JPS5849433A - Production of microcapsule - Google Patents

Abstract

PURPOSE:To produce product having dense and stable wall membranes efficiently by using an org. polysiloxane compd. as an assistant for forming the wall membranes and using ethyl cellulose contg. ethoxy groups in a specific range as a forming agent for the wall membranes. CONSTITUTION:Powder of a core material is dispersed in a soln. dissolved with ethyl cellulose and an org. polysiloxane compd. in cyclohexane by heating. The ethyl cellulose as a forming agent for wall membranes to be used here is of about 5-500cp in viscoisty at 25 deg.C, and the amt, to be used is about 0.02-5 times the weight of the core material, and is dissolved so as to be contained at about 0.1-10W/V% based on the weight of the cyclohexane. The soln. thus prepd. is cooled to allow the flocculation of the ethyl cellulose to form, whereby the gellike wall membranes of the ethyl cellulose contg. the core material therein are formed. The membranes are solidified and microcapsuled.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing fJenalcellulose microcapsules.

Microphone ci using phase separation of promoted rice and enal cellulose
/ J-1 Cell (・) manufactured by 1 For example, bunal rubber, polyltadie/, borieno [・/, a method of using ashed Mizuki Itoshima molecule 1+ material exclusively for polyisobutylene as a phase separation inducer is known. (Japanese Patent Publication Nos. 42-528, 44-11399 and 50-30136). According to this method, a wall film-forming agent such as ethyl cellulose is dissolved in a heated cyclohexane solution in which the phase separation inducer has been dissolved in advance, and the material called ethylcellulose is dispersed in fine particles, and then cooled. (t) By subjecting the wall-forming agent to liquid-liquid phase separation on the surface of the core material particles, microcapsules having the wall-forming agent as the capsule wall can be produced. (When using hydrocarbon-based polymer substances such as kashina, bunal rubber, polybutadiene, and polyisobutylene as a phase separation inducer.

Since all of these phase separation inducers are rubber-like adhesive substances, they are difficult to handle, and it takes a long time to dissolve them into the beef sun, which reduces the work efficiency of microcapsule production. There are low drawbacks. Moreover, when removing the phase separation inducing agent attached to the microcapsules with a solvent such as cyclohexane after manufacturing the microcapsules, the phase separation inducing agent is a rubber-like sticky substance and has a slow dissolution rate in cyclohexane. , requiring a long period of cleaning with a large amount of solvent. Furthermore, when polyethylene is used as a phase separation inducing agent, fine solid particles of polyethylene precipitate during the production process of microcapsules, and these solid particles of polyethylene are completely oxidized by poor solvents such as beef starch. Because sedimentation cannot be removed,
It is necessary to sieve the microcapsules and polyethylene particles, but when producing microcapsules with a small particle size, it is difficult to separate the microcapsules from the precipitated polyethylene particles. is not suitable as a method for producing microcapsules with small particle size.

On the other hand, a method is also known in which microcapsules are manufactured in an illumination manner by improving the above-mentioned known method and utilizing phase separation of ethyl cellulose, which is a wall-forming material, without using a phase separation inducing agent. No. 3,531,418). However, in the case of this C=) method, the deposited gel Q'
) It has thick elasticity (because it is difficult to form a pattern and a dense wall film is formed, making it rainbow-like. Moreover, it was formed!! The temperature was 45 to 65℃
Microcapsules absorb a small amount of cyclohexane in the vicinity and swell, exhibiting 1 g of viscosity, making it easy for microcapsules to aggregate with each other. Not only is it difficult to obtain capsules, but the capsule wall membrane is also likely to be damaged because the microcapsules themselves are highly adhesive and a forced WRm process using glue or the like is required during the microcapsule manufacturing process. Moreover, as described above, the obtained capsules aggregate and solidify with each other, which may lead to non-uniformity in the crude drug content.

In contrast to the above, the method of the present invention does not require a phase separation inducing agent, which is conventionally required to maintain liquid-liquid phase separation (coacervation).

Furthermore, an organic polysiloxane compound, which has never been used before, is used as a wall film forming aid, and ethyl cellulose with an ethoxy group content A of 49.5 < As25 W/W % is used as a wall film forming agent. be. That is, a core material powder is dispersed in a solution in which ethyl cellulose and an organic polysiloxane compound are heated and dissolved in cyclohexane, and this solution is cooled to form a flocculent molecule of ethyl cellulose. Form a wall membrane.

