JP2003063950A - Method for producing solid dispersion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method which is for producing a solid dispersion, having a uniform composition, and preventing the chemical change of a thermally unstable substance. SOLUTION: The method for producing the solid dispersion is characterized in that a solvent is added to a solid substance in an amount enough to cause the lowering of the melting point of the solid substance and then is heated and melted.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a solid dispersion.

[0002]

2. Description of the Related Art Mixing refers to an operation of mixing two or more different substances so as to form an apparently uniform composition. Mixing is one of the very important operations in the production of pharmaceutical compositions, etc., because if the mixing is insufficient, the quality of products such as preparations will have a problem of uniformity. Especially when mixing solids, it is difficult to obtain a uniform composition. As a method for sufficiently mixing solids, there are a melting method in which a physiologically active substance and other components are heated and melted at a temperature equal to or higher than a melting point, and a solvent method in which a physiologically active substance and other components are dissolved in an organic solvent. However, in the former, since the object is processed at high temperature,
There is a problem that it cannot be used for producing a solid dispersion containing a heat-labile substance. Also, in the latter,
Since a large amount of organic solvent is used, its removal becomes a problem. With respect to these problems, Japanese Patent No. 2527107 describes a method for producing a solid dispersion using a biaxial extruder. This method is an excellent method 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 and other components. Further, a technique of lowering the melting point by adding a low melting point compound (eg, a plasticizer) to a solid compound is known, but there is a problem that the low melting point compound remains in the solid dispersion.

[0003]

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

[0004]

Means for Solving the Problems In the mixing step, the inventors of the present invention prevent the chemical change of a heat-labile substance and make the components uniform by adding a solvent, heating and melting and mixing. As a result of discovering that they can be mixed with each other and further researching, the present invention has been completed. That is, the present invention provides: (1) a method for producing a solid dispersion, which comprises heating and melting a solid substance and an amount of a solvent that causes a melting point lowering; and (2) an amount of causing a solid substance to lower a melting point. (1) The production method according to the above (1), wherein the solvent is added and the mixture is heated and melted. (3) The production method according to the above (1), wherein the solvent is an alcohol, a ketone, or a water mixture thereof. 4) The production method according to the above (1), wherein the blending amount of the solvent with respect to the solid substance is about 0.01 to about 100% (w / w), and (5) the temperature for melting by heating is a boiling point of the solvent or more, and the solid substance. (6) The production method according to the above (1), wherein the solid substance is a substance which is unstable to heat, (7)
The production method according to (1) above, wherein the solid substance is a substance having a melting point of about 80 to about 350 ° C., (8) The production method according to (1) above, wherein the solid substance is a poorly water-soluble or water-insoluble pharmaceutical compound. (9) The production method described in (1) above, which further comprises adsorbing agent, (10) The method described in (1) above, in which the solid substance and the solvent in an amount that causes a melting point decrease are melted by heating and mixed with another substance. Production method, and (11) A solid dispersion produced by the production method according to (1) above is provided.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION "(Heating) melting" in the production method of the present invention means a state in which a solid substance is wet with a solvent and is liquefied by heating. In the present specification, the "melting point" of a solid substance means a melting point measured under 1 atm without adding any substance other than the solid substance, and is used separately from "actual melting point" and "falling melting point". .

The solid substances used in the present invention include pharmaceutical compounds (including animal drugs), agrochemical compounds, fertilizers, cosmetics, flavors, food materials, feeds, fungicides, antifungal agents, insect repellents, insecticides, It can be selected from a wide range of fields such as rust preventives, 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, poorly water-soluble or water-insoluble solid substances. "Slightly water-insoluble or water-insoluble" means that the solid substance is, for example, 2
Less than 1000 ppm with respect to water at 5 ° C, preferably 10
Having a solubility of less than ppm or having a solubility in water at 25 ° C. of less than 10 mg / mL, preferably 0.1 m
Indicates less than g / mL. The solubility can be measured according to a conventional method.

The following are examples of water-soluble pharmaceutical compounds. (1) Antibiotics tetracycline hydrochloride, ampicillin, piperacillin, etc. (2) Antipyretic / analgesic / anti-inflammatory agents sodium salicylate, sulpirine, indomethacin sodium, morphine hydrochloride, etc.
(4) Dihydrocodeine phosphate, isoproterenol hydrochloride, etc. (4) Sedative, chlorpromazine hydrochloride, atropine sulfate, etc. (5) Anti-ulcer drug, metaclopromide, histidine hydrochloride, etc. Antihypertensive diuretic hexamethonium bromide, clonidine hydrochloride, etc. (8) Anticoagulant heparin sodium, sodium citrate, etc.

Examples of poorly water-soluble or water-insoluble pharmaceutical compounds include the following. (1) Antipyretic, analgesic, anti-inflammatory drug salicylic acid, sulpirine, flufenamic acid, diclofenac, indomethacin, atropine, scopolamine,
Morphine, pethidine, levorfinol, ketoprofen, naproxen, ibuprofen, oxymorphone, aspirin, aminopyrine, phenacetin, acetaminophenone, phenylbutazone, ketophenylbutazone, mefenamic acid, bucolome, benzydamine, mepyrizole, thiaramid, tinoridine, xylocaine. , Pentazocine, dexamethasone, hydrocortisone, prednisolone, azulene, isopropylantipyrine,
(2) tranquilizers diazepam, lorazepam, oxazepam, oxazolam, clotiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, chlordiazeboxoxide, etc. (3) antipsychotic drug chlorpromazine Prochlorperazine, trifluoperazine, sulpiride, clocapramine hydrochloride, zotepine, haloperidol, etc. (4) Antibacterial drug Griseofulvin, Lancacidins [J. Antibiotics, 38,
877-885 (1985)], an azole compound [2
-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (2,2,3,3-tetrafluoropropoxy)
Phenyl-3- (2H, 4H) -1,2,4-triazolone, fluconazole, itraconazole, etc.], nalidixic acid, pyromidic acid, pipemidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciproxacin hydrochloride, sulfa (5) Antibiotics gentamicin, dipekacin, canendomycin, ribidomycin, topramycin, amikacin, dibekacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, loritetracycline, methoxazole / trimethoprim, etc.
Doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephaloridine, cefotiam, cefotiam hexetil, cefsulodin, cefmenoxime, cefmetazole, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, Azusureonamu, amoxicillin, cephalexin, erythromycin, Bakanpishin, minocycline , Chloramphenicol or salts thereof (6) antitumor drug 6-O- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine Arazinoside, fluorouracil, tetrahydr Frill-5-fluorouracil, Picibanil, lentinan, levamisole, bestatin, Ajimekison, glycyrrhizin, H
ER2 inhibitors (heterocyclic compounds described in WO 01/77107 etc.), taxol, doxorubicin hydrochloride, etoposide, mitoxantrone, mesna, dimesna, aminoglutethimide, tamoxifen, acroline, cisplatin, carboplatin, cyclophosphami (7) antihyperlipidemic agent clofibrate, 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] ethyl propionate [chemicals such as de, lomustine (CCNU), carmustine (BCNU))・ And Pharmaceuticals ・
Bulletin (Chem. Pharm. Bull), 38, 2792
-2796 (1990)], clinofibrate, cholestyramine, soysterol, tocopherol nicotinate, nicomol, niceritrol, probucol, elastase, etc.

