US 200400.52854A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0052854A1 Yoshinari et al. (43) Pub. Date: Mar. 18, 2004

(54) POROUS SUBSTANCES AND METHODS FOR (86) PCT No.: PCT/P01/11342 PRODUCING THE SAME (30) Foreign Application Priority Data (76) Inventors: Tomohiro Yoshinari, Kobe-shi (JP); Makoto Fukuta, Nara-shi (JP); Toshio Dec. 26, 2000 (JP) ------2000-395160 Yoshioka, Toyonaka-shi (JP) Publication Classification Correspondence Address: TAKEDA PHARMACEUTICALS NORTH (51) Int. Cl." ...... A61K 9/14 AMERICA, INC (52) U.S. Cl...... 424/489 INTELLECTUAL PROPERTY DEPARTMENT 475 HALF DAY ROAD (57) ABSTRACT SUTE 500 LINCOLNSHIRE, IL 60069 (US) A physiologically active porous Substance of the present invention obtained by treating a physiologically active Solid (21) Appl. No.: 10/451,212 Substance with a carbon dioxide in a Supercritical or Sub critical State or a liquid carbon dioxide has a significantly (22) PCT Filed: Dec. 25, 2001 improved dissolution rate and can easily be handled.

Patent Application Publication Mar. 18, 2004 Sheet 1 of 3 US 2004/0052854A1

Patent Application Publication Mar. 18, 2004 Sheet 2 of 3 US 2004/0052854A1

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POROUS SUBSTANCES AND METHODS FOR 0012 5) a physiologically active porous substance PRODUCING THE SAME according to the above-mentioned 1 or 2 wherein the physiologically active Substance is a pharmaceutical com TECHNICAL FIELD pound; 0001. The present invention relates to a porous substance 0013 6 a physiologically active porous substance having improved Solubility and compression properties and according to the above-mentioned 1 or 2 wherein the to a method for producing the Same. physiologically active Solid Substance is a sparingly water soluble or water-insoluble substance whose solubility in BACKGROUND ART water at 25 C. is less than 10 mg/mL, 0002. In the pharmaceutical industry, it is known that the 0014) 7 a composition comprising a Substance accord dissolution rate and the compression properties of a phar ing to the above-mentioned 1 or 2); maceutical compound can be improved by reducing the particle size by means of mechanical pulverization and 0015 8 a composition according to the above-men control of the crystallization rate. The dissolution rate is tioned 7 comprising a or a high molecular represented by Noyes-Whitney formula: dC/dt=kS(Cs-C) compound; wherein Cs is the saturated solubility of a solute, C is the 0016 9D a composition according to the above-men concentration of the solute at time point “t”, S is the surface tioned 8 wherein the high molecular compound is a high area of a Solid to be dissolved which is the Solute, and k is molecular polymer whose number-average molecular the dissolution kinetic constant. To reduce the particle size weight is about 3,000 to 30,000; means to increase the Specific Surface area of the Solid to be 0017 10 a composition according to the above-men dissolved mentioned above. tioned 9 wherein the high molecular polymer is one or a 0003. On the other hand, the improved compression copolymer or mixture of two or more Selected from the properties are due to an increase of the binding sites result group consisting of (1) poly-fatty acid ester, (2) poly-C.- ing from reducing the particle size. cyanoacrylate, (3) poly-hydroxybutyric acid, (4) polycar bonate Selected from polyalkylene oxalate, poly-Ortho-ester, 0004. However, just reducing the particle size of a phar poly-ortho-carbonate, polyethylene carbonate and polyeth maceutical has the disadvantages of dusting of the particles ylene propylene carbonate, (5) polyamino acid, (6) polysty and a decrease in the flowability, as a result, the handling is rene, (7) polyacrylic acid, (8) polymethacrylic acid, (9) difficult. Thus a proceSS for reducing the particle size is not copolymer of acrylic acid and methacrylic acid, (10) Silicon favorable for the Subsequent formulation processes. polymer, (11) dextran Stearate, (12) ethyl cellulose, (13) 0005 Accordingly, technology for improving the solu acetyl cellulose, (14) nitrocellulose, (15) polyurethane, (16) bility and the compression properties of a pharmaceutical maleic anhydride copolymer, (17) ethylene vinyl acetate compound without posing the problems described above is copolymer, (18) polyvinyl acetate, (19) polyvinyl desired. and (20) polyacrylamide; 0018 11 a composition according to the above-men DISCLOSURE OF INVENTION tioned 9 wherein the high molecular polymer is polylactic 0006 We made an effort to solve the problems described acid, a lactic acid/glycolic acid copolymer, a 2-hydroxybu above and finally discovered that a physiologically active tyric acid/glycolic acid copolymer or a mixture thereof; porous Substance could be obtained by treating a physiologi 0019 12 a composition according to the above-men cally active Substance with carbon dioxide in a Supercritical tioned 8 wherein the high molecular compound is a or Subcritical State or liquid carbon dioxide. In addition, we hydrophilic polymer; found that the porous Substance thus obtained had an unex 0020 13 a composition according to the above-men pectedly improved dissolution rate and could be handled tioned 12 wherein the hydrophilic polymer is one or a easily, and based on Such findings we made a further effort mixture of two or more Selected from the group consisting and completed the present invention. of (1) water-soluble polymer selected from hydroxyalkyl 0007 Thus, the present invention provides: cellulose, cellulose derivative, polyalkenyl pyrrolidone, polyalkylene glycol and polyvinyl alcohol; (2) enteric poly 0008) 1 a physiologically active porous substance mer Selected from hydroxypropylmethyl cellulose phthalate, obtained by treating a physiologically active Solid Substance hydroxypropylmethyl cellulose acetate Succinate, car with carbon dioxide in a Supercritical or Subcritical State or boxymethylethyl cellulose, cellulose acetate phthalate, liquid carbon dioxide, methacrylic acid copolymer L and methacrylic acid copoly 0009 2 a physiologically active porous substance mer S.; (3) gastric Soluble polymer Selected from aminoalkyl whose weight-average particle Size is about 1 um or more methacrylate copolymer E and polyvinyl acetal diethylami and whose specific Surface area is about 1.5 m/g or more; noacetate; (4) carboxymethyl cellulose; (5) Eudragit; (6) 0.010 3 a physiologically active porous substance carboxyvinyl polymer; (7) polyvinyl alcohol; according to the above-mentioned 2 wherein the weight 0021 (8) gum arabic; (9) sodium alginate; (10) alginic average particle size is about 10 Lim or more and the Specific acid propylene glycol ester; (11) agar; (12) gelatin and (13) Surface area is about 1.5 m/g or more; chitosan; 0.011) 4) a physiologically active porous substance 0022 14 a composition according to the above-men according to the above-mentioned 1 or 2 which is crys tiond 7 comprising a readily water-Soluble cyclodextrin talline; derivative; US 2004/0052854 A1 Mar. 18, 2004

0023 15 a composition according to the above-men ing the temperature of Said pressure-resistant container at the tioned 14 wherein the readily water-soluble cyclodextrin critical point or below, (3) filling carbon dioxide which may derivative is a compound represented by Formula: be optionally mixed with other Solvents into Said pressure resistant container, (4) stopping filling the carbon dioxide under the condition where the pressure in Said pressure resistant container does not exceed the critical point of carbon dioxide, (5) depressurizing after completing the carbon dioxide treatment and then collecting the resultant physiologically active porous Substance; 0032 23 a method according to the above-mentioned 18 or 19 wherein said other solvents are water, aromatic hydrocarbons, ethers, organochlorine organic Solvents, alky Initriles, nitroalkanes, amides, ketones, fatty acids, , Sulfoxides or mixture Solvents thereof; 0033 24 a method according to the above-mentioned 0024 wherein q is an integer of 6 to 12, R, R and Rare 18 or 19 wherein said other solvents are water; aromatic Same or different in individual repeating units and each is a hydrocarbons Selected from , , ethyl acetate, dihydroxyalkyl group, Sugar residue, hydroxyalkyl group or cyclohexane and Xylene, etherS Selected from dimethyl Sulfoalkyl group; ether, , dioxane, diethoxyethane, tetrahydrofu 0.025 16 a composition according to the above-men ran and 1,2-dimethoxyethane, organochlorine organic Sol tioned 15 wherein the dihydroxyalkyl group is a dihy vents Selected from dichloromethane, , carbon droxy-C alkyl group, the Sugar residue is erythroSyl, tetrachloride and 1,2-dichloroethane; alkylnitriles Selected threosyl, arabinosyl, ribosyl, glucosyl, galactosyl, glycero from acetonitrile and propionitrile, nitroalkanes Selected from nitromethane and nitroethane, amides Selected from gulcoheptosyl, maltosyl, lactosyl, maltotriosyl or dimalto N,N-dimethylformamide and N,N-dimethylacetoamide; Syl, the hydroxyalkyl group is a hydroxy-C alkyl group acetone, fatty acids Selected from acetic acid, acetic anhy and the Sulfoalkyl group is a Sulfo-Co alkyl group; dride and oleic acid; alcohols Selected from methanol, 0.026 17 a method for producing a physiologically ethanol and propanol, dimethyl Sulfoxide, or mixture Sol active porous Substance according to the above-mentioned vents thereof; 1) or 2) comprising treating a physiologically active Solid 0034 25 a method according to the above-mentioned Substance with carbon dioxide in a Supercritical or Subcriti 18 or 19 wherein said other solvent is ethanol or acetone; cal State or liquid carbon dioxide; and 0.027 18 a method according to the above-mentioned 0035 26 a method according to the above-mentioned 17 wherein the Supercritical or subcritical carbon dioxide 18 or 19 wherein the amount of said other solvents is -or the liquid carbon dioxide is mixed with other solvents; about 1 to 50% by volume based on the carbon dioxide 0028. 