WO1995001803A1

WO1995001803A1 - H2 antagonist-gastrointestinal motility agent combinations

Info

Publication number: WO1995001803A1
Application number: PCT/US1994/007520
Authority: WO
Inventors: Robert T. Sims; William Slivka
Original assignee: Merck & Co., Inc.; Mcneill-Ppc, Inc.
Priority date: 1993-07-06
Filing date: 1994-07-05
Publication date: 1995-01-19
Also published as: JPH08512322A; CA2166730A1; AU7397194A; EP0707492A1

Abstract

This invention relates to pharmaceutical compositions for use in the prevention, treatment and relief of indigestion, sour stomach, heartburn, gastroesophageal reflux, dyspepsia, constipation, over-indulgence and other gastrointestinal disorders in mammals, including humans, by administering compositions comprising: (i) an amount effective in the relief of gastrointestinal or esophagus disorders of an H2 antagonist selected from a compound of formula (I) and pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs thereof, and (ii) an amount effective in the relief of gastrointestinal or esophagus disorders and in the promotion of gastric emptying of a gastrointestinal motility agent such as cisapride, and optionally (iii) an amount effective in the relief of flatulence of simethicone or alpha-D-galactosidase.

Description

TITLE OF THE INVENTION

H2 ANTAGONIST-GASTROINTESTINAL MOTILITY AGENT

COMBINATIONS

BACKGROUND OF THE INVENTION

The present invention relates to a combination of H2 antagonists selected from famotidine and pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs thereof, with a gastro¬ intestinal motility agent, and optionally an antiflatulent. The invention further relates to pharmaceutically effective compositions which are used to treat gastrointestinal disorders and to methods of treating and preventing these disorders.

H2 antagonists are commonly prescribed to treat and prevent ulcers in the walls of the stomach, duodenum or esophagus. H2 antagonists are also used to treat non-ulcerative conditions. Damage to the mucus lining surrounding these tissues enables destructive action of stomach acids which erodes the underlying tissue. Commonly known H2 antagonists for the treatment of ulcers include cimetidine, ranitidine, nizatidine, roxatidine and famotidine.

Combinations of 5-HT3 receptor antagonists with certain H2 antagonists have been disclosed. See EP 269-452-A; EP 275-669-A. Cisapride has the molecular formula:

This compound is used as a peristaltic stimulant. See A. Reyntjens et al., Drug Div. Res., 8, 251 (1986) and Curr. Ther. Res., 36, 1029-1070 (1984). The compound is marketed internationally under trade names such as ACENALIN®, PREPSULID®, RISAMOL®, PULSAR®, and PROPULSIN®. See EP application 76,530. Cisapride stimulates gastrointestinal motility and beneficial responses have been reported in treating chronic constipation, chronic dyspepsia, post¬ operative gastroparesis and reflux-oesphagitis in children. See Martindale's The Extra Pharmacopoeia, p. 1086 (1989) and references cited therein.

There is a need to employ a combination wherein an advantage is that the overall symptoms of gastrointestinal distress can be effectively treated with a combination of the most powerful H2 antagonist available (famotidine) with a gastrointestinal motility agent such as cisapride, and optionally including an anti-flatulent. The instant combination provides a dual action approach to the treatment of gastrointestinal disorders in that a gastrointestinal motility agent such as cisapride offers enhanced motility while famotidine offers a systemic effect of reduced acid production. The instant combination simultaneously treats, relieves and/or prevents symptoms associated with excess gastric acid secretion or evolution in the stomach and esophagus respectively, while also promoting esophagal acid emptying with an effective motility agent such as cisapride. Promotility agents generally promote clearance of refluxed acid from the esophagus by increasing the pressure of the lower esophageal sphincter. Conditions or symptoms relieved by the promotion of gastric emptying include but are not limited to gastric stasis, flatulence, dyspepsia, peptic ulcer and reflux esophagitis.

