JPH021405A - Preparation of release control type and production thereof - Google Patents

Abstract

PURPOSE:To obtain a preparation of release control type having excellent water resistance, light resistance, water vapor resistance, wear resistance and shelf stability and desired elution rate by coating a core substance containing a drug active component with a porous film of hydrophobic polymer substance. CONSTITUTION:A core substance containing a drug active component is coated with a porous film (having preferably 0.4-0.9, especially 0.5-0.85 porosity) comprising a hydrophobic polymer substance (especially preferably cellulose ether, cellulose ester, polyvinyl ester, etc.) or the said polymer substance and a hydrophilic polymer substance (especially preferably polysaccharide which may contain sulfate group, methyl cellulose, polyvinyl pyrrolidone, etc.). The preparation can have desired elution rate by arbitrarily controlling the porosity of the film.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel controlled-release formulation and a method for producing the same.

[Prior art]

BACKGROUND ART Pharmaceutical preparations coated with a dense film of a hydrophobic polymeric substance have been known.

This formulation has the advantage of being excellent in water resistance, light resistance, moisture resistance, abrasion resistance, storage stability, etc.

[Problems to be solved by the present invention]

However, problems remain in that preparations coated with a dense film of hydrophobic polymeric substances have a slow release rate of the internal drug, and the drug is not completely released.

In other words, the release of the coated drug is based on the concentration difference and osmotic pressure difference between the coated drug and the outside, which are generated when the drug is dissolved to a saturation concentration by moisture such as digestive juices that have entered through gaps in the coating. However, because the dense film of a hydrophobic polymer substance has few pores, water permeation into the film is slow, and even if there is a difference in osmotic pressure sufficient to release the drug to the outside, the pores that contribute to drug release are completely absorbed. Since the area is small, the problem arises that the elution rate is not sufficient.

A known method to solve these problems is to embed particles of a water-soluble substance in a film of a hydrophobic polymer substance and make the film porous by dissolving and releasing the water-soluble substance in the gastrointestinal tract. There is.

However, with this method, special measures are required for the coating in order to embed water-soluble substances in the film, and various additives such as dispersants, plasticizers, and anti-agglomeration agents are required, making the formulation complex. Even if the membrane becomes a porous membrane in the gastrointestinal tract, the porosity is influenced by the particle size of the water-soluble substance and the degree of dispersion of the substance in the membrane, and it is not always possible to control the porosity to a positive value. [Structure and Effects of the Invention] The present inventors have developed a drug that makes it possible to control release while taking advantage of the strong physical strength and good storage stability of a preparation coated with a hydrophobic polymeric substance. As a result of intensive research, we succeeded in forming a porous film of a hydrophobic polymer substance, and by arbitrarily adjusting the porosity of the film, we were able to create a controlled-release formulation with a desired dissolution rate. The inventors have found that the above-mentioned problems can be solved.

That is, the present invention is a controlled-release drug in which a core material containing a pharmaceutically active ingredient is coated with a porous membrane of a hydrophobic polymer material, and a method for producing the same.

In the present invention, the form of the core substance coated with the porous membrane is not particularly limited, and various forms such as bare tablets, gunpowder, granules, and fine particles can be suitably used, and in particular,
It is preferable to use granules having an average particle size of about 3 (10 μm to about 2 (100 μm), particularly about 5 (10 μm to about 850 μm).The core material of the present invention may have a hydrophobic, water-soluble, or water-insoluble core. Any of these substances can be suitably used.

The hydrophobic polymeric substance constituting the porous membrane is not particularly limited as long as it has a film-forming ability and is insoluble in water but soluble in an organic solvent that is miscible with water. Examples of such hydrophobic polymer substances include evacellulose ether, cellulose ester, polyvinyl ester, quaternary
Examples include acrylic acid polymers having a grade ammonium alkyl group. Specifically, for example, ethyl cellulose, butyl cellulose; cellulose acetate, cellulose propionate; polyvinyl acetate, polyvinyl butyrate; Among them, preferred hydrophobic polymer substances include ethyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, and Eudragid R5. Among these, preferred is ethyl cellulose or cellulose acetate, and most preferred is ethyl cellulose. Ethylcellulose is particularly preferably water-insoluble ethylcellulose, for example, having an ethoxy content of about 40 to about 55%, especially about 43% to about 51%, and a viscosity of [toluene-ethanol (4:1)'
lR? A 5% concentration solution of ethyl cellulose with a viscosity of about 4 to about 350 cP at 25°C is preferred.

