US 2005O249806A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0249806A1 Proehl et al. (43) Pub. Date: Nov. 10, 2005

(54) COMBINATION OF PROTON PUMP Related U.S. Application Data INHIBITOR, BUFFERING AGENT, AND NONSTEROIDAL ANTI-NFLAMMATORY (60) Provisional application No. 60/543,636, filed on Feb. DRUG 10, 2004. (75) Inventors: Gerald T. Proehl, San Diego, CA (US); Publication Classification Kay Olmstead, San Diego, CA (US); Warren Hall, Del Mar, CA (US) (51) Int. Cl." ...... A61K 9/48; A61K 31/4439; A61K 9/20 Correspondence Address: (52) U.S. Cl...... 424/464; 514/338 WILSON SONS IN GOODRICH & ROSAT (57) ABSTRACT 650 PAGE MILL ROAD Pharmaceutical compositions comprising a proton pump PALO ALTO, CA 94304-1050 (US) inhibitor, one or more buffering agent and a nonsteroidal ASSignee: Santarus, Inc. anti-inflammatory drug are described. Methods are (73) described for treating gastric acid related disorders and Appl. No.: 11/051,260 treating inflammatory disorders, using pharmaceutical com (21) positions comprising a proton pump inhibitor, a buffering (22) Filed: Feb. 4, 2005 agent, and a nonsteroidal anti-inflammatory drug. US 2005/0249806 A1 Nov. 10, 2005

COMBINATION OF PROTON PUMP INHIBITOR, of the Stomach by raising the Stomach pH. See, e.g., U.S. BUFFERING AGENT, AND NONSTEROIDAL Pat. Nos. 5,840,737; 6,489,346; and 6,645,998. ANTI-NFLAMMATORY DRUG 0007 Proton pump inhibitors are typically prescribed for Short-term treatment of active duodenal ulcers, gastrointes CROSS REFERENCE TO RELATED tinal ulcers, gastroesophageal reflux disease (GERD), Severe APPLICATIONS erosive esophagitis, poorly responsive Symptomatic GERD, 0001. This application claims priority to U.S. Provisional and pathological hyperSecretory conditions Such as Application No. 60/543,636 filed Feb. 10, 2004, which is Zollinger Ellison syndrome. These above-listed conditions incorporated herein by reference in its entirety. commonly arise in healthy or critically ill patients of all ages, and may be accompanied by Significant upper gas FIELD OF THE INVENTION trointestinal bleeding. 0002 The present invention is related to pharmaceutical 0008. It is believed that omeprazole, lansoprazole and compositions comprising a proton pump inhibitor, a buffer other proton pump inhibiting agents reduce gastrointestinal ing agent, and a nonsteroidal anti-inflammatory drug. acid production by inhibiting H/K"-ATPase of the parietal cell, which is the final common pathway for gastrointestinal 0.003 Methods for manufacture of the pharmaceutical acid Secretion. See, e.g., Fellenius et al., Substituted Benz compositions and use of the pharmaceutical compositions in imidazoles Inhibit Gastrointestinal Acid Secretion by Block treating disease are disclosed. ing H/K"-ATPase, Nature, 290: 159-161 (1981); Wallmark et al., The Relationship Between Gastrointestinal Acid BACKGROUND OF THE INVENTION Secretion and Gastrointestinal H"/K"-ATPase Activity, J. Biol. Chem., 260: 13681-13684 (1985); and Fryklund et al., 0004 Proton Pump Inhibitors Function and Structure of Parietal Cells. After H/K-AT 0005 Proton pump inhibitors (PPIs) are a class of acid Pase Blockade, Am. J. Physiol., 254 (1988). labile pharmaceutical compounds that block gastric acid Secretion pathways. Exemplary proton pump inhibitors 0009 Proton pump inhibitors have the ability to act as include, omeprazole (Prilosec(R), lansoprazole (Prevacid(R), weak bases which reach parietal cells from the blood and esomeprazole (Nexium(R), rabeprazole (Aciphex(E), panto diffuse into the Secretory canaliculi. There the drugs become prazole (Protonix(R), pariprazole, tenatoprazole, and lemi protonated and thereby trapped. The protonated compound noprazole. The drugs of this class SuppreSS gastrointestinal can then rearrange to form a Sulfenamide which can acid secretion by the specific inhibition of the H/K"- covalently interact with Sulfhydryl groups at critical Sites in ATPase enzyme System (proton pump) at the Secretory the extra cellular (luminal) domain of the membrane-Span Surface of the gastrointestinal parietal cell. Most proton ning H/K-ATPase. See, e.g., Hardman et al., Goodman & pump inhibitors are Susceptible to acid degradation and, as Gilman 's The Pharmacological Basis of Therapeutics, 907 Such, are rapidly destroyed in an acidic pH environment in (9th ed. 1996). As such, proton pump inhibitors are prodrugs the Stomach. Therefore, proton pump inhibitors are often that must be activated within parietal cells to be effective. administered as enteric-coated dosage forms in order to The Specificity of the effects of proton pump inhibiting permit release of the drug in the duodenum after having agents is also dependent upon: (a) the Selective distribution passed through the Stomach. If the enteric-coating of these of H"/K"-ATPase; (b) the requirement for acidic conditions formulated products is disrupted (e.g., during trituration to to catalyze generation of the reactive inhibitor; and (c) the compound a liquid dosage form, or by chewing an enteri trapping of the protonated drug and the cationic Sulfenamide coated granular capsule or tablet), or if a co-administered within the acidic canaliculi and adjacent to the target buffering agent fails to Sufficiently neutralize the gastrointes enzyme. tinal pH, the uncoated drug is exposed to Stomach acid and 0010 Nonsteroidal Anti-Inflammatory Drugs may be degraded. 0011 Nonsteroidal anti-inflammatory drugs (“NSAIDs”) 0006. Omeprazole, a substituted bicyclic aryl-imidazole, are among the most commonly prescribed and used drugs 5-methoxy-2-(4-methoxy-3, 5-dimethyl-2-pyridinyl) world-wide. The ability of NSAIDs to treat inflammatory methylsulfinyl)-1H-benzimidazole, is a proton pump disorders is attributed to their ability to inhibit cyclooxyge inhibitor that inhibits gastrointestinal acid secretion. U.S. nase, the enzyme responsible for biosyntheses of the pros Pat. No. 4,786,505 to Lovgren et al. teaches that a pharma ceutical oral Solid dosage form of omeprazole must be taglandins and certain autocoid inhibitors, including inhibi protected from contact with acidic gastrointestinal juice by tors of lipoxygenase and cyclooxygenase (Such as an enteric-coating to maintain its pharmaceutical activity cyclooxygenase-I and cyclooxygenase-II). and describes an enteric-coated omeprazole preparation con 0012 However, despite the therapeutic benefits of taining one or more Subcoats between the core material and NSAIDs, their use is often limited by an increased risk of the enteric-coating. Non-enteric coated pharmaceutical gastrointestinal Side-effects, in particular upper gastrointes compositions have also been described, which facilitate tinal Side-effects Such as peptic ulceration and dyspeptic immediate release of the pharmaceutically active ingredient Symptoms. For example, Studies have indicated that during into the Stomach and permit Stomach uptake of pharmaceu NSAID treatment, the relative risk of developing a gastric tical agents. Use of non-enteric coated compositions ulcer is increased by a factor of 40-50, the relative risk of involves the administration of one or more buffering agents developing a duodenal ulcer is increased by a factor of 8-10, with an acid labile proton pump inhibitor. The buffering and the relative risk of developing an ulcer complication like agent is thought to prevent Substantial degradation of the bleeding or perforation of the Stomach is increased by a acid labile pharmaceutical agent in the acidic environment factor of 1.5-5. See, e.g., McCarty DSM., Gastroenterology US 2005/0249806 A1 Nov. 10, 2005

1989, 96:662; and Hawkey C., BMJ 1990; 300:278. Fur acid degradation of at least Some of the proton pump thermore, dyspeptic Symptoms are experienced in 30-60% inhibitor in the gastric fluid, and (c) a therapeutically effec of patients on NSAID treatment. See Larkai E. N., Am. J. tive amount of at least one nonsteroidal anti-inflammatory Gas. 1987; 82:1153. Additionally, NSAIDs are typically the drug, are provided herein. Methods are provided for treating prescribed treatment for chronic diseases like rheumatoid gastric acid related disorders and treating inflammatory arthritis and Osteoarthritis, Seen most often in the elderly disorders in a Subject, using pharmaceutical compositions of population. Compliance is especially important in elderly the present invention. Methods are also provided for pre and fragile patients, who have the highest risk of developing venting gastric acid related disorders during long-term a life-threatening complication of NSAID treatment, for administration of NSAID in a subject for the purpose of example bleeding or perforation. It has been reported that reducing the risk of heart attack or certain types of cancers 50% of all peptic ulcer deaths occur in NSAID users, and by administering the Subject pharmaceutical compositions that 68% of these deaths are in patients above the age of 75. of the present invention. See Catford Health Trends 1986, 18:38; and Guess, J. Clin. 0017 Proton pump inhibitors include, but are not limited Epidemiol., 1988, 41:35. to, omeprazole, hydroxyomeprazole, esomeprazole, tenato 0013 Attempts have been undertaken to modify the prazole, lanSoprazole, pantoprazole, rabeprazole, dontopra structure of NSAIDs in order to prevent undesired side Zole, habeprazole, periprazole, ranSoprazole, pariprazole, effects. The new family of NSAIDs which selectively inhibit leminoprazole; or a free base, free acid, Salt, hydrate, ester, only cyclooxygenase-II (“COX-II inhibitors”) represent one amide, enantiomer, isomer, tautomer, polymorph, or prodrug such advance. Although COX-II inhibitors are believed to thereof. In one embodiment, the proton pump inhibitor is cause leSS Stomach irritation than the older non-Selective omeprazole or a free base, free acid, Salt, hydrate, ester, NSAIDs, they still have the potential to cause irritation, amide, enantiomer, isomer, tautomer, polymorph, or prodrug ulceration, bleeding and perforation of the lining of the thereof. Compositions can contain between about 5 mgs to Stomach. about 200 mgs of proton pump inhibitor, Specifically about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, 0.014 Furthermore, there is emerging evidence of a pro about 40 mg, about 60 mg, or about 80 mg of the proton tective association between aspirin/NSAIDs and various pump inhibitor. In alternative embodiments, compositions cancer types Such as esophageal cancer, lung cancer, col can contain between about 250-3000 mg of proton pump Orectal cancer, breast cancer, and prostate cancer. See, e.g., inhibitor. Randall E. Harris et al., Inverse Association of Breast 0018 Nonsteroidal anti-inflammatory drugs include, but Cancer and NSAIDs. Results from the Women's Health are not limited to aminoarylcarboxylic acid derivatives Such Initiative (WH), AACR, Volume 44 (March 2003); Gonza as enfenamic acid, etofenamate, flufenamic acid, isonixin, lez-Perez A; Effects of Non-Steroidal Anti-Inflammatory meclofenamic acid, mefenamic acid, niflumic acid, talniflu Drugs on Cancer Sites Other than the Colon and Rectum: a mate, terofenamate, and tolfenamic acid, arylacetic acid Meta-Analysis, BMC Cancer 3(1):28 (2003); D A Corley et derivatives Such as aceclofenac, acemetacin, alclofenac, al., Protective Association of Aspirin/NSAIDs and Esoph amfenac, amtolimetin guacil, bromfenac, bufeXamac, cin ageal Cancer. A Systematic Review and Meta-Analysis, metacin, clopirac, diclofenac Sodium, etodolac, felbinac, Gastroenterology 2003 124:47-56; Khuder et al., Breast fenclozic acid, fentiazac, glucametacin, ibufenac, Cancer and NSAID Use: A Meta Analysis, British Journal of indomethacin, isofeZolac isoxepac, lonazolac, metiazinic Cancer (2001) 84, 1188-1192. It is believed that COX-II acid, mofeZolac, oxametacine, piraZolac, proglumetacin, may be important in certain types of cancer pathogenesis Sulindac, tiaramide, tolmetin, tropesin, and Zomepirac, aryl and animal Studies Suggest that long-term use of NSAIDS butyric acid derivatives Such as bumadizon, butibufen, fen may prevent the development of these tumors. bufen, Xenbucin, arylcarboxylic acids Such as clidanac, 0.015. One promising solution to the problem of healing ketorolac, tinoridine, arylpropionic acid derivatives Such as and preventing NSAID associated upper gastrointestinal alminoprofen, benoxaprofin, bermoprofen, bucloxic acid, problems, like ulcers and dyspeptic Symptoms in patients carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibupro needing continuous NSAID treatment, is to combine the fen, ibuproxam, indoprofen, ketoprofen, loxoprofen, NSAID treatment with an anti-ulcer drug approved for the naproxen, Oxaprozin, piketoprofin, pirprofen, pranoprofen, healing and/or prophylaxis of NSAID associated gas protizinic acid, Suprofen, tiaprofenic acid, Ximoprofen, and trointestinal Side-effects Such as prostaglandin analogues, Zaltoprofen; pyrazoles Such as difenamizole and epirozole; H-receptor antagonists, and proton pump inhibitors pyrazolones Such as apaZone, benzpiperylon, feprazone, (“PPIs”). Additionally, since many of the patients suffering mofebutaZone, moraZone, oxyphenbutaZone, phenylbuta from inflammatory disorders also Suffer from gastric acid Zone, pipebuZone, propyphenaZone, prostaglandins, ram related disorders, there is a need for pharmaceutical formu ifenaZone, SuxibuZone, and thiazolinobutaZone; Salicylic lations useful for co-administering a proton pump inhibitor acid derivatives Such as acetaminoSalol, aspirin, benorylate, for the treatment of a gastric acid related disorder and a bromosaligenin, calcium acetylsalicylate, diflunisal, eter nonsteroidal anti-inflammatory drug useful for treatment of Salate, fendosal, gentisic acid, glycol Salicylate, imidazole an inflammatory disorder. Salicylate, lysine acetylsalicylate, meSalamine, morpholine Salicylate, 1-naphtyl Salicylate, olSalazine, parSalmide, phe SUMMARY OF THE INVENTION nyl acetylsalicylate, phenyl Salicylate, Salacetamide, Salicy lamide O-acetic acid, Salicylsulfuiric acid, Salsalate, Sul 0016 Pharmaceutical compositions including (a) a thera fasalazine; thiazinecarboxamides Such as ampiroXicam, peutically effective amount of at least one acid labile proton droxicam, isoxicam, lomoxicam, piroXicam, and tenoxicam, pump inhibitor, (b) at least one buffering agent in an amount cyclooxygenase-II inhibitors (“COX-II) such as Celecoxib, Sufficient to increase gastric fluid pH to a pH that prevents Vioxx, Relafen, Lodine, and Voltaren; and otherS Such as US 2005/0249806 A1 Nov. 10, 2005 epsilon-acetamidocaproic acid, S-adenosylmethionine, area under Serum concentration time curve (AUC) for the 3-amino-4-hydroxybutytic acid, amiXetrine, bendazac, ben proton pump inhibitor occurs within about 2 hours after Zydamine, C.-bisabolol, bucololome, difenpiramide, ditaZol, administration of a single dose of the composition to the emorfaZone, fepradinol, guaiaZulene, nabumetone, nime Subject. Compositions are provided wherein, upon oral Sulide, Oxaceprol, paranyline, periSOXal, proguaZone, administration to the Subject, the area under the Serum tenidap and Zilenton. concentration time curve (AUC) for the proton pump inhibi 0.019 Compositions are provided such that an initial tor in the first 2 hours is at least about 60% of the total area. Serum concentration of the proton pump inhibitor is greater Compositions are provided wherein the area under the Serum than about 0.1 lug/ml at any time within about 30 minutes concentration time curve (AUC) for the proton pump inhibi after administering the formulation. Initial Serum concen tor in the first 2 hours is at least about 70% of the total area. tration of the proton pump inhibitor can be greater than 0024 Compositions are provided wherein at least about about 0.1 lug/ml at any time within about 15 minutes. Initial 50% of total area under the serum concentration time curve Serum concentration of the proton pump inhibitor can be (AUC) for the proton pump inhibitor occurs within about greater than about 0.2 lig/ml at any time within about 1 hour 1.75 hours after administration of a single dose of the after administration, greater than about 0.3 ug/ml at any time composition to the Subject. Compositions are provided within about 45 minutes after administration. wherein at least about 50% of total area under the serum 0020 Compositions are provided such that a serum con concentration time curve (AUC) for the proton pump inhibi centration of greater than about 0.1 ug/ml can be maintained tor occurs within about 1.5 hours after administration of a from at least about 30 minutes to about 1 hour after Single dose of the composition to the Subject. Compositions administration of the composition. Compositions are pro are provided wherein at least about 50% of total area under Vided Such that a Serum concentration of proton pump the Serum concentration time curve (AUC) for the proton inhibitor greater than about 0.1 lig/ml can be maintained pump inhibitor occurs within about 1 hour after administra from at least about 15 minutes to about 30 minutes. Com tion of a Single dose of the composition to the Subject. positions are provided Such that a Serum concentration of 0025 Compositions are provided wherein, upon oral greater than about 0.1 lig/ml can be maintained from at least administration to the Subject, the composition provides a about 30 minutes to about 45 minutes. Compositions are pharmacokinetic profile Such that the proton pump inhibitor provided Such that a Serum concentration of greater than reaches a maximum Serum concentration within about 1 about 0.25 ug/ml can be maintained from at least about 30 hour after administration of a single dose of the composition. minutes to about 1 hour. Compositions are provided Such Compositions are provided wherein the maximum Serum that a Serum concentration of greater than about 0.25 ug/ml concentration is reached within about 45 minutes after can be maintained from at least about 30 minutes to about 45 administration of the composition. Compositions are pro minutes. Compositions are provided Such that a Serum Vided wherein the maximum Serum concentration is reached concentration of greater than about 0.25 ug/ml can be within about 30 minutes after administration of the compo maintained from at least about 15 minutes to about 30 Sition. minutes. 0026 Compositions are provided wherein at least some 0021 Compositions of the invention can be administered of the proton pump inhibitor is microencapsulated with a in an amount to maintain a Serum concentration of the proton material that enhances the shelf-life of the pharmaceutical pump inhibitor greater than about 0.15 tug/ml from about 15 composition. Compositions are provided wherein at least minutes to about 1 hour after administration. Compositions Some of the nonsteroidal anti-inflammatory drug is microen of the invention can be administered in an amount to capsulated with a material that enhances the shelf-life of the maintain a Serum concentration of the proton pump inhibitor pharmaceutical composition. Compositions are provided greater than about 0.15 lug/ml from about 15 minutes to wherein Some of the proton pump inhibitor and Some of the about 1.5 hours after administration. Compositions of the nonsteroidal anti-inflammatory drug are microencapsulated invention can be administered in an amount to maintain a with a material that enhances the shelf-life of the pharma Serum concentration of the proton pump inhibitor greater ceutical composition. Materials that enhance the shelf-life of than about 0.1 lug/ml from about 15 minutes to about 1.5 the pharmaceutical composition include but are not limited hours after administration. Compositions of the invention to, cellulose hydroxypropyl ethers, low-Substituted hydrox can be administered in an amount to maintain a Serum ypropyl ethers, cellulose hydroxypropyl methyl ethers, concentration of the proton pump inhibitor greater than methylcellulose polymers, ethylcelluloses and mixtures about 0.15 lug/ml from about 15 minutes to about 30 minutes thereof, polyvinyl alcohol, hydroxyethylcelluloses, car after administration. boxymethylcelluloses, Salts of carboxymethylcelluloses, 0022 Compositions of the invention can be administered polyvinyl alcohol, polyethylene glycol co-polymers, in an amount to achieve an initial Serum concentration of the monoglycerides, triglycerides, polyethylene glycols, modi proton pump inhibitor greater than about 0.15ug/ml at any fied food Starch, acrylic polymers, mixtures of acrylic poly time from about 5 mintues to about 30 minutes after admin mers with cellulose ethers, cellulose acetate phthalate, Sepi istration. Compositions of the invention can be administered films, cyclodextrins; and mixtures thereof. The cellulose in an amount to achieve an initial Serum concentration of the hydroxypropyl ether can be, but is not limited to, Klucel(R) proton pump inhibitor greater than about 0.15ug/ml at any or Nisso HPC. The cellulose hydroxypropyl methyl ether time within about 30 minutes after administration. can be, but is not limited to, Seppifilm-LC, Pharmacoat(R), Metolose SR, Opadry YS, PrimaFlo, BenecelMP824, or 0023 Compositions are provided wherein, upon oral BenecelMP843. The mixture of methylcellulose and administration to the Subject, the composition provides a hydroxypropyl and methylcellulose polymers can be, but is pharmacokinetic profile such that at least about 50% of total not limited to, Methocel(R), Benecel-MC, or Metolose(R). The US 2005/0249806 A1 Nov. 10, 2005

ethylcellulose or mixture thereof can be, but are not limited proton pump inhibitor in the gastric fluid, (c) a therapeuti to, Ethocel(R), BenecelMO43, Celacal, Cumibak NC, and cally effective amount of at least one nonsteroidal anti E461. The polyvinyl alcohol can be, but is not limited to, inflammatory drug, and (d) at least one thickening agent, Opadry AMB. The acrylic polymers or mixtures thereof wherein the dosage form is a powder for Suspension. In include, but are not limited to, Eudragits(R EPO, Eudragits(R) Some embodiments, the powder for Suspension is Substan RD100, and Eudragits(R E100. Other materials that enhance tially uniform or creates a Substantially uniform Suspension the shelf-life of the pharmaceutical composition include, but when mixed. are not limited to, NatrosolE), Aqualon(R)-CMC, and Kolli coat IRE). The material that enhances the shelf-life of the 0030 Compositions are provided that include (a) a thera peutically effective amount of at least one acid labile proton pharmaceutical composition can further include other com pump inhibitor, (b) at least one buffering agent in an amount patible materials. Such as an antioxidant, a plasticizer, a Sufficient to increase gastric fluid pH to a pH that prevents buffering agent, and mixtures thereof. acid degradation of at least Some of the proton pump 0027) Compositions are provided that include (a) a thera inhibitor in the gastric fluid, (c) a therapeutically effective peutically effective amount of at least one acid labile proton amount of at least one nonsteroidal anti-inflammatory drug pump inhibitor, wherein at least Some of the proton pump wherein at least Some of the nonsteroidal anti-inflammatory inhibitor is coated, (b) at least one buffering agent in an drug is coated, and (d) at least one thickening agent, wherein amount Sufficient to increase gastric fluid pH to a pH that the dosage form is a powder for Suspension. In Some prevents acid degradation of at least Some of the proton embodiments, the powder for Suspension is Substantially pump inhibitor in the gastric fluid, and (c) a therapeutically uniform. effective amount of at least one nonsteroidal anti-inflamma tory drug, wherein the nonsteroidal anti-inflammatory drug 0031 Compositions including (a) a therapeutically effec is useful for treating an inflammatory disorder. Inflammatory tive amount of at least one acid labile proton pump inhibitor, diseases include, but are not limited to, reperfusion injury to (b) at least one buffering agent in an amount Sufficient to an ischemic organ (e.g., reperfusion injury to the ischemic increase gastric fluid pH to a pH that prevents acid degra myocardium), myocardinal infarction, inflammatory bowel dation of at least Some of the proton pump inhibitor in the disease, rheumatoid arthritis, osteroarthritis, psoriasis, organ gastric fluid, and (c) a therapeutically effective amount of at transplant rejection, inflammation of the ear, eye, throat, least one nonsteroidal anti-inflammatory drug, wherein the nose or Skin, organ preservation, a female or male Sexual compositions are free of Sucralfate are provided herein. dysfunction, radiation-induced injury, asthma, respiratory 0032 Compositions are provided that include (a) a thera disorder, metastasis, influenza, incontinence, Stroke, burn, peutically effective amount of at least one acid labile proton trauma, acute pancreatistis, pyelonephristis, hepatitis, an pump inhibitor wherein at least Some of the proton pump autoimmune disease, and immunological disorder, Senile inhibitor is coated, (b) at least one buffering agent in an dementia, insulin-dependent diabetes mellitus, disseminated amount Sufficient to increase gastric fluid pH to a pH that intravascular coagulation, fatty embolism, Alzheimer's dis prevents acid degradation of at least Some of the proton ease, adult or infantile respiratory disease, carcinogenesis in pump inhibitor in the gastric fluid, and (c) a therapeutically a neonate, hemorrhage in a neonate, restenosis, atherogen effective amount of at least one nonsteroidal anti-inflamma esis, angina, (particularly chronic, stable angina pectoris), tory drug, wherein the proton pump inhibitor is useful for ischemic disease, congestive heart failure or pulmonary treating a gastric acid related disorder and the nonsteroidal edema associated with acute myocardial infarction, throm anti-inflammatory drug is useful for treating an inflamma bosis, hypertension (especially hypertension associated with tory disorder or other disease treatable by a nonsteroidal cardiovascular Surgical procedures), platelet aggregation, anti-inflammatory drug. platelet adhesion, Smooth muscle cell proliferation, Vascular complications associated with the use of medical devices, 0033 Compositions are provided that include (a) a thera wounds associated with the use of medical devices, cere peutically effective amount of at least one acid labile proton brovascular ischemic events, and the like. pump inhibitor, (b) at least one buffering agent in an amount Sufficient to increase gastric fluid pH to a pH that prevents 0028 Compositions are provided that include (a) a thera acid degradation of at least Some of the proton pump peutically effective amount of at least one acid labile proton inhibitor in the gastric fluid, and (c) a therapeutically effec pump inhibitor wherein at least Some of the proton pump tive amount of at least one nonsteroidal anti-inflammatory inhibitor, (b) at least one buffering agent in an amount drug, wherein the nonsteroidal anti-inflammatory drug is Sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least Some of the proton pump useful for decreasing the risk of heart attack. inhibitor in the gastric fluid, (c) a therapeutically effective 0034 Compositions are provided that include (a) a thera amount of at least one nonsteroidal anti-inflammatory drug, peutically effective amount of at least one acid labile proton and (d) at least one thickening agent, wherein the dosage pump inhibitor, (b) at least one buffering agent in an amount form is a powder for Suspension. In Some embodiments, the Sufficient to increase gastric fluid pH to a pH that prevents powder for Suspension is Substantially uniform or creates a acid degradation of at least Some of the proton pump Substantially uniform Suspension when mixed. inhibitor in the gastric fluid, and (c) a therapeutically effec tive amount of at least one nonsteroidal anti-inflammatory 0029 Compositions are provided that include (a) a thera drug, wherein the pharmaceutical composition is useful for peutically effective amount of at least one acid labile proton preventing cancer. pump inhibitor wherein at least Some of the proton pump inhibitor is microencapsulated, (b) at least one buffering 0035 Compositions are provided that include (a) a thera agent in an amount Sufficient to increase gastric fluid pH to peutically effective amount of at least one acid labile proton a pH that prevents acid degradation of at least Some of the pump inhibitor, (b) at least one buffering agent in an amount US 2005/0249806 A1 Nov. 10, 2005

