JPS5910642B2 - Microcapsules containing hydrophobic pharmaceutical substances and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to microcapsules containing hydrophobic pharmaceutical substances and a method for producing the same.

Microencapsulation of pharmaceutical substances using the complex coacervation method is used for the purposes of powdering the active ingredient, improving fluidity, preventing side effects, prolonging the effect, stabilizing, preventing changes in formulation, and providing flavor correction and odor correction. This is a method often used.

It is also used in the production of pressure-sensitive copying paper, oily foods, etc.

Conventionally, microcapsules have been produced by the complex coacervation method using, for example, a positively charged polymer electrolyte that can be gelatinized (e.g., gelatin, etc.) and a negatively charged polymer electrolyte (e.g., gum arabic, gum tragacanth, etc.).
A first step of dispersing or emulsifying a hydrophobic pharmaceutical substance in an aqueous solution containing pectin, carrageenin, agar, sodium alginate, etc.) and adding water to the dispersion or emulsion or dispersing the polyelectrolytes in opposite directions. A second step in which the pH is adjusted to have an electric charge to cause coacervation, and the coacervate is deposited on the hydrophobic pharmaceutical substance particles to form a coacervate wall film, and the coacervate is cooled to a temperature below the gelation temperature of the formed coacervate. Thereafter, a third step of curing the coacervate wall film with a hardening agent (for example, formaldehyde, glutaraldehyde, malonic dialdehyde, tannin, heavy metal salts, etc.) is used to coat hydrophobic pharmaceutical substance particles with a complex coacervate wall film (U.S. (Japanese Patent No. 2800457), and as an improved method of this method, a film-forming substance such as a polyethylene/maleic anhydride copolymer is further added after the second step, and a wall film made of the film-forming substance is formed on the coacervate wall film. (Japanese Patent Publication No. 37-7724), in which a slow-acting curing agent such as formaldehyde, 2,3-dihydroxy-1,4-dioxane, or glyoxal is used as a curing agent when curing the coacervate wall film. and a fast-acting curing agent such as glutaraldehyde, 2-methylglutaraldehyde, or acrolein, or glyoxal or glutaraldehyde to prevent agglomeration of the capsule itself due to a sudden increase in the viscosity of the coacervate wall film. and a method for preventing yellowing (Special Publication No. 51-8877, No. 52-10427)
, before the curing process, a copolymer of acrylic acid or methacrylic acid, a vinyl acetate-maleic acid copolymer or a derivative thereof, or a polymer of vinylbenzenesulfonate or A method of adding a copolymer to thicken the capsule coating and lower the degree of porosity (Japanese Patent Publication No. 51-37272, No. 51-37)
No. 273, No. 53-12472), etc. are known.

However, in these methods, if the coacervate wall film that forms the capsule coating is not hardened, the wall film will dissolve in hot water, digestive juices, etc. that are above the gelation temperature, and instantly release the medicinal substance taken in. This can be used as a drug-containing microcapsule that requires controlled elution, such as a sustained-release preparation, and the microcapsule itself has high hygroscopicity.
Capsules attach to each other or fuse.

Therefore, in these methods, it is necessary to cure the formed coacervate wall film with the above-mentioned curing agent, but in this case, the curing agent cannot be completely washed away, so high safety and quality are highly required. There are problems with the microencapsulation method for pharmaceutical substances, such as the hardening of the wall film progressing over time and the elution of the core substance from the microcapsules changing over time.

As a result of various studies regarding the above, the present inventors have found that in a method for manufacturing microcapsules containing hydrophobic pharmaceutical substances by a complex coacervation method, gelatin is dissolved in water with a pH of 5 or more as a coacervate wall material. An enteric polymer electrolyte is used, and a polymer substance that dissolves in an organic solvent that is immiscible with water but does not dissolve in an organic solvent that is miscible with water is dissolved as a core substance in the organic solvent that is immiscible with water. (1) The coacervate wall film formed by gelatin and the enteric polymer electrolyte will have a strong electrostatic bond between the dissociable groups of both wall materials. Furthermore, the hydrophobicity of the main chain of enteric-coated polyelectrolytes works together to make it extremely hydrophobic, making it highly resistant not only to hot water but also to digestive fluids, acids, and alkalis. Since it is resistant, there is no particular need for curing of the coacervate wall film.