Further, the porous membrane in the present invention may be a porous membrane consisting of a hydrophobic polymeric substance and a hydrophilic polymeric substance, in addition to a porous membrane consisting only of a hydrophobic polymeric substance. In this case, as the hydrophilic polymeric substance, water-soluble polymeric substances, enteric-coated polymeric substances, gastric-soluble polymeric substances, gastrointestinal-compatible polymeric substances, etc. can be suitably used.

For example, preferred examples of water-soluble polymeric substances include polysaccharides that may have sulfate groups such as pullulan, dextrin, alginate alkali metal salts, hydroxyalkyl groups such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. Alternatively, polysaccharides having a carboxyalkyl group, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, etc. may be mentioned.

Among these, more preferable water-soluble polymer substances include hydroxypropyl cellulose and polyethylene glycol.

In addition, the enteric polymer substance may be any polymer substance that dissolves in water with a pH of 5 or more and has the ability to form a film, such as (
1) carboxyalkyl cellulose ether, (2) cellulose derivative having a dibasic acid monoester bond, (3) polyvinyl derivative having a dibasic acid monoester bond, (4) maleic acid-vinyl copolymer or (5) acrylic acid polymers. (Specific examples of 11 include carboxymethylethyl cellulose, (2
) Specific examples include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, etc. )
Specific examples include polyvinyl acetate phthalate,
Examples include polyvinyl butyrate/phthalate, polyvinyl acetoacetal/phthalate, etc. Specific examples of (4) include vinyl acetate/maleic anhydride copolymer, vinyl butyl ether/maleic anhydride copolymer, styrene/malein. Examples of acid monoester copolymers include methyl acrylate and (5).
Methacrylic acid copolymer, styrene/acrylic acid copolymer, methyl acrylate/methacrylic acid/octyl acrylate copolymer, Eudragisod L and S (Rohm Pharma Co., Ltd. trade name, methacrylic acid/methyl methacrylate copolymer) combination), etc. Among these, more preferred enteric polymeric substances are carboxymethylethylcellulose, hydroxypropyl methylcellulose acetate succinate, or eudragit.

Furthermore, the gastric soluble polymeric substance may be any polymeric substance that dissolves in water with a pH of 6 or less and has film-forming ability, such as (a) cellulose derivatives having mono- or di-substituted amino groups, (b) mono- or di-substituted amino groups, Or polyvinyl derivatives having a di-substituted amino group, acrylic acid polymers having a Cl-mono-substituted amino group, etc. Specific examples of (a) include benzylaminomethylcellulose, diethylaminomethylcellulose, piperidyl ethyl hydroxyethylcellulose, etc. Examples of (b) include aminocelluloses and aminocellulose esters such as cellulose acetate and diethylaminoacetate.Specific examples of (b) include vinylamines such as vinyldiethylamine/vinyl acetate copolymers and vinylbenzylamine/vinyl acetate copolymers. Examples of (C) include Eudragid E ( ROHM・
Examples include methyl methacrylate/butyl methacrylate/dimethylaminoethyl methacrylate copolymer), polydimethylaminoethyl methacrylate, and the like (product name of Pharma Co., Ltd.). Among these, more preferable gastrosoluble polymer substances are polyvinyl acecool diethylaminoacetate or Eudragid E.

