WO2002100379A1 - Method for preparing solid dispersion - Google Patents

Abstract

A method for preparing a solid dispersion, characterized in that it comprises admixing a solid substance with a solvent in an amount sufficient to depress the melting point of the solid substance and melting with heat the resulting mixture. The method allows the combination of the preparation of a solid dispersion having an uniform composition with the prevention of chemical change of a thermally unstable substance contained in the dispersion during the preparation thereof.

Description

 Description Manufacturing method of solid dispersion Technical field

 The present invention relates to a method for producing a solid dispersion. Background art

 Mixing refers to the operation of mixing two or more different substances into an apparently uniform composition. Insufficient mixing causes problems in the uniformity of the quality of products such as pharmaceuticals, and so mixing is one of the very important operations in the production of pharmaceutical compositions and the like. Particularly when mixing solids, it is difficult to obtain a uniform composition. Methods for sufficiently mixing the solid include a melting method in which the physiologically active substance and other components are heated and melted at a temperature equal to or higher than the melting point, and a solvent method in which the physiologically active substance and other components are dissolved in an organic solvent. However, the former has a problem that it cannot be used for producing a solid dispersion containing a substance that is unstable to heat because the object is treated at a high temperature. In the latter, removal of the organic solvent is problematic because a large amount of organic solvent is used.

 Regarding these problems, Japanese Patent No. 2527107 discloses a method for producing a solid dispersion using a two-axis extruder. This method is excellent in that it does not use an organic solvent, but there is still room for study from the viewpoint of sufficiently uniformly mixing a heat-labile substance with other components.

 Also, a technique of lowering the melting point by adding a low-melting compound (eg, a plasticizer, etc.) to a solid compound is known. there were. Summary of the Invention

 In view of the above problems, an object of the present invention is to provide a method for preventing a chemical change of a substance unstable to heat and producing a solid dispersion having a uniform composition.

In the mixing step, the present inventors add a solvent, and heat and melt to mix. As a result, the inventors have found that a chemical change of a substance unstable to heat can be prevented and the components can be uniformly mixed. As a result of further studies, the present invention has been completed.

 That is, the present invention

 (I) a method for producing a solid dispersion, which comprises heating and melting a solid substance and an amount of a solvent that causes a decrease in melting point;

 (2) The method according to the above (1), wherein an amount of a solvent that causes a melting point drop is added to the solid substance, and the mixture is heated and melted.

 (3) The production method according to the above (1), wherein the solvent is purcols or ketones or a water mixture thereof,

 (4) The production method according to (1), wherein the amount of the solvent relative to the solid substance is about 0.01 to about 100% (w / w),

 (5) The production method according to the above (1), wherein the temperature for carothermal melting is a temperature not lower than the boiling point of the solvent and lower than the melting point of the solid substance.

 (6) The production method according to (1), wherein the solid substance is a substance unstable to heat, (7) the production method according to (1), wherein the solid substance is a substance having a melting point of about 80 to about 350 ° C. Method,

 (8) The method according to (1) above, wherein the solid substance is a poorly water-soluble or water-insoluble pharmaceutical compound.

 (9) The method according to the above (1), wherein an adsorbent is further blended,

 (10) The production method according to (1), wherein the solid substance is heated and melted with a solvent capable of lowering the melting point, and mixed with another substance; and

 (II) A solid dispersion produced by the production method described in the above (1) is provided. BRIEF DESCRIPTION OF THE FIGURES

 Figure 1 is a graph of the differential calorific value versus temperature showing the melting point drop when ethanol is added.

 FIG. 2 is a graph of the differential calorific value versus temperature showing the melting point drop when purified water is added.

FIG. 3 is an elemental mapping of the pharmaceutical composition obtained in Example 1. FIG. 4 is an elemental mapping of the pharmaceutical composition obtained in Comparative Example 1.

 FIG. 5 is a powder X-ray diffraction pattern of the pharmaceutical composition obtained in Example 1.

 FIG. 6 is a powder X-ray diffraction pattern of the pharmaceutical composition obtained in Comparative Example 1. Embodiment of the Invention

 • “(Heating) melting” in the production method of the present invention refers to a state in which a solid substance is wetted by a solvent and liquefied by heating.

 In the present specification, the “melting point” of a solid substance refers to a melting point measured at 1 atm without adding any substance other than the solid substance, and is used separately from “actual melting point” and “falling melting point”. I have.

 Examples of the solid substance used in the present invention include a pharmaceutical compound (including an animal drug), an agrochemical compound, a fertilizer, a cosmetic, a fragrance, a food material, a feed, a fungicide, an antifungal, an insect repellent, an insecticide, It can be selected from a wide range of fields such as fire retardants, absorbents, and paints. The solid substance may be one kind, or two or more kinds.

 The properties of these solid substances are not particularly limited, and may be any water-soluble, hardly water-soluble or water-insoluble solid substance. "Slightly water-insoluble or water-insoluble" means that the solid substance has a solubility in water of, for example, less than 100 ppm, preferably less than 10 ppm at 25 ° C, or 25 ° C. C indicates that the solubility in water is less than 1 O mg / mL, preferably less than 0.1 mg / mL. The solubility can be measured according to a conventional method.

 The following are examples of the water-soluble drug conjugate.

 (1) Antibiotics

 Tetracycline hydrochloride, ampicillin, piperacillin, etc.

 (2) Antipyretic 'analgesic' anti-inflammatory

 Sodium salicylate, sulpyrine, indomethacin sodium, morphine hydrochloride, etc.

 (3) Stimulant remover

Ephedrine hydrochloride, nospin hydrochloride, codin phosphate, dihydrocodin phosphate, isoproterenol hydrochloride, etc. (4) sedative

Cuprolupromazine hydrochloride, sulfate pin, etc.

 (5) Anti-collapse

Metaclopromide, histidine hydrochloride, etc.

 (6) Arrhythmia treatment agent

Propranolol hydrochloride, alprenolol hydrochloride, etc.

 (7) Antihypertensive diuretic

Hexametone bromide, clonidine hydrochloride, etc.

 (8) Anticoagulant

Heparin sodium, sodium citrate, etc.

 Examples of the poorly water-soluble or water-insoluble pharmaceutical compound include the following.

(1) Antipyretic, analgesic, anti-inflammatory drugs

 Salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, atopin pin, scopolamine, morphine, pethidine, levorfuinol, ketoprofen, naproxen, ibuprofen, oxomorphone, aspirin, aminopyrine, fenacetin, eacenotamine, acetaminophen Keto pheninolebutazone, mefenamic acid, bucolome, benzidamine, mepirazinole, tiaramid, tinolidine, xylocaine, pentazocine, dexamethasone, hydrocortisone, prednisolone, azulene, isopropylantipyrine, sazapyrine, clofuezone, clofuezone or clofuezone

 (2) tranquilizer

 Jazepam, Lorazepam, Oxazepam, Lisaxazolam, Clotiazebam, Medazepam, Temazepam, Fludiazepam, Meprobamate, Nitrazepam, Chlordiazeboxide, etc.

 (3) Antipsychotics

Chlorpromazine, prochlorperazine, trifloperazine, sulpiride, clocapramine hydrochloride, zotepine, haloperidol, etc.

 (4) Antibacterial drug

Griseofulvin, Lankacidins Tas (J. Antibiotics), 38, 877-885 (1985)], an azole compound [2-[((1R, 2R) -12- (2,4-difluorophenyl)-2-hydroxy-11] —Methinolay 3— (1H-1,2,4-triazole-1_yl) propyl) -4--4- (4-1 (2,2,3,3-tetrafluoropropoxy) phenyl 2- (2H , 4H) — 1,2,4-triazolone, fluconazole, itraconazole, etc.), naliditasic acid, piromidic acid, pimidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciploxacin hydrochloride, sulfamethoxazole · Trimethoprim

 (5) Antibiotics

 Gentamicin, Dizukacin, Canendomycin, Ribidomycin, Topramisin, Amikacin, Divekacin, Fradiomycin, Sissomycin, Tetracycline, Oxytetracycline, Lolitetracycline, Doxycycline, Ampicillin, Piracillin, Ticanoresillin, Cephalotin, Cephaloridin, Cefotiam, Cefotiam Hexetinore, Cefsulodin, Cefmenoxime, Cefmetazol, Cefazolin, Cefotaxime, Cefoperazone, Ceftizoxsim, Moxalactam, Chenamycin, Sulfazecin, Azulcemin, Rixamin, Rixamin Nicole or their salts etc.

