JPH06211648A - Sustained release polynuclear microphere preparation and its production - Google Patents

Abstract

PURPOSE:To provide a sustained release microsphere preparation holding a drug in high efficiency, suppressing the initial burst release of drug and capable of releasing a drug at an arbitrary rate and to provide a process for the preparation of the microsphere. CONSTITUTION:This sustained release polynuclear microsphere preparation is composed of two or more kinds of polymers degradable in vivo and a drug, wherein a biodegradable polymer (1st polymer) containing the drug is dispersed in the form of microscopic particles in the other biodegradable polymer (2nd polymer). The incorporation ratio of the drug is high and the releasing pattern of the drug often takes the zeroth-order release pattern. The releasing pattern of the drug can be varied by varying the combination of the 1st polymer and the 2nd polymer and the compounding ratio of the polymers.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sustained-release composition containing a physiologically active substance using a biodegradable polymer. More specifically, the present invention relates to a sustained-release polynuclear microsphere preparation that efficiently encapsulates a drug and releases the drug at an arbitrary rate by selecting and using two or more kinds of biodegradable polymers, and a method for producing the same. .

[0002]

2. Description of the Related Art Microspheres using biodegradable polymers are extremely useful as dosage forms for sustaining the effects of physiologically active substances for a long period of time, and various production methods have been proposed. For example, JP-A-57-11851 discloses a method for preparing capsule-type microspheres by a phase separation method using a coacervation agent. However, in this preparation method, aggregation of particles is likely to occur in the manufacturing process, and since a nonvolatile mineral oil or vegetable oil is used as a dispersion medium, it is difficult to take out and wash, and often the inside becomes hollow. There are problems such as not being able to obtain a product of constant quality. As a method for overcoming these problems, a method of drying an emulsion in liquid to obtain microspheres is known, and it is disclosed in JP-A-60-10051.
6, JP-A-62-201816, W / O / W type, JP-A-1-216918, O / O type, JP-A-63-91325.
Discloses an O / W type technology.

In general, most physiologically active substances that require long-term sustainability are water-soluble. Therefore O /
The method of drying the O-type emulsion in the liquid is an advantageous method for efficiently incorporating the active substance into the microspheres, but a non-volatile solvent is often used in the dispersed phase, and the solvent is completely removed from the microspheres. It is difficult to remove, and it leaves many problems in work safety and environment. In the W / O method, since mineral oil and vegetable oil are used for the outer O phase, there are difficulties in taking out and washing, workability is poor, and the remaining oil phase poses a serious problem.

Since the W / O / W method and the O / W method do not have the problem of residual solvent as in the O / O method because the outer phase is an aqueous phase, the drug in the oil phase is often used in the liquid drying process. There was a problem that the drug was dissolved in the aqueous phase and the drug uptake into the microspheres was significantly reduced. In order to overcome this drawback, JP-A-60-100516 and JP-A-62-201816.
Discloses a W / O / W method in which gelatin is dissolved in an inner aqueous phase. However, in the W / O / W method, the operation is complicated, and in order to obtain a preparation of constant quality, it is necessary to control the production conditions in a wide variety and precisely. In addition, this method limits the types of drugs that can be effectively applied. Further, in this method, sterility and depyrogenation of gelatin and the like, which are usually used as additives in the drug holding phase, pose problems.

[0005]

From the viewpoint of workability and safety, it is desired to devise a microsphere which can be obtained by a simple operation and which does not reduce the drug uptake rate.
However, in the known phase separation method, in-liquid drying method from various emulsions, the drug uptake rate is generally low,
It is difficult to completely suppress burst elution in which a rapid drug release occurs at the initial stage of elution. This is because the drug in the oil phase is in direct contact with the water phase during the in-liquid drying operation, and may be easily leaked to the outer phase by distribution / diffusion.

[0006]

DISCLOSURE OF THE INVENTION The inventors of the present invention have made extensive studies in order to solve the above problems in the prior art. As a result, two kinds of biodegradable polymers are separately mixed with the same or different water. When dissolved in an organic solvent that does not exist and mixed together, the two types of biodegradable polymers do not mix with each other and separate, and when vigorously stirred, O /
It was found to form an O-type emulsion. When a drug was added here, the drug was more distributed in one polymer and formed a discontinuous phase. When the O / O type emulsion containing the drug thus prepared is dispersed in water, an O / O / W type emulsion is produced. Therefore, it was found that when this was dried in a liquid, microspheres in which the drug was dispersed in a plurality of islands were obtained. In this case, as shown in the schematic diagram (FIG. 3), the drug is distributed largely in one polymer phase which is dispersed in an alloy inside, and the distribution is small in the outer layer portion. This outer layer also plays a role of preventing contact between the drug and the outer aqueous phase or the eluate.
Due to having such a structure, O / O /
It was found that the multi-capsule type microspheres made of W-type emulsion have a high drug uptake rate and a property capable of suppressing the initial bursty dissolution in the dissolution test.