This is further solidified and microencapsulated.

According to this method, the gel of ethylcellulose coated with flocnylate has appropriate viscoelasticity and adhesiveness due to the plasticizing effect of the organopolysiloxane compound, and the organopolysiloxane compound adsorbed on the particle surface of the core becomes an anchor. As a result, the deposition and wettability of the ethylcellulose microgels on the core material particles are greatly improved, and the fusion of the ethylcellulose microgels facilitates the formation of a sea-less gel-like wall film. By proceeding, microcapsules with dense wall membranes can be produced.

In the present invention, the organopolysiloxane used as a wall film forming aid (hypothesis) is expressed by the general formula (however, R12
Yohi♂ are the same or @r1 represents a water atom, a radical, a lower alkyl group, or an aryl Ik. ] When the viscosity of the organopolysiloxane compound is 25'
C [jd, approximately 50-5,0L30,000 cSt
of about 100-2. OL) (J, 000
O9% can be used. Organoporsiloxane compounds preferably having an alkyl group or a phenyl group can be used.

Specific examples of such organopolysiloxane compounds include so-called organosilicon complex polymers such as dimethylpolysiloxane, methylphenylpolysiloxane, silicone-glycol copolymers, and polystyrene-polydimethylsiloxane block copolymers. . The organic polysiloxane compound may also be blended with a suitable dispersion aid or filler. Examples include those containing about 1 to 50 w/1% of a dispersion aid or filler such as calcium phosphate or talc.

In the present invention, in order to produce ethyl cellulose microcapsules, first, ethyl cellulose as a wall film forming agent and the above-mentioned organic polysiloxane and compound as a wall film forming aid are heated and dissolved in beef sun to Schiff O, and then the core substance and When dissolving ethyl cellulose and organic polysiloxane compounds in cyclohexane, the temperature is usually about 75 to 80°C.
It is preferable to carry out the heating under heating.

In addition, as the wall film forming agent ethyl cellulose, the viscosity [Ho1
1 constant conditions: toluene-ethanol mixture (mixing ratio -4:1
) in 51/II% solution] at 25°C, about 5 to 5 oocp,
In particular, it is preferable to use 40 to 250 cP, and the amount used is about 0.02 to 250 cP per layer of core material.
It may be about 5.0 times as much, but in cyclohexane it is best to dissolve it so that it is usually about 0.1 to 101/V times. By increasing or decreasing the amount of ethylcellulose used within the above range, the capsule wall membrane can be made thicker or thinner.

Further, the amount of the organic polysiloxane compound used as a wall film forming aid is hardly affected by the blending ratio of the core material and ethyl cellulose, and is usually 1 ethyl cellulose/L.

The porin for loin-containing cyclohebeef san solution.

The loxane compound is about 0.01 to 10%, especially 0.01 to 10%.
It is preferable to dissolve it so that it becomes 5 to 51/V%jllff.

Historically, when dispersing a core substance in a cyclohegyosan solution, it is appropriate to disperse it in a stirrer (normally about 100 to 600 degrees). Generally, the particle size of the core material to be dispersed can be uniform as long as it is about 1000μ or less, but in particular it is 100 to 450μ.
It is preferable if the amount is within a certain range because more uniform microcapsules can be obtained. When the core material dispersion obtained above is appropriately cooled, an ethylcellulose wall film is formed on the core material particles to produce ethylcellulose microcapsules. Cooling of the dispersion is approximately 0.05 to 4 per minute.
Preferably, the reaction is carried out at a rate of 1-2°C. Thus, from around 68°C, microscopic gels of ethylcellulose, which have extremely high viscoelasticity and stickiness, begin to separate, mainly due to the prochelation of ethylcellulose, and with continued cooling, these microgels form core material particles. A seamless gel-like wall membrane begins to settle on top? ! 1g made,
At about 40°C, this gel-like wall film solidifies and a stable wall film is formed.And when the carp is cooled to room temperature, the release of beef starch from the wall film to the cyclone occurs. The wall membrane is completed and stable ethylcellulose microcapsules are produced.