Sufficient to increase gastric fluid pH to a pH that prevents mixture of Sodium bicarbonate and magnesium hydroxide, acid degradation of at least Some of the proton pump and each buffering agent is present in about 0.1 mEq/mg inhibitor in the gastric fluid, and (c) a therapeutically effec proton pump inhibitor to about 5 mEq/mg proton pump tive amount of at least one nonsteroidal anti-inflammatory inhibitor. Compositions are provided as described herein, drug, wherein the nonsteroidal anti-inflammatory drug is a where the buffering agent is a mixture of Sodium bicarbon COX-II inhibitor. ate, calcium carbonate, and magnesium hydroxide, and each 0036 Compositions including (a) a therapeutically effec buffering agent is present in about 0.1 mEq/mg proton pump tive amount of at least one acid labile proton pump inhibitor, inhibitor to about 5 mEq/mg of the proton pump inhibitor. (b) at least one buffering agent in an amount Sufficient to 0039 Compositions are provided as described herein, increase gastric fluid pH to a pH that prevents acid degra wherein the buffering agent is present in an amount of about dation of at least Some of the proton pump inhibitor in the 0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibi gastric fluid, and (c) a therapeutically effective amount of at tor, or about 0.5 mEq/mg to about 3 mEq/mg of the proton least one nonsteroidal anti-inflammatory drug, wherein the pump inhibitor, or about 0.8 mEq/mg to about 2.5 mEq/mg buffering agent is an alkaline earth metal Salt or a Group IA of the proton pump inhibitor, or about 0.9 mEq/mg to about metal Selected from a bicarbonate Salt of a Group IA metal, 2.0 mEq/mg of the proton pump inhibitor, or about 0.9 a carbonate Salt of a Group IA metal. The buffering agent can mEq/mg to about 1.8 mEq/mg of the proton pump inhibitor. be, but is not limited to, an amino acid, an alkali metal Salt Compositions are provided as described herein, wherein the of an amino acid, aluminum hydroxide, aluminum hydrox buffering agent is present in an amount of at least 1.0 ide/magnesium carbonate/calcium carbonate co-precipitate, mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor, aluminum magnesium hydroxide, aluminum hydroxide/ or at least 0.5 mEq/mg of the proton pump inhibitor. magnesium hydroxide co-precipitate, aluminum hydroxide/ Compositions are provided as described herein, including Sodium bicarbonate coprecipitate, aluminum glycinate, cal about 200 to 3000 mg of buffering agent, or about 500 to cium acetate, calcium bicarbonate, calcium borate, calcium about 2500 mg of buffering agent, or about 1000 to about carbonate, calcium citrate, calcium gluconate, calcium glyc 2000 mg of buffering agent, or about 1500 to about 2000 mg erophosphate, calcium hydroxide, calcium lactate, calcium of buffering agent. phthalate, calcium phosphate, calcium Succinate, calcium tartrate, dibasic Sodium phosphate, dipotassium hydrogen 0040 Compositions including (a) a therapeutically effec phosphate, dipotassium phosphate, disodium hydrogen tive amount of at least one acid labile proton pump inhibitor, phosphate, disodium Succinate, dry aluminum hydroxide (b) at least one buffering agent in an amount Sufficient to gel, L-arginine, magnesium acetate, magnesium aluminate, increase gastric fluid pH to a pH that prevents acid degra magnesium borate, magnesium bicarbonate, magnesium dation of at least Some of the proton pump inhibitor in the carbonate, magnesium citrate, magnesium gluconate, mag gastric fluid, and (c) a therapeutically effective amount of at nesium hydroxide, magnesium lactate, magnesium metasili least one nonsteroidal anti-inflammatory drug are provided, cate aluminate, magnesium oxide, magnesium phthalate, wherein at least Some of the nonsteroidal anti-inflammatory magnesium phosphate, magnesium Silicate, magnesium Suc drug is coated. Sutiable coatings include, but are not limited cinate, magnesium tartrate, potassium acetate, potassium to, gastric resistant coatings Such as enteric coatings, con carbonate, potassium bicarbonate, potassium borate, potas trolled-release coatings, enzymatic-controlled coatings, film sium citrate, potassium metaphosphate, potassium phthalate, coatings, Sustained-release coatings, immediate-release potassium phosphate, potassium polyphosphate, potassium coatings, and delayed-release coatings. Compositions are also provided wherein the NSAID is a weakly acidic, pyrophosphate, potassium Succinate, potassium tartrate, lipid-Soluble compound. Sodium acetate, Sodium bicarbonate, Sodium borate, Sodium carbonate, Sodium citrate, Sodium gluconate, Sodium hydro 0041 Compositions including (a) a therapeutically effe gen phosphate, Sodium hydroxide, Sodium lactate, Sodium cive amount of at least one acid labile proton pump inhibitor, phthalate, Sodium phosphate, Sodium polyphosphate, (b) at least one buffering agent Selected from Sodium bicar Sodium pyrophosphate, Sodium Sesquicarbonate, Sodium bonate, calcium carbonate, and magnesium hydroxide, Succinate, Sodium tartrate, Sodium tripolyphosphate, Syn wherein the buffereing agent is present in an amount Suffi thetic hydrotalcite, tetrapotassium pyrophosphate, tetraso cient to increase gastric fluid, and (c) a therapeutically dium pyrophosphate, tripotassium phosphate, triSodium effective amount of at least one nonsteroidal anti-inflamma phosphate, trometamol, and mixtures thereof. In particular, tory drug are provided. the buffering agent can be Sodium bicarbonate, Sodium 0042 Compositions including (a) a therapeutically effec carbonate, calcium carbonate, magnesium oxide, magne tive amount of at least one acid, labile proton pump inhibi sium hydroxide, magnesium carbonate, aluminum hydrox tor, (b) at least one buffering agent in an amount Sufficient ide, and mixtures thereof. to increase gastric fluid pH to a pH that prevents acid 0037 Compositions are provided as described herein, degradation of at least Some of the proton pump inhibitor in where the buffering agent to proton pump inhibitor ratio is the gastric fluid, and (c) a therapeutically effective amount at least 10:1; at least 12:1, at least 15:1; at least 20:1; at least of at least one nonsteroidal anti-inflammatory drug, wherein 22:1; at least 25:1, at least 30:1; at least 35:1, and at least the composition is in a dosage form Selected from a powder, 40:1. a tablet, a bite-disintegration tablet, a chewable tablet, a capsule, an effervescent powder, a rapid-disintegration tab 0.038 Compositions are provided as described herein, let, or an aqueous Suspension produced from powder. where the buffering agent is Sodium bicarbonate and is present in about 0.1 mEq/mg proton pump inhibitor to about 0043 Compositions including (a) a therapeutically effec 5 mEq/mg proton pump inhibitor. Compositions are pro tive amount of at least one acid labile proton pump inhibitor, Vided as described herein, where the buffering agent is a (b) at least one buffering agent in an amount Sufficient to US 2005/0249806 A1 Nov. 10, 2005 increase gastric fluid pH to a pH that prevents acid degra optionally enteric-coated. Methods are provided wherein the dation of at least Some of the proton pump inhibitor in the proton pump inhibitor prevents or treats an NSAID induced gastric fluid, and (c) a therapeutically effective amount of at gastric acid related disorder, further wherein at least Some of least one nonsteroidal anti-inflammatory drug, wherein the the proton pump inhibitor is coated, optionally enteric composition is in the form of a tablet and the tablet consists coated. of a first and a Second layer where the first layer comprises at least Some of the nonsteroidal anti-inflammatory drug and 0048 Methods are provided for treating an inflammatory the Second layer comprises at least Some of the proton pump disorder including, but not limited to, reperfusion injury to an ischemic organ Such as reperfusion injury to the ischemic inhibitor and the buffering agent. myocardium, myocardinal infarction, inflammatory bowel 0044) Compositions are provided as described herein, disease, rheumatoid arthritis, osteroarthritis, psoriasis, organ further including one or more excipients including, but not transplant rejection, inflammation of the ear, eye, throat, limited to, parietal cell activators, erosion facilitators, fla nose or Skin, organ preservation, a female or male Sexual Voring agents, Sweetening agents, diffusion facilitators, anti dysfunction, radiation-induced injury, asthma, respiratory oxidants and carrier materials Selected from binders, Sus disorder, metastasis, influenza, incontinence, Stroke, burn, pending agents, disintegration agents, filling agents, trauma, acute pancreatistis, pyelonephristis, hepatitis, an Surfactants, Solubilizers, Stabilizers, lubricants, wetting autoimmune disease, and immunological disorder, Senile agents, diluents, anti-adherents, and antifoaming agents. dementia, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, Alzheimer's dis 0.045 Methods are provided for treating a gastric acid ease, adult or infantile respiratory disease, carcinogenesis in related disorder and treating an inflammatory disease by a neonate, hemorrhage in a neonate, restenosis, atherogen administering to the Subject a pharmaceutical composition esis, angina (including chronic, stable angina pectoris), including (a) a therapeutically effective amount of at least ischemic disease, congestive heart failure or pulmonary one acid labile proton pump inhibitor, (b) at least one edema associated with acute myocardial infarction, throm buffering agent in an amount Sufficient to increase gastric bosis, hypertension (including hypertension associated with fluid pH to a pH that prevents acid degradation of at least cardiovascular Surgical procedures), platelet aggregation, Some of the proton pump inhibitor in the gastric fluid, and platelet adhesion, Smooth muscle cell proliferation, Vascular (c) a therapeutically effective amount of at least one non complications associated with the use of medical devices, Steroidal anti-inflammatory drug, wherein the proton pump wounds associated with the use of medical devices, cere inhibitor treats the gastric acid related disorder and the nonsteroidal anti-inflammatory drug treats the inflammatory brovascular ischemic events, and the like. disorder. Methods are provided wherein the composition as 0049 Methods are provided for treating a gastric acid described herein is formulated for stomach delivery of at related disorder and decreasing the risk of a heart attack by least some of the proton pump inhibitor. Methods are administering to the Subject a pharmaceutical composition provided wherein the composition as described herein is including (a) a therapeutically effective amount of at least formulated for duodenal delivery of some of the proton one acid labile proton pump inhibitor, (b) at least one pump inhibitor. buffering agent in an amount Sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least 0.046 Methods are provided for treating a gastric acid Some of the proton pump inhibitor in the gastric fluid, and related disorder and treating an inflammatory disease by (c) a therapeutically effective amount of at least one non administering to a horse a pharmaceutical composition Steroidal anti-inflammatory drug, wherein the proton pump including (a) a therapeutically effective amount of at least inhibitor treats the gastric acid related disorder and the one acid labile proton pump inhibitor, (b) at least one nonsteroidal anti-inflammatory drug decreases the risk of buffering agent in an amount Sufficient to increase gastric heart attack. fluid pH to a pH that prevents acid degradation of at least Some of the proton pump inhibitor in the gastric fluid, and 0050 Methods are provided for treating a gastric acid (c) a therapeutically effective amount of at least one non related disorder and decreasing the risk of cancer by admin Steroidal anti-inflammatory drug, wherein the proton pump istering to the Subject a pharmaceutical composition includ inhibitor treats the gastric acid related disorder and the ing (a) a therapeutically effective amount of at least one acid nonsteroidal anti-inflammatory drug treats the inflammatory labile proton pump inhibitor, (b) at least one buffering agent disorder. in an amount Sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least Some of the proton 0047 Methods are provided for treating a gastric acid pump inhibitor in the gastric fluid, and (c) a therapeutically related disorder including, but not limited to duodenal ulcer effective amount of at least one nonsteroidal anti-inflamma disease, gastric ulcer disease, gastroesophageal reflux dis tory drug, wherein the proton pump inhibitor treats the ease, erosive esophagitis, poorly responsive Symptomatic gastric acid related disorder and the nonsteroidal anti-in gastroesophageal reflux disease, pathological gastrointesti flammatory drug decreases the risk of certain types of nal hyperSecretory disease, Zollinger Ellison Syndrome, cancers including, but not limited to esophageal cancer, lung heartburn, esophageal disorder, and acid dyspepsia. Method are provided wherein the proton pump inhibitor treats an cancer, colorectal cancer, breast cancer, and prostate cancer. episode of gastric acid related disorder. Methods are pro 0051 Methods are provided for protecting against an Vided wherein the proton pump inhibitor prevents or treats esophageal disorder or esophageal damage by administering an NSAID induced gastric acid related disorder. Methods are to the Subject a pharmaceutical composition including (a) a provided wherein the proton pump inhibitor prevents or therapeutically effective amount of at least one acid labile treats an NSAID induced gastric acid related disorder, proton pump inhibitor, (b) at least one buffering agent in an further wherein at least Some of the NSAID is coated, amount Sufficient to increase gastric fluid pH to a pH that US 2005/0249806 A1 Nov. 10, 2005

prevents acid degradation of at least Some of the proton provide relief from gastric acid related disorders and reduce pump inhibitor in the gastric fluid, and (c) a therapeutically the risk of cardiovascular disease in a Subject. It has been effective amount of at least one nonsteroidal anti-inflamma discovered that pharmaceutical compositions comprising (1) tory drug. an acid labile proton pump inhibitor, together with (2) one 0.052 Methods are provided for treating a gastric acid or more buffering agents, and (3) a nonsteroidal anti-inflam related disorder and treating inflammation, pain, or fever by matory drug, provide relief from gastric acid related disor administering to the Subject a pharmaceutical composition derS and reduce the risk of cancer in a Subject. including (a) a therapeutically effective amount of at least 0057. It has been discovered that pharmaceutical compo one acid labile proton pump inhibitor, (b) at least one Sitions comprising (1) an acid labile proton pump inhibitor buffering agent in an amount Sufficient to increase gastric which is microencapsulated with a material that enhances fluid pH to a pH that prevents acid degradation of at least the shelf-life of the pharmaceutical composition, together Some of the proton pump inhibitor in the gastric fluid, and with (2) one or more buffering agents, and (3) a nonsteroidal (c) a therapeutically effective amount of at least one non anti-inflammatory drug, provide Superior performance by Steroidal anti-inflammatory drug, wherein the proton pump enhancing shelf-life Stability of the pharmaceutical compo inhibitor treats the gastric acid related disorder and the Sition during manufacturing and Storage. It has been discov nonsteroidal anti-inflammatory drug treats inflammation, ered that pharmaceutical compositions comprising (1) an pain or fever in the Subject. Methods are provided wherein acid labile proton pump inhibitor, together with (2) one or the nonsteroidal anti-inflammatory drug is used to treat more buffering agents, and (3) a nonsteroidal anti-inflam Symptoms of arthritis in a patient in need. matory drug which is coated provide Superior performance 0.053 Methods are provided for treating a gastric acid by enhancing shelf-life Stability of the pharmaceutical com related disorder and treating an inflammatory disorder by position during manufacture and Storage. administering to a Subject a pharmaceutical composition 0.058 Glossary including (a) a therapeutically effective amount of at least one acid labile proton pump inhibitor, (b) at least one 0059) To more readily facilitate an understanding of the buffering agent in an amount Sufficient to increase gastric invention and its preferred embodiments, the meanings of fluid pH to a pH that prevents acid degradation of at least terms used herein will become apparent from the context of Some of the proton pump inhibitor in the gastric fluid, and this Specification in View of common usage of various terms (c) a therapeutically effective amount of at least one non and the explicit definitions of other terms provided in the Steroidal anti-inflammatory drug, wherein the composition is glossary below or in the ensuing description. in a dosage form including, but not limited to, a powder, a powder for Suspension, a tablet, a caplet, a bite-disintegra 0060 AS used herein, the terms “comprising,”“includ tion tablet, a chewable tablet, a capsule, an effervescent ing, and “Such as are used in their open, non-limiting powder, a rapid-disintegration tablet, or an aqueous Suspen SCSC. Sion produced from powder. 0061 The term “about” is used synonymously with the 0.054 Methods are provided wherein the composition term “approximately.” Illustratively, the use of the term further comprises one or more excipients including, but not “about” indicates that values slightly outside the cited val limited to, parietal cell activators, erosion facilitators, fla ues, i.e., plus or minus 0.1% to 10%, which are also effective Voring agents, Sweetening agents, diffusion facilitators, anti and Safe. Such dosages are thus encompassed by the Scope oxidants and carrier materials Selected from binders, Sus of the claims reciting the terms “about' and "approxi pending agents, disintegration agents, filling agents, mately.” Surfactants, Solubilizers, Stabilizers, lubricants, wetting 0062) The phrase “acid-labile pharmaceutical agent” agents, diluents, anti-adherents, and antifoaming agents. refers to any pharmacologically active drug Subject to acid catalyzed degradation. DETAILED DESCRIPTION OF THE INVENTION 0063 “Anti-adherents,”“glidants,” or “anti-adhesion” 0.055 The present invention is directed to pharmaceutical agents prevent components of the formulation from aggre compositions comprising a proton pump inhibitor, a buffer gating or Sticking and improve flow characteristics of a ing agent, and a nonsteroidal anti-inflammatory drug, material. wherein the compositions are useful for the treatment of a 0064. Such compounds include, e.g., colloidal silicon disease, condition or disorder, wherein treatment includes dioxide Such as Cab-O-Silf; tribasic calcium phosphate, talc, treating the Symptoms of the disease, condition or disorder. corn Starch, DL-leucine, Sodium lauryl Sulfate, magnesium Methods of treatment using the pharmaceutical composi Stearate, calcium Stearate, Sodium Stearate, kaolin, and tions of the present invention are also described. micronized amorphous silicon dioxide (Syloid(R) and the 0056. It has been discovered that pharmaceutical compo like. Sitions comprising (1) an acid labile proton pump inhibitor, 0065 “Antifoaming agents” reduce foaming during pro together with (2) one or more buffering agents, and (3) a cessing which can result in coagulation of aqueous disper nonsteroidal anti-inflammatory drug, provide relief from Sions, bubbles in the finished film, or generally impair gastric acid related disorders and provide relief from inflam processing. Exemplary anti-foaming agents include Silicon matory disorders in a Subject. It has been discovered that pharmaceutical compositions comprising (1) an acid labile emulsions or Sorbitan Sesquoleate. proton pump inhibitor, together with (2) one or more buff 0066 “Antioxidants” include, e.g., butylated hydroxy ering agents, and (3) a nonsteroidal anti-inflammatory drug, toluene (BHT), sodium ascorbate, and tocopherol. US 2005/0249806 A1 Nov. 10, 2005

0067 “Binders' impart cohesive qualities and include, tose, Starch; mannitol, Sorbitol; dextrose; microcrystalline e.g., alginic acid and Salts thereof; cellulose derivatives Such cellulose Such as AVicelf), dibasic calcium phosphate, dical as carboxymethylcellulose, methylcellulose (e.g., Metho cium phosphate dihydrate; tricalcium phosphate, calcium cel(R), hydroxypropylmethylcellulose, hydroxyethylcellu phosphate, anhydrous lactose; Spray-dried lactose; pregelat lose, hydroxypropylcellulose (e.g., Klucel(R), ethylcellulose inzed Starch; compressible Sugar, Such as Di-PacE) (Amstar); (e.g., Ethocel(B), and microcrystalline cellulose (e.g., mannitol, hydroxypropylmethylSellulose, Sucrose-based Avicelf); microcrystalline dextrose; amylose; magnesium diluents, confectioner's Sugar, monobasic calcium Sulfate aluminum Silicate; polysaccharide acids, bentonites, gelatin; monohydrate, calcium Sulfate dihydrate; calcium lactate polyvinylpyrrolidone/vinyl acetate copolymer; crospovi trihydrate; dextrates, hydrolyzed cereal Solids, amylose; done; poVidone, Starch; pregelatinized Starch; tragacanth, powdered cellulose, calcium carbonate, glycine; kaolin; dextrin, a Sugar, Such as Sucrose (e.g., DipacE), glucose, mannitol, Sodium chloride, inositol, bentonite, and the like. dextrose, molasses, mannitol, Sorbitol, xylitol (e.g., Xyl itab(E), and lactose; a natural or Synthetic gum Such as 0074 The term “disintegrate” includes both the dissolu acacia, tragacanth, ghatti gum, mucilage of isapol husks, tion and dispersion of the dosage form when contacted with polyvinylpyrrolidone (e.g., Polyvidone(R). CL, Kollidon(R) gastrointestinal fluid. CL, Polyplasdone(R) XL-10), larch arabogalactan, Veegum(R), 0075 “Disintegration agents' facilitate the breakup or polyethylene glycol, waxes, Sodium alginate, and the like. disintegration of a Substance. Examples of disintegration agents include a Starch, e.g., a natural Starch Such as corn 0068 “Bioavailability” refers to the extent to which an Starch or potato Starch, a pregelatinized Starch Such as active moiety, e.g., drug, prodrug, or metabolite, is absorbed National 1551 or Amijel.E), or sodium starch glycolate such into the general circulation and becomes available at the Site as Promogel(R) or ExplotabCE); a cellulose such as a wood of drug action in the body. product, methylcrystalline cellulose, e.g., Avice1(R), AVicel(R) 0069. “Carrier materials” include any commonly used PH101, Avice1(R) PH102, Avice1(R) PH105, Elcema(E) P100, excipients in pharmaceutics and should be Selected on the Emcocel(R), Vivacel(R), Ming Tia(E), and Solka-FloccE), meth basis of compatibility with the proton pump inhibitor and the ylcellulose, croScarmellose, or a cross-linked cellulose, Such release profile properties of the desired dosage form. Exem as cross-linked Sodium carboxymethylcellulose (Ac-Di plary carrier materials include, e.g., binders, Suspending Sol E), cross-linked carboxymethylcellulose, or cross-linked agents, disintegration agents, filling agents, Surfactants, croScarmelloSe; a cross-linked Starch Such as Sodium Starch Solubilizers, Stabilizers, lubricants, wetting agents, diluents, glycolate; a cross-linked polymer Such as croSpoVidone; a and the like. "Pharmaceutically compatible carrier materi cross-linked polyvinylpyrrolidone; alginate Such as alginic als' may comprise, e.g., acacia, gelatin, colloidal Silicon acid or a Salt of alginic acid Such as Sodium alginate, a clay dioxide, calcium glycerophosphate, calcium lactate, malto Such as Veegum(E) HV (magnesium aluminum silicate); a dextrin, glycerine, magnesium Silicate, Sodium caseinate, gum Such as agar, guar, locust bean, Karaya, pectin, or Soy lecithin, Sodium chloride, tricalcium phosphate, dipo tragacanth; Sodium Starch glycolate; bentonite; a natural tassium phosphate, Sodium Stearoyl lactylate, carrageenan, Sponge; a Surfactant; a resin Such as a cation-exchange resin; monoglyceride, diglyceride, pregelatinized Starch, and the citrus pulp; Sodium lauryl Sulfate, Sodium lauryl Sulfate in like. See, e.g., Remington. The Science and Practice of combination Starch; and the like. Pharmacy, Nineteenth Ed (Easton, Pa.; Mack Publishing Company, 1995); Hoover, John E., Remington ’s Pharma 0.076 “Drug absorption” or “absorption” refers to the ceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; process of movement from the Site of administration of a Liberman, H. A. and Lachman, L., Eds., Pharmaceutical drug toward the Systemic circulation, e.g., into the blood Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Stream of a Subject. Pharmaceutical Dosage Forms and Drug Delivery Systems, 0077. An “enteric coating” is a substance that remains Seventh Ed. (Lippincott Williams & Wilkins 1999). Substantially intact in the Stomach but dissolves and releases 0070 “Character notes” include, e.g., aromatics, basis the drug once the Small intestine is reached. Generally, the tastes, and feeling factors. The intensity of the character note enteric coating comprises a polymeric material that prevents can be Scaled from 0-none, 1-slight, 2-moderate, or 3-strong. release in the low pH environment of the stomach but that 0071 A“derivative” is a compound that is produced from ionizes at a slightly higer pH, typically a pH of 4 or 5, and another compound of Similar structure by the replacement of thus dissolves Sufficiently in the Small intestines to gradually Substitution of an atom, molecule or group by another release the active agent therein. Suitable atom, molecule or group. For example, one or more 0078 “Erosion facilitators' include materials that control hydrogen atom of a compound may be Substituted by one or the erosion of a particular material in gastrointestinal fluid. more alkyl, acyl, amino, hydroxyl, halo, haloalkyl, aryl, Erosion facilitators are generally known to those of ordinary heteroaryl, cycloaolkyl, heterocycloalkyl, or heteroalkyl skill in the art. Exemplary erosion facilitators include, e.g., group to produce a derivative of that compound. hydrophilic polymers, electrolytes, proteins, peptides, and 0.072 “Diffusion facilitators” and “dispersing agents' amino acids. include materials that control the diffusion of an aqueous 0079. “Filling agents” include compounds such as lac fluid through a coating. Exemplary diffusion facilitatorS/ tose, calcium carbonate, calcium phosphate, dibasic calcium dispersing agents include, e.g., hydrophilic polymers, elec phosphate, calcium Sulfate, microcrystalline cellulose, cel trolytes, Tween(F) 60 or 80, PEG and the like. Combinations lulose powder, dextrose; dextrates, dextran, Starches, prege of one or more erosion facilitator with one or more diffusion latinized Starch, Sucrose, Xylitol, lactitol, mannitol, Sorbitol, facilitator can also be used in the present invention. Sodium chloride, polyethylene glycol, and the like. 0.073 "Diluents” increase bulk of the composition to 0080) “Flavoring agents” or “sweeteners' useful in the facilitate compression. Such compounds include e.g., lac pharmaceutical compositions of the present invention US 2005/0249806 A1 Nov. 10, 2005

