JP2000198747A - Sustained-release particle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain sustained-release particles capable of being prevented from sticking when subjected to compression molding for forming sustained-release tablets for oral administration, by covering a medicament-containing core substance with a coating film comprising a mixture of a hydrophobic organic compound and a water-insoluble polymer. SOLUTION: This sustained-release particle comprises a medicament- containing core substance covered with a coating film comprising a mixture of a hydrophobic organic compound and a water-insoluble polymer, and has an average particle diameter of <=300 μm. The hydrophobic organic compound preferably comprises one or more kinds of compounds selected from the group consisting of a 6-22C higher fatty acid which may have one or more unsaturated bonds (for example, stearic acid), a higher alcohol (for example, lauryl alcohol) and a glycerol ester of the higher fatty acid (for example, glycerol stearate). The water-insoluble polymer preferably comprises one or more kinds of polymers selected from the group consisting of a water-insoluble cellulose derivative (for example, ethyl cellulose), a water-insoluble vinyl derivative (for example, polyvinyl acetate) and a water-insoluble acrylic acid-based polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to sustained release particles for tablets which can effectively control the dissolution of a drug and do not cause sticking during compression molding, and a method for producing the same.
The present invention also relates to a method for producing a tablet using sustained-release particles.

[0002]

2. Description of the Related Art Conventionally, as a method for producing an oral sustained-release preparation, a method of coating a drug-containing core substance with a water-insoluble polymer such as ethyl cellulose is known. Although this formulation has a high dissolution control ability and is excellent in water resistance, moisture resistance, abrasion resistance, storage stability, etc., the film made of only a water-insoluble polymer generally refers to water. When used for highly soluble drugs or microparticles having an average particle diameter of 100 μm or less, an enormous amount of coating is required for elution control. In addition, when the dissolution rate is delayed by increasing the coating amount, there is a problem that the drug is not completely eluted, that is, a so-called elution peaking phenomenon occurs.

On the other hand, Japanese Patent No. 2518882 (issue date:
(July 31, 1996), a long-acting oral preparation in which pellets of an inert material are coated with a drug-containing layer, and the drug-containing layer is further coated with a lipophilic compound such as stearic acid and a hardener such as ethyl cellulose. Is described. However, the preparation described in this patent contains pellets as a core substance,
The average particle diameter is as large as about 1 mm or more. When a tablet is produced using these large particles, the coating layer of the particles tends to be disintegrated during compression molding, making it difficult to control the dissolution of the drug, or has the disadvantage that it is necessary to increase the size of the tablet. Therefore, it is not practical as raw material particles for making tablets.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide sustained-release particles which prevent sticking during compression molding when preparing oral sustained-release tablets, and a method for producing the same.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that when manufacturing sustained-release tablets, the drug-containing core substance is replaced with a hydrophobic organic compound-water-insoluble polymer. By using particles having an average particle diameter of 300 μm or less coated with the mixed film, it is found that it is not necessary to add a lubricant, in order to effectively control the dissolution of the drug and prevent sticking during compression molding, The present invention has been completed.

That is, the present invention provides sustained-release particles having an average particle diameter of 300 μm or less, which is obtained by coating a drug-containing core substance with a mixed film of a hydrophobic organic compound and a water-insoluble polymer.

[0007] The sustained-release particles of the present invention include a step of coating a drug-containing core substance with a hydrophobic organic compound-water-insoluble polymer mixed film to prevent adhesion of fine particles to manufacturing equipment due to static electricity or the like and aggregation between particles. It also has the advantage that it can be prevented.

Further, the sustained-release particles of the present invention can effectively control the dissolution rate of a very water-soluble drug with a small amount of coating.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, examples of the hydrophobic organic compound include a higher fatty acid which may have an unsaturated bond having 6 to 22 carbon atoms and an unsaturated fatty acid having 6 to 22 carbon atoms. Glycerin esters of higher fatty acids which may have an unsaturated bond having 6 to 22 carbon atoms, and the like.

