JPH07196479A - Method for producing microcapsule - Google Patents

Abstract

PURPOSE:To provide a method for producing microcapsules, capable of obtaining the spherical microcapsules lowered in early bursting and good in needle penetrability in a simple operation. CONSTITUTION:The characteristic of a method for producing microcapsules comprising a physiologically active substance wrapped with a polymeric compound by an emulsion method comprises adding sugar to an oil layer or water layer composing the emulsion.

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 microcapsules containing physiologically active substances such as pharmaceuticals, cosmetics and agricultural chemicals.

[0002]

2. Description of the Related Art In recent years, microcapsules containing a physiologically active substance such as pharmaceuticals, cosmetics and agricultural chemicals in a polymer compound have been used in w / o emulsion method, o / o emulsion method and w / o emulsion method.
/ O / w emulsion method is used. Of those production methods, the w / o / w emulsion method is often used. For example, regarding the w / o / w emulsion method, in JP-A-2-124814, by adding a basic drug-holding substance to an inner water layer containing a water-soluble drug,
It is disclosed that microcapsules with low initial burst can be produced. Further, Japanese Patent Publication No. 1-57087 discloses that an inner water layer containing a water-soluble drug and a drug-holding substance has a viscosity of about 5,000.
A method of thickening or solidifying to more than cp, Japanese Patent Laid-Open No. 62-201816 discloses w / o when preparing w / o / w emulsion.
Adjust the viscosity of the emulsion to about 150 cp to 1000 by adjusting the concentration of the polymer compound in the oil layer and the amount ratio between the inner water layer and the oil layer.
Methods for adjusting to 0 cp have been disclosed, and it is said that these methods can produce microcapsules with well-ordered spherical shapes.

[0003]

However, in such a conventional w / o / w emulsion method, w / o
When a microcapsule is produced by drying an o / w emulsion in a liquid and drying in liquid for a short time by heating or the like, many pores are generated on the surface or large pores are formed, and It has been reported that the release rate changes and the initial burst increases, and it is said that it is preferable to perform in-liquid drying at low temperature for a long time in order to shape the microcapsules and reduce the initial burst. .

Further, in the w / o / w emulsion method, in order to obtain microcapsules having a true spherical shape and a low initial burst, a drug holding substance is added to the inner water layer containing a water-soluble substance, or the inner water layer or The method of adjusting the viscosity of the w / o / w emulsion is very troublesome in operation.
Further, the method of adding a drug holding substance cannot be used when the water-soluble substance and the drug holding substance have an interaction such as a chemical reaction. Further, the in-liquid drying of the w / o / w emulsion has a drawback that the content of the drug is lowered by performing the drying at a low temperature for a long time. Also,
Even if other microcapsule production methods are included, the shape and initial burst amount are not satisfactory. An object of the present invention is to provide a method capable of producing a microcapsule having a true spherical shape, a low initial burst, and a good needle-passing property by a simple operation.

[0005]

Means for Solving the Problems As a result of earnest studies to solve such problems, the present inventors have found that when a microcapsule containing a physiologically active substance in a high molecular compound is produced by an emulsion method, The present inventors have found that microcapsules of a physiologically active substance having a true spherical shape and a low initial burst can be produced by adding sugar to an oil layer or an aqueous layer that constitutes an emulsion, and arrived at the present invention. That is,
The present invention, when producing microcapsules containing a physiologically active substance with a polymer compound by an emulsion method,
The gist is a method for producing microcapsules characterized in that an oil layer or an aqueous layer constituting an emulsion contains sugar.

The present invention will be described in detail below. The physiologically active substance of the present invention may be hydrophilic or hydrophobic, and the type thereof is not particularly limited, and examples thereof include polypeptides having physiological activity, other antibiotics, antitumor agents, antipyretics, and sedatives. Agent, anti-inflammatory agent, antitussive antitussive agent, sedative,
Muscle relaxants, antiepileptic agents, antidepressants, antiallergic agents,
Cardiotonic agents, antiarrhythmic agents, vasodilators, antihypertensive diuretics, antidiabetic agents, vitamin agents, various enzyme agents, vaccine agents, antiprotozoal agents, interferon inducers, anthelmintic agents, pesticides, auxins, plant hormones, insect hormones, cosmetics Etc.

The above physiologically active substance is used by being dissolved or dispersed in water or an organic solvent. Examples of the organic solvent include halogenated alkanes (dichloromethane,
Examples thereof include chloroform, chloroethane, trichloroethane, carbon tetrachloride), ethyl acetate, ethyl ether, benzene, dimethylformaldehyde, liquid paraffin, and the like, and two or more kinds of them may be mixed and used.