 (6) Antitumor drug

 6 -0- (N-Chloroacetylcarbamoyl) Fumagillonole, Bleomycin, Methotrexate, Actinomycin D, Mitomycin C, Daunorubicin, Adriamycin, Neocarzinostatin, Cytosinaradinoside, Fluorolasinole, Tetrahydrofurinolate , Picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, HER2 inhibitor (heterocyclic compound described in WO 01/77107, etc.), taxol, doxorubicin hydrochloride, etoposide, mitoxantrone, mesna, Dimesna, Aminoglutethimide, Tamoxifen, Acroline, Cisplatin, Carboplatin, Cyclophosphamide, Oral Muscin (CCNU), Carmustine (BCNU), etc.

(7) Antihyperlipidemic agent Clofibrate, 2_cloth_3— [4- (2-Methyl-2-phenylpropoxy) phenyl] Ethyl propionate [Chemical and Pharmaceutical Chem. Pharm. Bull, 38, 2792 -2796 (1 990)], clinofibrate, cholestyramine, soysterol, tocopheronol nicotinate, nicomonole, niceri tronore, probucornore, elastase, etc.

 (8) 縝 晐. Expectorant

 Ephedrine, Methylephedrine, Noscapine, Kodin, Dihydrocodine, Glucolamide, Chlorphedianol, Picoperidamine, Kuguchiperastin, Protochlorol, Isoproterenol, Sulptamonole, Tereptalin, Bromhexine, Carbocysteine Chill cysteine, methyl cysteine or its salt, etc.

 (9) Muscle relaxant

 Pridinore, Toppoclarin, Panclodium, Chlorfenesin olebamate, Tolperisone hydrochloride, Eperisone hydrochloride, Tizanidine hydrochloride, Mephenesin, Chronorezoxazone, Fenprobamate, Metocarbamonole, Koutoremezanone, Mesi / priclolone Meclofenole Dantrolene trim etc.

 (10) Antiepileptic drug

 Phenitoin, ethosuximid, acetazolamide, chlordiazepoxide, phenobarbital, levamazepine, primidone, etc.

 (11) Anti-ulcer drug

 Lansoprazonole, metoclopramide, famotidine, memeprazosole, sul pyrido, trevibutone, cetraxate hydrochloride, gef; renate, ilsolgazine maleate, cimetidine, ranitidine hydrochloride, ezatidine, mouth oxatidine acetate, etc.

 (12) Antidepressant

 Imipramine, clomipramine, noxiptiline, phenelzine, etc.

(13) Antiallergic drug Diphenhydramine, chlorpheniramine, toliperenamine, methdilamine, clemizonole, diphenylpyralin, methoxphenamine, clemastine fumanolate, cyproheptadine hydrochloride, mequitazine, alimazine tartrate, etc.

 (14) Inotropic drugs

 Transpaixoxocamphor, telephilol, aminophylline, etilerefrin, etc.

 (15) Antiarrhythmic drug

 Propranolone, alprenolol, pfetrol, oxprenololone, proforce inamide hydrochloride, disopyramide, azimaline, quinidine sulfate, aprinzine hydrochloride, propaphenone hydrochloride, mexiletine hydrochloride, etc.

 (16) Vasodilator

 Oxyfuedrin, diltiazem, tolazoline, hexobendine, bamethane, difedipin, isosorbit dinitrate, diltiazem hydrochloride, travidil, dipyridamole, dilazep hydrochloride, verapamil, -cardipine hydrochloride, ifenpro di ^ / tartrate, cincladelate maleate Cinnarizine, pentoxyfilin, etc.

 (17) Antihypertensive diuretic

 Hexametonium bromide, pentridine, mecamami / amine, ecarazine, clonidine, di / retizazem, difezedine, furosemide, trichlormethiazide, methiclothiazide, hydroclothiazide, flumethiazide, clopentine , Fluorothiazide, ethacrynic acid, etc.

 (18) Antidiabetic drug

 Glymidine, glipizide, phonforenomin, pformin, metformin, dalibenclamide, tolptamide, etc.

 (19) Antituberculous drug

 Isodiazide, etampol, para-aminosalicylic acid, etc.

 (20) Narcotic antagonist

 Reparol Juan, Nalorufin, Naloxone or its salt etc.

(21) Hormonal drugs Steroid hormones, for example, dexamethasone, hexestronore, methimazole, petamethasone, triamcinolone, triamcinolone acetonide, funole osino mouth acetonide, prednisolone, hydroconoretisone, estriol, etc.

 (22) Bone

Prostaglandin A 1 derivative, Vitamin D derivative, Vitamin K ₂ derivative, Eicosapentaenoic acid derivative, Benzylphosphonic acid derivative, Bisphosphonic acid derivative, Sex holmon derivative, Phenol sulfophthalein derivative, Benzothiopyran or Benzochepine derivative, Thienoindazole derivative, Non-peptide bone formation promoting substances such as menatetrenone derivatives, heloxanthin derivatives, peptide bone formation promoting substances, etc.

 (23) Therapeutic agent for joint disease

 ρ38 MAP kinase inhibitor (thiazole compound described in WO 00/64894, etc.), matrix meta-oral protease inhibitor (MMP I), prednisolone, hydroconoretisone, methinoleprednisolone, dexbetamethasone, betamethasone, etc. Anti-inflammatory steroids, non-steroidal anti-inflammatory analgesics such as indomethacin, diclofenac, mouth kiss, oral fen, ibuprofen, piroxicam, sulindac, etc.

 (24) Treatment for pollakiuria

 Flavoxate hydrochloride, oxyptynin hydrochloride, terolidine hydrochloride, etc.

 (25) Antiandrogen

 Oxendron, arylestrenol, chlormadinone acetate, gestonolone dyprone, osapron acetate, flutamide, bicalutamide, etc.

 (26) Fat-soluble vitamin drug

①Vitamin Ks: Vitamin K or K ₂ , Κ _{3 and 4}

②Folic acid (vitamin Μ) etc.

 (27) Vitamin derivative

Various derivatives of vitamins, such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecanolecipherone, and α-hydroxycholecanoleciphere Vitamin D 3 derivatives such as rolls, and Vitamin D ₂ derivatives such as 5, 6-transergocalciferonole

 (2 8) Other

 Hydroxycam, diaserine, megestrone acetic acid, nicerogolin, prostaglandins, etc.

 In addition, drugs for ischemic diseases, drugs for immune diseases, drugs for Alzheimer's disease, drugs for osteoporosis, drugs for angiogenesis, drugs for retinopathy, drugs for retinal vein occlusion, senile disc-like macular degeneration Drugs for cerebral vasospasm, cerebral thrombosis, cerebral infarction, cerebral obstruction, cerebral hemorrhage, subarachnoid hemorrhage, hypertensive encephalopathy, transient ischemic attack , Multiple infarct dementia treatment, arteriosclerosis treatment, Huntington's disease treatment, brain tissue disorder treatment, optic neuropathy treatment, glaucoma treatment, ocular hypertension treatment, retinal detachment treatment arthritis treatment, Anti-rheumatic drugs, anti-sepsitic drugs, anti-sebotic shock drugs, anti-asthmatic drugs, atopic dermatitis drugs, allergic rhinitis drugs, etc. are also used.

 The following are examples of the hardly water-soluble or hardly soluble solid agricultural chemical compound.

(1) insecticide

 (a) Carbamate

 M I P C; isoprocarb, B PMC; fenobucalp

 (fenobucarb), MPMC; xylylcarb, XMC, NAC; canolebarinole (carbaryl), bendio canoleb (bendiocarb), canolebofuran

 (carbofuran; what

 (b) Synthetic pyrethroids

Cynomethrin (cypermethrinj, fenpropathrin), etofenprox (ethofenprox), resmethrin (resmethrin), etc.

(c) Organophosphorus

 EPN, cyanofenphos, PAP; Fentate

(phenthoate), C VMP; tetrachlorvinphos, monocrotophos, phosalone, chlorpyrifos-methyl, chlorpyrifos, pyridafen Thione (pyridaphenthion), quinalphos, DMT P; methidathion (methidathion, salicion (dioxabenzofos), etc.

(d) Organochlorine

Benzopine (endosulfan) etc.

(e) Other

Bensultap, buprofezin, bufenezuron, flufenoxuron, dilubenzuron, chlorfluazuron, imidacloprid, etc.

 (2) Fungicide

(a) N-heterocyclic ergosterol inhibitor

 Triflumizole, triforine, etc.

(b) Carboxamide

Mepronil, flutoluanil, pencicuron, oxycarboxin, etc.

(c) dicarboximide

Iprodione, vinclozolin, procymidone

(procymidone

(d) Benzimidazole type

Benomyl etc.

(e) Polyhaloalkylthio-based

Captan, etc.

 (f) Organochlorine

Fthalide, TPN; chlorothalonil, etc.

