United States Patent:  6,030,641

Assignee:  Uni Colloid Kabushiki Kaisha (Kanagawa-ken, JP)

Filed:  May 12, 1998

A sustained release capsule in which an outer surface of a hard capsule mainly composed of gelatin and containing a physiologically active substance is uniformly covered with a film material comprising a natural polysaccharide/polyhydric alcohol composition which is prepared by uniformly kneading at least one natural polysaccharide selected from the group consisting of carrageenan, alginic acid, salts of alginic acid, derivatives of alginic acid, agar, locust bean gum, guar gum, pectin, amylopectin, xanthane gum, glucomannan, chitin and pullulan in at least one system selected from the group consisting of polyhydric alcohols, sugar alcohols, monosaccharides, disaccharides, trisaccharides and oligosaccharides. A capsule formed merely of the natural polysaccharide/polyhydric alcohol composition swells and is permeated by water. It is poor in shape-retaining properties, failing to retain its shape in the stomach, although it is nondigestive. However, the gelatin capsule covered with this composition prevents digestion of gelatin, can be conveyed to the small intestine without deactivation of the physiologically active substance contained therein, and can gradually release the contents in the intestine at a speed according to its purpose, so that it is useful for the effective utilization of the physiologically active substance.

DETAILED DESCRIPTION OF THE INVENTION

The physiologically active substances used in the present invention mean substances exhibiting physiological activity in a broad sense, including food and medicines acting usefully on organisms.

The medicines as used herein include drugs efficacious against various kinds of diseases such as circulatory diseases, for example, cardiovascular diseases and diseases involving high blood pressure, respiratory diseases, gastrointestinal diseases, malignant tumors such as cancer, and diseases caused by endocrine metabolic errors such as diabetes.

Additionally, examples of the physiological active substances in a broad sense include various hormones such as pituitary hormone, insulin, glucagon, melatonin, and cytokinin, hormone-like substances; such as prostaglandin, caropeptide and kinin, and neurotransmitters, such as catecholamine, indoleamine and acetylcholine and substances derived from marine organisms occurring in nature. Further, examples thereof also include useful intestinal bacteria such as Bifidobacterium and Lactobacillus, and nutrient auxiliary food such as royal jelly, ginseng, chitosan, nanpao, taurine, lecithin, flavonoids, chlorella, fermented soybean kinase and chondroitin, as well as various vitamins and minerals.

The natural polysaccharide/polyhydric alcohol composition is obtained by uniformly kneading at least one natural polysaccharide selected from the group consisting of carrageenan, alginic acid, salts of alginic acid, derivatives of alginic acid, agar, locust bean gum, guar gum, pectin, amylopectin, xanthane gum, glucomannan, chitin, and pullulan in at least one system selected from the group consisting of polyhydric alcohols in a narrow sense, such as glycerin, ethylene glycol, propylene glycol and diglycerin, sugar alcohols, monosaccharides, disaccharides, trisaccharides and oligosaccharides. In the polyhydric alcohol system, the composition can be used as such or as a concentrated solution of 70% or more when it is liquid, and as an aqueous solution of 65% to 95%, preferably 70% to 90% when it is solid.

A viscous aqueous solution can be obtained by adjusting the concentration of an aqueous solution of the above-mentioned natural polysaccharide/polyhydric alcohol composition to a specified concentration and heating the resulting solution. The coating film strength can be increased by adding an alkali.

Commercially available shape-retaining capsules made of gelatin or mainly composed of gelatin can be used as the hard capsules.

The sustained release capsule of the present invention is obtained by enclosing a specified amount of the physiologically active substance in the hard capsule, allowing the viscous solution of the natural polysaccharide/polyhydric alcohol composition described above to adhere to the hard capsule, and then drying it. When the viscous solution of the composition is allowed to adhere to the hard capsule, dipping, coating or other means can be used.

The amount of the natural polysaccharide/polyhydric alcohol composition applied to the outer surface of the hard capsule varies depending on the kind of capsule and physiologically active substance contained therein. However, the amount of the composition is generally from 50 parts to 1000 parts by weight, and preferably from 100 parts to 500 parts by weight per 100 parts by weight of gelatin.

When a thin film of a fat having a melting point of 40^oC. or above, such as hardened oil, is formed on the outer surface of the gelatin capsule prior to coating thereof with the natural polysaccharide/polyhydric alcohol composition, the release or deactivation of the contents of the capsule in the stomach can be more inhibited. In order to form the thin film of hardened oil, an emulsifying agent such as lecithin and water or a lower alcohol are added to the fat, followed by emulsification. Then, the hard capsule is covered with the resulting emulsion by coating or spraying, and thereafter the solvent is removed by drying, or the hard capsule can also be directly immersed in the fat.

It is also effective to provide the fat layer on an outer surface of the natural polysaccharide/polyhydric alcohol composition layer.

In some cases, it is also possible to further provide a particular protein film on the outer surface of the capsule having the natural polysaccharide/polyhydric alcohol composition film to protect the capsule. The types of particular protein include corn protein and wheat protein containing a large amount of gluten. The formation of the protein film not only permits an improvement in digestive resistance of the capsule in the stomach, but also heightens the commercial value due to the surface treatment.

The term "being uniformly covered" as used herein means that there is no perforation or crack on the surface of the capsule, although some unevenness may be allowed to exist thereon. The film of the natural polysaccharide/polyhydric alcohol composition utilizes the permeability of the material for the purpose of gradually digesting the internal gelatin by the digestive juice such as the gastric juice and the pancreatic juice. Accordingly, the presence of the perforation or crack is unfavorable because it causes prompt elution of the contents.

The natural polysaccharide/polyhydric alcohol composition of the present invention is not digested, but has semipermeability. The natural polysaccharide/polyhydric alcohol composition swells in the presence of sufficient water in the stomach, and allows the gastric juice to pass therethrough in cooperation with the semipermeability, which brings the juice into contact with the gelatin of the capsule. Consequently, when the composition layer is thin or not sufficiently dense, the gelatin may be digested in the stomach to release the contents. The hard capsule made of gelatin is merely a support for the natural polysaccharide/polyhydric alcohol composition, and the physiologically active substance is released through the composition layer as the capsule passes through the stomach and intestines. The capsule material is ultimately crushed to a thin film piece.

Claim 1 of 14 Claims

1. A sustained release capsule, comprising:

an encapsulating structure which is shape-retaining and which is comprised of, gelatin the encapsulating structure being of sufficient hardness to resist physical degradation due to stomach peristalsis, the encapsulating structure presenting an outer surface; and

a coating of a film material uniformly covering the outer surface of the encapsulating structure, the film material being a polysaccharide/polyhydric alcohol composition which is prepared by uniformly kneading at least one polysaccharide selected from the group consisting of carrageenan, alginic acid, salts of alginic acid, derivatives of alginic acid, agar, locust bean gum, guar gum, pectin, amylopectin, xanthane gum, glucomannan, chitin and pullulan in at least one system selected from the group consisting of polyhydric alcohols, sugar alcohols, monosaccharides, disaccharides, trisaccharides and oligosaccharides.

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