# Patent

## Title
Organic compound nano-powder, method for producing the same and suspension

## Abstract

An organic compound nano-powder comprising a granular organic compound with an average particle diameter of 500 nm or less and a 90%-diameter of less than 1500 nm and a carbohydrate compound comprising at least any one of a sugar and a sugar alcohol and with amount of 0.3 times or more by mass relative to amount of the organic compound, a method for producing the same, and a suspension having the organic compound dispersed in a liquid dispersion medium in which the organic compound is insoluble or poorly soluble.

## Background
CROSS REFERENCE TO RELATED APPLICATION
The present patent application claims priority from Japanese Patent Application No. 2012-108972 filed in Japan on May 11, 2012, and the disclosures of thereof are incorporated herein by reference. In addition, the disclosures of the patents, patent applications and documents cited in the present application are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to an organic compound nano-powder, a method for producing the same, and a suspension having an organic compound dispersed therein.
BACKGROUND ART
In order to fulfill an inherent function of an active ingredient contained in a formulation or a health food without excessively taking it, it is necessary to enhance the bioavailability for the formulation or the health food. Taking the formulation as an example, while an oral formulation has the advantages of being convenient and causing little distress compared to an injectable formulation, it has the disadvantage of providing low bioavailability. The oral formulation enters into the intestine via the stomach and the duodenum, is absorbed into blood mainly through the intestinal tract and then is delivered to the liver via the portal vein. A part of the oral formulation is decomposed by undergoing the action of a gastric acid or the like or being metabolized in the liver during passing through such a long path, whereby converted into a totally different substance. One of the major reasons for the low bioavailability is that the oral formulation is difficult to be absorbed from digestive organs like the intestine. In order to enhance the bioavailability for the formulation, it is necessary to get the size down of the organic compound with medicinal ingredients to a level required to facilitate the absorption of the compound from the digestive organs into the blood.
In the case of the injectable formulation, a typical example of parenteral formulations, effective functioning of a medicinal ingredient in the formulation requires the reaching of the medicinal ingredient through blood vessels in the body to a target site. The inner diameter of a capillary blood vessel, which is the narrowest among the blood vessels, is about 5 μm. Accordingly, in order to make pass the organic compound with the medicinal ingredient through the capillary blood vessel without causing occlusion, the particle diameter of this organic compound needs to be 5 μm or less. Further, for the same reason as the oral formulation, it is necessary for a health food to get the size down of the organic compound with active ingredients to a level required to facilitate the absorption of the compound from the digestive organs into the blood.
In the case of a solid skin-lightening ingredient and a moisturizing ingredient contained in a cosmetic, less agglomeration and the smaller particle size are required in order to make them easily attached and thinly spread on a skin surface while if it is in the form of a milky lotion, not to cause phase separation in a container in which this cosmetic is contained so that a uniform dispersion state may be sustainable.
In accordance with recent development of a nanotechnology, the preparation of the nano-sized organic compound to satisfy the requirements as mentioned above has attracted high attention. For example, a particulate formulation which contains a steroid or a steroid derivative with median of the particle distribution in the range of 0.005 to 5 μm and with the 90%-diameter of 10 μm or less has been known (for example, see Patent Document 1). However, the coarse particles present with a small percentage in the particulate formulation due to so wideness of the particle diameter distribution causes a problem of instability of a suspension thereof, i.e., a problem of low dispersivity of the particulate formulation.
For example, as one of methods for finely-milling the organic compound to the level of nano-powder with a narrow particle diameter distribution, a method for milling the organic compound by a bead mill using beads made of ceramic, glass, or the like is well known (for example, see Patent Document 2). Nano-powder with a narrow particle diameter distribution can be obtained by applying such a mechanical impact or a grinding force to the particles of the organic compound. In addition, a wet milling method for milling the organic compound in organic liquid using salt particles as a milling medium is also known (for example, see Patent Documents 3 and 4). The method using salt particles is more advantageous than the method using the beads in view of less contamination with impurities coming from a milling medium. While the impurities coming from the beads are difficult to remove, the impurities coming from the salt particles are easy to remove by a water-washing process (also called salt-removing process) due to high water solubility of salt.
PRIOR ART PUBLICATIONS
Patent Documents
Patent Document 1: Japanese Patent Laid-Open Publication No. 2006-089386
Patent Document 2: Japanese Patent Laid-Open Publication No. H04-295420
Patent Document 3: International Publication WO/2008/126797
Patent Document 4: International Publication WO/2010/032434
SUMMARY OF INVENTION
Problem to be Solved by the Inventions
The wet milling method using the salt particles as milling medium is advantageous in view of avoiding contamination of irremovable impurities, but needs furthermore improvements. One of the improvements is to perform the production process as simple as possible with no water-washing to remove the salt that contaminates an organic compound after milling. When the salt particles are used as milling medium, usually the salt with the amount of preferably 10 to 30 times by mass relative to the organic compound to be milled is served into a wet milling apparatus. Unless thus large amount of salt is not removed after milling, the organic compound after milling cannot be safely used in or on a living body. Another of improvements is to prevent the wet milling apparatus from rusting out. Contamination due to rust must be definitely avoided when the organic compound is used in a living body. Use of an anti-rust agent as a general anti-rusting method is also well known, but contact thereof with the organic compound is not also allowed. Alternatively, a wet milling apparatus which is constructed by a material difficult to rust (for example, a personally-ordered apparatus which is coated with a ceramic on its inner surface) may be opted, but the apparatus is disadvantageous in view of high cost due to use of a special apparatus.
The present invention was made to satisfy the requirements as mentioned above and has an object to provide an organic compound nano-powder conveniently, with low cost and with less contamination of impurities to be removed.
