at least about or less than about 55 g, at least about less than about 130 g, at least about or less than about or less than about 60 g, at least about or less than about 10 135 g, at least about or less than about 140 g, at least 65 g, at least about or less than about 70 g, at least about about or less than about 145 g, or at least about or less or less than about 75 g, at least about or less than about than about 150 g of at least one bile acid sequestrant. In 80 g, at least about or less than about 85 g, at least about certain embodiments, the dosage unit comprises at least or less than about 90 g, at least about or less than about about or less than about 65 mg of at least one proton 95 g, at least about or less than about 100 g, at least15 pump inhibitor and at least about or less than about 5 g, about or less than about 105 g, at least about or less than at least about or less than about 10 g, at least about or about 110 g, at least about or less than about 115 g, at less than about 15 g, at least about or less than about least about or less than about 120 g, at least about or 20 g, at least about or less than about 25 g, at least about less than about 125 g, at least about or less than about or less than about 30 g, at least about or less than about 130 g, at least about or less than about 135 g, at least 20 35 g, at least about or less than about 40 g, at least about about or less than about 140 g, at least about or less than or less than about 45 g, at least about or less than about about 145 g, or at least about or less than about 150 g 50 g, at least about or less than about 55 g, at least about of at least one bile acid sequestrant. In certain embodi- or less than about 60 g, at least about or less than about ments, the dosage unit comprises at least about or less 65 g, at least about or less than about 70 g, at least about than about 55 mg of at least one proton pump inhibitor 25 or less than about 75 g, at least about or less than about and at least about or less than about 5 g, at least about 80 g, at least about or less than about 85 g, at least about or less than about 10 g, at least about or less than about or less than about 90 g, at least about or less than about 15 g, at least about or less than about 20 g, at least about 95 g, at least about or less than about 100 g, at least or less than about 25 g, at least about or less than about about or less than about 105 g, at least about or less than 30 g, at least about or less than about 35 g, at least about 30 about 110 g, at least about or less than about 115 g, at or less than about 40 g, at least about or less than about least about or less than about 120 g, at least about or 45 g, at least about or less than about 50 g, at least about less than about 125 g, at least about or less than about or less than about 55 g, at least about or less than about 130 g, at least about or less than about 135 g, at least 60 g, at least about or less than about 65 g, at least about about or less than about 140 g, at least about or less than or less than about 70 g, at least about or less than about 35 about 145 g, or at least about or less than about 150 g 75 g, at least about or less than about 80 g, at least about of at least one bile acid sequestrant. In certain embodi- or less than about 85 g, at least about or less than about ments, the dosage unit comprises at least about or less 90 g, at least about or less than about 95 g, at least about than about 70 mg of at least one proton pump inhibitor or less than about 100 g, at least about or less than about and at least about or less than about 5 g, at least about 105 g, at least about or less than about 110 g, at least 40 or less than about 10 g, at least about or less than about about or less than about 115 g, at least about or less than 15 g, at least about or less than about 20 g, at least about about 120 g, at least about or less than about 125 g, at or less than about 25 g, at least about or less than about least about or less than about 130 g, at least about or 30 g, at least about or less than about 35 g, at least about less than about 135 g, at least about or less than about or less than about 40 g, at least about or less than about 140 g, at least about or less than about 145 g, or at least 45 45 g, at least about or less than about 50 g, at least about about or less than about 150 g of at least one bile acid or less than about 55 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 60 g, at least about or less than about 65 g, at least about comprises at least about or less than about 60 mg of at or less than about 70 g, at least about or less than about least one proton pump inhibitor and at least about or less 75 g, at least about or less than about 80 g, at least about than about 5 g, at least about or less than about 10 g, at 50 or less than about 85 g, at least about or less than about least about or less than about 15 g, at least about or less 90 g, at least about or less than about 95 g, at least about than about 20 g, at least about or less than about 25 g, or less than about 100 g, at least about or less than about at least about or less than about 30 g, at least about or 105 g, at least about or less than about 110 g, at least less than about 35 g, at least about or less than about about or less than about 115 g, at least about or less than 40 g, at least about or less than about 45 g, at least about 55 about 120 g, at least about or less than about 125 g, at or less than about 50 g, at least about or less than about least about or less than about 130 g, at least about or 55 g, at least about or less than about 60 g, at least about less than about 135 g, at least about or less than about or less than about 65 g, at least about or less than about 140 g, at least about or less than about 145 g, or at least

51 101 EP 2 478 895 A2 102 about or less than about 150 g of at least one bile acid or less than about 55 g, at least about or less than about sequestrant. In certain embodiments, the dosage unit 60 g, at least about or less than about 65 g, at least about comprises at least about or less than about 75 mg of at or less than about 70 g, at least about or less than about least one proton pump inhibitor and at least about or less 75 g, at least about or less than about 80 g, at least about than about 5 g, at least about or less than about 10 g, at 5 or less than about 85 g, at least about or less than about least about or less than about 15 g, at least about or less 90 g, at least about or less than about 95 g, at least about than about 20 g, at least about or less than about 25 g, or less than about 100 g, at least about or less than about at least about or less than about 30 g, at least about or 105 g, at least about or less than about 110 g, at least less than about 35 g, at least about or less than about about or less than about 115 g, at least about or less than 40 g, at least about or less than about 45 g, at least about 10 about 120 g, at least about or less than about 125 g, at or less than about 50 g, at least about or less than about least about or less than about 130 g, at least about or 55 g, at least about or less than about 60 g, at least about less than about 135 g, at least about or less than about or less than about 65 g, at least about or less than about 140 g, at least about or less than about 145 g, or at least 70 g, at least about or less than about 75 g, at least about about or less than about 150 g of at least one bile acid or less than about 80 g, at least about or less than about 15 sequestrant. In certain embodiments, the dosage unit 85 g, at least about or less than about 90 g, at least about comprises at least about or less than about 90 mg of at or less than about 95 g, at least about or less than about least one proton pump inhibitor and at least about or less 100 g, at least about or less than about 105 g, at least than about 5 g, at least about or less than about 10 g, at about or less than about 110 g, at least about or less than least about or less than about 15 g, at least about or less about 115 g, at least about or less than about 120 g, at 20 than about 20 g, at least about or less than about 25 g, least about or less than about 125 g, at least about or at least about or less than about 30 g, at least about or less than about 130 g, at least about or less than about less than about 35 g, at least about or less than about 135 g, at least about or less than about 140 g, at least 40 g, at least about or less than about 45 g, at least about about or less than about 145 g, or at least about or less or less than about 50 g, at least about or less than about than about 150 g of at least one bile acid sequestrant. In 25 55 g, at least about or less than about 60 g, at least about certain embodiments, the dosage unit comprises at least or less than about 65 g, at least about or less than about about or less than about 80 mg of at least one proton 70 g, at least about or less than about 75 g, at least about pump inhibitor and at least about or less than about 5 g, or less than about 80 g, at least about or less than about at least about or less than about 10 g, at least about or 85 g, at least about or less than about 90 g, at least about less than about 15 g, at least about or less than about 30 or less than about 95 g, at least about or less than about 20 g, at least about or less than about 25 g, at least about 100 g, at least about or less than about 105 g, at least or less than about 30 g, at least about or less than about about or less than about 110 g, at least about or less than 35 g, at least about or less than about 40 g, at least about about 115 g, at least about or less than about 120 g, at or less than about 45 g, at least about or less than about least about or less than about 125 g, at least about or 50 g, at least about or less than about 55 g, at least about 35 less than about 130 g, at least about or less than about or less than about 60 g, at least about or less than about 135 g, at least about or less than about 140 g, at least 65 g, at least about or less than about 70 g, at least about about or less than about 145 g, or at least about or less or less than about 75 g, at least about or less than about than about 150 g of at least one bile acid sequestrant. In 80 g, at least about or less than about 85 g, at least about certain embodiments, the dosage unit comprises at least or less than about 90 g, at least about or less than about 40 about or less than about 95 mg of at least one proton 95 g, at least about or less than about 100 g, at least pump inhibitor and at least about or less than about 5 g, about or less than about 105 g, at least about or less than at least about or less than about 10 g, at least about or about 110 g, at least about or less than about 115 g, at less than about 15 g, at least about or less than about least about or less than about 120 g, at least about or 20 g, at least about or less than about 25 g, at least about less than about 125 g, at least about or less than about 45 or less than about 30 g, at least about or less than about 130 g, at least about or less than about 135 g, at least 35 g, at least about or less than about 40 g, at least about about or less than about 140 g, at least about or less than or less than about 45 g, at least about or less than about about 145 g, or at least about or less than about 150 g 50 g, at least about or less than about 55 g, at least about of at least one bile acid sequestrant. In certain embodi- or less than about 60 g, at least about or less than about ments, the dosage unit comprises at least about or less 50 65 g, at least about or less than about 70 g, at least about than about 85 mg of at least one proton pump inhibitor or less than about 75 g, at least about or less than about and at least about or less than about 5 g, at least about 80 g, at least about or less than about 85 g, at least about or less than about 10 g, at least about or less than about or less than about 90 g, at least about or less than about 15 g, at least about or less than about 20 g, at least about 95 g, at least about or less than about 100 g, at least or less than about 25 g, at least about or less than about 55 about or less than about 105 g, at least about or less than 30 g, at least about or less than about 35 g, at least about about 110 g, at least about or less than about 115 g, at or less than about 40 g, at least about or less than about least about or less than about 120 g, at least about or 45 g, at least about or less than about 50 g, at least about less than about 125 g, at least about or less than about

