JPS61227520A - Microsphere - Google Patents

Abstract

PURPOSE:Microspheres for controlling release of the third substance, obtained by packing the third substance into the hole part of porous powder and coating the surface of the powder with inorganic fine powder and/or organic fine powder. CONSTITUTION:The third substance (e.g., drug, food and drink, animal drug, agricultural chemical, fertilizer, etc.) is packed into the hole part of porous powder (e.g., porous cellulose, porous styrene resin, porous nylon, etc.) by dissolution in a solvent, blending, suspending, emulsification, etc. and the surface of the powder is coated with inorganic fine powder (e.g., titanium oxide, silica fine powder, various bentonites, aluminum oxide, etc.; preferably <=100mum particle diameter) and/or organic fine powder (e.g., methacrylate, polyethylene, nylon, etc.), to give microspheres. Since the properties and color of the microspheres can be controlled by regulating the kind and amount of the combination of the components, it is effective for various uses.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to microspheres containing medicines, foods and drinks, veterinary medicines, agricultural chemicals, fertilizers, etc., and whose release is controlled.

Microsphere means a microsphere, and usually has a diameter of O0.
The size is 11 to 5 μm, but the shape here does not necessarily mean a perfect sphere.

These microspheres are sometimes coated, but there are two types of coatings: irregular coatings and continuous waves (seamless).
Microspheres with a seamless coating are called microcapsules.

Various types of microspheres with controlled release of liquid or solid substances are known, but it cannot be said that there are enough forms suitable for various uses, and microsphere particles are The size also varies depending on the mixing and stirring conditions during manufacturing.

It is not easy to obtain certain things (Japanese Unexamined Patent Publication No. 58-1
53947, JP-A-58-1831301).

Structure of the Invention The present invention relates to microspheres in which the pores of a porous powder contain a third substance (medicine, etc.) and the surface thereof is coated with an inorganic fine powder and/or an organic fine powder.

Examples of porous powders include porous cellulose, porous styrene resin, porous silica, porous nylon, porous urethane, porous polyethylene, porous epoxy resin, and porous activated carbon. It is expected that porous materials will be developed. These can be selected and used depending on the purpose, i.e., 5 to 30 gta for electrostatic image developing toner, and 50 to 5 gta for oral medicine.
00IL layer, coffee capsules cost 250p~3.
35■ Intestines are considered suitable (Japanese Patent Application Laid-Open No. 58-15394)
No. 7, JP-A-58-58148, JP-A-55-288
(See No. 93).

An example of porous cellulose is Cellulofine GH.
-25 (manufactured by Chisso ■, 1 particle size 25-44 l■, 45 when wet)
~105μ-), and an example of porous nylon is organol (A, T, 0-Chi).
There are 5 particle sizes (5 to 40 μs+) manufactured by S+IE, and if these are used, it is possible to obtain a product with a constant particle size depending on the material.

A large number of substances can be considered as the third substance to be filled into the pores of the porous powder, and it can be said that the range of application of this technology is extremely wide. Most commonly, medicines, food and drink,
Examples include animal drugs, agricultural chemicals, and fertilizers. However, any substance can be used as long as it is necessary and useful to control the release (elution) when the microspheres come into contact with a liquid (particularly water). Also, release into other than liquids (e.g. release of perfume into the air) is possible in some cases.

When filling the pores of the porous powder with this third substance, it is used after being dissolved, mixed, suspended, or emulsified in a solvent, and when the third substance is liquid, it can also be used as it is. The solvent used needs to be a solvent that does not dissolve the porous powder.

For example, in the case of a poultice, methyl salicylate, camphor, menthol, etc. are dissolved in a lower alcohol such as ethanol and filled into the pores of porous cellulose. In the case of oral administration preparations and other cases, similar operations may be carried out using appropriate solvents depending on the respective active ingredients.

