JPH0372097B2 - - 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 polymeric materials.

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 a biodegradable aliphatic polyester as a polymer material and a physiologically active substance as a core material.

The core material of the desired particle size is dispersed in a continuous phase consisting of a solution of the coating material polymer, and the polymer is precipitated around the core material, such as by adding a non-solvent to the polymer and/or cooling the solution. The preparation of coalesced coated microcapsules is known as a phase separation method from organic solution systems, but such methods usually result in unfavorable agglomeration of the encapsulated particles and do not allow useful single particles with controlled particle size. No microcapsules were obtained.

In particular, in recent years, biodegradable polymers such as polylactic acid such as poly-DL-lactic acid and poly-L-lactic acid,
Biodegradable aliphatic polyesters such as copolymers of lactic acid and glycolic acid are attracting attention as coating materials for microcapsules or matrix materials for microspheres. However, even when attempts are made to produce microcapsules using such biodegradable polymers by the method described above, giant soft aggregates are produced, which is extremely insufficient as microcapsules.

As a method to suppress such aggregation, -40℃
A phase separation method at extremely low temperatures of ~-100℃ has been proposed (Japanese Patent Application Laid-Open No. 54-55717), but even with this method,
The agglomeration tendency of microcapsules or microspheres cannot be completely resolved, and when relatively low molecular weight polylactic acid or lactic acid copolymers are used, soft agglomerates result, making it difficult to obtain the desired microcapsules. I can't do it.

On the other hand, as a method for producing microparticles using polylactic acid or lactic acid copolymer as a coating material or as a homogeneous mixture with the core, the core material is dissolved in a low boiling point solvent such as methylene chloride or benzene. This is an application of the so-called "in-liquid drying method" in which microparticles are obtained by dissolving or dispersing a protective colloid such as gelatin or chitosan in an aqueous solution of a protective colloid such as gelatin or chitosan, and then raising the temperature of the system to volatilize the solvent. can also be considered. However, in this method, the core material, which generally has a considerable degree of water solubility, flows into the water layer and is not coated or mixed well with the polylactic acid or lactic acid copolymer, making it impossible to obtain the desired microparticles. Nakatsuta.

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. It has been found that if the treatment is carried out in the presence of polyvinylpyrrolidone, the tendency to agglomerate can be suppressed and desired microparticles can be produced, and the method of the present invention has been achieved.

That is, the method of the present invention is 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, in the presence of polyvinylpyrrolidone. This is a method for producing microparticles using a biodegradable polymer, which is characterized in that the microparticles are precipitated at a temperature of -20 to 50°C.

More specifically, (a) the biodegradable polymer is dissolved in a good solvent, the core material is dispersed or dissolved in this solution, (b) polyvinylpyrrolidone is then added, and (c)
Furthermore, liquid oils and fats are added as a poor solvent to cause coacelvation, and microparticles are precipitated at a temperature of -20 to 50℃, and (d) the precipitated microparticles are separated from the continuous phase. , is a method for obtaining microparticles.

Such microparticles obtained by the method of the present invention are microcapsules consisting of particles of a core material and an outer layer of polymeric material covering them, or microspheres which are a homogeneous mixture of the core material and the polymer. The microparticles mean individual microcapsules or microspheres or aggregates thereof having a particle size distribution between 1 and 500 microns, generally between 20 and 300 microns.

That is, in the method of the present invention, a biodegradable polymer is dissolved in a good solvent, and a poor solvent as a phase separation agent is added to a continuous phase in which a core material is dissolved or dispersed in this solution to form an organic solvent system. A feature of this method is that the presence of polyvinylpyrrolidone allows the microparticles to be obtained under mild temperature conditions when the microparticles are precipitated by the phase separation method.

In other words, the method of the present invention is more effective than the method of adding a phase separating agent at an extremely low temperature of -40 to -100°C as disclosed in JP-A No. 54-55717.
Biodegradable polymers such as polylactic acid or lactic acid-glycolic acid copolymers, which can undergo phase separation under mild temperature conditions of about ℃ degree and have a wide molecular weight range, prevent large aggregated particles that are inconvenient during phase separation. It is extremely useful industrially because it can be used without producing much product.