include, e.g., acacia Syrup, aceSulfame K, alitame, anise, the proton pump inhibitor. Parietal cell activators include, apple, aspartame, banana, Bavarian cream, berry, black e.g., chocolate; alkaline Substances Such as Sodium bicar currant, butterScotch, calcium citrate, camphor, caramel, bonate, calcium Such as calcium carbonate, calcium glucon cherry, cherry cream, chocolate, cinnamon, bubble gum, ate, calcium hydroxide, calcium acetate and calcium glyc citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, erophosphate, peppermint oil; Spearmint oil; coffee, tea and cool cherry, cool citrus, cyclamate, cylamate, dextrose, colas (even if decaffeinated); caffeine; theophylline; theo eucalyptus, eugenol, fructose, fruit punch, ginger, glycyr bromine; amino acids (particularly aromatic amino acids rhetinate, glycyrrhiza (licorice) Syrup, grape, grapefruit, Such as phenylalanine and tryptophan); and combinations honey, isomalt, lemon, lime, lemon cream, monoammonium thereof. glyrrhizinate (MagnaSweetB), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohes 0086) “Pharmacodynamics' refers to the factors which peridine DC, neotame, orange, pear, peach, peppermint, determine the biologic response observed relative to the peppermint cream, ProSweet(E Powder, raspberry, root beer, concentration of drug at a site of action. rum, Saccharin, Safrole, Sorbitol, Spearmint, Spearmint 0087) “Pharmacokinetics” refers to the factors which cream, Strawberry, Strawberry cream, Stevia, Sucralose, determine the attainment and maintenance of the appropriate Sucrose, Sodium Saccharin, Saccharin, aspartame, concentration of drug at a site of action. aceSulfame potassium, mannitol, talin, Sylitol, Sucralose, Sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti 0088 “Plasma concentration” refers to the concentration fruitti, Vanilla, walnut, watermelon, wild cherry, winter of a Substance in blood plasma or blood Serum of a Subject. green, Xylitol, or any combination of these flavoring ingre It is understood that the plasma concentration of a thera dients, e.g., anise-menthol, cherry-anise, cinnamon-Orange, peutic agent may vary many-fold between Subjects, due to cherry-cinnamon, chocolate-mint, honey-lemon, lemon variability with respect to metabolism of therapeutic agents. lime, lemon-mint, menthol-eucalyptus, orange-cream, In accordance with one aspect of the present invention, the Vanilla-mint, and mixtures thereof. plasma concentration of a proton pump inhibitors and/or nonsteroidal anti-inflammatory drug may vary from Subject 0081) “Gastrointestinal fluid” is the fluid of stomach to Subject. Likewise, values Such as maximum plasma Secretions of a Subject or the Saliva of a Subject after oral concentraton (C) or time to reach maximum serum administration of a composition of the present invention, or concentration (T,), or area under the Serum concentration the equivalent thereof. An "equivalent of Stomach Secretion' time curve (AUC) may vary from Subject to subject. Due to includes, e.g., an in vitro fluid having similar content and/or this variability, the amount necessary to constitute “a thera pH as Stomach Secretions Such as a 1% Sodium dodecyl peutically effective amount of proton pump inhibitor, non Sulfate Solution or 0.1N HCl Solution in water. Steroidal anti-inflammatory drug, or other therapeutic agent, 0082) “Half-life” refers to the time required for the may vary from Subject to Subject. It is understood that when plasma drug concentration or the amount in the body to mean plasma concentrations are disclosed for a population decrease by 50% from its maximum concentration. of Subjects, these mean values may include Substantial variation. 0.083 “Lubricants” are compounds which prevent, reduce or inhibit adhesion or friction of materials. Exem 0089. “Plasticizers” are compounds used to soften the plary lubricants include, e.g., Stearic acid, calcium hydrox microencapsulation material or film coatings to make them ide; talc, Sodium Stearyl fumerate; a hydrocarbon Such as leSS brittle. Suitable plasticizers include, e.g., polyethylene mineral oil, or hydrogenated vegetable oil Such as hydroge glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, nated soybean oil (Sterotex(R); higher fatty acids and their PEG 3350, and PEG 800, stearic acid, propylene glycol, alkali-metal and alkaline earth metal Salts, Such as alumi oleic acid, and triacetin. num, calcium, magnesium, Zinc, Stearic acid, Sodium Stear 0090) “Prevent” or “prevention” when used in the context ates, glycerol, talc, waxes, StearowetCE, boric acid, Sodium of a gastric acid related disorder means no gastrointestinal benzoate, Sodium acetate, Sodium chloride, leucine, a poly disorder or disease development if none had occurred, or no ethylene glycol or a methoxypolyethylene glycol Such as further gastrointestinal disorder or disease development if CarbowaxTM, Sodium oleate, glyceryl behenate, polyethyl there had already been development of the gastrointestinal ene glycol, magnesium or Sodium lauryl Sulfate, colloidal disorder or disease. Also considered is the ability of one to silica such as Syloid TM, Carb-O-Sile), a starch such as corn prevent Some or all of the Symptoms associated with the Starch, Silicone oil, a Surfactant, and the like. gastrointestinal disorder or disease. “Prevent' or “preven 0084. A “measurable serum concentration” or “measur tion” when used in the context of an inflammatory disorder able plasma concentration” describes the blood Serum or means no inflammatory disorder or disease development if blood plasma concentration, typically measured in mg, ug, none had yet occurred, or no further inflammatory disorder or ng of therapeutic agent per ml, dl, or 1 of blood Serum, of or disease if there had already been development of the a therapeutic agent that is absorbed into the bloodstream inflammatory disorder. Also considered is the ability of one after administration. One of ordinary skill in the art would to prevent Some or all of the Symptoms associated with the be able to measure the Serum concentration or plasma inflammatory disorder. concentration of a proton pump inhibitor or a nonsteroidal 0091 A“prodrug” refers to a drug or compound in which anti-inflammatory drug. See, e.g., Gonzalez H. et al., J. the pharmacological action results from conversion by meta Chromatogr. B. Analyt. Technol. Biomed. Life Sci., vol. 780, bolic processes within the body. Prodrugs are generally drug pp. 459-65, (Nov. 25, 2002). precursors that, following administration to a Subject and 0085 “Parietal cell activators” or “activators” stimulate Subsequent absorption, are converted to an active, or a more the parietal cells and enhance the pharmaceutical activity of active Species via Some process, Such as conversion by a US 2005/0249806 A1 Nov. 10, 2005 metabolic pathway. Some prodrugs have a chemical group 0096 “Surfactants' include compounds such as sodium present on the prodrug which renders it leSS active and/or lauryl Sulfate, Sorbitan monooleate, polyoxyethylene Sorbi conferS Solubility or Some other property to the drug. Once tan monooleate, polySorbates, polaxomers, bile Salts, glyc the chemical group has been cleaved and/or modified from eryl monoStearate, copolymers of ethylene oxide and pro the prodrug the active drug is generated. Prodrugs may be pylene oxide, e.g., Pluronic(R) (BASF); and the like. designed as reversible drug derivatives, for use as modifiers to enhance drug transport to Site-specific tissues. The design 0097. A “therapeutically effective amount” or “effective of prodrugs to date has been to increase the effective water amount' is that amount of a pharmaceutical agent to achieve Solubility of the therapeutic compound for targeting to a pharmacological effect. The term “therapeutically effective regions where water is the principal Solvent. See, e.g., amount' includes, for example, a prophylactically effective Fedorak, et al., Am. J. Physiol, 269:G210-218 (1995); amount. An “effective amount” of a proton pump inhibitor McLoed, et al., Gastroenterol., 106:405-413 (1994); Hoch is an amount effective to achieve a desired pharmacologic haus, et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen effect or therapeutic improvement without undue adverse and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Side effects. For example, an effective amount of a proton Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula pump inhibitor refers to an amount of proton pump inhibitor et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. that reduces acid Secretion, or raises gastrointestinal fluid Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the pH, or reduces gastrointestinal bleeding, or reduces the need A.C.S. Symposium Series; and Edward B. Roche, Bior for blood transfusion, or improves Survival rate, or provides eversible Carriers in Drug Design, American Pharmaceu for a more rapid recovery from a gastric acid related tical Association and Pergamon Press, 1987. disorder. An "effective amount of a nonsteroidal anti inflammatory drug is an amount effective to achieve a 0092) "Serum concentration” refers to the concentration desired pharmacological effect on the Subject's condition, of a Substance Such as a therapeutic agent, in blood plasma without undue adverse side effects. The effective amount of or blood serum of a subject. It is understood that the serum a pharmaceutical agent will be Selected by those skilled in concentration of a therapeutic agent may vary many-fold the art depending on the particular patient and the disease between Subjects, due to variability with respect to metabo level. It is understood that “an effect amount” or "a thera lism of therapeutic agents. In accordance with one aspect of peutically effective amount' can vary from Subject to Sub the present invention, the Serum concentration of a proton ject, due to variation in metabolism of therapeutic agents pump inhibitors and/or nonsteroidal anti-inflammatory drug Such as proton pump inhibitors and/or nonsteroidal anti may vary from Subject to Subject. Likewise, values Such as inflammatory agents, age, weight, general condition of the maximum serum concentraton (C) or time to reach Subject, the condition being treated, the Severity of the maximum serum concentration (T,), or total area under condition being treated, and the judgment of the prescribing the Serum concentration time curve (AUC) may vary from physician. Subject to Subject. Due to this variability, the amount nec essary to constitute “a therapeutically effective amount of 0.098 “Total intensity of aroma” is the overall immediate proton pump inhibitor, nonsteroidal anti-inflammatory drug, impression of the Strength of the aroma and includes both or other therapeutic agent, may vary from Subject to Subject. aromatics and nose feel Sensations. It is understood that when mean Serum concentrations are 0099. “Total intensity of flavor” is the overall immediate disclosed for a population of Subjects, these mean values impression of the Strength of the flavor including aromatics, may include Substantial variation. basic tastes and mouth feel Sensations. 0.093 “Solubilizers” include compounds such as citric 0100 “Treat” or “treatment” as used in the context of a acid, Succinic acid, fumaric acid, malic acid, tartaric acid, gastric acid related disorder refers to any treatment of a maleic acid, glutaric acid, Sodium bicarbonate, Sodium car disorder or disease associated with a gastrointestinal disor bonate and the like. der, Such as preventing the disorder or disease from occur 0094 “Stabilizers” include compounds such as any anti ring in a Subject which may be predisposed to the disorder oxidation agents, buffers, acids, and the like. or disease, but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, e.g., 0.095 “Suspending agents” or “thickening agents' arresting the development of the disorder or disease, reliev include compounds Such as polyvinylpyrrollidone, e.g., poly ing the disorder or disease, causing regression of the disor vinylpyrrolidone K12, polyvinylpyrrollidone K17, polyvi der or disease, relieving a condition caused by the disease or nylpyrrolidone K25, or polyvinylpyrrolidone K30; polyeth disorder, or Stopping the Symptoms of the disease or disor ylene glycol. e.g., the polyethylene glycol can have a der. “Treat' or “treatment” as used in the context of an molecular weight of about 300 to about 6000, or about 3350 inflammatory disorder refers to any treatment of a disorder to about 4000, or about 7000 to about 5400; Sodium car or disease associated with an inflammatory disorder, Such as boxymethylcellulose; methylcellulose, hydroxy-propylm preventing the disorder or disease from occurring in a ethylcellulose; polysorbate-80; hydroxyethylcellulose; Subject which may be predisposed to the disorder or disease, Sodium alginate, gums, Such as, e.g., gum tragacanth and but has not yet been diagnosed as having the disorder or gum acacia, guar gum, Xanthans, including Xanthan gum, disease; inhibiting the disorder or disease, e.g., arresting the Sugars, cellulosics, Such as, e.g., Sodium carboxymethylcel development of the disorder or disease, relieving the disor lulose, methylcellulose, Sodium carboxymethylcellulose, der or disease, causing regression of the disorder or disease, hydroxypropylmethylcellulose, hydroxyethylcellulose; relieving a condition caused by the disease or disorder, or polySorbate-80; Sodium alginate; polyethoxylated Sorbitan Stopping the Symptoms of the disease or disorder. Thus, as monolaurate; polyethoxylated Sorbitan monolaurate; povi used herein, the term “treat' is used synonymously with the done and the like. term “prevent.” US 2005/0249806 A1 Nov. 10, 2005

0101 “Wetting agents” include compounds such as oleic administration, or be at risk of developing a gastric acid acid, glyceryl monoStearate, Sorbitan monooleate, Sorbitan related disorder. The Symptoms or conditions of a gastric monolaurate, triethanolamine oleate, polyoxyethylene Sor acid related disorder in a Subject can be determined by one bitan monooleate, polyoxyethylene Sorbitan monolaurate, skilled in the art and are described in Standard textbooks. Sodium oleate, Sodium lauryl Sulfate, and the like. The method comprises the oral administration of an effective amount of one or more compositions of the present inven 0102) Combination Therapy tion to a Subject in need thereof. Gastric acid related 0103) Compositions and methods for combination disorderS Suitable for treatment using compositions and therapy are provided herein. In accordance with one aspect, methods of the present invention include, but are not limited the pharmaceutical compositions disclosed herein are used to, duodenal ulcer disease, gastrointestinal ulcer disease, to treat a gastric acid related disorder where treatment with gastroesophageal reflux disease (GERD), erosive esophagi a proton pump inhibitor is indicated, and to treat an inflam tis, poorly responsive Symptomatic gastroesophageal reflux matory disorder where treatment with a nonsteroidal anti disease, pathological gastrointestinal hyperSecretory dis inflammatory drug is indicated. In one embodiment, phar ease, Zollinger Ellison Syndrome, heartburn, esophageal maceutical compositions disclosed herein are used treat a disorder, and acid dyspepsia. Subject Suffering from a gastric acid related disorder and inflammation, pain, or fever. In another embodiment, phar 0107. In accordance with another aspect, compositions maceutical compositions disclosed herein are used to protect and methods of the present invention are designed to deliver against an esophageal disorder or esophageal damage. In nonsteroidal anti-inflammatory drugs to reduce inflamma another embodiment, pharmaceutical compositions dis tion, pain, or fever in a patient. The present invention closed herein are used to treat a gastric acid related disorder includes compositions and methods for treating inflamma where treatment with a proton pump inhibitor is indicated, tion or pain by administering to the Subject a composition of and to decrease the risk of cardiovascular disease Such as the present invention. In accordance with one aspect, com heart attack or Stroke by administration of an appropriate positions and methods for treating, preventing, reversing, nonsteroidal anti-inflammatory drug. In Still another halting or Slowing the progression of a inflammatory disor der once it becomes clinically evident, or treating the embodiment, pharmaceutical compositions disclosed herein Symptoms associated with or related to the inflammatory are used to treat a gastric acid related disorder where disorder, by administering to the Subject a composition of treatment with a proton pump inhibitor is indicated, and to the present invention. The Subject may already have an reduce the risk of certain types of cancers by administration inflammatory disorder at the time of administration, or be at of an appropriate nonsteroidal anti-inflammatory drug. risk of developing an inflammatory disorder. The Symptoms 0104 Combination therapies contemplated by the present or conditions of an inflammatory disorder in a Subject can be invention can be used as part of a specific treatment regimen determined by one skilled in the art and are described in intended to provide a beneficial effect from the co-action of Standard textbooks. The method comprises the oral admin the proton pump inhibitor and the nonsteroidal anti-inflam istration a effective amount of one or more compositions of matory drug. In one embodiment of the invention, the proton the present invention to a Subject in need thereof. The pump inhibitor is used to treat a medicament induced effective amount of a nonsteroidal anti-inflammatory agent inflammatory disorder. In another embodiment, the proton may be a therapeutically effective amount or a prophylac pump inhibitor and nonsteroidal anti-inflammatory agent are tically effective amount. Inflammatory disorders suitable for used to prevent cancer of the esophagus or upper gas treatment using compositions and methods of the present trointestinal tract. invention include, but are not limited to, reperfusion injury 0105. It is understood that the dosage regimen to treat, to an ischemic organ (e.g., reperfusion injury to the ischemic prevent, or ameliorate the condition(s) for which relief is myocardium), myocardinal infarction, inflammatory bowel Sought, can be modified in accordance with a variety of disease, rheumatoid arthritis, osteroarthritis, psoriasis, organ factors. These factors include the type of gastric acid dis transplant rejection, inflammation of the ear, eye, throat, order and the inflammatory disorder from which the subject nose or Skin, organ preservation, a female or male Sexual Suffers, the proton pump inhibitor being administered, the dysfunction, radiation-induced injury, asthma, respiratory nonsteroidal anti-inflammatory drug being administered, as disorder, metastasis, influenza, incontinence, Stroke, burn, well as the age, weight, Sex, diet, and medical condition of trauma, acute pancreatistis, pyelonephristis, hepatitis, an the Subject. Thus, the dosage regimen actually employed can autoimmune disease, and immunological disorder, Senile dementia, insulin-dependent diabetes mellitus, disseminated vary widely and therefore can deviate from the dosage intravascular coagulation, fatty embolism, Alzheimer's dis regimens Set forth herein. ease, adult or infantile respiratory disease, carcinogenesis in 0106. In accordance with one aspect, compositions and a neonate, hemorrhage in a neonate, restenosis, atherogen methods of the present invention are designed to produce esis, angina, (e.g., chronic, stable angina pectoris), ischemic release of the proton pump inhibitor to the site of delivery, disease, congestive heart failure or pulmonary edema asso while Substantially preventing or inhibiting acid degradation ciated with acute myocardial infarction, thrombosis, hyper of the proton pump inhibitor. The present invention includes tension (e.g., hypertension associated with cardiovascular compositions and methods for treating, preventing, revers Surgical procedures), platelet aggregation, platelet adhesion, ing, halting or slowing the progression of a gastric acid Smooth muscle cell proliferation, Vascular complications related disorder once it becomes clinically evident, or treat asSociated with the use of medical devices, wounds associ ing the Symptoms associated with or related to the gastric ated with the use of medical devices, cerebrovascular acid related disorder, by administering to the Subject a ischemic events, and the like. In accordance with one aspect, composition of the present invention. The Subject may compositions and methods of the present invention are already have a gastric acid related disorder at the time of useful for treating a Subject Suffering from rheumatoid US 2005/0249806 A1 Nov. 10, 2005

arthritis, osteroarthritis, high fever, familial adenomatous to give rapid relief for an episode of a gastric acid related polyposis, acute or mild pain, or high fever. In accordance disorder, and a long-acting nonsteroidal anti-inflammatory with another aspect, compositions and methods of the drug. In another embodiment, a Subject is administered a present invention are useful for preventing heart attack in a composition including uncoated proton pump inhibitor for Subject at risk thereof. In accordance with another aspect, mulated to provide rapid relief and coated proton pump compositions and methods of the present invention are inhibitor to prevent or treat recurring episodes of the gastric useful for decreasing the risk of an esophageal disorder or acid related disorder, where the composition also contains an esophageal damage. long-acting nonsteroidal anti-inflammatory drug to treat inflammation or pain. In another aspect of the invention, a 0108. In accordance with one aspect, compositions and Subject is administered a composition containing a proton methods of the present invention are useful for treating a pump inhibitor and a long-acting nonsteroidal anti-inflam Subject Suffering from a gastric acid related disorder and an matory drug, wherein at least Some of the long-acting inflammatory disorder. In one embodiment, compositions nonsteroidal anti-inflammatory drug is coated. In yet another and methods of the present invention are used to treat an aspect of the invention, a Subject is administered a compo inflammatory disorder in a Subject and to treat or prevent a Sition containing a proton pump inhibitor and a long-acting medicinment induced gastric-acid related disorder. In another nonsteroidal anti-inflammatory drug, wherein at least Some embodiment, compositions and methods of the present of the long-acting nonsteroidal anti-inflammatory drug is invention are used to treat a Subject Suffering from a gastric coated with an immediate release coating for improved acid related disorder and inflammation, pain, or fever. For a Shelf-life of the pharmaceutical composition. According to particular Subject, the most appropriate formulation or another aspect of the invention, a Subject is administered a method of use of a composition of the present invention may composition containing a proton pump inhibitor and a depend on the type of gastric acid disorder and the time long-acting nonsteroidal anti-inflammatory drug, wherein at period in which the proton pump inhibitor acts to treat the least Some of the long-acting nonsteroidal anti-inflammatory gastric acid related disorder, as well as the type of inflam drug is coated with an enteric coating which is designed for matory disorder and the time period in which the nonste a delayed release of the nonsteroidal anti-inflammatory roidal anti-inflammatory drug treats the inflammatory dis drug. order. 0112 The pharmaceutical agents which make up the 0109) A subject may suffer from a gastric acid related combination therapy disclosed herein may be a combined disorder caused by the nonsteroidal anti-inflammatory drug. dosage form or in Separate dosage forms intended for Alternately, a Subject may Suffer from a gastric acid related Substantially simultaneous administration. The pharmaceu disorder that is not caused by or related to the nonsteroidal tical agents that make up the combination therapy may also anti-inflammatory drug. AS disclosed below, nonsteroidal be administered Sequentially, with either therapeutic com anti-inflammatory drugs useful for treating or preventing pound being administered by a regimen calling for two-step inflammatory disorder are known in the art and composi administration. The two-step administration regimen may tions of the present invention can be formulated to provide call for Sequential administration of the active agents or the appropriate relief depending on the Subject's condition. Spaced-apart administration of the Separate active agents. In accordance with one aspect of the invention, composi The time period between the multiple administration Steps tions and methods of the present invention are useful for may range from, a few minutes to Several hours, depending treating a Subject Suffering from an inflammatory disorder upon the properties of each pharmaceutical agent, Such as and a gastric acid related disorder, that is not associated with potency, Solubility, bioavailability, plasma half-life and the inflammatory disorder or treatment of the inflammatory kinetic profile of the pharmaceutical agent. Circadian varia disorder. Accordingly, compositions and methods of the tion of the target molecule concentration may also determine present invention are useful for treating a Subject who is the optimal dose interval. Suffering from a gastric acid related disorder and is also 0113. The compositions and methods described herein Suffering from an inflammatory disorder. may also be used in conjunction with other well known 0110 Compositions of the present invention can be for therapeutic reagents that are Selected for their particular mulated to treat a gastric acid related disorder and inflam usefulneSS against the condition that is being treated. In matory disorder in accordance with one or both of the general, the compositions described herein and, in embodi conditions for which relief is Sought. AS disclosed below, ments where combinational therapy is employed, other proton pump inhibitors can be formulated to deliver rapid agents do not have to be administered in the same pharma relief and well as Sustained relief of a gastric acid related ceutical composition, and may, because of different physical disorder. AS disclosed below, nonsteroidal anti-inflamma and chemical characteristics, have to be administered by tory drugs can be formulate to be long-acting or to provide different routes. The determination of the mode of admin quick relief from the Symptoms of an inflammatory disorder. istration and the advisability of administration, where pos According to the methods of the invention, the formulation Sible, in the same pharmaceutical composition, is well of the proton pump inhibitor is chosen on the basis of the within the knowledge of the skilled clinician. The initial type of gastric acid related disorder Suffered by the Subject. administration can be made according to established proto According to the methods of the invention, the formulation cols known in the art, and then, based upon the observed of the nonsteroidal anti-inflammatory drug is chosen based effects, the dosage, modes of administration and times of on the the Symptoms of the inflammatory disease in the administration can be modified by the skilled clinician. The Subject. particular choice of compounds used will depend upon the diagnosis of the attending physicians and their judgment of 0111. In one embodiment, a subject is administered a the condition of the patient and the appropriate treatment composition containing a proton pump inhibitor formulated protocol. The compounds may be administered concurrently US 2005/0249806 A1 Nov. 10, 2005

(e.g., simultaneously, essentially simultaneously or within (EP 234485) (Aventis); SKandF-95601 (GSK, discontin the same treatment protocol) or sequentially, depending ued); Pharmaprojects No. 2522 (EP 204215) (Pfizer); upon the nature of the proliferative disease, the condition of S-3337 (Aventis); RS-13232A (Roche); AU-1363 (Merck); the patient, and the actual choice of compounds used. The SKandF-96067 (EP 259174) (Altana); SUN 8176 (Daiichi determination of the order of administration, and the number Phama); Ro-18-5362 (Roche); ufiprazole (EP74341) (Astra of repetitions of administration of each therapeutic agent Zeneca); and Bay-p-1455 (Bayer); or a free base, free acid, during a treatment protocol, is well within the knowledge of Salt, hydrate, ester, amide, enantiomer, isomer, tautomer, the Skilled physician after evaluation of the disease being polymorph, prodrug, or derivative of these compounds. treated and the condition of the patient. 0118 Still other proton pump inhibitors contemplated by 0114) Proton Pump Inhibitors the present invention include those described in the follow ing U.S. Pat. Nos. 4,628,098; 4,689,333; 4,786,505; 4.853, 0115 The terms “proton pump inhibitor,”“PPI,” and 230; 4.965,269; 5,021,433; 5,026,560; 5,045,321; 5,093, “proton pump inhibiting agent' can be used interchangeably 132; 5,430,042; 5,433,959; 5,576,025; 5,639,478; 5,703, to describe any acid labile pharmaceutical agent possessing 110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855, pharmacological activity as an inhibitor of H+/K+-ATPase. 914; 5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187, A proton pump inhibitor may, if desired, be in the form of 340; 6,296,875; 6,319,904; 6,328,994; 4,255.431; 4,508, free base, free acid, Salt, ester, hydrate, anhydrate, amide, 905; 4.636,499; 4,738,974; 5,690,960; 5,714,504; 5,753, enantiomer, isomer, tautomer, prodrug, polymorph, deriva 265; 5,817,338; 6,093,734; 6,013,281; 6,136,344; 6,183, tive, or the like, provided that the free base, Salt, ester, 776; 6.328,994; 6,479,075; 6,559,167. hydrate, amide, enantiomer, isomer, tautomer, prodrug, or any other pharmacologically Suitable derivative is therapeu 0119) Other substituted bicyclic aryl-imidazole com tically active. pounds as well as their Salts, hydrates, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and 0116. In various embodiments, the proton pump inhibitor derivatives may be prepared using Standard procedures can be a Substituted bicyclic aryl-imidazole, wherein the aryl known to those skilled in the art of Synthetic organic group can be, e.g., a pyridine, a phenyl, or a pyrimidine chemistry. See, e.g., March, Advanced Organic Chemistry. group and is attached to the 4- and 5-positions of the Reactions, Mechanisms and Structure, 4th Ed. (New York: imidazole ring. Proton pump inhibitors comprising a Sub Wiley-Interscience, 1992); Leonard et al., Advanced Prac Stituted bicyclic aryl-imidazoles include, but are not limited tical Organic Chemistry (1992); Howarth et al., Core to, omeprazole, hydroxyomeprazole, esomeprazole, lanSo Organic Chemistry (1998); and Weisermel et al., Industrial prazole, pantoprazole, rabeprazole, dontoprazole, habepra Organic Chemistry (2002). Zole, perprazole, tenatoprazole, ranSoprazole, pariprazole, 0120) “Pharmaceutically acceptable salts,” or “salts.” leminoprazole, or a free base, free acid, Salt, hydrate, ester, include, e.g., the Salt of a proton pump inhibitor prepared amide, enantiomer, isomer, tautomer, polymorph, prodrug, from formic, acetic, propionic, Succinic, glycolic, gluconic, or derivative thereof. See, e.g., The Merck Index, Merck & lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, Co. Rahway, N.J. (2001). fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 0117 Other proton pump inhibitors include but are not meSylic, Stearic, Salicylic, p-hydroxybenzoic, phenylacetic, limited to: Soraprazan (Altana); ilaprazole (U.S. Pat. No. mandelic, embonic, methaneSulfonic, ethaneSulfonic, ben 5,703,097) (Il-Yang); AZD-0865 (AstraZeneca); YH-1885 ZeneSulfonic, pantothenic, toluenesulfonic, 2-hydroxy (PCT Publication WO 96/05177) (SB-641257) (2-pyrimidi ethaneSulfonic, Sulfanilic, cyclohexylaminoSulfonic, namine, 4-(3,4-dihydro-1-methyl-2(1H)-isoquinolinyl)-N- algenic, 3-hydroxybutyric, galactaric and galacturonic (4-fluorophenyl)-5,6-dimethyl-monohydrochloride)(Yu acids. Han); BY-112 (Altana); SPI-447 (Imidazo(1,2-a)thieno(3,2- 0121. In one embodiment, acid addition salts are pre c)pyridin-3-amine.5-methyl-2-(2-methyl-3-thienyl) pared from the free base using conventional methodology (Shinnippon); 3-hydroxymethyl-2-methyl-9-phenyl-7H-8.9- involving reaction of the free base with a Suitable acid. dihydro-pyrano (2,3-c)-imidazo(1,2-a)pyridine (PCT Publi Suitable acids for preparing acid addition Salts include both cation WO95/27714) (AstraZeneca); Pharmaprojects No. organic acids, e.g., acetic acid, propionic acid, glycolic acid, 4950 (3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihy pyruvic acid, Oxalic acid, malic acid, malonic acid, Succinic dro-pyrano(2,3-c)-imidazo(1,2-a)pyridine) (AstraZeneca, acid, maleic acid, fumaric acid, tartaric acid, citric acid, ceased) WO 95/27714; Pharmaprojects No. 4891 (EP benzoic acid, cinnamic acid, mandelic acid, methaneSulfonic 700899) (Aventis); Pharmaprojects No. 4697 (PCT Publi acid, ethaneSulfonic acid, p-toluenesulfonic acid, Salicylic cation WO95/32959) (AstraZeneca); H-335/25 (AstraZen acid, and the like, as well as inorganic acids, e.g., hydro eca); T-330 (Saitama 335) (Pharmacological Research Lab); chloric acid, hydrobromic acid, Sulfuric acid, nitric acid, Pharmaprojects No. 3177 (Roche); BY-574 (Altana); Phar phosphoric acid, and the like. maprojects No. 2870 (Pfizer); AU-1421 (EP 264883) (Merck); AU-2064 (Merck); AY-28200 (Wyeth); Phar 0122) In other embodiments, an acid addition salt is maprojects No. 2126 (Aventis); WY-26769 (Wyeth); reconverted to the free base by treatment with a suitable pumaprazole (PCT Publication WO 96/05199) (Altana); base. In a further embodiment, the acid addition salts of the YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publi proton pump inhibitors are halide Salts, which are prepared cation WO 97/32854) (Dainippon); BY-686 (Altana); using hydrochloric or hydrobromic acids. In still other YM-020 (Yamanouchi); GYKI-34655 (Ivax); FPL-65372 embodiments, the basic Salts are alkali metal Salts, e.g., (Aventis); Pharmaprojects No. 3264 (EP 509974) (Astra Sodium Salt and copper Salt. Zeneca); nepaprazole (Toa Eiyo); HN-11203 (Nycomed 0123 Salt forms of proton pump inhibiting agents Pharma); OPC-22575; pumilacidin A (BMS); saviprazole include, but are not limite to: a Sodium Salt form Such as US 2005/0249806 A1 Nov. 10, 2005

