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US 2011 0104264A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0104264 A1 Pettersson (43) Pub. Date: May 5, 2011

(54) SECRETION INHIBITING A63L/435 (2006.01) COMPOSITION A63L/464 (2006.01) A6II 3/426 (2006.01) (75) Inventor: Anders Pettersson, Kode (SE) A6IPL/04 (2006.01) (52) U.S. Cl...... 424/451; 424/464; 424/489: 514/338: (73) Assignee: Orex0 AB 514/370

(22) Filed: Jul. 12, 2010 A method for the treatment of at least one symptom of gastro esophageal reflux disease (GERD) in a human suffering from Related U.S. Application Data GERD administers an oral pharmaceutical dosage form into a gastro-intestinal tract of a human suffering from GERD. The (62) Division of application No. 10/475,254, filed on Dec. oral pharmaceutical dosage form contains an acid Susceptible 12, 2003, now Pat. No. 7,815,940, filed as application proton pump inhibitor or salt thereof (PPI), an H2 No. PCT/SE02/00757 on Apr. 17, 2002. antagonist or salt thereof (H2RA), a pharmaceutically accept able carrier, and optionally an agent and/or alginate. (30) Foreign Application Priority Data The PPI is selected fromlansoprazole, , pantopra Zole, , pariprazole, leminoprazole, their pharma Apr. 18, 2001 (SE) ...... O101379-6 ceutically acceptable salts, enantiomers and salts of enanti omers and is in a form that protects the PPI from degradation Publication Classification in a . The H2RA is selected from , raniti (51) Int. Cl. dine, and , their pharmaceutically A6 IK 9/48 (2006.01) acceptable salts, isomers and salts of isomers. The PPI is A6 IK 9/20 (2006.01) administered in combination with the H2RA for passage into A6 IK 9/14 (2006.01) a small text missing or illegible when filed Patent Application Publication May 5, 2011 Sheet 1 of 2 US 2011/O104264 A1

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GASTRIC ACID SECRETION INHIBITING gastric acid into the esophagus. The main advantages of ant COMPOSITION acid agents and alginates are, that they provide fast relief of symptoms. The main disadvantage of antacid agents and algi RELATED APPLICATIONS nates is the extremely short duration of action and dosing has 0001. This application is a divisional application of co to be repeated frequently to keep the patients free of symp pending patent application Ser. No. 10/475,254, filed Dec. 12, toms, further that often do not provide symptom 2003 and entitled “Gastric Acid Secretion Inhibiting Compo resolution, i.e. complete relief of symptoms. sition.” which is a S371 national phase conversion of PCT/ 0008. Several classes of compounds are known which SE02/00757, filed Apr. 17, 2002, which claims priority ben affect the secretion of gastric acid. Among them proton pump efit based on Swedish Application No. 01 01379.6, filed Apr. inhibitors, such as the substituted benzimidazoles omepra 18, 2001, all of which are hereby incorporated by reference. Zole, , rabeprazole, , and H2 recep torantagonists, such as cimetidine, , famotidine, are the most prominent ones. H2 receptor antagonists and acid FIELD OF THE INVENTION susceptible proton pump inhibitors are widely prescribed for 0002 The present invention relates to a gastric acid secre reducing gastric acid secretion systemically. After days treat tion inhibiting composition, to a method for its manufacture ment, acid Susceptible proton pump inhibitors have in clinical and to its use in treating conditions which are related to the studies been proven to be very effective in providing symp secretion of gastric acid. tom resolution in patients with dyspepsia associated with gastric ulcers, duodenal ulcers, reflux and gas BACKGROUND OF THE INVENTION troesophageal reflux without esophagitis. Acid Susceptible 0003. Dyspepsia (acid dyspepsia) is a common disorder. proton pump inhibitors and H2 receptor antagonists, respec is a symptom of dyspepsia. It is estimated that 44% tively, have also proven to be effective in curing H. pylori of Americans have heartburn at least once monthly but that in combination with one or two only about 25% of them are seeing the doctor because of their (Gschwandtler M et al., Aliment Pharmacol Ther 1999, dyspepsia problem. Symptoms associated with dyspepsia are 13(8):1063-9). It is established that omeprazole is superior to for instance upper abdominal pain/discomfort and heartburn, H2 receptorantagonists regarding healing of gastro-duodenal , “sour stomach, and gastro-esophageal reflux. and esophageal lesions as well as providing dyspeptic symp 0004. Dyspepsia is a multi-factorial disease and may be tom resolution in these conditions (Eriksson S., European associated with organic pathology Such as duodenal ulcer, Journal of Gastroenterology & Hepatology 1995, 7:465). gastric ulcer, esophagitis, Barrett's esophagus or gastro 0009 Various combinations of antacid and/or mucosa duodenal inflammation (e.g., Helicobacter pylori infection). protecting agents with agents that reduce acid secretion have Dyspepsia also includes conditions where no organic pathol been disclosed to be useful in treating dyspepsia. ogy can be found, e.g., non-ulcer dyspepsia (NUD) or func (0010 WO95/017080 describes a composition for use in tional dyspepsia. the treatment of for instance heartburn comprising an H2 0005. Dyspepsia can be controlled by administration of , Such as famotidine, and an alginate and medicines that reduce the pH in the stomach. Therapeutic optionally simethicone (an activated polysiloxane). agents effective in the treatment of dyspepsia include gastric (0011 EP 33.8861. A describes a solid pharmaceutical acid Suppressing agents, such as H2 receptor preparation consisting of an antacid and excipients which is antagonists (in the following called H2 receptor antagonists), proposed to be used in combination with an acid Susceptible acid Susceptible proton pump inhibitors, antacids/alginates, proton pump inhibitor or any other Substance inhibiting gas and prokinetic agents. They can be distin tric acid secretion. There is no suggestion to combine these guished by their mechanism of action, safety profile, and Substances in a fixed unit dosage form. . The stomach pathogen Helicobacter (0012 U.S. Pat. No. 5.244,670 A describes an ingestible pylori has been associated with dyspepsia, gastro-duodenal pharmaceutical composition comprising a Substance selected ulcer disease and stomach cancer. The treatment of H. pylori from the group consisting of antacid agents, acid secretion infection usually comprises the administration of a combina prevention agents, bismuth-containing agents and their mix tion of acid secretion Suppressing agents and one or two tures, and 3-(1-menthoxy)-propane-1,2-diol which is present agents. to provide a cooling sensation to the throat. 