JPH09295933A - Composition for controlling release purpose - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition capable of suppressing release in stomach at the initial stage of administration of medicine for oral cavity, keeping the concentration in blood plasma constant and retaining pharmacodynamic effects. SOLUTION: This composition for controlling release is obtained by coating a nucleus containing a medicine such as morphine with a coating agent containing a water-insoluble substance and a swelling polymer free from a basic group. The water-insoluble substance includes cellulose ether, cellulose ester or ethylcellulose and the swelling polymer has an acidic group and exhibits pH dependence and includes a crosslinking type acrylic acid polymer. The swelling polymer has about 1000000 to about 10000000 molecular weight and about 1500 to about 60000cp viscosity in 0.2% neutralized liquid. An amount of the coating agent used is >=1%(W/W) based on the nucleus and the coating agent is hydroxypropylmethyl cellulose of polysaccharide and the water-insoluble substance content is about 40 to about 95%(w/w) and the swelling polymer content is about 1 to about 40% (w/w) and the hydrophillic substance content is about <=40% (w/w). The medicine is preferably a sympathomimetic medicine having >=0.5% (w/w) content. The composition is preferably prepared as granules, tablets, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a controlled release composition in which a drug-containing core is coated with a coating agent containing a water-insoluble substance and a swelling polymer having no basic group.

[0002]

2. Description of the Related Art Controlled-release preparations of drugs, particularly sustained-release preparations, have the advantage that the frequency of administration can be reduced by keeping the plasma concentration constant for a long time and maintaining the efficacy of the medicinal component. Furthermore, it is expected that side effects will be reduced by suppressing the rapid rise of the drug concentration in blood, and many controlled release systems have been studied so far, including capsule-type preparations in which the nucleus containing the drug is coated with a controlled release film. [JP-A-7-145056, JP-A-7-2
No. 06679, Canadian Patent Application No. 2,068,36
6 publication, WO 94/22431, EP037751
8 publication, EP0630646 publication, EP06317
No. 81, Japanese Patent Publication No. 7-72130]. In such capsule-type preparations, the release-controlling membrane is composed of a hydrophobic coating agent containing a hydrophilic or water-soluble component, and its release has been designed to control the release or release rate of the drug.

[0003]

There are many known drugs that are not as well absorbed by the large intestine as they are by the small intestine. Considering that the orally-administered controlled-release composition has a relatively short transit time to the small intestine (the time required for the active ingredient to reach the large intestine is about 5 to 6 hours), even if such a drug is designed as a sustained-release preparation, it is 5- Since absorption after 6 hours is suppressed, 12-2
1-2 daily requirement for sustained plasma concentration over 4 hours
It was difficult to design a single-dose sustained-release formulation. In addition, even if the drug is absorbed from all over the digestive tract, as the preparation moves in the digestive tract, the drug concentration in the large intestine decreases due to the decrease of the drug concentration inside the controlled release membrane and the depletion of water in the lower digestive tract. It is often difficult to obtain a sufficiently satisfactory sustained-release preparation, especially a sustained-release preparation of a drug that is mainly absorbed in the small intestine.

[0004]

In view of such circumstances, the present inventors have found that the intestine and the large intestine are more stable than those in the stomach in order to keep the plasma concentration of the drug in the body almost constant for a long time and maintain the drug effect. As a result of intensive studies aimed at developing a controlled-release oral administration composition coated with a coating agent so as to exhibit a large release rate, the nucleus containing the drug was swollen without a water-insoluble substance and a basic group. We have found that controlled release formulations coated with a coating containing a soluble polymer show a greater release rate in the small and large intestines than in the stomach, which is passed immediately after oral administration. As a result of further intensive studies based on this finding, the present invention has been completed. That is, the present invention provides (1) a controlled release composition in which a core containing a drug is coated with a coating agent containing a water-insoluble substance and a swelling polymer having no basic group, and (2) a water-insoluble substance is coated. The controlled release composition according to (1) above, which is a substance capable of forming, (3) The controlled release composition according to (1) above, wherein the water-insoluble substance is a cellulose ether or a cellulose ester, and (4) a water-insoluble substance. The controlled release composition according to (1) above, which is ethyl cellulose, (5) The controlled release composition according to (1) above, wherein the swellable polymer has an acidic group and exhibits pH-dependent swelling. ) The above (1), wherein the swellable polymer is a cross-linked acrylic acid polymer
The controlled release composition as described (7), wherein the swellable polymer has a molecular weight of from about 1,000,000 to about 10,000,000.
The controlled release composition according to (5) above. (8) The controlled release composition according to (5) above, wherein the swelling polymer has a viscosity of about 1,500 to about 60,000 cp in a 0.2% neutralized solution, and (9) the coating agent contains a hydrophilic substance. The controlled release composition according to (1) above, which may further contain:

(10) The controlled release composition according to the above (5), wherein the hydrophilic substance is a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, and (11) the above (9), wherein the hydrophilic substance is hydroxypropylmethylcellulose.
The controlled-release composition described above, (12) based on the core, 1% (w /
w) The content of the water-insoluble substance and the swelling polymer in the controlled release composition according to the above (1) coated with the above coating agent, (13) the coating agent is about 40 to about 95% (w).
/ W) and about 1 to about 40% (w / w) of the controlled release composition according to (1) above, and (14) the content of the water-insoluble substance, the swelling polymer and the hydrophilic substance in the coating agent, About 40 to about 95% (w / w), about 1 to about 4
The controlled-release composition according to (9) above, which is 0% (w / w) and 0 to about 40% (w / w), (15) the water-insoluble substance is ethyl cellulose, and the swellable polymer is a cross-linked acrylic acid polymer. (1) The controlled release composition according to (1) above,
6) The controlled release composition according to the above (1), wherein the drug is an opioid compound, (17) The controlled release composition according to the above (1), wherein the drug is morphine or a salt thereof, and (18) the sympathomimetic drug. (1) The controlled release composition according to the above (1), (19) The controlled release composition according to the above (1) containing 0.5% (w / w) or more of a drug, (20) Granules, fine granules, tablets. Alternatively, the release-controlling composition according to the above (1), which is a capsule, (21) a coating agent containing a water-insoluble substance and a swelling polymer having no basic group, and (22) a hydrophilic substance may be further contained. A controlled release composition characterized in that the core comprising the coating agent according to (21) above and (23) a drug is coated with a coating agent containing a water-insoluble substance and a swelling polymer having no basic group. Regarding manufacturing method.

The drug used in the present invention is not particularly limited, and examples thereof include morphine or a pharmacologically acceptable salt thereof (eg, hydrochloride, sulfate, etc.), hydromorphone, oxycodone, medadone, meperidine, dihydrocodeine,
Opioid compounds such as codeine, dihydromorphine, buprenorphine, fentanyl, anti-inflammatory drugs such as naproxen sodium, isopropylantipyrine, ibuprofen, ketoprofen, diclofenac sodium, sympathomimetics such as ephedrine hydrochloride, salbutamol sulfate, terbutaline sulfate, and phenylpropanolamine hydrochloride. , Anti-allergic agents such as pheniramine, terfenadine, chlorpheniramine maleate, diphenhydramine hydrochloride, antihistamines such as clemastine fumarate, procainamide hydrochloride, propranolol hydrochloride, cardiotonics such as quinidine sulfate, metoprolol, captopril, hydramidine hydrochloride, diltiazem Antihypertensive drugs such as amoxicillin, cephalexin, clarithromycin, peni Phosphorus V potassium, cloxacillin sodium, antibiotics such as metronidazole hydrochloride, bronchodilators such as theophylline and salbutamol, antitumor agents such as flutamide and fluorouracil, anti-arrhythmic agents such as procainamide and quinidine, sodium phenytoin, ethosuximide, Anticonvulsants such as sodium baproate, central agents such as diazepam, perphenazine, chlorpromazine hydrochloride, gastrointestinal agents such as famotidine, ranitidine, lametidine, omeprazole, lansoprazole, antidiabetic drugs such as voglibose, tolbutamide, acarbose, bethanechol hydrochloride , Cholinergic agents such as neostigmine bromide and carbachol, vitamins, amino acids, peptides and the like are used. Basic drugs are preferably used. Of these, the drug is preferably an opioid compound, more preferably morphine or a pharmacologically acceptable salt thereof. Examples of such salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acid salts such as tartaric acid and tartaric acid. As a salt of morphine, a salt with hydrochloric acid and sulfuric acid is generally used as a pharmacologically acceptable salt.

The water-insoluble substance used in the present invention is not particularly limited as long as it has a film forming ability. Specifically, for example, cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose acetates such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, acrylic acid / methacrylic acid copolymers,
Methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, polymetha Rylamide, aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride), glycidyl methacrylate copolymer, especially Eudragit RS-
100, RL-100, RS-30D, RL-30D,
RL-PO, RS-PO (Ethyl acrylate / methyl methacrylate / methacrylic acid trimethyl / ammonium ethyl copolymer), Eudragit L30D-5
5, L100-55 (methacrylic acid / ethyl acrylate / copolymer), Eudragit L100 (methacrylic acid / methyl methacrylate / copolymer), Eudragit NE-30D (methyl methacrylate / ethyl acrylate copolymer) Acrylic polymers such as Eudragits (ROHM PHARMA CORPORATION) such as polymers, hardened oils such as hydrogenated castor oil (eg, Lovely wax (Freund Industries), etc.), carnauba wax, monoglycerides, triglyces, waxes such as paraffin And polyglycerin fatty acid esters are used. Of these, the water-insoluble substance is preferably cellulose ester, more preferably ethyl cellulose. When a cellulose ester is used as the water-insoluble substance, its viscosity is about 5 to about 120 cP in a 5% solution, preferably about 5 to about 50.
cP.

As the swelling polymer having no basic group used in the present invention, a polymer having little pH dependency on swelling, a polymer having an acidic dissociative group and exhibiting pH dependency swelling, and the like are used. Among these, the swellable polymer is preferably a polymer having an acidic dissociative group that swells less in acidic regions such as the stomach and swells more in neutral regions such as the small intestine and the large intestine. Examples of polymers having a low pH dependency on swelling include hydroxypropyl celluloses, for example, high-viscosity hydroxypropyl cellulose (viscosity: about 1,000 to about 4,000 cp, 2% aqueous solution), low-substituted hydroxypropyl cellulose and the like. . Examples of the polymer having an acidic dissociative group and exhibiting pH-dependent swelling include, for example, Carbomer 934.
P, 940, 941, 974P, 980, 1342, etc.
Polycarbophil, calcium polycarbophil (all of which are manufactured by BF Goodsrich), Hibiswako 103,
104, 105, 304 (all manufactured by Wako Pure Chemical Industries, Ltd.)
Crosslinked polyacrylic acid polymers such as pH
The viscosity of polymers exhibiting dependent swelling is about 1,500 to about 60,000 cp, preferably about 3,000 to about 50,000 cp in a 0.2% neutralization solution. The molecular weight is about 1,000,000 to about 10,000,
000, preferably about 1,000,000 to about 5,
, 000,000, more preferably about 1,000,000
0 to about 3,500,000.