The higher fatty acids which may have an unsaturated bond having 6 to 22 carbon atoms include, for example, stearic acid, capric acid, lauric acid, myristic acid, palmitic acid, undecanoic acid, caproic acid, caprylic acid, arachidine. acid,
Behenic acid, oleic acid, linoleic acid, linolenic acid, and the like. Examples of the higher alcohol that may have an unsaturated bond having 6 to 22 carbon atoms include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, Undecanol, etc., having 6 to 22 carbon atoms.
Examples of the glycerin ester of a higher fatty acid which may have an unsaturated bond include glycerin esters of the higher fatty acid, for example, stearin, myristine, palmitin,
Laurin and the like. Of these, carbon numbers of 6 to 2
Higher fatty acids which may have two unsaturated bonds are preferred, and stearic acid is particularly preferred.

In the present invention, not only one kind of the above-mentioned hydrophobic organic compounds but also a mixture of two or more kinds thereof may be used.

The water-insoluble polymer used in the present invention includes, for example, water-insoluble cellulose derivatives,
Examples include a water-insoluble vinyl derivative and a water-insoluble acrylic acid-based polymer.

Specific examples of the water-insoluble cellulose derivative include ethyl cellulose and cellulose acetate. Examples of the water-insoluble vinyl derivative include polyvinyl acetate,
Examples include water-insoluble acrylic acid-based polymers such as ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer, and methyl methacrylate / ethyl acrylate copolymer. No. Among these, a water-insoluble cellulose derivative is preferable, and ethyl cellulose is particularly preferable.

In the present invention, not only one kind of the water-insoluble polymer but also a mixture of two or more kinds thereof may be used.

In the hydrophobic organic compound-water-insoluble polymer mixed film, the hydrophobic organic compound and the water-insoluble polymer can be used by appropriately combining the above-mentioned respective film agents. A mixture of two or more thereof and a mixture of one or more of the water-insoluble polymers can be used. Among them, preferred combinations include a higher fatty acid having 6 to 22 carbon atoms which may have an unsaturated bond and a water-insoluble cellulose derivative. Particularly preferred combinations include a combination of stearic acid and ethyl cellulose. Is mentioned.

In the mixed film of sustained release particles of the present invention,
The mixing ratio of the hydrophobic organic compound and the water-insoluble polymer and the coverage of the mixed film are not particularly limited, and are appropriately determined according to the effective dose of the drug to be used and the like. In this case, the elution rate is controlled as the ratio of the hydrophobic organic compound to the water-insoluble polymer in the mixed film increases. Also, the elution rate is controlled as the coverage of the mixed film with respect to the drug-containing core material is increased.

The mixing ratio of the hydrophobic organic compound and the water-insoluble polymer in the mixed film may be freely selected, but is usually within the range of 5:95 to 95: 5.
Particularly preferred is a range of 70 to 80:20.

The amount of the mixed film may be freely selected. The amount of coating varies depending on the type and size of the core material. For example, the coating rate (% by weight of the mixed film with respect to the core material) may be in the range of 20 to 200% by weight.
Particularly preferred is a range of 40 to 100% by weight.

A person skilled in the art can easily determine the mixing ratio and the amount of coating so as to obtain a desired dissolution rate by adjusting a preparation having various mixing ratios and coverages and conducting a dissolution test. . The dissolution test may be performed in accordance with the thirteenth revised Japanese Pharmacopoeia (hereinafter referred to as JP) dissolution test method (paddle method).

The average particle size of the sustained-release particles of the present invention is 300
μm or less, of which particles having a particle size of 50 to 250 μm are preferable, and 75 to 150 μm
Those having a particle size of are particularly preferred.

Further, various additives may be blended in the mixed film of the sustained-release particles of the present invention. Examples of such additives include a colorant, a masking agent, a plasticizer, and a lubricant. No.

Examples of the coloring agent include food coloring, lake coloring, caramel, carotene, annat, cochineal, iron dioxide and the like, as well as opaque coloring agent OPALUX mainly containing lake coloring and syrup. Is edible red No.2, No.3, yellow No.4, No.5, green No.3
No. 1, Blue No. 1, No. 2, Purple No. 1, etc., edible aluminum lakes, anat (a natural pigment derived from Acacia catechu), carmine (aluminum carminate), pearl essence (mainly containing guanine) and the like.