The microsphere preparation of the present invention is composed of two or more kinds of biodegradable polymers and a drug, and the microregions of one biodegradable polymer (first polymer) are used in the other biodegradable polymer. A sustained-release polynuclear microsphere preparation having an internal structure dispersed in a region (second polymer) and containing a drug in the microregion.

The drug contained in the preparation of the present invention is not particularly limited, and examples thereof include anticancer agents, antibiotics, bioactive polypeptides, antipyretics, analgesics, immunostimulants, immunosuppressants, and anti-inflammatory agents. Inflammatory agents, antitussives, antiepileptic agents, antihistamines, antihypertensive diuretics, antidiabetic agents, muscle relaxants,
Antiulcer agents, antidepressants, antiallergic agents, angina agents, antiarrhythmic agents, vasodilators, anticoagulants, hemostatic agents, antituberculosis agents, narcotics antagonists, hormone agents, etc. Of these, sparingly soluble drugs are preferred.

The biodegradable polymer used as the base material of the microsphere may be any polymer as long as it has no physiological activity and has the property of degrading and disappearing in vivo. Examples include homopolymers such as lactic acid, glycolic acid, malic acid and hydroxybutyric acid, and copolymers thereof. Especially, the average molecular weight is 1,
000 to 500,000 polylactic acid as well as lactic acid glycolic acid copolymers are preferred. The content of the drug with respect to the biodegradable polymer can be arbitrarily selected and varies depending on the kind of the drug, the desired pharmacological effect and the release time, but is about 0.01 to about 40% (W / W), particularly 0. .01-
20% is preferable.

In the microsphere preparation of the present invention, two or more kinds of biodegradable polymers are dissolved in the same or different water-immiscible organic solvents, and the drug is dissolved or dispersed in one of them and then both are dissolved. It can be produced by mixing to prepare an O / O type emulsion, dispersing this emulsion in water to prepare an O / O / W type emulsion, and then drying the resulting microspheres in liquid. .

The O / O type emulsion can be produced by a conventional method. For example, a drug is dissolved or dispersed in an organic solvent of one biodegradable polymer, and this is dissolved in the same organic solvent. It can be easily carried out by emulsifying in the biodegradable polymer of 1 or by adding a drug to an organic solvent solution in which both polymers are dissolved and emulsifying. The combination of the two types of polymers used here are each dissolved in an organic solvent system, but when the two are mixed, the respective phases are not compatible, and one polymer (first polymer) is the other polymer (second polymer). ), Any combination that forms an alloy may be used, such as a combination of a lactic acid homopolymer and a lactic acid glycolic acid copolymer. Further, each of these first and second polymers can be used in the form of a mixture of two or more polymers.

The organic solvent is a solvent which becomes an oil phase of the O / O / W type emulsion, and may be any solvent as long as it is volatile, has low solubility in water, and is a good solvent for the polymer. For example, chloroform, methylene chloride, carbon tetrachloride and the like can be mentioned. Further, a solvent compatible with these solvents (for example,
A mixed solvent added with ethyl ether, ethyl acetate, etc.) can also be used. In particular, methylene chloride is preferable when polylactic acid and lactic acid glycolic acid copolymer are used as the biodegradable polymer.

In the present invention, as the first polymer and the second polymer, generally, the polymer used in a large amount forms a continuous layer in the O / O type emulsion to become the second polymer, and the polymer used in a small amount is Since the O / O emulsion is dispersed in the continuous layer to form fine droplets to be the first polymer, it can be selected using this as an index. The weight ratio of the first polymer and the second polymer to be used may be determined based on the above index and is not particularly limited. For example, one having 1 to 1 of the first polymer and 1 to 10 of the second polymer is exemplified. To be Among these, a preferable weight ratio is 1 to 1 for the first polymer and 2 to 4 for the second polymer. For example, in the case of a combination of polylactic acid and lactic acid-glycolic acid copolymer,
When the molecular weights are the same and the weight ratio is 2 for polylactic acid and 1 for lactic acid-glycolic acid copolymer, the lactic acid-glycolic acid copolymer forms microdroplets to become the first polymer. In the case of the above combination, when the weight ratio is opposite, polylactic acid forms microdroplets and becomes the first polymer.