eSomeprazole Sodium, omeprazole Sodium, rabeprazole ticles; H =Stationary layer thickness, CS=concentration of Sodium, pantoprazole Sodium; or a magnesium Salt form Solution at Saturation; and C=concentration of Solution at Such as esomeprazole magnesium or omeprazole magne time t. sium, described in U.S. Pat. No. 5,900,424; a calcium salt form; or a potassium Salt form Such as the potassium Salt of 0132 Because omeprazole, as well as other proton pump eSomeprazole, described in U.S. patent application Ser. No. inhibitors, has poor water Solubility, to aid the rapid absorp 02/0198239 and U.S. Pat. No. 6,511,996. Other salts of tion of the drug product, various embodiments of the present esomeprazole are. described in U.S. Pat. Nos. 4,738,974 and invention use micronized proton pump inhibitor is used in 6,369,085. Salt forms of pantoprazole and lansoprazole are the drug product formulation. discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respec 0133. In some embodiments, the average particle size of tively. at least about 90% the micronized proton pump inhibitor is 0.124. In one embodiment, preparation of esters involves less than about 40 um, or less than about 35 um, or less than functionalization of hydroxyl and/or carboxyl groups which about 30 lum, or less than about 25 lum, or less than about 20 may be present within the molecular Structure of the drug. In tim, or less than about 15 lum, or less than about 10 um. In one embodiment, the esters are acyl-Substituted derivatives other embodiments, at least 80% of the micronized proton of free alcohol groups, e.g., moieties derived from carboxy pump inhibitor has an average particle size of less than about lic acids of the formula RCOOR where R is a lower alkyl 40 um, or less than about 35 um, or less than about 30 um, group. Esters can be reconverted to the free acids, if desired, or less than about 25 tim, or less than about 20 um, or less by using conventional procedures Such as hydrogenolysis or than about 15 lum, or less than about 10 um. In still other hydrolysis. embodiments, at least 70% of the micronized proton pump inhibitor has an average particle Size of less than about 40 0.125 “Amides' may be prepared using techniques tim, or less than about 35 um, or less than about 30 um, or known to those skilled in the art or described in the pertinent less than about 25 tim, or less than about 20 um, or less than literature. For example, amides may be prepared from esters, about 15 tim, or less than about 10 lim. using Suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with an amine 0.134 Compositions are provided wherein the micronized group Such as ammonia or a lower alkyl amine. proton pump inhibitor is of a size which allows greater than 75% of the proton pump inhibitor to be released within about 0.126 “Tautomers” of substituted bicyclic aryl-imida 1 hour, or within about 50 minutes, or within about 40 Zoles include, e.g., tautomers of omeprazole Such as those minutes, or within about 30 minutes, or within about 20 described in U.S. Pat. Nos. 6,262,085; 6,262,086; 6,268, minutes, or within about 10 minutes or within about 5 385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; and minutes of dissoluion testing. In another embodiment of the 6,444,689; and U.S. Patent Publication No. 02/0156103. invention, the micronized proton pump inhibitor is of a size 0127. An exemplary “isomer' of a substituted bicyclic which allows greater than 90% of the proton pump inhibitor aryl-imidazole is the isomer of omeprazole including but not to be released within about 1 hour, or within about 50 limited to isomers described in: Oishi et al., Acta Cryst. minutes, or within about 40 minutes, or within about 30 (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. minutes, or within about 20 minutes, or within about 10 Patent Publication No. 02/0156284; and PCT Publication minutes or within about 5 minutes of dissolution testing. See No. WO 02/085889. U.S. Provisional Application No. 60/488,324 filed Jul. 18, 2003, which is incorporated by reference in its entirety. 0128 Exemplary “polymorphs' include, but are not lim ited to, those described in PCT Publication No. WO 0135 Buffering Agents 92/08716, and U.S. Pat. Nos. 4,045,563; 4,182,766; 4,508, 0.136 The pharmaceutical composition of the invention 905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783, comprises one or more buffering agents. A class of buffering 974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013, agents useful in the present invention include, but are not 743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093, limited to, buffering agents possessing pharmacological 342; 5,433,959; 5,464,632; 5,536,735; 5,576,025; 5,599, activity as a weak base or a Strong base. In one embodiment, 794; 5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705, the buffering agent, when formulated or delivered with an 517; 5,714,504; 5,731,006; 5,879,708; 5,900,424; 5,948, proton pump inhibiting agent, functions to Substantially 773; 5,997,903; 6,017,560; 6,123,962; 6:147; 103; prevent or inhibit the acid degradation of the proton pump 6,150;380; 6:166,213; 6, 191;148; 5,187,340; 6,268,385; inhibitor by gastrointestinal fluid for a period of time, e.g., 6,262,086: 6,262,085; 6,296,875; 6,316,020; 6,328,994; for a period of time sufficient to preserve the bioavailability 6,326,384; 6,369,085; 6,369,087; 6,380,234; 6,428,810; of the proton pump inhibitor administered. The buffering 6,444,689; and 6,462,0577. agent can be delivered before, during and/or after delivery of 0129 Micronized Proton Pump Inhibitor the proton pump inhibitor. In one aspect of the present invention, the buffering agent includes a Salt of a Group IA 0130 Particle size of the proton pump inhibitor can affect metal (alkali metal), including, e.g., a bicarbonate Salt of a the Solid dosage form in numerous ways. Since decreased Group IA metal, a carbonate Salt of a Group IA metal; an particle size increases in Surface area (S), the particle size alkaline earth metal buffering agent (Group IIA metal); an reduction provides an increase in the rate of dissolution aluminum buffering agent; a calcium buffering agent, or a (dM/dt) as expressed in the Noyes-Whitney equation below: magnesium buffering agent. 0.137 Other buffering agents suitable for the present 0131 M=mass of drug dissolved; t=time; D=diffusion invention include, e.g., alkali metal (a Group IA metal coefficient of drug, S=effective Surface area of drug par including, but not limited to, lithium, Sodium, potassium, US 2005/0249806 A1 Nov. 10, 2005 rubidium, cesium, and francium) or alkaline earth metal are each present in about 0.1 mEq/mg proton pump inhibitor (Group IIA metal including, but not limited to, beryllium, to about 5 mEq/mg proton pump inhibitor. In Still another magnesium, calcium, strontium, barium, radium) carbon embodiment, the buffering agent is a mixture of at least two ates, phosphates, bicarbonates, citrates, borates, acetates, bufferS Selected from Sodium bicarbonate, calcium carbon phthalates, tartrate, Succinates and the like, Such as Sodium ate, and magnesium hydroxide, wherein each buffer is or potassium phosphate, citrate, borate, acetate, bicarbonate present in about 0.1 mEq/mg proton pump inhibitor to about and carbonate. 5 mEq/mg of the proton pump inhibitor. 0.138. In various embodiments, a buffering agent includes 0141 Compositions are provided as described herein, an amino acid, an alkali metal Salt of an amino acid, wherein the buffering agent is present in an amount of about aluminum hydroxide, aluminum hydroxide/magnesium car 0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibi bonate/calcium carbonate co-precipitate, aluminum magne tor, or about 0.25 mEq/mg to about 3 mEq/mg of the proton sium hydroxide, aluminum hydroxide/magnesium hydrox pump inhibitor, or about 0.3 mEq/mg to about 2.5 mEq/mg ide co-precipitate, aluminum hydroxide/sodium bicarbonate of the proton pump inhibitor, or about 0.4 mEq/mg to about coprecipitate, aluminum glycinate, calcium acetate, calcium 2.0 mEq/mg of the proton pump inhibitor, or about 0.5 bicarbonate, calcium borate, calcium carbonate, calcium mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor. citrate, calcium gluconate, calcium glycerophosphate, cal Compositions are provided as described herein, wherein the cium hydroxide, calcium lactate, calcium phthalate, calcium buffering agent is present in an amount of at least 0.25 phosphate, calcium Succinate, calcium tartrate, dibasic mEq/mg to about 2.5 mEq/mg of the proton pump inhibitor, Sodium phosphate, dipotassium hydrogen phosphate, dipo or at least about 0.4 mEq/mg of the proton pump inhibitor. tassium phosphate, disodium hydrogen phosphate, disodium Succinate, dry aluminum hydroxide gel, L-arginine, magne 0142. In one aspect of the invention, compositions are Sium acetate, magnesium aluminate, magnesium borate, provided wherein the buffering agent is present in the magnesium bicarbonate, magnesium carbonate, magnesium pharmaceutical compositions of the present invention in an citrate, magnesium gluconate, magnesium hydroxide, mag amount of about 1 mEq to about 160 mEq per dose, or about nesium lactate, magnesium metasilicate aluminate, magne 5 mEq, or about 10 mEq, or about 11 mEq, or about 15 mEq, sium oxide, magnesium phthalate, magnesium phosphate, or about 19 mEq, or about 20 mEq, or about 22 mEq, or magnesium Silicate, magnesium Succinate, magnesium tar about 23 mEq, or about 24 mEq, or about 25 mEq, or about trate, potassium acetate, potassium carbonate, potassium 30 mEq, or about 31 mEq, or about 35 mEq, or about 40 bicarbonate, potassium borate, potassium citrate, potassium mEq, or about 45 mEq or about 50 mEq, or about 60 mEq, metaphosphate, potassium phthalate, potassium phosphate, or about 70 mEq, or about 80 mEq, or about 90 mEq, or potassium polyphosphate, potassium pyrophosphate, potas about 100 mEq, or about 110 mEq, or about 120 mEq, or sium Succinate, potassium tartrate, Sodium acetate, Sodium about 130 mEq, or about 140 mEq, or about 150 mEq, or bicarbonate, Sodium borate, Sodium carbonate, Sodium cit about 160 mEq per dose. rate, Sodium gluconate, Sodium hydrogen phosphate, Sodium 0143. In another aspect of the invention, compositions hydroxide, Sodium lactate, Sodium phthalate, Sodium phos are provided wherein the buffering agent is present in the phate, Sodium polyphosphate, Sodium pyrophosphate, composition in an amount, on a weight to weight (w/w) Sodium Sesquicarbonate, Sodium Succinate, Sodium tartrate, basis, of more than about 5 times, or more than about 10 Sodium tripolyphosphate, Synthetic hydrotalcite, tetrapotas times, or more than about 20 times, or more than about 30 sium pyrophosphate, tetrasodium pyrophosphate, tripotas times, or more than about 40 times, or more than about 50 sium phosphate, trisodium phosphate, and trometamol. (See, times, or more than about 60 times, or more than about 70 e.g., lists provided in The Merck Index, Merck & Co. times, or more than about 80 times, or more than about 90 Rahway, N.J. (2001)). Certain proteins or protein hydroly times, or more than about 100 times the amount of the proton Sates that rapidly neutralize acids can Serve as buffering pump inhibiting agent. agents in the present invention. Combinations of the above mentioned buffering agents can be used in the pharmaceu 0144. In another aspect of the invention, compositions tical compositions described herein. are provided wherein the amount of buffering agent present in the pharmaceutical composition is between 200 and 3500 0.139. The buffering agents useful in the present invention mg. In Some embodiments, the amount of buffering agent also include buffering agents or combinations of buffering present in the pharmaceutical composition is about 200 mg, agents that interact with HCl (or other acids in the environ or about 300 mg, or about 400 mg, or about 500 mg, or about ment of interest) faster than the proton pump inhibitor 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, interacts with the Same acids. When placed in a liquid phase, or about 1000 mg, or about 1100 mg, or about 1200 mg, or Such as water, these buffering agents produce and maintain about 1300 mg, or about 1400 mg, or about 1500 mg, or a pH greater than the pKa of the proton pump inhibitor. about 1600 mg, or about 1700 mg, or about 1800 mg, or 0140. In various embodiments, the buffering agent is about 1900 mg, or about 2000 mg, or about 2100 mg, or Selected from Sodium bicarbonate, Sodium carbonate, cal about 2200 mg, or about 2300 mg, or about 2400 mg, or cium carbonate, magnesium oxide, magnesium hydroxide, about 2500 mg, or about 2600 mg, or about 2700 mg, or magnesium carbonate, aluminum hydroxide, and mixtures about 2800 mg, or about 2900 mg, or about 3000 mg, or thereof. In another embodiment, the buffering agent is about 3200 mg, or about 3500 mg. Sodium bicarbonate and is present in about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump 0145 NSAIDS inhibitor. In yet another embodiment, the buffering agent is 0146 Nonsteroidal anti-inflammatory drugs are useful a mixture of Sodium bicarbonate and magnesium hydroxide, for the treatment of inflammatory disorders. AS used herein wherein the Sodium bicarbonate and magnesium hydroxide “inflammatory disorder” includes, for example, reperfusion US 2005/0249806 A1 Nov. 10, 2005 injury to an ischemic organ (e.g., reperfusion injury to the Zole, and epirozole, pyrazolones Such as apaZone, benzpip ischemic myocardium), myocardinal infarction, inflamma erylon, feprazone, mofebutaZone, moraZone, oxyphenbuta tory bowel disease, rheumatoid arthritis, osteroarthritis, pSo Zone, phenylbutaZone, pipebuZone, propyphenaZone, riasis, organ transplant rejection, inflammation of the ear, prostaglandins, ramifenaZone, SuxibuZone, and thiazolinob eye, throat, nose or Skin, organ preservation, a female or utaZone, Salicylic acid derivatives Such as acetaminoSalol, male Sexual dysfunction, radiation-induced injury, asthma, aspirin, benorylate, bromosaligenin, calcium acetylsalicy respiratory disorder, metastasis, influenza, incontinence, late, diflunisal, etersalate, fendosal, gentisic acid, glycol Stroke, burn, trauma, acute pancreatistis, pyelonephristis, Salicylate, imidazole Salicylate, lysine acetylsalicylate, hepatitis, an autoimmune disease, and immunological dis meSalamine, morpholine Salicylate, 1-naphtyl Salicylate, order, Senile dementia, insulin-dependent diabetes mellitus, olsalazine, parSalmide, phenyl acetylsalicylate, phenyl Sali disseminated intravascular coagulation, fatty embolism, cylate, Salacetamide, Salicylamide O-acetic acid, Salicylsul Alzheimer's disease, adult or infantile respiratory disease, furic acid, Salsalate, SulfaSalazine; thiazinecarboxamides carcinogenesis in a neonate, hemorrhage in a neonate, Such as ampiroXicam, droxicam, isoxicam, lomoxicam, restenosis, atherogenesis, angina, (e.g., chronic, stable piroXicam, and tenoxicam, cyclooxygenase-II inhibitors angina pectoris), ischemic disease, congestive heart failure (“COX-II”) such as Celebrex (Celecoxib), Vioxx, Relafen, or pulmonary edema associated with acute myocardial inf Lodine, and Voltaren and others, Such as epsilon-acetami arction, thrombosis, hypertension (e.g., hypertension asso docaproic acid, S-adenosylmethionine, 3-amino-4-hydroxy ciated with cardiovascular Surgical procedures), platelet butytic acid, amiXetrine, bendazac, benzydamine, C.-bisab aggregation, platelet adhesion, Smooth muscle cell prolif olol, bucololome, difenpiramide, ditaZol, emorfaZone, eration, Vascular complications associated with the use of fepradinol, guaiaZulene, nabumetone, nimeSulide, medical devices, wounds associated with the use of medical Oxaceprol, paranyline, perisoxal, proguaZone, tenidap and devices, cerebrovascular ischemic events, and the like. Zilenton. Additionally, the nonsteroidal anti-inflammatory 0147 In accordance with one aspect of the invention, drug may be a specific enantiomer of a nonsteroidal anti compositions and methods are provided to alleviate Symp inflammatory drug. toms of an inflammatory disorder. In accordance with 0150. According to one aspect of the invention, compo another aspect of the invention, compositions and methods Sitions and methods including long-acting nonsteroidal anti are provided to treat or prevent an inflammatory disorder, inflammatory drugs. Such as naproxen Sodium, flurbiprofen, including Symptoms of the inflammatory disorder. ketoprofen, Oxaprozin, indomethacin, ketoralac, nabume tone, mefenamic, piroXicam, and COX-II inhibitors are 0.148. In accordance with one aspect of the invention, useful. “Long-acting,” in relation to NSAIDs, shall mean a compositions and methods are provided to treat or prevent pharmacokinetic half-life of at least about 2 hours, at least an inflammatory disorder and to treat or prevent a medica about 4 hours, and at least about 8-14 hours, where the ment induced gastric related disorder. A "medicament duration of action is equal to or exceeding about 6-8 hours. induced gastric related disorder” includes gastric ulcers Exemplary long-acting NSAIDs include: flurbiprofen with a induced or associated with the use of a medicament Such as half-life of about 6 hours; ketoprofen with a half-life of NSAIDs including selective COX-II inhibitors and nitric about 2 to 4 hours, naproxen and naproxen Sodium with oxide donor/nonsteroidal anti-inflammatory drugs (NO half-lives of about 12 to 15 hours and about 12 to 13 hours NSAIDs). In accordance with another aspect of the inven respectively; oxaprozin with a half-life of about 42 to 50 tion, compositions and methods are provided to treat an hours, etodolac with a half-life of about 7 hours; indometha inflammatory disorder and to treat a medicament induced cin with a half-life of about 4 to 6 hours; ketorolac with a gastric related disorder, wherein the medicament induced half-life of up to about 8-9 hours; nabumetone with a gastric related disorder is the result of prolonged use of one half-life of about 22 to 30 hours, mefenamic acid with a or more nonsteroidal anti-inflammatory drugs. half-life of up to about 4 hours; and piroxicam with a 0149 Examples of suitable nonsteroidal anti-inflamma half-life about of about 4 to 6 hours. Additionally, various tory drugs include, but are not limited to, aminoarylcarboxy NSAIDs not naturally having half-lives sufficient to be lic acid derivatives Such as enfenamic acid, etofenamate, long-acting, can be formulated into long-acting nonsteroidal flufenamic acid, isonixin, meclofenamic acid, mefenamic anti-inflammatory drugs. Methods for making appropriate acid, niflumic acid, talniflumate, terofenamate, and tolfe long-acting formulations are well known in the art. See, e.g., namic acid, arylacetic acid derivatives Such as aceclofenac, Remington's Pharmaceutical Sciences, 16" ed., A. Oslo acemetacin, alclofenac, amfenac, amtolimetin guacil, bro editor, Easton, Pa. (1980); and Controlled Drug Delivery, mfenac, bufeXamac, cinmetacin, clopirac, diclofenac Edith Mathiowitz, John Wiley & Sons (1999), ISBN: Sodium, etodolac, felbinac, fenclozic acid, fentiazac, gluca 04711.48288. metacin, ibufenac, indomethacin, isofeZolac isoxepac, lona 0151. According to one aspect of the invention, it may Zolac, metiaZinic acid, mofeZolac, Oxametacine, piraZolac, also be useful to coat the nonsteroidal anti-inflammatory proglumetacin, Sulindac, tiaramide, tolmetin, tropesin, and drug. Sutiable coatings include, but are not limited to, gastric Zomepirac, arylbutyric acid derivatives Such as bumadizon, resistant coatings Such as enteric coatings (See, e.g., WO91/ butibufen, fenbufen, Xenbucin, arylcarboxylic acids Such as 16895 and WO91/16886), controlled-release coatings, enzy clidanac, ketorolac, tinoridine, arylpropionic acid deriva matic-controlled coatings, film coatings, Sustained-release tives Such as alminoprofen, benoxaprofin, bermoprofen, coatings, immediate-release coatings, and delayed-release bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbi coatings. According to another aspect of the invention, it profen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loXo may be useful to formulate the the NSAID into delayed profen, naproxen, Oxaprozin, piketoprofin, pirprofen, prano release coated beads, pellets, or granules. According to profen, protizinic acid, Suprofen, tiaprofenic acid, various aspects of the invention, the coating may be useful Ximoprofen, and Zaltoprofen; pyrazoles Such as difenami for enhancing the Stability of the pharmaceutical composi US 2005/0249806 A1 Nov. 10, 2005 17 tons of the present invention or for enabling a pharmaceu the art will understand that any NSAID that has been tical release profile of the nonsteroidal anti-inflammatory approved for use in a Subject could be used in the compo drug useful for the Successful treatment of an inflammatory Sitions and methods of the present invention. Of course, the disorder. amount of NSAID actually administered to a subject will be dependent upon the age, weight, and general condition of the 0152 Commonly Used NSAIDs Subject, the condition being treated, the Severity of the 0153. The following table represents a partial listing of condition being treated, and the judgment of the prescribing NSAIDs suitable for the present invention. One of skill in physician.

TABLE 1.

REPRESENTATIVE NSAIDS AND THEIR EFFECTIVE DOSAGES* Drug Name Trade Name Exemplary Effective Dosages Diclofenac Voltaren: 50-100 mgs once or twice daily; maximum daily dose (Benzeneacetic Cataflam; of 225 mgs Acid Derivative) Diclowal 75INJ; Olfen Diclofenac Cataflam; Osteoarthritis: 100-150 mgs a day divided into smaller Potassium Voltaren: doses of 50 milligrams two or three times daily (for (Benzeneacetic Voltaren XR Voltaren or Cataflam) or 75 milligrams twice daily Acid Derivative) (for Voltaren); Voltaren-XR (extended-release) 100 mgs once daily. Rheumatoid Arthritis: 100-200 mgs daily; maximum daily dose of 225 mgs. Ankylosing Spondylitis: 100-125 mgs a day. Pain and menstrual discomfort: 50 mgs every 8 hours; or a starting dose of 100 mgs followed by two 50-mg doses. Etodolac Lodine; Lodine 200-400 mgs two to three times daily; 400-1200 mgs (Pyranocarboxylic XL once a day; maximum daily dose of 1200 mgs. Acid Derivative) Fenoprofen Nalfon 200-600 mgs. Flurbiprofen Oral Ansaid 300 mgs per day. (Phenylalkanoic Acid Derivative) Ibuprofen Advil; Motrin; 200-800 mgs three to four times daily; maximum daily (Propionic Acid Nuprin; dose of 1200 mgs. Derivative) Genpril; Midol; Menadol; Haitian: Brufen Asprin Bayer; Excedrin 50-1000 mgs per dose. (Salicilic Acid Migraine; Derivative) Astrix (enteric Coated); Cartia (Duentric Coated) Aspirin Sachet Aspegic 100-1000 mgs per dose. Aspirin + Caffeine Cafenol 500 mgs aspirin/30 mgs caffeine. Mornifluate Nifluri 700 mgs daily dose. Tramadol Tramal 50-100 mgs every 6 hours. Ketorolac Toradol IV: 15-30 mg ever 6 hours with maximum daily dose of 120 mgs; oral: 10 mgs every 4 to 6 hours with maximum dose of 40 mgs. Indomethacin Indocin; 25-50 mg three times daily; 75 mgs once or twice (Indole Derivative) Indocin SR: daily; suppositories 25-50 mgs three times daily; Indocin maximum daily dose of 200 mgs. Suppositories Ketoprofen Orudis; Oruvail 25-75 mgs three to four times daily; 200 mgs once (Arylacetic Acid daily; maximum daily dose of 300 mgs. Derivative) Meclofenamate Meclomen 50-100 mgs every 4-6 hours; maximum daily dose of (Anthranilic Acid) 400 mgs. Meloxicam Mobic 7.5-15 mgs once or twice daily; maximum daily dose (Oxicam of 15 mgs. Derivative) Nabumetone Relafen 000 mgs orally once or twice daily; maximum daily (Naphthyalkanone) dose of 2000 mgs. Naproxen Sodium Anaprox; EC- Mild to Moderate Pain, Menstrual Cramps, Acute (Arylacetic Acid Naprosyn Tendinitis and Bursitis: 550 mgs followed by 275 mgs Derivative) every 6 to 8 hours; 550 mgs every 12 hours; maximum daily dose of 1,375 mgs. Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis: 275-550 mgs twice daily. Acute Gout: 825 mgs followed by 275 mgs every 8 hours. US 2005/0249806 A1 Nov. 10, 2005 18

TABLE 1-continued

REPRESENTATIVE NSAIDS AND THEIR EFFECTIVE DOSAGES* Drug Name Trade Name Exemplary Effective Dosages Naproxen Naprosyn; 250-500 mgs twice daily; 750-1000 mgs once daily; (Arylacetic Acid) Naproxyn XL: maximum daily dose of 1375 mgs. Aleve; Naprelan Choline Trilisate Rheumatoid arthritis, osteoarthritis, more severe Magnesium arthritis, and acute painful shoulder: 1500 mgs twice Trisalicylate daily or 3,000 mgs once daily. (Salicylate) Mild to moderate pain or to reduce a high fever: 2,000-3,000 mgs daily. Oxaprozin Daypro 200 mgs once daily; maximum daily dose of 1800 (Propionic Acid mgs or 26 mgs per 2.2 lbs of body weight, whichever Derivative) is lower. Piroxicam Feldene: Rheumatoid Arthritis and Osteoarthritis: 20 mgs once (Oxicam Movon-20; daily. Derivative) Tolimetin Tolectin; Rheumatoid Arthritis or Osteoarthritis: 600-1,800 (Pyrroleacetic Tollectin DS mgs usually divided into 3 doses taken daily. Acid) Diflunisal Dolobid 250-500 mgs once or twice daily. Nabumentone Relafen -2 grams daily. Etodallac Ultradol 200-400 mgs once or twice daily. Floctafenine Idarac 200-400 mgs once or twice daily. Sulindac (Indene Clinoril 50-200 mgs twice daily; maximum daily dose of 400 Derivative) mgs. Osteoarthritis: 200 mgs once daily or 100 mgs twice daily. Rheumatoid Arthritis: 100-200 mgs twice daily. Acute Pain and Menstrual Cramps: 400 mgs, followed by an additional 200 mgs if needed on the first day. On Subsequent days, 200 mgs twice daily. Familial Adenomatous Polyposis: 400 mgs twice daily. Tenoxicam Mobiflex; 7.5-20 mgs daily dose. Tilcotill Tabs Tiaprophenic Acid Surgam 300 mgs once or twice daily. Mefenamic Acid Ponstyl; Mefac; 500 mgs as initial dose followed by 250 mgs evert 6 (Fenamate) Ponstan; hours. Diclofenac Diclofenac 100-200 mgs once or twice daily. (Benzene Acetic Acid Derivative) Aceclofenac Arital 100 mgs once or twice daily. (PhenylAcetic Acid Derivative) Morniflumate 750-1500 mgs daily in two or three doses. (Niflumic Acid) Diflunisal Dolobid Mild to Moderate Pain: Starting dose of 1,000 mgs (Salicylate) followed by 500 milligrams every 8 to 12 hours; Maximum daily dosage of 1,500 mgs. Osteoarthritis and Rheumatoid Arthritis: 250-500 mgs twice daily. Salsalate Disalcid 3000 mgs daily divided every 8-12 hours. (Salicylate) Valdecoxib (COX- Bextra Osteoarthritis and Rheumatoid Arthritis: 10 mgs once II inhibitor) daily. Painful Menstruation: 20 mgs twice daily. Celecoxib (COX-II Celebrex Osteroarthritis: 100 mgs once or twice daily inhibitor) Rheumatoid arthritis: 200 mgs once or twice daily Rofecoxib (COX-II Vioxx Osteroarthritis: 12.5–25 mgs once daily. inhibitor) Acute Pain: 50 mgs once daily. *For other dosages see any recent Physician's Desk Reference; Dosages are oral unless other wise indicated.