Means for Solving the Problem
The inventors of the present invention carried out an extensive investigation to solve the problems mentioned above, and as a result, found that, when an organic compound having a granular form was milled by adding at least a granular carbohydrate compound (or sugar compound), the organic compound could be milled efficiently, and in addition, a salt removing process after milling became unnecessary, as well as rusting of a wet milling apparatus could be avoidable, and based on these findings, the present invention could be accomplished. Alternatively, there may be some cases that salt is optionally added to the granular carbohydrate compound, in this case, because the amount of the salt was incomparably smaller than the amount in case of being used as a milling medium, it was found that not only the salt removing process was unnecessary but also the risk of the rust of the wet milling apparatus could be reduced. Specific content of the present invention is as following.
One embodiment according to the present invention is an organic compound nano-powder comprising:
a granular organic compound with an average particle diameter of 500 nm or less and a 90%-diameter of less than 1500 nm; and
a carbohydrate compound comprising at least any one of a sugar and a sugar alcohol and with amount of 0.3 times or more by mass relative to amount of the organic compound.
Other embodiment according to the present invention is the organic compound nano-powder, wherein the carbohydrate compound is in an amount of 0.5 to 30 times by mass relative to amount of the organic compound.
Further other embodiment according to the present invention is the organic compound nano-powder further comprising a physiologically acceptable polyol.
Further other embodiment according to the present invention is the organic compound nano-powder, wherein the carbohydrate compound are one or more kinds selected from the group consisting of mannitol, maltitol, xylitol, erythritol, glucose, fructose, inositol, lactose, trehalose, cellobiose and dextrin.
Further other embodiment according to the present invention is the organic compound nano-powder further comprising a physiologically acceptable salt.
Further other embodiment according to the present invention is the organic compound nano-powder, wherein the physiologically acceptable salt is sodium chloride.
Still further other embodiment according to the present invention is the organic compound nano-powder, wherein the organic compound is one or more kinds selected from the group consisting of clarithromycin, fexofenadine hydrochloride, fluorometholone, curcuminoid, curcumin, rutin, mefenamic acid, acetaminophen, ibuprofen, amphotericin B, diclofenac sodium, indomethacin, felbinac, pranlukast hydrate, dexamethasone and fenofibrate.
One embodiment according to the present invention is a suspension having at least an organic compound, which is contained in the organic compound nano-powder according to any one of the above-mentioned, dispersed in a liquid dispersion medium in which the organic compound is insoluble or poorly soluble.
One embodiment according to the present invention is a method for producing an organic compound nano-powder comprising:
mixing a granular organic compound, a granular carbohydrate compound comprising at least any one of a sugar and a sugar alcohol and with amount of 0.3 times or more by mass relative to amount of the organic compound, and liquid in which the organic compound is insoluble or poorly soluble; and
wet-milling the organic compound after the mixing so that an average particle diameter thereof becomes 500 nm or less and a 90%-diameter thereof becomes less than 1500 nm.
Other embodiment according to the present invention is the method for producing an organic compound nano-powder, wherein the carbohydrate compound is in an amount of 0.5 to 30 times by mass relative to amount of the organic compound.
Further other embodiment according to the present invention is the method for producing an organic compound nano-powder, wherein the mixing is carried out with adding a physiologically acceptable polyol as liquid in which the organic compound is insoluble or poorly soluble.
Further other embodiment according to the present invention is the method for producing an organic compound nano-powder, wherein the wet-milling of the organic compound is carried out while kneading the mixture obtained after the mixing in a kneader.
Further other embodiment according to the present invention is the method for producing an organic compound nano-powder, wherein a process of drying is carried out after the milling.
Further other embodiment according to the present invention is the method for producing an organic compound nano-powder, wherein the carbohydrate compound are one or more kinds selected from the group consisting of mannitol, maltitol, xylitol, erythritol, glucose, fructose, inositol, lactose, trehalose, cellobiose and dextrin.
Further other embodiment according to the present invention is the method for producing an organic compound nano-powder, wherein a physiologically acceptable salt is further mixed in the process of the mixing.
Further other embodiment according to the present invention is the method for producing an organic compound nano-powder, wherein the physiologically acceptable salt is sodium chloride.
Still further other embodiment according to the present invention is the method for producing an organic compound nano-powder, wherein the organic compound are one or more kinds selected from the group consisting of clarithromycin, fexofenadine hydrochloride, fluorometholone, curcuminoid, curcumin, rutin, mefenamic acid, acetaminophen, ibuprofen, amphotericin B, diclofenac sodium, indomethacin, felbinac, pranlukast hydrate, dexamethasone and fenofibrate.
Advantageous Effect of the Invention 
According to the present invention, an organic compound nano-powder can be provided conveniently, with low cost and with less contamination of impurities to be removed.


DESCRIPTION OF EMBODIMENTS
Next, the embodiments of the organic compound nano-powder, the method for producing the same, and the suspension according to the present invention will be described.
1. Organic Compound Nano-Powder
The organic compound nano-powder according to the embodiment comprises:
a granular organic compound (A) with an average particle diameter of 500 nm or less and a 90%-diameter of less than 1500 nm; and
a carbohydrate compound (B) comprising at least any one of a sugar and a sugar alcohol and with amount of 0.3 times or more by mass relative to amount of the organic compound.
The organic compound nano-powder may further comprise a physiologically acceptable salt (C).
Alternatively, the organic compound nano-powder may further comprise, in accordance with its use, one or more additives (D) other than the salt.
The term “average particle diameter” used in present specification means a mathematical average diameter (here, defined as the Dav value) in the particle diameter distribution as measured by a dynamic light scattering photon correlation method. The term “50%-diameter” (defined as median diameter or the D50 value) means a certain particle diameter when amount of a larger side becomes equal to amount of a smaller side of the particle diameters divided into two a powder from the certain particle diameter. The term “90%-diameter” (D90 value) means the particle diameter of the particle at the position of 90% when counted from the smallest size zero (minimum) to 100% (maximum) of the particle diameter in the particle diameter distribution as measured by the above-mentioned measurement method. The term “10%-diameter” (D10 value) means the particle diameter of the particle at the position of 10% when counted from the smallest size zero (minimum) to 100% (maximum) of the particle diameter in the particle diameter distribution as measured by the above-mentioned measurement method. The average particle diameter of the organic compound is more preferably in the range of 50 to 400 nm, further more preferably in the range of 100 to 350 nm. The D90 value of the organic compound is more preferably less than 700 nm, further more preferably less than 500 nm.
