KR-20260068083-A - MICROSPHERE HAVING PHYSIOLOGICALLY ACTIVE SUBSTANCE UNIFORMLY DISPERSED THEREIN, AND SUSTAINED-RELEASE PREPARATION CONTAINING SAME

Abstract

In the present application, a microsphere is provided that is a lactic acid-glycolic acid copolymer (PLGA) or polylactic acid (PLA) having a physiologically active substance uniformly dispersed therein as the main component, wherein the average volume-based particle diameter of the microsphere is 1 μm or more and 150 μm or less, a cross-sectional observation sample is prepared by cutting the microsphere, the cross-sectional observation sample is observed under an electron microscope at a magnification greater than that which allows for the identification of the physiologically active substance within the microsphere, the image observed under the electron microscope is divided into six parts, and the ratio (s/A) × 100 (%) of the area (A) of each divided region and the total cross-sectional area (s) of the physiologically active substance included in that region is calculated, and the coefficient of variation of the calculated ratio in the six regions is 0.35 or less. The microsphere of the present invention is capable of appropriately controlling the initial release amount of the physiologically active substance and the release rate during the subsequent release period, so that the physiologically active substance can be continuously released in vivo for a certain period.

Inventors

• 에노무라 마사카즈
• 아라키 카에코

Assignees

• 엠. 테크닉 가부시키가이샤

Dates

Publication Date

20260513

Application Date

20200911

Priority Date

20200508

Claims (5)

1. A method for manufacturing microspheres having lactic acid-glycolic acid copolymer (PLGA) or polylactic acid (PLA) as the main component, in which a physiologically active substance is uniformly dispersed, The process comprises continuously feeding a solution of PLGA or PLA and a physiologically active substance, obtained by dissolving or dispersing the PLGA or PLA and the physiologically active substance in a solvent of PLGA or PLA, and a solution containing a non-solvent of PLGA or PLA, into a particle processing device to produce emulsion particles, and precipitating microspheres by removing the solvent from the produced emulsion particles. The average volume particle size of the above microspheres is 1㎛ or more and 150㎛ or less, and A method for manufacturing a microsphere, characterized by preparing a cross-sectional observation sample by cutting the microsphere, observing the cross-sectional observation sample with an electron microscope at a magnification greater than that which allows for the identification of physiologically active substances within the microsphere, dividing the electron microscope cross-sectional observation image into six parts, calculating the ratio (s/A) × 100 (%) of the area (A) of each divided region and the total sum (s) of the cross-sectional areas of the physiologically active substances included in that region, and wherein the coefficient of variation of the calculated ratio in the six regions is 0.35 or less.
2. In Article 1, A method for manufacturing microspheres in which the above-mentioned physiologically active substance is a lipophilic physiologically active substance.
3. In Article 1, A method for manufacturing microspheres having an average volume-based particle diameter of the dispersed physiologically active substance of 5 nm to 500 nm.
4. In Article 1, A method for producing microspheres in which the content of the physiologically active substance in a solution of the above PLGA or PLA and the above physiologically active substance is 0.35 to 1.5 mass%.
5. In Article 1, A method for manufacturing microspheres that removes both solvents by flowing gas onto the liquid surface of a liquid containing the above-mentioned emulsion particles.

Description

Microspheres having physiologically active substances uniformly dispersed therein, and sustained-release formulation containing the same The present invention relates to microspheres in which a physiologically active substance is uniformly dispersed and sustained-release formulations containing the same. In particular, the present invention relates to microspheres having a lactic acid-glycolic acid copolymer (PLGA) or polylactic acid (PLA) as the main component in which a physiologically active substance is uniformly dispersed, and sustained-release formulations containing the same. Microspheres or nanospheres have recently attracted attention as sustained-release formulations, such as pharmaceuticals containing physiologically active substances. Microspheres typically refer to formulations with a particle size of about 1 μm to 150 μm, while formulations smaller than that, with a size of less than 1 μm, are called nanospheres. These can, for example, encapsulate physiologically active substances in biodegradable synthetic polymers or natural polymers to continuously release the physiologically active substances locally, or to target the physiologically active substances to tissues. Sustained-release microsphere formulations that slowly release physiologically active substances at a constant rate require formulations in which, for example, biodegradable polymers, physiologically active substances, additives, and solvents are appropriately controlled. In order for sustained-release microsphere formulations to effectively exert pharmacological effects in vivo for a certain period, it is necessary to appropriately control the initial release amount of the physiologically active substance and the release rate during the subsequent release period to continuously release the substance in vivo for a certain period. One of the important factors determining the release rate of the physiologically active substance is the type of biodegradable polymer. In particular, the most widely used lactic acid-glycolic acid copolymer (Polylactide-co-glycolide Acid, PLGA) and polylactic acid (PLA), which is a polymer of lactic acid, differ in their biodegradation rates due to their physicochemical properties, such as the ratio of constituent lactic acid and glycolic acid, molecular weight, and water affinity, so the desired release period can be adjusted based on these (Patent Document 1). Furthermore, in addition to this, in order to suppress the initial burst of physiologically active substances and to control the release rate consistently during the release period, the particle size of the microspheres and the dispersion state of the physiologically active substances within the microspheres are related. Although there are yield issues, the particle size of the microspheres can be adjusted to the target size through operations such as filtration. However, the dispersion state of the physiologically active substances within the microspheres is merely uniform and has not been verified. Microspheres of PLGA or PLA can be manufactured using, for example, liquid drying, spray drying, spray freeze-drying, drying using a supercritical fluid process, or double emulsion. Among these, the most common manufacturing method is the liquid drying method, in which, when the physiologically active substance is lipophilic, PLGA or PLA and the physiologically active substance are dissolved or dispersed in an organic solvent, mixed with an aqueous solution of dissolved polyvinyl alcohol (PVA) to form an emulsion, and then desolvated from the emulsion. Patent Document 1 discloses a method for preparing sustained-release microspheres containing a peptide drug and a biodegradable polymer such as PLGA by spray drying, spray freeze-drying, or a drying method using a supercritical fluid process. However, it does not describe how dispersed the particle size of the sustained-release microspheres is, whether the peptide drug is uniformly dispersed within the sustained-release microspheres, or whether a uniform result is obtained. Patent Document 2 discloses a method for preparing PLGA microparticles by a liquid-drying method using a mixed solvent comprising a halogenated hydrocarbon and a non-aqueous organic solvent having a drug solubility of 0.3% (W/V) or higher. Although it is described that the particle diameters (medium diameter) of the microparticles obtained in Preparation Examples 1 and 2 are 14 and 16 μm, respectively, the dispersion state of the drug within the microparticles is not described. Patent Document 3 discloses PLGA nanoparticles containing a drug. These nanoparticles are primarily intended for targeting specific tissues and are therefore nanoparticles of a size of tens to hundreds of nanometers that can pass through the minute pores of capillaries. However, Patent Document 3 does not describe microspheres of 1 μm or larger, which are much larger than these nanoparticles. Furthermore, even using the technology of Patent Document 3, a per