52 103 EP 2 478 895 A2 104

130 g, at least about or less than about 135 g, at least acid sequestrant is colesevelam-HCl. In certain embod- about or less than about 140 g, at least about or less than iments the at least one proton pump inhibitor is esome- about 145 g, or at least about or less than about 150 g prazole and the at least one bile acid sequestrant is of at least one bile acid sequestrant. In certain embodi- colestipol. In certain embodiments the at least one proton ments, the dosage unit comprises at least about or less 5 pump inhibitor is lansoprazole and the at least one bile than about 100 mg of at least one proton pump inhibitor acid sequestrant is cholestyramine. In certain embodi- and at least about or less than about 5 g, at least about ments the at least one proton pump inhibitor is lansopra- or less than about 10 g, at least about or less than about zole and the at least one bile acid sequestrant is cole- 15 g, at least about or less than about 20 g, at least about sevelam. In certain embodiments the at least one proton or less than about 25 g, at least about or less than about 10 pump inhibitor is lansoprazole and the at least one bile 30 g, at least about or less than about 35 g, at least about acid sequestrant is colesevelam-HCl. In certain embod- or less than about 40 g, at least about or less than about iments the at least one proton pump inhibitor is lanso- 45 g, at least about or less than about 50 g, at least about prazole and the at least one bile acid sequestrant is or less than about 55 g, at least about or less than about colestipol. In certain embodiments the at least one proton 60 g, at least about or less than about 65 g, at least about 15 pump inhibitor is pantoprazole and the at least one bile or less than about 70 g, at least about or less than about acid sequestrant is cholestyramine. In certain embodi- 75 g, at least about or less than about 80 g, at least about ments the at least one proton pump inhibitor is pantopra- or less than about 85 g, at least about or less than about zole and the at least one bile acid sequestrant is cole- 90 g, at least about or less than about 95 g, at least about sevelam. In certain embodiments the at least one proton or less than about 100 g, at least about or less than about 20 pump inhibitor is pantoprazole and the at least one bile 105 g, at least about or less than about 110 g, at least acid sequestrant is colesevelam-HCl. In certain embod- about or less than about 115 g, at least about or less than iments the at least one proton pump inhibitor is panto- about 120 g, at least about or less than about 125 g, at prazole and the at least one bile acid sequestrant is least about or less than about 130 g, at least about or colestipol. In certain embodiments the at least one proton less than about 135 g, at least about or less than about 25 pump inhibitor is rabeprazole and the at least one bile 140 g, at least about or less than about 145 g, or at least acid sequestrant is cholestyramine. In certain embodi- about or less than about 150 g of at least one bile acid ments the at least one proton pump inhibitor is rabepra- sequestrant. In certain embodiments the at least one pro- zole and the at least one bile acid sequestrant is cole- tonpump inhibitor is omeprazole. In certain embodiments sevelam. In certain embodiments the at least one proton the at least one proton pump inhibitor is esomeprazole. 30 pump inhibitor is rabeprazole and the at least one bile In certain embodiments the at least one proton pump acid sequestrant is colesevelam-HCl. In certain embod- inhibitor is lansoprazole. In certain embodiments the at iments the at least one proton pump inhibitor is rabepra- least one proton pump inhibitor is pantoprazole. In certain zole and the at least one bile acid sequestrant is embodiments the at least one proton pump inhibitor is colestipol. In certain embodiments the at least one proton rabeprazole. In certain embodiments the at least one pro- 35 pump inhibitor is tenatoprazole and the at least one bile ton pump inhibitor is tenatoprazole. In certain embodi- acid sequestrant is cholestyramine. In certain embodi- ments the at least one bile acid sequestrant is cholesty- ments the at least one proton pump inhibitor is tenato- ramine. In certain embodiments the at least one bile acid prazole and the at least one bile acid sequestrant is cole- sequestrant is colesevelam. In certain embodiments the sevelam. In certain embodiments the at least one proton at least one bile acid sequestrant is colesevelam- HCl. In 40 pump inhibitor is tenatoprazole and the at least one bile certain embodiments the at least one bile acid seques- acid sequestrant is colesevelam-HCl. In certain embod- trant is colestipol. In certain embodiments the at least iments the at least one proton pump inhibitor is tenato- one proton pump inhibitor is omeprazole and the at least prazole and the at least one bile acid sequestrant is one bile acid sequestrant is cholestyramine. In certain colestipol. In certain embodiments the dosage unit and embodiments the at least one proton pump inhibitor is 45 daily dose are equivalent. In various embodiments, the omeprazole and the at least one bile acid sequestrant is dosage unit is administered with food at anytime of the colesevelam. In certain embodiments the at least one day, without food at anytime of the day, with food after proton pump inhibitor is omeprazole and the at least one an overnight fast (e.g. with breakfast), at bedtime after a bile acid sequestrant is colesevelam-HCl. In certain em- low fat snack. In various embodiments, the dosage unit bodiments the at least one proton pump inhibitor is ome- 50 is administered once a day, twice a day, three times a prazole and the at least one bile acid sequestrant is day, four times a day. The dosage unit can optionally colestipol. In certain embodiments the at least one proton comprise other agents such as at least one antacid, at pump inhibitor is esomeprazole and the at least one bile least one histamine H 2-receptor antagonist, or combina- acid sequestrant is cholestyramine. In certain embodi- tions thereof. ments the at least one proton pump inhibitor is esome- 55 [0171] In certain embodiments, the dosage unit com- prazole and the at least one bile acid sequestrant is cole- prises at least about or less than about 5 mg of at least sevelam. In certain embodiments the at least one proton one proton pump inhibitor and at least about or less than pump inhibitor is esomeprazole and the at least one bile about 2 g, at least about or less than about 4 g, at least

53 105 EP 2 478 895 A2 106 about or less than about 6 g, at least about or less than about 40 g, at least about or less than about 42 g, at least about 8 g, at least about or less than about 10 g, at least about or less than about 44 g, at least about or less than about or less than about 12 g, at least about or less than about 46 g, at least about or less than about 48 g, at least about 14 g, at least about or less than about 16 g, at least about or less than about 50 g, at least about or less than about or less than about 18 g, at least about or less than 5 about 52 g, at least about or less than about 54 g, at least about 20 g, at least about or less than about 22 g, at least about or less than about 56 g, at least about or less than about or less than about 24 g, at least about or less than about 58 g, or at least about or less than about 60 g of about 26 g, at least about or less than about 28 g, at least at least one bile acid sequestrant. In certain embodi- about or less than about 30 g, at least about or less than ments, the dosage unit comprises at least about or less about 32 g, at least about or less than about 34 g, at least 10 than about 20 mg of at least one proton pump inhibitor about or less than about 36 g, at least about or less than and at least about or less than about 2 g, at least about about 38 g, at least about or less than about 40 g, at least or less than about 4 g, at least about or less than about about or less than about 42 g, at least about or less than 6 g, at least about or less than about 8 g, at least about about 44 g, at least about or less than about 46 g, at least or less than about 10 g, at least about or less than about about or less than about 48 g, at least about or less than 15 12 g, at least about or less than about 14 g, at least about about 50 g, at least about or less than about 52 g, at least or less than about 16 g, at least about or less than about about or less than about 54 g, at least about or less than 18 g, at least about or less than about 20 g, at least about about 56 g, at least about or less than about 58 g, or at or less than about 22 g, at least about or less than about least about or less than about 60 g of at least one bile 24 g, at least about or less than about 26 g, at least about acid sequestrant. In certain embodiments, the dosage 20 or less than about 28 g, at least about or less than about unit comprises at least about or less than about 10 mg 30 g, at least about or less than about 32 g, at least about of at least one proton pump inhibitor and at least about or less than about 34 g, at least about or less than about or less than about 2 g, at least about or less than about 36 g, at least about or less than about 38 g, at least about 4 g, at least about or less than about 6 g, at least about or less than about 40 g, at least about or less than about or less than about 8 g, at least about or less than about 25 42 g, at least about or less than about 44 g, at least about 10 g, at least about or less than about 12 g, at least about or less than about 46 g, at least about or less than about or less than about 14 g, at least about or less than about 48 g, at least about or less than about 50 g, at least about 16 g, at least about or less than about 18 g, at least about or less than about 52 g, at least about or less than about or less than about 20 g, at least about or less than about 54 g, at least about or less than about 56 g, at least about 22 g, at least about or less than about 24 g, at least about 30 or less than about 58 g, or at least about or less than or less than about 26 g, at least about or less than about about 60 g of at least one bile acid sequestrant. In certain 28 g, at least about or less than about 30 g, at least about embodiments, the dosage unit comprises at least about or less than about 32 g, at least about or less than about or less than about 25 mg of at least one proton pump 34 g, at least about or less than about 36 g, at least about inhibitor and at least about or less than about 2 g, at least or less than about 38 g, at least about or less than about 35 about or less than about 4 g, at least about or less than 40 g, at least about or less than about 42 g, at least about about 6 g, at least about or less than about 8 g, at least or less than about 44 g, at least about or less than about about or less than about 10 g, at least about or less than 46 g, at least about or less than about 48 g, at least about about 12 g, at least about or less than about 14 g, at least or less than about 50 g, at least about or less than about about or less than about 16 g, at least about or less than 52 g, at least about or less than about 54 g, at least about 40 about 18 g, at least about or less than about 20 g, at least or less than about 56 g, at least about or less than about about or less than about 22 g, at least about or less than 58 g, or at least about or less than about 60 g of at least about 24 g, at least about or less than about 26 g, at least one bile acid sequestrant. In certain embodiments, the about or less than about 28 g, at least about or less than dosage unit comprises at least about or less than about about 30 g, at least about or less than about 32 g, at least 15 mg of at least one proton pump inhibitor and at least 45 about or less than about 34 g, at least about or less than about or less than about 2 g, at least about or less than about 36 g, at least about or less than about 38 g, at least about 4 g, at least about or less than about 6 g, at least about or less than about 40 g, at least about or less than about or less than about 8 g, at least about or less than about 42 g, at least about or less than about 44 g, at least about 10 g, at least about or less than about 12 g, at least about or less than about 46 g, at least about or less than about or less than about 14 g, at least about or less than 50 about 48 g, at least about or less than about 50 g, at least about 16 g, at least about or less than about 18 g, at least about or less than about 52 g, at least about or less than about or less than about 20 g, at least about or less than about 54 g, at least about or less than about 56 g, at least about 22 g, at least about or less than about 24 g, at least about or less than about 58 g, or at least about or less about or less than about 26 g, at least about or less than than about 60 g of at least one bile acid sequestrant. In about 28 g, at least about or less than about 30 g, at least 55 certain embodiments, the dosage unit comprises at least about or less than about 32 g, at least about or less than about or less than about 30 mg of at least one proton about 34 g, at least about or less than about 36 g, at least pump inhibitor and at least about or less than about 2 g, about or less than about 38 g, at least about or less than at least about or less than about 4 g, at least about or

