Method for producing a pharmaceutical composition, pharmaceutical composition, and method for producing an aqueous dispersion of a pharmaceutical composition

Abstract

To provide pharmaceutical compositions comprising an atomized hardly water soluble drug and production methods thereof, and methods for preparing pharmaceutical composition-containing aqueous dispersions with excellent stability.SOLUTION: Disclosed is a method for producing a pharmaceutical composition comprising the steps of: (a) mechanically kneading a hardly water-soluble drug, a water soluble inorganic salt and a water soluble organic solvent; and (b) removing the water soluble inorganic salt and water soluble organic solvent following the step (a), where the water soluble organic solvent satisfies the following (i) to (iii): (i) its molecular weight is 100-350; (ii) it has two or more functional groups comprising hydroxy group and / or ester group; (iii) its viscosity at 60°C is 2-150 mPa s.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing fine particles of a poorly water-soluble drug and a method for producing the same. The present invention also relates to a method for producing an aqueous dispersion containing the pharmaceutical composition.

Background Art

[0002] In order for a drug to exhibit its pharmacological effect, it is necessary for the drug to dissolve at the absorption site. However, poorly water-soluble drugs have a slow dissolution rate, and the dissolution process often becomes the rate-limiting step for absorption. As a means of improving the solubility of poorly water-soluble drugs, micronization of the drug can be mentioned. This is an approach that expects to dramatically increase the specific surface area by micronizing the drug to a size on the nano-order or an order close to the nano-order, and as a result, improve the dissolution rate.

[0003] The methods for micronizing drugs are roughly classified into dry grinding in a gas and wet grinding in a liquid atmosphere. Generally, it is difficult to grind dry to particles of 10 μm or less. On the other hand, wet grinding can grind to particles of 10 μm or less (Non-Patent Document 1). Furthermore, wet grinding is roughly classified into a mechanical crushing method using a media mill or the like and a pressure crushing method using a high-pressure homogenizer or the like (Patent Documents 1 and 2). However, further improvement has been demanded because any of these methods has problems such as insufficient micronization or problems with the stability when the drug fine particles are made into an aqueous dispersion.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] The problem to be solved by the present invention is to provide a pharmaceutical composition containing a micronized poorly water-soluble drug, a method for producing the same, and a method for producing an aqueous dispersion excellent in stability containing the pharmaceutical composition.

Means for Solving the Problems

[0006] As a result of intensive studies to solve the above problems, the present inventors have found that a pharmaceutical composition containing a micronized poorly water-soluble drug can be obtained by a method for producing a pharmaceutical composition comprising a step (a) of mechanically kneading together a poorly water-soluble drug, a water-soluble inorganic salt, and a specific water-soluble organic solvent, and a step (b) of removing the water-soluble inorganic salt and the water-soluble organic solvent after step (a), and thus the present invention has been accomplished.

[0007] That is, the present invention comprises a step (a) of mechanically kneading together a poorly water-soluble drug, a water-soluble inorganic salt, and a water-soluble organic solvent, and a step (b) of removing the water-soluble inorganic salt and the water-soluble organic solvent after step (a), and relates to a method for producing a pharmaceutical composition, characterized in that the water-soluble organic solvent satisfies the following (i) to (iii). (i) It has a molecular weight of 100 to 350. (ii) It has a total of 2 or more functional groups consisting of hydroxyl groups and / or ester groups. (iii) Its viscosity at 60°C is 2 to 150 mPa·s.

[0008] In addition, in the present invention, the poorly water-soluble drug is acetaminophen, ibuprofen, nifedipine, nicardipine, nimodipine, dipyridamole, disopyramide, prazosin hydrochloride, prednisolone, cortisone acetate, dexamethasone, betamethasone, beclomethasone propionate, fluticasone propionate, budesonide, fluocinonide acetonide, indomethacin, naproxen, ketoprofen, 7-(3,The method for producing the pharmaceutical composition according to claim 1, characterized by comprising at least one selected from the group consisting of 5-dimethoxy-4-hydroxycinnamoylamino)-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, phenacetin, ethotoin, primidone, diazepam, nitrazepam, clonazepam, digitoxin, spironolactone, triamterene, chlorthalidone, polythiazide, benzthiazide, griseofulvin, nalidixic acid, chloramphenicol, chlorzoxazine, meprobamate, mequitazine, bisbentiamine, triamcinolone acetonide, fluconazole, miconazole, rifampicin, dacarbazine, mitomycin C, bicalutamide, paclitaxel, ubenimex, clemastine fumarate, erythromycin, amphotericin B, cefixime, sulfasalazine, sparfloxacin, tinidazole, vidarabine, acyclovir, milrinone, digoxin, dipyridamole, pindolol, propafenone hydrochloride, amrinone, hydrochlorothiazide,trandolapril, candesartan cilexetil, urapidil, reserpine, methyldopa, norepinephrine, simvastatin, fluoxymesterone, stanozolol, estradiol, chlormadinone acetate, paricalcitol, madindol, sildenafil citrate, minoxidil, droperidol, quazepam, pentazocine, propiomazine, thioperamide, sulpiride, amoxapine, lisuride maleate, nicergoline, biperiden, levodopa, chlorphenesin carbamate, dantrolene sodium, norepinephrine, formoterol fumarate, riluzole, flumazenil), theophylline, methotrexate, amidotrizoic acid, cilostazol, adenine, tolbutamide, famotidine, ursodeoxycholic acid, sulindac, pyrenoxine, flunisolide, danazol, tacrolimus hydrate, β-carotene, curcumin, tulobuterol, pranlukast hydrate, zafirlukast and fenofibrate.,

[0009] Furthermore, the present invention relates to a method for producing the pharmaceutical composition, characterized in that the water-soluble organic solvent contains at least one selected from the group consisting of triacetin, tripropionin, tributyrin, triethyl citrate, and acetyltriethyl citrate.

