JPS637091B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing non-agglomerated microcapsules. Conventionally, as a method for manufacturing microcapsules using phase separation of ethyl cellulose, for example, a method using a hydrocarbon-based polymer material such as butyl rubber, polybutadiene, polyethylene, polyisobutylene as a phase separation inducing agent (Japanese Patent Publication No. 1973-
No. 528, No. 44-11399 and No. 50-30136) are known. According to this method, a wall film forming agent such as ethyl cellulose is dissolved in a hot cyclohexane solution in which the phase separation inducing agent is dissolved in advance,
By uniformly dispersing the core substance therein and then cooling it to induce coacelvation, microcapsules having the wall film-forming agent as the capsule wall film can be produced. However, when hydrocarbon-based polymers such as butyl rubber, polybutadiene, and polyisobutylene are used as a phase separation inducer, many microcapsules adhere to each other during the microcapsule generation process, forming aggregates that are sufficiently fluid. There are disadvantages such as not being able to obtain mononuclear microcapsules, or adhesion to manufacturing equipment, which reduces the yield of microcapsules.
It is known that the above phenomenon is particularly remarkable when a relatively low molecular weight hydrocarbon polymer substance is used as a phase separation inducing agent. As a method to prevent such microcapsules from aggregating with each other and adhering to manufacturing equipment, it is possible to use a combination of high molecular weight hydrocarbon polymer substances and low molecular weight hydrocarbon polymer substances, or use surfactants and protective colloids. Usually done. However, in the above method, it is extremely difficult to adjust the strength of the anti-agglomeration effect, and if the anti-agglomeration effect is too strong, the core material may not be sufficiently covered with the wall film, or even if it is coated, a dense and uniform wall may not be formed. Microcapsules with membranes are difficult to obtain.
On the other hand, if the aggregation prevention effect is weak, it is difficult to obtain highly fluid, mononuclear microcapsules that are smoothly coated with a wall film with little damage. For this reason, there is also the drawback that the film-forming properties of the wall membrane and the release properties of the core substance are severely restricted. The present inventors have conducted various studies on a method for manufacturing microcapsules that does not have the above-mentioned difficulties, and have found that
When manufacturing microcapsules by forming an ethyl cellulose wall film on a core material through phase separation of ethyl cellulose, a certain type of organic solvent is used as an anti-aggregation agent to form a dense wall film and agglomerate. The present inventors have discovered that it is possible to produce microcapsules with excellent fluidity and are free from silica, leading to the completion of the present invention. That is, the method of the present invention involves dispersing a core material in a cyclohexane solution containing ethyl cellulose, and then forming an ethyl cellulose wall film on the core material through phase separation of ethyl cellulose to produce ethyl cellulose microcapsules. Hydrogen bond component δh of solubility parameter is 3.5 to 11.0 [(cal/cm ² ) ^1/2 ]
This is a method for producing non-aggregating microcapsules, which is characterized in that it is carried out in the presence of an organic solvent that dissolves or partially dissolves in cyclohexane. The agglomeration prevention mechanism of the organic solvent used in the method of the present invention and the aggregation prevention mechanism of the conventionally used aggregation inhibitor are completely different in the following points. In other words, the anti-aggregation mechanism of conventionally used anti-aggregation agents is that a protective colloid such as a polymeric substance or a surfactant is adsorbed onto the microcapsule wall to exert an anti-aggregation effect. The organic solvent aggregation prevention mechanism according to the present invention is that organic solvent molecules gather on the microcapsule wall film through interactions such as hydrogen bonds to form clusters, thereby preventing adhesion and aggregation between capsules. . The organic solvent used as an anti-aggregation agent in the present invention has the following formula δh=(Eh/V) ^1/2 (where Eh represents hydrogen bond energy and V
represents molar volume. ) The hydrogen bond component δh of the solubility parameter is
[Ind.Eng.Chem., Prod.Res.Dev., 8 , 2
(1969)] is approximately 3.5 to 11.0 (cal/cm ² ) ^1/2 , especially
3.8 to 9.5 (cal/cm ² ) ^1/2 , and an organic solvent that dissolves or partially dissolves in cyclohexane is used. Examples of such organic solvents include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 3-methyl-1-butanol. , 2-pentanol, 3-pentanol,
2-methyl-2-butanol, 1-hexanol, 2-ethyl-1-butanol, 4-methyl-
