JPH0665064A - Production of sustained-release type microcapsule - Google Patents

Abstract

PURPOSE:To efficiently produce a capsule excellent in the content of a medicine and the ratio of effective utilization and useful as a medicine, an agrichemical, etc., by drying a specified W/O type emulsion according to the drying method in a liquid. CONSTITUTION:The objective capsule can be produced by preparing a W/O type emulsion composed of (A) a liquid containing a water-soluble medicine such as a polypeptide or an antibiotic as the inner aqueous layer and (B) a liquid containing a high molecular polymer such as polylactic acid as the oil phase and exhibiting 10 to 145CP viscosity and drying the resultant W/O type emulsion according to the drying method in a liquid.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing sustained-release microcapsules of water-soluble drugs such as pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art In recent years, various studies have been conducted on a method for producing sustained-release microcapsules containing a drug such as a drug or an agricultural chemical in a polymer. For example, JP-A-57-118512 discloses microencapsulation by a phase separation method using a coacervation agent such as mineral oil and vegetable oil. Also known is a method of forming a W / O / W type emulsion in which a liquid containing a drug is used as an inner water layer and microcapsulating the drug by an in-liquid drying method (for example, Japanese Patent Publication No. 42-13703). Issue). Further, in Japanese Patent Publication No. 62-201816, a W / O in which a liquid containing a water-soluble drug is used as an inner water layer when a sustained-release type microcapsule of the water-soluble drug is produced by the same in-liquid drying method.
Disclosed is a method for producing microcapsules, which comprises increasing the viscosity of a mold emulsion to about 150 cp to 10,000 cp.

[0003]

However, at present, there are some problems in the above-mentioned microencapsulation method. This problem is that in the case of microencapsulation by the phase separation method, the microcapsules stick to each other during the production process and are likely to become aggregates. In the conventional method of subjecting to W / O / W emulsion production and subsequent drying in liquid, generally, the drug is easily dissipated to the outer water layer at the stage of W / O / W stirring or in-liquid drying, and the drug is effectively used as a microcapsule. Not be converted. W / O by the same in-liquid drying method
In the method of thickening the emulsion to a high viscosity, when the W / O type emulsion is added to the outer water layer, the emulsion adheres to the inner wall of the W / O stirring container and the inner wall of the introduction pipe to the outer water layer. Since it becomes easier, it is not effectively put into the outer water layer, the content rate of the drug and the effective utilization rate are reduced, and W / O / W stirring is not performed efficiently, and a string-like aggregate is generated. There is a drawback that sometimes.

[0004]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventor has found that when producing sustained-release microcapsules of a water-soluble drug, the W / O emulsion The present invention was found to increase the drug content and effective utilization rate in microcapsules by setting the viscosity to 10 cp to less than 145 cp.

That is, the present invention uses a liquid containing a water-soluble drug as an inner water layer and a liquid containing a polymer as an oil layer W /
When an O-type emulsion is prepared and the obtained W / O-type emulsion is subjected to a submerged drying method to produce sustained-release microcapsules of a water-soluble drug, the viscosity of the W / O-type emulsion is adjusted to 10 cp. From 1
The present invention relates to a method for producing a sustained-release microcapsule containing a water-soluble drug, which is characterized in having a length of less than 45 cp.

The present invention will be described in detail below. The type of the water-soluble drug in the present invention is not particularly limited, for example, a polypeptide having physiological activity, other antibiotics, antitumor agents, antipyretics, analgesics, antiphlogistics, antitussives, sedatives, Muscle relaxants, antiepileptics, antidepressants, antiallergic agents, cardiotonics, antiarrhythmic agents, vasodilators, antihypertensive diuretics, antidiabetic agents, vitamin agents, various enzyme agents, vaccine agents, antiprotozoal agents, interferons Inducers, anthelmintics, pesticides, auxins, plant hormones, insect hormones and the like can be mentioned.

In the present invention, the viscosity may be adjusted by adding a drug holding substance to the inner water layer. The drug-holding substance is
Examples thereof include natural or synthetic rubbery or polymer compounds. Examples of the natural gum substance include gum arabic and column gum, and examples of the natural polymer compound include gelatin, casein, collagen, albumin, cellulose, agar, dextrin and the like. These may be used as they are, or may be partially chemically modified or salts thereof. Among these compounds,
Gelatin, albumin, bectin, agar and the like are particularly preferable. These compounds may be used alone or as a mixture, and the amount to be used varies depending on the type of compound, and the concentration in the inner water layer is about 0.01% to 3%.
It is selected from the amount of 0% (W / W), but it is necessary to make it possible to adjust the viscosity of the W / O type emulsion described below to 10 cp to less than 145 cp.