0006. The therapeutic effect on dyspepsia related discom (0013 WO97/25066 discloses a pharmaceutical formula fort and organic lesions when inhibiting acid production by tion comprising a combination of an acid Susceptible proton administration of acid secretion-inhibiting drugs is related to pump inhibitor oran H2 receptor antagonist and one or more the degree of acid inhibition as well as to the onset and antacid agents or alginates. duration of action of the particular drug. The majority of 0014 Neither acid susceptible proton pump inhibitors nor patients who have symptomatic acid reflux disease have a H2 receptor antagonists, alone or in combination with antac normal esophageal mucosa or only a mild degree of esoph ids and/or alginates, provide fully satisfactory quick and last agitis. Treatment to relieve symptoms as they occur may be ing relief to patients, to whom the speed of symptom relief is the best way to manage these patients, to whom the speed of of primary importance but who also desire to be free of symptom relief is of primary importance. symptoms for a longer period of time. 0007 Antacid agents, that is, acid neutralizing agents, and alginates are the first therapeutic choice in the treatment of OBJECTS OF THE INVENTION mild heartburn. They have a extremely short duration of action but are seen as inexpensive and safe. Antacid agents 0015. It is an object of the invention to provide a medicine work locally through a neutralization of gastric acid. Algi which provides quick and lasting relief to a patient Suffering nates provide some mechanical protection against reflux of from conditions related to gastric acid secretion. US 2011/0104.264 A1 May 5, 2011

0016. It is another object of the invention to provide a tor or a salt thereof, and an H2 receptor antagonist or a salt method for treating a patient Suffering from conditions thereof, and a pharmaceutically acceptable carrier. The terms related to gastric acid secretion which provides quick and “proton pump inhibitor' and “H2 receptor antagonist' lasting relief. include their isomers, such as enantiomers of proton pump 0017. Further objects of the invention will be evident from inhibitors, as well as pharmaceutically acceptable salts of the following short description of the invention, a preferred Such isomers. embodiment thereof, and the appended claims. 0024. The invention is especially suitable for “on demand treatment of gastro-esophageal reflux complaints e.g. heart SUMMARY OF THE INVENTION burn, where potent acid reduction is needed for a shorter 0018. The present invention is based on the insight that period of time and where a rapid onset of action is most acid Susceptible proton pump inhibitors and H2 receptor important and a maximal acid reduction is to prefer. The antagonists possess mutually supplementing properties in maximal acid inhibitory effect would be able to be maintained respect of inhibiting acid secretion and that they can be used during a 7 days period by the elimination of the “fade-off for designing a pharmaceutical composition which provides phenomenon seen after H2-blocker given alone. This will be quick and lasting relief to a patient Suffering from conditions important in order to reduce the time for the treatment of related to gastric acid secretion. stomach ulcers, acid related lesions in the esophagus and 0019 Acid susceptible proton pump inhibitors are acid Helicobacter pylori eradication. activated prodrugs that covalently inhibit the gastric H+.K+- 0025. According to the invention is provided an oral dos ATPase, the proton-transporting involved in the pro age form comprising an H2 receptor antagonist in an amount duction of hydrochloric acid in the stomach. The action of effective to reduce the acidity in the stomach after adminis gastric H+K+-ATPase represents the final step in the tration and an acid Susceptible proton pump inhibitor in an sequence of events resulting in Secretion of hydrochloric acid amount effective to sustain the low acidity effected by the H2 by the . Thus inhibition of this enzyme is the most receptor antagonist over an extended period of time. It is effective and specific means of controlling acid secretion preferred for the pharmacologically effective amounts to be regardless of the nature of the stimulus to secretion. As would amounts capable of raising gastric pH to above 3 within 2 be expected with Sucha mechanism of action, omeprazole has hours from administration and to keep it above 3 for at least 4 been shown to inhibit both basal and stimulated acid secre hours, preferably for at least 8 hours. It is more preferred for tion. Omeprazole is a weak base which accumulates in the said pharmacologically effective amounts to be amounts acidic milieu of the secretory membrane of the parietal cell capable of raising gastric pH to above 4 within two hours after where it undergoes rearrangement in acid to its active Sulphe administration and to keep it above 4 for at least 4 hours, more namide form which subsequently reacts with sulfhydryl preferred for at least 8 hours. groups of the acid pump. 0026. According to a first preferred aspect of the invention 0020. In gastric mucosa, the acid Susceptible proton pump the H2 receptor antagonist is provided in an amount which is is situated in the apical membrane and in the tubovesicles capable of providing at least 80% of maximal reduction, more bordering the secretory canaliculi of the parietal cell. Thus, preferred at least 95% of maximal reduction, of the acidity in after a single dose, omeprazole rapidly accumulates in the the stomach within about two hours. “Maximal reduction' is acidic compartment of the secretory membrane where its the reduction of acidity which