Title:  Colon-specific drug release system

United States Patent:  6,368,629

Assignee:  Yamanouchi Pharmaceutical Company Ltd. (Tokyo, JP)

Filed:  October 30, 1998

Foreign Application Priority Data: Apr 22, 1994[JP] (6-85114)

A system for releasing a drug specifically in the colon of the gastrointestinal tract, which comprises a drug (b) coated with an organic acid-soluble polymer material (a), and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract; a colon-specific drug release oral preparation, which comprises a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, said composition being coated with an enteric coating polymer material (d). The invention provides a drug release system and a preparation which utilize enterobacteria, which do not form harmful substances due to the release-starting mechanism, show rapid degradation, and have higher colon specificity.

DISCLOSURE OF THE INVENTION

In their study on colon-specific drug release systems, the inventors of the present invention have considered that generation of an organic acid by taking advantage of enterobacteria, if possible, would make it possible to release a drug protected by a coat that is dissolved by an organic acid, thereby providing a colon-specific drug release system which is unaffected by the pH in the vicinity of the cecum and does not rely on time control. Carbohydrates, particularly saccharides, are first to be considered as a material degradable by enterobacteria to generate an organic acid. Saccharides that have conventionally been used as components of preparations are degraded by the digestive enzymes in the gastrointestinal tract or directly absorbed from the gastrointestinal tract. Hence, the inventors paid their notice to the fact that, among the saccharides which have scarcely been used as a component of pharmaceutical preparations, there are saccharides neither digested by digestive enzymes nor absorbed from the gastrointestinal tract. Such saccharides include lactulose, raffinose, cellobiose, stachyose, and fructooligosaccharides.

The inventors have first examined whether lactulose is degraded or not by enterobacteria present in the lower part of the gastrointestinal tract. As a result, it was found unexpectedly that lactulose is degraded rapidly to generate an organic acid. The inventors have then found that, when a drug (b) coated with an organic acid-soluble polymer material (a) is delivered to the lower part of the gastrointestinal tract together with lactulose, lactulose is degraded by enterobacteria to rapidly generate an organic acid, whereupon the polymer material (a) is dissolved to release the drug (b) specifically in the colon. The present invention has been completed based on this finding.

As a result of further investigation, the inventors have found that even a material that is degraded by digestive enzymes or absorbed directly through the gastrointestinal tract can also be used similarly to lactulose as far as it is degradable by enterobacteria to easily generate an organic acid, since it is possible to coat such a material with an enteric coating polymer material (d) (i.e., a polymer material which is not dissolved in the stomach but in the small intestine) so that the material can easily be delivered to the lower part of the gastrointestinal tract. In this case, in order to deliver the material to the lower part of the gastrointestinal tract more efficiently, it is preferable that the material be coated first with the organic acid-soluble polymer material (a) and then with the enteric coating polymer material (d).

From the structural viewpoint, the material which generates an organic acid by the action of enterobacteria is considered to include carbohydrates particularly saccharides and derivatives thereof such as sugar alcohols. Taking into account the conditions of the lower gastrointestinal tract where enterobacteria live, water solubility would be of importance for the material to generate an organic acid rapidly. As a result of various studies, it was found that lactose having medium water solubility and ribose having low water solubility hardly dissolve with such a small amount of water that has passed through the coating layer of the organic acid-soluble polymer material (a) and therefore show no rapid generation of an organic acid. On the other hand, sucrose, glucose, xylose, fructose, maltose, and galactose having high water solubility were proved to generate an organic acid rapidly, which is similar to lactulose. With reference to sugar alcohols, on the other hand, rapid generation of an organic acid was not observed even with sorbitol and xylitol having high solubility as well as mannitol having medium water solubility and maltol having low solubility. Accordingly, it has now ascertained that saccharides having high water solubility are especially suitable as a material for rapidly generating an organic acid.

That is, the present invention relates to a system for releasing a drug specifically in the colon of the gastrointestinal tract. More particularly, it relates to a colon-specific drug release system, which comprises a drug (b).coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract.

The system of the present invention is preferably embodied by coating the polymer material (a)-coated drug (b) and the organic acid-generating saccharide (c) with an enteric coating polymer material (d) in order to deliver them to the lower gastrointestinal tract. More specifically, there are two embodiments that the drug (b) and the saccharide (c) can be formulated separately or in the same composition as follows.

1) Formulation in separate compositions:

A system for releasing a drug specifically in the colon of the gastrointestinal tract, which comprises a composition (1) in which an organic acid-soluble polymer material (a)-coated drug (b) is further coated with an enteric coating polymer material (d), and a composition (2) comprising a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, which saccharide may optionally be coated with an enteric coating polymer material (d). The compositions (1) and (2) can be administered as a single preparation or separately prepared preparations.

