JPS6163613A - Sustained release preparation - Google Patents

Abstract

PURPOSE:The titled sustained release preparation having a microspherical structure usable for injection or implantation, capable of keeping always a constant concentration of drug activity during a necessary period, controlling a release rate of drug, comprising a polylactic acid, an additional matter, and a drug. CONSTITUTION:A drug such as a carcinostastic, etc. is blended with a fat-soluble additional matter such as preferably fatty acid ester, etc. soluble in an organic solvent to dissolve a polylactic acid, digestible in organisms, the additional matter is added to control release rate of the drug, the blend and a high polymer decomposable in organisms comprising a polylactic acid as a main ingredient are uniformly solidified, precipitated, and prepared in a granular state, to give a sustained release preparation having a microspherical structure with 10-500mu particle diameter wherein the drug to be released prolongably is uniformly dispersed. Insulin, prostaglandin, etc. may be used as the drug. EFFECT:Both a polylactic acid and an additional matter are hydrolyzed with enzymes in organisms into harmless substances, removal of them out of body is not required, and they do not remain in body.

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 in which the release rate of a physiologically active substance in the body is controlled.

(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 an effective concentration of a drug only to the affected area over a long period of time, for example, an anticancer drug is placed in a capsule, or a preparation formed into a tablet or pellet is used to treat cancer. A method of implanting it around the affected area, micro-encapsulation with a polymeric wave membrane through coacervasion, which is an anticancer drug, or a polymeric material? After dissolving or suspending the medicinal substance in 1 volume, it is prepared into microspheres and injected into the muscles or blood vessels around the local area to form microcapsules or microspheres in the blood vessels around the local area. Examples include a method that utilizes the fact that the drug seeps only into the local blood vessels that are closed off by embolization.

Conventionally, microspheres formed using polymer coatings or matrices include those formulated using ethyl cellulose or wax (Japanese Patent Application Laid-Open No. 163808/1982), and non-toxic biodegradable polymer materials. prepared into microcapsules or microspheres using polylactic acid, etc. (Japanese Patent Laid-Open No. 54-55717).

JP-A-59-33214) is known. However, polylactic acid has physical property limitations such as a low glass transition temperature and high melt viscosity, and it is difficult to obtain uniform microencapsulated microspheres with this biodegradable polymer material. has been done. 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. Sustained release over a long period of time cannot be obtained, and it is difficult to obtain a sustained release effect in which the drug is always supplied at a constant concentration.

On the other hand, when a microsphere preparation using polylactic acid as a matrix obtained by the method described in JP-A-59-33214 is administered, the sustained release effect over a long period of time is However, it was found that the release rate after 24 hours after administration became extremely low, almost regardless of the drug content and the molecular weight of the polylactic acid used.

In general, depending on the pharmacological action of the physiological activity of a drug, some drugs may not have a pharmacological effect unless they are present at a certain concentration in the affected area for a certain period of time, and the release rate must be increased within the necessary certain period of time. There is also a need to measure it.

(Problems to be Solved by the Invention) As mentioned above, conventional sustained-release preparations using polylactic acid do not have sustained release or have an extremely long release time, resulting in dilute active concentrations and poor pharmacology. They were either ineffective or not.

The present inventors have completed the present invention as a result of intensive studies to solve these problems. Therefore, the purpose of the present invention is to maintain the necessary active concentration at all times during the period when drug activity is required. The purpose of the present invention is to provide a sustained release formulation that can be maintained and whose release rate can be controlled.

(Means for Solving the Problems) The present invention provides a microsphere-structure sustained release preparation for injection or implantation using polylactic acid, which is a biodegradable polymer, During the production of the sustained-release preparation, a fat-soluble additive that can be digested in vivo was added to control the release rate of the drug, and this was uniformly solidified and precipitated with polylactic acids, and was prepared into granules. It is a sustained-release preparation. Therefore, the sustained-release preparation prepared in the form of granules of the present invention is a matrix in which a small amount of a fat-soluble additive is added to polylactic acid or its copolymer, and the drug is released in a sustained manner. It is a microsphere-structured preparation with a particle size of 10 to 500μ that is homogeneously dispersed with the drug, and this makes it possible to eliminate the shortcomings of conventional microsphere-structured sustained-release preparations using only polylactic acid after administration. It is possible to prevent a decrease in the release rate of the active ingredient after a certain period of time has elapsed.

The release rate controlling additive used in the present invention is added during the production of known microspheres obtained from a polylactic acid solution using an organic solvent, and therefore, the additive may be dissolved in the organic solvent. It must be fat-soluble and digested within the body. These additives include vegetable oil, cocoa butter, medium chain (CS to C22) fatty acid triglycerides, lower (C6 or lower) fatty acid triglycerides, difatty acid esters of propylene glycol, medium chain or higher (C8 or higher) fatty acid alkyl esters, and alkyl lactates. In addition to esters, aromatic mono- or dicarboxylic acid alkyl esters can also be used, but fatty acid esters are particularly preferred additives.