In the controlled release composition of the present invention (hereinafter sometimes abbreviated as the composition of the present invention), the coating agent may further contain a hydrophilic substance. In that case, as the hydrophilic substance, for example, pullulan, dextrin, polysaccharides which may have a sulfuric acid group such as alkali metal alginate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyalkyl group such as sodium carboxymethyl cellulose or carboxyalkyl. A group-containing polysaccharide, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like are used. Among them, the hydrophilic substance is preferably a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropylmethyl cellulose. The content of the water-insoluble substance in the coating agent of the present invention is about 40 to about 95% (w / w), preferably about 60 to about 90% (w.
/ w), content of swelling polymer is about 1 to about 40%
(W / w), preferably about 5 to about 40% (w / w). The coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 40%.
(W / w) or less, preferably about 30% (w / w) or less.
More preferably, it is about 1 to about 30% (w / w).

The composition of the present invention prepares a drug-containing core,
Then, the obtained core is coated with a coating agent solution in which a water-insoluble substance and a swelling polymer having no basic group are dissolved by heating or dissolved or dispersed in a solvent. The method for producing the composition of the present invention is described in detail below. I. Preparation of drug-containing nuclei. In the composition of the present invention, the form of the core containing the drug to be coated with the film agent (hereinafter sometimes simply referred to as the core) is not particularly limited, and examples thereof include tablets, pills, granules or fine particles. When the core is a granule or a fine particle, the average particle size thereof is preferably about 150 to 2,000 μm, more preferably about 500 to about 800 μm. Of these, in the present specification, fine particles have a particle size of about 500 μm.
The following particles are shown. The nucleus can be prepared by a usual production method. For example, a drug is mixed with an appropriate excipient, a binder, a disintegrating agent, a lubricant, etc., and a wet extrusion granulation method,
It is prepared by a fluidized bed granulation method or the like. The drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 60% (w / w), more preferably about 30 to about 60% (w / w). Is. As the excipient contained in the core, for example, saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate and the like are used. As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, macrogol, Pluronic F68, gum arabic, gelatin, starch and the like are used. As a disintegrant, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), polyvinylpyrrolidone, low-substituted hydroxypropylcellulose (L-HPC)
Are used. As the lubricant and the aggregation preventing agent, for example, talc, magnesium stearate and the like are used.

In addition to the above-mentioned production method, the nucleus is sprayed with a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) on the inert carrier particles which are the core of the nucleus. It can also be prepared by a tumbling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method, in which a drug or a mixture thereof with an excipient, a lubricant or the like is added little by little. As the inert carrier particles, for example, those produced from sucrose, lactose, starch, crystalline cellulose and waxes can be used, and the average particle diameter thereof is preferably about 100 μm to about 1,500 μm. The components contained in the nucleus are not particularly limited to the above-mentioned substances, and are not limited as long as they are pharmaceutically acceptable. The resulting core may then be coated on its surface with a protective agent to separate the drug from the coating. Examples of the protective agent include the hydrophilic substance and
A water-insoluble substance or the like is used. The protective agent is preferably a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropylmethyl cellulose. When a protective agent is used, its coverage is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to the core.
To about 8% (w / w). The protective agent can be coated by a usual coating method. Specifically, the protective agent can be coated by spray coating the nucleus by, for example, a fluidized bed coating method or a pan coating method.

II. Coating of Nucleus with Coating Agent The composition of the present invention is a coating agent liquid prepared by dissolving the core obtained in the above I with the water-insoluble substance and the swelling polymer, and optionally a hydrophilic substance by heating or dissolving or dispersing in a solvent. It is manufactured by coating with. Examples of the method of coating the core with the coating agent solution include a method of spray-coating the core obtained in the above I with the coating agent solution. The composition ratio of the water-insoluble substance, the swelling polymer or the hydrophilic substance in the coating agent liquid is appropriately selected so that the content of each component in the coating is the above content. The coating amount of the coating agent is about 1 relative to the core (excluding the coating amount of the protective agent)
To about 90% (w / w), preferably about 5 to about 50
% (W / w), more preferably about 10 to 40% (w /
w).

As the solvent for the coating agent liquid, water or an organic solvent may be used alone or a mixture of both may be used. The mixing ratio of water and the organic solvent (water / organic solvent: volume ratio) when using the mixed solution can be varied in the range of 1 to 100%, and preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance, for example, lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform, Methylene chloride or the like is used. Of these, lower alcohols are preferable, and ethyl alcohol and isopropyl alcohol are particularly preferable. Water and a mixed liquid of water and an organic solvent are preferably used as the solvent of the film forming agent. The operation of spray coating can be carried out by a usual coating method, and specifically, it can be carried out by spray coating the core with a coating agent solution by a fluidized bed coating method, a pan coating method or the like. At this time, if necessary, talc, titanium oxide, or the like may be added as a coagulant, and glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, or the like may be added as a plasticizer.