[0010] Furthermore, the present invention relates to a pharmaceutical composition comprising a poorly water-soluble drug having an average primary particle diameter of 5 to 300 nm and 0.003 to 0.3 parts by mass of a water-soluble organic solvent with respect to 100 parts by mass of the poorly water-soluble drug, wherein the water-soluble organic solvent satisfies the following (i) to (iii). (i) It has a molecular weight of 100 to 350. (ii) It has a total of 2 or more functional groups consisting of hydroxyl groups and / or ester groups. It has. (iii) Its viscosity at 60 °C is 2 to 150 mPa·s.

[0011] Furthermore, the present invention relates to a pharmaceutical composition further characterized by containing a resin or a surfactant as an additive.

[0012] In addition, in the present invention, the poorly water-soluble drug is acetaminophen, ibuprofen, nifedipine, nicardipine, nimodipine, dipyridamole, disopyramide, prazosin hydrochloride, prednisolone, cortisone acetate, dexamethasone, betamethasone, beclomethasone propionate, fluticasone propionate, budesonide, fluocinolone acetonide, indomethacin, naproxen, ketoprofen, 7-(3,5-dimethoxy-4-hydroxycinnamoylamino)-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, phenacetin, ethotoin, primidone, diazepam, nitrazepam, clonazepam, digitoxin, spironolactone, triamterene, chlorthalidone, polythiazide, benzthiazide, griseofulvin, nalidixic acid, chloramphenicol, chlorzoxazone, meprobamate, mequitazine, bisbentiamine, triamcinolone acetonide, fluconazole, miconazole, rifampicin, dacarbazine, mitomycin C, bicalutamide, paclitaxel, ubenimex, clemastine fumarate, erythromycin, amphotericin B, cefixime, sulfasalazine, sparfloxacin, tinidazole, vidarabine, acyclovir, milrinone, digoxin, dipyridamole, pindolol, propafenone hydrochloride, amrinone, hydrochlorothiazide,trandolapril, candesartan cilexetil, urapidil, reserpine, methyldopa, norepinephrine, simvastatin, fluoxymesterone, stanozolol, estradiol, chloramadinone acetate, falecalcitriol, madindol, sildenafil citrate, minoxidil, droperidol, quazepam, pentazocine, propiomazine, thioperamide, sulpiride, amoxapine, lisuride maleate, nicergoline, biperiden, levodopa, chlorphenesin carbamate, dantrolene sodium, norepinephrine, formoterol fumarate, riluzole, flumazenil), theophylline, methotrexate, amidotrizoic acid, cilostazol, adenine, tolbutamide, famotidine, ursodeoxycholic acid, sulindac, pyrenoxine, flunisolide, danazol, tacrolimus hydrate, β-carotene, curcumin, tulobuterol, pranlukast hydrate, zafirlukast and fenofibrate, characterized in that it comprises at least one selected from the group consisting of.,

[0013] Furthermore, the present invention relates to the pharmaceutical composition, characterized in that the water-soluble organic solvent contains at least one selected from the group consisting of triacetin, tripropionin, tributyrin, triethyl citrate, and acetyltriethyl citrate.

[0014] Furthermore, the present invention relates to a method for producing an aqueous dispersion of a pharmaceutical composition, characterized in that the pharmaceutical composition is suspended and dispersed in water by ultrasonic treatment, homogenizer treatment, or bead mill dispersion treatment.

Advantages of the Invention

[0015] According to the present invention, it is possible to provide a pharmaceutical composition containing a micronized poorly water-soluble drug, a method for producing the same, and a method for producing an aqueous dispersion having excellent stability containing the pharmaceutical composition.

Embodiments for Carrying Out the Invention

[0016] Hereinafter, the present invention will be described in detail.

[0017] <Method for Producing Pharmaceutical Composition> The method for producing the pharmaceutical composition of the present invention includes a step (a) of mechanically kneading a poorly water-soluble drug, a water-soluble inorganic salt, and a water-soluble organic solvent together, and after step (a), a step (b) of removing the water-soluble inorganic salt and the water-soluble organic solvent, and the water-soluble organic solvent is characterized by satisfying the following (i) to (iii). (i) It has a molecular weight of 100 to 350. (ii) It has a total of 2 or more functional groups consisting of hydroxyl groups and / or ester groups. (iii) Its viscosity at 60°C is 2 to 150 mPa·s.

[0018] <Poorly Water-Soluble Drug> As the drug in the present invention, components for pharmaceuticals and components for health foods can be mentioned, and examples thereof include pharmaceutical active ingredients described in "Japanese Pharmacopoeia", "Pharmaceutical Standards for Drugs Outside the Japanese Pharmacopoeia (Extra Pharmacopoeial Standards)", "United States Pharmacopoeia (USP)", "National Formulary (NF)", and "European Pharmacopoeia (EP)".

[0019] Examples of components for pharmaceuticals include antipyretic agents, analgesics, anti-inflammatory agents, gout medications, hyperuricemia treatment medications, sleeping pills, sedatives, anti-anxiety agents, antipsychotics, antidepressants, anti-manic agents, psychostimulants, anti-epileptic agents, muscle relaxants, Parkinson's disease treatment medications, autonomic nervous system acting agents, cerebral circulation and metabolism improving agents, allergy treatment medications, cardiotonic agents, anti-anginal agents, β-blockers, Ca antagonists, antiarrhythmic agents, antidiuretic agents, diuretics, antihypertensive agents, peripheral circulatory disorder treatment medications, hyperlipidemia medications, hypertensive agents, respiratory stimulants, bronchodilators, asthma treatment medications, chronic obstructive pulmonary disease treatment medications, antitussives, expectorants, peptic ulcer treatment medications, laxatives, antidiarrheal and intestinal regulators, diabetes medications, corticosteroid preparations, sex hormone preparations, osteoporosis medications, bone metabolism improving agents, vitamin preparations, hematopoietic agents, blood coagulation preparations, chemotherapeutic agents, antibiotics, antifungal agents, antiviral agents, anticancer agents, immunosuppressive agents, ophthalmic medications, otolaryngological medications, oral medications, dermatological medications, radiopharmaceuticals, diagnostic medications, life improvement medications, and traditional Chinese medicines, etc., and organic compounds applicable thereto.

