US 20140328917A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0328917 A1 Tada et al. (43) Pub. Date: Nov. 6, 2014

(54) ORGANIC COMPOUND NANO-POWDER, BO2C23/8 (2006.01) METHOD FOR PRODUCING THE SAME AND A63/67 (2006.01) SUSPENSION A63L/92 (2006.01) A613 L/405 (2006.01) (71) Applicant: Activus Pharma Co., Ltd., A613 L/4I (2006.01) Funabashi-shi, Chiba (JP) A 6LX3/573 (2006.01) A613 L/7048 (2006.01) (72) Inventors: Takahiro Tada, Funabashi-shi (JP); A63L/96 (2006.01) Kazuhiro Kagami, Funabashi-shi (JP): (52) U.S. Cl. Shiro Yokota, Funabashi-shi (JP) CPC ...... A61 K9/1682 (2013.01); A61 K3I/7048 (2013.01); A61 K3I/445 (2013.01); A61 K (21) Appl. No.: 14/001,645 3 1/57 (2013.01); A61 K3I/I2 (2013.01); A61 K 31/196 (2013.01); A61K 31/167 (2013.01); (22) PCT Filed: May 11, 2013 A6 IK3I/192 (2013.01); A61 K3I/405 (86). PCT No.: PCT/UP2013/003023 (2013.01); A61 K3I/41 (2013.01); A61 K 31/573 (2013.01); B02C 23/18 (2013.01) S371 (c)(1), USPC 424/489: 514/27: 514/317; 514/179; 514/29: (2), (4) Date: Aug. 26, 2013 514/679:514/567; 514/629; 514/570; 514/31; 514/.420, 514/382: 514/180; 24.1/15 (30) Foreign Application Priority Data (57) ABSTRACT May 11, 2012 (JP) ...... 2012-108.972 An organic compound nano-powder comprising a granular organic compound with an average particle diameter of 500 Publication Classification nm or less and a 90%-diameter of less than 1500 nm and a carbohydrate compound comprising at least any one of a (51) Int. Cl. Sugar and a Sugar alcohol and with amount of 0.3 times or A6 IK 9/16 (2006.01) more by mass relative to amount of the organic compound, a A6 IK3I/445 (2006.01) method for producing the same, and a Suspension having the A 6LX3/57 (2006.01) organic compound dispersed in a liquid dispersion medium in A6 IK3I/2 (2006.01) which the organic compound is insoluble or poorly soluble. US 2014/0328917 A1 Nov. 6, 2014

ORGANIC COMPOUND NANO-POWDER, 0006. In accordance with recent development of a nano METHOD FOR PRODUCING THE SAME AND technology, the preparation of the nano-sized organic com SUSPENSION pound to satisfy the requirements as mentioned above has attracted high attention. For example, a particulate formula CROSS REFERENCE TO RELATED tion which contains a steroid or a steroid derivative with APPLICATION median of the particle distribution in the range of 0.005 to 5 um and with the 90%-diameter of 10 um or less has been 0001. The present patent application claims priority from known (for example, see Patent Document 1). However, the Japanese Patent Application No. 2012-108972 filed in Japan coarse particles present with a small percentage in the par on May 11, 2012, and the disclosures of thereof are incorpo ticulate formulation due to so wideness of the particle diam rated herein by reference. In addition, the disclosures of the eter distribution causes a problem of instability of a suspen patents, patent applications and documents cited in the sion thereof, i.e., a problem of low dispersivity of the present application are incorporated herein by reference. particulate formulation. 0007 For example, as one of methods for finely-milling TECHNICAL FIELD the organic compound to the level of nano-powder with a 0002 The present invention relates to an organic com narrow particle diameter distribution, a method for milling pound nano-powder, a method for producing the same, and a the organic compound by a bead mill using beads made of Suspension having an organic compound dispersed therein. ceramic, glass, or the like is well known (for example, see Patent Document 2). Nano-powder with a narrow particle BACKGROUND ART diameter distribution can be obtained by applying such a 0003. In order to fulfill an inherent function of an active mechanical impact or a grinding force to the particles of the ingredient contained in a formulation or a health food without organic compound. In addition, a wet milling method for excessively taking it, it is necessary to enhance the bioavail milling the organic compound in organic liquid using salt ability for the formulation or the health food. Taking the particles as a milling medium is also known (for example, see formulation as an example, while an oral formulation has the Patent Documents 3 and 4). The method using salt particles is advantages of being convenient and causing little distress more advantageous than the method using the beads in view compared to an injectable formulation, it has the disadvan of less contamination with impurities coming from a milling tage of providing low bioavailability. The oral formulation medium. While the impurities coming from the beads are enters into the intestine via the stomach and the duodenum, is difficult to remove, the impurities coming from the Salt par absorbed into blood mainly through the intestinal tract and ticles are easy to remove by a water-washing process (also then is delivered to the liver via the portal vein. A part of the called salt-removing process) due to high water Solubility of oral formulation is decomposed by undergoing the action of a salt. gastric acid or the like or being metabolized in the liver during passing through Such a long path, whereby converted into a PRIOR ART PUBLICATIONS totally different substance. One of the major reasons for the Patent Documents low bioavailability is that the oral formulation is difficult to be absorbed from digestive organs like the intestine. In order to 0008 Patent Document 1: Japanese Patent Laid-Open enhance the bioavailability for the formulation, it is necessary Publication No. 2006-089386 to get the size down of the organic compound with medicinal 0009 Patent Document 2: Japanese Patent Laid-Open ingredients to a level required to facilitate the absorption of Publication No. HO4-29.5420 the compound from the digestive organs into the blood. 0010 Patent Document 3: International Publication 0004. In the case of the injectable formulation, a typical WO/2008/126,797 example of parenteral formulations, effective functioning of a 0011 Patent Document 4: International Publication medicinal ingredient in the formulation requires the reaching WOf2O1 O/O32434 of the medicinal ingredient through blood vessels in the body to a target site. The inner diameter of a capillary blood vessel, SUMMARY OF INVENTION which is the narrowest among the blood vessels, is about 5 um. Accordingly, in order to make pass the organic compound Problem to be Solved by the Inventions with the medicinal ingredient through the capillary blood 0012. The wet milling method using the salt particles as vessel without causing occlusion, the particle diameter of this milling medium is advantageous in view of avoiding contami organic compound needs to be 5 um or less. Further, for the nation of irremovable impurities, but needs furthermore same reason as the oral formulation, it is necessary for a improvements. One of the improvements is to perform the health food to get the size down of the organic compound with production process as simple as possible with no water-wash active ingredients to a level required to facilitate the absorp ing to remove the salt that contaminates an organic compound tion of the compound from the digestive organs into the after milling. When the salt particles are used as milling blood. medium, usually the salt with the amount of preferably 10 to 0005. In the case of a solid skin-lightening ingredient and 30 times by mass relative to the organic compound to be a moisturizing ingredient contained in a cosmetic, less milled is served into a wet milling apparatus. Unless thus agglomeration and the Smaller particle size are required in large amount of salt is not removed after milling, the organic order to make them easily attached and thinly spread on a skin compound after milling cannot be safely used in or on a living surface while if it is in the form of a milky lotion, not to cause body. Another of improvements is to prevent the wet milling phase separation in a container in which this cosmetic is apparatus from rusting out. Contamination due to rust must be contained so that a uniform dispersion state may be Sustain definitely avoided when the organic compound is used in a able. living body. Use of an anti-rust agent as a general anti-rusting US 2014/0328917 A1 Nov. 6, 2014

method is also well known, but contact thereof with the ericin B, sodium, indomethacin, , pran organic compound is not also allowed. Alternatively, a wet lukast hydrate, dexamethasone and fenofibrate. milling apparatus which is constructed by a material difficult 0024. One embodiment according to the present invention to rust (for example, a personally-ordered apparatus which is is a Suspension having at least an organic compound, which is coated with a ceramic on its inner Surface) may be opted, but contained in the organic compound nano-powder according the apparatus is disadvantageous in view of high cost due to to any one of the above-mentioned, dispersed in a liquid use of a special apparatus. dispersion medium in which the organic compound is 0013 The present invention was made to satisfy the insoluble or poorly soluble. requirements as mentioned above and has an object to provide 0025. One embodiment according to the present invention an organic compound nano-powder conveniently, with low is a method for producing an organic compound nano-powder cost and with less contamination of impurities to be removed. comprising: 0026 mixing a granular organic compound, a granular Means for Solving the Problem carbohydrate compound comprising at least any one of a 0014. The inventors of the present invention carried out an Sugar and a Sugar alcohol and with amount of 0.3 times or extensive investigation to solve the problems mentioned more by mass relative to amount of the organic compound, above, and as a result, found that, when an organic compound and liquid in which the organic compound is insoluble or having a granular form was milled by adding at least a granu poorly soluble; and lar carbohydrate compound (or Sugar compound), the organic 0027 wet-milling the organic compound after the mixing compound could be milled efficiently, and in addition, a salt so that an average particle diameter thereof becomes 500 nm removing process after milling became unnecessary, as well or less and a 90%-diameter thereof becomes less than 1500 as rusting of a wet milling apparatus could be avoidable, and based on these findings, the present invention could be 0028. Other embodiment according to the present inven accomplished. Alternatively, there may be some cases that tion is the method for producing an organic compound nano salt is optionally added to the granular carbohydrate com powder, wherein the carbohydrate compound is in an amount pound, in this case, because the amount of the salt was incom of 0.5 to 30 times by mass relative to amount of the organic parably smaller than the amount in case of being used as a compound. milling medium, it was found that not only the salt removing 0029. Further other embodiment according to the present process was unnecessary but also the risk of the rust of the wet invention is the method for producing an organic compound milling apparatus could be reduced. Specific content of the nano-powder, wherein the mixing is carried out with adding a present invention is as following. physiologically acceptable polyol as liquid in which the 0015. One embodiment according to the present invention organic compound is insoluble or poorly soluble. is an organic compound nano-powder comprising: 0030. Further other embodiment according to the present 0016 a granular organic compound with an average par invention is the method for producing an organic compound ticle diameter of 500 nm or less and a 90%-diameter of less nano-powder, wherein the wet-milling of the organic com than 1500 nmi; and 0017 a carbohydrate compound comprising at least any pound is carried out while kneading the mixture obtained one of a Sugar and a Sugar alcohol and with amount of 0.3 after the mixing in a kneader. times or more by mass relative to amount of the organic 0031. Further other embodiment according to the present compound. invention is the method for producing an organic compound 0018. Other embodiment according to the present inven nano-powder, wherein a process of drying is carried out after tion is the organic compound nano-powder, wherein the car the milling bohydrate compound is in an amount of 0.5 to 30 times by 0032. Further other embodiment according to the present mass relative to amount of the organic compound. invention is the method for producing an organic compound 0019. Further other embodiment according to the present nano-powder, wherein the carbohydrate compound are one or invention is the organic compound nano-powderfurther com more kinds selected from the group consisting of mannitol, prising a physiologically acceptable polyol. maltitol. Xylitol, erythritol, glucose, fructose, inositol, lac 0020. Further other embodiment according to the present tose, trehalose, cellobiose and dextrin. invention is the organic compound nano-powder, wherein the 0033. Further other embodiment according to the present carbohydrate compound are one or more kinds selected from invention is the method for producing an organic compound the group consisting of mannitol, maltitol. Xylitol, erythritol, nano-powder, wherein a physiologically acceptable salt is glucose, fructose, inositol, lactose, trehalose, cellobiose and further mixed in the process of the mixing. dextrin. 0034) Further other embodiment according to the present 0021. Further other embodiment according to the present invention is the method for producing an organic compound invention is the organic compound nano-powderfurther com nano-powder, wherein the physiologically acceptable salt is prising a physiologically acceptable salt. sodium chloride. 0022. Further other embodiment according to the present 0035) Still further other embodiment according to the invention is the organic compound nano-powder, wherein the present invention is the method for producing an organic physiologically acceptable salt is sodium chloride. compound nano-powder, wherein the organic compound are 0023 Still further other embodiment according to the one or more kinds selected from the group consisting of present invention is the organic compound nano-powder, clarithromycin, fexofenadine hydrochloride, fluo wherein the organic compound is one or more kinds selected rometholone, curcuminoid, , rutin, , from the group consisting of clarithromycin, fexofenadine acetaminophen, , amphotericin B, diclofenac hydrochloride, fluorometholone, curcuminoid, curcumin, Sodium, indomethacin, felbinac, hydrate, dexam rutin, mefenamic acid, acetaminophen, ibuprofen, amphot ethasone and fenofibrate. US 2014/0328917 A1 Nov. 6, 2014

Advantageous Effect of the Invention (A) Organic compound 0.036 According to the present invention, an organic com 0045. The organic compound includes those used as active pound nano-powder can be provided conveniently, with low ingredients in a medicine, a health food, a nutritional Supple cost and with less contamination of impurities to be removed. ment, a cosmetic and the like, but is not limited to them. Preferable examples as the use for the medicine include an DESCRIPTION OF EMBODIMENTS anti-obesity drug, a corticosteroid, an elastase inhibitor, an analgesics, an antifungal, a drug for cancer, an antiemetic, a 0037 Next, the embodiments of the organic compound cardiovascular drug, an anti-inflammatory drug, an anti-para nano-powder, the method for producing the same, and the sitic, an anti-arrhythmic, an antibiotic, an anticoagulant, an Suspension according to the present invention will be antidepressant, an anti-diabetic, an antiepileptic drug, an anti described. histamine, a hypotensive drug, an anti-muscarinic drug, an anti-mycobacteria drug, an antitumor drug, an immunosup 1. Organic Compound Nano-Powder pressant, an antithyroid, an antiviral, a sedative, a beta-adr 0038. The organic compound nano-powder according to energic , a blood product, a cardiac, a the embodiment comprises: contrast medium, an antitussive, a diagnostic agent, a diag 0.039 a granular organic compound (A) with an average nostic contrast medium, a diuretic, a dopaminergic drug, a particle diameter of 500 nm or less and a 90%-diameterofless hemostatic, an immunizing drug, a lipid regulator, a muscler than 1500 nmi; and elaxant agent, a parasympathomimetic drug, a parathyroid 0040 a carbohydrate compound (B) comprising at least calcitonin and its diphosphonate salt, a , a radio any one of a Sugar and a Sugar alcohol and with amount of 0.3 active drug, a sex hormone, an anti-allergic drug, a stimulant, times or more by mass relative to amount of the organic an appetite-suppressant, a , a thyroid compound. drug, a vasodilator, an anti-parkinson drug, a psychotropic 0041. The organic compound nano-powder may further agent, an agent affecting the central nervous system, an anti comprise a physiologically acceptable salt (C). pyretic, an anti-anxiety drug and a hypnotic. However, the 0.042 Alternatively, the organic compound nano-powder medicines are not limited to the above examples. may further comprise, in accordance with its use, one or more 0046 Specific examples of the organic compound used for additives (D) other than the salt. the medicines include 5-fluorourasil, 7-(3,5-dimethoxy-4- 0043. The term “average particle diameter' used in hydroxycinnamoylamino)-3-octyloxy-4-hydroxy-1-methyl present specification means a mathematical average diameter 2(1H)-quinoli none, acarbose, aciclovir, acetyl , (here, defined as the D value) in the particle diameter dis acetyl pheneturide, acetaminophen, adenine, atenolol, opium tribution as measured by a dynamic light scattering photon alkaloid, amidotrizoic acid, amphotericin B, amoxapine, correlation method. The term “50%-diameter' (defined as amobarbital, amurine, amoxicillin, aripiprazole, alprazolam, median diameter or the Dso value) means a certain particle allopurinol, amplicillin, , , isoproter diameter when amount of a larger side becomes equal to enol, ibuprofen, ipriflavone, imipramine, irbesartan, amount of a smaller side of the particle diameters divided into indomethacin, ubenimex, urapidil, ursodesoxycholic acid, two a powder from the certain particle diameter. The term estazolam, estradiol, etizolam, , ethotoin, enoxa "90%-diameter' (Do value) means the particle diameter of cin, eprosartan, emiglitate, erythromycin, praZosin hydro the particle at the position of 90% when counted from the chloride, propafenone hydrochloride, entacapone, oxazolam, smallest size Zero (minimum) to 100% (maximum) of the , oxycodone, Oxytetracycline, oxypertine, oxen particle diameter in the particle diameter distribution as mea dolone, omeprazole, olanzapine, ory Zanol, caffeine, capto sured by the above-mentioned measurement method. The pril, cabergoline, carbamazepine, chlorphenesin carbamate, term “10%-diameter' (Do value) means the particle diameter carpipramine maleate, carbochromen, carumonam Sodium, of the particle at the position of 10% when counted from the candesartan cilexetil, quazepam, guanfacine, sildenafil cit smallest size Zero (minimum) to 100% (maximum) of the rate, clarithromycin, griseofulvin, cloxazolam, clozapine, particle diameter in the particle diameter distribution as mea clotiazepam, clonazepam, clobazam, chloramphenicol, chlo sured by the above-mentioned measurement method. The rdiazepoxide, chlorZoxaZone, chlortalidone, chlorphe average particle diameter of the organic compound is more niramine, chlorpromazine, chlorhexidine, , preferably in the range of 50 to 400 nm, further more prefer cocaine, codeine, colchicine, chlormadinone acetate, corti ably in the range of 100 to 350 nm. The Do value of the Sone acetate, saccharin, , Salazosulfapyridine, salb organic compound is more preferably less than 700 nm, fur utamol, diastase, diazepam, digitoxin, ciclacillin, diclofenac ther more preferably less than 500 nm. Sodium, digoxin, disopyramide, citicoline, dihydrocholes 0044) “Organic compound nano-powder in the present terol, dipyridamole, dihydrocodeine, difenidol, diphenhy specification may be any powder So far as the powder contains dramine, cimetidine, dimenhydrinate, ciloStaZol, simvastatin, at least an organic compound (A) having a granular form and Scopolamine, stanozolol, sparfloxacin spiperone, spironolac a carbohydrate compound (B); and thus, one or more addi tone, , Sulpiride, Sulbenicillin Sodium, cephalexin, tives other than these compounds may be contained therein. cefixime, cefoZopran, cefotiam, cefsulodin Sodium, The particle diameter distribution by the dynamic light scat cefinenoXime, seratrodast, Serrapeptase, , Zotepine, tering photon correlation method is measured for the organic Zonisamide, Zopiclone, dacarbazine, tacrolimus hydrate, compound having a granular form. However, if the carbohy tasosartan, danazol, dantrolene Sodium, tiaprofen, timida drate compound is physically attached or chemically bonded Zole, timiperone, , dexamethasone, dex to the Surface of the particles of the organic compound, the tromethorphan, delapril, terguride, telmisartan, ipecac, particle diameter distribution is measured for the granular tofisopam, trandolapril, triazolam, , triamcino organic compound having this carbohydrate compound lone acetonide, triamterene, tolbutamide, trepibutone, trogli attached or bonded thereto. taZone, droperidol, , nalidixic acid, nicardipine, US 2014/0328917 A1 Nov. 6, 2014