“Organic compound nano-powder” in the present specification may be any powder so far as the powder contains at least an organic compound (A) having a granular form and a carbohydrate compound (B); and thus, one or more additives other than these compounds may be contained therein. The particle diameter distribution by the dynamic light scattering photon correlation method is measured for the organic compound having a granular form. However, if the carbohydrate compound is physically attached or chemically bonded to the surface of the particles of the organic compound, the particle diameter distribution is measured for the granular organic compound having this carbohydrate compound attached or bonded thereto.
(A) Organic Compound
The organic compound includes those used as active ingredients in a medicine, a health food, a nutritional supplement, a cosmetic and the like, but is not limited to them. Preferable examples as the use for the medicine include an anti-obesity drug, a corticosteroid, an elastase inhibitor, an analgesics, an antifungal, a drug for cancer, an antiemetic, a cardiovascular drug, an anti-inflammatory drug, an anti-parasitic, an anti-arrhythmic, an antibiotic, an anticoagulant, an antidepressant, an anti-diabetic, an antiepileptic drug, an antihistamine, a hypotensive drug, an anti-muscarinic drug, an anti-mycobacteria drug, an antitumor drug, an immunosuppressant, an antithyroid, an antiviral, a sedative, a beta-adrenergic receptor antagonist, a blood product, a cardiac, a contrast medium, an antitussive, a diagnostic agent, a diagnostic contrast medium, a diuretic, a dopaminergic drug, a hemostatic, an immunizing drug, a lipid regulator, a musclerelaxant agent, a parasympathomimetic drug, a parathyroid calcitonin and its diphosphonate salt, a prostaglandin, a radioactive drug, a sex hormone, an anti-allergic drug, a stimulant, an appetite-suppressant, a sympathomimetic drug, a thyroid drug, a vasodilator, an anti-parkinson drug, a psychotropic agent, an agent affecting the central nervous system, an antipyretic, an anti-anxiety drug and a hypnotic. However, the medicines are not limited to the above examples.
Specific examples of the organic compound used for the medicines include 5-fluorourasil, 7-(3,5-dimethoxy-4-hydroxycinnamoylamino)-3-octyloxy-4-hydroxy-1-methyl-2(1H)-quinoli none, acarbose, aciclovir, acetyl salicylic acid, acetyl pheneturide, acetaminophen, adenine, atenolol, opium alkaloid, amidotrizoic acid, amphotericin B, amoxapine, amobarbital, amurine, amoxicillin, aripiprazole, alprazolam, allopurinol, ampicillin, ampiroxicam, amlexanox, isoproterenol, ibuprofen, ipriflavone, imipramine, irbesartan, indomethacin, ubenimex, urapidil, ursodesoxycholic acid, estazolam, estradiol, etizolam, ethenzamide, ethotoin, enoxacin, eprosartan, emiglitate, erythromycin, prazosin hydrochloride, propafenone hydrochloride, entacapone, oxazolam, oxaprozin, oxycodone, oxytetracycline, oxypertine, oxendolone, omeprazole, olanzapine, oryzanol, caffeine, captopril, cabergoline, carbamazepine, chlorphenesin carbamate, carpipramine maleate, carbochromen, carumonam sodium, candesartan cilexetil, quazepam, guanfacine, sildenafil citrate, clarithromycin, griseofulvin, cloxazolam, clozapine, clotiazepam, clonazepam, clobazam, chloramphenicol, chlordiazepoxide, chlorzoxazone, chlortalidone, chlorpheniramine, chlorpromazine, chlorhexidine, ketoprofen, cocaine, codeine, colchicine, chlormadinone acetate, cortisone acetate, saccharin, zafirlukast, salazosulfapyridine, salbutamol, diastase, diazepam, digitoxin, ciclacillin, diclofenac sodium, digoxin, disopyramide, citicoline, dihydrocholesterol, dipyridamole, dihydrocodeine, difenidol, diphenhydramine, cimetidine, dimenhydrinate, cilostazol, simvastatin, scopolamine, stanozolol, sparfloxacin spiperone, spironolactone, sulindac, sulpiride, sulbenicillin sodium, cephalexin, cefixime, cefozopran, cefotiam, cefsulodin sodium, cefinenoxime, seratrodast, serrapeptase, celecoxib, zotepine, zonisamide, zopiclone, dacarbazine, tacrolimus hydrate, tasosartan, danazol, dantrolene sodium, tiaprofen, timidazole, timiperone, theophylline, dexamethasone, dextromethorphan, delapril, terguride, telmisartan, ipecac, tofisopam, trandolapril, triazolam, triamcinolone, triamcinolone acetonide, triamterene, tolbutamide, trepibutone, troglitazone, droperidol, naproxen, nalidixic acid, nicardipine, nicergoline, nitrazepam, nifedipine, nimetazepam, nimodipine, nemonapride, noscapine, paclitaxel, papaverine, valsartan, haloperidol, pioglitazone, bicalutamide, bisbentiamine, hydralazine, hydroxyzine pamoate, pivmecillinam, biperiden, pimozide, pirenoxine, piroxicam, pindolol, famotidine, falecalcitriol, fexofenadine hydrochloride, phenacemide, phenyloin, phenylephrine, phenobarbital sodium, fenofibrate, felbinac, phenprobamate, forasartan, bucolome, budesonide, clemastine fumarate, formoterol fumarate, pranoprofen, pravastatin, pranlukast hydrate, primidone, fludiazepam, flunitrazepam, proglumetacin maleate, blonanserin, profenamine hibenzate, bromazepam, flutazolam, fluocinolone acetonide, fluorometholone, fluconazole, flutoprazepam, flunisolide, fluphenazine decanoate, flufenamic acid aluminum, flumazenil, flurbiprofen, prednisolone, procainamide, furosemide, brotizolam, fluticasone propionate, beclomethasone propionate, propranolol, propericiazine, promethazine, bromperidol, bromocriptine mesilate, beta-carotene, betamethasone, verapamil, benzthiazide, pentazocine, voglibose, propyl gallate, polythiazid, mitomycin C, mazindol, manidipine, maprotiline, maltol, lisuride maleate, miglitol, miconazole, midazolam, minoxidil, milrinone, mexazolam, mequitazine, meclizine, meclofenoxate, medazepam, methylephedrine, methyldopa, methocarbamol, metoclopramide, methotrexate, mefenamic acid, meloxicam, modafinil, mofezolac, molsidomine, folic acid, ranitidine, labetalol, rabeprazole, ramelteon, lansoprazole, liothyronine sodium, risperidone, lysozyme, lidocaine, rifampicin, leuprorelin, reserpine, levallorphan, L-dopa, riluzole, losartan, lofepramine hydrochloride, lorazepam and lormetazepam. However, the organic compound is not limited to these compounds. Especially, clarithromycin, fexofenadine hydrochloride and fluorometholone are preferably used in the above organic compounds.