(g) Sulfur-based

Zineb, maneb, etc.

 (h) Other

Diclomezin, tricyclazole (tricyclazole), isoprothiolane, frobenane 1 / re probenazole zo, nirasin

(anilazine), oxolinic acid, ferimzone (ferimzone) etc.

 (3) Herbicide

(a) Sulfururea

Imazos 7 reflon, bensulfuron-methyl, etc.

(b) Triazine type

Simetryn (dimetry), dimethametryn, etc.

 (c) Urea-based

Daimron etc.

 (d) acid amide

Propaninole, mefenacet, etc.

 (e) Force bamate

Swep, etc.

 (f) Diazole type

Oxadiazon, pyrazolate, etc.

(g) dinitroaniline-based

 Trifluralin etc.

(h) Other

Dithiopyr, etc.

 The solid substance is preferably a substance that undergoes a chemical change such as decomposition by heat, that is, a substance that is unstable to heat. For example, a substance that undergoes a chemical change (eg, decomposition) due to heat at a temperature below the melting point (for example, a temperature in the range from the melting point to 150 ° C) is a substance that is thermally unstable. The melting point of the solid material is not particularly limited, but is preferably about 80 to about 350 ° C, more preferably about 100 to about 270 ° C, and particularly preferably about 150 to about 2 ° C. 20 ° C.

 In the present specification, a solid dispersion refers to a solid composition in which the above-mentioned solid substance and another substance are uniformly mixed. Other substances refer to substances other than the above-mentioned solid substances, and are not particularly limited.

For example, when the solid substance is a pharmaceutical compound or a pesticide compound, examples of the other substance include a polymer carrier (eg, a polymer compound, a surfactant, and the like). Solid dispersion The other substances in the body may be of one type or of two or more types.

 The polymer carrier used in the present invention is preferably a polymer carrier that can be softened by an amount of a solvent that causes a decrease in melting point. Here, softening means that the glass transition temperature decreases.

 As the polymer compound, a polymer, a hydrophilic polymer, or the like is used. The number average molecular weight of the high molecular weight polymer is preferably about 3,000 to 300,000, more preferably about 5,000 to 300,000, and Those having a size of from 000 to 20 and 000 are particularly preferred. In the present specification, the weight average molecular weight and the dispersity mean values measured by gel permeation chromatography (GPC) using polystyrene as a reference substance. The measurement is. ? 〇 Column? 8 0 4 2 (Showa Denko) is used.

 Examples of high molecular weight polymers include, for example, biodegradable

 ①Poly fatty acid esters [Examples: fatty acid homopolymers (eg, polylactic acid, polydalicholic acid, polycunic acid, polymalic acid, etc.), two or more fatty acid copolymers (eg, lactic acid Z-glycolic acid copolymer, 2-hydroxybutyric acid / glycolic acid copolymer, etc.), and a mixture thereof (eg, a mixture of polylactic acid and 2-hydroxybutyric acid Z-glycolic acid copolymer), wherein the fatty acid is For example, α-hydroxy fatty acids (eg, glycolic acid, lactic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-13-methinolebutyric acid, 2-hydroxycaproic acid, 2-hydroxyisocaproic acid, -Hydroxycapric acid, etc.) Cyclic dimer of hyperhydroxy fatty acid (eg, glycoside, lactide, etc.), hydroxydicarboxylic acid (eg, malic acid, etc.), hydroxy Polycarboxylic acid (e.g., Kuen acid) refers to]

 ②Poly monocyano acrylate,

 ③ poly-hydroxybutyric acid,

④ polyalkylene oxalates (eg, poly trimethylene oxalate, polytetramethylene oxalate, etc.),

⑤Polyorthoesters, polyorthocarbonates or other polycarbonates (eg, polyethylene carbonate, polyethylene propylene carbonate, etc.), ⑥Polyamino acids (eg, poly-γ-benzyl-l-glutamic acid, poly-l-alanine, poly-V-methyl-l-glutamic acid, etc.).

 Other biocompatible polymer polymers include polystyrene, polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid, silicone polymers, dextranstearate, and ethynoleate. Examples include cenorellose, acetylsilanolose, nitrocellulose, polyurethane, maleic anhydride copolymer, ethylene vinyl acetate copolymer, polyvinyl acetate, polyvinyl alcohol, and polyacrylamide. These polymers may be a single kind, a copolymer of two or more kinds, a simple mixture, or a salt thereof.

 Among these high molecular weight polymers, poly fatty acid esters and poly α-cyanoacrylic acid esters are preferable. Furthermore, poly fatty acid esters are particularly preferred.

Among polyfatty acid esters, homopolymers of cyclic dimers of α-hydroxy fatty acids or parahydroxy fatty acids, copolymers of cyclic dimers of two or more α-hydroxy fatty acids or α-hydroxy fatty acids, or Mixtures of these are preferred. Further, a homopolymer of _α -hydroxy fatty acid, a copolymer of two or more α-hydroxy fatty acids or a mixture thereof is more preferable. Among them, polylactic acid, lactic acid / glycolic acid copolymer, 2-hydroxyacid / glycolic acid copolymer or a mixture thereof is particularly preferred.

 Any of these monohydroxycarboxylic acids having a D-form, an L-form and a D, L-form may be used, but the D, L-form is preferred. When a lactic acid-Z glycolic acid copolymer is used as the above polymer, the composition ratio is preferably about 100/0 to 50 Z50, and when a butyric acid-glycolic acid copolymer is used. The composition ratio is preferably about 100 to 25/75.

 The weight average molecular weight of the lactic acid / glycolic acid copolymer is from about 5,000 to about 30,000.

00 is preferred. Further, those of about 5,000 to 20,000 are particularly preferred.

For example, when a mixture of polylactic acid (Α) and glycolic acid Ζ2-hydroxybutyric acid copolymer (Β) is used as the above high molecular weight polymer, the mixture represented by (Α) Α (ノ) The ratio is used in the range of about 10 Z 90 to about 90 10 (weight ratio). Preferably it is in the range of about 25/75 to about 75 Z25 (weight ratio).

 The polylactic acid preferably has a weight average molecular weight of about 5,000 to about 30,000. Particularly preferred are those from about 6,000 to about 20,000.

 The glycolic acid Z 2 -hydroxybutyric acid copolymer preferably has a composition in which glycolic acid is about 40 to about 70 mol and the balance is 2-hydroxybutyric acid. The weight average molecular weight of the glycolic acid Z 2 -hydroxybutyric acid copolymer is preferably from about 5,000 to about 2,500. Particularly preferred are those from about 5,000 to about 20,000.

 As the hydrophilic polymer, for example, a water-soluble polymer, an enteric polymer, a gastric polymer and the like are used.

 Examples of the water-soluble polymer include cellulose derivatives such as hydroxyalkylcellulose such as hydroxypropylcellulose and hydroxypropyl / remethylcellulose, and alkylcellulose such as methylcellulose, and polyanolekeninolepyrrolidone such as polyvinylpyrrolidone. And polyalkylene glycols such as polyethylene glycol and polyvinyl alcohol.

 Examples of the enteric polymer include, for example, hydroxypropyl methylcellulose phthalate, hydroxypropylmethinolecellulose acetate succinate, canoleboxy simethinolethinolecellulose, cellulose acetate phthalenoleate, methacrylate copolymer L, methacrylinoleic acid Copolymer S or the like is used.

 As the gastric-soluble polymer, for example, aminoalkyl methacrylate copolymer E, polyvinyl acetyl tert-yl acetyl acetate and the like are used.

 In addition, carboxymethylcellulose, Eudragit, lipoxyvinyl polymer, polyvinyl alcohol, gum arabic, sodium alginate, propylene dalicol alginate, agar, gelatin, chitosan and the like can also be used. These hydrophilic polymers may be used alone or in combination of two or more.

Examples of the surfactant include a nonionic surfactant, an anionic surfactant, a cation surfactant, an amphoteric surfactant, and a surfactant derived from a natural product. Nonionic surfactants include higher alcohol ethylene oxide adducts, alkyl phenol ethylene oxide adducts, fatty acid ethylene oxide adducts, polyhydric alcohol fatty acid ester ethylene oxide adducts, higher alkyl amines Ethylene oxide adducts, fatty acid amides Ethylene oxide adducts, oil and fat ethylenoxide adducts, glycerin fatty acid esters, pentaerythritol fatty acid esters, polyhydric alcohol alkyl ethers, alkanolamines Acid amides and the like are used.

