JP2001055322A - Pulse release type preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pulse release type preparation capable of rapidly releasing a drug at a desirable part in the digestive tract even when the drug is administrated at high doses or is slightly soluble by coating a core substance containing the drug and a water-swelling substance with a film comprising a specific polymer mixture. SOLUTION: This pulse release type preparation is obtained by coating (A) a core substance containing (i) a drug and (ii) a water-swelling substance with (B) a film containing (iii) an enteric polymer and (iv) a water-insoluble polymer. On this preparation, it is favorable that the difference between T 10 and T 90 in Japanese pharmacopoeia disintegration test second solution is not more than 3 hr. Further on this preparation, it is favorable that the formulation amount of the component ii in the component A is 1-29 wt.%, the coating proportion of the component B is 1-200 wt.% and, in addition, the weight ratio between the components iii and iv is 95:5 to 5:95. This preparation is effectively applicable to a high dosage drug administrated at a single dose of more than 0.2 g or a slightly soluble drug with a water solubility of not more than 0.01 g/ml.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an oral solid preparation for rapidly releasing a drug, especially a poorly soluble drug or a high-dose drug, at a desired site in the digestive tract.

[0002]

2. Description of the Related Art In order to selectively deliver a drug to an appropriate site in the gastrointestinal tract, a release time of the drug is controlled by using a transit time of the drug in the gastrointestinal tract. Various oral administration preparations having pulse-type release characteristics such that the drug is rapidly released after reaching a desired site in the digestive tract have been studied.

For example, (1) JP-A-8-26977 and JP-A-8-143476 disclose that a drug-containing nucleus is coated with a mixture of a water-insoluble polymer and an enteric polymer, and in a low pH region such as the stomach. Does not release any drugs,
Preparations are described that release the drug only after a certain period of time (lag time), that is, after the preparation reaches the desired site in the intestine, only in a relatively neutral pH range, such as in the intestine.

[0004] However, in the above-mentioned preparations, since the drug's membrane permeability is an important factor in determining the dissolution characteristics, when applied to poorly soluble drugs, the release behavior of releasing the entire drug immediately after a certain period of time has elapsed. There was a problem that can not be obtained.

On the other hand, Japanese Patent Application Laid-Open No. Sho 62-30709 describes a sustained-release preparation in which a core containing a drug and a water-swellable substance is coated with a water-insoluble coating substance. In this preparation, after administration, the water-swellable substance expands in the gastrointestinal tract due to water gradually penetrating the water-insoluble coating substance, and the swelling force breaks the film of the water-insoluble coating substance, thereby rapidly releasing the drug. However, in order to start the release of the drug after a certain period of time after administration, it is necessary to provide a water-insoluble coating substance film having a certain thickness,
In order to rupture this, a large amount of water-swellable substance is required, and when applied to a high-dose drug, there has been a problem that the dosage of the administered preparation is inevitably increased and the ingestibility is reduced.

[0006] Therefore, there has been a demand for a preparation which can release a drug at a desired site in the gastrointestinal tract quickly even with a poorly soluble or high-dose drug, and which has good ingestibility.

[0007]

DISCLOSURE OF THE INVENTION The present invention aims to provide a preparation capable of rapidly releasing a drug even at a high dose or poorly soluble at a desired site in the digestive tract. is there.

[0008]

Means for Solving the Problems The present inventors have developed a preparation in which a core material containing a drug and a water-swellable substance is coated with a film composed of a mixture of a water-insoluble polymer and an enteric polymer. In the low pH region, the drug is not released at all, and only in the relatively neutral pH region such as the small intestine and large intestine, the film gradually weakens and the core material due to the moisture that has permeated the film The film ruptures due to the increase in the volume of the water-swellable substance, and the drug is released quickly (pulse release)
And completed the present invention.

In the preparation of the present invention, since a water-swellable substance for rupture of the film is incorporated into the core material, even if the drug is hardly soluble, the intestinal release is not suppressed by the film without inhibiting the drug release. It can be released quickly at the desired site in the stomach, and because the film gradually weakens in the intestine, the amount of the water-swellable substance required to rupture it is small. Often, even with high doses of the drug, the formulation can be miniaturized and do not impair ingestibility.

[0010] That is, the present invention is a pulsed release preparation in which a core substance containing a drug and a water-swellable substance is coated with a film containing an enteric polymer and a water-insoluble polymer.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a core substance is a drug,
The form is not particularly limited as long as it contains a water-swellable substance, and may be, for example, a granular material such as fine granules or granules, or a tablet.