[0020] Specifically, for example, aspirin, aluminum aspirin, acetaminophen, ethenzamide, salsalate, salicylamide, lactylphenetidine, isothipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheteolol hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, tonzylamine hydrochloride, phenetidine hydrochloride, methdilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyl disulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theophyllinate, mebumhydrolin napadisilate, promethazine methylene disalicylate, carbinoxamine maleate, d l - chlorpheniramine maleate, d - chlorpheniramine maleate, dipheteolol phosphate, alloclamide hydrochloride, cloperastine hydrochloride, pentoxyverine citrate (carbetapentane citrate), tipepidine citrate, dibunate sodium, dextromethorphan hydrobromide, dextromethorphan - phenolphthalein phosphate, tipepidine hibenzate, cloperastine fendizoate, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl - methylphenidate hydrochloride, dl - methylphenidate saccharin salt, potassium guaiacolsulfonate, guaifenesin, sodium benzoate caffeine, caffeine, anhydrous caffeine, vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivatives and their salts, vitamin B6 and its derivatives and their salts, nicotinamide, calcium pantothenate, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum - aminoacetate (aluminum glycinate), aluminum hydroxide gel (as dry aluminum hydroxide gel), dried aluminum hydroxide gel, aluminum hydroxide - magnesium carbonate mixed dried gel, coprecipitated product of aluminum hydroxide - sodium bicarbonate, coprecipitated product of aluminum hydroxide - calcium carbonate - magnesium carbonate, coprecipitated product of magnesium hydroxide - potassium aluminum sulfate, magnesium carbonate, magnesium aluminometasilicate, ranitidine hydrochloride, cimetidine, famotidine, naproxen, diclofenac sodium, piroxicam, azulene, indomethacin, ketoprofen, ibuprofen, diphenidol hydrochloride, diphenhydramine hydrochloride, promethazine hydrochloride, meclizine hydrochloride, dimenhydrinate, diphenhydramine tannate, phenethazine tannate, diphenhydramine theoclate, diphenhydramine fumarate, promethazine methylenedisalicylate, scopolamine hydrobromide, oxyfencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, methylatropine bromide, methylanisotropine bromide, methylscopolamine bromide, methyl - 1 - bromideThiamine, Methylbenactyzium Bromide, Belladonna Extract, Isopropamide Iodide, Diphenylpiperidinomethyl Dioxolane Iodide, Papaverine Hydrochloride, Aminobenzoic Acid, Cesium Oxalate, Ethyl Piperidylacetylaminobenzoate, Aminophylline, Diprophylline, Theophylline, Sodium Bicarbonate, Fursultiamine, Isosorbide Nitrate, Ephedrine, Cephalexin, Ampicillin, Sulfisoxazole, Scralfate, Allylisopropylacetylurea, Bromvalerylurea, etc., Ma Huang, Nanten Ditsu, Aconite Root, Ondgi, Licorice Root, Platycodon Root, Schizandra Fruit, Schizandra Stem, Senega Root, Baimo, Wikyou, Oubaku, Ouren, Gadutsu, Chamomile Flower, Cinnamon Bark, Gentiana Root, Gouou, Animal Gallbladder (including Yutan), Shajin, Ginger Rhizome, Sosojutsu, Clove Bud, Chinpi, Byakujutsu, Earth Dragon, Ginseng Root, Carrot Root, Canokoso, Buttonpi, Sansho Fruit and their extracts, etc., Insulin, Vasopressin, Interferon, Urokinase, Serratiopeptidase, Somatostatin, etc., the pharmaceutical active ingredients described in the "Japanese Pharmacopoeia", "Japanese Pharmaceutical Excipients Standard (Outside the Pharmacopoeia)", "United States Pharmacopoeia (USP)", "National Formulary (NF)", "European Pharmacopoeia (EP)".

[0021] As active ingredients for health foods, there is no limitation as long as they are ingredients formulated for the purpose of enhancing health. For example, green juice powder, aglycon, agaricus, ashwagandha, astaxanthin, acerola, amino acids (valine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cystine, tyrosine, arginine, alanine, aspartic acid, seaweed powder, glutamine, glutamic acid, glycine, proline, serine, etc.), alginic acid, ginkgo leaf extract, sardine peptide, turmeric, uronic acid, echinacea, houttuynia cordata, oligosaccharide, oleic acid, nucleoprotein, bonito peptide, catechin, potassium, calcium, carotenoid, garcinia, L-carnitine, chitosan, conjugated linoleic acid, aloe vera, gymnema sylvestre extract, citric acid, cumiskutin, glyceride, glycerol, glucagon, curcumin, glucosamine, L-glutamine, chlorella, cranberry extract, cat's claw, germanium, enzyme, ginseng extract, coenzyme Q10, collagen, collagen peptide, coleus forskolin, chondroitin, psyllium husk powder, hawthorn extract, saponin, lipid, L-cystine, perilla extract, citrimax, fatty acid, plant sterol, seed extract, spirulina, squalene, white willow, ceramide, selenium, St. John's wort extract, soy isoflavone, soy saponin, soy peptide, soy lecithin, monosaccharide, protein, chestnut tree extract, iron, copper, docosahexaenoic acid, tocotrienol, nattokinase, nattokinase culture extract, sodium niacinate, nicotinic acid, disaccharide, lactic acid bacteria, garlic, saw palmetto, germinated rice, adlay extract, herb extract, valerian extract, pantothenic acid, hyaluronic acid, biotin, chromium picolinate, vitamin A, vitamin A2, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, hydroxytyrosol, bifidobacteria, brewer's yeast, fructooligosaccharide, flavonoid, butcher's broom extract, black cohosh, blueberry, prune extract, proanthocyanidin, protein, propolis, bromelain, probiotics, phosphatidylcholine, phosphatidylserine, β-carotene, peptide, safflower extract, maitake extract, maca extract, magnesium, maria thistle, manganese, mitochondria, mineral, mucopolysaccharide, melatonin, mesima cob, merilot extract powder, molybdenum, vegetable powder, folic acid, lactose, lycopene, linoleic acid, lipoic acid, phosphorus, lutein, lecithin, rosmarinic acid, royal jelly, DHA, EPA, etc.