The present invention therefore provides an effective dual treatment of gastrointestinal disorders using the combination of famotidine with a gastrointestinal motility agent such as cisapride, and optionally with simethicone or ADG. The claimed combination is particularly useful for treating gastrointestinal distress. Other H2 antagonists that can be used with this invention include ranitidine, cimetidine, nizatidine and roxatidine.

DETAILED DESCRIPTION OF THE INVENTION

This invention claims pharmaceutical compositions for use in the prevention, treatment and relief of mild to moderate gastro¬ intestinal distress and disorders including heartburn, indigestion, sour stomach, overindulgence, gastroesophogeal reflux (GER), constipation, dyspepsia and optionally flatulence. The composition comprises:

(i) an amount effective in the relief of gastrointestinal or esophagus disorders of an H2 antagonist selected from a compound of the formula:

and pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs thereof, and

(ii) an amount effective in the promotion of motility and the treatment of dysfunction of the control mechanism for gastrointestinal motility and in the treatment of symptoms such as nausea, vomiting, anorexia, dysphagia, abdominal distension, constipation or diarrhea, of a compound selected from bethanechol, acylatonium (cholinergic drugs); neostigmine (cholinesterase inhibitors); metoclopramide, clebopride, domperidone (dopamine antagonists); trimebutine and acetylcholine releasing drugs including cisapride; or a therapeutically active stereoisomer thereof substantially free of its other inactive or less active stereoisomers or a pharmaceutically acceptable salt, hydrate, or polymorph thereof, and optionally

(iϋ) an amount effective in the relief of flatulence of simethicone or alpha-D-galactosidase (ADG).

This invention is also directed to a method of preventing, treating and relieving heartburn, indigestion, sour stomach, over¬ indulgence, gastroesophogeal reflux, constipation, dyspepsia and other gastrointestinal disorders, and optionally flatulence, in mammals, including humans, in need of treatment thereof, comprising administering to such organism:

(iii) an amount effective in the relief of flatulence of simethicone or alpha-D-galactosidase. The terms mammal or mammalian organism or patient are used interchangeably herein and include but are not limited to humans, dogs, cats, horses and cows. The preferred patients are humans.

The term treatment encompasses the complete range of therapeutically positive effects associated with pharmaceutical medication including reduction of, alleviation of and relief from the symptoms or illness which affect the organism.

Famotidine may be purchased in bulk quantities as it is currently available on the market, and formulated via typical formulation processes with motility agents selected from cisapride or a stereoisomer, salt or hydrate thereof which is suitable for tablet, capsule, effervescent, chewable tablet, or liquid formulations of the claimed combination. Famotidine as a prescription drug product is sold in the United States under the trademark PEPCID®. Janssen is a listed manufacturer of cisapride. See also European Patent Application 0,076,530 published on April 13, 1983. Simethicone or alpha-D- galactosidase (ADG) antiflatulents may be added to the above combination to provide maximum and broad relief of gastrointestinal disorders. Simethicone is a well-known and commercially available antiflatulent. ADG is a commercially available enzyme preparation used to hydrolyze indigestible sugars found in beans or bean products. The active ingredients in the claimed combination are therefore readily available.

Where only a single stereoisomer of the gastrointestinal motility agent is active as the therapeutically active stereoisomer, the absence of the inactive stereoisomer of the gastrointestinal motility agent in the present composition avoids undesirable side effects that may accompany ingestion and metabolism of the non-biologically active stereoisomer. These include any toxic interactions and in addition metabolic energy is saved when only one stereoisomer of the gastro¬ intestinal motility agent is used in the claimed combination. The use of the potent H2 antagonist such as famotidine combined with a gastro¬ intestinal motility agent or an active stereoisomer of a gastrointestinal motility agent provides significant dosage form advantages since less of the H2 antagonist and the gastrointestinal motility agent is needed to formulate a suitable dosage form and provides for a more practical size tablet or capsule.

