JPS5855413A - Production of enteric microcapsules - Google Patents

Abstract

PURPOSE:The core constituents and an auxiliary agent for forming coating films are dispersed in a hot solution of hydroxypropyl methyl cellulose phthalate (A) and ethyl cellulose as an antiblocking agent and they are cooled to form the coating film of compound A over the surface of the core constituents, thus producing the titled substance. CONSTITUTION:The core constituents (medicines) and an auxiliary agent for forming coating films (fluid paraffin) are dispersed in a hot solution of hydroxypropyl methyl cellulose phthalate (A) and ethyl cellulose as an antiblocking agent in an organic solvent, then they are cooled to induce the phase separation of compound A, thus producing the titled microcasules containing the core constituents coated with compound A over the surfaces. As the above organic solvent, is preferred the one that is a poor solvent of compound A on cooling, but becoming a good one on heating and a lower alkanol is used. The above- stated process readily gives enteric microcapsules with relatively narrow distribution of particle sizes and high fluidity.

Description

[Detailed description of the invention] The present invention relates to a method for producing enteric-coated microcapsules.

Conventionally, from an organic solvent system, hydroxypropyl methylcellulose phthalate C or less is referred to as rHPMCP. ) As a method for manufacturing microcapsules using phase separation, a core material is dispersed in a good solvent solution of HPMCP,
A method is known in which a nonsolvent is added to the dispersion liquid to cause phase separation of HPMCP, thereby forming a wall film of HPMCP on the core material (Japanese Patent Laid-Open No. 48-39620).
. However, this method requires a large carp non-solvent in an amount several times the amount of a good solvent in order to cause phase separation of HPMCP, and as a result, the amount of polymer and core @ negative charged as a wall film agent is reduced. There is also the disadvantage that the polymer wall film of microcapsules obtained by such a method tends to be porous due to the strong demixing property of the non-solvent, and becomes less dense.

Considering these points, the present inventors have developed a method for producing enteric-coated microcapsules using phase separation of HPMCP, and have developed 81
[As a result of repeated research, we found that using an organic solvent that is a poor solvent for HPMCP when cold but a good solvent when hot is used as a solvent for dissolving HPMCP.
It has been found that simply by cooling a hot solution of MCP, phase separation of HPMCP occurs and the core material is coated.

In addition, during phase separation, if a wall-forming agent that has a plasticizing effect on HPMCP is present in the HPMCP hot solution, the capsule wall becomes thicker and denser, and moreover, Is it a core substance or is it difficult to elute?

They found that enteric-coated microcapsules that are easily eluted can be obtained in the HPMCP solution, and that the presence of ethyl cellulose in the HPMCP solution suppresses the coagulation of HPMCP itself and the aggregation of microcapsules. 1
It has been found that enteric-coated microcapsules having a comparatively narrow particle size distribution width and high fluidity can be obtained very easily.

This book was completed based on this knowledge.

In other words, the method of the present invention uses HPMCP, which is a wall-like polymer, and ethyl cellulose, which is an M aggregation inhibitor.

For the HPMCP, a core substance and a wall film forming aid are dispersed in a hot solution dissolved in an organic solvent that is a poor solvent when cold but a good solvent when it is cold.

This is a method for producing enteric-coated microcapsules, which is characterized in that the dispersion is then cooled to induce phase separation of HPMCP to form a wall of HPMCP on the core material.

HPMCP used in the method of the present invention contains 18 to 24 W/Vi 1% of methoxy-containing material and 1% of hydroxypropoxy-containing material.
is 5-10 W/W%, carboxybenzoyl-containing 2
It is preferable to use 1 to 35 W/W%. The wrinkles used should be about 0.02 to 10 times the overlap of the core material, and usually about 0.05 to 10 W/V% to the solvent.
It is preferable to use a suitable amount. Also, by increasing or decreasing HPMCP within the range of the lid used, the capsule wall membrane can be made thicker.

Or you can comb it thinly.

The ethyl cellulose used as an anti-aggregation agent in the present invention has an ethoxy content of about 47 to 55 W/W% and a viscosity (in the present invention, the ethyl cellulose has a viscosity of 4-ethyl cellulose mixed with toluene:ethanol = 4:1). It is preferable to use a solution having a viscosity of about 3 to 500 eP (expressed in terms of viscosity at 25 DEG C.) of the bath solution at 25 DEG C. Use of ethyl cellulose M
It is preferable to use about 0.05 to 5 times the amount of HPMCP, particularly about 0.1 to 2 times the amount of HPMCP.

