JPS6353966B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a new sustained-release microcapsule and a method for producing the same. In recent years, sustained-release pharmaceutical formulations have been devised to avoid the side effects of administered drugs and allow the pharmacological action of the drug to be expressed for a long time in vivo to obtain desired therapeutic effects. Such pharmaceutical preparations include, for example, preparations in which sulfamethizole is matrixed with cellulose acetate, a water-insoluble polymer, as a core material, and microcapsules are formed with ethylcellulose [Chem.Pharm.Bull.
vol. 28 2816-1819 (1980)] is known,
Although this preparation can achieve a drug sustained release effect, it has the disadvantage that the drug in the matrix is not sufficiently released even after reaching the intestinal tract because the matrix itself is water-insoluble. In view of this situation, the present inventors have conducted extensive research and have developed a new sustained-release microcapsule that exhibits a sustained drug release effect in the stomach and intestines, and is also capable of reliably releasing drugs within these gastrointestinal tracts. It was completed. That is, the present invention is a core material-containing ethyl cellulose microcapsule in which a core material is a particle formed by granulating a medicinal substance and an enteric polymer material, and an ethyl cellulose wall film is formed on the core material. According to the present invention, such microcapsules are produced by dispersing particles obtained by granulating an enteric polymer substance solution and a pharmaceutical substance in an ethyl cellulose-containing solution, and then dispersing the particles in the presence or absence of the enteric polymer substance. It can be produced by forming an ethylcellulose wall film on a core material through phase separation of the ethylcellulose. As the enteric polymer material which is one of the core components in the microcapsules of the present invention, any enteric polymer material that is soluble in water with a pH of 5 or higher can be used. Specifically, for example, (i) polysaccharide acetate, organic dibasic acid ester of alkylated polysaccharide or hydroxyalkylated polysaccharide, (ii) alkyl ether of carboxyalkylated polysaccharide, (iii) which dissolves in water with a pH of 5 or more. ) organic dibasic acid esters of polyvinyl alcohol, polyvinyl acetate, or polyvinyl acetal; and (iv) two- or three-component copolymers selected from acrylic acid, methacrylic acid, or esters thereof. In (i), examples of organic dibasic acid esters of polysaccharide acetate include cellulose,
Acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, starch acetate phthalate,
Examples include amylose acetate and phthalate, and examples of organic dibasic acid esters of alkylated polysaccharides include, for example, methylcellulose phthalate. Furthermore, specific examples of organic dibasic acid esters of hydroxyalkylated polysaccharides include hydroxyethyl, ethylcellulose,
Examples include phthalate and hydroxypropyl methylcellulose phthalate. An example of the alkyl ether of carboxyalkylated polysaccharide (ii) is carboxymethylethylcellulose. In (iii), specific examples of the organic dibasic acid ester of polyvinyl alcohol, polyvinyl acetate, or polyvinyl acetal include polyvinyl alcohol phthalate, polyvinyl acetate phthalate, polyvinyl acetal phthalate, and polyvinyl butyrate phthalate. Further in (iv) acrylic acid,
Specific examples of two- to three-component copolymers selected from methacrylic acid or esters thereof include methyl acrylate/methacrylic acid copolymer, methyl acrylate/methacrylic acid/octyl acrylate copolymer, and methyl acrylate/methacrylic acid/methyl methacrylate copolymer. , methyl methacrylate/methacrylic acid copolymer, and ethyl acrylate/methacrylic acid copolymer. Among these, preferred are hydroxypropyl methylcellulose phthalate, methacrylic acid/methyl methacrylate copolymer, methacrylic acid/ethyl acrylate copolymer, methyl acrylate/methacrylic acid copolymer, and methyl acrylate/methacrylic acid copolymer, which are soluble in water with a pH of 5.0 or higher. , methyl acrylate/methacrylic acid/methyl methacrylate, carboxymethyl/ethyl cellulose,
Mention may be made of cellulose acetate phthalate. On the other hand, the medicinal substance that forms the core substance together with these enteric polymeric substances is not particularly limited, and any medicinal substance suitable for oral administration can be used. You can. Furthermore, even muddy substances can be used. When these medicinal substances are solid, they are approximately 5 to
It is preferable to use particles with a particle size of 1000 μm, especially about 50 to 500 μm. The core material particles consisting of a pharmaceutical substance and an enteric polymeric substance as described above can be produced by granulating these two components using an inert solvent as an auxiliary agent. It can be produced by adding a medicinal substance to a solution or gel in which a molecular substance is dissolved or swollen, dissolving or dispersing it, and granulating the mixture. Furthermore, excipients and the like can also be used during granulation. The content of each of these components in the core material particles can be arbitrarily changed depending on the use and purpose of the microcapsules of the present invention, but in particular, the content of the enteric polymer substance in the core material is approximately 15 to 70%. %, more preferably about 20-60%, and most preferably about 25-50%. As the solvent used during granulation, for example, lower alkanols such as methanol and ethanol, lower alkanones such as acetone, methyl acetone, and methyl ethyl ketone, or mixtures of these and water can be used, and in particular methanol, ethanol, acetone, or these and water can be used. A mixture with is preferred.