The microcapsules produced in this manner can be separated by decantation, centrifugation, 9-mouth filtration, etc., then washed and dried to obtain microcapsules that do not substantially contain the wall film forming aid. I can do it.

As a washing solvent for the separated microcapsules, it is preferable to use an organic solvent that dissolves the wall film 111 forming aid but does not dissolve the ethyl cellulose 1 capsule and the core material.
For example, Schiff's beef sanitation, petroleum ether, n-hexane, etc. can be appropriately used for this purpose.

According to the method of the present invention, an organic polysiloxane compound and a surfactant can also be used together as a wall film forming aid. In this case, if the same microcapsule manufacturing operation as above &1 is carried out, a protective layer consisting mainly of the mixture of the above-mentioned wall film forming aid will be formed on the surface of the wall film formed during the microcapsule production process. is 1l
Since there is almost no aggregation between microcapsules, the capsule wall film is not damaged, and a more uniform particle size distribution and a higher wall ratio are achieved. It is possible to obtain microcubal with more fluidity than ever before.

Examples of the surfactants used include sorbitan fatty acid esters and glycerin fatty acid esters.

The carbon chain length of fatty acids such as citric acid-sugar fatty acid ester, polyoxyethylene sorbitol fatty acid ester, and polyoxyethylene fatty acid ester is C6 to CI! Fatty acid ester surfactants whose alkyl carbon chains are Cm to Cs-, V-acid trialkyl esters and polyoxyethylene phenyl ether; Ionic surfactants, phospholipids; ionic surfactants such as dialkyl succinates with alkyl carbon chain lengths of 04 to C1o, fatty acid gold salts with fatty acid urea chain lengths of 08 to mainly CB4; Gold-soap can also be mentioned in the same way. For example sorbitan monolaurate, among others.

The carbon chain length of fatty acids such as nrubitan sesquioleate, nrubitan trilaurate, nrubitan monooleate, sorbitan sesquioleate, sorbitan trioleate, and sorbitan monostearate is CI! ~C18
Sorbitan fatty acid ester: fats such as glycerin monocaprylate, glycerin monolaurate, glycerin dilaurate, glycerin monooleate + 1/J
Glycerin fatty acid ester whose acid carbon chain length is C8 to C1s; sucrose monomyristate, sea sugar simiristate.

With HLB, such as sucrose trimyristate, sucrose monopalmitate, citric sugar ciba I remitate, 7 day tripa I remitate, cylosaccharide monostearate, sucrose distearate, sucrose tristearate,! ! Sugar fatty acid esters, which are mixtures of esters and triesters; Ethylene sorbitol fatty acid ester; polyoxyethylene fat v1!! ester, such as polyoxyethylene monolaurate and polyoxyethylene monooleate, whose HLB value is 6 or less and whose fatty acid carbon chain length is from Cn to Cl8; Phosphate trialkyl esters whose alkyl carbon chain length is C1 or CIt-, such as rail phosphate and trilauryl phosphate; non-ionic surfactants such as polyoxyethylene alkylphenol ethers with an alkyl carbon chain length of C@ or C9;
Phospholipids such as soybean phospholipid, J yellow phospholipid, phosphatidylethanolamine, phosphatidylcodan, phosphatidylserine, inositol phosphatide; di-n
-Octyl sodium sulfosuccinate, di-n-hexyl sodium sulfosuccinate, diamyl sodium sulfosuccinate, bis(1-methylamyl)
Ionic surfactants such as alkali metal salts of alkyl sulfosuccinates having an alkyl carbon chain length of (J7') to Cs, such as sodium sulfosuccinate and bis(2-ethylhexyl) sodium sulfosuccinate; monostearin aluminum, aluminum distearate,
Aluminum salts or iron salts of fatty acids with a carbon chain length of Df+ II/j @ or Cl11, such as aluminum tristearate and iron tristearate. Metal soaps such as Cn fatty acid calcium can be suitably used. These surfactants are about 0.001 to 10 times stronger than the dissolved amount of the organic polysiloxane compound, especially 0.004 to 4
About double the amount is used for v and ethylcellulose-containing cyclohexane #*, about 0.003 to 10 W.
It is preferable to replace the rod so that the concentration is 0.008 to 4 W/V%. In cooperation with the organopolysiloxane compound, the formation of a wall film is significantly promoted due to the good plasticizing effect and anchoring effect, and at the same time, the aggregation of the produced macrocapsules is prevented.

