Slow-release base

Abstract

Provided is a novel sustained release base.　The sustained release base is a combination of a polyvinyl alcohol polymer and a low degree of substitution hydroxypropyl cellulose.

Description

[Technical field]

[0001] The present invention relates to a sustained release base and the like. [Background technology]

[0002] Sustained-release preparations are preparations in which the drug is released into the body little by little over a long period of time after administration, and have the advantage that the frequency of administration can be reduced compared to immediate-release preparations. This is expected to reduce the burden on patients and improve compliance, and therefore they are widely used both in Japan and overseas.

[0003] Various polymers are used as bases for sustained-release preparations, and polyvinyl alcohol (hereinafter, also abbreviated as PVA) has also been used in some cases.

[0004] For example, Patent Documents 1 and 2 disclose that a preparation exhibiting excellent moldability and sustained release properties can be obtained by directly compressing a mixture of PVA or a PVA derivative and microcrystalline cellulose (hereinafter also abbreviated as MCC). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 6629835 [Patent Document 2] JP 2013-241341 A Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a novel sustained release base.

[0007] Another object of the present invention is to provide a novel formulation.

[0008] It is yet another object of the present invention to provide a method for producing a novel formulation. [Means for solving the problem]

[0009] Although the preparations described in Patent Documents 1 and 2 have improved moldability and sustained release properties, their effects are sometimes insufficient.

[0010] Means for Solving the Problems The present inventors conducted extensive research to solve the above problems and discovered that a combination of PVA and low-substituted hydroxypropyl cellulose can function as a base for sustained-release preparations. After further research, they completed the present invention.

[0011] That is, the present invention relates to the following inventions. [1] A sustained release base combining polyvinyl alcohol polymer and low-substituted hydroxypropyl cellulose. [2] A solid preparation comprising a polyvinyl alcohol polymer and low-substituted hydroxypropyl cellulose. [3] The formulation described in [2], which is a sustained release formulation. [4] The formulation according to [2] or [3], which is an oral dosage form. [5] The formulation according to any one of [2] to [4], wherein the subject of the formulation contains a drug. [6] The agent or preparation according to any one of [1] to [5], wherein the polyvinyl alcohol-based polymer has a viscosity of 15.0 mPa·s or more in a 4% by mass aqueous solution as measured in accordance with JIS K6726. [7] The agent or preparation according to any one of [1] to [6], wherein the polyvinyl alcohol polymer has an average degree of saponification of 65.0 to 90.0 mol %. [8] The agent or preparation according to any one of [1] to [7], wherein the polyvinyl alcohol polymer has an average degree of polymerization of 1,000 or more. [9] The agent or preparation according to any one of [1] to [8], wherein a mass ratio of the polyvinyl alcohol polymer:low-substituted hydroxypropyl cellulose is 40:60 to 80:20.

[10] The agent or preparation according to any one of [1] to [9], wherein the average degree of polymerization of the polyvinyl alcohol polymer is 1000 or more, and the mass ratio of the polyvinyl alcohol polymer:low-substituted hydroxypropyl cellulose is 40:60 to 80:20.

[11] A method for producing a solid formulation, comprising a step of directly compressing a mixture containing the agent according to any one of [1] and [6] to

[10] and a target substance of the formulation.

[12] Use of a combination of a polyvinyl alcohol polymer and low-substituted hydroxypropyl cellulose as a sustained-release base.

[13] A method for improving the sustained release properties of a solid preparation using a combination of a polyvinyl alcohol polymer and low-substituted hydroxypropyl cellulose. Effect of the Invention

[0012] In one aspect of the present invention, a novel sustained release base can be provided.

[0013] In one embodiment of the present invention, a sustained-release base useful for obtaining a solid preparation can be provided. For example, by compressing a mixture containing the sustained-release base of the present invention into tablets, a solid preparation (tablet) advantageous in terms of hardness and sustained release can be efficiently provided.

[0014] According to one aspect of the present invention, a solid preparation having high hardness can be provided. Such a preparation is less likely to crumble after molding, and therefore has excellent moldability.

[0015] In one aspect of the present invention, a novel formulation (particularly a solid formulation) can be provided.

[0016] In one aspect of the present invention, a method for producing a novel formulation may be provided. [Brief description of the drawings]

[0017] [Figure 1] 1 is a graph showing the change over time in dissolution rate in Examples 1 to 8. [Diagram 2] 1 is a graph showing the change over time in dissolution rate in Reference Examples 1 and 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] [Sustained release base] The sustained-release base of the present invention combines a polyvinyl alcohol polymer and low-substituted hydroxypropyl cellulose. The sustained-release base of the present invention may be a combination of these two components, and may contain both components in a single base, or may be a base in which multiple bases are combined so that the entire combination contains both components. In other words, the system in which multiple bases are combined may be a sustained-release base containing a polyvinyl alcohol polymer to be combined with low-substituted hydroxypropyl cellulose.