(8) Antitussive / Expectorant Ephedrine, Methylephedrine, Noscapine, Codeine, Dihydrocodeine, Alloclamide, Chlorphedianol, Picoperidamine, Cloperastine, Protoxylol, Isoproterenol, Sartamol, Tereptaline, Bromhexine, Carbocystin, Ethylcystine , Methylcystine or its salt (9) Muscle relaxant pridinol, tubocurarine, pancuronium, chlorphenesin carbamate, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesin, chlorzoxazone, fenprobamate, methocarbamol, chlormezanone, mesylate Pridinol, afloqualone, baclofen, dantrolene sodium, etc. (10) Antiepileptic drug phenytoin, etosa Shimido, acetazolamide, chlordiazepoxide, phenobarbital, carbamazepine, primidone, etc. (11) Antiulcer agents lansoprazole, metoclopramide, famotidine,
Omeprazole, sulpiride, trepibutone, cetraxate hydrochloride, gefernate, irsogladine maleate, cimetidine, ranitidine hydrochloride, nizatidine, roxatidine acetate hydrochloride (12) Antidepressant imipramine, clomipramine, noxiptiline, phenelzine (13) Antiallergic drug diphenhydramine, Chlorpheniramine, triperenamine, methodilamine, clemizole, diphenylpyraline, methoxyphenamine, clemastine fumarate, cyproheptadine hydrochloride, mequitazine, alimemazine tartrate, etc. (14) Cardiotonic transbioxocamphor, terephylol, aminophylline, etilefrine, etc. Drugs propranolol, alprenolol, pufetrol, oxprenolol, pu hydrochloride Cainamide, disopyramide, ajmaline, quinidine sulfate, aplindine hydrochloride, propafenone hydrochloride, mexiletine hydrochloride, etc. (16) Vasodilator oxyfedrine, diltiazem, tolazoline, hexobendine, bamethane, nifedipine, isosorbite dinitrate, diltiazem hydrochloride, trapidil, dipyridamole , Dilazep hydrochloride, verapamil, nicardipine hydrochloride, ifenprodil tartrate, cinepaside maleate, cyclanderate, cinnarizine, pentoxifylline, etc. , Trichlormethiazide, methycrothiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, citric acid Lopenthiazide, fluorothiazide, ethacryic acid, etc. (18) Antidiabetic drug Glimidine, glipzide, phenformin, pformin, metformin, glibenclamide, tolbutamide (19) Antituberculosis drug isoniazid, ethambutol, paraaminosalicylic acid, etc. (20) Narcotic antagonist levallorphan (21) Hormonal drugs Steroid hormones such as dexamethasone, hexestrol, methimazole, petamethasone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, prednisolone, hydrocortisone, estriol, etc. (22) ) bone and cartilage disease preventive and therapeutic agent prostaglandin A1 derivative, vitamin D derivative, vitamin K ₂ derivative, Eikosapen Non-peptidic bone formation promoting substances such as enoic acid derivatives, benzylphosphonic acid, bisphosphonic acid derivatives, sex hormone derivatives, phenolsulfophthalein derivatives, benzothiopyran or benzothiepine derivatives, thienoindazole derivatives, menatetrenone derivatives, helioxanthin derivatives, peptides (23) Joint disease therapeutic agent p38MAP kinase inhibitor (WO 00/64894)
Etc., etc.), matrix metalloprotease inhibitor (MMPI), prednisolone,
Anti-inflammatory steroids such as hydrocortisone, methylprednisolone, dexabetamethasone and betamethasone, non-steroidal anti-inflammatory analgesics such as indomethacin, diclofenac, loxoprofen, ibuprofen, piroxicam, sulindac (24) Frequental hydrochloride, oxybutynin hydrochloride, hydrochloric acid (25) Antiandrogens such as oxelendron, allylestrenol, chlormadinone acetate, gestanolone caproate, osaprone acetate, flutamide, bicalutamide, etc.

(26) Fat-soluble vitamin drugs Vitamin Ks: vitamins K ₁ , K ₂ , K ₃ and K ₄ folic acid (vitamin M), etc. (27) Vitamin derivatives Various derivatives of vitamins such as 5,6-trans- Vitamin D ₃ derivatives such as cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, vitamin D ₂ derivatives such as 5,6-trans-ergocalciferol (28) Other hydroxycams , Diacerine, megestrol acetic acid,
Nicerogolin, prostaglandins, etc.Furthermore, ischemic disease therapeutic agents, immune disease therapeutic agents, Alzheimer's disease therapeutic agents, osteoporosis therapeutic agents, angiogenesis therapeutic agents, retinopathy therapeutic agents, retinal vein occlusion therapeutic agents, senile discs Macular degeneration, cerebral vasospasm treatment, cerebral thrombosis treatment, cerebral infarction treatment, cerebral obstruction treatment, intracerebral hemorrhage treatment, subarachnoid hemorrhage treatment, hypertensive encephalopathy treatment, transient cerebral ischemia Seizure remedy,
Multiple infarction 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-rheumatism Drugs, anti-septic drugs, anti-septic shock drugs, anti-asthma drugs, drugs for treating atopic dermatitis, drugs for treating allergic rhinitis and the like are also used.

The following are examples of solid pesticide compounds that are sparingly soluble in water or sparingly soluble. (1) Insecticide (a) Carbamate MIPC; isoprocarb, BPMC;
Fenobucarb, MPMC; xylylcarb, XMC, NAC; carbaryl
baryl, bendiocarb, carbofuran, etc. (b) Synthetic pyrethroids cypermethrin, fenpropathrin, ethofenpr
ox), resmethrin, etc. (c) Organophosphorus EPN, cyanofenphos, PAP;
Phenthoate, CVMP; tetrachlorvinphos, monocrotophos (m
onocrotophos), phosalone, chlorpyrifos-methyl, chlorpyrifos, pyridaphenthion
ion), quinalphos, DMTP; methidathion, salicione (dioxabenzofo)
s) etc. (d) Organochlorine benzoepine (endosulfan) etc. (e) Other bensultap, buprofezin (bupro)
fezin), flufenoxuron (flufenoxuron), diflubenzuron (diflubenzuron), chlorfluazuron (chlorfluazuron), imidacloprid, etc.

(2) Fungicide (a) N-heterocyclic ergosterol inhibitors triflumizole, trifolin
(b) Carboxamide-based mepronil, flutoluani
l), pencicuron, oxycarboxin, etc. (c) dicarboximide iprodione, vinclozolin
lin), procymidone, etc. (d) Benzimidazole-type benomyl, etc. (e) Polyhaloalkylthio-type captan (captan), etc. (f) Organochlorine phthalides (fthalide), TPN; Chlorothalonil (ch)
lorothalonil), etc. (g) Sulfur-based zineb (zineb), maneb (maneb), etc. (h) Other dichromedin (diclomezin), tricyclazole (tric)
yclazole), isoprothiolane (isoprothiolane), probenazole (probenazole), anilazine (anilazin)
e), oxolinic acid, ferimzone, etc.

(3) Herbicides (a) Sulfonylurea-based imazosulfuron, bensulfuron-methyl (bensulfuro)
n-methyl) etc. (b) Triazine type simetryn, dimethamet
ryn) etc. (c) Urea type dymron etc. (d) Acid amide type propanil (propanil), mefenacet (mefenace)
t) etc. (e) Carbamate-based suep (swep) etc. (f) Diazole-based oxadiazon, pyrazolate (pyrazol)
ate) etc. (g) Dinitroaniline-based trifluralin etc. (h) Other dithiopyr etc.

The solid substance is preferably a substance which undergoes a chemical change such as decomposition by heat, that is, a substance which is unstable to heat. For example, a substance that undergoes a chemical change (eg, decomposition) due to heat at a temperature equal to or lower than the melting point (for example, a temperature in the range from the melting point or lower to the melting point −50 ° C.) is a thermally unstable substance. The melting point of the solid substance is not particularly limited, but is preferably about 80 to about 350 ° C., more preferably about 100 to about 100 ° C.
It is about 270 ° C, particularly preferably about 150 to about 220 ° C.

In the present specification, the solid dispersion means a solid composition in which the above solid substance and another substance are uniformly mixed.
The other substance means a substance other than the above solid substance and is not particularly limited. For example, when the solid substance is a pharmaceutical compound or an agrochemical compound, examples of the other substance include a polymer carrier (eg, polymer compound, surfactant, etc.).
The other substance in the solid dispersion may be one type or two or more types. The polymer carrier used in the present invention is preferably one that is softened by an amount of a solvent that causes a melting point decrease. Here, softening means that the glass transition temperature is lowered.