The drug is unevenly distributed in either polymer solution due to its affinity with the first or second polymer. Therefore, in the present invention, by utilizing the above relationship, it is possible to obtain a microsphere having an excellent sustained release property by incorporating a drug in a polymer forming microdroplets. For example, when the drug is unevenly distributed in the continuous phase (that is, the second polymer) in the O / O emulsion, the drug can be contained in the microdroplets by changing the weight ratio of the polymer. , The combination of drug and polymer can be easily selected.

Generally, when the viscosity increases, coalescence between particles is suppressed, so that the O / O type emulsion is stabilized, and it is possible to manufacture microspheres having a small particle size in the internal fine region. By adopting a high molecular weight polymer as one of the two biodegradable polymers, it may be possible to produce a microsphere having a small particle size in the internal microscopic region as described above. It is possible to control the particle size of minute regions inside the microsphere.

In the present invention, the effects of the first polymer and the second polymer are as follows. Since the first polymer has a higher affinity for the drug than the second polymer, the drug can be selectively retained. The second polymer has two major effects. First, the O prepared according to the present invention
/ O-type emulsion is further emulsified in the water phase to produce O / O /
When it is a W-type emulsion, it has the effect of not letting the drug held in the first polymer escape into the aqueous phase. By this,
A high uptake rate can be obtained. Secondly, when the microspheres come into contact with the body fluid, the alloy of the inner phase composed of the first polymer is prevented from directly contacting with water, and as a result, it has the effect of controlling the release such as the suppression of the initial burst-like elution.

The O / O / W type emulsion can be prepared by adding the O / O type emulsion to the aqueous phase and emulsifying. An anticoagulant may be added to the aqueous phase in order to prevent coalescence of the oil phase and aggregation of the produced microspheres. Any anticoagulant may be used as long as it is generally used, and examples thereof include polyhydric alcohols such as polyvinyl alcohol and polyethylene glycol, surfactants, polysaccharides such as chitosan, gelatin, and gum arabic. The concentration of this anti-aggregating agent in the aqueous phase is 0.01 to 10% (w / v), especially 0.1 to 10.
2% (w / v) is preferred. It is possible to control the particle size and the particle size distribution of the microspheres by changing the type and concentration of the anticoagulant added. The emulsification operation can be easily performed by a propeller-type stirrer, a turbine-type emulsifier, an ultrasonic disperser, a high-pressure emulsifier, or the like.

The emulsion thus obtained is dried in a liquid to produce microspheres. In-liquid drying is a heating method,
It can be carried out by a conventional method such as a reduced pressure method. For example, in the heating method, the temperature is raised while stirring the emulsion with a propeller type or turbine type stirrer to distill off the solvent. The stirring speed varies slightly depending on the equipment and the charged amount, but it is about 10
To about 25,000 rpm, particularly preferably 50 to 100
It is 00 rpm. The temperature is raised for about 0.5 to about 4 hours. The initial temperature is preferably 0 to 25 ° C, and the maximum temperature after the increase is preferably 25 to 50 ° C. In the depressurization method, the emulsion is gradually depressurized with a suitable depressurizing device such as a rotary evaporator to about 0.1 to 50 mm / Hg, and the solvent is distilled off. The microspheres obtained by in-liquid drying are separated by a method such as centrifugation or filtration, washed with distilled water, and the solvent is completely distilled off by air-drying or vacuum-drying to give the microspheres of the present invention. You get a sphere. Depending on the dosage form, the washed microspheres are suspended in an appropriate solution and lyophilized to prepare the final formulation. The particle size of the microspheres obtained by the above method has an average particle size of 0.01 μm to 50 μm.
It is 0 μm. Generally, by increasing the ratio of the amount of the organic solvent to the amount of the polymer in the oil phase, the particle size of the obtained microspheres becomes fine.

The thus-obtained microspheres have a high drug uptake amount, and the elution pattern is often a zero-order release type as shown in Examples. Further, the elution pattern can be variously changed by changing the combination of the first polymer and the second polymer and the compounding ratio. The microsphere of the present invention can be directly administered to a living body as an implant. It can also be used as a raw material when manufacturing various preparations. Examples of such preparations include injections, oral administrations, transdermal administrations, suppositories, nasal administrations, buccal administrations and intraocular administrations.