can be maximally obtained by active sulphenamide form irreversible binds to the H+.K+- administering an H2 receptor antagonist alone in therapeuti ATPase. The H+K+-ATPase situated in the tubovesicles will cally accepted amounts, that is, in amounts in which Such however not be exposed for activated omeprazole. A major drugs are administered in the art. The term “H2 receptor portion of synthesized H+K+-ATPase will thus escape antagonist(s) as used herein includes all agents that Substan blockade after a single omeprazole dose. This may explain tially inhibitor block the secretion of gastric acid by binding why the maximal acid inhibitory effect of omeprazole is to a in the stomach. At therapeutic doses reached only after about five days treatment. Such H2 receptor antagonists are capable not only of decreas 0021 H2 receptor antagonists competitively inhibit the ing basal and nocturnal acid secretion, but also secretion action of histamine on all H2 receptors, mainly on the Surface stimulated by food, histamine, insulin and pentagastrin. of the parietal cells. At therapeutic doses these agents are Exemplary H2 receptor antagonists according to the inven capable not only of decreasing both basal and nocturnal acid tion are cimetidine, ranitidine, nizatidine and famotidine secretion, but also secretion stimulated by food, histamine, which are normally used in form of their pharmacologically insulin and pentagastrin. A single dose of an H2 receptor acceptable salts, in particular hydrochlorides. The dosage antagonist results in maximal acid inhibitory effect already form of the invention preferably comprises from 1 mg to 800 within 2 hours after intake. Furthermore, the acid inhibitory mg of H2 receptor antagonist or salt thereof, more preferred effect obtained with high doses of an H2 receptor antagonist from 5 mg to 400 mg. is built up rapidly but has a tendency to fade substantially 0027. According to a second preferred aspect of the inven during the following 2-7 days, while the acid inhibitory effect tion the acid susceptible proton inhibitor is provided in an of omeprazole gradually is built up during the same period of amount which is capable of maintaining the low acidity time. effected by the histamine H2 antagonist over at least 6 hours. 0022. According to the invention, by combining an H2-re Acid Susceptible proton pump inhibitors are rapidly taking ceptor antagonist with an acid Susceptible proton pump market share from H2 receptor antagonists. The term “acid inhibitor, it is possible to obtain rapid onset of action as well Susceptible proton pump inhibitor(s)', as used herein, com as good long-term efficacy. prises benzimidazole derivatives having Substantial H+.K+- 0023 Thus, according to the invention, is provided an oral ATPase inhibiting activity, in particular omeprazole, panto pharmaceutical dosage form comprising pharmacologically prazole, lanZoprazole, rabeprazole, pariprazole, effective amounts of an acid Susceptible proton pump inhibi leminoprazole and their pharmaceutically acceptable salts US 2011/0104.264 A1 May 5, 2011

and enantiomers and salts of enantiomers, but include also the form of a powder or granules compressed into a tablet. The other compounds disclosed on pages 7-11 of WO 97/25066 enteric coating layer(s) covering the individual units of the which are hereby incorporated by reference as well as those acid Susceptible proton pump inhibitor has properties Such disclosed in EP 005 129 A1 EP 174726A1 EP 166287 A1, that the compression of the units into a tablet does not sig GB 2163 747, WO 90/06925, WO91/19711, WO91/19712, nificantly affect the acid resistance of the individually enteric WO94/27988, WO95/01977. Omeprazole is known to offer coating layered units. Furthermore, the multiple unit tableted significant gain over H2 receptor antagonists in terms of dosage form provides a good stability to the active substances symptom resolution, healing and prevention of relapse. during long-term storage. 0028. Thus the dosage form of the invention comprises 0035. According to the invention is also provided a mul preferably from 1 mg to 100 mg, more preferred from 5 mg to tiple unit tableted dosage form, which is divisible and easy to 50 mg, per single dose of an acid Susceptible proton pump handle. Such a multiple unit tableted dosage form comprises inhibitor or a salt thereof. Preferably the acid susceptible enteric coating layered pellets of an acid Susceptible proton proton pump inhibitor or salt thereof is separated from the H2 pump inhibitor compacted with a pulverous H2-antagonist. receptor antagonist by an enteric coating. This dosage form may also contain effervescent components 0029. According to a fourth preferred aspect of the inven for making it rapidly disintegrate when put into water, the pH tion the H2 receptor antagonist and the acid Susceptible pro of the aqueous phase thereby must be made slightly acidic to ton pump inhibitor need not to be comprised by the same prevent dissolution of the enteric layer. This dosage for can be pharmaceutical composition but may be administered sepa given to patients with Swallowing disorders and in pediatrics. rately but within a narrow time interval, such as a time interval Such a suspension of dispersed units/pellets of appropriate of one hour, in particular a time interval of 30 min, most size can be used for oral administration and also for feeding preferred a time interval of 10 min. Thus is disclosed a cor through a naso-gastric tube. responding dose regimen for separate but administration 0036. According to the invention is also provided a tablet of an acid Susceptible proton pump inhibitor and an H2 recep preparation comprising an acid susceptible proton pump torantagonist to treat a condition related to gastric acid secre inhibitor in admixture with tablet excipients forming a tablet tion. core which is enterically coated, and a separate layer Sur 0030 The oral dosage form of the invention thus com rounding the tablet core. The Surrounding layer comprises an prises an acid Susceptible proton pump inhibitor, an H2 recep H2 receptor antagonist in admixture with a pharmaceutical tor antagonist and a pharmaceutical carrier and, optionally, a carrier. Optionally