The gastrointestinal-compatible polymeric substance may be any polymeric substance that dissolves in water with a pH of 4.5 or lower and in water with a pH of 6 or higher and has a film-forming ability, such as vinylpyridine-acrylic acid copolymer, mono- or di-copolymer. Carboxymethyl multi-IJ with substituted amino group! and polyvinyl amino acid derivatives. Specific examples of vinylpyridine-acrylic acid copolymers include 2-methyl-5-vinylpyridine/methyl methacrylate/methacrylic acid copolymer 1.2-methyl-5-vinylpyridine/methyl acrylate/methacrylic acid copolymer Acid copolymer, 2-vinyl-5-ethylpyridine/methacrylic acid/styrene copolymer, 2-vinyl-5
Examples include -ethylpyridine/methacrylic acid/methyl acrylate copolymer, 2-vinylpyridine/methacrylic acid/methyl acrylate copolymer, and 2-vinylpyridine/methacrylic acid/acrylonitrile copolymer. Also, carboxymethyl poly(I) having a mono- or di-substituted amino group! Specific examples of these include carboxymethyl piperidyl starch, carboxymethyl benzylaminocellulose, etc. Specific examples of polyvinyl amino acid derivatives include poly 2-vinylphenylglycine, N-vinylglycine-styrene copolymer, etc. Although there are no particular limitations on the combinations that can be mentioned, preferred combinations include combinations of hydrophobic polymeric substances and water-soluble polymeric substances or enteric polymeric substances. Particularly preferred combinations include ethyl cellulose as a hydrophobic polymer and hydroxypropyl cellulose as a water-soluble polymer, carboxymethylethyl cellulose or hydroxypropyl methylcellulose as an enteric polymer.
A combination with acetate succinate is mentioned. The ratio of the hydrophobic polymeric substance to the hydrophilic polymeric substance used is preferably about 0.05 to 0.5 parts by weight of the hydrophilic polymeric substance per 1 part by weight of the hydrophobic polymeric substance.

A porous membrane made of a hydrophobic polymeric material or a hydrophobic polymeric material and a hydrophilic polymeric material as described above generally has a spongy appearance, and has microscopically interconnected regular or irregular structures. It has many pores.

The porosity of a porous membrane can generally be expressed by a combination of a hydrophobic polymeric material and a hydrophilic polymeric material, and the porosity can be changed arbitrarily, but is usually about 0.4. It is preferably in the range from 0.9 to 0.9, especially from 0.5 to 0.85.

The thickness of the film may be adjusted by adjusting the coating amount of the hydrophobic polymer material to the core material. It is desirable to use it so that it is about 5 to 548%.Also, when using a hydrophobic polymer substance and a hydrophilic polymer substance together,
It is preferable that the coating amount including the art dealer molecular substance be within the above range.

In the preparation of the present invention, by appropriately adjusting the thickness and porosity of the film, it is possible to obtain a preparation with a desired dissolution rate. If the drug is desired to have a medicinal effect, the coating should be thinner and the porosity should be increased (and if the drug is desired to be released continuously for a long time, the coating should be thicker and the porosity should be increased). Just make it smaller.

Furthermore, the pharmaceutically active ingredient that can be contained in the core substance is not particularly limited as long as it is an orally administrable drug. Such pharmaceutical active ingredients include, for example, vitamins, amino acids, peptides, chemotherapeutic agents, antibiotics, respiratory stimulants, antitussive expectorants, antineoplastic agents, agents for autonomic nerves, agents for psychiatric nerves, 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. drugs, anticoagulants, liver drugs, hypoglycemic agents, antihypertensive agents, etc. Also,
The core material usually contains various compounding agents commonly used in this field,
For example, binders, excipients, anti-aggregation agents, buffers, etc. may be included.

Examples of excipients include sugars such as lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate, and calcium lactate; examples of binders include polyvinyl alcohol, polyacrylic acid, and polymethacrylate. acid, polyvinylpyrrolidone,
Glucose, white tang, milk tL barley WtL sorbitol,
Examples include mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogols, gum arabic, gelatin, agar, and starch. In addition, as lubricants and anti-aggregation agents, talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hydrogenated oils, polyethylene glycols, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, etc. can give. Furthermore, examples of buffering agents include organic acids such as fumaric acid, succinic acid, citric acid, and malic acid, or salts thereof, in addition to commonly used inorganic salts.

In the preparation of the present invention, the core material of a bare tablet, granule, gunpowder, fine granule, etc. containing a pharmaceutically active ingredient is replaced with a hydrophobic polymeric material, or an aqueous-organic material containing a hydrophobic polymeric material and a hydrophilic polymeric material. It can be manufactured by spray coating with a solvent mixture to form a porous film of the polymer material on the surface of the core material.