The drug is not particularly limited as long as it is intended for oral administration. Examples thereof include (1) antipyretic analgesic and anti-inflammatory drugs (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 hibenzate, methylephedrine hydrochloride, codeine phosphate, tranilast, dextromethorphan hydrobromide, dimemorphane phosphate, clobutinol hydrochloride, hominoben hydrochloride, benproperin phosphate, epradinone hydrochloride, clofedanol 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, etc., (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
(25) antiepileptic agents (eg, phenytoin, sodium valproate, metalpital, carbamazepine), (26) antihistamines (eg, 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, resinamine, 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) Sympathomimetics (eg, dihydroergotamine mesylate, isoproterenol hydrochloride, etilephrine hydrochloride, 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) Frequent urinary treatment (eg, flavoxate hydrochloride, oxybutynin hydrochloride,
And various drugs such as (36) angiotensin converting enzyme inhibitor (eg, imidapril hydrochloride, enalapril maleate, alacepril, delapril hydrochloride).

In the preparation of the present invention, the drug is not particularly limited, but a high-dose drug, for example, a drug having a dose of 0.2 g or more per dose, or a poorly soluble drug, for example, having a solubility in water of 0.1 g. The desired release pattern is obtained even when applied to drugs below 01 g / ml.

Examples of such a drug include docarpamine and 5-aminosalicylic acid, which are high-dose and hardly soluble, and indomethacin as a hardly soluble drug.

The amount of the drug in the core substance is not particularly limited, and may be appropriately selected within the range of 1 to 200% by weight based on the core substance.

The water-swellable substance is not particularly limited as long as it is a substance which swells with water, but disintegrants usually used in the technical field of pharmaceutical preparations can be suitably used.

Specific examples of the above-mentioned disintegrants include water-swellable cellulose derivatives such as carboxymethylcellulose, carboxymethylcellulose calcium, crosslinked sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose, starches such as corn starch, and partially pregelatinized. Water-swellable starch derivatives such as starch and sodium carboxymethyl starch; and water-swellable polyvinyl derivatives such as cross-linked polyvinylpyrrolidone.

The amount of the water-swellable substance in the core substance is not particularly limited. However, the preparation of the present invention requires a water-swellable substance to be ruptured in the intestine because the film becomes brittle with time. Is not necessary to be incorporated in a large amount, and usually in the range of 1 to 29% by weight with respect to the core substance, it is sufficient, particularly preferably in the range of 5 to 10% by weight.

The core substance may contain, in addition to the drug and the water-swellable substance, various pharmaceutical additives usually used in this field. Examples of such pharmaceutical additives include lactose, sucrose, and the like. Excipients such as mannitol, xylitol, erythritol, sorbitol, maltitol, calcium citrate, calcium phosphate, crystalline cellulose, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, dextrin, pregelatinized starch, stearin Lubricants such as magnesium phosphate, calcium stearate, talc, light anhydrous silicic acid, and hydrous silicon dioxide, as well as phospholipids, glycerin fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene fatty acid esters Surfactants such as 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, edible yellow No. 5, Food Yellow 4, coloring agents such as aluminum chelate, saccharin, sweeteners such as aspartame, citric acid, sodium citrate, flavoring agents such as succinic acid, tartaric acid, fumaric acid, glutamic acid, cyclodextrin, arginine,
Solubilizing agents such as lysine and trisaminomethane are exemplified.

In the present invention, the water-insoluble polymer in the film containing the water-insoluble polymer and the enteric polymer is a polymer which is generally known in the field of pharmaceutical technology as a polymer which is hardly dissolved in water independently of pH. Any of them can be suitably used, and examples thereof include a water-insoluble cellulose derivative, a water-insoluble vinyl derivative, and a water-insoluble acrylic acid polymer. Specific examples of the water-insoluble cellulose derivative include water-insoluble cellulose ethers such as ethyl cellulose, and water-insoluble cellulose esters such as cellulose acetate. Specific examples of the water-insoluble vinyl derivative include polyvinyl acetate and polyvinyl chloride. Specific examples of the water-insoluble acrylic acid-based polymer include ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate copolymer (for example, trade names; Eudragit RS, Eudragit RSL, Laem Pharma Co., Ltd.). Manufactured), methyl methacrylate-ethyl acrylate copolymer (for example,
(Product name: Eudragit NE, manufactured by Laem Pharma)
And the like.

Among these, preferred water-insoluble polymers include a water-insoluble cellulose derivative and a water-insoluble acrylic acid polymer.
Ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate copolymer is particularly preferred. In addition, as the enteric polymer, those which can be usually used for coating a preparation in the field of preparation technology,
Polymers that dissolve in water at about 5 to 7 but are substantially insoluble in water at a pH below this point. Examples of such a polymer include an enteric cellulose derivative, an enteric starch sugar derivative, an enteric natural polymer compound, an enteric polyvinyl alcohol derivative, an enteric maleic polymer, and an enteric acrylic polymer. Examples of the enteric cellulose derivative include an ester of cellulose or a derivative thereof and an organic acid, and examples of the organic acid include acetic acid, phthalic acid, succinic acid, and maleic acid. Specific examples of the enteric cellulose derivative include cellulose acetate phthalate, cellulose acetate succinate, cellulose benzoate phthalate, methyl cellulose phthalate, ethyl hydroxyethyl cellulose phthalate, cellulose acetate maleate, hydroxyethyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl Methylcellulose acetate succinate-L, hydroxypropylmethylcellulose acetate succinate-M, hydroxypropylmethylcellulose acetate succinate-H
Etc.), hydroxypropylmethylcellulose phthalate, polyoxyethylcellulose phthalate, cellulose propionate, carboxymethylethylcellulose and the like.