nicergoline, nitrazepam, nifedipine, nimetazepam, nimo kinetin, casein, caffeic acid, caffeic acid salt, glabridin, gly dipine, nemonapride, noscapine, paclitaxel, papaverine, Val cyrrhizic acid, glutathione, glutathione ester, glutathione salt, Sartan, haloperidol, pioglitaZone, bicalutamide, bisben kojic acid, retinol acetate, cysteine, tannic acid, tranexamic tiamine, hydralazine, hydroxy Zine pamoate, pivmecillinam, acid, transferrin, tretinoin, hydroquinone, hydroquinone salt, biperiden, pimozide, pirenoXine, , pindolol, famo phytic acid, fibrin, fibroin, fibronectin, ferulic acid, ferulic tidine, falecalcitriol, fexofenadine hydrochloride, phenace acid salt, lycopene, retinyl acetate, retinyl palmitate, retinol, mide, phenyloin, phenylephrine, phenobarbital Sodium, retinoic acid and retinoic acid tocopheryl. However, the fenofibrate, felbinac, phenprobamate, forasartan, bucolome, organic compound is not limited to these compounds. , clemastine fumarate, fumarate, pra noprofen, pravastatin, pranlukast hydrate, primidone, flu (B) Carbohydrate Compound diazepam, flunitrazepam, maleate, blo 0050. The carbohydrate compound includes at least one nanserin, profenamine hibenzate, bromazepam, flutazolam, kind selected from the group consisting of Sugars (monosac fluocinolone acetonide, fluorometholone, fluconazole, fluto charide, disaccharide, polysaccharides including trisaccha prazepam, , fluiphenazine decanoate, flufenamic ride and higher than trisaccharide, and oligosaccharides) and acid aluminum, flumazenil, , prednisolone, Sugar alcohols. The carbohydrate compound is selected Such procainamide, furosemide, brotizolam, propi that it may not be overlapped with the foregoing organic onate, beclomethasone propionate, propranolol, propericiaz compounds. ine, promethazine, bromperidol, bromocriptine mesilate, 0051 Examples of the monosaccharide include glucose, beta-carotene, , Verapamil, benzthiazide, pen galactose, mannose, fructose, inositol, ribose and Xylose. tazocine, Voglibose, propyl gallate, polythiazid, mitomycin Examples of the disaccharide include lactose, Sucrose, cello C, mazindol, manidipine, maprotiline, maltol, lisuride male biose, trehalose and maltose. Examples of the polysaccharide ate, miglitol, miconazole, midazolam, minoxidil, milrinone, include pullulan, Sodium hyaluronate, raffinose, melezitose, mexazolam, meduitazine, meclizine, meclofenoxate, Sodium chondroitin Sulfate, cellulose, cluster dextrin, cyclo medazepam, methylephedrine, methyldopa, methocarbamol. dextrin, dextrin, dextran, Xanthan gum, chitin and chitosan. metoclopramide, methotrexate, mefenamic acid, , Examples of the oligosaccharide include fructo oligosaccha modafinil, , molsidomine, folic acid, ranitidine, ride, galacto oligosaccharide, mannan oligosaccharide, gen labetalol, rabeprazole, ramelteon, lanSoprazole, liothyronine tio oligosaccharide, Xylo oligosaccharide, cello oligosaccha Sodium, risperidone, lysozyme, lidocaine, rifampicin, leupro ride, isomalto oligosaccharide, nigero oligosaccharide, chito relin, reserpine, levallorphan, L-dopa, riluzole, losartan, oligosaccharide, fucoidan oligosaccharide, soy bean oli lofepramine hydrochloride, lorazepam and lormetazepam. gosaccharide and lactosucrose. Examples of the Sugar alco However, the organic compound is not limited to these com hol include palatinose, Sorbitol, lactitol, erythritol, pen pounds. Especially, clarithromycin, fexofenadine hydrochlo taerythritol, xylitol, maltitol, mannitol and dulcitol. In this ride and fluorometholone are preferably used in the above embodiment, Sugar alcohols, monosaccharide or disaccha organic compounds. ride may be preferably used as the carbohydrate compound, 0047. Examples of the organic compound used for health while mannitol, maltitol, erythritol. Xylitol, glucose, fructose, food or nutritional Supplement include astaxanthin, allin, lactose, trehalose or cellobiose may be used more preferably, alysine, anthocyanin, isoflavone, isorhamnetin, C.-lipoic and D-mannitol. Xylitol, glucose, fructose ortrehalose may be acid, oleuropein, ornithine, catechin, capsaicin, capsanthin, used further more preferably. capsorubin, beta-carotene, carnitine, carminic acid, canthax 0052. In the organic compound nano-powder, the carbo anthin, ginkgolide, glucan, chitosan, quinone, gymnemic hydrate compound may be contained in the form of particles acid, beta-cryptoxanthin, curcuminoids, curcumin, glu independent of particles of the organic compound or may be cosamin, creatine, chlorophyll, quercetin, Sesame lignan, in the form physically attached or chemically bonded to the Zeaxanthin, bixin, biotin, vitaminA and its derivative, vitamin Surface of particles of the organic compound. D2, vitamin D3, phytosterol, phosphatidylserine, beta-apo-4- 0053. The carbohydrate compound is contained in the carotenal, ethyl beta-apo-8-carotenoate, flavonoid, proantho organic compound nano-powder with the amount of 0.3 times cyanidin, pectin, polyphenol, monacolin K., ubiquinone, or more, preferably 0.3 to 100 times, more preferably 0.5 to lycopene, , lutein and rutin. However, the organic 30 times, or further more preferably 0.8 to 20 times by mass compound is not limited to these compounds. Especially, relative to the organic compound. For the purpose of no curcuminoid, curcumin and rutin are preferably used in the excess exclusion of the carbohydrate compounds after mill above organic compounds. ing the organic compound and the inhibition of excessively 0048 Examples of the cosmetic include an anti-aging high osmotic pressure of liquid including the carbohydrate agent, a UV-screening material, a tightening-up agent, an compounds at using the liquid due to inclusion of excess antioxidant, an anti-wrinkling material, a moistening agent, a amount of the carbohydrate compounds in the liquid, the blood circulation promoter, an antibacterial agent, a disinfect additive amount of the carbohydrate compounds is preferably ing agent, a drying agent, a cooling agent, a warming agent, 0.3 to 100 times, more preferably 0.5 to 30 times, further Vitamins, amino acids, a wound-heal acceleration agent, an preferably 0.8 to 20 times, still further preferably 1 to 8 times irritation relaxation agent, a painkiller, a cellular stimulant by mass relative to the organic compound. Above-mentioned and various enzymes. However, the cosmetic is not limited to carbohydrate compounds may be used singly or as a mixture these examples. of two or more of them. In addition, the carbohydrate com 0049. Examples of the organic compound used for these pounds may be used in the form of fine particles. cosmetics include 4-n-butyl resorcinol, N-acylated glu 0054 The carbohydrate compound can function as a mill tathione, ascorbic acid, ascorbic acid salt, ascorbic acid glu ing medium or as an auxiliary agent for milling during milling coside, magnesium ascorbyl phosphate, arbutin, isoferulic the organic compound. Here, the term “milling medium’ acid, isoferulic acid salt, elagic acid, ergo acid, ergo acid salt, means a medium which directly applies an impact or a grind US 2014/0328917 A1 Nov. 6, 2014 ing action to the organic compound. The term 'auxiliary 0059. The organic compound nano-powder tends to agent’ means a material which does not directly apply above agglomerate very easily because individual particles thereof actions to the organic compound but facilitates the milling of are in the level of nano-size. The organic compound nano the organic compound by working indirectly. Further, the powder may keep containing all or a part of anti-agglomera carbohydrate compound can work to reduce agglomeration tion agent added during or after milling in order to prevent the among particles of the organic compound. particles of the organic compound nano-powder from agglu tinating. Examples of the anti-agglomeration agent include (C) Physiologically Acceptable Salt ethanol, glycerin, propylene glycol, Sodium citrate, purified Soybean lecithin, phospholipid, D-Sorbitol, lactose, Xylitol, 0055. The salt that can be mixed with the organic com Gum arabic, Sucrose fatty acid ester, sodium dodecylsulfate, pound nano-powder of this embodiment is one that can be polyoxyethylene hydrogenated castor oil, polyoxyethylene used without notably causing a physiological problem. In fatty acid ester, polyoxyethylene glycol, polyoxyethylene other words, the salt is not particularly limited as far as it does sorbitan fatty acid ester, alkylsulfate salt, alkylbenzene not pose a significant problem even if it enters into a living Sulfonate, Sulfo Succinate salt, polyoxyethylene polyoxypro body or contacts to a skin. A physiologically acceptable salt pylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, preferably has sufficient hardness to finely mill the organic hydroxypropyl cellulose, methylcellulose, hydroxyethyl cel compound. In addition, the amount of the physiologically lulose, hydroxypropyl methyl cellulose, Sodium carmellose, acceptable salt mixed with the organic compounds and the Sodium carboxymethyl cellulose, carboxymethyl polymer, carbohydrate compounds means such amount of the salt that N-acyl-glutamate salt, acrylic acid copolymer, sodium myris the salt does not bring critical matters to a biological body toylmethyl taurine, polyoxyl Stearate, carboxylvinyl poly when it is consumed in the biological body. mer, Sodium dioctyl SulfoSuccinate, Xanthan gum, meth 0056. Examples of the preferable salt include sodium acrylic acid copolymer, casein sodium, L-valine, L-leucine, chloride, potassium chloride, ammonium chloride, sodium L-isoleucine, benzarconium chloride and benzethonium Sulfate, magnesium Sulfate, potassium Sulfate, calcium Sul chloride. The anti-agglomeration agents may be preferably fate, sodium malate, sodium citrate, disodium citrate, sodium glycerin, Sucrose fatty acid ester, sodium dodecylsulfate, dihydrogen citrate, potassium dihydrogen citrate, sodium polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cel dihydrogen phosphate, potassium dihydrogen phosphate, lulose, sodium carboxymethyl cellulose, sodium myristoyl disodium hydrogen phosphate and dipotassium hydrogen methyl taurine, polyoxyl Stearate, carboxylvinyl polymer, phosphate. More preferable examples of the salt include Sodium dioctyl sulfoSuccinate and Xanthan gum. Above anti Sodium chloride, potassium chloride, magnesium Sulfate, cal agglomeration agents may be used singly or as a mixture of cium Sulfate, Sodium citrate, Sodium dihydrogen phosphate, two or more of them. Meanwhile, above-mentioned other potassium dihydrogen phosphate, disodium hydrogen phos additives are selected such that they may not overlap with the phate and dipotassium hydrogen phosphate and most prefer organic compound, the carbohydrate compound and the salt. able salt is sodium chloride. 2. Suspension Dispersed Organic Compound Nano-Powder 0057 The salt may be adjusted in its particle diameter by milling and the like before it is mixed with the organic com 0060. The suspension according to the embodiment of the pound or the carbohydrate compound. In the case of prelimi present invention comprises the organic compound (A) in nary adjustment of the particle diameter, the average particle liquid dispersing medium in which the organic compound is diameter of the salt is preferably 0.01 to 300 um, more pref insoluble or poorly soluble. erably 0.1 to 100 um or further more preferably 0.5 to 50 um. 0061. The term “insoluble or poorly soluble' used in the Amount of the salt contained in the organic compound nano present specification means that solubility of the organic powder may be in the range of 0.02 to 4 times by mass, compound in the liquid dispersing medium is 10 mg/mL or preferably 0.05 to 2 times by mass, or more preferably 0.1 to less, or preferably 1 mg/mL or less, at the temperature of a 1.5 times by mass, relative to total amount of the organic normal operation, for example, at room temperature of compound and the carbohydrate compound. The salts may be around 25 degrees C. The liquid dispersing medium in which used singly or as a mixture of two or more of them. The salt the organic compound is insoluble or poorly soluble may can function as a milling medium or as an auxiliary agent for include water, organic solvent like ethanol; or polyol like milling during the milling of the organic compound. glycerin, propylene glycol, polyethylene glycol, ethylene glycol, diethylene glycol. However, the liquid dispersing (D) Other Additives mediums are not limited to above-exemplified some liquids and may be any kinds of mediums as long as the mediums are 0058. The organic compound nano-powder may contain in the form of liquid at room temperature of around 25 all or a part of Viscosity modifier added during the manufac degrees C. Thus, for example, when polyol is used as the turing thereof. A physiologically acceptable polyol may be liquid dispersing medium, the polyol may also operate as a preferably used as the viscosity modifier. The term “physi Viscosity modifier or an anti-agglomeration agent. For ologically acceptable' has the same meaning as the term example, when the organic compound is water-soluble, the “physiologically acceptable' of the physiologically accept liquid dispersing medium in which the organic compound is able salt mentioned above. Examples of the physiologically insoluble or poorly soluble means one other than water. Fur acceptable polyol include glycerin, propylene glycol, poly ther, when the organic compound is soluble in a certain ethylene glycol, dipropylene glycol, ethylene glycol, dieth organic solvent, the liquid dispersing medium means one ylene glycol, citric acid, DL-malic acid, tartaric acid, lactic other than the certain organic solvent. In other words, the acid, urea, maleic acid and malonic acid, and preferably citric liquid dispersing medium needs to be selected Such that the acid, propylene glycol and glycerin. These viscosity modifi organic compound may exist in the dispersed state without ers may be used singly or as a mixture of two or more of them. being completely dissolved therein. When the suspension is US 2014/0328917 A1 Nov. 6, 2014

used as it is as a medicine, a health food, or a cosmetic, the ably 0.3 to 100 times, more preferably 0.5 to 30 times, further dispersing medium including mainly water is preferably more preferably 0.8 to 20 times, or still further preferably 1 to used. 8 times by mass relative to the organic compound. 0062. The suspension according to the present embodi 0068. The carbohydrate compound has a function as the ment may contain various viscosity modifiers and anti-ag anti-agglomeration agent. But, if the carbohydrate compound glomeration agents mentioned in the section of other addi is added only to work this function, addition of the carbohy tives (D), and may further contain an emulsifying agent, a pH drate compound “in the granular form with the amount of modifier, a buffering agent, a preservative or the like. “0.3 times or more by mass relative to the organic compound Examples of the materials that may be contained in this sus is not necessary as its condition. The reason why the carbo pension include: phosphate salts such as Sodium dihydrogen hydrate compound is added “in the granular form' with the phosphate, disodium hydrogen phosphate, trisodium phos amount of "0.3 times or more by mass relative to the organic phate, Sodium pyrophosphate, Sodium tripolyphosphate, compound is as follows. It is necessary to work the function Sodium tetrapolyphosphate, Sodium hexametaphosphate, of a milling medium that provides an impact or a grinding acidic sodium hexametaphosphate and potassium dihydrogen action directly with the granular organic compound or the phosphate; hydrates of these salts; sodium edetate; and function of a milling auxiliary agent that indirectly relates to Sodium hydroxide. facilitate collision and grinding among the granular organic compound by themselves. 3. Method for Producing the Organic Compound 0069 Various kinds of sugars and sugar alcohols already Nano-Powder explained in the section of the organic compound nano-pow 0063. The method for producing an organic compound der, including a mixture of two or more of them may be used nano-powder according to the present embodiment com as the granular carbohydrate compound. Especially, Sugar prises: alcohols, monosaccharide or disaccharide may be preferably 0.064 (A) a process of mixing a granular organic com used as the carbohydrate compound, while mannitol, malti pound, a granular carbohydrate compound comprising at tol, erythritol. Xylitol, glucose, fructose, lactose, trehalose or cellobiose may be used more preferably, and D-mannitol, least any one of a Sugar and a Sugar alcohol and with amount Xylitol, glucose, fructose or trehalose may be used further of 0.3 times or more by mass relative to amount of the organic more preferably. Although particle diameters of the granular compound, and liquid in which the organic compound is carbohydrate compound may be selected in accordance with insoluble or poorly soluble; and milling conditions, the average particle diameter of the car 0065 (B) a process of wet-milling the organic compound bohydrate compound is preferably in the range of 0.5 to 1000 until an average particle diameter thereof becomes 500 nm or um, more preferably 1 to 700 um or further more preferably 5 less and a 90%-diameter thereof becomes less than 1500 nm. to 200 um, in order to effectively make function as the milling after the process of mixing. medium or as the milling auxiliary agent. 0066. The method for producing an organic compound 0070. In the process of mixing, a physiologically accept nano-powder may further comprise (C) a process of drying able salt may be additionally mixed. In this case, for example, the product after (B) the process of milling. In the following, amount of the physiologically acceptable salt to be mixed is “a process of mixing, “a process of milling' and “a process preferably 0.02 to 4 times by mass relative to total amount of of drying will be explained. the organic compound and the carbohydrate compound. As long as above-mentioned amount of the Salt is mixed with the (A) Process of Mixing organic compound and the carbohydrate compound, it is not 0067. The method for producing the organic compound necessary to remove the salt and it is also possible to reduce nano-powder includes the process of mixing at least a granu the rusting of a milling apparatus. Various salts already lar organic compound, a granular carbohydrate compound explained in the section of the organic compound nano-pow and liquid in which the organic compound is not soluble or der may be used as the salt. Especially, Sodium chloride is poorly soluble. The process of mixing may be done by adding preferably used. Although various particle diameters of one or more additives other than above materials (such as an granular salts may be selected, for example, from the range of anti-agglomeration agent, a viscosity modifier, a pH-modi preferably 0.01 to 300 um, more preferably 0.1 to 100 um or fier). The process of mixing has a feature that the granular further more preferably 0.5 to 50 lum. carbohydrate compound is added to the granular organic 0071. The liquid in which the organic compound is compound with the amount of 0.3 times or more by mass insoluble or poorly soluble means that solubility of the relative to the organic compound. When the milling is per organic compound in the liquid is 10 mg/mL or less, or formed by adding the carbohydrate compound with the preferably 1 mg/mL or less, at the temperature of a normal amount of 0.3 times or more by mass relative to the organic operation, for example, at room temperature of around 25 compound, the organic compound may be milled more finely. degrees C. The liquid dispersing medium in which the organic The organic compound may be milled finely even if the car compound is insoluble or poorly soluble may include water; bohydrate compound is added more excessively than 0.3 organic solvent like ethanol; or polyol like glycerin, propy times by mass relative to the organic compound. However, in lene glycol, polyethylene glycol, ethylene glycol, diethylene this case, it is needed to decrease the amount of the organic glycol. However, the liquid is not limited to above-exempli compound to enter in a milling apparatus, thus the amount of fied liquid and may be any kinds of liquid as long as it is in the the organic compound produced per one process of the mill form of liquid at room temperature of around 25 degrees C. ing decreases. For the purpose of producing organic com When polyol is used as the liquid, the polyol may also operate pound fine particles more than a certain amount and milling as a viscosity modifier or an anti-agglomeration agent. For the organic compound more finely, the amount of the carbo example, when the organic compound is water-soluble, the hydrate compound to enter in the milling apparatus is prefer liquid in which the organic compound is insoluble or poorly US 2014/0328917 A1 Nov. 6, 2014

