Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-04-18
2004-06-29
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S424000
Reexamination Certificate
active
06756048
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a sustained release preparation for the purpose of maintaining sustained efficacy of a medicine for a human being and an animal.
BACKGROUND OF THE INVENTION
Sustained release of a lipophilic drug has been studied by using a hydrophobic polymer substance as a carrier for a preparation. A principle of release of a lipophilic drug from a hydrophobic polymer is based on diffusion. That is, after a preparation is implanted into the living body, a lipophilic drug moves to surrounding tissues by diffusion from the surface of the preparation, and released thereby. The decreased concentration of the lipophilic drug adjacent to the surface of the preparation leads to movement of the lipophilic drug from an area where the concentration of the drug is high to an area where the concentration of the drug is low, in the state that the drugs were dissolved in a hydrophobic polymer. The movement speed is determined by the concentration gradient and the diffusion coefficient of the drug as described by Fick's first law. Accordingly, as a factor which influences the release rate of the lipophilic drug, there are the concentration of the lipophilic drug in the preparation, the dissolution rate of the lipophilic drug in a carrier, and the diffusion coefficient which is determined by a combination of the lipophilic drug and a carrier.
As a method of controlling the release of a lipophilic drug according to the principle as described above, there are mainly two methods as follows: one of which is a method of coating a layer which contains the lipophilic drug by using a polymer film (capsule method), and another is a method of dispersing the lipophilic drug in a polymer layer (matrix method).
An example of capsule includes Norplant™ (described in U.S. Pat. No. 3,279,996). Norplant™ is a preparation wherein a powdery levonorgestrel is filled in a cylindrical silicone container, of which efficacy can be maintained in the living body during 5 years. A capsule is designed so that the diffusion of a lipophilic drug in a polymer becomes a time-limiting factor. Accordingly, over a period when the concentration of the lipophilic drug in a capsule is higher than the solubility of the lipophilic drug to a polymer film, the drug-release is kept at a constant rate. However, as described in Contraception, 27(5),483-495,1983, the release rate of the drugs is not constant and gradually decline with time. Since the article discloses that the body fluid infiltrates into a capsule in a period during which the preparation has been implanted, it is considered that the concentration of a lipophilic drug in a capsule declined with time, and it led to failure in keeping the release rate of the drug constant. Another example of a capsule is that wherein 50%(w/w) levonorgestrel in a silicone without a filler is filled into a silicone container. A filler is micro particles such as silica (anhydrous silicic acid) which are added to silicone for enhancing the physical strength thereof, of which content is known to influence the release rate of a lipophilic drug. While the preparation shows an almost zero-order release behavior, such zero-order release can be accomplished only when the following conditions are satisfied as described in the above article. Namely, it is necessary that the dissolution and diffusion of a lipophilic drug in a carrier are very rapid and that the rate of the drug diffusing in the wall of a container becomes a rate-limiting factor, thereby the concentration of a lipophilic drug on the surface of the preparation is always kept constant. Because the rates of the lipophilic drug dissolving and diffusing in carrier and container materials depend on the physical features of the lipophilic drug, the carrier and the container materials, a combination of the materials suitable for each of lipophilic drugs must have been determined.
An example of a matrix includes Compudose™ wherein estradiol disperses in silicone (Japanese Patent Publication(Tokkaisho) No. 45694/1980). In the case of the matrix, a lipophilic drug is released from the surface of the preparation, and the concentration of the lipophilic drug around the surface decreases, which leads to diffusion of the lipophilic drug from the central part of the preparation with high concentration of the drug thereby the release of the drug continues. The concentration of the lipophilic drug in a carrier polymer decreases with time, and therefore, the drug usually shows the first-order release behavior that the release rate of the drug decreases with time (Contraception, 27(5),483-495,1983).
In addition to the purpose of accomplishing the release of the lipophilic drug at a constant rate, several studies have been performed for the purpose of enhancing the release rate of the lipophilic drug from a hydrophobic polymer material. For example, controlling the release rate of a lipophilic drug has been studied by using a liquid additive which has a compatibility with a hydrophobic polymer material such as polyethylene glycol, glycerol and the (Drug Development and Industrial Pharmacy, 13(9-11),1915-1932(1987), Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 14, 223-224(1987), and Arch. Pharm. Res. 12(3), 191-195 (1989)). This aims at enhancing the drug-release by mixing a lipophilic drug with a homogeneous mixture of a hydrophobic polymer material and an additive to improve diffusion of the lipophilic drug in the hydrophobic polymer. In addition, a method using a solid additive such as sodium chloride was also studied (IL PHARMACO, 50(7,8), 549-554(1995)), by which a marked enhancement effect of the drug-release was not obtained. In Proceed Intern. Symp. Control. Rel. Bioact. Mater., 12, 145-146(1985), the rate of a lipophilic drug permeating a film which was prepared by mixing a solid additive such as lactose and sorbitol with silicone was tested, which showed that addition of these substances led to decrease in the permeation rate of the lipophilic drug. In addition, Japanese Patent Publication (Tokkaisho) No. 100315/1980 discloses a silicone rubber-based depot formulation for sustained release of an active component which is characterized by containing a release-enhancing substance dissolved in an amount corresponding to 2-50% by weight of silicone rubber, and specifically the release-enhancing substance includes alcohols, esters, ethers, and ketones which are lipophilic but practically water-insoluble. In all of the method stated above, although the release rate of the lipophilic drug may be enhanced, the typical first-order release behavior is found wherein the drug-release progresses from the entire surface of the preparation and wherein diffusion of lipophilic drug in a carrier is a rate-limiting factor. Thus, the method failed to accomplish a drug-release at a constant rate.
On the other hand, Japanese Patent Publication (Tokkaihei) No. 18799411995 discloses a technique which allows a sustained release of water-soluble drugs at a constant rate. However, as described in said specification, the mechanism of the release of a lipophilic drug and a water-soluble drug quite differs each other, and therefore, such technique for controlling the release of a water-soluble drug cannot be applied to a lipophilic drug.
As stated above, there is no technique which allows sustained release of a lipophilic drug at a constant rate and which is applicable to various lipophilic drugs until now.
PROBLEM TO BE SOLUBLED BY THE INVENTION
It is generally considered that drug-release in the sustained-release preparation of lipophilic drugs depends on the elution of the drug from the surface of the preparation, at which the drug contacts water, thereby the concentration of the drug in the inside of the preparation decreases, and on the accompanying diffusion of the drug in the preparation. A lipophilic drug is hard to dissolve in water, which suppresses the drug-release from the preparation. Accordingly, in some drugs, the release of a sufficiently effective amount of the drug may not be accomplished. In addition, the
Kajihara Masako
Maeda Hiroo
Sano Akihiko
Sugie Toshihiko
Tani Shunsuke
Bennett Rachel M.
Page Thurman K.
Sumitomo Pharmaceuticals Company Limited
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