JP2002179554A - Medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine capable of maintaining an effective drug concentration in plasma for a long time right after administration and sustaining drug effectiveness. SOLUTION: There is disclosed a medicine comprising combining a rapid- releasing composition containing a drug substance and having within about 60 minutes of time when maximum drug concentration in blood is reached, and a release-controlling composition comprising coating a nucleus containing a drug substance by a coating agent containing a water-insoluble substance and a pH-dependent swellable polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a medicament capable of promptly obtaining an effective blood concentration and maintaining its efficacy for a long period of time, especially a preparation comprising a combination of an immediate release composition and a controlled release composition. .

[0002]

BACKGROUND OF THE INVENTION Opioid analgesics have recently received attention in the symptomatic treatment of severe pain in patients with terminal cancer. Conventional fast-acting opioid preparations such as oral morphine water require frequent administration to maintain the blood concentration at an effective concentration, and there are side effects and habitual problems due to rapid rise in blood drug concentration after administration. Therefore, the dose had to be carefully set. For the purpose of keeping the blood concentration of the medicinal component constant for a long time and reducing the number of administrations by maintaining the medicinal effect, sustained-release preparations of various drugs have been widely studied. For example, many controlled release systems have been studied, including capsule-type preparations in which a nucleus containing a drug is coated with a controlled-release membrane [Japanese Patent Laid-Open No. 7-14].
5056, JP-A-7-165609, JP-A-7-206679, Canadian Patent Application No. 2,062
8,366, JP-A-3-2114, JP-A-7-138189, EP0631781,
JP-T 8-501319, JP-T 9-50560
No. 52, Japanese Patent Publication No. 7-72130]. In such a capsule-type preparation, the controlled-release film usually comprises a hydrophobic coating containing a hydrophilic or water-soluble component, and is designed to control the release or release rate of the drug depending on the composition.

[0003]

DISCLOSURE OF THE INVENTION The present invention can achieve an effective blood concentration immediately after administration and can maintain its efficacy for a long time in the alleviation or resolution of severe pain associated with a disease and the suppression of the occurrence of pain. Pharmaceuticals, especially those that combine an immediate release composition containing an opioid analgesic and a controlled release composition containing the same, especially once a day, can control (prevent and treat) pain in patients Morphine preparation for oral administration.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies for the purpose of developing the above-mentioned medicine, and as a result, have found that a rapid-release drug containing a drug and having a maximum blood drug concentration reaching time of about 60 minutes or less is obtained. A water-insoluble substance and a nucleus comprising a drug,
Formulations in combination with a controlled release composition coated with a coating containing a pH dependent swellable polymer have been found to exhibit the desired drug release. After further study, the present invention was completed. That is, the present invention provides (1) a quick-release composition containing a drug and having a time to reach the maximum blood drug concentration of about 60 minutes or less, a nucleus containing the drug and a water-insoluble substance, and
A medicament in combination with a controlled release composition coated with a coating agent containing an H-dependent swellable polymer, (2) the medicament according to (1) above, wherein the drug is an opioid analgesic,
(3) the medicament according to the above (2), wherein the opioid analgesic is morphine or a pharmacologically acceptable salt thereof, and (4) an oral administration preparation comprising an immediate release composition and a controlled release composition (5) The medicine according to (1), wherein the coating agent further comprises a hydrophilic substance.
(6) the medicine according to the above (1), wherein the coating agent further contains an acid; (7) the medicine according to the above (5), wherein the hydrophilic substance is hydroxypropylmethylcellulose, hydroxypropylcellulose or polyethylene glycol;
The medicine according to (1), wherein the water-insoluble substance is ethyl cellulose; (9) the medicine according to (1), wherein the swellable polymer is a cross-linked acrylic acid polymer; and (10) a water-insoluble substance. About 30-90% (w / w), about 5-30% (w / w)
w) and a coating agent containing about 5 to 40% (w / w) and a nucleus coated about 5 to 35% (w / w) with respect to the nucleus; The weight ratio of the content of the opioid analgesic in the release composition and the controlled release composition is 3:
97 to 40:60, the medicine according to the above (1),
2) A quick-release composition comprising the medicament according to the above (1), which is a capsule, and (13) an opioid analgesic, wherein the time to reach the maximum drug concentration in blood is within about 60 minutes.

