WO1995001784A1

WO1995001784A1 - H2 antagonist-sucralfate-antiflatulent combinations

Info

Publication number: WO1995001784A1
Application number: PCT/US1994/007525
Authority: WO
Inventors: Robert T. Sims; William Slivka
Original assignee: Merck & Co., Inc.; Mcneil-Ppc, Inc.
Priority date: 1993-07-06
Filing date: 1994-07-05
Publication date: 1995-01-19
Also published as: AU7322394A

Abstract

This invention relates to pharmaceutical compositions for use in the treatment and relief of indigestion, sour stomach, heartburn and other gastrointestinal disorders in mammals, including humans, by administering compositions comprising (i) an amount effective in the prevention and/or treatment and 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 promotion of healing of tissue damage or ulcers associated with excess secretion of gastric acid of a glucopyranoside compound 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 (iii) an antiflatulent effective amount of an antiflatulent.

Description

TITLE OF THE INVENTION

H₂ ANTAGONIST-SUCRALFATE-ANΗFLATULENT

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 glucopyranosides which are known to promote or enhance healing associated with damage caused or induced by excess gastric acid and 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. In the present invention, the H2 antagonist is used to treat and prevent mild to moderate gastrointestinal disorders. It is further known that certain glucopyranoside analogues are useful in the treatment of stomach disorders such as ulcers. For example, sucralfate, a compound of the formula:

wherein R is Sθ3[Al2(OH)5-(H2θ)2], is classified as a β-D- fructofuranosyl-α-D-glucopyranoside octakis(hydrogen sulfate) aluminum complex, and is known to heal ulcers. See Martindale's The Extra Pharmacopoeia. 1108 (1989) and references cited therein. Sucralfate is useful in accelarating the healing of duodenal ulcers by forming an ulcer-adherent complex with proteinaceous exudate at the ulcer site and further is known to form a barrier in in vitro studies to diffusion of hydrogen ions. Combinations of sucralfate and H2 antagonists, including famotidine, have been disclosed. See EPA 0403 048 which discloses a combination of sucralfate and a therapeutically active medicament including an H2 receptor blocker such as famotidine. See also PCT WO 92/09286 and U.S. Pat. No. 5,116,821.

There is a need, however, 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 sucralfate and an antiflatulent such as simethicone or alpha-D-galactosidase ("ADG"). The instant combination provides a dual action approach to the treatment of gastrointestinal disorders in that a glucopyranoside such as sucralfate offers localized action at the site of the ulcer while famotidine offers a systemic effect of reduced acid production. The instant combination simultaneously relieves, treats and/or prevents symptoms associated with excess gastric acid secretion or evolution in the stomach and esophagus respectively while also promoting stomach healing with an known healant such as sucralfate. The invention is not limited to the above combination and other glucopyranosides may also be used in the combinations used to treat stomach disorders.

The present invention provides an effective treatment of gastrointestinal disorders using the combination of famotidine with a glucopyranoside such as sucralfate, and an antiflatulent such as simethicone or ADG. The claimed combination is particularly useful for treating gastrointestinal distress such as gastro-esophageal reflux ("GER") and is advantageously administered at nightime prior to bed. Other H2 antagonists that can be used with this invention include ranitidine, cimetidine, nizatidine and roxatidine. DETAILED DESCRIPΗON OF THE INVENTION

This invention claims pharmaceutical compositions for use in the prevention, relief and treatment of mild to moderate stomach and esophagus disorders including heartburn, indigestion, sour stomach, overindulgence, gastro-esophogeal reflux (GER), and flatulence. Famotidine or its biologically active forms is beneficial because it has a long-lasting systemic effect (about 9 hours) and it suppresses both the gastric acid concentration and secretion volume. This effect aids in the continued control and prevention of heartburn and other gastro-intestinal distress in humans, while sucralfate achieves a local ulcerative healing effect and simethicone or ADG provide simultaneous antiflatulent relief. The tri-component composition therefore provides a broad spectrum attack on the symptoms associated with excess gastric acid secretion. 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 healing of tissue damage or ulcers associated with excess secretion of gastric acid of a glucopyranoside compound 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

(iii) an antiflatulent effective amount of an antiflatulent. This invention is also directed to a method of preventing, relieving and treating indigestion, sour stomach, heartburn, overindulgence, gastro-esophageal reflux and other gastrointestinal disorders including flatulence in patients in need of treatment thereof, comprising administering to such organism:

(iii) an antiflatulent effective amount of an antiflatulent.