Examples of the enteric starch derivative include an ester of starch or amylose and an organic acid, particularly preferably an ester of acetic acid, phthalic acid, succinic acid, maleic acid and the like. Specific examples of the enteric starch derivative include, for example, starch acetate phthalate, amylose acetate phthalate and the like. Specific examples of the enteric natural polymer compound include shellac and the like. Examples of the enteric polyvinyl alcohol derivative include an ester of polyvinyl alcohol and an organic acid, and examples of the organic acid include acetic acid, phthalic acid, succinic acid, and maleic acid. Specific examples of the enteric polyvinyl alcohol derivative include, for example, polyvinyl alcohol phthalate, polyvinyl alcohol acetate phthalate, polyvinyl propionate phthalate, polyvinyl butyrate phthalate, polyvinyl acetal phthalate, polyvinyl acetoacetal phthalate, polyvinyl acetoacetal succinate, polyvinyl acetal diethylamino Acetate and the like. Examples of the enteric maleic acid-based polymer include a copolymer of maleic anhydride and a vinyl monomer, and examples of the vinyl monomer include vinyl acetate, styrene, vinyl methyl ether, and acrylic acid. Specific examples of the enteric maleic acid polymer include, for example, vinyl acetate / maleic acid copolymer, styrene / maleic acid copolymer, ethylene / styrene / maleic acid copolymer, acrylonitrile / methyl acrylate / maleic acid copolymer And butyl acrylate / styrene / maleic acid copolymer, vinyl methyl ether / maleic acid copolymer.

Examples of the enteric acrylic acid-based polymer include copolymers composed of acrylic acid, methacrylic acid or esters thereof. Specific examples of the enteric acrylic polymer include styrene / acrylic acid copolymer, acrylic acid / methyl acrylate copolymer, methacrylic acid / methyl acrylate copolymer, and methacrylic acid / methyl methacrylate copolymer. Polymers (eg, trade names;
Eudraggid L100, Eudraggid S, Laem
Pharma Co., Ltd.), methacrylic acid / ethyl acrylate copolymer (for example, trade name; Eudragit L100-5)
5, Eudragged L30D-55, manufactured by Rohm Pharma Co., Ltd.), and acrylic acid / butyl acrylate copolymer.

Among these, preferred enteric coating agents include enteric cellulose derivatives, enteric natural high molecular compounds, enteric acrylic polymers, and the like. Specifically, enteric cellulose derivatives include: Cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, etc., as enteric natural polymer compounds, shellac, etc., as enteric acrylic polymer, meta Acrylic acid / methyl methacrylate copolymer, methacrylic acid / ethyl acrylate copolymer and the like can be mentioned. Among these, more preferred enteric coating agents include enteric cellulose derivatives and enteric acrylic polymers, most preferably hydroxypropylmethylcellulose acetate succinate, methacrylic acid / methyl methacrylate copolymer. And methacrylic acid / ethyl acrylate copolymer. These enteric polymers may be used alone or in combination of two or more.