The high molecular compound is a high molecular 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 30,000, and particularly preferably about 5,000 to 20,000. In the present specification, the weight average molecular weight and the polydispersity mean values measured by gel permeation chromatography (GPC) using polystyrene as a reference substance. For the measurement, GPC column KF804 × 2 (manufactured by Showa Denko) is used, and chloroform is used as a mobile phase. Examples of high molecular weight polymers include, for example, biodegradable type, polyfatty acid ester [eg, homopolymer of fatty acid (eg, polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, etc.), two or more fatty acids Copolymers (eg, lactic acid / glycolic acid copolymer, 2-hydroxybutyric acid / glycolic acid copolymer, etc.), mixtures thereof (eg, polylactic acid and 2-hydroxybutyric acid / glycolic acid copolymer, etc.) Here, as the fatty acid, for example, α-hydroxy fatty acid (eg, glycolic acid, lactic acid, 2-hydroxybutyric acid, 2-
Hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid,
2-hydroxycaproic acid, 2-hydroxyisocaproic acid, 2-hydroxycapric acid, etc.) α-hydroxy fatty acid cyclic dimer (eg, glycoside, lactide, etc.), hydroxydicarboxylic acid (eg, malic acid, etc.), hydroxy Tricarboxylic acid (eg, citric acid, etc.)], poly-α-cyanoacrylic acid ester, poly-hydroxybutyric acid, polyalkylene oxalate (eg, polytrimethylene oxalate, polytetramethylene oxalate, etc.), polyortho Esters, polyorthocarbonates or other polycarbonates (eg, polyethylene carbonate, polyethylene propylene carbonate, etc.), polyamino acids (eg, poly-γ-benzyl-L-glutamic acid, poly-L-alanine, poly-γ-methyl-L-)
Glutamic acid, etc.) and the like. Further, as other biopolymers having biocompatibility, polystyrene, polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid, silicone polymers, dextrans tearate, ethyl cellulose, acetyl cellulose, Examples thereof include nitrocellulose, polyurethane, maleic anhydride-based copolymer, ethylene vinyl acetate-based copolymer, polyvinyl acetate, polyvinyl alcohol, and polyacrylamide. These polymers may be one kind, a copolymer of two or more kinds, or a simple mixture, or a salt thereof.

Among these high molecular weight polymers, polyfatty acid esters and poly-α-cyanoacrylic acid esters are preferable. Furthermore, polyfatty acid esters are particularly preferred. Among polyfatty acid esters, α-hydroxy fatty acids or homopolymers of α-hydroxy fatty acid cyclic dimers, copolymers of two or more types of α-hydroxy fatty acids or cyclic dimers of α-hydroxy fatty acids, or these Is preferred. Furthermore, a homopolymer of α-hydroxy fatty acid, a copolymer of two or more types of α-hydroxy fatty acid, or a mixture thereof is more preferable. Above all, polylactic acid, lactic acid /
A glycolic acid copolymer, a 2-hydroxybutyric acid / glycolic acid copolymer, or a mixture thereof is particularly preferable.
In these α-hydroxycarboxylic acids, D-form,
The L-form and the D, L-form may be used, but the D, L-form is preferable. When a lactic acid / glycolic acid copolymer is used as the high molecular weight polymer, the composition ratio is preferably about 100/0 to 50/50, and when a butyric acid-glycolic acid copolymer is used, the composition ratio is about 100/0 to 25/75 are preferable. The weight average molecular weight of the lactic acid / glycolic acid copolymer is about 5,000.
To about 30,000 are preferred. About another 5,000
Those of 0 to 20,000 are particularly preferred. As the above-mentioned polymer, for example, polylactic acid (A) and glycolic acid / 2
When the mixture with the hydroxybutyric acid copolymer (B) is used, the mixing ratio represented by (A) / (B) is used in the range of about 10/90 to about 90/10 (weight ratio). It is preferably in the range of about 25/75 to about 75/25 (weight ratio). The weight average molecular weight of polylactic acid is preferably about 5,000 to about 30,000. Further, those of about 6,000 to about 20,000 are particularly preferable. Glycolic acid /
The 2-hydroxybutyric acid copolymer preferably has a composition of about 40 to about 70 mol of glycolic acid and the balance of 2-hydroxybutyric acid. The weight average molecular weight of the glycolic acid / 2-hydroxybutyric acid copolymer is preferably about 5,000 to about 25,000. Further, those of about 5,000 to about 20,000 are particularly preferable.

As the hydrophilic polymer, for example, a water-soluble polymer, an enteric polymer, a gastric soluble polymer and the like are used.
Examples of the water-soluble polymer include hydroxypropylcellulose, hydroxyalkylcellulose such as hydroxypropylmethylcellulose, cellulose derivatives such as alkylcellulose such as methylcellulose, polyalkenylpyrrolidone such as polyvinylpyrrolidone, polyalkylene glycol such as polyethylene glycol, and polyvinyl alcohol. Are used. As the enteric polymer, for example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose,
Cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer S and the like are used. As the gastric-soluble polymer, for example, aminoalkylmethacrylate copolymer E, polyvinyl acetal diethylaminoacetate and the like are used. In addition, carboxymethyl cellulose, Eudragit, carboxyvinyl polymer, polyvinyl alcohol, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, chitosan and the like can be used. These hydrophilic polymers may be used alone or in combination.
You may use it by mixing more than one kind.

As the above-mentioned surfactants, nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, surfactants derived from natural products and the like are used. Nonionic surfactants include higher alcohol ethylene oxide adducts, alkylphenol ethylene oxide adducts, fatty acid ethylene oxide adducts, polyhydric alcohol fatty acid ester ethylene oxide adducts, higher alkylamine ethylene oxide adducts, fatty acid amide ethylene oxide adducts. Products, ethylenoxide adducts of fats and oils, glycerin fatty acid esters, pentaerythritol fatty acid esters, polyhydric alcohol alkyl ethers, alkanolamines fatty acid amides,
Are used. Among the nonionic surfactants, for example, fatty acid esters of sorbitol and sorbitan, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, polyoxyethylene castor oil (polyethoxylate).
d castor oil), polyoxyethylene hydrogenated castor oil (po
lyethoxylated hydrogenated castor oil), polyoxyethylene polypropylene glycol copolymer, glycerin fatty acid ester, polyglycerin fatty acid ester and the like are preferably used. As the sorbitan fatty acid ester, sorbitan monostearate (trade name:
SS-10, Nikko Chemicals Co., Ltd., sorbitan sesquioleate (trade name: SO-15, Nikko Chemicals Co., Ltd.),
Sorbitan trioleate (trade name: SO-30, Nikko Chemicals Co., Ltd.) and the like are suitable. As the polyoxyethylene sorbitan fatty acid ester, in particular, polysorbate 20 (trade name: TL-10, Nikko Chemicals Co., Ltd.),
40 (trade name: TP-10, Nikko Chemicals Co., Ltd.), 60
(Product name: TS-10, Nikko Chemicals Co., Ltd.), 80 (Product name: TO-10, Nikko Chemicals Co., Ltd.) and the like are suitable. As polyethylene glycol fatty acid ester,
In particular, polyethylene glycol monolaurate (10E.
O.) (trade name: MYL-10, Nikko Chemicals Co., Ltd.) and the like are suitable. As the sucrose fatty acid ester, sucrose palmitate ester (for example, trade name: S-1670,
Mitsubishi Chemical Foods Co., Ltd., sucrose stearates (eg, trade name: P-1670, Mitsubishi Chemical Foods Co., Ltd.) and the like are suitable. Polyoxyethylene castor oil (polyet
As the hoxylated castor oil, in particular, polyoxyethylene glycerol triricinolate 35 (Polyoxy 35
Castor Oil, trade name Cremo Hall EL or EL-
P, BSF Japan Co., Ltd., etc. are suitable. Polyoxyethylene hydrogenated castor oil (polyethoxylate
As the d hydrogenated castor oil, especially, polyoxyethylene hydrogenated castor oil 50 (Polyoxyethylene Hydr)
ogenated Castor Oil 50), Polyoxyethylene Hydrogenated Castor Oil 60
l 60) and the like are suitable. As the polyoxyethylene-polyoxypropylene glycol copolymer, polyoxyethylene (160) polyoxypropylene (30) glycol (trade name: ADEKA Pluronic F-68, Asahi Denka Kogyo Co., Ltd.) and the like are particularly preferable. . As the glycerin fatty acid ester, glyceryl monostearate (MGS series, Nikko Chemicals Co., Ltd.) and the like are preferable. As the polyglycerin fatty acid ester, especially tetraglycerin monostearic acid (MS-310, Sakamoto Yakuhin Kogyo Co., Ltd.)
Decaglycerin monolauric acid (Decaglyn 1-L, Nikko Chemicals Co., Ltd.) and the like are preferable.