The composition of the present invention thus obtained is used as it is as a parenteral agent (eg, implant agent for intramuscular, subcutaneous, organ, transmucosal agent for nasal cavity, rectum, uterus, etc.) or oral agent. (Eg, granules, fine granules, tablets, etc.), and when the composition is granules or fine granules, it can be filled in a capsule or the like and used as an oral preparation. The composition of the present invention is preferably an oral preparation. INDUSTRIAL APPLICABILITY The composition of the present invention has low toxicity and can be safely used for the prevention / treatment of mammals (eg, humans, cows, pigs, dogs, cats, mice, rats, rabbits, etc.) for their diseases. The dose of the composition of the present invention is the type and content of the drug, the dosage form, the duration of drug release, and the target disease (the drug contained in the composition of the present invention is used in the same manner for the diseases for which they were conventionally used. Yes), but the effective amount of the drug may vary depending on the target animal and the like. The dosage of the drug per administration is, for example, once a day when the drug is morphine hydrochloride, and in the case of the prevention / treatment of pain in cancer patients, the dose is about 4 mg to about 600 mg per patient.
It can be appropriately selected from the range of mg / day, preferably about 50 mg to about 500 mg. However, as long as safety can be ensured, administration may be performed outside the above range, if necessary. The dose of the composition of the present invention per administration is
For example, when the drug is morphine hydrochloride, about 10 mg to about 2,000 mg / day per patient for the purpose of treating pain,
Preferably, it can be appropriately selected from the range of about 100 mg to about 1,500 mg. Since the composition of the present invention contains a swelling polymer in the coating agent, the release of the medicinal component is slight in the stomach immediately after administration, but thereafter the upper small intestine, the lower small intestine,
The release rate increases due to increased swelling of the swellable polymer with the passage of time in the large intestine and after administration. Therefore, the decrease in the release of the drug from the composition due to water depletion is compensated, the release of the drug is sustained in vivo for a long time of 6 hours or more, specifically 12 to 24 hours, and a constant drug plasma concentration is maintained. It has the advantage of Thus, the composition of the present invention can be advantageously used in oral administration once a day. In particular, the present invention provides a once-daily oral administration of a morphine compound which exhibits high bioavailability. For this purpose, the swelling is pH-dependent,
It is preferable to use a film-forming agent containing a polymer having an acidic group because the swelling property increases with an increase in The composition of the present invention can also be expected to delay the movement of the composition in the digestive tract due to the high viscosity of the swelling polymer in the coating agent. Furthermore, by using the composition of the present invention in combination with an immediate release preparation, It is also possible to design a sustained-release preparation that can maintain the plasma concentration immediately after administration for a long time.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail based on Examples and Experimental Examples, but the present invention is not limited to these Examples and Experimental Examples.

[0016]

【Example】

Example 1 Morphine hydrochloride 110 g, lactose 480 g, corn starch 300 g, crystalline cellulose (Avicel) 150 g, carboxymethyl cellulose calcium (ECG-505) 30
g and 30 g of hydroxypropyl cellulose were mixed, an appropriate amount of Pluronic F-68 aqueous solution (7% (W / W)) was added, and the mixture was kneaded with a vertical granulator (FM-VG type Fuji Sangyo). The obtained mixture was extruded with Dome Gran (DG-L1 Fuji Paudal) and granulated with Marumerizer (OJ-230 Fuji Paudal). The obtained granular material was dried under reduced pressure (40 ° C., 15 hours), and then sieved and classified to obtain core granules of 500 to 1250 μm. The obtained core granules were put into a spiral flow type coating device (SFC-Labo Freund Sangyo), and sprayed with hydroxypropylmethylcellulose dissolved in a mixed solution of ethanol and water (4: 1 volume ratio) to obtain coated core granules. It was The amount of hydroxypropylmethyl cellulose coated was 3% (w /
w). Next, the obtained coated granules were sprayed with a coating liquid consisting of ethyl cellulose, hydroxypropylmethyl cellulose and a cross-linked polyacrylic acid polymer (Hibiswako 104 Wako Pure Chemical Industries, Ltd.) (70:10:20 weight ratio) to obtain the desired product. A composition was obtained. Spiral flow type coating equipment (SFC-Labo Freund Industrial)
The coating amount is 20% by weight based on the core granules not containing the coating amount of hydroxypropylmethylcellulose.
The coating liquid is a mixture of ethanol and water (7: 1 volume ratio).
Ethyl cellulose, hydroxypropyl methyl cellulose, and a cross-linking acrylic acid polymer were added to the above in the above ratio, and an appropriate amount of a plasticizer was added to the uniformly dispersed liquid to prepare.

Example 2 750 g of phenylpropanolamine hydrochloride, 103 g of corn starch, 162 g of crystalline cellulose (Avicel),
Low-substituted hydroxypropyl cellulose (32.4 g) and hydroxypropyl cellulose (32.4 g) were mixed, water was added in an appropriate amount, and the mixture was kneaded with a vertical granulator (FM-VG type Fuji Sangyo). The obtained mixture is Dome Gran
It was extruded with (DG-L1 Fuji Paudal) and granulated with Marumerizer (OJ-230 Fuji Paudal). The obtained granules are dried under reduced pressure (40 ° C, 15 hours), then sieved and classified, and 5
Nuclear granules of 00 to 1250 μm were obtained. The obtained nuclear granules were put into a spiral flow type coating device (SFC-Labo Freund Industries) and mixed with ethanol and water (4: 1).
Hydroxypropylmethylcellulose dissolved in a volume ratio was sprayed for coating to obtain coated granules. The amount of hydroxypropylmethyl cellulose coated is 10% based on the core granules
(W / w). Then, the obtained coated granules were mixed with ethyl cellulose, hydroxypropylmethyl cellulose and a cross-linked acrylic acid polymer (Carbomer 934P) (80: 5: 1).
(5 weight ratio) was sprayed and coated to obtain the desired composition. The coating operation was performed with a spiral flow type coating apparatus (Freund Sangyo SFC-Labo), and the coating amount was 20% (w / w) with respect to the core granules that did not contain the coating amount of hydroxypropylmethylcellulose. For the coating solution, add ethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymer to the mixture of ethanol and water (6: 1 volume ratio) at the above ratio, and add an appropriate amount of plasticizer and stir until uniform. Was prepared.