(11) When the produced microcapsules are dehydrated and dried with cold air, heat drying, vacuum drying, or (and) polar solvents, the extraction or transpiration of organic solvents that are immiscible with water, which is a dispersion medium for pharmaceutical substances, occurs at the same time, and coacervate A polymeric substance is further precipitated and deposited on the inside of the wall membrane to obtain microcapsules having a double-walled membrane consisting of a coacervate wall membrane and a polymeric substance wall membrane.

(II1) The thickness of the polymeric material wall formed inside the coacervate wall film can be adjusted by adjusting the amount of the polymeric material dissolved in the water-immiscible organic solvent.
This also allows the release of the main drug to be adjusted to the desired rate.

We have discovered that new microcapsules can be obtained that exhibit remarkable effects such as:

Based on this knowledge, the present invention provides hydrophobic pharmaceutical substances, gelatin, enteric polyelectrolytes that can be dissolved in water with a pH of 5 or more, and organic solvents that are soluble in water-immiscible organic solvents but soluble in water-miscible organic solvents. A microcapsule containing the above-mentioned hydrophobic pharmaceutical substance having a macromolecular substance as a constituent component, wherein the capsule coating has (a) a wall membrane made of the above-mentioned macromolecular substance surrounding the hydrophobic drug substance particles; ) A hydrophobic pharmaceutical substance-containing microcapsule having a double structure of the gelatin and a complex coacervate wall film made of a polymer electrolyte surrounding the wall film.

Hereinafter, the microcapsules of the present invention will be explained in detail.

In the microcapsules of the present invention, gelatin, one of the components forming the complex coacervate wall film, may be acid-treated gelatin or alkali-treated gelatin, but acid-treated gelatin with a high isoelectric point is particularly preferred. Since the charge increases, the amount of the other enteric polyelectrolyte to cause complex coacervation can be increased, and the coacervate wall film formed thereby has water resistance, alkali resistance, acid resistance, etc. This is preferable because it will be reinforced.

The other component, the enteric polymer electrolyte, may be any one as long as it can be dissolved in water with a pH of 5 or higher, but in reality, electrostatic bonds or hydrophobic bonds cooperate with the hydrophobicity of the electrolyte to form a coacervate. Preferably, those that enhance the hydrophobization of

Specific examples of such enteric polymer electrolytes include methyl acrylate/methacrylic acid copolymer, ethyl acrylate/methacrylic acid copolymer, methyl methacrylate/methacrylic acid copolymer, and methyl acrylate/methacrylate. Copolymers of methacrylic acid and acrylic esters or (and) methacrylic esters such as acid/methyl methacrylate copolymers, polyvinyl alcohol phthalate, vinyl acetate/maleic anhydride copolymers, styrene/
Examples include polyvinyl derivatives such as maleic acid monoester copolymers, cellulose phthalate derivatives such as hydroxypropyl cellulose phthalate, and acetyl cellulose phthalate.

The ratio of the above components constituting the coacervate wall membrane varies slightly depending on the enteric polymer electrolyte, but approximately 0.05 parts by weight of enteric polymer electrolyte to 1 part by weight of gelatin.
~0.4 parts by weight, especially 0.2 to 0.4 parts by weight, resulting in a film with excellent water resistance, alkali resistance, and acid resistance.

Further, as another constituent component, the polymer material wall material formed inside the above-mentioned coacervate wall film includes, for example, n-hebutane, cyclohexanebenzene, xylene,
It is soluble in water-immiscible organic solvents such as chloroform, carbon tetrachloride, dichloroethane, oleic acid, oleyl alcohol, and soybean oil, but it is soluble in methanol, ethanol,
Any organic solvent that is miscible with water, such as a lower alkanol such as inpropanol, dioxane, or acetone, or a polar solvent that does not dissolve the coacervate wall film, may be used. Examples include polyisobutylene, polybutene, polybutadiene, polystyrene, styrene/isobutylene copolymer, styrene/methyl methacrylate copolymer, and the like.

The component ratio of these polymeric substances and hydrophobic pharmaceutical substances is approximately 0.05 to 50 parts by weight of the polymeric substance to 1 part by weight of the hydrophobic pharmaceutical substance.
By changing the ratio of the polymeric substance to the hydrophobic drug substance, the rate of release of the hydrophobic drug substance from the capsule can be freely adjusted to a considerable extent.