[0019] (Polyvinyl alcohol polymer) A polyvinyl alcohol polymer (also referred to as a PVA polymer, PVA, etc.) may usually be a saponification product of a vinyl ester polymer (a polymer having at least a vinyl ester as a polymerization component).

[0020] The average degree of saponification of the PVA-based polymer may be, for example, 90.0 mol% or less (e.g., 89.5 mol% or less), preferably 89.0 mol% or less (e.g., 88.5 mol% or less, 88.0 mol% or less), from the viewpoint of making it easier to suppress the expression of disintegration properties of low-substituted hydroxypropyl cellulose in the preparation or making it easier for the preparation to exhibit a sustained-release effect. The lower limit of the average saponification degree of the PVA polymer may be, for example, 60.0 mol% or more (e.g., 62.0 mol% or more), preferably 65.0 mol% or more (e.g., 68.0 mol% or more, 70.0 mol% or more, 75.0 mol% or more, 80.0 mol% or more).

[0021] The average degree of saponification of the PVA-based polymer may be set within an appropriate range (e.g., 60.0 mol% or more and 90.0 mol% or less) by appropriately combining these upper and lower limits (the same applies to others), and all combinations of the above upper and lower limits are included.

[0022] The average degree of saponification of the PVA polymer is not particularly limited, but may be measured, for example, by the saponification degree measuring method of JIS K6726.

[0023] The average degree of polymerization of the PVA-based polymer may be, for example, 800 or more (e.g., 900 or more, 1000 or more, 1100 or more, 1200 or more, 1300 or more, 1400 or more), preferably 1500 or more (e.g., 1600 or more), more preferably 2000 or more (e.g., 2100 or more, 2400 or more), etc., from the viewpoint of making it easier to suppress the expression of disintegration properties of low-substituted hydroxypropyl cellulose in the formulation or making it easier for the formulation to exhibit a sustained-release effect. The upper limit of the average polymerization degree of the PVA polymer may be, for example, 5000 or less (eg, 4900 or less), preferably 4500 or less (eg, 4400 or less), and more preferably 3500 or less (eg, 3400 or less).

[0024] The average degree of polymerization of the PVA-based polymer may be set within an appropriate range (e.g., 1500 or more and 3500 or less) by appropriately combining these upper and lower limits (the same applies to others), and all combinations of the above upper and lower limits are included.

[0025] The average degree of polymerization of the PVA polymer is not particularly limited, but may be measured, for example, by the average degree of polymerization measurement method of JIS K6726.

[0026] The viscosity of a 4% by mass aqueous solution of the PVA-based polymer (measured according to JIS K6726) may be, for example, 6.0 mPa·s or more (e.g., 8.0 mPa·s or more), preferably 10.0 mPa·s or more (e.g., 12.0 mPa·s or more), and particularly preferably 15.0 mPa·s or more (e.g., 18.0 mPa·s or more, 20.0 mPa·s or more), from the viewpoint of the sustained release properties of the formulation, etc. The upper limit of the viscosity of a 4 mass% aqueous solution of the PVA polymer (measured according to JIS K6726) may be, for example, 300 mPa·s or less (e.g., 280 mPa·s or less), preferably 240 mPa·s or less (e.g., 220 mPa·s or less), and more preferably 100 mPa·s or less (e.g., 80 mPa·s or less).

[0027] The viscosity of a 4% by mass aqueous solution of the PVA polymer may be set within an appropriate range (e.g., 15 mPa s or more and 240 mPa s or less) by appropriately combining these upper and lower limits (the same applies to others), and all combinations of the above upper and lower limits are included.

[0028] The PVA-based polymers may be used alone or in combination of two or more.

[0029] The PVA polymer may be a commercially available product or a synthesized product. The PVA polymer may be produced by a known method such as saponifying a polymer (vinyl ester polymer) of a polymerization component containing a vinyl ester monomer.

[0030] The vinyl ester monomer (vinyl ester monomer) is not particularly limited, but examples thereof include fatty acid vinyl esters [e.g., C esters such as vinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl caprylate, vinyl versatate, and vinyl monochloroacetate]. 1-20 Fatty acid vinyl esters (e.g., C 1-16 alkanoic acid vinyl esters, etc.], aromatic carboxylic acid vinyl esters [e.g., arene carboxylate vinyl esters such as vinyl benzoate (e.g., C 7-12arene carboxylic acid vinyl esters, etc.

[0031] The vinyl ester monomers may be used alone or in combination of two or more.

[0032] The vinyl ester monomer is at least a fatty acid vinyl ester (e.g., C 3 such as vinyl formate, vinyl acetate, vinyl propionate, and vinyl butyrate). 1-10 It is preferable that the acrylic acid-based copolymer contains a vinyl alkanoate, and from an industrial viewpoint, it may contain vinyl acetate.