As a solvent for dissolving the above HPMCP and ethylcellulose, m% of ethylcellulose or HPMC
Any organic solvent that is a poor solvent for P when cold but is a good solvent when hot is sufficient. Examples of such organic solvents include ethanol, 1-propanol, 2-propanol, and l-butanol. , 2-butanol, 2-methyl-2-propano-7, and a mixed solvent of these lower alkanols with petroleum ether, N-hexane, or cyclohexane.

In addition, as a wall film forming aid to be dispersed in a hot solution containing HPMCP and ethylcellulose, it does not mix with the HPMCP solution, is dispersed as liquid fine droplets in the HPMCP hot solution, and has plasticity in the precipitated HPMCP wall film. Examples of such wall film forming aids include aliphatic hydrocarbons such as white petrolatum, yellow petrolatum, liquid paraffin, polybutene, polyisobutylene, butyl rubber, and polybutadiene, and dimethylpolysiloxane. Examples include organic polysiloxane compounds. Further, the above-mentioned organic polysiloxane compound may be blended with an appropriate dispersant or filler.

For example, silicon dioxide-based, dimethylpolysiloxane,
Examples include those containing a dispersant or filler such as titanium oxide, calcium stearate, and talc in an amount of about 1 to 50 W/V%. The amount of wall film forming aid to be used is almost not influenced by the amount of the core@negative compound, and it is appropriate that the amount is approximately 0,001 to 5 times higher than that of HPMCP, which is a normal wall membrane complex.

The core material used in the present invention is HP
Pharmaceutical compounds from each building are used as long as they are not practically soluble in the hot solution of MCP. Further, the core material may be solid, gel-like, or even mud-like. There is no particular restriction on the particle size of the core material, but it is generally preferable to use a particle size of about 10 to 1000 P, especially about 50 to 500 P. There are no particular restrictions on the pharmaceutical compounds that can be used as core substances, such as vitamins, amino acids, peptides, chemotherapeutic agents, anti-inflammatory agents, respiratory stimulants, antitussive expectorants, antineoplastic agents, and autonomic nervous system agents. , central nervous system drugs 1 Local anesthetics, muscle relaxants, gastrointestinal drugs, antiepileptic drugs.

Antipyretic analgesic anti-inflammatory agent 1 Cardiac agent, arrhythmia treatment agent, antihypertensive diuretic agent,
Vasodilator, antilipemic agent, nourishing tonic agent, anticoagulant,
A wide range of drugs are available, including liver drugs, hypoglycemic agents, and antihypertensive agents.

To prepare enteric microcapsules by the method of the present invention, first, HPMCP, ethyl cellulose, a wall-forming aid, and a core material are added to a && solvent in any order until the temperature approaches the boiling point of the solvent or the azeotropic point of the mixed solvent. A dispersion containing HPMCP, ethyl cellulose, a wall film forming aid, and a core substance is prepared. Next, this dispersion is cooled to room temperature (30°C or less) while stirring, preferably at a rate of about 0.2 to 4°C per minute, to cause phase separation of HPMCP from the dispersion. , a wall film of HPMCP is formed on the core material to produce microcapsules.

The microcapsules thus produced can be easily separated and collected by known means such as filtration, centrifugation, or tilting. By washing the collected microcapsules with an appropriate solvent, the ethyl cellulose and wall film forming aid adsorbed on the microcapsules can be removed. For example, first wash with a solvent that dissolves only ethyl cellulose without dissolving the core@negative and HPMCP (for example, a mixed solvent of a good solvent such as ethanol and a poor solvent such as cyclohexane), and then dissolve only the wall film forming aid. (e.g., poor solvents such as cyclohexane)
By sequentially washing the microcapsules with water, the ethyl cellulose and wall film forming aid adsorbed in the microcapsules can be easily removed. Enteric-coated microcapsules are obtained by drying the microcapsules thus obtained.

According to the method of the present invention as described above, HPMCP is obtained from the 9 dispersion.
When producing microcapsules by phase separation, there is no need to cool the dispersion liquid as in conventional methods,
Microcapsules can be produced simply by cooling the dispersion.