The pharmaceutical compositions of the present invention are useful in the prevention, treatment and relief of various mild to moderate gastrointestinal disorders including indigestion, sour stomach, overindulgence, heartburn, gastroesophageal reflux, constipation, dyspepsia, other gastrointestinal disorders and optionally flatulence. In particular, a gastrointestinal motility agent selected from cisapride or a therapeutically active stereoisomer or a pharmaceutically acceptable salt, hydrate, or polymorph thereof, combined with an H2 antagonist selected from famotidine, a compound of the formula:

or the pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs thereof, is useful for the prevention and treatment of various gastrointestinal disorders such as indigestion, sour stomach, heartburn, overindulgence, gastroesophageal reflux, constipation, dyspepsia, and other gastrointestinal disorders. Simethicone or alpha- D-galactosidase may be added to this preferred combination to provide anti-flatulent relief. The utilization of the currently known biologically active stereoisomers and/or salts, hydrates or polymorphs of famotidine in combination with cisapride or its pharmacologically active stereoisomers, salts, hydrates, or polymorphs is advantageously used to prevent, relieve and treat mild to moderate gastrointestinal disorders. In particular, the claimed combination is used to prevent, relieve and treat the symptoms associated with gastric acid secretion while simultaneously treating the symptoms of gastrointestinal distress, and optionally flatulence. Therefore, the animal, patient, or organism in need of treatment thereof benefits from the claimed pharmaceutical composition. H2 antagonists are well known in the treatment of ulcers and other gastrointestinal disorders and may be used according to the present invention in combination with a gastrointestinal motility agent such as cisapride and optionally simethicone or ADG. H2 antagonists used for ulcer therapy fall into four major structural classes: imidazole derivatives; substituted furans; aminoalkylphenoxy derivatives and guanidinothiazole compounds. Famotidine (N'-(aminosulfonyl)-3-[[[2- [(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide), a member of the last named class above, is a competitive inhibitor of histamine H2-receptors and its primary pharmacological activity is the inhibition of gastric acid secretion. Famotidine suppresses both the acid concentration and the volume of gastric acid secretion. Famotidine is well tolerated and has minimal side effects and thus advantageously may be used in the present invention in combination with cisapride and optionally simethicone or ADG. Famotidine is also the most potent and selective H2 antagonist.

Cisapride (cis-4-amino-5-chloro-N-(l -[3-(4-fluoro- phenoxy)propyl] -3-methoxy-4-piperidinyl)-2-methoxybenzamide) is known to stimulate gastrointestinal motility and apparently is also devoid of antidopaminergic activity. Cisapride is also known to provide beneficial effects in a number of gastrointestinal disorders including chronic constipation, chronic dyspepsia, improvement in stool characteristics in patients that have cystic fibrosis, pseudoobstruction in neonatal short gut, severe postoperative gastroparisis, possible prevention of the aeration syndrome and reflux esophagitis in children. See Martindale's The Extra Pharmacopoeia, 1086 (1989). Symptoms associated with the dysfunction of the control mechanism for motility of the gastrointestinal tract or with abnormality of the smooth muscle include nausea, vomiting, anorexia, dysphagia, abdominal distension, constipation and diarrhea. Drugs known to affect the smooth muscle to relieve the above symptoms include bethanechol, acylatonium (cholinergic drugs); neostigmine (cholinesterase inhibitors); metoclopramide, clebopride, domperidone (dopamine antagonists); trimebutine and acetylcholine releasing drugs including cisapride. The claimed invention is also directed to combinations of famotidine with any of the known motility drugs listed above wherein the combination is useful to broadly relieve, treat and prevent the symptoms listed above.

Included within this invention are any diastereomers and/or enantiomers of the gastrointestinal motility agent. In particular, a therapeutically active stereoisomer of a gastrointestinal motility agent, such as cisapride, substantially free of its other inactive or less active stereoisomers may be employed in the instant invention. As used herein, the phrase "a therapeutically active stereoisomer substantially free of its other inactive or less active stereoisomers" means that the ratio of active stereoisomer to inactive or less active stereoisomer(s) is at least 90:10. Where a particular therapeutically active stereoisomer is not commercially available it may readily be prepared following standard resolution chemistry or purification technology known in the art. For example, high performance liquid chromatography ("HPLC") or other suitable chromatographic or separation means may be used to purify or isolate the active stereoisomer (enantiomer or diastereomer) from its readily available racemic mixture.