As the core substance to which the above-mentioned microencapsulation method of the present invention can be applied, a substance selected from cyclohexane, an organic polysiloxane compound, a surfactant, and ethyl cellulose is generally added to a cyclohexane solution containing 1 [above]. Any substance may be used as long as it does not dissolve, and the core substance does not necessarily have to be solid, but may be gel-like or mud-like. Specific examples of core substances that can meet the above conditions include 1, for example, ascorbic acid,
Vitamins such as thiamine hydrochloride, pyridoxine hydrochloride, calcium indothenate, bisbenziamine, methylmethionine sulfonyl chloride; potassium asparagine, magnesium asparagine, sodium glutamate, lysine hydrochloride.

Sulfa drugs such as amino acids and peptides such as glutathione, sulfamethomi, gin, sulfitumezole; cardiovascular drugs such as calcium fobantenate, papaverine hydrochloride, diltiazem hydrochloride, reserpine; trimethoquinol hydrochloride, bromhexine hydrochloride, Respiratory/antitussive expectorants such as tipepidine hibenzate; antibiotics such as benzylpenicillin potassium, benzylpenicillin sodium, phenoxymethylpenicillin potassium, ampicillin; 5-fluorouracil, N-(2-tetrahydrofuryl-2-5- Antineoplastic agents such as leolouracil, pleomycin hydrochloride; neuropsychiatric agents such as thimepidium bromide, lidocaine hydrochloride, chlorpromazine hydrochloride; gastrointestinal agents such as magnesium silicate, precipitated calcium carbonate; diphenhydramine hydrochloride, Antihistamines such as chlorpheniramine maleate; antipyretic, analgesic and antiinflammatory drug compounds such as aspirin, quinine hydrochloride, sulpirine, ammonium sulfate, ammonium chloride A, ammonium nitrate, lime nitrogen.

Nitrogen fertilizers such as urea; potassic fertilizers such as potassium sulfate and potassium chloride; pharmaceuticals and fertilizers such as chemical fertilizers such as phosphoric acid fertilizers such as bisulfate lime, molten phosphorus fertilizer, and sodium phosphate; And pesticides.

It can be applied to various industrial fields such as cosmetics and printing. Especially in the case of pharmaceutical compounds, their stabilization.

The goal is to maintain its effectiveness or to alleviate taste, odor, irritation, etc., and to obtain accurate improvement effects. In addition, in the case of chemical fertilizers, since the active ingredients can be eluted from the microcapsules at a desired rate, it is possible to suppress the loss of the ingredients, and therefore it is possible to measure the sustainability, residual effect, or stabilization of the efficacy. .

According to the present invention-tAM method, during the phase separation of ethyl cellulose-containing cyclohexane solution, an organic polysiloxane compound is used alone or in combination with a surfactant as a wall film forming aid, so that it is produced after 70 Kiele scenes. The surface of the capsule wall membrane is

Since the microcapsules are stably protected or coated with a dense layer of the above-mentioned wall film forming aid, agglomeration of the microcapsules or adhesion to the manufacturing equipment during cooling is prevented, resulting in a uniform particle size distribution with extremely high τ drive properties. microcapsules can be efficiently produced.

Further, according to the method of the present invention, there is also an advantage that the working efficiency of microcapsule production can be significantly improved.

For example, in the conventional method, polyimbutylene (Staudinger's viscosity average molecular weight, 3-.10), which is a hydrocarbon polymer substance used as a phase separation inducer, is 78
Although it is necessary to dissolve the wall film forming aid of the present invention in cyclohexane 100°C for at least 4 hours, for example, at 25°C.
Dimenalpolysiloxane and soybean phospholipid, which have a viscosity of 2,000,000 C8t, can be dissolved within just 5 minutes. In the present invention, since such a wall film forming aid having a high dissolution rate is used, it is extremely easy to wash and remove the wall film forming aid from the produced microcapsules. Furthermore,
In the conventional method, the cyclohexane solution in which the phase separation inducer is dissolved has a high viscosity (.