Examples of the anionic surfactant include sulfuric acid esters (eg, higher alcohol sulfuric acid ester salts, higher alkyl ether sulfuric acid ester salts, sulfated oils, sulfated fatty acid esters, sulfated fatty acids, sulfated olefins),
Sulfonates (eg, sodium alkylbenzene sulfonate, oil-soluble alkylbenzene sulfonate, α-olefin sulfonate, Igepon T type, aerosol OT
Type), phosphoric acid esters (eg, phosphoric acid ester salts of higher alcohol ethylene oxide adducts), dithiophosphoric acid ester salts and the like. Among the anionic surfactants, for example, bile salts such as sodium glycocholate and sodium deoxycholate, fatty acids and salts thereof such as stearic acid and sodium caprate, and sodium lauryl sulfate are preferable. Examples of cationic surfactants include amine salt-type cationic surfactants (eg, amine salt-type cationic surfactants made from higher alkylamines, amine salt-type cationic surfactants made from lower higher alkylamines), Quaternary 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), etc. are used. . As the amphoteric surfactant, for example, amino acid type amphoteric surfactant, betaine type amphoteric surfactant and the like are used. As a naturally-occurring surfactant, purified egg yolk lecithin (trade name: PL-1
Lecithins such as 00H, Kewpie Co., Ltd. and hydrogenated soybean lecithin (trade name: Recinol S-10, Nikko Chemicals Co., Ltd.) are used. Among the above surfactants, sodium deoxycholate, sodium lauryl sulfate, polysorbate 80, polyoxyethylene (16
0) polyoxypropylene (30), polyoxyethylene glycerol triricinolate 35, lecithins, polyoxyethylene hydrogenated castor oils, sucrose fatty acid esters,
Polyglycerin fatty acid esters are more preferred, and sodium deoxycholate is even more preferred. These surfactants may be used alone or in combination of two or more.

Further, the solid dispersion may contain a readily water-soluble cyclodextrin derivative as another substance. . As the water-soluble cyclodextrin derivative, a commercially available product may be used, or it can be produced according to a method known per se. The easily water-soluble cyclodextrin derivative is preferably a cyclic oligosaccharide consisting of 6 to 12 glucose units, which has hydrogen atoms at some or all of the hydroxyl groups at the 2,3 and 6 positions of glucose as another functional group (for example, dihydroxy group). Compounds substituted with alkyl groups, sugar residues, hydroxyalkyl groups, sulfoalkyl groups, etc. are used. The water-soluble derivative has a solubility in water of about 100 mg / mL or more, preferably about 130 mg / mL or more.

Preferred specific examples of the easily water-soluble cyclodextrin derivative are represented by the general formula:

[Chemical 1] [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 each represents a dihydroxyalkyl group, a sugar residue, a hydroxyalkyl group or a sulfoalkyl group. Indicates a group. ] The compound represented by these is mentioned. Specific examples thereof include α-CyD (q = 6), β-CyD (q = 7), and γ-C.
Examples include ether derivatives of hydroxyl groups such as yD (q = 8) and δ-CyD (q = 9). Of these, ether derivatives of β-CyD hydroxyl groups are preferred.

R⁶~ R⁸Dihydroxyalky
Group, for example, dihydroxy-C_1-6Alkyl
Groups (eg, dihydroxymethyl, 2,2-dihydroxyethyl)
Chill, 2,2-dihydroxypropyl, 2,2-dihydride
Roxypentyl, 2,2-dihydroxyhexyl, etc.),
Preferably a dihydroxy-C1-4 alkyl group (eg, di-
Hydroxymethyl, 2,2-dihydroxyethyl, 2,
2-dihydroxypropyl etc.) is used. R⁶~ R
⁸Examples of the sugar residue represented by are C_3-24Sugar residue
(Erythrosyl, threosyl, arabinosyl, ribosi
Le, glucosyl, galactosyl, glycero-gluco-he
Putosyl, maltosyl, lactosyl, maltotrios
Le, dimaltosyl, etc.), preferably C_6-24Sugar residue
(Eg, glucosyl, galactosyl, glycero-gluco-
Heptosyl, maltosyl, lactosyl, maltotrios
Le, dimaltosyl, etc.), particularly preferably C_6-12Sugar residue
Groups (eg, glucosyl, galactosyl, glycero-gluco)
-Heptosyl, maltosyl, lactosyl, etc.)
It R⁶~ R⁸As a hydroxyalkyl group represented by
Is, for example, hydroxy-C _1-6Alkyl group (eg, hydr
Roxymethyl, 2-hydroxyethyl, 2-hydroxy
Propyl, 2-hydroxypentyl, 2-hydroxyhexyl
Xyl, etc.), preferably hydroxy-C_1-4Alkyl
A group (eg, hydroxymethyl, 2-hydroxyethyl,
2-hydroxypropyl etc.), especially 2-hydroxypropyl
Pill groups are preferably used. R⁶~ R⁸Is indicated by
Examples of the ruphoalkyl group include sulfo-C_1-6Al
Kill group (eg, sulfomethyl, sulfoethyl, sulfopro
Pill, sulfopentyl, sulfohexyl, etc.), preferably
Is sulfo-C_1-4Alkyl group (eg, sulfomethyl, sulfur
Rufoethyl, sulfopropyl, etc.), especially sulfobutyl group
Is preferably used.

As a more preferable specific example of the easily water-soluble cyclodextrin derivative, in the compound represented by the general formula (II), at least one of R ^{6 to} R ⁸ is a sugar residue, a hydroxyalkyl group or a sulfoalkyl group. What is. Examples of the compound (II) in which at least one of R ^{6 to} R ⁸ is a sugar residue include, for example, glucosyl-α, β, γ, δ-CyD, maltosyl-α, β,
γ, δ-CyD, maltotriosyl-α, β, γ, δ-
CyD, dimaltosyl-α, β, γ, δ-CyD and the like can be mentioned. Among these, maltosyl-α, β, γ, δ
-CyD, glucosyl-α, β, γ, δ-CyD are preferable. Furthermore, maltosyl-β-CyD (hereinafter, G2-β
(Abbreviated as -CyD), glucosyl-β-CyD is particularly preferable. Examples of the compound (II) in which at least one of R ^{6 to} R ⁸ is a hydroxyalkyl group include hydroxypropyl-α, β, γ, δ-CyD.
Among these, hydroxypropyl-β-CyD is particularly preferable. Examples of the compound (II) in which at least one of R ^{6 to} R ⁸ is a sulfoalkyl group include sulfobutyl-α, β, γ, δ-CyD. Among these, sulfobutyl-β-CyD is particularly preferable.

