WO1995001795A1 - H2 antagonist-alginate-antacid combinations - Google Patents

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 relief of gastrointestinal or esophagus disorders of an H2 antagonist selected from a compound of formula (I) and its pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs and (ii) an amount effective in relief of gastrointestinal or esophagus disorders of at least one of the alginates and (iii) an amount effective in relief of gastrointestinal distress of an antacid wherein the antacid provides a buffering effect and generates carbon dioxide to aerate the alginate.

Description

TITLE OF THE INVENTION

H2 ANTAGONIST- ALGINATE- ANTACID COMBINATIONS

BACKGROUND OF THE INVENTION

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 alginates with certain H2 antagonists have been disclosed. See U.S. Pat No. 5,007,790 which discloses a solid state drug containing (cimetidine)/polymer (sodium alginate); GB 2222772 which discloses the H2 antagonist ranitidine and alginic acid. GB 2,207,865 discloses a wound healing agent comprising H-2 antagonist (famotidine) with carrier such as an alginate wherein the composition is used to treat wounds rather than as a gastric acid inhibitor. EP- 290,229-B discloses an H2-antagonist (cimetidine) plus an antacid and/or alginate. See also U.S. Pat. No. 4,996,222. It is known that with certain H2 antagonists, an alginate added to treat gastroesophageal reflux can promote oxidation of the H2 antagonist to a biological inactive form and additional ingredients have to be added to prevent this reaction. Combinations of antacids and alginates have been used to provide symptomatic relief of gastroesophageal reflux. See Martindale's Extra Pharmacopoeia at page 1432. Combinations of H2 antagonists and antacids have been disclosed: See FR2648710, GB2219940, EP- 294933-A, EP-286_.781-A, SU 1,362,477-A, U.S. 4,824,664, EP 233,853 and WO 9209286 Al. There is a need, however, to employ a drug combination with the advantages of an alginate or alginic acid and an antacid to prevent gastroesophageal reflux (GER) in combination with an H2 antagonist selected from famotidine or its salts, hydrates, stereoisomers or polymorphs to treat and prevent the discomfort associated with indigestion, sour stomach, heartburn or other gastrointestinal disorders including GER. Additional antoxidants may be added to the claimed famotidine/ alginate/antacid combination to prevent oxidation of famotidine to a less active metabolite.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 with an alginate and an antacid such as a carbonate salt or magnesium or aluminum hydroxide wherein the combination simultaneously relieves and prevents symptoms associated with excess gastric acid secretion or evolution in the stomach and esophagus respectively.

The present invention therefore provides an effective synergistic treatment of gastrointestinal disorders using the combination of famotidine and its salts, hydrates, or pharmacologically active stereoisomers or polymorphs with an alginate and an antacid. The claimed combination is particularly useful for treating gastro¬ esophageal reflux disorder at nightime since famotidine or the biologically active forms of famotidine has a long-lasting effect (9 hours) thereby aiding in the prevention of heartburn and other gastrointestinal distress while the alginate aids in eliminating the rafting effect and the antacid provides rapid buffering relief in the stomach. Other H2 antagonists that may be employed in this invention include cimeditine, ranitidine, nizatidine, and roxatidine.

DETAILED DESCRIPTION OF THE INVENTION

This invention claims pharmaceutical compositions for use in the treatment of mild stomach and esophagus disorders including the prevention and treatment of heartburn. The composition comprises: (i) an ampunt effective in the relief of gastrointestinal or esophagus disorders of an H2 antagonist selected from a compound of the formula:

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

(ii) an amount effective in relief of gastrointestinal or esophagus disorders of at least one of an alginate and

(iii) an amount effective in relief of gastrointestinal distress of an antacid wherein the antacid provides a buffering effect and generates carbon dioxide to aerate the alginate and optionally

(iv) an antiflatulent amount of simethicone.

This invention is also directed to a method of preventing and treating indigestion, sour stomach, heartburn, overindulgence, gastroesophageal reflux and other gastrointestinal disorders in mammals, including humans, in need of treatment thereof, comprising administering to such organism:

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

and its pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs and (ii) an amount effective in relief of gastrointestinal or esophagus disorders of at least one of an alginate

(iii) an amount effective in relief of gastrointestinal distress of an antacid wherein the antacid provides a buffering effect and generates carbon dioxide to aerate the alginate and optionally

(iv) an antiflatulent amount of simethicone.

The term mammals or mammalian organism includes but is not limited to humans, dogs, cats, horses and cows.

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 or other suitable quantities as it is currently available on the market and formulated via typical formulation processes with alginates selected from alginic acid which is suitable for tablet formulations or sodium alginate which is suitable for liquid formulations of the claimed combination and antacids which are also known including calcium carbonate and other carbonate salts as well as aluminum and magnesium hydroxides. In addition, simethicone, a known antiflatulent, may be added to the above combination to provide maximum and broad relief of gastrointestinal disturbances and distress. Famotidine as a prescription drug product is sold in the United States under the trademark PEPCID®.