The drug used in the present invention is not particularly limited. For example, opioid compounds of morphine, hydromorphone, oxycodone, methadone, meperidine, dihydrocodeine, codeine, dihydromorphine, buprenorphine, fentanyl and pharmacologically acceptable salts thereof Opioid analgesics such as naproxen sodium,
Anti-inflammatory drugs, such as isopropylantipyrine, ibuprofen, ketoprofen, diclofenac sodium,
Sympathomimetics such as ephedrine hydrochloride, salbutamol sulfate, terbutaline sulfate, and phenylpropanolamine hydrochloride; antiallergic drugs such as phenylamine and terfenadine; antihistamines such as chlorpheniramine maleate, diphenhydramine hydrochloride, and clemastine fumarate; procainamide hydrochloride , Propranolol hydrochloride,
Cardiotonic drugs such as quinidine sulfate, antihypertensive drugs such as metoprolol, captopril, hydralazine hydrochloride, diltiazem, antibiotics such as amoxicillin, cephalexin, clarithromycin, penicillin V potassium, cloxacillin sodium, metronidazole hydrochloride, theophylline, salbutamol, etc. Bronchodilators, flutamide,
Antitumor drugs such as fluorouracil, procainamide,
Antiarrhythmic drugs such as quinidine, phenytoin sodium,
Anticonvulsants such as ethosuximide and sodium baproate, centrally acting substances such as diazepam, perphenazine, chlorpromazine hydrochloride, gastrointestinal drugs such as famotidine, ranitidine, lamethidine, omeprazole, lansoprazole, antidiabetic drugs such as tolbutamide, acarbose, voglibose, Cholinergic agents such as bethanechol hydrochloride, neostigmine bromide and carbachol, vitamins, amino acids, peptides and the like are used. Of these, an opioid analgesic, more preferably morphine or a pharmaceutically acceptable salt thereof is used. 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 bitartaric acid. As a salt of morphine, a salt with hydrochloric acid and sulfuric acid is preferably used. A drug in the immediate release composition,
The drugs in the controlled release composition are preferably the same drug in that the blood concentration of the drug can be maintained at a certain level or more for a long time immediately after administration. The drugs may be different as long as they show the same medicinal effect.

In the present invention, examples of the water-insoluble substance used in the coating agent of the controlled release composition include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl acetate, and the like.
Polyvinyl esters such as polyvinyl butyrate, acrylic acid / methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid Alkyl amide copolymer, poly (methyl methacrylate), polymethacrylate, polymethacrylamide,
Aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, especially Eudragit RS-100, RL-1
00, RS-30D, RL-30D, RL-PO, RS
Eudragits such as -PO (ethyl acrylate / methyl methacrylate / trimethyl methacrylate / ammonium ethyl copolymer) and Eudragit NE-30D (methyl methacrylate / ethyl acrylate copolymer) Acrylic acid-based polymers such as Co., Ltd., hardened oils such as hardened castor oil (eg, Lovely wax (Freund Corporation), etc.), waxes such as carnauba wax, fatty acid glycerin ester, paraffin,
Polyglycerin fatty acid esters and the like are used, preferably cellulose ether, and more preferably ethyl cellulose. When a cellulose ether is used as a water-insoluble substance, its viscosity is 5% solution (toluene:
Ethanol = 8: 2 (25 ° C.)) and about 5 to about 120
cps, preferably about 5 to about 50 cps.

The pH-dependent swellable polymer used in the present invention may be any polymer having an acidic dissociating group and exhibiting pH-dependent swelling, and has little swelling in an acidic region such as in the stomach. Further, a polymer having an acidic dissociating group which swells in a neutral region such as the small intestine and the large intestine is preferable.
Examples of such a polymer having an acidic dissociating group and exhibiting a pH-dependent swelling include, for example, Carbomer 93
4P, 940, 941, 974P, 980, 1342
Polycarbophil, calcium polycarbophil (both manufactured by BF Goodrich), Hibiswako 10
3, 104, 105, 304 (Wako Pure Chemical Industries, Ltd.)
And a cross-linked polyacrylic acid polymer such as
The viscosity of a polymer exhibiting pH-dependent swelling in water is
It is about 1,500 to about 60,000 cps, preferably about 3,000 to about 50,000 cps, more preferably about 10,000 to about 30,000 cps in a 0.2% neutralized solution. The molecular weight is about 1,000,000 to about 10,000,000.
00, preferably from about 1,000,000 to about 5,000,000.
00, more preferably from about 1,000,000 to about 3.5.
00,000.