Chain or cyclic alkanols having 1 to 8 carbon atoms such as 2-pentanol, 2-ethyl-1-hexanol, cyclohexanol; methyl lactate, ethyl lactate, n-butyl lactate, isobutyl lactate, n-amyl lactate, lactic acid Lactic acid lower alkyl esters such as isoamyl; 2-methoxyethanol, 2-
Lower alkoxy-substituted lower alkanols such as ethoxyethanol, 2-butoxyethanol; 2-
(2-methoxyethoxy)ethanol, 2-(2-
lower alkoxy-substituted lower alkanols such as (butoxyethoxy) ethanol; lower alkoxy-substituted lower alkyl esters of acetic acid such as 2-ethoxyethyl acetate; formic acid, acetic acid,
lower fatty acids such as propionic acid, butyric acid, and isobutyric acid; tetrahydrofuran; diethylene glycol dilower alkyl ethers such as diethylene glycol dimethyl ether; trilower alkyl phosphates such as trimethyl phosphate and triethyl phosphate; lower alkanoyl-substituted lower alkanols such as diacetone alcohol. Can be mentioned. Among these, particularly preferred organic solvents include ethanol, 1-propanol, 2-ethoxyethanol, 2-butoxyethanol, acetic acid 2-ethoxyethyl ester, acetic acid, and tetrahydrofuran. The amount of these organic solvents used is slightly influenced by the amount of ethyl cellulose used as a wall film forming agent, but usually the above organic solvents are added at a concentration of about 0.05 to 20 V/V%, especially 0.5
It is preferable to use it at a concentration of ~10 V/V%. In the present invention, the ethoxy cellulose that surrounds the core substance and forms the microcapsule wall has an ethoxy content of about 46.5 to 55%, and has a viscosity [5% concentration of ethyl cellulose in a toluene-ethanol (4:1) mixture]. Soluble. 25 of the solution
It is preferable to use one having a viscosity of about 3 to 500 cP. It is appropriate to use ethyl cellulose in an amount of about 0.05 to 5 times the core material, and for cyclohexane it is usually 0.5 to 10 W/
It is preferred to use W%, especially about 1 to 5 W/W%. Furthermore, the core material to which the microencapsulation method of the present invention can be applied is generally cyclohexane,
Alternatively, any substance may be used as long as it does not dissolve in the cyclohexane solution containing the organic solvent and ethyl cellulose which are anti-aggregation agents, and these may be in the form of solid, liquid, slurry or gel. In addition, there is no particular restriction on the particle size when using these core materials, but the particle size is approximately 5.
Preference is given to using particle sizes of ~1000 .mu.m, especially about 50-500 .mu.m. In the present invention, when producing ethyl cellulose microcapsules, first, an organic solvent as an anti-aggregation agent, ethyl cellulose as a wall film forming agent, and a core material are added to cyclohexane, and the mixture is heated to 80°C and stirred. When a dispersion of the core material is prepared and the dispersion is appropriately cooled while stirring, a wall film of ethylcellulose is formed on the core material particles to produce ethylcellulose microcapsules. Preferably, the dispersion is cooled at a rate of about 0.05 DEG to 4 DEG C., particularly 0.5 DEG to 2 DEG C., per minute.
In this way, phase separation of ethyl cellulose first occurs and ethyl cellulose begins to separate, and by further cooling, an ethyl cellulose wall film is formed, which is further solidified to form a stable wall film. Further cooling to room temperature causes the release of cyclohexane from the wall film, completing the wall film and producing stable ethyl cellulose microcapsules. The microcapsules produced above can be further stabilized by adding a non-solvent such as cyclohexane, petroleum ether, n-hexane, etc., if necessary, when stable microcapsules are produced. The microcapsules produced in this way can be separated using conventional separation methods such as decantation,
This can be carried out by filtration, centrifugation, etc. The obtained microcapsules can then be washed with cyclohexane, petroleum ether, n-hexane, etc., if necessary, and dried by a conventional method such as hot air drying or heat transfer drying. In this way, microcapsules with low aggregation and high fluidity can be obtained. Furthermore, in the method of the present invention, the phase separation of ethyl cellulose from the core material dispersion can be carried out in the presence of a phase separation inducing agent or a wall film forming aid, and the phase separation phenomenon is caused by coacelvation or flocculence. It can be carried out using any phase separation phenomenon of ration. As the phase separation inducing agent, for example, polyethylene, butyl rubber, polyisobutylene, polybutadiene, etc. can be used. Further, as the wall film forming aid, for example, dimethylpolysiloxane, methylphenylpolysiloxane, etc. can be used. These phase separation inducers or wall film forming aids include cyclohexane, an organic solvent that is an anti-aggregation agent, ethyl cellulose,
It can be added at the same time as adding the core material, and the amount added is approximately 0.1 to 10 W/V% for the phase separation inducer and 0.01% for the wall film forming aid relative to the ethyl cellulose-containing solution.