soluble means one other than water. Further, when the organic apparatus and the like. Time for milling is, for example, about compound is soluble in a certain organic solvent, the liquid 1 to 50 hours, preferably 2 to 20 hours, or more preferably 3 means one other than the certain organic solvent. In other to 10 hours. words, the liquid is selected Such that the organic compound may exist in the state without being completely dissolved (C) A Process of Drying therein in the process of mixing and the process of milling 0075 When a process of drying is carried out after the after the mixing. foregoing process of milling, the organic compound nano 0072 The process of mixing may be performed before the powder may be obtained in the form of not a dispersion milling or simultaneously with the milling in a milling appa solution but a solid. Method for drying the milled product is ratus used in the process of milling that will be explained not particularly limited. Thus, any convenient methods for later, or may be performed in a mixing vessel prepared as the drying the organic compound may be used. Examples of the apparatus different from the milling apparatus. In the latter drying method include a vacuum drying method, a freeze case, the mixing may be performed by using an agitating drying method, a spray drying method and a freeze spray machine wherein a mixing blade is rotated, a magnetic stirrer drying method. Drying temperature, drying time and the like wherein a stirring chip is rotated by using a magnetic force in are not particularly limited. The drying may be carried out a vessel, a vibration mill wherein a vessel is moved up and preferably at lower temperature to maintain chemical stabil down, a bath wherein an ultrasonic wave is oscillated and the ity of individual particles that constitute the organic com like. pound nano-powder and to prevent the particles from agglu tinating secondarily. The Vacuum drying method, the freeze drying method, the spray drying method and the freeze spray (B) A Process of Milling drying method are more preferable as the drying method. 0073. In the method for producing the organic compound nano-powder according to the present embodiment, the mill (D) Other Process ing apparatus usable for wet milling of the organic compound 0076. The product obtained after the process of milling is not particularly limited as far as the apparatus is capable of (the product is usually obtained in the form of “dough’) may milling the organic compound finely by mechanical means. be taken out and then sent to the process of drying as it is, but Examples of the milling apparatus include any convenient it may also be subjected to a process of dispersion before the milling apparatuses such as a kneader, a twin roll mill, a triple process of drying. For example, the process of drying may be roll mill, a fret mill, a Hoover Muller mill, a disk blade preferably performed after agglomerated particles in the kneader and a biaxial extruder. The significant feature of the product obtained after the process of milling are dispersed process of milling is no use of milling media like balls and into water (or an organic solvent) by using a dispersing beads. In a prior milling method in which the organic com machine like a magnetic stirrer, an ultrasonic disperser or a pound to be milled is entered with balls or beads into the high pressure homogenizer. milling apparatus, the organic compound is contaminated by abrasion particles coming from the balls or beads, whereby 4. Formulation removal of the contaminants is impossible or requires tremen 0077. The organic compound nano-powder obtained by dous work and cost even if removal thereof may be theoreti the method according to the present embodiment has excel cally possible. To eliminate such a demerit in the prior meth lent formulation properties so that the powder may be applied ods, in the process of milling, a milling apparatus giving a to various formulations. For example, when the powder is force only to knead the compound to be milled is used so that applied to an inhalant agent, the product obtained after the the organic compound may be finely milled by utilizing an process of milling may be mixed with water to prepare a impact or agrinding action applied among the particles of the Suspension. Then, the porous particles having the particle organic compound themselves or between the particles of the diameter of about 1 to 30 um may be prepared by freeze spray organic compound and the carbohydrate compound. With the drying of the Suspension. To improve dispersing quality of the basis of Such a technical concept, among the milling appara particles, Small amount of surfactant may be added to above tuses mentioned above, a disk blade kneader which can gen mentioned water. Alternatively, for the same reason, Small erate a strong kneading force by a planetary motion of a blade amount of volatile additive like ethanol may be added to the is preferably used. In this case, the process of milling is water. When the volatile additive is added, the additive can be performed by the milling the organic compound while knead removed during drying. Thus, an irritation may be lowered as ing in the kneader the mixture after the process of mixing. compared with the case of adding a surfactant. 0074. In the process of milling the organic compound, the 0078. When the organic compound nano-powder is milling may be done, after the organic compound, the carbo applied to an injectable formulation, an ophthalmic formula hydrate compound and a small amount of the liquid are all tion, an ointment, a transdermal absorbing formulation and entered into the milling apparatus, or be done with adding the the like, a water-dispersion product may be prepared by add carbohydrate compound and/or the liquid little by little. Tem ing an anti-agglomeration agent to the product obtained after perature at the milling may be determined arbitrarily in con the process of milling. For example, convenient Surfactants sidering the organic compound to be milled, the milling appa may be used as the anti-agglomeration agents. Specifically, ratus and the like. The temperature is not particularly limited various anti-agglomeration agents mentioned in the section as far as it can inhibit melting or decomposition of the organic of the organic compound nano-powder may be used. A water compound, is preferably -50 to 50 degrees C., more prefer dispersion product using a polymer like an acrylic acid ably -20 to 30 degrees C., or at most preferably -10 to 25 copolymer and a methacrylic acid copolymer, which is also degrees C. Time for milling may be determined arbitrarily in the anti-agglomeration agent may be used as a DDS formu considering the organic compound to be milled, the milling lation. The water-dispersion product may be prepared by US 2014/0328917 A1 Nov. 6, 2014 using a usually used machine. Examples of the machine weighed into a 50-mL glass vial. After that, 10 mL of purified include a homogenizer, a homomixer, an ultrasonic disperser water was put into the glass vial, and then a mixture of the and a high-pressure homogenizer. kneaded product and water was served to the dispersion treat 007.9 The water-dispersion product may be made to pow ment using a bath-type ultrasonic disperser (type of US 100 der by a vacuum drying, a spray drying, a freeze drying, a freeze spray drying or the like. The powder prepared by such III, manufactured by AS ONE Corp.) for 1 to 2 minutes. The a method has an excellent re-dispersing quality into water and particle diameter distribution of the kneaded product mea thus is excellent for the applications to an injectable formu Sured by the foregoing particle diameter distribution mea lation, an ophthalmic formulation and an oral formulation to Surement instrument after the dispersion treatment was as be prepared before use. follows: the average particle diameter (D)=202 nm, the 0080. Alternatively, the organic compound nano-powder value of Do-78 nm, the value of Dso 162 nm, and the value may be used for an ointment, a capsule formulation, a trans of Do-338 nm dermal absorption formulation and the like by dispersing it into an oily Substance. The oily Substance is not particularly (2) A Process of Dispersion limited as far as it is usable in a usual formulation. Examples I0083 54 g of purified water was added to above-men of the oily Substance include liquid paraffin, Vaseline, propy tioned dough (6 g). Then, a mixture of the dough and water lene glycol, glycerin, polyethylene glycol and a vegetable oil. was agitated by using a magnetic stirrer and then was served The oily Substances may be used singly or as a mixture of two to the dispersion treatment using a probe-type ultrasonic dis or more of them. A dispersion product in the oily Substance perser (probe-type 406 HWS with Amp. of 30 for 2 minutes, may be prepared by using a convenient machine. Examples of S4000 type, Astrason). the machine include a homogenizer, a homomixer, an ultra Sonic disperser, a high-pressure homogenizer, a twin roll mill, (3) A Process of Drying a triple roll mill, a disk blade kneader disperser and a biaxial I0084. Next, the dispersion solution obtained in the fore extruder. going process of dispersion was served into a spray dryer EXAMPLES (type of B-290, manufactured by Buchi Labortechnik AG, with flow of 45, inlet temperature of 150 degrees C., aspirator 0081. Next, Examples of the present invention will be of 100%, and feed pump of 35%). As a result, 4.35 g of dry explained. However, the present invention is not limited to the powder was obtained. A part (10 mg) of the obtained dry following Examples. powder was mixed with 10 mL of purified water. Then, a Experiment 1 mixture of the dry powder and water was served to the dis persion treatment using the foregoing bath-type ultrasonic Preparation of an Organic Compound Nano-Powder disperser for 1 to 2 minutes. The particle diameter distribution of turmeric nano-powder measured by the foregoing particle Example 1 diameter distribution measurement instrument after the dis persion treatment was as follows: the average particle diam Preparation of Powder Containing 10% by Weight of eter (D)=223 nm, the value of Do-99 nm, the value of Turmeric Do 185 nm, and the value of Do-336 nm. (1) Processes of Mixing and Milling Example 2 0082) 10 g of turmeric powder (>90% purity of curcumi noid, manufactured by Bio Actives Japan Corp.), 78 g of Preparation of Powder Containing 20% by Weight of D-(-)-mannitol (particle diameter distribution in the range of Turmeric 10 to 300 um, manufactured by Wako Pure Chemical Indus tries, Ltd.), 10 g of a Sucrose fatty acid ester (trade name of (1) Processes of Mixing and Milling DK Ester SS, manufactured by Dai-Ichi Kogyo Seiyaku Co., I0085 20g of the turmeric powder used in Example 1,65g Ltd.), 1.7g of sodium carboxymethylcellulose (trade name of of the D-(-)-mannitol used in Example 1, 10 g of the sucrose Cellogen F-3H, manufactured by Dai-Ichi Kogyo Seiyaku fatty acid ester used in Example 1, 1.6 g of the Sodium car Co., Ltd.) and 9 g of purified water were introduced into a boxymethyl cellulose used in Example 1 and 9 g of purified 500-mL trimix kneader (manufactured by Inoue MFG, Inc.) water were introduced into the trimix kneader used in and then were mixed and kneaded with keeping the load Example 1 and then were mixed and kneaded under the same current of 0.95 to 1.2 A for about 3 hours. The particle diam conditions as Example 1. A part (10 mg) of the dough was eter distribution of the turmeric powder measured before the weighed into a 50-mL glass vial. After that, 20 mL of purified process of mixing by the particle diameter distribution mea water was put into the glass vial, and then a mixture of the dough and water was served to same dispersion treatment as Surement instrument (instrument name of Delsa Nano, manu Example 1. The particle diameter distribution of turmeric factured by Beckman Coulter Inc.) was as follows: the aver nano-powder measured by the particle diameter distribution age particle diameter (D)=12820 nm, the value of measurement instrument used in Example 1 was as follows: Do-3793 nm, the value of Dso-10530 nm, and the value of the average particle diameter (D)-379 nm, the value of Doo 25520 nm. A part (10 mg) of the kneaded product (re Do 155 nm, the value of Dso 298 nm, and the value of ferred as "dough') taken out after mixing and kneading was Doo-603 nm. US 2014/0328917 A1 Nov. 6, 2014

(2) A Process of Dispersion persion treatment was as follows: the average particle diam I0086 270 mg of purified water was added to 30g of the eter (D)=96 nm, the value of Do 37 nm, the value of dough. Then, a mixture of the dough and water was served to Dso-78 nm, and the value of Doo-162 nm. the dispersion treatment by the same conditions as Example 1. (2) A Process of Water-Washing I0089 300 mg of the dough was weighed into a 50-mL (3) A Process of Drying falcon tube and then added 10 mL of purified water. After 0087 Next, the dispersion solution obtained in the fore dispersed by a Vortex, centrifugal separation was carried out going process of dispersion was served into a freeze dryer by using a table-top centrifugal separator (number of rotation: (type of FDU-2100, EYELA). As a result, 27.5 g of dry 6000 rpm, for 10 minutes). Thereafter, the supernatant solu powder was obtained. A part (10 mg) of the obtained dry tion was discarded. Then, the centrifugal separation was car powder was mixed with 20 mL of purified water. Then, a ried out again after 10 mL of purified water was added to the mixture of the dry powder and water was served to the dis residue. Such a set of operation was repeated until the electric persion treatment using the bath-type ultrasonic disperser conductivity of the final supernatant solution became 10 used in Example 1 for 1 to 2 minutes. The particle diameter LS/cm or less, whereby producing a wet cake (this contained about 30 mg of curcumin). The Wet cake was added 5 mL of distribution of turmeric nano-powder measured by the fore a mixed solution of 0.1% SDS (sodium dodecylsulfate) and going particle diameter distribution measurement instrument 0.1% hydrogenated soybean lecithin, and then was subjected after the dispersion treatment was as follows: the average to a dispersion treatment by using the foregoing bath-type particle diameter (D)=463 nm, the value of Do-147 nm, ultrasonic disperser for 1 to 2 minutes. Then, the solution the value of Dso 359 nm, and the value of Doo-802 nm. dispersed above was added 45 mL of purified water, and was Comparative Example 1 again Subjected to a dispersion treatment by using the fore going bath-type ultrasonic disperser for 1 to 2 minutes. The Preparation of a Turmeric-Containing Powder by particle diameter distribution of the synthetic curcumin nano Milling with Salt powder measured by the foregoing particle diameter distri bution measurement instrument after the dispersion treatment (1) Processes of Mixing and Milling was as follows: the average particle diameter (D)=255 nm, 0088 10 g of synthetic curcumin powder (manufactured the value of D)=102 nm, the value of Ds-192 nm, and the by Wako Pure Chemical Industries, Ltd.), 80 g of milled salt value of Do-431 nm (manufactured by Wako Pure Chemical Industries, Ltd.) and (3) A Process of Drying 17.2 g of glycerin (manufactured by Kanto Chemical Co., Inc.) were introduced into the trimix kneader used in Example 0090 The wet cake obtained by the same procedure as the 1 and then were mixed and kneaded under the same condi water-washing process was dried under vacuum (conditions: tions as Example 1. The particle diameter distribution of the 30 degrees C. or lower, 1 hPa and 18 hours) to obtain 28 mg synthetic curcumin powder measured by using the particle of dry powder. The dry powder obtained using above method diameter distribution measurement instrument used in was added 5 mL of a mixed solution of 0.1% SDS (sodium Example 1 before the process of mixing was as follows: the dodecylsulfate) and 0.1% hydrogenated soybean lecithin and average particle diameter (D)=17270 nm, the value of then was subjected to a dispersion treatment by using the Do 4422 nm, the value of Dso 15070 nm, and the value of foregoing bath-type ultrasonic disperser for 1 to 2 minutes. Do 33850 nm. 300 mg of the dough obtained after kneading Then, the solution dispersed above was added 45 mL of was weighed into a 50-mL glass vial. After that, 5 mL of purified water, and was again subjected to a dispersion treat mixed solution of 0.1% SDS (sodium dodecylsulfate) and ment by using the foregoing bath-type ultrasonic disperser for 0.1% hydrogenated soybean lecithin was put into the glass 1 to 2 minutes. The particle diameter distribution of the syn vial. The content in the glass vial was served to the dispersion thetic curcumin powder measured by the foregoing particle treatment by using the bath-type ultrasonic disperser used in diameterdistribution measurement instrument after the dis Example 1 for 1 to 2 minutes. Dispersed content was added 45 persion treatment was as follows: the average particle diam mL of purified water and then was again served to the disper eter (D)=3048 nm, the value of Do 133 nm, the value of sion treatment by using the bath-type ultrasonic disperser for Dso 507 nm, and the value of Doo-9376 mm 1 to 2 minutes. The particle diameter distribution of synthetic 0091 Table 1 shows the particle diameter distributions of curcumin nano-powder measured by the foregoing particle the products obtained in each process of Example 1. Example diameter distribution measurement instrument after the dis 2 and Comparative Example 1. TABLE 1

Particle diameter distribution (nm After milling After waterwashing After drying Day D10 DSO D90 Day D10 DSO D90 Day D10 DSO D90

Example 1 2O2 78 162 338 223 99 18S 336 Example 2 379 1SS 298 603 463 147 359 802 Comparative 96 37 78 162 2SS 102 192 431 3048 133 SOf 9376 Example 1 US 2014/0328917 A1 Nov. 6, 2014