[0033] The vinyl ester polymer may contain vinyl ester units, and may contain units derived from other monomers (monomers copolymerizable with vinyl ester monomers) as necessary (may be modified with other monomers).

[0034] The other monomer is not particularly limited, but examples thereof include α-olefins (e.g., ethylene, propylene, etc.), (meth)acrylic acid esters [e.g., (meth)acrylic acid alkyl esters such as methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, etc.], unsaturated amides [e.g., (meth)acrylamide, diacetone acrylamide, N-methylol acrylamide, etc.], unsaturated acids {e.g., unsaturated acids [e.g., (meth)acrylic acid, crotonic acid, maleic acid, itaconic acid, fumaric acid, etc.], unsaturated acid esters [unsaturated acid esters other than (meth)acrylic acid, for example, alkyl (methyl, ethyl, propyl esters, etc.), unsaturated acid anhydrides (maleic anhydride, etc.), salts of unsaturated acids [for example, alkali metal salts (for example, sodium salts, potassium salts, etc.), ammonium salts, etc.], glycidyl group-containing monomers [for example, allyl glycidyl ether, glycidyl (meth)acrylate, etc.], sulfonic acid group-containing monomers (for example, 2-acrylamido-2-methylpropanesulfonic acid, salts thereof, etc.), phosphoric acid group-containing monomers [for example, acid phosphooxyethyl (meth)acrylate, acid phosphooxypropyl (meth)acrylate, etc.], vinyl ethers (for example, alkyl vinyl ethers), allyl alcohol, etc., but are not particularly limited thereto.

[0035] The other monomers may be used alone or in combination of two or more.

[0036] When the polymerization components contain other monomers, the proportion of the other monomers in the polymerization components may be, for example, 50% by mass or less, 30% by mass or less, 20% by mass or less, or 10% by mass or less.

[0037] The proportion of the vinyl ester monomer in the polymerization components may be, for example, 50% by mass or more, preferably 70% by mass or more, and more preferably 90% by mass or more, or may be 100% by mass.

[0038] The PVA polymer may be one in which a part of the vinyl alcohol units has been modified by a reaction such as acetalization, etherification, acetoacetylation, or cationization.

[0039] The polymerization method of the polymerization components (for example, polymerization components containing vinyl ester monomers such as vinyl acetate) is not particularly limited, and examples thereof include conventionally known bulk polymerization, solution polymerization, suspension polymerization, emulsion polymerization, etc., but solution polymerization using methanol as a solvent is industrially preferred. For the solution polymerization, known initiators such as peroxides and azos can be used, and the polymerization degree of the vinyl ester polymer can be adjusted by changing the blending ratio of the polymerization components and methanol and the polymerization yield. In addition, commercially available vinyl ester polymers (such as polyvinyl acetate resins) can also be used as raw materials for obtaining PVA polymers.

[0040] As a method for saponifying a vinyl ester polymer (e.g., polyvinyl acetate), a conventionally known saponification method using an alkali catalyst or an acid catalyst can be applied, and among them, a method in which an alkali such as sodium hydroxide is added to a methanol solution of a vinyl ester polymer (e.g., polyvinyl acetate) or a mixed solution of a vinyl ester polymer (e.g., polyvinyl acetate) in methanol, water, methyl acetate, etc., and the acyl group (e.g., acetyl group) of the vinyl ester polymer (e.g., polyvinyl acetate) is subjected to alcoholysis while stirring and mixing is preferred from an industrial standpoint.

[0041] Thereafter, the obtained lump, gel or granule is pulverized, and the alkali added as necessary is neutralized. The solid and liquid components are then separated, and the solid is dried to obtain a PVA polymer.

[0042] The low-substituted hydroxypropyl cellulose may have a degree of substitution (degree of etherification) of, for example, about 0.05 to 1.0 (eg, 0.07 to 0.8), and preferably about 0.1 to 0.6 (eg, 0.15 to 0.5). The degree of substitution may be the average number of substituted hydroxyl groups per glucose unit in low-substituted hydroxypropyl cellulose.

[0043] In the low-substituted hydroxypropyl cellulose, the content (mass %) of the hydroxyl group substituents may be, for example, such that the hydroxypropoxy group content is 5 to 16 mass %.

[0044] The low-substituted hydroxypropyl cellulose may be used alone or in combination of two or more kinds.

[0045] In the sustained-release base of the present invention, the blending ratio of the polyvinyl alcohol polymer to the low-substituted hydroxypropyl cellulose may be, from the viewpoints of the sustained release properties and moldability of the preparation, for example, the polyvinyl alcohol polymer:low-substituted hydroxypropyl cellulose (mass ratio) may be about 30:70 to 90:10 (e.g., 33:67 to 87:13), preferably about 35:65 to 85:15 (e.g., 40:60 to 80:20), and more preferably about 43:57 to 78:22 (e.g., 45:55 to 75:25).