a separating layer is applied on the tablet gastric acid suppressing agent and/or an alginate. Preferably, core before the core is enteric coating layered. Alternatively, the dosage form, of the invention comprises from 100 mg to the prepared tablet is sectioned in separate layers, each one 1000 mg of antacid agent and/or alginate. The antacid agent comprising different active Substances. One of the layers, of the invention comprises one or several of aluminum preferably the innermost layer (core), comprises the acid hydroxide, calcium carbonate, magnesium carbonate, basic susceptible proton pump inhibitor in the form of enteric coat magnesium carbonate, magnesium hydroxide, magnesium ing layered pellets in admixture with pharmaceutical excipi oxide, Sodium hydrogen carbonate. ents and the other layer(s) comprise(s) the histamine H2-an 0031. According to a fifth preferred aspect of the invention tagonist(s), respectively in admixture with pharmaceutical the bioavailability of the acid susceptible proton pump inhibi excipient(s). Optionally the two layers are separated by a tor is improved for the first three consecutive doses of a dose separating layer to prevent tacking between the two layers. regimen or composition of the invention in the treatment of The core comprising the acid Susceptible proton pump inhibi dyspepsia, in particular the first five consecutive doses, since tor may also be advantageously coated directly with an less proton pump inhibitor will be degraded during passage of enteric layer by following, for instance, procedures disclosed the drug through the stomach. in WO 00/78284 which is incorporated herein by reference. 0032. Due to the fact that acid susceptible proton pump 0037 According to the invention the acid susceptible pro inhibitors are generally sensitive to acid (acid Susceptible ton pump inhibitor in the form of enteric coating layered proton pump inhibitors) they need to be administered in a pellets may be mixed with histamine H2-antagonist(s) and form which protects them from degradation in the stomach to optionally pharmaceutical excipient(s) to be administered in make them pass into the Small intestine where they are a Sachet intended for oral administration after dispersion in a absorbed. H2 receptor antagonists, on the other hand, can be slightly acidic aqueous solution. administered without such protection. According to a further 0038. It is thus preferred for the dosage form of the inven preferred aspect of the invention, compositions can be tion to comprise the acid Susceptible proton pump inhibitor or adapted to Suit the purpose of the present invention are among a salt thereof protected by an enteric coating layer and, those disclosed in WO97725066. optionally, a layer separating it from the enteric coating. 0033. The oral dosage forms of WO97/25066 comprise an Preferably the dosage form of the invention comprises two acid Susceptible proton pump inhibitor in an amount similar concentric layers optionally separated by one or more sepa or identical to that used in the composition of the present rating layer(s), one layer comprising said acid Susceptible invention, and one or several antacid agents and/or alginate proton pump inhibitor or salt thereof, the other layer compris (s). The adaptation of the compositions of WO 97/25066 ing said H2 receptorantagonist or salt thereof. The inner layer essentially consists in Substituting a pharmacologically effec comprises the acid Susceptible proton pump inhibitor or salt tive amount of an H2 receptor antagonist for a portion of or thereof and the outer layer comprises the H2 receptor antago the entire amount of the antacid agent(s) and/or alginate. nist or salt thereof. According to the invention it is also pos 0034. According to the invention is provided an oral, mul sible for the outer layer to comprise the acid susceptible tiple unit tableted dosage form comprising an acid Susceptible proton pump inhibitor or salt thereof and fort the inner layer proton pump inhibitor in individually enteric coating layered to comprise the H2 receptor antagonist or salt thereof. units in combination with an H2 receptor antagonist in the According to a preferred aspect the inner layer comprises a US 2011/0104.264 A1 May 5, 2011

disintegrant. The oral dosage form of the invention may take 0045. The dosage form of the invention can also be used, different shapes, such as a tablet, a capsule, a divided powder/ in association with one or more antibiotic agent(s), for the pellet formulation, and the like. eradication of Helicobacter pylori. 0039. According to the invention is also disclosed a 0046 According to the invention is also disclosed a method for the manufacture of an oral tableted dosage form method of treating disorders associated with gastric acid comprising amounts of an acid Susceptible proton pump secretion, the method comprising the administration of the inhibitor or salt thereof and an H2 receptor antagonist or salt dosage form of the invention or the concomitant administra thereof pharmacologically effective in treating a condition tion of two separate oral dosage forms, one comprising a related to dyspepsia, the method comprising forming a first pharmacologically effective amount of an acid Susceptible layer comprising said acid Susceptible proton pump inhibitor proton pump inhibitor or salt thereof, the other comprising a or salt thereof, an enteric coat Surrounding said first layer, and pharmacologically effective amount of an H2 receptor a second layer comprising said H2 receptor antagonist or salt antagonist or salt thereof. thereof Surrounding said first layer and said enteric coat. Also 0047. Furthermore, according to the invention is disclosed disclosed is a method for the manufacture of an oral dosage a method of treating an infection by Helicobacter pylori, form comprising amounts of an acid susceptible proton pump comprising the administration of the dosage form of the inhibitor or salt thereof and an H2 receptor antagonist or salt invention or the concomitant administration of two separate thereof pharmacologically effective in treating a condition oral dosage forms, one comprising a pharmacologically related to dyspepsia, the method comprising