JPS6341416A - Production of microcapsule containing analgesic peptide - Google Patents

Abstract

PURPOSE:To produce the titled microcapsule in high trapping yield of principal drug, by producing a W/O-type emulsion from an oily layer containing a polymer and an aqueous layer containing a specific amount of encephalin, mixing the emulsion with an aqueous solution of a dispersing agent and distilling out the solvent from the resultant emulsion. CONSTITUTION:A W/O-type emulsion is produced from (A) an oily phase containing a polymer having bio-compatibility and hardly soluble or insoluble in water, preferably a polymer having acidic residue (e.g. a polylactic acid, a copolymer of lactic acid and glycolic acid, etc.) and (B) an aqueous layer containing 5-20wt%, preferably 5.0-15.0wt% (based on the polymer) encephalin, its analog or its salt with a weak acid having a pKa of >=4.0, preferably 4.0-9.5 (e.g. acetic acid, propionic acid, etc.). The obtained W/O-type emulsion is mixed with an aqueous solution of a dispersing agent to form a W/O/W-type emulsion. A microcapsule having tough wall membrane effective in suppressing excessive initial release of the content can be produced by distilling the oily layer solvent from the obtained emulsion.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing analgesic peptide-containing microcapsules.

BACKGROUND OF THE INVENTION Various microcapsules have already been proposed. For example, JP-A-57-118512 describes microcapsules prepared by a phase separation method using a coacervation agent such as mineral oil or vegetable oil.

However, during the manufacturing process, the microcapsules obtained by this method tend to coalesce due to adhesion between particles and generate fractured surfaces, which may lead to a decrease in redispersibility and an increase in initial burst. In addition, multiple organic solvents are used,
There is a problem of residual solvent in the prepared microcapsules.

JP-A-60-00516 discloses a method for preparing microcapsules by drying in water. According to this method, drugs can be efficiently incorporated into microcapsules, and their sustained release properties can be improved. drug effects can be expected.

Problems that sales outlets are trying to solve When administering drugs to living organisms as microcapsules, there are multifaceted demands for microcapsules that are highly dependent on interaction with the body's natural functions.
Furthermore, since this is a field related to pharmaceuticals, there is a need to provide Uro microcapsules that satisfy these multifaceted requirements as much as possible.

Under the above circumstances, it is difficult to say that a satisfactory gyroscope effect has been technically achieved using known microcapsules.

For example, for some drugs, the structure of the microcapsule wall membrane may be relatively linear, which may result in an initial release of drug that is larger than necessary and may deviate significantly from a constant rate of release.

In addition, the trapping rate (intake rate) of drugs into microcapsules has been observed to decrease in the concentration range for which certain drugs are normally used, which poses practical difficulties.

Means to Solve the Problems In view of the above circumstances, the present inventors conducted intensive alpha research in order to develop a sustained release formulation of water-soluble peptides.
The inventors discovered that there is a strong correlation between the good properties of microcapsules, the physicochemical properties of the drug used, and the concentration of the drug, and completed the present invention after further research.

That is, the present invention provides an oil layer containing a polymer and water containing a salt of enkephalin, an analog thereof, or a weak acid having a pKa of 4.0 or more, in an amount of 5 to 20% by weight based on the polymer. A microcapsule characterized in that a W/O emulsion is formed with the layers, a W/O/W emulsion is formed by mixing this with an aqueous dispersant solution, and then the oil layer solvent is distilled off. The present invention provides a method for manufacturing.

Enkephalin and its analogues include peptides consisting of 3-6 amino acids or derivatives thereof that have analgesic activity, such as those with the formula (%) [wherein R1 is hydrogen or lower alkyl, and R2 is hydrogen or a substituted Lower alkyl which may have a group is aryl, R3 is hydrogen or lower alkyl, X is a bond or a neutral amino acid residue which may be D- or L-, and Y is a hydroxyl group or substituted Examples include compounds represented by:

In addition, when compound (1) has an asymmetric carbon, the L-configuration is indicated unless otherwise noted.

The lower alkyl in II' above includes Cl-ff alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.).

Examples of aryl such as lower alkyl which may have a substituent in R2 include hydroxyl group, lower (C, -3) alkylthio which may be oxidized, carboquine which may be amidated as esterification, and polmyl. Amino, guanino, imidazole which may be
C2-, which may be substituted with -yl, etc., and phenyl as an example of alkyl.