19 a method according to the above-mentioned which is in a Supercritical, Subcritical or liquid State. 17 comprising the steps of (1) placing a physiologically active Solid Substance in a pressure-resistant container, (2) BRIEF DESCRIPTION OF DRAWINGS keeping the temperature of Said pressure-resistant container 0036 FIG. 1 shows a SEM photograph of the porous at a level allowing carbon dioxide to be in a Supercritical or Substance obtained in Example 1. subcritical state, (3) filling carbon dioxide which may be optionally mixed with other Solvents into Said pressure 0037 FIG. 2 shows a magnified SEM photograph of the resistant container, (4) stopping filling the carbon dioxide at porous Substance obtained in Example 1. the time point when the pressure in Said preSSure-resistant 0038 FIG. 3 shows a SEM photograph of . container reaches a level allowing carbon dioxide to be in a Supercritical or Subcritical State, (5) depressurizing after BEST MODE FOR CARRYING OUT THE completing the carbon dioxide treatment and then collecting INVENTION the resultant physiologically active porous Substance; 0039) Physiological active substances employed in the 0029 20 a method according to any one of the above present invention can be Selected from a wide range of mentioned 17 to 19 wherein the Supercritical carbon Substances including pharmaceutical compounds (including dioxide is carbon dioxide in a State exceeding both the those for veterinary use), pesticidal compounds, fertilizers, critical pressure of about 7.38 MPa and the critical tempera cosmetics, perfumes, food materials, feeds, bactericides, ture of about 304.1 K, fungicides, insect repellents, insecticides, antirusts and 0030 21 a method according to any one of the above absorbents. mentioned 17 to 19 wherein the Subcritical carbon diox 0040. The characteristics of such physiologically active ide is carbon dioxide in a State exceeding either the critical Substances are not limited particularly. They are any of pressure of about 7.38 MPa or the critical temperature of water-Soluble, Sparingly water-Soluble or water-insoluble about 304.1 K, Solid Substances. Such physiologically active Substances 0.031) 22 a method according to the above-mentioned may also be crystalline. 17 comprising the steps of (1) placing a physiologically 0041. The expression “sparingly water-soluble or water active Substance in a pressure-resistant container, (2) keep insoluble” means that a physiologically active Substance has US 2004/0052854 A1 Mar. 18, 2004 a solubility in water at 25 C. of less than 1000 ppm, 0068 (5) Antibiotics preferably less than 10 ppm or that the solubility in water at 0069 Gentamycin, dibekacin, kanendomycin, lividomy 25 C. is less than 10 mg/mL, preferably less than 0.1 cin, tobramycin, amikacin, fradiomycin, Sisomicin, tetracy mg/mL. The Solubility can be measured by a Standard cline, Oxytetracylcine, rollitetracycline, doxicycline, amplicil method. lin, piperacillin, ticarcillin, cefalotin, cefaloridine, cefotiam, 0.042 Water-soluble pharmaceutical compounds include cefotiam-hexetil, cefSulodin, cefimenoXime, cefimetazole, those listed below. cefazolin, cefotaxime, cefoperaZone, ceftizOXime, moxalac tam, thienamycin, Sulfazecine, aztreonam or a Salt thereof 0043 (1) Antibiotics and the like. 0044) hydrochloride, ampicillin, piperacillin 0070 (6) Anti-tumor Agents and the like. 0071 6-O-(N-Chloroacetylcarbamoyl) fumagillol, bleo 0045 (2) Antipyretics, Analgesics or Antiphlogistics mycin, methotrexate, actinomycin D, mitomycin C, dauno 0.046 Sodium salicylate, Sulpirine, sodium indomethacin, rubicin, adriamycin, neocarZinostatin, cytosine adabinoside, hydrochloride and the like. fluorouracil, tetrahydrofuryl-5-fluorouracil, picibanil, len tinan, levamisole, bestatin, azimeXon, glycyrrhizin and the 0047 (3) Antitussives and Expectorants like. 0.048 Ephedrin hydrochloride, noscapine hydrochloride, 0072 (7) Anti-hyperlipidemic Agents phosphate, dihydrocodeine phosphate, isoproter 0073 Clofibrate, ethyl 2-chloro-3-4-(2-methyl-2-phe enol hydrochloride and the like. nylpropoxy)phenyl propionate Chem. Pharm. Bull., 38, 0049 (4) Sedatives 2792-2796 (1990) and the like. 0050 hydrochloride, sulfate 0074 (8) Antitussives and Expectorants and the like. 0075 Ephedrine, methylephedrine, noscapine, codeine, 0051 (5) Anti-ulcerative Agents dihydrocodeine, alloclamide, clorpheZianol, pico peridamine, cloperastine, protokylol, isoproterenol, Salbuta 0.052 Metachlopromide, histidine monohydrochloride mol, tereputarine or a Salt thereof and the like. and the like. 0053 (6) Anti-arrhythmic Agents 0.076 (9) Muscle Relaxants 0077 Pridinol, tubocurarine, pancuronium and the like. 0.054 Propranolol hydrochloride, alprenolol hydrochlo ride and the like. 0078 (10) Antiepileptics 0079 , ethoSuximide, acetazolamide, chlor 0055 (7) Hypotenssive Diuretics diazepoxide and the like. 0056 Hexamethonium bromide, clonidine hydrochloride and the like. 0080 (11) Anti-ulcerative Agents 0057 (8) Anti-coagulants 0081 Lansoprazole, metoclopramide and the like. 0.058 Heparin sodium, sodium citrate and the like. 0082 (12) Antidepressants 0083. , clomipramine, noxiptiline, phenelzine 0059 Sparingly water-soluble or water-insoluble phar maceutical compounds include those listed below. and the like. 0060 (1) Antipyretics, Analgesics or Antiphlogistics 0084 (13) Anti-allergic Agents 0085 Diphenhydramine, chlorpheniramine, tripelen 0061 Salicylic acid, Sulpyrine, flufenamic acid, diclofenac, indomethacin, atropine, Scopolamine, morphine, namine, metodiramine, clemizole, diphenylpyraline, meth , , ketoprofen, naproxen, ibuprofen, Oxyphenamine and the like. Oxymorphone or a Salt thereof and the like. 0.086 (14) Cardiotonics 0062 (2) Ataractics 0087 Trans-n-oxocamphor, terephylol, aminophylline, etillefrine and the like. 0.063 , lorazepam, oxazepam and the like. 0088 (15) Anti-arrhythmic Agents 0064 (3) Anti-psychotics 0089 Propranolol, alprenolol, bufetolol, Oxprenolol and 0065 Chlorpromazine, prochlorperazine, trifluoperazine the like. and the like. 0090 (16) Vasodilators 0.066 (4) Antibacterial Agents 0091. Oxyfedrine, diltiazem, tolazoline, hexobendine, 0067 , Lankacidin J. Antibiotics, 38,877 bamethan and the like. 885 (1985)), azole-based compounds 2-(1R,2R)-2-(2,4- difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1- 0092 (17) Hypotensive Diuretics yl)propyl-4-4-(2,2,3,3-tetrafluoropropoxy)phenyl-3-(2H, 0093. Hexamethonium bromide, pentolinium, mecamy 4H)-1,2,4-triazolone, fluconazole, itraconazole and the like lamine, ecarazine, clonidine, diltiazem, nifedipin and the and the like. like. US 2004/0052854 A1 Mar. 18, 2004

0094) (18) Anti-diabetic Agents 0118 (d) Organochlorine 0.095 Glymidine, glipizide, phenformin, buformin, met 0119) Endosulfan and the like. formin and the like. 0120 (e) Others 0096] (19) Anti-tuberculotic Agents 0121 Bensultap, buprofezin, flufenoxuron, diflubenzu O097 Isoniazid, ethambutol, paraaminoSalicylate and the ron, chlorfluaZuron, imidacloprid and the like. like. 0122) (2) Bactericides 0098 (20) Narcotic Antagonists 0123 (a) N-Heterocyclic Ergosterol Inhibitors 0099 Levallorphan, nalorphine, naloxone or a salt thereof and the like. 0.124 Triflumizole, triforine and the like. 0100 (21) Hormones 0.125 (b) Carboxyamide 0101 Steroid hormones, for example, , 0.126 Mepronil, flutoluanil, pencycuron, oxycarboxin hexestrol, methimazole, betamethasone, triamcinolone, tri and the like. amcinolone acetonide, fluocinolon acetonide, , 0127 (c) Dicarboxyimide hydrocortisone, estriol and the like. 0128 Iprodione, Vinclozolin, procymidone and the like. 0102 (22) Fat-soluble Vitamins 0129 (d) Benzoimidazole (0103) (1) Vitamin K. Vitamin K, K, K, and K. 0130 Benomyl and the like. 0104] 2 Folic acid (vitamin M) and the like. 0131) (e) Polyhaloalkylthio 0105 (23) Vitamin Derivatives 0132 Captain and the like. 0106 Various vitamin derivatives, for example, vitamin D, derivatives Such as 5,6-trans-cholecalciferol, 2.5-hy 0.133 (f) Organochlorine droxycholecalciferol, 1-O-hydroxycholecalciferol, Vitamin 0134) Fthalide, TPN; chlorothalonil and the like. D, derivatives such as 5,6-trans-ergocalciferol and the like. 0135 (g) Sulfur 01.07 (24) Others 0.136 Zineb, maneb and the like. 0108 Hydroxycam, diaserine, megestrol acetate, nicer goline, prostaglandins and the like. 0137 (h) Others 0109. In addition, therapeutic agents for ischemic dis 0.138. Diclomezin, tricyclazole, isoprothiolane, probena ease, immune disease, Alzheimer's disease, osteoporosis, Zole, anilazine, OXolinic acid, ferimZone and the like. neovascularization, retinopathy, retinal vein occlusion, 0139 (3) Herbicides Senile discoid macular degeneration, cerebrovascular spasm, cerebral thrombosis, cerebral infarction, cerebral occlusion, 0140 (a) Sulfonylurea intracerebral hemorrhage, Subarachnoid hemorrhage, hyper 0141 Imazosulfuron, bensulfuron-methyl and the like. tensive encephalopathy, transient cerebral ischemia attack, multi-infarct dementia, arterial Sclerosis, Huntington's dis 0142 (b) Triazine ease, cerebral tissue impairment, optic neuropathy, glau 0.143 Simetryn, dimethametryn and the like. coma, ocular hypertension, retinal detachment, arthritis, rheumatism, Sepsis, Septic shock, asthma, pollakiuria, uri 0144) (c) Urea nary incontinence, atopic dermatitis, allergic rhinitis and the 0145. Dymron and the like. like are also employed. 