Preparation of core materials is described in Remington's Pharmaceutical Science, 17th edition, 1603-1632.16
It can be carried out by conventional formulation techniques such as those described on pages 33-1643 (published by Mark Publishing Company, 1985). For example, the pharmaceutical compound may be mixed with suitable excipients, binders, lubricants, etc., and prepared by wet extrusion granulation, fluidized bed granulation, etc., or the binder may be mixed with water, lower alcohol, etc. (methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, etc.), lower alkanones (acetone, methyl ethyl ketone, etc.), chloroform,
A small amount of the pharmaceutical compound or its mixture with excipients, lubricants, etc. is sprayed onto the core inert carrier particles by dissolving the solution in a suitable solvent such as dichloromethane, dichloroethane or a mixture thereof. It can also be prepared by a transfer granulation method, a pan coating method, a fluidized bed coating method, etc. in which the components are added in batches. In this case, as the inert carrier particles, for example, those manufactured from white sugar, lactose, starch, crystalline cellulose, etc. can be suitably used. The average particle diameter is about 3 (10 μm to about 15 μm)
It is preferable that

When covering the core material thus obtained with a porous membrane,
The organic solvent that forms the mixed solvent with water is not particularly limited and can be used as long as it dissolves the hydrophobic polymeric substance, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-propyl alcohol, n7 Examples include lower alcohols such as methyl alcohol, lower alkanones such as acetone and methyl ethyl ketone, and acetonitrile. Among these, more preferred solvents are lower alcohols, and particularly preferred solvents are ethyl alcohol and isopropyl alcohol. The mixing ratio of water and organic solvent can be changed as appropriate within the range of 9 to 0.5 volumes of organic solvent per 1 volume of water, and depending on the ratio, hydrophobic polymeric substances or hydrophobic polymeric substances can be mixed. The porosity of the porous membrane made of the hydrophilic polymer material and the hydrophilic polymer material can be adjusted as desired. Generally speaking, the porosity of a porous membrane increases as the proportion of water in the water-organic solvent mixture increases, and decreases as the proportion of organic solvent increases.

The concentration of the hydrophobic polymer substance in the water-organic solvent mixture is about 2~
Preferably, it is 30 W/W/%. Also, when a hydrophobic polymeric substance and a hydrophilic polymeric substance are used together, it is preferable that the concentration of the artist's molecular substance is within the above range.

Spray coating can be carried out by conventional coating methods. For example, a coating liquid in which a hydrophobic polymer substance or a hydrophobic polymer substance and a hydrophilic polymer substance are dissolved in a mixture of water and an organic solvent is coated on the core material by, for example, a fluidized bed coating method or a pan coating method. This can be easily done by spray coating. For example, when using the pan coating method, the core material is placed in a coating pan, and while the coating pan is rotated, a hydrophobic polymer material or water containing a hydrophobic polymer material and a hydrophilic polymer material is sprayed from a spray gun nozzle. This can be carried out by spraying an organic solvent mixture at an appropriate rate and then drying.

At this time, if desired, talc, titanium dioxide, etc. can be added as an anti-aggregation agent.

The thus obtained controlled-release preparation of the present invention may be administered as is, or if the preparation is in the form of granules or fine particles, it may be filled into a capsule or the like and administered.

Since the formulation of the present invention has a porous film, body fluids permeate into the formulation immediately after administration, and dissolution of the pharmaceutically active ingredient begins, resulting in a rapid onset of release. Moreover, since the porosity of the porous membrane can be adjusted at the same time, adjusting the porosity not only improves the rise time but also makes it possible to control the release rate, unlike conventional formulations. It has excellent advantages not found in other countries. Specifically, for example, when the main effect of the active pharmaceutical ingredient and the concentration at which side effects occur are close to each other and the concentration range needs to be kept within a narrow range, or when it is necessary to maintain a constant blood concentration for a long period of time. The desired concentration and release time can be obtained by reducing the porosity. In addition, if it is necessary to give the pharmaceutically active ingredient immediate effect, by covering it with a highly porous film, the pharmaceutically active ingredient can be eluted immediately after administration. Furthermore, in preparations coated with a porous membrane consisting of a hydrophobic polymeric substance and a hydrophilic polymeric substance, the medicinal ingredient elutes quickly after administration, and the hydrophilic polymeric substance that forms part of the porous membrane layer also dissolves, and the porosity of the membrane itself becomes even greater, allowing the release of pharmaceutically active ingredients in a short period of time.