Examples of lower alkyl in R3 include Cl-3 alkyl (methyl, ethyl, propyl, isopropyl).

Examples of neutral amino acid residues substituted by X include residues such as methionine, leunon, and proline, which may be oxidized.

Amino-like hydrazino which may have a substituent represented by Y is lower (C, -3) alkoxy (
e.g., methoxy, etquin, propoxy).

Halogens (e.g. fluorine, chlorine, bromine, iodine), oxo.

Lower (c, -3) thioalkyl which may be oxidized.

Aminocarbonyl, aminothiocarbonyl, 4,5-dihydro-2I-(-thiophen-2one-3-yl, etc. as a substituent) Straight chain or branched alkyl, lower alkenyl or lower aliphatic Group acyl-substituted amino or hydrazino, unsubstituted amino or hydrazino, and the like.

As a compound included in compound (1), H-Tyr
-D -Met(0) -Gly -EtPhe -N
IINII COCII, (E K-399), H-Ty
r-D-Met(0)-Gly-MePhe-NH
NIICOCH3 (E K -333), I-(-T
yr-D-Ala-Gly-! 4ePhe −
Met-Nl12(metkephN112(,H-
Tyr-D-LysO(CIip)-Giy-Phe-NH2(floe-8
25),! -(-Tyr-D-Met-Gly-P
he -Pro-N11t, H-Tyr -D -A
la -Gly -MePhe-Met(0) -of
(PK-33824), H-Tyr-D-Al
a-Gly-Phe-D-Lea-NHt, H-T
yr −D −Thr −Gly −Phe −L −
thiazolidine-4-carboxami
de, H-Tyr-D-Ala-Gly-P
Examples include he-NHt, 0isine enkephalin, methionine enkephalin, and the like.

In particular, in the present invention, E K -399, E K
-333 etc. are advantageously used.

The physical, chemical, biological properties and manufacturing methods of these compounds are described, for example, in the Chemical and Pharmaceutical Bulletin (Chem, Pharm, Bull).
29.3630-3638 (1981), same magazine, - Shadow 9
, 3639-3645 (1981), same magazine, ■, 36
46-3659 (1981), Pharmacia (Pha
rmacia), 13, 932-936 (197
7), Life Sciences
), 23, 2053-2056 (1978), same magazine.

Dan, 1371-1376 (197g), FEBS Letters, 76 9l-92
(1977) and US Pat. No. 4,277,394.

The weak acid with a pKa (i separation index) of 4.0 or more that can form a salt with the above compound (peptide) may be either an inorganic acid or an organic acid. Examples of the inorganic acid include carbonic acid, monobicarbonic acid,
Examples include boric acid, and the organic acid is preferably a monocarboxylic acid, especially a lower (CI-3) alkane monocarboxylic acid, such as acetic acid.

Examples include propionic acid.

These weak acids preferably have a pKa of 4.5 or more, with an upper limit of pKa of 13 or less, especially a pKa of 4.5 or more.
It is preferably 9.5 or less.

The polymer contained in the oil layer in the method of the present invention is a polymer that is poorly soluble or insoluble in water and has biocompatibility, and preferably has acidic residues, such as , biodegradable polyfatty acid esters (e.g., polylactic acid, polyglycolic acid, polylactic acid-
Glycolic acid.

poly-ε-caprolactone, polycitric acid, polymalic acid, etc.), polyalkyl-α-cyanoacrylic acid esters (e.g., polybutyl-2-cyanoacrylate), poly-β-hydroquinebutyric acid’, polyalkylene oxalate (e.g., polytributyric acid), methylene oxalate, polytetramethylene oxalate, etc.).

Polyorthoesters, polyorthocarbonates or other polycarbonates (eg, polyethylene carbonate, polyethylene propylene carbonate, etc.), polyamino acids (eg, poly-gubentrue monoglutamic acid, poly L-alanine).

(poly γ-methyl-L-glutamic acid, etc.). Furthermore, other biocompatible polymers include polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid, dextran stearate, methylcellulose, ethylcellulose,
Acetylcellulose.

Examples include nitrocellulose and maleic anhydride copolymers. These polymers may be used alone, or may be a copolymer of two or more types, or a mere mixture.