As the combination of the water-insoluble polymer and the enteric polymer in the film containing the water-insoluble polymer and the enteric polymer, a combination of the water-insoluble cellulose derivative and the enteric cellulose derivative (for example, ethyl cellulose and hydroxypropylmethyl cellulose acetate succinate) Combinations, combinations of ethylcellulose and hydroxypropylmethylcellulose phthalate, combinations of ethylcellulose and carboxymethylethylcellulose, combinations of ethylcellulose and cellulose acetate phthalate), combinations of water-insoluble cellulose derivatives and enteric starch derivatives (eg, ethylcellulose and starch acetate phthalate) Combinations), water-insoluble cellulose derivatives and enteric-coated natural polymers Combination with a compound (for example, a combination of ethyl cellulose and shellac), combination of a water-insoluble cellulose derivative and an enteric polyvinyl alcohol derivative (for example, combination of ethyl cellulose and polyvinyl alcohol phthalate, combination of ethyl cellulose and polyvinyl alcohol acetate phthalate) A combination of a water-insoluble cellulose derivative and an enteric maleic acid-based polymer (for example, a combination of ethyl cellulose and a vinyl acetate-maleic acid copolymer, a combination of ethyl cellulose and a styrene-maleic acid copolymer), and a water-insoluble cellulose derivative. Combinations with enteric acrylic polymers (for example, combinations of ethyl cellulose with methacrylic acid / methyl methacrylate copolymer, Such as a combination of cellulose acetate and a methacrylic acid / ethyl acrylate copolymer), a combination of a water-insoluble vinyl derivative and an enteric cellulose derivative (eg, a combination of polyvinyl acetate and hydroxypropylmethylcellulose acetate succinate), water A combination of an insoluble vinyl derivative and an enteric starch derivative (for example, a combination of polyvinyl acetate and starch phthalate), a combination of a water-insoluble vinyl derivative and an enteric natural polymer compound (for example, a combination of polyvinyl acetate and shellac) ), A combination of a water-insoluble vinyl derivative and an enteric polyvinyl alcohol derivative (for example, a combination of polyvinyl acetate and polyvinyl alcohol phthalate), a water-insoluble vinyl derivative and an enteric maleic acid-based polymer. A combination with a polymer (for example, a combination of polyvinyl acetate and vinyl acetate / maleic acid copolymer), a combination of a water-insoluble vinyl derivative and an enteric acrylic acid-based polymer (for example, polyvinyl acetate and methacrylic acid / methacrylate). A combination of a water-insoluble acrylic polymer and an enteric cellulose derivative (eg, ethyl acrylate / methyl methacrylate / trimethyl ammonium ethyl methacrylate copolymer and hydroxypropyl) Combination with methylcellulose acetate succinate, combination of ethyl acrylate, methyl methacrylate, methacrylated trimethylammoniumethyl copolymer and hydroxypropylmethylcellulose phthalate, ethyl acrylate A combination of a methyl methacrylate / methacrylated trimethylammonium ethyl copolymer and carboxymethylethyl cellulose), a combination of a water-insoluble acrylic polymer and an enteric starch derivative (eg, ethyl acrylate / methyl methacrylate) A combination of a methacrylated trimethylammonium ethyl copolymer and starch acetoacetate phthalate), a combination of a water-insoluble acrylic acid-based polymer and an enteric natural polymer compound (for example,
A combination of ethyl acrylate / methyl methacrylate / trimethyl ammonium ethyl methacrylate copolymer and shellac), a combination of a water-insoluble acrylic acid-based polymer and an enteric polyvinyl alcohol derivative (for example, ethyl acrylate / meth Combination of methyl acrylate / methacrylated trimethylammonium ethyl copolymer and polyvinyl alcohol phthalate), combination of water-insoluble acrylic acid polymer and enteric maleic acid polymer (for example, ethyl acrylate / methyl methacrylate)・ A combination of methacrylated trimethylammonium ethyl copolymer and vinyl acetate / maleic acid copolymer), a combination of water-insoluble acrylic acid polymer and enteric acrylic acid polymer (example) For example, a combination of ethyl acrylate / methyl methacrylate / trimethyl ammonium methacrylate copolymer and methacrylic acid / methyl methacrylate copolymer, ethyl acrylate / methyl methacrylate / meth acrylate A combination of a trimethylammonium ethyl copolymer and a methacrylic acid / ethyl acrylate copolymer).

Among the above combinations of the water-insoluble polymer and the enteric polymer, particularly preferred combinations include:
Combination of ethylcellulose and hydroxypropylmethylcellulose acetate succinate, combination of ethylcellulose and methacrylic acid / methyl methacrylate copolymer, ethyl acrylate / methyl methacrylate / trimethylammonium chloride methacrylate ethyl copolymer and hydroxy Examples thereof include a combination with propylmethylcellulose acetate succinate, and a combination of ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer and methacrylic acid / methyl methacrylate copolymer.

The mixing ratio of the water-insoluble polymer and the enteric polymer may be appropriately selected within the range of 95: 5 to 5:95, preferably 8: 2 to 1: 9, particularly preferably 7: 3 to 2. : 8 By varying the mixing ratio, the time (lag time) until the drug is released in the intestine can be adjusted. That is, by increasing the mixing ratio of the enteric polymer,
The lag time is shortened, and the lag time can be increased by increasing the mixing ratio of the water-insoluble polymer.

The weight ratio of the coating containing the water-insoluble polymer and the enteric polymer to the core substance, that is, the coating rate, is as follows:
It may be selected from the range of 1 to 200% by weight, preferably 2 to 50% by weight, particularly preferably 3 to 50% by weight.
% By weight. In the preparation of the present invention, the lag time can also be adjusted by changing the coverage. That is, the lag time can be lengthened by increasing the coverage, and the lag time can be shortened by decreasing the coverage.

Therefore, based on the above findings, it is possible to adjust the time until the drug is released in the intestine by appropriately selecting the combination of the water-insoluble polymer and the enteric polymer in the film and the coverage of the film. By setting the lag time to about 3 hours, the lower ileum can be obtained by setting it to about 4 hours, the ascending colon can be obtained by about 4 hours, and the preparation capable of releasing the drug near the transverse colon by setting it to about 7 hours can be obtained. By setting a longer lag time, it is possible to obtain a preparation which is expected to be released near the lower part of the large intestine.