The amount of solvent used is not particularly limited, but it is preferable to use an amount that can completely dissolve or swell the enteric polymeric substance. Granulation can be suitably carried out by employing, for example, a wet granulation method, a fluidized bed granulation method, a spray granulation method, or the like. Specifically, after dissolving or uniformly dispersing the medicinal substance in an enteric polymer substance solution or gel, a commercially available granulator suitable for the above granulation method is used, or a conventional granulation method is used. Therefore, it can be implemented. Particles of a desired size can then be obtained by drying and sizing the obtained particles. In addition, when using excipients, excipients (such as lactose, starch, calcium citrate,
Core material particles can be obtained by adding mannite, etc.) to an enteric polymeric material solution together with a medicinal substance and carrying out the same procedure as described above. The core material particles thus obtained uniformly contain the medicinal substance in the enteric polymeric material, and especially when the content of the enteric polymeric material in the core material is 15% or more, the polymeric material is in the matrix. Since the structure is formed and the medicinal substance is encapsulated in the matrix of this polymeric substance, an accurate sustained release effect of the medicinal substance can be obtained. There is no particular restriction on the particle size of the core material particles, but
Generally about 5~1000μ, especially about 50~
Preferably, a particle size of 500μ is used. Microcapsules can then be produced by dispersing the obtained particles in a solution containing ethylcellulose as a wall agent, and then forming an ethylcellulose wall on the particles by phase separation of the ethylcellulose. As ethyl cellulose, the ethoxy content is approximately
46.5-55% and viscosity (in the present invention, the viscosity of ethyl cellulose is toluene/ethanol (4:
1) Ethyl cellulose is dissolved in the mixed solution to a concentration of 5%, and the viscosity of the solution is expressed as the viscosity at 25°C. ) It is preferable to use one with a value of about 3 to 500 cP. The amount of ethyl cellulose used is approximately
A suitable amount is 0.05 to 5 times. As a solvent for dissolving ethyl cellulose, any solvent can be used as long as it does not dissolve the core substance and dissolves the wall agent ethyl cellulose when heated and makes it insolubilized when cold. Specific examples include cyclohexane and a mixture of cyclohexane and n-hexane, with cyclohexane being particularly preferred. The concentration of ethylcellulose in solution is about 0.5~
It is preferable to use 10 W/W%, especially about 1 to 5 W/W%. Further, the operation of dispersing the core substance in this solution is preferably carried out under stirring at a temperature of about 80°C or less, particularly about 55 to 75°C. The phase separation of ethyl cellulose from the core material particle dispersion thus obtained is carried out at a rate of 0.05 to 4 per minute.