 Among the non-ionic surfactants, for example, fatty acid esters of sorbitol and sorbitan, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, and polyethoxylated castor oil oil), polyoxyethylene hydrogenated castor oil

 (polyethoxylated hydrogenated castor oil), positoxyethylene polypropylene glycol copolymer, glycerin fatty acid ester, and polyglycerin fatty acid ester are preferably used. Examples of the sorbitan fatty acid esters include sorbitan monostearate (trade name: SS-10, Nikko Chemicals Co., Ltd.), sesquioleic acid sorbitan (trade name: S0-15, Nikko Chemicals Co., Ltd.), and sorbitan trioleate (Trade name: S0-30, Nikko Chemicals Co., Ltd.) and the like are suitable. Examples of the polyoxoxylene sorbitan fatty acid ester include polysorbate 20 (trade name: TL-10, Nikko Chemicals Co., Ltd.), 40 (trade name: TP-10, Nikko Chemicals Co., Ltd.), 6 0 (trade name: TS-10, Nikko Chemicals Co., Ltd.), 80 (trade name: $ 0-10, Nikko Chemicals Co., Ltd.) and the like are suitable. Polyethylene glycol fatty acid esters include, in particular, polyethylene glycol monolaurate.

(10E. 0.) (trade name: MYL-10, Nikko Chemicals Co., Ltd.) and the like are suitable. Examples of sucrose fatty acid esters include sucrose palmitate esters (for example, trade name: S-1670, Mitsubishi Chemical Foods Co., Ltd.) and sucrose stearic acid esters (for example, trade name: II-1670, Mitsubishi Chemical Foods Co., Ltd.) Is preferred. As the polyethoxylated castor oil, polyoxyethylene glycerol triricinoleate 35 (Polyoxy 35 Castor 0il, trade name Cremophor EL or EL_P, BSF Japan Ltd.) is particularly preferable. is there. As polyoxyethylene hydrogenated castor oil, in particular, polyoxyethylene hydrogenated castor oil is used.

 (Polyoxyethylene Hydrogenated Castor Oil 50) and Polyoxyethylene Hydrogenated Castor Oil 60 (Polyoxyethylene Hydrogenated Castor Oil 60) are suitable. Examples of the polyoxyethylene polyoxypropylene glycol copolymer include, in particular, polyoxyethylene (160) polyoxypropylene (30) glycomono (trade name: Ade Kapuruguchi Nick F-68, Asahi Denka Kogyo Co., Ltd.) Is preferred. As the glycerin fatty acid ester, glyceryl monostearate (MGS series, Nikko Chemicals Co., Ltd.) and the like are suitable. As the polyglycerin fatty acid ester, tetraglycerin monostearic acid (MS-310, Sakamoto Yakuhin Kogyo Co., Ltd.), and decaglycerin monolauric acid (Decaglyn 1-Le Nikko Chemicals Co., Ltd.) are particularly suitable. Examples of the a-on surfactant include sulfates (eg, higher alcohol sulfates, higher alkyl ether sulfates, sulfated oils, sulfated fatty acid esters, sulfated fatty acids, sulfated olefins), and sulfones. Acid salts (eg, sodium alkyl benzene sulfonate, oil-soluble alkyl benzene sulfonate, α-olefin sulfonate, igepon Τ type, aerosol Ο Τ type), phosphate esters

(Eg, phosphate ester salts of higher alcohol ethylene oxide adducts), dithiophosphate ester salts and the like.

 Among the anionic surfactants, for example, bile salts such as sodium dalicocholate / sodium dexcholate, fatty acids such as sodium stearate / potassium phosphinate, salts thereof, and sodium lauryl sulfate are preferable.

 Examples of the cationic surfactant include amine salt type cationic surfactants (eg, amine salt type cationic surfactants made from higher alkylamines, amine salt type cationic surfactants made from lower alkylamines), and the like. Grade ammonium salt-type cationic surfactants (eg, quaternary ammonium salt-type cationic surfactants made from higher alkylamines, quaternary ammonium salt-type surfactants made from lower higher alkylamines) and the like are used.

As the amphoteric surfactant, for example, an amino acid type amphoteric surfactant, a betaine type amphoteric surfactant and the like are used. Examples of naturally-derived surfactants include purified egg yolk lecithin (trade name: PL-100H, Cupy Corp.) and hydrogenated soybean lecithin (trade name: Resinol ^ / S-10, Nikko Chemicals Co., Ltd.) ) And the like.

 Among the above surfactants, sodium deoxycholate, sodium lauryl sulfate, polysonolate 80, polyoxyethylene (160) polyoxypropylene

(30), polyoxyethylene glycerol tri-ricinoleate 35, lecithins, polyoxetylene, castor oil, sucrose fatty acid esters, polyglycerin fatty acid esters are more preferable, and sodium deoxycholate is more preferable. It is.

 These surfactants may be used alone or in combination of two or more.

 Further, the solid dispersion may contain a water-soluble cyclodextrin derivative as another substance. .

 As the water-soluble cyclodextrin derivative, a commercially available product may be used, or it may be produced according to a method known per se.

 As the easily water-soluble cyclodextrin derivative, preferably, a part of the 2, 3, 6-position or all of the hydroxyl groups of glucose in the cyclic oligosaccharide composed of 6 to 12 darcose units is replaced with another functional group. For example, compounds substituted with a dihydroxyalkyl group, a sugar residue, a hydroxyalkyl group, a sulfoalkyl group and the like are used. The water-soluble derivative has a solubility in water of about 10 Omg / mL or more, preferably about 13 Omg / mL or more.

 Desirable specific examples of the water-soluble cyclodextrin derivative include the general formula

(In the formula, q is an integer satisfying ⁶ to 12, and R ⁶ , R ⁷ and R ⁸ are the same or different in each repeating unit, and represent a dihydroxyalkyl group, a sugar residue, a hydroxy group, respectively. Indicates an alkyl group or a sulfoalkyl group. ] The compound represented by Can be Specific examples thereof include ether derivatives of hydroxyl groups such as α-CyD (q = 6), β-ΟγΌ (q = 7), γ-CyD (q = 8), and δ-CyD (q = 9). Can be Among them, an ether derivative of a hydroxyl group of j3-CyD is preferable.

Examples of the dihydroxyalkyl group represented by R ^{6 to} R ⁸ include a dihydroxy monoalkyl group (eg, dihydroxymethyl, 2,2-dihydroxyethyl,

2,2-dihydroxypropynole, 2,2-dihydroxypentynole, 2,2-dihydroxyhexyl, etc., preferably a dihydroxy-1-C.sub.14alkyl group (eg, dimethyloxymethyl, 2,2- Dihydroxyethyl, 2,2-dihydroxypropyl, etc.) are used.

The sugar residue represented by R ⁶ to R ^8, for example, C ₃ _ ₂₄ sugar residues (Ellis port sills, Toreoshiru, Arabinoshiru, Riposhiru, Darukoshiru, galactosyl, Gurisero Darco one Heputoshinore, Marutoshinore, Rakutoshinore, maltotriosyl, Jimanoretoshi Le etc.), preferably C ₆ - ₂₄ sugar residues (e.g., Darukoshiru, galactosyl, glycerin port - Gunoreko - Heputoshinore, Manoretoshiru, Rakutoshinore, Marutotori old sill, Jimaruto sills, etc.), particularly preferably C 6 ^ ₂ sugar Groups (eg, darkosyl, galactosyl, glyceroglucosheptosyl, maltosyl, lactosyl, etc.) are used.

The hydroxyalkyl group represented by R ⁶ to R ^8, for example, hydroxy-C _t - ₆ alkyl group (e.g., hydroxymethyl, 2-hydroxyethyl E chill, 2-hydroxy Shipuropiru, 2-hydroxycarboxylic pliers Honoré, 2-hydroxy Hexyl), preferably a hydroxy-alkyl group (eg, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, etc.), and particularly a 2-hydroxypropyl group.

Examples of the sulfoalkyl group represented by R ^{6 to} R ⁸ include a sulfo C ^ ₆ alkyl group (eg, sulfomethyl, snorehoetyl, sulfopropyl, sulfopentyl, sulfohexyl, etc.), preferably a sulfoalkyl group (eg, Sulfomethyl, sulfoethyl, sulfopropyl, etc.), and especially a sulfobutyl group are preferably used. More preferable specific examples of the water-soluble cyclodextrin derivative include a compound represented by the general formula (II), wherein at least one of R ^{6 to} R ⁸ is a sugar residue, a hydroxyalkyl group or a sulfoalkyl group. Is mentioned. Examples of the conjugate (II) in which at least one of R ^{6 to} R ⁸ is a sugar residue include, for example, darkosyl, β, γ, δ-Cy D, maltosyl α, β, y, δ-Cy D, maltotriosyl, β, γ, δ-CyD, dimanoletocinole, β, γ, δ-CyD and the like. Of these, maltosyl-α, β, γ, 5-CyD and darkosyl- _α , β, _γ , δ-CyD are preferred. Manoletosil

D (hereinafter abbreviated as G2-iS-CyD), darkosyl] 3-CyD is particularly preferred.