Also, Chem.Pharm.Bull., 29 , (11)3363−3368
(1981), hydrophilic colloid substances,
For example, in an aqueous solution of gelatin, alginate, etc., a low-boiling organic solvent solution of polylactic acid (polylactic acid dissolved as microparticles) is added, stirred and emulsified, and the low-boiling organic solvent is vaporized and distilled off at elevated temperature or under reduced pressure. This method of obtaining polylactic acid microspheres or microcapsules is inappropriate for water-soluble physiologically active substances because they elute into the water layer and form aggregates. Ta.

However, since the method of the present invention does not use water, an appropriate solvent is selected for phase separation, and a wide range of compounds, including the water-soluble biologically active substances mentioned above, are added to the core material. Microcapsules or microspheres can be produced in high yield.

Therefore, the method of the present invention having the various features described above is suitable for producing microparticles of water-soluble pharmaceutical agents. In other words, the obtained microparticles exhibit sustained release in the living body, and the polyvinylpyrrolidone used hardly remains in the microparticles, and even if a small amount remains, it will have no adverse effect on the living body. Never.

For example, anticancer drugs, especially water-soluble 5-fluorouracil, are known to have strong side effects, and when administered orally,
The concentration in the blood increases rapidly, causing serious side effects.
On the other hand, it is not possible to maintain the medicinal effect for a long period of time. Administration of such anticancer agents in the form of microparticles produced by the method of the invention (oral, injection, or local administration by surgical therapy, implantation)
By doing so, the release of the anticancer agent is suppressed, and it is gradually released along with the hydrolysis of the polymer, allowing its blood concentration to be maintained over a long period of time.

The biodegradable polymers used as coatings or matrix materials for microparticles in the method of the present invention include lactic acid, glycolic acid, hydroxybutyric acid, which hydrolyzes in vivo, is harmless to living organisms, and is easily sprayed. It is a biodegradable aliphatic polyester. Specifically, polylactic acid, poly(ε-caprolactone), polyglycolic acid or polyhydroxybutyric acid, or copolymers thereof, preferably poly-L-lactic acid, poly-DL-lactic acid, and lactic acid, are used. % or more, and generally has an intrinsic viscosity of 0.2 to 1.5 (measured at a concentration of 0.5% at 30±0.1°C in a mixed solvent of 10 parts by weight of phenol and 7 parts by weight of trichlorophenol). What you have is used.

Such biodegradable aliphatic polyesters include, for example, ethyl cellulose, acrylic acid polymers,
To provide microparticles for sustained release drugs that are extremely useful and do not leave behind foreign substances that are not ultimately metabolized in the living body, such as non-biodegradable polymers such as various synthetic resins such as polycarbonate. Become.
The core materials used in the method of the present invention include various physiologically active substances, such as various pharmaceuticals, insecticides, seedlings, herbicides, acaricides, pheromones, insect hormones, and agricultural chemicals such as plant growth regulators. etc. In particular, the core material used in a preferred embodiment is an anticancer agent, such as 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil, 1-hexylcarbamoyl-5-fluorouracil, mitomycin C, adreamycin. , carcinophylline, bleomycin, cytarabine, carmustine, nimustine, etc. More suitable core materials include 5-fluorouracil and mitomycin-C, which have high water solubility and have large side effects.

In the method of the present invention, the polyvinylpyrrolidone used as a phase separation inducer and an agglomeration prevention agent for the obtained microcapsules or microspheres is not particularly limited, and generally has a molecular weight of 1 to 10.
Ten thousand things are used.

Examples of good solvents for aliphatic polyesters in the method of the present invention include organic solvents such as toluene, xylene, chloroform, methylene chloride, acetone, ethyl acetate, methyl acetate, tetrahydrofuran, dioxane, and hexafluoroisopropanol. Particularly preferred are methylene chloride and chloroform.

