JPH0789848A - Production of sustained release type microcapsule - Google Patents

Abstract

PURPOSE:To increase take-in ratio of a medicine in microcupsulation of a water- soluble medicine. CONSTITUTION:The characteristic of this method for producing a sustained release microcapsule of a water-soluble medicine comprises preparing a W/O emulsion containing a liquid containing a water-soluble medicine as inner water phase and containing a solution containing a high polymer substance as an oil phase, increasing viscosity of the inner water phase to >=50cp or solidifying the water phase by controlling an amount of the water-soluble medicine of the inner water phase in this case and then, subjecting the resultant emulsion to drying method in water.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing sustained-release microcapsules containing water-soluble drugs such as pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art In recent years, various studies have been attempted on a method for producing microcapsules containing a drug such as a drug or an agricultural chemical in a polymer. For example, JP-A-57
JP-A-118512 discloses microencapsulation by a phase separation method using a coacervation agent such as mineral oil and vegetable oil. Further, there is known a method of forming a W / O / W type emulsion having an aqueous solution containing a drug as an inner aqueous phase and microcapsulating the drug by an in-liquid drying method (for example, Japanese Patent Publication No. 42-13703). ).

[0003]

However, at present, there are some problems in the above-mentioned microencapsulation method. This problem means that, in the microencapsulation by the phase separation method, the microcapsules stick to each other during the preparation process and easily form aggregates, which are then dried in liquid after the conventional W / O / W emulsion preparation. In the method, generally, the drug is easily dissipated in the outer aqueous phase at the stage of W / O / W stirring or in-liquid drying, and thus the drug is not effectively microencapsulated.

[0004]

Means for Solving the Problems As a result of intensive studies made by the present inventors to solve the above-mentioned problems, W / O /
When the drug is microencapsulated by the in-liquid drying method after the W-type emulsion is prepared, the W / O emulsion is prepared by mixing and stirring the inner aqueous phase in which the amount of the water-soluble drug is adjusted and the oil phase containing the polymer. The present invention was made by discovering the fact that the drug can be efficiently contained by thickening or solidifying the inner aqueous phase in this emulsion after the preparation. That is, in the present invention, a liquid containing a water-soluble drug is used as an inner aqueous phase and a solution containing a polymer is used as an oil phase.
By making an O emulsion and adjusting the amount of the water-soluble drug in the inner water phase in this case, the viscosity of the inner water phase is increased to about 50 cp or more to solidify, and then the obtained emulsion is subjected to the in-water drying method. The gist is a method for producing sustained-release microcapsules of a water-soluble drug, which is characterized by being attached.

The present invention will be described in detail below.

The water-soluble drug in the present invention may be any one as long as the viscosity of the inner aqueous phase can be adjusted to 50 cp or more by adjusting the amount of dissolution in an aqueous solution. Further, in the present invention, the action of some external factors such as temperature, pH, metal ions (copper ion, aluminum ion, zinc ion, calcium ion, etc.) on the inner aqueous phase in which the amount of the water-soluble drug dissolved is adjusted. The viscosity of the aqueous solution is increased to 50 cp
You may thicken or solidify above.

The water-soluble drug is not particularly limited to the kind of drug, but is preferably a hormonal agent, an antibiotic, an anticancer agent, a blood pressure lowering agent, a vasodilator, a vascular reinforcer, a gastric digestive agent, an intestinal agent, a contraceptive agent. , Disinfectant for outer skin, parasitic skin disease agent, antiphlogistic, analgesic, choleretic agent, antirheumatic agent, cardiotonic agent, hemorrhoids therapeutic agent, constipation therapeutic agent, vitamin agent, various enzyme preparations, vaccine agent, antiprotozoal agent , Interferon inducer, anthelmintic, fish, pesticide, auxin, plant hormone,
Examples include drugs such as insect hormones. Of these, anti-cancer bone, hormonal agents, antibiotics, and antihypertensive agents are particularly preferably used.