Preferably, this is carried out by cooling at a rate of .degree. Cooling may be carried out until the temperature of the dispersion reaches about 30° C., whereby the ethyl cellulose wall film deposited on the core material particles is solidified and stabilized. Furthermore, in the microcapsules of the present invention, an enteric polymeric substance can be contained in the ethylcellulose wall to provide microcapsules containing the enteric polymeric substance both in the core particle and in the wall. In this case, the enteric polymeric substances described above can be suitably used as the enteric polymeric substance, and it is preferable to use fine powders of these substances, particularly fine powders having a particle size of about 300 μm or less. It is preferable to use these enteric polymeric substances in an amount of about 0.01 times or more, especially about 0.05 to 20 times the amount of the wall film agent. In order to incorporate an enteric polymeric substance into the ethylcellulose wall film, the polymeric substance may be added to the ethylcellulose-containing core material particle dispersion to cause phase separation in the same manner as described above. The enteric polymer material may be added before the start of cooling or at any stage during the cooling process, but especially during the process in which ethyl cellulose is deposited on the core material by cooling, that is, the gel-like wall film of ethyl cellulose is deposited on the core material. The period when the above is completed and still has some degree of fluidity (specifically, when the viscosity of the ethyl cellulose wall film is about 0.05~
It is preferable to add the enteric polymeric substance to the solution (with a viscosity of 50P, especially 0.5 to 10P) under stirring. To be more specific, the timing of addition of the enteric polymer substance varies somewhat depending on the scale of implementation, cooling rate, etc., but in general, the timing of addition of the enteric polymer substance is when the temperature of the dispersion is about 55 to 75°C, especially about 65°C. If this happens, a fluidized ethyl cellulose wall film will be completed on the core material, so it is preferable to add the enteric polymer material using this temperature as an indicator. By adding in this manner, the enteric polymer substance is suitably permeated and dispersed into the capsule wall membrane. When the addition of the enteric polymeric substance is completed, the ethyl cellulose wall film containing the enteric polymeric substance is solidified and stabilized by continuing cooling. Furthermore, when producing the microcapsules of the present invention, a wall film forming aid or a surfactant may be used in combination as appropriate. As the phase separation inducer, for example, polyethylene, butyl rubber, polyisobutylene, polybutadiene can be used, as the wall film forming aid, for example, dimethylpolysiloxane, methylphenylpolysiloxane, etc. can be used, and as the surfactant, for example, sorbitan fatty acid can be used. Ester, soybean phospholipid, egg yolk phospholipid, calcium stearyl lactate, glycerin fatty acid ester, propylene glycol fatty acid ester, sucrose fatty acid ester, etc. can be used. These additions can be added at the same time when dissolving ethyl cellulose.
The amount added is approximately 0.1 to 10% for the phase separation inducer and approximately 0.1 to 10% for the wall film forming aid in the ethyl cellulose-containing solution.
0.01-10%, surfactant approximately 0.001-10%. The microcapsules thus produced can be separated by a conventional separation method, such as decantation, filtration, centrifugation, etc. When using any of these methods, the capsules hardly adhere to each other or aggregate. The microcapsules obtained in this way are
Then, if necessary, it can be washed with cyclohexane, petroleum ether, n-hexane, etc., and dried by a conventional method (hot air drying, heat transfer drying, etc.). The above-mentioned pharmaceutical products to which the microcapsules and manufacturing method of the present invention can be applied include vitamins, amino acids, peptides, chemotherapeutic agents, antibiotics, respiratory stimulants, antitussive expectorants, anti-malignant tumor agents, anti-cancer agents, etc. Nervous agents, psychiatric agents, local anesthetics, muscle relaxants, gastrointestinal agents, antihistamines, addiction treatment agents, hypnotic sedatives, antiepileptic agents, antipyretic, analgesic, antiinflammatory agents, cardiac agents, antiarrhythmia agents, antihypertensive diuretics , vasodilators, antilipidemic agents, tonic and altering agents, anticoagulants, liver drugs, hypoglycemic agents, antihypertensive agents, and the like. In the thus obtained microcapsules of the present invention, the medicinal substance is uniformly dispersed or dissolved in the enteric polymeric substance in the core substance and encapsulated in the matrix, so that