Examples of the compound (II) wherein at least one of R ^{6 to} R ⁸ is a hydroxyalkyl group include hydroxypropyl mono-α, β, γ, δ-CyD. Among these, hydroxypropyl 1 / 3-CyD is particularly preferred.

Examples of the compound (II) in which at least one of R ^{6 to} R ⁸ is a sulfoalkynole group include sulfobutyl-, β, γ, δ-CyD, and the like. Of these, sulfobutyl-i3-CyD is particularly preferred.

 Further, as the easily water-soluble cyclodextrin derivative, a branched cyclodextrin monocarboxylic acid can also be used. This branched cyclodextrin monocarboxylic acid includes not only its free carboxylic acid, but also its salts with alkali metals (eg, lithium, sodium, potassium, etc.) and alkaline earth metals (eg, calcium, magnesium, etc.). Is included. These branched cyclodextrin monocarboxylic acids may be used alone or in combination of two or more, and may be used in a state where a free carboxylic acid and a salt thereof are mixed.

 The branched cyclodextrin monocarboxylic acid is a cyclodextrin having an organic group containing at least one carboxyl group at the 60 position of at least one glucose unit of the cyclodextrin ring.

 The cyclodextrin ring of the branched cyclodextrin monocarboxylic acid has, for example, 6, 7 or 8 glucose units. Preferably, the cyclodextrin ring has 7 glucose units. Examples of the cyclodextrin include α-cyclodextrin, —cyclodextrin, and γ-cyclodextrin.

The organic group containing at least one carboxyl group has 1 to 3 Darcos units, and the organic group has a small number of hydroxymethyl groups of glucose units. It is preferred if at least one is acidified by the carboxylic group.

 Specific examples of the above-mentioned branched cyclodextrin monocarboxylic acid include 6-O-cyclohexyl manoletohexanosinole (6 → 1) -α-D-glucosinolate (4 → 1) —0—aD-darc acid ( Cyclic maltohexaosyl- (6 → l) -aD-Darcovyranosil-1 (4 → 1) -1 O—Hi-1 D—Darcovyranosideuronic acid (hereinafter CyD—G

₂ —COOH; sometimes abbreviated as COOH; abbreviations of the following compounds are also shown in parentheses), 6—O—manoletohepta syrup (6 → 1) —- D-glucosinole (4 → l ) -0— a— D—Gnorec oxalate (6 → 1) — O— a— D—Darcopyranosyl (4 → 1) — Ο— α—D—Darcobilanosiduronic acid) jS—CyD—G ₂ —COOH), 6—O—cyclomaltooctaosyl

— (6 → 1)-—Ό—Gnorecosyl (4 → 1) _0— α-D—Darc oxalic acid (Six mouth maltoctaosyl (6 → 1) — Ο— c — D—glucopyranosyl ( 4 → 1) 1 O—Hi D—Gnorecopyranosideuronic acid—CyD—G ₂ —COOH), 6—O One-mouth maltohexaosyl- (6 → 1) _Hi-D—Darc (Six-mouth maltohexaosyl- (6 → 1) —O—Hi-D-Darcovyranoside uronic acid) (a—CyD-G G “COOH), 6—O—Cyclomaltoheptaosyl-1 (6 → 1) —α — D— Darctic acid (cyclomanoletoheptaosyl- (6 → 1) -0-α-D_darcopyranosiduronic acid) (3 _CyD_G “COOH), 6—O—Silicone maltoocta silou (6 → 1) —Hiichi D-Darctic acid (cyclomasoletooctaosyl (6 → 1) _0—a_D—Darcovyranoside uronic acid) (γ-CyD—Gi—COOH), 2-

O— (6-cyclomaltohexaosyl) monoacetic acid — CyD_CH ₂ COOH), 2 _0— (6 _cyclomaltoheptaosyl) -acetic acid (-〇0—.11 ₂ 000 «0, 2—0— (6-cyclomal Toctaosyl) monoacetic acid (γ-CyD—CH ₂ CO〇H :),

3— 0— (6-cyclomaltoheptaosyl) monopropionic acid (j8— CyD— CH ₂ CH ₂ COOH), 2-hydroxy-13— O— (6-cyclomaltoheptaosyl) -butanoic acid (3 —〇- (6-cyclomaltoheptaosyl) -1-hydroxypropionic acid) (13—CyD—CH ₂ CH (OH) —COOH), 7 ^A , 7 ^C —Gee O— [α—D—Gluc Mouth linolee (l → 4) —0—o; —D—Gnorecosinole] — (1 → 6) 1 maltoheptaose (i3—CyD— (G ₂ COOH) ₂ ), 6—O—cyclomaltoheptao Shiru O _ α— D—maltosyl (4 → 1) _〇 一 a—D—Darc oxalic acid (sic mouth maltoheptaosyl (6 → l) —0—a—D—Darcopyranosyl (4 → 1) — Ο-a— D—Darcovyranosyl mono (4 → 1) -0-a—D—Darcodylanosidic acid) (i3—CyD—G ₃ —COOH), and their salts [eg, CyD — G _2- COOH sodium salt (cyclomaltoheptaosyl- (6 → 1) -〇α- D

- Darko Pila waves * Lou (4 → 1) -0_α- D- Darco Vila Roh starting opening phosphate sodium © arm (Similarly i8- CyD- G ₂ - abbreviated to COONa))] and the like. Among them, i3—CyD—G ₂ —COONa is preferred.

More particularly, Kisaoshiru (6 → 1) to 6- O-Shikuromaruto - CK-D-Darukoshiru one (4 → 1) one O-a- D-glucuronic acid (shed one C y D- G ₂ _COO

H), 6-O-cyclomanoletoheptaosinole (6 → 1) -a-D-gunolecosinole (4 → 1) —Ο—α—D-glucuronic acid (j3—CyD—G ₂ —COOH), andぴ 6— O—Cyclomanoletooctanocinol CK—D—Gnorecocsolezole (4 → 1) -0-Hiichi D—Glucuronic acid (γ—CyD— G ₂ —COOH) is α-cyclodextrin (glucose) A branched cyclodextrin containing ruthenic acid containing 6 units, β-cyclodextrin (7 glucose units) and γ-cyclodextrin (8 glucose units), and one glucose unit of the cyclodextrin ring. In this case, maltose is _α- (1 → 6) -linked, and the 6-hydroxymethyl group of the terminal glucose of maltose is oxidized to a carboxyl group to form dalc vulcanic acid.

 In addition, 6-cyclomaltohexacinolenoyl (6 → 1) -α-D-darctic acid (Hi-CyD——COOH), 6—O-cyclomaltoheptaosyl- (6 → 1) —Hichi-D— Glucuronic acid (one CyD—one COOH) and 6-O—cyclomaltooctaosyl (6 → 1) —α—D—darconic acid (γ—CyD—G—COOH) are the cyclodextrins A branched cyclodextrin monocarboxylic acid in which glucose is bound to a single glucose unit of the ring (1 → 6), and the 6-hydroxymethyl group of the branched glucose is oxidized to a carboxyl group to form glucuronic acid. It is.

And 2-D- (1-cyclomaltohexaosyl) monoacetic acid—CyD_CH ₂ COOH), 2- O- (6- Shikuromaruto to Putaoshiru) monoacetate (one CyD- CH ₂ COOH)ゝ2-O-(6- cyclomaltodextrin O click Tao Sil) monoacetate (γ- CyD- CH ₂ COOH) is It is a branched cyclodextrin monocarboxylic acid having a carboxymethyl group bonded to one glucose unit of the cyclodextrin ring. These branched cyclodextrin monocarboxylic acids or salts thereof are disclosed in

It is described in, for example, Japanese Patent Application Laid-Open No. 76594/1995, Japanese Patent Application Laid-Open No. 7-215895, and for example, by a method described in the Japanese Patent Application Laid-Open No. 10-210996, Japanese Patent Application Laid-Open No. 10-210996, or a method analogous thereto. be able to.

 When the solid substance is a pharmaceutical compound, the solid dispersion may contain, as another substance, an additive generally used in the field of pharmaceutical preparation as exemplified below.

 When the solid substance is an agrochemical compound, the solid dispersion may contain a solid carrier, a binder and the like exemplified below as other substances.

 The ratio of the solid substance to the other substance can be arbitrarily determined according to the purpose. For example, when the solid substance is a pharmaceutical compound, the content of the pharmaceutical compound in the solid substance varies depending on the form of the preparation and the like, but is usually about 0.01 to 99 to the entire solid dispersion. It is about 99% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 30% by weight.