Among these polymers, particularly when used as an injection, biodegradable polymers are preferred, and the most preferred are polylactic acid, a copolymer of lactic acid and glycolic acid, or a mixture thereof. can be mentioned. The ratio of lactic acid and glycolic acid in this copolymer is preferably about 40 to 95 mol% of lactic acid and about 60 to 5 mol% of glycolic acid, preferably about 50 to 95 mol% of lactic acid and about 60 to 5 mol% of glycolic acid. 50
-5 mol% is good, more preferably lactic acid is about 60-9
0 mol%, glycolic acid is preferably about 40 to 10 mol%.

The average molecular weight of these polymers used in the present invention is preferably selected from the range of about /O00 to +00000, more preferably from about 2000 to 5000.

The solution (oil layer) containing the above-mentioned high-molecular polymer is a solution in which the high-molecular polymer is dissolved in an organic solvent.

The organic solvent may be one that has a boiling point of about 120° C. or less, is not easily miscible with water, and can dissolve the polymer, such as halogenated alkanes (e.g.
Dichloromethane, chloroform, chloroethane, tricloconitane. carbon tetrachloride, etc.), ethyl acetate, ethyl ether, fuclohexane. Examples include benzene, n-hexane, and toluene, and two or more of these may be used in combination.

Particularly preferred are dichloromethane and chloroform, which are relatively polar and have a low boiling point.

In the method for producing microcapsules of the present invention, first, enkephalin or its analogue free form or salt of a weak acid is added in an amount corresponding to 5 to 20% by weight, preferably 5.0 to 15.0%, based on the polymer. An amount equivalent to , is dissolved in water to form an inner water layer. If desired, add a drug-retaining substance or pHf within a range that does not interfere with the interaction between the drug and the polymer.
A stabilizer and a preservative may be added to the drug.

The above-mentioned drug-retaining substance is water-soluble and difficult to dissolve in the organic solvent of the oil layer, and when dissolved in water, it is already in a highly viscous semi-solid state, or due to some external factor,
For example, temperature, pH, metal ions (e.g. Cu++,
By applying the action of a chemical condensing agent (e.g., glutaraldehyde, acetaldehyde, etc.), the viscosity increases more significantly.
Examples include substances that have the property of forming a semi-solid or solid matrix.

Examples of the drug-retaining substance include natural or synthetic gums and polymer compounds. [)H regulators include, for example, carbonic acid, acetic acid, and oxalic acid.

Citric acid, tartaric acid, or their sodium or potassium salts, hydrochloric acid, sodium hydroxide, etc. may be added. Examples of stabilizers include albumin, gelatin, citric acid, sodium ethylenenoaminetetraacetate, dextrin, glucose, sugars such as sorbitol, polyols such as glycerin, sodium bisulfite, etc., and preservatives such as paraoxybenzoic acid. Esters (e.g. medylparaben, propylparaben, etc.).

Benzyl alcohol, chlorobutanol, thimerosal, etc. may be added.

In the present invention, the concentration of peptide in the inner water layer relative to water is approximately 0.01 to 90% (W/W), preferably 0.
．． It is preferable to set it to 1 to 70% (W/W).

The aqueous solution for the inner aqueous layer thus obtained is added to the solution (oil layer) containing the polymer, and then an emulsification operation is performed to produce a W/O emulsion.

A known dispersion method is used for the emulsification operation. Examples of the method include an intermittent shaking method, a method using a mixer such as a propeller type stirrer or a turbine type stirrer, a colloid mill method, a homogenizer method, and an ultrasonic irradiation method.

Next, the W/O emulsion thus prepared is emulsified into three layers of W/O/W and subjected to an underwater drying method. That is, the W/O emulsion is further added to the third aqueous layer to form a W/O/W emulsion, and then the solvent in the oil layer is removed to prepare microcapsules. When preparing this W/O/W type emulsion, the viscosity of the inner aqueous layer and the W/O type emulsion affects the shape of the target microcapsules, the drug trapping rate, etc. It is preferable to set In particular, the viscosity of the W/O emulsion has a large effect on the drug trapping rate, and it is preferable that the viscosity is 150 to /O000 cp.

However, during this process and when drying in water as a W/O/W type emulsion, another important factor that affects the shape of microcapsules, drug trapping rate, and initial release amount of drug is that the drug and polymer There is an interaction between polymers, and by setting the above conditions in consideration of this, it became possible to prepare microcapsules with even better drug release function.