In addition, according to the method of the present invention, HPM generated by phase separation
The CP microdroplets have excessive viscoelasticity and adhesion due to the plasticizing effect of the wall film forming aid, and also have a tendency to deposit on the particles of the core material and to wet the core material. Enteric-coated microcapsules, which have a thick and dense capsule wall and whose core material is easily released in gastric fluid, are being developed as HPMCP is used more and more as a capsule wall. can be obtained.

First in history, the method of the present invention prevents HPMCP itself from coagulating and agglomerating between microcapsules during the microcapsule production process due to the action of ethyl cellulose, which is an anti-aggregation agent. enteric-coated microcapsules can be obtained.

The following is an explanation using experimental examples and examples.

Experimental Example 1 Microcapsules containing pyridoxal phosphate were subjected to mW,
Yield of capsules, content of pyridoxal phosphate in capsules, leaching rate of pyridoxal phosphate after 2 hours in liquid 1 (37°C) of disintegration test of the 10th revised Japanese Pharmacopoeia Law, and disintegration test of the 10th revised Japanese Pharmacopoeia Law 2i& 100% pyridoxal phosphate in microcapsules at (37°C)
The effect of the present invention was subtracted by measuring the time required for it to become popular.

Experimental method (1) Core material Pyridoxal phosphate having a particle size of 105 to 177 microns was used as the core material.

(!) MW of microcapsules (microcapsules of the present invention) Hydroxypropyl methylcellulose phthalate (methoxy content 20.2 WOW%, hydroxypropoxy content 6.9 WOW%, carboxyhen) in a mixed solvent of 400d ethanol and 200d cyclohexane. Soil content 30.5 WOW%) 40g, -r-thyl cellulose (Ethoxy content 48 WOW%, viscosity Jf 85cP) 2
09. Pyridoxal phosphate 602 and 15 parts of the wall film forming aid shown in Table IJ1 were added, heated to 65°C and dispersed, and then pressed a o o r, p, m.
Cooled to room temperature (approximately 25°C). The microcapsules thus produced were separated, and those that passed through a mixed solvent of ethanol/cyclohexane (1:2.5) and an Is standard sieve were collected to meet the powder standards of the 10th revised Japanese Musical Instruments Act. (hereinafter simply referred to as powder standard) were obtained.

(Control microcapsules) Control microcapsules were obtained by performing the same treatment as above except that the wall film forming aid 10f was not added.+31 Results The results are shown in Table 1 below.

vs　　　　　　　　Table' Note 1: Conforms to the standards of the 4th edition of the Official Standards for Food Additives.

Dimethylpolysiloxane with a viscosity of 100 to 1 to 100C8t at 25°C and 3 to 15% of silicon dioxide
% blended.

Example 1 Adding hydroxypropyl to isopronofnol 600Wi
Methylcellulose phthalate (methoxy content 20.2
w/vtr%, hydroxypropoxy content 69W/W
%, carboxybenzoyl content 30.5 WOW%) 6
0y, ethylcellulose (contains ethoxy*48W#%
, viscosity [85cP) 30F, silicone resin (Experimental example 1
) 20F and particle size 149-210
P's glutathione 90f! was added, heated to 80°C and dispersed at 300 r, p, m.

The mixture was cooled to about 25° C. while stirring vigorously.

The microcapsules thus produced were separated, washed successively with a mixed solvent of ethanol/cyclohexane (1:L5) and cyclohexane, and dried. The obtained microcapsules were processed through a JIS standard sieve having a mesh size of 350P to obtain glutathione-containing microcapsules 140F that met powder standards.

The microcapsules obtained above contain 61 glutathione.
．． It contained 2%. When this microcapsule was put into disintegration test liquid S1 (37° C.) according to the 14th edition of the Japanese Pharmacopoeia, the amount of glutathione leached out after 2 hours was 9%. In addition, the disintegration test liquid 2 (37
℃), glutathione is converted to 10% within 40 minutes.
0% eluted.

Example 2 Hydroxypropyl methylcellulose phthalate (methoxy content 2 g, g W#%, hydroxypropoxy content 7.1 f#%, carboxybenzoyl content II 26.13 W/ W%) 4'oy, ethylcellulose (containing ethoxy M 47.5 IF/If%
, viscosity 105cP) 20? , polybutene (molecule f
Trimethoquinol hydrochloride (chemical name: / -1-(3,45-) with ilo00) 15F and particle size 125-149P
(rimethoxybenzyl) -6,7-cyhydroxy 1.
2.3.4-Tetrahydroisoquinoline hydrochloride 1 water-
60y was added, heated to 65°C and dispersed.