In the present invention, a drug-holding substance may be added to the water layer or oil layer to adjust the viscosity of the water layer, oil layer or emulsion. Examples of the drug-holding substance include natural or synthetic rubber substances or polymer compounds. Examples of the natural rubber substance include gum arabic and column gum, and examples of the natural polymer compound include gelatin, casein, collagen, albumin, cellulose and agar. You can leave these as they are, or
It may be partially chemically modified or a salt 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 used varies depending on the type of compound, and the concentration is about 0.01.
% To 30% (W / W).

The polymer compound in the present invention refers to a polymer compound which is sparingly soluble or insoluble in water. For example, olefin, styrene, vinyl acetate, vinyl chloride, vinylidene chloride, vinyl ester, acrylic ester, methacrylic ester. , Acrylonitrile, methacrylonitrile,
Polycarbonates, sulfonates, polyesters, polyurethanes, polyureas, polyamides and the like can be mentioned, among which biodegradable polyesters such as polylactic acid, polyglycolic acid, poly-ε-caprolactone, poly-γ-butyrolactone, poly-δ-barrel. Lactone and a copolymer of two or more kinds thereof (for example, lactic acid-glycolic acid copolymer) are preferable.

The concentration of the polymer compound in the oil layer is 2 to
95% (W / W), more preferably 5 to 70% (W / W). As the oil layer of the polymer compound, a polymer compound dissolved in a solvent is used. The organic solvent may be any one capable of dissolving a polymer compound, and examples thereof include halogenated alkanes (dichloromethane, chloroform,
Chloroethane, trichloroethane, carbon tetrachloride), ethyl acetate, ethyl ether, benzene, dimethylformaldehyde, liquid paraffin and the like can be mentioned, and these may be used as a mixture of two or more kinds.

The sugars used in the present invention include monosaccharides (glucose, galactose, talose, mannose,
Sorbose, tagatose, fructose, psicose,
Erythrose, threose, erythrulose, arabinose, xylose, ribose, lyxose, ribulose, etc.), disaccharides (maltose, lactose, sucrose, cellobiose,
Trepers, gentiobiose, isomaltose, etc.),
Oligosaccharides (raffinose, gentianose, etc.), polysaccharides (cellulose, starch, glycogen, inulin,
Dextran, etc.) or a derivative of the above saccharides (sugar alcohol such as mannitol, allitol, iditol, galactitol, glucitol, carboxymethylated derivative,
Acetylated derivative, phosphorylated derivative, carboxylated derivative, aminated derivative, etc.), and one kind can be used alone or two or more kinds can be used as a mixture.

These sugars may be added to any of the water layer or the oil layer constituting the emulsion when producing the microcapsules. The layer to which sugar is added is not limited to one place and may be two or more places. When sugar is added to two or more layers, the sugar to be added may be different for each layer.

The concentration of sugar in the water layer or oil layer is preferably 0.1% to 95% (W / W), more preferably 1 to
75% (W / W), with 3 to 20% (W / W) being optimal.

The emulsion method used as the method for producing the microcapsules of the present invention includes a w / o emulsion method and an o / o emulsion method.
Examples thereof include o emulsion method and w / o / w emulsion method, and the w / o / w emulsion method is preferable.

In the w / o emulsion method, after adding a water layer containing a physiologically active substance to an oil layer containing a polymer compound,
A w / o emulsion is prepared by performing an emulsification operation, and a solvent is desorbed to produce microcapsules. Sugar may be added to either the aqueous layer or the oil layer, and at the same time, both the aqueous layer and the oil layer may be added. May be added to.

In the o / o emulsion method, after adding the oil layer 2 to the oil layer 1 containing the physiologically active substance and the polymer compound, an emulsification operation is performed to prepare an o / o emulsion, and the solvent is desorbed to remove the microcapsules. To manufacture. The organic solvent used for the oil layer 2 may be one that does not mix with the oil layer 1. The sugar may be added to either the oil layer 1 or the oil layer 2 and may be added to both the oil layer 1 and the oil layer 2 at the same time.

In the w / o / w emulsion method, an inner water layer containing a physiologically active substance is added to an oil layer containing a polymer compound and then emulsified to prepare a w / o emulsion,
The obtained w / o emulsion was added to the outer water layer, and the w / o /
A w emulsion is prepared, and the solvent in the oil layer is desorbed to produce microcapsules. An emulsifier or the like may be added to the outer water layer, and examples thereof include an anionic surfactant,
Nonionic surfactant or polyvinyl alcohol,
Gelatin etc. are mentioned. These may be used alone or in combination of two or more. The sugar may be added to any of the inner water layer, the outer water layer, and the oil layer, and may be added to any two layers at the same time, or to all layers at the same time, but preferably to the outer water layer. It is good to add. Moreover, when adding to any two layers at the same time, any combination of an inner water layer and an oil layer, an outer water layer and an oil layer, and an inner water layer and an outer water layer may be used.

As the emulsification operation, known methods such as a method using a stirrer such as a propeller stirrer and a turbine stirrer, a homogenizer method, an ultrasonic method and the like are used.