Examples of the organic compound used for health food or nutritional supplement include astaxanthin, alliin, allysine, anthocyanin, isoflavone, isorhamnetin, α-lipoic acid, oleuropein, ornithine, catechin, capsaicin, capsanthin, capsorubin, beta-carotene, carnitine, carminic acid, canthaxanthin, ginkgolide, glucan, chitosan, quinone, gymnemic acid, beta-cryptoxanthin, curcuminoids, curcumin, glucosamin, creatine, chlorophyll, quercetin, sesame lignan, zeaxanthin, bixin, biotin, vitamin A and its derivative, vitamin D2, vitamin D3, phytosterol, phosphatidylserine, beta-apo-4-carotenal, ethyl beta-apo-8-carotenoate, flavonoid, proanthocyanidin, pectin, polyphenol, monacolin K, ubiquinone, lycopene, resveratrol, lutein and rutin. However, the organic compound is not limited to these compounds. Especially, curcuminoid, curcumin and rutin are preferably used in the above organic compounds.
Examples of the cosmetic include an anti-aging agent, a UV-screening material, a tightening-up agent, an antioxidant, an anti-wrinkling material, a moistening agent, a blood circulation promoter, an antibacterial agent, a disinfecting agent, a drying agent, a cooling agent, a warming agent, vitamins, amino acids, a wound-heal acceleration agent, an irritation relaxation agent, a painkiller, a cellular stimulant and various enzymes. However, the cosmetic is not limited to these examples.
Examples of the organic compound used for these cosmetics include 4-n-butyl resorcinol, N-acylated glutathione, ascorbic acid, ascorbic acid salt, ascorbic acid glucoside, magnesium ascorbyl phosphate, arbutin, isoferulic acid, isoferulic acid salt, ellagic acid, ergo acid, ergo acid salt, kinetin, casein, caffeic acid, caffeic acid salt, glabridin, glycyrrhizic acid, glutathione, glutathione ester, glutathione salt, kojic acid, retinol acetate, cysteine, tannic acid, tranexamic acid, transferrin, tretinoin, hydroquinone, hydroquinone salt, phytic acid, fibrin, fibroin, fibronectin, ferulic acid, ferulic acid salt, lycopene, retinyl acetate, retinyl palmitate, retinol, retinoic acid and retinoic acid tocopheryl. However, the organic compound is not limited to these compounds.
(B) Carbohydrate Compound
The carbohydrate compound includes at least one kind selected from the group consisting of sugars (monosaccharide, disaccharide, polysaccharides including trisaccharide and higher than trisaccharide, and oligosaccharides) and sugar alcohols. The carbohydrate compound is selected such that it may not be overlapped with the foregoing organic compounds.
Examples of the monosaccharide include glucose, galactose, mannose, fructose, inositol, ribose and xylose. Examples of the disaccharide include lactose, sucrose, cellobiose, trehalose and maltose. Examples of the polysaccharide include pullulan, sodium hyaluronate, raffinose, melezitose, sodium chondroitin sulfate, cellulose, cluster dextrin, cyclodextrin, dextrin, dextran, xanthan gum, chitin and chitosan. Examples of the oligosaccharide include fructo oligosaccharide, galacto oligosaccharide, mannan oligosaccharide, gentio oligosaccharide, xylo oligosaccharide, cello oligosaccharide, isomalto oligosaccharide, nigero oligosaccharide, chito oligosaccharide, fucoidan oligosaccharide, soy bean oligosaccharide and lactosucrose. Examples of the sugar alcohol include palatinose, sorbitol, lactitol, erythritol, pentaerythritol, xylitol, maltitol, mannitol and dulcitol. In this embodiment, sugar alcohols, monosaccharide or disaccharide may be preferably used as the carbohydrate compound, while mannitol, maltitol, erythritol, xylitol, glucose, fructose, lactose, trehalose or cellobiose may be used more preferably, and D-mannitol, xylitol, glucose, fructose or trehalose may be used further more preferably.
In the organic compound nano-powder, the carbohydrate compound may be contained in the form of particles independent of particles of the organic compound or may be in the form physically attached or chemically bonded to the surface of particles of the organic compound.
The carbohydrate compound is contained in the organic compound nano-powder with the amount of 0.3 times or more, preferably 0.3 to 100 times, more preferably 0.5 to 30 times, or further more preferably 0.8 to 20 times by mass relative to the organic compound. For the purpose of no excess exclusion of the carbohydrate compounds after milling the organic compound and the inhibition of excessively high osmotic pressure of liquid including the carbohydrate compounds at using the liquid due to inclusion of excess amount of the carbohydrate compounds in the liquid, the additive amount of the carbohydrate compounds is preferably 0.3 to 100 times, more preferably 0.5 to 30 times, further preferably 0.8 to 20 times, still further preferably 1 to 8 times by mass relative to the organic compound. Above-mentioned carbohydrate compounds may be used singly or as a mixture of two or more of them. In addition, the carbohydrate compounds may be used in the form of fine particles.