[0046] The subject of the sustained release base of the present invention is not particularly limited, and may be, for example, a medicine, a quasi-drug, a food, an agricultural chemical, etc. In addition, the subject may be an active ingredient, a nutrient (or a nutritional component), etc., or a drug (such as an active pharmaceutical ingredient). The target object may be either an organic or inorganic substance, or may be a mixture of these or an organic-inorganic hybrid.

[0047] Among such objects, the drug or active ingredient (or the drug or active ingredient contained in the object) is not particularly limited. Examples of such drugs include central nervous system drugs, brain metabolism improvers, brain circulation improvers, antiepileptic drugs, sympathomimetics, circulatory system drugs, respiratory system drugs, digestive system drugs, antibiotics, antitussives / expectorants, allergy drugs, antihistamines, dental and oral drugs, cardiac stimulants, arrhythmia drugs, diuretics, antipyretic analgesics / anti-inflammatory drugs, autonomic nerve acting drugs, antidepressants, antipsychotic drugs, antianxiety drugs, hypnotic sedatives, vasodilators, antihypertensive drugs, vasoconstrictors, peripheral vasodilators, blood coagulation inhibitors, hyperlipidemic drugs, choleretic drugs, antimalarials, lagogic drugs, psychotropic drugs, chemotherapy drugs, diabetes drugs, osteoporosis drugs, skeletal muscle relaxants, tonics and health medicines, antispasmodics, antirheumatic drugs, hormone drugs, alkaloid narcotics, sulfa drugs, gout treatment drugs, antineoplastic drugs, etc.

[0048] Examples of central nervous system drugs include diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethenzamide, ketoprofen, chlordiazepoxide, and citicoline.

[0049] Examples of cerebral metabolism improvers include meclofenixate hydrochloride and the like. An example of the cerebral circulation improver is vinpocetine. Antiepileptic drugs include, for example, phenytoin, carbamazepine, sodium valproate, etc. Sympathomimetics include, for example, isoproterenol hydrochloride.

[0050] Examples of cardiovascular drugs include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedivine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide dinitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrine hydrochloride, digitoxin, propranolol hydrochloride, alprenolol hydrochloride, etc.

[0051] Examples of respiratory system drugs include cough suppressants / expectorants, respiratory stimulants, bronchodilators, and the like. Examples of antitussives and expectorants include noscapine hydrochloride, carbetapentane citrate, dextromethorphan, dextromethorphan hydrobromide, isoaminyl citrate, dimemorfan phosphate, cloperastine hydrochloride, dextromertophan hydrobromide, theophylline, potassium guaiacolsulfonate, guaifenesin, guaifenesin codeine phosphate, and amproxol hydrochloride. Respiratory stimulants include, for example, levallorphan tartrate. Bronchodilators include, for example, theophylline, salbutamol, salbutamol sulfate, and the like.

[0052] Examples of digestive system drugs include gastrointestinal drugs, antacids, antiulcer drugs, digestive enzyme drugs, defecation promoters, antiemetic drugs, and the like. Examples of gastrointestinal drugs include stomachic digestive agents (e.g., diastase, sugar-containing pepsin, Scopolia extract, cellulase AP3, lipase AP, cinnamon oil), intestinal regulators (e.g., berberine chloride, resistant lactic acid bacteria, bifidobacteria), and the like. Examples of antacids include magnesium carbonate, sodium bicarbonate, magnesium aluminometasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide, and the like. Examples of antiulcer agents include benzimidazole drugs having antiulcer activity, such as 5-aminosalicylic acid, lansoprazole, omeprazole, rabeprazole, cimetidine, famotidine, ranitidine, ranitidine hydrochloride, pirenzepine hydrochloride, 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole. An example of a digestive enzyme agent is pancreatin. Examples of defecation promoters include bisacodyl. Antiemetics include, for example, diphenidol hydrochloride, metoclopramide and the like.

[0053] Examples of antibiotics include cephalexin, amoxicillin, cefaclor, pipmecillinam hydrochloride, cefotiam hexetil hydrochloride, cefadroxil, cefixime, cefditoren pivoxil, cefteram pivoxil, and cefpodoximiproxetil, monobactams such as synthetic antibacterial agents carumonam sodium, ampicillin, ciclacin, nalidixic acid, and enoxacin, macrolides such as erythromycin, penems, and carbapenem antibiotics.

[0054] Antiallergic drugs include, for example, amlexanox, seratrodast, and the like.

[0055] Examples of antihistamines include diphenhydramine hydrochloride, promethazine, promethazine hydrochloride, isothipendyl hydrochloride, dl-chlorpheniramine maleate, and the like.

[0056] Examples of dental and oral medications include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, and lidocaine. Cardiac stimulants include, for example, digoxin and caffeine. Examples of antiarrhythmic agents include procainamide hydrochloride, propranolol hydrochloride, pindolol, etc. Diuretics include, for example, caffeine, furosemide, isosorbide, hydrochlorothiazide, and the like.