[0008] The coating agent used in the controlled release composition (sustained release preparation) of the medicament of the present invention may further contain a hydrophilic substance. In this case, as the hydrophilic substance, for example, pullulan, dextrin, polysaccharides which may have a sulfate group such as an alkali metal alginate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyalkyl groups such as sodium carboxymethyl cellulose or carboxyalkyl Polysaccharides having a group, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like are used. Among these, as the hydrophilic substance, a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group or polyethylene glycol is preferably used, and hydroxypropylmethylcellulose, hydroxypropylcellulose or polyethylene glycol is more preferably used. Particularly, hydroxypropyl cellulose and polyethylene glycol are preferred. About 15 to 33% of methoxyl groups as the hydroxypropyl methylcellulose
(Preferably about 28-30%) and about 4.0-12.0% (preferably about 7.0-1%) hydroxypropoxyl groups.
2.0%) having a molecular weight of about 10,000 to about 1,2.
A thing of 00,000 is preferred. The hydroxypropyl cellulose has a molecular weight of about 10,000 to about 1,2.
50,000, preferably from about 10,000 to about 100,
000 are used. In addition, a 2% aqueous solution (20
C) is preferably 10.0 cps or less. The polyethylene glycol has a molecular weight of about 800 to about 1
Those having a molecular weight of 000, preferably 7,000 to 9,500 are preferably used. Especially polyethylene glycol 6
000 is preferred. The content of the water-insoluble substance in the coating agent of the controlled release composition is about 30 to about 90% (w / w);
Preferably about 35 to about 80% (w / w), more preferably about 40 to 75% (w / w), the swellable polymer content is about 3 to about 30% (w / w), preferably about 3
To about 15% (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 not more than about 50% (w / w), preferably about 5 to 5%.
About 40% (w / w), more preferably about 5 to about 35% (w / w)
/ w). Here, the above-mentioned% (w / w) indicates the weight% based on the coating agent composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating agent liquid.

[0009] The controlled-release composition of the medicament of the present invention comprises:
A core containing a drug is prepared as exemplified below, and then the obtained core is coated with a coating agent solution in which a water-insoluble substance and a pH-dependent swellable polymer are dissolved by heating or dissolved or dispersed in a solvent. It is manufactured by I. Preparation of core containing drug. The form of the nucleus containing the drug to be coated with the coating agent (hereinafter, may be simply referred to as the nucleus) is not particularly limited, but is preferably formed into particles such as granules or fine granules. When the core is granules or fine granules, the average particle size is preferably about 150 to 2,000 μm, more preferably about 50 to 2,000 μm.
0 to about 1,400 μm. Among them, in the present specification, the fine particles indicate particles having a particle diameter of about 75 to 500 μm. The nucleus can be prepared by a usual production method. For example, a drug is mixed with an appropriate excipient, binder, disintegrant, lubricant, stabilizer and the like, and is prepared by a wet extrusion granulation method, a fluidized bed granulation method and the like. The drug content of the nucleus is about 0.5
5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70
% (W / w). Examples of excipients contained in the core include sucrose, lactose, mannitol, sugars such as glucose,
Starch, crystalline cellulose, calcium phosphate, corn starch and the like are used. Among them, crystalline cellulose and corn starch are preferred. As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gum arabic, gelatin, starch and the like are used. As the disintegrant, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), crosslinked polyvinylpyrrolidone (crospovidone), low-substituted hydroxypropylcellulose (L-HPC) and the like are used. Among them, hydroxypropylcellulose, polyvinylpyrrolidone and low-substituted hydroxypropylcellulose are preferred. For example, talc, magnesium stearate and inorganic salts thereof are used as a lubricant and an anti-agglomeration agent, and polyethylene glycol and the like are used as a lubricant. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as stabilizers.

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.) onto inert carrier particles serving as the center 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 small amount of a drug or a mixture thereof with an excipient, a lubricant and the like is added. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and those having an average particle diameter of about 100 μm to about 1,500 μm are preferable. 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. In order to separate the drug contained in the nucleus from the coating agent, the surface of the nucleus may be coated with a protective agent. As the protective agent, for example, the above-mentioned hydrophilic substance, water-insoluble substance and the like are used. As the protective agent, polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose is used. The protective agent may contain, as a stabilizer, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid, and a lubricant such as talc. When a protective agent is used, its coverage is about 1 to about 15
% (W / w), preferably about 1 to about 10% (w / w), and more preferably about 2 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 core with, for example, a fluidized bed coating method or a pan coating method.

II. Coating of nucleus with coating agent The nucleus obtained in I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swellable polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. Produces a controlled release composition. Examples of the method of coating the nucleus with a coating agent solution include a spray coating method. The composition ratio of the water-insoluble substance, the swellable polymer or the hydrophilic substance in the coating solution is appropriately selected so that the content of each component in the coating becomes the above-mentioned content. The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), more preferably, about the core (not including the protective agent). About 5
To 35% (w / w).