The carbohydrate compound can function as a milling medium or as an auxiliary agent for milling during milling the organic compound. Here, the term “milling medium” means a medium which directly applies an impact or a grinding action to the organic compound. The term “auxiliary agent” means a material which does not directly apply above actions to the organic compound but facilitates the milling of the organic compound by working indirectly. Further, the carbohydrate compound can work to reduce agglomeration among particles of the organic compound.
(C) Physiologically Acceptable Salt
The salt that can be mixed with the organic compound nano-powder of this embodiment is one that can be used without notably causing a physiological problem. In other words, the salt is not particularly limited as far as it does not pose a significant problem even if it enters into a living body or contacts to a skin. A physiologically acceptable salt preferably has sufficient hardness to finely mill the organic compound. In addition, the amount of the physiologically acceptable salt mixed with the organic compounds and the carbohydrate compounds means such amount of the salt that the salt does not bring critical matters to a biological body when it is consumed in the biological body.
Examples of the preferable salt include sodium chloride, potassium chloride, ammonium chloride, sodium sulfate, magnesium sulfate, potassium sulfate, calcium sulfate, sodium malate, sodium citrate, disodium citrate, sodium dihydrogen citrate, potassium dihydrogen citrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate and dipotassium hydrogen phosphate. More preferable examples of the salt include sodium chloride, potassium chloride, magnesium sulfate, calcium sulfate, sodium citrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate and dipotassium hydrogen phosphate and most preferable salt is sodium chloride.
The salt may be adjusted in its particle diameter by milling and the like before it is mixed with the organic compound or the carbohydrate compound. In the case of preliminary adjustment of the particle diameter, the average particle diameter of the salt is preferably 0.01 to 300 μm, more preferably 0.1 to 100 μm or further more preferably 0.5 to 50 μm. Amount of the salt contained in the organic compound nano-powder may be in the range of 0.02 to 4 times by mass, preferably 0.05 to 2 times by mass, or more preferably 0.1 to 1.5 times by mass, relative to total amount of the organic compound and the carbohydrate compound. The salts may be used singly or as a mixture of two or more of them. The salt can function as a milling medium or as an auxiliary agent for milling during the milling of the organic compound.
(D) Other Additives
The organic compound nano-powder may contain all or a part of viscosity modifier added during the manufacturing thereof. A physiologically acceptable polyol may be preferably used as the viscosity modifier. The term “physiologically acceptable” has the same meaning as the term “physiologically acceptable” of the physiologically acceptable salt mentioned above. Examples of the physiologically acceptable polyol include glycerin, propylene glycol, polyethylene glycol, dipropylene glycol, ethylene glycol, diethylene glycol, citric acid, DL-malic acid, tartaric acid, lactic acid, urea, maleic acid and malonic acid, and preferably citric acid, propylene glycol and glycerin. These viscosity modifiers may be used singly or as a mixture of two or more of them.
The organic compound nano-powder tends to agglomerate very easily because individual particles thereof are in the level of nano-size. The organic compound nano-powder may keep containing all or a part of anti-agglomeration agent added during or after milling in order to prevent the particles of the organic compound nano-powder from agglutinating. Examples of the anti-agglomeration agent include ethanol, glycerin, propylene glycol, sodium citrate, purified soy bean lecithin, phospholipid, D-sorbitol, lactose, xylitol, Gum arabic, sucrose fatty acid ester, sodium dodecylsulfate, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ester, polyoxyethylene glycol, polyoxyethylene sorbitan fatty acid ester, alkylsulfate salt, alkylbenzenesulfonate, sulfosuccinate salt, polyoxyethylene polyoxypropylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carmellose, sodium carboxymethyl cellulose, carboxymethyl polymer, N-acyl-glutamate salt, acrylic acid copolymer, sodium myristoylmethyl taurine, polyoxyl stearate, carboxylvinyl polymer, sodium dioctyl sulfosuccinate, xanthan gum, methacrylic acid copolymer, casein sodium, L-valine, L-leucine, L-isoleucine, benzarconium chloride and benzethonium chloride. The anti-agglomeration agents may be preferably glycerin, sucrose fatty acid ester, sodium dodecylsulfate, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium myristoylmethyl taurine, polyoxyl stearate, carboxylvinyl polymer, sodium dioctyl sulfosuccinate and xanthan gum. Above anti-agglomeration agents may be used singly or as a mixture of two or more of them. Meanwhile, above-mentioned other additives are selected such that they may not overlap with the organic compound, the carbohydrate compound and the salt.
2. Suspension Dispersed Organic Compound Nano-Powder
The suspension according to the embodiment of the present invention comprises the organic compound (A) in liquid dispersing medium in which the organic compound is insoluble or poorly soluble.
The term “insoluble or poorly soluble” used in the present specification means that solubility of the organic compound in the liquid dispersing medium is 10 mg/mL or less, or preferably 1 mg/mL or less, at the temperature of a normal operation, for example, at room temperature of around 25 degrees C. The liquid dispersing medium in which the organic compound is insoluble or poorly soluble may include water; organic solvent like ethanol; or polyol like glycerin, propylene glycol, polyethylene glycol, ethylene glycol, diethylene glycol. However, the liquid dispersing mediums are not limited to above-exemplified some liquids and may be any kinds of mediums as long as the mediums are in the form of liquid at room temperature of around 25 degrees C. Thus, for example, when polyol is used as the liquid dispersing medium, the polyol may also operate as a viscosity modifier or an anti-agglomeration agent. For example, when the organic compound is water-soluble, the liquid dispersing medium in which the organic compound is insoluble or poorly soluble means one other than water. Further, when the organic compound is soluble in a certain organic solvent, the liquid dispersing medium means one other than the certain organic solvent. In other words, the liquid dispersing medium needs to be selected such that the organic compound may exist in the dispersed state without being completely dissolved therein. When the suspension is used as it is as a medicine, a health food, or a cosmetic, the dispersing medium including mainly water is preferably used.
