COMPOSITIONS AND METHODS FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS BACKGROUND OF THE INVENTION Upper abdominal pain and other gastrointestinal disorders are common and chronic problems for a vast number of the population. Of the individuals examined and diagnosed by their physicians, many can be shown to have diseases such as gastritis, esophageal reflux, peptic or other ulcers, or non-ulcer dyspepsia. Other disorders such as heartburn, indigestion, bloating, fullness, and pain and/or nausea associated with such disorders are also common. Factors which can cause and/or exacerbate the many types of gastrointestinal disorders vary widely and include diet, stress, various drug therapies, environmental factors and even microbial agents such as Helicobacterpylori.

Various methods and agents have been used to treat and/or eradicate gastrointestinal disorders. These include special diets, omission of ingestion of certain foods, exercise, meditation, and administration of various pharmaceutical agents such as antacids, H2 antagonists, and antimicrobials. In addition, a new class of pharmaceutical agents, referred to as proton pump inhibitors, has also been developed for treating gastrointestinal disorders. Publications describing proton pump inhibitors include the following: U.S. Patent No. 4,182,766 to Krasso et al., issued January 8, 1980; U.S.

Patent 4,045,563 to Berntsson et al., issued August 30, 1977; and U.S. Patent No.

5,430,042 to Lindberg et al., issued July 4, 1995; all of which are incorporated herein by reference in their entireties. However, given the prevalence and incidence of gastrointestinal disorders, the difficulty in treating many patients suffering from such disorders, and the potential for resistance with antibiotic-containing regimens, a continuing need exists for safe and effective treatments which are convenient, have good patient compliance and which provide individuals relief from their discomfort.

Compositions and methods have been discovered by the present invention for the treatment of one or more gastrointestinal disorders comprising the administration of a proton pump inhibit and an antacid rafting agent. Such compositions and methods are easy to administer and provide a safe and effective therapy for treating and providing relief from various gastrointestinal disorders.

SUMMARY OF THE INVENTION

The present invention relates to a composition for treating one or more gastrointestinal disorders comprising a therapeutically effective amount of a proton pump inhibitor; and a therapeutically effective amount of an antacid rafting agent.

The present invention also relates to a method for treatment of a human or lower animal subject having one or more gastrointestinal disorders comprising administering to the subject a therapeutically effective amount of a proton pump inhibitor; and a therapeutically effective amount of an antacid rafting agent.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods and compositions for treating one or more gastrointestinal disorders comprising a proton pump inhibitor and an antacid rafting agent. The compositions can also comprise pharmaceutically acceptable carriers.

The term "therapeutically effective amount", as used herein, refers to a dosage and duration of administration which is commonly known in the art and recognized and utilized by the medical community. Such an amount will vary depending on the particular agent(s) administered, the size and/or condition of the individual receiving treatment or other medical factors determined by the administering physician.

The present invention and the essential and optional components therein are described fully below.

Proton Pump Inhibitor The present invention comprises a therapeutically effective amount of a proton pump inhibitor. The term "proton pump inhibitor", as used herein refers to any agent within the class of antisecretory compounds which suppress gastric acid secretion by specific competitive or non-competitive inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the parietal cell. Phvsicians' Desk Reference, (1995) Edition 49, p. 547. These agents block the final step of acid production therein inhibiting both basal and stimulated acid secretion irrespective of the stimulus. Id.

Proton pump inhibitors are described in greater detail in Remington: The Science and Practice of Pharmacy Vol. II, Nineteenth Edition, 892-3 (1995), incorporated herein by reference.

Omeprazole is a proton pump inhibitor sold under the tradename Prilosec(gx by Astra/Merck, (Wayne, Pennsylvania) and may be administered in an amount of 20 to about 360 milligrams daily. Omeprazole is described in greater detail in Phvsicians' Desk Reference, Edition 49, 546-549 (1995), which is incorporated herein by reference in its entirety. Other publications which describe proton pump inhibitors in greater detail include: U.S. Patent No. 4,786,505 to Lovgren et al., issued November 22, 1988; U. S. Patent No. 4,255,431 to Junggren et al., issued March 10, 1981; and U.S. Patent

No. 4,853,230 to Lovgren et al., issued August 1, 1989; all of which are incorporated by reference herein in their entireties.

Omeprazole; lansoprazole by Lederle, licensed from Takeda; pantoprazole by Knoll, licensed from Byk Gulden; pariprazole by Eisai; and mixtures thereof, are proton pump inhibitors which are preferred for use in the present invention. Omeprazole is most preferred. While proton pump inhibitors may be administered long-term for up to about 5 years, typically the duration of administration for proton pump inhibitors in the present invention is for up to about 56 days, and preferably for up to about 28 days.

Antacid Ratting Agent The term "antacid rafting agent", as used herein, refers to the combination of one or more antacid agents and at least one alginate compound wherein, after ingested, the antacid floats on the stomach contents. Any alginate compound can be utilized herein and includes, but is not limited to: alginic acid, sodium, calcium, and potassium alginate, and propylene glycol alginate.

Antacid agents are compounds which react with hydrochloric acid to form salt and water. Antacid agents are fully described in the following publications which are incorporated herein by reference in their entireties: G.B. 925,001, to Fielding et al., published May 1, 1963; and Remington: The Science and Practice of Pharmacv, Vol.

II, Nineteenth Edition, 886-890 (1995).

