DETAILED DESCRIPTION OF THE ¹⁰ PREFERRED EMBODIMENTS

The calcium polycarbophil used in the present invention may have any degree of polymerization. An example of preferably used calcium polycarbophil is that 15 described on pages from 218 to 219 of the United States Pharmacopoeia XXII.

The cellulose derivative used in the present invention is a macromolecular compound prepared by chemical derivatization of cellulose. Examples of the cellulose 20 derivative include polycarboxymethylethers of cellulose such as, for example, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, and croscannellose sodium; hydroxypropylethers of cellulose such as, for example, hydroxypropylcel- 25 lulose and low substituted hydroxypropylcellulose； methyl and hydroxypropyl mixed ethers such as, for example, hydroxypropylmethylcellulose; and methylethers of cellulose such as, for example, methylcellulose. These cellulose derivatives may be used alone or in 30 combination. These cellulose derivatives are phanna- ceutically acceptable ingredients described in the Japanese Pharmacopoeia or the Japanese Standards of Pharmaceutical Ingredients. The cellulose derivatives standardized by the Japanese Pharmacopoeia or the Japa- 35 nese Standards of Pharmaceutical Ingredients are pre「 erably used in the present invention.

The pharmaceutical composition of the present invention comprises calcium polycarbophil and from 1 to 80% by weight, preferably from 1 to 40% by weight of 40 the cellulose derivative based on the weight of calcium polycarbophil. The pharmaceutical composition of the present invention, which can be prepared by formulating the ingredients in the above-described ratio, is capable of being disintegrated in an aqueous solution in a 45 wide variety of pHs, particularly in an acidic environment such as in an acidic solution.

Where carboxymethylcellulose, low substituted hydroxypropylcellulose, carboxymethylcellulose calcium, or croscannellose sodium are used as the cellulose de- 50 rivative, the ratio of the cellulose derivative to calcium polycarbophil may preferably be from 2 to 40% by weight. Where hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or carboxymethylcellulose sodium are used as the cellulose deriva- 55 tive, the ratio of the cellulose derivative to calcium polycarbophil may preferably be from 1 to 10% by weight.

If the ratio of the cellulose derivative to calcium polycarbophil is lower than 1% by weight, the pharma- 60 ceutical composition will become unstable and the disintegration will be prolonged. If the ratio of the cellulose derivative to calcium polycarobophil is more than 80% by weight, the pharmaceutical composition will become too bulky to be taken easily by a patient. 65

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier or coating other than the ingredients described above. Examples of the pharmaceutically acceptable carrier or coating include, for example, lactose, microcrystalline cellulose, D-mannitol, starch, sucrose, crospovidone, sodium carboxymethylstarch, stearic acid, magnesium stearate, talc, carnauba wax, white beeswax, polyvinylacetal diethylaminoacetate, and polyoxyl 40 stearate, which are useful as a excipient, a binder, a lubricant, and a polishing agent. These carrier or coating may be used in a ratio of not more than 300% by weight based on the calcium polycarbophil.

According to the present invention, there is also provided a method for preparing the phannaceutical composition of the present invention, which comprises the steps of adding the cellulose derivative and a pharmaceutically acceptable optional carrier or coating to a prescribed amount of calcium polycarbophil, mixing the ingredients in a mixer, such as, for example, a twincylinder mixer to obtain a uniform dispersion for the preparation of the pharmaceutical composition of the present invention. The phannaceutical composition of the present invention may be in a form for example, a tablet, a capsule, or granules.

Where two or more different cellulose derivatives are used for the preparation of the dispersion, each cellulose derivative may be independently added to calcium polycarbophil, or alternatively, the cellulose derivatives may be mixed to prepare a mixture of the cellulose derivatives before being added to calcium polycarbophil. The mixing process may generally be carried out at a temperature of not more than 40° C., preferably at room temperature, under a preferable relative humidity of not more than 75%.

The above-described dispersion may optionally be granulated. The granulation may be carried out by shattering, extruding, agitating, and/or tumbing the powdered dispersion obtained in the manner described above, together with a solvent such as, for example, water, ethanol, or isopropanol in a ratio of not more than 100% by weight based on calcium polycarbophil； drying the granules at a temperature of from 40° to 80° C., for 1 to 24 hours； or alternatively, granulating the dispersion and drying the granules in a fluidized bed granulating and drying apparatus at a temperature of from 40° to 80° C. for 15 to 120 minutes; and lastly followed by passing through a screen, if desired. Generally, granules having a particle size of from about 50 to 2,000 呻 are preferable. The granules may further be mixed with the remaining amount of cellulose derivative and other additives which are commonly used as pharmaceutically acceptable carriers or coatings.

