Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
1999-05-25
2002-07-02
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C127S029000, C424S451000, C424S463000, C424S464000, C424S474000, C424S479000, C424S488000, C424S493000, C424S499000, C514S054000, C514S777000, C514S960000, C514S962000, C536S001110, C536S002000, C536S123100, C536S124000
Reexamination Certificate
active
06413494
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a composition and oral pharmaceutical dosage form for selective delivery of drugs to the colon. More particularly, the invention relates to compositions and oral pharmaceutical dosage forms for release of biologically active ingredients in the colon while avoiding or minimizing release into the upper gastrointestinal tract, such the stomach and small intestine.
BACKGROUND OF THE INVENTION
Numerous drug entities based on oral delivery have been successfully commercialized, but many others are not readily available by oral administration, which are incompatible with the physical and/or chemical environments of the upper GI tract and/or demonstrate poor uptake in the upper GI tract. Due to the lack of digestive enzymes, colon is considered a suitable site for the absorption of various drugs. However, colon drug delivery is hardly achieved in that the oral dosage form should pass through the stomach and small intestine, where many drugs are deactivated by their digestive materials. Ideally, a colon specific drug delivery system is designed such that it remains intact in stomach and small intestine but releases encapsulated drugs only in colon. CSDS system is useful in administering a drug that is an irritant to the upper GI tract, such as non-steroidal anti-inflammatory agents, or drugs that are degraded by gastric juice or an enzyme present in the upper GI tract, such as peptide or protein. Further, the colonic drug delivery system allows local, direct treatment of colonic disease, e.g., ulcerative colitis, Crohn's disease, or colon cancer, thus reducing the dosage of the drugs and minimizing undesirable or harmful side effects. Similarly, colonic drug delivery is useful for administering drugs, e.g. non-steroidal anti-inflammatory drugs (NSAIDS), which are irritants to the mucosa of the upper gastrointestinal tract such as the stomach or small intestine. Recently, it is believed that colonic drug delivery systems maintain the efficacy of drugs for a longer time and increase the bioavailability of the drugs as compared to other oral routes of administration. As the colon has a longer retention time, drug absorption is prolonged, and total bioavailability is increased. A. Sintov et al., 143 Int. J. Pharma. 101-106 (1996).
Although colon is attracting interest as a site for delivering several drugs such as unstable drugs in upper GI tract or poorly-absorbed drugs, it is very difficult to diver the drug into colon effectively. In order to deliver a drug to the colon selectively, a composition generally should meet the following requirements: (1) the composition is not degraded or disintegrated in the upper GI tract; (2) the composition does not release the loaded drug in the upper GI tract; (3) the composition releases the drug effectively at the target site, the colon, more particularly the ascending colon; and (4) the composition is easy to formulate in a form suitable for loading the drug. Further, the composition preferably can be easily processed for manufacture.
Several approaches have been used in developing colon-specific drug delivery systems. One is based on the different pH of each compartment of the gastrointestinal tract, with the pH of the proximal GI tract being lower than that of the distal GI tract. Thus, polymers that are insoluble at low pH and soluble at higher pH have been used to deliver drugs to the distal GI tract
Another approach is based on the fact that transit time through the stomach is approximately 2 hours, whereas transit time through the small intestine is approximately 4-6 hours. Thus, in this approach, the delivery system is designed to withhold the release of the drugs for about 6-8 hours from the time of administration.
Moreover, it is well known that enzymes capable of reducing azo bonds or hydrolyzing glycosidic bonds, which are not degraded in the stomach and small intestine, are present in the colon. Thus, many approaches to colonic drug delivery use azo bond-containing polymers (azo polymers) or glycosidic bond-containing materials. The glycosidic bond-containing polymers include disaccharides, oligosaccharides, and polysaccharides.