[0020]

EXAMPLES Next, the present invention will be described more specifically by way of examples, but the present invention is not limited to these examples as a matter of course.

Example 1 A lactic acid-glycolic acid copolymer (hereinafter referred to as PLG) having a molar ratio of lactic acid and glycolic acid of 50:50 and a molecular weight of 20,000.
A5020) 300 mg, and cisplatin (CDDP) 100 mg as a drug, methylene chloride 500 mg.
Was added (solution A). Separately, 600 mg of polylactic acid having a molecular weight of 20,000 (hereinafter abbreviated as PLA0020) was dissolved in 1 g of methylene chloride (solution B). Solution A is added to solution B and the emulsifier [Polytron (Kinematica, AG, Ritau (Ki
nematica Ag Littau) (trade name, Switzerland)] was emulsified for 30 seconds at a rotation speed of 12,000 rpm to obtain an O / O type emulsion containing the liquid A in the internal phase. It was added to 400 ml of a 0.5% polyvinyl alcohol aqueous solution at 15 ° C. using a Pasteur pipette, and emulsified with a Polytron at a rotation speed of 12,000 rpm for 5 minutes to obtain an O / O / W type emulsion. Then, while stirring at 400 rpm with a four-bladed paddle, the temperature was raised to 15 to 30 ° C. over 3 hours to perform in-liquid drying to obtain microspheres. Then, the microspheres were collected by centrifugation, washed with distilled water three times, and filtered with a membrane filter, and then dried under reduced pressure at room temperature for a whole day and night. The resulting microspheres have an average particle size of about 50 μm and mostly 10
The particles were yellow spherical particles of 0 μm or less (Preparation 1).

Example 2 PLGA5020 (300 mg), CDDP (100 m
g), PLA0020 (600 mg) was added with methylene chloride (1.5 g). Rotate this with Polytron 1
The mixture was mixed at 2,000 rpm for 30 seconds to obtain an O / O type emulsion in which cisplatin was distributed in the inner phase. Microspheres were obtained in the same manner as in Example 1 below (Formulation 2).

Example 3 PLGA5020 (300 mg) and CDDP (100 m)
Methylene chloride (500 mg) was added to g) (Liquid A).
Separately, polylactic acid having a molecular weight of 10,000 (hereinafter PLA0010
(Abbreviated) (600 mg) was dissolved in methylene chloride (1 g) (solution B). Solution A was added to solution B and emulsified with a polytron at a rotation speed of 12,000 rpm for 30 seconds to obtain an O / O type emulsion containing solution A in the internal phase. Microspheres were obtained in the same manner as in Example 1 below (Formulation 3).

Comparative Examples 1-3 PLGA5020 as a comparison of formulations 1, 2 and 3
Methylene chloride (1.5 g) was added to (900 mg) and CDDP (100 mg), and the rotation speed was 12.0 with a polytron.
The mixture was emulsified at 00 rpm for 30 seconds. Microspheres were obtained in the same manner as in Example 1 below (Comparative Formulation 1). Also,
PLA0020 (900 mg) and CDDP (100 m
Methylene chloride (1.5 g) was added to g), and the mixture was emulsified with a Polytron at a rotation speed of 12,000 rpm for 30 seconds. Microspheres were obtained in the same manner as in Example 1 below (Comparative Formulation 2). Furthermore, PLA0010 (900 mg) and C
Add methylene chloride (1 g) to DDP (100 mg),
The emulsion was emulsified with a Polytron at a rotation speed of 12,000 rpm for 30 seconds. Microspheres were obtained in the same manner as in Example 1 (Comparative Formulation 3).

Experimental Example 1 Measurement of the drug uptake rate (% of the amount actually taken in relative to the prescribed amount) of the microspheres obtained by the above method,
And an in vitro dissolution test was carried out against isotonic phosphate buffer of pH 7.4 at 37 ° C. The quantification of CDDP was performed with an atomic absorption meter (HITACHI 180-80). The incorporation rates of CDDP in Formulations 1 to 3 and Comparative Formulations 1 to 3 are shown in Table 1. It was found that the uptake rate of the microspheres produced by the production method according to the present invention was significantly higher than that of the comparative preparation. The results of the dissolution test of Formulations 1 and 2 are shown in FIGS. 1 and 2. From these results, it was shown that the microspheres prepared by this method had a higher uptake rate than the microspheres prepared by one kind of polymer and was a zero-order release type formulation.