Further, a branched cyclodextrin-carboxylic acid can be used as the easily water-soluble cyclodextrin derivative. This branched cyclodextrin-carboxylic acid includes not only its free carboxylic acid but also its salts with alkali metals (eg, lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), etc. Be done. These branched cyclodextrin-carboxylic acids may be used alone or in combination of two or more kinds, or may be used in a state where a free carboxylic acid and a salt thereof are mixed. The branched cyclodextrin-carboxylic acid is a cyclodextrin having an organic group containing at least one carboxyl group at the 6-O position of at least one glucose unit of the cyclodextrin ring. The cyclodextrin ring of the branched cyclodextrin-carboxylic 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 and β-
Examples thereof include cyclodextrin and γ-cyclodextrin. It is preferable that the organic group containing at least one carboxyl group has 1 to 3 glucose units, and at least one of hydroxymethyl groups of glucose units in the organic group is oxidized to a carboxyl group. .

The above branched cyclodextrin-carboxylic acid
As a specific example of, 6-O-cyclomaltohexaosyl
-(6 → 1) -α-D-glucosyl- (4 → 1) -O-α-
D-glucuronic acid (cyclomaltohexaosyl- (6 →
1) -α-D-glucopyranosyl- (4 → 1) -O-α-
D-glucopyranoside uronic acid) (hereinafter, α-CyD-G
_Two-COOH may be abbreviated; abbreviations of the following compounds
The names are also shown in parentheses), 6-O-cyclomer
Ruthheptaosyl- (6 → 1) -α-D-glucosyl-
(4 → 1) -O-α-D-glucuronic acid (cyclomalto
Ptaosyl- (6 → 1) -O-α-D-glucopyranosyl
-(4 → 1) -O-α-D-glucopyranoside uronic acid)
(β-CyD-G_Two-COOH), 6-O-cyclomalto
Octaosyl- (6 → 1) -α-D-glucosyl- (4 →
1) -O-α-D-glucuronic acid (cyclomaltooctao
Syl- (6 → 1) -O-α-D-glucopyranosyl- (4
→ 1) -O-α-D-glucopyranoside uronic acid (γ-C
yD-G_Two-COOH), 6-O-cyclomaltohexao
Syl- (6 → 1) -α-D-glucuronic acid (cyclomalto
Hexaosyl- (6 → 1) -O-α-D-glucopyranosi
Douronic acid) (α-CyD-G₁-COOH), 6-O-Si
Chromaltoheptaosyl- (6 → 1) -α-D-glucuro
Acid (Cyclomaltoheptaosyl- (6 → 1) -O-α-
D-glucopyranoside uronic acid) (β-CyD-G₁-C
OOH), 6-O-cyclomaltooctaosyl- (6 →
1) -α-D-glucuronic acid (cyclomaltooctaosyl
-(6 → 1) -O-α-D-glucopyranoside uronic acid)
(γ-CyD-G₁-COOH), 2-O- (6-cyclomer
Ruthohexaosyl) -acetic acid (α-CyD-CH_TwoCOO
H), 2-O- (6-cyclomaltoheptaosyl) -acetic acid
(β-CyD-CH_TwoCOOH), 2-O- (6-cyclomer
Lutooctaocyl) -acetic acid (γ-CyD-CH_TwoCOO
H), 3-O- (6-cyclomaltoheptaosyl) -pro
Pionic acid (β-CyD-CH_TwoCH_TwoCOOH), 2-hi
Droxy-3-O- (6-cyclomaltoheptaosyl)-
Propionic acid (3-O- (6-cyclomaltoheptaoxy)
2-hydroxy-propionic acid) (β-CyD-C
H_TwoCH (OH) -COOH), 7^A, 7^C-Di-O- [α
-D-glucuronyl- (1 → 4) -O-α-D-glucosyl
]-(1 → 6) -maltoheptaose (β-CyD- (G_Two
COOH)_Two), 6-O-cyclomaltoheptaosyl-O
-Α-D-maltosyl- (4 → 1) -O-α-D-gluc
Lonic acid (cyclomaltoheptaosyl- (6 → 1) -O-α
-D-glucopyranosyl- (4 → 1) -O-α-D-glu
Copyranosyl- (4 → 1) -O-α-D-glucopyranosi
Douronic acid) (β-CyD-G_Three-COOH), and this
The above salts [eg, β-CyD-G _Two-COOH Natri
Umium salt (cyclomaltoheptaosyl- (6 → 1) -O-α
-D-glucopyranosyl- (4 → 1) -O-α-D-glu
Sodium copyranoside uronate (also β-CyD-G
_Two-COONa is abbreviated))]. in
Also β-CyD-G_Two-COONa is preferred.

More specifically, 6-O-cyclomaltohe
Xaosayl- (6 → 1) -α-D-glucosyl- (4 →
1) -O-α-D-glucuronic acid (α-CyD-G_Two−
COOH), 6-O-cyclomaltoheptaosyl- (6
→ 1) -α-D-glucosyl- (4 → 1) -O-α-D
-Glucuronic acid (β-CyD-G_Two-COOH), and
And 6-O-cyclomaltooctaosyl-α-D-gluco
Syl- (4 → 1) -O-α-D-glucuronic acid (γ-C
yD-G_Two-COOH) is α-cyclodex
Trin (6 glucose units), β-cyclodextrin
(7 glucose units) and γ-cyclodextrin
Branched cyclodex containing glucose (8 glucose units)
Trin-carboxylic acid and its cyclodextrin ring
Maltose is α- (1 → 6) in one glucose unit of
6-hydroxy of the terminal glucose of the maltose bound.
The dimethyl group is oxidized to the carboxyl group and glucuronic acid
Are formed. In addition, 6-O-cyclomaltohexa
Osyl- (6 → 1) -α-D-glucuronic acid (α-CyD-
G₁-COOH), 6-O-cyclomaltoheptaosyl
-(6 → 1) -α-D-glucuronic acid (β-CyD-G₁−
COOH), and 6-O-cyclomaltooctaosyl
-(6 → 1) -α-D-glucuronic acid (γ-CyD-G₁−
COOH) is one group of its cyclodextrin ring.
Glucose is α- (1 → 6) bound to the course unit, and
The 6-hydroxymethyl group of the branched glucose is
Branches that are oxidized to sil groups to form glucuronic acid
Cyclodextrin-carboxylic acid. And 2-
O- (6-cyclomaltohexaosyl) -acetic acid (α-CyD
-CH_TwoCOOH), 2-O- (6-cyclomaltohepta
Osyl) -acetic acid (β-CyD-CH _TwoCOOH), 2-O-
(6-Cyclomaltooctaosyl) -acetic acid (γ-CyD-C
H_TwoCOOH) is one of the cyclodextrin rings
Branching into glucose units and binding carboxymethyl groups
Branched cyclodextrin-carboxylic acid. these
Branched cyclodextrin-carboxylic acid or salts thereof
Are disclosed in JP-A-7-76594 and JP-A-7-2158.
Japanese Patent Publication No.
JP-A-10-210996, JP-A-10-210996
By the method described in the Gazette or similar method.
Can be manufactured.

When the solid substance is a pharmaceutical compound, the solid dispersion may contain, as another substance, the additives exemplified below and generally used in the field of pharmaceutical preparation. 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 99.99% by weight based on the whole solid dispersion, It is preferably about 0.1 to 50% by weight, more preferably about 0.5 to 30% by weight.