Regarding the microcapsule components as described above, the ratio of the components to the hydrophobic pharmaceutical substance is approximately 0.05 to 1 part by weight of the polymeric substance to 1 part by weight of the hydrophobic pharmaceutical substance.
50 parts by weight, about 0.1 to 2 parts by weight of gelatin, and about 0.005 to 0.8 parts by weight of polyelectrolyte.

The above hydrophobic drug substance-containing microcapsules are prepared by sequentially performing the following steps.

(a) A step of dissolving the polymeric substance in the water-immiscible organic solvent and dispersing or dissolving the hydrophobic pharmaceutical substance therein (core substance preparation step).

(b) A step of emulsifying the core material in a warm aqueous solution of gelatin (core material emulsification step).

(e) After mixing the warm aqueous solution of the enteric polyelectrolyte in the emulsion, the pH is adjusted to cause complex coacervation to deposit coacervate around the core material droplet, forming a coacervate wall. process (wall film formation process).

(d) Step of cooling and gelling the coacervate wall (gelling step).

(e) Separating the generated microcapsules (
separation process).

(f) A step of washing the generated microcapsules with water (water washing step).

(g) A step of washing the separated microcapsules with an organic solvent that is miscible with the water but hardly dissolves the hydrophobic pharmaceutical substance, or drying without washing (washing/drying step).

Each step will be explained in detail below.

[(a) Process]

In preparing the core material, first, a polymeric substance is dissolved in an organic solvent that is immiscible with water to a concentration of about 0.5 to 50 w/w%, and a hydrophobic pharmaceutical substance is dissolved in this to a concentration of about 0.1 to 50 w/w.
It is prepared by dissolving or dispersing the hydrophobic drug substance so that it is 0.05% to 1%.
Preferably, the amount is 50 parts by weight.

By increasing the ratio of the polymeric substance to the hydrophobic drug substance, it is possible to thicken the polymeric substance wall formed inside the coacervate wall, and conversely, by adjusting the usage ratio, the main drug can be removed from the capsule. The release rate can be freely adjusted.

[(b) Process]

About 0.5-4w/gelatin in warm water (35°-55°C)
Dissolve to give w%.

Add 1 to 30% of the core material obtained in step (a) above to this solution.
Add and emulsify at w/w%.

Any conventional emulsification method can be used for emulsification.

Note that making the size of the emulsion droplets uniform is as follows:
This is preferred because it facilitates the separation and removal of the coacervate wall film that does not contain the medicinal substance produced as a by-product in the encapsulation process, and the washing operation with an organic solvent that is miscible with water but hardly dissolves the hydrophobic medicinal substance.

The droplet diameter of the core material that meets this purpose is approximately 50
It is preferable that the thickness is about 500μ.

[(C) Process]

An aqueous solution of enteric polymer electrolyte is added to the emulsion obtained in step αb) above.

Prior to mixing, add approximately 0.5 ml of enteric polyelectrolyte to water.
Dissolve to a concentration of ~4w/w%.

In this case, all or part of the acid groups in the enteric polymer electrolyte may be used as alkali metal salts such as sodium salts and potassium salts, or ammonium salts.

The mixing ratio of enteric-coated polyelectrolyte and gelatin varies not only depending on the isoelectric point of gelatin and the acid content of enteric-coated polyelectrolyte, but also on the pH of the water in which complex coacervation occurs. At the optimum pH for complex coacervation, there is usually about 0% enteric polyelectrolyte per 1 part by weight of gelatin.
．． A suitable amount is about 0.05 to 0.4 parts by weight.

Next, to adjust the pH of this mixture to cause complex coacervation, the pH of the mixture should be adjusted to about 4.
It is preferable to adjust it to about 6.5.

As the pH adjuster, for example, acetic acid, hydrochloric acid, etc. are preferably used.

Coacervation thus occurs, and a complex coacervate consisting of gelatin and a polymer electrolyte is deposited around the core material droplet.

[Steps (d) and (e)]

The coacervate liquid wall is gelled by cooling the solution system in step (d) above at a rate of about 0.5 to 1°C per minute, thus forming a coacervate liquid wall deposited around the core material droplet. The walls are gelled.