54 107 EP 2 478 895 A2 108 less than about 6 g, at least about or less than about 8 about 40 g, at least about or less than about 42 g, at least g, at least about or less than about 10 g, at least about about or less than about 44 g, at least about or less than or less than about 12 g, at least about or less than about about 46 g, at least about or less than about 48 g, at least 14 g, at least about or less than about 16 g, at least about about or less than about 50 g, at least about or less than or less than about 18 g, at least about or less than about 5 about 52 g, at least about or less than about 54 g, at least 20 g, at least about or less than about 22 g, at least about about or less than about 56 g, at least about or less than or less than about 24 g, at least about or less than about about 58 g, or at least about or less than about 60 g of 26 g, at least about or less than about 28 g, at least about at least one bile acid sequestrant. In certain embodi- or less than about 30 g, at least about or less than about ments, the dosage unit comprises at least about or less 32 g, at least about or less than about 34 g, at least about 10 than about 45 mg of at least one proton pump inhibitor or less than about 36 g, at least about or less than about and at least about or less than about 2 g, at least about 38 g, at least about or less than about 40 g, at least about or less than about 4 g, at least about or less than about or less than about 42 g, at least about or less than about 6 g, at least about or less than about 8 g, at least about 44 g, at least about or less than about 46 g, at least about or less than about 10 g, at least about or less than about or less than about 48 g, at least about or less than about 15 12 g, at least about or less than about 14 g, at least about 50 g, at least about or less than about 52 g, at least about or less than about 16 g, at least about or less than about or less than about 54 g, at least about or less than about 18 g, at least about or less than about 20 g, at least about 56 g, at least about or less than about 58 g, or at least or less than about 22 g, at least about or less than about about or less than about 60 g of at least one bile acid 24 g, at least about or less than about 26 g, at least about sequestrant. In certain embodiments, the dosage unit 20 or less than about 28 g, at least about or less than about comprises at least about or less than about 35 mg of at 30 g, at least about or less than about 32 g, at least about least one proton pump inhibitor and at least about or less or less than about 34 g, at least about or less than about than about 2 g, at least about or less than about 4 g, at 36 g, at least about or less than about 38 g, at least about least about or less than about 6 g, at least about or less or less than about 40 g, at least about or less than about than about 8 g, at least about or less than about 10 g, at 25 42 g, at least about or less than about 44 g, at least about least about or less than about 12 g, at least about or less or less than about 46 g, at least about or less than about than about 14 g, at least about or less than about 16 g, 48 g, at least about or less than about 50 g, at least about at least about or less than about 18 g, at least about or or less than about 52 g, at least about or less than about less than about 20 g, at least about or less than about 54 g, at least about or less than about 56 g, at least about 22 g, at least about or less than about 24 g, at least about 30 or less than about 58 g, or at least about or less than or less than about 26 g, at least about or less than about about 60 g of at least one bile acid sequestrant. In certain 28 g, at least about or less than about 30 g, at least about embodiments, the dosage unit comprises at least about or less than about 32 g, at least about or less than about or less than about 50 mg of at least one proton pump 34 g, at least about or less than about 36 g, at least about inhibitor and at least about or less than about 2 g, at least or less than about 38 g, at least about or less than about 35 about or less than about 4 g, at least about or less than 40 g, at least about or less than about 42 g, at least about about 6 g, at least about or less than about 8 g, at least or less than about 44 g, at least about or less than about about or less than about 10 g, at least about or less than 46 g, at least about or less than about 48 g, at least about about 12 g, at least about or less than about 14 g, at least or less than about 50 g, at least about or less than about about or less than about 16 g, at least about or less than 52 g, at least about or less than about 54 g, at least about 40 about 18 g, at least about or less than about 20 g, at least or less than about 56 g, at least about or less than about about or less than about 22 g, at least about or less than 58 g, or at least about or less than about 60 g of at least about 24 g, at least about or less than about 26 g, at least one bile acid sequestrant. In certain embodiments, the about or less than about 28 g, at least about or less than dosage unit comprises at least about or less than about about 30 g, at least about or less than about 32 g, at least 40 mg of at least one proton pump inhibitor and at least 45 about or less than about 34 g, at least about or less than about or less than about 2 g, at least about or less than about 36 g, at least about or less than about 38 g, at least about 4 g, at least about or less than about 6 g, at least about or less than about 40 g, at least about or less than about or less than about 8 g, at least about or less than about 42 g, at least about or less than about 44 g, at least about 10 g, at least about or less than about 12 g, at least about or less than about 46 g, at least about or less than about or less than about 14 g, at least about or less than 50 about 48 g, at least about or less than about 50 g, at least about 16 g, at least about or less than about 18 g, at least about or less than about 52 g, at least about or less than about or less than about 20 g, at least about or less than about 54 g, at least about or less than about 56 g, at least about 22 g, at least about or less than about 24 g, at least about or less than about 58 g, or at least about or less about or less than about 26 g, at least about or less than than about 60 g of at least one bile acid sequestrant. In about 28 g, at least about or less than about 30 g, at least 55 certain embodiments, the dosage unit comprises at least about or less than about 32 g, at least about or less than about or less than about 55 mg of at least one proton about 34 g, at least about or less than about 36 g, at least pump inhibitor and at least about or less than about 2 g, about or less than about 38 g, at least about or less than at least about or less than about 4 g, at least about or

55 109 EP 2 478 895 A2 110 less than about 6 g, at least about or less than about 8 about 40 g, at least about or less than about 42 g, at least g, at least about or less than about 10 g, at least about about or less than about 44 g, at least about or less than or less than about 12 g, at least about or less than about about 46 g, at least about or less than about 48 g, at least 14 g, at least about or less than about 16 g, at least about about or less than about 50 g, at least about or less than or less than about 18 g, at least about or less than about 5 about 52 g, at least about or less than about 54 g, at least 20 g, at least about or less than about 22 g, at least about about or less than about 56 g, at least about or less than or less than about 24 g, at least about or less than about about 58 g, or at least about or less than about 60 g of 26 g, at least about or less than about 28 g, at least about at least one bile acid sequestrant. In certain embodi- or less than about 30 g, at least about or less than about ments, the dosage unit comprises at least about or less 32 g, at least about or less than about 34 g, at least about 10 than about 70 mg of at least one proton pump inhibitor or less than about 36 g, at least about or less than about and at least about or less than about 2 g, at least about 38 g, at least about or less than about 40 g, at least about or less than about 4 g, at least about or less than about or less than about 42 g, at least about or less than about 6 g, at least about or less than about 8 g, at least about 44 g, at least about or less than about 46 g, at least about or less than about 10 g, at least about or less than about or less than about 48 g, at least about or less than about 15 12 g, at least about or less than about 14 g, at least about 50 g, at least about or less than about 52 g, at least about or less than about 16 g, at least about or less than about or less than about 54 g, at least about or less than about 18 g, at least about or less than about 20 g, at least about 56 g, at least about or less than about 58 g, or at least or less than about 22 g, at least about or less than about about or less than about 60 g of at least one bile acid 24 g, at least about or less than about 26 g, at least about sequestrant. In certain embodiments, the dosage unit 20 or less than about 28 g, at least about or less than about comprises at least about or less than about 60 mg of at 30 g, at least about or less than about 32 g, at least about least one proton pump inhibitor and at least about or less or less than about 34 g, at least about or less than about than about 2 g, at least about or less than about 4 g, at 36 g, at least about or less than about 38 g, at least about least about or less than about 6 g, at least about or less or less than about 40 g, at least about or less than about than about 8 g, at least about or less than about 10 g, at 25 42 g, at least about or less than about 44 g, at least about least about or less than about 12 g, at least about or less or less than about 46 g, at least about or less than about than about 14 g, at least about or less than about 16 g, 48 g, at least about or less than about 50 g, at least about at least about or less than about 18 g, at least about or or less than about 52 g, at least about or less than about less than about 20 g, at least about or less than about 54 g, at least about or less than about 56 g, at least about 22 g, at least about or less than about 24 g, at least about 30 or less than about 58 g, or at least about or less than or less than about 26 g, at least about or less than about about 60 g of at least one bile acid sequestrant. In certain 28 g, at least about or less than about 30 g, at least about embodiments, the dosage unit comprises at least about or less than about 32 g, at least about or less than about or less than about 75 mg of at least one proton pump 34 g, at least about or less than about 36 g, at least about inhibitor and at least about or less than about 2 g, at least or less than about 38 g, at least about or less than about 35 about or less than about 4 g, at least about or less than 40 g, at least about or less than about 42 g, at least about about 6 g, at least about or less than about 8 g, at least or less than about 44 g, at least about or less than about about or less than about 10 g, at least about or less than 46 g, at least about or less than about 48 g, at least about about 12 g, at least about or less than about 14 g, at least or less than about 50 g, at least about or less than about about or less than about 16 g, at least about or less than 52 g, at least about or less than about 54 g, at least about 40 about 18 g, at least about or less than about 20 g, at least or less than about 56 g, at least about or less than about about or less than about 22 g, at least about or less than 58 g, or at least about or less than about 60 g of at least about 24 g, at least about or less than about 26 g, at least one bile acid sequestrant. In certain embodiments, the about or less than about 28 g, at least about or less than dosage unit comprises at least about or less than about about 30 g, at least about or less than about 32 g, at least 65 mg of at least one proton pump inhibitor and at least 45 about or less than about 34 g, at least about or less than about or less than about 2 g, at least about or less than about 36 g, at least about or less than about 38 g, at least about 4 g, at least about or less than about 6 g, at least about or less than about 40 g, at least about or less than about or less than about 8 g, at least about or less than about 42 g, at least about or less than about 44 g, at least about 10 g, at least about or less than about 12 g, at least about or less than about 46 g, at least about or less than about or less than about 14 g, at least about or less than 50 about 48 g, at least about or less than about 50 g, at least about 16 g, at least about or less than about 18 g, at least about or less than about 52 g, at least about or less than about or less than about 20 g, at least about or less than about 54 g, at least about or less than about 56 g, at least about 22 g, at least about or less than about 24 g, at least about or less than about 58 g, or at least about or less about or less than about 26 g, at least about or less than than about 60 g of at least one bile acid sequestrant. In about 28 g, at least about or less than about 30 g, at least 55 certain embodiments, the dosage unit comprises at least about or less than about 32 g, at least about or less than about or less than about 80 mg of at least one proton about 34 g, at least about or less than about 36 g, at least pump inhibitor and at least about or less than about 2 g, about or less than about 38 g, at least about or less than at least about or less than about 4 g, at least about or

56 111 EP 2 478 895 A2 112 less than about 6 g, at least about or less than about 8 about 40 g, at least about or less than about 42 g, at least g, at least about or less than about 10 g, at least about about or less than about 44 g, at least about or less than or less than about 12 g, at least about or less than about about 46 g, at least about or less than about 48 g, at least 14 g, at least about or less than about 16 g, at least about about or less than about 50 g, at least about or less than or less than about 18 g, at least about or less than about 5 about 52 g, at least about or less than about 54 g, at least 20 g, at least about or less than about 22 g, at least about about or less than about 56 g, at least about or less than or less than about 24 g, at least about or less than about about 58 g, or at least about or less than about 60 g of 26 g, at least about or less than about 28 g, at least about at least one bile acid sequestrant. In certain embodi- or less than about 30 g, at least about or less than about ments, the dosage unit comprises at least about or less 32 g, at least about or less than about 34 g, at least about 10 than about 95 mg of at least one proton pump inhibitor or less than about 36 g, at least about or less than about and at least about or less than about 2 g, at least about 38 g, at least about or less than about 40 g, at least about or less than about 4 g, at least about or less than about or less than about 42 g, at least about or less than about 6 g, at least about or less than about 8 g, at least about 44 g, at least about or less than about 46 g, at least about or less than about 10 g, at least about or less than about or less than about 48 g, at least about or less than about 15 12 g, at least about or less than about 14 g, at least about 50 g, at least about or less than about 52 g, at least about or less than about 16 g, at least about or less than about or less than about 54 g, at least about or less than about 18 g, at least about or less than about 20 g, at least about 56 g, at least about or less than about 58 g, or at least or less than about 22 g, at least about or less than about about or less than about 60 g of at least one bile acid 24 g, at least about or less than about 26 g, at least about sequestrant. In certain embodiments, the dosage unit 20 or less than about 28 g, at least about or less than about comprises at least about or less than about 85 mg of at 30 g, at least about or less than about 32 g, at least about least one proton pump inhibitor and at least about or less or less than about 34 g, at least about or less than about than about 2 g, at least about or less than about 4 g, at 36 g, at least about or less than about 38 g, at least about least about or less than about 6 g, at least about or less or less than about 40 g, at least about or less than about than about 8 g, at least about or less than about 10 g, at 25 42 g, at least about or less than about 44 g, at least about least about or less than about 12 g, at least about or less or less than about 46 g, at least about or less than about than about 14 g, at least about or less than about 16 g, 48 g, at least about or less than about 50 g, at least about at least about or less than about 18 g, at least about or or less than about 52 g, at least about or less than about less than about 20 g, at least about or less than about 54 g, at least about or less than about 56 g, at least about 22 g, at least about or less than about 24 g, at least about 30 or less than about 58 g, or at least about or less than or less than about 26 g, at least about or less than about about 60 g of at least one bile acid sequestrant. In certain 28 g, at least about or less than about 30 g, at least about embodiments, the dosage unit comprises at least about or less than about 32 g, at least about or less than about or less than about 100 mg of at least one proton pump 34 g, at least about or less than about 36 g, at least about inhibitor and at least about or less than about 2 g, at least or less than about 38 g, at least about or less than about 35 about or less than about 4 g, at least about or less than 40 g, at least about or less than about 42 g, at least about about 6 g, at least about or less than about 8 g, at least or less than about 44 g, at least about or less than about about or less than about 10 g, at least about or less than 46 g, at least about or less than about 48 g, at least about about 12 g, at least about or less than about 14 g, at least or less than about 50 g, at least about or less than about about or less than about 16 g, at least about or less than 52 g, at least about or less than about 54 g, at least about 40 about 18 g, at least about or less than about 20 g, at least or less than about 56 g, at least about or less than about about or less than about 22 g, at least about or less than 58 g, or at least about or less than about 60 g of at least about 24 g, at least about or less than about 26 g, at least one bile acid sequestrant. In certain embodiments, the about or less than about 28 g, at least about or less than dosage unit comprises at least about or less than about about 30 g, at least about or less than about 32 g, at least 90 mg of at least one proton pump inhibitor and at least 45 about or less than about 34 g, at least about or less than about or less than about 2 g, at least about or less than about 36 g, at least about or less than about 38 g, at least about 4 g, at least about or less than about 6 g, at least about or less than about 40 g, at least about or less than about or less than about 8 g, at least about or less than about 42 g, at least about or less than about 44 g, at least about 10 g, at least about or less than about 12 g, at least about or less than about 46 g, at least about or less than about or less than about 14 g, at least about or less than 50 about 48 g, at least about or less than about 50 g, at least about 16 g, at least about or less than about 18 g, at least about or less than about 52 g, at least about or less than about or less than about 20 g, at least about or less than about 54 g, at least about or less than about 56 g, at least about 22 g, at least about or less than about 24 g, at least about or less than about 58 g, or at least about or less about or less than about 26 g, at least about or less than than about 60 g of at least one bile acid sequestrant. In about 28 g, at least about or less than about 30 g, at least 55 certain embodiments the at least one proton pump inhib- about or less than about 32 g, at least about or less than itor is omeprazole. In certain embodiments the at least about 34 g, at least about or less than about 36 g, at least one proton pump inhibitor is esomeprazole. In certain about or less than about 38 g, at least about or less than embodiments the at least one proton pump inhibitor is