The pharmaceutical compositions of the present invention are useful in the treatment of various mild gastrointestinal disorders including indigestion, sour stomach, overindulgence and heartburn. In particular, an alginate and antacid combined with an H2 antagonist selected from famotidine, a compound of the formula:

or its pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs is useful for the prevention and treatment of various gastrointestinal disorders such as indigestion, sour stomach, or heartburn. The utilization of the currently known biologically active forms and/or salts or hydrates of famotidine in combination with an alginate selected from alginic acid or sodium alginate or other pharmaceutically acceptable alginate salts or hydrates and an antacid is advantageously used to treat mild gastrointestinal disorders. Simethicone or another anti-flatulent such as alpha-galactosidase (ADG) may be added to this preferred combination to provide anti-flatulent relief. In particular, the claimed combination is used to treat the symptoms associated with gastric acid secretion while simultaneously treating the symptoms of gastroesophageal reflux and 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 an alginate and an antacid and optional anti-flatulent. 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 latter 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. Famotidme is well tolerated and has minimal side effects and thus advantageously may be used in the present invention in combination with an alginate and an antacid. Famotidine is also the most potent and selective H2 antagonist. The combination of famotidine or its pharmaceutically effective salts, hydrates, stereoisomers or polymoφhs with an antacid and an alginate and optionally simethicone provides a combination which simultaneously and selectively provides relief from and prevention of discomfort and injury to the stomach, esophagus, or duodenum from excess production of gastric acid. Furthermore, famotidine in combination with an alginate and an antacid 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 an alginate and antacid with famotidine provides relief of gastroesophageal reflux while also providing long acting relief from and treatment of gastrointestinal disorders associated with gastric acid secretion. The antacid administered in the claimed combination provides both a buffering effect and simultaneously generates carbon dioxide to aerate the alginate raft formed from the alginate. The raft has a lower density after this aeration effect and floats on the stomach contents.

A therapeutically active stereoisomer or polymoφh of famotidine may be employed substantially free of other stereoisomeric forms of polymoφhs, substantially free should be taken to mean at least 90% of one distinct stereoisomer or polymoφh.

The combination of famotidine which is a highly potent H2 antagonist with an alginate and an antacid 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 its pharmaceutically acceptable salts, hydrates, stereoisomers or polymoφhs is advantageously used in the present invention in combination with alginic acid or sodium alginate and calcium carbonate. Of course, other suitable and known antacids such as the aluminum hydroxide or magnesium hydroxide salts or mixtures or combinations thereof may be used in the claimed formulation. For example, a one to one ratio of magnesium hydroxide to aluminum hydroxide salts may be utilized in the present invention. The amount of famotidine used in the present invention in humans may range from 2.5 mg/day to 80 mg/day. Advantageously, 2.5 to 40 mgs/day is administered in combination with 200-500 mgs/day mg of an alginate and 250-750 mgs/day of calcium carbonate. 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 treatment thereof. 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. The antacid employed herein may be selected from any of the commercially available or known antacids or combinations thereof such as aluminum hydroxide, calcium carbonate, magnesium hydroxide or sodium bicarbonate. The simethicone optionally employed herein is also available commerically and the administered oral dosage may range in humans from 10-1,000 mgs/day. This amount varies depending upon the severity of the condition and typical dosages are described in the Physicians Desk Reference at pages 1155-56 (1992). ADG may be employed as an anti¬ flatulent in doses of 290 to 31,000 Galactosidase International Units (GalU) particularly 675 to 2250 GalU.

The present composition may be administered to a patient in need of treatment thereof in the form of tablets, caplets, gelcaps, capsules, elixirs, lozenges, wafers, effervescent formulations, chewable tablets, syrups, or suspensions or via other known and effective delivery methods. 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 alginate, 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 inactive ingredients may also include magnesium or aluminum trisilicate, sodium or potassium salts including carbonate salts, aluminum hydroxide gel, lactose, sorbitol, aspartame or sodium saccharide.