[0022] In the present invention, among these drugs, "poorly water-soluble drugs" are used. "Poorly water-soluble" means that in the 17th revised Japanese Pharmacopoeia, it refers to the fact that the amount of water required to dissolve 1 g of solute is 30 mL or more.

[0023] Examples of poorly water-soluble drugs used in the present invention include acetaminophen, ibuprofen, nifedipine, nicardipine, nimodipine, dipyridamole, disopyramide, prazosin hydrochloride, prednisolone, cortisone acetate, dexamethasone, betamethasone, beclomethasone propionate, fluticasone propionate, budesonide, fluocinolone acetonide, indomethacin, naproxen, ketoprofen, 7-(3,5-dimethoxy-4-hydroxycinnamoylamino)-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinolinone, phenacetin, ethotoin, primidone, diazepam, nitrazepam, clonazepam, digitoxin, spironolactone, triamterene, chlorthalidone, polythiazide, benzthiazide, griseofulvin, nalidixic acid, chloramphenicol, chlorzoxazine, meprobamate, mequitazine, bisbentiamine, triamcinolone acetonide, fluconazole, miconazole, rifampicin, dacarbazine, mitomycin C, bicalutamide, paclitaxel, ubenimex, clemastine fumarate, erythromycin, amphotericin B, cefixime, sulfasalazine, sparfloxacin, tinidazole, vidarabine, acyclovir, milrinone, digoxin, dipyridamole, pindolol, propafenone hydrochloride, amrinone, hydrochlorothiazide,trandolapril, candesartan cilexetil, urapidil, reserpine, methyldopa, norepinephrine, simvastatin, fluoxymesterone, stanozolol, estradiol, chloramadinone acetate, paricalcitol, mazindol, sildenafil citrate, minoxidil, droperidol, quazepam, pentazocine, propiomazine, thioperamide, sulpiride, amoxapine, lisuride maleate, nicergoline, biperiden, levodopa, chlorphenesin carbamate, dantrolene sodium, norepinephrine, formoterol fumarate, riluzole, flumazenil, theophylline, methotrexate, amidotrizoic acid, cilostazol, adenine, tolbutamide, famotidine, ursodeoxycholic acid, sulindac, pyrenoxine, flunisolide, danazol, tacrolimus hydrate, β-carotene, curcumin, tulobuterol, pranlukast hydrate, zafirlukast, fenofibrate and the like.,

[0024] <Water-soluble inorganic salt> The "water-soluble inorganic salt" used in the production method of the present invention has an effect of grinding and micronizing poorly water-soluble drugs. By using water-soluble ones, it is possible to remove them by washing. Examples of the inorganic salts that can be used include, for example, sodium chloride, potassium chloride, ammonium chloride, sodium sulfate, magnesium sulfate, potassium sulfate, calcium sulfate, sodium malate, sodium citrate, disodium citrate, sodium dihydrogen citrate, potassium dihydrogen citrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate, etc. Among these, sodium chloride is preferably used.

[0025] The addition amount of the water-soluble inorganic salt used in the production method of the present invention is not particularly limited, but from the viewpoints of both treatment efficiency and production efficiency, it is preferably 50 to 2000 parts by mass, more preferably 300 to 1000 parts by mass, based on 100 parts by mass of the poorly water-soluble drug. Further, the inorganic salt may be used alone or in combination of a plurality of types.

[0026] <Water-soluble organic solvent> The water-soluble organic solvent in the present invention serves to moisten the poorly water-soluble drug and the water-soluble inorganic salt, and it is necessary that it dissolves (mixes) in water and does not substantially dissolve the water-soluble inorganic salt used. Further, the water-soluble organic solvent used in the present invention satisfies the following (i) to (iii). That is, (i) The molecular weight is 100 to 350. (ii) The total number of functional groups composed of hydroxyl groups and / or ester groups is 2 or more and has. (iii) The viscosity at 60 °C is 2 to 150 mPa·s. It satisfies all of the above conditions. If the viscosity is high, the viscosity of the kneaded product of the drug and the inorganic salt increases, the movement of the inorganic salt as the grinding agent is inhibited, and the effect of micronizing the drug cannot be sufficiently obtained. The viscosity of the water-soluble organic solvent in the specification of the present application is a value measured using a cone and plate type rotational viscometer (viscosity measuring instrument manufactured by Toki Sangyo Co., Ltd.: TVE-20L) in accordance with the provisions of JIS Z 8803.

[0027] Examples of water-soluble organic solvents that satisfy the above (i) to (iii) include 2-ethyl-1,3-hexanediol (16.6 mPa·s), 2,4-diethyl-1,5-pentanediol (67.2 mPa·s), monoacetin (13.7 mPa·s), diacetin (8.2 mPa·s), triacetin (4.1 mPa·s), tripropionin (2.7 mPa·s), tributyrin (3.3 mPa·s), 2-methylpentane-2,4-diol (5.8 mPa·s), 2-butyl-2-ethyl-1,3-propanediol (43.7 mPa·s), 1,5-pentanediol (20.9 mPa·s), 1,6-hexanediol (25.2 mPa·s), 1,2,6-hexanetriol (137.6 mPa·s), triethyl citrate (35.2 mPa·s), and acetyltriethyl citrate (53.7 mPa·s).

[0028] In the pharmaceutical composition of the present invention, it is preferable that the water-soluble organic solvent remains within a specific range. As the residual amount, the water-soluble organic solvent is in the range of 0.003 to 0.3 parts by mass per 100 parts by mass of the poorly water-soluble drug contained in the pharmaceutical composition. This is because when the water-soluble organic solvent remains within a specific range, it has the effect of suppressing the aggregation of the micronized poorly water-soluble drug. From the perspective of residue, a water-soluble organic solvent having no hydroxyl group functional group and a total of 2 or more ester groups is more preferable. This is because the hydroxyl group promotes aggregation by hydrogen bonding. Considering these comprehensively, among the water-soluble organic solvents described above, diacetin, triacetin, tripropionin, tributyrin, triethyl citrate, and acetyltriethyl citrate are desirable.