As the solvent for the coating agent solution, water or an organic solvent can be used alone or in a mixture of both. The mixing ratio of water and organic solvent (water / organic solvent: weight ratio) when using the mixed solution can be changed in the range of 1 to 100%, preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance.For example, methyl alcohol, ethyl alcohol, isopropyl alcohol, lower alcohols such as n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform, Methylene chloride or the like is used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred. Water and a mixture of water and an organic solvent are preferably used as a solvent for the coating agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid may be added to the coating agent solution for stabilizing the coating agent solution. The operation in the case of coating by spray coating can be carried out by a usual coating method. Specifically, it is carried out by spray-coating a coating solution onto a nucleus by, for example, a fluidized bed coating method or a pan coating method. Can be. At this time, if necessary, talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid, etc. as a lubricant,
Glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol and the like may be added as a plasticizer. After coating with the coating agent, an antistatic agent such as talc may be mixed as necessary.

The immediate-release composition of the medicament of the present invention rapidly increases the blood drug concentration of the contained drug, and the time (Tmax) to reach the maximum blood drug concentration (Cmax) is within about 60 minutes. The shape of the pharmaceutical composition is not particularly limited as long as it is a regulated pharmaceutical composition, and may be liquid (solution, suspension, emulsion, etc.) or solid (particles, pills, tablets, etc.). Good.
Oral administration, parenteral administration such as injection is used,
Oral dosage forms are preferred. The quick-release composition may contain a carrier, an additive or an excipient (hereinafter, sometimes abbreviated as an excipient) commonly used in the field of formulation, in addition to the drug as the active ingredient. Good. The formulation excipient used is not particularly limited as long as it is a commonly used excipient.
For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Corporation)
Manufactured by Avicel PH101), powdered sugar, granulated sugar,
Mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine and the like are preferred, and corn starch and mannitol are preferred. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, and more preferably about 3 to 3 w / w% based on the total amount of the immediate release composition.
0 to about 97% w / w. The content of the drug in the immediate release composition is from about 0.5 to about 9 based on the total amount of the immediate release composition.
5%, preferably in the range of about 1 to about 60%. When the immediate release composition is an oral solid preparation,
Usually, it contains a disintegrant in addition to the above components. Examples of such disintegrants include carboxymethylcellulose calcium (ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.), croscarmellose sodium (e.g., Aczisol, manufactured by Asahi Kasei Corporation), and crospovidone (e.g., BASF Corp., Kollidon CL). Low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.) (The low-substituted hydroxypropylcellulose has a hydroxypropoxyl group of about 7.0.
１６16.0%, preferably about 10-12.9%, and those having an average particle diameter of 30 μm or less are preferred. ), Carboxymethyl starch (Matsuya Chemical Co., Ltd.,
Sodium carboxymethyl starch (produced by Kimura Sangyo Co., Ltd.), partially pregelatinized starch (produced by Asahi Kasei Corporation,
PCS) and the like, for example, those that disintegrate the granules by absorbing water, swelling upon contact with water, or forming a channel between the active ingredient constituting the core and the excipient can be used. These disintegrants can be used alone or in combination of two or more. The compounding amount of the disintegrant is appropriately selected depending on the kind and compounding amount of the drug to be used, the design of the release preparation, and the like. For example, about 0.05 to about 30 w / w%, Preferably it is about 0.5 to about 15% w / w. When the immediate release composition is an oral solid preparation, in addition to the above composition in the case of an oral solid preparation,
If desired, the solid preparation may further contain conventional additives. Examples of such additives include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.), lubricants (for example, , Polyethylene glycol,
Magnesium stearate, talc, light silicic anhydride (eg, Aerosil (Nippon Aerosil)), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid esters and polyoxyethylene sorbitan fatty acid esters, Non-ionic surfactants such as polyoxyethylene castor oil derivatives, etc.), coloring agents (eg, tar pigments, caramel, red pepper, titanium oxide, riboflavins), if necessary,
Flavoring agents (eg, sweeteners, flavors, etc.), adsorbents, preservatives, wetting agents, antistatic agents and the like are used. Further, an organic acid such as tartaric acid, citric acid, succinic acid and fumaric acid may be added as a stabilizer. As the binder, hydroxypropylcellulose (having a molecular weight of about 10,000 to
Those having about 1,250,000 are preferable. ), Polyethylene glycol (eg, PEG4000, PEG6000) and polyvinylpyrrolidone (having a molecular weight of about 25,000 to 3,000).
000, but preferably about 25,
000 to 1,200. ) Are preferably used. The quick-release composition can be prepared by mixing the above-mentioned components, kneading and molding as necessary, based on a usual preparation manufacturing technique. The mixing is performed by a generally used method such as mixing and kneading. Specifically, for example, when the rapid release composition is formed into particles, a vertical granulator, a universal kneading machine (manufactured by Hata Iron Works) by a method similar to the method for preparing the core of the sustained release composition. The mixture can be prepared by mixing using a fluidized bed granulator FD-5S (manufactured by Powrex Co., Ltd.) and then granulating by a wet extrusion granulation method, a fluidized bed granulation method, or the like.