0154 Stability Enhancers anti-inflammatory drug, or the buffering agent, in order to O155 Stability enhancers are described in U.S. applica enhance the shelf-life of the composition. See U.S. Provi tion Ser. No. 10/893,203 filed Jul. 16, 2004, which is sional Application No. 60/488,321 filed Jul.18, 2003, which incorporated herein by reference in its entirety. is incorporated by reference in its entirety. Materials useful 0156. In accordance with one aspect of the present inven for enhancing the shelf-life of the pharmaceutical composi tion, compositions may include microencapsulation of one tions of the present invention include materials compatible or more of the proton pump inhibitor; the nonsteroidal with the proton pump inhibitor of the pharmaceutical com US 2005/0249806 A1 Nov. 10, 2005 positions which Sufficiently isolate the proton pump inhibi dation after one month of Storage at room temperature, or tor from other non-compatible excipients. Materials com less than about 1% degradation after one month at room patible with the proton pump inhibitors of the present temperature, or less than about 1.5% degradation after one invention are those that enhance the shelf-life of the proton month of Storage at room temperature, or less than about 2% pump inhibitor, i.e., by slowing or stopping degradation of degradation after one month Storage at room temperature, or the proton pump inhibitor. less than about 2.5% degradation after one month of Storage O157 Exemplary microencapsulation materials useful for at room temperature, or less than about 3% degradation after enhancing the shelf-life of pharmaceutical compositions one month of Storage at room temperature. comprising a proton pump inhibitor include, but are not 0162. In other embodiments, a pharmaceutical composi limited to: cellulose hydroxypropyl ethers (HPC) such as tion of the present invention may have an enhanced shelf Klucel(R) or Nisso HPC; low-substituted hydroxypropyl life Stability if the pharmaceutical composition contains leSS ethers (L-HPC); cellulose hydroxypropyl methyl ethers than about 5% total impurities after about 3 years of storage, (HPMC) such as Seppifilm-LC, Pharmacoat(R), Metolose or after about 2.5 years of Storage, or about 2 years of SR, Opadry YS, PrimaFlo, Benecel MP824, and Benecel Storage, or about 1.5 years of Storage, or about 1 year of MP843; methylcellulose polymers such as Methocel(R) and Storage, or after 11 months of Storage, or after 10 months of Metolose(R); Ethylcelluloses (EC) and mixtures thereof such Storage, or after 9 months of Storage, or after 8 months of as E461, Ethocel(R), Aqualon(RD-EC, Surelease(R); Polyvinyl Storage, or after 7 months of Storage, or after 6 months of alcohol (PVA) such as Opadry AMB; hydroxyethylcellulo Storage, or after 5 months of Storage, or after 4 months of ses such as Natrosol(R); carboxymethylcelluloses and salts of Storage, or after 3 months of Storage, or after 2 months of carboxymethylcelluloses (CMC) such as Aqualon(R)-CMC; Storage, or after 1 month of Storage. polyvinyl alcohol and polyethylene glycol co-polymerS Such as Kollicoat IRS; monoglycerides (Myverol), triglycerides 0163. In further embodiments, a pharmaceutical compo (KLX), polyethylene glycols, modified food Starch, acrylic Sitions of the present invention may have an enhanced polymers and mixtures of acrylic polymers with cellulose Shelf-life Stability if the pharmaceutical composition con ethers such as Eudragit(R) EPO, Eudragit(R) RD100, and tains leSS degradation of the proton pump inhibitor than EudragitE E 100; cellulose acetate phthalate; sepifilms such proton pump inhibitor in the same formulation where the as mixtures of HPMC and stearic acid, cyclodextrins; and proton pump inhibitor or non-Steroidal anti-inflammatory mixtures of these materials. agent are not microencapsulated, or the non-Steroidal anti inflammatory drug is not coated, Sometimes referred to as 0158. In various embodiments, a buffering agent such as “bare.” For example, if proton pump inhibitor in the phar Sodium bicarbonate is incorporated into the microencapsu maceutical composition degrades at room temperature by lation material: In other embodiments, an antioxidant Such more than about 2% after one month of Storage and the as BHT is incorporated into the microencapsulation mate microencapsulated or coated material degrades at room rial. In Still other embodiments, plasticizerS Such as poly temperature by less than about 2% after one month of ethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG Storage, then the proton pump inhibitor has been microen 1450, PEG 3350, and PEG 800, stearic acid, propylene capsulated with a compatible material that enhances the glycol, oleic acid, and triacetin are incorporated into the Shelf-life of the pharmaceutical composition, or the nonste microencapsulation material. In other embodiments, the roidal anti-inflammatory drug has been coated with a com microencapsulating material useful for enhancing the shelf patible material that enhances the shelf-life of the pharma life of the pharmaceutical compositions is from the USP or ceutical composition. the National Formulary (NF). 0164. In some embodiments, the pharmaceutical compo 0159. In further embodiments, one or more other com sitions have an increased shelf-life stability of at least about patible materials are present in the microencapsulation mate 5 days at room temperature, or at least about 10 days at room rial. Exemplary materials include, but are not limited to, pH temperature, or at least about 15 days at room temperature, modifiers, parietal cell activators, erosion facilitators, diffu or at least about 20 days at room temperature, or at least Sion facilitators, anti-adherents, anti-foaming agents, anti about 25 days at room temperature, or at least about 30 days oxidants, flavoring agents, and carrier materials. Such as at room temperature or at least about 2 months at room binders, Suspending agents, disintegration agents, filling temperature, or at least about 3 months at room temperature, agents, Surfactants, Solubilizers, Stabilizers, lubricants, wet or at least about 4 months at room temperature, or at least ting agents, and diluents. about 5 months at room temperature, or at least about 6 0160 According to one aspect of the invention, the months at room temperature, or at least about 7 months at nonsteroidal anti-inflammatory drug is coated. The coating room temperature, or at least about 8 months at room may be, for example, a gastric resistant coating Such as an temperature or at least about 9 months at room temperature, enteric coating (See, e.g., WO91/16895 and WO91/16886), or at least about 10 months at room temperature, or at least a controlled-release coating, an enzymatic-controlled coat about 11 months at room temperature, or at least about one ing, a film coating, a Sustained-release coating, an immedi year at room temperature, or at least about 1.5 years at room ate-release coating, or a delayed-release coating. According temperature, or at least about 2 years at room temperature, to another aspect of the invention, the coating may be useful or at least about 2.5 years at room temperature, or about 3 for enhancing the Stability of the pharmaceutical composi years at room temperature. tons of the present invention. 0.165. In some embodiments of the present invention, the 0.161 A pharmaceutical composition of the present final formulation of the pharmaceutical composition will be invention may have an enhanced shelf-life Stability if, e.g., in the form of a tablet or caplet and at least about 50%, or the proton pump inhibitor has less than about 0.5% degra at least about 55%, or at least about 60%, or at least about US 2005/0249806 A1 Nov. 10, 2005 2O

65%, or at least about 70%, or at least about 75%, or at least nation tests for testing differences between Samples and for about 80%, or at least about 85% or at least about 90%, or ranking a Series of Samples in order of a specific character at least about 92%, or at least about 95%, or at least about istic, Scaling tests used for Scoring the Specific product 98%, or at least about 99% of the microspheres survive the attributes Such as flavor and appearance; expert tasters used tabletting process, wherein microSpheres that have Survived to both quantitatively and qualitatively evaluate a specific the manufacturing process are those which provide the Sample, affective tests for either measuring the response desired properties described herein. between two products, measuring the degree of like or 0166 In other embodiments, the final formulation of the dislike of a product or Specific attribute, or determine the pharmaceutical composition is in the form of a powder for appropriateness of a specific attribute; and descriptive meth oral Suspension and the microencapsulation material Sur ods used in flavor profiling to provide objective description rounding the proton pump inhibitor or nonsteroidal anti of a product are all methods used in the field. inflanimatory agent or the coating Surrounding the non 0173 Different sensory qualities of a pharmaceutical Steroidal anti-inflammatory agent will Sufficiently dissolve composition Such as aroma, flavor, character notes, and in water, with or without Stirring, in less than 1 hour, or leSS aftertaste can be measured using tests know in the art. See, than 50 minutes, or less than 40 minutes, or less than 30 e.g., Roy et al., Modifying Bitterness. Mechanism, Ingredi minutes, or less than 25 minutes, or less than 20 minutes, or ents, and Applications (1997). For example, aftertaste of a less than 15 minutes, or less than 10 minutes or less than 5 product can be measured by using a time VS. intensity minutes, or less than 1 minute. “Sufficiently dissolves' Sensory measurement. ASSays have been developed to alert means that at least about 50% of the encapsulation or coating a processor of formulations to the bitter taste of certain material has dissolved. Substances. Using information known to one of ordinary 0167. In various embodiments the material useful for skill in the art, one would readily be able to determine enhancing the Shelf-life of the pharmaceutical composition whether one or more Sensory quality of a pharmaceutical Sufficiently disintegrates to release the proton pump inhibitor composition of the present invention has been improved by into the gastrointestinal fluid of the Stomach within less than the use of the taste-masking material. about 1.5 hours, or within about 10 minutes, or within about 0.174 Taste of a pharmaceutical composition is important 20 minutes, or within about 30 minutes, or within about 40 for both increasing patient compliance as well as for com minutes, or within about 50 minutes, or within about 1 hour, peting with other marketed products used for Similar dis or within about 1.25 hours, or within about 1.5 hours after eases, conditions and disorders. Taste, especially bitterness, exposure to the gastrointestinal fluid. Sufficiently disinte is particularly important in pharmaceutical compositions for grates means that at least about 50% of the microencapsu children Since, because they cannot weigh the positive lation material has dissolved. outcome (getting better) against the immediate negative 0168 Taste-Masking Materials experience (the bitter taste in their mouth), they are more 0169 Taste-masking materials are described in U.S. likely to refuse a drug that tastes bad. Thus, for pharmaceu application Ser. No. 10/893,203 filed Jul. 16, 2004 which is tical compositions for children, it becomes even more incorporated herein by reference in its entirety. important to mask the bitter taste. 0170 In accordance with another aspect, compositions 0.175 Microencapsulation of the proton pump inhibitor and methods of the present invention may include taste can (1) lower the amount of flavoring agents necessary to masking materials to enhance the taste of the composition. create a palatable product and/or (2) mask the bitter taste of Proton pump inhibitors and Some nonsteroidal anti-inflam the proton pump inhibitor by Separating the drug from the matory drugs are inherently bitter tasting. In one embodi taste receptors. ment of the present invention, these bitter tasting pharma 0176 Taste-masking materials include, but are not lim ceuticals are microencapsulated with a taste-masking ited to: cellulose hydroxypropyl ethers (HPC) such as material. Materials useful for masking the taste of a phar Klucel(R) or Nisswo HPC; low-substituted hydroxypropyl maceutical compositions include those materials capable of ethers (L-HPC); cellulose hydroxypropyl methyl ethers microencapsulating the proton pump inhibitor and/or non (HPMC) such as Seppifilm-LC, Pharmacoat(R), Metolose Steroidal anti-inflammatory drug, thereby protecting the SR, Opadry YS, PrimaFlo, Benecel MP824, and Benecel Senses from its bitter taste. Taste-masking materials of the MP843; methylcellulose polymers such as Methocel(R) and present invention provide Superior pharmaceutical compo Metolose(R); ethylcelluloses (EC) and mixtures thereof such Sitions by e.g., creating a more palatable pharmaceutical as E461, Ethocel(R), Aqualon(R)-EC, Surelease(R); polyvinyl composition as compared to pharmaceutical compositions alcohol (PVA) such as Opadry AMB; hydroxyethylcellulo without taste-masking and/or by creating a dosage form ses such as Natrosol(R); carboxymethylcelluloses and salts of requiring less of the traditional flavoring agents. carboxymethylcelluloses (CMC) such as Aqualon(R) CMC; 0171 The “flavor leadership' criteria used to develop a polyvinyl alcohol and polyethylene glycol co-polymerS Such palatable product include (1) immediate impact of identify as Kollicoat IRCR); monoglycerides (Myverol), triglycerides ing flavor, (2) rapid development of balanced, full flavor, (3) (KLX), polyethylene glycols, modified food Starch, acrylic compatible mouth feel factors, (4) no “off” flavors, and (5) polymers and mixtures of acrylic polymers with cellulose short aftertaste. See, e.g., Worthington, A Matter of Taste, ethers such as Eudragit(R) EPO, Eudragit R RD100, and Pharmaceutical Executive (April 2001). The pharmaceutical Eudragit(R) E100; cellulose acetate phthalate; sepifilms such compositions of the present invention improve upon one or as mixtures of HPMC and stearic acid, cyclodextrins, and more of these criteria. mixtures of these materials. 0172 There are a number of known methods to deter 0177. In other embodiments of the present invention, mine the effect of a taste-masking material Such as discrimi additional taste-masking materials contemplated are those US 2005/0249806 A1 Nov. 10, 2005

described in U.S. Pat. Nos. 4,851,226, 5,075,114, and 5,876, to provide the optimally flavored product for consumer 759. For further examples of taste-masking materials. See, demand and compliance. See, e.g., Roy et al., Modifying e.g., Remington. The Science and Practice of Pharmacy, Bitterness. Mechanism, Ingredients, and Applications Nineteenth Ed. (Easton, Pa.; Mack Publishing Company, (1997). 1995); Hoover, John E., Remington's Pharmaceutical Sci 0182. In one embodiment, one or more flavoring agents ences (Mack Publishing Co., Easton, Pa. 1975); Liberman, are mixed with the taste-masking material prior to microen H. A. and Lachman, L., Eds., Pharmaceutical DOSage capsulating the proton pump inhibitor and/or nonsteroid Forms (Marcel Decker, New York, N.Y., 1980); and Phar anti-inflammatory drug, and are therefore part of the taste maceutical Dosage Forms and Drug Delivery Systems, masking material. In other embodiments, the flavoring agent Seventh Ed. (Lippincott Williams & Wilkins, 1999). is mixed with non-compatible excipients during the formu 0178. In various embodiments, a buffering agent such as lation proceSS and is therefore not in contact with the proton Sodium bicarbonate is incorporated into the microencapsu pump inhibitor and/or the nonsteroidal anti-inflammatory lation material. In other embodiments, an antioxidant Such drug, and not part of the microencapsulation material. as BHT is incorporated into the microencapsulation mate 0183 In another embodiment, a buffering agent, such as rial. In yet another embodiment, Sodium chloride is incor Sodium bicarbonate, is also microencapsulated with one or porated into the taste masking material. In Still other more taste-masking materials. embodiments, plasticizerS Such as polyethylene glycol and/ or Stearic acid are incorporated into the microencapsulation 0184. In another embodiment, the weight fraction of the material. taste masking material is, e.g., about 98% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or 0179. In further embodiments, one or more other com less, about 75% or less, about 70% or less, about 65% or patible materials are present in the microencapsulation mate less, about 60% or less, about 55% or less, about 50% or rial. Exemplary materials include, e.g., pH modifiers, pari less, about 45% or less, about 40% or less, about 35% or etal cell activators, erosion facilitators, diffusion facilitators, less, about 30% or less, about 25% or less, about 20% or anti-adherents, anti-foaming agents, antioxidants, flavoring less, about 15% or less, about 10% or less, about 5% or less, agents, and carrier materials. Such as binders, Suspending about 2%, or about 1% or less of the total weight of the agents, disintegration agents, filling agents, Surfactants, pharmaceutical composition. Solubilizers, Stabilizers, lubricants, wetting agents, diluents. 0185. In other embodiments of the present invention, the 0180. In addition to microencapsulating the proton pump amount of flavoring agent necessary to create a palatable inhibitors and/or the nonsteroidal anti-inflammatory drug product, as compared to a pharmaceutical composition com with a taste-masking material as described herein, the phar prising non-microencapulated proton pump inhibitor and/or maceutical compositions of the present invention may also the nonsteroidal anti-inflammatory drug, is decreased by 5% comprise one or more flavoring agents. or less, or by 5% to 10%, or by 10% to 20%, or by 20% to 30%, or by 30% to 40%, or by 40% to 50%, or by 50% to 0181 “Flavoring agents” or “sweeteners' useful in the 60%, or by 60% to 70%, or by 70% to 80%, or by 80% to pharmaceutical compositions of the present invention 90%, or by 90% to 95%, or by greater than 95%. In still include, e.g., acacia Syrup, aceSulfame K, alitame, anise, other embodiments, no flavoring agent is necessary to create apple, aspartame, banana, Bavarian cream, berry, black a more palatable pharmaceutical composition as compared currant, butterScotch, calcium citrate, camphor, caramel, to a similar pharmaceutical composition comprising non cherry, cherry cream, chocolate, cinnamon, bubble gum, microencapulated proton pump inhibitor and/or the nonste citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, roidal anti-inflammatory drug. cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyr 0186. In various embodiments of the invention, the total rhetinate, glycyrrhiza (licorice) Syrup, grape, grapefruit, amount of flavoring agent present in the pharmaceutical honey, isomalt, lemon, lime, lemon cream, monoammonium composition is less than 20 grams, or less than 15 grams, or glyrrhizinate (MagnaSweetB), maltol, mannitol, maple, less than 10 grams, or less than 8 grams, or less than 5 marshmallow, menthol, mint cream, mixed berry, neohes grams, or less than 4 grams, or less than 3.5 grams, or leSS peridine DC, neotame, orange, pear, peach, peppermint, than 3 grams, or less than 2.5 grams or less than 2 grams, or peppermint cream, ProSweet(E Powder, raspberry, root beer, less than 1.5 grams, or less than 1 gram, or less than 500 mg, rum, Saccharin, Safrole, Sorbitol, Spearmint, Spearmint or less than 250 mg, or less than 150 mg, or less than 100 cream, Strawberry, Strawberry cream, Stevia, Sucralose, mg, or less than 50 mg. Sucrose, Sodium Saccharin, Saccharin, aspartame, aceSulfame potassium, mannitol, talin, Sucralose, Sorbitol, 0187 Methods of Microencapsulation Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, 0188 The proton pump inhibitor, buffering agent, and/or Vanilla, walnut, watermelon, wild cherry, wintergreen, Xyli nonsteroidal anti-inflammatory drug may be microencapsu tol, or any combination of these flavoring ingredients, e.g., lated by methods known by one of ordinary skill in the art. anise-menthol, cherry-anise, cinnamon-orange, cherry-cin Such known methods include, e.g., Spray drying processes, namon, chocolate-mint, honey-lemon, lemon-lime, lemon Spinning disk-Solvent processes, hot melt processes, Spray mint, menthol-eucalyptus, orange-cream, Vanilla-mint, and chilling methods, fluidized bed, electroStatic deposition, mixtures thereof. In other embodiments, Sodium chloride is centrifugal extrusion, rotational Suspension Separation, poly incorporated into the pharmaceutical composition. Based on merization at liquid-gas or Solid-gas interface, preSSure the proton pump inhibitor, buffering agent, and excipients, extrusion, or Spraying Solvent extraction bath. In addition to as well as the amounts of each one, one of skill in the art these, Several chemical techniques, e.g., complex coacerVa would be able to determine the best combination of flavors tion, Solvent evaporation, polymer-polymer incompatibility, US 2005/0249806 A1 Nov. 10, 2005 22 interfacial polymerization in liquid media, in Situ polymer copolymerS Such as those formed from methyl acrylate, ization, in-liquid drying, and desolvation in liquid media theyl acrylate, methyl methacrylate and/or ehtyl methacry could also be used. late with copolymers of acrylic and methacrylic acid esters (e.g., Eudragit NE, Eudragit RL, Eudragit RS). In accor 0189 The spinning disk method allows for: 1) an dance with one aspect of the present invention, all or part of increased production rate due to, higher feed rates and use the proton pump inhibitor may be coated. In various embodi of higher Solids loading in feed Solution, 2) the production ments contemplated by the present invention, the proton of more spherical particles, 3) the production of a more even pump inhibitor is coated with, for example, a gastric resis coating, and 4) limited clogging of the spray nozzle during tant coating Such as an enteric coating, a controlled-release the process. coating, an enzymatic-controlled coating, a film coating, a 0.190 Spray drying is often more readily available for Sustained-release coating, an immediate-release coating, a Scale-up. In various embodiments, the material used in the delayed-release coating, or a moisture barrier coating. See, Spray-dry encapsulation proceSS is emulsified or dispersed e.g., Remington ’s Pharmaceutical Sciences, 20th Edition into the core material in a concentrated form, e.g., 10-60% (2000). Solids. The microencapsulation material is, in one embodi 0196. In accordance with another aspect of the invention, ment, emulsified until about 1 to 3 um droplets are obtained. either the proton pump inhibiting agent or the nonsterodial Once a dispersion of proton pump inhibitor and encapsula anti-inflammatory agent is coated. In other aspectes of the tion material are obtained, the emulsion is fed as droplets invention, Some or all of the proton pump inhibitor and Some into the heated chamber of the spray drier. In some embodi or all of the nonsteroidal anti-inflammatory agent are coated. ments, the droplets are sprayed into the chamber or Spun off In accordance with another aspect of the invention, the a rotating disk. The microSpheres are then dried in the heated dosage form (Such as a tablet, caplet, or capsule) is coated chamber and fall to the bottom of the spray drying chamber to aid Swallowing. The proton pump inhibiting agent may be where they are harvested. coated with the same material as used to coat the nonste 0191 In some embodiments of the present invention, the roidal anti-inflammatory agent or a different material. Addi micropheres have irregular geometries. In other embodi tionally, the coating used to coat the whole dosage form ments, the microSpheres are aggregates of Smaller particles. (Such as a film coating) may be the same as or different from 0.192 In various embodiments, the proton pump inhibitor the coating used to coat the proton pump inhibiting agent and/or the nonsteroidal anti-inflammatory agents are present and/or the nonsteroidal anti-inflammatory agent. in the microSpheres in an amount greater than 1%, greater 0197) Pharmaceutical compositions having multisite than 2.5%, greater than 5%, greater than 10%, greater than absorption profiles of the nonsteroidal anti-inflammatory 15%, greater than 20%, greater than 25%, greater than 30%, drug are provided herein. In accordance with one aspect of greater than 35%, greater than 40%, greater than 45%, the invention, Some of the nonsteroidal anti-inflammatory greater than 50%, greater than 55%, greater than 60%, drug is formulated for immediate release and Some of the greater than 65%, greater than 70%, greater than 75%, nonsteroidal anti-inflammatory drug is formulated for greater than 80%, greater than 85%, greater than 90% delayed release. In accordance with one aspect of the greater than 95% or greater than 98% weight percent of the invention, the delayed release coating is an enteric coating. proton pump inhibitor to the microencapsulation material 0198 Pharmaceutical compositions having multisite used to enhance the Stability of the pharmaceutical compo absorption profiles of the proton pump inhibitor are provided Sition or the taste-masking material. herein. In accordance with one aspect of the invention, Some 0193 Coatings of the proton pump inhibitor is formulated for immediate 0194 In accordance with another aspect of the present release and Some of the part of the proton pump inhibitor is invention, all or part of the nonsteroidal anti-inflammatory formulated for delayed release. In accordance with one drug may be coated. In various embodiments contemplated aspect of the invention, the delayed release coating is an by the present invention, the nonsteroidal anti-inflammatory enteric coating. drug is coated with, for example, a gastric resistant coating 0199 Dosage Such as an enteric coating, a controlled-release coating, an 0200. The pharmaceutical compositions of the present enzymatic-controlled coating, a film coating, a Sustained invention comprising a proton pump inhibiting agent and a release coating, an immediate-release coating, a delayed nonsteroidal anti-inflammatory agent are administered and release coating, or a moisture barrier coating. See, e.g., dosed in accordance with good medical practice, taking into Remington's Pharmaceutical Sciences, 20th Edition (2000). account the clinical condition of the individual patient, the 0.195. In accordance with another aspect of the invention, Site and method of administration, Scheduling of adminis the nonsteroidal anti-inflammatory agent is enterically tration, and other factors known to medical practitioners. In coated. Suitable enteric coating materials include, but are human therapy, it is important to provide a dosage form that not limited to, polymerized gelatin, shellac, methacrylic acid delivers the required therapeutic amount of the each thera copolymer type C NF, cellulose butyrate, phthalate, cellu peutic agent in Vivo, and renders therapeutic agent bioavail lose hydrogen phthalate, cellulose proprionate phthalate, able in a rapid manner. polyvinyl acetate phthalate (PVAP), cellulose acetate phtha late (CAP), cellulose acetate trimellitate (CAT), hydrox 0201 Proton Pump Inhibiting Agents ypropyl methylcellulose phthalate, hydroxypropyl methyl 0202) The proton pump inhibiting agent is administered cellulose acetate, dioxypropyl methylcellulose Succinate, and dosed in accordance with good medical practice, taking carboxymethyl ethylcellulose (CMEC), hydroxypropyl into account the clinical condition of the individual patient, methylcellulose Succinate, and acrylic acid polymers and the site and method of administration, Scheduling of admin US 2005/0249806 A1 Nov. 10, 2005 23 istration, and other factors known to medical practitioners. amount to achieve a measurable Serum concentration of a In human therapy, it is important to provide a dosage form non-acid degraded proton pump inhibiting agent greater than that delivers the required therapeutic amount of the each about 0.1 ug/ml within about 30 minutes after administration therapeutic agent in Vivo, and renders therapeutic agent of the pharmaceutical composition. In another embodiment bioavailable in a rapid manner. In addition to the dosage of the present invention, the pharmaceutical composition is forms described herein, the dosage forms described by administered to the Subject in an amount to achieve a Phillips et al. in U.S. Pat. Nos. 6,489,346, 6,780,882 and measurable Serum concentration of a non-acid degraded or 6,645,988 are incorporated herein by reference. non-acid reacted proton pump inhibiting agent greater than about 0.1 ug/ml within about 15 minutes after administration 0203 The percent of intact drug that is absorbed into the of the pharmaceutical composition. In yet another embodi bloodstream is not narrowly critical, as long as a therapeu ment, the pharmaceutical composition is administered to the tically effective amount, e.g., a gastrointestinal-disorder Subject in an amount to achieve a measurable Serum con effective amount of a proton pump inhibiting agent, is centration of a non-acide degraded or non-acid reacted absorbed following administration of the pharmaceutical proton pump inhibiting agent greater than about 0.1 ug/ml composition to a Subject. Gastrointestinal-disorder-effective within about 10 minutes after administration of the pharma amounts in tablets may be found in U.S. Pat. No. 5,622,719. ceutical composition. It is understood that the amount of proton pump inhibiting agent and/or buffering agent that is administered to a Subject 0209. In another embodiment of the present invention, is dependent on a number of factors, e.g., the Sex, general the composition is administered to the Subject in an amount health, diet, and/or body weight of the Subject. to achieve a measurable Serum concentration of the proton pump inhibiting agent greater than about 0.15 lug/ml within 0204 Illustratively, administration of a substituted bicy about 15 minutes and to maintain a Serum concentration of clic aryl-imidazole to a young child or a Small animal, Such the proton pump inhibiting agent of greater than about 0.15 as a dog, a relatively low amount of the proton pump tug/ml from about 15 minutes to about 1 hour after admin inhibitor, e.g., about 1 mg to about 30 mg, will often provide istration of the composition. In yet another embodiment of blood Serum concentrations consistent with therapeutic the present invention, the composition is administered to the effectiveness. Where the Subject is an adult human or a large Subject in an amount to achieve a measurable Serum con animal, Such as a horse, achievement of a therapeutically centration of the proton pump inhibiting agent greater than effective blood Serum concentration will require larger doS about 0.25 ug/ml within about 15 minutes and to maintain a age units, e.g., about 10 mg, about 15 mg, about 20 mg, Serum concentration of the proton pump inhibiting agent of about 30 mg, about 40 mg, about 80 mg, or about 120 mg greater than about 0.25 ug/ml from about 15 minutes to dose for an adult human, or about 150 mg, or about 200 mg, about 1 hour after administration of the composition. In or about 400 mg, or about 800 mg, or about 1000 mg dose, another embodiment of the present invention, the composi or about 1500 mg dose, or about 2000 mg dose, or about tion is administered to the Subject in an amount to achieve 2500 mg dose, or about 3000 mg dose or about 3200 mg a measurable Serum concentration of the proton pump dose or about 3500 mg dose for an adult horse. inhibiting agent greater than about 0.35 ug/ml within about 15 minutes and to maintain a Serum concentration of the 0205. In various other embodiments of the present inven proton pump inhibiting agent of greater than about 0.35 tion, the amount of proton pump inhibitor administered to a tug/ml from about 15 minutes to about 1 hour after admin Subject is, e.g., about 0.5-2 mg/Kg of body weight, or about istration of the composition. In another embodiment of the 0.5 mg/Kg of body weight, or about 1 mg/Kg of body present invention, the composition is administered to the weight, or about 1.5 mg/Kg of body weight, or about 2 Subject in an amount to achieve a measurable Serum con mg/Kg of body weight. centration of the proton pump inhibiting agent greater than 0206 Treatment dosages generally may be titrated to about 0.45 lug/ml within about 15 minutes and to maintain a optimize Safety and efficacy. Typically, dosage-effect rela Serum concentration of the proton pump inhibiting agent of tionships from in vitro and/or in Vivo tests initially can greater than about 0.45 lug/ml from about 15 minutes to provide useful guidance on the proper doses for Subject about 1 hour after administration of the composition. administration. Studies in animal models generally may be 0210. In another embodiment of the present invention, used for guidance regarding effective dosages for treatment the composition is administered to the Subject in an amount of gastrointestinal disorders or diseases in accordance with to achieve a measurable Serum concentration of the proton the present invention. In terms of treatment protocols, it pump inhibiting agent greater than about 0.15 lug/ml within should be appreciated that the dosage to be administered will about 30 minutes and to maintain a Serum concentration of depend on Several factors, including the particular agent that the proton pump inhibiting agent of greater than about 0.15 is administered, the route chosen for administration, the lug/ml from about 30 minutes to about 1 hour after admin condition of the particular Subject. istration of the composition. In yet another embodiment of 0207. In various embodiments, unit dosage forms for the present invention, the composition is administered to the humans contain about 1 mg to about 120 mg, or about 1 mg, Subject in an amount to achieve a measurable Serum con or about 5 mg, or about 16 mg, or about 15 mg, or about 20 centration of the proton pump inhibiting agent greater than mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 0.25 ug/ml within about 30 minutes and to maintain a about 60 mg, or about 70 mg, or about 80 mg, or about 90 Serum concentration of the proton pump inhibiting agent of mg, or about 100 mg, or about 110 mg, or about 120 mg of greater than about 0.25 ug/ml from about 30 minutes to a proton pump inhibitor. about 1 hour after administration of the composition. In another embodiment of the present invention, the composi 0208. In a further embodiment of the present invention, tion is administered to the Subject in an amount to achieve the pharmaceutical composition is administered in an a measurable Serum concentration of the proton pump US 2005/0249806 A1 Nov. 10, 2005 24 inhibiting agent greater than about 0.35 ug/ml within about greater than about 75%; or greater than about 50% of the 30 minutes and to maintain a Serum concentration of the drug absorbed into the bloodstream is in a non-acid proton pump inhibiting agent of greater than about 0.35 degraded or a non-acid reacted form. lug/ml from about 30 minutes to about 1 hour after admin istration of the composition. In another embodiment of the 0216) In other embodiments, the pharmaceutical compo present invention, the composition is administered to the Sitions provide a release profile of the proton pump inhibitor, Subject in an amount to achieve a measurable Serum con using USP dissolution methods, whereby greater than about centration of the proton pump inhibiting agent greater than 50% of the proton pump inhibitor is released from the about 0.45 lug/ml within about 30 minutes and to maintain a composition within about 2 hours; or greater than 50% of the Serum concentration of the proton pump inhibiting agent of proton pump inhibitor is released from the composition within about 1.5 hours; or greater than 50% of the proton greater than about 0.45 lug/ml from about 30 minutes to pump inhibitor is released from the composition within about I hour after administration of the composition. about 1 hour after exposure to gastrointestinal fluid. In 0211. In still another embodiment of the present inven another embodiment, greater than about 60% of the proton tion, the composition is administered to the Subject in an pump inhibitor is released from the composition within amount to achieve a measurable Serum concentration of a about 2 hours; or greater than 60% of the proton pump non-acid degraded or non-acid reacted proton pump inhib inhibitor is released from the composition within about 1.5 iting agent greater than about 0.5 lug/ml within about I hour hours; or greater than 60% of the proton pump inhibitor is after administration of the composition. In yet another released from the composition within about 1 hour after embodiment of the present invention, the composition is exposure to gastrointestinal fluid. In yet another embodi administered to the Subject in an amount to achieve a ment, greater than about 70% of the proton pump inhibitor measurable Serum concentration of a non-acid degraded or is released from the composition within about 2 hours, or non-acid reacted proton pump inhibiting agent greater than greater than 70% of the proton pump inhibitor is released about 0.3 ug/ml within about 45 minutes after administration from the composition within about 1.5 hours, or greater than of the composition. 70% of the proton pump inhibitor is released from the 0212 Contemplated compositions of the present inven composition within about 1 hour after exposure to gas tion provide a therapeutic effect as proton pump inhibiting trointestinal fluid. agent medications over an interval of about 5 minutes to about 24 hours after administration, enabling, for example, 0217 Nonsteroidal Anti-Inflammatory Agents once-a-day, twice-a-day, three times a day, etc. administra 0218. The nonsteroidal anti-inflammatory agent is tion if desired. administered and dosed in accordance with good medical 0213 Generally speaking, one will desire to administer practice, taking into account the clinical condition of the an amount of the compound that is effective to achieve a individual patient, the Site and method of administration, Serum level commensurate with the concentrations found to Scheduling of administration, and other factors known to be effective in vivo for a period of time effective to elicit a medical practitioners. According to one aspect of the inven therapeutic effect. Determination of these parameters is well tion, the pharmaceutical composition comprises two differ within the skill of the art. These considerations are well ent nonsteroidal anti-inflammatory drugs. According to known in the art and are described in Standard textbookS. another aspect of the invention, the pharmaceutical com 0214. In one embodiment of the present invention, the position comprises two different nonsteroidal anti-inflamma composition is administered to a Subject in a gastrointesti tory drugs wherein at least one of the nonsteroidal anti nal-disorder-effective amount, that is, the composition is inflammatory drugs is a COX-II inhibitor. administered in an amount that achieves a therapeutically 0219. In human therapy, it is important to provide a effective dose of a proton pump inhibiting agent in the blood dosage form that delivers the required therapeutic amount of Serum of a Subject for a period of time to elicit a desired the drug in Vivo, and renders the drug bioavailable at the therapeutic effect. Illustratively, in a fasting adult human appropriate time. According to one aspect of the invention, (fasting for generally at least 10 hours) the composition is part of the nonsteroidal anti-inflammatory drug is in an administered to achieve a therapeutically-effective dose of a immediate release form and part of the nonsteroidal anti proton pump inhibiting agent in the blood Serum of a Subject inflammatory drug is in a delayed release form. According within about 45 minutes after administration of the compo to another aspect of the invention, two therapeutically effec Sition. In another embodiment of the present invention, a tive doses are present in the pharmaceutical composition, therapeutically-effective dose of the proton pump inhibiting one in an immediate release form and another in a delayed agent is achieved in the blood Serum of a Subject within release form. The dosing of nonsteroidal anti-inflammatory about 30 minutes from the time of administration of the agents will vary but can be readily determined by one of skill composition to the Subject. In yet another embodiment, a in the art. therapeutically-effective dose of the proton pump inhibiting agent is achieved in the blood Serum of a Subject within 0220 Dosage Form about 20 minutes from the time of administration to the 0221) The pharmaceutical compositions of the present Subject. In Still another embodiment of the present invention, invention contain desired amounts of proton pump inhibitor, a therapeutically-effective dose of the proton pump inhibit a buffering agent and a nonsteroidal anti-inflammatory drug ing agent is achieved in the blood Serum of a Subject at about and can be in the form of: a tablet, (including a Suspension 15 minutes from the time of administration of the compo tablet, a chewable tablet, a fast-melt tablet, a bite-disinte Sition to the Subject. gration tablet, a rapid-disintegration tablet, an effervescent 0215. In further embodiments, greater than about 98%; or tablet, or a caplet), a pill, a powder (including a sterile greater than about 95%; or greater than about 90%; or packaged powder, a dispensable powder, or an effervescent US 2005/0249806 A1 Nov. 10, 2005 25 powder) a capsule (including both Soft or hard capsules, e.g., prepared by mixing the proton pump inhibitor, one or more capsules made from animal-derived gelatin or plant-derived buffering agent, at least one nonsteroidal anti-inflammatory HPMC) a lozenge, a Sachet, a troche, pellets, granules, or an drug, and pharmaceutical excipients to form a bulk blend aeroSol. These pharmaceutical compositions of the present composition. When referring to these bulk blend composi invention can be manufactured by conventional pharmaco tions as homogeneous, it is meant that the proton pump logical techniques. inhibitor, buffering agent, and nonsteroidal anti-inflamma 0222 Conventional pharmacological techniques include, tory drug are dispersed evenly throughout the composition e.g., one or a combination of methods: (1) dry mixing, (2) so that the composition may be readily Subdivided into direct compression, (3) milling, (4) dry or non-aqueous equally effective unit dosage forms, Such as tablets, pills, granulation, (5) wet granulation, or (6) fusion. See, e.g., and capsules. The individual unit dosages may also comprise Lachman et al., The Theory and Practice of Industrial film coatings, which disintegrate upon oral ingestion or upon Pharmacy (1986). Other methods include, e.g., prilling, contact with diluent. Spray drying, pan coating, melt granulation, granulation, 0229 Compressed tablets are solid dosage forms pre Wurster coating, tangential coating, top Spraying, tableting, pared by compacting the bulk blend compositions described extruding, coacervation and the like. above. In various embodiments, compressed tablets of the 0223) In one embodiment, the proton pump inhibitor and present invention will comprise one or more functional nonsteroidal anti-inflammatory drug are microencapsulated excipients Such as binding agents and/or disintegrants. In prior to being formulated into one of the above forms. In other embodiments, the compressed tablets will comprise a another embodiment, all or Some of the proton pump inhibi film Surrounding the final compressed tablet. In other tor is microencapsualted prior to being formulated into one embodiments, the compressed tablets comprise one or more of the above forms. In another embodiment, Some or all of excipients and/or flavoring agents. the buffering agent is microencapsulated prior to being 0230. A chewable tablet may be prepared by compacting formulated into one of the above forms. In other embodi bulk blend compositions, described above. In one embodi ments, all or Some of the nonsteroidal anti-inflammatory ment, the chewable tablet comprises a material useful for drug is microencapsulated prior to being further formulated enhancing the shelf-life of the pharmaceutical composition. into one of the above forms. In still another embodiment, In another embodiment, microencapsulated material has Some or all of the nonsteroidal anti-inflammatory drug is taste-masking properties. In various other embodiments, the coated prior to being further formulated into one of the chewable tablet comprises one or more flavoring agents and above forms by using Standard coating procedures, Such as one or more taste-masking materials. In yet other embodi those described in Remington's Pharmaceutical Sciences, ments the chewable tablet comprised both a material useful 20th Edition (2000). In yet other embodiments contemplated for enhancing the shelf-life of the pharmaceutical formula by the present invention, a film coating is provided around tion and one or more flavoring agents. the pharmaceutical composition. 0231. In various embodiments, the microencapsulated 0224. In other embodiments, the pharmaceutical compo proton pump inhibitor, buffering agent, nonsteroidal anti Sitions further comprise one or more additional materials inflammatory drug, and optionally one or more excipients, Such as a pharmaceutically compatible carrier, binder, filling are dry blended and compressed into a mass, Such as a tablet, agent, Suspending agent, flavoring agent, Sweetening agent, having a hardness Sufficient to provide a pharmaceutical disintegrating agent, Surfactant, preservative, lubricant, composition that Substantially disintegrates within less than colorant, diluent, Solubilizer, moistening agent, Stabilizer, about 30 minutes, less than about 35 minutes, less than about wetting agent, anti-adherent, parietal cell activator, anti 40 minutes, less than about 45 minutes, less than about 50 foaming agent, antioxidant, chelating agent, antifungal minutes, less than about 55 minutes, or less than about 60 agent, antibacterial agent, or one or more combination minutes, after oral administration, thereby releasing the thereof. buffering agent and the proton pump inhibitor into the 0225 Parietal cell activators are administered in an gastrointestinal fluid. When at least 50% of the pharmaceu amount Sufficient to produce the desired Stimulatory effect tical composition has disintegrated, the compressed mass without causing untoward Side effects to patients. In one has Substantially disintegrated. embodiment, the parietal cell activator is administered in an 0232 A capsule may be prepared by placing the bulk amount of about 5 mg to about 2.5 grams per 20 mg dose of blend composition, described above, inside a capsule. the proton pump inhibitor. 0233 Exemplary Powder Compositions 0226. In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, a 0234. A powder for suspension may be prepared by plasticizer is generally a high boiling point Solid or liquid. combining proton pump inhibitor, one or more buffering Suitable plasticizers can be added from about 0.01% to agent and one or more nonsteroidal anti-inflammatory drugs. about 50% by weight (w/w) of the coating composition. In various embodiments, the powder may comprise one or Plasticizers include, e.g., diethyl phthalate, citrate esters, more pharmaceutical excipients and flavors. Powder for polyethylene glycol, glycerol, acetylated glycerides, triace Suspension is prepared by mixing the proton pump inhibitor, tin, polypropylene glycol, polyethylene glycol, triethyl cit one or emore buffering agetns, one or more nonsteroidal rate, dibutyl Sebacate, Stearic acid, Stearol, Stearate, and anti-inflammatory drgu, and optional pharmaceutical excipi castor oil. ents to form a bulk blend composition. This bulk blend is uniformly Subdivided into unit dosage packaging or multi 0227 Exemplary Solid Oral Dosage Compositions dosage packaging units. The term “uniform' means the 0228 Solid oral dosage compositions, e.g., tablets, chew homogeneity of the bulk blend is substantially maintained able tablets, effervescent tablets, caplets, and capsules, are during the packaging process. US 2005/0249806 A1 Nov. 10, 2005 26