0092. As shown in Table 1, without the process of drying, mannitol used in Example 1, 2 g of hydroxypropyl cellulose finer nano-powder was obtained by the conventional milling (trade name of SSL, manufactured by Nippon Soda Co., Ltd.) method used the salt, while with the process of drying, the and 13.3 g of 10% polyvinyl alcohol (trade name of Poval powder obtained by milling method used the salt tended to 217C, manufactured by Kuraray Co., Ltd.) were introduced agglomerate more easily. On the other hand, in the milling into the trimix kneader used in Example 1 and then were methods of Examples 1 and 2 used D-mannitol, even with the mixed and kneaded under the same conditions as Example 1. process of drying, nano-powder having the particle diameter The particle diameter distribution of the fexofenadine hydro distribution not significantly changed from the particle diam chloride powder measured by the particle diameter distribu eter distribution of the powder immediately after the milling tion measurement instrument used in Example 1 before the could be obtained. This means that the particles in the powder process of mixing was as follows: the average particle diam become difficult to agglomerate after drying by milling with eter (D)=45660 nm, the value of Do-3225 nm, the value of D-mannitol. Dso-27320 nm, and the value of Doo-139600 nm. A part of the dough (15 mg) after the mixing and kneading was Example 3 weighed into a 50-mL glass vial and then added 5 mL of a Preparation of Powder Containing 10% by Weight of 0.4% aqueous sodium chloride solution. Then, the solution Rutin obtained above was subjected to a dispersion treatment by using the bath-type ultrasonic disperser used in Example 1 for (1) Processes of Mixing and Milling 0.5 to 1 minutes. The particle diameter distribution offex 0093. 10 g of rutin powder (manufactured by Wako Pure ofenadine hydrochloride nano-powder measured by the fore Chemical Industries, Ltd.), 80 g of D-(-)-mannitol used in going particle diameter distribution measurement instrument Example 1, 10 g of the sucrose fatty acid ester used in after the dispersion treatment of the kneaded product was as Example 1, 2.0 g of sodium carboxymethyl cellulose used in follows: the average particle diameter (D)=316 nm, the Example 1 and 10 g of purified water were introduced into a value of Do-142 nm, the value of Do 250 nm, and the value 500-mL trimix kneader (manufactured by Inoue MFG, Inc.), of Do-489 nm. and then were mixed and kneaded under the same conditions as Example 1. The particle diameter distribution of the rutin (2) A Process of Drying powder measured by the particle diameter distribution mea 0096. The dough (20g) obtained in the foregoing process surement instrument used in Example 1 before the process of was dried in the vacuum dryer used in Example 3 to obtain mixing was as follows: the average particle diameter (D) 15.5g of dry powder. A part of the obtained dry powder (15 =8949 nm, the value of Do-1972 nm, the value of Ds 5007 mg) was mixed with 5 mL of a 0.4% aqueous sodium chloride nm, and the value of Do-21450 nm. A part of the dough (30 Solution and then was subjected to a dispersion treatment by mg) after the mixing and kneading was weighed into a 50-mL using a probe-type ultrasonic disperser (probe-type 419 with glass vial and then added 3 mL of 10% mannitol solution. Amp. of 25 for 1 minute, S4000 type, Astrason). The particle Then, the solution obtained above was subjected to a disper diameter distribution of the fexofenadine hydrochloride sion treatment by using the bath-type ultrasonic disperser nano-powder measured by the foregoing particle diameter used in Example 1 for 0.5 to 1 minutes. The particle diameter distribution measurement instrument after the dispersion distribution of rutin nano-powder measured by the foregoing treatment was as follows: the average particle diameter (D) particle diameter distribution measurement instrument after =230 nm, the value of D-129 nm, the value of Dso 198 nm, the dispersion treatment of the kneaded product was as fol and the value of D309 mm. lows: the average particle diameter (D)=277 nm, the value of Do 136 nm, the value of Ds 226 nm, and the value of Example 5 Do 410 nm. Experiment 2 (2) A Process of Drying 0094. The dough (10 g) obtained in the foregoing process Preparation of Fluorometholone-Containing was dried in a vacuum dryer (type of VOS-300VD, EYELA) Ophthalmic Formulation to obtain 9.27 g of dry powder. A part of the obtained dry powder (30 mg) was mixed with 3 mL of 10% mannitol (1) Processes of Mixing and Milling Solution and then was subjected to a dispersion treatment by 0097 8 g of fluorometholone powder (manufactured by using the foregoing bath-type ultrasonic disperser for 0.5 to 1 Sicor Biotech UAB), 32 g of D-(-)-mannitol used in Example minutes. The particle diameter distribution of the rutin nano 1, 40 g of milled salt (trade name of Tomita Salt K-30, manu powder measured by the foregoing particle diameter distri factured by Tomita Pharmaceutical Co., Ltd.) and 14 g of bution measurement instrument after the dispersion treatment glycerin (manufactured by Wako Pure Chemical Industries, was as follows: the average particle diameter (D) 321 nm, Ltd.) were introduced into the trimix kneader used in the value of Do 140 nm, the value of D-265 nm, and the Example 1 and then were mixed and kneaded under the same value of Do-492 nm. conditions as Example 1. The particle diameter distribution of Example 4 the fluorometholone powder measured by the particle diam eter distribution measurement instrument used in Example 1 Preparation of Kneaded Product Containing 45% by before the process of mixing was as follows: the average Weight of Fexofenadine Hydrochloride particle diameter (D)-3148 nm, the value of D-1389 nm, the value of Dso 2636 nm, and the value of Doo-5709 nm. A (1) Processes of Mixing and Milling part of the dough (60 mg) after the mixing and kneading was 0095 20 g offexofenadine hydrochloride powder (manu weighed into a 50-mL glass vial and then added 5 mL of a factured by Sumitomo Chemical Co., Ltd.), 20 g of D-(-)- mixed solution of 0.1% SDS and 0.1% hydrogenated soy US 2014/0328917 A1 Nov. 6, 2014 11 bean lecithin. Then, the solution obtained above was sub nm, the value of Dso-6872 nm, and the value of Do 22850 jected to a dispersion treatment by using the foregoing bath nm. A part of the dough (100 mg) after the mixing and type ultrasonic disperser for 1 to 2 minutes. The particle kneading was weighed into a 50-mL glass vial and then added diameter distribution of fluorometholone nano-powder mea 3 mL of 0.1% HCO60. The Solution obtained above was Sured by the foregoing particle diameter distribution mea Subjected to a dispersion treatment by using the foregoing Surement instrument after the dispersion treatment was as bath-type ultrasonic disperser for 3 minutes. The particle follows: the average particle diameter (D)=136 nm, the diameter distribution of clarithromycin nano-powder mea value of Do-68 nm, the value of Dso 114 nm, and the value Sured by the foregoing particle diameter distribution mea of Do 202 nm. Surement instrument after the dispersion treatment was as follows: the average particle diameter (D)=145 nm, the (2) A Process of Dispersion value of Do-81 nm, the value of Ds-125 nm, and the value 0098 4.5g of the dough obtained in the foregoing process of Doo-197 nm. was added 36 g of 1.0% HCO60, 36 g of 1.0% HEC and 36 g (2) A Process of Dispersion of 0.01% benzarconium chloride and then was subjected to a 0100 1.3 g of the obtained dough was added 65 g of 0.1% dispersion treatment by using a probe-type ultrasonic dis HCO60 and 13 g of 2.0% hypromellose and then was sub perser (probe-type 406HWS with Amp. of 30 for 4 minutes, jected to a dispersion treatment by using the foregoing bath 54000 type, Astrason). Then, 36 g of a mixture solution com type ultrasonic disperser for 10 minutes. Then, purified water prising 6% disodium phosphate dodecahydrate, 0.6% sodium was added thereinto in order to prepare 130 g of the mixture, dihydrogen phosphate dihydrate and 0.1% EDTA.2Na, and which was then further subjected to a dispersion treatment by 36 g of 1.0% methyl cellulose was added thereinto and then using the foregoing bath-type ultrasonic disperser for 1 purified water was further added thereinto in order to preapre minute. Thus prepared formulation had the quality of passing 360 g of the mixture. Then, the solution obtained above was through a 0.2-um membrane filter almost thoroughly (passing Subjected to a dispersion treatment by using the probe-type rate of 90% or higher by HPLC analysis) and was with the ultrasonic disperser (probe-type 406HWS with Amp. of 30 particle diameter thereof coincident very well with that of the for 1 minute, 54000 type, Astrason). Thus prepared formula dough. Meanwhile, the osmotic pressure rate of the prepared tion had the quality of passing through a 0.2 Lum membrane formulation was about 1 (0.3 Osmol/kg HO), so the formu filter almost thoroughly (passing rate of 90% or higher by lation could be used as an ophthalmic formulation as it was. HPLC analysis) and was with the particle diameter thereof 0101. As shown above, when the organic compound is coincident very well with that of the dough. Meanwhile, the milled by using a carbohydrate compound Such as mannitol, osmotic pressure rate of the prepared formulation was about an organic compound nano-powder or a suspension contain 1 (0.3 Osmol/kg HO), so the formulation could be used as an ing the powder can be produced in so simple process without ophthalmic formulation as it was. the water-washing process, so that recovery loss of the pow der can be avoided. In addition, because the water-washing Example 6 process is not necessary, the particles of the organic com Experiment 3 pound are difficult to agglomerate. As a result, the diameter of the particles in the dough obtained immediately after milling Preparation of Clarithromycin-Containing Drug may be kept. 0102 Table 2 shows granular carbohydrate compounds (1) Processes of Mixing and Milling used in following experiments. The term “Dav’ means an average particle diameter (D). In the table, the term “D10 0099 10 g of clarithromycin powder (manufactured by means the particle diameter (Do value) of the particle at the Assia Chemical Industries Ltd.), 60 g of D-(-)-mannitol used position of 10% when counted from the smallest size Zero in Example 1, 10g of the milled salt used in Example 5.3 g of (minimum) to 100% (maximum) of the particle diameter in a polyvinyl pyrrolidone, 5.0 g of hydrogenated Soybean leci particle diameter distribution. The term “D50” means a cer thin (manufactured by H. Holstein GmbH) and 20 g of glyc tain particle diameter (Dso value) when amount of a larger erin were introduced into the trimix kneader used in Example side becomes equal to amount of a smaller side of the particle 1, and then were mixed and kneaded under the same condi diameters divided into two a powder from the certain particle tions as Example 1. The particle diameter distribution of the diameter. The term “D90” means the particle diameter (Do clarithromycin powder measured by the particle diameter value) of the particle at the position of 90% when counted distribution measurement instrument used in Example 1 from the smallest size Zero (minimum) to 100% (maximum) before the process of mixing was as follows: the average of the particle diameter in the particle diameter distribution. particle diameter (D)=10160 nm, the value of Do 2277 The same definitions shall apply to following tables. TABLE 2 Melting Carbohydrate Particle Size (In point compound Dav D10 DSO D90 (Degrees C.) Supplyer Mannitol 79 24 66 144 166-168 Kanto Chemical Co., Inc. (High grade) Maltitol 33 7 30 64 145 Mitsubishi Shoji Foodtech Co., Ltd. Sorbitol 159 75 154. 249 95 Kanto Chemical Co., Inc (Cica first grade). US 2014/0328917 A1 Nov. 6, 2014

TABLE 2-continued Melting Carbohydrate Particle Size (In point compound Day D10 DSO D90 (Degrees C.) Supplyer Erythritol 147 63 138 237 121 B Food Science Co., Ltd. Xylitol 631 383 615 912 92-96 Wako Pure Chemical Industries, Ltd. (High grade) Inositol 28O 116 247 496 225-227 Tsuno Rice Fine Chemicals Co., Ltd. Glucose 238 135 231 355 146-150 Wako Pure Chemical Industries, Ltd. (High grade) Fructose 339 158 311 S66 104 Wako Pure Chemical Industries, Ltd. (High grade) Lactose 45 3 2O 123 2O2 Kanto Chemical Co., Inc. monohydrate (High grade) Trehalose 25 7 2O 50 2O3 Hayashibara Co., Ltd. Cellobiose 41 7 38 76 225 Nippon Paper Industries Co., (Decomposition) Ltd. Chemical division Dextrin 38 16 38 63 Wako Pure Chemical Industries, Ltd.

Experiment 4 Example 7 except changing from 100 mg of turmeric powder to 100 mg of mefenamic acid powder (manufactured by Milling with D-Mannitol Tokyo Chemical Industry Co., Ltd.). As a result, the particle diameter distribution of mefenamic acid nano-powder Example 7 obtained after above procedures was as follows: D-247 nm, the value of Do-99 nm, the value of Dso 198 nm, and the Preparation of a Curcumin Nano-Powder value of Do-403 nm. (0103 100 mg of turmeric powder (70% or more purity of curcumin, or 90% or more purity of curcuminoid, manufac Example 9 tured by BioActives Japan Corp.), 325 mg of D-(-)-mannitol used in Example 1, 50 mg of sucrose fatty acid ester (trade Preparation of an Acetaminophen Nano-Powder name of DK Ester SS, manufactured by Dai-Ichi Kogyo Seiy 0105. An acetaminophen powder was milled under the aku Co., Ltd.), 9 mg of sodium carboxymethyl cellulose same conditions as Example 7 except both changing from 100 (trade name of Cellogen F-3H, manufactured by Dai-Ichi mg of turmeric powder to 100 mg of acetaminophen powder Kogyo Seiyaku Co., Ltd.) and 110 mg of purified water were (manufactured by Tokyo Chemical Industry Co., Ltd.) and served on a glass disk of a Hoover muller (manufactured by changing from Sucrose fatty acid ester to decaglyceryl Imoto Machinery Co., Ltd.) and then kneaded by repeating monostearate (trade name of Decaglyn 1-SV, manufactured five times to rotate the disk in 20 turns per time. Above-served by Nikko Chemicals Co., Ltd.). Then, 100 mg of the dough contents formed a kind of dough during kneading and obtained after milling was weighed and then subjected to a whereby the turmeric powder was finely milled. Hereinafter, dispersion treatment under the same conditions as Example 7 the term “turmeric powder will be also called as another term except adding only 5 mL of 0.1% sodium dodecylsulfate 'curcumin’ for the reason that curcumin is a major ingredient (same as used in Example 7 and also used in following experi in the turmeric powder. 10 mg of the dough obtained after ments) but no 0.01% hydrogenated soybean lecithin (same as milling was weighed into a 50-mL glass vial and then added used in Example 7 and also used in following experiments). 5 mL of a mixed solution of 0.1% sodium dodecylsulfate As a result, the particle diameter distribution of acetami (manufactured by Wako Pure Chemical Industries, Ltd.) and nophen nano-powder obtained after above procedures was as 0.01% hydrogenated soybean lecithin (trade name of Phos follows: D-443 nm, the value of D-92 nm, the value of pholipon 90H, manufactured by Lipoid GmbH). Then, the Ds 286 nm, and the value of Doo-886 nm. Solution obtained above was subjected to a dispersion treat ment by using a bath-type ultrasonic disperser (type of US Example 10 100III, manufactured by ASONE Corp., the same shall apply hereinafter) for 1 to 2 minutes. The particle diameter distri Preparation of an Ibuprofen Nano-Powder bution of curcumin nano-powder measured by the same par 010.6 An ibuprofen powder was milled under the same ticle diameter distribution measurement instrument as used in conditions as Example 7 except both changing from 100 mg Example 1 was as follows: D384 nm, the value of Do 154 of turmeric powder to 100 mg of ibuprofen powder (manu nm, the value of Ds 280 nm, and the value of Doo-569 nm. factured by Tokyo Chemical Industry Co., Ltd.) and changing from Sucrose fatty acid ester to hydrogenated soybean leci Example 8 thin. Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example Preparation of a Mefenamic Acid Nano-Powder 7 except adding 10 mL of a mixed solution of 0.1% sodium 0104 Amefenamic acid powder was milled and then sub dodecylsulfate and 0.01% hydrogenated soybean lecithin. As jected to a dispersion treatment under the same conditions as a result, the particle diameter distribution of ibuprofen nano US 2014/0328917 A1 Nov. 6, 2014 powder obtained after above procedures was as follows: obtained after milling was subjected to a dispersion treatment D=286 nm, the value of Do-71 nm, the value of Dso-122 under the same conditions as Example 7 except adding 10 mL nm, and the value of Doo 257 nm. of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soybean lecithin. As a result, the particle diameter distribu Example 11 tion offelbinac nano-powder obtained after above procedures was as follows: D-335 nm, the value of Do 170 nm, the Preparation of an Amphotericin B Nano-Powder value of Dso-279 nm, and the value of Do-48.1 nm. 0107 An amphotericin B powder was milled under the same conditions as Example 7 except both changing from 100 Example 15 mg of turmeric powder to 100 mg of amphotericin B powder (manufactured by Wako Pure Chemical Industries, Ltd.) and Preparation of a Pranlukast Hydrate Nano-Powder changing from Sucrose fatty acid ester to hydrogenated Soy 0111 A pranlukast hydrate powder was milled under the bean lecithin. Then, the dough obtained after milling was same conditions as Example 7 except changing from 100 mg Subjected to a dispersion treatment under the same conditions of turmeric powder to 100 mg of pranlukast hydrate powder as Example 7 except adding only 5 mL of 0.1% sodium (manufactured by Hallochem Pharma. Co., Ltd., China). dodecylsulfate but no 0.01% hydrogenated soybean lecithin. Then, the dough obtained after milling was subjected to a As a result, the particle diameter distribution of amphotericin dispersion treatment under the same conditions as Example 7 B nano-powder obtained after above procedures was as fol except adding only 10 mL of 0.1% sodium dodecylsulfate but lows: D-242 nm, the value of Do-87 nm, the value of no 0.01% hydrogenated soybean lecithin. As a result, the Dso-195 nm, and the value of Do-397 nm. particle diameter distribution of pranlukast hydrate nano powder obtained after above procedures was as follows: Example 12 D=152 nm, the value of Do-85 nm, the value of Dso-132 nm, and the value of Do 208 nm. Preparation of a Diclofenac Sodium Nano-Powder 0108. A diclofenac sodium powder was milled under the Example 16 same conditions as Example 7 except both changing from 100 mg of turmeric powder to 100 mg of diclofenac sodium Preparation of a Dexamethasone Nano-Powder powder (manufactured by Tokyo Chemical Industry Co., 0112 A dexamethasone powder was milled under the Ltd.) and changing from Sucrose fatty acid ester to decaglyc same conditions as Example 7 except changing from 100 mg eryl monostearate (same as used in Example 9 and also used of turmeric powder to 100 mg of dexamethasone powder in following experiments). Then, 100 mg of the dough (manufactured by Wako Pure Chemical Industries, Ltd.). obtained after milling was weighed and then subjected to a Then, 20 mg of the dough obtained after milling was weighed dispersion treatment under the same conditions as Example 7 and then Subjected to a dispersion treatment under the same except adding only 5 mL of 0.1% sodium dodecylsulfate but conditions as Example 7 except adding only 5 mL of 0.1% no 0.01% hydrogenated soybean lecithin. As a result, the Polyoxyethylene Hydrogenated Castor Oil 60 (trade name of particle diameter distribution of diclofenac sodium nano NIKKOL HCO-60, manufactured by Nikko Chemicals Co., powder obtained after above procedures was as follows: Ltd.). As a result, the particle diameter distribution of dexam D-303 nm, the value of Do-99 nm, the value of Dso 228 ethasone nano-powder obtained after above procedures was nm, and the value of Doo-536 nm. as follows: D-179 nm, the value of Do-102 nm, the value of Dso-155 nm, and the value of Doo 240 nm. Example 13 Comparative Example 2 Preparation of an Indomethacin Nano-Powder 0109 An indomethacin powder was milled under the Milling of a Curcumin Powder without Using same conditions as Example 7 except changing from 100 mg D-Mannitol of turmeric powder to 100 mg of indomethacin powder 0113. The turmeric powder used in Example 7 was milled (manufactured by Wako Pure Chemical Industries, Ltd.). under the same conditions as Example 7 except adding no Then, the dough obtained after milling was subjected to a D-(-)-mannitol. Then, 2 mg of the dough obtained after mill dispersion treatment under the same conditions as Example 7 ing was weighed into a 50-mL glass vial and then Subjected to except adding only 10 mL of 0.1% sodium dodecylsulfate but a dispersion treatment under the same conditions as Example no 0.01% hydrogenated soybean lecithin. As a result, the 7. As a result, the particle diameter distribution of curcumin particle diameter distribution of indomethacin nano-powder powder obtained after above procedures was as follows: obtained after above procedures was as follows: D353 nm, D-716 nm, the value of Do-131 nm, the value of Do 216 the value of Do-155 nm, the value of Ds 289 nm, and the nm, and the value of Doo 2983 nm. Thus, the D and the Do value of D539 mm. of the particle diameter distribution were more than 500 nm and 1500 nm, respectively. Example 14 Comparative Example 3 Preparation of a Felbinac Nano-Powder 0110. A felbinac powder was milled under the same con Milling of a Mefenamic Acid Powder without Using ditions as Example 7 except changing from 100 mg of tur D-Mannitol meric powder to 100mg offelbinac powder (manufactured by 0114. The mefenamic acid powder used in Example 8 was Wako Pure Chemical Industries, Ltd.). Then, the dough milled under the same conditions as Example 8 except adding US 2014/0328917 A1 Nov. 6, 2014 14 no D-(-)-mannitol. Then, 2 mg of the dough obtained after adding no D-(-)-mannitol. Then, 20 mg of the dough milling was weighed into a 50-mL glass vial and then Sub obtained after milling was weighed into a 50-mL glass vial jected to a dispersion treatment under the same conditions as and then Subjected to a dispersion treatment under the same Example 8. As a result, the particle diameter distribution of conditions as Example 12. As a result, the particle diameter mefenamic acid powder obtained after above procedures was distribution of diclofenac sodium powder obtained after as follows: D926 nm, the value of Do-155 nm, the value above procedures was as follows: D-589 nm, the value of of Ds 276 nm, and the value of Doo3673 nm. Thus, the D Do-78 nm, the value of Dso-196 nm, and the value of and the Doo of the particle diameter distribution were more Doo 2364 nm. Thus, the D and the Doo of the particle than 500 nm and 1500 nm, respectively. diameter distribution were more than 500 nm and 1500 nm, Comparative Example 4 respectively. Milling of an Acetaminophen Powder without Using Comparative Example 8 D-Mannitol 0115 The acetaminophen powder used in Example 9 was Milling of an Indomethacin Powder without Using milled under the same conditions as Example 9 except adding D-Mannitol no D-(-)-mannitol. Then, 20 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then Sub 0119 The indomethacin powder used in Example 13, 30 jected to a dispersion treatment under the same conditions as mg of polyvinylpyrrolidone (trade name of K25, manufac Example 9. As a result, the particle diameter distribution of tured by Wako Pure Chemical Industries, Ltd.), 50 mg of acetaminophen powder obtained after above procedures was hydrogenated Soybean lecithin and 50 mg of glycerin (manu as follows: D1124 nm, the value of Do-134 nm, the value of Dso 400 nm, and the value of Doo 2899 nm. Thus, the D factured by Junsei Chemical Co., Ltd.) were served on a glass and the Doo of the particle diameter distribution were more disk of a Hoover muller (same as used in Example 7 and also than 500 nm and 1500 nm, respectively. used in following experiments) without adding D-(-)-man nitol and then kneaded by repeating five times to rotate the Comparative Example 5 disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the indometha Milling of an Ibuprofen Powder without Using cin powder was milled 2 mg of the dough obtained after D-Mannitol milling was weighed into a 50-mL glass vial and then Sub 0116. The ibuprofen powder used in Example 10 was jected to a dispersion treatment under the same conditions as milled under the same conditions as Example 10 except add Example 13. As a result, the particle diameter distribution of ing no D-(-)-mannitol. Then, 2 mg of the dough obtained indomethacin powder obtained after above procedures was as after milling was weighed into a 50-mL glass vial and then follows: D1346 nm, the value of Do-145 nm, the value of Subjected to a dispersion treatment under the same conditions Do 219 nm, and the value of Do-4154 nm. Thus, the D as Example 10. As a result, the particle diameter distribution and the Doo of the particle diameter distribution were more of ibuprofen powder obtained after above procedures was as than 500 nm and 1500 nm, respectively. follows: D-2873 nm, the value of Do-403 nm, the value of Dso-619 nm, and the value of Doo-10421 nm. Thus, the D Comparative Example 9 and the Doo of the particle diameter distribution were more than 500 nm and 1500 nm, respectively. Milling of a Felbinac Powder without Using Comparative Example 6 D-Mannitol Milling of an Amphotericin B Powder without Using 0.120. The felbinac powder used in Example 14, 30 mg of D-Mannitol polyvinylpyrrolidone (same as used in Comparative Example 0117 The amphotericin B powder used in Example 11 8 and also used in following experiments), 50 mg of hydro was milled under the same conditions as Example 11 except genated soybean lecithin and 50 mg of glycerin (same as used adding no D-(-)-mannitol. Then, 2 mg of the dough obtained in Comparative Example 8 and also used in following experi after milling was weighed into a 50-mL glass vial and then ments) were served on a glass disk of the foregoing Hoover Subjected to a dispersion treatment under the same conditions muller without adding D-(-)-mannitol and then kneaded by as Example 11. As a result, the particle diameter distribution repeating five times to rotate the disk in 20 turns per time. of amphotericin B powder obtained after above procedures Above-served contents formed a kind of dough during knead was as follows: D-750 nm, the value of Do 159 nm, the ing and whereby the felbinac powder was milled 2 mg of the value of Do-314 nm, and the value of Do841 nm Thus, the dough obtained after milling was weighed into a 50-mL glass D of the particle diameter distribution was more than 500 vial and then subjected to a dispersion treatment under the same conditions as Example 14. As a result, the particle Comparative Example 7 diameter distribution offelbinac powder obtained after above procedures was as follows: D1457 nm, the value of Milling of a Diclofenac Sodium Powder without Do 154 nm, the value of Ds 309 mm, and the value of Using D-Mannitol Do 5452 nm. Thus, the D and the Do of the particle 0118. The diclofenac sodium powder used in Example 12 diameter distribution were more than 500 nm and 1500 nm, was milled under the same conditions as Example 12 except respectively. US 2014/0328917 A1 Nov. 6, 2014 15