In the present invention, the immediate-release composition and the controlled-release composition thus obtained may be separately formulated as they are or appropriately, together with excipients and the like, by a conventional method.
They may be administered at the same time or in combination at an arbitrary administration interval, or both may be used alone or as appropriate, together with excipients, etc., in one oral administration preparation (eg, granules, fine granules, tablets, capsules, etc.) And may be administered.
Both compositions may be made into granules or fine granules and filled into the same capsule or the like to prepare an oral administration preparation. In the medicament of the present invention, the administration ratio of the immediate release composition and the controlled release composition is appropriately selected depending on the administration protocol, and when the drug is an opioid analgesic, the amount of the opioid analgesic usually present in each composition. But 3:97 to 4 by weight
Both compositions may be administered in a range of 0:60, preferably 5:95 to 40:60.

The medicament of the present invention has low toxicity and can be used in mammals (eg, human, cow, pig, dog, cat, mouse, rat,
Rabbit, etc.) can be administered orally and can be used safely for the prevention and treatment of various diseases and the prevention and treatment of pain associated with diseases and injuries. The dosage of the medicament of the present invention varies depending on the type and content of the drug, the dosage form, the duration of drug release, the target disease, the target animal, and the like, but may be any effective amount of the drug. The dose of the drug per dose is, for example, once a day, the drug is morphine hydrochloride, and in the case of the prevention and treatment of pain in cancer patients and the like, the patient 1
About 4 mg to about 1000 mg / day, preferably about 20 mg to about 600 mg, as morphine hydrochloride, a drug per person
/ Day, more preferably in the range of about 50 mg to about 500 mg / day. However, as long as safety can be ensured, if necessary, beyond the above range,
It can also be administered. The dose of the medicament of the present invention is, for example, in the case of a once-daily oral preparation in which the drug is morphine hydrochloride, about 10 mg to about 2,000 mg per patient, preferably about 10 mg to about 2,000 mg / day for the purpose of treating pain. 1,50
It can be appropriately selected from the range of 0 mg.

[0016]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

[0017]

Example 1 Preparation of immediate release granules Morphine hydrochloride 13 g Corn starch 86 g Crystalline cellulose (Avicel) 83 g Carboxymethyl cellulose calcium (ECG-505) 6 g Hydroxypropyl cellulose (HPC-L) 6 g is mixed. And 100 ml of an aqueous solution (6 w / w%) of a polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68) solution, and kneaded. The resulting kneaded product was extruded with Dome Gran (DG-L1 Fuji Paudal) and granulated with a marmellaizer (OJ-230 Fuji Paudal). The obtained granules are dried under reduced pressure (40
℃, 16 hours), then sieved and classified, then the particle size 50
Granules of 0-1250 μm were obtained.

Example 2 Preparation of immediate release granules 88 g of morphine hydrochloride 300 g of mannitol 502 g corn starch 300 g 150 g of crystalline cellulose (Avicel) 30 g of calcium carboxymethylcellulose (ECG-505) 30 g of hydroxypropyl cellulose (HPC-L) The mixture was mixed, an appropriate amount of an aqueous solution of polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68) (7 w / w%) was added, and the mixture was kneaded with a vertical granulator (FM-VG type Powrex). The obtained kneaded material was extruded with Dome Gran (DG-L1 Fuji Paudal) and granulated with a marmellaizer (OJ-230 Fuji Paudal). The obtained granules were dried under reduced pressure (40 ° C., 16 hours), sieved and classified to obtain a particle size of 5
Granules of 00-1250 μm were obtained.