Example 3 750 g of phenylpropanolamine hydrochloride, 103 g of corn starch, 162 g of crystalline cellulose (Avicel),
Low-substituted hydroxypropyl cellulose (32.4 g) and hydroxypropyl cellulose (32.4 g) were mixed, water was added in an appropriate amount, and the mixture was kneaded with a vertical granulator (FM-VG type Fuji Sangyo). The obtained mixture is Dome Gran
It was extruded with (DG-L1 Fuji Paudal) and granulated with Marumerizer (OJ-230 Fuji Paudal). The obtained granules are dried under reduced pressure (40 ° C, 15 hours), then sieved and classified, and 5
Nuclear granules of 00 to 1250 μm were obtained. The obtained nuclear granules were put into a spiral flow type coating device (SFC-Labo Freund Industries) and mixed with ethanol and water (4: 1).
Hydroxypropylmethyl cellulose dissolved in (volume ratio) was sprayed and coated to obtain coated granules. The amount of hydroxypropylmethyl cellulose coated was 3% (w /
w). Then, the obtained coated granules were mixed with ethyl cellulose, hydroxypropylmethyl cellulose and a cross-linked acrylic acid polymer (Hibiswako 104 Wako Pure Chemical Industries) (7
(0:15:15 weight ratio) was sprayed and coated to obtain the desired composition. The coating operation was performed with a spiral flow type coating apparatus (Freund Sangyo SFC-Labo), and the coating amount was 20% (w / w) with respect to the core granules that did not contain the coating amount of hydroxypropylmethylcellulose. The coating liquid is a mixture of ethanol and water (8: 1 volume ratio), to which ethyl cellulose, hydroxypropylmethyl cellulose and a cross-linking acrylic acid polymer are added in the above ratio,
An appropriate amount of a plasticizer and talc were added, and the mixture was uniformly dispersed and used with sufficient stirring.

Example 4 Morphine hydrochloride was mixed in tetraglycerin pentabehenate ester heated and melted at 80 ° C. to a content of 10% (w / w), and the mixture was sufficiently stirred and then spherical particles were obtained by a spray chilling method. After preparation, screen and classify 177 to 5
Fine particles of 00 μm were obtained. Ethyl cellulose dissolved in ethanol and cross-linked acrylic acid polymer uniformly dispersed in the obtained fine particles (Hibiswako 104 Wako Pure Chemical) (7
A coating liquid consisting of 0:30 weight ratio) was sprayed and coated to obtain the desired composition. The coating operation was performed with a spiral flow type coating device (SFC-Labo Freund Industries), and the coating amount was 20% (w / w) with respect to the core granules.

Example 5 Phenylpropanolamine hydrochloride 7.7 g, lactose 42
g, 30 g of crystalline cellulose (Avicel), 30 g of croscarmellose sodium (AC-Di-Sol) and 0.3 g of magnesium stearate were mixed, and tablets (diameter 6 mm) were produced by a direct compression method. Ethyl cellulose, hydroxypropyl methyl cellulose, cross-linked acrylic acid polymer (Hibiswako 104 Wako Pure Chemical Industries, Ltd.) (7
(0:15:15 weight ratio) was sprayed and coated to obtain the desired composition. The coating operation was performed with a spiral flow type coating device (SFC-Labo Freund Industries), and the coating amount was 20% by weight without including the coating amount of hydroxypropylmethylcellulose on the core granules. Also,
The coating solution is a mixture of ethanol and water (8: 1 volume ratio) with ethyl cellulose, hydroxypropylmethyl cellulose,
After the cross-linked acrylic acid polymer was added in the above ratio, an appropriate amount of a plasticizer was added and uniformly dispersed before use.

Example 6 100 g of morphine hydrochloride, 42 g of corn starch, 40 g of crystalline cellulose (Avicel), 36 g of carboxymethyl cellulose calcium (ECG-505) and 36 g of hydroxypropyl cellulose were mixed to give polyoxyethylene (1
60) An appropriate amount of polyoxypropylene (30) glycol (Pluronic F-68) aqueous solution (6% (W / W)) was added and kneaded in a mortar. The obtained mixture was used as Dome Gran (DG-L
Extrude with 1 Fuji Paudal, and use Malmizer (OJ-2
30 Fuji Paudal). The obtained granules are dried under reduced pressure (40 ° C., 15 hours), and then sieved and classified to 5
Nuclear granules of 00 to 1250 μm were obtained. The obtained nuclear granules were put into a spiral flow type coating device (SFC-Labo Freund Industries) and mixed with ethanol and water (4: 1).
Hydroxypropylmethyl cellulose dissolved in (volume ratio) was sprayed for coating to obtain coated core granules. The amount of hydroxypropylmethylcellulose coated is 3% based on the core granules
(W / w). Then, the obtained coated granules were sprayed with a coating liquid consisting of ethyl cellulose, hydroxypropylmethyl cellulose and a cross-linked polyacrylic acid polymer (Hibiswako 104 Wako Pure Chemical Industries, Ltd.) (70:20:10 weight ratio), to obtain the desired mixture. A composition was obtained. The coating operation was performed with a spiral flow type coating device (SFC-Labo Freund Industries), and the coating amount was 20% by weight based on the core granules not containing the coating amount of hydroxypropylmethylcellulose. The coating liquid is a mixture of ethanol and water (7: 1 by volume) with ethyl cellulose, hydroxypropylmethyl cellulose, and a cross-linked acrylic acid polymer in the above ratios, and an appropriate amount of a plasticizer is added to the uniformly dispersed liquid. Prepared.