Comparative Example 10 lecithin and 50 mg of glycerin were served on a glass disk of the foregoing Hoover muller without adding D-(-)-mannitol Milling of a Pranlukast Hydrate Powder without and then kneaded by repeating five times to rotate the disk in Using D-Mannitol 20 turns per time. Above-served contents formed a kind of 0121 The pranlukast hydrate powder used in Example 15 dough during kneading and whereby the dexamethasone (also used in following experiments), 30 mg of polyvinylpyr powder was milled 4 mg of the dough obtained after milling rolidone, 50 mg of hydrogenated soybean lecithin and 75 mg was weighed into a 50-mL glass vial and then Subjected to a of glycerin were served on a glass disk of the foregoing dispersion treatment under the same conditions as Example Hoover muller without adding D-(-)-mannitol and then 16. As a result, the particle diameter distribution of dexam kneaded by repeating five times to rotate the disk in 20 turns ethasone powder obtained after above procedures was as per time. Above-served contents formed a kind of dough follows: D-3704 nm, the value of D-138 nm, the value of during kneading and whereby the pranlukast hydrate powder Dso-852 nm, and the value of D-12321 nm. Thus, the D was milled 2 mg of the dough obtained after milling was and the Do of the particle diameter distribution were more weighed into a 50-mL glass vial and then Subjected to a than 500 nm and 1500 nm, respectively. dispersion treatment under the same conditions as Example 15. As a result, the particle diameter distribution of pranlukast I0123 Table 3 shows the particle diameter distributions of hydrate powder obtained after above procedures was as fol various organic compound powders prepared in Examples 7 lows: D-1102 nm, the value of Do 129 nm, the value of to 16 and Comparative Examples 2 to 11 as compared with the Dso 408 nm, and the value of Do-4226 mm. Thus, the D. particle diameter distributions of the powders before milling. and the Doo of the particle diameter distribution were more The term “Cur’ in the table means curcumin. The term “Mef than 500 nm and 1500 nm, respectively. in the table means mefenamic acid. The term ‘Ace’ in the table means acetaminophen. The term "Ibu' in the table Comparative Example 11 means ibuprofen. The term “Amp” in the table means ampho tericin B. The term “Dic' in the table means diclofenac Milling of a Dexamethasone Powder without Using sodium. The term "Ind' in the table means indomethacin. The D-Mannitol term “Fel’ in the table means felbinac. The term “Pra’ in the 0122) The dexamethasone powder used in Example 16,30 table means pranlukast hydrate. The term “Dex' in the table mg of polyvinylpyrrolidone, 50 mg of hydrogenated Soybean means dexamethasone. TABLE 3

Paticle diameter distribution (nm) Organic Before milling After milling

compound Dav D10 D50 D90 Day D10 DSO D90

Exam Cur 664O 930 121SO 3.587O 384 154 280 569 Exam Mef 6130 77O 13290 3 SSSO 247 99 198 403 Exam Ace 10994O 41240 10346O 18851O 443 92 286 886 Exam Ibu 7903O 231 OO 6944O 14966O 286 71 122 257 Exam e 1 1 Amp 966O S10 12S2O S1740 242 87 19:S 397 Exam Dic 7778O 234OO 68380 152090 3O3 99 228 536 Exam Ind 24OO 630 867O 3O820 353 1 SS 289 539 Exam Fel 19072O 4627O 166710 35686O 33S 17O 279 481 Exam Pra 9SOO 1050 61SO 23660 152 85 132 208 Exam Dex 2690 280 258O 536O 179 102 155 240 Comparative Cur 664O 930 121SO 3.5870 716 131 216 2983 Exam e 2 Comparative Mef 6130 77O 13290 3555O 926 155 276 3673 Exam e 3 Comparative Ace 10994O 41240 10346O 18851O 1124 134 400 2899 Exam e 4 Comparative Ibu 7903O 231 OO 6944O 14966O 2873 403 619 10421 Exam e 5 Comparative Amp 1966O S10 12S2O S1740 7SO 159 314 841 Exam e 6 Comparative Dic 7778O 234OO 68380 152090 S89 78 196 2364 Exam e 7 Comparative Ind 124OO 630 867O 3O82O 1346 145 219 4154 Exam e 8 Comparative Fel 19072O 4627O 166710 35686O 1457 154 309 S452 Exam Comparative Pra 9SOO 1050 61SO 23660 1102 129 408 4226 Exam e 1 O US 2014/0328917 A1 Nov. 6, 2014 16

TABLE 3-continued

Paticle diameter distribution (nm Organic Before milling After milling compound Dav D10 D50 D90 Daw D10 DSO D90

Comparative Dex 2690 28O 258O S360 3704 138 852 12321 Example 11

0124. As shown in Table 3, organic compound nano-pow result, the particle diameter distribution of mefenamic acid der consisting of the particles with so Small particle diameter nano-powder obtained after above procedures was as follows: was prepared when organic compound powder was milled D241 nm, the value of Do-98 nm, the value of Dso-191 with using D-mannitol as one of carbohydrate compounds. nm, and the value of Do-398 mm On the other hand, organic compound nano-powder consist ing of the particles with D of 500 nm or less and Doo of 1500 Example 19 nm or less were unable to prepare when the organic com pound powder was milled without using D-mannitol. Accord Preparation of an Ibuprofen Nano-Powder ing to above results, it is considered that the carbohydrate I0127. An ibuprofen powder was milled under the same compound contributes to increase the efficiency of milling the conditions as Example 17 except changing from 100 mg of organic compound. turmeric powder to 100 mg of ibuprofen powder (same as used in Example 10 and also used in following experiments). Experiment 5 Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example Milling with Xylitol 17 except adding 10 mL of a mixed solution of 0.1% sodium Example 17 dodecylsulfate and 0.01% hydrogenated soybean lecithin. As a result, the particle diameter distribution of ibuprofen nano Preparation of a Curcumin Nano-Powder powder obtained after above procedures was as follows: D-321 nm, the value of Do 150 nm, the value of Dso 265 0.125 100 mg of turmeric powder (same as used in nm, and the value of Do-477 mm Example 7 and also used in following experiments), 325 mg of xylitol. 50 mg of Sucrose fatty acid ester (same as used in Example 20 Example 7 and also used in following experiments), 9 mg of Sodium carboxymethyl cellulose (same as used in Example 7 Preparation of an Amphotericin B Nano-Powder and also used in following experiments) and 110 mg of puri I0128. An amphotericin B powder was milled under the fied water were served on a glass disk of the foregoing Hoover same conditions as Example 17 except both changing from muller and then kneaded by repeating five times to rotate the 100 mg of turmeric powder to 100 mg of amphotericin B disk in 20 turns per time. Above-served contents formed a powder (same as used in Example 11 and also used in follow kind of dough during kneading and whereby the turmeric ing experiments) and changing from Sucrose fatty acid ester powder was finely milled 10 mg of the dough obtained after to hydrogenated Soybean lecithin. Then, the dough obtained milling was weighed into a 50-mL glass vial and then added after milling was subjected to a dispersion treatment under the 5 mL of a mixed solution of 0.1% sodium dodecylsulfate and same conditions as Example 17 except adding only 5 mL of 0.01% hydrogenated soy bean lecithin. Then, the solution 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy obtained above was subjected to a dispersion treatment by bean lecithin. As a result, the particle diameter distribution of using a bath-type ultrasonic disperser (same as used in amphotericin B nano-powder obtained after above proce Example 7 and also used in following experiments) for 1 to 2 dures was as follows: D343 nm, the value of Do-107 nm, minutes. As a result, the particle diameter distribution of the value of Do 170 nm, and the value of Do-326 nm curcumin nano-powder obtained after above procedures was as follows: D-283 nm, the value of Do 138 nm, the value Example 21 of Do 234 nm, and the value of Do-418 nm. Preparation of a Diclofenac Sodium Nano-Powder Example 18 I0129. A diclofenac sodium powder was milled under the same conditions as Example 17 except both changing from Preparation of a Mefenamic Acid Nano-Powder 100 mg of turmeric powder to 100 mg of diclofenac sodium 0126 Amefenamic acid powder was milled and then sub powder (same as used in Example 12 and also used in follow jected to a dispersion treatment under the same conditions as ing experiments) and changing from Sucrose fatty acid ester Example 17 except changing from 100 mg of turmeric pow to decaglyceryl monostearate (same as used in Example 9 and der to 100 mg of mefenamic acid powder (same as used in also used in following experiments). Then, 100 mg of the Example 8 and also used in following experiments). As a dough obtained after milling was weighed and then Subjected US 2014/0328917 A1 Nov. 6, 2014 17 to a dispersion treatment under the same conditions as der to 100 mg of mefenamic acid powder. As a result, the Example 17 except adding only 5 mL of 0.1% sodium dode particle diameter distribution of mefenamic acid nano-pow cylsulfate but no 0.01% hydrogenated soybean lecithin. As a der obtained after above procedures was as follows: D-224 result, the particle diameter distribution of diclofenac sodium nm, the value of Do-85 nm, the value of Ds-193 nm, and nano-powder obtained after above procedures was as follows: the value of Do-339 mm D=200 nm, the value of D58 nm, the value of Do 178 Example 24 nm, and the value of Do 300 nm. 0130 Table 4 shows the particle diameter distributions of various organic compound powders prepared in Examples 17 Preparation of an Ibuprofen Nano-Powder to 21 as compared with the particle diameter distributions of I0134. An ibuprofen powder was milled under the same the powders before milling. conditions as Example 22 except both changing from 100 mg TABLE 4

Particle diameter distribution (nm) Before milling After milling

Organic compound Dav D10 D50 D90 Day D10 DSO D90

Example 17 Cur 1664O 930 121SO 3587O 283 138 234 418 Example 18 Mef 16130 77O 1329O 3SSSO 241 98 191 398 Example 19 Ibu 7903O 231 OO 6944O 14966O 321 150 26S 477 Example 20 Amp 1966O S10 12S2O S174O 343 107 17O 326 Example 21 Dic 7778O 234OO 68380 152090 200 S8 178 300

0131. As shown in Table 4, organic compound nano-pow- of turmeric powder to 100 mg of ibuprofen powder and der consisting of the particles with so Small particle diameter changing from Sucrose fatty acid ester to hydrogenated Soy was prepared when organic compound powder was milled bean lecithin. Then, the dough obtained after milling was with using Xylitol as one of carbohydrate compounds. Subjected to a dispersion treatment under the same conditions Experiment 6 as Example 22 except adding 10 mL of a mixed solution of 0.1% sodium dodecylsulfate and 0.01% hydrogenated soy Milling with Glucose bean lecithin. As a result, the particle diameter distribution of ibuprofen nano-powder obtained after above procedures was Example 22 as follows: D327 nm, the value of Do 156 nm, the value Preparation of a Curcumin Nano-Powder of Dso 266 nm, and the value of Do-489 mm. 0132 100 mg of turmeric powder, 325 mg of glucose, 50 mg of sucrose fatty acid ester, 9 mg of sodium carboxymethyl Example 25 cellulose and 110 mg of purified water were served on a glass disk of the foregoing Hoover muller and then kneaded by Preparation of a Diclofenac Sodium Nano-Powder repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during knead 0.135 A diclofenac sodium powder was milled under the ing and whereby the turmeric powder was finely milled 10 mg of the dough obtained after milling was weighed into a 50-mL same conditions as Example 22 except both changing from glass vial and then added 5 mL of a mixed solution of 0.1% 100 mg of turmeric powder to 100 mg of diclofenac sodium sodium dodecylsulfate and 0.01% hydrogenated soy bean powder and changing from Sucrose fatty acid ester to decag lecithin. Then, the solution obtained above was subjected to a lyceryl monostearate. Then, 100 mg of the dough obtained dispersion treatment by using the foregoing bath-type ultra after milling was weighed and then Subjected to a dispersion Sonic disperser for 1 to 2 minutes. As a result, the particle treatment under the same conditions as Example 22 except diameter distribution of curcumin nano-powder obtained adding only 5 mL of 0.1% sodium dodecylsulfate but no after above procedures was as follows: D345 nm, the value 0.01% hydrogenated soybean lecithin. As a result, the par of D-96 nm, the value of D-242 nm, and the value of ticle diameter distribution of diclofenac sodium nano-powder Doo-648 nm. obtained after above procedures was as follows: D-244 nm, Example 23 the value of Do-78 nm, the value of Dso-130 nm, and the value of Doo 266 mm. Preparation of a Mefenamic Acid Nano-Powder 0.136 Table 5 shows the particle diameter distributions of 0.133 Amefenamic acid powder was milled and then sub various organic compound powders prepared in Examples 22 jected to a dispersion treatment under the same conditions as to 25 as compared with the particle diameter distributions of Example 22 except changing from 100 mg of turmeric pow the powders before milling. US 2014/0328917 A1 Nov. 6, 2014 18

TABLE 5

Particle diameter distibution (nm Before milling After milling Organic compound Dav D10 D50 D90 Daw D10 DSO D90 Example 22 Cur 1664O 930 121SO 3587O 345 96 242 648 Example 23 Mef 16130 77O 1329O 3SSSO 224 85 193 339 Example 24 Ibu 7903O 231 OO 6944O 14966O 327 156 266 489 Example 25 Dic 7778O 234OO 68380 152090 244 78 130 266

0.137 As shown in Table 5, organic compound nano-pow powder (same as used in Example 9 and also used in follow der consisting of the particles with so Small particle diameter ing experiments) and changing from Sucrose fatty acid ester was prepared when organic compound powder was milled to decaglyceryl monostearate. Then, 100 mg of the dough with using glucose as one of carbohydrate compounds. obtained after milling was weighed and then subjected to a dispersion treatment under the same conditions as Example Experiment 7 26 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soybean lecithin. As a result, the Milling with Fructose particle diameter distribution of acetaminophen nano-powder obtained after above procedures was as follows: D186 nm, Example 26 the value of D82 nm, the value of Dso-148 nm, and the value of Do 296 nm. Preparation of a Curcumin Nano-Powder Example 29 0138 100 mg of turmeric powder, 325 mg of fructose, 50 mg of sucrose fatty acid ester, 9 mg of sodium carboxymethyl cellulose and 110 mg of purified water were served on a glass Preparation of an Ibuprofen Nano-Powder disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. 0.141. An ibuprofen powder was milled under the same Above-served contents formed a kind of dough during knead conditions as Example 26 except changing from 100 mg of ing and whereby the turmeric powder was finely milled 10 mg turmeric powder to 100 mg of ibuprofen powder. Then, the of the dough obtained after milling was weighed into a 50-mL dough obtained after milling was Subjected to a dispersion glass vial and then added 5 mL of a mixed solution of 0.1% treatment under the same conditions as Example 26 except sodium dodecylsulfate and 0.01% hydrogenated soy bean adding 10 mL of a mixed solution of 0.1% sodium dodecyl lecithin. Then, the solution obtained above was subjected to a sulfate and 0.01% hydrogenated soybean lecithin. As a result, dispersion treatment by using the foregoing bath-type ultra the particle diameter distribution of ibuprofen nano-powder Sonic disperser for 1 to 2 minutes. As a result, the particle obtained after above procedures was as follows: D-434 nm, diameter distribution of curcumin nano-powder obtained the value of Do 176 nm, the value of Do-335 nm, and the after above procedures was as follows: D-181 nm, the value value of Doo-711 nm. of Do-82 nm, the value of Dso-144 nm, and the value of Do 286 nm. Example 30 Example 27 Preparation of an Amphotericin B Nano-Powder Preparation of a Mefenamic Acid Nano-Powder 0142. An amphotericin B powder was milled under the 0139 Amefenamic acid powder was milled and then sub same conditions as Example 26 except both changing from jected to a dispersion treatment under the same conditions as 100 mg of turmeric powder to 100 mg of amphotericin B Example 26 except changing from 100 mg of turmeric pow powder and changing from Sucrose fatty acid ester to hydro der to 100 mg of mefenamic acid powder. As a result, the genated Soybean lecithin. Then, the dough obtained after particle diameter distribution of mefenamic acid nano-pow milling was Subjected to a dispersion treatment under the der obtained after above procedures was as follows: D-205 same conditions as Example 26 except adding only 5 mL of nm, the value of Do-84 nm, the value of Dso 165 nm, and 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy the value of Doo328 nm. bean lecithin. As a result, the particle diameter distribution of amphotericin B nano-powder obtained after above proce Example 28 dures was as follows: D-376 nm, the value of Do-132 nm, the value of Dso 298 nm, and the value of Doo-625 nm. Preparation of an Acetaminophen Nano-Powder 0.143 Table 6 shows the particle diameter distributions of 0140. The acetaminophen powder was milled under the various organic compound powders prepared in Examples 26 same conditions as Example 26 except both changing from to 30 as compared with the particle diameter distributions of 100 mg of turmeric powder to 100 mg of acetaminophen the powders before milling. US 2014/0328917 A1 Nov. 6, 2014 19