0146) (d) Acid Amide 0110 Sparingly water-soluble or sparingly soluble solid pesticidal compounds include those listed below. 0147 Propanil, mefenacet and the like. 0111 (1) Insecticides 0148 (e) Carbamate 0112 (a) Carbamate 0149 Swep and the like. 0113 MIPC; isoprocarb, BPMC; fenobucarb, MPMC; 0150 (f) Diazole xylylcarb, XMC, NAC; carbaryl, bendiocarb, carbofuran and the like. 0151. Oxadiazon, pyrazolate and the like. 0114 (b) Synthetic Pyrethroids 0152) (g) Dinitroaniline 0115 , fenpropathrin, ethofenprox, res 0153 Trifluralin and the like. methrin and the like. 0154) (h) Others 0116 (c) Organophosphorus O155) Dithiopyr and the like. 0117 EPN, cyanofenphos, PAP; phenthoate, CVMP; tet 0156 A physiologically active porous substance accord rachlorVinphos, monocrotophos, phosalone, chlorpyrifos ing to the present invention (hereinafter abbreviated as the methyl, chlorpyrifos, pyridaphenthion, quinalphos, DMTP; inventive porous Substance) can be produced, for example, methidathion, dioxabenzofoS and the like. by treating the physiologically active Substance described US 2004/0052854 A1 Mar. 18, 2004 above with carbon dioxide in a Supercritical or Subcritical 0168 For the treatment, other solvents in addition to State (including a critical State) or liquid carbon dioxide. carbon dioxide may be employed, for example, as a mixture thereof. O157. A process for such a treatment may be any process capable of avoiding complete dissolution of the physiologi 0169. Such other solvents include water; aromatic hydro cally active Substance in carbon dioxide in a Supercritical or carbons Such as benzene, toluene, ethyl acetate, cyclohexane Subcritical State or liquid carbon dioxide, which may for and Xylene; etherS Such as dimethyl ether, diethyl ether, example be a dispersing (preferably, just dispersing rather dioxane, diethoxyethane, tetrahydrofuran and 1,2- than dissolving completely), wetting, infiltrating, contacting dimethoxyethane, organochlorine organic Solvents Such as or mixing process, with a dispersing (preferably, just dis dichloromethane, chloroform, carbon tetrachloride and 1,2- persing rather than dissolving completely) process being dichloroethane, alkylnitriles Such as acetonitrile and propi preferred especially. onitrile, nitroalkanes Such as nitromethane and nitroethane; amides such as N,N-dimethylformamide and N,N-dimethy 0158 A Supercritical state means a state in which both lacetoamide, ketones Such as acetone; fatty acids Such as preSSure and temperature exceed the respective critical acetic acid, acetic anhydride and oleic acid; alcohols Such as points. methanol, ethanol and propanol; Sulfoxides Such as dimethyl 0159. A subcritical state means a state in which either Sulfoxide; and mixtures solvents thereof, with ethanol or preSSure or temperature exceeds the critical point. acetone being preferred. 0160 A critical point is defined, for example, by J. W. 0170 The amount of such other solvents is about 0.1 to Tom and P. G. Debenedetti in FIG. 1 in “Particle Formation 99.9% by volume, preferably about 1 to 50% by volume with Supercritical Fluids-A Review”, J. Aerosol Sci., based on the carbon dioxide in a Supercritical, Subcritical or 22(5), p.555-584 (1991). liquid State. 0171 More specifically, the inventive porous substance 0.161. A state in which neither pressure nor temperature can be produced in accordance with the procedure (1) or (2) exceeds the respective critical points is referred to as liquid. described below. 0162 Typically, carbon dioxide in a Supercritical state is 0172 (1) Procedure 1 in a State exceeding both the critical preSSure of about 7.38 megapascal (MPa) and the critical temperature of about 0173 1 Place a physiologically active substance in a 3.04.1 kelvin (K). preSSure-resistant container, 0163 When a physiologically active substance is treated 0.174 (2 Keep the temperature of said pressure-resistant with carbon dioxide in a Supercritical or Subcritical State or container at a level allowing carbon dioxide to be in a liquid carbon dioxide, the ratio of the carbon dioxide to the Supercritical or Subcritical State, physiologically active Substance may vary depending on the 0175 3 Fill carbon dioxide (if necessary in a mixture Size and type of a container employed. Usually, about 0.5g with other Solvents) from said pressure-resistant container, to 20 kg, preferably about 10 g to 2 kg of a physiologically active Substance is treated with about 50 ml to 2000 L of 0176) 4 Stop filling the carbon dioxide at the time point carbon dioxide in a Supercritical or Subcritical State or liquid when the pressure in Said preSSure-resistant container carbon dioxide. reaches a level allowing carbon dioxide to be in a Super critical or Subcritical State, 0164. The treatment period is usually about 1 minute to 0177 5 Depressurize after completing the carbon diox 24 hours, preferably about 0.05 to 12 hours, more preferably ide treatment and then collect the resultant physiologically about 5 to 120 minutes. active porous Substance; 0.165. The treatment for example by dispersing is prefer 0178 Preferably, ably usually conducted in a preSSure-resistant container. For example, a Supercritical fluid extraction System SCF-get 0179 1 Place a physiologically active substance in a (NIPPON BUNKO) (said system consists of a supercritical preSSure-resistant container, CO Supply pump SCF-get, a fully automatic pressure adjusting valve SGF-Bpq and a thermostat chamber 0180 2 Keep the temperature of said pressure-resistant container at a level allowing carbon dioxide to be in a CO-1560) may be employed. Supercritical or Subcritical State, 0166 The treatment temperature is usually about 40 C. to about 100 C., while it may vary depending on the type 0181 (3 Fill carbon dioxide (if necessary in a mixture of the Starting physiologically active Substance. For with other Solvents) from a cylinder connected into Said example, when the Starting physiologically active Substance preSSure-resistant container, is nifedipine, then the temperature is about 30° C. to about 0.182) 4 Stop filling the carbon dioxide at the time point 60° C. when the pressure in Said preSSure-resistant container 0167 The treatment pressure is usually about 3 mega reaches a level allowing carbon dioxide to be in a Super pascal (MPa) to about 50 MPa, while it may vary depending critical or Subcritical State, on the type of the Starting physiologically active Substance. 0183 5 Depressurize after allowing to stand for about 1 For example, when the Starting physiologically active Sub minute to 24 hours (preferably about 5 to 120 minutes) and stance is nifedipine, then the pressure is about 15 MPa to then collect the resultant physiologically active porous Sub about 20 MPa. Stance. US 2004/0052854 A1 Mar. 18, 2004

0184 (2) Procedure 2 0202) The term “improved water solubility” means, for example, an increased dissolution rate in water. Typically, it 0185. 1 Place a physiologically active substance in a means that a dissolution rate in water at 25 C. increases by preSSure-resistant container, about 2 times, preferably about 5 times, more preferably 0186 2. Keep the temperature of said pressure-resistant about 10 times, especially 100 times or more. container at the critical point of carbon dioxide or below, 0203 A composition containing the inventive porous 0187 (3 Fill carbon dioxide (if necessary in a mixture Substance (hereinafter referred to as the inventive composi with other Solvents) from said pressure-resistant container, tion) can be used as appropriate depending on the type of a physiologically active Substance contained as an active 0188 4 Stop filling the carbon dioxide under the con ingredient. dition where the pressure in Said pressure-resistant container does not exceed the critical point of carbon dioxide, 0204. The inventive composition may contain appropri ate additives. Preferred additives include or high 0189 5 Depressurize after completing the carbon diox molecular compounds capable of modifying the Surface of ide treatment and then collect the resultant physiologically the porous Substance, which may be employed alone or in a active porous Substance; combination of two or more of them. 0190. Preferably, 0205 Surfactants for use include nonionic surfactants, 0191 1 Place a physiologically active substance in a anionic Surfactants, cationic Surfactants, amphoteric Surfac preSSure-resistant container, tants and naturally occurring Surfactants. 