The suspension according to the present embodiment may contain various viscosity modifiers and anti-agglomeration agents mentioned in the section of other additives (D), and may further contain an emulsifying agent, a pH modifier, a buffering agent, a preservative or the like. Examples of the materials that may be contained in this suspension include: phosphate salts such as sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium pyrophosphate, sodium tripolyphosphate, sodium tetrapolyphosphate, sodium hexametaphosphate, acidic sodium hexametaphosphate and potassium dihydrogen phosphate; hydrates of these salts; sodium edetate; and sodium hydroxide.
3. Method for Producing the Organic Compound Nano-Powder
The method for producing an organic compound nano-powder according to the present embodiment comprises:
(A) a process of mixing a granular organic compound, a granular carbohydrate compound comprising at least any one of a sugar and a sugar alcohol and with amount of 0.3 times or more by mass relative to amount of the organic compound, and liquid in which the organic compound is insoluble or poorly soluble; and
(B) a process of wet-milling the organic compound until an average particle diameter thereof becomes 500 nm or less and a 90%-diameter thereof becomes less than 1500 nm after the process of mixing.
The method for producing an organic compound nano-powder may further comprise (C) a process of drying the product after (B) the process of milling. In the following, “a process of mixing”, “a process of milling” and “a process of drying” will be explained.
(A) Process of Mixing
The method for producing the organic compound nano-powder includes the process of mixing at least a granular organic compound, a granular carbohydrate compound and liquid in which the organic compound is not soluble or poorly soluble. The process of mixing may be done by adding one or more additives other than above materials (such as an anti-agglomeration agent, a viscosity modifier, a pH-modifier). The process of mixing has a feature that the granular carbohydrate compound is added to the granular organic compound with the amount of 0.3 times or more by mass relative to the organic compound. When the milling is performed by adding the carbohydrate compound with the amount of 0.3 times or more by mass relative to the organic compound, the organic compound may be milled more finely. The organic compound may be milled finely even if the carbohydrate compound is added more excessively than 0.3 times by mass relative to the organic compound. However, in this case, it is needed to decrease the amount of the organic compound to enter in a milling apparatus, thus the amount of the organic compound produced per one process of the milling decreases. For the purpose of producing organic compound fine particles more than a certain amount and milling the organic compound more finely, the amount of the carbohydrate compound to enter in the milling apparatus is preferably 0.3 to 100 times, more preferably 0.5 to 30 times, further more preferably 0.8 to 20 times, or still further preferably 1 to 8 times by mass relative to the organic compound.
The carbohydrate compound has a function as the anti-agglomeration agent. But, if the carbohydrate compound is added only to work this function, addition of the carbohydrate compound “in the granular form” with the amount of “0.3 times or more by mass relative to the organic compound” is not necessary as its condition. The reason why the carbohydrate compound is added “in the granular form” with the amount of “0.3 times or more by mass relative to the organic compound” is as follows. It is necessary to work the function of a milling medium that provides an impact or a grinding action directly with the granular organic compound or the function of a milling auxiliary agent that indirectly relates to facilitate collision and grinding among the granular organic compound by themselves.
Various kinds of sugars and sugar alcohols already explained in the section of the organic compound nano-powder, including a mixture of two or more of them may be used as the granular carbohydrate compound. Especially, sugar alcohols, monosaccharide or disaccharide may be preferably used as the carbohydrate compound, while mannitol, maltitol, erythritol, xylitol, glucose, fructose, lactose, trehalose or cellobiose may be used more preferably, and D-mannitol, xylitol, glucose, fructose or trehalose may be used further more preferably. Although particle diameters of the granular carbohydrate compound may be selected in accordance with milling conditions, the average particle diameter of the carbohydrate compound is preferably in the range of 0.5 to 1000 μm, more preferably 1 to 700 μm or further more preferably 5 to 200 μm, in order to effectively make function as the milling medium or as the milling auxiliary agent.
In the process of mixing, a physiologically acceptable salt may be additionally mixed. In this case, for example, amount of the physiologically acceptable salt to be mixed is preferably 0.02 to 4 times by mass relative to total amount of the organic compound and the carbohydrate compound. As long as above-mentioned amount of the salt is mixed with the organic compound and the carbohydrate compound, it is not necessary to remove the salt and it is also possible to reduce the rusting of a milling apparatus. Various salts already explained in the section of the organic compound nano-powder may be used as the salt. Especially, sodium chloride is preferably used. Although various particle diameters of granular salts may be selected, for example, from the range of preferably 0.01 to 300 μm, more preferably 0.1 to 100 μm or further more preferably 0.5 to 50 μm.
The liquid in which the organic compound is insoluble or poorly soluble means that solubility of the organic compound in the liquid is 10 mg/mL or less, or preferably 1 mg/mL or less, at the temperature of a normal operation, for example, at room temperature of around 25 degrees C. The liquid dispersing medium in which the organic compound is insoluble or poorly soluble may include water; organic solvent like ethanol; or polyol like glycerin, propylene glycol, polyethylene glycol, ethylene glycol, diethylene glycol. However, the liquid is not limited to above-exemplified liquid and may be any kinds of liquid as long as it is in the form of liquid at room temperature of around 25 degrees C. When polyol is used as the liquid, the polyol may also operate as a viscosity modifier or an anti-agglomeration agent. For example, when the organic compound is water-soluble, the liquid in which the organic compound is insoluble or poorly soluble means one other than water. Further, when the organic compound is soluble in a certain organic solvent, the liquid means one other than the certain organic solvent. In other words, the liquid is selected such that the organic compound may exist in the state without being completely dissolved therein in the process of mixing and the process of milling after the mixing.