TABLE 6

Particle diameter distribution (nm Organic Before milling After milling compound Dav D10 D50 D90 Daw D10 DSO D90

Example 26 Cur 1664O 930 121SO 3.587O 181 82 144 286 Example 27 Mef 16130 77O 13290 3 SSSO 20S 84 16S 328 Example 28 Ace 10994O 41240 10346O 188510 186 82 148. 296 Example 29 Ibu 7903O 231 OO 6944O 14966O 434 176 335 711 Example 30 Amp 1966O S10 12S2O S1740 376 132 298 625

0144. As shown in Table 6, organic compound nano-pow Example 33 der consisting of the particles with so Small particle diameter was prepared when organic compound powder was milled with using fructose as one of carbohydrate compounds. Preparation of an Acetaminophen Nano-Powder Experiment 8 0147 The acetaminophen powder was milled under the same conditions as Example 31 except both changing from Milling with Trehalose 100 mg of turmeric powder to 100 mg of acetaminophen powder and changing from Sucrose fatty acid ester to decag Example 31 lyceryl monostearate. Then, 100 mg of the dough obtained Preparation of a Curcumin Nano-Powder after milling was weighed and then Subjected to a dispersion treatment under the same conditions as Example 31 except 0145 100 mg of turmeric powder, 325 mg of trehalose, 50 mg of sucrose fatty acid ester, 9 mg of sodium carboxymethyl adding only 5 mL of 0.1% sodium dodecylsulfate but no cellulose and 110 mg of purified water were served on a glass 0.01% hydrogenated soybean lecithin. As a result, the par disk of the foregoing Hoover muller and then kneaded by ticle diameter distribution of acetaminophen nano-powder repeating five times to rotate the disk in 20 turns per time. obtained after above procedures was as follows: D-238 nm, Above-served contents formed a kind of dough during knead the value of D87 nm, the value of Dso-196 nm, and the ing and whereby the turmeric powder was finely milled 10 mg value of Do-381 nm. of the dough obtained after milling was weighed into a 50-mL glass vial and then added 5 mL of a mixed solution of 0.1% Example 34 sodium dodecylsulfate and 0.01% hydrogenated soy bean lecithin. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultra Preparation of an Amphotericin B Nano-Powder Sonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of curcumin nano-powder obtained 0.148. An amphotericin B powder was milled under the after above procedures was as follows: D-263 nm, the value same conditions as Example 31 except both changing from of Do-86 nm, the value of Do 211 nm, and the value of 100 mg of turmeric powder to 100 mg of amphotericin B Do 444 nm. powder and changing from Sucrose fatty acid ester to hydro genated Soybean lecithin. Then, the dough obtained after Example 32 milling was Subjected to a dispersion treatment under the same conditions as Example 31 except adding only 5 mL of Preparation of a Mefenamic Acid Nano-Powder 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy 0146 Amefenamic acid powder was milled and then sub bean lecithin. As a result, the particle diameter distribution of jected to a dispersion treatment under the same conditions as amphotericin B nano-powder obtained after above proce Example 31 except changing from 100 mg of turmeric pow dures was as follows: D162 nm, the value of Do-83 nm, der to 100 mg of mefenamic acid powder. As a result, the the value of Dso-137 nm, and the value of Do 229 nm. particle diameter distribution of mefenamic acid nano-pow 0149 Table 7 shows the particle diameter distributions of der obtained after above procedures was as follows: D-193 various organic compound powders prepared in Examples 31 nm, the value of Do 105 nm, the value of Dso 167 nm, and to 34 as compared with the particle diameter distributions of the value of Do 264 nm. the powders before milling. TABLE 7

Particle diameter distribution (nm Organic Before milling After milling

compound Dav D10 D50 D90 Day D10 DSO D90

Example 31 Cur 1664O 93O 121SO 3.587O 263 86 2.11 444 Example 32 Mef 16130 77O 13290 3 SSSO 193 105 167 264 US 2014/0328917 A1 Nov. 6, 2014 20

TABLE 7-continued

Particle diameter distribution (nm Organic Before milling After milling compound Dav D10 D50 D90 Daw D10 DSO D90

Example 33 Ace 10994O 41240 10346O 18851O 238 87 196 381 Example 34 Amp 1966O S10 12S2O S1740 162 83 137 229

0150. As shown in Table 7, organic compound nano-pow Example 39 der consisting of the particles with so Small particle diameter was prepared when organic compound powder was milled Carbohydrate Compound: Glucose with using trehalose as one of carbohydrate compounds. 0156 Example 39 is same one as Example 22. The particle diameter distribution of curcumin nano-powder obtained in Experiment 9 Example 39 was as follows: D345 nm, the value of Do-96 nm, the value of D-242 nm, and the value of Do-648 nm. Milling with Various Carbohydrate Compounds Example 40 (1) Milling of a Curcumin Powder Carbohydrate Compound: Fructose Example 35 0157 Example 40 is same one as Example 26. The particle diameter distribution of curcumin nano-powder obtained in Carbohydrate Compound: D-Mannitol Example 40 was as follows: D-181 nm, the value of Do-82 nm, the value of Dso-144 nm, and the value of Do 286 mm. 0151 Example 35 is same one as Example 7. The particle diameter distribution of curcumin nano-powder obtained in Example 41 Example 35 was as follows: D384 nm, the value of Do 154 nm, the value of Ds 280 nm, and the value of Carbohydrate Compound: Lactose Monohydrate Do 569 nm 0158. A curcumin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 36 Example 35 except using lactose monohydrate as the carbo 0152 Carbohydrate Compound: Maltitol hydrate compound. As a result, the particle diameter distri bution of curcumin nano-powder obtained after above proce 0153. A curcumin powder was milled and then subjected to a dispersion treatment under the same conditions as dures was as follows: D320 nm, the value of Do-102 nm, Example 35 except using maltitol as the carbohydrate com the value of Do 232 nm, and the value of D574 nm. pound. As a result, the particle diameter distribution of cur Example 42 cumin nano-powder obtained after above procedures was as follows: D-199 nm, the value of Do-95 nm, the value of Carbohydrate Compound: Trehalose Do 176 nm, and the value of Do 286 nm. 0159. Example 42 is same one as Example 31. The particle Example 37 diameter distribution of curcumin nano-powder obtained in Example 42 was as follows: D-263 nm, the value of Do-86 Carbohydrate Compound: Erythritol nm, the value of Do 211 nm, and the value of Do-444 nm. Example 43 0154) A curcumin powder was milled and then subjected to a dispersion treatment under the same conditions as Carbohydrate Compound: Cellobiose Example 35 except using erythritol as the carbohydrate com pound. As a result, the particle diameter distribution of cur 0160 A curcumin powder was milled and then subjected cumin nano-powder obtained after above procedures was as to a dispersion treatment under the same conditions as follows: D-275 nm, the value of Do-98 nm, the value of Example 35 except using cellobiose as the carbohydrate com Dso 201 nm, and the value of Do-483 nm. pound. As a result, the particle diameter distribution of cur cumin nano-powder obtained after above procedures was as Example 38 follows: D-273 nm, the value of Do-41 nm, the value of D.s 241 nm, and the value of Do-435 nm. Carbohydrate Compound: Xylitol 0.161 (2) Milling of a mefenamic acid powder 0155 Example 38 is same one as Example 17. The particle Example 44 diameter distribution of curcumin nano-powder obtained in Carbohydrate Compound: D-Mannitol Example 38 was as follows: D-283 nm, the value of Do 138 nm, the value of Dso 234 nm, and the value of 0162 Example 44 is same one as Example 8. The particle Do 418 nm diameter distribution of mefenamic acid nano-powder US 2014/0328917 A1 Nov. 6, 2014

obtained in Example 44 was as follows: D-247 nm, the procedures was as follows: D-261 nm, the value of value of D-99 nm, the value of Dso 198 nm, and the value Do 114 nm, the value of Ds 207 nm, and the value of of Do-403 nm. Do 417 nm. Example 45 Example 51 Carbohydrate Compound: Maltitol Carbohydrate Compound: Trehalose 0163 Amefenamic acid powder was milled and then sub 0169. Example 51 is same one as Example 32. The particle jected to a dispersion treatment under the same conditions as diameter distribution of mefenamic acid nano-powder Example 44 except using maltitol as the carbohydrate com obtained in Example 51 was as follows: D-193 nm, the pound. As a result, the particle diameter distribution of mefe value of Do-105 nm, the value of Dso-167 nm, and the value namic acid nano-powder obtained after above procedures was of Doo 264 nm. as follows: D-209 nm, the value of Do 115 nm, the value Example 52 of Do 185 nm, and the value of Doo 284 nm. Carbohydrate Compound: Cellobiose Example 46 0170 Amefenamic acid powder was milled and then sub Carbohydrate Compound: Erythritol jected to a dispersion treatment under the same conditions as Example 44 except using cellobiose as the carbohydrate com 0164 Amefenamic acid powder was milled and then sub pound. As a result, the particle diameter distribution of mefe jected to a dispersion treatment under the same conditions as namic acid nano-powder obtained after above procedures was Example 44 except using erythritol as the carbohydrate com as follows: D-271 nm, the value of Do 122 nm, the value pound. As a result, the particle diameter distribution of mefe of Do 217 nm, and the value of Do-424 nm. namic acid nano-powder obtained after above procedures was as follows: D-185 nm, the value of Do 119 nm, the value Example 53 of Dso-164 nm, and the value of Do 230 nm. Carbohydrate Compound: Inositol Example 47 0171 Amefenamic acid powder was milled and then sub jected to a dispersion treatment under the same conditions as Carbohydrate Compound: Xylitol Example 44 except using inositol as the carbohydrate com pound. As a result, the particle diameter distribution of mefe 0.165 Example 47 is same one as Example 18. The particle namic acid nano-powder obtained after above procedures was diameter distribution of mefenamic acid nano-powder as follows: D223 nm, the value of Do-101 nm, the value obtained in Example 47 was as follows: D-241 nm, the of Dso 183 nm, and the value of Do-341 nm. value of D-98 nm, the value of Dso-191 nm, and the value 0172 Tables 8 and 9 show the particle diameter distribu of Do-398 nm. tions of various organic compound powders prepared in Examples 35 to 43 and Examples 44 to 53, respectively as Example 48 compared with the particle diameter distributions of the pow ders before milling. The term “Man’ in the tables means Carbohydrate Compound: Glucose D-mannitol. The term "Mal” in the tables means maltitol. The 0166 Example 48 is same one as Example 23. The particle term “Ery” in the tables means erythritol. The term “Xyl” in diameter distribution of mefenamic acid nano-powder the tables means xylitol. The term “Glu' in the tables means obtained in Example 48 was as follows: D-224 nm, the glucose. The term “Fru' in the tables means fructose. The value of Do-85 nm, the value of Dso-193 nm, and the value term “Lac' in the tables means lactose. The term “Tre’ in the of Do-339 nm. tables means trehalose. The term “Cel' in the tables means cellobiose. The term “Ino' in the tables means inositol. These Example 49 definitions shall apply to following tables. Carbohydrate Compound: Fructose TABLE 8 0167 Example 49 is same one as Example 27. The particle Carbo diameter distribution of mefenamic acid nano-powder hydrate Particle diameter distribution (nm obtained in Example 49 was as follows: D-205 nm, the CO- Before milling After milling value of Do-84 nm, the value of Dso 165 nm, and the value of Doo328 nm. pound Dav D10 D50 D90 Dav D10 D50 D90 Exam- Man 1664O 930 121SO 3587.0 384 154 280 569 Example 50 ple 35 Exam- Mal 199 9S 176 286 Carbohydrate Compound: Lactose Monohydrate ple 36 Exam- Ery 275 98 201 483 ple 37 0168 Amefenamic acid powder was milled and then sub Exam- Xyl 283 138 234 418 jected to a dispersion treatment under the same conditions as ple 38 Example 44 except using lactose monohydrate as the carbo Exam- Glu 345 96 242 648 hydrate compound. As a result, the particle diameter distri ple 39 bution of mefenamic acid nano-powder obtained after above US 2014/0328917 A1 Nov. 6, 2014 22

TABLE 8-continued muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a Carbo kind of dough during kneading and whereby the turmeric hydrate Particle diameter distribution (nm powder was finely milled 10 mg of the dough obtained after CO Before milling After milling milling was weighed into a 50-mL glass vial and then added 5 mL of a mixed solution of 0.1% sodium dodecylsulfate and pound Dav D10 D50 D90 Dav D10 D50 D90 0.01% hydrogenated soy bean lecithin. Then, the solution Exam- Fru 181 82 144 286 obtained above was subjected to a dispersion treatment by ple 40 using the foregoing bath-type ultrasonic disperser for 1 to 2 Exam- Lac 320 102 232 S74 minutes. As a result, the particle diameter distribution of ple 41 Exam- Tre 263 86 2.11 444 curcumin nano-powder obtained after above procedures was ple 42 as follows: D-421 nm, the value of D-80 nm, the value of Exam- Cel 273 41 241 435 Dso-199 nm, and the value of D–685 nm. ple 43 Example 55 Mixture Group: D-Mannitol and Xylitol TABLE 9 0.175. A curcumin powder was milled and then subjected Carbo to a dispersion treatment under the same conditions as hydrate Particle diameter distribution (nm Example 54 except using a mixed carbohydrate compound of CO- Before milling After milling 162.5 mg of D-(-)-mannitol and 162.5 mg of xylitol (mass ratio=1:1) instead of the mixed carbohydrate compound of pound Dav D10 D50 D90 Dav D10 D50 D90 162.5 mg of D-(-)-mannitol and 162.5 mg of sorbitol (mass X8- Man 16130 77O 1329O 3SSSO 247 99 98 403 ratio=1:1). As a result, the particle diameter distribution of ble 44 curcumin nano-powder obtained after above procedures was Exam- Mal 209 115 85 284 as follows: D-237 nm, the value of D-98 nm, the value of ble 45 Exam- Ery 18S 119 64 230 Do 183 nm, and the value of Do-394 nm ble 46 Exam- Xyl 241 98 91 398 Example 56 ble 47 Exam- Glu 224 85 93 339 Mixture Group: D-Mannitol and Dextrin ble 48 Exam- Fru 205 84 6S 328 0176 A curcumin powder was milled and then subjected ble 49 to a dispersion treatment under the same conditions as Exam- Lac 261 114 207 417 ble SO Example 54 except using a mixed carbohydrate compound of Exam- Tre 193 105 67 264 162.5 mg of D-(-)-mannitol and 162.5 mg of dextrin (mass ble 51 ratio=1:1) instead of the mixed carbohydrate compound of Exam- Cel 271 122 217 424 162.5 mg of D-(-)-mannitol and 162.5 mg of sorbitol (mass ble 52 Exam- Ino 223 101 83 341 ratio=1:1). As a result, the particle diameter distribution of ble 53 curcumin nano-powder obtained after above procedures was as follows: D-254 nm, the value of Do-83 nm, the value of Do 189 nm, and the value of Do-454 nm. 0173 As shown in Tables 8 and 9, organic compound 0177 (1) Milling of a mefenamic acid powder nano-powder consisting of the particles with so Small particle diameter was prepared even when organic compound powder Example 57 was milled with using the Sugar alcohol like mannitol, malti tol, erythritol or xylitol; the monosaccharide like inositol, Mixture Group: D-Mannitol and Sorbitol glucose or fructose; or the disaccharide like lactose, trehalose 0.178 The processes of milling and dispersion treatment or cellobiose. were performed under the same conditions as Example 54 except using a mefenamic acid powder instead of the cur Experiment 10 cumin powder. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above proce Milling with a Mixture of Carbohydrate Compounds dures was as follows: D 365 nm, the value of Do 127 nm, the value of Do 239 mm, and the value of D518 nm. (1) Milling of a Curcumin Powder Example 58 Example 54 Mixture Group: D-Mannitol and Xylitol Mixture Group: D-Mannitol and Sorbitol 0179 The processes of milling and dispersion treatment were performed under the same conditions as Example 55 0.174 100 mg of turmeric powder, a mixed carbohydrate except using a mefenamic acid powder instead of the cur compound of 162.5 mg of D-(-)-mannitol and 162.5 mg of cumin powder. As a result, the particle diameter distribution sorbitol (mass ratio=1:1), 50 mg of sucrose fatty acid ester, 9 of mefenamic acid nano-powder obtained after above proce mg of sodium carboxymethyl cellulose and 110 mg of puri dures was as follows: D226 nm, the value of Do 105 nm, fied water were served on a glass disk of the foregoing Hoover the value of Dso-182 nm, and the value of Do-350 nm. US 2014/0328917 A1 Nov. 6, 2014 23

Example 59 salt K30, manufactured by Tomita Pharmaceutical Co., Ltd.), 30 mg of polyvinylpyrrolidone, 50 mg of hydrogenated Soy Mixture Group: D-Mannitol and Dextrin bean lecithin and 200 mg of glycerin were served on a glass 0180. The processes of milling and dispersion treatment disk of the foregoing Hoover muller and then kneaded by were performed under the same conditions as Example 56 repeating five times to rotate the disk in 20 turns per time. except using a mefenamic acid powder instead of the cur Above-served contents formed a kind of dough during knead cumin powder. As a result, the particle diameter distribution ing and whereby the indomethacin powder was finely milled of mefenamic acid nano-powder obtained after above proce 10 mg of the dough obtained after milling was weighed into a dures was as follows: D-238 nm, the value of Do 123 nm, 50-mL glass vial and then added 10 mL of 0.1% sodium the value of Dso-193 nm, and the value of D-351 nm. dodecylsulfate. Then, the solution obtained above was sub 0181 Tables 10 and 11 show the particle diameter distri jected to a dispersion treatment by using the foregoing bath butions of various organic compound powders prepared in type ultrasonic disperser for 1 to 2 minutes. As a result, the Examples 54 to 56 and Examples 57 to 59, respectively as particle diameter distribution of indomethacin nano-powder compared with the particle diameter distributions of the pow obtained after above procedures was as follows: D-283 nm, ders before milling. The term “Sor in the tables means sor the value of Do-104 nm, the value of Ds 204 nm, and the bitol. The term “Dext in the tables means dextrin. value of Doo 500 nm TABLE 10

Particle diameter distribution (nm Carbohydrate Organic Before milling After milling compound compound Dav D10 D50 D90 Dav D10 D50 D90 Example 54 Man + Sor Cur 1664O 930 121SO 3.587O 421 8O 199 685 Example 55 Man + Xyl 237 98 183 394 Example 56 Man + Dext 2S4 83 189 454

TABLE 11

Particle diameter distribution (nm Carbohydrate Organic Before milling After milling compound compound Dav D10 D50 D90 Day D10 D50 D90 Example 57 Man + Sor Mef 16130 77O 13290 355SO 365 127 239 518 Example 58 Man + Xyl 226 105 182 350 Example 59 Man + Dext 238 123 193 351