[0029] The amount of the water-soluble organic solvent used in the production method of the present invention is not particularly limited, but it is preferably 5 to 1000 parts by mass, more preferably 50 to 500 parts by mass, based on 100 parts by mass of the poorly water-soluble drug. Also, the water-soluble organic solvent in the present invention may be used alone or in combination of a plurality of types. The use of solvents other than the water-soluble organic solvent in the present invention is not excluded as long as it does not depart from the gist of the present invention. However, from the viewpoint of effectively enhancing the micronization of the poorly water-soluble drug, it is preferably substantially the water-soluble organic solvent in the present invention that is used.

[0030] <Pharmaceutical composition> The pharmaceutical composition of the present invention comprises a step (a) of mechanically kneading together a poorly water-soluble drug, a water-soluble inorganic salt and a water-soluble organic solvent, and after step (a), a step (b) of removing the water-soluble inorganic salt and the water-soluble organic solvent, and is produced by a production method characterized in that the water-soluble organic solvent is the above-mentioned water-soluble organic solvent. By passing through this step, a pharmaceutical composition containing micronized poorly water-soluble drug can be prepared. Also, in the pharmaceutical composition of the present invention, as described above, it is preferable that the water-soluble organic solvent remains within a specific range.

[0031] In the pharmaceutical composition of the present invention, it is desirable to micronize the average particle diameter of the poorly water-soluble drug to 5 to 300 nm. By micronizing to a level of 300 nm or less, the solubility in water can be improved. In the present invention, the "average particle diameter" refers to the average particle diameter in equivalent diameters such as Stokes diameter, light scattering equivalent diameter, diffusion equivalent diameter, volume sphere equivalent diameter, surface area sphere equivalent diameter, area circle equivalent diameter, perimeter circle equivalent diameter, etc., preferably the surface area sphere equivalent diameter or the light scattering equivalent diameter, more preferably the surface area sphere equivalent diameter. The surface area sphere equivalent diameter is more specifically the particle diameter measured by the BET method or the like. Preferably, the particle shape can be confirmed by using observation with an electron microscope in combination. Also, the light scattering equivalent diameter is more specifically the particle diameter measured by the laser diffraction scattering light method or the dynamic light scattering method.

[0032] In the manufacturing method of the present invention, the kneading device used for mechanically kneading and grinding poorly water-soluble drugs can be used without particular limitation as long as it has the ability to knead and disperse poorly water-soluble drugs, water-soluble inorganic salts, and water-soluble organic solvents by mechanical means. As such a kneading device, for example, devices such as a kneader, a two-roll mill, a three-roll mill, a ball mill, an attritor, a horizontal sand mill, a vertical sand mill, a fret mill, a Hoover muller, a disk blade kneading and dispersing machine, etc. can be mentioned. Using these, the processing conditions, etc. can be appropriately adjusted according to the type of drug and the required degree of refinement, etc. The water-soluble inorganic salt acts as a crushing aid and crushes the poorly water-soluble drug by utilizing the high hardness of the water-soluble inorganic salt during kneading. By optimizing the kneading conditions (temperature, rotation speed, etc.), it is possible to obtain poorly water-soluble drug fine particles with a very fine primary particle size, a narrow distribution width, and a sharp particle size distribution.

[0033] After completion of the kneading and grinding of the poorly water-soluble drug, the target poorly water-soluble drug fine particles can be obtained by removing the water-soluble inorganic salt and water-soluble organic solvent used for the kneading and grinding. Specifically, in a solvent, after homogenizing the mixture of the poorly water-soluble drug, water-soluble inorganic salt, and water-soluble organic solvent using a stirring blade, a dissolver, a homogenizer, etc., the water-soluble inorganic salt and water-soluble solvent are removed by filtration and washing with water. The solvent used for homogenizing the mixture is not particularly limited as long as it is a solvent in which the water-soluble inorganic salt and water-soluble organic solvent are easily dissolved and the ground poorly water-soluble drug is hardly dissolved, and is a physiologically acceptable solvent. Water is preferable as the solvent, but solvents other than water can also be used. As the solvent other than water, for example, there is a mixed solution of an organic solvent such as acetic acid, methanol, ethanol, etc. and water. Also, the filtration method is not particularly limited and can usually be carried out by a known method used for filtering organic compound-containing substances. As the filtration method, for example, there are a vacuum filtration method, a pressure filtration method, an ultrafiltration membrane method, etc.

[0034] After removing the water-soluble inorganic salts and water-soluble organic solvents and then performing a drying treatment, the solvents used for removing salts and the like can be removed from the obtained poorly water-soluble drug fine particles. The drying method is not particularly limited and can usually be carried out by a method used for drying organic compounds. Examples of the drying method include a vacuum drying method, a freeze-drying method, a spray-drying method, a freeze-spray drying method, and the like. The drying temperature, drying time, etc. in the drying are not particularly limited, but in order to maintain the chemical stability of the poorly water-soluble drug and prevent secondary aggregation of the particles, it is preferable to carry out the drying at a low temperature, and it is preferably carried out by a freeze-drying method, a spray-drying method, or a freeze-spray drying method.

[0035] <Additive> In the pharmaceutical composition of the present invention, an additive may be added for promoting refinement during mechanical kneading and suppressing dry aggregation. Examples of the additive include resins and surfactants, and those described in books such as the Pharmaceutical Additives Dictionary 2016 (Yakujitsu Shimbunsha), the Pharmaceutical Additives Standards 2018 (Yakujitsu Shimbunsha), and the Food Additives Dictionary Revised Second Edition (Shokuhin Kagaku Shinbunsha).

[0036] Examples of the resin include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, gum arabic, starch, trehalose, monoglyceride stearate, triglyceride stearate, sucrose stearate ester, paraffins such as liquid paraffin, hardened oils such as carnauba wax and hydrogenated castor oil, castor oil, stearic acid, stearyl alcohol, polyethylene glycol, and the like.