Cooled to about 25° C. with stirring at 300 r, #m, teca. The microcapsules thus produced were separated, washed successively with a mixed solvent of ethanol/cyclohexane (1:2.5) and cyclohexane, and dried.

The obtained microcapsules were opened at 35oP.
By treating with a semi-sieve, trimethoquinol hydrochloride-containing microcapsules 93f having a consistency meeting powder standards were obtained.

The microcapsules obtained above are
It contained 63.8%. When this microcapsule was put into the disintegration test first liquid (37°C), the elution rate of trimethoquinol hydrochloride after 2 hours was 69%.

Furthermore, when the sample was placed in the second disintegration test (37°C), 100% of trimethoquinol hydrochloride was eluted within 40 minutes.

Example 3 Hydroxypropyl methylcellulose phthalate (methoxy content 2), 2-butanol 600-
W1%, hydroxypropoxy content B, IWN%, carboxybenzoyl content 3'4 Q WOW%) 60y
, ethyl, cellulose (ethoxy content 49.0 WOW%
, viscosity 80 cP) 309. 25f liquid paraffin and 90f potassium aspartate with particle size 105-177P
was added, heated to 100°C and dispersed, and then heated at 300r.
The mixture was cooled to about 25°C while stirring vigorously. The microcapsules thus produced were separated, washed successively with a mixed solvent of ethanol/cyclohexane (1:2.5°) and cyclohexane, and dried. By treating the obtained microcapsules with a 350P mesh sieve, powder base]? The most suitable potassium aspartate-containing microcapsules 1452 were obtained.

The microcapsules obtained above contained 61.5% of Asunocarium laginate. When the microcapsules were put into the first disintegration test liquid (3'7°C), the amount of dissolved potassium aspartate after 2 hours was 23%. When added, 100% of the potassium aspartate eluted within 30 minutes.

Example 4 In Example 3, a mixed solvent of ethanol 400 and cyclohexane 200 was used in place of 2-butanol 600, and butyl rubber [Mouni viscosity 41 CML - 8 minutes/100°C] and non-alcoholic rubber were used in place of liquid paraffin 25F. Saturation level 0.
8%] using 10y.

Potassium aspartate-containing microcapsules 143 adapted to powder base yarn by treatment in the same manner as in Example 3
I got 2.

Claims (1)

[Scope of Claims] (1) Hydroxypropyl methylcellulose phthalate, which is a wall-forming polymer, and ethylcellulose, which is an anti-aggregation agent, are either a poor solvent for the hydroxypropyl methylcellulose phthalate when cold or a good solvent when hot. The core material and the wall film forming aid are dispersed in a hot solution dissolved in an organic solvent, and then this dispersion is cooled to induce phase separation of hydroxypropyl, methyl cellulose, and phthalate, and then the core material and the wall film forming aid are dissolved on the core material. Method for manufacturing enteric microcapsules characterized by forming a wall of hydroxypropyl methylcellulose 7-talate (2) It is a poor solvent for hydroxypropyl methylcellulose phthalate when cold, but becomes a good solvent when hot. (3) The manufacturing method according to claim 1, wherein the organic solvent is a lower alkanol, or a mixed solvent of the lower alkanol and petroleum ether, n-hexane or cyclohexane. (3) The lower alkanol is ethanol 21-propanol, 2-propatol, 1-butanol, 2-butanol or 2-methyl-2-propatol (4) according to claim 2, wherein the methoxy content is from 18 to
24w7w%, and the hydroxypropoxy content is 5~
l Q WOW%. Claim 1, which uses hydroxypropyl methylcellulose phthalate and has a carboxybenzoyl content of 21 to 35 WIW%. The manufacturing method according to claim 2 or 3 uses ethyl cellulose having an ethoxy content of 47 to 55 W/W%. Claim 1. Manufacturing method according to item 2 or 3 (6) Wall film forming aid, liquid paraffin, vaseline. The manufacturing method according to claim 1, 2, or 3, which is polybutene, polyisobutylene, butyl rubber, dimethylpolysiloxane, or polybutadiene.