In the preparation of the present invention, all the drugs in the preparation are released immediately after the lag time. For example, for the preparation of the present invention, the dissolution test method (paddle method) of the 13th revision of the Japanese Pharmacopoeia (JP) When a dissolution test was performed using the Japanese Pharmacopoeia Disintegration Test Second Solution (pH 6.8), T10 (the time required for 10% of the drug in the formulation to be released after the start of the test) and T9
The difference between 0 (time required to release 90% of the drug in the formulation after the start of the test) is 3 hours or less.

In the preparation of the present invention, various additives may be blended in the film, and such additives include coating aids, coloring agents, concealing agents, plasticizers, lubricants and the like. . Examples of the coating aid include hardened oil (trade name; K-3 wax, etc., manufactured by Kawaken Fine Chemical Co., Ltd.), stearic acid (trade name, NAA-174, etc., manufactured by NOF Corporation), calcium stearate, polyoxyl stearate (trade name) Nonionic S-154, etc., manufactured by Matsumoto Trading Co., Ltd.), magnesium stearate, cetanol (trade name, NAA-44, etc., manufactured by NOF Corporation) and the like. Examples of the coloring agent include food coloring, lake coloring, caramel, carotene, annat, cochineal, iron dioxide, and the like, as well as an opaque coloring agent OPALUX mainly composed of lake coloring and syrup. No. 2, No. 3, Yellow No. 4, No. 5, Green No. 3, Blue No. 1,
Edible aluminum lakes such as No. 2 and No. 1 purple, anat (a natural pigment derived from Acacia catechu), carmine (aluminum carminate), pearl essence (mainly containing guanine) and the like. As the masking agent, for example, titanium dioxide, precipitated calcium carbonate, dibasic calcium phosphate,
Calcium sulfate and the like.

Examples of the plasticizer include fulleric acid derivatives such as diethyl phthalate, dibutyl phthalate and butyl phthalyl butyl glycolate, as well as silicone oil, triacetin, propylene glycol, polyethylene glycol and the like. As the lubricant, for example, magnesium stearate, talc, synthetic magnesium silicate,
Fine particle silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide and the like can be mentioned. The amount and timing of addition of these additives can be used without any problem as long as they are within the range based on knowledge commonly used in the field of formulation technology. The preparation of the present invention may be prepared by appropriately selecting a water-swellable substance to be incorporated into the core substance, and a film containing a water-insoluble polymer and an enteric polymer, but preferred embodiments of the preparation of the present invention are not limited. For example, for example, a preparation in which a carboxymethylcellulose calcium-containing core material is coated with a film containing ethyl acrylate / methyl methacrylate / methacrylated trimethylammoniumethyl copolymer and hydroxypropylmethylcellulose acetate succinate A preparation in which a carboxymethylcellulose calcium-containing core material is coated with a film containing ethylcellulose and a methacrylic acid / methyl methacrylate copolymer, and a carboxymethylcellulose calcium-containing core material is coated with ethylcellulose and methacrylic acid / ethyl acrylate Formulations coated with a film containing a copolymer, such formulations coated with a film containing a low-substituted hydroxypropylcellulose containing core material ethyl cellulose and methacrylic acid-ethyl acrylate copolymer.

The preparation of the present invention can be produced by spraying a solution obtained by dissolving both a water-insoluble polymer and an enteric polymer on a core substance containing a drug and a water-swellable substance, and then drying the resultant. The core substance can be prepared by a known granulation method such as wet granulation, dry granulation, and powder coating.

In the case of wet granulation, a drug, a water-swellable substance, and various preparation additives are mixed according to a conventional method, and then a binder solution is added. The mixture is granulated by a stirring granulator, a high-speed stirring granulator, or the like. Alternatively, a binder solution may be added to a mixture of a drug, a water-swellable substance, and various formulation additives, kneaded, and then granulated and sized using an extrusion granulator. Also, drugs, water-swellable substances,
A mixture of various formulation additives may be granulated by spraying a 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, a water-swellable substance, and various preparation additives may be granulated using a roller compactor, a roll granulator, or the like.

When prepared by powder coating,
Using a centrifugal flow granulator, etc., add the drug and water-swellable substance (if necessary with various formulation additives) while spraying the binder solution onto the tumbled inert carrier, and place it on the carrier. The drug and the water-swellable substance may be attached,
The drug and the water-swellable substance may be simultaneously attached, or only the drug may be attached first, and then the water-swellable substance may be attached.

In powder coating, instead of a binder solution, a substance that is melted by heating (heat-fused substance), such as fats and oils, is added under heating and melted. A substance may be deposited.

As the inert carrier, for example, crystalline lactose,
Crystals of sugars or inorganic salts such as crystalline cellulose and crystalline sodium chloride, spherical granules (for example, spherical granules of crystalline cellulose (Abicel SP, manufactured by Asahi Kasei), spherical granules of crystalline cellulose and lactose (products) Name; Non-pareil NP
-5, NP-7, manufactured by Freund), spherical granules of purified sucrose (trade name; Nonparel-103, manufactured by Freund), spherical granules of lactose and pregelatinized starch, and the like.