0182. As shown in Tables 10 and 11, with regard to the Example 61 milling capacity of the carbohydrate compound, the mixture system of mannitol and Xylitol or the mixture system of 0186. An indomethacin powder was milled and then sub mannitol and dextrin was more advantageous than the mix jected to a dispersion treatment under the same conditions as ture system of mannitol and Sorbitol. Example 60 except using only a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol: Experiment 11 sodium chloride=6:1 and no hydrogenated soybean lecithin. As a result, the particle diameter distribution of indomethacin Milling with a Mixture of Carbohydrate Compound nano-powder obtained after above procedures was as follows: and Salt D253 nm, the value of Do-98 nm, the value of Dso 189 nm, and the value of Doo. 432 nm. 0183 Various organic compounds were milled with a mix ture of carbohydrate compound and salt. Example 62 (1) Preparation of an Indomethacin Nano-Powder 0187. An indomethacin powder was milled and then sub jected to a dispersion treatment under the same conditions as Example 60 Example 60 except using a mixture of carbohydrate com pound and salt which was in a mass ratio of D-mannitol: 0184 An indomethacin powder was milled with using a sodium chloride=1:1 (350 mg of D-(-)-mannitol and 350 mg mixture of carbohydrate compound and salt which was in a of sodium chloride). As a result, the particle diameter distri mass ratio of D-mannitol:sodium chloride=6:1 and a hydro bution of indomethacin nano-powder obtained after above genated Soybean lecithin under following conditions. procedures was as follows: D340 nm, the value of 0185. 100 mg of indomethacin powder, 600 mg of D-(-)- Do 171 nm, the value of Dso 296 nm, and the value of mannitol, 100 mg of sodium chloride (trade name of Tomita Doo. 474 nm. US 2014/0328917 A1 Nov. 6, 2014 24

Example 63 follows: D-211 nm, the value of Do 115 nm, the value of Do 181 nm, and the value of Do 292 nm. 0188 An indomethacin powder was milled and then sub jected to a dispersion treatment under the same conditions as Example 67 Example 61 except using only a mixture of carbohydrate 0193 A felbinac powder was milled and then subjected to compound and salt which was in a mass ratio of D-mannitol: a dispersion treatment under the same conditions as Example sodium chloride=1:1 (350 mg of D-(-)-mannitol and 350 mg 65 except using a mixture of carbohydrate compound and salt of Sodium chloride) and no hydrogenated Soybean lecithin. which was in a mass ratio of D-mannitol:Sodium chlo As a result, the particle diameter distribution of indomethacin ride=1:1 (350 mg of D-(-)-mannitol and 350 mg of sodium nano-powder obtained after above procedures was as follows: chloride). As a result, the particle diameter distribution of D-255 nm, the value of Do 100 nm, the value of Dso-199 felbinac nano-powder obtained after above procedures was as nm, and the value of Do-419 nm follows: D228 nm, the value of Do 126 nm, the value of Dso-199 nm, and the value of Do 305 nm. (2) Preparation of a Felbinac Nano-Powder (3) Preparation of a Pranlukast Hydrate Nano-Powder Example 64 Example 68 0189 A felbinac powder was milled with using a mixture 0.194. A pranlukast hydrate powder was milled with using of carbohydrate compound and salt which was in a mass ratio a mixture of carbohydrate compound and salt which was in a of D-mannitol: sodium chloride=6:1 and a hydrogenated soy mass ratio of D-mannitol:sodium chloride=6:1 and a hydro bean lecithin under following conditions. genated Soybean lecithin under following conditions. 0.190 100 mg of felbinac powder (same as used in 0.195 100 mg of pranlukast hydrate powder, 600 mg of Example 14 and also used in following experiments), 600 mg D-(-)-mannitol, 100 mg of sodium chloride, 30 mg of poly of D-(-)-mannitol, 100 mg of sodium chloride (same as used vinylpyrrolidone, 50 mg of hydrogenated soybean lecithin in Example 60 and also used in following experiments), 30 and 200 mg of glycerin were served on a glass disk of the mg of polyvinylpyrrolidone, 50 mg of hydrogenated Soybean foregoing Hoover muller and then kneaded by repeating five lecithin and 200 mg of glycerin were served on a glass disk of times to rotate the disk in 20 turns per time. Above-served the foregoing Hoover muller and then kneaded by repeating contents formed a kind of dough during kneading and five times to rotate the disk in 20 turns per time. Above-served whereby the pranlukast hydrate powder was finely milled. 10 contents formed a kind of dough during kneading and mg of the dough obtained after milling was weighed into a whereby the felbinac powder was finely milled. 10 mg of the 50-mL glass vial and then added 10 mL of 0.1% sodium dough obtained after milling was weighed into a 50-mL glass dodecylsulfate. Then, the solution obtained above was sub vial and then added 10 mL of 0.1% sodium dodecylsulfate. jected to a dispersion treatment by using the foregoing bath Then, the solution obtained above was subjected to a disper type ultrasonic disperser for 1 to 2 minutes. As a result, the sion treatment by using the foregoing bath-type ultrasonic particle diameter distribution of pranlukast hydrate nano disperser for 1 to 2 minutes. As a result, the particle diameter powder obtained after above procedures was as follows: distribution of felbinac nano-powder obtained after above D=151 nm, the value of Do-60 nm, the value of D-116 procedures was as follows: D-246 nm, the value of nm, and the value of Doo 253 nm. Do 137 nm, the value of Do 212 nm, and the value of Do 330 nm. Example 69 0196. A pranlukast hydrate powder was milled and then Example 65 Subjected to a dispersion treatment under the same conditions 0191) A felbinac powder was milled and then subjected to as Example 68 except using only a mixture of carbohydrate a dispersion treatment under the same conditions as Example compound and salt which was in a mass ratio of D-mannitol: 64 except using only a mixture of carbohydrate compound sodium chloride=6:1 and no hydrogenated soybean lecithin. and salt which was in a mass ratio of D-mannitol:Sodium As a result, the particle diameter distribution of pranlukast chloride=6:1 and no hydrogenated soybean lecithin. As a hydrate nano-powder obtained after above procedures was as result, the particle diameter distribution of felbinac nano follows: D-195 nm, the value of Do 56 nm, the value of powder obtained after above procedures was as follows: Do 152 nm, and the value of Do-345 nm. D=228 nm, the value of Do 105 nm, the value of Dso 186 nm, and the value of Do-349 nm. Example 70 0.197 A pranlukast hydrate powder was milled and then Example 66 Subjected to a dispersion treatment under the same conditions as Example 68 except using a mixture of carbohydrate com 0.192 A felbinac powder was milled and then subjected to pound and salt which was in a mass ratio of D-mannitol: a dispersion treatment under the same conditions as Example sodium chloride=1:1 (350 mg of D-(-)-mannitol and 350 mg 64 except using a mixture of carbohydrate compound and salt of sodium chloride). As a result, the particle diameter distri which was in a mass ratio of D-mannitol:Sodium chlo bution of pranlukast hydrate nano-powder obtained after ride=1:1 (350 mg of D-(-)-mannitol and 350 mg of sodium above procedures was as follows: D-192 nm, the value of chloride). As a result, the particle diameter distribution of Do-90 nm, the value of Dso-158 nm, and the value of felbinac nano-powder obtained after above procedures was as Doo-295 nm. US 2014/0328917 A1 Nov. 6, 2014

Example 71 Example 75 0198 A pranlukast hydrate powder was milled and then 0203) A dexamethasone powder was milled and then sub Subjected to a dispersion treatment under the same conditions jected to a dispersion treatment under the same conditions as as Example 69 except using a mixture of carbohydrate com Example 73 except using a mixture of carbohydrate com pound and salt which was in a mass ratio of D-mannitol: pound and salt which was in a mass ratio of D-mannitol: sodium chloride=1:1 (350 mg of D-(-)-mannitol and 350 mg sodium chloride=1:1 (350 mg of D-(-)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distri of sodium chloride). As a result, the particle diameter distri bution of pranlukast hydrate nano-powder obtained after bution of dexamethasone nano-powder obtained after above above procedures was as follows: D204 nm, the value of procedures was as follows: D-185 nm, the value of Do-81 nm, the value of Dso-166 nm, and the value of Do 108 nm, the value of Dso 162 nm, and the value of Doo326 nm Doo 243 nm. (4) Preparation of a Dexamethasone Nano-Powder (5) Preparation of a Fenofibrate Nano-Powder Example 72 Example 76 0199. A dexamethasone powder was milled with using a 0204. A fenofibrate powder was milled with using a mix mixture of carbohydrate compound and salt which was in a ture of carbohydrate compound and salt which was in a mass mass ratio of D-mannitol:sodium chloride=6:1 and a hydro ratio of D-mannitol: sodium chloride=6:1 and a hydrogenated genated Soybean lecithin under following conditions. Soybean lecithin under following conditions. 0205 100 mg of fenofibrate powder (manufactured by 0200 100 mg of dexamethasone powder, 600 mg of Sigma-Aldrich Corporation, D.: 48170 nm, the value of Do: D-(-)-mannitol, 100 mg of sodium chloride, 30 mg of poly 3520 nm, the value of Ds: 33720 nm, and the value of Do: vinylpyrrolidone, 50 mg of hydrogenated soybean lecithin 115590 nm), 600 mg of D-(-)-mannitol, 100 mg of sodium and 200 mg of glycerin were served on a glass disk of the chloride, 30 mg of polyvinylpyrrolidone, 50 mg of hydroge foregoing Hoover muller and then kneaded by repeating five nated soybean lecithin and 200 mg of glycerin were served on times to rotate the disk in 20 turns per time. Above-served a glass disk of the foregoing Hoover muller and then kneaded contents formed a kind of dough during kneading and by repeating five times to rotate the disk in 20 turns per time. whereby the dexamethasone powder was finely milled. 20 mg Above-served contents formed a kind of dough during knead of the dough obtained after milling was weighed into a 50-mL ing and whereby the fenofibrate powder was finely milled 10 glass vial and then added 5 mL of Polyoxyethylene Hydro mg of the dough obtained after milling was weighed into a genated Castor Oil 60 (NIKKOL HCO-60, manufactured by 50-mL glass vial and then added 10 mL of 0.1% sodium Nikko Chemicals Co., Ltd.). Then, the solution obtained dodecylsulfate. Then, the solution obtained above was sub above was Subjected to a dispersion treatment by using the jected to a dispersion treatment by using the foregoing bath foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As type ultrasonic disperser for 1 to 2 minutes. As a result, the a result, the particle diameter distribution of dexamethasone particle diameter distribution of fenofibrate nano-powder nano-powder obtained after above procedures was as follows: obtained after above procedures was as follows: D-320 nm, D217 nm, the value of Do-74 nm, the value of Dso-158 the value of Do 149 nm, the value of Dso-265 nm, and the nm, and the value of Do-389 mm. value of Do-474 nm. Example 73 Example 77 0201 A dexamethasone powder was milled and then sub 0206. A fenofibrate powder was milled and then subjected jected to a dispersion treatment under the same conditions as to a dispersion treatment under the same conditions as Example 72 except using only a mixture of carbohydrate Example 76 except using only a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol: compound and salt which was in a mass ratio of D-mannitol: sodium chloride=6:1 and no hydrogenated soybean lecithin. sodium chloride=6:1 and no hydrogenated soybean lecithin. As a result, the particle diameter distribution of dexametha As a result, the particle diameter distribution offenofibrate Sone nano-powder obtained after above procedures was as nano-powder obtained after above procedures was as follows: follows: D168 nm, the value of D82 nm, the value of D-269 nm, the value of Do 132 nm, the value of Dso 223 D149 nm, and the value of D-240 nm. nm, and the value of Doo397 nm. Example 74 Example 78 0202) A dexamethasone powder was milled and then sub 0207. A fenofibrate powder was milled and then subjected jected to a dispersion treatment under the same conditions as to a dispersion treatment under the same conditions as Example 72 except using a mixture of carbohydrate com Example 76 except using a mixture of carbohydrate com pound and salt which was in a mass ratio of D-mannitol: pound and salt which was in a mass ratio of D-mannitol: sodium chloride=1:1 (350 mg of D-(-)-mannitol and 350 mg sodium chloride=1:1 (350 mg of D-(-)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distri of sodium chloride). As a result, the particle diameter distri bution of dexamethasone nano-powder obtained after above bution offenofibrate nano-powder obtained after above pro procedures was as follows: D205 nm, the value of Do-75 cedures was as follows: D-368 nm, the value of Do 182 nm, the value of Dso-166 nm, and the value of Do-336 nm. nm, the value of Ds 298 nm, and the value of Doo 547 nm. US 2014/0328917 A1 Nov. 6, 2014 26

Example 79 using the foregoing bath-type ultrasonic disperser for 1 to 2 0208 A fenofibrate powder was milled and then subjected minutes. As a result, the particle diameter distribution of to a dispersion treatment under the same conditions as indomethacin nano-powder obtained after above procedures Example 77 except using a mixture of carbohydrate com was as follows: D-335 nm, the value of D-115 nm, the pound and salt which was in a mass ratio of D-mannitol: value of Do 237 nm, and the value of Doo-609 mm. sodium chloride=1:1 (350 mg of D-(-)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distri Example 81 bution offenofibrate nano-powder obtained after above pro cedures was as follows: D.311 nm, the value of Do 172 0213. An indomethacin powder was milled and then sub nm, the value of Dso 264 nm, and the value of Do-427 nm. jected to a dispersion treatment under the same conditions as 0209 Table 12 shows the particle diameter distributions of Example 80 except using 350 mg of D-(-)-mannitol and 350 various organic compound powders prepared in Examples 60 mg of sodium chloride. As a result, the particle diameter to 79. The term “Fen in the table means fenofibrate. distribution of indomethacin nano-powder obtained after TABLE 12 hydrogenated Particle diameter distribution (nm Organic Carbohydrate Carbohydrate: soybean Before milling After milling compound compound Salt Salt lecithin Dav D10 D50 D90 Day D10 DSO D90

Exam e 60 Ind Man NaC 6: Exis 12400 630 867O 3O820 283 104 204 SOO Exam e 61 No 253 98 189 432 Exam e 62 Exis 340 171 296 474 Exam e 63 No 2SS 100 199 419 Exam e 64 Fel Man NaC 6: Exis 19072O 4627O 166710 35686O 246 137 212 330 Exam e 65 No 228 1 OS 186 349 Exam e 66 Exsist 211 115 181 292 Exam e 67 No 228 126 199 30S Exam e 68 Pra Man NaC 6: Exis 9500 1 OSO 61SO 23660 151 6O 116 253 Exam e 69 No 195 S6 1S2 345 Exam e 70 Exis 192 90 158. 295 Exam e 71 No 204 81 166 326 Exam e 72 Dex Man NaC 6: Exis 2690 28O 258O 5360 217 74 158 389 Exam e 73 No 168 82 149 240 Exam e 74 Exis 205 7S 166 336 Exam e 75 No 18S 108 162 243 Exam e 76 Fen Man NaC 6: Exis 4817O 3S2O 3372O 115590 320 149 26S 474 Exam e 77 No 269 132 223 397 Exam e 78 Exis 368 182 298 S47 Exam e 79 No 311 172 264 427

0210. As shown in Table 12, the diameter distributions of above procedures was as follows: D-243 nm, the value of nano-powders obtained after milling various organic com Do 132 nm, the value of Ds 209 nm, and the value of pounds were almost same one in spite of changing the mass Do 332 nm. ratio of the carbohydrate compound and the salt, or the pres Example 82 ence or absence of lecithin. 0214. An indomethacin powder was milled and then sub jected to a dispersion treatment under the same conditions as Experiment 12 Example 80 except using 700 mg of D-(-)-mannitol and no sodium chloride. As a result, the particle diameter distribution Milling without Anti-Agglomeration Agent of indomethacin nano-powder obtained after above proce 0211 Various organic compounds were milled with car dures was as follows: D-283 nm, the value of Do 128 nm, bohydrate compound and polyol, further with salt optionally. the value of Dso 231 nm, and the value of Do-433 nm (1) Preparation of a Felbinac Nano-Powder (1) Preparation of an Indomethacin Nano-Powder Example 83 Example 80 0215 100 mg offelbinac powder, 600 mg of D-(-)-man nitol, 100 mg of sodium chloride and 200 mg of glycerin were 0212 100 mg of indomethacin powder, 600 mg of D-(-)- served on a glass disk of the foregoing Hoover muller and mannitol, 100 mg of sodium chloride and 200 mg of glycerin then kneaded by repeating five times to rotate the disk in 20 were served on a glass disk of the foregoing Hoover muller turns pertime. Above-served contents formed a kind of dough and then kneaded by repeating five times to rotate the disk in during kneading and whereby the felbinac powder was finely 20 turns per time. Above-served contents formed a kind of milled. 10 mg of the dough obtained after milling was dough during kneading and whereby the indomethacin pow weighed into a 50-mL glass vial and then added 10 mL of der was finely milled. 10 mg of the dough obtained after 0.1% sodium dodecylsulfate. Then, the solution obtained milling was weighed into a 50-mL glass vial and then added above was subjected to a dispersion treatment by using the 10 mL of 0.1% sodium dodecylsulfate. Then, the solution foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As obtained above was subjected to a dispersion treatment by a result, the particle diameter distribution of felbinac nano US 2014/0328917 A1 Nov. 6, 2014 27 powder obtained after above procedures was as follows: Example 88 D=415 nm, the value of Do 236 nm, the value of Dso 360 0220 A pranlukast hydrate powder was milled and then nm, and the value of Doo-588 nm. Subjected to a dispersion treatment under the same conditions Example 84 as Example 86 except using 700 mg of D-(-)-mannitol and no sodium chloride. As a result, the particle diameter distribution 0216 A felbinac powder was milled and then subjected to of pranlukast hydrate nano-powder obtained after above pro a dispersion treatment under the same conditions as Example cedures was as follows: D-188 nm, the value of Do 100 83 except using 350 mg of D-(-)-mannitol and 350 mg of nm, the value of Dso-159 nm, and the value of Doo-265 nm. sodium chloride. As a result, the particle diameter distribution offelbinac nano-powder obtained after above procedures was (4) Preparation of a Dexamethasone Nano-Powder as follows: D-479 nm, the value of Do 257 nm, the value of Dso. 414 nm, and the value of Doo-690 nm. Example 89 Example 85 0221 100 mg of dexamethasone powder, 600 mg of D-(-)-mannitol, 100 mg of sodium chloride and 200 mg of 0217. A felbinac powder was milled and then subjected to glycerin were served on a glass disk of the foregoing Hoover a dispersion treatment under the same conditions as Example muller and then kneaded by repeating five times to rotate the 83 except using 700 mg of D-(-)-mannitol and no sodium disk in 20 turns per time. Above-served contents formed a chloride. As a result, the particle diameter distribution of kind of dough during kneading and whereby the dexametha felbinac nano-powder obtained after above procedures was as sone powder was finely milled 20 mg of the dough obtained follows: D-488 nm, the value of D-242 nm, the value of after milling was weighed into a 50-mL glass vial and then Do 410 nm, and the value of D–744 nm. added 5 mL of 0.1% Polyoxyethylene Hydrogenated Castor Oil 60. Then, the solution obtained above was subjected to a (3) Preparation of a Pranlukast Hydrate Nano-Powder dispersion treatment by using the foregoing bath-type ultra Example 86 Sonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of dexamethasone nano-powder 0218 100 mg of pranlukast hydrate powder, 600 mg of obtained after above procedures was as follows: D 221 nm, D-(-)-mannitol, 100 mg of sodium chloride and 200 mg of the value of Do 114 nm, the value of D-185 nm, and the glycerin were served on a glass disk of the foregoing Hoover value of Doo318 nm. muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a Example 90 kind of dough during kneading and whereby the pranlukast hydrate powder was finely milled 10 mg of the dough 0222. A dexamethasone powder was milled and then sub obtained after milling was weighed into a 50-mL glass vial jected to a dispersion treatment under the same conditions as and then added 10 mL of 0.1% Polyoxyethylene Hydroge Example 89 except using 350 mg of D-(-)-mannitol and 350 nated Castor Oil 60. Then, the solution obtained above was mg of sodium chloride. As a result, the particle diameter Subjected to a dispersion treatment by using the foregoing distribution of dexamethasone nano-powder obtained after bath-type ultrasonic disperser for 1 to 2 minutes. As a result, above procedures was as follows: D-227 nm, the value of the particle diameter distribution of pranlukast hydrate nano Do 133 nm, the value of Dso 198 nm, and the value of powder obtained after above procedures was as follows: Doo-295 nm. D=286 nm, the value of Do-95 nm, the value of Do 171 nm, and the value of Do-327 nm. Example 91 0223) A dexamethasone powder was milled and then sub Example 87 jected to a dispersion treatment under the same conditions as 0219. A pranlukast hydrate powder was milled and then Example 89 except using 700 mg of D-(-)-mannitol and no Subjected to a dispersion treatment under the same conditions sodium chloride. As a result, the particle diameter distribution as Example 86 except using 350 mg of D-(-)-mannitol and of dexamethasone nano-powder obtained after above proce 350 mg of sodium chloride. As a result, the particle diameter dures was as follows: D-270 nm, the value of D-125 nm, distribution of pranlukast hydrate nano-powder obtained the value of Dso 225 nm, and the value of Do-401 nm. after above procedures was as follows: D-190 nm, the value 0224 Table 13 shows the particle diameter distributions of of Do-93 nm, the value of Dso-158 nm, and the value of various organic compound powders prepared in Examples 80 Do 282 nm. to 91. TABLE 13