0235. In some embodiments, some or all of the proton posed of approximately the same concentration of proton pump inhibitor is micronized. In other embodiments, Some pump inhibitor at any point throughout the Suspension. A or all of the nonsteroidal anti-inflammatory drug is micron Suspension is determined to be composed of approximately ized. Additional embodiments of the present invention also the same concentration of proton pump inhibitor throughout comprise a Suspending agent and/or a Wetting agent. the suspension when there is less than about 20%, less than 0236 Effervescent powders are also prepared in accor about 15%, less than about 13%, less than about 11%, less dance with the present invention. Effervescent Salts have than about 10%, less than about 8%, less than about 5%, or been used to disperse medicines in water for oral adminis less than about 3% variation in concentration among tration. Effervescent Salts are granules or coarse powders Samples taken from various points in the Suspension. containing a medicinal agent in a dry mixture, usually 0243 The concentration at various points throughout the composed of Sodium bicarbonate, citric acid and/or tartaric Suspension can be determined by any Suitable means known acid. When salts of the present invention are added to water, in the art. For example, one Suitable method of determining the acids and the base react to liberate carbon dioxide gas, concentration at various points involves dividing the Sus thereby causing “effervescence.” Examples of effervescent pension into three Substantially equal Sections: top, middle Salts include the following ingredients: Sodium bicarbonate and bottom. The layers are divided starting at the top of the or a mixture of Sodium bicarbonate and Sodium carbonate, Suspension and ending at the bottom of the Suspension. Any citric acid and/or tartaric acid. Any acid-base combination number of Sections Suitable for determining the uniformity that results in the liberation of carbon dioxide can be used in of the Suspension can be used, Such as for example, two place of the combination of Sodium bicarbonate and citric Sections, three Sections, four Sections, five Sections, or Six or and tartaric acids, as long as the ingredients were Suitable for more Sections. The Sections can be named in any appropriate pharmaceutical use and result in a pH of about 6.0 or higher. manner, Such as relating to their location (e.g., top, middle, 0237) The method of preparation of the effervescent bottom), numbered (e.g., one, two, three, four, five, Six, etc.), granules of the present invention employs three basic pro or lettered (e.g., A, B, C, D, E, F, G, etc.). The Sections can cesses: wet granulation, dry granulation and fusion. The be divided in any Suitable configuration. In one embodiment, fusion method is used for the preparation of most commer the sections are divided from top to bottom, which allows a cial effervescent powders. It should be noted that, although comparison of Sections from the top and Sections from the these methods are intended for the preparation of granules, bottom in order to determine whether and at what rate the the formulations of effervescent salts of the present inven proton pump inhibitor is Settling into the bottom Sections. tion could also be prepared as tablets, according to known Any number of the assigned sections Suitable for determin technology for tablet preparation. ing uniformity of the Suspension can be evaluated, Such as, e.g., all sections, 90% of the sections, 75% of the sections, 0238 Wet granulation is one the oldest methods of gran 50% of the sections, or any other suitable number of ule preparation. The individual Steps in the wet granulation Sections. process of tablet preparation include milling and Sieving of the ingredients, dry powder mixing, wet massing, granula 0244 Concentration is easily determined by methods tion, and final grinding. In various embodiments, the known in the art, Such as, e.g., methods described herein. In microencapsulated PPI is added to the other excipients of the one embodiment, concentration is determined using percent pharmaceutical composition after they have been wet granu label claim. “Percent label claim” (% label claim) is calcu lated using the actual amount of proton pump inhibitor or lated. nonsteroidal anti-inflammatory drug per Sample compared 0239) Dry granulation involves compressing a powder with the intended amount of proton pump inhibitor or mixture into a rough tablet or “slug on a heavy-duty rotary nonsteroidal anti-inflammatory drug per Sample. The tablet press. The Slugs are then broken up into granular intended amount of proton pump inhibitor or nonsteroidal particles by a grinding operation, usually by passage through anti-inflammatory drug per Sample can be determined based an oscillation granulator. The individual Steps include mix on the formulation protocol or from any other Suitable ing of the powders, compressing (slugging) and grinding method, Such as, for example, by referencing the "label (slug reduction or granulation). No wet binder or moisture is claim,” that is, the intended amount of proton pump inhibitor involved in any of the Steps. In Some embodiments, the or nonsteroidal anti-inflammatory drug depicted on labeling microencapsulated PPI is dry granulated with other excipi complying with the regulations promulgated by the United ents in the pharmaceutical composition. In other embodi States Food and Drug Administration. ments, the microencapsulated omeprazole is added to other excipients of the pharmaceutical composition after they have 0245. In one aspect of the present invention, the suspen been dry granulated. Sion is divided into Sections and the percent label claim is determined for each Section. The Suspension is determined 0240 Powder for Suspension to be Substantially uniform if the Suspension comprises at 0241 Copositions are provided comprising a pharmaceu least one of (a) at least about a set threshold percent label claim throughout the evaluated Sections or (b) has less than tical composition comprising at least one proton pump a Set percentage variation in percent label claim throughout inhibitor, at least one buffering agent, at least one nonste the evaluated Sections. The Suspension can comprise either roidal anti-inflammatory agent, and at least one Suspending (a) or (b) or can comprise both (a) and (b). The evaluated agent for oral administration to a Subject. The composition Sections of the Suspension can have any Set threshold percent may be a powder for Suspension, and upon admixture with label claim Suitable for determining that the Suspension is water, a Substantially uniform Suspension is obtained. Substantially uniform. For example, the Sections can com 0242 A suspension is “substantially uniform” when it is prise, e.g., at least about 70, at least about 75, at least about mostly homogenous, that is, when the Suspension is com 80, at least about 85, at least about 87, at least about 88, at US 2005/0249806 A1 Nov. 10, 2005 27 least about 89, at least about 90, at least about 93, at least 75 minutes, about 90 minutes, about 105 minutes, about 120 about 95, at least about 98, at least about 100, at least about minutes (2 hours), about 150 minutes, about 180 minutes (3 105, at least about 110, at least about 115 percent label claim hours), about 210 minutes, about 4 hours, about 5 hours or of proton pump inhibitor or any range that falls therein, Such more after admixture with water. In one embodiment, the as, e.g., from about 80 to about 115, from about 85 to about Suspension is prepared for administration to the patient from 110, from about 87 to about 108, from about 89 to about 106, about 5 minutes to about 4 hours after admixture. In another from about 90 to about 105, and so on, percent label claim embodiment, the Suspension is prepared for administration of proton pump inhibitor. The evaluated sections of the to the patient from about 15 minutes to about 3 hours after Suspension can have less than any Set percentage variation in admixture. In yet another embodiment, the Suspension is percent label claim Suitable for determining that the Suspen prepared for administration to the patient from at least about Sion is Substantially uniform, Such as, e.g., about 25%, about 1 to at least about 3 hours after admixture. 20%, about 17%, about 15%, about 13%, about 11%, about 0250 In an alternate embodiment, the composition 10%, about 7%, about 5%, about 3% or about 0% variation. remains Substantially uniform until the composition is actu 0246. In another aspect of the present invention, the ally administered to the patient. The Suspension can be Suspension is Substantially uniform if it comprises at least administered to the patient at any time after admixture as one of (a) at least about 87% label claim of proton pump long as the Suspension remains Substantially uniform. In one inhibitor in top, middle and bottom sections determined by embodiment, the Suspension is administered to the patient Separating the Suspension into three Substantially equal from any time after admixture until the Suspension is no Sections from top to bottom for at least about five minutes longer uniform. For example, the Suspension can be admin after admixture with water, or (b) less than about 11% istered to the patient from about 5 minutes, about 10 variation in % label claim among each of the top, middle and minutes, about 15 minutes, about 20 minutes, about 30 bottom Sections for at least about five minutes after admix minutes, about 45 minutes, about 60 minutes (1 hour), about ture with water. 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes (2 hours), about 150 minutes, about 180 minutes (3 0247. In an alternate aspect of the present invention, the hours), about 210 minutes, about 4 hours, about 5 hours or Suspension is Substantially uniform if it comprises at least more after admixture with water. In one embodiment, the one of (a) at least about 80% label claim of proton pump Suspension is administered to the patient from about 5 inhibitor in top, middle and bottom sections determined by minutes to about 4 hours after admixture. In another embodi Separating the Suspension into three Substantially equal ment, the Suspension is administered to the patient from sections from top to bottom for at least about 60 minutes about 15 minutes to about 3 hours after admixture. In yet after admixture with water, or (b) less than about 15% another embodiment, the Suspension is administered to the variation in % label claim among each of the top, middle and patient from at least about 1 to at least about 3 hours after bottom Sections for at least about Sixty minutes after admix admixture. ture with water. 0251. In one embodiment, the composition comprises at 0248. In some embodiments, the composition will remain least one proton pump inhibitor, at least one buffering agent, Substantially uniform for a Suitable amount of time corre at least one nonsteroidal anti-inflammatory agent, and Xan sponding to the intended use of the composition, Such as, than gum. The composition is a powder for Suspension, and e.g., for at least about 5 minutes, about 10 minutes, about 15 upon admixture with water, a first Suspension is obtained minutes, about 20 minutes, about 30 minutes, about 45 that is Substantially more uniform when compared to a minutes, about 60 minutes (1 hour), about 75 minutes, about Second Suspension comprising the proton pump inhibitor, 90 minutes, about 105 minutes, about 120 minutes (2 hours), the buffering agent, the nonsteroidal anti-inflammatory about 150 minutes, about 180 minutes (3 hours), about 210 agent, and Suspending agent, wherein the Suspending agent minutes, about 4 hours, about 5 hours or more after admix is not Xanthan gum. In one embodiment, the first Suspension ture with water. In one embodiment, the Suspension remains comprises at least one of (a) at least about 87% label claim substantially uniform from about 5 minutes to about 4 hours of proton pump inhibitor in top, middle and bottom Sections after admixture with water. In another embodiment, the determined by Separating the Suspension into three Substan Suspension remains Substantially uniform from about 15 tially equal Sections from top to bottom for at least about five minutes to about 3 hours after admixture with water. In yet minutes after admixture with water, or (b) less than about another embodiment, the Suspension is remains Substantially 11% variation in % label claim among each of the top, uniform from at least about 1 to at least about 3 hours after middle and bottom sections for at least about five minutes admixture with water. after admixture with water. 0249. In one embodiment of the present invention, the 0252) In another embodiment, the first suspension com composition will remain Substantially uniform at least until prises at least one of (a) at least about 80% label claim of the Suspension is prepared for administration to the patient. proton pump inhibitor in top, middle and bottom Sections The Suspension can be prepared for administration to the determined by Separating the Suspension into three Substan patient at any time after admixture as long as the Suspension tially equal Sections from top to bottom for at least about remains Substantially uniform. In another embodiment, the Sixty minutes after admixture with water, or (b) less than Suspension is prepared for administration to the patient from about 15% variation in % label claim among each of the top, any time after admixture until the Suspension is no longer middle and bottom Sections for at least about Sixty minutes uniform. For example, the Suspension can be prepared for after admixture with water. administration to the patient from about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 0253) In one embodiment, the composition comprises minutes, about 45 minutes, about 60 minutes (1 hour), about omeprazole, Sodium bicarbonate and Xanthan gum. The US 2005/0249806 A1 Nov. 10, 2005 28 composition is a powder for Suspension, and upon admixture 0258. The following are additional embodiments of the with water, a Substantially uniform Suspension is obtained. present invention: In one embodiment, the Suspension comprises at least one of 0259 39. A method of treating a gastric acid related (a) at least about 87% label claim of proton pump inhibitor disorder and treating an inflammatory disorder in a in top, middle and bottom Sections determined by Separating Subject by administering: the Suspension into three Substantially equal Sections from 0260 (a) a therapeutically effective amount of at top to bottom for at least about five minutes after admixture least one acid labile proton pump inhibitor, with water, or (b) less than about 11% variation in % label 0261 (b) at least one buffering agent in an amount claim among each of the top, middle and bottom Sections for Sufficient to increase gastric fluid pH to a pH that at least about five minutes after admixture with water. In prevents acid degradation of at least Some of the another embodiment, the Suspension comprises at least one proton pump inhibitor in the gastric fluid; and of (a) at least about 80% label claim of proton pump inhibitor in top, middle and bottom sections determined by 0262 (c) a therapeutically effective amount of at Separating the Suspension into three Substantially equal least one nonsteroidal anti-inflammatory drug. Sections from top to bottom for at least about Sixty minutes 0263. 40. The method of 39, wherein the pharma after admixture with water, or (b) less than about 15% ceutical composition is formulated for Stomach variation in % label claim among each of the top, middle and delivery of at least Some of the proton pump inhibi bottom Sections for at least about Sixty minutes after admix tOr. ture with water. 0264 41. The method of 40, wherein the gastric acid related disorder is duodenal ulcer disease, gastric 0254. In yet another embodiment, the composition com ulcer disease, gastroesophageal reflux disease, ero prises omeprazole, Sodium bicarbonate, at least one nonste Sive esophagitis, poorly responsive Symptomatic roidal anti-inflammatory agent, Xanthan gum, and at least gastroesophageal reflux disease, pathological gas one Sweetener or flavoring agent. The composition is a trointestinal hyperSecretory disease, Zollinger Elli powder for Suspension. Upon admixture with water, a Sub Son Syndrome, heartburn, esophageal disorder, or Stantially uniform Suspension is obtained. In one embodi acid dyspepsia. ment, the Suspension comprises at least one of (a) at least 0265 42. The method of 40, wherein the inflamma about 87% label claim of proton pump inhibitor in top, tory disorder is Selected from reperfusion injury to an middle and bottom Sections determined by Separating the ischemic organ, myocardinal infarction, inflamma tory bowel disease, rheumatoid arthritis, osteroar Suspension into three Substantially equal Sections from top to thritis, pSoriasis, organ transplant rejection, inflam bottom for at least about five minutes after admixture with mation of the ear, eye, throat, nose or Skin, organ water, or (b) less than about 11% variation in % label claim preservation, a female or male Sexual dysfunction, among each of the top, middle and bottom Sections for at radiation-induced injury, asthma, respiratory disor least about five minutes after admixture with water. In der, metastasis, influenza, incontinence, Stroke, burn, another embodiment, the Suspension comprises at least one trauma, acute pancreatistis, pyelonephristis, hepati of (a) at least about 80% label claim of proton pump tis, an autoimmune disease, and immunological dis inhibitor in top, middle and bottom sections determined by order, Senile dementia, insulin-dependent diabetes Separating the Suspension into three Substantially equal mellitus, disseminated intravascular coagulation, fatty embolism, Alzheimer's disease, adult or infan Sections from top to bottom for at least about Sixty minutes tile respiratory disease, carcinogenesis in a neonate, after admixture with water, or (b) less than about 15% hemorrhage in a neonate, restenosis, atherogenesis, variation in % label claim among each of the top, middle and angina, ischemic disease, congestive heart failure or bottom Sections for at least about Sixty minutes after admix pulmonary edema associated with acute myocardial ture with water. infarction, thrombosis, hypertension, platelet aggre gation, platelet adhesion, Smooth muscle cell prolif 0255. Other Exemplary Compositions eration, Vascular complications associated with the 0256 Pharmaceutical compositions suitable for buccal or use of medical devices, wounds associated with the Sublingual administration include intra-oral batch or Solid use of medical devices, and cerebrovascular dosage forms, e.g., lozenges. ischemic events. 0266 43. The method of 40, wherein the proton 0257). Other types of release delivery systems are avail pump inhibitor treats an episode of gastric acid able and known to those of skill in the art. Examples of Such related disorder. delivery Systems include, but are not limitd to: polymer 0267 44. The method of 40, wherein the proton based Systems Such as polylactic acid, polyglycolic acid, pump inhibitor treats a medicament induced gastric polyanhydrides and polycaprolactone; nonpolymer-based acid related disorder. Systems that are lipids, including Sterols Such as cholesterol, 0268 45. The method of 44, wherein the treatment cholesterol esters and fatty acids, or neutral fats, Such as of a medicament induced gastric acid related disor mono-, di- and triglycerides, hydrogel release Systems, der includes the prevention of a medicament induced Silastic Systems, peptide-based Systems, wax coatings, com gastric acid related disorder. pressed tablets using conventional binders and excipients 0269 46. A method for treating a gastric acid related partially fused implants and the like. See, e.g., Liberman et disorder and reducing the risk of cardiovascular al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, 209 disease in a Subject by administering a composition (1990). comprising: US 2005/0249806 A1 Nov. 10, 2005 29