 The solvent used in the present invention refers to a liquid medium in which the solid substance is dissolved. The solvent should be one that lowers the melting point when added to a solid substance, but the degree of the melting point drop increases as the amount of added calorie increases (that is, it has a high affinity). Is preferred. The melting point drop can be measured, for example, by using a thermal analyzer such as DSC-820 (Mettler, Switzerland) and comparing the melting points when no solvent is added and when a solvent is added.

 From the viewpoint of removing the solvent after heating and melting, a solvent having a boiling point of 100 ° C or less is preferred.

As the solvent used in this effort, a solvent that effectively lowers the melting point of the solid substance, is easily removed after the production of the solid dispersion, or is acceptable even if it remains is preferable. When the solid substance is a hydrophobic substance, the solvent is preferably an organic solvent, and in particular, aromatic hydrocarbons such as benzene, toluene, and xylene; Aethenoles such as tyl ether, dioxane, jetoxetane, tetrahydrofuran and 1,2-dimethoxyethane; organic chlorine-based organic solvents such as dichloromethane, chloropho / rem, carbon tetrachloride and 1,2-dichloroethane; acetonitrile, propioni Alkyl nitriles such as tolyl; nitroalkanes such as nitromethane and nitroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; ketones such as acetone; ethyl acetate; Fatty acids such as acetic acid, acetic anhydride, and oleic acid; alcohols such as methanol, ethanol, and propanol; sulfoxides such as dimethyl sulfoxide; and a mixed solvent thereof and a mixed solvent with water are used. Rucols (E.g., ethanol, etc.) or ketones (e.g., acetone, etc.) or a water mixture thereof (usually water 1 to 90% (w / w), alcohols and the like 99 to 10% (w / w), preferably Water is preferably 1 to 70% (w / w), and alcohols and the like are mixed at a rate of 99 to 30% (w / w).

 The amount of the solvent may be determined according to the type of the solid substance, the desired degree of melting point drop, and the like, and is usually preferably about 0.01 to about 100% (w / w), more preferably from about 0.05 to about 50% (w / w), particularly preferably from about 0.1 to about 10% (w / w). The amount of the solvent is preferably about 0.01 to about 100 times (w / w), more preferably about 0.05 to about 50 times (wZw) the solid substance. Particularly preferably, the amount may be about 0.1 to about 10 times (wZw). If the amount of the solvent is too small, a sufficient melting point drop cannot be obtained. If the amount is too large, it becomes difficult to remove the solvent.

 In the production method of the present invention, both the solid substance and the solvent that causes the melting point to be reduced are present (preferably mixed), and are heated and melted. Usually, an amount of a solvent that causes a melting point drop is added to a solid substance, but conversely, a solid substance may be added to an amount of a solvent that causes a melting point drop.

In the production method of the present invention, the solid substance is melted at a temperature lower than the melting point of the solid substance due to the melting point drop. That is, the temperature at which the solid substance is heated and melted may be higher than the lowered melting point (actual melting point), and may be lower than the melting point of the solid substance. This heats and melts the solid material with low energy Can be Furthermore, since the “actual melting point” can be adjusted by the amount of the solvent added as described above, when the solid substance is a substance unstable to heat, the “actual melting point” is set to the temperature at which the solid substance does not thermally change. The solid substance can be heated and melted at a temperature at which the solid substance does not thermally change.

 In the production method of the present invention, the temperature at which the solid substance is heated and melted is set at a temperature higher than the boiling point of the solvent from the viewpoint that no chemical change occurs in the solid substance and a subsequent desolvation step is not required. Temperatures below the melting point of the substance are preferred!

 From the viewpoint of obtaining a solid dispersion having a uniform composition, it is desirable that the solid substance be completely melted, but it is not essential that the solid substance be completely melted.

 In this way, the solid substance is heated and melted, mixed with other substances, and then, if necessary, the solvent is removed to obtain a solid dispersion having a uniform composition.

 In addition, by performing the heating and melting and mixing under pressure, evaporation of the solvent during the step can be prevented. However, if the pressure increases, the melting point of the solid substance increases, and the effect of lowering the melting point by the solvent is hardly obtained. Therefore, the pressure should be high enough to prevent evaporation of the solvent used. Specifically, the pressure is from about 0.11 MPa to about 5 OMPa, preferably from about 0.15 MPa to about 1 OMPa.

 The “heating and melting”, “mixing” and “removal of the solvent” may be performed using conventional methods and apparatuses, respectively.

 “Heat melting” and “mixing” can be performed, for example, using a commonly used stirrer or kneader having a heat source. Further, it is preferable to have a structure that can pressurize the inside.

 "Removal of the solvent" can be performed by, for example, drying under reduced pressure, drying with hot air, or the like. Alternatively, an injection device such as an extruder having a screw in a cylinder (eg, a single screw extruder, a twin screw extruder, etc.) or an injection molding machine (eg, a twin screw type extruder, etc.) can be used. . Among them, an injection device of a two-axis type ethtruder is preferable.

In this case, the solid material, the amount of solvent that causes the melting point to fall, and the other materials are introduced from the hopper of these devices into the device maintained at an appropriate heating and melting temperature, and the screw is rotated. This causes the solid material to melt and mix with other materials. Since the outlet of the solid dispersion is a small hole, the inside of the cylinder is pressurized and the evaporation of the solvent is prevented. A solid dispersion having a uniform composition can be obtained by removing the solvent as needed from the solid dispersion extruded from the small holes. In this method, when selecting the type of solvent and determining the production conditions so that the heating and melting temperature is higher than the boiling point of the solvent, the solid dispersion extruded from the small holes and exposed to normal pressure The solvent is removed by evaporation of the solvent from the body.

 When the solid substance is a pharmaceutical compound, the following solid dispersion (pharmaceutical composition) can be obtained by the production method of the present invention.

 The pharmaceutical composition does not contain lumps of a pharmaceutical compound having a particle size of about 10 microns or more, and the amount of the drug compound in a 20-micron square meter at any point in the pharmaceutical composition is determined based on the theoretical composition. A pharmaceutical composition of about 70 to about 130%, more preferably a pharmaceutical composition containing no lumps of the pharmaceutical mixture of 5 or more micro-mouths at any position in the pharmaceutical composition; A pharmaceutical composition wherein the amount of the pharmaceutical compound in a 10 micron square meter is from about 80% to about 120% of the theoretical composition.

 Here, the amount of the pharmaceutical compound per unit area can be measured by elemental mapping using EPMA.

 When the solid substance is a pharmaceutical compound, the solid dispersion obtained by the production method of the present invention can be used as a pharmaceutical preparation for oral administration or the like by, for example, pulverizing as necessary. In addition, additives generally used in the field of pharmaceutical preparations can be added to obtain pharmaceutical preparations such as fine granules, fine granules, granules, tablets, capsules, and injections in a usual manner.

 As the additive, pharmaceutically acceptable carriers such as various organic and inorganic carrier materials commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants, surface active agents It is blended as an agent. In addition, it is preferable to add an adsorbent for the purpose of retaining an amount of a solvent that causes a melting point drop used in the production method of the present invention. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.

Suitable examples of excipients include, for example, lactose, sucrose, D-mantol, starch, crystalline cellulose, sucrose, perforated starch, mannitol, calcium silicate Shim (trade name: Florite RE), magnesium aluminate metasilicate (trade name: Neusilin), light anhydrous silicic acid (trade name: Silicia), sucrose, starch spherical granules (brand name: nonpareil), crystalline cellulose, carboxymethyl cellulose (Product name: Avicel RC), hydroxypropyl starch and the like are used. Preferable examples of the lubricant include, for example, magnesium stearate, calcium stearate, ta / lek, colloidal silica and the like.

 Preferred examples of the binder include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like.

 Preferred examples of the disintegrant include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, methylcellulose (trade name: METROSE SM), croscanolemelose sodium, Norremellose calcium, low-substituted hydroxypropylcellulose, sodium starch glycolate, partially alpha-yi starch, and the like are used.

 As the lubricant, for example, talc, crystalline cellulose, magnesium stearate, corn starch, magnesium oxide and the like are used.

 Examples of surface active agents include polyoxyethylene polyoxypropylene daricol (trade name: Pull Mouth Nick) glycerin fatty acid ester, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate 80, Cetanol is used.

 As the adsorption ^ W, for example, perforated starch, canolecidium silicate (trade name: FLORITE RE), magnesium aluminate metasilicate (trade name: Neusilin), light silicic anhydride (trade name: Silicia), etc. are used. Preferred examples of preservatives include, for example, estenoles paraoxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

These additives may be used alone or in combination of two or more. For example, when the solid dispersion obtained by the production method of the present invention is used for an injection, it is prepared by dissolving, suspending or emulsifying the solid dispersion in a sterile aqueous or oily liquid.