Particle diameter distribution (nm Organic Carbohydrate Carbohydrate: Before milling After milling

compound compound Salt Salt Dav D10 D50 D90 Dav D10 DSO D90

Example 80 Ind Man NaCl 6:1 124OO 630 867O 3O820 335 115 237 609 Example 81 1:1 243 132 209 332 Example 82 1:O 283 128 231 433 Example 83 Fel Man NaCl 6:1 19072O 4627O 166710 35686O 415 236 360 S88 US 2014/0328917 A1 Nov. 6, 2014 28

TABLE 13-continued

Particle diameter distribution (nm Organic Carbohydrate Carbohydrate: Before milling After milling compound compound Salt Salt Dav D10 D50 D90 Dav D10 DSO D90 Example 84 1:1 479 257 414 690 Example 85 1:O 488 242 410 744 Example 86 Pra Man NaCl 6:1 9500 1OSO 61SO 2366O 286 95 171 327 Example 87 1:1 190 93 158 282 Example 88 1:O 188 100 159 265 Example 89 Dex Man NaCl 6:1 2690 280 2S8O S360 221 114 185 318 Example 90 1:1 227 133 198 295 Example 91 1:O 270 125 22S 401

0225. As shown clearly from Table 13, it was achieved to (2) Milling with Propylene Glycol as Polyol mill the organic compound to nanoscale even without adding any anti-agglomeration agents like lecithin and polyvinylpyr Example 95 rolidone at the process of milling. 0230. An indomethacin powder was milled and then sub jected to a dispersion treatment under the same conditions as Experiment 13 Example 92 except using propylene glycol (manufactured by Wako Pure Chemical Industries, Ltd. and also used in follow Milling with Using Various Polyols ing experiments) instead of ethylene glycol. As a result, the 0226. An indomethacin powder was milled with adding particle diameter distribution of indomethacin nano-powder carbohydrate compound and polyols other than glycerin. obtained after above procedures was as follows: D217 nm, (1) Milling with Ethylene Glycol as Polyol the value of Do 125 nm, the value of D-189 nm, and the value of Doo 284 nm. Example 92 Example 96 0227 100 mg of indomethacin powder, 700 mg of xylitol and 200 mg of ethylene glycol (manufactured by Wako Pure 0231. An indomethacin powder was milled and then sub Chemical Industries, Ltd.) were served on a glass disk of the jected to a dispersion treatment under the same conditions as foregoing Hoover muller and then kneaded by repeating five Example 95 except using fructose instead of xylitol. As a times to rotate the disk in 20 turns per time. Above-served result, the particle diameter distribution of indomethacin contents formed a kind of dough during kneading and nano-powder obtained after above procedures was as follows: whereby the indomethacin powder was finely milled. 10 mg D-316 nm, the value of Do 118 nm, the value of Dso-222 of the dough obtained after milling was weighed into a 50-mL nm, and the value of Do-497 nm. glass vial and then added 10 mL of 0.1% sodium dodecylsul fate. Then, the solution obtained above was subjected to a Example 97 dispersion treatment by using the foregoing bath-type ultra 0232 An indomethacin powder was milled and then sub Sonic disperser for 1 to 2 minutes. As a result, the particle jected to a dispersion treatment under the same conditions as diameter distribution of indomethacinnano-powder obtained Example 95 except using trehalose instead of xylitol. As a after above procedures was as follows: D-487 nm, the value result, the particle diameter distribution of indomethacin of Do 121 nm, the value of Ds 204 nm, and the value of nano-powder obtained after above procedures was as follows: Do 498 nm. D 365 nm, the value of Do 158 nm, the value of Ds 283 nm, and the value of D.598 nm. Example 93 (3) Milling with Polyethylene Glycolas Polyol 0228. An indomethacin powder was milled and then sub jected to a dispersion treatment under the same conditions as Example 98 Example 92 except using fructose instead of xylitol. As a 0233. An indomethacin powder was milled and then sub result, the particle diameter distribution of indomethacin jected to a dispersion treatment under the same conditions as nano-powder obtained after above procedures was as follows: Example 92 except using polyethylene glycol 400 (manufac D=261 nm, the value of Do 142 nm, the value of Dso 227 tured by Wako Pure Chemical Industries, Ltd. and also used in nm, and the value of Doo353 nm. following experiments) instead of ethylene glycol. As a result, the particle diameter distribution of indomethacin Example 94 nano-powder obtained after above procedures was as follows: 0229. An indomethacin powder was milled and then sub D-456 nm, the value of Do 136 nm, the value of Ds 278 jected to a dispersion treatment under the same conditions as nm, and the value of Doo-726 mm. Example 92 except using trehalose instead of Xylitol. As a Example 99 result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: 0234. An indomethacin powder was milled and then sub D=420 nm, the value of Do-130 nm, the value of Ds 309 jected to a dispersion treatment under the same conditions as nm, and the value of Doo-749 nm. Example 98 except using fructose instead of xylitol. As a US 2014/0328917 A1 Nov. 6, 2014 29 result, the particle diameter distribution of indomethacin D-926 nm, the value of Do-155 nm, the value of Ds 276 nano-powder obtained after above procedures was as follows: nm, and the value of Doo3673 nm. D-368 nm, the value of Do 145 nm, the value of Ds 281 nm, and the value of Doo-616 mm. Comparative Example 13 0241. A mefenamic acid powder was milled under the Example 100 condition using D-mannitol of 0.1 times by mass relative to 0235 An indomethacin powder was milled and then sub the mefenamic acid powder. Specifically, the mefenamic acid jected to a dispersion treatment under the same conditions as powder was milled and then Subjected to a dispersion treat Example 98 except using trehalose instead of xylitol. As a ment under the same conditions as Comparative Example 12 result, the particle diameter distribution of indomethacin except both milling with adding 10 mg of D-(-)-mannitol and nano-powder obtained after above procedures was as follows: weighing 4 mg of the dough obtained after milling into the D=454 nm, the value of Do 151 nm, the value of Dso 351 foregoing glass vial. As a result, the particle diameter distri nm, and the value of Doo-776 nm. bution of mefenamic acid powder obtained after above pro 0236 Table 14 shows the particle diameter distributions of cedures was as follows: D1013 nm, the value of Do 212 indomethacin powders prepared in Examples 92 to 100. nm, the value of Do-467 nm, and the value of Do 1722 nm. TABLE 1.4

Particle diameter distribution (nm Organic Carbohydrate Before milling After milling compound Polyol compound Dav D10 D50 D90 Day D10 DSO D90 Example 92 Ind Ethylene Xyl 124OO 630 867O 3O820 487 121 204 498 Example 93 glycol Fru 261 142 227 353 Example 94 Tre 42O 130 309 749 Example 95 Propylene Xyl 217 125 189 284 Example 96 glycol Fru 31 6 11.8 222 497 Example 97 Tre 36S 158 283 598 Example 98 Polyethylene Xyl 456 136 278 726 Example 99 glycol 400 Fru 368 145 281 616 Example 100 Tre 454. 151 351 776

0237 As shown clearly from Table 14, it was achieved to Example 101 mill the organic compound to nanoscale even with using 0242. A mefenamic acid powder was milled under the polyols other than glycerin. condition using D-mannitol of 0.3 times by mass relative to the mefenamic acid powder. Specifically, the mefenamic acid Experiment 14 powder was milled and then Subjected to a dispersion treat ment under the same conditions as Comparative Example 12 Investigation of the Additive Ratio of Carbohydrate except both milling with adding 33 mg of D-(-)-mannitol and Compound weighing 5 mg of the dough obtained after milling into the 0238 Amefenamic acid powder was milled with using a foregoing glass vial. As a result, the particle diameter distri variety of the additive ratios of a carbohydrate compound bution of mefenamic acid nano-powder obtained after above relative to an organic compound. procedures was as follows: D326 nm, the value of Do 150 nm, the value of Ds 265 nm, and the value of Comparative Example 12 Do-495 nm. 0239 Amefenamic acid powder was milled without add Example 102 ing D-mannitol under following conditions. 0240 100 mg of mefenamic acid powder used at Example 0243 A mefenamic acid powder was milled under the 8 in EXPERIMENT 4, 0 mg of D-(-)-mannitol, 50 mg of condition using D-mannitol of 0.5 times by mass relative to Sucrose fatty acid ester, 9 mg of sodium carboxymethyl cel the mefenamic acid powder. Specifically, the mefenamic acid lulose and 110 mg of purified water were served on a glass powder was milled and then Subjected to a dispersion treat disk of the foregoing Hoover muller and then kneaded by ment under the same conditions as Comparative Example 12 repeating five times to rotate the disk in 20 turns per time. except both milling with adding 50 mg of D-(-)-mannitol and Above-served contents formed a kind of dough during knead weighing 7 mg of the dough obtained after milling into the ing and whereby the mefenamic acid powder was finely foregoing glass vial. As a result, the particle diameter distri milled. 2 mg of the dough obtained after milling was weighed bution of mefenamic acid nano-powder obtained after above into a 50-mL glass vial and then added 5 mL of a mixed procedures was as follows: D382 nm, the value of solution of 0.1% sodium dodecylsulfate and 0.01% hydroge Do 169 nm, the value of Dso-316 nm, and the value of nated soybean lecithin. Then, the solution obtained above Do 573 nm. was subjected to a dispersion treatment by using the forego ing bath-type ultrasonic disperser for 1 to 2 minutes. As a Example 103 result, the particle diameter distribution of mefenamic acid 0244. A mefenamic acid powder was milled under the powder obtained after above procedures was as follows: condition using D-mannitol of 1.0 time by mass relative to the US 2014/0328917 A1 Nov. 6, 2014 30 mefenamic acid powder. Specifically, the mefenamic acid nano-powder obtained after above procedures was as follows: powder was milled and then Subjected to a dispersion treat D-271 nm, the value of Do 126 nm, the value of Dso 227 ment under the same conditions as Comparative Example 12 nm, and the value of Do-403 nm. except both milling with adding 100 mg of D-(-)-mannitol and weighing 10 mg of the dough obtained after milling into Example 106 the foregoing glass vial. As a result, the particle diameter 0247. A mefenamic acid powder was milled under the distribution of mefenamic acid nano-powder obtained after condition using D-mannitol of 50 times by mass relative to above procedures was as follows: D-267 nm, the value of the mefenamic acid powder. Specifically, the mefenamic acid D125 nm, the value of Do 217 nm, and the value of powder was milled and then Subjected to a dispersion treat Doo. 404 nm. ment under the same conditions as Example 105 except both milling with adding 500 mg of D-(-)-mannitol and weighing Example 104 150 mg of the dough obtained after milling into the foregoing 0245. A mefenamic acid powder was milled under the glass vial. As a result, the particle diameter distribution of condition using D-mannitol of about 3.3 times by mass rela mefenamic acid nano-powder obtained after above proce tive to the mefenamic acid powder. Specifically, the mefe dures was as follows: D-245 nm, the value of Do 117 nm, namic acid powder was milled and then Subjected to a disper the value of Ds 207 nm, and the value of Doo358 nm. sion treatment under the same conditions as Comparative Example 107 Example 12 except both milling with adding 325 mg of D-(-)-mannitol and weighing 10 mg of the dough obtained 0248. A mefenamic acid powder was milled under the after milling into the foregoing glass vial. As a result, the condition using D-mannitol of 100 times by mass relative to particle diameter distribution of mefenamic acid nano-pow the mefenamic acid powder. Specifically, the mefenamic acid der obtained after above procedures was as follows: D-247 powder was milled and then Subjected to a dispersion treat nm, the value of D-99 nm, the value of Dso 198 nm, and ment under the same conditions as Example 105 except both milling with adding 1000 mg of D-(-)-mannitol and 250 mg the value of Do-403 nm. of purified water and weighing 300 mg of the dough obtained Example 105 after milling into the foregoing glass vial. As a result, the particle diameter distribution of mefenamic acid nano-pow 0246 A mefenamic acid powder was milled under the der obtained after above procedures was as follows: D-264 condition using D-mannitol of 30 times by mass relative to nm, the value of Do 132 nm, the value of Do 217 nm, and the mefenamic acid powder. Specifically, 10 mg of mefe the value of Doo386 nm. namic acid powder, 300 mg of D-(-)-mannitol, 5 mg of 0249 Table 15 shows the particle diameter distributions of Sucrose fatty acid ester, 1 mg of sodium carboxymethyl cel mefenamic acid powders prepared in Comparative Examples lulose and 200 mg of purified water were served on a glass 12, 13 and Examples 101 to 107. TABLE 1.5

Additive ratio of a carbohydrate Particle diameter distibution (nm Organic Carbohydrate compound Before milling After milling compound compound (times) Day D10 DSO D90 Day D10 DSO D90 Comparative Mef Man O 16130 77O 13290 355SO 926 155 276 3673 Example 12 Comparative O.1 1013 212 467 1722 Example 13 Example 101 O.3 326 1SO 265 495 Example 102 O.S 382 169 316 573 Example 103 1 267 125 217 404 Example 104 3.3 247 99 198 403 Example 105 30 271 126 227 403 Example 106 50 245 117 207 358 Example 107 100 264 132 217 386 disk of the foregoing Hoover muller and then kneaded by 0250) As shown clearly from Table 15, the organic com repeating five times to rotate the disk in 20 turns per time. pound nano-powder with an average particle diameter of 500 Above-served contents formed a kind of dough during knead nm or less and a 90%-diameter of less than 1500 nm was ing and whereby the mefenamic acid powder was finely Successfully produced when an organic compound powder milled. 100 mg of the dough obtained after milling was was milled under the condition using the carbohydrate com weighed into a 50-mL glass vial and then added 5 mL of a pound with the additive ratio of 0.3 times or more by mass mixed solution of 0.1% sodium dodecylsulfate and 0.01% relative to the organic compound powder. hydrogenated soybean lecithin. Then, the solution obtained above was Subjected to a dispersion treatment by using the INDUSTRIAL APPLICABILITY foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As 0251. The present invention can be used in such fields as a a result, the particle diameter distribution of mefenamic acid drug, a health food and a cosmetic. US 2014/0328917 A1 Nov. 6, 2014

1. An organic compound nano-powder comprising: by mass relative to amount of the organic compound, a granular organic compound with an average particle and liquid in which the organic compound is insoluble or diameter of 500 nm or less and a 90%-diameter of less poorly soluble; and than 1500 nmi; and wet-milling the organic compound after the mixing so that an average particle diameter thereof becomes 500 nm or a carbohydrate compound comprising at least any one of a less and a 90%-diameter thereof becomes less than 1500 Sugar and a Sugar alcohol and with amount of 0.3 times . or more by mass relative to amount of the organic com 10. The method for producing an organic compound nano pound. powder according to claim 9, wherein the carbohydrate com 2. The organic compound nano-powder according to claim pound is in an amount of 0.5 to 30 times by mass relative to 1, wherein the carbohydrate compound is in an amount of 0.5 amount of the organic compound. to 30 times by mass relative to amount of the organic com 11. The method for producing an organic compound nano pound. powder according to claim 9, wherein the mixing is carried 3. The organic compound nano-powder according to claim out with adding a physiologically acceptable polyol as liquid 1, further comprising a physiologically acceptable polyol. in which the organic compound is insoluble or poorly soluble. 4. The organic compound nano-powder according to claim 12. The method for producing an organic compound nano 1, wherein the carbohydrate compound are one or more kinds powder according to claim 9, wherein the wet-milling of the selected from the group consisting of mannitol, maltitol. Xyli organic compound is carried out while kneading the mixture obtained after the mixing in a kneader. tol, erythritol, glucose, fructose, inositol, lactose, trehalose, 13. The method for producing an organic compound nano cellobiose and dextrin. powder according to claim 9, wherein a drying is carried out 5. The organic compound nano-powder according to claim after the milling. 1, further comprising a physiologically acceptable salt. 14. The method for producing an organic compound nano 6. The organic compound nano-powder according to claim powder according to claim 9, wherein the carbohydrate com 5, wherein the physiologically acceptable salt is sodium chlo pound are one or more kinds selected from the group consist ride. ing of mannitol, maltitol, Xylitol, erythritol, glucose, fructose, 7. The organic compound nano-powder according to claim inositol, lactose, trehalose, cellobiose and dextrin. 1, wherein the organic compound are one or more kinds 15. The method for producing an organic compound nano selected from the group consisting of clarithromycin, fex powder according to claim 9, wherein a physiologically ofenadine hydrochloride, fluorometholone, curcuminoid, acceptable salt is further mixed in the process of the mixing. curcumin, rutin, mefenamic acid, acetaminophen, ibuprofen, 16. The method for producing an organic compound nano amphotericin B, diclofenac sodium, indomethacin, felbinac, powder according to claim 15, wherein the physiologically pranlukast hydrate, dexamethasone and fenofibrate. acceptable salt is sodium chloride. 8. A Suspension having at least an organic compound, 17. The method for producing an organic compound nano which is contained in the organic compound nano-powder powder according to claim 9, wherein the organic compound according to claim 1, dispersed in a liquid dispersion medium are one or more kinds selected from the group consisting of in which the organic compound is insoluble or poorly soluble. clarithromycin, fexofenadine hydrochloride, fluo 9. A method for producing an organic compound nano rometholone, curcuminoid, curcumin, rutin, mefenamic acid, powder comprising: acetaminophen, ibuprofen, amphotericin B, diclofenac mixing a granular organic compound, a granular carbohy Sodium, indomethacin, felbinac, pranlukast hydrate, dexam drate compound comprising at least any one of a Sugar ethasone and fenofibrate. and a Sugar alcohol and with amount of 0.3 times or more k k k k k