[0037] Examples of surfactants include phospholipids, glycerol fatty acid esters, polyethylene glycol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene nonyl phenyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan monolaurate, polysorbate, sorbitan monooleate, glycerol monostearate, monooxyethylene sorbitan monopalmitate, monooxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, sorbitan monopalmitate, sodium lauryl sulfate, rhamnolipid, sophorolipid, trehalolipid, fitoglycolipid, lipoteichoic acid, colinomic acid, open ring acid, agaricic acid, sebacic acid, emulzan, kelsan, pullulan, curdlan, dextran, cyclodextrin, gum arabic, tragacanth gum, chitosan, ornithine lipid, serilipin, surfactin, gramicidin S, lecithin, deoxycholic acid, cholic acid, lithocholic acid, chenodeoxycholic acid, ursodeoxycholic acid, glycyrrhizin, esdin, quillaia saponin, and the like.

[0038] <Aqueous dispersion of pharmaceutical composition> When the pharmaceutical composition of the present invention is used in an oral administration solution, an injection, an eye drop, an ointment, a transdermal absorbent, etc., an aqueous dispersion can be prepared and used. When preparing the aqueous dispersion, devices commonly used can be used. Examples of such devices include homogenizers (broadly classified into ultrasonic homogenizers, stirring homogenizers, high-pressure homogenizers, etc.), homomixers, ultrasonic dispersers, bead mill dispersers, etc. By suspending and dispersing the pharmaceutical composition of the present invention in water using these, an aqueous dispersion of the pharmaceutical composition can be produced. When preparing the dispersion, additives may be added as dispersion aids, and examples include resins and surfactants described in the item of additives. Also, when creating the aqueous dispersion, in order to prevent dry aggregation of the pharmaceutical composition, an aqueous dispersion may be prepared using the pharmaceutical composition in a water-containing state after removing water-soluble inorganic salts and water-soluble organic solvents.

[0039] The aqueous dispersion can also be powdered by spray drying, freeze drying, freeze spray drying, etc. The powder prepared in this way has excellent redispersibility in water, and thus has excellent properties as an injection, an eye drop, and an oral preparation for on-demand preparation. .

[0040] In addition, the pharmaceutical composition containing the poorly water-soluble drug and fine particles of the present invention can also be dispersed in an oily substance and used in an ointment, a capsule, a transdermal absorbent, etc. The oily substance is not particularly limited as long as it is a substance commonly used in formulation. Examples of the oily substance include liquid paraffin, petrolatum, propylene glycol, glycerin, polyethylene glycol, vegetable oil, etc. The oily substance may be used alone or a mixture of two or more oily substances may be used. Also, when preparing the oily substance dispersion, devices commonly used can be used. Examples of such devices include homogenizers, homomixers, ultrasonic dispersers, two-roll mills, three-roll mills, disk blade kneading dispersers, etc.

Examples

[0041] Hereinafter, the present invention will be described based on examples, but the present invention is not limited thereto. In the examples and comparative examples, "parts" means "parts by mass".

[0042] (Measurement of average primary particle diameter) The average primary particle diameter of the obtained pharmaceutical composition was measured using a transmission electron microscope ("JEM-1200EX" manufactured by JEOL Ltd.) at a magnification of 100,000 times, and the average value of the primary particle diameters of all pigment particles in the observation sample was used. When the particle shape was not spherical, the major axis and the minor axis were measured, and the value obtained by (major axis + minor axis) / 2 was taken as the particle diameter.

[0043] (Measurement of residual water-soluble organic solvent) The residual water-soluble organic solvent in the obtained pharmaceutical composition was quantified by gas chromatography, and the residual amount of the water-soluble organic solvent was calculated based on 100 parts by mass of the poorly water-soluble drug in the pharmaceutical composition. The conditions of gas chromatography are shown below. · Separation instrument: GC2010 manufactured by Shimadzu Corporation · Column: DM-5MS (30 m x 0.25 mm x 0.25 μm Film, Agilent Technologies) · Carrier gas: He · Pressure: 120.0 kPa · Total flow rate: 50.0 ml / min · Column flow rate: 1.77 ml / min · Linear velocity: 49.0 cm / sec · Purge flow rate: 3.0 ml / min · Column temperature: Held at 80°C for 4 minutes, then heated up in 16 minutes and held at 320°C for 5 minutes Injection mode: Split-less Mode Injection volume: 1 μL

[0044] The conditions of the mass spectrometer are shown below. · Measuring instrument: GC2010 manufactured by Shimadzu Corporation · Interface temperature: 250°C · Ion source temperature: 200°C ·Measurement Mode: Scan Mode ·Measurement Range: m / z = 30 - 500 ·Measurement Time: 5 - 20 min ·Event Time: 0.5 sec

[0045] [Example 1] 100 parts by mass of acetaminophen, 1000 parts by mass of sodium chloride, and 150 parts by mass of monoacetin were charged into a 1 - gallon stainless - steel kneader (manufactured by Inoue Seisakusho) and kneaded at 50°C for 8 hours. Next, this kneaded product was put into 10 liters of water, stirred for 1 hour to form a slurry, and filtration and washing were repeated to remove sodium chloride and monoacetin, followed by freeze - drying to obtain 98 parts by mass of pharmaceutical composition M - 1. The average primary particle diameter of the obtained pharmaceutical composition was 230 nm, and the residual solvent amount was 0.012 parts by mass.

[0046] [Examples 2 - 24 · Comparative Example 1] Pharmaceutical compositions M - 2 to 25 were prepared in the same manner as in Example 1, except that the drug species / amount, organic solvent species / amount, sodium chloride amount, additive species / amount, and kneading conditions were changed to those described in Table 1.

[0047]

Table 1

[0048] [Comparative Example 2] Using a jet mill (manufactured by Hosokawa Alpine, model "50 - AS"), acetaminophen was pulverized at a supply air pressure of 0.5 MPa and a pulverizing air pressure of 0.3 MPa to prepare pharmaceutical composition M - 26. The average particle diameter of the obtained pharmaceutical composition was 1110 nm.