forming pellets effective amount of an acid susceptible proton inhibitor or salt comprising said acid Susceptible proton pump inhibitor or salt thereof, the other comprising a pharmacologically effective thereof, covering said pellets with enteric coat, and mixing amount of an H2 receptor antagonist or salt thereof, in asso said pellets covered with said enteric coat with a carrier ciation with the administration of one or more antibiotic comprising said H2 receptor antagonist or salt thereof; the agent(s) effective against H. pylori. carrier may comprise a disintegrant. The aforementioned 0048. It is preferred for the aforementioned methods of methods of the invention further comprise a final tablet form treatment according to the invention to comprise a dose regi ing step, possibly followed by a film-covering step. men capable of maintaining gastric pH above 4 for at least 0040 Another method for the manufacture of the oral 95% of the time period starting at 2 hours from the adminis dosage form of the invention comprises filling a capsule tration of the first dose and extending until 6 hours from the capable of disintegrating in gastrointestinal fluids to release administration of the last dose, in particular a regiment its contents with the mixture comprising enteric proton pump wherein the time period is one week or more, preferably two inhibitorpellets and a H2 receptorantagonist in powderous or weeks or more, even more preferred four weeks or more. Also granular form. preferred in this context is a dose regimen capable of main 0041. A further method for the manufacture of the oral taining gastric pH above 3 for at least 95% of the time period dosage form of the invention comprises forming a layer com starting at 2 hours from the administration of the first dose and prising an acid susceptible proton pump inhibitor or salt extending until 6 hours from the administration of the last thereof and an H2 receptor antagonist or salt thereof, and dose, in particular for four weeks or more. covering said layer with an enteric coat. 0049. The invention will now be described in greater detail 0042. A still further method for the manufacture of the oral by reference to a number of preferred but not limiting dosage form of the invention comprises forming a mixture embodiments illustrated in a drawing. comprising an acid Susceptible proton pump inhibitor or salt thereof and an H2 receptor antagonist or salt thereof, filling the mixture in a capsule capable of disintegrating in gas BRIEF DESCRIPTION OF THE FIGURES trointestinal fluids to release its contents, and covering the 0050 FIGS. 1-6 are schematic cross sections illustrating: capsule with an enteric coat. 0051 FIG. 1 a multiple unit tableted dosage form com 0043. The use of the pharmaceutical dosage form of the prising an acid susceptible proton pump inhibitor in the form invention is however not restricted to provide quick and last of enteric coating layered pellets in admixture with an H2-re ing relief to a patient Suffering from conditions related to ceptor antagonist dispersed in a pharmaceutical carrier; gastric acid secretion. The rapid onset of inhibition of gastric acid secretion combined with the maintenance of inhibition 0.052 FIG. 2 a tableted dosage form consisting of two as long as desired (by repeated administration of a composi halves, one of which comprises enteric coating layered pellets tion comprising an acid Susceptible proton pump inhibitor, of an acid Susceptible proton pump inhibitor in admixture preferably by repeated administration of the composition of with excipients whereas the other comprises an H2 receptor the invention) can be expected to have a positive effect on the antagonist in admixture with excipients; healing of esophagitis for which the maintenance of intra 0053 FIG. 3 a multiple-layered tableted dosage form gastric pH above 4 for a maximal duration is acknowledged comprising an acid Susceptible proton pump inhibitor in a (Huang J. Q and Hunt R. H. pH, healing rate and symptom core Surrounded by an enteric coating layer and a layer con relief in patients with GERD, Yale J Biol Med 1999, 72: 181 taining an H2 receptor antagonist dispersed in a pharmaceu 94). The composition of the invention thus is also preferred tical carrier Surrounding the core; for maintaining gastric pH above 4 for extended periods of 0054 FIG. 4 a tableted dosage form comprising an acid time, such as 4 hours and more. Susceptible proton pump inhibitor, an H2-receptor antagonist 0044 According to the invention the aforementioned mix and excipients in admixture, provided with an enteric coating: ture comprising an acid Susceptible proton pump inhibitor or 0055 FIG. 5 a capsule dosage form containing an acid salt thereof and an H2 receptor antagonist or salt thereof can Susceptible proton pump inhibitor in enteric coating layered be used for the manufacture of a medicament for the treatment pellets in admixture with an H2 receptor antagonist and phar of a disorder associated with gastric acid secretion. maceutical excipients; US 2011/0104.264 A1 May 5, 2011

0056 FIG. 6 an acid resistant capsule dosage form con prepared dry mixture comprising the H2 receptor antagonist. taining an acid Susceptible proton pump inhibitor, an H2 The mixture is admixed with lubricant(s) and compressed receptor antagonist and excipients; into a multiple unit tableted dosage form. Suitable lubricants 0057 FIG. 7 is a diagram of the gastric pH trace in a person for the tableting process are, for instance, Sodium Stearyl after administration of a conventional omeprazole oral dos fumarate, magnesium Stearate and talc. The compressed tab age form; lets are optionally covered with film forming agent(s) to 0058 FIG. 8 is a diagram of the gastric pH trace in the obtain a smooth Surface. Such coating layer may further com same person after joint administration of omeprazole and prise additives Such as anti-tacking agents, colorants and famotidine according to the invention. pigments or other additives. 