Examples of the concealing agent include titanium dioxide, precipitated calcium carbonate, calcium hydrogen phosphate, calcium sulfate and the like.

Examples of the plasticizer include phthalic acid derivatives such as diethyl phthalate, dibutyl phthalate and butyl phthalyl butyl glycolate, as well as silicone oil, triethyl citrate, triacetin, propylene glycol,
Polyethylene glycol and the like.

Examples of the lubricant include magnesium stearate, talc, synthetic magnesium silicate, finely divided silicon oxide and the like.

The amount and timing of addition of these additives can be used without any problems as long as they are within the range based on knowledge commonly used in the field of pharmaceutical technology.

The sustained-release particles of the present invention can be easily obtained by coating a solution obtained by dissolving a hydrophobic organic compound and a water-insoluble polymer in the same solvent and spray-coating the solution onto a drug-containing core material. Can be

The solvent of the coating solution is not particularly limited as long as the hydrophobic organic compound and the water-insoluble polymer can be dissolved together. For example, methanol, ethanol, n-propanol, isopropanol, n-
Alcohols such as butanol, 2-methoxyethanol (trade name; methyl cellosolve, manufactured by Katayama Chemical Industry), 2-ethoxyethanol (trade name: cellosolve, manufactured by Katayama Chemical Industry), hexane, cyclohexane, petroleum ether, petroleum benzine, ligroin , Benzene, toluene, hydrocarbons such as xylene, acetone, ketones such as methyl ethyl ketone, dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, trichloroethylene, 1,
Examples include halogenated hydrocarbons such as 1,1-trichloroethane and the like, esters such as methyl acetate, ethyl acetate and butyl acetate, and ethers such as isopropyl ether and dioxane. These solvents may be selected according to the hydrophobic organic compound and the water-insoluble polymer to be used, and two or more of them may be used by appropriately mixing.

Among these, particularly preferred solvents are alcohols, and among them, ethanol is particularly preferred.

The coating may be carried out using a known coating apparatus. Specific examples of the coating apparatus include a fluidized bed coating apparatus, a centrifugal fluidized bed coating apparatus, and a pan coating apparatus.

The drug-containing core substance used in the present invention comprises a drug alone or a drug and various pharmaceutical additives usually used in this field.

The average particle size of the drug-containing core material is 40 to 2
00 nm, preferably 60-150 n
m.