[0057] Examples of antipyretic, analgesic, and anti-inflammatory agents include acetaminophen, aspirin, ibuprofen, ethenzamide, diphenhydramine hydrochloride, dl-chlorpheniramine maleate, diclofenac sodium, dihydrocodeine phosphate, salicylamide, aminopyrine, noscapine, methylephedrine hydrochloride, phenylpropanolamine hydrochloride, serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid, flufenamic acid, ketoprofen, indomethacin, bucolome, pentazocine, caffeine, anhydrous caffeine, sulpyrine, hydromorphone hydrochloride, and tapentadol hydrochloride.

[0058] Examples of autonomic nervous system agonists include dihydrocodeine phosphate, dl-methylephedrine hydrochloride, atropine sulfate, acetylcholine chloride, neostigmine, and the like.

[0059] Examples of vasodilators include nifedipine, carbocromene hydrochloride, molsidomine, and verapamil hydrochloride.

[0060] Examples of antihypertensive agents include captopril, delapril hydrochloride, hydralazine hydrochloride, labetalol hydrochloride, manidipine hydrochloride, candesartan cilexetil, methyldopa, perindopril erbumine, and the like.

[0061] The vasoconstrictor includes, for example, phenylephrine hydrochloride.

[0062] Examples of peripheral vasodilators include cinnarizine and the like.

[0063] Examples of blood coagulation inhibitors include dicoumarol.

[0064] Examples of antihyperlipidemic agents include cerivastatin sodium, simvastatin, pravastatin sodium, atorvastatin calcium hydrate, and the like.

[0065] Examples of the cholagogue include dehydrocholic acid and trepiptone.

[0066] Antimalarial agents include, for example, quinine hydrochloride.

[0067] Examples of antidiarrheal agents include loperamide hydrochloride.

[0068] Psychotropic drugs include, for example, chlorpromazine, reserpine, and the like.

[0069] Antidepressants include, for example, amphetamine, imipramine, maprotiline hydrochloride, paroxetine hydrochloride, and the like.

[0070] Antipsychotic drugs include, for example, paliperidone and the like.

[0071] Examples of anti-anxiety drugs include diazepam, alprazolam, chlordiazepoxide, etc.

[0072] Examples of hypnotic sedatives include estazolam, diazepam, nitrazepam, perlapine, and phenobarbital sodium.

[0073] Chemotherapeutic agents include, for example, sulfamethizole and the like.

[0074] Examples of the antidiabetic agent include glymidine sodium, glipizide, phenformin hydrochloride, buformin hydrochloride, metformin, metformin hydrochloride, tolbutamide, voglibose, pioglitazone hydrochloride, glibenclamide, troglidazone and the like. An example of an anti-osteoporosis drug is ipriflavone. Skeletal muscle relaxants include, for example, methocarbamol.

[0075] Examples of tonic health medicines include vitamins and their derivatives [e.g., vitamin A, vitamin B1, fursultiamine, vitamin B2 (riboflavin), vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate, tranexamic acid, etc.], minerals (e.g., calcium, magnesium, iron, etc.), proteins, amino acids, oligosaccharides, herbal medicines, etc.

[0076] Examples of the antispasmodic include meclizine hydrochloride, dimenhydrinate, scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride, etc. Antirheumatic drugs include, for example, methotrexate, bucillamine, and the like. Examples of hormone drugs include liothyronine sodium, dexmethasone sodium phosphate, prednisolone, oxendolone, leuprorelin acetate, and the like. Examples of alkaloid narcotics include opium, morphine hydrochloride, ipecac, oxycodone hydrochloride, opium alkaloid hydrochloride, cocaine hydrochloride, and the like. Examples of sulfa drugs include sulfisomidine and sulfamethizole. Examples of gout treatment drugs include allopurinol and colchicine. Anti-cancer agents include, for example, 5-fluorouracil, uracil, mitomycin, and the like.

[0077] The target substance may contain other ingredients (for example, various additives commonly used in this field, such as excipients, disintegrants, lubricants, anti-aggregating agents, and solubilizing agents).

[0078] Examples of the excipient include sugars such as sucrose, lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, and calcium sulfate, and preferably lactose, mannitol, and crystalline cellulose. Examples of disintegrants include carmellose or its salts, croscarmellose sodium, sodium carboxymethylstarch, crospovidone, crystalline cellulose, crystalline cellulose-carmellose sodium, and the like. Examples of the lubricant and anti-aggregating agent include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hardened oils, polyethylene glycols, and sodium benzoate. Examples of the solubilizing agent include organic acids such as fumaric acid, succinic acid, malic acid, and adipic acid. These additives can be used alone or in combination with one or more other additives. The content of other components (additives) can be appropriately determined depending on the type of drug, etc.

[0079] The objects may be used alone or in combination of two or more.

[0080] The object may be a solid at room temperature (eg, 10 to 40° C.).