[0049] [Comparative Examples 3 - 16] Pharmaceutical compositions M - 27 to 40 were prepared in the same manner as in Comparative Example 1, except that the drug species was changed to those described in Table 2.

[0050]

Table 2

[0051] As shown in Table 1 and Table 2, by performing the micronization treatment of the present invention, a pharmaceutical composition micronized to an average primary particle size of 300 nm or less could be prepared. Comparing Examples 3, 16, and 17, the particle size of Example 3 was smaller, and it was found that as the water-soluble organic solvent, the solvent having an ester group was superior to the organic solvent having a hydroxyl group in the micronization effect. Comparing Example 3 with Examples 18 to 23, it was found that when polyvinylpyrrolidone, trehalose as resins, Tween-80, deoxycholic acid as surfactants, and hydroxypropylcellulose were used in combination during kneading with water-soluble inorganic salts, the micronization effect was improved. Comparing Example 3 with Example 24, it was found that Example 3 in which the amount of residual water-soluble organic solvent corresponded to 0.003 to 0.3 parts by mass with respect to 100 parts by mass of the poorly water-soluble drug was superior in the micronization effect. In addition, an example using glycerin as the water-soluble organic solvent in Comparative Example 1 is shown. Comparing with Example 3, the particle size was large. This result is presumably because glycerin has a high viscosity of 1499 mPa·s, so sodium chloride, which is an abrasive, could not move well during kneading and a sufficient grinding effect could not be obtained. Thus, it was found that it is important to use an organic solvent with an appropriate viscosity for the micronization of drug particles.

[0052] <Evaluation of Aqueous Dispersion> Subsequently, an aqueous dispersion was prepared using the prepared pharmaceutical composition. Regarding the obtained aqueous dispersion, the particle size (50% median diameter) of the dispersion was measured using a particle size distribution measuring device (Microtrac UPA manufactured by Nikkiso Co., Ltd.).

[0053] <Stability Evaluation of Aqueous Dispersion> The prepared aqueous dispersion was stored for 7 days in an environment of temperature: 25°C · relative humidity: 60% RH, and the particle size (50% median diameter) was measured to evaluate the stability of the aqueous dispersion.

[0054] [Example 25] Mix 1 part by mass of pharmaceutical composition · M-3, 0.5 part by mass of polyvinylpyrrolidone, and 98.5 parts by mass of purified water, and perform ultrasonic irradiation for 2 hours using an ultrasonic device ("UT-105" manufactured by Sharp Manufacturing System Co., Ltd.) to obtain an aqueous dispersion S-1.

[0055] [Example 26] Mix 1 part by mass of pharmaceutical composition · M-3, 0.5 part by mass of polyvinylpyrrolidone, and 98.5 parts by mass of purified water, and perform homogenizer treatment for 2 hours using a stir-type homogenizer ("ClearMix CLM-0.8S" manufactured by M-Technique Co., Ltd.) to obtain an aqueous dispersion S-2.

[0056] [Example 27] Mix 1 part by mass of pharmaceutical composition · M-3, 0.5 part by mass of polyvinylpyrrolidone, and 98.5 parts by mass of purified water, and perform high-pressure treatment at 100 MPa 10 times using a high-pressure homogenizer ("Starburst Mini" manufactured by Sugino Machine Ltd.) to obtain an aqueous dispersion S-3.

[0057] [Example 28] Mix 1 part by mass of pharmaceutical composition · M-3, 0.5 part by mass of polyvinylpyrrolidone, and 98.5 parts by mass of purified water, disperse with zirconia beads with a diameter of 0.5 mm using an Aiger mill ("Mini Model M-250 MKII" manufactured by Aiger Japan Co., Ltd.) for 3 hours, and then filter with a filter having a pore size of 5.0 μm to obtain an aqueous dispersion S-4.

[0058] [Example 29] Mix 1 part by mass of pharmaceutical composition · M-17, 0.5 part by mass of polyvinylpyrrolidone, and 98.5 parts by mass of purified water, disperse with zirconia beads with a diameter of 0.5 mm using an Aiger mill ("Mini Model M-250 MKII" manufactured by Aiger Japan Co., Ltd.) for 3 hours, and then filter with a filter having a pore size of 5.0 μm to obtain an aqueous dispersion S-5.

[0059] [Example 30] 1 part by mass of pharmaceutical composition · M-18, 0.5 part by mass of polyvinylpyrrolidone, and 98.5 parts by mass of purified water were mixed, and using zirconia beads with a diameter of 0.5 mm, they were dispersed for 3 hours with an Igar mill ("Mini Model M-250 MKII" manufactured by Igar Japan Co., Ltd.), and then filtered through a filter with a pore size of 5.0 μm to obtain an aqueous dispersion S-6.

[0060] [Comparative Example 17] 1 part by weight of pharmaceutical composition · M-25, 0.5 part by weight of polyvinylpyrrolidone, and 98.5 parts by weight of purified water were mixed, and using an ultrasonic device ("UT-105" manufactured by Yarp Manufacturing System Co., Ltd.), ultrasonic irradiation was performed for 2 hours to obtain an aqueous dispersion S-8.

[0061] Table 3 shows the results of the particle diameters of each aqueous dispersion. In the aqueous dispersions of the examples, all were micronized to 300 nm or less, and the bead dispersion method was found to be the most optimal for the treatment method. Comparing Examples 28 and 29, when a solvent having an ester group in the water-soluble organic solvent was used, an increase in the particle diameter over time was suppressed, and it was found to have excellent stability. From the above, when the micronized pharmaceutical composition of the present invention was used, it was confirmed that it was also micronized and had excellent stability in the aqueous dispersion.