The drug is not particularly limited as long as it is intended for oral administration. Examples thereof include (1) antipyretic analgesic and anti-inflammatory agents (eg, indomethacin, aspirin, diclofenac sodium, ketoprofen, ibuprofen, mefenamic acid, azulene) Phenacetin, isopropylantipyrine, acetaminophenone, benzadac, phenylbutazone, flufenamic acid, sodium salicylate, salicylamide, sazapyrine, etodolac, etc., (2) steroidal anti-inflammatory agents (eg, dexamethasone, hydrocortisone, prednisolone, triamcinolone, etc.) ), (3) anti-ulcer agents (eg, ecabet sodium, emprostil, sulpiride, cetraxate hydrochloride, gefarnate, irsogladine maleate, cimetidine, hydrochloride) (4) coronary vasodilators (nifedipine, isosorbide dinitrate, diltiazem hydrochloride, trapidil, diviridamol, dilazep hydrochloride, verapamil, nicardipine, nicardipine hydrochloride, veraparimil hydrochloride), etc. 5) Peripheral vasodilators (eg, ifenprodil tartrate, cinepaside maleate)
(6) antibiotics (eg, ampicillin, amoxicillin, cephalexin, erythromycin ethylsuccinate, bacampicillin hydrochloride, minocycline hydrochloride, chlorphenicol, tetracycline, erythromycin, ceftazidime, cefuroxime sodium, Aspoxycillin, lipipenemucoxil hydrate, etc.),
(7) Synthetic antibacterial agents (eg, nalidixic acid, pyromidic acid, pipemidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, sulfamethoxazole / trimethoprim), (8) anti- Viral agents (eg, acyclovir,
Ganciclovir), (9) antispasmodic agents (for example, propantheline bromide, atropine sulfate, oxapium bromide,
Thimepidium bromide, butyl scopolamine bromide, trospium chloride, butropium bromide, N-methylscopolamine methyl sulfate, methyl octalopine bromide, etc.), (10)
Antitussives (eg, tipepidine hibenzanate, methylephedrine hydrochloride, codeine phosphate, tranilast, dextromethorphan hydrobromide, dimemorphane phosphate, clobutinol hydrochloride, hominoben hydrochloride, benproperin phosphate, epradinone hydrochloride, clofedanol hydrochloride, hydrochloride hydrochloride Ephedrine, noscapine, pentoxiverine citrate, oxerazine citrate, isoaminyl citrate, etc., (11) antiseptics (for example, bromhexine hydrochloride, carbocysteine, ethylcysteine hydrochloride, methylcysteine hydrochloride), (12) bronchodilation Agents (eg, theophylline, aminophylline, sodium cromoglycate, procaterol hydrochloride, trimethoquinol hydrochloride, diprofylline, salbutamol sulfate, chlorprenaline hydrochloride, formo fumarate Roll, orciprenaline sulfuric acid, hydrochloric acid pirbuterol, hexoprenaline sulfuric acid,
Vitorterol mesylate, clenbuterol hydrochloride, terbutaline sulfate, mabuterol hydrochloride, fenoterol hydrobromide, methoxyphenamine hydrochloride, (13) cardiotonic agents (for example, dopamine hydrochloride, dobutamine hydrochloride, docarpamine, denopamine, caffeine, digoxin, digitoxin, (14) diuretics (for example, furosemide, acetazolamide, trichlormethiazide, methyclothiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopentiazide, spironolactone, triamterene, florothiazide, piretanide, mefluazotide, mefluazotide, mefluazotide, meflusideide) , Clofenamide, etc.), (15) muscle relaxants (eg, chlorphenesin carbamate, tolperisone hydrochloride, eperisone hydrochloride, chiza hydrochloride) Jin, mephenesin, chlorzoxazone, phenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone,
Baclofen, dantrolene sodium, etc.), (1
6) Brain metabolism improving agents (for example, nicergoline, meclofenoxate hydrochloride, taltirelin, etc.), (17) minor tranquilizers (for example, oxazolam, diazepam, clothiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, chlordiazepoxide, etc.) (18) Major tranquilizers (for example, sulpiride, clocapramine hydrochloride, zotepine, chlorpromazine, haloperidol, etc.), (1)
9) β-blockers (eg, bisoprolol fumarate, pindolol, propranolol hydrochloride, carteolol hydrochloride, metoprolol tartrate, labetanol hydrochloride,
Acebutolol hydrochloride, bufetrol hydrochloride, alprenolol hydrochloride, arotinolol hydrochloride, oxprenolol hydrochloride, nadolol, bucmolol hydrochloride, indenolol hydrochloride, timolol maleate, befnolol hydrochloride, bupranolol hydrochloride, etc.), (20) antiarrhythmic agent (for example,
Procainamide hydrochloride, disopyramide, azimaline, quinidine sulfate, aprindine hydrochloride, propafenone hydrochloride,
Mexiletine hydrochloride, azimilide hydrochloride, etc.), (21)
Gout remedies (eg, allopurinol, probenecid,
Colchicine, sulfinpyrazone, benzbromarone,
(22) blood coagulation inhibitors (eg,
Ticlopidine hydrochloride, dicoumarol, warfarin potassium, (2R, 3R) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-8-methyl-2- (4-methylphenyl) -1 , 5-benzothiazepine-4 (5H) -one maleate, etc.), (2
3) thrombolytic agent (eg, methyl (2E, 3Z) -3-
Benzylidene-4- (3,5-dimethoxy-α-methylbenzylidene) -N- (4-methylpiperazin-1-yl) succinate / hydrochloride, etc., (24) agents for liver diseases (eg, (±) r -5-hydroxymethyl-t-
7- (3,4-dimethoxyphenyl) -4-oxo-
4,5,6,7-tetrahydrobenzo [b] furan-c
-6-carboxylic acid lactone), (25) antiepileptic agent (for example, phenytoin, sodium valproate, metalpital, carbamazepine, etc.), (26) antihistamine (for example, chlorpheniramine maleate, clemastine fumarate, mequitazine, tartaric acid) Alimemazine, cycloheptadine hydrochloride, bepotastine besylate, etc.), (27) an antiemetic (for example, difenidol hydrochloride,
(28) antihypertensives (eg, dimethylaminoethyl reserpine hydrochloride, rescinamine, methyldopa, pralozosine hydrochloride, bunazosin hydrochloride, clondin hydrochloride, budralazine, urapidil, N)
-[6- [2-[(5-Bromo-2-pyrimidinyl) oxy] ethoxy] -5- (4-methylphenyl) -4-
Pyrimidinyl] -4- (2-hydroxy-1,1-dimethylethyl) benzenesulfonamide sodium salt), (29) agents for hyperlipidemia (eg, pravastatin sodium, fluvastatin sodium), (3)
0) Sympathetic stimulants (eg, dihydroergotamine mesylate, isoproterenol hydrochloride, etilephrine hydrochloride, etc.), (31) Oral diabetes therapeutic agents (eg, glibenclamide, tolbutamide, sodium glymidine, etc.),
(32) an oral anticancer agent (for example, Marimastat etc.),
(33) alkaloid narcotics (eg, morphine, codeine, cocaine, etc.), (34) vitamins (eg,
Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B12, Vitamin C, folic acid, etc.), (35) therapeutic agents for pollakiuria (for example, flavoxate hydrochloride, oxybutynin hydrochloride,
And various drugs such as (36) angiotensin converting enzyme inhibitor (for example, imidapril hydrochloride, enalapril maleate, alacepril, delapril hydrochloride, etc.).