0270 (a) a therapeutically effective amount of at a pH that prevents acid degradation of at least least one acid labile proton pump inhibitor, Some of the proton pump inhibitor in the gastric 0271 (b) at least one buffering agent in an amount fluid; and Sufficient to increase gastric fluid pH to a pH that 0291 (b) a second pharmaceutical composition prevents acid degradation of at least Some of the comprising therapeutically effective amount of at proton pump inhibitor in the gastric fluid; and least one nonsteroidal anti-inflammatory drug. 0272 (c) a therapeutically effective amount of at least one nonsteroidal anti-inflammatory drug. 0292 For the sake of brevity, all patents and other references cited herein are incorporated by reference in their 0273 47. The method of 46, wherein the cardiovas entirety. cular disease is heart attack or Stroke. 0274) 48. A method for treating a gastric acid related EXAMPLES disorder and reducing the risk of cancer in a Subject by administering a composition comprising: 0293. The present invention is further illustrated by the following examples, which should not be construed as 0275 (a) a therapeutically effective amount of at limiting in any way. The experimental procedures to gener least one acid labile proton pump inhibitor, ate the data shown are discussed in more detail below. For 0276 (b) at least one buffering agent in an amount all formulations herein, multiple doses may be proportion Sufficient to increase gastric fluid pH to a pH that ally compounded as is known in the art. The coatings, layers, prevents acid degradation of at least Some of the and encapsulations are applied in conventional ways using proton pump inhibitor in the gastric fluid; and equipment customary for these purposes. 0277 (c) a therapeutically effective amount of at 0294 The invention has been described in an illustrative least one nonsteroidal anti-inflammatory drug. manner, and it is to be understood that the terminology used 0278 49. The method of 48, wherein the cancer is is intended to be in the nature of description rather than of Selected from esophageal cancer, lung cancer, col limitation. orectal cancer, breast cancer, and prostate cancer. Example 1 0279 50. A method for protecting against an esoph ageal disorder or esophageal damage in a Subject by administering a composition comprising: Spinning Disk Microencapsulation ProceSS 0280 (a) a therapeutically effective amount of at 0295) The basic operation for the spinning disk-solvent least one acid labile proton pump inhibitor, process used is as follows: An encapsulation Solution is prepared by dissolving the encapsulation material in the 0281 (b) at least one buffering agent in an amount appropriate solvent. Proton pump inhibitor (PPI) in combi Sufficient to increase gastric fluid pH to a pH that nation with buffering agent and nonsteroidal anti-inflamma prevents acid degradation of at least Some of the tory agent, or proton pump inhibitor alone if intended to be proton pump inhibitor in the gastric fluid; and microencapsulated and then combined with a buffering 0282 (c) a therapeutically effective amount of at agent and nonsteroidal anti-inflammatory agent, is dispersed least one nonsteroidal anti-inflammatory drug. in the coating Solution and fed onto the center of the Spinning disk. A thin film is produced across the Surface of 0283 51. A method of treating a gastric acid related the disk and atomization occurs as the coating material left disorder and treating a chronic inflammatory disor the periphery of the disk. The microspheres are formed by der in a Subject by administering: removal of the solvent using heated airflow inside the atomization chamber and collected as a free-flowing powder 0284 (a) a therapeutically effective amount of at using a cyclone Separator. least one acid labile proton pump inhibitor, 0285) (b) at least one buffering agent in an amount Example 2 Sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least Some of the Spray Drying Microencapsulation ProceSS proton pump inhibitor in the gastric fluid; and 0296. A spray dryer consists of the same components as 0286 (c) a therapeutically effective amount of at a spinning disk except atomization is achieved through an least one nonsteroidal anti-inflammatory drug. air nozzle instead of a spinning disk. 0287 52. A method of treating a gastric acid related disorder and treating an inflammatory disorder in a Example 3 Subject by administering: 0288 (a) a first pharmaceutical composition com Preparation of Powder for Suspension for Oral prising: Dosing 0297 Powder for suspension (liquid oral pharmaceutical 0289 (i) a therapeutically effective amount of composition) according to the present invention, is prepared at least one acid labile proton pump inhibitor; by mixing PPI (40 mg omeprazole in the form of microen and capsulated omeprazole, omeprazole powder or omeprazole 0290 (ii) at least one buffering agent in an base) with at least one buffering agent and a nonsteroidal amount Sufficient to increase gastric fluid pH to anti-inflammatory agent. In one embodiment, omeprazole or US 2005/0249806 A1 Nov. 10, 2005 30 other proton pump inhibitor, which can be obtained from 0299 Omeprazole microspheres were prepared using a powder, capsules, tablets, or from the Solution for parenteral high-speed rotary tablet press (TBCB Pharmaceutical administration, is mixed with sodium bicarbonate (1680 Equipment Group, Model ZPY15). Round, convex tablets mg), nonsteroidal anti-inflammatory drug, and Sweeteners with diameters of about 10 mm and an average weight of and flavors. approximately 600 mg per tablet were prepared.

TABLE 4A No Microencapsulation Material Method Size Myverol Disk-hot melt 120-200 micron Myverol Disk-hot melt 120-200 micron KLX & BHT (0.1% of KLX) Disk-hot melt 25-125 micron KLX & BHT (0.1% of KLX) Disk-hot melt 25-125 micron Methocel A15LV & PEG 3350 (5%) Spray dry 5-30 micron Methocel A15LV, PEG 300 (5%) & BKT (0.1%) Spray dry 5-30 micron Methocel A15LV, Span 20 (5%) & BHT (0.1%) Spray dry 5-30 micron Methocel A15LV BHT (0.1%) Spray dry 5-30 micron 9 Modified food starch, PEG 3350 (2.5%) & BHT (0.1%) Spray dry 5-30 micron 10 Methocel A15LV, PEG 3350 (5%), BHT (0.1%) & Sodium bicarbonate Spray dry 5-30 micron 11 Opadry YS-1-7003 PEG 3350 (5%) BHT (0.1%) Spray dry 5-30 micron 12 Methocel K4M PEG 3350 (10%) BHT Spray dry 5-30 micron 13 Kollicoat IR, PEG 3350 (5%) & BHT Spray dry 5-30 micron 14 Eudragit RD 100, PEG 3350 (5%) & BHT (0.1%) Spray dry 5-30 micron 15 Klucel (HPC), PEG 3350 (5%) & BHT (0.1%) Spray dry 5-30 micron 16 Ethocel Disk-solvent 25-125 micron 17 Ethocel (50%) Methocel E5 (50%) Disk-solvent 25-125 micron 18 Ethocel (75%) Methocel (25%) Disk-solvent 25-125 micron 19 Methocel Disk-solvent 25-125 micron 20 Ethocel Sodium Bicarbonate Disk-solvent 25-125 micron 21 Ethocel & PEG 3350 (5%) Disk-solvent 25-125 micron 22 Ethocel (50%) & Klucel EXAF (50%) Disk-solvent 25-125 micron 23 Klucel Disk-solvent 25-100 micron 24 Sepifilm LP Disk-solvent 25-100 micron 25 Eudragit E100 Disk-solvent 25-80 micron 26 Eudragit E100 Disk-solvent 25-80 micron 27 Eudragit E100 & Span 20 (5%) Disk-solvent 25-80 micron 28 Eudragit E100 & PEG 300 (5%) Disk-solvent 25-80 micron 29 Eudragit EPO Disk-solvent 25-80 micron 30 Eudragit EPO Disk-solvent 25-90 micron 31 Opadry AMB Spray dry <30 micron 32 Sucralose Spray dry 33 Sepifilm LP Spray dry 34 Kollicoat IR Spray dry 35 Kollicoat IR & Sodium bicarbonate Spray dry <30 micron 36 Klucel & Sucralose (20%) Spray dry 37 Klucel & Sucrose (20%) Spray dry 38 Klucel & Sodium bicarbonate Spray dry <30 micron 39 Klucel (60%) Sucraolse (10%) Sodium bicarbonate (30%) Spray dry <50 micron 40 Eudragit EPO Disk-solvent 20-75 micron 41 Eudragit EPO Disk-solvent 20-90 micron 42 Eudragit EPO(67%) Sodium bicarb(33%) Disk-solvent 20-85 micron 43 EudragitEPO(61.5%) PEG 300(11.5%) PEG 3350 (3.8%) Sod Bicarb (23.2%) Disk-solvent 20-110 micron 44 Eudragit EPO Disk-solvent 20-100 micron 45 Opadry AMB (No TiO.) Spray dry 46 Opadry AMB (No TiO) Spray dry 47 Opadry AMB (No TiO.) BHT (0.1%) Spray dry 48 Cavamax W8 (gamma-CD) Spray dry (pH = 10) 5-30 microns 49 Cavamax W8 & L-lysine Spray dry (pH = 10) 5-30 micron 50 Cavamax W8 & Methocel A15 LV Spray dry (pH = 10) 5-40 micron 52 Opadry AMB & BHT Spray Dry (aqueous) 5-30 micron

Example 4 0300 Stability studies were performed on the microen capsulated omeprazole. The various tablets used in the Microencapsulated Proton Pump Inhibitor Stability Studies were manufactured using the following materials: Encapsulated omeprazole, Sodium bicarbonate 0298 The amount of microencapsulated omeprazole (1260 mg), calcium carbonate (790 mg), croScarmellose used in each tablet batch varies based on the actual payload sodium (64 mg), Klucel (160 mg), Xylitab 100 (380 mg), of each Set of microcapsules to achieve the theoretical dose microcrystalline cellulose (128 mg), Sucralose (162 mg), of 40 mg. The omeprazole is microencapsulated in a similar peppermint duraromer (34 mg), peach duraromer (100 mg), manner as that described in Example 1 and Example 2. All masking powder (60 mg), FD&C Lake No. 40 Red (3 mg), ingredients are mixed well to achieve a homogenious blend. and magnesium Stearate (32 mg). An exemplary formulation US 2005/0249806 A1 Nov. 10, 2005 31 used to make each of the tablets, as well as the blending controlled environmental chambers which were maintained methods used, are shown in Table 4.B., below. at 252 C./60.5% RH and 402 C./755% RH.

TABLE 4B

Feed Method and Microencapsulation Wt 9% of Rate Inlet/Outlet Sample Solvent Material material (g/min) Temp( C.) 53 Spray dry Methocel A15 LV 5% 4.2 125/70 Water PEG 3350 54 Spray dry Methocel A15 LV 5% 4.0 125/70 Water BHT 55 Spray dry Opadry YS-1-7003 5% 4.2 126/60 Water PEG 3350 BHT 56 Spray dry Kollicoat IR 10% 3.0 128/85 Water PEG 3350 BHT 57 Spray dry Eudragit RD100 5% 4.0 127/87 Water PEG 3350 BHT 58 Spray dry Klucel 5% 4.2 126/83 Water PEG 3350 BHT 59 Spinning disk** Klucel 10% 90 f52 75% Methanol 25% Acetone 60 Spray dry Kollicoat 5% 4.5 129/86 Water Sodium Bicarb 61 Spray dry Klucel 5% 4.5 122/84 Water Sodium Bicarb 62 Spinning disk Eudragit EPO 10% 90 150 75% Methanol 25% Acetone 63 Spray dry Opadry AMB 10% 4.4 124f79 Water BHT *Used a concentric nozzle with 0.055 inch air opening and a 0.028 inch fluid opening. **Used a 3-inch stainless steel disk rotating at approximately 4,500 rpm.

Example 5 0302 Microspheres that exhibited dissolution results with greater than 80% omeprazole release after 2 hours were Stability of Microencapsulated Omeprazole placed on Stability. The microSpheres were Stored in opened 0301 The tablets used in the stability study were pack vials at 25 C. All samples showed degradation after 4 weeks aged into 60 ml HDPE 33/400 bottles with two 1 gram, 2 in at elevated temperatures. The open vials stored at 25 C. 1 desiccant canisters. The HDPE bottles were closed hand were analyzed after 6-8 weeks for potency and for impurities tight and induction sealed using a 33/400 CRC SFGD 75M using the Omeprazole EP method. The stability results are cap with a polypropylene liner. Samples were placed in Summarized in the Table 5.A.

TABLE 5.A OME Loading 4-Week Potency Values AUC Microencapsulation Material (Initial) (Omeprazole Loading) Purity Methocel A15LV & PEG 3350 (5%) 23.3 25.0(107% of initial)(a)25° C. 95.65 Methocel A15LV, PEG 300 (5%) & BHT (0.1%) 26.0 24.9(95.8% of initial) (a 25° C. 99.90 Methocel A15LV BHT (0.1%) 24.8 26.4(106.6% of initial)(a)25° C. 99.95 Methocel A15LV, PEG 3350 (5%), BHT (0.1%) & 2.2 2.3 (106% of initial) (a 25° C. 76.16 Sodium bicarbonate Opadry YS-1-7003 PEG 3350 (5%) BHT (0.1%) 20.5 22.6(110% of initial) (a)25° C. 1OO.O Kollicoat IR, PEG 3350 (5%) & BHT 26.2 23.8(90.8% of initial) (a 25° C. 99.54 Eudragit RD 100, PEG 3350 (5%) & BHT (0.1%) 21.3 19.1(89.5% of initial) (a 25° C. 98.88 Klucel (HPC), PEG 3350 (5%) & BHT (0.1%) 26.0 22.8(87.8% of initial)(a)25° C. 99.70 Ethocel (50%) Methocel E5 (50%) 25.8 21.9(84.9% of initial) (a 25° C. 98.22 (99.3(aT) Klucel 22.2 20.7 (93.2% of initial) (a 25° C. 97.69 Kollicoat IR & Sodium bicarbonate 26.0 21.7(83.6% of initial) (a 25° C. 97.88 * AUC Purity = Area Under the Curve after 6-8 weeks at 25 C. in open container. US 2005/0249806 A1 Nov. 10, 2005 32

Example 6 0306 Capsule Formulations TABLE 6.D 0303. The following specific formulations are provided Lansoprazole (30 mg)-Piroxicam (20 mg) Capsule by way of reference only and are not intended to limit the PPI Buffering Agent NSAID Excipient Scope of the invention. Each formulation contains therapeu 30 mg 17.1 mEq or 500 20 mg 20 mg Ac-Di-Sol tically effective doses of PPI and nonsteroidal anti-inflam lansoprazole mg Mg(OH)2 piroxicam 30 mg Klucel matory as well as Sufficient buffering agent to prevent acid per capsule 4.2 mEq or 350 per capsule 10 mg magnesium mg NaHCOs Stearate degradation of at least some of the PPI by raising the pH of 21.3 mEq or 850 gastric fluid. Amounts of buffer are expressed in weight as mg total buffer well as in molar equivalents (mEq). Amounts of nonsteroi dal anti-inflammatory agents are typically expressed in a per unit dose amount. The capsules are prepared by blending the 0307) PPI and nonsteroidal anti-inflammatory agent with buffering agents, and homogeneously blending with excipients as TABLE 6.E shown in Tables 6.A. to 6.H. below. The appropriate weight Omeprazole (60 mg)-Rofecoxib (25 mgs) Capsule of bulk blend composition is filled into a hard gelatine capsule (e.g., size 00) using an automatic encapsualtor (H & PPI Buffering Agent NSAID Excipient K 1500 or MG2 G60). 60 mg 17.1 mEq or 500 25 mgs 20 mg Ac-Di-Sol ompeprazole mg Mg(OH)2 rofecoxib 25 mg Klucel per capsule 3.0 mEq or 250 per capsule 10 mg magnesium TABLE 6A mg NaHCOs Stearate 20.1 mEq or 750 Omeprazole (20 mg)-Ibuprofen (250mg) Capsule mg total buffer

PPI Buffering Agent NSAID Excipient 0308) 20 mg 17.1 mEq or 500 250 mg ibupro- 50 mg Ac-Di-Sol omepra- mg Mg(OH)2 fen per capsule 30 mg Klucel TABLE 6.F Zole per 3.0 mEq or 250 10 mg magnesium capsule mg NaHCOs Stearate Omeprazole (60 mg)-Valdecoxib (20 mg) Capsule 20.1 mEq or 750 mg PPI Buffering Agent NSAID Excipient total buffer 60 mg 17.1 mEq or 500 20 mg 30 mg Ac-Di-Sol ompeprazole mg Mg(OH)2 valdecoxib 15 mg Klucel per capsule 3.0 mEq or 250 per capsule 7 mg magnesium mg NaHCO Stearate 0304 20.1 mEq or 750 mg total buffer TABLE 6.B Qmpeprazole (40 mg)-Meloxicam (15 mg) Capsule 0309 PPI Buffering Agent NSAID Excipient TABLE 6.G 40 mg 20.6 mEq or 600 15 mg 40 mg Ac-Di-Sol omepra- mg Mg(OH)2 meloxicam 35 mg Klucel Zole per 4.2 mEq or 350 per capsule 10 mg magnesium Omeprazole (10 mg)-Piroxicam (10 mg) Capsule capsule mg NaHCO Stearate 24.8 mEq or 950 PPI Buffering Agent NSAID Excipient mg total buffer 10 mg 17.1 mEq or 500 10 mg 30 mg Ac-Di-Sol ompeprazole mg Mg(OH), piroxicam 15 mg Klucel per capsule 3.0 mEq or 250 per capsule 7 mg magnesium mg NaHCOs Stearate 0305 20.1 mEq or 750 mg total buffer TABLE 6.C LanSoprazole (15 mg)-Ketoprofen (75 mg) Capsule 0310 PPI Buffering Agent NSAID Excipient TABLE 6H 15 mg 17.1 mEq or 500 75 mg 30 mg Ac-Di-Sol microencap- mg Mg(OH)2 ketoprofen 15 mg Klucel Omeprazole (40 mg)-Enterie Coated Asprin (100 mg) Capsule sulated lan- 3.0 mEq or 250 per capsule 7 mg magnesium soprazole per mg NaHCO Stearate PPI Buffering Agent NSAID Excipient capsule 20.7 mEq or 750 mg total buffer 40 mg 15.4 mEq or 450 100 mg enteric 30 mg Ac-Di-Sol microencap- mg Mg(OH)2 coated asprin 7 mg magnesium US 2005/0249806 A1 Nov. 10, 2005 33

0313) TABLE 6.H-continued TABLE 7C Omeprazole (40 mg)-Enteric Coated Asprin (100 mg) Capsule Lansoprazole (15 mg)-Indomethacin (75 mg) Tablet PPI Buffering Agent NSAID Excipient PPI Buffering Agent NSAID Excipient 15 mg 17.1 mEq or 500 75 mg indo- 20 mg Ac-Di-Sol microencap- mg Mg(OH)2 methacin 80 mg Klucel sulated 2.4 mEq or 200 per capsule Stearate sulated 3.0 mEq or 250 per tablet 10 mg magnesium ompeprazole mg NaHCO lansoprazole mg NaHCOs Stearate per tablet 20.1 mEq or 750 per capsule 17.8 mEq or 650 mg total buffer mg total buffer 0314)

Example 7 TABLE 7D

Tablet Formulations Lansoprazole (30 mg)-Celecoxib (100 mg) Tablet PPI Buffering Agent NSAID Excipient 0311. The following specific formulations are provided 30 mg 20.6 mEq or 500 100 mg 20 mg Ac-Di-Sol by way of reference only and are not intended to limit the lansoprazole mg Mg(OH)2 celecoxib 80 mg Klucel Scope of the invention. Each formulation contains therapeu per tablet 4.2 mEq or 350 per tablet 10 mg magnesium tically effective doses of PPI and nonsteroidal anti-inflam mg NaHCOs Stearate 24.8 mEq or 850 matory drug as well as Sufficient buffering agent to prevent mg total buffer acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of buffer are expressed in weight as well as in molar equivalents (mEq). Amounts of nonste 0315) roidal anti-inflammatory drugs are typically expressed in a per unit dose amount. The tablets are prepared by blending TABLE 7...E the PPI and nonsteroidal anti-inflammatory drug with buff ering agents, and homogeneously blending with excipients Omeprazole (60 mg)-Sulindac (200 mg) Tablet as shown in Tables 7.A. to 7.H. below. The appropriate PPI Buffering Agent NSAID Excipient weight of bulk blended composition is compressed using 60 mg 20.6 mEq or 600 200 mg 20 mg Ac-Di-Sol %-inch FFBE toolings in a rotary press (Manesty Epxress) omeprazole mg Mg(OH)2 Sulindac 80 mg Klucel per tablet 3.0 mEq or 250 per tablet 10 mg magnesium to achieve a hardness of 20-24 kPa. mg NaHCO Stearate 23.6 mEq or 850 TABLE 7. A mg total buffer Qmpeprazole (20 mg)-Paracetamol (300 mg) Tablet PPI Buffering Agent NSAID Excipient 0316) 20 mg 13.7 mEq or 400 300 mg 30 mg Ac-Di-Sol TABLE 7.F omeprazole mg Mg(OH)2 paracetamol 80 mg Klucel per tablet 3.0 mEq or 250 per tablet 10 mg magnesium Omeprazole (60 mg)-Naproxen (200 mg) Tablet mg NaHCOs Stearate 16.7 mEq or 650 mg PPI Buffering Agent NSAID Excipient total buffer 60 mg 17.1 mEq or 500 200 mg 20 mg Ac-Di-Sol omprazole mg Mg(OH), naproxen 60 mg Klucel per tablet 3.0 mEq or 250 per tablet 10 mg magnesium mg NaHCOs Stearate 0312) 20.1 mEq or 850 mg total buffer TABLE 7.B Omeprazole (40 mg)-Asprin (81 mg) Tablet 0317) PPI Buffering Agent NSAID Excipient TABLE 7.G 40 mg 17.1 mEq or 500 81 mg 20 mg Ac-Di-Sol microencap- mg Mg(OH)2 asprin per 80 mg Klucel Ompeprazole (10 mg)-Ibuprolen (200) Tablet sulated 3.0 mEq or 250 tablet 10 mg magnesium omeprazole mg NaHCO Stearate PPI Buffering Agent NSAID Excipient per tablet 20.1 mEq or 850 mg total buffer 10 mg 13.7 mEq or 400 200 mgs 20 mg Ac-Di-Sol microencap- mg Mg(OH)2 Ibupropene 80 mg Klucel US 2005/0249806 A1 Nov. 10, 2005 34

0320 TABLE 7. G-continued TABLE 8B Ompeprazole (10 mg)-Ibuprolen (200) Tablet Omeprazole (40 mg)-Diclofenac (100 mg) Chewable Tablet PPI Buffering Agent NSAID Excipient PPI Buffering Agent NSAID Excipient sulated 3.0 mEq or 250 per tablet 10 mg magnesium 40 mg 170 mg Dipac Sugar omeprazole mg NaHCOs Stearate 24.0 mEq or 700 100 mg microencap mg Mg(OH)2 diclofenac 30 mg Ac-Di-Sol per tablet 16.7 mEq or 650 sulated 7.1 mEq or 600 per tablet 120 mg Klucel mg total buffer omeprazole mg NaHCO 27 mg grape flavor per tablet 27.1 mEq or 1300 15 mg magnesium mg total buffer Stearate 0318) 1 mg Red #40 Lake 1 mg Blue #2 Lake TABLE 7.H Ompeprazole (40 mg)-Asprin (100 mg) Tablet 0321) PPI Buffering Agent NSAID Excipient 40 mg 20.6 mEq or 600 100 mgs 20 mg Ac-Di-Sol TABLE 8C microencap- mg Mg(OH)2 asprin 80 mg Klucel sulated 3.0 mEq or 250 per tablet 10 mg magnesium Lansoprazole (15 mg)-Ibuprofen (600 mg) Chewable Tablet omeprazole mg NaHCOs Stearate per tablet 23.6 mEq or 850 PPI Buffering Agent NSAID Excipient mg total buffer 15 mg 17.1 mEq or 500 600 mg 170 mg Xylitab lansoprazole mg Mg(OH), ibuprofen 30 mg Ac-Di-Sol per tablet 8.0 mEq or 672 per tablet 120 mg Klucel mg NaHCO 100 mg Asulfame-K Example 8 25.1 mEq or 1172 27 mg grape flavor mg total buffer 15 mg magnesium Stearate Chewable Tablet Formulations 1 mg red #40 lake 03.19. The following specific formulations are provided 1 mg blue #2 lake by way of reference only and are not intended to limit the Scope of the invention. Each formulation contains therapeu 0322) tically effective doses of PPI and nonsteroidal anti-inflam matory drug as well as Sufficient buffering agent to prevent TABLE 8.D acid degradation of at least some of the PPI by raising the pH of gastric fluid. Amounts of buffer are expressed in weight Lansoprazole (30 mg)-Aspirin (800 mg) Chewable Tablet as well as in molar equivalents (mEq). Amounts of nonste PPI Buffering Agent NSAID Excipient roidal anti-inflammatory drugs are typically expressed in a 30 mg 24.0 mEq or 700 400 mg 170 mg Xylitab per unit dose amount. The tablets are prepared by blending microencap mg Mg(OH), asprin and 30 mg Ac-Di-Sol the PPI and nonsteroidal anti-inflammatory agent with buff sulated 5.0 mEq or 420 400 mg 100 mg Klucel lansoprazole mg NaHCOs enteric 25 mg cherry flavor ering agents, and homogeneously blending with excipients per tablet 29.0 mEq or 1120 coated 15 mg magnesium as shown in Tables 8. A to 8.H. below. The appropriate mg total buffer aspirin Stearate weight of bulk blended composition is compressed using per tablet 3 mg Red #40 Lake 5/8-inch FFBE toolings in a rotary press (Manesty Epxress) to achieve a hardness of 17-20 kPa. 0323) TABLE 8A TABLE 8.E Ompeprazole (20 mg)-Rofecoxib (25 mg) Chewable Tablet Omeprazole (60 mg)-Oxaprozin (600 mg) Chewable Tablet PPI Buffering Agent NSAID Excipient PPI Buffering Agent NSAID Excipient 20 mg 20.6 mEq or 600 25 mg 170 mg Xylitab microencap- mg Mg(OH)2 rofecoxib 30 mg Ac-Di-Sol 60 mg 15 mEq or 750 600 mg 170 mg Xylitab sulated 5.0 mEq or 420 per tablet 100 mg Klucel microencap mg Ca(OH)2 Oxaprozin 30 mg Ac-Di-Sol omeprazole mg NaHCOs 40 mg Sucralose sulated 15 mEq or 1260 per tablet 100 mg Klucel per tablet 25.6 mEq or 1020 25 mg cherry flavor omeprazole mg NaHCOs 25 mg cherry flavor mg total buffer 15 mg magnesium per tablet 30 mEq or 2010 15 mg magnesium Stearate mg total buffer Stearate 3 mg Red #40 Lake 3 mg Red #40 Lake US 2005/0249806 A1 Nov. 10, 2005 35