The process of mixing may be performed before the milling or simultaneously with the milling in a milling apparatus used in the process of milling that will be explained later, or may be performed in a mixing vessel prepared as the apparatus different from the milling apparatus. In the latter case, the mixing may be performed by using an agitating machine wherein a mixing blade is rotated, a magnetic stirrer wherein a stirring chip is rotated by using a magnetic force in a vessel, a vibration mill wherein a vessel is moved up and down, a bath wherein an ultrasonic wave is oscillated and the like.
(B) A Process of Milling
In the method for producing the organic compound nano-powder according to the present embodiment, the milling apparatus usable for wet milling of the organic compound is not particularly limited as far as the apparatus is capable of milling the organic compound finely by mechanical means. Examples of the milling apparatus include any convenient milling apparatuses such as a kneader, a twin roll mill, a triple roll mill, a fret mill, a Hoover Muller mill, a disk blade kneader and a biaxial extruder. The significant feature of the process of milling is no use of milling media like balls and beads. In a prior milling method in which the organic compound to be milled is entered with balls or beads into the milling apparatus, the organic compound is contaminated by abrasion particles coming from the balls or beads, whereby removal of the contaminants is impossible or requires tremendous work and cost even if removal thereof may be theoretically possible. To eliminate such a demerit in the prior methods, in the process of milling, a milling apparatus giving a force only to knead the compound to be milled is used so that the organic compound may be finely milled by utilizing an impact or a grinding action applied among the particles of the organic compound themselves or between the particles of the organic compound and the carbohydrate compound. With the basis of such a technical concept, among the milling apparatuses mentioned above, a disk blade kneader which can generate a strong kneading force by a planetary motion of a blade is preferably used. In this case, the process of milling is performed by the milling the organic compound while kneading in the kneader the mixture after the process of mixing.
In the process of milling the organic compound, the milling may be done, after the organic compound, the carbohydrate compound and a small amount of the liquid are all entered into the milling apparatus, or be done with adding the carbohydrate compound and/or the liquid little by little. Temperature at the milling may be determined arbitrarily in considering the organic compound to be milled, the milling apparatus and the like. The temperature is not particularly limited as far as it can inhibit melting or decomposition of the organic compound, is preferably −50 to 50 degrees C., more preferably −20 to 30 degrees C., or at most preferably −10 to 25 degrees C. Time for milling may be determined arbitrarily in considering the organic compound to be milled, the milling apparatus and the like. Time for milling is, for example, about 1 to 50 hours, preferably 2 to 20 hours, or more preferably 3 to 10 hours.
(C) A Process of Drying
When a process of drying is carried out after the foregoing process of milling, the organic compound nano-powder may be obtained in the form of not a dispersion solution but a solid. Method for drying the milled product is not particularly limited. Thus, any convenient methods for drying the organic compound may be used. Examples of the drying method include a vacuum drying method, a freeze drying method, a spray drying method and a freeze spray drying method. Drying temperature, drying time and the like are not particularly limited. The drying may be carried out preferably at lower temperature to maintain chemical stability of individual particles that constitute the organic compound nano-powder and to prevent the particles from agglutinating secondarily. The vacuum drying method, the freeze drying method, the spray drying method and the freeze spray drying method are more preferable as the drying method.
(D) Other Process
The product obtained after the process of milling (the product is usually obtained in the form of “dough”) may be taken out and then sent to the process of drying as it is, but it may also be subjected to a process of dispersion before the process of drying. For example, the process of drying may be preferably performed after agglomerated particles in the product obtained after the process of milling are dispersed into water (or an organic solvent) by using a dispersing machine like a magnetic stirrer, an ultrasonic disperser or a high pressure homogenizer.
4. Formulation
The organic compound nano-powder obtained by the method according to the present embodiment has excellent formulation properties so that the powder may be applied to various formulations. For example, when the powder is applied to an inhalant agent, the product obtained after the process of milling may be mixed with water to prepare a suspension. Then, the porous particles having the particle diameter of about 1 to 30 μm may be prepared by freeze spray drying of the suspension. To improve dispersing quality of the particles, small amount of surfactant may be added to above-mentioned water. Alternatively, for the same reason, small amount of volatile additive like ethanol may be added to the water. When the volatile additive is added, the additive can be removed during drying. Thus, an irritation may be lowered as compared with the case of adding a surfactant.
When the organic compound nano-powder is applied to an injectable formulation, an ophthalmic formulation, an ointment, a transdermal absorbing formulation and the like, a water-dispersion product may be prepared by adding an anti-agglomeration agent to the product obtained after the process of milling. For example, convenient surfactants may be used as the anti-agglomeration agents. Specifically, various anti-agglomeration agents mentioned in the section of the organic compound nano-powder may be used. A water-dispersion product using a polymer like an acrylic acid copolymer and a methacrylic acid copolymer, which is also the anti-agglomeration agent may be used as a DDS formulation. The water-dispersion product may be prepared by using a usually used machine. Examples of the machine include a homogenizer, a homomixer, an ultrasonic disperser and a high-pressure homogenizer.
The water-dispersion product may be made to powder by a vacuum drying, a spray drying, a freeze drying, a freeze spray drying or the like. The powder prepared by such a method has an excellent re-dispersing quality into water and thus is excellent for the applications to an injectable formulation, an ophthalmic formulation and an oral formulation to be prepared before use.
Alternatively, the organic compound nano-powder may be used for an ointment, a capsule formulation, a transdermal absorption formulation and the like by dispersing it into an oily substance. The oily substance is not particularly limited as far as it is usable in a usual formulation. Examples of the oily substance include liquid paraffin, vaseline, propylene glycol, glycerin, polyethylene glycol and a vegetable oil. The oily substances may be used singly or as a mixture of two or more of them. A dispersion product in the oily substance may be prepared by using a convenient machine. Examples of the machine include a homogenizer, a homomixer, an ultrasonic disperser, a high-pressure homogenizer, a twin roll mill, a triple roll mill, a disk blade kneader disperser and a biaxial extruder.