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 or patient. Famotidine may be purchased in bulk quantities as it is currently available on the market, and formulated via typical formulation processes with ulcer healants selected from sucralfate or a stereoisomer, salt or hydrate thereof, which is suitable for tablet, capsule or liquid formulations of the claimed combination. Famotidine as a prescription drug product is sold in the United States under the trademark PEPCID®. Sucralfate may be obtained from, for example Marion Merrel Dow and is sold in the United States under the trademark CARAFATE®. Simethicone or alpha-D-galactosidase (ADG) antiflatulents are 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 glucopyranoside is active as the therapeutically active stereoisomer, the absence of the inactive stereoisomer of the glucopyranoside 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 glucopyranoside is used in the claimed combination. The use of the potent H2 antagonist such as famotidine combined with a glucopyranoside or an active stereoisomer of a glucopyranoside provides significant dosage form advantages since less of the H2 antagonist and the glucopyranoside 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, GER, heartburn and flatulence. In particular, an ulcer- healant selected from a glucopyranoside, combined with an H2 antagonist selected from famotidine, a compound of the formula:

or its pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs thereof, and an antiflatulent such as simethicone or ADG, is useful for the prevention and treatment of various gastrointestinal disorders such as indigestion, sour stomach, overindulgence, heartburn, GER or flatulence. The utilization of the currently known biologically active stereoisomers and/or salts, hydrates or polymorphs of famotidine in combination with sucralfate or its pharmacologically active stereoisomers, salts, hydrates, or polymorphs is advantageously used to prevent, treat and relieve mild to moderate gastrointestinal disorders. In particular, the claimed combination is used to prevent, treat and relieve the symptoms associated with gastric acid secretion while simultaneously treating the symptoms of gastrointestinal distress, as well as flatulence. The animal, patient, or organism in need of treatment thereof therefore 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 glucopyranoside, such as sucralfate, and an antiflatulent, such as 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-[(diamino- methylene)amino]-4-thiazolyl]methyl]thio]- propanimidamide), a member of the last named class, 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 sucralfate and simethicone or ADG. Famotidine is also the most potent and selective H2 antagonist. Sucralfate is known to promote the healing of ulcers. See The Physicians Desk Reference, pp. 1326-27 (1992). The claimed combination of famotidine or the pharmaceutically effective salts, hydrates, stereoisomers or polymorphs thereof, with sucralfate and an antiflatulent provides a 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 and from flatulence as an associated symptom or from ingestion of indigestible food products.

Included within this invention are any diastereomers and/or enantiomers of the glucopyranoside. In particular, a therapeutically active stereoisomer of a glucopyranoside, such as sucralfate, 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.

Furthermore, famotidine in combination with sucralfate and an antiflatulent such as 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 sucralfate with famotidine provides relief of gastro-esophageal reflux while also providing long acting relief from and treatment of gastrointestinal disorders associated with gastric acid secretion. The sucralfate administered in the claimed combination provides a localized healing effect while the H2 antagonist provides systemic relief of long duration.

The combination of famotidine, which is a highly potent H2 antagonist, with sucralfate and an antiflatulent 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 salt, hydrate, stereoisomer or polymorph thereof, is advantageously used in the present invention in combination with sucralfate and 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. The amount of sucralfate may range from 250 mg/dosage to 4000 mg/dosage. Advantageously, 5 to 40 mgs/dosage of famotidine is administered in combination with 250 to 1000 mg/dosage of sucralfate.

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 sucralfate, 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