0061 The fraction of enteric coating layered pellets con DESCRIPTION OF PREFERRED stitutes preferably less than 60% by weight of the total tablet EMBODIMENTS weight. The preferred multiple unit table formulation thus 0059 Multiple unit tableted dosage form. The multiple consists of enteric coated layered pellets comprising the acid unit tableted dosage form of the invention illustrated in FIG. Susceptible proton pump inhibitor, optionally in admixture 1 consists of a tablet body1 optionally covered by a film layer with alkaline reacting compound(s), compressed into tablets 3 and small pellets 2 distributed at random in the tablet body with the prepared H2 receptor antagonist/excipient(s) mix 2. The pellets 2 contain an acid Susceptible proton pump ture. The enteric coating layer(s) make(s) the pellets of the inhibitor inform of the racemate, an alkaline salt or one of its dosage form insoluble in acidic media but disintegrating/ enantiomers. The individually enteric coating layered units 2 dissolving in near neutral to alkaline media such as, for (Small beads, granules or pellets) containing the acid Suscep instance, the gastric fluid present in the proximal part of the tible proton pump inhibitor and optionally containing alka small intestine where the dissolution and uptake of the acid line Substances, are mixed with the H2 receptor antagonist susceptible proton pump inhibitor is desired. The enteric and conventional tablet excipients forming, in combination, coating layered proton pump inhibitor pellets may also be the tablet body 1. The H2 receptor antagonist and tablet covered with an overcoating layer before being formulated excipients may be dry mixed or wet mixed into granules. The into tablets, and they may also contain one or more separating mixture of enteric coated layered units, H2 receptor antago layer(s) in between the core material and the enteric coating nist and excipients are compressed into the multiple unit layer(s). tableted dosage forms. By the expression “individual units” is 0062 Process for making multi-unit tablets. The process meant small beads, granules or pellets, in the following for the manufacture of the dosage form represents a further referred to as proton pump inhibitor pellets. In compressing aspect of the invention. After formulating the pellets by dry the mixture into tablets, care must be taken not to significantly mixing (ordered mixture), spray coating or layering of the affect the acid resistance of the enteric coated layered pellets. acid Susceptible proton pump inhibitor onto seeds, or by In regard of the core material for enteric coating layered extrusion/spheronization or granulation, the pellets are first pellets comprising an acid Susceptible proton pump inhibitor optionally covered with the separating layer(s) and then with reference is made to WO 97/25066, page 13, next but last the enteric coating layer(s), or a separating layer is spontane paragraph, to page 15, end of second paragraph, which are ously developed in situ between the core material and the hereby incorporated by reference. In regard of the enteric enteric coating layer material. The coating is carried out as coating layer(s) reference is made to WO97/25066, page 15, described above and in the accompanying examples. next but last paragraph, to page 18, end of second paragraph, 0063. The preparation of the H2 receptor antagonist mix which are hereby incorporated by reference. The acid suscep ture is also described in the examples. tible proton pump inhibitor pellets covered with enteric coat 0064. The enteric coating layered pellets, with or without ing layer(s) may be further covered with one or more over an overcoat, are mixed with the prepared H2 receptor antago coating layers. In regard of Such over-coating layer(s) nist granules or dry powder, tablet excipients and other phar reference is made to WO97/25066, page 18, last paragraph, maceutically acceptable additives and compressed into tab to page 19, end of first paragraph, which are hereby incorpo lets. Alternatively, the enteric coated proton pump inhibitor rated by reference. The H2 receptor antagonist is dry mixed pellets may be covered by a second layer containing the H2 with inactive excipients such as filler, binders, disintegrants, receptor antagonist as described in the following examples. and other pharmaceutically acceptable additives. The mixture Furthermore, as illustrated in FIG. 2, the enteric coating lay is wet massed with a granulation liquid. The wet mass is dried ered pellets 4 may be intimately mixed with excipients 5 and preferably to a loss on drying of less than 3% by weight. Then precompressed and further layered with the H2 receptor the dry mass is milled to a suitable size for granules, prefer antagonist preparation 7 and finally compressed into a tablet, ably smaller than 1 mm. Suitable inactive excipients are, for optionally with film-forming agent(s) 6 to obtain a smooth instance, mannitol, corn starch, potato starch, low Substituted surface. As a further alternative illustrated in FIG. 3 the acid hydroxypropyl cellulose, microcrystalline cellulose and susceptible proton pump inhibitor inform of a powder may be crosslinked polyvinylpyrrolidone. The dry mixture compris mixed with tablet excipients and compressed into a tablet 8 ing the H2 receptor antagonist may be mixed with a suitable which is optionally layered with a separating layer and there granulation liquid comprising, for instance, hydroxypropyl after enteric coating 9 layered. The thus produced tablet core cellulose or polyvinyl-pyrrolidone dissolved in water or alco is press.coated with the H2 receptorantagonist preparation 10. hol or their mixtures. Alternatively the H2 receptor antagonist Finally the table may be covered with a tablet coat 11 to obtain is dry mixed with pharmaceutically acceptable excipients a Smooth surface. (see Supra). 0065. It is also possible to fill the acid susceptible proton 0060 Multi unit tablets. The enteric coated layer pellets pump inhibitor in form of enteric coated layered pellets in a comprising an acid Susceptible proton pump inhibitor are Sachet together with H2 receptor antagonist optionally mixed mixed with the H2 receptor antagonist granules or with the with excipients. US 2011/0104.264 A1 May 5, 2011