The claimed combination of famotidine or its pharmaceutically effective salts, hydrates, stereoisomers or polymorphs thereof with cisapride provides an effective combination which simultaneously and selectively provides prevention, treatment and relief from discomfort and injury to the stomach, esophagus, or duodenum from excess production of gastric acid. Furthermore, famotidine in combination with cisapride and optionally simethicone or ADG may not interact with alcohol so that it may be administered prior to or during ingestion of meals or beverages which contain alcohol and, therefore, a patient in need of rapid treatment of gastrointestinal distress may take the drug combination at an appropriate time which may be during a meal in which alcohol was consumed. The combination of cisapride with famotidine provides relief of gastroesophageal reflux while also providing long acting relief from and treatment of gastrointestinal disorders associated with gastric acid secretion. With the optional addition of simethicone or ADG, the claimed combination further provides antiflatulent relief.

The combination of famotidine which is a highly potent H2 antagonist with cisapride, and optionally simethicone or ADG, reduces the size and weight of all pharmaceutical delivery forms or combination formulations and therefore improves patient compliance or tolerance. The tablet or capsule form of this combination is more readily swallowable by patients in need of treatment thereof.

Famotidine, or a pharmaceutically acceptable salt, hydrate stereoisomer or polymorph thereof, is advantageously used in the present invention in combination with cisapride and optionally with simethicone or ADG. The amount of famotidine used in the present invention in humans may range from 2.5 mgs/dosage to 80 mgs/dosage. Advantageously, 5 to 40 mgs/dosage is administered in combination with 5 to 40 mgs/dosage of cisapride. For example, a tablet containing 5 mgs of famotidine may be administered 4 times daily with an effective amount of cisapride and suitable inert ingredients also contained within the tablet.

When employed, the amount of simethicone per dosage may vary depending upon the degree of antiflatulent strength desired, and may range from 20 to 80 mgs. Maxium strength antiflatulents administered in tablet form four times per day may contain 125 mgs of simethicone per tablet. Currently marketed and available antacid/anti- gas formulations contain, for example, 20-40 mgs/chewable tablet or teaspoonful of liquid suspension of simethicone and 200 mgs of aluminum hydroxide and 200 mgs of magnesium hydroxide. Two to four tablets between meals or at bedtime or 2-4 teaspoonfuls between meals and at bedtime containing the above quantities are administered daily. ADG is an enzyme known to assist in the hydrolysis of indigestible sugars which are often found in beans or bean products. The quantity of ADG utilized in the present invention depends upon the concentration of active enzyme and upon the quantity of beans or other source of indigestible sugars ingested. Generally, the amount of ADG that may be employed ranges from about 675 to 31,000 GalU ("alpha- galactosidase units"), and preferably from about 675 to 2250 GalU. See WO90/14101 or PCT/US90/02643.

The quantities of each of the active ingredients may vary depending upon the severity of the condition and the particular biochemistry and need of the patient or other organism in need of such treatment. The quantities of the active ingredients may also vary depending upon whether the active ingredients are administered in tablet or liquid form or via some other suitable delivery method. A physician or clinician or veterinarian of ordinary skill in the art may readily determine suitable dosages of any prescription medication containing the claimed invention. The combination claimed in the instant invention is advantageously administered orally. However, in patients with hypersecretory conditions, intractable ulcers, or in patients who are unable to take oral medication, the claimed combination may be administered intravenously in a suitable dosage within the limits described for oral treatment.

