Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-08-10
2001-10-16
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S453000, C424S454000, C424S464000, C424S468000, C514S964000
Reexamination Certificate
active
06303144
ABSTRACT:
This application is a 371 application of PCT/JP99/00570 filed Feb. 10, 1999.
1. Technical Field
The present invention relates to a novel preparation used for controlling the release of an active substance, particularly a pharmaceutically active ingredient. More particularly, the present invention relates to a preparation suitable for releasing a drug in a comparatively short time following a given period of lag time (time during which a drug is not released) after administration, namely, a pulse release preparation.
2. Background Art
In the treatment using drugs, a selective delivery of a drug to the lower part of the small bowel and the large bowel is desired in the fields of (1) a local treatment of inflammatory bowel diseases such as ulcerative colitis, (2) a treatment by oral administration of a peptide drug which is susceptible to chemical decomposition and enzymatic degradation in the small bowel, and the like. For a selective drug delivery to the lower part of the small bowel and the large bowel, therefore, the preparation design in recent years involves consideration of the physical and physiological environment in the gastrointestinal tract of humans and the time necessary for the transfer of the preparation within the gastrointestinal tract.
For instance, conventional enteric preparations and sustained release preparations are not designed from these viewpoints. As a result, although the former preparation effectively inhibits the dissolution of a drug in the stomach, it fails to deliver the drug to the large bowel, because the drug is rapidly dissolved in the upper part of the small bowel and mostly absorbed or decomposed there. The latter preparation is associated with a problem in that a considerable part of the drug is dissolved during the passage of the preparation through the stomach and the small bowel, because the drug is dissolved in a sustained manner.
In addition, preparations having a release control film made from a water insoluble polymer and an enteric polymer in combination are known (JP-A-3-7238, EP-B-40590). In these preparations, a drug is gradually dissolved after oral administration or after transfer into the small bowel, which means that the time of start of dissolution and pH at which the dissolution is started are not controlled, thus failing to direct the drug concentratively to the lower part of the gastrointestinal tract.
In view of the above-mentioned defects of the conventional enteric preparations and sustained release preparations and with the aim of providing a higher level and higher performance drug delivery system targeting a specific region of an appropriate part in the gastrointestinal tract (particularly, lower part of the gastrointestinal tract, such as the small bowel, the large bowel and the like), a new controlled release preparation that enables accurate drug release at this region is being developed.
As an oral administration system to release a drug site-specifically at various lower parts of the gastrointestinal tract based on a preparation formulation method, for example, there have been known a method for controlling the release start time by utilizing the time necessary for transfer of the preparation in the gastrointestinal tract, a method for determining the release site by utilizing enterobacteria, and other methods.
JP-B-2-58246 discloses a compressed tablet that is specifically disintegrated in the colon to release an active ingredient, irrespective of the length of drug residence time in the stomach. Because this compressed tablet utilizes bacteria present in the colon, however, the time of disintegration varies depending on the inter-individual difference in the bacteria present in the colon, and the decomposition takes defectively long when the enterobacteria have a lower decomposition activity.
JP-A-4-235123 discloses a controlled release preparation having a film coating made from an ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer (Eudragit RS; trademark, Röhm Pharma) and a water-repellent salt (calcium stearate). This is a so-called sigmoid type controlled release preparation that releases a pharmaceutical compound after a given time. This preparation controls the time before the start of dissolution by controlling the water-permeation rate of the film coating, and requires an accurate control of the amount of the film coating, so as to appropriately control the time before the start of dissolution. The preparation also has a defect in that a thicker film makes quick dissolution of the drug after the start of the dissolution difficult to achieve. Moreover, the system of this preparation involves a drug release after a given time from the oral administration of the preparation, which makes it difficult to specify the site where the release occurs.
JP-A-4-264022 discloses an oral preparation for release in the lower part of the gastrointestinal tract, which is obtained by filling a hard capsule made from a base mainly composed of chitosan with a solid preparation containing a solid organic acid and the principal agent ingredient, and forming an enteric film e coating on the surface of the capsule. This preparation controls the time before the start of dissolution by changing the thickness of the hard capsule, and requires an accurate control of the thickness of the capsule wall for controlling the dissolution start time.
Japanese Patent Application under PCT laid-open under kohyo No. 4-505004 discloses a controlled release preparation based on the system wherein a water insoluble capsule is capped with a water swellable plug, and the plug begins to swell upon water absorption, and, after a given time, comes out to release the drug in the capsule. This preparation employs a system of releasing a drug after a given time from oral administration. This makes specification of the release site in the gastrointestinal tract very difficult, because the residence time of the preparation in the stomach varies due to the inter-individual difference.
These conventional enteric preparations for topical treatment are defective because they have complicated structures and the time before the start of dissolution varies depending on pH and inter-individual difference in the residence time in the stomach and the like, which in turn makes the control of the lag time difficult and makes these preparations insufficient to achieve an effective blood concentration by quick dissolution of the entire amount of the drug after the start of dissolution.
As a system that utilizes the transfer time of a preparation in the gastrointestinal tract, several systems based on the transfer time in the small bowel, that disregards the variation in the residence time of the preparation in the stomach, have been developed noting the fact that the passage of the preparation through the small bowel takes almost the same length of time for any individual. These systems are free of drug release during the intragastric residence time and enable a specified release of the drug after a certain time after transfer into the small bowel following discharge from the stomach, namely, at a site a certain distance away from the stomach, such as in the large bowel which is in the lower part of the gastrointestinal tract.
To be specific, for example, JP-A-4-501411 discloses a preparation that releases a drug after a given lag time, which is achieved by applying a three-layer coating comprising an inner layer coated with an anionic copolymer that dissolves at a pH of not less than 7.0, an intermediate layer comprising a gelling polymer that swells and gels in a pH non-dependent manner to form a gel layer, and an outer layer comprising an appropriate amount of a stomach resistant polymer that quickly dissolves in the bowels. However, this preparation is defective in that the dissolution rate of the gelling polymer often changes due to the kinetics within the gastrointestinal tract, resulting in inconsistent lag time, and the system is extremely complicated both in the structure and production method, as mentioned in the abov
Bennett Rachel M.
Spear James M.
Welfide Corporation
Wenderoth , Lind & Ponack, L.L.P.
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