0.192 (2 Keep the temperature of said pressure-resistant 0206 Nonionic surfactants include higher alcohol ethyl ene oxide adducts, alkylphenol ethylene oxide adducts, fatty container at the critical point of carbon dioxide or below, acid ethylene oxide adducts, polyhydric alcohol fatty acid 0193 3 Fill carbon dioxide (if necessary in a mixture ester ethylene oxide adducts, higher alkylamine ethylene with other Solvents) from a cylinder connected into said oxide adducts, fatty acid amide ethylene oxide adducts, fat preSSure-resistant container, ethylene oxide adducts, glycerin fatty acid esters, pen 0194 4 Stop filling the carbon dioxide under the con taerythritol fatty acid esters, polyhydric alcohol alkyl ethers, dition where the pressure in Said pressure-resistant container and fatty acid amides of alkanolamines. does not exceed the critical point of carbon dioxide, 0207 Among the nonionic surfactants listed above, those employed preferably are fatty acid esters of Sorbitol and 0195 5 Depressurize after allowing to stand for about 1 Sorbitan, polyoxyethylene Sorbitan fatty acid esters, poly minute to 24 hours (preferably about 5 to 120 minutes) and ethylene glycol fatty acid esters, Sucrose fatty acid esters, then collect the resultant physiologically active porous Sub polyethoxylated castor oil, polyethoxylated hydrogenated Stance. castor oil, polyoxyethylene polypropylene glycol copoly 0196. By allowing to stand for about 1 minute to 24 hours mers, glycerin fatty acid esters, polyglycerin fatty acid esters in Step 5), the physiologically active Solid Substance is and the like. The Sorbitan fatty acid ester is preferably infiltrated or wetted with the carbon dioxide. sorbitan monostearate (trade name: SS-10, NIKKO CHEMI CALS), sorbitan sesquioleate (trade name: SO-15, NIKKO 0197). In the production method according to the present CHEMICALS), sorbitan trioleate (trade name: SO-30, invention, a part of the Starting physiologically active Solid NIKKO CHEMICALS) or the like. The polyoxyethylene Substance, which is not dissolved in the carbon dioxide, sorbitan fatty acid ester is preferably Polysorbate 20 (trade becomes porous. name: TL-10, NIKKO CHEMICALS), 40 (trade name: 0198 The inventive porous substance thus obtained usu TP-10, NIKKO CHEMICALS), 60 (trade name: TS-10, ally has a weight-average particle size of 1 um or more, NIKKO CHEMICALS), 80 (trade name: TO-10, NIKKO preferably about 1 um to about 2000 um. More preferably, CHEMICALS) or the like. The polyethylene glycol fatty the weight-average particle Size is 10 um or more, particu acid ester is preferably polyethylene glycol monolaurate larly about 10 um to about 500 um. The weight-average (10E.O.) (trade name: MYL-10, NIKKO CHEMICALS) or particle size can be measured by a laser diffraction method. the like. The Sucrose fatty acid ester is preferably Sucrose palmitate (for example, trade name: S-1670, MITSUBISHI 0199 The specific surface area of the inventive porous KAGAKU FOODS), sucrose stearate (for example, trade Substance is usually about 1.5 m/g or more, preferably name: P-1670, MITSUBISHI KAGAKU FOODS) or the about 1.5 m/g to about 100 m/g, more preferably about 1.5 like. The polyethoxylated castor oil is preferably polyoxy m°/g to about 50 m/g, while the upper limit is not set ethylene glycerol triricinoleate 35 (Polyoxy 35 Castor Oil, particularly. The Specific Surface area can be measured by a trade name: Cremophor EL or EL-P, BASF Japan) or the BET method. like. The polyethoxylated hydrogenated castor oil is prefer ably Polyoxyethylene Hydrogenated Castor Oil 50, Poly 0200. The inventive porous substance is preferably crys oxyethylene Hydrogenated Castor Oil 60 or the like. The talline. polyoxyethylene polyoxypropylene glycol copolymer is 0201 The inventive porous substance has an increased preferably polyoxyethylene (160) polyoxypropylene (30) Specific Surface area as compared with the Starting physi glycol (trade name: Adeka Pluronic F-68, ASAHI DENKA ologically active Substance, which leads to an improved KOGYO) or the like. The glycerin fatty acid ester is pref dissolution rate. In addition, it has a sufficient flowability, erably glyceryl monostearate (MGS series, NIKKO can be handled readily and allows formulation to be accom CHEMICALS) or the like. The polyglycerin fatty acid ester plished easily. is preferably tetraglycerin monostearic acid (MS-310, US 2004/0052854 A1 Mar. 18, 2004

SAKAMOTO YAKUHIN KOGYO), decaglycerin mono a 2-hydroxybutyric acid/glycolic acid copolymer and the lauric acid (Decaglyn 1-L, NIKKO CHEMICALS) or the like), mixtures thereof (e.g., a mixture of polylactic acid and like. 2-hydroxybutyric acid/glycolic acid copolymer), wherein said fatty acids include C.-hydroxyfatty acids (e.g., glycolic 0208 Anionic surfactants include sulfates (e.g., higher acid, lactic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric alcohol Sulfuric acid ester Salts, higher alkyl ether Sulfuric acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxycaproic acid ester Salts, Sulfated oils, Sulfated fatty acid esters, Sulfated fatty acids, Sulfated olefins), (e.g., acid, 2-hydroxyisocaproic acid, 2-hydroxycapric acid and Sodium , oil-Soluble alkylbenzene the like), cyclic dimers of C-hydroxyfatty acids (e.g., gly Sulfonates, C.-olefin Sulfonates, Igepon type T, aerosol type coside, lactide and the like), hydroxydicarboxylic acids OT), phsophates (e.g., phosphoric acid ester salts of higher (e.g., malic acid and the like), hydroxytricarboxylic acids alcohol ethylene oxide adducts), and dithiophosphoric acid (e.g., citric acid and the like), ester Salts. 0219 2 Poly-C.-cyanoacrylates; 0209 Among the anionic surfactants listed above, those 0220 2. Polyhydroxybutyric acids; employed preferably are Salts Such as Sodium glycocholate or Sodium deoxycholate, fatty acids and their 0221 (3) Polyalkylene oxalates (e.g., polytrimethylene Salts. Such as Stearic acid or Sodium caprate, Sodium lauryl oxalates, polytetramethylene oxalates and the like); Sulfate and the like. 0222 4 Polyorthoesters, polyorthocarbonates or other 0210 Cationic surfactants include cationic surfactants of polycarbonates (e.g., polyethylene carbonates, polyethylene an amine Salt type (e.g., cationic Surfactants of an amine Salt propylene carbonates and the like), type produced from higher alkylamine, cationic Surfactants of an amine Salt type produced from lower alkylamine) and 0223 5 Polyamino acids (e.g., poly-Y-benzyl-L- cationic Surfactants of a quaternary ammonium Salt type glutamic acids, poly-L-, poly-Y-methyl-L-glutamic (e.g., cationic Surfactants of a quaternary ammonium Salt acids and the like); and the like. type produced from higher alkylamine, cationic Surfactants of a quaternary ammonium Salt type produced from lower 0224. In addition, other biocompatible high molecular alkylamine). polymerS Such as polystyrenes, polyacrylic acids, poly methacrylic acid, copolymers of acrylic acid and meth 0211 Amphoteric surfactants include amphoteric Surfac acrylic acid, Silicon polymers, dextran Stearate, ethyl cellu tants of an amino acid type and amphoteric Surfactants of a lose, acetyl cellulose, nitrocellulose, polyurethanes, maleic betaine type. anhydride copolymers, ethylene vinyl acetate copolymers, 0212 Naturally occurring surfactants include lecithin polyvinyl acetates, polyvinyl alcohols, polyacrylamides and such as purified egg yolk lecithin (trade name: PL-100H, the like are included. Any of these polymers may be QP) or hydrogenated Soybean lecithin (trade name: Lecinol employed alone, as a copolymer or just a mixture of two or S-10, NIKKO CHEMICALS). more, or may be employed as a Salt thereof. 0213 Among the surfactants listed above, those 0225. Among the high molecular polymers listed above, employed preferably are Sodium deoxycholate, Sodium lau those employed preferably are poly-fatty acid esters and ryl Sulfate, Polysorbate 80, polyoxyethylene (160) polyox poly-C-cyanoacrylates. Those employed more preferably ypropylene (30), polyoxyethylene glycerol triricinoleate 35, are poly-fatty acid esters. lecithins, polyethoxylated hydrogenated castor oils, Sucrose 0226. Among poly-fatty acid esters, those employed pref fatty acid esters and polyglycerin fatty acid esters, with erably are homopolymers of C-hydroxyfatty acid or a cyclic Sodium deoxycholate being more preferred. dimer of C-hydroxyfatty acid, copolymers of two or more 0214) Any of these surfactants may be employed alone or C-hydroxyfatty acids or cyclic dimers of C-hydroxyfatty in a combination of two or more. acids, as well as the mixtures thereof. Those employed more preferably are homopolymers of C-hydroxyfatty acids, 0215 High molecular compounds for use include high copolymers of two or more C-hydroxyfatty acids or mixtures molecular polymers and hydrophilic polymers. thereof. Those preferred especially are polylactic acids, 0216) The number-average molecular weight of a high lactic acid/glycolic acid copolymers, 2-hydroxylbutyric molecular polymer is preferably about 3,000 to 30,000, acid/glycolic acid copolymers as well as the mixtures more preferably about 5,000 to 25,000, especially about thereof. 5,000 to 20,000. When used herein, the terms “weight average molecular weight' and “dispersion degree” mean 0227. These C-hydroxycarboxylic acids may be in the those measured by gel permeation chromatography (GPC) D-form, L-form or D.L-form, if present, with the D.L-form using polystyrene as a reference Standard. The measurement being employed preferably. uses a GPC column KF804x2 (SHOWADENKO) together 0228. When a lactic acid/glycolic acid copolymer is with chloroform as a mobile phase. employed as the high molecular polymer described above, 0217 Examples of such a high molecular polymer, for its ratio is preferably about 100/0 to 50/50. When a butyric example, of an in Vivo degradable type are: acid-glycolic acid copolymer is employed, its ratio is pref 0218 1 poly-fatty acid esters e.g. homopolymers of erably about 100/0 to 25/75. fatty acids (e.g., polylactic acid, polyglycolic acid, polycitric 0229. The weight-average molecular weight of the lactic acid, polymalic acid and the like), copolymers of two or acid/glycolic acid copolymer is preferably about 5,000 to more fatty acids (e.g., a lactic acid/glycolic acid copolymer, about 30,000, more preferably about 5,000 to 20,000. US 2004/0052854 A1 Mar. 18, 2004