There are no particular restrictions on the pharmaceutical additives, and all those that can be used as solid pharmaceuticals can be suitably used. Such additives include excipients such as lactose, sucrose, mannitol, xylitol, erythritol, sorbitol, maltitol, calcium citrate, calcium phosphate, crystalline cellulose, corn starch, potato starch, sodium carboxymethyl starch, partially pregelatinized Starch, carboxymethylcellulose calcium, carboxymethylcellulose,
Disintegrators such as low-substituted hydroxypropylcellulose, crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, dextrin, pregelatinized starch, magnesium stearate, calcium stearate , Talc, light anhydrous silicic acid, lubricants such as hydrous silicon dioxide, and further phospholipids,
Surfactants such as glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sucrose fatty acid ester, or flavors such as orange and strawberry, Iron sesquioxide, yellow iron sesquioxide,
Food Yellow 5, Food Yellow 4, coloring agents such as aluminum chelates, sweeteners such as saccharin and aspartame, flavoring agents such as citric acid, sodium citrate, succinic acid, tartaric acid, fumaric acid, glutamic acid, cyclodextrin, arginine , Lysine, trisaminomethane and the like.

The drug-containing core substance can be prepared by a known granulation method such as wet granulation and dry granulation.

In the case of wet granulation, a drug and various preparation additives are mixed according to a conventional method, and a binder solution is added.
After granulating with a stirring granulator, high-speed stirring granulator, or adding a binder solution to a mixture of a drug and various formulation additives and kneading, granulating and sizing using an extrusion granulator Good. Also,
The mixture of the drug and various formulation additives may be granulated by spraying the binder solution under flow using a fluidized bed granulator, a tumbling stirred fluidized bed granulator, or the like.

In the case of dry granulation, a mixture of a drug and various preparation additives may be granulated using a roller compactor, a roll granulator, or the like.

Further, in the sustained release particles of the present invention,
To prevent the interaction between the drug-containing core material and the mixed film component, or to adjust the elution rate of the drug, a water-soluble substance is added between the core material and the hydrophobic organic compound-water-insoluble polymer mixed film. A layer of a water-insoluble substance, a gastric-soluble substance or the like can be applied.