Continuing on, the generated microcapsules are separated by cooling the above solution system to below 10°C.Separation methods include decantation, filtration, and centrifugation. Microcapsules rarely adhere to each other or aggregate.

[Ge) Process]

The separated microcapsules are thoroughly washed with cold water, washed with an organic solvent that is miscible with water but hardly dissolves hydrophobic pharmaceutical substances, and then dried with cold air, hot air, or vacuum to dissolve the inside of the coacervate wall membrane. It can extract or evaporate the organic solvent that is immiscible with water in the core material droplets taken into the core material, and it is miscible with water, which is a poor solvent for polymeric substances, but it hardly dissolves hydrophobic pharmaceutical substances. As the microcapsule coating is diluted with an organic solvent, phase separation of the polymer substance occurs and the polymer substance is deposited on the inside of the coacervate wall film, forming a wall film of the polymer substance. It is doubled by a wall film and a polymer material wall film.

In addition, this polymer material wall film is not miscible with the water in the core substance incorporated into the coacervate wall film by directly drying with cold air or heating or vacuum drying without washing the microcapsules to be separated, as described above. The organic solvent can be removed, and the polymeric substance can be deposited on the inside of the coacervate wall film in the same manner as described above, thereby making it possible to double the capsule coating.

According to the microcapsules of the present invention, even if the coacervate wall film made of gelatin and enteric polyelectrolyte is not treated with a hardening agent, the capsules hardly adhere to each other or aggregate.

The hydrophobic pharmaceutical substance incorporated into the microcapsules is surrounded by a double wall consisting of the above-mentioned coacervate wall film and a wall film made of a polymeric substance formed inside the coacervate wall film, so that it remains stable over time. Moreover, the coacervate wall film does not immediately disintegrate or dissolve in hot water or digestive fluids, and the thickness of the other polymeric material wall film can be adjusted quite freely, so both walls The release of the main drug from the capsule can be controlled arbitrarily to some extent by the membrane, and it has particularly excellent characteristics as a sustained-release or sustained-release preparation.

Experimental example 1 CI) Sample preparation 1. Preparation of microcapsules of the present invention (1) Polybutene 101 and soybean oil 30f? Dissolved in a mixed solvent of cyclohexane 201 and bisbenziamine 20? is dispersed to form a core material.

24g of acid-treated gelatin (isoelectric point 8o9) was soaked in warm water (40°C).
), and the above-mentioned core substance was added thereto and emulsified until the particle size of the core substance became about 50μ.

To this emulsion, add 5.41 y of methyl acrylate-methacrylic acid copolymer and 1.6 y of sodium bicarbonate with 3 y of warm water.
00ml and mix.

After adjusting the pH to 5.5 by adding IN acetic acid to the mixture, the mixture was cooled to 10°C or less at a rate of 0.5°C per minute.

The generated microcapsules were collected by filtration, washed with cold water (10°C), washed with a mixed solvent of inpropanol and n-hebutane:acetone (1:1), and dried to obtain 43 grams of bisbenziamine-containing capsules. obtain.

(2) In the above (1), 10 g of polybutene was replaced with 3.61 g of polyisobutylene, and 56.4 P of cyclohexane was replaced with a mixed solvent of 30 g of soybean oil and 201 g of cyclohexane.
Microcapsules produced by processing in the same manner as in Experimental Example 1 are collected by filtration, mixed with 500 g of cornstarch, dried with ventilation/hot air, and then the cornstarch is removed with a sieve to obtain bisbenziamine-containing microcapsules 631.

2. Preparation of control microcapsules (3) The bisbenziamine used as the core material in (1) and (2) above is used as a powder as a control.

(4) 20g of bisbenziamine and 60I of soybean oil? to form a core material.

15 grams of gum arabic and acid-treated gelatin (isoelectric point 8.
9) Dissolve 15 g in 1500 ml of water, add the above core material and mix.

After adjusting the pH of this mixture to 4.1,
Cool to below 10°C at a rate of

Thereafter, 25 g of bisbenchiamine-containing microcapsules are obtained by the same treatment as in (1) above.

(5) Instead of the core material prepared in (1) above,
) Using the core material prepared in (1) above, the same procedure as in (1) is performed to obtain bisbenziamine-containing microcapsules 28P.