[0026]

[Table 1]

Example 4 A solution of PLA0020 (333 mg) in acetonitrile (1 ml) and human calcitonin (1 mg) in methanol (0.5 ml) were mixed in advance and the solvent was distilled off under reduced pressure, followed by methylene chloride (500 mg). ) Was added (A
liquid). Separately, PLGA5020 (667 mg) was dissolved in methylene chloride (1 g) (solution B). Solution B was added to solution A, and the mixture was emulsified with a polytron at a rotation speed of 12,000 rpm for 30 seconds. Microspheres were obtained in the same manner as in Example 1 below (Formulation 4).

Experimental Example 2 The drug uptake rate of the microspheres obtained in the above Example 4 was measured by the HPLC method. As shown in Table 2 below, human calcitonin was almost 100% contained in the microspheres. It was

[Table 2]

Example 5 PLA0010 (300 mg) and (4S) -as a drug
3-[(2S) -N-[(1S) -1-ethoxycarbonyl-3-phenylpropyl] alanyl] -1-methyl-2-oxo-4-imidazolidinecarboxylic acid hydrochloride (100 mg) in methylene chloride (500 mg) was added (solution A). Separately, PLGA5020 (600 mg) was dissolved in methylene chloride (1 g) (solution B). Add solution A to solution B, and rotate with Polytron at 12,000 rpm for 3
Emulsified for 0 seconds. Microspheres were obtained in the same manner as in Example 1 below (Preparation 5).

Comparative Example 4 As a comparison with Formulation 4, PLGA5020 (900 mg)
And (4S) -3-[(2S) -N-[(1S) -1-ethoxycarbonyl-3-phenylpropyl] alanyl]
Methylene chloride (1 g) was added to -1-methyl-2-oxo-4-imidazolidinecarboxylic acid / hydrochloride (100 mg), and a polytron was used at a rotation speed of 12,000 rpm for 30 minutes.
Emulsified for seconds. Microspheres were obtained in the same manner as in Example 1 below (Comparative Formulation 4).

Experimental Example 3 The drug uptake rate of the microspheres obtained in Example 5 and Comparative Example 4 was measured by an absorptiometer (HITACHI 20).
00, W1 = 280 nm, W2 = 220 nm).
2.4 mg of (4S) -3-[(2S) -N-[(1
S) -1-Ethoxycarbonyl-3-phenylpropyl] alanyl] -1-methyl-2-oxo-4-imidazolidinecarboxylic acid hydrochloride was incorporated. On the other hand, the uptake rate of Comparative Preparation 4 was almost zero.

Example 6 PLGA5020 (300 mg) and TRH (100 m
g) were mixed, and methylene chloride (500 mg) was added thereto (Liquid A). Separately PLA0020 (600 mg)
Was dissolved in methylene chloride (1 g) (Liquid B). Liquid A to B
In addition to the liquid, it was emulsified with a Polytron at a rotation speed of 12,000 rpm for 30 seconds. Microspheres were obtained in the same manner as in Example 1 below.

Example 7 PLGA5020 (300 mg) and LHRH (100 m
g) were mixed, and methylene chloride (500 mg) was added thereto (Liquid A). Separately PLA0020 (600 mg)
Was dissolved in methylene chloride (1 g) (Liquid B). Liquid A to B
In addition to the liquid, it was emulsified with a Polytron at a rotation speed of 12,000 rpm for 30 seconds. Microspheres were obtained in the same manner as in Example 1 below.

Example 8 PLGA5020 (300 mg) and vitamin B ₁₂ (1
00 mg) and mixed with methylene chloride (500 m
g) was added (solution A). In addition, PLA0020 (60
0 mg) was dissolved in methylene chloride (1 g) (solution B).
Add solution A to solution B, and rotate at 12,000 rpm with a polytron.
Emulsified at rpm for 30 seconds. Microspheres were obtained in the same manner as in Example 1 below.

