WO1996002262A2

WO1996002262A2 - Pharmaceutical compositions for the treatment of gastrointestinal distress comprising h2 receptor antagonists and antacids

Info

Publication number: WO1996002262A2
Application number: PCT/US1995/009004
Authority: WO
Inventors: Michael Alan Brandley; Dolores Dimaria; Jeanette Louise Brandley
Original assignee: American Home Products Corp
Current assignee: Wyeth LLC
Priority date: 1994-07-20
Filing date: 1995-07-18
Publication date: 1996-02-01
Anticipated expiration: 1997-01-20
Also published as: PE33896A1; AU3132495A; CO4410201A1; WO1996002262A3

Abstract

Pharmaceutical compositions and methods of treatment are disclosed for providing instant and sustained relief from pain or symptoms associated with episodic heartburn or gastric distress in humans, comprising H2-receptor antagonists and antacids, more particularly compositions and methods of treatment comprising (1) nizatidine and (2) calcium carbonate or magaldrate.

Description

PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF GASTROINTESTINAL DISTRESS COMPRISING H2 RECEPTOR ANTAGONISTS AND ANTACIDS

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical compositions and

10 methods for providing relief from the symptoms associated with gastrointestinal distress. The invention relates specifically to concomitant administration of an antacid and a histamine H₂-receptor antagonist for the treatment of such disorders.

Antacids are basic compounds that neutralize acid in the gastric

15 contents. They are employed by physicians chiefly in the treatment of reflux esophagitis, gastroesophageal reflux disease, and peptic ulcer, and by lay people in self-medication for a wide variety of symptoms associated with gastric acidity. The clinical status of antacids is in a state of evolution. There have been predictions in the past that the availability of histamine H₂-receptor

20 antagonists (hereinafter "H₂-receptor antagonists") would eliminate antacids from the group of drugs used to treat ulcers. However, that has not happened.

H₂-receptor antagonists are characterized as a family by their ability to inhibit the secretion of gastric acid. H₂-receptor antagonists are indicated for the treatment of duodenal ulcers as well as other hyper secretory states. Prior

25 to FDA approval of the H₂-receptor antagonists, the mainstay of therapy in the reduction of gastric acidity involved the neutralization of gastric acid with antacids.

While the invention is subject to a wide range of applications, it is especially suited for use in a pharmaceutical composition and a method of treating gastric distress using the pharmaceutical composition, and will be particularly described in that connection.

DESCRIPTION OF RELATED ART

There are many drugs on the market to treat gastrointestinal distress. At present, the primary treatment for gastric disorders is based upon the neutralization of gastric acids and pepsin with antacids, for example, aluminum hydroxides, calcium carbonates, magnesium hydroxides and sodium bicarbonates. Additionally, treatment may be based upon the inhibition of acid secretion by H₂-receptor antagonists, such as cimetidine, nizatidine and ranitidine.

Examined separately, both nizatidine and antacids have demonstrated efficacy in the treatment and relief of gastric acid-related disorders. Antacids are marketed for over-the-counter use for the relief of heartburn, sour stomach, and acid indigestion. In addition, the widespread use of antacids by the general public has confirmed the important role of over-the-counter antacids in treating symptomatic gastric acid-related ailments. Nizatidine is marketed for prescription use at doses of 150 mg and

300 mg for treatment of duodenal ulcer disease and at a dose of 150 mg for maintenance of healed duodenal ulcers. It is anticipated that nizatidine may also be marketed for nonprescription use at doses equal to or lower than these currently employed for prescription use. Use of these treatments individually has some drawbacks. The problem with antacids is that they provide only short-term relief. The problem with histamine H₂-receptor antagonists is that they have a somewhat delayed onset of action.

The concomitant administration of antacids and H₂-receptor antagonists is an effective treatment for gastric distress, including symptoms associated with ulcers, heartburn, or gastroesophageal reflux. It is, therefore, advantageous to have a pharmaceutical composition which combines an antacid and H₂-receptor antagonist in a single stable dosage form.

Consequently, there is a need for a stable composition and treatment which can effectively provide both fast and sustained relief from pain, discomfort, or symptoms associated with gastrointestinal distress in humans. Furthermore, there is a need for stability in such compositions.