It is preferable that it is 10 W/V%. According to the method of the present invention as described above, the organic solvent molecules in cyclohexane interact mainly with the ethyl cellulose molecules in the capsule wall film made of coacervate or gel deposited on the core material through interactions such as hydrogen bonds. They gather to form a cluster of organic solvent molecules on the wall membrane, and this cluster acts as a barrier to mutual adhesion and aggregation of microcapsules, so that the formation, solidification, and stabilization of the capsule wall membrane proceed smoothly. In addition, due to the plasticizing effect of the organic solvent cluster, the viscoelasticity and adhesiveness of the phase-separated ethylcellulose become appropriate, and the deposition and "wetting" of ethylcellulose on the core material particles are significantly improved, resulting in a dense layer. It is possible to produce highly fluid microcapsules that have wall membranes and are free from agglomeration.
Furthermore, according to the method of the present invention using an organic solvent as an anti-aggregation agent, the microcapsules produced during the microcapsule manufacturing process hardly adhere to the manufacturing equipment. Therefore, the method of the present invention is a very advantageous method for industrially producing microcapsules. The above microencapsulation method of the present invention can be widely applied to various substances such as pharmaceuticals, veterinary drugs, agricultural chemicals, cosmetics, foods, and printing inks. Particularly in the case of pharmaceuticals, it is possible to obtain accurate improvement effects by stabilizing them, prolonging their efficacy, or alleviating taste, odor, irritation, etc. Pharmaceutical products to which the microencapsulation method of the present invention can be applied include, for example, vitamins, amino acids, peptides, chemotherapeutic agents, antibiotics, respiratory stimulants, antitussive expectorants, antineoplastic agents,
Autonomic nerve agents, psychiatric nerve agents, local anesthetics,
Muscle relaxant, gastrointestinal agent, antihistamine, poison treatment agent, hypnotic sedative, antiepileptic agent, antipyretic, analgesic, antiinflammatory agent, cardiotonic agent, antiarrhythmia agent, antihypertensive diuretic, vasodilator, antilipidemic agent, nourishing tonic and altering agent. A wide range of drugs can be listed, including anticoagulants, liver drugs, hypoglycemic agents, and antihypertensive agents. The present invention will be explained below with reference to experimental examples and examples. In addition, in this specification, "lower alkyl",
"Lower alkoxy", "lower alkanol" and "lower fatty acid" mean alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanol having 1 to 3 carbon atoms, and fatty acid having 1 to 5 carbon atoms, respectively. . Experimental example 1 1-methyl-5-methoxy-3-(dithiene-
Microcapsules containing 2-ylmethylene) piperidinium hydrobromide (hereinafter referred to as the active ingredient) were prepared by the following method, and were prepared according to the fine granule standards of the 10th edition of the Japanese Pharmacopoeia (hereinafter simply referred to as fine granule standards). ), the content of the active ingredient in the microcapsules, and the time required for 50% of the active ingredient to elute from the microcapsules (50% elution time) in a 0.2% sodium chloride aqueous solution at 37°C were measured. The results are shown in Table 1. (Preparation of microcapsules) (1) Preparation of core substance Add 7 parts of a 40V/V% ethanol aqueous solution to a mixed powder of 11.8 parts of the main drug, 82.8 parts of lactose, and 5.4 parts of white dextrin, and knead using a conventional method. After granulating, it was dried and sized into particles with a particle size of 105 to 350 μm, and used as a core material. (2) Preparation of microcapsules Add 2-ethoxyethyl acetate in the amount shown in Table 1 to 1000 ml of cyclohexane, and add a silicone resin that meets the standards of the Japanese Food Additives Standard, 4th edition (viscosity at 25°C is 100 to 1100 cSt). 3 silicon dioxide to dimethylpolysiloxane
Add 30g of ethyl cellulose (ethyl cellulose (ethoxy content: 48.2%, viscosity: 101cP)), 212g of the core material obtained in (1) and heat to 80°C and stir to prepare a core material dispersion. This dispersion
The mixture was cooled to room temperature while stirring at 400 rpm. The microcapsules thus produced were separated by a conventional method, washed with n-hexane, and then dried. The opening of the obtained microcapsules
Passes through a 500μm JIS standard sieve with an opening of 105μ
By collecting the residue on a JIS standard sieve, the active ingredient complies with fine granule standards.