That is, the peptide aqueous solution dissolved under the above conditions is made into a W/O type emulsion with a predetermined volume ratio using the above drug/polymer compounding ratio, and then the temperature is set at a certain temperature range, which is also kept at a certain temperature range. It is injected into the outer aqueous layer kept at temperature, and the organic solvent is removed to form microcapsules. In this case, the interaction between the drug and the polymer is also affected by the W/O volume ratio, the temperature of the W/O type emulsion, and even the temperature of the outside water tank. kinds,
Depending on the amount, it may be necessary to set the optimum conditions.

The concentration of the polymer in the oil sump varies depending on its type, but is preferably about 5% to 80% (W/W).

The volume ratio of the W/O type emulsion varies depending on the type and amount of the drug, polymer, and solvent used, but the volume ratio is 1 to the aqueous layer! The value should be within the range of 1 to 200, more preferably 1 to /O0.

W/O type emulsion, the temperature of the upper and outer water layers is approximately -/O
Although emulsification can be carried out at a temperature of from 0.degree. C. to the boiling point of the organic solvent used, it is usually preferable to carry out emulsification at a temperature within the range of about .theta..degree. C. to 35.degree.

An emulsifier may be added to the outer aqueous layer, and any emulsifier that generally forms a stable O/W type emulsion may be added. For example, anionic surfactants (e.g., oleic acid (sodium, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants [polyoxyethylene sorbitan fatty acid ester (Tween 8G, tween 60. manufactured by Atlas Powder Co., USA), polyoxyethylene castor oil derivative (HCO-60゜HCO-30, manufactured by Nikko Chemicals)
], or polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethylcellulose. lecithin.

Examples include gelatin, and one or a combination of these may be used. In particular, it is preferable to use one type or a combination of two or three types of polyvinyl alcohol, carboxymethyl cellulose, and gelatin. The concentration during use is approximately 0.0! It can be appropriately selected from the range of % to 20%, more preferably from about 0.05% to /O%.

In the underwater drying method, a commonly used method is employed to remove the solvent from the oil layer. As the method, for example, simply W
The /O/W type emulsion may be left to stand while being stirred with a propeller type stirrer or a magnetic cooler, heated, or blown with nitrogen gas or the like. Alternatively, the removal may be carried out by gradually reducing the pressure, or by using a rotary evaporator or the like, while adjusting the degree of vacuum. In the solvent removal process, once the solidification of the polymer has progressed to a certain extent, the W/O/W type emulsion is gradually heated in order to remove the solvent more completely. Can be shortened.

After the microcapsules obtained in this way are separated by centrifugation or filtration, free water-soluble drugs adhering to the surface of the microcapsules are washed several times with distilled water, and as needed. The water in the microcapsules and the solvent in the microcapsule membrane are more completely removed by lyophilization, lyophilization, or heating under reduced pressure.

The microcapsules obtained above are subjected to sieving, if necessary, to remove excessively large microcapsules and separate the necessary particle size. The particle size of the microcapsules depends on the degree of sustained release, and when used as a suspension agent, the particle size of the microcapsules may be within a range that satisfies the dispersibility and transportability.For example, the average size is about 0.5 to
A range of 400 μm is mentioned, and more preferably about 2 to 400 μm.
It is desirable that the thickness be in the range of 00 μm.

As described above, according to the method of the present invention, it is possible to increase the trapping rate of peptides, which are herbal medicines, in microcapsules, and it is possible to produce microcapsules having strong wall membranes with little initial excessive release.

In addition, the microcapsules produced by the method of the present invention have little aggregation of microcapsules during the production process, and it is possible to obtain well-defined spherical microcapsules. It is easy to control the surface structure of the microcapsules that affects the drug release rate (e.g., the size and size of the pores that are the main drug release route). It has its advantages.

The microcapsules produced by the method of the present invention can be administered to a living body as is as an implant. It can also be administered by forming into various preparations, and can also be used as a raw material when manufacturing such preparations.

The above preparations include injections, oral preparations, nasal preparations,
Examples include direct, positive, urethral, and vaginal suppositories.

For example, in order to make the microcapsules of the present invention into an injection, the microcapsules of the present invention may be mixed with a dispersing agent (e.g., Twee).
n 80. HCO-60, carboxymethyl cellulose, sodium alginate, etc.), preservatives (e.g., medylparaben, propylparaben, etc.).

