PHARMACEUTICAL COMPOSmON
COMPRISING CALCIUM POLYCARBOPHIL

BACKGROUND OF THE INVENTION 5

1. Field of the Invention

The present invention relates to a pharmaceutical composition comprising calcium polycarbophil which is useful for the treatment of irritable bowel syndrome (IBS) as well as the treatment of constipation and diar- ¹⁰ rhea caused by dysfunction of the lower digestive tract.

More specifically, the present invention relates to a pharmaceutical composition capable of being disintegrated in an acidic environment, comprising the widely used bulk-forming laxative and an antidiarrheic agent ¹⁵ calcium polycarbophil.

2. Description of the Related Art

Calcium polycarbophil is the calcium salt of polyacrylic acid cross-linked with divinyl glycol (Merck Index, 11th edition, No. 1704). The specification of the ²⁰ U.S. Pat. No. 3,297,664 describes the use of calcium polycarbophil for the treatment of constipation and diarrhea. Some physicochemical effects, described below, are considered to participate in the mechanism of action make calcium polycarbophil effective. When 25 calcium polycarbophil is administered orally, carboxyl groups of polyacrylic acid moiety in calcium polycarbophil are converted to free acids, by the release of calcium ions, to form free polycarbophil in the acidic environment of gastric juice. Then, the free carboxyl 30 groups formed are ionized after the free polycarbophil is transferred to the intestines and exposed to neutral or weekly basic enteral environment. As a result, the crosslinking polymer absorbs water to form colloidal bulk. During constipation, the water-containing colloi- 35 dal bulk may ease defecation by softening and bulking the feces. On the other hand, during diarrhea, it brings about an antidiarrheal effect by lowering fluidity of the intestinal water (Pharmacotherapy 2(1), 18-28, 1982). Accordingly, the release of calcium ions from calcium 40 polycarbophil in the stomach as well as the formation of uniform dispersion of the colloidal bulk in a digestive tract play important roles in making calcium polycarbophil effective.

However, free polycarbophil with free carboxyl 45 groups has extremely high adhesive properties, so that free polycarbophil can be used as a mucoadhesive base material for the slow release of drugs (J. Pharm. Sci., 74, 399-405, 1985). Such properties may result in the problem that medicaments containing calcium polycar- 50 bophil cannot easily be disintegrated in an aqueous acidic solution such as, for example, artificial gastric juice (about pH 1.2). More specifically, calcium polycarbophil on the surface of a medicament is converted to polycarbophil by releasing calcium ions after contact 55 is made with an acidic solution, and then a highly adhesive layer comprising free polycarbophil is formed on the surface of the medicament, which will block the penetration of water into the inside part of the medicament and will significantly restrain the medicament 60 from disintegrating. As a result, when a medicament comprising calcium polycarbophil is administered orally, a uniform dispersion of its ingredients cannot be formed in the digestive tract because of the failure of disintegration, which may result in insufficient clinical 65 effect by the medicament.

A chewable tablet (trade name： Mitrolan, A. H. Robins Co., U. S.) is one of commercially available compositions comprising calcium polycarbophil, which has been developed specifically to solve above-mentioned problems. The means adapted by chewable tablet are to prepare a disintegrated composition by mastication of the medicament and then transfer the masticated composition to the stomach so as to avoid an insufficient disintegration of the medicament in the stomach. However, the medicament is hardly be acceptable to patients because of its unpleasant taste during mastication and rough and unpleasant feelings on the palate.

Japanese Patent Unexamined Publication (hereinafter referred to as JP KOKAI) No. 1988 (Sho-63)/253027, assigned to American Cyanamide Company, discloses a pharmaceutical composition in the form of tablet, which comprises calcium polycarbophil together with microcrystaUine cellulose (crystalline cellulose), magnesium stearate, crosslinked polyvinyl pyrrolidone (Crospovidone), polyvinyl pyrrolidone, silica gel (silicic anhydride), and stearic acid. The tablets further comprise caramel powder and are film-coated so that patients can take the tablets easily. An example of such commercially-available such tablets is Fibercon (trade name) from Lederle Laboratory. However, the effectiveness of these tablets is found to be insufficient, since the disintegration time of these tablets is not less than 60 minutes without exception when measured by the disintegration test adopted by the Japanese Pharmacopoeia.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a pharmaceutical composition comprising calcium polycarbophil which can be disintegrated readily in an acidic environment.

Another object of the present invention is to provide a pharmaceutical composition useful as a bulk-forming laxative and an antidiarrheic, which comprises calcium polycarbophil and can be disintegrated readily in the stomach and form a complete dispersion of polycarbophil in the digestive tract. *

A further object of the present invention is to provide a method for treating irritable bowel syndrome, constipation, or diarrhea comprising the step of administering the above pharmaceutical composition to a patient.

The inventors of the present invention have conducted various studies to achieve the foregoing objects and found that the objects can be effectively attained by providing a pharmaceutical composition comprising calcium polycarbophil and a cellulose derivative. The inventors have also found that the above pharmaceutical composition can be disintegrated readily in an acidic environment such as in the stomach when administered orally.

Thus, in accordance with the above objects, the present invention provides a pharmaceutical composition capable of being disintegrated in an acidic environment, which comprises calcium polycarbophil and 1 to 80% by weight of a cellulose derivative based on the calcium polycarbophil.

In accordance with another embodiment of the present invention, there is provided a pharmaceutical composition which is useful as a bulk-forming laxative and an antidiarrheic and is capable of being disintegrated readily in the stomach and forming a complete dispersion of polycarbophil in the digestive tract, which comprises calcium polycarbophil and 1 to 80% by weight of a cellulose derivative based on the calcium polycarbophil.

In accordance with yet another embodiment, the present invention provides a method for treating irritable bowel syndrome, constipation, or diarrhea which comprises the step of administering the above pharmaceutical composition to a patient. 5

Further objects, features and advantages of the present invention will become apparent from the Description of. the Preferred Embodiments which follows, when read in light of the accompanying Examples.