57 113 EP 2 478 895 A2 114 lansoprazole. In certain embodiments the at least one iments the at least one proton pump inhibitor is rabepra- proton pump inhibitor is pantoprazole. In certain embod- zole and the at least one bile acid sequestrant is iments the at least one proton pump inhibitor is rabepra- colestipol. In certain embodiments the at least one proton zole. In certain embodiments the at least one proton pump inhibitor is tenatoprazole and the at least one bile pump inhibitor is tenatoprazole. In certain embodiments 5 acid sequestrant is cholestyramine. In certain embodi- the at least one bile acid sequestrant is cholestyramine. ments the at least one proton pump inhibitor is tenato- In certain embodiments the at least one bile acid seques- prazole and the at least one bile acid sequestrant is cole- trant is colesevelam. In certain embodiments the at least sevelam. In certain embodiments the at least one proton one bile acid sequestrant is colesevelam- HCl. In certain pump inhibitor is tenatoprazole and the at least one bile embodiments the at least one bile acid sequestrant is 10 acid sequestrant is colesevelam-HCl. In certain embod- colestipol. In certain embodiments the at least one proton iments the at least one proton pump inhibitor is tenato- pump inhibitor is omeprazole and the at least one bile prazole and the at least one bile acid sequestrant is acid sequestrant is cholestyramine. In certain embodi- colestipol. In certain embodiments the dosage unit and ments the at least one proton pump inhibitor is omepra- daily dose are equivalent. In various embodiments, the zole and the at least one bile acid sequestrant is cole- 15 dosage unit is administered with food at anytime of the sevelam. In certain embodiments the at least one proton day, without food at anytime of the day, with food after pump inhibitor is omeprazole and the at least one bile an overnight fast (e.g. with breakfast), at bedtime after a acid sequestrant is colesevelam-HCl. In certain embod- low fat snack. In various embodiments, the dosage unit iments the at least one proton pump inhibitor is omepra- is administered once a day, twice a day, three times a zole and the at least one bile acid sequestrant20 isday, four times a day. The dosage unit can optionally colestipol. In certain embodiments the at least one proton comprise other agents such as at least one antacid, at pump inhibitor is esomeprazole and the at least one bile least one histamine H 2-receptor antagonist, or combina- acid sequestrant is cholestyramine. In certain embodi- tions thereof. ments the at least one proton pump inhibitor is esome- [0172] In certain embodiments, the dosage unit com- prazole and the at least one bile acid sequestrant is cole- 25 prises at least about or less than about 5 mg of at least sevelam. In certain embodiments the at least one proton one proton pump inhibitor and at least about or less than pump inhibitor is esomeprazole and the at least one bile about 10 g, at least about or less than about 20 g, at least acid sequestrant is colesevelam-HCl. In certain embod- about or less than about 30 g, at least about or less than iments the at least one proton pump inhibitor is esome- about 40 g, at least about or less than about 50 g, at least prazole and the at least one bile acid sequestrant is30 about or less than about 60 g, at least about or less than colestipol. In certain embodiments the at least one proton about 70 g, at least about or less than about 80 g, at least pump inhibitor is lansoprazole and the at least one bile about or less than about 90 g, at least about or less than acid sequestrant is cholestyramine. In certain embodi- about 100 g, at least about or less than about 110 g, at ments the at least one proton pump inhibitor is lansopra- least about or less than about 120 g, at least about or zole and the at least one bile acid sequestrant is cole- 35 less than about 130 g, at least about or less than about sevelam. In certain embodiments the at least one proton 140 g, at least about or less than about 150 g, at least pump inhibitor is lansoprazole and the at least one bile about or less than about 160 g, at least about or less than acid sequestrant is colesevelam-HCl. In certain embod- about 170 g, at least about or less than about 180 g, at iments the at least one proton pump inhibitor is lanso- least about or less than about 190 g, at least about or prazole and the at least one bile acid sequestrant is40 less than about 200 g, at least about or less than about colestipol. In certain embodiments the at least one proton 210 g, at least about or less than about 220 g, at least pump inhibitor is pantoprazole and the at least one bile about or less than about 230 g, at least about or less than acid sequestrant is cholestyramine. In certain embodi- about 240 g, at least about or less than about 250 g, at ments the at least one proton pump inhibitor is pantopra- least about or less than about 260 g, at least about or zole and the at least one bile acid sequestrant is cole- 45 less than about 270 g, at least about or less than about sevelam. In certain embodiments the at least one proton 280 g, at least about or less than about 290 g, or at least pump inhibitor is pantoprazole and the at least one bile about or less than about 300 g of at least one bile acid acid sequestrant is colesevelam-HCl. In certain embod- sequestrant. In certain embodiments, the dosage unit iments the at least one proton pump inhibitor is panto- comprises at least about or less than about 10 mg of at prazole and the at least one bile acid sequestrant is50 least one proton pump inhibitor and at least about or less colestipol. In certain embodiments the at least one proton than about 10 g, at least about or less than about 20 g, pump inhibitor is rabeprazole and the at least one bile at least about or less than about 30 g, at least about or acid sequestrant is cholestyramine. In certain embodi- less than about 40 g, at least about or less than about ments the at least one proton pump inhibitor is rabepra- 50 g, at least about or less than about 60 g, at least about zole and the at least one bile acid sequestrant is cole- 55 or less than about 70 g, at least about or less than about sevelam. In certain embodiments the at least one proton 80 g, at least about or less than about 90 g, at least about pump inhibitor is rabeprazole and the at least one bile or less than about 100 g, at least about or less than about acid sequestrant is colesevelam-HCl. In certain embod- 110 g, at least about or less than about 120 g, at least

58 115 EP 2 478 895 A2 116 about or less than about 130 g, at least about or less than about 260 g, at least about or less than about 270 g, at about 140 g, at least about or less than about 150 g, at least about or less than about 280 g, at least about or least about or less than about 160 g, at least about or less than about 290 g, or at least about or less than about less than about 170 g, at least about or less than about 300 g of at least one bile acid sequestrant. In certain 180 g, at least about or less than about 190 g, at least 5 embodiments, the dosage unit comprises at least about about or less than about 200 g, at least about or less than or less than about 25 mg of at least one proton pump about 210 g, at least about or less than about 220 g, at inhibitor and at least about or less than about 10 g, at least about or less than about 230 g, at least about or least about or less than about 20 g, at least about or less less than about 240 g, at least about or less than about than about 30 g, at least about or less than about 40 g, 250 g, at least about or less than about 260 g, at least 10 at least about or less than about 50 g, at least about or about or less than about 270 g, at least about or less than less than about 60 g, at least about or less than about about 280 g, at least about or less than about 290 g, or 70 g, at least about or less than about 80 g, at least about at least about or less than about 300 g of at least one or less than about 90 g, at least about or less than about bile acid sequestrant. In certain embodiments, the dos- 100 g, at least about or less than about 110 g, at least age unit comprises at least about or less than about 15 15 about or less than about 120 g, at least about or less than mg of at least one proton pump inhibitor and at least about 130 g, at least about or less than about 140 g, at about or less than about 10 g, at least about or less than least about or less than about 150 g, at least about or about 20 g, at least about or less than about 30 g, at least less than about 160 g, at least about or less than about about or less than about 40 g, at least about or less than 170 g, at least about or less than about 180 g, at least about 50 g, at least about or less than about 60 g, at least 20 about or less than about 190 g, at least about or less than about or less than about 70 g, at least about or less than about 200 g, at least about or less than about 210 g, at about 80 g, at least about or less than about 90 g, at least least about or less than about 220 g, at least about or about or less than about 100 g, at least about or less than less than about 230 g, at least about or less than about about 110 g, at least about or less than about 120 g, at 240 g, at least about or less than about 250 g, at least least about or less than about 130 g, at least about or 25 about or less than about 260 g, at least about or less than less than about 140 g, at least about or less than about about 270 g, at least about or less than about 280 g, at 150 g, at least about or less than about 160 g, at least least about or less than about 290 g, or at least about or about or less than about 170 g, at least about or less than less than about 300 g of at least one bile acid sequestrant. about 180 g, at least about or less than about 190 g, at In certain embodiments, the dosage unit comprises at least about or less than about 200 g, at least about or 30 least about or less than about 30 mg of at least one proton less than about 210 g, at least about or less than about pump inhibitor and at least about or less than about 10 220 g, at least about or less than about 230 g, at least g, at least about or less than about 20 g, at least about about or less than about 240 g, at least about or less than or less than about 30 g, at least about or less than about about 250 g, at least about or less than about 260 g, at 40 g, at least about or less than about 50 g, at least about least about or less than about 270 g, at least about or 35 or less than about 60 g, at least about or less than about less than about 280 g, at least about or less than about 70 g, at least about or less than about 80 g, at least about 290 g, or at least about or less than about 300 g of at or less than about 90 g, at least about or less than about least one bile acid sequestrant. In certain embodiments, 100 g, at least about or less than about 110 g, at least the dosage unit comprises at least about or less than about or less than about 120 g, at least about or less than about 20 mg of at least one proton pump inhibitor and at 40 about 130 g, at least about or less than about 140 g, at least about or less than about 10 g, at least about or less least about or less than about 150 g, at least about or than about 20 g, at least about or less than about 30 g, less than about 160 g, at least about or less than about at least about or less than about 40 g, at least about or 170 g, at least about or less than about 180 g, at least less than about 50 g, at least about or less than about about or less than about 190 g, at least about or less than 60 g, at least about or less than about 70 g, at least about 45 about 200 g, at least about or less than about 210 g, at or less than about 80 g, at least about or less than about least about or less than about 220 g, at least about or 90 g, at least about or less than about 100 g, at least less than about 230 g, at least about or less than about about or less than about 110 g, at least about or less than 240 g, at least about or less than about 250 g, at least about 120 g, at least about or less than about 130 g, at about or less than about 260 g, at least about or less than least about or less than about 140 g, at least about or 50 about 270 g, at least about or less than about 280 g, at less than about 150 g, at least about or less than about least about or less than about 290 g, or at least about or 160 g, at least about or less than about 170 g, at least less than about 300 g of at least one bile acid sequestrant. about or less than about 180 g, at least about or less than In certain embodiments, the dosage unit comprises at about 190 g, at least about or less than about 200 g, at least about or less than about 35 mg of at least one proton least about or less than about 210 g, at least about or 55 pump inhibitor and at least about or less than about 10 less than about 220 g, at least about or less than about g, at least about or less than about 20 g, at least about 230 g, at least about or less than about 240 g, at least or less than about 30 g, at least about or less than about about or less than about 250 g, at least about or less than 40 g, at least about or less than about 50 g, at least about