Sustained-release injection that can actually be used as an aqueous suspension with isotonic agents (e.g., sodium chloride, mannitol, sorbitol, glucose, etc.) or as an oil-based suspension by dispersing it with vegetable oils such as sesame oil and corn ura. as a drug.

Furthermore, the above-mentioned microcapsule sustained-release injection is!
8. As a clouding agent, in addition to the above composition, excipients (for example,
Adding mannitol, sorbitol, lactose, glucose, etc.), redispersing it, solidifying it by freeze-drying or spray-drying, and adding distilled water for injection or a suitable dispersion medium at the same time will result in more stable sustained release. An injection is obtained.

The dosage of the sustained release preparation of the present invention depends on the type and content of the peptide, which is a crude drug, the dosage form, and the duration of drug release.

Animals to be administered [Example 11.1 blood-fed mammals (e.g. mice,
(rats, horses, 979 people)j, although it varies depending on the purpose of administration, it may be an effective amount of the main drug. For example, the weight of the microcapsules is preferably about 0.05 kg as a single administration dose to the above-mentioned warm-blooded mammals. Img? ,fish/O0
mg/kg body weight, more preferably about 0,2 mg
One can be selected as appropriate from the range of 50 to 50 mg/kg body weight. The volume of the suspension solution to be administered as the above-mentioned injection can be appropriately selected from the range of about 0.1 to 5 ml, preferably about 0.2 to 3 ml.

In this way, the drug can be continuously released over a long period of time by containing an effective amount of a water-soluble drug and a biocompatible polymer, which is larger than the usual single dose. A pharmaceutical composition prepared as microcapsules is obtained.

In the present invention, a polymer having acidic residues forms a strong microcapsule wall and a portion relatively close to the surface layer of the microcapsule is formed by the interaction between the peptide and the residues that obtain the above-mentioned basic residue. It is thought that by reducing the diffusion rate in , the trapping rate can be improved and unnecessary initial release can be suppressed. Therefore, among peptides having basic residues, the higher the basicity of the residues and the greater the number of residues, the more excessive initial release can be prevented and the trapping rate will be higher. That is, lysine, arginine, hisdecine residues, etc. may be chemically added to existing peptides, and furthermore, peptide chains containing these basic residues may be chemically bonded to organic compounds with physiological activity other than peptides. Similar excellent microcapsules can be produced by this method.

The sustained release preparation produced according to the present invention has, for example, the following characteristics.

(1) Good sustained release properties of peptides can be obtained in various dosage forms, and especially in injections, when long-term administration is required to perform the expected treatment, instead of daily administration, peptides can be administered for -weeks. The desired pharmacological effect can be stably obtained with injections once every month, once a month, or once a year, and it provides sustained release over a longer period of time compared to conventional sustained release formulations. It will be done.

(2) When administering a biodegradable polymer as an injection, no surgical procedures such as implantation are required, and it can be easily administered subcutaneously and intramuscularly in the same way as general suspension injections. There is no need to take it out again.

(3) A traditional W/O/W type three-layer emulsion is made and then dried in water. The herbal drug peptide is placed in microcapsules without adding any particular drug-retaining substance to the inner aqueous layer. It is possible to efficiently incorporate microcapsules into fine, spherical, well-formed microcapsules.

(4) Compared to the conventional manufacturing method of preparing a W/O/W type emulsion and drying it in water, microcapsules with less unnecessary initial release can be obtained, resulting in a safer and superior sustained release at a more constant rate. It can be a sex preparation.

Effects and Examples The present invention will be explained in more detail with reference to Examples below.

Example 1 Enkephalin derivative H-Tyr-D-Met(0)-
Gly-EtPhe-NH-N1(COCH,-A
cO■(E K-399, U.S. Patent No. 4277394
40.80, 200.300 and 400m
g (1 to 0% by weight based on PLGA) was dissolved in 0.5 g of distilled water, and 4 g of PLGA dissolved in 5 g of dichloromethane was added thereto. Mix for ~60 seconds, W/
A type O emulsion was prepared. After cooling this to 3 to 12℃, it was cooled to 11 to 5℃.
% polyvinyl alcohol (PVA) aqueous solution, and a W/O/w type emulsion was prepared using a turbine homomixer. After that, while stirring the W/O/W type emulsion liquid, the internal W is removed by volatilization of dichloromethane.
After the /O type emulsion was solidified, it was collected using a centrifuge. This was dispersed again in distilled water and further centrifuged to wash away free drugs and the like.