The active components may also be formulated in sustained release or effervescent formulations. The sustained release formulations also include layered formulations which provide for distinct release ratios 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

alginate/antacid/famotidine Tablet

alginic acid 500 mg famotidine 40 mg

PVP 15 mg

Avicel PH101 40 mg

Magnesium Stearate 4 mg calcium carbonate 500 mg magnesium trisilicate 25 mg sodium bicarbonate 170 mg aluminum hydroxide gel 100 mg EXAMPLE 2

alginate/antacid/famotidine Tablet

alginic acid 500 mg famotidine 20 mg

PVP 15 mg

Avicel PH101 40 mg

Magnesium Stearate 4 mg calcium carbonate 500 mg

EXAMPLE 3

alginate/antacid/famotidine Tablet

alginic acid 500 mg famotidine 15 mg

PVP 15 mg

Avicel PH101 40 mg

Magnesium Stearate 4 mg calcium carbonate 500 mg

EXAMPLE 4

alginate/antacid/famotidine Tablet

alginic acid 500 mg famotidine 10 mg

PVP 15 mg

Avicel PH101 40 mg

Magnesium Stearate 4 mg calcium carbonate 500 mg EXAMPLE 5

alginate/antacid/famotidine Tablet

alginic acid 500mg famotidine 5 mg

PVP 15 mg

Avicel PH101 40 mg

Magnesium Stearate 4 mg calcium carbonate 500 mg

EXAMPLE 6

alginate/antacid/famotidine Sustained Release

alginic acid 600 mg famotidine 40 mg

PVP 30 mg

Avicel PH101 80 mg

Magnesium Stearate 8 mg

Methocel E10MCR 66 mg

Methocel K100MLV 200 mg calcium carbonate 600 mg

EXAMPLE 7

alginate/famotidine/antacid Sustained Release

alginic acid 600 mg famotidine 20 mg

PVP 30 mg

Avicel PH101 80 mg

Magnesium Stearate 8 mg Methocel El OMCR 66 mg

Methocel K100MLV 200 mg calcium carbonate 600 mg

EXAMPLE 8

alginate/antacid/famotidine Solution

sodium alginate 500 mg famotidine 10 mg g.s. syrup 5 ml calcium carbonate 500 mg

EXAMPLE 9

alginate/antacid/famotidine Solution

sodium alginate 500 mg famotidine 20 mg g.s. syrup 5 ml calcium carbonate 500 mg

Simethicone 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 is the typical known dosage range to treat flatulence. The dose may be, for example 20-40 mgs of simethicone per 5 mis of a liquid form claimed combination or per chewable tablet wherein the other active ingredients include famotidine (20-40 mgs), magnesium hydroxide (200 mg), aluminum hydroxide (dried gel, 200 mg). 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, carboxymethylcellulose 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 treatment of gastrointestinal disorders such as indigestion, sour stomach, overindulgence and heartburn in a mammals, including humans comprising:

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

and its pharmaceutically acceptable salts, hydrates, stereoisomers or polymoφhs and

(ii) an amount effective in relief of gastrointestinal or esophagus disorders of at least one of an alginate; and

(iii) an amount effective in relief of gastrointestinal distress of an antacid wherein the antacid provides a buffering effect and generates carbon dioxide to aerate the alginate and optionally

(iv) an antiflatulent amount of simethicone.

2. The composition of Claim 1 comprising between 5 mg to 40 mgs of famotidine.

3. The composition of Claim 2 comprising 200-500 mgs of an alginate selected from alginic acid or sodium alginate and 500- 1000 mgs of an antacid wherein the antacid is selected from sodium or calcium carbonate salts or aluminum hydroxide or magnesium hydroxide salts.

4. The composition according to Claim 3 comprising

(i) a tablet of 10 mgs of famotidine and

(ii) 500 mgs of alginic acid and

(iii) 500 mgs of calcium carbonate and optionally

(iv) 20-40 mgs of simethicone.

5. A method of 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:

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

and its pharmaceutically acceptable salts, hydrates, stereoisomers or polymoφhs and

(ii) an amount effective in relief of gastrointestinal or esophagus disorders of at least one of the alginates and

(iii) an amount effective in relief of gastrointestinal distress of an antacid wherein the antacid provides a buffering effect and generates carbon dioxide to aerate the alginate and optionally

(iv) an antiflatulent amount of simethicone.

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

(i) a tablet of 10 mgs of famotidine and

(ii) 500 mgs of alginic acid and

(iii) 500 mgs of calcium carbonate and optionally

(iv) 20-40 mgs of simethicone.

7. A method of reducing the size and weight of a pharmaceutically effective amount of an alginate/antacid/H2 antagonist combination dosage form which comprises combining

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

and its pharmaceutically acceptable salts, hydrates, stereoisomers or polymoφhs and

(ii) an amount effective in relief of gastrointestinal or esophagus disorders of at least one of the alginates and (iii) an amount effective in relief of gastrointestinal distress of an antacid wherein the antacid provides a buffering effect and generates carbon dioxide to aerate the alginate and optionally

(iv) an antiflatulent amount of simethicone.

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

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

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

(ii) an amount effective in relief of gastrointestinal or esophagus disorders of at least one of the alginates wherein the alginate absorbs the ethanol; and

(iii) an amount effective in relief of gastrointestinal distress of an antacid wherein the antacid provides a buffering effect and generates carbon dioxide to aerate the alginate and optionally

(iv) an antiflatulent amount of simethicone.