Examples of the water-soluble substance include water-soluble cellulose ethers such as methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose; water-soluble polyvinyl derivatives such as polyvinylpyrrolidone and polyvinyl alcohol; and alkylene oxide polymers such as polyethylene glycol. Examples of the water-insoluble substance include water-insoluble cellulose ethers such as ethyl cellulose, and ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer (for example, trade name: Eudragit RS,
Water-insoluble acrylic acid-based copolymers such as methyl methacrylate / ethyl acrylate copolymer (for example, trade name: Eudragit NE30D, manufactured by Laem Pharma), and hardened oil. Examples of the soluble substance include gastric soluble polyvinyl derivatives such as polyvinyl acetal diethylaminoacetate, and methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (for example, trade name: Eudragit E, manufactured by Laem Pharma). Gastric-soluble acrylic acid-based copolymer.

The sustained-release particles of the present invention thus obtained are
It can be used as raw material particles for tablets, and after adding various additives as necessary, it can be compressed and formed into tablets by a conventional method, but for oral administration in various forms such as fine granules and suspensions It can also be used as a formulation. The tablet can be produced by, for example, a usual production method. Specifically, an excipient (eg, mannitol, crystalline cellulose, lactose, sucrose, calcium phosphate, calcium citrate, etc.) and a binder (eg, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, dextrin, etc.) are mixed or mixed. After preliminarily producing the kneaded granules for compression molding, the granules can be mixed with sustained-release particles and compression-molded. The compression molding can be carried out using an ordinary tableting machine, for example, a rotary tableting machine. The tableting speed can be suitably carried out under ordinary conditions at 10 to 50 rpm. The tableting pressure is a normal tableting pressure, 200 to 1
It is preferable to set in the range of 100 kg / punch.

The obtained compression-molded preparation may be, if desired, formed into a coated tablet by sugar coating or film coating, and the coating may be carried out by a conventional method.

Hereinafter, the present invention will be described in more detail with reference to Comparative Examples and Examples, but the present invention is not limited thereto.

[0043]

EXAMPLES Example 1 (1) Preparation of core particles Hydroxypropyl was added to 100 g of diltiazem hydrochloride, 50 g of mannitol and 50 g of crystalline cellulose (grade: PH-M25, manufactured by Asahi Kasei) using a stirring granulator (Powrex). 400 g of a water-ethanol mixed solution (ethanol content 80% by weight) in which 4 g of cellulose (grade: HPC-SL, manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved, and granulated;
After drying, the particles were sized to obtain core particles having an average particle diameter of 79 μm.

(2) Preparation of Sustained-Release Particles A Wurster-type fluidized bed granulation coating apparatus (Glatt)
100g of the obtained core particles using GPCG-1)
On the other hand, a solution obtained by dissolving 25 g of ethyl cellulose (grade: # 10, manufactured by Dow Chemical Company) and 25 g of stearic acid in 1000 g of ethanol has a coverage of 20%, 30% or 40% by weight on the core particles. By coating as described above, three types of particles coated with ethyl cellulose and stearic acid and having different coverages were obtained.
The average particle diameter was 300 μm or less in all cases.

(3) Dissolution test According to the dissolution test (paddle method) of the thirteenth revised Japanese Pharmacopoeia, the particles obtained above were subjected to the Japanese Pharmacopoeia disintegration test second solution (pH
6.8) Using 900 ml, 37 ° C., paddle rotation speed 10
The dissolution test was performed under the condition of 0 rpm. The result is shown in FIG.

(4) Results and Discussion The dissolution behavior of the above three types of preparations is as shown in FIG.
For example, 50% elution time is 11.7 hours for particles coated so that the coating ratio with respect to the core particles is 40% by weight, the elution rate is sufficiently controlled, and almost no elution peaks. Did not. Also, when coating the coating layer, almost no static electricity was generated, and adhesion of particles to the wall of the apparatus was hardly observed. Further, at the time of coating, aggregation between particles is small, and for example, the coating rate is 4%.
In the particles coated so as to be 0% by weight, the obtained sustained-release particles had an average particle diameter of 116 μm and the distribution of particles of 80 mesh or more was only 8.3%.