For example, the viscosity of the above-mentioned polyimbutylene at 30 DEG C. is 150 oP.

For this reason, it is not possible to prepare core@page at a high concentration.

It is about 2017W% at most. However, in the method of the present invention, the viscosity of the cyclohexane solution is low; 9 For example, the viscosity of the 3-volume cyclohexane solution of the above-mentioned dimethylpolysiloxane at 30°C is 5oP. Furthermore, since the dispersion force is strong, the core material can be charged to about sow/ws level, and other advantages can be obtained.

Experimental Example 1 All microcapsules containing 1-methyl-5-methoxy-3-(dithen-2-ylmethylenepiperidium A/bromide aqueous acid salt [■]), capsule yield, crude drug content in capsules, and temperature at 37°C The time required for 50% of the crude drug to dissolve from the capsule in water was measured.

(1) Preparation of core substance (I) 13.3 parts, lactose 81.7 parts and dextrin 5
Add 5 parts of 45% tanol water KI solution to the mixture and knead and granulate it in the usual manner.
The particles were sized to a size of 05 to 350μ.

(2) Fragment of microcapsule■ FIi! , Surfactant 16F and silicone resin (subjected to the standards of the 4th edition of the Food Additives Official Standards) shown in Table 1.The viscosity at 25°C is IDO ~, 11 (1
Dimenalpolysiloxane with 0eSt is mixed with silicon dioxide 7) 3 to 15% and mixed with 1) 489f cyclo to beef san 1. Ethylcellulose [ethoxy content 52.7%; viscosity 250oP (hereinafter, viscosity is toluene/ethanol (4:)) was dissolved in a mixture of toluene and ethanol (4:1) to give a concentration of 5%. (expressed as viscosity at °C)] was added and dissolved by heating at 80 °C. Next, 96 pieces of core material were added to this solution and dispersed, and the mixture was heated for 350 r.

Cool to room temperature (approximately 25°C) while stirring at speeds P and I. Separate the generated microcapsules and
- Wash with hexane and dry. The resulting microcapsules were sieved, passed through a JIS standard sieve with a mesh size of 500 μm, and the remaining material was collected on a JISSU sieve with a mesh size of 105 μm, thereby conforming to the fine granule standards of the Japanese Pharmacopoeia, revised by Deshi. ] Obtain microcapsules containing

In addition, as a control microcapsule, the equity was 18 as shown in CF.
50-30 ] 36 and U.S. Patent No. 3,531,418
Microcapsules were prepared by the method described in the issue.

■ Method of Japanese Patent Publication No. 50-30136 Polyisobutylene 489 having an average molecular weight of 1,200,000 was dissolved in 1.614 cl of cyclohexine, and to this was added 32 f of ethyl cellulose similar to that used in ■ above, and dissolved by heating at 80°C. let Next, add core substance 96 to this.
Add 9 and disperse, 350 r.

Cool while stirring at a speed of P, IIl until it reaches a room temperature. Thereafter, microcapsules containing [I] are obtained by processing in the same manner as in (1) above.

■ Microcapsules containing [1] were obtained by deception in the same manner as in US Pat.

(3) Results The details are listed in Table 1 below.

Table 1 (note); a L B 3 sucrose fatty acid modified Z-tyl [Composition of bound fatty acids: stearic acid, palmitic acid and myristic acid, composition of esters: mixture of mono-, di-, and triesters] Experimental examples Viscosity Trimethoquinol hydrochloride-containing microcapsules were prepared using different ethylcelluloses.

Capsule yield, crude drug content in the capsules, and 50% elution time in water at 37°C were measured.

(IF) Trimethoquinol hydrochloride crystals with a core material particle size of 149 to 210# were used.

(2) Preparation of microcapsules Experimental example 2-
By carrying out the same procedure as 421, microcapsules meeting the powder standards were obtained.

(3) Results As shown in Table 2.