2) Test method and results The bisbenchiamine-containing microcapsules obtained in (1) to (5) above were placed in the first solution for the disintegration test described in the 9th revised Japanese Pharmacopoeia, and the bisbenchiamine-containing microcapsules were
The time until 0% elution (t5o) was measured.

The results are shown in Table 1.

In addition, the amount of bisbenziamine eluted from the microcapsules was measured over time.

The results are shown in Figure 1. Experimental example 2 [I] Sample preparation 1. Preparation of microcapsules of the present invention (6) 3.61% polyisobutylene and 56% cyclohexane
．． =1, and oxolinic acid 20f? is dispersed to form a core material.

24 g of acid-treated gelatin (isoelectric point 8.9) was soaked in warm water (40°C).
) Dissolve in 120゛Oml, add the above core substance to it,
Emulsify until the particle size of the core substance becomes about 50 μm.

Add 5.4S' of methyl acrylate-methacrylic acid copolymer and 1.61% of sodium bicarbonate to this emulsion with 3.
00ml and mix.

After adjusting the pH to 5.5 by adding IN acetic acid to the mixture, the mixture was cooled to 10°C at a rate of 0.5°C per minute.

The produced microcapsules are collected by filtration, washed five times with cold water (10°C), then washed with isopropanol and acetone, and then dried to obtain 39 grams of oxolinic acid-containing microcapsules.

2. Preparation of control microcapsules (20 g of oxolinic acid is dispersed in 60 g of cyclohexane to form a core material.

Methyl acrylate-methacrylic acid copolymer 5.41 and sodium hydrogen carbonate 1.61 were mixed in warm water (40°C) 300
By dissolving in rrLl, adding the above-mentioned core substance thereto, and treating in the same manner as in (6) above, 39 grams of oxolinic acid-containing microcapsules are obtained.

CIO Test Method and Results Above (6) and (Pour the oxolinic acid-containing microcapsules obtained by force into a 0.01N aqueous sodium hydroxide solution, and measure the time t50 until 50% of oxolinic acid is eluted from the microcapsules. did.

The results are shown in Table 2. Additionally, the amount of oxolinic acid eluted into the microcapsules was measured over time.

The results are shown in Figure 2.

Experimental Example 3 CI) Sample Preparation 1, Preparation of Microcapsules of the Invention (8) 20 g of polystyrene is dissolved in 115 ml of carbon tetrachloride, and allopurinol 20P is dispersed therein to form a core material.

24 g of acid-treated gelatin (isoelectric point 8.9) was soaked in warm water (40°C).
) 1200rILl, add the above-mentioned core substance thereto, and emulsify until the particle size of the core substance becomes about 50μ.

Add 5.41 parts of methyl acrylate-methacrylic acid copolymer and 1.62 parts of sodium bicarbonate to this emulsion with 3 parts of warm water.
00ml and mix.

After adjusting the pH to 5.5 by adding IN acetic acid to this liquid mixture, it was cooled to 10°C at a rate of 0.5°C per minute.

Allopurinol-containing microcapsules 531 are obtained by filtering the produced microcapsules, washing them with cold water (10° C.) five times, and drying them.

(9) In (8) above, carbon tetrachloride 115TLl and polystyrene 20f? Chloroform 60 instead of
ml and 60,771 liters of cyclohexane and 10 g of polyisobutylene, the same procedure as in (8) above is performed to obtain 46 g of allopurinol-containing microcapsules.

α0) In (8) above, 45 g of soybean oil and 30 g of polybutene were used in place of 115 ml of carbon tetrachloride and 20 fI of polystyrene, the amount of allopurinol was further increased to 351, and the amount of allopurinol was increased to 351, and the treatment was carried out in the same manner as in (8) above. 72 grams of microcapsules were obtained.

2. Preparation of control microcapsules (11) Allopurinol, which was used as the core material in (8), (9), and 00) above, is used as a control as a powder.

(12) 20 g of allopurinol in 115 ml of carbon tetrachloride
．． to form a core material.

24 g of acid-treated gelatin (isoelectric point 8.9) was soaked in warm water (40°C).
) Dissolve in 1200 ml and add the above core substance to this.

Thereafter, 36 grams of allopurinol-containing microcapsules are obtained by the same treatment as in (8) above.