The solvent used in the present invention means a liquid medium in which the above solid substance is dissolved. The solvent may be one that lowers the melting point when added to a solid substance,
It is preferable that the degree of melting point drop increases as the addition amount increases (that is, the one with high affinity).
The melting point decrease is, for example, DSC-820 (Metter,
(Switzerland) and the like, and can be measured by comparing the melting points when a solvent is not 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 lower is preferable. The solvent used in the present invention is preferably one that effectively lowers the melting point of the solid substance, is easily removed after the solid dispersion is produced, or is allowed to remain. When the solid substance is a hydrophobic substance, the solvent is preferably an organic solvent, among which benzene, toluene,
Aromatic hydrocarbons such as xylene; for example, ethers such as dimethyl ether, diethyl ether, dioxane, diethoxyethane, tetrahydrofuran, 1,2-dimethoxyethane; for example, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Organic chlorinated organic solvents such as; Alkyl nitriles such as acetonitrile and propionitrile; Nitroalkanes such as nitromethane and nitroethane; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Ketones such as acetone Kinds; ethyl acetate, cyclohexane,
Acetic acid, acetic anhydride, fatty acids such as oleic acid; alcohols such as methanol, ethanol and propanol; sulfoxides such as dimethyl sulfoxide; or a mixed solvent thereof and a mixed solvent with water, etc. are used.
Among them, alcohols (such as ethanol) or ketones (such as acetone) or their water mixtures (usually water 1 to 90% (w / w), alcohols and the like 99 to
10% (w / w), preferably 1-70% water (w / w),
Alcohols and the like (mixing ratio of 99 to 30% (w / w)) are preferable.

The blending amount of the solvent may be determined according to the type of solid substance, the desired degree of melting point drop, etc., but normally it is preferably about 0.01 to about 100 with respect to the solid substance.
% (W / w), more preferably about 0.05 to about 50%
(W / w), particularly preferably about 0.1 to about 10% (w /
w). The amount of the solvent blended is preferably about 0.01 to about 100 times the amount (w / w) of the solid substance, more preferably about 0.05 to about 50 times the amount (w / w), and particularly preferably. May be about 0.1 to about 10 times (w / w). If the blending amount of the solvent is too small, a sufficient melting point reduction cannot be obtained, and if it is too large, it becomes difficult to remove the solvent.

In the production method of the present invention, both a solid substance and an amount of a solvent that causes a melting point decrease are present (preferably mixed) and heated and melted. Normally, an amount of solvent that causes a melting point decrease is added to the solid substance, but conversely, the solid substance may be added to an amount of solvent that causes a melting point reduction. In the production method of the present invention, the solid substance melts at a temperature lower than the melting point of the solid substance due to the melting point decrease. That is, the temperature at which the solid substance is heated and melted may be a temperature above the lowered melting point (actual melting point), and can be lower than the melting point of the solid substance.
As a result, the solid substance can be heated and melted with low energy. 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 that is thermally unstable, the "actual melting point" is lowered to a temperature at which the solid substance does not change thermally. The solid substance may be heated and melted at a temperature at which the solid substance does not change thermally. In the production method of the present invention, the temperature for heating and melting the solid substance does not cause a chemical change of the solid substance, and from the viewpoint that the subsequent desolvation step is unnecessary, the melting point of the solid substance or more and less than the melting point of the solid substance. Is 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 to completely melt it.

In this way, the solid substance is heated and melted,
A solid dispersion having a uniform composition can be obtained by mixing with another substance and then removing the solvent if necessary. Also,
By carrying out the heating and melting and mixing under pressure, evaporation of the solvent during the step can be prevented. However,
When the pressure increases, the melting point of the solid substance rises, and it becomes difficult to obtain the effect of lowering the melting point by the solvent. Therefore, the pressure may be high enough to prevent evaporation of the solvent used. Specifically, the pressure is about 0.11 MPa to about 50 MPa, preferably about 0.15 MPa to about 10 MPa.

The "heating and melting", the "mixing" and the "removal of the solvent" may be carried out using conventional methods and devices. "Heating and melting" and "mixing" can be performed using, for example, a commonly used stirrer having a heat source, a kneader, and the like. Further, it is preferable to have a structure capable of pressurizing the inside. The “removal of the solvent” can be performed by, for example, reduced pressure drying, hot air drying, or the like.

Alternatively, use an injection device of 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 extruder, etc.). You can Of these, a twin-screw extruder injection device is preferable. In this case, the solid substance, the amount of solvent causing the melting point lowering, and the other substance,
From the hopper of these devices, the solid substance is melted by being charged into the inside of the device maintained at an appropriate heating and melting temperature, and the screw is rotated to be mixed with other substances. Since the outlet of the solid dispersion has small holes, the inside of the cylinder is pressurized and the evaporation of the solvent is prevented. If necessary, the solvent is removed from the solid dispersion extruded through the small holes to obtain a solid dispersion having a uniform composition. In this method, when the type of solvent and the manufacturing conditions are determined so that the heating and melting temperature is higher than the boiling point of the solvent, the solid dispersion extruded through the small holes and exposed to atmospheric pressure is used. The solvent is removed by evaporating the solvent.

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. Particle size of about 10 in pharmaceutical composition
A pharmaceutical composition, more preferably a pharmaceutical composition, which is free of agglomerates of pharmaceutical compounds greater than or equal to micron and whose amount in 20 micron square meters anywhere in the pharmaceutical composition is from about 70 to about 130% of theoretical composition. It does not contain a lump of a pharmaceutical compound of 5 microns or more, and is 1 at any position in the pharmaceutical composition.
A pharmaceutical composition wherein the amount of pharmaceutical compound in 0 micron square meter is about 80 to about 120% of theoretical composition. Here, the amount of the pharmaceutical compound in the unit area can be measured by elemental mapping by EPMA.

When the solid substance is a pharmaceutical compound, the solid dispersion obtained by the production method of the present invention can be pulverized, if necessary, and used as such as a pharmaceutical preparation for oral administration. It is also possible to add additives generally used in the field of pharmaceutical preparations and prepare pharmaceutical preparations such as fine granules, fine granules, granules, tablets, capsules and injections by a conventional method. As the additive, pharmaceutically acceptable carriers such as various organic and inorganic carrier substances that are commonly used as pharmaceutical materials are used. Excipients, lubricants, binders,
It is blended as a disintegrant, a surfactant and the like. Further, it is preferable to add an adsorbent for the purpose of holding an amount of the solvent used in the production method of the present invention that causes a melting point decrease. If necessary, antiseptics, antioxidants, colorants,
Pharmaceutical additives such as sweeteners can also be used. Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, sucrose, perforated starch, mannitol, calcium silicate (trade name: Fluorite RE), aluminometasilicate. Magnesium acid (brand name: Neusilin), light anhydrous silicic acid (brand name: Thylicia), sucrose / starch spherical granules (brand name: nonpareil), crystalline cellulose / carboxymethyl cellulose (brand name: Avicel RC), hydroxypropyl starch, etc. To be Suitable examples of lubricants include
Examples thereof include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include, for example, crystalline cellulose, sucrose,
Examples thereof include D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of disintegrants include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, methyl cellulose (trade name: Metroze S
M), croscarmellose sodium, carmellose calcium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, partially pregelatinized 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. As the surfactant, for example, polyoxyethylene polyoxypropylene glycol (trade name: Pluronic) glycerin fatty acid ester, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate 80, cetanol and the like are used. As an adsorbent,
For example, perforated starch, calcium silicate (trade name: Fluorite RE), magnesium aluminometasilicate (trade name: Neusilin), light anhydrous silicic acid (trade name: Sylysia), etc. are used, and are suitable as preservatives. For example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. are used. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like. These additives, alone,
Alternatively, two or more kinds may be mixed and used.

For example, when the solid dispersion obtained by the production method of the present invention is used as an injection, the injection prepared by dissolving, suspending or emulsifying the solid dispersion in a sterile aqueous liquid or oily liquid. As the carrier for use, for example, a solvent, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent, a soothing agent and the like are used. Examples of the solvent include water for injection, physiological saline, Ringer's solution and the like. Examples of the solubilizing agent 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,
Examples thereof include glycerin and D-mannitol. Examples of the buffer include phosphate buffer, acetate buffer, carbonate buffer, citrate buffer, and the like. Examples of soothing agents include benzyl alcohol and the like. The injection thus obtained can be stored in a powder state by freeze-drying it with a sterilized freeze-dryer after removing the pyrogen by a method known per se, if necessary, or as it is, an injection container ( For example, it can be stored in an ampoule) sealed.