59 117 EP 2 478 895 A2 118 or less than about 60 g, at least about or less than about about 200 g, at least about or less than about 210 g, at 70 g, at least about or less than about 80 g, at least about least about or less than about 220 g, at least about or or less than about 90 g, at least about or less than about less than about 230 g, at least about or less than about 100 g, at least about or less than about 110 g, at least 240 g, at least about or less than about 250 g, at least about or less than about 120 g, at least about or less than 5 about or less than about 260 g, at least about or less than about 130 g, at least about or less than about 140 g, at about 270 g, at least about or less than about 280 g, at least about or less than about 150 g, at least about or least about or less than about 290 g, or at least about or less than about 160 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 170 g, at least about or less than about 180 g, at least In certain embodiments, the dosage unit comprises at about or less than about 190 g, at least about or less than 10 least about or less than about 50 mg of at least one proton about 200 g, at least about or less than about 210 g, at pump inhibitor and at least about or less than about 10 least about or less than about 220 g, at least about or g, at least about or less than about 20 g, at least about less than about 230 g, at least about or less than about or less than about 30 g, at least about or less than about 240 g, at least about or less than about 250 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 260 g, at least about or less than 15 or less than about 60 g, at least about or less than about about 270 g, at least about or less than about 280 g, at 70 g, at least about or less than about 80 g, at least about least about or less than about 290 g, or at least about or or less than about 90 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 100 g, at least about or less than about 110 g, at least In certain embodiments, the dosage unit comprises at about or less than about 120 g, at least about or less than least about or less than about 40 mg of at least one proton 20 about 130 g, at least about or less than about 140 g, at pump inhibitor and at least about or less than about 10 least about or less than about 150 g, at least about or g, at least about or less than about 20 g, at least about less than about 160 g, at least about or less than about or less than about 30 g, at least about or less than about 170 g, at least about or less than about 180 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 190 g, at least about or less than or less than about 60 g, at least about or less than about 25 about 200 g, at least about or less than about 210 g, at 70 g, at least about or less than about 80 g, at least about least about or less than about 220 g, at least about or or less than about 90 g, at least about or less than about less than about 230 g, at least about or less than about 100 g, at least about or less than about 110 g, at least 240 g, at least about or less than about 250 g, at least about or less than about 120 g, at least about or less than about or less than about 260 g, at least about or less than about 130 g, at least about or less than about 140 g, at 30 about 270 g, at least about or less than about 280 g, at least about or less than about 150 g, at least about or least about or less than about 290 g, or at least about or less than about 160 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 170 g, at least about or less than about 180 g, at least In certain embodiments, the dosage unit comprises at about or less than about 190 g, at least about or less than least about or less than about 55 mg of at least one proton about 200 g, at least about or less than about 210 g, at 35 pump inhibitor and at least about or less than about 10 least about or less than about 220 g, at least about or g, at least about or less than about 20 g, at least about less than about 230 g, at least about or less than about or less than about 30 g, at least about or less than about 240 g, at least about or less than about 250 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 260 g, at least about or less than or less than about 60 g, at least about or less than about about 270 g, at least about or less than about 280 g, at 40 70 g, at least about or less than about 80 g, at least about least about or less than about 290 g, or at least about or or less than about 90 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 100 g, at least about or less than about 110 g, at least In certain embodiments, the dosage unit comprises at about or less than about 120 g, at least about or less than least about or less than about 45 mg of at least one proton about 130 g, at least about or less than about 140 g, at pump inhibitor and at least about or less than about 10 45 least about or less than about 150 g, at least about or g, at least about or less than about 20 g, at least about less than about 160 g, at least about or less than about or less than about 30 g, at least about or less than about 170 g, at least about or less than about 180 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 190 g, at least about or less than or less than about 60 g, at least about or less than about about 200 g, at least about or less than about 210 g, at 70 g, at least about or less than about 80 g, at least about 50 least about or less than about 220 g, at least about or or less than about 90 g, at least about or less than about less than about 230 g, at least about or less than about 100 g, at least about or less than about 110 g, at least 240 g, at least about or less than about 250 g, at least about or less than about 120 g, at least about or less than about or less than about 260 g, at least about or less than about 130 g, at least about or less than about 140 g, at about 270 g, at least about or less than about 280 g, at least about or less than about 150 g, at least about or 55 least about or less than about 290 g, or at least about or less than about 160 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 170 g, at least about or less than about 180 g, at least In certain embodiments, the dosage unit comprises at about or less than about 190 g, at least about or less than least about or less than about 60 mg of at least one proton

60 119 EP 2 478 895 A2 120 pump inhibitor and at least about or less than about 10 least about or less than about 150 g, at least about or g, at least about or less than about 20 g, at least about less than about 160 g, at least about or less than about or less than about 30 g, at least about or less than about 170 g, at least about or less than about 180 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 190 g, at least about or less than or less than about 60 g, at least about or less than about 5 about 200 g, at least about or less than about 210 g, at 70 g, at least about or less than about 80 g, at least about least about or less than about 220 g, at least about or or less than about 90 g, at least about or less than about less than about 230 g, at least about or less than about 100 g, at least about or less than about 110 g, at least 240 g, at least about or less than about 250 g, at least about or less than about 120 g, at least about or less than about or less than about 260 g, at least about or less than about 130 g, at least about or less than about 140 g, at 10 about 270 g, at least about or less than about 280 g, at least about or less than about 150 g, at least about or least about or less than about 290 g, or at least about or less than about 160 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 170 g, at least about or less than about 180 g, at least In certain embodiments, the dosage unit comprises at about or less than about 190 g, at least about or less than least about or less than about 75 mg of at least one proton about 200 g, at least about or less than about 210 g, at 15 pump inhibitor and at least about or less than about 10 least about or less than about 220 g, at least about or g, at least about or less than about 20 g, at least about less than about 230 g, at least about or less than about or less than about 30 g, at least about or less than about 240 g, at least about or less than about 250 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 260 g, at least about or less than or less than about 60 g, at least about or less than about about 270 g, at least about or less than about 280 g, at 20 70 g, at least about or less than about 80 g, at least about least about or less than about 290 g, or at least about or or less than about 90 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 100 g, at least about or less than about 110 g, at least In certain embodiments, the dosage unit comprises at about or less than about 120 g, at least about or less than least about or less than about 65 mg of at least one proton about 130 g, at least about or less than about 140 g, at pump inhibitor and at least about or less than about 10 25 least about or less than about 150 g, at least about or g, at least about or less than about 20 g, at least about less than about 160 g, at least about or less than about or less than about 30 g, at least about or less than about 170 g, at least about or less than about 180 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 190 g, at least about or less than or less than about 60 g, at least about or less than about about 200 g, at least about or less than about 210 g, at 70 g, at least about or less than about 80 g, at least about 30 least about or less than about 220 g, at least about or or less than about 90 g, at least about or less than about less than about 230 g, at least about or less than about 100 g, at least about or less than about 110 g, at least 240 g, at least about or less than about 250 g, at least about or less than about 120 g, at least about or less than about or less than about 260 g, at least about or less than about 130 g, at least about or less than about 140 g, at about 270 g, at least about or less than about 280 g, at least about or less than about 150 g, at least about or 35 least about or less than about 290 g, or at least about or less than about 160 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 170 g, at least about or less than about 180 g, at least In certain embodiments, the dosage unit comprises at about or less than about 190 g, at least about or less than least about or less than about 80 mg of at least one proton about 200 g, at least about or less than about 210 g, at pump inhibitor and at least about or less than about 10 least about or less than about 220 g, at least about or 40 g, at least about or less than about 20 g, at least about less than about 230 g, at least about or less than about or less than about 30 g, at least about or less than about 240 g, at least about or less than about 250 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 260 g, at least about or less than or less than about 60 g, at least about or less than about about 270 g, at least about or less than about 280 g, at 70 g, at least about or less than about 80 g, at least about least about or less than about 290 g, or at least about or 45 or less than about 90 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 100 g, at least about or less than about 110 g, at least In certain embodiments, the dosage unit comprises at about or less than about 120 g, at least about or less than least about or less than about 70 mg of at least one proton about 130 g, at least about or less than about 140 g, at pump inhibitor and at least about or less than about 10 least about or less than about 150 g, at least about or g, at least about or less than about 20 g, at least about 50 less than about 160 g, at least about or less than about or less than about 30 g, at least about or less than about 170 g, at least about or less than about 180 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 190 g, at least about or less than or less than about 60 g, at least about or less than about about 200 g, at least about or less than about 210 g, at 70 g, at least about or less than about 80 g, at least about least about or less than about 220 g, at least about or or less than about 90 g, at least about or less than about 55 less than about 230 g, at least about or less than about 100 g, at least about or less than about 110 g, at least 240 g, at least about or less than about 250 g, at least about or less than about 120 g, at least about or less than about or less than about 260 g, at least about or less than about 130 g, at least about or less than about 140 g, at about 270 g, at least about or less than about 280 g, at