The oils and fats used as a poor solvent for phase separation in the method of the present invention include vegetable oils and animal oils, and specific examples of vegetable oils include soybean oil, linseed oil,
Liquid at room temperature such as tung oil, sesame oil, cottonseed oil, olive oil, camellia oil, castor oil, corn oil, rapeseed oil, coconut oil, wheat oil, barley oil, poppy oil, shiitake oil, perilla oil, tangerine oil, lemon oil, etc. drying oils, semi-drying oils or non-drying vegetable oils, or animal fats and oils that are liquid at room temperature.

The method of the invention is carried out as follows.

That is, (A) the biodegradable polymer is dissolved in its good solvent, and the fine powder of the core material is dispersed or dissolved in the solution, (B) polyvinylpyrrolidone is then added, and (C) the biodegradable polymer is further dissolved at room temperature as a poor solvent. (D)
The continuous phase is removed to obtain microparticles, which are (E) washed with the core material and a common poor solvent for biodegradable polymers and dried.

In such a method, the biodegradable polymer is dissolved in advance at a concentration of 0.5 to 10 wt% in a good solvent.

The core material is added to this solution and dissolved or dispersed. When the solvent selected as a good solvent is also a good solvent for the core material, it is appropriately dissolved in the solution. By melting the matrix material and the core material together in this manner, microspheres in which both are homogeneously mixed are obtained.

On the other hand, when the core material is insoluble in a good solvent for the biodegradable polymer, the core material is finely ground and dispersed in the solution depending on the size of the desired microparticles.

In the method of the present invention, the desired microparticles can be obtained without the core material of these microparticles forming a large agglomerate.

Note that the core material may coexist in a dissolved state and a dispersed state. The ratio of the core material to the coating or matrix polymer is 5:95 to 95:5 (weight ratio), taking into consideration the sustained release effect in the body and the required amount of anticancer drug.
generally selected within the range of

or more coating or matrix material,
Polyvinylpyrrolidone is added to the solution in which the core material is dissolved or dispersed.

The amount of polyvinylpyrrolidone added is 10 to 1000 parts by weight per 100 parts by weight of the biodegradable aliphatic polyester used as the coating or matrix material.

The method of addition is not particularly limited, and it is generally preferable to add it as a solution dissolved in the same solvent as the above-mentioned solvent.

The subsequent precipitation and separation of microparticles follows a known phase separation method. For example, a biodegradable polymer is precipitated as a coacervate on the surface of a physiologically active substance as a core material or uniformly with the core material by adding the above-mentioned fats and oils as a phase separating agent as a poor solvent, and depositing the biodegradable polymer as a coacervate at room temperature to -20°C. After cooling to harden the precipitated coacervate and removing the supernatant, the biodegradable polymer used and the bioactive substance used as the core material are treated with a low boiling point organic solvent that has no solubility, such as fat. Group hydrocarbons, n-hexane, heptane, i-octane, cyclohexane,
After washing, the resulting microcapsules or microspheres are dried to form a dry free-flowing powder. Drying can be carried out according to known methods such as air drying, reduced pressure drying, or freeze drying.

Hereinafter, the present invention will be specifically explained with reference to Examples and Comparative Examples.

Example 1 1 g of 5-fluorouracil (manufactured by Mitsui Toatsu Chemicals), which had been crushed in advance to have an average particle size of 100μ, was
Poly-DL-lactic acid [intrinsic viscosity [η] = 0.53...phenol/trichlorophenol = 10/7 (weight ratio)
Measured at a concentration of 0.5% at 30℃ in a mixed solvent of
It was dispersed in 100 ml of a 3 w/v% dichloromethane solution with stirring. To this, polyvinylpyrrolidone [manufactured by GAF, trade name Plasdone C-30]
A suspension of 5-fluorouracil is prepared by adding 100 ml of a 3 w/v % dichloromethane solution under stirring. After gradually adding 50 ml of soybean oil while stirring, the mixture was cooled to 0°C and left for 30 minutes to cause precipitation of coacervate of poly-DL-lactic acid on the surface of 5-fluorouracil and hardening of the coacervate. After that, the supernatant liquid was removed by decantation and washed three times with 100 ml of n-hexane.
Remove the solvent under reduced pressure and dry to form a free-flowing polyurethane.
DL-lactic acid coated 5-fluorouracil microcapsules are obtained. The obtained microcapsules had no undesirable agglomeration and fusion tendency, and were monodispersed microcapsules having almost the same shape as 5-fluorouracil used as the core material.