2) Formulation in one composition:

A system for releasing a drug specifically in the colon of the gastrointestinal tract, which comprises a composition containing an organic acid-soluble polymer material (a)-coated drug (b) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, the composition being coated with an enteric coating polymer material (d).

In this composition, the saccharide (c) can be used either as a mixture with the drug (b) or as a coating layer on the drug (b). The latter system includes an embodiment in which the polymer material (a)-coated drug (b) is coated with the saccharide (c), an embodiment in which the saccharide (c)-coated drug (b) is coated with the polymer material (a), and an embodiment in which the drug (b) is coated with the saccharide (c) and the polymer material (a).

The present invention also relates to a colon-specific drug release oral composition, more particularly to a colon-specific drug release oral composition, which comprises a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a), and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, the composition being coated with an enteric coating polymer material (d). In the composition, the saccharide (c) can be used either as a mixture with the drug (b) or as a coating layer on the drug (b). The latter composition includes an embodiment in which the polymer material (a)-coated drug (b) is coated with the saccharide (c), an embodiment in which the saccharide (c)-coated drug (b) is coated with the polymer material (a), and an embodiment in which the drug (b) is coated with the saccharide (c) and the polymer material (a).

More specifically, the present invention relates to the following compositions.

1) A colon-specific drug release oral composition in which a drug (b) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract are coated with an organic acid-soluble polymer material (a), and the coating polymer material (a) is further coated with an enteric coating polymer material (d).

2) A colon-specific drug release oral composition in which a drug (b) is coated with an organic acid-soluble polymer material (a), the coated drug (b) is further coated with a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, and the coating saccharide (c) is further coated with an enteric coating polymer material (d).

3) A colon-specific drug release oral composition in which a drug (b) is coated with a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, the coated drug (b) is further coated with an organic acid-soluble polymer material (a), the coating polymer material (a) is further coated with an enteric coating polymer material (d).

4) A colon-specific drug release oral- composition in which a drug (b) is coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract, and the coated drug (b) is further coated with an enteric coating polymer material (d).

The present invention also relates to a composition according to an embodiment in which separate compositions according to the above-described system are administered as a single preparation, and more particularly to a colon-specific drug release oral composition, which comprises a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract and which may optionally be coated with an organic acid-soluble polymer material (a), the composition being further coated with an enteric coating polymer material (d).

The invention further relates to a colon-specific drug release oral composition, which comprises a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria and which may optionally be coated with a water-insoluble release-controlling material (e), the composition being coated with a water-insoluble release-controlling material (e) and optionally with a hole-making material (f) and further coated with an enteric coating polymer material (d). In this composition, a coating layer comprising a water-permeable release-controlling material (e) (optionally with coexistence with a hole-making material (f)) is optionally provided on the inner side of the coating layer comprising an enteric coating polymer material (d) so as to increase the efficiency of organic acid generation by the action of enterobacteria, dissolution of the polymer material (a), and release of the drug (b). Provision of the coating layer (e) on the inside of the coating layer (d) is applicable to any composition of the present invention.

The present invention furthermore relates to a method for releasing a drug specifically in the colon of the gastrointestinal tract, more particularly to a method for releasing a drug specifically in the colon of the gastrointestinal tract, which comprises coating a composition comprising a drug (b) coated with an organic acid-soluble polymer material (a) and a saccharide (c) which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract with an enteric coating polymer material (d).

Claim 1 of 16 Claims

What is claimed is:

1. An oral drug delivery system for releasing a drug specifically in the colon of the gastrointestinal tract, wherein said system comprises a drug (b) coated with a pharmaceutically acceptable acrylic or cellulosic organic acid-soluble polymer material which dissolves at a pH lower than 6 (a), in an amount of from 2.5% to 40% and a saccharide (c) comprising lactulose which rapidly generates an organic acid by the action of enterobacteria in the lower part of the gastrointestinal tract in an amount of from 10% to 99.9%, wherein said composition comprising the drug (b) coated with the organic acid-soluble polymer material (a) and saccharide (c) is further coated with a pharmaceutically acceptable enteric coating polymer material which dissolves at a pH not lower than 6 (d) and wherein said composition when orally administered, is delivered to the lower part of the gastrointestinal tract without releasing the drug (b) at the upper part of the gastrointestinal tract and, at the lower part of the gastrointestinal tract, the polymer (a) coating the drug (b) is dissolved by organic acids generated by degradation of the saccharide (c) by the enterobacteria, and wherein the system is in the form of a tablet or granule.

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