The collected microcapsules were freeze-dried to remove solvent and dehydrate more completely, and then were obtained as a powder.

In the above method, 1-10% EK for P L GA
-399-loaded microcapsules (% of the amount actually taken up with respect to the loaded amount) and the in-
In the in vitro dissolution test, microcubs after 1 day
The amount remaining in the pill was measured and shown in Table 1.

Table-I E-399 Microcapsule Ell
I 71.721.7E112.
2 69.9 ・47,
7E113. ,, 5 78,6
73.0E114 7.5 97,3
82.63>% b for PLGA
) (Average value of n = 3) In the case of E K -399, acetate is a weak acid, but in lots with low loadings of 1% and 2%, a tendency for the trapping rate to decrease and a large initial release were observed.
Good microcapsules were obtained when the concentration of EK-399 relative to PLGA was in the range of 5 to 0%.

Example 2 Enkephalin derivative H-Tyr-D-Met(0
)-Gly-MePhe-NH-NHCOCH3-
40-800 mg (P
1-20% of LGA) and 0.5% of distilled water, respectively.
- and the following procedure was carried out in the same manner as in Example 1 to prepare E K
33 8 types of microcapsules were obtained.

Table 2 shows the trapping rate of these microcapsules, in
Initial release in vitro dissolution test is shown.

Table-2E K-333 Microcapsule E3111
1 69.7 16.5E3
112 2 60.2 29
．． 9E 3113 5 80.0
72.2E3114 7.5 83
．． 4 82□4E3115 /O
87.6 91.1E3116 12
90.4 90.5E3117
15 90.7 87.0a
)% relative to PLGA b), average value E of n73
Similar to K-399, at low loadings of 1% and 2%, the trapping rate was low and the initial release was significantly large.

At 20% loading, a slight decrease in trapping rate was observed, but the initial release was not so large. Good microcapsules were obtained at a concentration of E K-333 relative to PLGA of 5 to 20%.

Example 3 Example! The in vitro and in vivo drug release properties of the microcapsules obtained by method 2 and subcutaneous administration to rats (measurement of the amount of drug remaining in the microcapsules at the administration site) were investigated, and the results are shown in Table 3.
and shown in Table 4.

Table-3 EK-333E3115 91.1 77.2 58,
3 25.3 1.48 Table-4 Both are PLGA (lactic acid/glycolic acid ratio near 5/25
The microcapsules were prepared using microcapsules with an average molecular weight of 14,000) containing /0% of the drug based on the polymer, but in vitro they showed low initial release and good near zero-order release over 4 weeks. This shows that microcapsules with controlled release have been obtained. As a result of observation using a scanning electron microscope, these microcapsules had a well-ordered, clean spherical shape with an average particle diameter of 20 to 30 microns. Moreover, it could be smoothly and easily injected with a 23-22 gauge needle using an appropriate dispersion medium.

Example 4 Using the method of Example 2, citric acid was added in an amount equivalent to 0.01 to 4 M based on the drug to the internal aqueous phase containing EK-333 at a charge amount of 5% based on PLGA. , pKa4
．． The effect of less than 0 acid addition salts on microcapsule preparation was investigated. The results are shown in Table-5.

Table-5E K-333 Microcapsule Citric Acid °)
Tora Pu E3172 after 1 day 0.1 57.7
42.5E3173 1
61.0 27.9E3174
2 81.0 11.3
a) E K using molar ratio to E K -333
-333 is an acetate salt, but when citric acid was further added, an increase in initial release depending on the added concentration was observed at a ratio of 0.1M or higher, and at a ratio of 1M, 72.1% was released in one day.

Effects of the Invention According to the production method of the present invention, sustained-release microcapsules can be obtained that have a high rate of incorporation of crude drugs into microcapsules, have little initial excessive release, and stably release the active drug over a long period of time.

Claims (1)

[Claims] An oil layer containing a high molecular weight polymer, and 5% for the high molecular weight polymer.
A W/O emulsion is formed with an aqueous layer containing ~20% by weight of enkephalin, its analog, or their salt with a weak acid with a pKa of 4.0 or more, and this is mixed with an aqueous dispersant solution to form a W/O emulsion. 1. A method for producing microcapsules, which comprises forming a /O/W type emulsion and then distilling off an oil layer solvent.