JPH058687B2 - - Google Patents

Description

[Detailed description of the invention]

(Field of Industrial Application) The present invention relates to a sustained-release preparation prepared in the form of granules with a controlled release rate of physiologically active substances in vivo, more specifically, polyhydroxybutyric acid is the main material, and additives are added to the sustained-release preparation. The present invention relates to a sustained release preparation prepared in the form of granules in which the release rate of a physiologically active substance is controlled by adding (Conventional technology) In recent anticancer therapy, anticancer drugs are distributed only around the cancerous area to prevent side effects on normal cells, and at the same time, polymeric excipients such as resins are used to maintain drug efficacy. Research on the administration methods and dosage forms is being actively conducted. As a so-called sustained-release local administration method that continuously supplies a drug at an effective concentration only to the affected area over a long period of time, for example, anticancer drugs are placed in capsules or prepared in the form of tablets or pellets. , a method of implanting the anticancer drug locally around the cancer-affected area, a method of microencapsulating the anticancer drug with a polymer film using coacervation, or a method of dissolving the polymer in a solvent and dissolving or suspending the drug in this and then placing it in a microsphere. The drug is injected into the muscles or blood vessels around the local area, and the drug leaks out only into the local blood vessels that have been embolized with microcapsules or microspheres. Examples include methods to do so. Conventionally, microspheres formed using polymer coatings or matrices have been formulated using ethyl cellulose or wax (Japanese Patent Application Laid-Open No. 1989-1999).
163808), and those formulated into microcapsules or microspheres using polylactic acid, a non-toxic biodegradable polymer (Japanese Patent Application Laid-Open No. 54-55717,
Japanese Patent Application Laid-Open No. 59-33214) is known. However, polylactic acid has physical property limitations such as a low glass transition temperature and high melt viscosity.
It is said that it is difficult to obtain uniform microencapsulated microspheres using this biodegradable polymer material. Particularly when the shape of the drug particles is non-uniform, some particles may not be completely encapsulated. Therefore, when a preparation microencapsulated with polylactic acid is administered to the affected area, the drug release rate at the initial stage of administration is very fast. It is not possible to obtain sustained release over a long period of time,
It is difficult to obtain a sustained release effect in which the drug is always supplied at a constant concentration. As mentioned above, there are various problems in the preparation of microspheres due to the biodegradable polymers used as the coating and matrix of the microspheres. Appropriate measures must be taken to (Problems to be Solved by the Invention) Recently, polyhydroxybutyric acid (hereinafter referred to as PHB) has been produced on a commercial production basis by a fermentation method, and has become available at a relatively low cost. PHB is a biodegradable polymer like polyglycolic acid and polylactic acid, but it has the following structure. As shown by , it is a polymer similar to polypropylene, and its physical properties are different from those of polyglycolic acid and polylactic acid, which have been well known for a long time, and its melting point is slightly lower than that of l-polylactic acid (mp 175 ° C). Although similar in degree, it has a low glass transition temperature, an extremely high molecular weight (average molecular weight 500,000), and is brittle. Therefore, despite being a biodegradable polymer,
It has problems in molding compared to polylactic acid, polyglycolic acid, etc., and is currently hardly used as a medical polymer material. The present inventors have diligently studied the use of such biodegradable PHB as a sustained release preparation, and found that the preparation did not work well with microspheres containing an anticancer drug using only PHB as a matrix. It was also found that the sustained release rate of the obtained matrix was extremely low. That is, the object of the present invention is to provide a sustained-release preparation that uses PHB, which has not been widely used as a medical polymer, as a matrix and that can maintain the required active concentration and control the release rate during the period when the drug effect is required. The goal is to provide the following. (Means for Solving the Problems) The present invention provides a microsphere-structure sustained release preparation for injection or implantation using polyhydroxybutyric acid, which is a biodegradable polymer, as a matrix. When producing this sustained-release preparation, 40 to 100 parts by weight of a fat-soluble additive that can be digested in the body is added to 100 parts by weight of PHB, and this is uniformly solidified and precipitated with PHB, and is made into granules. This is a sustained-release preparation in which the release rate of the drug is controlled by preparing the drug. Therefore, the sustained release preparation prepared in the form of granules of the present invention means that the fat-soluble additive added to PHB or its copolymer serves as a matrix, and the drug to be sustained release is homogeneously dispersed in the particle size 10. It is a preparation with a microsphere structure having a size of 500μ to 500μ. By adding fat-soluble additives to the microsphere matrix in this way, it is possible to produce microspheres whose main material is PHB, thereby reducing the release rate of the active ingredient after a certain period of time after administration. release rate can be controlled to the desired rate. The release rate controlling additive used in the present invention is:
It is added during the production of known microspheres obtained from a PHB solution using an organic solvent. Therefore, the additive must be soluble in this organic solvent and must be fat-soluble and digested in vivo. Must be. These additives include vegetable oils, hydrogenated vegetable oils, cocoa butter, medium chain (C ₈ to C ₂₂ ) aliphatic triglycerides, lower (C ₆ or less) aliphatic triglycerides, difatty acid esters of propylene glycol, medium chain or Examples include alkyl esters of higher ( _C8 or higher) fatty acids, alkyl esters of lactic acid, alkyl esters of aromatic monocarboxylic acids, dialkyl esters of aromatic dicarboxylic acids, dialkyl esters of aliphatic dicarboxylic acids, and higher alcohols. Particularly preferred additives are fatty acid esters. The amount of additive used is determined appropriately depending on the release rate based on the type of additive, the type of drug, and the dosage form, but it is usually 40 to 100 parts by weight per 100 parts by weight of PHB.
Parts by weight. If it is less than 40 parts by weight, the sustained release effect will be poor, and if it exceeds 100 parts by weight, it will be difficult to shape it to obtain uniform microspheres. The sustained release preparation of the present invention can be prepared according to a conventional method, for example, as follows. i.e. PHB
and additives are completely dissolved in an organic solvent such as methylene chloride, the drug is dissolved or suspended therein, and this is dropped into an aqueous medium containing a protective colloid such as Zentin and suspended under stirring, and then the solvent is removed. The granular microspheres obtained by evaporation may be separated from the aqueous medium. The drug used in the present invention can be applied to all drugs that are conventionally known as drugs for which sustained release is desired, but it is particularly effective when applied to anticancer drugs whose action is highly time-dependent. is large,
In addition, it can be used for insulin, prostaglandins, local anesthetics, etc. These drugs are usually contained in an amount of 10 to 50 parts by weight per 100 parts by weight of the microspheres. The higher the amount of drug, the less additives need to be used. The polyhydroxybutyric acid used in the present invention is poly(3-hydroxybutyric acid) and is represented by the above structure. Its molecular weight is preferably 200,000 to 1,000,000. The amount of polyhydroxybutyric acid used is 30 to 90 parts by weight per 100 parts by weight of the microspheres obtained.
Preferably, 50 to 80 parts by weight are used. In particular, if it is less than 30 parts by weight, it is difficult to obtain the desired strength and uniform microspheres. (Action and Effect of the Invention) The sustained release preparation of the present invention comprising PHB, an additive, and a drug is a sustained release preparation with a microsphere structure that can be used for injection or implantation,
By appropriately selecting the types of additives and their usage ratios, the release rate of the drug can be controlled and, therefore, its constant concentration can be maintained. In addition, both PHB and additives are hydrolyzed by enzymes in the body and become harmless substances, so there is no need to take them out of the body.
It does not remain in the body. (Example) The present invention will be explained below with reference to Examples and Test Examples. Example 1 After dissolving 0.9 g of poly(3-hydroxybutyric acid) in 40 ml of methylene dichloride with stirring, a solution was obtained in which 0.6 g of isopropyl myristate (IPM) was dissolved and further 0.3 g of doxorubicin hydrochloride was added. Separately, add 2 g of acid-treated gelatin (manufactured by Miyagi Chemical Co., Ltd., Jelly Strength 250 Bloom) to 198 g of water and add 50 g of gelatin to 198 g of water.
A 1% aqueous solution was prepared by heating and dissolving at °C. The gelatin aqueous solution was transferred to a 500 ml beaker, the methylene chloride solution was added thereto, and the mixture was emulsified by stirring at 500 rpm for 5 minutes using a 5 cm paddle-shaped stirring blade.
The methylene chloride was evaporated while gradually heating from the outside, and it took about 60 minutes to reach an internal temperature of 50°C, and microsphere formation was completed when it was confirmed that the methylene chloride odor had completely disappeared. After removing some condensate from the upper layer, it was filtered and washed with warm water. after that,
The mixture was air-dried under reduced pressure to obtain 1.6 g of white spherical microspheres (yield: 89%) with a particle size of 150 to 250 μm. The obtained microspheres were subjected to solvent extraction to completely isolate doxorubicin, and as a result of quantitative analysis by absorbance measurement at 290 nm, the content of doxorubicin in the microspheres was determined.
It was 15.0%. Also, in the microsphere
It was confirmed that PHB was 0.85g and IPM was 0.5g. Test Example 100 mg of the microspheres containing 15.0% doxorubicin obtained in Example 1 were placed in 50 ml of physiological saline, 1 to 3 ml was directly sampled at each measurement time, and the absorbance at 290 nm was measured. At the same time, under exactly the same conditions as in the above example, the absorbance at 290 nm of the microspheres in physiological saline obtained without adding the additive IPM was also measured as a comparative test, and calculated based on these absorbances. , the relationship between elapsed time and release rate as shown in Table 1 was obtained.

[Table] As is clear from the results in Table 1, the release rate of the PHB microsphere preparation prepared without additives is extremely low, whereas the microspheres according to the present invention exhibit good sustained release properties. , about 40 in 5 hours
%, the entire amount was released in 120 hours.

Claims (1)

[Scope of Claims] 1 A biodegradable polymer mainly composed of polyhydroxybutyric acid, a fat-soluble additive that is soluble in an organic solvent that dissolves polyhydroxybutyric acid and can be digested in vivo, is polyhydroxybutyric acid 100. A sustained release preparation prepared in the form of granules consisting of 40 to 100 parts by weight and a drug. 2. The preparation according to claim 1, wherein the fat-soluble additive is a fatty acid ester. 3. The preparation according to claim 1, wherein the drug is an anticancer drug.