Example 2 2 g of 1-(2-tetrahydrofuryl)-5-fluorouracil, which was pre-pulverized to have an average particle size of 50 μ, was added to 2.5% dichloromethane of poly-DL-lactic acid [intrinsic viscosity [η] = 0.71]. solution 200
ml, a 1w/v% dichloromethane solution of polyvinylpyrrolidone (GAF, Plasdone C-15) was added under stirring to form a suspension of 1-(2-tetrahydrofuryl)-5-fluorouracil. It was created.

After slowly adding 200 ml of oil while stirring, the system was slowly cooled to -5℃ and left stirring for 1 hour.
Coacervate precipitation of poly-DL-lactic acid on the surface of -tetrahydrofuryl)-5-fluorouracil and curing of the coacervate were performed. The supernatant was then removed, washed three times with 100 ml of n-heptane, and lyophilized to form a free-flowing polyurethane.
DL-Lactic acid coated 1-(2-tetrahydrofuryl)-
Microcapsules of 5-fluorouracil were obtained.
The obtained microcapsules were free from undesirable aggregation and fusion.

Example 3 Example-1 except that mitomycin-C (manufactured by Kyowa Hakko Co., Ltd.) was used instead of 5-fluorouracil.
Microcapsules of mitomycin-C coated with free-flowing poly-DL-lactic acid were obtained in the same manner as above.

Comparative Example 1 A solution of 1.0 g of poly-DL-lactic acid [intrinsic viscosity [η] = 0.53] in 50 ml of toluene was placed on dry ice.
Cooled to about -65°C in an isopropanol bath. Finely ground in advance to an average particle size of 100μ,
0.5 g of 5-fluorouracil was added to the polymer solution.
Dispersion was performed while stirring at 160 rpm.

Add isopropanol (150ml) to the dispersion first.
When the solution was added dropwise for 1 hour for 50 ml and 0.5 hour for the remaining 100 ml, coacervate of poly-DL-lactic acid precipitated around 5-fluorouracil. However, when the dry ice bath is removed and the system is gradually returned to room temperature, the coacervates begin to soften and aggregate, and when the temperature is returned to room temperature, they completely become soft aggregates and form the desired 5-fluorouracil microcapsules. I couldn't get it.

Comparative Example 2 1.8 g of poly-DL-lactic acid was dissolved in 40 g of methylene chloride with stirring, and then 0.2 g of 1-(2-tetrahydrofuryl)-5-fluorouracil, which had been ground to an average particle size of 50 μ, was added. The mixture was added and dispersed under stirring.

Separately, acid-treated gelatin [manufactured by Miyagi Chemical, jelly strength]
250 Bloom] was added to 198 g of water and dissolved by heating at 50°C to prepare a 1% aqueous solution, which was then cooled to room temperature. Transfer the gelatin aqueous solution into a beaker and stir for 1 hour.
A methylene chloride solution in which -(2-tetrahydrofuryl)-5-fluorouracil was dispersed was added and emulsified by stirring at a speed of 300 vpm. After methylene chloride was evaporated by gradually heating from the outside, some aggregates in the upper layer were removed, and the mixture was further washed with warm water and air-dried to obtain spherical particles with a particle size of 30 to 200 μm.

However, as a result of elemental analysis, such spherical particles contain only 0.1% of 1-(2-tetrahydrofuryl)-5-fluorouracil, and 1-(2-tetrahydrofuryl)-5-fluorouracil. )−
Due to its own water solubility (1.60 g/100 ml water at 24°C), the majority of 5-fluorouracil was eluted into the water layer, making it impossible to obtain microparticles with the desired sustained release properties. Ta.

Claims (1)

[Claims] 1. A method for producing microparticles using a phase separation method from an organic solution system, in which a physiologically active substance is used as a core material and a biodegradable polymer is used as a coating or matrix material, in the presence of polyvinylpyrrolidone, -20
A method for producing microparticles using a biodegradable polymer, characterized by performing a precipitation treatment of microparticles at a temperature of ~50°C.