0230. When a mixture of polylactic acid (A) and a glycolic acid/2-hydroxybutyric acid copolymer (B) is employed as the high molecular polymer described above, the ratio represented by (A)/(B) is within the range from about 10/90 to about 90/10 (weight ratio), preferably within the range from about 25/75 to about 75/25. 0231. The weight-average molecular weight of the poly lactic acid is preferably about 5,000 to about 30,000, more preferably about 6,000 to about 20,000. 0232 The glycolic acid/2-hydroxybutyric acid copoly mer is preferably composed of about 40 to 70 moles of glycolic acid, with the reminder being 2-hydroxybutyric acid. The weight-average molecular weight of the glycolic 0243 wherein q is an integer of 6 to 12, R, R and Rare acid/2-hydroxybutyric acid copolymer is preferably about Same or different in individual repeating units and each is a 5,000 to about 25,000, more preferably about 5,000 to about dihydroxyalkyl group, Sugar residue, hydroxyalkyl group or 20,000. Sulfoalkyl group. Those exemplified typically are C-CyD(q= 6), B-CyD(q=7), Y-CyD(q=8) and 8-CyD(q=9) whose 0233 Hydrophilic polymers include water-soluble poly hydroxyl groups are ether-derivatized. Among these, B-CyD mers, enteric polymers and gastric Soluble polymers. whose hydroxyl groups are ether-derivatized is preferred. 0234 Water-soluble polymers include cellulose deriva 0244.) The dihydroalkyl group represented by R to R tives including hydroxyalkyl cellulose Such as hydroxypro may for example be a dihydroxy-C alkyl group (e.g., pyl cellulose and hydroxypropylmethyl cellulose and alkyl dihydroxymethyl, 2,2-dihydroxyethyl, 2,2-dihydroxypro cellulose Such as methyl cellulose, polyalkenyl pyrrollidone pyl, 2,2-dihydroxypentyl, 2,2-dihydroxyhexyl), preferably a Such as polyvinyl pyrrolidone, polyalkylene glycol Such as dihydroxy-C alkyl group (e.g., dihydroxymethyl, 2,2- polyethylene glycol and polyvinyl alcohol. dihydroxyethyl, 2,2-dihydroxypropyl). 0235 Enteric polymers include hydroxypropylmethyl 0245) The sugar residue represented by R to R may for cellulose phthalate, hydroxypropylmethyl cellulose acetate example be a C. Sugar residue (erythrosyl, threosyl, Succinate, carboxymethylethyl cellulose, cellulose acetate arabinosyl, ribosyl, glucosyl, galactosyl, glycero-gulco-hep phthalate, methacrylic acid copolymer L and methacrylic tosyl, maltosyl, lactosyl, maltotriosyl or dimaltosyl), pref acid copolymer S. erably a C-2 Sugar residue (e.g., glucosyl, galactosyl, glycero-gulco-heptosyl, maltosyl, lactosyl, maltotriosyl and 0236 Gastric soluble polymers include aminoalkyl meth dimaltosyl), more preferably a C-1 Sugar residue (e.g., acrylate copolymer E and polyvinyl acetal diethyl aminoac glucosyl, galactosyl, glycero-gulco-heptosyl, maltosyl, lac etate. tosyl). 0237. In addition, carboxymethyl cellulose, Eudragit, a 0246) The hydroalkyl group represented by R to R may carboxyvinyl polymer, polyvinyl alcohol, gum arabic, for example be a hydroxy-C alkyl group (e.g., hydroxym Sodium alginate, alginic acid propylene glycol ester, agar, ethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxypentyl, gelatin, chitosan and the like can be also employed. Any of 2-hydroxyhexyl), preferably a hydroxy-C alkyl group these hydrophilic polymerS may be employed alone or in a (e.g., hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl), combination of two or more. especially a 2-hydroxypropyl group. 0238. The inventive composition may also contain a 0247 The sulfoalkyl group represented by R to R may readily water-Soluble cyclodextrin derivative for the purpose for example be a Sulfo-Co alkyl group (e.g., Sulfomethyl, of further improving the Solubility of the porous Substance. Sulfoethyl, Sulfopropyl, Sulfopentyl, Sulfohexyl), preferably a Sulfo-Cl alkyl group (e.g., Sulfomethyl, Sulfoethyl, Sul 0239). Such a readily water-soluble cyclodextrin deriva fopropyl), especially a Sulfobutyl group. tive may be commercially available, or can be produced in accordance with a method known per Se. 0248. A further preferred example of such a readily water-Soluble cyclodextrin derivative is a compound repre 0240 Such a readily water-soluble cyclodextrin deriva sented by Formula (II) wherein at least one of R to R is a tive is preferably a compound in which a part or all of the Sugar residue, hydroxyalkyl group or Sulfoalkyl group. hydrogen atoms of the hydroxyl groups in the 2, 3 and 6-positions on a glucose in a cyclic oligosaccharide consist 0249. A compound (II) in which at least one of R to R ing of 6 to 12 glucose units are Substituted by other func is a Sugar residue includes glucosyl-O.B.Y.ö-CyD, maltosyl tional groups (for example, dihydroxyalkyl groups, Sugar C.f3,Y,ö-CyD, maltotriosyl-C,B,Y,ö-CyD and dimaltosyl-C.f3, residues, hydroxyalkyl groups, Sulfoalkyl groups). Y,ö-CyD. Among these, maltosyl-C,B,Y,ö-CyD and glucosyl C.f3,Y,ö-CyD are preferred. Maltosyl-f-CyD (hereinafter 0241. Such a readily water-soluble cyclodextrin deriva abbreviated as G2-B-CyD) and glucosyl-B-CyD are espe tive has a solubility in water of about 100 mg/ml or more, cially preferred. preferably about 130 mg/ml or more. 0250) A compound (II) in which at least one of R to R 0242 A preferred example of such a readily water is a hydroxyalkyl group includes hydroxypropyl-O.B.Y.,ö- Soluble cyclodextrin derivative is a compound represented CyD. Among these, hydroxypropyl-f-CyD is preferred by Formula (I): especially. US 2004/0052854 A1 Mar. 18, 2004

0251 A compound (II) in which at least one of R to R copyranoside uronate (similarly abbreviated as f-CyD-G- is a Sulfoalkyl group includes Sulfobutyl-C,B,Y,ö-CyD. COONa))). Among those listed above, B-CyD-G-COONa Among these, Sulfobutyl-B-CyD is preferred especially. is preferred. 0252) In addition, branched cyclodextrin-carboxylic acid 0257 More particularly, 6-O-cyclomaltohexaosyl-(6-> can be also used as the readily water-Soluble cyclodextrin 1)-O-D-glucosyl-(4->1)-O-O-D-glucuronic acid (C-CyD derivative. The branched cyclodextrin-carboxylic acid G-COOH), 6-O-cyclomaltoheptaosyl-(6->1)-O-D-gluco includes not only its free carboxylic acid but also its alkaline syl-(4->1)-O-O-D-glucuronic acid (B-CyD-G-COOH) and metal Salts (e.g., lithium, Sodium, potassium) and alkaline 6-O-cyclomaltooctaosyl-C-D-glucosyl-(4->1)-O-C-D-glu earth metal salts (e.g., calcium, magnesium). Any of these curonic acid (Y-CyD-G-COOH) are branched cyclodextrin branched cyclodextrin-carblxylic acids may be employed carboxylic acids containing C-cyclodextrin (6 glucose alone or in a combination of two or more, or also in a units), f-cyclodextrin (7 glucose units) and Y-cyclodextrin (8 mixture of free carboxylic acid with its salt. glucose units) respectively, wherein maltose is linked to one of the glucose units of the cyclodextrin ring via an O-(1->6) 0253) Such branched cyclodextrin-carboxylic acid is bond and the hydroxymethyl group in the 6-position on the cyclodextrin in which an organic group containing at least terminal glucose of Said maltose is oxidized into a carboxy one carboxyl group is in the 6-O position on at least one lic group, whereby forming glucuronic acid. glucose unit of Said cyclodextrin ring. 0258. On the other hand, 6-O-cyclomaltohexaosyl-(6-> 0254 The cyclodextrin ring of said branched cyclodex 1)-O-D-glucuronic acid (C-CyD-G-COOH), 6-O-cycloma trin-carboxylic acid has, for example, 6, 7 or 8 glucose units. Itoheptaosyl-(6->1)-C-D-glucuronic acid (B-CyD-G- Preferably Said cyclodextrin ring has 7 glucose units. Such COOH) and 6-O-cyclomaltooctaosyl-(6->1)-O-D- cyclodextrin includes C-cyclodextrin, B-cyclodextrin and glucuronic acid (Y-CyD-G-COOH) are branched Y-cyclodextrin. cyclodextrin-carboxylic acids wherein glucose is linked to one glucose unit of the cyclodextrin ring via an O-(1->6) 0255 In a preferred case, the organic group having at bond and the hydroxymethyl group in the 6-position on Said least one carboxyl group has 1 to 3 glucose units, and at least branched glucose is oxidized into a carboxylic group, one hydroxylmethyl group in the glucose unit in Said organic whereby forming glucuronic acid. group is oxidized into a carboxylic group. 