Containing microcapsules were obtained.

Table 1 shows that microcapsules meeting the standards for fine granules can be obtained in good yield by the method of the present invention. Experimental Example 2 Microcapsules containing the same main drug as in Experimental Example 1 were prepared in the presence of various organic solvents as anti-aggregation agents, and the yield of the microcapsules and the content of the main drug in the microcapsules were measured. The results are shown in Table 2 below. (Preparation of microcapsules) (1) Adjustment of core substance Add 10 parts of a 45V/V% ethanol aqueous solution to a mixed powder of 5 parts of the main drug, 87 parts of lactose, and 8 parts of white dextrin, and knead using a conventional method. After granulating, it was dried and sized into particles with a particle size of 105 to 350 μm, and used as a core material. (2) Preparation of microcapsules 800 ml of cyclohexane, 24 ml of the organic solvent shown in Table 2, 24 g of silicone resin (same as that used in Experimental Example 1), 22.4 g of ethyl cellulose (ethoxy content: 47.8%, viscosity: 80 cp), and
Add 112g of the core material obtained in (1) and heat and stir at 80℃ to prepare a core material dispersion.
Cool to room temperature while stirring at 300 rpm.
500 ml of n-hexane was added. The microcapsules thus produced are separated by a conventional method, and n-
Wash with hexane and dry. Thereafter, microcapsules containing the main drug that met the standards for fine granules were obtained by processing in the same manner as in Experimental Example 1.

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[Table] Experimental Example 3 Microcapsules containing thimepidium bromide (chemical name: 1,1-dimethyl-5-methoxy-3-(dithien-2-ylmethylene) piperidinium hydrobromide) were incubated in the presence of various organic solvents. Prepared below. Tables 3 to 6 below show the particle size distribution of the obtained microcapsules, the yield of microcapsules meeting the fine granule standards, and the yield of microcapsules with respect to the charge amount calculated by the following formula. Yield of microcapsules (%) with respect to the amount charged = [yield of microcapsules/amount of ethyl cellulose charged + amount of core material charged]x100 Tables 3 and 4 show the experimental results according to the method of the present invention, and Tables 5 and 6 shows, as a comparative example, experimental results when using an organic solvent whose hydrogen bond component is outside the range of the method of the present invention. (Preparation of microcapsules) (1) Adjustment of core substance Particles were granulated in the same manner as in Experimental Example 2-(1) except that thimepidium bromide was used as the main drug.
Particles of 350 μm were prepared and used as core material. (2) Preparation of microcapsules To 80 ml of cyclohexane, 2.4 ml of the organic solvent shown in Tables 3 to 6 below, polyisobutylene (molecular weight
9000), 2.24 g of ethyl cellulose (ethoxy content: 47.8%, viscosity: 80 cp), and 11.2 g of the core material obtained in (1) were treated in the same manner as in Experimental Example 1-(2) to obtain thimepidium bromide-containing microorganisms. Got the capsule. (Results) According to the method of the present invention (Tables 3 and 4), the yield of microcapsules that meet the standards for fine granules is approximately 81%.
In contrast, it was about 14 to 33% in the comparative examples (Tables 5 and 6).