61 121 EP 2 478 895 A2 122 least about or less than about 290 g, or at least about or or less than about 90 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 100 g, at least about or less than about 110 g, at least In certain embodiments, the dosage unit comprises at about or less than about 120 g, at least about or less than least about or less than about 85 mg of at least one proton about 130 g, at least about or less than about 140 g, at pump inhibitor and at least about or less than about 10 5 least about or less than about 150 g, at least about or g, at least about or less than about 20 g, at least about less than about 160 g, at least about or less than about or less than about 30 g, at least about or less than about 170 g, at least about or less than about 180 g, at least 40 g, at least about or less than about 50 g, at least about about or less than about 190 g, at least about or less than or less than about 60 g, at least about or less than about about 200 g, at least about or less than about 210 g, at 70 g, at least about or less than about 80 g, at least about 10 least about or less than about 220 g, at least about or or less than about 90 g, at least about or less than about less than about 230 g, at least about or less than about 100 g, at least about or less than about 110 g, at least 240 g, at least about or less than about 250 g, at least about or less than about 120 g, at least about or less than about or less than about 260 g, at least about or less than about 130 g, at least about or less than about 140 g, at about 270 g, at least about or less than about 280 g, at least about or less than about 150 g, at least about or 15 least about or less than about 290 g, or at least about or less than about 160 g, at least about or less than about less than about 300 g of at least one bile acid sequestrant. 170 g, at least about or less than about 180 g, at least In certain embodiments, the dosage unit comprises at about or less than about 190 g, at least about or less than least about or less than about 100 mg of at least one about 200 g, at least about or less than about 210 g, at proton pump inhibitor and at least about or less than least about or less than about 220 g, at least about or 20 about 10 g, at least about or less than about 20 g, at least less than about 230 g, at least about or less than about about or less than about 30 g, at least about or less than 240 g, at least about or less than about 250 g, at least about 40 g, at least about or less than about 50 g, at least about or less than about 260 g, at least about or less than about or less than about 60 g, at least about or less than about 270 g, at least about or less than about 280 g, at about 70 g, at least about or less than about 80 g, at least least about or less than about 290 g, or at least about or 25 about or less than about 90 g, at least about or less than less than about 300 g of at least one bile acid sequestrant. about 100 g, at least about or less than about 110 g, at In certain embodiments, the dosage unit comprises at least about or less than about 120 g, at least about or least about or less than about 90 mg of at least one proton less than about 130 g, at least about or less than about pump inhibitor and at least about or less than about 10 140 g, at least about or less than about 150 g, at least g, at least about or less than about 20 g, at least about 30 about or less than about 160 g, at least about or less than or less than about 30 g, at least about or less than about about 170 g, at least about or less than about 180 g, at 40 g, at least about or less than about 50 g, at least about least about or less than about 190 g, at least about or or less than about 60 g, at least about or less than about less than about 200 g, at least about or less than about 70 g, at least about or less than about 80 g, at least about 210 g, at least about or less than about 220 g, at least or less than about 90 g, at least about or less than about 35 about or less than about 230 g, at least about or less than 100 g, at least about or less than about 110 g, at least about 240 g, at least about or less than about 250 g, at about or less than about 120 g, at least about or less than least about or less than about 260 g, at least about or about 130 g, at least about or less than about 140 g, at less than about 270 g, at least about or less than about least about or less than about 150 g, at least about or 280 g, at least about or less than about 290 g, or at least less than about 160 g, at least about or less than about 40 about or less than about 300 g of at least one bile acid 170 g, at least about or less than about 180 g, at least sequestrant. In certain embodiments the at least one pro- about or less than about 190 g, at least about or less than tonpump inhibitor is omeprazole. In certain embodiments about 200 g, at least about or less than about 210 g, at the at least one proton pump inhibitor is esomeprazole. least about or less than about 220 g, at least about or In certain embodiments the at least one proton pump less than about 230 g, at least about or less than about 45 inhibitor is lansoprazole. In certain embodiments the at 240 g, at least about or less than about 250 g, at least least one proton pump inhibitor is pantoprazole. In certain about or less than about 260 g, at least about or less than embodiments the at least one proton pump inhibitor is about 270 g, at least about or less than about 280 g, at rabeprazole. In certain embodiments the at least one pro- least about or less than about 290 g, or at least about or ton pump inhibitor is tenatoprazole. In certain embodi- less than about 300 g of at least one bile acid sequestrant. 50 ments the at least one bile acid sequestrant is cholesty- In certain embodiments, the dosage unit comprises at ramine. In certain embodiments the at least one bile acid least about or less than about 95 mg of at least one proton sequestrant is colesevelam. In certain embodiments the pump inhibitor and at least about or less than about 10 at least one bile acid sequestrant is colesevelam- HCl. In g, at least about or less than about 20 g, at least about certain embodiments the at least one bile acid seques- or less than about 30 g, at least about or less than about 55 trant is colestipol. In certain embodiments the at least 40 g, at least about or less than about 50 g, at least about one proton pump inhibitor is omeprazole and the at least or less than about 60 g, at least about or less than about one bile acid sequestrant is cholestyramine. In certain 70 g, at least about or less than about 80 g, at least about embodiments the at least one proton pump inhibitor is

62 123 EP 2 478 895 A2 124 omeprazole and the at least one bile acid sequestrant is dosage unit is administered with food at anytime of the colesevelam. In certain embodiments the at least one day, without food at anytime of the day, with food after proton pump inhibitor is omeprazole and the at least one an overnight fast (e.g. with breakfast), at bedtime after a bile acid sequestrant is colesevelam-HCl. In certain em- low fat snack. In various embodiments, the dosage unit bodiments the at least one proton pump inhibitor is ome- 5 is administered once a day, twice a day, three times a prazole and the at least one bile acid sequestrant is day, four times a day. The dosage unit can optionally colestipol. In certain embodiments the at least one proton comprise other agents such as at least one antacid, at pump inhibitor is esomeprazole and the at least one bile least one histamine H 2-receptor antagonist, or combina- acid sequestrant is cholestyramine. In certain embodi- tions thereof. ments the at least one proton pump inhibitor is esome- 10 prazole and the at least one bile acid sequestrant is cole- Kits sevelam. In certain embodiments the at least one proton pump inhibitor is esomeprazole and the at least one bile [0173] The compounds and pharmaceutical formula- acid sequestrant is colesevelam-HCl. In certain embod- tions described herein may be contained in a kit. The kit iments the at least one proton pump inhibitor is esome- 15 may include single or multiple doses of one or more prazole and the at least one bile acid sequestrant is agent, each packaged or formulated individually, or sin- colestipol. In certain embodiments the at least one proton gle or multiple doses of two or more agents packaged or pump inhibitor is lansoprazole and the at least one bile formulated in combination. Thus, one or more agents can acid sequestrant is cholestyramine. In certain embodi- be present in a first container, and the kit can optionally ments the at least one proton pump inhibitor is lansopra- 20 include one or more agents in a second container. The zole and the at least one bile acid sequestrant is cole- container or containers are placed within a package, and sevelam. In certain embodiments the at least one proton the package can optionally include administration or dos- pump inhibitor is lansoprazole and the at least one bile age instructions in the form of a label on the package or acid sequestrant is colesevelam-HCl. In certain embod- in the form of an insert included in the packaging of the iments the at least one proton pump inhibitor is lanso- 25 kit. A kit can include additional components such as sy- prazole and the at least one bile acid sequestrant is ringes or other means for administering the agents as colestipol. In certain embodiments the at least one proton well as diluents or other means for formulation. pump inhibitor is pantoprazole and the at least one bile [0174] Thus, the kits can comprise: a) a pharmaceuti- acid sequestrant is cholestyramine. In certain embodi- cal composition comprising at least one bile acid seques- ments the at least one proton pump inhibitor is pantopra- 30 trant and a pharmaceutically acceptable carrier, vehicle zole and the at least one bile acid sequestrant is cole- (e.g., a gastric- retention vehicle) or diluent; and b) a con- sevelam. In certain embodiments the at least one proton tainer or packaging. In another embodiment, the kit can pump inhibitor is pantoprazole and the at least one bile comprise: a) a pharmaceutical composition comprising acid sequestrant is colesevelam-HCl. In certain embod- at least on bile acid sequestrant, at least one proton pump iments the at least one proton pump inhibitor is panto- 35 inhibitor, and a pharmaceutically acceptable carrier, ve- prazole and the at least one bile acid sequestrant is hicle (e.g. a gastric-retention vehicle), or diluent; and b) colestipol. In certain embodiments the at least one proton a container or packaging. The kits may optionally com- pump inhibitor is rabeprazole and the at least one bile prise instructions describing a method of using the phar- acid sequestrant is cholestyramine. In certain embodi- maceutical compositions in one or more of the methods ments the at least one proton pump inhibitor is rabepra- 40 described herein (e.g., preventing or treating dyspepsia, zole and the at least one bile acid sequestrant is cole- heartburn, erosive esophagitis, GERD, peptic ulcer, es- sevelam. In certain embodiments the at least one proton ophagitis, Barrett’s esophagus, and esophageal adeno- pump inhibitor is rabeprazole and the at least one bile carcinoma). The kit may optionally comprise a second acid sequestrant is colesevelam-HCl. In certain embod- pharmaceutical composition comprising any of at least 45 iments the at least one proton pump inhibitor is rabepra- one antacid, at least one histamine H2-receptor antago- zole and the at least one bile acid sequestrant isnist, at least one GABA-B agonist, at least one prodrug colestipol. In certain embodiments the at least one proton of a GABA-B agonist, at least one protease inhibitor, or pump inhibitor is tenatoprazole and the at least one bile combinations thereof and a pharmaceutically acceptable acid sequestrant is cholestyramine. In certain embodi- carrier, vehicle or diluent. The pharmaceutical composi- ments the at least one proton pump inhibitor is tenato- 50 tion comprising the at least one bile acid sequestrant (or prazole and the at least one bile acid sequestrant is cole- the at least one bile acid sequestrant and at least one sevelam. In certain embodiments the at least one proton proton pump inhibitor), and the second pharmaceutical pump inhibitor is tenatoprazole and the at least one bile composition contained in the kit may be optionally com- acid sequestrant is colesevelam-HCl. In certain embod- bined in the same pharmaceutical composition. iments the at least one proton pump inhibitor is tenato- 55 [0175] A kit includes a container or packaging for con- prazole and the at least one bile acid sequestrant is taining the pharmaceutical compositions and may also colestipol. In certain embodiments the dosage unit and include divided containers such as a divided bottle or a daily dose are equivalent. In various embodiments, the divided foil packet. The container can be, for example a