SUMMARY OF THE INVENTION

Pharmaceutical compositions and methods of treatment for providing immediate and sustained relief from the pain or discomfort, or symptoms related to gastric distress, such as heartburn, are disclosed. More specifically, a stable single dosage formulation comprising an antacid and an H₂-receptor antagonist is disclosed.

A method is described for providing immediate and sustained relief from pain, discomfort and/or symptoms associated with gastric distress, such as symptoms associated with heartburn, ulcers, and gastroesophageal reflux, in a human comprising orally administering together or substantially together an antacid in an amount effective to substantially neutralize gastric acid and a histamine H₂-receptor antagonist in an amount effective to substantially inhibit or block gastric acid secretion for providing immediate and sustained relief from pain, discomfort and/or symptoms associated with gastric distress, the immediate and sustained relief provided lasting longer in duration than when the human is orally treated with only the antacid, and the immediate and sustained relief provided being faster than and lasting at least about as long in duration as when the human is orally treated with only the histamine H₂-receptor antagonist. The principal advantage of the present invention is the provision of a stable pharmaceutical composition and method of treatment which substantially obviates one or more of the limitations and disadvantages of prior compositions and treatments. Additional features and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the pharmaceutical compositions and method of treatment, particularly pointed out in the written description and claims hereof.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph showing stability data based upon the highest individual degradation product for two layer tablets comprising nizatidine and antacids;

Fig. 2 is a graph showing stability data based upon the total degradation products for two layer tablets comprising nizatidine and antacids;

Fig. 3 is a graph showing stability data based upon the highest individual degradation product for single layer tablets comprising nizatidine and antacids; and

Fig. 4 is a graph showing stability data based upon the total degradation products for single layer tablets comprising nizatidine and antacids; DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to the present preferred embodiments of the invention. Generally, the pharmaceutical compositions described include an effective amount of an antacid and a histamine

H₂-receptor antagonist, and a method of treatment involving the administration together or substantially together of this antacid and histamine H₂-receptor antagonist at or after the onset of pain or discomfort associated with gastrointestinal distress. Pharmaceutical compositions and methods of these types are described in Wolfe, U.S. Patent No. 5,229,137, issued July 20,

1993, assigned to Brigham and Women's Hospital, Inc., which is specifically incorporated by reference herein.

H₂-receptor antagonists are indicated for the treatment of duodenal ulcers and pathological hypersecretory states, such as Zollinger-Ellison syndrome.

The term "histamine H₂-receptor antagonist" is referred to herein in a broad sense, and is meant to include those agents that inhibit or block the secretion of gastric acid by binding to a specific histamine receptor on the parietal cell membrane located in the stomach. Exemplary histamine H₂-receptor antagonists include cimetidine, ranitidine, nizatidine, and famotidine.

The term "antacid" refers to those agents which can block gastric acid and/or bile salts by neutralization, and/or inhibit the proteolytic activity of pepsin. Antacids which may be used in combination with the histamine H₂-receptor antagonist are conventional antacids which are well-known and widely used in the treatment of a variety of excess acid-related gastrointestinal dysfunctions including acid indigestion, heartburn, sour stomach and ulcers. Antacids include, for example, aluminum hydroxides, calcium carbonates, magnesium hydroxides, sodium bicarbonates, magaldrate and the like, as well as those antacids that are commercially available such as Turns^®, Mylanta-II^®, Mylanta Double Strength*, Maalox-Plus*, Extra-Strength Maalox-Plus^®, and Gelusil^®. Magaldrate is a magnesium aluminate hydrate, described in Hallmann et al., U.S. Patent No. 2,923,600. Magaldrate is a chemical union of aluminum and magnesium hydroxide, corresponding approximately to the formula AljMg₁₀(OH)₃-(SO₄)₂xH₂O, according to the official monograph USP

XX, third supplement USP-NF, and has a molecular weight of about 1097. Magaldrate, also sometimes referred to in said monograph as aluminum magnesium hydroxide sulfate, contains not less than 29.0 percent and not more than 40.0 percent of magnesium oxide (MgO) and the equivalent of not less than 18.0 percent and not more than 26.0 percent of aluminum oxide (Al₂O₃).

