Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-09-14
2003-01-14
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S464000, C424S465000, C424S474000, C424S480000, C424S482000, C424S489000, C424S490000, C424S499000, C424S502000
Reexamination Certificate
active
06506407
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a drug release system and particularly a system for releasing a drug specifically in the colon of the gastrointestinal tract. More particularly, the present invention relates to 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; and 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).
BACKGROUND OF THE INVENTION
In recent ten years, rapid development occurred in the field of drug delivery or release. In particular, a number of drug delivery or release systems have been developed, giving influences on drug release control.
In the topical treatment of ulcerative colitis, etc., drug release in the colon of the gastrointestinal tract topically accumulates the drug in a high concentration without involving absorption in the small intestine, which leads to reduction of systemic side effects and is obviously favorable for improvement of therapeutic effect. Considering a systemic drug, on the other hand, release in the colon is disadvantageous in that the colon is shorter and poorer in development of microvilli than the small intestine and therefore has a smaller surface area available for absorption and is less permeable to a polar compound. However, the average retention time in the ascending colon is about 3 hours in younger people and about 10 hours in older people (see Hongo, et al.,
NICHIHEIKATSUKINSHI,
24, 55-60, 1988), which is equal to or even longer than that in the small intestine (about 3 to 4 hours), and it means long effective absorption time. Considering the aspect of the colon as a site of administration of peptide or protein-based drugs, the colon is advantageous in that no digestive enzymes is secreted and that the peptidase activity of the membrane of the large intestine is lower than that of the small intestine (Kopecek, et al.,
Proc. Int. Symp. Control. Rel. Bioact. Mat.,
17, 130-131 (1990)). Therefore, a drug release in the colon is expected to give improved systemic bioavailability.
A large number of preparations targeting the lower part of gastrointestinal tract, especially the colon, have been reported. These systems are roughly divided into four types: the first is a delayed release system designed to release a drug in agreement with change in pH, the second is a timed-release system designed to release a drug after a predetermined time, the third is a microflora enzyme system making use of the abundant enterobacteria in the lower part of the gastrointestinal tract, and the fourth is a system making use of a lectin-like substance specific to the large intestine.
The first delayed release system is a system that uses an acrylic or cellulosic enteric coating material and dissolves on pH change. Because of ease of preparation, many reports on this system have been made. Taking the system using an acrylic enteric coating material, Eudragit S as an example, many reports can be found, such as those by Behringer, Manchester University, Saale Co., and the like. However, the group of Manchester University made a report at AAPS in 1993 on their single unit preparations using an enteric coating material, revealing that the timing of drug release is decided by the transit of the preparation in the gastrointestinal tract rather than pH change and, therefore, the specificity to the colon is low. It is very likely that the other similar delayed release systems are also unsuccessful in colon-specific drug release.
The second timed release system is represented by Time Erosion System (TES) by Fujisawa Pharmaceutical Co., Ltd. and Pulsincap by R. P. Scherer. According to these systems, the site of drug release is decided by the time of transit of a preparation in the gastrointestinal tract, which makes it difficult to release a drug certainly in the targeted lower part of the gastrointestinal tract. Since the transit of a preparation in the gastrointestinal tract is largely influenced by the gastric emptying time, some preparations are made enteric. Nevertheless, it is difficult to release a drug specifically in the colon, considering that the transit time of a preparation in the small intestine has the intra- and inter-variation and also largely varies according to the disease as reported.
The third system making use of the enterobacteria has recently increased in number. The system is classified into those utilizing degradation of azoaromatic polymers by an azo reductase produced from enterobacteria as reported by the group of Ohio University (M. Saffran et al.,
Science
, Vol. 233: 1081 (1986)) and the group of Utah University (J. Kopecek et al.,
Pharmaceutical Research,
9(12), 1540-1545 (1992)); and those utilizing degradation of polysaccharides by &bgr;-galactosidase of enterobacteria as reported by the group of Hebrew University (unexamined published Japanese patent application No. 5-50863 based on a PCT application) and the group of Freiberg University (K. H. Bauer et al.,
Pharmaceutical Research,
10(10), S218 (1993)). In addition, the system using chitosan degradable by chitosanase by Teikoku Seiyaku K. K. (unexamined published Japanese patent application No. 4-217924 and unexamined published Japanese patent application No. 4-225922) is also included. Of these systems, degradation of an azoaromatic polymer by enterobacteria is slow (J. Kopecek et al.,
Pharmaceutical Research,
9(12), 1540-1545 (1992)) and has a fear of producing a harmful substance originated in an azo linkage so that the system may be unsuitable for long-term use. An insulin-containing preparation according to this system was actually administered to beagle dogs only to manifest low effects (M. Saffran et al.,
Biochemical Society Transactions,
18(5), 752-754 (1990)). The system using a polysaccharide is considered to cause no safety problem because a material that has been taken as dietary fiber is used. However, according to the report of the group of Nottingham University, pectin is slowly degraded by enterobacteria, and a drug is released earlier in an artificial intestinal juice (W. G. Cook et al.,
Pharmaceutical Research,
10(10), S223 (1993)). Therefore, this system cannot be regarded to be a colon-specific drug release system. Similarly, the drug release in an artificial intestinal juice is uncontrollable in the report by Hebrew University.
The fourth system utilizing a lectin-like substance present in the large intestine has been reported by Kopecek et al. of Utah University (J. Kopecek et al.,
Proc. Int. Symp. Control. Rel. Bioact. Mat.,
17, 130-131 (1990)). This technique relates to a polymer preparation prepared by binding fucose and a drug to a polymer via an azo bond, which is to utilize a lectine-like substance present in the guinea pig's large intestine, recognizing fucose and to control transit of the preparation in the colon so as to let the preparation release the drug by the action of an azo reductase. However, the fucose-recognizing lectin is specific to guinea pigs, not found in rats. Therefore, the technique cannot be applied directly to humans.
As described above, any of the various systems heretofore proposed for drug release in the colon is unsatisfactory.
The inventors of the present invention made studies with paying their attention to the third system using enterobacteria.
Bacteria which live within the body are abundant in the oral cavity, rare in the stomach due to the acidicity, and also scarce in the upper part of the small intestine. The enterobacteria increases drastically in the order of the ileum, the cecum, and the colon. It
Fukui Muneo
Katsuma Masataka
Kawai Hitoshi
Watanabe Shunsuke
Oh Simon J.
Page Thurman K.
Townsend and Towsend and Crew LLP
Yamanouchi Pharmaceutical Co. Ltd.
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