The content of the solid dispersion obtained by the production method of the present invention in the thus-obtained preparation varies depending on the dosage form, administration method, carrier, etc., but is usually 0.1 to 100 relative to the total amount of the preparation. % (W / w).

A pharmaceutical preparation comprising the solid dispersion obtained by the production method of the present invention or a pharmaceutical preparation containing the same is a mammal (eg, rat, mouse, guinea pig, monkey, depending on the kind of the pharmaceutical compound). Bovine, dog, pig, human etc.). Although the dose 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 when administered intraarticularly as an aqueous suspension injection, an adult (body weight 5
As a single dose per person, the amount of compound (A) is, for example, about 0.1 mg or more, preferably about 0.2 mg to about 500 mg, more preferably about 0.1 mg.
5 mg to about 200 mg is used. In this case, the administration frequency is, for example, about once a day or more, preferably about once every 2 days to 3 months, more preferably about once every 3 days to about 3 months, further preferably about 1 week to 1 month. It is once a month.

When the solid substance is an agrochemical compound, the solid dispersion obtained by the production method of the present invention can be used as an agrochemical composition itself after pulverization or the like if necessary.
Or according to the method for producing a pesticide composition known per se, by mixing a suitable pesticide formulation carrier, a surfactant, a hydrophilic polymer, a readily soluble cyclodextrin derivative, etc.,
Emulsions, liquids, oils, powders, DL (driftless) powders, granules, fine granules, fine granules F, fine granules F, wettable powders, wettable granules, water solutions, flowables, tablets, jumbo preparations It can be molded into a spray, paste or the like. Examples of the surfactant and the like include those exemplified when the solid substance is a pharmaceutical compound and those which are unstable. Specifically, the solid dispersion containing one or more (preferably 1 to 3) of the agrochemical compound obtained by the production method of the present invention is dissolved in a suitable liquid carrier depending on the purpose of use. It is dispersed or mixed with a suitable solid carrier or adsorbed, and if necessary, mixed with a surfactant, a hydrophilic polymer or a readily soluble cyclodextrin derivative. These formulations may be added with an emulsifier, a dispersant, a spreading agent, a penetrating agent, a wetting agent, a binder, a thickening agent, etc., if necessary, and can be prepared by a method known per se.

The liquid carrier (solvent) used is, for example, water, alcohols (eg, methanol, ethanol,
1-propanol, 2-propanol, ethylene glycol etc.), ketones (eg acetone, methyl ethyl ketone etc.), ethers (eg dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, propylene glycol monomethyl ether etc.), fat Group hydrocarbons (eg,
Kerosene, kerosene, fuel oil, machine oil, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, solvent naphtha, methylnaphthalene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.) ), Acid amides (eg, dimethylformamide, dimethylacetamide, etc.), esters (eg, ethyl acetate, acetic acid butyl ester, fatty acid glycerin ester, etc.), nitriles (eg, acetonitrile, propionitrile, etc.), etc. Is used. These are 1 or 2
One or more species (preferably 1 to 3 species) are mixed and used at an appropriate ratio.

Examples of the solid carrier (diluting / extending agent) include vegetable powder (eg, soybean powder, tobacco powder, wheat flour, wood powder, etc.), mineral powder (eg, kaolin, bentonite, acid clay, clay, etc.). Clays, talc powder, talc powder such as wax powder, diatomaceous earth, silica such as mica powder), alumina, sulfur powder, activated carbon, sugars (eg, lactose, glucose, etc.), inorganic salts (eg, calcium carbonate, Sodium bicarbonate, etc.), glass hollow bodies (natural glassy materials which are fired to have air bubbles included 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 carrier or solid carrier can be used usually in an amount of about 1 to 99% by weight, preferably about 10 to 99% by weight, based on the whole agrochemical composition. As the emulsifier, the dispersant, the spreading agent, the penetrating agent, the wetting agent, etc., a surfactant is used as necessary. Examples of these surfactants include polyoxyethylene alkyl ethers (eg, Sanyo Kasei Kogyo Co., Ltd., Emarumin 110, etc.),
Polyoxyethylene alkylaryl ether (eg, Sanyo Kasei Co., Ltd., Nonipol 85, Nonipol 10)
0, nonipol 160, etc.), polyoxyethylene lanolin alcohol, polyoxyethylene alkylphenol formalin condensate, polyoxyethylene sorbitan fatty acid ester (eg, Kao Corporation, Tween 20, Tween 80, Daiichi Kogyo Seiyaku Co., Ltd.) , Sorgen TW-2
0, 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, Nonionic surfactants such as sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene polyoxypropylene block polymer, polyoxyethylene fatty acid amide, alkylolamide, polyoxyethylene alkylamine, alkylamine hydrochloride (eg, dodecyl Amine hydrochloride, etc.), alkyl quaternary ammonium salt, alkyl trimethyl quaternary ammonium salt (eg, dodecyl trimethyl ammonium salt, etc.), alkyl dimethyl benzyl Cationic surfactants such as ammonium salts, alkylpyridinium salts, alkylisoquinolinium salts, dialkylmorpholinium salts, benzethonium chloride, polyalkylvinylpyridinium salts, higher fatty acid sodium salts (eg sodium palmitate, etc.), ethers Carboxylic acid sodium salt (eg, sodium polyoxyethylene lauryl ether carboxylate), amino acid condensate of higher fatty acid (eg, sodium lauroyl sarcosine, sodium N-lauroyl glutamate, etc.),
Higher alkyl sulfonate, higher fatty acid ester sulfonate (eg, laurate ester sulfonate, etc.), lignin sulfonate (eg, sodium lignin sulfonate, etc.), alkyl sulfosuccinate (eg, sodium diheptyl sulfosuccinate) , Sodium dioctylsulfosuccinate, sodium dinonylsulfosuccinate, etc.),
Higher fatty acid amide sulfonate (eg, oleic acid amide sulfonate, etc.), dodecylbenzene sulfonate, diisopropylnaphthalene sulfonate, alkylaryl sulfonate formalin condensate, higher alcohol sulfate ester salt (eg, pentadecane-2) -Yl sulfate, etc.), polyoxyethylene alkyl ether sulfate ester salt (eg, sodium polyoxyethylene dodecyl ether sulfate, etc.), polyoxyethylene alkyl phosphate ester (eg, dipolyoxyethylene dodecyl ether phosphate ester, etc.), Anionic surfactants such as polyoxyethylene alkylaryl phosphate ester salts, styrene-maleic acid copolymers, alkyl vinyl ether-maleic acid copolymers, N-laurylalanine, N, N, N-
Trimethylaminopropionic acid, N, N, N-trihydroxyethylaminopropionic acid, N-hexyl-N,
Examples include amphoteric surfactants such as N-dimethylaminoacetic acid and 1- (2-carboxyethyl) pyridinium betaine. Of these, one kind or two or more kinds (preferably 1 to 5 kinds) are used. The surfactant can be used usually in an amount of about 0.1 to 50% by weight, preferably about 0.1 to 25% by weight, based on the whole composition.

As the binder, for example, dextrin (eg, dextrin ND-S manufactured by Nitto Kagaku Co., Ltd.),
Sodium salt of carboxymethyl cellulose (eg, Dai-ichi Kogyo Seiyaku Co., Ltd., serogen 5A, serogen 6A, serogen 7A, serogen PR, etc.), polycarboxylic acid type polymer compound (eg, Sanyo Kasei Co., Ltd., Toxanone) GR-
30, Toxanone GR-31A, Toxanone GR-50
L, Toxanone GR-60L; Kao Corporation, Poise 5
30, Poise 532A, etc.), polyvinylpyrrolidone, polyvinyl alcohol, sodium lignin sulfonate,
Calcium lignin sulfonate, sodium polyacrylate, gum arabic, sodium alginate, glucose, sucrose, mannitol, sorbitol and the like are used. The binder can be usually used in an amount of about 0 to 20% by weight based on the whole preparation. As the thickener, for example,
Bentonite mineral substances (eg, high-purity sodium montmorillonite, etc.), polyacrylic acid and its derivatives, sodium salt of carboxymethyl cellulose (eg, Dai-ichi Kogyo Seiyaku Co., Ltd., serogen 5A, serogen 6A, serogen 7)
A, serogen PR, etc.), white carbons, natural saccharide derivatives (eg, xanthan gum, guar gum, etc.) and the like are used. The thickener is usually about 0.0 to the total composition.
About 1 to 10% by weight is used.