For the desorption of the solvent in the oil layer, a commonly used method is used. For example, a method of gradually reducing the pressure with a propeller stirrer or a magnetic stirrer, a method of desorbing while adjusting the degree of vacuum using a rotary evaporator, a spray drying method and the like can be mentioned.

The microcapsules produced by the above operation 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 obtained microcapsules are used for sustained release of a therapeutic agent for diseases, for example, the microcapsules may be dispersed in a suspending agent or the like and then subcutaneously or intramuscularly injected. When used for the sustained release of agricultural chemicals, it can be used by spraying the microcapsules on soil or the like.

[0021]

EXAMPLES The present invention will be specifically described below with reference to examples. In the following examples, about 25 mg of microcapsules was taken as an initial burst, and the microcapsules were suspended in 5 ml of physiological saline containing 0.01% Tween80 (polyoxyethylene sorbitan monooleate) and rotator (TAITEC) at 37 ° C and 30 rpm. It was rotated by RT-50 high speed type) and expressed as the amount of drug eluted after 3 hours. In addition, the needleability is 100 mg of microcapsules as a dispersion medium (Dextran 40 200 mg,
Tween40 (5 mg, sodium chloride 9 mg) was dispersed in 1 ml, and 0.5 ml thereof was subcutaneously administered to a rat and evaluated by the smallest needle diameter that can be administered.

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 to prepare a solution of a polymer compound. Separately, 100 mg of benzylpenicillin potassium (manufactured by Asahi Kasei) was dissolved in 0.8 ml of distilled water to prepare a drug solution. Then, the both were mixed and stirred at room temperature for 1 minute at 9000 rpm using a homogenizer (Yamato Scientific; LK-22). Got w
The / o emulsion was ice-cooled for 2 minutes. On the other hand, polyvinyl alcohol (manufactured by Unitika Chemical; average molecular weight 88,000,
(Saponification degree: 88 mol%) is dissolved in distilled water to prepare a 0.5% w / v aqueous solution, and 3% of mannitol (manufactured by Wako Pure Chemical Industries) is added to the solution.
The external water layer was prepared by adding and dissolving the mixture so that the w / v ratio was reached.
The above w / o emulsion was added to 500 ml of an outer water layer at 20 ° C, and a homogenizer (manufactured by Yamato Scientific; LK-42) was used.
The mixture was stirred under ice-cooling (4000 rpm) to obtain a w / o / w emulsion. Thereafter, the emulsion was stirred with a lab stirrer (Tokyo Scientific Instruments; DC-2S) for 1 hour under ice cooling (200 rpm), and then at 20 ° C. for 2 hours (200 rpm).
And dried in the liquid. Then, the microcapsules were collected by filtration and dried under reduced pressure at 25 ° C for 24 hours. The shape of the obtained microcapsules was spherical and the surface condition was good.

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 to prepare a solution of a polymer compound. Separately, 100 mg of benzylpenicillin potassium (manufactured by Asahi Kasei) was dissolved in 0.8 ml of distilled water to prepare a drug solution. Then, the both were mixed and stirred at room temperature for 1 minute at 9000 rpm using a homogenizer (Yamato Scientific; LK-22). Got w
/ O Emulsion was ice-cooled for 2 minutes and this was 0.5% w /
v Polyvinyl alcohol (manufactured by Unitika Chemical; average molecular weight: 88,000, saponification degree: 88 mol%) was put into an aqueous solution of 500 ml and stirred with a homogenizer (manufactured by Yamato Scientific; LK-42) to obtain a w / o / w emulsion. Then, this emulsion was added to a lab stirrer (Tokyo Science Equipment; D
C-2S) under ice cooling for 1 hour with stirring (200 rpm), then
The mixture was stirred (200 rpm) at 20 ° C. for 2 hours and dried in the liquid. After that, the microcapsules were collected by filtration and stored at 25 ° C for 24 hours.
It was dried under reduced pressure for an hour. The shape of the obtained microcapsules was amorphous and had pores on the surface. The initial burst and needle penetration of the obtained microcapsules are shown in Table 1.

[0024]

[Table 1]

As is clear from Table 1, the microcapsules produced by the method of the present invention have a low initial burst and good needle penetration.

[0026]

EFFECTS OF THE INVENTION According to the present invention, it is possible to obtain a microcapsule having a true spherical shape, a low initial burst, and a good needle-passing property by a simple operation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 47/36 Z B01J 13/12 (72) Inventor Akemi Morimoto 23 Uji Kozakura Uji City, Kyoto Prefecture Unitika (72) Inventor, Izumi Sakamoto, 23 Uji Kozakura, Uji City, Kyoto Prefecture Unitika Central Research Institute

Claims (1)

[Claims] 1. A method for producing microcapsules, characterized in that, when a microcapsule containing a physiologically active substance in a polymer compound is produced by an emulsion method, a sugar is contained in an oil layer or an aqueous layer constituting the emulsion.