CID test method and results The allopurinol-containing microcapsules obtained in (8) to (12) above were subjected to disintegration test No. 1 described in the 9th revised Japanese Pharmacopoeia.
Allopurinol is added to the liquid from the microcapsules.
The time t50 until 0% elution occurred was measured.

The results are shown in Table 3.

In addition, the amount of allopurinol eluted from the microcapsules was measured over time.

The results are shown in FIG.

Experimental Example 4 Polyimbutylene was dissolved in the amount shown in Table 4 below in a mixed solvent of 100 ml of cyclohexane and 100 ml of toluene, and 25 g of allopurinol was dispersed therein to form a core material.

Acid-treated gelatin (isoelectric point 8.9) 24f? The hot water 120
0 ml, add the above-mentioned core substance thereto, and emulsify until the particle size of the core substance becomes about 100μ.

Add 5.41 parts of methyl acrylate-methacrylic acid copolymer and 1.61 parts of sodium bicarbonate to this emulsion with 30% of warm water.
Add the solution to be dissolved in 0.1 ml and mix.

After adjusting the pH to 5.5 by adding IN acetic acid to the mixture, the mixture was cooled to 10°C at a rate of 0.5°C per minute.

The produced microcapsules are collected by filtration, washed with cold water (10° C.), then washed with impropanol and acetone, and then dried to obtain about 501 allopurinol-containing microcapsules.

Cff) Test method and results Amount of allopurinol incorporated into the microcapsules and time t until 50% of the medicinal substance is eluted from the capsules when placed in the first solution of Japanese Pharmacopoeia disintegration test ,.

are as shown in Table 4, and it was confirmed that the release of the main drug from the capsule could be arbitrarily controlled by increasing or decreasing the amount of the polymeric substance.

In addition, the amount of allopurinol eluted from the microcapsules was measured over time.

The results are shown in FIG. Example 1 4v of polyisobutylene was dissolved in 30g of cyclohexane, and 30g of vitamin A acetate was added to this. (2.8 million vitamin A units/1) is dissolved to form a core substance.

Acid-treated gelatin (isoelectric point 8.9) 24? with warm water (40℃
) Dissolve 1200 ml of K, add the above core substance, and emulsify until the particle size of the core substance becomes about 50μ.

A solution of 5.4 P of acetyl cellulose phthalate and 1.61 P of sodium bicarbonate dissolved in 300 ml of warm water is added to this emulsion and mixed.

After adjusting the pH to 5.5 by adding IN acetic acid to the mixture, the mixture was cooled to 10°C or less at a rate of 0.5°C per minute.

The produced capsules were collected by filtration, washed with cold water (below 10°C), further washed with 60% inpropanol, and dried to obtain 1 microcapsule 48S' containing vitamin A acetate.

Book microcapsule 1? Contains 1.2 million vitamin A
units (0.43 g as vitamin A acetate).

When this microcapsule was stored for 2 months at 45°C and 75% relative humidity, the residual rate of vitamin A was 96%.
．． 3% (potency 1.16 million vitamin A units/ku).

However, as a control, vitamin A acetate was used without coating and stored under the above conditions.
The residual rate is 65.1% (potency 1.82 million vitamin A units/
It decreased to 1).

Example 2 Styrene-in-butylene copolymer 4? Toluene 130
Dissolve in oxolinic acid and add 20% oxolinic acid. is dispersed to form a core material.

Acid-treated gelatin (isoelectric point 8.9) at 24F was soaked in warm water (50℃).
) 1200rILl, and the above-mentioned core substance was added thereto and emulsified until the particle size of the core substance became about 100μ.

Add 5.41 parts of methyl methacrylate-methacrylic acid copolymer and 1.21 parts of sodium hydroxide to this emulsion with 30% of warm water.
Add the solution that can be dissolved in the 0-puncture solution and mix.

After adjusting the pH to 5.8 by adding IN acetic acid to the mixture, the mixture was cooled to 10°C or less at a rate of 0.5°C per minute.

The generated microcapsules are collected by filtration, washed with cold water (below 10°C), further washed with inpropanol, and dried to obtain approximately 4 oxolinic acid-containing microcapsules.
Get 21.

This microcapsule 11 contains 0.33S of oxolinic acid.
Contains '.