0066 FIG. 4 illustrates a tableted dosage form with a core hydrochloride, the rest of potato starch and microcrystalline 12 comprising an acid Susceptible proton pump inhibitor and cellulose are dry mixed. The granulation liquid is added to the an H2 receptor antagonist dispersed in a pharmaceutical car dry mixture and the mass is wet mixed. The wet mass is dried rier, the core 12 being surrounded by an enteric coat 13. in an oven at 50° C. The prepared granulation is milled 0067 FIG. 5 illustrates a hard gelatin capsule 16 filled through sieve 1 mm in an oscillating mill equipment. The with the uncompressed core material 14, 15 of the embodi enteric coating layered pellets with an over-coating layer, the ment of FIG. 1. prepared receptor antagonist granules, crosslinked polyvi 0068 FIG. 6 illustrates a hard gelatin capsule 18 compris nylpyrrolidone and sodium Stearyl fumarate are mixed and ing an enteric coat filled with the uncompressed core material compressed into tablets using a tableting machine equipped 17 of the embodiment of FIG. 4. with oval punches. The amount of omeprazole in each tablet 0069. In general, the methods of WO97/25066 for making is approx. 10 mg and the amount of cimetidine hydrochloride oral pharmaceutical dosage forms comprising an acid Suscep is approx. 100 mg. tible proton pump inhibitor and an antacid agent or alginate 0075. By a slight modification this multiple unit tablet can be adapted to suit the purpose of the invention by substi form can be made to comprise an antacid agent (instead of tuting part or the entire amount of antacid agent oralginate by microcrystalline cellulose, 300 mg: microcrystalline cellu a pharmacologically effective amount of an H2 receptor lose, 100 g, calcium carbonate, 100 mg; magnesium oxide, antagonist, the remainder of the antacid agent or alginate (if 100 mg; all other constituents, except water, in the amounts substitution is not 1:1 by weight) being omitted or substituted given above). by excipients like microcrystalline cellulose, silica, lactose, mannitol, and the like. Example 2 0070 Use of the Dosage Forms According to the Inven tion. (0076. Three-layered tableted dosage form. The tablet 0071. The dosage forms according to the invention are comprises the acid Susceptible proton pump inhibitor ome especially advantageous in the treatment of dyspepsia and prazole, a separating layer and a core layer comprising cime other gastrointestinal disorders related to the production of tidine hydrochloride. Batch size 1000 tablets. gastric acid to provide quick and lasting relief from Symp toms. The dosage forms are administered once or several First Tablet Layer times a day. The typical daily dose of the acid susceptible proton pump inhibitor and the H2 receptor antagonist will 0.077 depend on various factors such as individual requirements of patients, the mode of administration, and the particular con dition to be treated. In general each dosage form will com Cimetidine hydrochloride 200.0 g prise from 1 mg to 100 mg of acid Susceptible proton pump Microcrystalline cellulose 250.0 g inhibitor and from 1 to BOO mg of the H2 receptor antago PVP crosslinked 13.0 g nist. Preferably each dosage form will comprise from 5 to 50 Sodium stearyl fumarate 3.8 g. mg of the acid Susceptible proton pump inhibitor and from 5 to 200 mg of the H2 receptor antagonist. The multiple unit tablet preparation is also suitable for dispersion in water Separating Layer which had been made slightly acidic by the addition of citric acid. 0078 Example 1 0072 Multiple unit tableted dosage form comprising Microcrystalline cellulose 80.0 g magnesium omeprazole and ranitidine hydrochloride; batch size 400 tablets. For omeprazole Mg-salt pellet production (core material, separating layer, enteric coating layer and Second Tablet Layer over-coating layer, see WO97/25066, p. 22-23 under respec tive headings), see WO97/25066, first two paragraphs, all of 0079 which is hereby incorporated by reference. Tablets Enteric coating layered pellets comprising 78.3g 0073 omeprazole magnesium salt (same as in EXAMPLE 1) Microcrystalline cellulose 174.0 g PVP crosslinked 26.Og 10 Sodium stearyl fumarate 1.4g Prepared pellets comprising omeprazole Mg-Salt 31.3g Microcrystalline cellulose 300.0 g Cimetidine hydrochloride 40.0 g 0080. The constituents of the first tablet layer are dry Potato starch 50.0 g mixed and precompressed as a first layer in a tableting Water 200.0 g machine equipped with oval punches. Microcrystalline cel PVP crosslinked 38.0 g lulose is filled on the top of the first layer to form a separating Sodium stearyl fumarate 4.6 g. layer to the next layer. The constituents of the second tablet layer are dry mixed and filled on top of the separating layer. 0074. A small amount of the potato starch is dissolved in The three layers are compressed into a three layer tablet purified hot water to form the granulation liquid. Cimetidine which may be coated by a tablet coating layer. The amount of US 2011/0104.264 A1 May 5, 2011

omeprazole is approx. 10 mg and that of cimetidine hydro the electrode was performed before and after each 24 h chloride approx. 200 mg per tablet. recording, using standard buffers of pH 7.0 and 1.7. The electrode was placed 10 cm below the lower esophagal Example 3 sphincter during the pH recording and the position marked on the electrode lead to ensure proper positioning during con 0081 Capsule dosage form. No. 1 hard gelatin capsules secutive recordings. A commercially available omeprazole (16) (FIG. 5; Volume 0.48 ml) were filled with enteric coated (Losec(R) capsule containing 20 mg omeprazole was care omeprazole pellets (15) containing 20 mg omeprazole recov fully opened and the contents (pellets) placed in a plastic ered from commercially available omeprazole (LosecR) cap Syringe which had been put into communication with one of sules and a dry mixture 14 of commercially available famo the lumina of the nasogastric tube. The syringe was filled with tidine 20 mg for injection (Pepcidin R; containing 20 mg 20 ml tap water and the pellets injected through the nasogas famotidine hydrochloride, 8 mg aspartic acid and 40 mg tric tube immediately thereafter. The syringe was flushed with mannitol), and closed. 