When a tablet is used as the core substance, a mixture of a drug, a water-swellable substance, and various preparation additives is directly compression-molded into a tablet, or the mixture is granulated according to the above-mentioned method. A tablet may be formed by adding a lubricant or the like and compression-molding the tablet. Alternatively, a drug and various preparation additives may be granulated by the above-described method, and then a water-swellable substance may be added and compression-molded. Furthermore, the drug, various formulation additives are granulated by the above method, and after compression-molding the same, a water-swellable substance may be coated as a core substance by ordinary coating means,
The coating of the water-swellable substance can be performed by, for example, compression coating or spraying the water-swellable substance while spraying a binder.

For coating the obtained core substance with a film containing a water-insoluble polymer and an enteric polymer, a solution prepared by dissolving or dispersing the water-insoluble polymer and the enteric polymer in the same solvent is used as a coating liquid. Can be carried out by spray coating.

Examples of the solvent for the coating solution include methanol, ethanol, n-propanol, isopropanol, n-butanol and 2-methoxyethanol (trade name: methyl cellosolve, manufactured by Katayama Chemical Industry), 2
Alcohols such as ethoxyethanol (trade name; cellosolve, manufactured by Katayama Chemical Industry), hydrocarbons such as hexane, cyclohexane, petroleum ether, petroleum benzine, ligroin, benzene, toluene, xylene; ketones such as acetone and methyl ethyl ketone; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, trichloroethylene, 1,1,1-trichloroethane, esters such as methyl acetate, ethyl acetate and butyl acetate; ethers such as isopropyl ether and dioxane And water. These solvents may be selected according to the hydrophobic organic compound and the enteric polymer used, and two or more of them may be used as appropriate.

Among them, preferred solvents are alcohols,
Halogenated hydrocarbons, ketones, water and the like, among which ethanol, dichloromethane, acetone and the like are particularly preferable.

The coating may be performed 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 thus-obtained preparation of the present invention can be used as it is as an oral preparation, but when fine granules or granules are used as a core substance, it is necessary to further prepare the coated granules (or fine granules). In addition to the above, various additives can be added and then compression-molded into tablets, or filled into capsules to form capsules, or formed into various dosage forms suitable for oral administration. 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.

[0045]

Example 1 Nonpareil-103 (Freund Industrial) using a centrifugal flow coating apparatus (CF, Freund Industrial)
In 150 g, a binder solution (36.1 g of white sugar, TC-5E)
24 g of W (hydroxypropyl methylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.) in a water-ethanol mixture (ethanol content:
25 wt%) (solution dissolved in 776 g) was sprayed, and a mixture of 360 g of docarpamine and 40 g of ECG505 (carboxymethylcellulose calcium, manufactured by Gotoku Pharmaceutical Co., Ltd.) was added, followed by powder coating to obtain a docarpamine-containing core material.

Ethyl cellulose, Eudragit L10
0 (methacrylic acid / methyl methacrylate copolymer,
Ream Pharma Co., Ltd.) was dissolved in a water-ethanol mixture (ethanol content: 80% by weight) to prepare a coating solution (ethyl cellulose concentration: 1.5% by weight, Eudragit L100 concentration: 3.5% by weight), This was spray-coated on 180 g of the above docarpamine-containing core material using a centrifugal flow type coating apparatus, and a coating rate of 15 to
25% by weight of coated granules were obtained.

According to the dissolution test method (paddle method) of the thirteenth revised Japanese Pharmacopoeia (JP) of the obtained preparation, Japanese Pharmacopoeia disintegration test first solution (pH 1.2), second solution (pH 6.8) The dissolution test was carried out under the conditions of 37 ° C. and a paddle rotation speed of 100 rpm. The results are shown in FIGS.

In the Japanese Pharmacopoeia Disintegration Test No. 1 (pH 1.2), no drug was released for 10 hours (FIG. 1).

In the second solution (pH 6.8) of the Japanese Pharmacopoeia disintegration test, the drug was rapidly released after a certain period of time (lag time) (FIG. 2).

In the present preparation, since the film becomes brittle with time, even if the amount of the water-swellable substance in the core substance is small, the film can be ruptured and the drug can be released quickly.

The lag time can also be changed by changing the coverage.

Comparative Example 1 Ethyl cellulose and talc were dissolved and suspended in an ethanol-dichloromethane mixture (3: 2, v / v) to prepare a coating solution (ethyl cellulose concentration: 6.4% by weight, talc concentration: 1). This was spray-coated with 180 g of the docarpamine-containing core material obtained in Example 1 using a centrifugal flow type coating apparatus to obtain coated granules having a coverage of 5 to 30% by weight.

The obtained preparation was subjected to the Japanese Pharmacopoeia disintegration test second liquid (pH 6.
Using 8), a dissolution test was carried out under the conditions of 37 ° C. and a paddle rotation speed of 100 rpm. The result is shown in FIG.