The present composition may be administered in the form of tablets, caplets, gelcaps, capsules, elixirs, syrups, chewable tablets, lozenges, fast-dissolving wafers, effervescent formulations or suspensions or other known and effective delivery modes. For oral administration, the active ingredients may be admixed with a pharmaceutically acceptable diluent such as lactose, sucrose, cellulose, dicalcium phosphate, calcium sulfate, mannitol, and, in a liquid composition, ethyl alcohol. Acceptable emulsifying or suspending agents such as PVP, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium cisapride, guar gum, agar, bentonite, carboxymethylcellulose sodium, polyethylene glycol and waxes, may also be admixed with the active components. Where necessary, lubricants such as magnesium stearic acid talc or magnesium stearate, and disintegrators or superdisintegrators such as starch, sodium starch glycolate or cross-linked PVP may also be included. Electrolytes such as dicalcium phosphate, sodium benzoate, sodium acetate and sodium chloride may also be used. The active components may also be formulated in sustained release or effervescent formulations. These formulations depending upon whether they are sustained release or effervescent may be employed in oral, dermal, rectal or vaginal administrations. The sustained release formulations also include layered formulations which provide for distinct release ratio and thus may be more effective in allowing for short and long term relief.

The following examples illustrate the compositions of the present invention which may be readily prepared and as such are not to be considered as limiting the invention set forth in the claims.

EXAMPLE 1

cisapride/famotidine Tablet

cisapride 40 mg famotidine 40 mg

PVP 15 mg

Avicel PHlOl 40 mg

Magnesium Stearate 4 mg

EXAMPLE 2

cisapride/famotidine Tablet

cisapride 20 mg famotidine 20 mg

PVP 15 mg

Avicel PH101 40 mg Magnesium Stearate 4 mg EXAMPLE 3

cisapride/famotidine Tablet

cisapride 15 mg famotidine 15 mg

PVP 15 mg

Avicel PHlOl 40 mg

Magnesium Stearate 4 mgs

EXAMPLE 4

cisapride/famotidine Tablet

cisapride 10 mg famotidine 10 mg

PVP 15 mg

Avicel PH101 40 mg

Magnesium Stearate 4 mg

EXAMPLE 5

cisapride/famotidine Tablet

cisapride 5 mg famotidine 5 mg

PVP 15 mg

Avicel PHlOl 40 mg

Magnesium Stearate 4 mg EXAMPLE 6

cisapride/famotidine Sustained Release

cisapride 40 mg famotidine 40 mg

PVP 30 mg

Avicel PH101 80 mg

Magnesium Stearate 8 mg Methocel ElOMCR 66 mg

Methocel K100MLV 200 mg

EXAMPLE 7

cisapride/famotidine Sustained Release

cisapride 20 mg famotidine 20 mg

PVP 30 mg Avicel PHlOl 80 mg

Magnesium Stearate 8 mg

Methocel E10MCR 66 mg

Methocel K100MLV 200 mg

EXAMPLE 8

cisapride/famotidine Solution

cisapride 10 mg famotidine 10 mg g.s. syrup 5 ml EXAMPLE 9

cisapride/famotidine Solution

cisapride 20 mg famotidine 20 mg g.s. syrup 5 ml

Simethicone or alpha-D-galactosidase may be added to each of the above formulations or examples to provide anti-flatulent relief. The quantity of simethicone administered to a patient in need of treatment thereof may vary according to patient need, but may be, for example, the typical known dosage range to treat flatulence (20-40 mgs per tablet or per 5 ml liquid dosage for ) or may be increased as necessary. Generally, the amount of ADG that may be employed in the above formulations ranges from about 675 to about 2250 GalU or may be increased as necessary. The inactive ingredients in the tablet form may further include dextrates, mannitol, magnesium stearate, Yellow 10, collodial silicon dioxide and Blue 1 or Red 27 while the liquid form(s) may further include inactives such as butylparaben, carboxy- methylcellulose sodium, flavors, hydroxypropyl methylcellulose, microcrystalline cellulose, propylparaben, and purified water. The previous examples are to be construed as non-limiting and additional dosages and dosage forms or routes of administration may be varied depending upon the individual patient being treated for either the primary (excess acid leading to gastrointestinal or esophageal disturbance or damage) or secondary (infections) symptoms of gastrointestinal disorders. In addition, known pharmaceutically acceptable excipients or agents may be added as inactive ingredients to the claimed active combination in a variety of forms including tablets, capsules, or time-release medicaments.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition for use in the prevention, relief and treatment of gastrointestinal distress and disorders such as indigestion, sour stomach, overindulgence, heartbum, gastroesophageal reflux, dyspepsia, and constipation in a patient in need of treatment thereof comprising:

(ii) an amount effective in the promotion of motility and gastric emptying and the treatment of dysfunction of the control mechanism for gastrointestinal motility, of a compound selected from bethanechol, acylatonium, neostigmine, metoclopramide, clebopride, domperidone, trimebutine and acetylcholine releasing drugs including cisapride; or a therapeutically active stereoisomer thereof substantially free of its other inactive or less active stereoisomers or a pharmaceutically acceptable salt, hydrate, or polymo h thereof, and optionally

(iii) an amount effective in the relief of flatulence of simethicone or alpha-D-galactosidase.

2. The composition of Claim 1 wherein the compound selected for the promotion of motility is cisapride or a therapeutically active stereoisomer thereof substantially free of its other inactive or less active stereoisomers or a pharmaceutically acceptable salt, hydrate, or polymorph thereof.

3. The composition of Claim 2 comprising from 2.5 mgs to 80 mgs of famotidine and from 5 mgs to 40 mgs of cisapride, and optionally 20 to 125 mgs of simethicone or 675 to 31,000 GalU of alpha-D-galactosidase.

4. The composition of Claim 3 comprising from 5 mg to 40 mgs of famotidine and from 5 to 40 mgs of cisapride, and optionally 20 to 80 mgs of simethicone or 675 to 2250 GalU of alpha- D-galactosidase.

5. The composition of Claim 4 comprising: (i) 10 mgs of famotidine or a pharmaceutically acceptable salt, hydrate, stereoisomer or polymorph thereof, and

(ii) 10 mgs of cisapride or a pharmaceutically acceptable salt, hydrate, stereoisomer or polymorph thereof, and optionally

(iii) 20 to 40 mgs of simethicone or 675 to 2250 GalU of alpha-D-galactosidase.

6. A method of preventing, relieving and treating gastrointestinal disorders such as indigestion, sour stomach, overindulgence, gastroesophageal reflux and heartburn in a mammalian organism in need of such treatment, comprising administering to such organism:

(ii) an amount effective in the promotion of motility and gastric emptying and the treatment of dysfunction of the control mechanism for gastrointestinal motility, of a compound selected from bethanechol, acylatonium, neostigmine, metoclopramide, clebopride, domperidone, trimebutine and acetylcholine releasing drugs including cisapride; or a therapeutically active stereoisomer thereof substantially free of its other inactive or less active stereoisomers or a pharmaceutically acceptable salt, hydrate, or polymorph thereof, and optionally

7. The method of Claim 6 wherein the compound selected for the promotion of motility is cisapride or a therapeutically active stereoisomer thereof substantially free of its other inactive or less active stereoisomers or a pharmaceutically acceptable salt, hydrate, or polymorph thereof.

8. The method according to Claim 7 wherein the composition administered to a mammalian organism in need thereof comprises:

(i) 10 mgs of famotidine or a pharmaceutically acceptable salt, hydrate, stereoisomer or polymorph thereof, and (ii) 10 mgs of cisapride or a pharmaceutically acceptable salt, hydrate, stereoisomer or polymorph thereof, and optionally

(iii) 20 to 40 mgs of simethicone or 870 to 2900 GalU of alpha-D-galactosidase.

9. A method of reducing the size and weight of a pharmaceutically effective amount of a cisapride/H2 antagonist combination dosage form which comprises combining:

(ii) an amount effective in the relief of gastrointestinal or esophagus disorders and of promotion of gastric emptying of cisapride or a therapeutically active stereoisomer thereof substantially free of its other inactive or less active stereoisomers or a pharmaceutically acceptable salt, hydrate, or polymorph thereof, and optionally

10. A method of preventing, relieving and treating gastrointestinal disorders, overindulgence and pain before or during ingestion of a meal accompamed by alcoholic beverages, comprising administration of a combination of:

and pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs thereof wherein the famotidine does not interact with ethanol from the ingestion of the alcoholic beverage, and