JPH054365B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing microparticles by a phase separation method using biodegradable poly-L-lactic acid.

More specifically, the present invention relates to a method for producing improved sustained-release microparticles using a phase separation method from an organic solution system using biodegradable poly-L-lactic acid as a polymer material and a physiologically active substance as a core material.

A core material of a desired particle size is dispersed in a continuous phase consisting of a solution of a polymer that is a coating material, and the polymer is precipitated around the core material by adding a non-solvent to the polymer and/or cooling the solution. The preparation of polymer-coated microcapsules is known as a phase separation method from an organic solvent system, but such methods usually result in undesirable agglomeration between the encapsulated particles and do not provide useful single particles with controlled particle size. It was difficult to obtain microcapsules. In particular, in recent years, the application of biodegradable polymers to medical applications as coating materials for microcapsules or matrix materials for microspheres has attracted attention. This produced soft aggregates and was extremely unsatisfactory as a microcapsule.

As a method to suppress such aggregation, poly-
A phase separation method using D,L-lactic acid at an extremely low temperature of -40 to -100°C has been proposed (Japanese Patent Application Laid-Open No. 1989-1999).
55717), this method does not completely solve the tendency of microcapsules or microspheres to agglomerate, and relatively low molecular weight polylactic acid,
Alternatively, when a lactic acid copolymer or the like is used, soft aggregates are formed and the desired microcapsules cannot be obtained.

On the other hand, as a method of producing microparticles with a biodegradable polymer as a coating material or as a homogeneous mixture with a core material, biodegradable polymers are dissolved,
For example, a core substance is dissolved or dispersed in a low-boiling point solvent such as methylene chloride or benzene, and this is dispersed in an aqueous solution of a protective colloid substance such as gelatin or chitosan.The solvent is evaporated by raising the temperature of the system to form microparticles. It is also possible to apply the so-called "in-liquid drying method" to obtain the biodegradable polymer. However, in this method, the core material, which is generally quite water-soluble, flows into the water layer and is not properly coated or mixed with the biodegradable polymer, which results in the drying of the desired material. It was not possible to obtain microparticles.

An object of the present invention is to provide a method for producing fine particles using a phase separation method that can suppress aggregation of produced fine particles during the manufacturing process.

The present inventors have conducted intensive studies on a method for producing microparticles using a phase separation method from an organic solution system using a biodegradable polymer as a coating or matrix material and a physiologically active substance as a core material, and found that poly-L-lactic acid The present inventors have discovered that it is possible to suppress the agglomeration tendency and produce desired microparticles by using the following methods.

The method for producing microparticles of the present invention involves producing microparticles of a physiologically active substance by a phase separation method, using poly-L-lactic acid as a coating material, and using a physiologically active substance that is insoluble in a good solvent for poly-L-lactic acid. The core material is:

Specifically, the method for producing fine particles of the present invention involves dissolving poly-L-lactic acid in a good solvent such as dichloromethane, chloroform, or toluene,
In this, a physiologically active substance insoluble in the above solvent is dispersed, and n is used as a poor solvent for poly-L-lactic acid.
- Paraffin is added to normalize the coacervation and then cooled to harden the coacervate of poly-L-lactic acid.

The poly-L-lactic acid used in the present invention preferably has an intrinsic viscosity of 0.3 to 3.0 in chloroform, particularly preferably 1.0 to 1.5. poly
If the intrinsic viscosity of L-lactic acid is less than 0.3, it tends to soften and agglomerate due to its low Tg, while if it is more than 3.0, it is difficult to obtain under general polymerization conditions and its solubility in solvents decreases.

This method makes it possible to efficiently coat a physiologically active substance, particularly a water-soluble physiologically active substance, with poly-L-lactic acid, and has a great effect on sustained release of the physiologically active substance.

Poly-lactic acid is known as a biodegradable polymer, but as mentioned above, when poly-D,L-lactic acid is used, the poly-L-lactic acid of the present invention can be coated or used as a matrix material. The production of microparticles without a tendency to agglomerate cannot be expected under mild conditions, such as in the method for producing microparticles.

In this way, the microparticles coated with poly-L-lactic acid of the present invention or using it as a matrix material can be heated at 0°C.
~ By adding a poor solvent under mild conditions at room temperature, fine particles without agglomeration can be obtained, and poly-L
- Lactic acid coats the physiologically active substance in honey, providing excellent sustained release properties.

Further, preferred embodiments for producing the microparticles of the present invention include (1) dissolving poly-L-lactic acid in advance in a good solvent for poly-L-lactic acid, such as toluene, xylene, chloroform, methylene chloride, etc.; (2) Disperse or dissolve the fine powder of the physiologically active substance, (3) add paraffin as a poor solvent while stirring, cool on ice to precipitate coacervate, (4) precipitate coacervate. After sedimentation, the supernatant liquid is discarded and the coacervate is redispersed in acetone. (5) The acetone supernatant liquid is discarded and paraffins are added again to solidify the coacervate. Then, (6) the resulting microparticles are dispersed. The particles are taken out by filtration or decantation, and the residual solvent is removed by air drying or vacuum drying to obtain dry fine particles.

When dispersing a physiologically active substance in a poly-L-lactic acid solution, a lipophilic surfactant such as sorbitanic acid esters can be added to improve dispersibility.

Furthermore, in order to further enhance the sustained release properties of the microparticles, we have added lecithin, chitosan, and other physiologically active substances.
So-called gelling agents, such as sodium alginate, gelatin, agar, carboxymethylcellulose, and gum arabic, which gel when they come into contact with water and further enhance sustained release properties, are used by dispersing them in poly-L-lactic acid. You can also do it.