[0081] The shape of the target object is preferably a powder (or powder). The size of such a powder (such as bulk material or bulk powder) is not particularly limited, but may be, for example, an average particle size of 500 μm or less (e.g., 5 to 400 μm), preferably 300 μm or less, and more preferably 100 μm or less (e.g., 10 to 80 μm).

[0082] The average particle size of the powder may be measured by a laser type particle size distribution measuring device or the like.

[0083] [Solid preparations, etc.] The present invention also includes a solid preparation comprising a polyvinyl alcohol-based polymer and low-substituted hydroxypropyl cellulose. The polyvinyl alcohol-based polymer and low-substituted hydroxypropyl cellulose may be those exemplified above. The subject of the preparation may be the subject exemplified above (subject of sustained-release base), and may generally be a powder.

[0084] The formulation of the present invention may be, for example, tablets, granules, capsules, etc., with tablets being preferred.

[0085] The formulation of the present invention may be suitably used as an oral preparation.

[0086] The preparation of the present invention may contain other components in addition to the polyvinyl alcohol polymer and low-substituted hydroxypropyl cellulose (and further, the subject of the preparation).

[0087] The other components may include additives that are commonly used in this field (for example, disintegrants, lubricants, anti-aggregating agents, solubilizing agents, etc.).

[0088] Examples of disintegrants include carmellose or its salts, croscarmellose sodium, sodium carboxymethylstarch, crospovidone, crystalline cellulose, crystalline cellulose-carmellose sodium, and the like.

[0089] Examples of the lubricant or anti-agglomerating agent include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hardened oils, polyethylene glycols, and sodium benzoate.

[0090] Examples of the solubilizing agent include organic acids such as fumaric acid, succinic acid, malic acid, and adipic acid.

[0091] These additives may be used alone or in combination of two or more.

[0092] The content of these additives can be appropriately determined depending on the types of ingredients in the preparation.

[0093] In the formulation, the proportion of the sustained release base of the present invention may be, for example, about 40 to 99.5 mass% (e.g., 42 to 99 mass%), preferably about 45 to 98.5 mass% (e.g., 50 to 98 mass%), and more preferably about 52 to 97.5 mass% (e.g., 55 to 97 mass%).

[0094] In the preparation, the proportion of the polyvinyl alcohol polymer may be, for example, about 20 to 60 mass% (e.g., 22 to 58 mass%), preferably about 25 to 55 mass% (e.g., 27 to 52 mass%), and more preferably about 30 to 50 mass% (e.g., 33 to 48 mass%).

[0095] In the preparation, the proportion of low-substituted hydroxypropyl cellulose may be, for example, about 5 to 60 mass% (e.g., 7 to 58 mass%), preferably about 10 to 55 mass% (e.g., 12 to 52 mass%), and more preferably about 15 to 50 mass% (e.g., 33 to 48 mass%).

[0096] In the preparation, the blending ratio of the polyvinyl alcohol polymer to the low-substituted hydroxypropyl cellulose may be, from the viewpoint of the sustained release properties, moldability, and the like of the preparation, the polyvinyl alcohol polymer:low-substituted hydroxypropyl cellulose (mass ratio) may be, for example, about 30:70 to 90:10 (e.g., 33:67 to 87:13), preferably about 35:65 to 85:15 (e.g., 40:60 to 80:20), and more preferably about 43:57 to 78:22 (e.g., 45:55 to 75:25).

[0097] The shape of the preparation of the present invention is not particularly limited, but when the preparation is a tablet, the shape of the tablet may be, for example, any of a disk shape, a lens shape, a rod shape, and the like.

[0098] Furthermore, the size of the formulation of the present invention is not particularly limited, but particularly when the formulation is a tablet, the size of the tablet may be, for example, a diameter (maximum diameter) of 3 mm or more (e.g., 4 to 15 mm, 5 to 12 mm, 8 to 11 mm, etc.).

[0099] The tablets can be produced by tableting a mixture (tabletting powder) containing at least a polyvinyl alcohol polymer, low-substituted hydroxypropyl cellulose, and the target substance of the formulation (or the sustained-release base of the present invention and the target substance of the formulation). The tablet powder may contain other ingredients as described above.

[0100] The tableting method is not particularly limited and any conventional tableting method can be used, but the direct compression method is particularly preferred. Direct compression can be carried out by compressing the tablet powder as it is in a tablet press.

[0101] The tablet may have a coating layer on the surface of the tablet.

[0102] In coated tablets, the components of the coating layer are not particularly limited, but examples thereof include resin materials such as cellulose-based resins (e.g., hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, etc.) and polyvinyl alcohol-based polymers.

[0103] The formulation of the present invention may be a sustained release formulation.