For example, U.S. Pat. No. 5,482,718; U.S. Pat. No. 4,627,851; U.S. Pat. No. 4,693,895; U.S. Pat. No. 4,705,515; U.S. Pat. No. 4,904,474; EP 621 032 A1; JP 34929/1991A; U.S. Pat. No. 5,536,507; EP 453 001 A1; U.S. Pat. No. 5,171,580; and EP 572 942 A2 disclose time dependent drug delivery system. They are designed to prevent drug release for a period of time expected to be sufficient for the composition to pass through the upper gastrointestinal tract. Further, U.S. Pat. No. 5,401,512; U.S. Pat. No. 5,541,170;and WO 95/11024 describe drug compositions for selectively releasing the drug in the colon by way of exploiting the difference in pH between the colon and other parts of the GI tract.
The above-mentioned compositions, however, are not effective in delivering the drug to the colon. The pH in the terminal ileum and colon is higher than other region of the GI tract and thus composition which disintegrate at high pH level have the potential for site specific delivery into this region. However, because the pH is higher in the terminal ileum region than in the colon, and the dosage forms are often delayed at the ileo-cecal junction, the dosage forms based on pH dependent system are often disintegrate in the terminal ileum instead of disintegrate in colon. Further, the colon specific delivery based on GI transit time-dependent system is hardly to be achieved. The transit time in the upper gastrointestinal tract tends to be highly variable among individuals.
Many approaches to colonic drug delivery use azo bond or glycosidic bond-containing drugs, i.e. prodrug and have been successfully come into the market. The prodrug that is activated only in the colon requires covalent bonding between the drug molecule and carrier molecules such that the covalent bonds are broken only by enzymes produced by colonic bacteria. WO 84/04041, WO 93/22334; A. D. McLeod et al., 83 J. Pharm. Sci. 1284-1288(1994); D. R. Friend et al., 27 J. Med. Chem. 261-266 (1984); B. Haeberlin et al., 10 Pharm. Res. 1553-1562 (1993); D. R Friend et al. 28 J. Med. Chem. 51-57 (1985); DR Friend, 5 S.T.P. Pharma Sci. 70-76 (1995); J. P. Brown et al., 26 J. Med. Chem. 1300-1307(1983).
It is well known that enzymes capable of breaking an azo, disulphide bonds and glycosidic bond are present in the colon, but not in the upper GI tract. WO 91/16057 and EP 398 472 A2 disclose compositions containing an azo polymer having azo bonds as a colonic drug delivery system. Although the composition is relatively stable in the upper gastrointestinal tract, the dosage form coated by azo polymer does not showed colon specificity effectively. Azo reductase produced by colonic microflora cannot easily reach the azo bond of azo-polymers due to the hydrophobic nature of the azo-polymer, thus resulting in slow degradation in the colon of the composition containing the azo polymer. P. Y. Yeh et al., 196 Macromol. Chem. Phys. 2183-2202 (1995).
A number of delivery systems based on polysaccharides which are selectively degraded by colonic enzyme have been reported, since polysaccharides are natural polymers with proven final toxicity
U.S. Pat. No. 5,505,966 discloses a pharmaceutical composition containing calcium pectinate as a major component and a filler such as pectin, dextran, avicel, or mixture thereof. U.S. Pat. No. 5,525,634 discloses a pharmaceutical composition containing a synthetic or natural polymer that is degradable by a colonic enzyme, herein calcium pectinate is disclosed as an example of a natural polymer.
In U.S. Pat. No. 5,505,966, the calcium pectinate composition is used in the form of a coacervate pellet. It is believed that calcium pectinate, which is insoluble in water, is converted to a water-soluble matrix by sodium ions or potassium ions present in the digestion solution of upper GI. Therefore, the system mainly depends on transit time of upper GI, thus the pellets often disintegrate and release t
Lee Seung Seo
Lee Sujung
Lim Chang Baeg
Pai Chaul Min
Park Heenam
Choi Frank
Dees Jose′ G.
Gates & Cooper LLP
Samyang Corporation
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