Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1997-12-18
2002-04-09
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S486000
Reexamination Certificate
active
06368635
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a gastrointestinal mucosa-adherent matrix adapted to stay long in the gastrointestinal tract for sustained drug release, a pharmaceutical preparation based on the matrix, and a coating composition which renders dosage forms adherent to the mucosa.
BACKGROUND OF THE INVENTION
Controlled-release drug delivery systems, particularly sustained-release preparations, are advantageous in that they help to reduce the frequency of administration of a drug without detracting from the effect of medication, prevent any sudden elevation of the blood concentration of the drug to reduce the risk of side effects, and maintain a therapeutically effective blood concentration for an extended period of time. Therefore, much research has been undertaken in the field of controlled release technology from the aspects of active drug, formulation and dosage form. By way of illustration, there are known an encapsulated preparation such that a core containing an active ingredient is covered with a shell, and a matrix type preparation such that an active ingredient has been dispersed in a release-controlling layer. These preparations are generally provided in such dosage forms as tablets, capsules and granules.
Meanwhile, many drug substances are absorbed mostly from the small intestine and, to a lesser extent, from the large intestine. Moreover, in humans, reportedly it takes about 5 to 6 hours for an orally administered drug to reach the large intestine.
However, in oral administration, the residence time of the drug in the digestive canal is of necessity limited even if its release is critically controlled by a sophisticated controlled release system, so that the drug is not efficiently absorbed but is excreted from the body without being fully utilized. Furthermore, in the case of a drug substance which acts directly and locally to produce the expected effect, it is likewise excreted without being utilized if the duration of contact is short. Particularly in cases in which the drug substance is sparingly soluble, its pharmacologic actions cannot be effectively utilized. Therefore, in the conventional drug delivery systems, it is difficult to insure absorption of active ingredients beyond a limited time period.
European Patent Publication No. 0368247A3 discloses a matrix preparation such that a pharmaceutically active ingredient is dispersed in a polyglycerol fatty acid ester-based matrix which is solid at ambient temperature. Moreover, European Patent Publication No. 0406856A2 discloses an FGF protein composition which is a granulated preparation using a polyglycerol fatty acid ester. Furthermore, European Patent Publication No. 0455391 proposes a granulated preparation prepared by thermal fluidization of a particulate composition containing a granular polyglycerol fatty ester having a melting point of 40 to 800° C. and an active ingredient.
However, none of these prior art literature teach or suggest a pharmaceutical preparation having a gastrointestinal mucosa-adherent property.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a gastrointestinal mucosa-adherent matrix adapted to attach itself to the gastrointestinal mucosa to thereby remain within the gastrointestinal tract for a long period of time and promote absorption of the active ingredient for improved bioavailability.
It is another object of the invention to provide a gastrointestinal mucosa-adherent matrix adapted to attach itself to a specific site within the gastrointestinal tract to thereby allow an active ingredient to act directly on the living body.
It is still another object of the invention to provide a gastrointestinal mucosa-adherent matrix which allows even a sparingly water-soluble active ingredient to be effectively utilized by the body.
A further object of the invention is to provide a pharmaceutical preparation having the above-mentioned beneficial characteristics.
Yet another object of the invention is to provide a coating composition which renders a drug substance or dosage form adherent to the gastrointestinal mucosa.
The inventors of the present invention found that the duration of action of various active ingredients can be prolonged by incorporating a certain substance having the property to become viscous on contact with water (hereinafter referred to as “viscogenic agent”) in a pharmaceutical composition or coating a pharmaceutical composition with such a viscogenic agent. The present invention has been completed based on these findings.
Thus, the present invention provides a gastrointestinal mucosa-adherent matrix which is solid at ambient temperature, and which contains a viscogenic agent as dispersed at least in the neighborhood of the surface layer of a matrix particle containing a polyglycerol fatty acid ester and/or a lipid and an active ingredient.
The above gastrointestinal mucosa-adherent matrix which is solid at ambient temperature includes a matrix in which each matrix particle containing a polyglycerol fatty acid ester and/or a lipid and an active ingredient has a coating layer comprising or containing the viscogenic agent.
The present invention further provides a solid pharmaceutical preparation based on the matrix, which may be in the form of fine granules or granules.
The present invention further provides a coating composition comprising at least the viscogenic agent. The coating composition may further contain at least one member selected from the group consisting of polyglycerol fatty acid esters, lipids, enteric polymers and water-insoluble polymers.
As used throughout this specification, the term “gastrointestinal mucosa-adherent” refers to any and all cases in which the property of adhering to the gastrointestinal mucosa is exhibited or imparted by the viscogenic agent, including cases in which the matrix additionally has an enteric or gastric coating layer which does not contain the viscogenic agent. The term “the neighborhood of the surface layer” means not only the surface of the matrix particle but also the region adjoining to the surface, including a coating layer such as the one mentioned above.
The term “coating” is used herein to mean not only a process in which the whole surface of a matrix particle is covered with a coating composition containing the viscogenic agent but also a process in which the surface of the matrix particle is partially covered with such a coating composition.
It should also be understood that where the matrix and/or the polyglycerol fatty acid ester or the like is a mixture, the composition does not show a distinct melting point but softens at a specific temperature. The term “melting point” as used in this specification includes the softening point displayed by such a mixture.
DETAILED DESCRIPTION OF THE INVENTION
The viscogenic agent used in the present invention may be any substance that develops a sufficient degree of viscosity in the presence of water to adhere to the gastrointestinal mucosa and is pharmaceutically acceptable. Preferred species of the viscogenic agent swell or gain in viscosity to a remarkable extent on contact with water. As examples of such viscogenic agent, there may be mentioned polymers containing carboxyl groups or salts thereof, cellulose ethers, polyethylene glycols having molecular weights not less than 200,000, and naturally-occurring mucous substances. The preferable viscogenic agents are those having a viscosity in the range of 3 to 50,000 cps, preferably 10 to 30,000 cps, and more preferably 15 to 30,000 cps as a 2 percent by weight aqueous solution thereof at 20° C. When a polymer becomes viscous by neutralization, the viscosity of a 0.2 percent by weight aqueous solution of the viscogenic agent is, for example, in the range of 100 to 500,000 cps, preferably 100 to 200,000 cps, and more preferably 1,500 to 100,000 cps at 20° C. In the present invention, at least one of such viscogenic agents is employed, and needless to say, two or more species of said viscogenic agents may be employed in combination.
The polymers containing carboxyl groups or sa
Akiyama Yohko
Hirai Shin-ichiro
Nagahara Naoki
Takeda Chemical Industries Ltd.
Webman Edward J.
Wenderoth , Lind & Ponack, L.L.P.
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