The preparation of magaldrate is described in U.S. Patent

No. 2,923,660. A commercially suitable procedure is described in said patent, for example, beginning in column 2, line 40. Aluminum sulfate is employed as at column 2, line 58 in order to obtain magaldrate "all sulfate" material and, to maintain a low sodium content for the final product. The use of potassium oxide (or hydroxide) is preferred over the disclosed sodium oxide. Typically the magaldrate is precipitated to provide a 6% weight/volume mixture (fluid when fresh) and diluted to 3% for washing prior to concentration and formulation into a suspension providing a so called single strength acid neutralization capacity (ANC) of 13.5 to 15 meq per 5 milliliters of suspension which is equivalent to a magaldrate weight/weight concentration in the range of about 12 to 13 percent solids. At this concentration, unformulated magaldrate is a paste-like gel. Formulated magaldrate is sold under the RIOPAN trademark. The antacids may be used in dosage amounts conventionally used for treatment of a variety of excess acid-related gastrointestinal dysfunctions, as discussed above.

The pharmaceutical compositions described can be conventionally prepared from, for example, commercially available antacids and histamine H₂-receptor antagonists and may be formulated into liquid or solid dosage forms or combinations thereof. Preferably, the pharmaceutical medications may be taken as a single unitary dose containing both the antacid and the histamine H₂-receptor antagonist in a liquid or solid dosage form.

In this regard, the antacids and the histamine H₂-receptor antagonist may be formulated into single liquid mixtures or solid tablets which can be co-ingested as a single unitary dosage on an as-needed basis. For example, they may be administered after the onset of pain or discomfort or symptoms associated with gastric distress. They may also be administered periodically in a prophylactic treatment regimen. Antiflatulants may also be used in combination with the antacids and histamine H₂-receptor antagonists in the present invention, and include those antiflatulants which are conventionally used in the treatment of gastrointestinal distress, such as, for example, simethicone.

The pharmaceutical compositions may be in a form suitable for oral use, for example, as tablets, lozenges, aqueous or oily suspensions, dispersible powders, granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents such as, for example, flavoring agents, sweetening agents, coloring agents and the like, in order to provide a pharmaceutically elegant and palatable preparation.

Furthermore, inactive ingredients may be included in the preparation. For example, nontoxic pharmaceutically acceptable excipients may be, inert diluents, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example, starch, gelatin, or acacia, and lubricating agents, for example, magnesium stearate or stearic acid. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide an even longer sustained action over a period of time. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, soft gelatin capsules wherein the active ingredient is mixed with a suitable oil medium. Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may be suitable suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxy propyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, or gum acacia; dispersing or wetting agents may be any suitable naturally occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol. The aqueous suspensions may also contain one or more suitable preservatives, for example, ethyl or n-propyl, p-hydroxy benzoate, one or more suitable coloring agents, one or more suitable flavoring agents and one or more suitable sweetening agents, such as sucrose, saccharin, or sodium or calcium cyclamate. The compositions and methods of treatment relate to gastrointestinal distress associated with hyperacidity. For example, such distress includes ulcers, acid-related disorders such as gastroesophageal reflux disease, episodic heartburn, and others. Of all the acid-related disorders afflicting humans, gastroesophageal reflux disease is the most prevalent. Heartburn is its most prevalent symptom and is experienced by the vast majority of adult Americans at some point during their lifetime. Although the majority of these individuals do not seek medical attention, many of those who do will develop serious complications of chronic reflux, including erosive esophagitis, peptic esophageal strictures, and metaplasia. The preferred pharmaceutical composition provides fast symptomatic relief by virtue of the antacid, until the H₂-receptor antagonist ingredient can begin its effects. The combination of antacid with H₂-receptor antagonist rests on the complementary mechanisms of action by which these two agents diminish gastric acidity. Clinically, the effects of the longer-lasting, slower-onset H₂-receptor antagonist will augment the more short-term, early-onset relief provided by the antacid. Pharmacologically, antacids act locally within the gastric cavity to neutralize already present hydrochloric acid. This event effectively ameliorates the gastric acid, presumed to be the source of inciting symptoms. Alternatively, H₂-receptor antagonists act systemically to inhibit ongoing gastric acid secretion. This action diminishes the amount of freshly produced acid likely to exacerbate or reinstate the acid-related distress.