0324) TABLE 9A TABLE 8.F Ompeprazole (20 mg)-Celecoxib (100 mg) Omeprazole (60 mg)-Piroxicam (10 mg) Chewable Tablet Bite-Disintegration Chewable Tablet PPI Buffering Agent NSAID Excipient PPI Buffering Agent NSAID Excipient 20 mg per 20.6 mEq or 600 100 mg 60 mg sucralose 60 mg 15 mEq or 750 10 mg 170 mg Xylitab tablet mg Mg(OH)2 Celecoxib 60 mg Ac-Di-Sol omprazole mg Ca(OH)2 piroxicam 30 mg Ac-Di-Sol 5.0 mEq or 420 per tablet 60 mg pregelatinized per tablet 10 mEq or 840 per tablet 100 mg Klucel mg NaHCOs starch mg NaHCOs 15 mg mint flavor 25.6 mEq or 1020 30 mg Klucel 25 mEq or 1590 15 mg magnesium mg total buffer 25 mg cherry flavor mg total buffer Stearate 15 mg magnesium Stearate 3 mg Red #40 Lake 0325) TABLE 8.G 0328) Omeprazole (10 mg)-Ibuprofen (600 mg) Chewable Tablet TABLE 9.B PPI Buffering Agent NSAID Excipient Omeprazole (40 mg)-Diclofenac (100 mg) 10 mg 15 mEq or 750 600 mg 170 mg Xylitab Bite-Disintegration Chewable Tablet omprazole mg Ca(OH)2 ibuprofen 30 mg Ac-Di-Sol per tablet 10 mEq or 840 per tablet 100 mg Klucel PPI Buffering Agent NSAID Excipient mg NaHCOs 15 mg mint flavor 40 mg 23.7 mEq or 700 100 mg 60 mg sucralose 25 mEq or 1590 15 mg magnesium microencap- mg Mg(OH)2 diclofenac 60 mg Ac-Di-Sol mg total buffer Stearate sulated 7.2 mEq or 600 per tablet 60 mg pregelatinized omeprazole mg NaHCO starch per tablet 30.9 mEq or 1300 30 mg Klucel mg total buffer 27 mg grape flavor 0326 15 mg magnesium Stearate TABLE 8.H 1 mg Red #40 Lake 1 mg Blue #2 Lake Omeprazole (40 mg)-Asprin (100 mg) Chewable Tablet PPI Buffering Agent NSAID Excipient 0329 40 mg 15 mEq or 750 100 mg 170 mg Xylitab microencap- mg Ca(OH)2 asprin 30 mg Ac-Di-Sol sulated 10 mEq or 840 per tablet 100 mg Klucel TABLE 9C omprazole mg NaHCOs 15 mg mint flavor per tablet 25 mEq or 1590 15 mg magnesium Lansoprazole (15 mg)-Ibuprofen (600 mg) mg total buffer Stearate Bite-Disintegration Chewable Tablet PPI Buffering Agent NSAID Excipient 15 mg 17.1 mEq or 500 600 mg 60 mg sucralose Example 9 lansoprazole mg Mg(OH), ibuprofen 70 mg Ac-Di-Sol per tablet 7.2 mEq or 600 per tablet 70 mg pregelatinized mg NaHCOs starch Bite-Disintegration Chewable Tablet Formulations 24.2 mEq or 1100 30 mg Klucel mg total buffer 27 mg grape flavor 0327. The following specific formulations are provided 15 mg magnesium Stearate by way of reference only and are not intended to limit the 1 mg Red #40 Lake Scope of the invention. Each formulation contains therapeu 1 mg Blue #2 lake tically effective doses of PPI and nonsteroidal anti-inflam matory drug as well as Sufficient buffering agent to prevent acid degradation of at least some of the PPI by raising the pH 0330 of gastric fluid. Amounts of buffer are expressed in weight as well as in molar equivalents (mEq). Amounts of nonste TABLE 9D roidal anti-inflammatory drug are typically expressed in a Lansoprazole (30 mg)-Aspirin (200 mg) per unit dose amount. The tablets are prepared by blending Bite-Disintegration Chewable Tablet the PPI and nonsteroidal anti-inflammatory drug with buff ering agents, and homogeneously blending with excipients PPI Buffering Agent NSAID Excipient as shown in Tables 9. A to 9.H. below. The appropriate 30 mg 17.1 mEq or 500 200 mg 60 mg sucralose microencap- mg Mg(OH)2 microencap- 60 mg Ac-Di-Sol weight of bulk blended composition is compressed using sulated 5 mEq or 420 sulated 70 mg pregelatinized 5/8-inch FFBE toolings in a rotary press (Manesty Epxress) lansoprazole mg NaHCOs asprin starch to achieve a hardness of 8-12 kPa. US 2005/0249806 A1 Nov. 10, 2005 36

0333) TABLE 9.D-continued TABLE 9.G Lansoprazole (30 mg)-Aspirin (200 mg) Bite-Disintegration Chewable Tablet Omeprazole (10 mg)-Ibuprofen (500 mg) PPI Buffering Agent NSAID Excipient Bite-Disintegratbn Chewable Tablet per tablet 22.1 mEq or 1020 per tablet 30 mg Klucel PPI Buffering Agent NSAID Excipient mg total buffer 25 mg cherry flavor 15 mg magnesium 10 mg 15 mEq or 750 500 mg 60 mg sucralose Stearate omprazole mg Ca(OH)2 ibuprofen 60 mg Ac-Di-Sol 3 mg Red #40 Lake per tablet 10 mEq or 840 per tablet 60 mg pregelatinized mg NaHCOs starch 25 mEq or 1590 30 mg Klucel 0331) mg total buffer 15 mg mint flavor 15 mg magnesium TABLE 9.E Stearate Omeprazole (60 mg)-Ketoprofen (100 mg) Bite-Disintegration Chewable Tablet PPI Buffering Agent NSAID Excipient 0334) 60 mg 15 mEq or 750 100 mg 60 mg sucralose microencap- mg Ca(OH)2 ketoprofen 60 mg Ac-Di-Sol TABLE 9.H sulated 15 mEq or 1260 per tablet 60 mg pregelatinized omeprazole mg NaHCOs starch Omeprazole (40 mg)-Asprin (100 mg) per tablet 30 mEq or 2010 30 mg Klucel Bite-Disintegration Chewable Tablet mg total buffer 25 mg cherry flavor 15 mg magnesium PPI Buffering Agent NSAID Excipient Stearate 40 mg 15 mEq or 750 100 mg 60 mg sucralose 3 mg Red #40 Lake microencap- mg Ca(OH)2 asprin 60 mg Ac-Di-Sol sulated 10 mEq or 840 per tablet 60 mg pregelatinized omprazole mg NaHCO starch per tablet 25 mEq or 1590 30 mg Klucel 0332) mg total buffer 15 mg mint flavor 15 mg magnesium TABLE 9.F Stearate Omeprazole (60 mg)-Tenoxicam (20 mg) Bite-Disintegration Chewable Tablet Example 10 PPI Buffering Agent NSAID Excipient 60 mg 15 mEq or 750 20 mg 60 mg sucralose Powder for Suspension Formulations omprazole mg Ca(OH)2 tenoxicam 60 mg Ac-Di-Sol per tablet 10 mEq or 840 per tablet 60 mg pregelatinized mg NaHCOs starch 0335 The following specific formulations are provided by 25 mEq or 1590 30 mg Klucel way of reference only and are not intended to limit the Scope mg total buffer 15 mg mint flavor of the invention. Each formulation contains therapeutically 15 mg magnesium effective doses of PPI and NSAIDs as well as Sufficient Stearate buffereing agent to prevent acid degredation of at least Some of the PPI by raising the pH of gastric fluid.

TABLE 1.O.A Omeprazole (20 mg) - Ibuprofen

1. 2 3 4 5 6 7 8 9 1O Omeprazole 2O 2O 2O 2O 2O 2O 2O 2O 2O 2O Ibuprofen 4OO 2SO 100 20O 600 4OO 2SO 100 200 100 Sodium Bicarbonate 1895 168O 1825 1895 1375 16SO 1825 165O 162O 16OO Xylitol 300 (sweetener) 2OOO 2000 1500 1750 1750 2500 2000 1500 2000 2500 Sucrose-powder (sweetener) 1750 2000 2250 2000 2500 1500 1750 2500 2000 1500 Sucralose (sweetener) 125 100 150 75 100 70 8O 130 125 8O Xanthan Gum 17 55 31 8O 39 48 72 25 64 68 Peach Flavor 47 15 75 32 60 50 77 38 35 62 Peppermint 26 1O 29 28 36 42 56 17 16 50 Total Weight 588O 5880 588O 588O 5880 588O 588O 5880 588O 588O US 2005/0249806 A1 Nov. 10, 2005 37

0336)

TABLE 10.B Omeprazole (40 mg) - Indomethaein

1. 2 3 4 5 6

Omeprazole 40 40 40 40 40 40 40 40 40 40 Indomethacin 50 50 50 50 50 50 25 25 25 25 Sodium Bicarbonate 2O1O 1375 1680 152O 1400 1825 16SO 203O 1375 Xylitol 300 (sweetener) 1500 2750 2000 2500 2000 1750 25OO 1500 1750 Sucrose-powder (sweetener) 2OOO 15OO 2OOO 15OO 225O 2OOO 1SOO 2000 2500 Sucralose (sweetener) 1SO 100 75 125 100 95 8O 8O 130 125 Xanthan Gum 75 74 22 45 8O 17 58 39 40 64 33 Peach Flavor 64 8O 28 76 55 68 30 35 82 32 Peppermint 42 13 12 39 18 44 11 35 34 25 Total Weight 588O 5880 5880 588O 5880 588O 588O 5880 588O

0337

TABLE 1.O.C Omeprazole (60 mg) - Asprin

1. 2 3 4 5 6

Omeprazole 60 60 60 60 60 60 60 60 60 60 Asprin 1OO 2OO 3OO 4OO SOO 600 7OO 8OO 900 1OOO Sodium Bicarbonate 17SO 247S 131O 2130 2005 1580 1110 23OO 1325 1400 Xylitol 300 (sweetener) 2OOO 15OO 2OOO 15OO 2000 2500 2250 1500 1750 2500 Sucrose-powder (sweetener) 1750 1500 225O 2OOO 1500 1500 2250 1750 2500 1750 Sucralose (sweetener) 145 130 75 7O 150 150 60 100 8O 75 Xanthan Gum 75 15 57 22 19 64 39 33 29 44 50 Peach Flavor 92 105 87 78 57 31 69 95 88 25 Peppermint 68 53 76 23 44 2O 48 46 33 2O Total Weight 588O 5880 5880 588O 5880 588O 588O 5880 588O

Example 11 related disorder in the patient. Treament is delivered via a capsule or enterically coated tablet. Typical dosing is as Combination Therapy for Treatment of GERD follows 20-40 mg coated PPI, e.g., omeprazole); a nonste and/or Ulcers Including NSAID Caused Ulcers and roidal anti-inflammatory drug, e.g., 200-800 mg Ibuprofen Inflammation/Pain or 12-25 mg Rofecoxib; and 750 to 1500 mg buffering agent. 0338 For a combined treatment when a patient experi Effective amounts of other nonsteroidal anti-inflammatory ences both GERD and an inflammatory disease state or drugs are found in Table 1. disorder, a formulation of the present invention is adminis 0340 Modifications, equivalents, and variations of the tered for relief of both the gastric acid disorder and the present invention are possible in light of the teachings inflammatory disease State or disorder. Administration of a above, such that the invention may be embodied in other therapeutic amount of buffered, non-enteric-coated PPI, forms without departing from the Spirit or essential charac formulated for rapid uptake Via Stomach delivery, in com terics of the invention. The present embodiments are there bination with a therapeutically effective amount of a non fore to be considered as illustrative and not restrictive, the Steroidal anti-inflammatory drug, gives rapid relief from Scope of the inventinion being indicated by the appended gastric acid pain and the inflammatory disease. Treatment claims rather than by the foregoing description. All changes may be delivered via a chewable tablet, a Suspension tablet, that come within the meaning and range of equivalency of an effervescent tablet, a rapid dissolving tablet, or various the claims are therefore intended to be embraced therein. liquid formulations and aqueous Suspensions. Typical dos ing is as follows: 10-60 mg PPI (omeprazole); 200-800 mgs of Ibuprofen; and 750-1500 mg buffering agent. Effective We claim: amounts of other nonsteroidal anti-inflammatory agents are 1. A pharmaceutical composition comprising: found in Table 1. (a) a therapeutically effective amount of at least one acid 0339. To prevent a gastric acid disorder, a formulation of labile proton pump inhibitor; the present invention may be administered. Administration of a therapeutic amount of enteric-coated buffered PPI along (b) at least one buffering agent in an amount Sufficient to in combination with a therapeutically effective amount of a increase gastric fluid pH to a pH that prevents acid nonsferoidal anti-inflammatory drug, prevents the nonste degradation of at least Some of the proton pump inhibi roidal anti-inflammatory drug from inducing a gastric acid tor in the gastric fluid; and US 2005/0249806 A1 Nov. 10, 2005 38

(c) a therapeutically effective amount of at least one 14. The composition of claim 1, wherein some of the nonsteroidal anti-inflammatory drug. proton pump inhibitor is coated. 2. The composition of claim 1, wherein an initial Serum 15. The composition of claim 1, wherein the buffering concentration of the proton pump inhibitor is greater than agent is an alkaline earth metal Salt or a Group IA metal about 0.1 lug/ml at any time within about 30 minutes after Selected from a bicarbonate Salt of a Group IA metal, a administration of the composition. carbonate Salt of a Group IA metal. 3. The composition of claim 1, wherein the proton pump 16. The composition of claim 1, wherein the buffering inhibitor Selected from the group consisting of omeprazole, agent is Selected from the group consisting of an amino acid, hydroxyomeprazole, esomeprazole, tenatoprazole, lanSopra an alkali metal Salt of an amino acid, aluminum hydroxide, Zole, pantoprazole, rabeprazole, dontoprazole, habeprazole, aluminum hydroxide/magnesium carbonate/calcium carbon perprazole, ranSoprazole, pariprazole, leminoprazole, or a ate co-precipitate, aluminum magnesium hydroxide, alumi free base, free acid, Salt, hydrate, ester, amide, enantiomer, num hydroxide/magnesium hydroxide co-precipitate, alumi isomer, tautomer, polymorph, or prodrug thereof. num hydroxide/sodium bicarbonate coprecipitate, aluminum 4. The composition of claim 3, wherein the proton pump glycinate, calcium acetate, calcium bicarbonate, calcium inhibitor is omeprazole or a free base, free acid, Salt, hydrate, borate, calcium carbonate, calcium citrate, calcium glucon ester, amide, enantiomer, isomer, tautomer, polymorph, or ate, calcium glycerophosphate, calcium hydroxide, calcium prodrug thereof. lactate, calcium phthalate, calcium phosphate, calcium Suc 5. The composition of claim 1 comprising about 10 mg, cinate, calcium tartrate, dibasic Sodium phosphate, dipotas 15 mg, 20 mg, 30 mg, 40 mg, or 80 mg of the proton pump sium hydrogen phosphate, dipotassium phosphate, disodium inhibitor. hydrogen phosphate, disodium Succinate, dry aluminum 6. The composition of claim 1, wherein an initial Serum hydroxide gel, L-arginine, magnesium acetate, magnesium concentration of the proton pump inhibitor is greater than aluminate, magnesium borate, magnesium bicarbonate, about 0.5 lug/ml at any time within about 1 hour after magnesium carbonate, magnesium citrate, magnesium glu administration of the composition. conate, magnesium hydroxide, magnesium lactate, magne 7. The composition of claim 1, wherein the composition sium metasilicate aluminate, magnesium oxide, magnesium is administered in an amount to maintain a Serum concen phthalate, magnesium phosphate, magnesium Silicate, mag nesium Succinate, magnesium tartrate, potassium acetate, tration of the proton pump inhibitor greater than about 0.15 potassium carbonate, potassium bicarbonate, potassium tug/ml from about 15 minutes to about 1 hour after admin borate, potassium citrate, potassium metaphosphate, potas istration of the composition. sium phthalate, potassium phosphate, potassium polyphos 8. The composition of claim 1, wherein upon oral admin phate, potassium pyrophosphate, potassium Succinate, istration to a Subject, the composition provides a pharma potassium tartrate, Sodium acetate, Sodium bicarbonate, cokinetic profile such that at least about 50% of total area Sodium borate, Sodium carbonate, Sodium citrate, Sodium under Serum concentration time curve (AUC) for the proton gluconate, Sodium hydrogen phosphate, Sodium hydroxide, pump inhibitor occurs within about 2 hours after adminis Sodium lactate, Sodium phthalate, Sodium phosphate, tration of a Single dose of the composition to the Subject. Sodium polyphosphate, Sodium pyrophosphate, Sodium Ses 9. The composition of claim 1, wherein upon oral admin quicarbonate, Sodium Succinate, Sodium tartrate, Sodium istration to the Subject, the composition provides a pharma tripolyphosphate, Synthetic hydrotalcite, tetrapotassium cokinetic profile Such that the proton pump inhibitor reaches pyrophosphate, tetrasodium pyrophosphate, tripotassium a maximum Serum concentration within about 1 hour after phosphate, triSodium phosphate, trometamol, and mixtures administration of a single dose of the composition. thereof. 10. The composition of claim 1, wherein the proton pump 17. The composition of claim 1, wherein the buffering inhibitor is microencapsulated with a material that enhances agent is Selected from Sodium bicarbonate, Sodium carbon the shelf-life of the pharmaceutical composition. ate, magnesium carbonate, aluminum hydroxide, calcium 11. The composition of claim 10, wherein the material that carbonate, magnesium hydroxide, magnesium oxide and enhances the shelf-life of the pharmaceutical composition is mixtures thereof. Selected from the group consisting of cellulose hydroxypro 18. The composition of claim 1, wherein the buffering pyl ethers, low-Substituted hydroxypropyl ethers, cellulose agent is Selected from Sodium bicarbonate, calcium carbon hydroxypropyl methyl ethers, ethylcellulose polymers, eth ate, magnesium hydroxide, and mixtures thereof. ylcelluloses and mixtures thereof, polyvinyl alcohol, hydroxyethylcelluloses, carboxymethylcelluloses and Salts 19. The composition of claim 1, wherein the buffering of carboxymethylcelluloses, polyvinyl alcohol and polyeth agent is Sodium bicarbonate in an amount from about 0.1 ylene glycol co-polymers, monoglycerides, triglycerides, mEq/mg proton pump inhibitor to about 5 mEq/mg proton polyethylene glycols, modified food Starch, acrylic poly pump inhibitor. mers, mixtures of acrylic polymers with cellulose ethers, 20. The composition of claim 1, wherein the buffering cellulose acetate phthalate, Sepifilms, cyclodextrins, and agent is present in an amount of at least about 5 mEq/mg. mixtures thereof. 21. The composition of claim 1, wherein the buffering 12. The composition of claim 1, wherein at least Some of agent is present in an amount of at least about 10 mEq/mg. the nonsteroidal anti-inflammatory drug is coated. 22. The composition of claim 1, wherein the buffering 13. The composition of claim 12, wherein the coating is agent is present in an amount of about 5-40 mEq/mg. Selected from a gastric resistant coating, a controlled-release 23. The composition of claim 1 comprising from about coating, an enzymatic-controlled coating, a film coating, a 200 to about 3000 mg of buffering agent. Sustained-release coating, an immediate-release coating, and 24. The composition of claim 1 comprising from about a delayed-release coating. 1000 to about 2000 mg of buffering agent. US 2005/0249806 A1 Nov. 10, 2005 39

25. The composition of claim 1, wherein the nonsteroidal 32. The composition of claim 25, wherein the arylbutyric anti-inflammatory drug is Selected from the group consisting acid derivative is bumadizon, butibufen, fenbufen, Xenbu of aminoarylcarboxylic acid derivatives, arylacetic acid cin, or a free base, free acid, Salt, hydrate, ester, amide, derivatives, arylbutyric acid derivatives, arylcarboxylic enantiomer, isomer, tautomer, polymorph, or prodrug acids, arylpropionic acid derivatives, pyrazoles, Salicylic thereof. acid derivatives, thiazinecarboxamides, epsilon-acetami docaproic acid, S-adenosylmethionine, 3-amino-4-hydroxy 33. The composition of claim 25, wherein the arylcar butytic acid, amiXetrine, bendazac, benzydamine, C.-bisab boxylic acid is clidanac, ketorolac, tinoridine, or a free base, olol, bucololome, difenpiramide, ditazol, emorfaZone, free acid, Salt, hydrate, ester, amide, enantiomer, isomer, fepradinol, guaiaZulene, nabumetone, nimeSulide, tautomer, polymorph, or prodrug thereof. Oxaceprol, paranyline, perisoxal, proguaZone, tenidap, Zilen 34. The composition of claim 25, wherein the arylpropi ton, and cyclooxygenase-II inhibitors, or a free base, free onic acid derivative is alminoprofen, benoxaprofin, bermo acid, Salt, hydrate, ester, amide, enantiomer, isomer, tau profen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, tomer, polymorph, or prodrug thereof. flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, 26. The composition of claim 25, wherein the nonsteroi loxoprofen, naproxen, Oxaprozin, piketoprofin, pirprofen, dal anti-inflammatory drug is a long-acting nonsteroidal pranoprofen, protizinic acid, Suprofen, tiaprofenic acid, anti-inflammatory drug. Ximoprofen, Zaltoprofen, or a free base, free acid, Salt, 27. The composition of claim 26, wherein the long-acting hydrate, ester, amide, enantiomer, isomer, tautomer, poly nonsteroidal anti-inflammatory drug is Selected from morph, or prodrug thereof. naproxen Sodium, flurobiprofen, ketoprofen, oxapriozin, 35. The composition of claim 25, wherein the pyrazole is indomethacin, ketoralac, nabumetone, mefenamic, piroxi difenamizole epirozole, or a free base, free acid, Salt, cam, and cyxlooxygenase-II inhibitors, or a free base, free hydrate, ester, amide, enantiomer, isomer, tautomer, poly acid, Salt, hydrate, ester, amide, enantiomer, isomer, tau morph, or prodrug thereof; the pyrazolone is apaZone, tomer, polymorph, or prodrug thereof. benzpiperylon, feprazone, mofebutaZone, moraZone, 28. The composition of claim 25, wherein the nonsteroi OxyphenbutaZone, phenylbutaZone, pipebuZone, propy dal anti-inflammatory drug is Selected from diclofenac, phenaZone, prostaglandins, ramifenaZone, SuxibuZone, thia etodolac, fenoprofen, fluorbiprofen oral, ibuprofen, asprin, ZolinobutaZone, or a free base, free acid, Salt, hydrate, ester, aspirin Sachet, paracetamol, momifluate, tramadol, ketora amide, enantiomer, isomer, tautomer, polymorph, or prodrug lac, indomethacin, ketoprofen, meclofenamate, meloxicam, thereof, and the thiazinecarboxamide is ampiroxicam, droxi nabumetone, naproxen, choline magnesium trisalicylate, cam, iSoxicam, lomoxicam, piroXicam, tenoxicam, or a free Oxaprozin, piroXicam, tolmetin, diflunisal, nabumentone, base, free acid, Salt, hydrate, ester, amide, enantiomer, etodalac, flocafenine, Sulindac, tenoxicam, tiaprophenic isomer, tautomer, polymorph, or prodrug thereof. acid, mefenamic acid, diclofenac, aceclofenac, momiflu 36. The composition of claim 25, wherein the salicylic mate, diflunisal, Salsalate, Valdecoxib, celecoxib, and rofe acid derivative is acetaminoSalol, aspirin, benorylate, bro coxib, or a free base, free acid, Salt, hydrate, ester, amide, mosaligenin, calcium acetylsalicylate, diflunisal, eterSalate, enantiomer, isomer, tautomer, polymorph, or prodrug fendosal, gentisic acid, glycol Salicylate, imidazole Salicy thereof. late, lysine acetylsalicylate, meSalamine, morpholine Salicy 29. The composition of claim 25, wherein the cyclooxy late, 1-naphtyl Salicylate, olSalazine, parSalmide, phenyl genase-II inhibitor is Celecoxib, Vioxx, Relafen, Lodine, acetylsalicylate, phenyl Salicylate, Salacetamide, Salicyla Voltaren, or a free base, free acid, Salt, hydrate, ester, amide, mide O-acetic acid, Salicylsulfiric acid, Salsalate, SulfaSala enantiomer, isomer, tautomer, polymorph, or prodrug Zine, or a free base, free acid, Salt, hydrate, ester, amide, thereof. enantiomer, isomer, tautomer, polymorph, or prodrug 30. The composition of claim 25, wherein the aminoaryl thereof. carboxylic acid derivative is enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic 37. The composition of claim 1, wherein the composition acid, niflumic acid, talniflumate, terofenamate, tolfenamic is in a dosage form Selected from a powder, a tablet, a acid, or a free base, free acid, Salt, hydrate, ester, amide, bite-disintegration tablet, a chewable tablet, a caplet, a enantiomer, isomer, tautomer, polymorph, or prodrug capsule, an effervescent powder, a rapid-disintegration tab thereof. let, or an aqueous Suspension produced from powder. 31. The composition of claim 25, wherein the arylacetic 38. The composition of claim 1, further comprising one or acid derivative is aceclofenac, acemetacin, alclofenac, more excipients Selected from the group consisting of pari amfenac, amtolimetin guacil, bromfenac, bufeXamac, cin etal cell activators, erosion facilitators, flavoring agents, metacin, clopirac, diclofenac Sodium, etodolac, felbinac, Sweetening agents, diffusion facilitators, antioxidants and fenclozic acid, fentiazac, glucametacin, ibufenac, carrier materials Selected from binders, Suspending agents, indomethacin, isofeZolac isoxepac, lonazolac, metiazinic disintegration agents, filling agents, Surfactants, Solubilizers, acid, mofeZolac, oxametacine, piraZolac, proglumetacin, Stabilizers, lubricants, wetting agents, diluents, anti-adher Sulindac, tiaramide, tolmetin, tropesin, Zomepirac, or a free ents, and antifoaming agents. base, free acid, Salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, or prodrug thereof.