0259 Moreover, 2-O-(6-cyclomaltohexaosyl) -acetic 0256 Examples of such branched cyclodextrin-carboxy acid (C-CyD-CHCOOH), 2-O-(6-cyclomaltoheptaosyl)- lic acid are 6-O-cyclomaltohexaosyl-(6->1)-O-D-glucosyl acetic acid (B-CyD-CHCOOH) and 2-O-(6-cyclomaltooc (4->1)-O-C-D-glucuronic acid (cyclomaltohexaosyl-(6-> taosyl)-acetic acid (Y-CyD-CHCOOH) are the branched 1)-O-D-glucopyranosyl-(4-> 1)-O-O-D-glucopyranoside cyclodextrin-carboxylic acids, wherein a carboxymethyl uronic acid) (hereinafter Sometimes abbreviated as C.-CyD group is linked to one glucose unit of the cyclodextrin ring G-COOH; the following compounds are also abbreviated to form a branch. similarly in brackets), 6-O-cyclomaltoheptaosyl-(6->1)-O- D-glucosyl-(4-> 1)-O-O-D-glucuronic acid (cyclomaltohep 0260 These branched cyclodextrin-carboxylic acids or taosyl-(6->1)-O-C-D-glucopyranosyl-(4->1)-O-O-D-glu their salts are described in JP-A7-76594 and JP-A7-215895, copyranoside uronic acid) (B-CyD-G-COOH), 6-O- and can be produced by the methods disclosed in these cyclomaltooctaosyl-(6-> 1)-C-D-glucosyl-(4->1)-O-C-D- publications as well as in JP-A 10-210996 and JP-A glucuronic acid (cyclomaltooctaosyl-(6-> 1)-O-O-D- 10-210996 or analogous methods. glucopyranosyl-(4-> 1)-O-O-D-glucopyranoside uronic acid) (Y-CyD-G-COOH), 6-O-cyclomaltohexaosyl-(6->1)- 0261) When the physiologically active substance is a C-D-glucuronic acid (cyclomaltohexaosyl-(6->1)-O-C-D- pharmaceutical compound, the inventive composition (here glucopyranoside uronic acid) (C-CyD-G-COOH), 6-O-cy inafter Composition A) can be formulated into an oral clomaltoheptaosyl-(6-> 1)-O-D-glucuronic acid formulation Such as a tablet (including Sugar-coated tablet, (cyclomaltoheptaosyl-(6->)-O-O-D-glucopyranoside uronic film-coated tablet and buccal disintegration tablet), powder, acid) (B-CyD-G-COOH), 6-O-cyclomaltooctaosyl-(6->1)- granule, capsule (including Soft capsule), liquid and the like; C-D-glucuronic acid (cyclomaltooctaosyl-(6->1)-O-C-D- or a parenteral formulation Such as an injection, Suppository, glucopyranoside uronic acid) (Y-CyD-G-COOH), 2-O-(6- intravaginal Suppository, Sublingual tablet, cataplasm, per cyclomaltohexaosyl)-acetic acid (C-CyD-CHCOOH), 2-O- cutaneous formulation by mixing the pharmaceutical com (6-cyclomaltoheptaosyl)-acetic acid (B-CyD-CHCOOH), pound with pharmaceutically acceptable carriers, Surfac 2-O-(6-cyclomaltooctaosyl)-acetic acid (Y-CyD tants, high molecular compounds and readily Soluble CHCOOH), 3-O-(6-cyclomaltoheptaosyl)-propionic acid cyclodextrin derivatives described above and the like in (B-CyD-CH, CHCOOH), 2-hydroxy-3-O-(6-cyclomalto accordance with a method known per Se for producing oral heptaosyl)-propionic acid (3-O-(6-cyclomaltoheptaosyl)-2- or parenteral compositions, and then can be administered hydroxy-propionic acid) (B-CyD-CH-CH(OH)-COOH), Safely. An injection formulation can be used by means of 7,7-di-O-O-D-glucuronyl-(1->4)-O-O-D-glucosyl-(1-> intravenous, intramuscular, Subcutaneous or intraorganic 6)-maltoheptaose (B-CyD-(GCOOH)), 6-O-cyclomalto administration or by means of direct administration to a heptaosyl-O-O-D-maltosyl-(4->1)-O-O-D-glucuronic acid lesion. A Suppository can be used also by topical adminis (cyclomaltoheptaosyl-(6 l)-O-O-D-glucopyranosyl-(4-> 1)- tration or rectal administration. O-O-D-glucopyranosyl-(4-> 1)-O-O-D-glucopyranoside 0262 Pharmaceutically acceptable carriers which may be uronic acid) (B-CyD-G-COOH) as well as their salts e.g., used for producing the inventive Composition A include sodium salt of B-CyD-G-COOH (sodium cyclomaltohep various organic and inorganic carriers employed routinely as taosyl-(6->1)-O-C-D-glucopyranosyl-(4->1)-O-O-D-glu formulation bases, for example, excipients, lubricants, bind US 2004/0052854 A1 Mar. 18, 2004

erS and disintegrants for a Solid dosage form; and Solvents, buffer Solutions of phosphates, acetates, carbonates, citrates Solubilizing agents, Suspending agents, isotonicities, buffer and the like. The Soothing agent includes benzyl alcohol. ing agents, Soothing agents for a liquid dosage form. If 0278. The injection thus obtained may be lyophilized necessary, conventional additives Such as preservatives, with an aseptic freeze drying machine after, if necessary, antioxidants, colorants, Sweeteners, absorbents, wetting removing pyrogens by a method known per Se and then agents and the like can also be employed. Stored in the form of powder, or may be Stored as it is in a 0263. Excipients include lactose, white Sugar, D-manni tightly closed container for injection (e.g., ampoule). tol, Starch, cornstarch, crystalline cellulose and light Silicic 0279 While the amount of the pharmaceutical compound anhydride. in the inventive Composition A may vary depending on the 0264 Lubricants include magnesium Stearate, calcium dosage form, it is usually about 0.01 to 99.99% by weight, Stearate, talc and colloidal Silica. preferably about 0.1 to 50% by weight, more preferably 0265 Binders include crystalline cellulose, white sugar, about 0.5 to 20% by weight based on the total weight of the D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypro composition. pylmethyl cellulose, polyvinyl pyrrollidone, Starch, Sucrose, 0280 When a surfactant, hydrophilic polymer or readily gelatin, methyl cellulose and Sodium carboxymethyl cellu soluble cyclodextrin derivative is contained in the inventive lose. Composition A, each amount is usually about 1 to 99.99% 0266 Disintegrants include starch, carboxymethyl cellu by weight, preferably about 10 to 90% by weight based on lose, calcium carboxymethyl cellulose, Sodium croScarmel the total weight of the composition, while it may vary lose, Sodium carboxymethyl Starch and L-hydroxypropyl depending on the dosage form. cellulose. 0281. The amount of the pharmaceutically acceptable carrier in the inventive Composition A is usually about 1 to 0267 Solvents include water for injection, alcohols, pro 99.99% by weight, preferably about 10 to 90% by weight pylene glycol, macrogol, Sesame oil, corn oil and olive oil. based on the total weight of the composition, while it may 0268 Solubilizing agents include polyethylene glycol, vary depending on the dosage form. propylene glycol, D-mannitol, benzyl benzoate, ethanol, 0282. The inventive Composition A can be administered trisaminomethane, cholesterol, triethanolamine, Sodium car to mammals (e.g., rat, mouse, guinea pig, monkey, cattle, bonate and Sodium citrate. dog, pig, human and the like) depending on the type of the 0269 Suspending agents include Surfactants Such as pharmaceutical compound. Stearyl triethanolamine, Sodium lauryl Sulfate, laurylamino 0283 The dose of the inventive Compound A may vary propionic acid, lecithin, benzalkonium chloride, benzetho depending on the Subject of administration, route of admin nium chloride, glycerin monoStearate and the like; and istration and disease. For example, when the Composition A hydrophilic polymerS Such as polyvinyl alcohol, polyvinyl is administered orally as an antihypertensive to an adult pyrrollidone, Sodium carboxymethyl cellulose, methyl cel (weighing about 60 kg), its dose is about 0.1 to about 20 lulose, hydroxymethyl cellulose, hydroxyethyl cellulose, mg/kg body weight, preferably about 0.2 to about 10 mg/kg hydroxypropyl cellulose and the like. body weight, more preferably about 0.5 to about 10 mg/kg 0270 Isotonicities include glucose, D-Sorbitol, sodium body weight of the pharmaceutical compound for antihy chloride, glycerin and D-mannitol. pertensive, which may be given in one to Several portions 0271 Buffering agents include buffer solutions of phos per day. phates, acetates, carbonates, citrates and the like. 0284. When the inventive Composition A is an injection, it can be given by means of intravenous, intramuscular, 0272. Soothing agents include benzyl alcohol. Subcutaneous or intraorganic administration, or can be given 0273 Preservatives include p-hydroxybenzoic esters, directly to a lesion. The dose of an injection may vary , benzyl alcohol, phenethyl alcohol, dehy depending on the Subject of administration, route of admin droacetic acid and Sorbic acid. istration, disease and the like. For example, when the injection is administered as an antihypertensive to an adult 0274 Antioxidants include sulfite, ascorbic acid and ato (weighing about 60 kg), its dose is about 0.1 to 500 mg, copherol. preferably about 1 to 100 mg, more preferably about 5 to 100 0275 When the inventive Composition A is formulated mg of the pharmaceutical compound for antihypertensive into an injection, a pharmaceutical compound is dissolved, per time, which may be given intravenously one to Several Suspended or emulsified in an aseptic aqueous or oily fluid. portions per day. 0276 A carrier for injection may for example be a 0285. It is also possible that two or more pharmaceutical Solvent, Solubilizing agent, Suspending agent, isotonicity, compounds are formulated individually and then given to an buffering agent, Soothing agent and the like. identical Subject Simultaneously or Sequentially. 0277. The solvent includes water for injection, physi 0286. When the pharmaceutically active compound is a ological Saline and Ringer's Solution. The Solubilizing agent pesticidal compound, the inventive composition (hereinafter includes polyethylene glycol, propylenen glycol, D-manni referred to as Composition B) can be formulated into an tol, benzyl benzoate, ethanol, trisaminomethane, choles emulsion, liquid, oil Solution, dust, DL (driftless) type dust, terol, triethanolamine, Sodium carbonate and Sodium citrate. granule, microgranule, microgranule F, fine granule F, wet The isotonicity includes glucose, D-Sorbitol, Sodium chlo table powder, granular wettable powder, water-Soluble pow ride, glycerin and D-mannitol. The buffering agent includes der, flowable formulation, tablet, JUMBO formulation, US 2004/0052854 A1 Mar. 18, 2004