In this preparation, since the film does not become brittle with time, if the amount of the water-swellable substance in the core substance is small, the drug cannot be rapidly released.

Comparative Example 2 Non-Parallel-103 (manufactured by Freund Industrial) using a centrifugal flow type coating apparatus (manufactured by Freund Industrial).
In 150 g, a binder solution (36.1 g of white sugar, TC-5E)
24 g of W (hydroxypropyl methylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.) in a water-ethanol mixture (ethanol content:
225 g of docarpamine was added thereto while spraying (25% by weight) a solution dissolved in 776 g), followed by powder coating to obtain a docarpamine-containing core material.

Ethyl cellulose, Eudragit L10
0 (methacrylic acid / methyl methacrylate copolymer,
Ream Pharma Co., Ltd.) was dissolved in a water-ethanol mixture (ethanol content: 80% by weight) to prepare a coating solution (ethyl cellulose concentration: 1.5% by weight, Eudragit L100 concentration: 3.5% by weight), This was spray-coated on 180 g of the above docarpamine-containing core material using a centrifugal flow type coating apparatus, and the coating rate was 5 to 3%.
5% by weight of coated granules were obtained.

The obtained preparation was subjected to a Japanese Pharmacopoeia disintegration test second liquid (pH 6.
Using 8), a dissolution test was carried out under the conditions of 37 ° C. and a paddle rotation speed of 100 rpm. The result is shown in FIG.

This preparation does not contain a water-swellable substance in the core substance, and the drug release depends on the membrane permeability.
In the case of poorly soluble drugs such as docarpamine, they cannot be released quickly.

Example 2 Eudragit RS (ethyl acrylate / methyl methacrylate / methacrylated trimethylammoniumethyl copolymer, manufactured by Rohm Pharma Co., Ltd.), HPMC-
AS (hydroxypropyl methylcellulose acetate succinate, Shin-Etsu Chemical Co., Ltd.) is dissolved in a water-ethanol mixture (ethanol content: 80% by weight) to prepare a coating solution (Eudragit RS concentration: 3.5% by weight, HPMC-AS This was spray-coated on 180 g of the docarpamine-containing core material obtained in Example 1 using a centrifugal flow type coating apparatus to obtain coated granules having a coverage of 15% by weight.

Example 3 Ethyl cellulose and Eudragit L100-55 (methacrylic acid / ethyl acrylate copolymer, manufactured by Laem Pharma) were dissolved in a water-ethanol mixture (ethanol content: 80% by weight) to form a coating solution. Was prepared (ethyl cellulose concentration: 1.5% by weight, Eudragit L100-55 concentration: 3.5% by weight), and this was applied to 180 g of the docarpamine-containing core material obtained in Example 1 using a centrifugal flow type coating apparatus. Spray coating,
Coated granules having a coverage of 30% by weight were obtained.

Example 4 Using a centrifugal flow type coating apparatus (CF, manufactured by Freund Corporation), non-parrel-103 (manufactured by Freund Corporation)
In 150 g, a binder solution (36.1 g of white sugar, TC-5E)
24 g of W (hydroxypropyl methylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd.) in a water-ethanol mixture (ethanol content:
A solution of 360 g of indomethacin and 40 g of ECG505 (carboxymethylcellulose calcium, manufactured by Gotoku Pharmaceutical Co., Ltd.) was added thereto while spraying the solution (solution dissolved in 776 g of 25% by weight), followed by powder coating to obtain a core material containing indomethacin.

Ethyl cellulose, Eudraggid L10
0 (methacrylic acid / methyl methacrylate copolymer,
Ream Pharma Co., Ltd.) was dissolved in a water-ethanol mixture (ethanol content: 80% by weight) to prepare a coating solution (ethyl cellulose concentration: 1.5% by weight, Eudragit L100 concentration: 3.5% by weight), This was spray-coated on 180 g of the above indomethacin-containing core material using a centrifugal flow coating apparatus, and the coating rate was 20%.
By weight, coated granules were obtained.

[0063]

EFFECTS OF THE INVENTION The preparation of the present invention does not release any drug in a low pH region such as the stomach, and a certain period of time only in a relatively neutral pH region such as the small intestine and large intestine. Since it is possible to release the drug later (lag time) quickly, it is possible to release the drug at a desired site in the intestine by adjusting the lag time.

In the preparation of the present invention, since the water-swellable substance in the core substance ruptures the film to release the drug, the release of the drug does not depend on the permeability of the film. Even if it is, it can be released quickly after a certain time.

Furthermore, since the film of the present invention becomes brittle with time, the film can be ruptured even with a small amount of a water-swellable substance. A good-to-take formulation can be obtained without the need.

[Brief description of the drawings]

FIG. 1 is a Japanese Pharmacopoeia disintegration test first liquid (pH 1.2) of a preparation in which a water-swellable substance (ECG505) -containing core substance is coated with a film containing ethylcellulose and Eudragit L100.
The graph which showed the elution behavior in 2).