In addition, the formulation of the present invention is comparable to conventional formulations having a dense hydrophobic film in terms of moisture resistance, light shielding properties, water resistance, abrasion resistance, etc.

As described above, the formulation of the present invention has excellent release control that solves the problems of conventional coatings with hydrophobic polymer substances, and also exhibits excellent effects while maintaining the advantages of conventional formulations. .

Experimental Example +11 Preparation of Preparation 1 kg of non-barrel (trade name of crystalline white sugar, manufactured by Freund) with a particle size of 710 to 840 μm was placed in a centrifugal fluid granulator (CF-
360EX (manufactured by Freund) and was transferred to a new location, and a white tJ! 4 (water-ethanol solution containing 10g (
1 kg of diltiazem hydrochloride powder is gradually added while spraying at a weight ratio of 3:1) to coat the area around the non-barrel. Then, to the obtained diltiazem hydrochloride elementary granules,
Ethyl cellulose (ethoxy content, 49.6χ)
3 (10g was mixed with water-ethanol mixture (weight ratio = 3 = 7.
2;8 or 1.5:8.5) Spray the solution dissolved in 2.7 kg while blowing hot air. By each spraying and drying process, preparations containing diltiazem hydrochloride coated with porous ethylcellulose membranes having different porosities are obtained.

(2) Comparison of release rate Each of the preparations obtained above was subjected to a dissolution test based on the paddle method dissolution test specifications of the 11th edition of the Japanese Pharmacopoeia.

(3) Results The results are shown in Table 1 below.

Table 1 (note) Umbrella 2: Porosity was calculated according to the above formula (1).

As is clear from Table 1 above, the formulation (A) using a water-ethanol (3:7) mixture as a solvent during coating had the following properties:
The porosity of the film is so thick that diltiazem hydrochloride can be absorbed by 1 in 24 hours.
(10% elution) For formulations (B) to (C), it is observed that as the ratio of water in the water-ethanol mixture decreases, the porosity decreases and the time required to reach 10% elution increases.

Example 1 Non-barrel 5 (10 g with a particle size of 710 to 840 μm was placed in a centrifugal flow granulator and rolled, and 270 g of white tl.
Theophylline (chemical name: 3,7-sihydro-1,3-dimethyl-1) was sprayed while spraying a solution of
Gradually add 1 kg of fine powder (11-purine-2,6-dione) and coat around the non-barrel. Next, 1 kg of the obtained theophylline granules was placed in a centrifugal flow granulator, and 90 g of ethyl cellulose and 10 g of hydroxypropyl cellulose were mixed with water-ethanol (3:
A solution dissolved in 1.9 kg of the mixture of 7) is sprayed while blowing hot air. Then, by drying, 1.1 kg of controlled-release theophylline granules coated with a porous ethylcellulose-hydroxypropylcellulose membrane are obtained.

The resulting formulation had a film porosity of 0.81.

Example 2 1 kg of a non-barrel with a particle size of 710 to 840 μm was placed in a centrifugal fluid granulator, and 1 kg of sodium salicylate powder was added to it while spraying 8 (10 g) of a water-ethanol mixture containing 10 g of White W4 (1 kg). Gradually add the sodium salicylate raw granules 5 (10 g) to a centrifugal fluid granulator, and while blowing air and transferring the ethyl cellulose 1 (
A mixture of 10 g of water-ethanol (2:8) mixed solution 9 (10 g) and 50 g of talc added thereto is sprayed while blowing hot air. After spraying, the mixture is dried and coated with a porous ethyl cellulose membrane. Obtain Controlled Sodium Salicylate Granules 6 (10 g).

The resulting formulation had a film porosity of 0.68.

Example 3 Particle size 5 (10-71017 m non-barrel 1.33 k
g into a centrifugal fluid granulator, and add 652 g of white sugar to it.
(+)-(2S,3S)- while spraying a solution prepared by dissolving g in 1957 g of water-ethanol (3:1) mixture.
3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5
11) A mixture of 1 kg of fine powder of -one maleate and 1.67 kg of succinic acid is gradually added and coated around the non-barrel.