The high molecular weight polymer used in the present invention includes olefin, styrene, vinyl acetate, vinyl chloride,
Vinylidene chloride, vinyl ester, vinyl ether, acrylic acid ester, methacrylic acid ester, acrylonitrile, methacrylonitrile, polycarbonate resulfonate, polyester, polyurethane, polyurea polyamide and the like, but among them, degradable polyester, for example, polylactic acid, Examples thereof include polyglycolic acid, lactic acid glycolic acid copolymer, polycaprolactone, polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxyisobutyrate, and γ-hydroxyvaleric acid. These polymers may be one kind, a copolymer of two or more kinds, or a simple mixture.
It may be a copolymer of more than one kind, or a simple mixture,
Moreover, the salt may be sufficient.

The method for producing the sustained-release microcapsules of the water-soluble drug of the present invention will be described below. First, a water-soluble drug is added to water and dissolved to form an inner aqueous phase. At this time, the amount of the water-soluble drug dissolved in water is adjusted to adjust the viscosity of the inner aqueous phase. This is mixed with a solution (oil phase) containing a polymer, and then emulsified to prepare a W / O emulsion. As the emulsifying operation, a known method is used. Examples thereof include a method using a stirrer such as a propeller type stirrer and a turbine type stirrer, a homogenizer method, an ultrasonic method and the like.

When the viscosity of the inner aqueous phase of the W / O type emulsion thus obtained is 50 cp or more, and more preferably 200 cp or more from the beginning, the solvent can be directly desorbed in the next oil phase. However, if not, the viscosity of the inner aqueous phase may be increased to about 50 cp or more, and more preferably 200 cp or more by some external factor.

Examples of the method for increasing or solidifying the viscosity of the inner aqueous phase by an external factor include, for example, a method of cooling to a low temperature, a method of freezing, a method of making pH acidic or alkaline, a metal ion (copper ion). , Aluminum ions, zinc ions, calcium ions, etc.) and the like.

As a cooling method, for example, a method of cooling with stirring under ice cooling can be mentioned.

Next, W / prepared by the above method
The O-type emulsion is emulsified into three phases of W / O / W and subjected to an in-water drying method. That is, the W / O type emulsion is further added to the aqueous phase of the third phase to form a W / O / W type emulsion, and then the solvent in the oil phase is removed to prepare microcapsules.

An emulsifier may be added to the outer aqueous phase,
Examples thereof include any one that generally forms a stable W / O / W type emulsion. For example, an anionic surfactant (eg, sodium oleate,
Sodium stearate, sodium lauryl sulfate, etc., nonionic surfactant [polyoxyethylene sorbitan fatty acid ester (Tween 80, Tween 60, manufactured by Atlas Powder Co., USA), polyoxyethylene castor oil derivative (HCO-60, HCO) -50, manufactured by Nikko Chemicals)
Etc.), or polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin, gelatin, etc., one of these,
You may use it in combination of some. The concentration at the time of use can be appropriately selected from the range of about 0.01 W / V% to 20 W / V%, more preferably about 0.05 W / V% to 10 W / V%.
Used in the range of.

After that, the microcapsules are separated by centrifugation or filtration, and the remaining solvent and water are removed by vacuum drying, freeze drying and the like. 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. Can be used.

[0016]

EXAMPLES Hereinafter, the present invention will be described more specifically by way of 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.).
It was measured by. The drug uptake rate into the microcapsules was determined by adding a predetermined amount of capsules to an acetonitrile / water mixture to extract the drug, and then measuring the amount of the drug in the extract by high performance liquid chromatography (Hitachi L- Fifty
00) was used for the calculation.