The phannaceutical composition of the present invention can be prepared by compressing the powdered dispersion or granules described above by the method well known to a person skilled in the art to obtain a tablet, or alternatively, filling the powdered dispersion or granules in capsules such as, for example, gelatin hard capsules or gelatin soft capsules to obtain a pharmaceutical composition in the form of capsule. These pharmaceutical compositions such as, for example, tablets, capsules, or granules are readily disintegrated in the stomach when administered orally and are useful for the treatment of diseases of digestive tract which include for example, constipation and diarrhea.

The following is a non-limiting preferred example of the method for preparing the pharmaceutical composition of the present invention. Not more than 60% by weight of the cellulose derivative is added to calcium

polycarbophil, and after 2 to 100% by weight of water or ethanol is added the mixture, the resulting mixture is granulated. The granules are dried at from 50° to 60° C., for 5 to 20 hours to obtain granules having a particle size of from 50 to 500 p.m. If necessary, an additional 5 amount of the cellulose derivative is added to the granules and mixed to obtain the composition containing calcium polycarbophil and 1 to 80% by weight of cellulose derivative based on the calcium polycarbophil. After 10 to 50% by weight of microcrystalline cellulose ¹⁰ or lactose, and 0.5 to 5% by weight of magnesium stearate are added to the composition obtained above, the mixture is compressed to obtain tablets or is filled into capsules to obtain the phannaceutical composition in the form of capsule.

Where tablets or granules are prepared according to the above-described method, the phannaceutical composition may be film-coated according to a method well known to a person skilled in the art. Examples of the ₂₀ coating material include, for example, hydroxypropylmethylcellulose, polyethylene glycol 6,000 (macrogol 6,000), and titanium oxide, which may be used in a ratio of not more than 20% by weight of the total weight of the tablet.

The above-described processes fbr preparing the pharmaceutical composition are given by way of illustration only and are not to be construed as limiting. Further, it is to be understood that the processes can be modified by one of ordinary skilled in the art within the 30 scope of the present invention.

The phannaceutical composition of the present invention, prepared according to the methods described above, is capable of being disintegrated in an acidic environment, for example, in an acidic solution having a 35 pH of from 1 to 4. The phannaceutical composition of the present invention can preferably be disintegrated in 60 minutes, preferably in 20 minutes in an artificial gastric juice such as, for example, the first test solution for disintegration described in the 11th edition of the Japa- ⁴⁰ nese Pharmacopoeia. The pharmaceutical composition disintegrated in the stomach can form a uniform dispersion in digestive tract. By virtue of these effects, the present composition can make calcium polycarbophil effective and is quite useful fbr the treatment of irritable ⁴⁵ bowel syndrome as well as the treatment of diseases of digestive tract such as, for example, constipation and diarrhea caused by dysfunction of lower digestive tract. Further, the present composition is useful as a medicament since it does not cause rough and unpleasant sensations on the palate and is sufficiently stable if stored for a long period. The dose of the pharmaceutical composition of the present invention for an adult patient may generally be from about 1 to 8 grams per day, in 1 to 4 ₅₅ oral administrations, which may be increased or decreased depending on the age or condition of the patient to be treated.

The present invention will be further illustrated by the following Examples. The Examples are given by 贝 way of illustration only and are not to be construed as limiting.

Example 1

-continued

Example 1

total 970 mg

A portion of carboxymethylcellulose (about half of the total carboxymethylcellulose) was added to calcium polycarbophil and mixed at room temperature. To the mixture obtained, 7% by weight of water based on calcium polycarbophil was added, and then the mixture was granulated and dried at 50° C. for 10 hours. The granules were passed through a 18 mesh screen and the remaining amount of carboxymethylcellulose and microcrystalline cellulose were added to the granules mixed. After magnesium stearate was added to the granules, the resulting mixture was compressed to obtain tablets containing 625 mg of calcium polycarbophil per tablet.

A portion of carboxymethylcellulose (about half of the total carboxymethylcellulose) was added to calcium polycarbophil and mixed at room temperature. To the mixture obtained, 5% by weight of water based on calcium polycarbophil was added, and then the mixture was granulated and dried at 60° C. for 10 hours. The granules were passed through a 18 mesh screen and the remaining amount of carboxymethylcellulose and microcrystalline cellulose were added to the granules. After magnesium stearate was added to the granules and mixed, the resulting mixture was compressed to obtain tablets containing 625 mg of calcium polycarbophil per tablet, which were film-coated by using hy- droxypropylniethylcellulose, polyethylene glycol 6000, and titanium oxide to afford film-coated tablets.