 As carriers for injections, for example, solvents, dissolution aids, suspending agents, isotonic agents, buffering agents, soothing agents and the like are used.

 Examples of the solvent include water for injection, physiological saline, Ringer's solution and the like. Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like.

 Injectable preparations obtained by vigorous removal of pyrogens, if necessary, can be removed by a method known per se, then lyophilized in a sterilized freeze dryer and stored in powder form, or injected as is It can also be stored in a sealed container (eg, ampoule).

 The content of the solid dispersion obtained by the production method of the present invention in the preparation obtained by force is usually 0.1 to 1: 1 based on the total amount of the power preparation which varies depending on the dosage form, administration method, carrier and the like. 0 0% (w / w).

 The pharmaceutical preparation comprising the solid dispersion obtained by the production method of the present invention or the pharmaceutical preparation containing the same may be selected from mammals (eg, rats, mice, guinea pigs, monkeys, etc.) depending on the type of the drug conjugate. , Dogs, dogs, pigs, humans, etc.).

The dosage of the pharmaceutical preparation varies depending on the administration subject, administration route, disease and the like.For example, when the pharmaceutical compound is the following compound A or a salt thereof, and is administered into a joint as an aqueous suspension injection, The amount of compound (A), for example, about 0.1 mg or more, preferably about 0.2 mg to about 500 mg, more preferably, as a single dose per adult (body weight: 50 kg) Is used in an amount of about 0.5 mg to about 20 mg. In this case, the administration frequency is, for example, about once a day or more, preferably about 2 days to 3 months. About once every three days to about three months, and more preferably about once a week to once a month.

 When the solid substance is a pesticide compound, the solid dispersion obtained by the production method of the present invention can be used as a pesticide composition by itself, if necessary, by pulverization or the like. Alternatively, an emulsion, a liquid, an oil, or the like may be prepared by mixing a suitable agricultural chemical preparation carrier, a surfactant, a hydrophilic polymer, a readily soluble cyclodextrin derivative, or the like according to a method for producing an agricultural chemical composition known per se. Powder, DL (driftless) type powder, granule, fine granule, fine granule F, fine granule F, wettable powder, wettable granule, 7i solvent, flowable, tablet, jumbo, spray, paste Etc. Examples of the surfactant include those exemplified in the case where the solid substance is a pharmaceutical compound and those oscillating.

 Specifically, the solid dispersion containing one or more (preferably one to three) pesticidal compounds obtained by the production method of the present invention is dissolved in a suitable liquid carrier depending on the purpose of use. Or adsorb it with a suitable solid carrier or adsorb it and mix it with a surfactant, a hydrophilic polymer or a readily soluble cyclodextrin derivative as required. These preparations may contain an emulsifier, a dispersant, a spreading agent, a penetrant, a wetting agent, a binder, a thickener and the like, if necessary, and can be prepared by a method known per se.

Examples of the liquid carrier (solvent) used include water, alcohols (eg, methanol, ethanol, 1-propanol, 2-propanol, ethylene glycol, etc.), ketones (eg, acetone, methylethyl) Ketones), ethers (eg, dioxane, tetrahydrofuran, ethylene glycol 'monomethinoleate ether, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, etc.), aliphatic hydrocarbons (eg, kerosene, kerosene, Fuel oils, machine oils, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, solvent naphtha, methyl naphthalene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.), Acid amides (eg, dimethyl pho Muamido, dimethyl § Seth amides), esters (e.g., acetate Echiruesuteru, acetic heptyl esters, fatty acid glycerin ester, etc.), nitriles such (eg, Aseto - tolyl, propionic nitrile, etc.) solvents such as are used. These are one or more (preferably one to three) Mix and use at an appropriate ratio.

 Examples of solid carriers (diluents and extenders) include vegetable powders (eg, soybean powder, tapaco powder, flour, wood flour, etc.) and mineral powders (eg, kaolin, bentonite, acid clay, clay, etc.) , Talc powder, talc powder such as talcum powder, diatomaceous earth, silica powder such as mica powder, etc.), alumina, sulfur powder, activated carbon, sugars (eg, lactose, glucose, etc.), inorganic salts (eg, calcium carbonate, heavy For example, sodium carbonate or the like, a hollow glass body (a natural glass material which is fired and air bubbles are contained therein) and the like are used. These are used alone or in combination of two or more (preferably 1 to 3) in an appropriate ratio. The liquid or solid carrier is usually about :! to the entire pesticidal composition. To about 99% by weight, preferably about 10 to 99% by weight.

As an emulsifier, a dispersant, a spreading agent, a penetrant, a wetting agent and the like, a surfactant is used as required. Examples of these surfactant surfactants include polyoxyethylene alkyl ethers (eg, Sanyo Kasei Kogyo Co., Ltd., Emulmin 110), polyoxyethylene alkyl aryl ethers (eg, Sanyo Kasei Kogyo Co., Ltd.) Nonipol 85, Nonipol 100, Nonipol 160, etc.), polyoxyethylene lanolin alcohol, polyoxyethylene alkyl phenol honoremarin condensate, polyoxyethylene sorbitan fatty acid ester (eg, Kao Corporation) Tween 20, Tween 80, Daiichi Kogyo Seiyaku Co., Ltd., Sorgen TW-20, Sorgen TW-80, etc., polyoxyethylene glyceryl monofatty acid ester, polyoxypropylene glycol monofatty acid ester , Polyoxyethylene sorbitol fatty acid ester, polyoxyethylene Castor oil derivative, polyoxyethylene fatty acid ester, higher fatty acid glycerin ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene polyoxypropylene block polymer, polyoxyethylene fatty acid amide, alkylolamide, polyoxyethylene alkylamine, etc. Nonionic surfactants, alkylamine hydrochloride (eg, dodecylamine hydrochloride, etc.), alkyl quaternary ammonium salts, alkyltrimethyl quaternary ammonium salts (eg, dodecyltrimethylammonium salt, etc.), alkyldimethyl Benzyl ammonium salt, alkylpyridinium salt, alkylisoquinolinium salt, alkyl morphodium salt, benzethonium chloride. Polyalkylvinylpyridinium Cationic surfactants such as sodium salt, higher fatty acid sodium salt (eg, sodium palmitate, etc.), ether carboxylic acid sodium salt (eg, sodium polyoxyethylene lauryl ether carboxylate, etc.), amino acid condensate of higher fatty acid (E.g., sodium peroxyl sarcosine, sodium N-lauroylglutamate), higher alkyl sulfonates, higher fatty acid ester sulfonates (e.g., lauric ester sulfonate, etc.), lignin sulfonates (e.g., Ligninsulfonate, etc.), alkinolesulfosuccinates (eg, sodium diheptylsulfosuccinate, sodium dioctylsulfosuccinate, sodium dinoelsulfosuccinate), higher fatty acid amide sulfonates (eg, olein) Acid amide sulf Acid salt), dodecylbenzenesulfonate, diisopropylnaphthalenesulfonate, alkylarylsulfonate formalin condensate, higher alcohol sulfate ester salt (eg, pentadecane-2-ylsulfate, etc.), polyoxyethylene Alkyl ether sulfates (eg, polyoxyethylene dodecyl ether sulfate, etc.), polyoxyethylene alkyl phosphates (eg, dipolyethylene dodecyl ether phosphate, etc.), polyoxyethylene alkyl aryl phosphates, styrene Anionic surfactants such as mono-maleic acid copolymer, alkyl butyl ether-maleic acid copolymer, N-lauryl lanine, N, N, N-trimethylaminopropionic acid, N, N, N-trihydroxyethylaminopropane Acid, hexyl one to N-N, N-Jimechiruamino acetate, 1 i (2 one Karubokishechiru) amphoteric surface active agents such Pirijiniumu betaine and the like. One or more (preferably 1 to 5) of these are used.

 The surfactant can be used usually in an amount of about 0 :! to about 50% by weight, preferably about 0.1 to 25% by weight, based on the whole composition.

Examples of the binder include dextrin (eg, Nissei Chemical Co., Ltd., dextrin ND-S, etc.), sodium salt of carboxymethylcellulose (eg, Daiichi Kogyo Yakuhin Co., Ltd., Cellogen 5A, Cellogen 6A, cellogen 7A, cellogen PR, etc.), polycarboxylic acid polymer compound (eg, manufactured by Sanyo Chemical Industries, Ltd., Toxanone GR—30, Toxanone GR—31A, Toxanone GR—50L, Toxanone GR—60 L; manufactured by Kao Corporation, Boyes 530, Boys 532 A, etc.), polyvinyl pyrrolide , Polybutyl alcohol, sodium ligninsulfonate, calcium ligninsulfonate, sodium polyacrynolate, gum arabic, sodium alginate, glucose, sucrose, mannitol, sorbitol and the like. The combined IJ can be used usually in an amount of about 0 to 20% by weight based on the whole preparation.