The disclosed compositions are contemplated as a treatment for the relief of gastric distress, including, but not limited to heartburn, acid indigestion, gastroesophageal reflux, sour stomach and upset stomach, hyperacidity and symptoms relating thereto as well as for the relief of the symptoms of overindulgence.

The preferred formulation comprises nizatidine and calcium carbonate, or nizatidine and magaldrate, with the latter being particularly preferred.

These two combinations are chemically compatible and produce a superior physical and chemical stability profile. The combination of nizatidine and calcium carbonate or nizatidine and magaldrate show superior results in terms of compatibility as evidenced by the test results depicted in Figs. 1-4. The following examples are illustrative, nonlimiting examples of embodiments in the claimed invention. Example 1

Combinations of nizatidine and various antacids were formulated into two layer tablets (one layer containing nizatidine and conventional excipients and one layer containing the antacid with conventional excipients). The two layer tablets were stored under conventional conditions for the assessment of the storage stability of pharmaceutical dosage forms. The tablets were assayed for stability (i.e., measurement of degradation products) by high performance liquid chromatography (HPLC) after one month and after two months. The compositions of the tablets were:

Sample 1 - 75 mg nizatidine

625 mg CaCo₃ Sample 2 - 75 mg nizatidine

534 mg magaldrate Sample 3 - 75 mg nizatidine

200 mg Mg(OH)₂ 200 mg Al(OH)₃ Stability was determined at 45°C for each sample. The highest individual degradation product and the total degradation products were determined and recorded in Figures 1 and 2, respectively.

Example 2

Example 1 was repeated except that the combinations of nizatidine and antacid in Samples 1, 2, and 3 were formulated into single layer tablets by conventional techniques and containing conventional excipients. Fig. 3 is a graph showing stability data based upon the highest individual degradation product, and Figure 4 shows the stability data based upon the total degradation products. Dosage forms will typically include an amount of antacid sufficient to neutralize from about 5 to about 40, more preferably from about 10 to about 15, milliequivalents of hydrochloric acid together with an amount of H₂- receptor antagonist equivalent to about 25 to about 150, more preferably about 60 to about 80, milligrams of nizatidine. Particularly preferred dosage forms are single or multi-layer tablets or capsules each containing an amount of antacid, preferably magaldrate, sufficient to neutralize 12.5 milliequivalents of hydrochloric acid and 75 milligrams of nizatidine, with the usual dosage consisting of two tablets or capsules administered from about one to about four times a day as needed.

It will be apparent to those skilled in the art that various modifications and variations can be made in the pharmaceutical composition and method of treatment of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims

WHAT IS CLAIMED IS:

1. A storage stable unitary dosage form of a pharmaceutical composition for the treatment of gastrointestinal distress associated with hyperacidity in humans comprising an effective amount of (1) nizatidine and (2) an antacid selected from the group consisting of calcium carbonate or magaldrate.

2. The composition of claim 1 wherein the pharmaceutical composition is a single layered tablet.

3. The composition of claim 2 wherein the effective amount of nizatidine is 625 mg.

4. The composition of claim 2 wherein the effective amount of nizatidine is 225 mg.

5. The composition of claim 2 wherein the effective amount of nizatidine is 75 mg.

6. The composition of claim 2 wherein the effective amount of nizatidine is 25 mg.

7. The composition of claim 1 wherein the pharmaceutical composition is double-layered tablet.

8. The composition of claim 7 wherein the effective amount of nizatidine is 625 mg.

9. The composition of claim 7 wherein the effective amount of nizatidine is 225 mg.

10. The composition of claim 7 wherein the effective amount of nizatidine is 75 mg.

11. The composition of claim 7 wherein the effective amount of nizatidine is 25 mg.

12. The composition of claim 1 wherein the pharmaceutical composition is a capsule.

13. The composition of claim 1 wherein the pharmaceutical composition is a liquid.

14. A method of treating gastrointestinal distress in humans by administering a storage stable unitary dosage form of a pharmaceutical composition comprising (1) nizatidine and (2) an antacid selected from the group consisting of calcium carbonate or magaldrate.