Further, the viscosity of the inner water phase is measured by an E-type viscometer (VISCON
It was measured using IC ED type Tokimec Co., Ltd. Further, the viscosity of the inner aqueous phase in the W / O emulsion after ice cooling of Example 1 was 0.8 ml of bacitracin 400 mg.
Dissolved in distilled water and cooled with ice for 5 minutes
The viscosity of the internal water phase in the W / O emulsion after cooling with ice of Comparative Example 1 is 200 m as measured by bacitracin, which is expressed by a viscometer (VISCONIC ED type Tokimec Co., Ltd.).
g was dissolved in 0.8 ml of distilled water and ice-cooled for 5 minutes, and the viscosity of the aqueous phase was measured by an E-type viscometer (VISCONIC ED type Tokimec Co., Ltd.).

Example 1 Lactic acid / glycolic acid copolymer (manufactured by Wako Pure Chemical Industries, Ltd .; molar ratio of lactic acid to glycolic acid: 75/25, average molecular weight: 10,
000) 2 g was dissolved in 10 ml of dichloromethane.
On the other hand, 400 mg of bacitracin was dissolved in 0.8 ml of distilled water (internal aqueous phase viscosity: 20 cp). Both were mixed and stirred at 10,000 rpm for 1 minute using a homogenizer (Yamato Scientific; LK-22). After the obtained W / O emulsion was ice-cooled for 5 minutes (viscosity of the inner aqueous phase: 200 cp), 0.5 w / v% polyvinyl alcohol (manufactured by Unitika Chemical; average molecular weight 88,000, saponification degree 88 mol%) The mixture was put into an aqueous solution at a volume of 500 ml, and stirred with an homogenizer (Yamato Scientific Co .; LK-42) under ice cooling at 3,000 rpm to obtain a W / O / W type emulsion. After this, Lab Stirrer (Tokyo Rika Kikai; DC
-2S) was stirred at 500 rpm for 1 hour under ice-cooling and at 20 ° C for 2 hours and dried in the liquid, and then the microcapsules were collected by filtration and freeze-dried. The average particle size of the obtained microcapsules was 32 μm, and the drug uptake rate was 45%.

Comparative Example 1 Lactic acid / glycolic acid copolymer (manufactured by Wako Pure Chemical Industries, Ltd .; molar ratio of lactic acid to glycolic acid 75/25, average molecular weight 10,
000) 2 g was dissolved in 10 ml of dichloromethane.
On the other hand, 200 mg of bacitracin was dissolved in 0.8 ml of distilled water (viscosity of inner aqueous phase: 15 cp). Both were mixed and stirred at 10,000 rpm for 1 minute using a homogenizer (Yamato Scientific; LK-22). The obtained W / O emulsion was ice-cooled for 5 minutes (viscosity of inner aqueous phase: 40 cp), and then 0.5 w / v% polyvinyl alcohol (manufactured by Unitika Chemical; average molecular weight 88,000, saponification degree 88 mol%) Add 500 ml to the aqueous solution and use a homogenizer (Yamato Scientific; LK-42) under ice cooling.
The mixture was stirred at 000 rpm to obtain a W / O / W type emulsion. After this, Lab Stirrer (Tokyo Rika Kikai; DC-
2S) at 500 rpm for 1 hour under ice cooling and 2 at 20 ° C.
After stirring for an hour and drying in the liquid, the microcapsules were collected by filtration and freeze-dried. The average particle size of the obtained microcapsules was 29 μm, and the drug uptake rate was 15%.

[0020]

According to the present invention, the rate of drug uptake in microencapsulation of water-soluble drugs can be increased.

Claims (1)

[Claims] 1. A W / O emulsion comprising a liquid containing a water-soluble drug as an inner aqueous phase and a solution containing a polymer as an oil phase, in which case the amount of the water-soluble drug in the inner aqueous phase is adjusted. A method for producing sustained-release microcapsules of a water-soluble drug, characterized by increasing the viscosity of the inner aqueous phase to about 50 cp or more to solidify, and subjecting the resulting emulsion to an in-water drying method.