This microcapsule was placed in a 0.01N aqueous sodium hydroxide solution, and 50% of oxolinic acid was extracted from the microcapsule.
% elution time t.

When measured, it was 36 minutes.

[Brief explanation of the drawing]

Figure 1 is a curve showing the elution of bisbenchiamine from microcapsules over time, Figure 2 is a curve showing the elution of oxolinic acid from microcapsules over time, and Figure 3 is a curve showing the elution of allopurinol from microcapsules over time. FIG. 4 is a curve showing elution of allopurinol from microcapsules over time. In FIGS. 1 to 4, 1 to 15 represent each sample shop in the experimental example. 121-22

Claims (1)

[Scope of Claims] 1 Hydrophobic pharmaceutical substances, gelatin, enteric polyelectrolytes that can be dissolved in water with a pH of 5 or more, and polymers that are soluble in water-immiscible organic solvents but not in water-miscible organic solvents. A microcapsule containing the hydrophobic pharmaceutical substance having a molecular substance as a constituent, the capsule coating comprising: (a) a wall membrane made of the polymer substance surrounding the hydrophobic pharmaceutical substance particles; A hydrophobic pharmaceutical substance-containing microcapsule having a double structure of the gelatin and a complex coacervate wall made of an enteric polymer electrolyte surrounding the wall. 2 Enteric polymer electrolytes that can be dissolved in water with a pH of 5 or higher include copolymers of methacrylic acid and acrylic esters or (and) methacrylic esters, polyvinyl alcohol phthalate, vinyl acetate, maleic anhydride copolymers, styrene/maleic Acid monoester copolymers or cellulose phthalate derivatives, which are polymeric substances that dissolve in water-immiscible organic solvents but do not dissolve in water-miscible organic solvents, include n-hebutane, cyclohexane, benzene,
Dissolved in at least one organic solvent selected from xylene, chloroform, carbon tetrachloride, dichloroethane, oleic acid, oleyl alcohol and soybean oil, and dissolved in at least one organic solvent selected from methanol, ethanol, propanol, impropanol, dioxane and acetone 2. The microcapsules according to claim 1, wherein both of the microcapsules are polymeric substances that are insoluble in one or more organic solvents. 3 The enteric polymer electrolyte is methyl acrylate/methacrylic acid copolymer, ethyl acrylate/methacrylic acid copolymer, methyl methacrylate/methacrylic acid copolymer, methyl acrylate, methacrylic acid/methyl methacrylate copolymer , polyvinyl alcohol phthalate, vinyl acetate,
Maleic anhydride copolymer, styrene/maleic acid monoester copolymer, hydroxypropyl methylcellulose phthalate or acetylcellulose phthalate, and the polymeric substance is polystyrene, polybutadiene, polybutene, polyisobutylene, styrene/methyl methacrylate copolymer. , or a styrene-imbutylene copolymer. 4 In a method for producing microcapsules containing a hydrophobic pharmaceutical substance by a complex coacervation method using gelatin and an enteric polyelectrolyte that is soluble in water with a pH of 5 or more, ■ soluble in an organic solvent that is immiscible with water. A step of dissolving a polymeric substance that does not dissolve in an organic solvent that is miscible with water in the organic solvent that is immiscible with water, and dissolving or dispersing a hydrophobic pharmaceutical substance therein; Step of mixing and emulsifying with gelatin aqueous solution ◎ After adding enteric polymer electrolyte aqueous solution to the obtained emulsion, the pH of the entire system is made acidic to cause coacervation, and gelatin and enteric polymer electrolyte are mixed together. A step of forming a complex coacervate wall film; ■ A step of gelling the coacervate wall film by cooling the entire system; ■ A step of extracting or evaporating the water-immiscible organic solvent from the microcapsules thus obtained. (a) a wall film made of the polymer substance surrounding a hydrophobic pharmaceutical substance; and (b) a complex coacervate made of the gelatin and enteric polymer electrolyte surrounding the wall film. A method for producing microcapsules containing a hydrophobic pharmaceutical substance, which are double-layered with a wall membrane. 5 In the above, coacerpation is carried out at a pH of approximately 4 to 6.
5. The method of claim 4, wherein the coacervate wall film is gelled at a temperature below about 30°C.