the capsule wall membrane does not form inside the stomach after ingestion. The enteric polymer material matrix serves as a barrier for the gastric juice that has passed through the capsule, slowing its penetration into the core substance, thereby reducing the dissolution of the medicinal substance inside the capsule, thereby controlling the release of the medicinal substance. It happens. Moreover, when the release is controlled in this way and the particles reach the intestines, the enteric polymeric substance in the core material dissolves, thereby gradually dissolving or swelling the core material particles. As a result, the release of the medicinal substance from the microcapsules is more rapid in the intestine than in the stomach, and the release can be more complete. In this case, the release rate of the medicinal substance can be adjusted as desired by changing the ratio of the enteric polymeric substance and the medicinal substance in the core material. In addition, when microcapsules containing enteric polymer substances not only in the core substance but also in the ethyl cellulose wall are administered, the enteric polymer substance in the core substance acts in the stomach in the same manner as above. As a result, the release of the medicinal substance from the capsule is suppressed, but when it reaches the intestines, the release of the medicinal substance is further promoted. That is, once it reaches the intestine, the enteric polymeric substance in the ethylcellulose wall rapidly dissolves,
The wall membrane becomes porous, further promoting the penetration of intestinal fluid into the interior of the core substance, and as described above, accelerating the dissolution of the medicinal substance. As a result, the two work together to promote release in the intestine more than in microcapsules that do not contain enteric polymeric substances in their walls. Therefore, the release rate of the microcapsules of the present invention can be appropriately determined according to the medicinal substance by selecting one of the above-mentioned means depending on the purpose and use thereof. The present invention will be explained in more detail below using experimental examples and examples. Experimental Example 1 Diltiazem hydrochloride (chemical name: d-3-acetoxy-cis-
2,3-dihydro-5-[2-(dimethylamino)
ethyl]-2-(P-methoxyphenyl)1,5-
Benzothiazepine-4(5H)-one hydrochloride)-containing microcapsules were prepared, and the capsule yield, active ingredient content in the capsules, and disintegration test according to the 10th edition of the Japanese Pharmacopoeia in liquids 1 and 2 (at 37°C) were evaluated. The elution of the main drug from the capsules was measured over time to compare the effects of the present invention. Experimental method (1) Core material Part a of fine powder of hydroxypropyl methylcellulose phthalate [methoxyl group content: 22.2%, hydroxypropoxyl group content: 7.5%, carboxybenzoyl group content 21.6% (hereinafter referred to as HPMCP)] and Add 0.5a part of a 30% aqueous ethanol solution to a mixture of 100-a parts of fine powder of diltiazem hydrochloride. Then, the mixture was kneaded and granulated by a conventional method, dried, and sized into particles having a particle size of 105 to 350 μm. (2) Preparation of microcapsules Add silicone resin to 700 ml of cyclohexane (conforming to the standards of the 4th edition of the Food Additives Official Standards).
3 to 3 silicon dioxide to dimethylpolysiloxane with a viscosity of 100 to 1100 cSt at 25°C.
Add 21 g of ethyl cellulose (ethoxy group content: 48.2%, viscosity: 98.5 cP) and 87.5 g of core material and heat to 80°C to dissolve and disperse. Then, the mixture is stirred at 400 rpm and cooled to room temperature (approximately 25 DEG C.), and the formed microcapsules are separated, washed with n-hexane, and dried. The opening of the obtained microcapsules
Passes through a 500μm JIS standard sieve with an opening of 105μ
Microcapsules containing diltiazem hydrochloride that conformed to the fine granule standards of the 10th edition Japanese Pharmacopoeia (hereinafter simply referred to as fine granule standards) were obtained by collecting those that remained on a JIS standard sieve of 500 m. (3) Results The results are shown in Table 1 and Figure 1 below.

[Table] (Note); Experiment No. 5 was used only as core material particles.
Experimental Example 2 Microcapsules containing diltiazem hydrochloride containing enteric polymeric substances in both the core material and the capsule wall membrane were prepared, and the capsule yield, active ingredient content in the capsules, and disintegration test liquid 2 according to the 10th revised Japanese Pharmacopoeia ( 37
The effects of the present invention were compared by measuring the elution of the active ingredient from the capsules over time in 30°C. <Experiment method> (1) Core material: 50 parts of diltiazem hydrochloride powder and 6 parts of ethanol.