Example 9 PLGA5020 (90 mg), CDDP (50 mg;
Methylene chloride (150 mg) was added to the average particle size: 1 μm (A suspension). Separately, PLA0020 (360
mg) was dissolved in methylene chloride (600 mg) to give a solution B. The suspension A was added to the solution B, which was emulsified with a polytron at a rotation speed of 12,000 rpm for 30 seconds, and the solution A (P
An O / O type emulsion containing LGA and CDDP) was obtained. Hereinafter, microspheres were obtained by the same operation as in Example 1 (Preparation 6). Further, an in vitro dissolution test of the preparation 6 obtained above was carried out in the same manner as in Experimental Example 1 (the results of this dissolution test are shown in FIG. 4).

Example 10 PLGA5020 (90 mg), CDDP (50 mg;
Methylene chloride (150 mg) was added to the average particle diameter: 1 μm (Liquid A). Separately PLA0020 (270m
g) and polylactic acid having an average molecular weight of 130,000 (90
mg, DuPont) was dissolved in methylene chloride (825 mg) to prepare a solution B. Solution A was added to solution B and emulsified with Polytron at a rotation speed of 12,000 rpm for 30 seconds to obtain an O / O type emulsion containing solution A (PLGA and CDDP) in the internal phase. Hereinafter, microspheres were obtained by the same operation as in Example 1 (Formulation 7). Further, the in vitro dissolution test of the preparation 7 obtained above was carried out in the same manner as in Experimental Example 1 (the results of this dissolution test are shown in FIG. 5).

[0037]

EFFECT OF THE INVENTION An O / O type emulsion is prepared by using two kinds of biodegradable polymers, and this is dispersed in an aqueous phase and dried in liquid as an O / O / W type. Provided is a microsphere formulation in which a drug is highly taken up and the drug is released over a long period of time.

[Brief description of drawings]

1 shows a drug dissolution curve of the microsphere preparation of the present invention (Preparation 1) obtained in Example 1. FIG.

FIG. 2 shows a drug dissolution curve of the microsphere preparation of the present invention (Formulation 2) obtained in Example 2.

FIG. 3 is a schematic diagram showing a schematic structure of the microsphere preparation of the present invention.

FIG. 4 shows a drug dissolution curve of the microsphere preparation of the present invention (Formulation 6) obtained in Example 9.

5 shows a drug dissolution curve of the microsphere preparation of the present invention (Formulation 7) obtained in Example 10. FIG.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical display location B01J 13/02 (72) Inventor Akihiro Matsumoto 1-13-13 Kitachu-shing, Hirakata-shi, Osaka (72) ) Inventor Seio Kobayashi No. 1 Shimogawara-machi, Nanzenji Temple, Sakyo-ku, Kyoto City, Kyoto Prefecture

Claims (9)

[Claims] 1. A microregion composed of two or more kinds of biodegradable polymers and a drug, wherein a micro region composed of one biodegradable polymer (first polymer) is formed from another biodegradable polymer (second polymer). A sustained-release polynuclear microsphere preparation having an internal structure dispersed in the following region and containing a drug in the microregion. 2. The biodegradable polymer is a homopolymer of lactic acid, glycolic acid, malic acid or hydroxybutyric acid, or a copolymer of at least two kinds of lactic acid, glycolic acid, malic acid and hydroxybutyric acid. The sustained-release polynuclear microsphere preparation according to claim 1. 3. The sustained-release polynuclear microsphere preparation according to claim 2, wherein the biodegradable polymer is a lactic acid homopolymer or a copolymer of lactic acid and glycolic acid. 4. A homopolymer of lactic acid or a copolymer of lactic acid and glycolic acid has a molecular weight of 1,000 to 5,000.
The sustained release polynuclear microsphere preparation according to claim 3, which is 00. 5. The sustained-release polynuclear microsphere preparation according to claim 1, wherein the first polymer is a mixture of two or more kinds of biodegradable polymers. 6. The sustained-release polynuclear microsphere preparation according to claim 1, wherein the second polymer is a mixture of two or more kinds of biodegradable polymers. 7. The sustained-release polynuclear microsphere preparation according to claim 1, wherein the weight ratio of the first polymer to the second polymer used is in the range of 1: 2-4. 8. The sustained-release polynuclear microsphere preparation according to claim 1, wherein the content of the drug is 0.01 to 40% (W / W) based on the microsphere. 9. Two or more kinds of biodegradable polymers are dissolved in the same or different water-immiscible organic solvents, and the drug is dissolved or dispersed in one of them, and then both are mixed to obtain O / O. A method for producing a sustained-release polynuclear microsphere preparation, which comprises: preparing an emulsion of a type, dispersing the emulsion in water to prepare an O / O / W emulsion, and then drying the emulsion in a liquid.