Example 3 Preparation of immediate-release preparation Morphine hydrochloride 100 g Corn starch 42 g Crystalline cellulose (Avicel) 40 g Carboxymethylcellulose calcium (ECG-505) 6 g Hydroxypropyl cellulose (HPC-L) 6 g was mixed, Polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68) aqueous solution (6
(w / w%) and 100 ml, and kneaded. The obtained kneaded material was extruded with Dome Gran (DG-L1 Fuji Paudal) and granulated with a marmellaizer (OJ-230 Fuji Paudal). The obtained granules are dried under reduced pressure (40
℃, 16 hours), after sieving and classification, 500-1
250 μm granules were obtained. The obtained granules are put into a spiral flow type coating apparatus (SFC-Labo Freund Corporation), and a mixture of ethanol and water (volume ratio: 4: 1)
Hydroxypropyl methylcellulose (HP
MC) to obtain a coated granule. HP coated
The amount of MC was adjusted to be 3% (w / w) based on the nuclear granules.

Example 4 Preparation of sustained-release (controlled-release) granules 200 g of the granules obtained in Example 3 were put into a spiral flow type coating apparatus (SFC-Labo Freund Corporation) and mixed with ethanol and water (volume ratio, 4: 1) Hydroxypropyl methylcellulose (HPMC)
Was sprayed to obtain coated granules. The amount of HPMC coated was adjusted to be 3% (w / w) based on the nuclear granules. Next, ethyl cellulose, HP
A coating solution composed of MC and a crosslinked polyacrylic acid polymer (Hibiswako 104, Wako Pure Chemical Industries, Ltd.) (70:10:20, weight ratio) was sprayed and coated to obtain a target composition. The coating operation is performed by a spiral flow type coating device (SFC-
Labo Freund Sangyo) and the coating amount is HPMC
10% w / w with respect to nuclear granules containing no. The coating solution was prepared by adding ethylcellulose, HPMC, and a cross-linked polyacrylic acid polymer (Hibiswako 104) to a mixture of ethanol and water (volume ratio, 7: 1) at the above ratio, and adding a suitable amount of a plasticizer to coat. Sieved, classified, particle size 500-1
250 μm sustained release granules were obtained.

Example 5 18.5 mg of the granules obtained in Example 3 and granules 1 obtained in Example 4
15 mg was filled in a No. 3 capsule to obtain a capsule containing the immediate release composition and the controlled release composition. Example 6 6 mg of granules obtained in Example 3 and 129 mg of granules obtained in Example 4
Was filled in a No. 3 capsule to obtain a capsule containing the immediate release composition and the controlled release composition. Example 7 37.5 mg of granules obtained in Example 2 and granules 1 obtained in Example 4
29 mg was filled in a No. 3 capsule to obtain a capsule containing the immediate release composition and the controlled release composition.

Example 8 Preparation of immediate-release granules An example of formulation of immediate-release granules is shown below. Ingredients Formulation 1 Formulation 2 Formulation 3 Formulation 4 Formulation 5 Morphine hydrochloride 24 mg 48 mg 48 mg 24 mg 48 mg D-mannitol 14 20 20--Microcrystalline cellulose---14.2 20 Corn starch 6.7 6.5 6.5 4.5 4.5 Low-substituted human hydroxypropyl Cellulose 1.5 1.5 1.5 1.5 1.5 Human peroxypropyl cellulose 1.5 1.5 1.5 1.0 1.0 Polyvinyl cellulose---3.0 3.0 Polyethylene glycol 6000---0.5 0.5 Tartaric acid 2.0 2.0-1.0 1.0 Citric acid--2.0--Magnesium stearate 0.3 0.5 0.5 0.3 0.5 Total 50 mg 80 mg 80 mg 50 mg 80 mg

[0023] After mixing, 3 g of human hydroxypropyl cellulose and 4 g of tartaric acid
Was added and the mixture was kneaded in a mortar. The obtained kneaded product was dried under reduced pressure (40 ° C., 16 hours), and then sized with a 16-mesh sieve. To 89.5 g of this sized powder, add 0.54 g of magnesium stearate,
Immediate release granules 1 were obtained.

[0024] After mixing, 1.5 g of human hydroxypropyl cellulose and tartaric acid 2
Then, 15 g of an aqueous solution containing g was added and kneaded in a mortar. The obtained kneaded product was dried under reduced pressure (40 ° C., 16 hours), and then sized using a 16 mesh sieve. To 71.5 g of the sized powder, 0.45 g of magnesium stearate was added to obtain immediate-release granules 2.

[0025] After mixing, add 2 g of human hydroxypropyl cellulose and polyhydroxy cellulose.
25 g of an aqueous solution containing 6 g and 2 g of tartaric acid was added and kneaded in a mortar. The obtained kneaded product was dried under reduced pressure (40 ° C., 16 hours), and then sized using a 16 mesh sieve. To 89.5 g of the sized powder, 0.54 g of magnesium magnesium stearate was added to obtain immediate-release granules 3.