Example 7 100 g of morphine hydrochloride, 42 g of corn starch, 40 g of crystalline cellulose (Avicel), 36 g of carboxymethyl cellulose calcium (ECG-505) and 36 g of hydroxypropyl cellulose were mixed to give polyoxyethylene (1
60) An appropriate amount of polyoxypropylene (30) glycol (Pluronic F-68) aqueous solution (6% (W / W)) was added and kneaded in a mortar. The obtained mixture was used as Dome Gran (DG-L
Extrude with 1 Fuji Paudal, and use Malmizer (OJ-2
30 Fuji Paudal). The obtained granular material is dried under reduced pressure (40 ° C., 16 hours), then sieved and classified, and 5
Nuclear granules of 00 to 1250 μm were obtained. The obtained nuclear granules were put into a spiral flow type coating device (SFC-Labo Freund Industries) and mixed with ethanol and water (4: 1).
Hydroxypropylmethyl cellulose dissolved in (volume ratio) was sprayed for coating to obtain coated core granules. The amount of hydroxypropylmethylcellulose coated is 3% based on the core granules
(W / w). Then, the obtained coated granules were sprayed with a coating liquid consisting of ethyl cellulose, hydroxypropylmethyl cellulose and a cross-linked polyacrylic acid polymer (Hibiswako 104 Wako Pure Chemical Industries, Ltd.) (70:20:10 weight ratio), to obtain the desired mixture. A composition was obtained. The coating operation was carried out by a spiral flow type coating device (SFC-Labo Freund Industries), and the coating amount was 30% by weight based on the core granules not containing the coating amount of hydroxypropylmethylcellulose. The coating liquid is a mixture of ethanol and water (7: 1 by volume) with ethyl cellulose, hydroxypropylmethyl cellulose, and a cross-linked acrylic acid polymer in the above ratios, and an appropriate amount of a plasticizer is added to the uniformly dispersed liquid. Prepared.

Example 8 100 g of morphine hydrochloride, 42 g of corn starch, 40 g of crystalline cellulose (Avicel), 36 g of carboxymethyl cellulose calcium (ECG-505) and 36 g of hydroxypropyl cellulose were mixed, and polyoxyethylene (1
60) An appropriate amount of polyoxypropylene (30) glycol (Pluronic F-68) aqueous solution (7% (W / W)) was added and kneaded in a mortar. The obtained mixture was used as Dome Gran (DG-L
Extrude with 1 Fuji Paudal, and use Malmizer (OJ-2
30 Fuji Paudal). The obtained granules are dried under reduced pressure (40 ° C., 15 hours), and then sieved and classified to 5
Nuclear granules of 00 to 1250 μm were obtained. The obtained nuclear granules were put into a spiral flow type coating device (SFC-Labo Freund Industries) and mixed with ethanol and water (4: 1).
Hydroxypropylmethyl cellulose dissolved in (volume ratio) was sprayed for coating to obtain coated core granules. The amount of hydroxypropylmethylcellulose coated is 3% based on the core granules
(W / w). Next, the obtained coated granules were sprayed with a coating liquid consisting of ethyl cellulose, hydroxypropylmethyl cellulose and a cross-linked polyacrylic acid polymer (Hibiswako 104 Wako Pure Chemical Industries, Ltd.) (60:25:15 weight ratio) to obtain the desired mixture. A composition was obtained. The coating operation was carried out by a spiral flow type coating device (SFC-Labo Freund Industries), and the coating amount was 30% by weight based on the core granules not containing the coating amount of hydroxypropylmethylcellulose. The coating solution is a mixture of ethanol and water (7: 1 volume ratio), in which ethyl cellulose, hydroxypropylmethyl cellulose and a cross-linked acrylic acid polymer are added in the above proportions, and an appropriate amount of a plasticizer is added to the uniformly dispersed solution. Prepared.

Example 9 Morphine hydrochloride 150 g, corn starch 63 g, crystalline cellulose (Avicel) 60 g, carboxymethyl cellulose calcium (ECG-505) 9 g, hydroxypropyl cellulose 9
Mix g, add an appropriate amount of Pluronic F-68 aqueous solution (6% (w / w)), and knead in a mortar. Next, the mixture was extruded with Dome Gran (DG-L1 Fuji Paudal) and granulated with Marumerizer (OJ-230 Fuji Paudal). The obtained granules were dried under reduced pressure (40 ° C., 15 hours), and then sieved and classified to obtain core granules of 500 to 1250 μm. The above-mentioned core granules were placed in a spiral flow type coating apparatus (SFC-Labo Freund Industries) and sprayed with hydroxypropylmethylcellulose dissolved in a mixed solution of ethanol and water (4: 1 volume ratio) to obtain coated granules. The amount of hydroxypropylmethylcellulose coated is 3% (w / w) based on the nuclear granules.
It is. Then, the obtained coated granules were mixed with ethyl cellulose, hydroxypropylmethyl cellulose, cross-linked polyacrylic acid polymer (Hibiswako 104 Wako Pure Chemical Industries, Ltd.) (7
(0:10:20 weight ratio) was sprayed and coated to obtain the desired composition. The coating operation is performed with a spiral flow type coating device (SFC-Labo Freund Industries), and the coating amount is 10% by weight based on the core granules. In addition, the dispersion is a mixture of ethanol and water (6: 1 volume ratio) ethyl cellulose, hydroxypropylmethyl cellulose, cross-linked acrylic acid polymer in the above ratio, add an appropriate amount of plasticizer to the uniformly dispersed liquid Prepared.