 Examples of the thickener include bentonite mineral substances (eg, high-purity sodium montmorillonite), polyacrylic acid and its derivatives, sodium salts of carboxymethylcellulose (eg, Daiichi Kogyo Seiyaku Co., Ltd., Cellogen 5A, Cellogen 6A, cellogen 7A, cellogen PR, etc.), white carbons, natural saccharide derivatives (eg, xanthan gum, guar gum, etc.) are used. The thickener is usually used in an amount of about 0.01 to about 10% by weight based on the whole composition.

 The content of the pesticide compound in the pesticidal composition obtained by crushing is suitably about 1 to 90% by weight for emulsions, wettable powders, wettable powders, liquids, aqueous solvents, floor pulls and the like. , Powder, DL-type powder, etc., about 0.01 to about 10% by weight is appropriate. For fine granules, fine granules F, fine granules F, granules, etc., about 0.05 to 10 wt. % Is appropriate, but these concentrations may be appropriately changed depending on the purpose of use. Emulsions, wettable powders, wettable powders, wettable powders, liquids, water solvents, flowables, etc. are used by diluting them appropriately with water, etc. (for example, about 100 to 100,000 times) before use. You can also.

 When a surfactant, a hydrophilic polymer or a readily soluble cyclodextrin derivative is used in the composition, its content varies depending on the form of the preparation. Usually, about 1 to 99.99% by weight based on the whole preparation. It is preferably about 10 to 90% by weight.

 The content of the carrier for a pesticide formulation in the pesticide composition varies depending on the form of the formulation, but is usually about 1 to 99.99% by weight, preferably about 10 to 9% by weight based on the whole formulation. It is about 0% by weight.

 The method of application can be the same as the method of application of ordinary pesticides, for example, aerial application, soil application, foliage application, nursery box application, lateral application, seed treatment and the like. For example, when applied to a paddy field, it is applied by a method known per se (eg, hand spreading, power spraying, etc.).

For example, when a herbicide is used as a pesticide conjugate, the amount of the pesticide composition used is Although there are differences depending on the scene, application time, application method, target grass species, cultivated crops, etc., generally about 0.05 to 50 g of herbicide per 1 are of paddy field, preferably about 0. Approximately 0.05 to 50 g per field, preferably about 0:! To 10 g.

 When the pesticidal composition is applied to paddy field weeds, it is preferable to use it as a pre-emergence soil treatment agent or a foliage / soil treatment agent. Example

 Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples, but the scope of the present invention is not limited thereto.

 In the present specification, the compound A is (2R, 4S)-(-1) -1-N- [4- (diethoxyphosphorylmethyl) phenyl] -1,2,4,5-tetrahydro_-4-monomethyl_7,8 — It is methylenedioxy-5-oxo-3-3-benzozopine-12-carboxamide. As the compound A, a compound produced by the same method as described in Example 1 of JP-A-8-231569 (European Patent Application Publication No. 711,972) was used. The structure of compound A is represented by the following formula.

Example 1

100 g of Compound A, 100 g of hydroxypropylmethylcellulose, 50 g of partially pregelatinized starch, and 50 g of light caustic anhydride were mixed to obtain a mixed powder. The mixed powder was supplied to a twin-screw type Eatstruder (¾: £ -25 type, Kurimoto Tetsue) at a rate of 35 g / min, and at the same time, a 50% (w / w) aqueous ethanol solution was added as a solvent to a three-axis type ethanol trusser. It was fed at a rate of 5 g / min. The processing conditions were a barrel temperature of 100 ° C, a shaft rotation speed of 250 rpm, and a die size of 3.5 mm *. The obtained fire The product (solid dispersion) was dried in a vacuum drier (Kusu Seisakusho, 40 ° C, 16 hr), and then turned into a powder with a hammer mill (Atomizer 1, Fuji Padal). The pressure was controlled at 2 to 6 MPa at a value detected near the outlet. Comparative Example 1

 100 g of Compound A, 100 g of hydroxypropylmethylcellulose, 50 g of partially arsenic starch, and 50 g of light caustic anhydride were mixed to obtain a mixed powder. The mixed powder is supplied at a rate of 35 g / min to a twin-shaft eta-struder (type £ 125, Kurimoto Tetsue), and at the same time purified water is supplied at a rate of 3.5 g / min as a solvent. did. The processing conditions were a barrel temperature of 100 ° C, a shaft rotation speed of 250 rpm, and a die size of 3.5 mm. The obtained ejected material (solid dispersion) was dried by a vacuum dryer (Kusu Seisakusho, 40 ° C, 16 hr), and then powdered by a hammer mill (Atomizer, Fuji Padal). Test Example 1 (Confirmation of affinity between solvent and drug)

The affinity between Compound A and the solvent was confirmed using a thermal analyzer (DSC-820, Meter, Switzerland). Ethanol or purified water was used as a solvent, and the melting point drop was observed at each addition amount. About 5 mg of Compound A and each amount of ethanol or water were sealed in a sealed sample cell for thermal pressure analysis. The amount of Etanonore is 0 as weight%, 10, 20, 40 and 80% (w / w), the amount of water is 0 as weight _{^{0/0, 12. 5, 25}} , 50, 100% (w / w ). Scanning was performed at a heating rate of 10 ° C./mi η, and the affinity between the solvent and the drug was evaluated from the obtained differential caloric-temperature curve. When no solvent was added, the melting point of Compound I was about 187 ° C (onset value). The melting point was lowered by the addition of ethanol, and the magnitude of the drop was significantly reduced as the amount of ethanol added increased. With the addition of 10% (w / w), it was confirmed that the endotherm accompanying melting started at about 80 ° C. Further, as the amount of ethanol added increased, the endothermic peak value due to melting shifted to a lower temperature side. On the other hand, in the system to which purified water was added, the melting point decreased slightly to about 145 ° C (onset value), but no effect was observed depending on the amount added. Graphs of the differential calorie-temperature curve are shown in Figs. 1 and 2. Show. Test example 2 (element mapping by EP MA)

 The dispersion state of Compound A in the pharmaceutical compositions produced in Examples and Comparative Example 1 was evaluated by EPSA elemental mapping (sulfur, silicon, phosphorus). As a result, the comparative example

In the composition of Example 1, a lump of Compound A was observed, whereas in the composition of Example 1, uniform dispersion of Compound A was observed. FIG. 3 shows the element mapping of the composition of Example 1 and FIG. 4 shows the element mapping of the composition of Comparative Example 1 together with SEM images. Figure

The white circle of 4 indicates a lump of compound A. Test example 3 (powder X-ray diffraction analysis)

 The pharmaceutical compositions produced in Example 1 and Comparative Example 1 were subjected to powder X-ray diffraction analysis. In the composition of Example 1, the peak derived from the crystal of Compound A completely disappeared (FIG. 5). In Comparative Example 1, a peak derived from the crystal was confirmed (FIG. 6). Industrial applicability

 As is apparent from the above, according to the present invention, there is provided a method for preventing a chemical change of a thermally unstable substance and producing a solid dispersion having a uniform composition.

Claims

The scope of the claims I. A method for producing a solid dispersion, which comprises heating and melting a solid substance and a solvent in an amount that causes a decrease in melting point. 2. The production method according to claim 1, wherein an amount of a solvent that causes a decrease in melting point is added to the solid substance, and the mixture is heated and melted.  3. The method according to claim 1, wherein the solvent is an alcohol or a ketone or a water mixture thereof.  4. The production method according to claim 1, wherein the amount of the solvent relative to the solid substance is about 0.01 to about 100% (w / w).  5. The production method according to claim 1, wherein the temperature for heating and melting is a temperature higher than the boiling point of the solvent and lower than the melting point of the solid substance.  6. The method according to claim 1, wherein the solid substance is a substance unstable to heat. 7. The method according to claim 1, wherein the solid substance has a melting point of about 80 to about 350 ° C.  8. The method according to claim 1, wherein the solid substance is a poorly water-soluble or water-insoluble drug conjugate.  9. The production method according to claim 1, further comprising an adsorbent.  10. The production method according to claim 1, wherein the solid substance is heated and melted with an amount of a solvent capable of lowering the melting point, and mixed with another substance.  I I. A solid dispersion produced by the production method according to claim 1.