[0104] In the sustained release preparation of the present invention, the time (dissolution time) until the dissolution rate of the active ingredient reaches 80% or more (e.g., 80%) may be at least 2 hours or more, and preferably 3 hours or more (e.g., 4 hours or more, 5 hours or more, 6 hours or more, 7 hours or more, etc., depending on the type of active ingredient (e.g., active ingredient, nutrient, drug, etc.). In the sustained release formulation of the present invention, the upper limit of the time until the dissolution rate of the active ingredient reaches 80% or more (e.g., 80%) is not particularly limited, and may be, for example, 20 hours or less, 19 hours or less, 18 hours or less, 17 hours or less, 16 hours or less, 15 hours or less, etc.

[0105] Furthermore, in the sustained release formulation of the present invention, the time until the dissolution rate of the active ingredient reaches 50% may be, for example, 20 minutes or more, preferably 30 minutes or more (e.g., 40 minutes or more), more preferably 60 minutes or more (e.g., 80 minutes or more), depending on the type of active ingredient, etc. In the sustained release formulation of the present invention, the upper limit of the time for the dissolution rate of the active ingredient to reach 50% is not particularly limited, and may be, for example, 20 hours or less, 19 hours or less, 18 hours or less, 17 hours or less, 16 hours or less, 15 hours or less, etc.

[0106] The method for measuring the dissolution time is not particularly limited, but may be, for example, Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method), in which the test liquid is 900 mL of distilled water and the paddle rotation speed is 50 rpm. EXAMPLES

[0107] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these. In the following examples and comparative examples, unless otherwise specified, "%" and "parts" are by weight.

[0108] The various conditions are as follows:

[0109] <Average Degree of Saponification, Average Degree of Polymerization, and Viscosity of 4% by Mass Aqueous Solution> Measurements were performed in accordance with JIS K6726.

[0110] <Tableting conditions> Equipment used: Rotary tablet press VIRGO (manufactured by Kikusui Seisakusho) Tableting pressure: 15kN Rotation speed: 10 rpm Tablet weight: 200mg Tablet diameter: 8mmφ

[0111] <Evaluation of tablet hardness> The hardness of the obtained tablets was measured using a tablet hardness tester (TBH125, manufactured by ERWEKA). The measurement was carried out six times, and the average value was recorded as the measured value.

[0112] <Evaluation of dissolution rate> The dissolution test was carried out under the following test conditions. The time required for the dissolution rate to reach 80% was measured and calculated. Test method: Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) Test liquid: Distilled water 900mL Paddle rotation speed: 50 rpm Measurement sample: Tablets shown in the examples and comparative examples Detection wavelength: UV444nm (riboflavin) UV270nm (theophylline)

[0113] Table 1 shows the PVA polymers (PVA1 to 3) used in the following Examples and Reference Examples. The PVA whose product name is listed in Table 1 is manufactured by Nippon Vinyl Acetate & Poval. In addition, all of the PVA-based polymers were pulverized to adjust the average particle size to about 100 μm.

[0114] [Table 1]

[0115] The method for synthesizing PVA3 is shown below.

[0116] (Synthesis Example 1) A reaction vessel equipped with a stirrer, a condenser, a nitrogen gas inlet, and an initiator inlet was charged with 140 parts of methanol and 860 parts of vinyl acetate monomer in advance, and the system was replaced with nitrogen and then heated to 60°C. When reflux occurred, 2.0 parts of a 1.5% methanol solution of 2,2'-azobis 2,4-dimethylvaleronitrile was added as an initiator to start polymerization. The system was kept at 70°C during polymerization, and the pressure was adjusted to normal while nitrogen gas was flowing through the system. Furthermore, 2.0 parts of a 2% methanol solution of 2,2'-azobis 2,4-dimethylvaleronitrile was added 15 minutes after the start of polymerization. 2.3 hours after the start of polymerization, when the reaction yield of vinyl acetate reached 52%, the system was cooled and the polymerization was terminated. While adding methanol vapor to the resulting reaction product, the remaining vinyl acetate monomer was distilled off, and a 40% methanol solution of polyvinyl acetate was obtained. Next, 100 parts of methanol, 6 parts of water, and 6.3 parts of a 5.2% methanol solution of sodium hydroxide were added to 500 parts of the 40% methanol solution of polyvinyl acetate obtained above, and mixed thoroughly. A saponification reaction was carried out at 40°C for 40 minutes. The resulting gel-like substance was crushed, neutralized, washed with methanol, and then dried to obtain a PVA-based polymer 3 (PVA3) having a saponification degree of 65.0 mol% and an average polymerization degree of 2400.

[0117] Example 1 The ingredients other than magnesium stearate (St-Mg) were placed in a polyethylene bag in the blending ratio shown in Table 2, and the bag was inflated with air, and then mixed 100 times (the bag was shaken). St-Mg was then added to the bag, and the bag was inflated with air, and then mixed 30 times (the bag was shaken). The resulting mixture was compressed to prepare tablets. The tablet hardness and dissolution time of the obtained tablets were measured. The results are shown in Table 2. In Table 2, L-HPC refers to low-substituted hydroxypropyl cellulose. NBD-021 (Shin-Etsu Chemical Co., Ltd.) was used as L-HPC.