Example 2 (1) Preparation of sustained-release particles Ethyl cellulose (grade: # 10, manufactured by Dow Chemical Co.) and 80 g of stearic acid in ethanol 20
Example 1 (1) except that a solution dissolved in 00 g was used.
And by treating in the same manner as in (2) and coating the core particles so as to have a coating ratio of 30% by weight, 60% by weight or 80% by weight, so that the coating ratio of ethyl cellulose and stearic acid is different. Different kinds of particles were obtained. The average particle diameter was 300 μm or less in all cases.

(2) Results of Dissolution Test and Discussion The results of the same dissolution test as in Example 1 (3) are shown in FIG. For example, when the coverage of the core particles is 80,
The 50% elution time of the particles coated so as to have a weight percentage of 9.5 hours was 9.5 hours, the elution rate was sufficiently controlled, and the elution amount after 24 hours was 92%. Was hardly recognized. Also, when coating the coating layer, almost no static electricity was generated, and adhesion of particles to the wall of the apparatus was hardly observed.

Example 3 (Preparation of tablets containing sustained-release particles) Using a Shinagawa mixer (manufactured by Shinagawa Kogyo KK), 300 g of mannitol and polyvinylpyrrolidone (grade: # 3)
0, BASF) (18 g). The obtained granules were sized with 12-mesh and 24-mesh sieves, and then dried to obtain 30 g of granules for compression molding.

A mixture of 150 g of the particles obtained in Example 1 and 225 g of granules for compression molding was mixed with a rotary tableting machine (F-9).
Using a mold, manufactured by Kikusui Seisakusho Co., Ltd.)
As a result of compression molding with a tableting pressure of 400 kg / punch, sticking did not occur, and tablets containing sustained release particles having a diameter of 16 mm and a weight of 375 mg per tablet were obtained.

Comparative Example 1 (1) Preparation of Particles A Wurster-type fluidized bed granulation coating apparatus (Glatt)
A solution prepared by dissolving 200 g of ethylcellulose (grade: # 10, manufactured by Dow Chemical Company) in 4000 g of ethanol with respect to 100 g of the core particles obtained in Example 1 (1) using GPCG-1). By coating the core particles so that the coating ratio was 30% by weight, 100% by weight, or 160% by weight, three types of particles coated with ethyl cellulose and having different coating ratios were obtained.

(2) Results of Dissolution Test and Discussion The results of the same dissolution test as in Example 1 (3) are shown in FIG. For example, the coverage ratio for the core particles is 160
Even in particles coated to be 50% by weight, 50%
The elution time was 2.3 hours, and the elution rate could not be controlled sufficiently. Further, when coating the coating layer, extremely strong static electricity was generated, and adhesion of the particles to the wall of the apparatus was observed.

Further, during the coating, remarkable agglomeration between the particles was observed. For example, in the particles coated so as to have a coating rate of 30% by weight, the obtained sustained-release particles had an average particle size of 137 μm and 80%. The distribution of particles larger than the mesh is also 21.
7%.

[0054]

The sustained-release particles of the present invention can control the elution of a drug extremely efficiently. Further, static electricity is not generated when the sustained-release particles of the present invention are produced, so that adhesion of the particles to the wall of the production machine and aggregation between the particles can be prevented. Furthermore, since sticking does not occur when tablets are produced by tableting the sustained-release particles of the present invention, there is also a feature that addition of a lubricant is unnecessary.

[Brief description of the drawings]

FIG. 1 is a graph showing the elution behavior of diltiazem hydrochloride from sustained release particles coated with ethyl cellulose-stearic acid = 1: 1 in a second liquid.

FIG. 2 is a graph showing the elution behavior of diltiazem hydrochloride from sustained release particles coated with ethyl cellulose-stearic acid = 4: 1 in a second liquid.