After adding 50 parts of the fine powder of hydroxypropyl methylcellulose phthalate used in Experimental Example 1 and mixing it with 40 parts of water, the wet mixture is added and kneaded and granulated using a conventional method. . Then, it was dried and sized into matrix particles having a particle size of 105 to 350 μm. (2) Preparation of microcapsules Add 21 g of the silicone resin used in Experimental Example 1, 17.5 g of ethyl cellulose, and 70 g of the core substance to 700 ml of cyclohexane and heat to 80°C to dissolve and disperse. Next, it is cooled while stirring at 400 rpm, and when it reaches about 65°C, the fine powder of hydroxypropyl methyl cellulose phthalate is added to the
After adding the amount shown in the table and incorporating it into the wall film, it is cooled to room temperature. The produced microcapsules are separated, washed with n-hexane, and dried. The obtained microcapsules were opened to 500 μm.
Diltiazem hydrochloride-containing microcapsules meeting the standards for fine granules were obtained by processing with a JIS standard sieve of 105 μm and 105 μm. (3) Results The results are shown in Table 2 and Figure 2 below, and when the enteric polymer was contained in the capsule wall membrane, the elution of the active ingredient in the second liquid was further promoted.

[Table] Example 1 Trimethoquinol hydrochloride (chemical name: l-1-(3,
60 parts of methacrylic acid/methyl methacrylate copolymer (molar ratio 1:1) Add 40 parts to a solution of 40 parts of ethanol and knead to form a slurry. After stretching this into a thread and drying it, it is crushed and the particle size is 105 ~
Size the particles to 350μm. Cyclohexane 700ml
silicone resin (used in Experimental Example 1) 21
g, ethyl cellulose (ethoxy group content 48.2%,
Viscosity 98.5cP) 17.5g and previously sized core material
Add 52.5g and heat to 80℃ to dissolve and disperse. Next, the mixture is cooled while stirring at 400 rpm, and when the temperature reaches about 65°C, 35 g of fine powder of methacrylic acid/methyl methacrylate copolymer (1:1) is added to be incorporated into the wall film, and then cooled to room temperature. The generated microcapsules are separated, washed with petroleum ether, and dried. The obtained microcapsules were opened to 500 μm.
96 g of sustained-release trimethoquinol hydrochloride-containing microcapsules meeting fine granule standards were obtained by processing with a JIS standard sieve of 105 μm and 105 μm. The active ingredient content in this microcapsule was 31.5%. Examples 2 to 8 The following experiments were carried out as in Example 1 using the same sized trimetoquinol hydrochloride as the core material and the enteric polymer substances and solvents shown in Table 3 below as the wall agent and solvent. By carrying out the same procedure, sustained-release microcapsules containing trimethoquinol hydrochloride shown in Table 3 below were obtained.

【table】

[Table] Example 9 80 parts of trimethoquinol hydrochloride was added to a solution of 20 parts of hydroxypropyl methylcellulose phthalate (used in Experimental Example 1) dissolved in 30 parts of a water/ethanol (2:8) mixture and kneaded. Combine to make slurry. Then, after being stretched into a thread and dried, it is crushed and sized into particles with a particle size of 105 to 210 μm to obtain a core material. 14 g of ethyl cellulose (ethoxy group content 89.5%, viscosity 81 cP) in 700 ml of cyclohexane, 98 g of core material
g and 14 g of a phase separation inducer (or wall film forming aid) shown in Table 4 below were added and heated to 80°C to dissolve and disperse. Then, while stirring at 400 rpm, cool to room temperature. The produced microcapsules are separated, washed with n-hexane, and dried. Among the microcapsules obtained, those that passed through a JIS standard sieve with an opening of 350 μm were collected to obtain trimethoquinol hydrochloride-containing microcapsules that met the powder standards of the 10th edition of the Japanese Pharmacopoeia.