[0118] (Examples 2 to 8) Tableting was carried out in the same manner as in Example 1, except that the PVA polymer shown in Table 2 was used and the types and blending ratios of each component were shown in Table 2, and the tablet hardness and dissolution time were measured. The results are shown in Table 2.

[0119] Moreover, the change over time in the dissolution rates of Examples 1 to 8 is shown in FIG.

[0120] (Reference examples 1~2) Tabletting was carried out in the same manner as in Example 1, except that the PVA polymer shown in Table 2 was used and the type and blending ratio of each component was shown in Table 2, and the tablet hardness and dissolution time were measured. The results are shown in Table 2. In Table 2, Cl-PVP refers to crosslinked polyvinylpyrrolidone (Kollidon CL, BASF Japan). The change over time in dissolution rate in Reference Examples 1 and 2 is shown in FIG.

[0121] [Table 2]

[0122] As shown in Table 2, in the Examples, a preparation having both high moldability and excellent sustained release properties could be prepared by using a PVA polymer and low-substituted hydroxypropyl cellulose in combination. [Industrial Applicability]

[0123] According to the present invention, a novel sustained-release base can be provided. Such a base is useful for obtaining sustained-release preparations and the like.

Claims

1. A sustained-release base which is a combination of a polyvinyl alcohol polymer and low-substituted hydroxypropyl cellulose, and in which the mass ratio of polyvinyl alcohol polymer:low-substituted hydroxypropyl cellulose is 30:70 to 90:10 (excluding the case where the sustained-release base constitutes a preparation containing 2,480 g of ibuprofen, 161.2 g of croscarmellose sodium, 446.8 g of light anhydrous silicic acid, 1,169.1 g of crystalline cellulose, 139.9 g of low-substituted hydroxypropyl cellulose, 1,500 g of allylisopropylacetylurea, and 2,000 g of anhydrous caffeine).

2. A solid preparation comprising a polyvinyl alcohol polymer and low-substituted hydroxypropyl cellulose, in which the mass ratio of the polyvinyl alcohol polymer:low-substituted hydroxypropyl cellulose is 30:70 to 90:10 (excluding the case where the solid preparation comprises 2,480 g of ibuprofen, 161.2 g of croscarmellose sodium, 446.8 g of light anhydrous silicic acid, 1,169.1 g of crystalline cellulose, 139.9 g of low-substituted hydroxypropyl cellulose, 1,500 g of allylisopropylacetylurea, and 2,000 g of anhydrous caffeine).

3. 2. The agent according to claim 1, wherein the sustained release base does not contain any of ibuprofen, allylisopropylacetylurea, and anhydrous caffeine.

4. 3. The preparation according to claim 2, which is not a solid preparation containing ibuprofen and one member selected from the group consisting of allylisopropylacetylurea and anhydrous caffeine.

5. 5. The formulation according to claim 2 or 4, which is a sustained release formulation.

6. The preparation according to any one of claims 2 and 4 to 5, which is an oral preparation.

7. The formulation according to any one of claims 2 and 4 to 6, wherein the object of the formulation comprises a drug.

8. The base according to claim 1 or 3, or the preparation according to claims 2 or 4 to 7, wherein the polyvinyl alcohol-based polymer has a viscosity of 15.0 mPa·s or more in a 4% by weight aqueous solution as measured in accordance with JIS K6726.

9. The base according to claims 1, 3 and 8, or the preparation according to claims 2, 4 to 8, wherein the average degree of saponification of the polyvinyl alcohol polymer is 65.0 to 90.0 mol %.

10. The base according to claims 1, 3, and 8 to 9, or the preparation according to claims 2, 4 to 9, wherein the average degree of polymerization of the polyvinyl alcohol polymer is 1,000 or more.

11. The base according to claims 1, 3, and 8 to 10, or the preparation according to claims 2, 4 to 10, wherein the polyvinyl alcohol polymer is a saponified vinyl ester polymer and does not have a unit derived from a monomer copolymerizable with a vinyl ester monomer.

12. The base according to claims 1, 3, and 8 to 11, or the preparation according to claims 2, 4 to 11, wherein the mass ratio of polyvinyl alcohol polymer:low-substituted hydroxypropyl cellulose is 40:60 to 80:

20.

13. The base according to claims 1, 3, and 8 to 12, or the preparation according to claims 2, 4 to 12, wherein the average degree of polymerization of the polyvinyl alcohol-based polymer is 1000 or more, and the mass ratio of the polyvinyl alcohol-based polymer to the low-substituted hydroxypropyl cellulose is 40:60 to 80:

20.

14. A method for producing a solid preparation, comprising a step of directly compressing a mixture containing the base according to any one of claims 1, 3, and 8 to 13 and an object of a sustained-release base.

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