Examples of inorganic 1a impersonators include titanium oxide, silica fine powder, various bentonites, aluminum oxide, carbon black,
Examples include calcium carbonate, talc, kaolin, and ceramic powders, and it is preferable to use powders that are one tenth or less of the size of porous powders.

Usually, a diameter of 100 JLm or less is suitable.

Examples of the organic fine powder include fine powders of synthetic resins such as methacrylate, polyethylene, nylon, polyethylene, and epoxy resins, and the size thereof is the same as that of the above-mentioned inorganic fine powders.

The amount of inorganic fine powder and organic fine powder added to porous powder is theoretically the amount that covers the surface of the porous powder, and can be determined by calculating the surface area and particle size. 1
~2 times the amount is appropriate. Note that the amount added may be adjusted depending on the manufacturing method, taking into account scattering during preparation, adhesion to the preparation container, etc. Generally, by coating with an inorganic fine powder and/or an organic fine powder, release of a third substance in the porous powder (particularly elution into water) tends to be suppressed.

However, if coating is performed using a substance (usually an organic fine powder) that dissolves in the third substance or its solvent (solvent used for dissolving, mixing, suspending, etc.), the third substance tends to diffuse and is not released. It may be promoted. However, if only soluble substances (organic fine powder) are present, the surface of the microsphere may become sticky and the overall fluidity may deteriorate. It is usually appropriate to use a soluble substance and an insoluble substance in a ratio of about 1:10 to 1:1.

Also, the use of soluble materials generally tends to increase sealing properties and stability of the third material. It is appropriate to confirm the solubility of organic fine powders, etc. by referring to literature and conducting experiments.

Thus, the microspheres of the present invention.

By adjusting the type and amount of the combination of the third substance, solvent, porous powder, inorganic fine powder, and organic fine powder, the properties can be controlled in various ways, making it useful for various uses.

The method for preparing microspheres of the present invention will be explained in two steps: filling the pores of the porous powder with a third substance and coating the surface of the powder.

In the first step, a porous powder whose particle size is adjusted to suit the purpose (for example, by sieving) is used, and the third substance is dissolved or dispersed in a solvent as necessary.

There are two methods for introducing the third substance into the pores of the porous powder. One of them is a wet method, in which, for example, 1 to 3 parts of a liquid third substance is added to 1 part of porous powder and stirred thoroughly to penetrate into the pores. At this time, the time can be shortened by applying ultrasonic waves. This penetration time is determined by the size of the pore and the compatibility (wetting) between the pore and the liquid.
It may be effective to add a surfactant to the liquid or to treat the porous powder with a surfactant in advance to improve its compatibility. After removing the remaining liquid, dry it.

Another method is a dry method, in which a liquid of a third substance is added to porous powder, and then the powder is stirred with a mortar, spatula, stirring rod, etc., and the liquid permeates into the pores.

Although this method is easy to operate, there is a risk of producing voids. As in the previous method, it may be effective to use a surfactant to speed up the penetration rate.

Second step: A conventional method can be used to coat the surface of the porous powder, for example, stirring and mixing in an automatic mortar may be used.

The microspheres obtained as described below are particles of a desired size depending on the size of the raw material porous powder, and the desired third substance is contained in the pores of the porous powder. It has advantages such as being easy to handle, allowing sustained release of the third substance, and maintaining the chemical stability of the third substance due to less contact with air.

Example 1 30 parts of methyl salicylate was added as a third substance to 50 parts of Cellulofine GH-25 (manufactured by Chisso Corporation) as a porous powder.
Add 100 parts of Maha% ethanol solution, mix gently, and then apply ultrasonic waves (Brannon 3).
2. The paste-like residue obtained was spread as thinly as possible and dried for 3 hours to form a porous cellulose containing a third substance in the pores. Microspheres) were obtained.

Add 100 parts of this material to titanium dioxide (
Made by Ishihara Sangyo ■, Thai Bake A100, average particle size 0.1
Add 8 parts of 48gm) and place in an automatic mortar (manufactured by Nichinan Scientific, A
Microspheres (secondary microsquares) coated with titanium dioxide were obtained by mixing for 60 minutes using a NM-100 model.