Example 10 150 g of morphine hydrochloride, 63 g of corn starch, 60 g of crystalline cellulose (Avicel), 9 g of calcium carboxymethyl cellulose (ECG-505), 9 of hydroxypropyl cellulose
Mix g, add an appropriate amount of Pluronic F-68 aqueous solution (6% (w / w)), and knead in a mortar. Next, the mixture was extruded with Dome Gran (DG-L1 Fuji Paudal) and granulated with Marumerizer (OJ-230 Fuji Paudal). The obtained granular material was dried under reduced pressure (40 ° C., 15 hours), and then sieved and classified to obtain 500-1250 μm core granules. The obtained core granules were put into a spiral flow type coating device (SFC-Labo Freund's industry) and sprayed with an aqueous solution of hydroxypropylmethyl cellulose to obtain coated core granules. The amount of hydroxypropylmethyl cellulose coated was 5 for nuclear granules.
% (W / w). Next, the obtained coated core granules were mixed with ethyl cellulose and a cross-linked acrylic acid polymer (BF Goodrich.
An aqueous dispersion containing Carbomer 934P) was sprayed to form a coating film composed of a polymer mixture (weight ratio: ethyl cellulose: cross-linked acrylic acid polymer = 80: 20) to obtain a desired composition. Spiral flow type coating equipment (SF
C-Labo Freund Industries), the coating amount is 35% (w / w) with respect to the nuclear granules. The coating solution was prepared by adding a suitable amount of acetylated monoglyceride (Myvaset 9- as a plasticizer) to a commercially available water suspension of ethyl cellulose (Aquacoat Asahi Kasei).
40 Koyo Shokai Co., Ltd.) and a cross-linking type acrylic acid polymer were added at the above ratio, and the mixture was diluted with an appropriate amount of water and used as a uniform dispersion liquid.

Example 11 Morphine hydrochloride 150 g, corn starch 63 g, crystalline cellulose (Avicel) 60 g, carboxymethyl cellulose calcium (ECG-505) 9 g, hydroxypropyl cellulose 9
Mix g, add an appropriate amount of Pluronic F-68 aqueous solution (6% (w / w)), and knead in a mortar. Next, the mixture was extruded with Dome Gran (DG-L1 Fuji Paudal) and granulated with Marumerizer (OJ-230 Fuji Paudal). The obtained granular material was dried under reduced pressure (40 ° C., 15 hours), and then sieved and classified to obtain 500-1250 μm core granules. The obtained core granules were put into a spiral flow type coating apparatus (SFC-Labo Freund Industries), and 7% (w / w) of the core granules were coated with ethyl cellulose as an intermediate layer. The coating solution was prepared by mixing a commercially available water suspension of ethyl cellulose (Aquacoat Asahi Kasei) with an appropriate amount of triethyl citrate (Citroflex Pfizer Pharmaceutical) and then diluting with an appropriate amount of water.
Next, Spiral Flow type coating equipment (SFC-Labo
Freund Industrial Co., Ltd. was used to coat the coated core granules with ethyl cellulose, hydroxypropylmethyl cellulose, cross-linked acrylic acid polymer (Hibiswako 104 Wako Pure Chemical Industries, Ltd.)
To form a coating film (composition ratio: 70:10:20 weight ratio, coating amount: 35% (w / w) with respect to core granules) and dry at 80 ° C for 2 hours to obtain the target composition. It was The coating solution was prepared by mixing a commercially available water suspension of ethyl cellulose (Aquacoat Asahi Kasei) with an appropriate amount of triethyl citrate (Citroflex Pfizer Pharmaceuticals) as a plasticizer, and further adding hydroxypropylmethyl cellulose and a cross-linking acrylic acid polymer in the above ratio. After the addition, the mixture was stirred until it became uniform.

Experimental Example 1 The composition obtained in Example 1 was subjected to an in vitro dissolution test. As the test method, the following test method I (acidic conditions) and test method II (neutral conditions) described in the Japanese Pharmacopoeia were used. Test Method I: 12th Revised Japanese Pharmacopoeia Dissolution Test I (Paddle Method) [First Solution (pH 1.2), 900 ml, 37 ° C., 1
00 rpm] Test method II: 12th revised Japanese Pharmacopoeia Dissolution test I (paddle method) [50 mM citrate buffer (pH 6.8), 900 m
1, 37 ° C., 100 rpm] The test results are shown in FIG. As is clear from the results shown in FIG. 1, the amount of drug (morphine hydrochloride) eluted was determined by the p
It is suppressed at pH 1.2 corresponding to H (-
○-), and even after 24 hours from the start of the test, it reached only about 40%. On the other hand, at pH 6.8, fast dissolution was shown (-●-), and at 6 hours after the start of the test, the dissolution amount of the drug was about the same as that of the drug at pH 1.2 for 24 hours, and about 100 hours after the start of the test. % Drug release was indicated.

Experimental Example 2 The composition obtained in Example 9 was subjected to an in vitro dissolution test. For the dissolution test, the above test method described in the Japanese Pharmacopoeia
I (acidic conditions) and Test Method II (neutral conditions) were used.
The results of the dissolution test are shown in [Fig. 2]. As is clear from the results shown in FIG. 2, the amount of drug (morphine hydrochloride) eluted at pH 1.2 (− ◯ −), which corresponds to the pH in the stomach, was suppressed more than that at pH 6.8 ( -●-). The elution amount at 6 hours after the start of the test was about 35% at pH 1.2.
Showed about 100% drug release.