The content ratio of the agrochemical compound in the agrochemical composition thus obtained is appropriately about 1 to 90% by weight in the case of emulsions, wettable powders, wettable granules, liquids, water solvents, flowable agents, etc. , Powder, DL type powder, etc., about 0.0
1 to 10% by weight is suitable, and fine granules, fine granules F,
About 0.05 to 10% by weight is suitable for the fine granules F, granules and the like, but the concentration thereof may be appropriately changed depending on the purpose of use. Emulsions, wettable powders, wettable granules, liquids, water solutions, flowable agents and the like can be sprayed by appropriately diluting with water or the like (for example, about 100 to 100,000 times) before use. When a surfactant, a hydrophilic polymer or an easily soluble cyclodextrin derivative is used in the composition, its content varies depending on the form of the preparation, but it is usually about 1 to 99.99% by weight, preferably the whole preparation. Is about 10 to 90% by weight. The content of the carrier for pesticide formulation in the pesticide composition varies depending on the form of the formulation, but is usually about 1 to 99.99 based on the whole formulation.
It is about 10% by weight, preferably about 10 to 90% by weight. As the application method, the same method as the usual application method of agricultural chemicals can be used, and examples thereof include aerial application, soil application, foliage application, nursery box application, side row 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 the herbicide is used as the agrochemical compound, the amount of the agrochemical composition used varies depending on the application scene, application time, application method, target grass species, cultivated crop, etc. About 0.05 to 50 g, preferably about 0.1
The amount is about 10 g, about 0.05 to 50 g, and preferably about 0.1 to 10 g per 1 are. When the pesticide composition is applied to paddy weeds, it is preferably used as a pre-emergence soil treatment or a foliage / soil treatment agent.

[0046]

EXAMPLES 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 means (2R, 4S)-(-)-N- [4- (diethoxyphosphorylmethyl) phenyl] -1,2,4,5-tetrahydro-
4-methyl-7,8-methylenedioxy-5-oxo-
3-benzothiepine-2-carboxamide. As the compound A, one produced by the same method as that described in Example 1 of JP-A-8-231569 (European Patent Application Publication No. 719782) was used. The structure of compound A is shown by the following formula.

[0047]

[Chemical 2]

Example 1 100 g of compound A, 100 g of hydroxypropylmethylcellulose, 50 g of partially pregelatinized starch, and 50 g of light anhydrous silicic acid were mixed to obtain a mixed powder. For a twin-screw extruder (KEX-25 type, Kurimoto)
The mixed powder was supplied at a rate of 35 g / min, and at the same time, 3.5 g of a 50% (w / w) ethanol aqueous solution was used as a solvent.
It was supplied at a rate of / min. The processing conditions were such that the barrel temperature was set to 100 ° C., the shaft rotation speed was 250 rpm, and the die size was 3.5 mmφ. The obtained injection product (solid dispersion) was dried with a vacuum dryer (Kusu Seisakusho, 40 ° C., 16 hr) and then powdered with a hammer mill (atomizer, Fuji Paudal). The pressure was controlled so that the value detected near the outlet was 2 to 6 MPa.

Comparative Example 1 100 g of Compound A, 100 g of hydroxypropylmethyl cellulose, 50 g of partially pregelatinized starch and 50 g of light anhydrous silicic acid were mixed to obtain a mixed powder. For a twin-screw extruder (KEX-25 type, Kurimoto)
The mixed powder was supplied at a rate of 35 g / min, and at the same time, purified water was supplied as a solvent at a rate of 3.5 g / min.
The processing conditions were such that the barrel temperature was set to 100 ° C., the shaft rotation speed was 250 rpm, and the die size was 3.5 mmφ. The obtained injection product (solid dispersion) was vacuum-dried (Kusu Seisakusho, 40
After drying at 16 ° C. for 16 hours, it was made into powder with a hammer mill (atomizer, Fuji Paudal).

Test Example 1 (Confirmation of affinity between solvent and drug) Thermal analyzer (DSC-820, Metter, Switch)
Zernland), the affinity between compound A and the solvent was confirmed. Use ethanol or purified water as the solvent,
The melting point decrease at each addition amount was observed. About 5 mg of Compound A and each amount of ethanol or water were enclosed in a sealed sample cell for pressure-resistant thermal analysis. The amount of ethanol is% by weight
As 0, 10, 20, 40 and 80% (w / w),
The amount of water is 0, 12.5, 25, 50, 1 as weight%
It was set to 00% (w / w). Scanning was performed at a heating rate of 10 ° C / min, and the affinity between the solvent and the drug was evaluated from the obtained differential calorific value-temperature curve. Compound A when no solvent is added
Had a melting point of about 187 ° C. (onset value). This melting point was lowered by the addition of ethanol, and the magnitude of the drop was remarkably lowered as the amount of ethanol added was increased. 10
With the addition of% (w / w), it was confirmed that the endotherm started with melting from about 80 ° C. In addition, the endothermic peak value due to melting shifted to the low temperature side as the amount of ethanol added increased.
On the other hand, in the system to which purified water was added, the melting point slightly decreased to about 145 ° C. (onset value), but the effect depending on the amount added was not observed. The graph of the differential calorific value-temperature curve is shown in FIG.
And shown in FIG.

Test Example 2 (Elemental mapping by EPMA) The dispersion state of Compound A in the pharmaceutical compositions prepared in Example and Comparative Example 1 was evaluated by EPMA elemental mapping (sulfur, silicon, phosphorus). As a result, in the composition of Comparative Example 1, lumps of Compound A were observed, whereas in the composition of Example 1, uniform dispersion of Compound A was observed. Figure 3
FIG. 4 shows the elemental mapping of the composition of Example 1 and FIG. 4 shows the elemental mapping of the composition of Comparative Example 1 together with SEM images. The white circles in FIG. 4 indicate the lumps of compound A.

Test Example 3 (Powder X-Ray Diffraction Analysis) Powder X-ray diffraction analysis was carried out on the pharmaceutical compositions prepared in Example 1 and Comparative Example 1. In the composition of Example 1, the peak derived from the crystal of Compound A was completely disappeared (FIG. 5). In Comparative Example 1, a peak derived from crystals was confirmed (Fig. 6).

[0053]

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.

[Brief description of drawings]

FIG. 1 is a graph of a differential calorific value-temperature transition showing a melting point decrease when ethanol is added.

FIG. 2 is a graph of differential calorific value-temperature transition showing a 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.

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. FIG.

Claims (11)

[Claims] 1. A method for producing a solid dispersion, which comprises heating and melting a solid substance and an amount of a solvent that causes a melting point decrease. 2. The manufacturing method according to claim 1, wherein a solvent is added to the solid substance in an amount that causes a melting point drop, and the solid substance is heated and melted. 3. The production method according to claim 1, wherein the solvent is an alcohol, a ketone, or a water mixture thereof. 4. The amount of the solvent blended with the solid substance is about 0.
The production method according to claim 1, which is from 01 to about 100% (w / w). 5. The method according to claim 1, wherein the temperature for heating and 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 claim 1, wherein the solid substance is a substance which is unstable to heat. 7. The method according to claim 1, wherein the solid substance is a substance having 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 pharmaceutical compound. 9. The production method according to claim 1, further comprising an adsorbent. 10. The production method according to claim 1, wherein the solid substance and the amount of the solvent that causes a melting point decrease are melted by heating and mixed with another substance. 11. A solid dispersion produced by the production method according to claim 1.