The amount of additive used is determined as appropriate depending on the type of additive, the type of drug, and the release rate based on the dosage form, but it is usually used within the range of 5 to 100 parts by weight per 100 parts by weight of polylactic acid. Ru.

The sustained release preparation of the present invention can be prepared according to a conventional method, for example, as follows. In other words, polylactic acids and additives are completely dissolved in an organic solvent such as methylene chloride, and the drug is dissolved or suspended in this, and this is dropped and suspended in an aqueous medium containing a protective colloid such as gelatin while stirring. The granular microspheres obtained by evaporating and removing the solvent may be superfractionated from an aqueous medium.

The present invention (=applicable to all drugs that are conventionally known as drugs for which sustained release is desired)
However, it is especially effective when applied to anticancer drugs whose action is highly time-dependent, and can also be used for insulin, prostaglandins, local anesthetics, etc.

The polylactic acids used in the present invention, that is, the biodegradable polymers mainly made of polylactic acid, are poly-4-lactic acid, poly-d, l-lactic acid, or a copolymer of lactic acid-glycolic acid, In the case of poly-1-lactic acid, the molecular weight of 1 is 10
,000 to 200,000 is suitable, and d
, l is suitable for use with an intrinsic viscosity of about 0.6 to 1.2 (measured in chloroform at 25°C).

The amount of polylactic acids used is 10
0 parts by weight, polylactic acids are used in an amount of 30 to 90 parts by weight, preferably 50 to 80 parts by weight. In particular, if the amount is less than 30 parts by weight, the desired strength and uniform microspheres cannot be obtained (2. and
Further, the drug is usually contained in 10 to 50 parts by weight in 100 parts by weight of microspheres, but if the amount of drug used is large, the amount of additives may be small.

(Actions and Effects of the Invention) The sustained-release preparation of the present invention comprising polylactic acids, additives, and drugs is a sustained-release preparation with a microsphere structure that can be used for injection or implantation. By appropriately selecting the type of drug and the ratio of its use, the release rate of the drug can be controlled and its concentration can therefore be maintained at a constant level. Furthermore, since both polylactic acid and additives are hydrolyzed by enzymes in the body and become harmless substances, there is no need to take them out of the body and they do not remain in the body.

Example-1 Bo 9-1 having intrinsic viscosity value (yJ) = 1.32
-Lactic acid (measured in chloroform at 25°C, molecular weight 43.0
00) 1.81 in methylene chloride 40.9 with stirring, isopropyl myrite) (IPM) 0.
Dissolve 4g, add 6g of bleomycin,
A suspension was obtained.

Separately, add 2 g of alkali-treated gelatin [manufactured by Miyagi Chemical, jelly strength 250 Plume] 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, and the mixture was cooled to room temperature.

The aqueous gelatin solution was transferred to a 500-meter copy car, and the methylene chloride solution was added thereto, stirred at 500 rpm using a 5-meter paddle-type stirring blade, and emulsified. After confirming that it had completely disappeared, microsphere formation was completed. After removing some aggregates in the upper layer, it was filtered, washed with distilled water, and dried under reduced pressure at room temperature to form white spherical particles with a particle size of 180 to 200μ. Microspheres of 2.0 g were obtained.

The obtained microspheres were subjected to solvent extraction to completely isolate pleomycin, and as a result of quantitative analysis by absorbance measurement at 290 nm, the content of pleomycin in the microspheres was 15.1%. .

Test Example-1 100 m9 of microspheres containing 15.1% pleomine obtained in Example-1 were placed in 5 Q ml of physiological saline, and 1 to 3 ml was directly sampled at each measurement time.
Absorbance was measured at 90 nm. Example at the same time
290 in saline of microspheres obtained under exactly the same conditions as in 1 without adding any additive IPM.
The absorbance at nm was also measured as a comparative test.

By calculating from these absorbances, the relationship between elapsed time and release rate as shown in FIG. 1 was obtained.

Example 2 and Test Example 2 Pleomycin-containing microspheres were obtained in exactly the same manner as in Example 1, except that poly-d,l-lactic acid having an intrinsic viscosity of 0.88 was used. Pleomycin content in the microspheres was 16.0%.

The obtained microsphere preparation was subjected to an in vitro release test in the same manner as in Test Example 1, and the results shown in FIG. 2 were obtained.

[Brief explanation of drawings]

Figures 1 and 2 show 1nvi of formulations of examples of the invention.
The relationship between elapsed time and drug release rate in the tro release test was compared with that of a formulation without IPM. △: In the case of the formulation of the example ○: In the case of the formulation that does not contain IPM Patent applicant Mitsui Toatsu Chemical Co., Ltd. Figure 1 Jikai (!our)

Claims (3)

[Claims] (1) A biodegradable polymer mainly made of polylactic acid,
A sustained release preparation prepared in the form of granules, comprising a drug and a fat-soluble additive that is soluble in an organic solvent that dissolves polylactic acid and can be digested in vivo. (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.