Table 2 Example 1 Sorbitan trioleate 16Pa and the silicone tree used in Experimental Example 1, Ill 489, were combined with cyclohexane > 1
．． 6e Ni-sol HL, ethyl cellulose (ethoxy content 52.7%, viscosity 250 cP) 32F is processed into this and heated and dissolved at 80°C. Then, Example 1 was added to this solution.
Add and disperse core material 96f similar to the core material used in
Cool to room temperature (approximately 25°C) while stirring at a speed of 35 (l r, p, m). The formed microcapsules are separated, washed with n-hexane, and dried to meet the fine granule standards. Compatible [■]°-containing microcapsules 121f are obtained.The crystal contains 10.5% of the crude drug CI), and its tiO in water at 37°C is 55 minutes.
Ta.

Example 2 Silicone tree III (used in Experimental Example 1) 48t
was dissolved in 1.6% cyclohexane, and ethyl cellulose (ethoxy content 49.7%, Mi&]00
oP) Add 32 f and heat to dissolve at 80°C.

Next, trimethoquinol hydrochloride (particle size 149~
Add 210μ>1609 and disperse 350r, p, -m
Cool to room temperature while stirring at a speed of . mosquito(
The microcapsules produced are separated, washed with petroleum ether, and dried. The obtained microcapsules were opened 3 times.
Microcapsules 182F containing trimethokino hydrochloride, which met the powder standards described in the Yushi Revised Japanese Pharmacopoeia, were obtained by sieving through a 50# JTSa semi-sieve and collecting what passed through the sieve. The crystal contains trimethoquinol hydrochloride at 83%.
The 5 mouths that can be poured into 37℃ water containing 5cl is 139
It was a minute.

Example 4751.5 ethoxy-containing brown ethyl cellulose with a viscosity of 100oP was used.The needle was made in the same manner as in Example E111 to obtain a needle containing trimethoquinol hydrochloride that complied with the standards for powders in the Revised 6th Hydropharmacopoeia. The crystals contain 841 units of trimethoquinol hydrochloride, and the tSO in water at 37°C is obtained.
was 111 minutes.

Small Example Meeting Microcapsules containing trimethoquinol hydrochloride that met the powder standards described in the Yuji Revised Japanese Pharmacopoeia were obtained by carrying out the same procedure as in Example 1 except that ethyl cellulose with an ethoxy content of 55.1 cm and a viscosity of IQQcP was used. 18
Obtain 6g. Crystal contains 83.5% trimethoquinol hydrochloride
The t5o in water at 37°C was 88 minutes.

Spontaneous procedure amendment 1995 Gen 1/σ month λρ, Commissioner of the Japan Patent Office 1, Indication of the case, Showa Kamo 1997 Patent Application No. 1 Komiya 7 Toki No. 2, Name of the invention 174° Gihere no 3t 3, Relationship with the case of the person making the amendment Patent applicant 3-21 Doshomachi, Higashi-ku, Osaka-shi, Osaka (541)
295) I'i Ilbe Pharmaceutical Co., Ltd. Representative Matsubara - Department 4, Agent 3-16-89 Kashima, Yodogawa-ku, Osaka-shi, Osaka Prefecture (532
) 5. Contents of the amendment to the number of inventions that will be increased by the amendment 1. "Storage" on page 6, line 4 of the specification is corrected to rlL<J.

2, page 7, line 4 [Porsiloxane] Corrected to "polysiloxane".

3 rO, 01 to In, J on page 9, line 1, r, 0. (l l ~101./V%," 2 correction.

4, page 23, line 15 [2-12N] Corrected to rl-i21J.

5. 5th row from the bottom of 24 IJ members "Example 1" Corrected to "Experimental Example 1".

Claims (1)

[Scope of Claims] +11 When producing ethyl cellulose microcapsules by dispersing a core material in a cyclohexane solution containing ethyl cellulose and using 70 mL of ethyl cellulose, the ethoxy group content of the ethyl cellulose is 49.5<A≦55W/ A method for manufacturing ethyl cellulose microcapsules characterized by using W%° of ethyl cellulose and a ζ organopolysiloxane compound as a wall film forming aid (2) A surfactant is used together with an organopolysiloxane compound as a wall film forming aid. Manufacturing method (3) according to claim 1, in which the organic polysiloxane compound has the general formula (1% formula% (however, ol and ol are the same, and ol and ol are different and represent a water bulk atom, a lower alkyl group, or an aryl group). The manufacturing method according to claim 1 or 2, in which the bonding proboscis 1b has a siloxane bond bonded by T).