Experimental Example 3 The composition obtained in Example 9 was administered to beagle dogs,
Comparison was made with the plasma concentration transition during administration of MS Contin, a commercial morphine sustained-release preparation used as a control preparation. Five fasting Beagle dogs were administered 30 mg morphine-containing composition or MS Contin, and 1,2,4,6,8,10,12,15,1 after administration.
Blood samples were taken at 8 and 24 hours to measure morphine concentration in plasma. After another drug washout period of 1 week, the same administration experiment was conducted. The results are shown in FIG. MS
The Tmax (time to reach the maximum plasma drug concentration) at the time of administration of Contin was 2 hours, after which the drug plasma concentration rapidly decreased. On the other hand, in the composition obtained in Example 9,
Tmax is 6 hours and then 10 ng / ml until 18 hours after administration
The above high drug concentration in plasma was sustained. AU up to 24 hours
C (area under the plasma concentration-time curve) was 276 ng · hr / ml at the time of MS-contin administration, whereas it was 460 ng · hr / ml in the composition obtained in Example 9, It was shown that the composition of the present invention can sustain the drug concentration in plasma without decreasing the bioavailability of the drug.

[0030]

INDUSTRIAL APPLICABILITY The controlled-release composition of the present invention, particularly the oral composition, suppresses drug release in the stomach that passes through the initial administration and then enhances release in the small intestine and the large intestine, so that the composition is extended over a long period of time. Therefore, the blood concentration of the drug can be sustained.

[Brief description of drawings]

FIG. 1 shows the effect of pH on the release amount of a drug (morphine hydrochloride) in vitro. In the figure, the horizontal axis is the time after the start of the test, and the vertical axis is the drug (morphine hydrochloride) elution amount (%).
-O- represents the time-dependent change in the release amount of the drug (morphine hydrochloride) under the condition of pH 1.2, and-●-represents the time-dependent change in the release amount of the drug under the condition of pH 6.8.

FIG. 2 shows the effect of pH on the release amount of a drug (morphine hydrochloride) in vitro. In the figure, the horizontal axis represents the time after the start of the test, and the vertical axis represents the elution amount (%) of the drug (morphine hydrochloride). In addition,-○-indicates the time-dependent change in the amount of drug released under the condition of pH 1.2, and-●-indicates the time-dependent change in the amount of drug released under the condition of pH 6.8.

FIG. 3 shows changes in plasma concentration of a drug (morphine) after administration to fasting Beagle dogs. In the figure, the horizontal axis represents the time after administration and the vertical axis represents the plasma concentration of the drug (morphine). In addition,-●-indicates the change with time of the plasma concentration of the drug (morphine) after administration of the composition obtained in Example 9,-○-
Shows the time course of plasma concentration of the drug (morphine) after administration of MS Contin used as a control.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area A61K 47/38 A61K 47/38 CD // A61K 31/135 31/135 31/485 AAH 31 / 485 AAH

Claims (23)

[Claims] 1. A controlled-release composition in which a drug-containing core is coated with a coating agent containing a water-insoluble substance and a swelling polymer having no basic group. 2. The controlled release composition according to claim 1, wherein the water-insoluble substance is a substance capable of forming a film. 3. The controlled release composition according to claim 1, wherein the water-insoluble substance is cellulose ether or cellulose ester. 4. The controlled release composition according to claim 1, wherein the water-insoluble substance is ethyl cellulose. 5. The controlled release composition according to claim 1, wherein the swellable polymer has an acidic group and exhibits pH-dependent swelling. 6. The controlled release composition according to claim 1, wherein the swellable polymer is a cross-linked acrylic acid polymer. 7. The swellable polymer has a molecular weight of about 1,000.
6. The controlled release composition according to claim 5, which is 000 to about 10,000,000. 8. The viscosity of the swellable polymer is from about 1,500 to about 60,000 cp in a 0.2% neutralization solution.
The controlled release composition described. 9. The controlled release composition according to claim 1, wherein the coating agent may further contain a hydrophilic substance. 10. The hydrophilic substance is a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group.
The controlled release composition described. 11. The controlled release composition according to claim 9, wherein the hydrophilic substance is hydroxypropylmethyl cellulose. 12. The controlled release composition according to claim 1, wherein the core is coated with a coating agent of 1% (w / w) or more. 13. The content of the water-insoluble substance and the swelling polymer in the coating agent is about 40 to about 95% (w / w).
And the controlled release composition of claim 1 which is about 1 to about 40% (w / w). 14. The content of the water-insoluble substance, the swelling polymer and the hydrophilic substance in the coating agent is about 40 to about 9.
10. The controlled release composition of claim 9 which is 5% (w / w), about 1 to about 40% (w / w) and 0 to about 40% (w / w). 15. The controlled release composition according to claim 1, wherein the water-insoluble substance is ethyl cellulose and the swelling polymer is a cross-linked acrylic acid polymer. 16. The drug according to claim 1, which is an opioid compound.
The controlled release composition described. 17. The controlled release composition according to claim 1, wherein the drug is morphine or a salt thereof. 18. The controlled release composition according to claim 1, wherein the drug is a sympathomimetic drug. 19. The controlled release composition according to claim 1, which contains a drug in an amount of 0.5% (w / w) or more. 20. The controlled release composition according to claim 1, which is a granule, a fine granule, a tablet or a capsule. 21. A coating agent comprising a water-insoluble substance and a swelling polymer having no basic group. 22. The coating agent according to claim 21, which may further contain a hydrophilic substance. 23. A method for producing a controlled release composition, which comprises coating a drug-containing core with a coating agent containing a water-insoluble substance and a swelling polymer having no basic group.