Example 2 10 parts of titanium dioxide and organic fine powder polymethyl methacrylate (manufactured by Souken Kagaku, MP-1000, particle size 0.2~
Add 8 parts of 1 part mixture (0.5 lm) and mix in an automatic mortar to 60
The mixture was stirred and mixed for a minute to obtain secondary microspheres (■).

& Risa Example Ball Test Example 12 (Confirmation Observation of Microspheres) Microsphere surface condition was observed using a scanning electron microscope (JEOL Co., Ltd.)
Observation was made using a magnification of 500 to 5,000 times using a model JSM-720 (manufactured by Kogyo Co., Ltd.). The raw material cellulose particles used in Example 1 have a spherical shape with holes and a diameter of approximately 30IL11.

The secondary micro square ■ obtained in Example 1 (covered with titanium dioxide) has no surface pores and is covered with fine particles, and the secondary micro square ■ obtained in Example 2 (covered with titanium dioxide and polymethyl methacrylate) has no surface pores and is covered with fine particles. The surface of 1) is also covered with fine particles, and this is because the titanium dioxide acts as a wedge and is immobilized on the surface of the polymethyl methacrylate primary microspheres. It is thought that methyl methacrylate acts as a binder and binds titanium dioxide together to form a film.

In addition, for those coated only with polymethyl methacrylate, polymethyl methacrylate is coated with methyl salicylate (
It was observed that the spherical cellulose particles did not remain on the surface of the spherical cellulose particles, but instead entered the spaces between the spherical particles. Therefore, it can be seen that the fine powder to be used as the coating material should not be used alone, but should be mixed with another fine powder that is not soluble, rather than being easily dissolved by the third substance or solvent present in the pores.

Test Example 2: (Elution) As an example for determining how easily the third substance contained in the pores of the microspheres can be used externally (in other words, the degree of sealing covered by the fine particles), A dissolution test was conducted.

In order to determine the dissolution into water through a membrane filter used in the dissolution test of poultices, a paste sample was used since microspheres cannot be used in solid form. Furthermore, since there is a concern that the elution of the third substance may be affected by the diffusion phenomenon, the viscosity of the sample was kept constant as follows. That is, when microspheres are added to a 3:5 (by weight) mixture of water and glycerin and suspended, the viscosity is 2000 cp (slipping speed is 18.85 ec-3).
Samples were prepared to contain 1% methyl salicylate.

A control was prepared by adding only methyl salicylate to a glycerin-water mixture without using microspheres.

10g of the sample was placed on a membrane filter (Japan Millibore Limited FCLP 04700 pore size 0.2p), and 10Q of purified water with methyl salicylate at the bottom was passed through it.
The amount eluted into Oml was measured over time.

This purified water was kept at 37° C. and stirred at 240 rpm using a magnetic stirrer to maintain a constant concentration. Methyl salicylate was determined using a spectrophotometer (Shimadzu ■, UV-2
The absorbance at 240 nta was measured and calculated using 1OA).

The obtained elution curve is shown in FIG. 1, and it can be seen that in the case of no treatment (), methyl salicylate elutes at a rapid rate. On the other hand, secondary microspheres ■ (titanium dioxide coated φ)
About 6 mg was eluted after 8 hours, and about 10 mg was eluted after 8 hours in the case of secondary micro square (2) (coated with mixed fine particles). The test results show that the coated fine particles have good sealing properties and are useful as a means for sustained release of a third substance. It can also be understood that elution can be controlled by using a mixture of inorganic fine particles and organic fine particles as a coating agent.

[Brief explanation of drawings]

FIG. 1 is an elution curve.

Claims (2)

[Claims] (1) Microspheres in which the pores of porous powder are filled with a third substance and the surface is coated with inorganic fine powder and/or organic fine powder (2) The microsphere according to claim 1, wherein the coating is in the form of a film.