The high molecular weight polymer in the present invention means a high molecular weight polymer which is sparingly soluble or insoluble in water. For example, olefin, styrene, vinyl acetate, vinyl chloride, vinylidene chloride, vinyl ester, acrylic acid ester, methacrylic acid. Acid ester, acrylonitrile, methacrylonitrile,
Polycarbonates, sulfonates, polyesters, polyurethanes, polyureas, polyamides and the like can be mentioned. Among them, degradable polyesters such as polylactic acid, polyglycolic acid, poly-ε-caprolactone, poly-γ-butyrolactone, poly-δ-barrellactone. , And copolymers (for example, lactic acid-glycolic acid copolymers) of two or more kinds thereof, and blends thereof are preferably used.

The concentration of the high molecular weight polymer in the oil layer is 2 to 95% (W / W), more preferably 5 to 70% (W / W).
Chosen from. Solution containing the above polymer (oil layer)
As the polymer, a high molecular polymer dissolved in a solvent is used. The solvent may be any solvent which has a boiling point of about 100 ° C. or less and is immiscible with water and which dissolves a high molecular weight polymer, and examples thereof include halogenated alkanes (dichloromethane, chloroform, chloroethane, trichloroethane, tetrachloride). Carbon), ethyl acetate, ethyl ether and the like, and these may be used as a mixture of two or more kinds.

In the method for producing microcapsules, first, an inner water layer containing a water-soluble drug is added to a solution (oil layer) containing a polymer, followed by an emulsification operation to obtain a W / O type emulsion. . As the emulsification operation, for example, a known method such as a method using a stirrer such as a propeller stirrer or a turbine stirrer, a homogenizer method, and an ultrasonic method is used. If the viscosity of the W / O type emulsion thus obtained is from 10 cp to less than 145 cp from the beginning, the process proceeds directly to desorption of the solvent in the next oil layer. It is necessary to adjust the viscosity of the / O emulsion to 10 cp to less than 145 cp. Examples of the method include a method of cooling the W / O type emulsion, a method of making the pH acidic or alkaline, a method of adding a metal ion or an organic acid and its salt, and the like.

In this operation, it is particularly important to adjust the viscosity of the W / O type emulsion to 10 cp to less than 145 cp in order to increase the content rate and effective utilization rate of the water-soluble drug. When the viscosity is less than 10 cp, the water-soluble drug is not sufficiently contained in the microcapsules, and when it exceeds 145 cp, when the W / O emulsion is added to the outer water layer, Since it easily adheres to the inner wall of the introduction pipe, the W
The / O type emulsion is not effectively added to the outer water layer, and the content of the drug and the effective utilization rate are reduced.

Then, the W / O prepared in this way
The mold emulsion is dried in the liquid. That is, the W / O type emulsion is further added to the outer water layer to form a W / O / W type emulsion, and then the solvent in the oil layer is desorbed to prepare microcapsules. An emulsifier or the like may be added to the outer water layer, and examples thereof include anionic surfactants, nonionic surfactants, polyvinyl alcohol, gelatin and the like. These may be used alone or in combination of two or more. A commonly used method is used for desorption of the solvent of the oil layer. As the method, the pressure is gradually reduced with a propeller stirrer, a magnetic stirrer, or the like, or desorption is performed using a rotary evaporator or the like while adjusting the degree of vacuum.

The microcapsules thus obtained are separated by centrifugation or filtration and, if necessary, dried under reduced pressure or freeze-dried to completely desorb the solvent and water in the microcapsules. When the microcapsules of the present invention thus obtained are used, for example, for the purpose of sustained release of a therapeutic agent for a disease, they may be dispersed in a suspending agent or the like and then subcutaneously or intramuscularly injected. Further, when the pesticide is gradually released, it can be used by spraying the microcapsules on soil or the like.