Next, 2 kg of the obtained elementary granules were transferred to a centrifugal fluid granulator, and a solution of 190 g of ethyl cellulose and 10 g of hydroxypropyl cellulose dissolved in 1.8 kg of a water-ethanol (3:7) mixture was heated therein. Spray while blowing in the wind. Then, by drying, 2.2 kg of controlled release granules coated with a porous ethylcellulose-hydroxypropylcellulose membrane are obtained.

The resulting formulation had a film porosity of 0.85.

Example 4 Diltiazem hydrochloride 3 (10 g), lactose 611 g, and corn starch 150 g are mixed, and a mixture of 30 g polyvinylpyrrolidone and water 1 (10) is added, kneaded, and sized to prepare granules for tabletting. Add 8g of magnesium stearate to this and use a rotary tablet press (RT F-9).
-2 type, manufactured by Kikusui Seisakusho) to produce tablets with a diameter of 811 mm. Obtained uncoated tablets containing diltiazem hydrochloride 5 (10g
into a coach bread, and add a water-ethanol mixture (3:7) containing 5 W/Wx of ethyl cellulose.
Spray 1.0 kg at room temperature. Then, by drying, controlled-release diltiazem hydrochloride tablets coated with a porous ethylcellulose membrane are obtained.

The resulting formulation had a film porosity of 0.67.

Example 5 Theophylline granules 5 (10
g into a centrifugal fluid granulator, and add 5 ml of ethyl cellulose to it.
0 g to water-ituburobanol mixture '1 (1 (4:6) 95
A solution dissolved in 0 g is sprayed while blowing hot air. Then, by drying, about 550 g of controlled release theophylline granules coated with a porous ethylcellulose membrane are obtained.

The resulting formulation had a film porosity of 0.78.

Example 6 Sodium salicylate base granules obtained in the same manner as in Example 2 5 (10 g was placed in a fluidized bed coating device, cellulose acetate) 1 (10 g was dissolved in a water-acetone (2:8) mixture 9 (10 g) Then, a mixture of 50 g of talc and 50 g of talc is sprayed while blowing hot air. After spraying, the mixture is dried to obtain 10 g of controlled-release sodium salicylate granules 6 coated with a porous cellulose acetate membrane.

The resulting formulation had a film porosity of 0.74.

Example 7 A controlled release type coated with a porous cellulose acetate butyrate membrane was prepared by carrying out the same procedure as in Example 6 except that cellulose acetate butyrate 1 (10 g was used instead of cellulose acetate). Sodium salicylate granules 6 (obtain 10 g).

The resulting formulation had a film porosity of 0.78.

Example 8 1.0 kg of elementary granules obtained in Example 3 was transferred to a centrifugal flow granulator, and a solution of 95 g of ethyl cellulose and 5 g of polyvinylpyrrolidone dissolved in 10 g of water-ethanol <377) was added. is sprayed while blowing hot air. After spraying, the mixture is dried to obtain 1.1 kg of controlled-release granules coated with a porous ethyl cellulose-polyvinylpyrrolidone membrane.

The resulting formulation had a film porosity of 0.81.

Example 9 Using 95 g of ethyl cellulose and 5 g of polyethylene glycol (P E 04 (100)) as a coating agent,
By treating in the same manner as in Example 8, 1.1 kg of controlled release granules subjected to MJI with a porous ethyl cellulose-polyethylene glycol membrane are obtained.

The resulting formulation had a film porosity of 0.79.

Example 10 Using 95 g of ethyl cellulose and 5 g of methyl cellulose as coating agents, the same procedure as in Example 8 was carried out to obtain 1.1 kg of controlled release granules coated with a porous ethyl cellulose-methyl cellulose membrane.

The resulting formulation had a film porosity of 0.82.

Example 11 Using 95 g of ethyl cellulose and 5 g of hydroxypropyl methyl cellulose as coating agents, 1.1 kg of controlled release granules coated with a porous ethyl cellulose-hydroxypropyl methyl cellulose membrane are obtained by the same treatment as in Example 8.

The resulting formulation had a film porosity of 0.76.