[FIG. 2] Japanese Pharmacopoeia Disintegration Test 2nd Solution (pH 6.0) in which a core material containing a water-swellable substance (ECG505) is coated with a film containing ethylcellulose and Eudragit L100.
8 is a graph showing the dissolution behavior in 8).

FIG. 3 is a graph showing the dissolution behavior of a preparation in which a core material containing a water-swellable substance (ECG505) is coated with a film containing ethyl cellulose and talc in a second liquid (pH 6.8) in a Japanese Pharmacopoeia test.

FIG. 4 is a graph showing the dissolution behavior of a preparation in which a core substance containing no water-swellable substance is coated with a film containing ethyl cellulose and Eudragit L100 in a Japanese Pharmacopoeia disintegration test second liquid (pH 6.8).

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Claims (14)

[Claims] 1. A pulse-release preparation in which a core substance containing a drug and a water-swellable substance is coated with a film containing an enteric polymer and a water-insoluble polymer. 2. In the second liquid of the Japanese Pharmacopoeia Disintegration Test, T10
The formulation according to claim 1, wherein the difference between T90 and T90 is 3 hours or less. 3. The preparation according to claim 1, wherein the amount of the water-swellable substance in the core substance is 1 to 29% by weight. 4. The preparation according to claim 1, wherein the coating ratio of the film is 1 to 200% by weight. 5. The preparation according to claim 1, wherein the drug is a high-dose drug with a dose of 0.2 g or more per dose. 6. The drug has a solubility in water of 0.01 g /
6. The drug according to any one of claims 1 to 5, wherein the drug is a poorly soluble drug in an amount of less than 1 ml.
Item. 7. The water-swellable substance is a disintegrant.
7. The preparation according to any one of 6 above. 8. The preparation according to claim 7, wherein the disintegrant is one or more selected from the group consisting of water-swellable cellulose derivatives, starches, water-swellable starch derivatives and water-swellable polyvinyl derivatives. 9. The water-swellable cellulose derivative is carboxymethylcellulose, carboxymethylcellulose calcium, cross-linked sodium carboxymethylcellulose or low-substituted hydroxypropylcellulose, the starch is corn starch, and the water-swellable starch derivative is partially pregelatinized starch. Or the sodium carboxymethyl starch, and the water-swellable polyvinyl derivative is a cross-linked polyvinyl pyrrolidone. 10. The preparation according to claim 1, wherein the weight ratio of the water-insoluble polymer to the enteric polymer in the film is in the range of 95: 5 to 5:95. 11. 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 polymer, and the enteric polymer is an enteric cellulose derivative,
11. One or more selected from an enteric starch derivative, an enteric natural polymer compound, an enteric polyvinyl alcohol derivative, an enteric maleic polymer and an enteric acrylic acid polymer. The preparation according to claim 1. 12. The water-insoluble cellulose derivative is ethyl cellulose or cellulose acetate, the water-insoluble vinyl derivative is polyvinyl acetate or polyvinyl chloride,
The water-insoluble acrylic polymer is ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer or methyl methacrylate / ethyl acrylate copolymer, and the enteric cellulose derivative is cellulose acetate phthalate, Cellulose acetate succinate, cellulose benzoate phthalate, methyl cellulose phthalate, ethyl hydroxyethyl cellulose phthalate, cellulose acetate maleate, hydroxyethyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, polyoxyethyl cellulose phthalate, cellulose propionate or carboxy With methyl ethyl cellulose The enteric starch derivative is star thiacetate phthalate or amylose acetate phthalate, the enteric natural polymer compound is shellac, and the enteric polyvinyl alcohol derivative is polyvinyl alcohol phthalate, polyvinyl alcohol acetate phthalate, polyvinyl propionate phthalate, polyvinyl Butyrate phthalate, polyvinyl acetal phthalate, polyvinyl acetoacetal phthalate, polyvinyl acetoacetal succinate or polyvinyl acetal diethylaminoacetate, and the enteric maleic polymer is vinyl acetate.
Maleic acid copolymer, styrene / maleic acid copolymer,
Ethylene-styrene-maleic acid copolymer, acrylonitrile-methyl acrylate-maleic acid copolymer, butyl acrylate-styrene-maleic acid copolymer or vinyl methyl ether-maleic acid copolymer; enteric acrylic acid Styrene-acrylic acid copolymer, acrylic acid-methyl acrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid
The preparation according to claim 11, which is a methyl methacrylate copolymer, a methacrylic acid / ethyl acrylate copolymer or an acrylic acid / butyl acrylate copolymer. 13. The water-insoluble polymer is ethyl cellulose or ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer, and the enteric polymer is hydroxypropyl methylcellulose acetate succinate, methacrylic acid / methacrylic. The preparation according to any one of claims 1 to 10, which is a methyl acrylate copolymer or a methacrylic acid / ethyl acrylate copolymer. 14. The method according to claim 1, wherein the drug is docarpamine.
14. The preparation according to any one of 13 above.