63 125 EP 2 478 895 A2 126 paper or cardboard box, a glass or plastic bottle or jar, a one of ordinary skill in the art will be able to practice the re-sealable bag (for example, to hold a "refill" of tablets disclosure as claimed without undue experimentation. for placement into a different container), or a blister pack The foregoing will be better understood with reference with individual doses for pressing out of the pack accord- to the following Examples that detail certain procedures ing to a therapeutic schedule. It is feasible that more than 5 for the preparation of formulations according to the one container can be used together in a single package present disclosure. All references made to these Exam- to market a single dosage form. For example, tablets may ples are for the purposes of illustration. The following be contained in a bottle which is in turn contained within Examples should not be considered exhaustive, but a box. merely illustrative of only a few of the many embodiments [0176] An example of a kit is a so-called blister pack. 10 contemplated by the present disclosure. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharma- Examples ceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of rela- [0179] Example 1. Effects of bile acid sequestrant tively stiff material covered with a foil of a preferably trans- 15 alone and in combination, on esophageal epithelial cells. parent plastic material. During the packaging process, Epithelial cells are isolated from normal human esopha- recesses are formed in the plastic foil. The recesses have gus and Barrett’s esophagus samples (e.g. biopsies) and the size and shape of individual tablets or capsules to be established in monolayer cell cultures as described in packed or may have the size and shape to accommodate Burg-Kurland et al. (1986) Methods in Cell Science 10: multiple tablets and/or capsules to be packed. Next, the 20 227-232 or cultured as described in Trier, J.S. (1980) tablets or capsules are placed in the recesses accord- Methods Cell Biol. 18:365-384. Barrett’s Esophagus is ingly and the sheet of relatively stiff material is sealed induced or exacerbated by the addition of bile acid(s), against the plastic foil at the face of the foil which is op- stomach acid(s), and/or other acids or acidified media posite from the direction in which the recesses were (for example as in Fitzgerald et al. (1996) J Clin Invest formed. As a result, the tablets or capsules are individu- 25 98:2120-8). Acid exposure is continuous or as a timed ally sealed or collectively sealed, as desired, in the re- pulse (e.g. 1 hour). Test article (e.g. vehicle alone, proton cesses between the plastic foil and the sheet. Preferably pump inhibitor, bile acid sequestrant, proton pump inhib- the strength of the sheet is such that the tablets or cap- itor and bile acid sequestrant) at various doses (for ex- sules can be removed from the blister pack by manually ample, as described in the present application) is added applying pressure on the recesses whereby an opening 30 either before, simultaneously with, or after acid addition. is formed in the sheet at the place of the recess. The Barrett’s Esophagus development is monitored visually tablet or capsule can then be removed via said opening. by microscope by the transformation of squamous cells [0177] It maybe desirable to provide a written memory to columnar cells. Cell proliferation is determined by tri- aid containing information and/or instructions for the phy- tiated thymidine incorporation and proliferating cell nu- sician, pharmacist or subject regarding when the medi- 35 clear antigen expression. Cell differentiation is deter- cation is to be taken. A "daily dose" can be a single tablet mined by villin expression (see Fitzgerald et al. supra). or capsule or several tablets or capsules to be taken on [0180] Example 2: Effects of bile acid sequestrant, a given day. When the kit contains separate composi- alone and in combination, on in vivo model of Barrett’s tions, a daily dose of one or more compositions of the kit Esophagus. Test article (e.g. vehicle alone, proton pump can consist of one tablet or capsule while a daily dose of 40 inhibitor, bile acid sequestrant, proton pump inhibitor and another one or more compositions of the kit can consist bile acid sequestrant) at various doses (for example, as of several tablets or capsules. A kit can take the form of described in the present application) is evaluated for ef- a dispenser designed to dispense the daily doses one at fectson 2 different rodentmodels of Barrett’s Esophagus, a time in the order of their intended use. The dispenser for example as described in Buskens et al. (2006) J Surg can be equipped with a memory-aid, so as to further fa- 45 Res. 135:337-44. cilitate compliance with the regimen. An example of such [0181] Although the foregoing disclosure has been de- a memory-aid is a mechanical counter which indicates scribed and depicted in terms of certain preferred em- the number of daily doses that have been dispensed. bodiments, other specific embodiments may be effected Another example of such a memory- aid is a battery-pow- by those skilled in the art to accomplish the same objec- ered micro-chip memory coupled with a liquid crystal re- 50 tives and without departing from the true spirit of the adout, or audible reminder signal which, for example, scope of the present disclosure. Accordingly, the scope reads out the date that the last daily dose has been taken of the Applicant’s disclosure is to be determined by ref- and/or reminds one when the next dose is to be taken. erence to the attached claims, which are not limited to [0178] Various patent and/or scientific literature refer- any of the particular embodiments disclosed herein. ences have been referred to throughout this application. 55 The disclosures of these publications in their entireties In summary, the invention relates to: are hereby incorporated by reference as if written herein. In view of the above description and the examples below, [0182]

64 127 EP 2 478 895 A2 128

[1]. A composition for treating or preventing an upper wherein the at least one proton pump inhibitor is pan- GI tract disorder comprising a therapeutically effec- toprazole. tive amount of at least one bile acid sequestrant. [15]. A composition according to the above [10], [2]. A composition according to the above [1] further 5 wherein the at least one proton pump inhibitor is rab- comprising a pharmaceutically acceptable excipient, eprazole. diluent, or carrier. [16]. A composition according to the above [10], [3]. A composition according to the above [1] or [2], wherein the at least one proton pump inhibitor is tan- wherein the at least one bile acid sequestrant is cho- 10 atoprazole. sen from one or more of cholestyramine, coleseve- lam, colesevelam hydrochloride, ursodeoxycholic [17]. A composition according to the above [10], acid, colestipol, sevelamer, dialkylaminoalkyl deriv- wherein the at least one proton pump inhibitor is lem- atives of a cross-linked dextran, and N-(cycloalkyl) inoprazole. alkylamines. 15 [18]. A composition according to the above [10], [4]. A composition according to the above [3], where- wherein the at least one proton pump inhibitor is don- in the at least one bile acid sequestrant is cholesty- toprazole. ramine. 20 [19]. A composition according to the above [10], [5]. A composition according to the above [3], where- wherein the at least one proton pump inhibitor is ran- in the at least one bile acid sequestrant is coleseve- soprazole. lam [20]. A composition according to any of the above [6]. A composition according to the above [3], where- 25 [1] -[19] further comprising a therapeuticallyeffective in the at least one bile acid sequestrant is coleseve- amount of at least one agent chosen from an antacid, lam hydrochloride a histamine H 2-receptor antagonist, a γ-aminobutyr- icacid-b (GABA-B) agonist, a prodrug of a GABA-B [7]. A composition according to the above [3], where- agonist, and a protease inhibitor optionally formulat- in the at least one bile acid sequestrant is colestipol 30 ed in combination with the at least one bile acid se- questrant. [8]. A composition according to the above [ [3], wherein the at least one bile acid sequestrant is seve- [21]. A composition according to the above [20], lamer wherein the at least one agent is an antacid. 35 [9]. A composition according to any of the above [1] [22]. A composition according to the above [21], to [9] further comprising a therapeutically effective wherein the antacid is chosen from one or more of amount of at least one proton pump inhibitor. calcium carbonate, magnesium carbonate, calcium hydroxide, , and aluminum hy- [10]. A composition according to the above [9],40 droxide. wherein the at least one proton pump inhibitor is cho- sen from omeprazole, esomeprazole, lansoprazole, [23]. A composition according to the above [20], pantoprazole, rabeprazole, tenatoprazole, lemino- wherein the at least one agent is a histamine H 2-re- prazole, dontoprazole, and ransoprazole. ceptor antagonist. 45 [11]. A composition according to the above [10], [24]. A composition according to the above [23], wherein the at least one proton pump inhibitor is wherein the histamine H 2-receptor antagonist is cho- omeprazole. sen from one or more of cimetidine, famotidine, ni- zatidine, and ranitidine. [12]. A composition according to the above [10],50 wherein the at least one proton pump inhibitor is es- [25]. A composition according to the above [20], omeprazole. wherein the at least one agent is a GABA- B agonist.

[13]. A composition according to the above [10], [26]. A composition according to the above [25], wherein the at least one proton pump inhibitor is lan- 55 wherein the GABA-B agonist is R-baclofen. soprazole. [27]. A composition according to the above [20] [14]. A composition according to the above [10], wherein the at least one agent is a GABA-B agonist

65 129 EP 2 478 895 A2 130 prodrug. dosage form in the person’s stomach for a period of 24 hours or more. [28]. A composition according to the above [27], wherein the GABA-B agonist prodrug is XP 19986. [39]. A sustained-release pharmaceutical dosage 5 form according to the above [35], wherein the gastric [29]. A composition according to the above [20], retention vehicle composition further comprises at wherein the agent is a protease inhibitor chosen from least one binder and at least one gas-generating aspartyl protease inhibitors, chymostrypsin inhibi- agent. tors, and trypsin inhibitors. 10 [40]. A sustained-release pharmaceutical dosage [30]. A composition according to the above [29], form according to the above [39], wherein the binder wherein the aspartyl protease inhibitor is a pepstatin is chosen from one or more of poloxamers, polyeth- inhibitor. ylene glycols, polyethylene glycol fatty acid esters, glyceryl palmitostearate, polyoxyethylene alkyl [31]. A composition according to the above [29],15 ethers, glyceryl behenate, stearoyl macrogol-32- wherein the aspartyl protease inhibitor is a pepsin glyceride, polyoxyethylene castor oil derivatives, inhibitor. polyoxyethylene sorbitan fatty acid derivatives, poly- oxyethylene stearates, polyoxyethylene-polyoxy- [32]. A composition according to the above [29], propylene copolymers, starches, gelatin, sugars wherein the protease inhibitor is a chymotrypsin in- 20 such as lactose, sucrose, glucose and molasses, hibitor. natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, methylcellulose, [33]. A composition according to the above [29], polyvinylpyrrolidone, ethyl cellulose and waxes. wherein the protease inhibitor is a trypsin inhibitor. 25 [41]. A sustained-release pharmaceutical dosage [34]. A composition according to any of the above form according to the above [39], wherein the gas- [1] to [33], wherein the upper GI tract disorder is cho- generating agent is chosen from one or more of so- sen from dyspepsia, heartburn, erosive esophagitis, dium hydrogen carbonate, sodium carbonate, potas- GERD, peptic ulcer, esophagitis, Barrett’s esopha- sium carbonate,calcium carbonate,magnesium car- gus, esophageal adenocarcinoma, pharyngitis, and 30 bonate, and sodium glycine carbonate. GERD-related pulmonary dysfunctions. [42]. A sustained-release pharmaceutical dosage [35]. A sustained-release pharmaceutical dosage form according to the above [35], wherein the gastric form for oral administration to a subject in need there- retention vehicle composition further comprises a of comprising a composition according to any of the 35 superdisintegrant. above [1]-[33] and a gastric-retention vehicle com- position comprising one or more hydrogels, wherein [43]. A sustained-release pharmaceutical dosage the dosage form expands upon contact with gastric form according to the above [42], wherein the super- fluid. disintegrant is chosen from one or more of crospovi- 40 done, croscarmellose sodium, and sodium starch [36]. A sustained-release pharmaceutical dosage glycolate. form according to the above [35], wherein after in- gestion by a person in need thereof the gastric re- [44]. A sustained-release pharmaceutical dosage tention vehicle composition expands to retain the form according to the above [35], wherein the hydro- dosage form in the person’s stomach for a period of 45 gel is chosen from one or more of hydroxypropyl three hours or more. methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, agar, agarose, locust bean [37]. A sustained-release pharmaceutical dosage gum, carageenan, alginic acid, konjac gum, guar form according to the above [35], wherein after in- gum, and xanthan gum. gestion by a person in need thereof the gastric re- 50 tention vehicle composition expands to retain the [45]. A sustained-release pharmaceutical dosage dosage form in the person’s stomach for a period of form according to any of the above [35]-[44], wherein 8 hours or more. the percentage of active ingredient(s) is present in an amount from between 10% to about 75% of the [38]. A sustained-release pharmaceutical dosage 55 total weight. form according to the above [35], wherein after in- gestion by a person in need thereof the gastric re- [46]. A sustained-release pharmaceutical dosage tention vehicle composition expands to retain the form according to the above [45], wherein the per-

66 131 EP 2 478 895 A2 132 centage of active ingredient(s) is 15% of the total above [57], wherein the therapeutically effective weight. amount of at least one proton pump inhibitor is in a range from 10 mg to 120 mg. [47]. A sustained-release pharmaceutical dosage form according to the above [45], wherein the per- 5 [60]. A pharmaceutical dosage form according to the centage of active ingredient(s) is 40% of the total above [57], wherein the therapeutically effective weight. amount of at least one proton pump inhibitor is in a range from 20 mg to 100 mg. [48]. A pharmaceutical dosage form according to any of the above [1]-[33] or according to any of the above 10 [61]. A pharmaceutical dosage form according to the [35]-[47], wherein the therapeutically effective above [57], wherein the therapeutically effective amount of bile acid sequestrant is in a range from amount of at least one proton pump inhibitor is in a 0.01 g to 300 g. range from 40 mg to 100 mg.