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[Table] Example 1 800 ml of cyclohexane, 24 ml of acetic acid, ethyl cellulose (ethoxy content: 47.8%, viscosity: 80 cP)
20g polyisobutylene (Staudinger viscosity average molecular weight 9000)
Add 18.7 g and 100 g of trimebutine maleate (chemical name: 2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxybenzoate hydrodiene maleate) with a particle size of 105 to 177 μm to 80 g.
A dispersion of the core substance was prepared by heating and stirring at ℃, and this dispersion was cooled to room temperature while stirring at 350 rpm.
500 ml of n-hexane was added. The microcapsules thus produced were separated by a conventional method, washed with n-hexane, and then dried. The obtained microcapsules were processed through a JIS standard sieve with an opening of 350 μm to obtain 114 g of trimebutine maleate-containing microcapsules that met the powder standards of the 10th edition of the Japanese Pharmacopoeia (hereinafter simply referred to as powder standards). Example 2 In place of polyisobutylene in Example 1,
By using 18.7 g of polyethylene (viscosity average molecular weight: 7000) and treating in the same manner as in Example 1, 118 g of trimebutine maleate-containing microcapsules meeting powder standards were obtained. Example 3 In place of polyisobutylene in Example 1,
Butyl rubber [Mouni viscosity: 67 (ML-8/100℃)]
By using 18.7 g and treating in the same manner as in Example 1, 118 g of trimebutine maleate-containing microcapsules meeting the powder standards were obtained. Example 4 In place of polyisobutylene in Example 1,
Dimethylpolysiloxane (viscosity at 25℃:
500,000 cSt) was treated in the same manner as in Example 1 to obtain 114 g of trimebutine maleate-containing microcapsules that met powder standards. Example 5 In Example 1, ethanol 16 was used instead of acetic acid.
ml and was treated in the same manner as in Example 1 to obtain 115 g of maleic acid-containing microcapsules that met powder standards. Example 6 In place of trimebutine maleate in Example 1, 100 g of vitamin C with a particle size of 105 to 177 μm was used, and the following treatment was carried out in the same manner as in Example 1.
116 g of vitamin C-containing microcapsules meeting powder standards were obtained. Example 7 In Example 1, instead of acetic acid and trimebutine maleate, 16 ml of methanol and a particle size of 105 to 177 μm were used.
By using 100 g of glutathione and treating in the same manner as in Example 1, 112 g of glutathione-containing microcapsules meeting powder standards were obtained. Example 8 In Example 1, the ethoxy content was 47.8% and the viscosity was
In place of 80 cP ethyl cellulose, 20 g of ethyl cellulose with an ethoxy content of 49.0% and a viscosity of 45 cP was used, and the following treatment was carried out in the same manner as in Example 1.
115 g of trimebutine maleate-containing microcapsules meeting powder standards were obtained.

Claims (1)

[Scope of Claims] 1. A method for manufacturing ethylcellulose microcapsules by dispersing a core material in a cyclohexane solution containing ethylcellulose and then forming an ethylcellulose wall film on the core material by phase separation of the ethylcellulose. Hydrogen bond component δh of solubility parameter is 3.5 to 11.0
[(cal/cm ² ) ^1/2 ] A method for producing non-aggregating microcapsules, which is carried out in the presence of an organic solvent that dissolves or partially dissolves in cyclohexane. 2 The organic solvent is a linear or cyclic alkanol having 1 to 8 carbon atoms, lower alkyl lactic acid ester, lower alkoxy-substituted lower alkanol, lower alkoxy-substituted lower alkanol, lower alkoxy-substituted acetic acid lower alkyl ester, lower fatty acid, tetrahydrofuran, diethylene glycol di The method according to claim 1, which is a lower alkyl ether, a tri-lower alkyl phosphate, or a lower alkanoyl-substituted lower alkanol. 3 The organic solvent is ethanol, 1-propanol,
Claim 1: 2-ethoxyethanol, 2-butoxyethanol, acetic acid 2-ethoxyethyl ester, acetic acid or tetrahydrofuran
Manufacturing method described in section. 4. The manufacturing method according to claim 1, 2 or 3, wherein the phase separation of ethylcellulose is carried out in the presence of an organic solvent and a phase separation inducing agent. 5. The manufacturing method according to claim 1, 2 or 3, wherein the phase separation of ethyl cellulose is carried out together with an organic solvent in the presence of a wall film forming aid.