FIG. 3 is a graph showing the elution behavior of diltiazem hydrochloride from ethyl cellulose-coated particles in a second liquid.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/38 A61K 9/14 (72) Inventor Kosuke Yoshino 2-8-A9 Yamada Nishi, Suita-shi, Osaka −101 (72) Inventor Masakazu Mizobe 29-5 Minami-Ohi-cho, Takatsuki-shi, Osaka

Claims (11)

[Claims] 1. The method according to claim 1, wherein the drug-containing core substance is a hydrophobic organic compound
Sustained-release particles coated with a water-insoluble polymer mixed film and having an average particle size of 300 μm or less. 2. A higher fatty acid, wherein the hydrophobic organic compound may have an unsaturated bond having 6 to 22 carbon atoms,
1 selected from the group consisting of 22 higher alcohols which may have an unsaturated bond and glycerin esters of higher fatty acids which may have 6 to 22 carbon atoms and an unsaturated bond;
One or two or more, wherein the water-insoluble polymer is one or two selected from the group consisting of a water-insoluble cellulose derivative, a water-insoluble vinyl derivative and a water-insoluble acrylic acid-based polymer.
The sustained-release particles according to claim 1, which are at least one species. 3. The higher fatty acid which may have an unsaturated bond having 6 to 22 carbon atoms includes stearic acid, capric acid, lauric acid, myristic acid, palmitic acid, undecanoic acid, caproic acid, caprylic acid, and arachidine. Acids, behenic acid, oleic acid, linoleic acid or linolenic acid, and higher alcohols which may have an unsaturated bond having 6 to 22 carbon atoms are lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol or undecanol Wherein the glycerol ester of a higher fatty acid which may have an unsaturated bond having 6 to 22 carbon atoms is stearin, myristine, palmitin or laurin;
The water-insoluble cellulose derivative is ethyl cellulose or cellulose acetate, the water-insoluble vinyl derivative is polyvinyl acetate or polyvinyl chloride, and the water-insoluble acrylic acid-based polymer is ethyl acrylate / methyl methacrylate / methacrylate. The sustained-release particles according to claim 2, which are a trimethylammonium ethyl copolymer or a methyl methacrylate / ethyl acrylate copolymer. 4. The method according to claim 1, wherein the hydrophobic organic compound is stearic acid, and the water-insoluble polymer is ethyl cellulose.
The sustained release particles according to the above. 5. The hydrophobic organic compound / water-insoluble polymer mixed film according to claim 1, wherein the mixture ratio of the hydrophobic organic compound and the water-insoluble polymer is in the range of 5:95 to 95: 5. A sustained-release particle according to any one of the preceding claims. 6. The sustained-release particles according to claim 1, wherein the coverage of the hydrophobic organic compound-water-insoluble polymer mixed film is in the range of 20 to 200% by weight. 7. The sustained-release particles according to claim 1, which are raw particles for tablets. 8. A drug-containing core substance, comprising a hydrophobic organic compound
A method for producing sustained-release particles having an average particle diameter of 300 μm or less, which comprises spray-coating a solution containing a water-insoluble polymer mixture. 9. The hydrophobic organic compound, wherein the higher fatty acid, which may have an unsaturated bond having 6 to 22 carbon atoms, has 6 to 22 carbon atoms,
1 selected from the group consisting of 22 higher alcohols which may have an unsaturated bond and glycerin esters of higher fatty acids which may have 6 to 22 carbon atoms and an unsaturated bond;
One or two or more, wherein the water-insoluble polymer is one or two selected from the group consisting of a water-insoluble cellulose derivative, a water-insoluble vinyl derivative and a water-insoluble acrylic acid-based polymer.
9. The method for producing sustained-release particles according to claim 8, which is at least one species. 10. A drug-containing core substance is spray-coated with a solution containing a mixture of a hydrophobic organic compound and a water-insoluble polymer, and compression molded using the obtained sustained-release particles having an average particle diameter of 300 μm or less. A method for producing a tablet, comprising: 11. The hydrophobic organic compound has 6 to 22 carbon atoms.
Higher fatty acid optionally having an unsaturated bond, having 6 carbon atoms
One or more selected from the group consisting of a higher alcohol which may have an unsaturated bond of from 22 to 22 and a glycerin ester of a higher fatty acid which may have an unsaturated bond having 6 to 22 carbon atoms. The tablet manufacturing method according to claim 10, wherein the water-insoluble polymer is at least one member selected from the group consisting of a water-insoluble cellulose derivative, a water-insoluble vinyl derivative, and a water-insoluble acrylic acid-based polymer.