[0026] After mixing, 1 g of human hydroxy cellulose and polyhydroxy cellulose
14 g of an aqueous solution containing 3 g and 1 g of tartaric acid was added and kneaded in a mortar. The obtained kneaded product was dried under reduced pressure (40 ° C., 16 hours), and then sized using a 16 mesh sieve. To 71.5 g of the sized powder, 0.45 g of magnesium magnesium stearate was added to obtain immediate-release granules 4.

[0027] After mixing, 12 g of polyethylene glycol 6000 and tartaric acid 2
Add 290 g of an aqueous solution containing 4 g, and add a vertical granulator (FM-VG-10).
(Hauleck). The obtained kneaded product is tom coulomb (DG-
(L1 type, Fujibattle) and granulated with Malmerizer (QJ-230). Dry the obtained granules under reduced pressure (40 ° C, 16 hours)
After that, it is sieved and classified.
1050 g was obtained.

(2) Production of underlay granules 22.5 g of human peroxyfluoromethyl methylcellulose 0.45 g of tartaric acid in aqueous ethanol
After dissolving in 340 ml (80% ethanol (W / W)), a suspension solution in which 4.05 g of talc was dispersed was prepared. Element obtained in (1)
450 g of (core) granules were placed in a Wurster-type fluidized granulator (FD-3, Powellec), and the undercoat liquid was sprayed to obtain about 470 g of undercoated granules.

[0029] (3) a controlled release membrane solution (coating agent solution) of Formulation Example Ingredient Formulation 1 Formulation 2 Formulation 3 ethylcellulose (45cps) 11.6 mg 12.2 mg 12.6 mg crosslinked port Riakuriru acid polymer (Haihi Bu Suwako 103) 1.6 1.6 1.6 Human peroxyfluorocellulose 4 4 4 Polyethylene glycol 6000 2.4 1.8 1.4 Tartaric acid 0.4 0.4 0.4 Cetyl alcohol 0.7 0.7 0.7 Talc 6 66 Ethanol / water (90/10 w / w) 480 480 480 Total 506.7 mg 506.7 mg 506.7 mg

(I) Production Example 1 of Sustained-Release Granules 200 g of the underlay granules obtained in (2) was placed in a Wurster-type fluidized granulator (FD-3, Powellec), and a controlled release membrane liquid formulation 1 was prepared. Was sprayed to obtain sustained-release granules. The coating amount was 25% by weight as a solid based on the underlay granules. After sieving and classification, about 250 g of sustained-release granules having a particle size of 600 to 1600 μm were obtained. This granule
0.25 g of talc was mixed with 250 g to obtain sustained-release granules 1

(Ii) Production Example 2 of Sustained-Release Granules 200 g of the underlay granules obtained in (2) was placed in a Wurster-type fluidized granulator (FD-3, Powellec), and a controlled release membrane liquid formulation 2 was prepared. And produced in the same manner as in (i).
0 g was obtained.

Example 10 Example of capsule formulation 150 mg of the immediate-release granules obtained in Example 8 (1) and Example 9
(3) 2184 mg of the sustained-release granules obtained in (ii) were packed in a capsule of size 2 to obtain a capsule containing 120 mg of morphine hydrochloride.

Example 11 Example of Capsule Preparation Example 4 The immediate-release granules (4 40 mg) obtained in Example 8 (4) and Example 9 were used.
(3) 169 mg of the sustained-release granules obtained in (i) were filled in a capsule of size 3 to obtain a capsule containing 60 mg of morphine hydrochloride.

Example 12 Example of Capsule Preparation Example 4 The immediate-release granules 4 20 mg obtained in Example 8 (4) and Example 9 were used.
(3) 235 mg of the sustained release granules obtained in (ii) were filled in a capsule of size 4 to obtain a capsule containing 30 mg of morphine hydrochloride.