[0062]

Table 3

Claims

1. A method for producing a pharmaceutical composition comprising: a step (a) of mechanically kneading together a poorly water-soluble drug, a water-soluble inorganic salt, and a water-soluble organic solvent; and a step (b) of removing the water-soluble inorganic salt and the water-soluble organic solvent after step (a), wherein the poorly water-soluble drug is a drug that requires 30 mL or more of water to dissolve 1 g of the solute in the 17th revised Japanese Pharmacopoeia, the water-soluble inorganic salt is at least one selected from the group consisting of sodium chloride, potassium chloride, ammonium chloride, sodium sulfate, magnesium sulfate, potassium sulfate, calcium sulfate, sodium malate, sodium citrate, disodium citrate, sodium dihydrogen citrate, potassium dihydrogen citrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate, and the water-soluble organic solvent contains at least one selected from the group consisting of triacetin, tripropionin, tributyrin, triethyl citrate, and acetyltriethyl citrate. A method for producing a pharmaceutical composition characterized by this.

2. The poorly water-soluble drug is acetaminophen, ibuprofen, nifedipine, nicardipine, nimodipine, dipyridamole, disopyramide, prazosin hydrochloride, prednisolone, cortisone acetate, dexamethasone, betamethasone, beclomethasone propionate, fluticasone propionate, budesonide, fluocinolone acetonide, indomethacin, naproxen, ketoprofen, 7-(3,5 - dimethoxy - 4 - hydroxysinnamoylamino) - 3 - octyloxy - 4 - hydroxy - 1 - methyl - 2(1H) - quinolinone, phenacetin, ethotoin, primidone, diazepam, nitrazepam, clonazepam, digitoxin, spironolactone, triamterene, chlorthalidone, polythiazide, benzthiazide, griseofulvin, nalidixic acid, chloramphenicol, chlorzoxazine, meprobamate, mequitazine, bisbentiamine, triamcinolone acetonide, fluconazole, miconazole, rifampicin, dacarbazine, mitomycin C, bicalutamide, paclitaxel, ubenimex, clemastine fumarate, erythromycin, amphotericin B, cefixime, sulfasalazine, sparfloxacin, tinidazole, vidarabine, acyclovir, milrinone, digoxin, dipyridamole, pindolol, propafenone hydrochloride, amrinone, hydrochlorothiazide,trandolapril, candesartan cilexetil, urapidil, reserpine, methyldopa, norepinephrine, simvastatin, fluoxymesterone, stanozolol, estradiol, chloramadinone acetate, falecalcitriol, madindol, sildenafil citrate, minoxidil, droperidol, quazepam, pentazocine, propiomazine, thioperamide, sulpiride, amoxapine, lisuride maleate, nicergoline, biperiden, levodopa, chlorphenesin carbamate, dantrolene sodium, norepinephrine, formoterol fumarate, riluzole, flumazenil, theophylline, methotrexate, amidotrizoic acid, cilostazol, adenine, tolbutamide, famotidine, ursodeoxycholic acid, sulindac, pyrenoxine, flunisolide, danazol, tacrolimus hydrate, β - carotene, curcumin, tulobuterol, pranlukast hydrate, zafirlukast and fenofibrate, characterized in that it comprises at least one selected from the group consisting of, the method for producing a pharmaceutical composition according to claim 1.,

3. A pharmaceutical composition comprising a poorly water-soluble drug having an average primary particle diameter of 5 to 300 nm and 0.003 to 0.3 parts by mass of a water-soluble organic solvent with respect to 100 parts by mass of the poorly water-soluble drug, wherein the poorly water-soluble drug is a drug that requires 30 mL or more of water to dissolve 1 g of the solute in the 17th revised Japanese Pharmacopoeia, and the water-soluble organic solvent contains at least one selected from the group consisting of triacetin, tripropionin, tributyrin, triethyl citrate, and acetyltriethyl citrate. A pharmaceutical composition characterized by this.

4. The pharmaceutical composition according to claim 3, further comprising a resin or a surfactant as an additive.

5. The poorly water-soluble drug is acetaminophen, ibuprofen, nifedipine, nicardipine, nimodipine, dipyridamole, disopyramide, prazosin hydrochloride, prednisolone, cortisone acetate, dexamethasone, betamethasone, beclomethasone propionate, fluticasone propionate, budesonide, fluocinolone acetonide, indomethacin, naproxen, ketoprofen, 7-(3,5 - dimethoxy - 4 - hydroxysinnamoylamino) - 3 - octyloxy - 4 - hydroxy - 1 - methyl - 2(1H) - quinolinone, phenacetin, ethotoin, primidone, diazepam, nitrazepam, clonazepam, digitoxin, spironolactone, triamterene, chlorthalidone, polythiazide, benzthiazide, griseofulvin, nalidixic acid, chloramphenicol, chlorzoxazine, meprobamate, mequitazine, bisbentiamine, triamcinolone acetonide, fluconazole, miconazole, rifampicin, dacarbazine, mitomycin C, bicalutamide, paclitaxel, ubenimex, clemastine fumarate, erythromycin, amphotericin B, cefixime, sulfasalazine, sparfloxacin, tinidazole, vidarabine, acyclovir, milrinone, digoxin, dipyridamole, pindolol, propafenone hydrochloride, amrinone, hydrochlorothiazide,trandolapril, candesartan cilexetil, urapidil, reserpine, methyldopa, norepinephrine, simvastatin, fluoxymesterone, stanozolol, estradiol, chlormadinone acetate, falecalcitriol, mazindol, sildenafil citrate, minoxidil, droperidol, quazepam, pentazocine, propiomazine, thioperamide, sulpiride, amoxapine, lisuride maleate, nicergoline, biperiden, levodopa, chlorphenesin carbamate, dantrolene sodium, norepinephrine, formoterol fumarate, riluzole, flumazenil, theophylline, methotrexate, amidotrizoic acid, cilostazol, adenine, tolbutamide, famotidine, ursodeoxycholic acid, sulindac, pyrenoxine, flunisolide, danazol, tacrolimus hydrate, β - carotene, curcumin, tulobuterol, pranlukast hydrate, zafirlukast and fenofibrate, characterized in that it contains at least one selected from the group consisting of. The pharmaceutical composition according to claim 3 or 4.,

6. A method for producing an aqueous dispersion of a pharmaceutical composition, characterized by suspending and dispersing the pharmaceutical composition according to claims 3 to 5 in water by ultrasonic treatment, homogenizer treatment, or bead mill dispersion treatment.

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