Antacid agents useful herein include but are not limited to: aluminum carbonate, aluminum hydroxide, aluminum phosphate, aluminum hydroxy-carbonate, dihydroxy aluminum sodium carbonate, aluminum magnesium glycinate, dihydroxy aluminum amino acetate, dihydroxy aluminum aminoacetic acid, calcium carbonate, calcium phosphate, aluminum magnesium hydrated sulfates, magnesium aluminate, magnesium alumino silicates, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, sucralfate, sodium bicarbonate, and mixtures thereof.

A commercially available antacid rafting agent useful herein is GavisconX, available over-the-counter in liquid and tablet form, and manufactured by SmithKline Beecham, (Pittsburgh, Pennsylvania). GavisconX tablets, in regular or extra strength formulations, contain the active ingredients aluminum hydroxide and magnesium carbonate or magnesium trisilicate. Gaviscon(g) liquid, also in regular or extra strength formulations, contains the active ingredients aluminum hydroxide and magnesium carbonate. These formulations and directions for use are described in greater detail in PDR For Non-Prescription Drugs, Sixteen Edition, 819-820 (1995), incorporated herein by reference.

While the duration of administration may be determined by the physician prescribing treatment, in general the duration of administration for the antacid rafting agent according to the present invention is the same as that for the proton pump inhibitor utilized herein.

Gastrointestinal Disorders The term "gastrointestinal disorder", as used herein, encompasses any infection, disease or other disorder(s) of the upper gastrointestinal tract. Such disorders include, for example, heartburn; sour stomach; acid ingestion; upset stomach and/or pain associated with heartburn, sour stomach and acid ingestion; bloating; fullness; dyspepsia; hiatal hernia; esophagitis; nocturnal heartburn; erosive esophagitis; disorders not manifested by the presence of ulcerations in the gastric mucosa, including chronic active or atrophic gastritis, Zollinger-Ellison syndrome; non-ulcer dyspepsia, esophageal reflux disease and gastric motility disorders; peptic ulcer disease, i.e., pre- pyloric, marginal, and/or gastric, duodenal ulcers; and combinations thereof. Preferred for treatment by the present invention include heartburn with and without stomach upset and/or pain, dyspepsia, esophagitis. erosive esophagitis, nocturnal heartburn; chronic active or atrophic gastritis, esophageal reflux disease, and mixtures thereof.

Pharmaceuticallv Acceptable Carriers The compositions of the present invention may contain optional components which affect the physical and therapeutic characteristics of the present compositions. In particular, a variety of pharmaceutically-acceptable carriers and excipients may be included, depending upon the particular dosage form to be used. Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions, and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring, and flavoring agents.

Specific examples of pharmaceutically-acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U.

S. Patent 3,903,297, Robert, issued September 2, 1975, incorporated by reference herein. Techniques and compositions for making dosage forms useful herein are described in the following references, all incorporated by reference herein: 7 Modern

Pharmaceutics, Chapters 9 and 10 (Banker and Rhodes, editors, 1979); an Lieberman, et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms (2d edition, 1976).

The compositions of this invention may be used according to the methods of this invention by administering the composition from 1 to 4 times per day, and preferably from 1 to 2 times per day; for up to about 56 days, and preferably for up to about 28 days. The specific frequency of administration will depend upon such factors as the specific proton pump inhibitor and antacid rafting agent compounds or compositions used, the levels at which the components are incorporated in the composition, the nature and severity of the condition to be treated, and the nature of any concurrent therapy, if any.

Method of Use The methods of the present invention comprise the treatment of a human or lower animal subject having one or more gastrointestinal disorders comprising administering to the subject a therapeutically effective amount of a proton pump inhibitor and a therapeutically effective amount of an antacid rafting agent.

As used herein, the term "administering" refers to any method which, in sound medical practice delivers the compounds or compositions used in this invention to the subject to be treated in such a manner so as to be effective in the treatment of the gastrointestinal disorder. Preferably, the proton pump inhibitor and antacid rafting agent are administered orally.

The present invention encompasses methods wherein the administering of the proton pump inhibitor and antacid rafting agent are performed simultaneously (beginning and ending on the same day), concurrently (overlapping but not of the same duration of administration), or consecutively (sequential, but where the course of treatment is substantially continuous). Preferably, the proton pump inhibitor and antacid rafting agent are administered concurrently and administration for both the proton pump inhibitor and antacid rafting agent is commenced on the same day.

The following non-limiting examples illustrate the composition and methods of use of the present invention. The examples are for the purpose of illustration and intended to limit the scope and/or embodiments of the present invention.

EXAMPLE I A middle-aged woman visits her physician complaining of heartburn, bloating and fullness. Her physician determines that she also has esophageal reflux disease. The physician treats the woman by orally administering approximately 40 milligrams of omeprazole daily, for about 28 days; and approximately 4 tablets of regular strength

Gaviscon, administered four times a day, for about days, which delivers a total of about 1280 milligrams of aluminum hydroxide and 320 milligrams of magnesium silicate per day. The woman is re-examined one month later and shows no evidence of gastrointestinal disorders.

EXAMPLE II A 50 year old man experiences pain and nausea with heartburn and acid indigestion. After being examined, his physician diagnoses him with chronic active gastritis and peptic ulcer disease. The physician treats the man by orally administering approximately 80 milligrams of lansoprazole daily, for about 56 days; and orally administering 2 teaspoonfuls (about 10 milliliters) of Gaviscon) extra strength liquid, in four equal daily doses, for 56 days, which delivers about 1016 milligrams of aluminum hydroxide and 950 milligrams of magnesium carbonate per day. The man is examined after two months. He is symptom free and shows no evidence of gastrointestinal disease.