The core material used in the present invention includes various physiologically active substances such as various insecticides, fungicides,
Herbicides, acaricides, pheromones, insect hormones,
Examples include agricultural chemicals such as plant growth regulators, but in a particularly preferred embodiment, the core material used is an anticancer agent, such as 5-fluorouracil, 1-(2
-tetrahydrofuryl)-5-fluorouracil,
1-hexylcarbamoyl-5-fluorouracil, mitomycin-C, adreamycin, carcinophilin, bleomycin, cytarabine,
Examples include carmustine and nimustine, and more suitable core materials include 5-fluorouracil and mitomycin-C, which have high water solubility and have large side effects.

Example 1 0.5 g of 5-fluorouracil (manufactured by Mitsui Toatsu Chemical Co., Ltd.), which was pre-pulverized to an average particle size of 50 μm, was added to poly-L-lactic acid [intrinsic viscosity value (η) = 0.85 (measured in chloroform)] ] was dispersed at room temperature with stirring in 30 ml of a /W/V% dichloromethane solution. After adding 33 ml of n-heptane while stirring, the mixture was left to cool on ice. 5-fluorouracil coated with coacervate precipitates in the lower layer.

After removing the supernatant by decantation, 20 ml of acetone was added, stirred at room temperature, left to stand again, and the supernatant was removed.Furthermore, 35 ml of n-heptane was added and thoroughly stirred to completely solidify the coacervate. After filtration, 0.7 g of microparticles in which 5-fluorouracil was coated with poly-L-lactic acid was obtained. The microparticles showed no tendency to agglomerate and were in the form of white fine powder.

An electron micrograph (x500) of the crystals of 5-fluorouracil used here is shown in Figure 1, and an electron micrograph (x500) of poly-L-lactic acid microcapsules of 5-fluorouracil is shown in Figure 2. Shown in the figure.

Comparative Example 1 A solution of 1.0 g of poly-D,L-lactic acid [intrinsic viscosity [η] = 0.53] in 50 ml of toluene was cooled to about -65°C in a dry ice isopropanol bath. 0.5 g of 5-fluorouracil, which had been finely ground in advance to have an average particle size of 100 μm, was added to the polymer solution with stirring and dispersed.

Add isopropanol (150ml) to the dispersion first.
When the solution was added dropwise for 1 hour to 50 ml and 0.5 hour to the remaining 100 ml, coacervate of poly-D,L-lactic acid was precipitated around 5-fluorouracil. However, when the dry ice bath was removed and the system was gradually returned to normal temperature, the coacervates began to soften and aggregate from around -30°C, and when the temperature returned to room temperature, they completely became soft aggregates, producing the desired poly-D, L.
- It was not possible to obtain microparticles of 5-fluorouracil coated with lactic acid.

Comparative Example 2 The same process as in Example 1 was carried out except that poly-D,L-lactic acid (intrinsic viscosity [η]=0.71) was used instead of poly-L-lactic acid. When the first n-heptane was added, the precipitated poly-D,L-lactic acid softened and agglomerated, and the desired microparticles could not be obtained.

Example 2 Poly-L-lactic acid obtained by heating and dehydrating 1 g of mitomycin-C fine powder (manufactured by Kyowa Hakko Kogyo) with L-lactic acid in the presence of a tin octoate catalyst [intrinsic viscosity value in chloroform] η〕=0.96〕1w/
% dichloromethane solution at room temperature with stirring. When 30 ml of n-hexane is added with stirring and the system is cooled to 5 DEG C. with stirring, coacervate of poly-L-lactic acid precipitates around mitomycin-C and hardens. After leaving to stand and removing about half of the supernatant, add 0.2 g of powdered lecithin and mix and dissolve. Further, 30 ml of acetone is added, stirred at room temperature, and left to stand again to allow lecithin to accumulate on the coacervate wall, and then the supernatant is removed. Further, 50 ml of n-hexane was added and thoroughly stirred to completely solidify the coacervate membrane, followed by filtration and drying to form mitomycin coated with poly-L-lactic acid modified with lecithin.
1.2 g of C was obtained. The microparticles showed no tendency to agglomerate and were in the form of a purple fine powder.

Example 3 5-G was crushed in advance to have an average particle size of 50μ.
0.5 g of fluorouracil and 0.5 g of finely pulverized chitosan (manufactured by Kyowa Yushi Kogyo) were dissolved in 30 ml of a 2 w/v % dichloromethane solution of poly-L-lactic acid [intrinsic viscosity value in chloroform: 0.78] with stirring. . Thereafter, the same treatment as in Example 1 was carried out to obtain 1.3 g of white fine powder particles.

Example 4 5 coated with lecithin-modified poly-L-lactic acid treated in the same manner as in Example 2 except that 5-fluorouracil was used in place of mitomycin-C.
- Microparticles of fluorouracil were obtained.

[Brief explanation of the drawing]

Figure 1 is an electron micrograph (×500) used as a drawing of 5-fluorouracil used in Example 1.
FIG. 2 is an electron micrograph (×500) used as a drawing of the poly-L-lactic acid microcapsules of 5-fluorouracil obtained in Example 1.

Claims (1)

[Claims] 1. In producing microparticles of a physiologically active substance by a phase separation method, poly-L-lactic acid is used as a coating material, and a physiologically active substance that is insoluble in a good solvent for poly-L-lactic acid is used as a coating material. A method for producing microparticles, characterized in that the core material is used as a core material. 2. The method according to claim 1, which uses poly-L-lactic acid having an intrinsic viscosity of 0.3 to 3.0 in chloroform.