[49]. A pharmaceutical dosage form according to the 15 [62]. A pharmaceutical dosage form according to the above [48], the therapeutically effective amount of above [57], wherein the therapeutically effective bile acid sequestrant is in a range from 1 g to 30 g. amount of at least one proton pump inhibitor is in a range from 5 mg to 80 mg. [50]. A pharmaceutical dosage form according to the above [48], the therapeutically effective amount of 20 [63]. A pharmaceutical dosage form according to the bile acid sequestrant is in a range from 0.2 g to 6 g. above [57], wherein the therapeutically effective amount of at least one proton pump inhibitor is in a [51]. A pharmaceutical dosage form according to the range from 10 mg to 40 mg. above [48], the therapeutically effective amount of bile acid sequestrant is in a range from 0.1 g to 3 g. 25 [64]. A pharmaceutical dosage form according to the above [57], wherein the therapeutically effective [52]. A pharmaceutical dosage form according to the amount of at least one proton pump inhibitor is in a above [48], the therapeutically effective amount of range from 10 mg to 60 mg. bile acid sequestrant is in a range from 0.02 g to 0.6 g. 30 [65]. A method for preventing or treating an upper [53]. A pharmaceutical dosage form according to the gastrointestinal (GI) tract disorder, the method com- above [48], the therapeutically effective amount of prising administering to a patient in need thereof a bile acid sequestrant is in a range from 0.01 g to 0.3 g. therapeutically effective amount of a composition ac- cording to any of the above [1]-[33] or a pharmaceu- [54]. A pharmaceutical dosage form according to the 35 tical dosage form according to any of the above above [48], the therapeutically effective amount of [35]-[64]. bile acid sequestrant is in a range from 2 g to 60 g. [66]. A method for preventing or treating an upper [55]. A pharmaceutical dosage form according to the gastrointestinal (GI) tract disorder, the method com- above [48], the therapeutically effective amount of 40 prising administering to a patient in need thereof a bile acid sequestrant is in a range from 5 g to 150 g. therapeutically effective amount of a composition ac- cording to the above [1]. [56]. A pharmaceutical dosage form according to the above [48], the therapeutically effective amount of [67]. A method according to the above [66], wherein bile acid sequestrant is in a range from 10 g to 300 g. 45 the at least one bile acid sequestrant is chosen from one or more of cholestyramine, colesevelam, cole- [57]. A pharmaceutical dosage form according to any sevelam hydrochloride, ursodeoxycholic acid, of the above [9]-[33] or according to any of the above colestipol, sevelamer, dialkylaminoalkyl derivatives [s 35-56, wherein the therapeutically effective of a cross-linked dextran, and N-(cycloalkyl) amount of at least one proton pump inhibitor is in a 50 alkylamines. range from 1 mg to 200 mg. [68]. A method according to the above [67], wherein [58]. A pharmaceutical dosage form according to the the at least one bile acid sequestrant is cholesty- above [57], wherein the therapeutically effective ramine. amount of at least one proton pump inhibitor is in a 55 range from 5 mg to 100 mg. [69]. A method according to the above [67], wherein the at least one bile acid sequestrant is colesevelam. [59]. A pharmaceutical dosage form according to the

67 133 EP 2 478 895 A2 134

[70]. A method according to the above [67], wherein effective amount of at least one agent chosen from the at least one bile acid sequestrant is colesevelam an antacid, a histamine H 2-receptor antagonist, a γ- hydrochloride. aminobutyricacid-b (GABA-B) agonist, a prodrug of a GABA-B agonist, and a protease inhibitor option- [71]. A method according to the above [67], wherein 5 ally formulated in combination with the at least one the at least one bile acid sequestrant is colestipol. bile acid sequestrant.

[72]. A method according to the above [67], wherein [85]. A method according to the above [84], wherein the at least one bile acid sequestrant is sevelamer. the at least one agent is an antacid. 10 [73]. A method according to any of the above [86]. A method according to the above [85], wherein [66]-[72] further comprising administering simultane- the antacid is chosen from one or more of calcium ously, separately, or sequentially at least one proton carbonate, magnesium carbonate, calcium hydrox- pump inhibitor. ide, magnesium hydroxide, and aluminum hydrox- 15 ide. [74]. A method according to the above [73] wherein the at least one proton pump inhibitor is chosen from [87]. A method according to the above [84], wherein one or more of omeprazole, esomeprazole, lanso- the at least one agent is a histamine 2 H-receptor prazole, pantoprazole, rabeprazole, tenatoprazole, antagonist. leminoprazole, dontoprazole, and ransoprazole. 20 [88]. A method according to the above [ 87, wherein [75]. A method according to the above [74] wherein the histamine H 2-receptor antagonist is chosen from the at least one proton pump inhibitor is omeprazole. one or more of cimetidine, famotidine, nizatidine, and ranitidine. [76]. A method according to the above [74] wherein 25 the at least one proton pump inhibitor is esomepra- [89]. A method according to the above [84], wherein zole. the at least one agent is a GABA-B agonist.

[77]. A method according to the above [74] wherein [90]. A method according to the above [89], wherein the at least one proton pump inhibitor is lansopra- 30 the GABA-B agonist is R-baclofen. zole. [91]. A method according to the above [84], wherein [78]. A method according to the above [74] wherein the at least one agent is a GABA-B agonist prodrug. the at least one proton pump inhibitor is pantopra- zole. 35 [92]. A method according to the above [91], wherein the GABA-B agonist prodrug is XP19986. [79]. A method according to the above [74] wherein the at least one proton pump inhibitor is rabeprazole. [93]. A method according to the above [84], wherein the agent is a protease inhibitor chosen from aspartyl [80]. A method according to the above [74] wherein 40 protease inhibitors, chymostrypsin inhibitors, and the at least one proton pump inhibitor is tanatopra- trypsin inhibitors. zole. [94]. A method according to the above [93], wherein [81]. A method according to the above [74] wherein the aspartyl protease inhibitor is a pepstatin inhibitor. the at least one proton pump inhibitor is leminopra- 45 zole. [95]. A method according to the above [93], wherein the aspartyl protease inhibitor is a pepsin inhibitor. [82]. A method according to the above [74] wherein the at least one proton pump inhibitor is dontopra- [96]. A method according to the above [93], wherein zole. 50 the protease inhibitor is a chymotrypsin inhibitor.

[83]. A method according to the above [74] wherein [97]. A method according to the above [93], wherein the at least one proton pump inhibitor is ransopra- the protease inhibitor is a trypsin inhibitor. zole. 55 [98]. A method according to any of the above [84]. A method according to any of the above [65]-[97] wherein the upper gastrointestinal tract dis- [66]-[83] further comprising administering simultane- order is selected from the group consisting of dys- ously, separately, or sequentially a therapeutically pepsia, heartburn, erosive esophagitis, GERD, pep-

68 135 EP 2 478 895 A2 136

tic ulcer, esophagitis, Barrett’s esophagus, esopha- 2. A composition according to claim 1 further compris- geal adenocarcinoma, pharyngitis, and GERD- relat- ing a pharmaceutically acceptable excipient, diluent, ed pulmonary dysfunctions. or carrier.

[99]. A method according to the above [98], wherein 5 3. A composition according to claim 1 or 2, wherein the the upper GI tract disorder is GERD at least one bile acid sequestrant is chosen from one or more of cholestyramine, colesevelam, coleseve- [100]. A method according to the above [99], wherein lam hydrochloride, ursodeoxycholic acid, colestipol, the GERD is non-responsive GERD sevelamer, dialkylaminoalkyl derivatives of a cross- 10 linked dextran, and N-(cycloalkyl)alkylamines. [101]. A method according to the above [98], wherein the upper GI tract disorder is a peptic ulcer. 4. A composition according to claim 1, wherein the GABA-B agonist is R-baclofen. [102]. A method according to the above [101], where- in the peptic ulcer is an esophageal ulcer. 15 5. A composition according to claim 1, wherein the GABA-B agonist prodrug is XP19986. [103]. A method according to the above [98], wherein the upper GI tract disorder is Barrett’s esophagus. 6. A sustained-release pharmaceutical dosage form for oral administration to a subject in need thereof com- [104]. A method according to the above [98], wherein 20 prising a composition according to any of claims 1-5 the upper GI tract disorder is esophageal adenocar- and a gastric- retention vehicle composition compris- cinoma. ing one or more hydrogels, wherein the dosage form expands upon contact with gastric fluid. [105]. A method according to the above [98], wherein the upper GI tract disorder is pharyngitis. 25 7. A sustained-release pharmaceutical dosage form according to claim 6, wherein after ingestion by a [106]. A method according to the above [98], wherein person in need thereof the gastric retention vehicle the upper GI tract disorder is a GERD-related pul- composition expands to retain the dosage form in monary dysfunction chosen from asthma and cough. the person’s stomach for a period of three hours or 30 more. [107]. A method for protecting stratified squamous epithelium against injury by a noxious substance 8. A sustained-release pharmaceutical dosage form comprising administering to a patient in need thereof according to claim 6, wherein the gastric retention a therapeutically effective amount of a composition vehicle composition further comprises at least one according to any of the above [1]-[33] or a pharma- 35 binder and at least one gas-generating agent. ceutical dosage form according to any of the above [35]-[64]. 9. A sustained-release pharmaceutical dosage form according to claim 6, wherein the gastric retention [108]. A kit for treating an upper GI tract disorder vehicle composition further comprises a superdisin- comprising, in one or more containers, a therapeu- 40 tegrant. tically effective amount of the a composition accord- ing to any of the above [1]-[33] or a pharmaceutical 10. A sustained-release pharmaceutical dosage form dosage form according to any of the above [35]-[64], according to claim 6, wherein the hydrogel is chosen and a label or packaging insert containing instruc- from one or more of hydroxypropyl methylcellulose, tions for use. 45 hydroxypropylcellulose, sodium carboxymethylcel- lulose,agar, agarose, locust bean gum, carageenan, alginic acid, konjac gum, guar gum, and xanthan Claims gum.

1. A composition for treating or preventing an upper GI 50 11. A composition according to any one of claims 1-5 or tract disorder comprising a therapeutically effective a sustained-release dosage form according to any amount of at least one bile acid sequestrant and fur- one of claims 6-10 for use in preventing or treating ther comprising a therapeutically effective amount an upper gastrointestinal (GI) tract disorder. of at least one agent chosen from a γ-aminobutyri- cacid-b (GABA-B) agonist and a prodrug of a GABA- 55 12. Use of a composition according to any one of claims B agonist, optionally formulated in combination with 1-5 or a sustained-release dosage form according the at least one bile acid sequestrant. to any one of claims 6-10 in the preparation of a medicament for preventing or treating an upper gas-

69 137 EP 2 478 895 A2 138

trointestinal (GI) tract disorder.

13. A composition for use or a sustained-release dosage form according to claim 11 or a use according to claim 12, wherein the GABA-B agonist or a prodrug 5 of a GABA-B agonist is administered simultaneous- ly, separately, or sequentially.

14. A composition for use or a sustained-release dosage form according to claim 11 or a use according to10 claim 12, wherein the upper gastrointestinal tract dis- order is selected from the group consisting of dys- pepsia, heartburn, erosive esophagitis, GERD, pep- tic ulcer, esophagitis, Barrett’s esophagus, esopha- geal adenocarcinoma, pharyngitis, and GERD- relat- 15 ed pulmonary dysfunctions.

15. A kit for treating an upper GI tract disorder compris- ing, in one or more containers, a therapeutically ef- fective amount of the a composition according to any 20 of claims 1-5, or a pharmaceutical dosage form ac- cording to any of claims 6-10, and a label or pack- aging insert containing instructions for use.

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This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

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