Example 13 A formulation example of an immediate release preparation is shown below. Ingredients Formulation 1 Formulation 2 Formulation 3 Morphine hydrochloride 5 mg 10 mg 10 mg D-mannitol 33 28 38 Corn starch 6.7 6.7 6.65 Low-substituted human peroxyfluoro cellulose 1.5 1.5 1.5 Human peroxyfluoro cellulose 1.5 1.5 1.5 Tartaric acid 2.0-2.0 Citric acid-2.0- Magnesium stearate 0.3 0.3 0.35 Total 50 mg 50 mg 60 mg

[0036] After mixing, 15 g of human hydroxypropyl cellulose and 20 g of tartaric acid
150 g of an aqueous solution containing g.
(Hauleck). Dry the resulting kneaded product under reduced pressure (40
After 16 hours), the mixture was sieved using a power mill (Model P-3, Showa Kagaku Kikai Seisakusho) with a 1.0 mm punching screen to obtain sized powder.
To 447 g of the sized powder, 2.7 g of magnesium magnesium stearate was added to obtain a granule for filling. Using a capsule filling machine (6F type, Sanashiny), 50 mg of granules for filling are filled into a capsule of size 5, and morphine hydrochloride is filled with 5 m
About 3,000 capsules containing g were obtained.

[0037] After mixing, 15 g of human hydroxypropyl cellulose and 20 g of tartaric acid
150 g of an aqueous solution containing g.
(Hauleck). Dry the resulting kneaded product under reduced pressure (40
After 16 hours), the mixture was sieved using a power mill (Model P-3, Showa Kagaku Kikai Seisakusho) with a 1.0 mm punching screen to obtain sized powder.
To 536 g of the sized powder, 3.2 g of magnesium stearate was added to obtain granules for filling. Using a capsule filling machine (6F type, Sanashini), fill 60 mg of granules for filling into a capsule of size 5, and add 10 mg of morphine hydrochloride.
Approximately 1,500 capsules were obtained. In addition, 30 mg of the filled granules were similarly filled into a capsule of size 5 to obtain about 2,000 capsules containing 5 mg of morphine hydrochloride.

[0038]

According to the medicament of the present invention, the controlled-release composition releases a small amount of a medicinal ingredient in the stomach due to the action of a pH-dependent swellable polymer in the coating agent, but thereafter releases the upper and lower small intestine, The release rate increases with increasing swelling of the swellable polymer over 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 for, and the release of the drug is sustained in the living body for 6 hours or more, specifically, for 12 to 24 hours. On the other hand, since the immediate-release composition can reach an effective blood drug concentration immediately after administration, it has an effective advantage that plasma concentration can be maintained for a long time immediately after administration. Therefore, for example, when an opioid analgesic is used as a drug, according to the present invention, once-a-day administration for the prevention and treatment of pain, it is fast-acting and shows high bioavailability for as long as one day. And a medicament for an opioid analgesic.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/38 A61K 47/38 A61P 25/04 A61P 25/04 (72) Inventor Tomohiro Yoshinari Kobe City, Hyogo Prefecture 4-12-17 Suzurandai-Nishicho, Kita-ku F-term (reference) 4C076 AA54 BB01 CC01 EE09H EE23H EE32H EE45H FF31 FF33 4C086 AA01 AA02 CB23 MA02 MA03 MA05 MA37 MA52 NA11 NA12 ZA08

Claims (13)

[Claims] Claims: 1. An immediate-release composition containing a drug and having a maximum blood drug concentration reaching time of about 60 minutes or less, and a nucleus containing the drug comprising a water-insoluble substance and a pH-dependent swellable polymer. A medicine comprising a combination with a controlled release composition coated with a coating agent. 2. The method of claim 1, wherein the drug is an opioid analgesic.
The medicament according to claim. 3. The medicament according to claim 2, wherein the opioid analgesic is morphine or a pharmacologically acceptable salt thereof. 4. The medicament according to claim 1, which is an oral administration preparation containing an immediate release composition and a controlled release composition. 5. The medicament according to claim 1, wherein the coating agent further contains a hydrophilic substance. 6. The coating agent according to claim 1, further comprising an acid.
The medicament according to claim. 7. The medicament according to claim 5, wherein the hydrophilic substance is hydroxypropylmethylcellulose, hydroxypropylcellulose or polyethylene glycol. 8. The medicament according to claim 1, wherein the water-insoluble substance is ethyl cellulose. 9. The medicament according to claim 1, wherein the swellable polymer is a crosslinked acrylic acid polymer. 10. The controlled-release composition comprises a water-insoluble substance, a swellable polymer and a hydrophilic substance, each in an amount of about 30-90.
% (W / w), about 3-30% (w / w) and about 5-40%
(W / w) about 5 to 35% (w / w)
/ w) The medicament according to claim 5, which is coated. 11. The weight ratio of the content of the opioid analgesic in the immediate release composition and the controlled release composition is 3: 97-4.
2. The medicament according to claim 1, wherein the ratio is 0:60. 12. The medicament according to claim 1, which is a capsule. 13. An immediate-release composition containing an opioid analgesic and having a time to reach a maximum blood drug concentration of about 60 minutes or less.