Example 12 Using 95 g of ethyl cellulose and 5 g of hydroxypropyl cellulose acetate succinate as a coating agent,
1.1 kg of controlled release granules coated with a porous ethylcellulose-hydroxypropylcellulose acetate succinate membrane are obtained by the same treatment as in Example 8.

The resulting formulation had a film porosity of 0.84.

Example 13 Using 95 g of ethyl cellulose and 5 g of Eudragid L as a coating agent, the same procedure as in Example 8 was carried out to obtain 1.1 kg of controlled release granules coated with a porous ethyl cellulose-Eudragid L membrane.

The resulting formulation had a film porosity of 0.79.

Claims (1)

[Scope of Claims] (1) A controlled-release preparation in which a core material containing a pharmaceutically active ingredient is coated with a porous membrane consisting of a hydrophobic polymeric material or a hydrophobic polymeric material and a hydrophilic polymeric material. 2. The formulation of claim 1, wherein the porous membrane has a porosity of about 0.4 to 0.9. 3. The formulation of claim 1, wherein the porous membrane has a porosity of about 0.5 to 0.85. (4) The preparation according to claim 1 or 2, wherein the porous membrane is a porous membrane made of a hydrophobic polymeric substance. (5) The preparation according to claim 1 or 2, wherein the porous membrane is a porous membrane composed of a hydrophobic polymeric substance and a hydrophilic polymeric substance. (6) The preparation according to claim 5, wherein the porous membrane is a porous membrane consisting of about 0.05 to 0.5 parts by weight of a hydrophilic polymeric substance per 1 part by weight of a hydrophobic polymeric substance. (7) The preparation according to claim 4, wherein the hydrophobic polymeric substance is one selected from the group consisting of cellulose ether, cellulose ester, polyvinyl ester, and acrylic acid polymer having an aminoalkyl group. (8) The hydrophobic polymer substance is a type selected from the group consisting of cellulose ether, cellulose ester, polyvinyl ester, and acrylic acid polymer having a quaternary ammonium alkyl group, and the hydrophilic polymer substance is a water-soluble polymer. 7. The preparation according to claim 6, which is one selected from the group consisting of molecular substances, enteric-coated polymeric substances, gastric-soluble polymeric substances, and gastrointestinal-compatible polymeric substances. (9) The water-soluble polymer substance is a polysaccharide that may have a sulfate group, a polysaccharide that has a hydroxyalkyl group, a polysaccharide that has a carboxyalkyl group,
It is a type selected from the group consisting of methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol, and the enteric polymer substance is a carboxyalkyl cellulose ether, a cellulose derivative having a monoester bond of a dibasic acid, or a cellulose derivative having a monoester bond of a dibasic acid. It is a type selected from the group consisting of polyvinyl derivatives having monoester bonds, maleic acid-vinyl copolymers, and acrylic acid polymers, and the gastrosoluble polymer substance is a cellulose derivative having mono- or di-substituted amino groups, It is a type selected from the group consisting of polyvinyl derivatives having a mono- or di-substituted amino group and acrylic acid polymers having a mono-substituted amino group, and the gastrointestinal-compatible polymer substance is a vinylpyridine-acrylic acid copolymer, 9. The preparation according to claim 8, which is one selected from the group consisting of carboxymethyl polysaccharides and polyvinyl amino acid derivatives having mono- or di-substituted amino groups. (10) The preparation according to claim 9, wherein the porous membrane is a porous membrane consisting of a hydrophobic polymeric substance and a water-soluble polymeric substance, or a hydrophobic polymeric substance and an enteric polymeric substance. (11) The preparation according to claim 10, wherein the porous membrane is a porous membrane consisting of ethyl cellulose and hydroxypropyl cellulose. (12) The preparation according to claim 11, wherein the core substance contains an organic acid together with a pharmaceutically active ingredient. (13) The formulation according to claim 12, wherein the organic acid is succinic acid. (14) Spray coating a core material containing a pharmaceutically active ingredient with a hydrophobic polymeric substance or a water-organic solvent mixture containing a hydrophobic polymeric substance and a hydrophilic polymeric substance to make the surface of the core substance hydrophobic. A method for producing a controlled-release preparation, which comprises forming a porous membrane consisting of a polymeric substance or a hydrophobic polymeric substance and a hydrophilic polymeric substance.