[Table] Example 10 50 parts of diltiazem hydrochloride and hydroxypropyl
30 parts of talc is dispersed in a solution in which 50 parts of methylcellulose phthalate (used in Experimental Example 1) is dissolved in 1000 parts of 30% aqueous ethanol. This dispersion
Spray drying is carried out at 100° C. using a high-speed rotating disc at 30,000 rpm to form particles with a particle size of 74 to 125 μm to obtain a core material. Next, 14 g of silicone resin (used in Experimental Example 1), 21 g of ethyl cellulose (used in Experimental Example 1), and 105 g of the core material obtained above were added to 700 ml of cyclohexane and heated to 80° C. to form a dispersion. Cool to approximately 25℃ while stirring at 400rpm. The produced microcapsules are separated, washed with n-hexane, and then dried. By processing the obtained microcapsules through a JIS standard sieve with an opening of 350 μm, microcapsules containing diltiazem hydrochloride that meet the powder standards of the 10th edition of the Japanese Pharmacopoeia are produced.
Obtained 118g.

[Brief explanation of the drawing]

Figure 1 shows the elution rate of diltiazem hydrochloride in the first and second liquids (both at 37°C) of the disintegration test of the 10th edition Japanese Pharmacopoeia of the microcapsules obtained in Experimental Example 1 Nos. 1 to 5. In the drawing, the solid line indicates the dissolution rate in the first solution, and the broken line indicates the dissolution rate in the second solution. Figure 2 shows Nos. 1 to 4 of Experimental Example 2.
This figure shows the dissolution rate of diltiazem hydrochloride in the second solution (37°C) of the disintegration test according to the 10th edition Japanese Pharmacopoeia of the microcapsules obtained in .

Claims (1)

[Scope of Claims] 1. A core material-containing ethyl cellulose microcapsule in which a core material is a particle formed by granulating a medicinal substance and an enteric polymeric material, and an ethyl cellulose wall film is formed on the core material. 2 The content of enteric polymer material in the core material is 15~
70 W/W% microcapsules according to claim 1. 3. The microcapsule according to claim 1 or 2, wherein the core material is a particle obtained by granulating a pharmaceutical substance and an enteric polymer substance using an inert solvent as an auxiliary agent. 4. Microcapsules according to claim 1, 2 or 3, which contain an enteric polymeric substance in the ethyl cellulose wall. 5 Enteric-coated polymer substances dissolve in water with a pH of 5.0 or higher (i) organic dibasic acid esters of polysaccharide acetate, alkylated polysaccharides or hydroxyalkylated polysaccharides, (ii) alkyl of carboxyalkylated polysaccharides ether, (iii) an organic dibasic acid ester of polyvinyl alcohol, polyvinyl acetate or polyvinyl acetal, or (iv) acrylic acid, methacrylic acid or an ester thereof. Microcapsules according to item 1 or 2. 6 Hydroxypropyl methylcellulose phthalate, methacrylic acid/methyl methacrylate copolymer, methacrylic acid/ethyl acrylate copolymer, methyl acrylate/methacrylic acid copolymer, methyl acrylate/methacrylic acid copolymer in which enteric polymer substances are soluble in water with a pH of 5.0 or higher. , methyl acrylate/methacrylic acid/
Claims 1, 2, and 3 are methyl methacrylate, carboxymethyl ethylcellulose, and cellulose acetate phthalate.
5. Microcapsules according to item 1, 4 or 5. 7. After dispersing particles obtained by granulating an enteric polymer substance solution and a pharmaceutical substance in an ethyl cellulose-containing solution, a core is formed by phase separation of the ethyl cellulose in the presence or absence of an enteric polymer substance. A method for producing microcapsules characterized by forming an ethylcellulose wall film on a substance. 8. The method according to claim 7, wherein particles obtained by dissolving or dispersing a pharmaceutical substance in an inert solvent solution containing an enteric polymeric substance and then granulating the mixture are used as the core material. 9. The method according to claim 8, wherein lower alkanol, lower alkanone, tetrahydrofuran or a mixture thereof, or a mixture thereof with water is used as the inert solvent. 10 After dispersing the core material in a solution containing ethyl cellulose, which is a wall agent, when forming an ethyl cellulose wall film on the core material by phase separation of the ethyl sululose, a phase separation inducing agent, wall film forming aid, or surfactant is used. The method according to claim 7, 8 or 9, in which one or more of these are used.