[0014]

EXAMPLES Next, the present invention will be specifically described with reference to examples. The average particle size of the fine particles in the examples was measured by a laser diffraction type particle size distribution measuring device (manufactured by Horiba Ltd.). The content rate and effective utilization rate of the drug were calculated by the following formulas. Drug content = amount of drug in microcapsule (g) / amount of microcapsule (g) x 100% Effective drug utilization rate = total amount of drug incorporated in microcapsule (g) / amount of loaded drug (g) × 100%

Example 1 2 g of a lactic acid / glycolic acid copolymer (molar ratio 75/25, average molecular weight 10,000) was dissolved in 10 ml of dichloromethane. On the other hand, 100 mg of potassium benzylpenicillin (manufactured by Toyo Shuzo) was dissolved in 0.8 ml of distilled water. A homogenizer (made by Yamato Scientific;
LK-22) and stirred for 1 minute. W / O obtained
The mold emulsion was ice-cooled for 5 minutes. The viscosity of this W / O type emulsion was 25 cp. This W / O type emulsion is 0.5 w / v
% Polyvinyl alcohol (manufactured by Unitika Chemical; average molecular weight 88,000, saponification degree 88 mol%) aqueous solution 500
Add to homogenizer (Yamato Scientific; LK)
At -42), the mixture was stirred under ice cooling to obtain a W / O / W type emulsion.
After this, Lab Stirrer (Tokyo Rika Kikai; DC-2
In S), the mixture was stirred under ice-cooling for 1 hour and at 20 ° C. for 2 hours and dried in the liquid. Then, the microcapsules were collected by filtration and freeze-dried. The average particle size of the obtained microcapsules was 45.
μm, the drug content was 6%, and the effective utilization rate was 45%.

Comparative Example 1 2 g of a lactic acid / glycolic acid copolymer (molar ratio 75/25, average molecular weight 10,000) was dissolved in 10 ml of dichloromethane. On the other hand, 100 mg of potassium benzylpenicillin (manufactured by Toyo Shuzo) was dissolved in 0.8 ml of distilled water. A homogenizer (made by Yamato Scientific;
LK-22) and stirred for 1 minute. W / O obtained
The viscosity of the mold emulsion was 6 cp. Add this to 20.degree.
5 w / v% polyvinyl alcohol (manufactured by Unitika Chemical; average molecular weight 88,000, saponification degree 88 mol%) was added to 500 ml, and the mixture was stirred with a homogenizer (Yamato Scientific Co., Ltd .; LK-42), and W / O / W. A type emulsion was obtained. After this, Lab Stirrer (Tokyo Rika Kikai; DC-
The mixture was stirred in 2S) for 1 hour under ice-cooling and 2 hours under 20 ° C. for drying in the liquid, and then the microcapsules were collected by filtration and freeze-dried. The average particle size of the obtained microcapsules was 40.
μm, the content rate of the drug was 3%, and the effective utilization rate was 30%.

Comparative Example 2 2 g of a lactic acid / glycolic acid copolymer (molar ratio 75/25, average molecular weight 10,000) was dissolved in 10 ml of dichloromethane. On the other hand, 0.8 ml of 100 mg of benzylpenicillin potassium (manufactured by Toyo Shuzo) and 10 mg of gelatin.
Was dissolved in distilled water. Both were mixed and stirred for 1 minute using a homogenizer (manufactured by Yamato Scientific; LK-22). The viscosity of the obtained W / O type emulsion was 260 cp. After ice-cooling this for 5 minutes, 0.5 w / v% polyvinyl alcohol (manufactured by Unitika Chemical; average molecular weight 88,
000, saponification degree 88 mol%) aqueous solution (500 ml) and stirred with a homogenizer (Yamato Scientific; LK-42) under ice cooling to obtain a W / O / W type emulsion. After that, the mixture was stirred in a lab stirrer (manufactured by Tokyo Rika Kikai; DC-2S) for 1 hour under ice cooling and 2 hours under 20 ° C. for drying in the liquid, and then the microcapsules were collected by filtration and freeze-dried. The average particle size of the obtained microcapsules was 51 μm, the drug content was 5%, and the effective utilization rate was 28%.

[0018]

EFFECTS OF THE INVENTION According to the present invention, it is possible to increase the drug content rate and effective utilization rate in microcapsules in microencapsulation of water-soluble drugs.

Claims (1)

[Claims] 1. A W / O type emulsion having a liquid containing a water-soluble drug as an inner water layer and a liquid containing a polymer as an oil layer, and drying the obtained W / O type emulsion in the liquid. Of a water-soluble drug-containing sustained-release microcapsule, wherein the W / O emulsion has a viscosity of 10 cp to less than 145 cp. Manufacturing method.