Spray, paste and the like by mixing the pesticidal compound polyoxyethylene fatty acid esters, higher fatty acid glycerin with Suitable pesticidal carriers, Surfactants, hydrophilic esters, Sorbitan fatty acid esters, Sucrose fatty acid esters, polymers and readily Soluble cyclodextrin derivatives polyoxyethylene polyoxypropylene block polymers, poly described above and the like in accordance with a method oxyethylene fatty acid amides, alkylolamides, polyoxyeth known per Se for producing pesticidal compositions. ylene alkylamine and the like, cationic Surfactants Such as alkylamine hydrochlorides (e.g., dodecylamine hydrochlo 0287) Typically, one or more (preferably one to three) ride), alkyl quaternary ammonium salts, alkyltrimethyl qua pesticidal compounds are, depending on the purpose of use, ternary ammonium salts (e.g., dodecyltrimethylammonium dissolved or dispersed in a Suitable liquid carrier, or mixed Salts), alkyldimethylbenzylammonium Salts, alkylpyri with or adsorbed on a Suitable Solid carrier, and then mixed dinium Salts, alkylisoquinolinium Salts, dialkylmorpho if necessary with a Surfactant, hydrophilic polymer or linium Salts, benzethonium chloride, polyalkylvinylpyri readily soluble cyclodextrin derivative. These formulations dinium Salts and the like, anionic Surfactants Such as higher may be Supplemented if necessary with an emulsifier, dis fatty acid Sodium salts (e.g., Sodium palmitate), Sodium persant, spreading agent, penetrating agent, Wetting agent, ether carboxylates (e.g., Sodium polyoxyethylene lauryl binder, thickening agent and the like, and can be prepared by ether carboxylate), amino acid condensates of higher fatty a method known per se. acids (e.g., Sodium lauroyl sarcosinate, Sodium N-lauroyl 0288 Liquid carriers (solvents) employed include sol glutamate), higher alkyl Sulfonates, higher fatty acid ester vents Such as water, alcohols (e.g., methanol, ethanol, 1-pro Sulfonates (e.g., lauric acid ester ), lignine panol, 2-propanol, ethylene glycol), ketones (e.g., acetone, Sulfonates (e.g., Sodium lignineSulfonate), alkyl SulfoSucci methyl ethyl ketone), ethers (e.g., dioxane, tetrahydrofuran, nates (e.g., Sodium diheptyl SulfoSuccinate, Sodium dioctyl ethylene glycol monomethyl ether, diethylene glycol SulfoSuccinate, Sodium dinonyl SulfoSuccinate), fatty acid monomethyl ether, propylene glycol monomethyl ether), amide Sulfonates (e.g., oleic acid amide Sulfonate), dodecyl aliphatic hydrocarbons (e.g., kerosine, kerosene, fuel oil, benzeneSulfonates, diisopropylnaphthaleneSulfonates, alky machine oil), aromatic hydrocarbons (e.g., benzene, toluene, laryl Sulfonate formalin condensates, higher alcohol Sulfates Xylene, Solvent naphtha, methylnaphthalene), halogenated (e.g., pentadecan-2-yl Sulfate), polyoxyethylene alkyl ether hydrocarbons (e.g., dichloromethane, chloroform, carbon Sulfates (e.g., Sodium polyoxyethylene dodecyl ether Sul tetrachloride), acid amides (e.g., dimethylformamide, dim fate), polyoxyethylene alkyl phosphates (e.g., dipolyoxyeth ethylacetoamide), esters (e.g., ethyl acetate, butyl acetate, ylene dodecyl ether phosphate), polyoxyethylene alkylaryl fatty acid glycerin ester), nitrites (e.g., acetonitrile, propi phosphates, Styrene-maleic acid copolymers, alkyl vinyl onitrile) and the like. Any of these may be employed alone ether-maleic acid copolymer and the like, amphoteric Sur or in a combination of two or more (preferably one to three) factants such as N-laurylalanine, N,N,N-trimethylaminopro in an appropriate ratio. pionic acid, N,N,N-trihydroxyethylaminopropionic acid, 0289 Solid carriers (diluents or extenders) employed N-hexyl-N,N-dimethylaminoacetic acid, 1-(2-carboxyeth include vegetable powder (e.g., Soybean powder, tobacco yl)pyridinium betaine and the like. Any of these may be powder, wheat powder, wood powder), mineral powder employed alone or in a combination of two or more (pref (e.g., clays Such as kaolin, bentonite, acid terra alba and clay, erably one to five). talcS Such as talc and agalmatolite, Silicas Such as kieselguhr 0292 Such a surfactant can be used usually in an amount and mica powder), alumina, Sulfur powder, activated carbon, of about 0.1 to 50% by weight, preferably about 0.1 to 25% Saccharides (e.g., lactose, glucose), inorganic Salts (e.g., by weight based on the total weight of the composition. calcium carbonate, Sodium bicarbonate) and hollow glasses 0293 Binders employed include dextrin (e.g., dextrin (produced by Sintering a naturally occurring glass material ND-S produced by NICHIDEN KAGAKU), sodium salts of to encapsulate air bubbles). Any of these may be employed carboxymethylcellulose (e.g., CELLOGEN5A, 6A, 7A, PR alone or in a combination of two or more (preferably one to produced by DAIICHI KOGYO SEIYAKU), polycarboxy three) in an appropriate ratio. lic acid-based polymeric compounds (e.g., TOXANON 0290. Such a liquid carrier or solid carrier can be GR-30, 31A, GR-50L, GR-60L produced by SANYO employed usually in an amount of about 1 to 99% by weight, KASEI KOGYO; POIS 530, 532A produced by KAO), preferably about 10 to 99% by weight based on the total polyvinyl pyrrolidone, polyvinyl alcohol, Sodium lignine weight of the composition. Sulfonate, calcium lignineSulfonate, Sodium polyacrylate, gum arabic, Sodium alginate, glucose, Sucrose, mannitol and 0291 AS an emulsifier, dispersant, spreading agent, pen Sorbitol. Such binder may be employed usually in an amount etrating agent, wetting agent and the like, a Surfactant is of about 0 to 20% by weight based on the total weight of the employed as appropriate. Examples of Such a Surfactant are formulation. nonionic Surfactants Such as polyoxyethylene alkyl ethers (e.g., EMULMIN 110 produced by SANYO KASEI 0294. Thickening agents employed include bentonite KOGYO), polyoxyethylene alkylaryl ethers (e.g., NON based minerals (e.g., highly purified Sodium montmorillo IPOL 85, NONIPOL 100, NONIPOL 160 produced by nite), polyacrylic acids and derivatives thereof, Sodium Salts SANYO KASEI KOGYO), polyoxyethylene lanolin alco of carboxymethyl cellulose (e.g., CELLOGEN 5A, 6A, 7A, hols, polyoyethylene alkylphenol formalin condensates, PR produced by DAIICHI KOGYO SEIYAKU), white polyoxyethylene Sorbitan fatty acid esters (e.g., Tween 20, carbons and naturally occurring Saccharide derivatives (e.g., Tween 80 produced by KAO, SOLGEN TW-20, SOLGEN Xanthane gum, guar gum). Such thickening agents may be TW-80 produced by DAIICHI KOGYO SEIYAKU), poly employed usually in an amount of about 0.01 to 10% by poxyethylene glyceryl mono-fatty acid esters, polyoxypro weight based on the total weight of the formulation. pylene glycol mono-fatty acid esters, polyoxyethylene Sor 0295) The content of a pesticidal compound in the inven bitol fatty acid esters, polyoxyethylene castor oil derivatives, tive Composition B is suitably about 1 to 90% by weight for US 2004/0052854 A1 Mar. 18, 2004 an emulsion, wettable powder, granular wettable powder, 1. A physiologically active porous Substance obtained by liquid, water-soluble powder, flowable formulation and the treating a physiologically active Solid Substance with carbon like, about 0.01 to 10% by weight for an oil solution, dust, dioxide in a Supercritical or Subcritical State or liquid carbon DL dust formulation and the like, and about 0.05 to 10% by dioxide. weight for a microgranule, microgranule F, fine granule F, granule and the like, while it may vary depending on the 2. A physiologically active porous Substance whose purpose of use. An emulsion, wettable powder, granular weight-average particle size is about 1 um or more and wettable powder, liquid, water-soluble powder and flowable whose specific Surface area is about 1.5 m/g or more. formulation may be applied after diluting and extending (for 3. A physiologically active porous Substance according to example by about 100 to 100,000-fold dilution) with water claim 2 wherein the weight-average particle Size is about 10 or the like as appropriate. tum or more and the specific Surface area is about 1.5 m/g 0296. When a surfactant, hydrophilic polymer or readily O OC. soluble cyclodextrin derivative is contained in the inventive 4. A physiologically active porous Substance according to Composition B, the content is usually about 1 to 99.99% by claim 1 or 2 which is crystalline. weight, preferably about 10 to 90% by weight based on the 5. A physiologically active porous Substance according to total weight of the composition, while it may vary depending claim 1 or 2 wherein the physiologically active Substance is on the dosage form. a pharmaceutical compound. 