20 ml water. The gastric pH trace recorded by the microelec Example 4 trode during a period of more than four hours is illustrated in FIG. 7. In a second experiment 10 the syringe was filled with 0082 Divided powder/pellet formulation. Enteric pellets the same amount of omeprazole micropellets and famotidine containing 15 mglansoprazole recovered from commercially 20 mg for injection (Pepcidin R; containing 20 mg famoti available capsules (Lanzo(R), enterocapsules) and the famoti dine, 8 mg aspartic acid and 40 mg mannitol), the procedure dine preparation for injection of EXAMPLE 4 were dry of injection and measurement being the same as with ome mixed with citric acid. Single dose portions thereof contain prazole. The gastric pH trace for the combination is illustrated ing 10 mg each of lansoprazole and famotidine hydrochloride in FIG.8. The experiments demonstrate that a reduction of pH and 200 mg powderous citric acid were dry packed in plastic to about 6 is obtained with the omeprazole/famotidine within laminate. The composition is intended to be poured into 20 ml about 2 hours and maintained until the end of recording (4 of water, stirred for a short time, and swallowed. hours from injection) whereas with omeprazole alone no increase in pH can be noted after 4 hours from injection. Example 5 0083 Multiple unit capsule dosage form. The tabled com prises magnesium omeprazole and famotidine hydrochloride. I claim: For enteric coating layer and over-coating layer, see WO 1. A method for the treatment of at least one symptom of 97/25066, page 22-23 under respective headings, the infor gastro-esophageal reflux disease (GERD) in a human Suffer mation under which is hereby incorporated by reference. ing from GERD consisting essentially of administering an 0084. Magnesium omeprazole is mixed with microcrys oral pharmaceutical dosage form into a gastro-intestinal tract talline cellulose spheres to an ordered mixture. The ordered of a human suffering from GERD, the oral pharmaceutical mixture is coated with an enteric coating layer consisting of dosage form consisting essentially of an acid Susceptible methacrylic acid copolymer, mono- and diglycerides, triethyl proton pump inhibitor or salt thereof (PPI), an H2 receptor citrate and polysorbate in a fluid bed apparatus. The enteric antagonist or salt thereof (H2RA), a pharmaceutically accept coated ordered mixture is then over-coated with a water sus able carrier, and optionally an antacid agent and/or alginate, pension containing famotidine hydrochloride, hydroxypro wherein the PPI is selected from lansoprazole, omeprazole, pylmethyl cellulose and magnesium Stearate in a fluid bed pantoprazole, rabeprazole, pariprazole, leminoprazole, their apparatus. The enteric coated ordered mixture with an over pharmaceutically acceptable salts, enantiomers and salts of coating layer was filled in hard gelatin capsules. The amount enantiomers and is in a form that protects the PPI from deg of omeprazole is approx. 10 mg and that of famotidine hydro radation in a stomach, wherein the H2RA is selected from chloride approx. 20 mg per capsule. cimetidine, ranitidine, nizatidine and famotidine, their phar maceutically acceptable salts, isomers and salts of isomers, Example 7 and wherein administering the oral pharmaceutical dosage form orally introduces into the gastro-intestinal tract of the 0085 Multiple unit tableted dosage form comprising human suffering from GERD the PPI in combination with the magnesium omeprazole and cimetidine hydrochloride. Mag H2RA for passage into a small intestine for absorption. nesium omeprazole is mixed with microcrystalline cellulose 2. The method of claim 1, wherein the oral pharmaceutical spheres to an ordered mixture which is coated with an enteric dosage form is administered to affect a rise in gastric pH coating layer as described in EXAMPLE 6. Cimetidine above 3 within about 2 hours from the administration of the hydrochloride is granulated as described in EXAMPLE 1. first dose, thereby treating the human suffering from GERD The enteric coated ordered mixture comprising magnesium promptly, and wherein the administering is repeated, if nec omeprazole, the cimetidine granules and excipients are dry essary to treat the human suffering from GERD over a pro mixed and compressed into tablets. The amount of omepra longed period until 6 hours from the administration of the last Zole in each tablet is approx. 10 mg and that of cimetidine is dose. approx. 100 mg. 3. The method of claim 1, wherein the at least one symptom of gastro-esophageal reflux disease is indigestion, heartburn, Example 8 Sour stomach and/or upper abdominal pain and/or discom I0086 Inhibition of gastric acid secretion. A healthy sub fort. ject (male, 31 years of age, having fasted for 10 hours) was 4. The method of claim 1, wherein the method is suitable provided with a double lumen nasogastric tube through one for on demand treatment of at least one symptom of gastro nasal passage and with a microelectrode for pH registration esophageal reflux disease (GERD) in a human suffering from through the second nasal passage. A two point calibration of GERD. US 2011/0104.264 A1 May 5, 2011

5. The method of claim 1, wherein the PPI is in the amount 8. The method of claim 1, wherein the oral pharmaceutical of from 1 mg to 100 mg and/or the H2RA is in the amount of dosage form is in the form of a capsule, a divided powder/ from 1 mg to 800 mg in combination with the PPI. 6. The method of claim 1, wherein the oral pharmaceutical pellet formulation or a tablet. dosage form contains the optional antacid agent, and wherein 9. The method of claim 1, wherein the oral pharmaceutical the optional antacid agent S one or several of aluminum dosage form is in the form of a core and a layer Surrounding hydroxide, calcium carbonate, magnesium carbonate, basic the core, wherein the core is the PPI and the layer is the magnesium carbonate, magnesium hydroxide, magnesium H2RA. oxide, and sodium hydrogen carbonate. 7. The method of claim 1, wherein the oral pharmaceutical 10. The method of claim 1, wherein the oral pharmaceuti dosage form is in the form of two concentric layers optionally cal dosage form contains the antacid agent or the alginate. separated by one or more separating layer(s), wherein the inner concentric layer is the PPI and the outer concentric layer is the H2RA.