sucralfate/famotidine Tablet

sucralfate 1000 mg famotidine 40 mg

PVP 15 mg

Avicel PHlOl 40 mg

Magnesium Stearate 4 mg simethicone 20 mg

EXAMPLE 2

sucralfate/famotidine Tablet

sucralfate 1000 mg famotidine 20 mg

PVP 15 mg

Avicel PH101 40 mg

Magnesium Stearate 4 mg simethicone 40 mg EXAMPLE 3

sucralfate/famotidine Tablet

sucralfate 700 mg famotidine 15 mg

PVP 15 mg

Avicel PH101 40 mg

Magnesium Stearate 4 mg simethicone 80 mg

EXAMPLE 4

sucralfate/famotidine Tablet

sucralfate 500 mg famotidine lO mg

PVP 15 mg

Avicel PH101 40 mg

Magnesium Stearate 4 mg simethicone 125 mg

EXAMPLE 5

sucralfate/famotidine Tablet

sucralfate 500 mg famotidine 5 mg

PVP 15 mg Avicel PH101 40 mg

Magnesium Stearate 4 mg simethicone 100 mg EXAMPLE 6

sucralfate/famotidine Sustained Release

sucralfate 2000 mg famotidine 40 mg

PVP 30 mg

Avicel PH101 80 mg

Magnesium Stearate 8 mg Methocel E 10MCR 66 mg

Methocel K100MLV 200 mg simethicone 100 mg

EXAMPLE 7

sucralfate/famotidine Sustained Release

sucralfate 1000 mg famotidine 20 mg

PVP 30 mg

Avicel PH101 80 mg

Magnesium Stearate 8 mg

Methocel E10MCR 66 mg

Methocel K100MLV 200 mg simethicone 100 mg

EXAMPLE 8

sucralfate/famotidine Solution

sucralfate 500 mg famotidine 10 mg g.s. syrup 5 ml simethicone 125 mg EXAMPLE 9

sucralfate/famotidine Solution

sucralfate 1000 mg famotidine 20 mg g.s. syrup 5 ml simethicone 150 mg

EXAMPLE 10

sucralfate/famotidine Solution

sucralfate 1000 mg famotidine 5 mg g.s. syrup 5 ml simethicone 150 mg

Simethicone or alpha-D-galactosidase is 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 can 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 form) 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, carboxymethyl - cellulose sodium, flavors, hydroxypropyl methylcellulose, micro- crystalline 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, gastro-esophageal reflux, overindulgence, heartburn and flatulence in a patient in need of treatment thereof, comprising:

(iii) an antiflatulent effective amount of an antiflatulent.

2. The composition according to Claim 1 comprising:

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

10 (ii) an amount effective in the promotion of healing of tissue damage or ulcers associated with excess secretion of gastric acid of a glucopyranoside compound or a therapeutically active stereoisomer thereof substantially free of its other inactive or less active stereoisomers or a pharmaceutically -, ₅ acceptable hydrate or polymorph thereof, wherein the glucopyranoside compound is sucralfate, and

(iii) an antiflatulent effective amount of an antiflatulent. wherein the antiflatulent is selected from simethicone or alpha-D- ₂₀ galactosidase.

3. The composition of Claim 2 comprising

(i) from 2.5 mgs to 80 mgs of famotidine or a pharmaceutically ₂₅ acceptable salt, hydrate, stereoisomer or polymorph thereof,

(ii) from 250 mgs to 4000 mgs of sucralfate or a pharmaceutically acceptable hydrate, stereoisomer or polymorph thereof, and

30

(iii) from 20 mgs to 150 mgs of simethicone or from 675 to 31,000 GalU of alpha-D-galactosidase.

4. The composition of Claim 3 comprising

(i) from 5 mgs to 40 mgs of famotidine or a pharmaceutically acceptable salt, hydrate, stereoisomer or polymorph thereof,

(ii) from 250 mgs to 1000 mgs of sucralfate or a pharmaceutically acceptable hydrate, stereoisomer or polymorph thereof, and

(iii) from 20 mgs to 80 mgs of simethicone or from 675 to 2250 GalU of alpha-D-galactosidase.

5. The composition according to Claim 4 wherein the amount of simethicone is from 20 mgs to 40 mgs.

6. A pharmaceutical composition, comprising

(i) famotidine or a pharmaceutically acceptable salt, hydrate, stereoisomer or polymorph thereof;

(ii) sucralfate or a pharmaceutically acceptable hydrate, stereoisomer or polymorph thereof;

(iii) simethicone or alpha-D-galactosidase; and

(iv) a pharmaceutically acceptable excipient.

7. A method of preventing, relieving and treating gastrointestinal disorders such as indigestion, sour stomach, overindulgence, gastro-esophageal reflux and heartburn in a patient in need of such treatment, comprising administering to such patient: (i) an amount effective in the relief of gastrointestinal or esophagus disorders of an H2 antagonist selected from a compound of the formula:

⁰ and pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs thereof, and

(ii) an amount effective in the promotion of healing of tissue damage or ulcers associated with excess secretion of gastric ⁵ acid of a glucopyranoside compound 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

° (iii) an antiflatulent effective amount of an antiflatulent.

8. The method according to Claim 6 wherein the composition administered to a mammalian organism in need thereof comprises: 5

(ii) sucralfate or a pharmaceutically acceptable hydrate, ° stereoi somer or polymorph thereof;

(iii) simethicone or alpha-D-galactosidase; and

(iv) a pharmaceutically acceptable excipient.

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

(iii) an antiflatulent effective amount of an antiflatulent.

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

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

(ii) an amount effective in the promotion of healing of tissue damage or ulcers associated with excess secretion of gastric acid of a glucopyranoside compound or a therapeutically active stereoisomer thereof substantially free of its other inactive or less active stereoisomers or a pharmaceutically acceptable salt, hydrate, or polymoφh thereof, and

(iii) an antiflatulent effective amount of an antiflatulent.