0297. The content of a pesticidal carrier in the inventive 6. A physiologically active porous Substance according to Composition B is usually about 1 to 99.99% by weight, claim 1 or 2 wherein the physiologically active Solid Sub preferably about 10 to 90% by weight based on the total stance is a sparingly water-Soluble or water-insoluble Sub weight of the composition, while it may vary depending on stance whose solubility in water at 25 C. is less than 10 the dosage form. mg/mL. 0298. Application of the inventive Composition B may 7. A composition comprising a Substance according to be conducted in a manner Similar to that for applying claim 1 or 2. conventional pesticides, Such as aerial application, Soil 8. A composition according to claim 7 comprising a application, foliar application, nursery box application, Side Surfactant or a high molecular compound. row application, Seed treatment and the like. For example, a 9. A composition according to claim 8 wherein the high paddy field can be treated by a method known per Se (e.g., molecular compound is a high molecular polymer whose hand application and mechanical application). number-average molecular weight is about 3,000 to 30,000. 0299 For example, the amount of the inventive Compo 10. A composition according to claim 9 wherein the high Sition B wherein the pesticidal compound is a herbicide, is molecular polymer is one or a copolymer or mixture of two usually about 0.05 to 50 g, preferably about 0.1 to 10 g of or more Selected from the group consisting of (1) poly-fatty the herbicide per are of a paddy field, and about 0.05 to 50 acid ester, (2) poly-C-cyanoacrylate, (3) poly-hydroxybu g, preferably about 0.1 to 10 g of the herbicide per are of a tyric acid, (4) polycarbonate Selected from polyalkylene farmland, while it may vary depending on the application oxalate, poly-Ortho-ester, poly-Ortho-carbonate, polyethyl Site, application Season, application mode, Subject weeds, ene carbonate and polyethylene propylene carbonate, (5) crop plant and the like. polyamino acid, (6) polystyrene, (7) polyacrylic acid, (8) polymethacrylic acid, (9) copolymer of acrylic acid and 0300 When the inventive Composition B is applied to methacrylic acid, (10) silicon polymer, (11) dextran Stearate, paddy field weeds, it is given preferably by pre-emergence (12) ethyl cellulose, (13) acetyl cellulose, (14) nitrocellu Soil treatment or foliage-Soil dual treatment. lose, (15) polyurethane, (16) maleic anhydride copolymer, EXAMPLES (17) ethylene vinyl acetate copolymer, (18) polyvinyl acetate, (19) polyvinyl alcohol and (20) polyacrylamide. 0301 The present invention is further detailed in the 11. A composition according to claim 9 wherein the high following Examples which are not intended to restrict the molecular polymer is polylactic acid, a lactic acid/glycolic present invention. acid copolymer, a 2-hydroxybutyric acid/glycolic acid Example 1 copolymer or a mixture thereof. 0302 About 1 g of nifedipine was placed in a 90 mL 12. A composition according to claim 8 wherein the high pressure resistance container, which was then warmed to 60 molecular compound is a hydrophilic polymer. C. and received carbon dioxide at the rate of 20 mL/min via 13. A composition according to claim 12 wherein the a cylinder connected thereto, whereby dispersing the nife hydrophilic polymer is one or a mixture of two or more dipine in the carbon dioxide. At the time when the pressure Selected from the group consisting of (1) water-soluble in the container reached 20 MPa, the carbon dioxide Supply polymer Selected from hydroxyalkyl cellulose, cellulose was Stopped, and the container was allowed to Stand for derivative, polyalkenylpyrrolidone, polyalkylene glycol and about 10 minutes, and then depressurized. A SEM photo polyvinyl alcohol; (2) enteric polymer Selected from hydrox graph of the resultant product is shown in FIG. 1, while the ypropylmethyl cellulose phthalate, hydroxypropylmethyl magnified photograph is shown in FIG. 2. A SEM photo cellulose acetate Succinate, carboxymethylethyl cellulose, graph of nifedipine before the treatment is shown in FIG. 3. cellulose acetate phthalate, methacrylic acid copolymer L and methacrylic acid copolymer S.; (3) gastric Soluble poly INDUSTRIAL APPLICABILITY mer Selected from aminoalkyl methacrylate copolymer E 0303. The inventive porous substance has an extremely and polyvinyl acetal diethylaminoacetate; (4) carboxym improved dissolution rate and can readily be handled. ethyl cellulose; (5) Eudragit; (6) carboxyvinyl polymer; (7) US 2004/0052854 A1 Mar. 18, 2004 polyvinyl alcohol; (8) gum arabic; (9) Sodium alginate; (10) depressurizing after completing the carbon dioxide treat alginic acid propylene glycol ester; (11) agar; (12) gelatin ment and then collecting the resultant physiologically active and (13) chitosan. porous Substance. 14. A composition according to claim 7 comprising a 20. A method according to any one of claims 17 to 19 readily water-soluble cyclodextrin derivative. wherein the Supercritical carbon dioxide is carbon dioxide in 15. A composition according to claim 14 wherein the a state exceeding both the critical pressure of about 7.38 readily water-Soluble cyclodextrin derivative is a compound MPa and the critical temperature of about 304.1 K. represented by Formula: 21. A method according to any one of claims 17 to 19 wherein the Subcritical carbon dioxide is carbon dioxide in a State exceeding either the critical pressure of about 7.38 MPa or the critical temperature of about 304.1 K. 22. A method according to claim 17 comprising the Steps of (1) placing a physiologically active Substance in a pres Sure-resistant container, (2) keeping the temperature of Said pressure-resistant container at the critical point or below, (3) filling carbon dioxide which may be optionally mixed with other Solvents into Said pressure-resistant container, (4) Stopping filling the carbon dioxide under the condition where the pressure in Said preSSure-resistant container does not exceed the critical point of carbon dioxide, (5) depres Surizing after completing the carbon dioxide treatment and wherein q is an integer of 6 to 12, R, R and Rare same then collecting the resultant physiologically active porous or different in individual repeating units and each is a Substance. dihydroxyalkyl group, Sugar residue, hydroxyalkyl group or 23. A method according to claim 18 or 19 wherein said Sulfoalkyl group. other Solvents are water, aromatic hydrocarbons, ethers, 16. A composition according to claim 15 wherein the organochlorine organic Solvents, alkylnitriles, nitroalkanes, dihydroxyalkyl group is a dihydroxy-C alkyl group, the amides, ketones, fatty acids, alcohols, Sulfoxides or mixture Sugar residue is erythrosyl, threosyl, arabinosyl, ribosyl, Solvents thereof. glucosyl, galactosyl, glycero-gulco-heptosyl, maltosyl, lac 24. A method according to claim 18 or 19 wherein said tosyl, maltotriosyl or dimaltosyl, the hydroxyalkyl group is other Solvents are water, aromatic hydrocarbons Selected a hydroxy-C alkyl group and the Sulfoalkyl group is a from benzene, toluene, ethyl acetate, cyclohexane and Sulfo-C, alkyl group. Xylene; ethers selected from dimethyl ether, diethyl ether, 17. A method for producing a physiologically active dioxane, diethoxyethane, tetrahydrofuran and 1,2- porous Substance according to claim 1 or 2 comprising dimethoxyethane, organochlorine organic Solvents Selected treating a physiologically active Solid Substance with carbon from dichloromethane, chloroform, carbon tetrachloride and dioxide in a Supercritical or Subcritical State or liquid carbon 1,2-dichloroethane; alkylnitriles Selected from acetonitrile dioxide. and propionitrile, nitroalkanes Selected from nitromethane 18. A method according to claim 17 wherein the Super and nitroethane; amides selected from N,N-dimethylforma critical or Subcritical carbon dioxide or the liquid carbon mide and N,N-dimethylacetoamide; acetone; fatty acids dioxide is mixed with other Solvents. Selected from acetic acid, acetic anhydride and oleic acid; 19. A method according to claim 17 comprising the Steps alcohols Selected from methanol, ethanol and propanol; of (1) placing a physiologically active Solid Substance in a dimethylsulfoxides; or mixture solvents thereof. pressure-resistant container, (2) keeping the temperature of 25. A method according to claim 18 or 19 wherein said Said pressure-resistant container at a level allowing carbon other Solvent is ethanol or acetone. dioxide to be in a Supercritical or Subcritical State, (3) filling 26. A method according to claim 18 or 19 wherein the carbon dioxide which may be optionally mixed with other amount of said other solvents is about 1 to 50% by volume Solvents into said pressure-resistant container, (4) stopping based on the carbon dioxide which is in a Supercritical, filling the carbon dioxide at the time point when the pressure Subcritical or liquid State. in Said pressure-resistant container reaches a level allowing carbon dioxide to be in a Supercritical or Subcritical state, (5) k k k k k