EXAMPLES
Next, Examples of the present invention will be explained. However, the present invention is not limited to the following Examples.
Experiment 1
Preparation of an Organic Compound Nano-Powder
Example 1
Preparation of Powder Containing 10% by Weight of Turmeric
(1) Processes of Mixing and Milling
10 g of turmeric powder (>90% purity of curcuminoid, manufactured by Bio Actives Japan Corp.), 78 g of D-(−)-mannitol (particle diameter distribution in the range of 10 to 300 μm, manufactured by Wako Pure Chemical Industries, Ltd.), 10 g of a sucrose fatty acid ester (trade name of DK Ester SS, manufactured by Dai-Ichi Kogyo Seiyaku Co., Ltd.), 1.7 g of sodium carboxymethyl cellulose (trade name of Cellogen F-3H, manufactured by Dai-Ichi Kogyo Seiyaku Co., Ltd.) and 9 g of purified water were introduced into a 500-mL trimix kneader (manufactured by Inoue MFG, Inc.) and then were mixed and kneaded with keeping the load current of 0.95 to 1.2 A for about 3 hours. The particle diameter distribution of the turmeric powder measured before the process of mixing by the particle diameter distribution measurement instrument (instrument name of Delsa Nano, manufactured by Beckman Coulter Inc.) was as follows: the average particle diameter (Dav)=12820 nm, the value of D10=3793 nm, the value of D50=10530 nm, and the value of D90=25520 nm. A part (10 mg) of the kneaded product (referred as “dough”) taken out after mixing and kneading was weighed into a 50-mL glass vial. After that, 10 mL of purified water was put into the glass vial, and then a mixture of the kneaded product and water was served to the dispersion treatment using a bath-type ultrasonic disperser (type of US100 III, manufactured by AS ONE Corp.) for 1 to 2 minutes. The particle diameter distribution of the kneaded product measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=202 nm, the value of D10=78 nm, the value of D50=162 nm, and the value of D90=338 nm.
(2) A Process of Dispersion
54 g of purified water was added to above-mentioned dough (6 g). Then, a mixture of the dough and water was agitated by using a magnetic stirrer and then was served to the dispersion treatment using a probe-type ultrasonic disperser (probe-type 406 HWS with Amp. of 30 for 2 minutes, S4000 type, Astrason).
(3) A Process of Drying
Next, the dispersion solution obtained in the foregoing process of dispersion was served into a spray dryer (type of B-290, manufactured by Buchi Labortechnik AG, with flow of 45, inlet temperature of 150 degrees C., aspirator of 100%, and feed pump of 35%). As a result, 4.35 g of dry powder was obtained. A part (10 mg) of the obtained dry powder was mixed with 10 mL of purified water. Then, a mixture of the dry powder and water was served to the dispersion treatment using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. The particle diameter distribution of turmeric nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=223 nm, the value of D10=99 nm, the value of D50=185 nm, and the value of D90=336 nm.
Example 2
Preparation of Powder Containing 20% by Weight of Turmeric
(1) Processes of Mixing and Milling
20 g of the turmeric powder used in Example 1, 65 g of the D-(−)-mannitol used in Example 1, 10 g of the sucrose fatty acid ester used in Example 1, 1.6 g of the sodium carboxymethyl cellulose used in Example 1 and 9 g of purified water were introduced into the trimix kneader used in Example 1 and then were mixed and kneaded under the same conditions as Example 1. A part (10 mg) of the dough was weighed into a 50-mL glass vial. After that, 20 mL of purified water was put into the glass vial, and then a mixture of the dough and water was served to same dispersion treatment as Example 1. The particle diameter distribution of turmeric nano-powder measured by the particle diameter distribution measurement instrument used in Example 1 was as follows: the average particle diameter (Dav)=379 nm, the value of D10=155 nm, the value of D50=298 nm, and the value of D90=603 nm.
(2) A Process of Dispersion
270 g of purified water was added to 30 g of the dough. Then, a mixture of the dough and water was served to the dispersion treatment by the same conditions as Example 1.
(3) A Process of Drying
Next, the dispersion solution obtained in the foregoing process of dispersion was served into a freeze dryer (type of FDU-2100, EYELA). As a result, 27.5 g of dry powder was obtained. A part (10 mg) of the obtained dry powder was mixed with 20 mL of purified water. Then, a mixture of the dry powder and water was served to the dispersion treatment using the bath-type ultrasonic disperser used in Example 1 for 1 to 2 minutes. The particle diameter distribution of turmeric nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=463 nm, the value of D10=147 nm, the value of D50=359 nm, and the value of D90=802 nm.
Comparative Example 1
Preparation of a Turmeric-Containing Powder by Milling with Salt
(1) Processes of Mixing and Milling
10 g of synthetic curcumin powder (manufactured by Wako Pure Chemical Industries, Ltd.), 80 g of milled salt (manufactured by Wako Pure Chemical Industries, Ltd.) and 17.2 g of glycerin (manufactured by Kanto Chemical Co., Inc.) were introduced into the trimix kneader used in Example 1 and then were mixed and kneaded under the same conditions as Example 1. The particle diameter distribution of the synthetic curcumin powder measured by using the particle diameter distribution measurement instrument used in Example 1 before the process of mixing was as follows: the average particle diameter (Dav)=17270 nm, the value of D10=4422 nm, the value of D50=15070 nm, and the value of D90=33850 nm. 300 mg of the dough obtained after kneading was weighed into a 50-mL glass vial. After that, 5 mL of mixed solution of 0.1% SDS (sodium dodecylsulfate) and 0.1% hydrogenated soy bean lecithin was put into the glass vial. The content in the glass vial was served to the dispersion treatment by using the bath-type ultrasonic disperser used in Example 1 for 1 to 2 minutes. Dispersed content was added 45 mL of purified water and then was again served to the dispersion treatment by using the bath-type ultrasonic disperser for 1 to 2 minutes. The particle diameter distribution of synthetic curcumin nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=96 nm, the value of D10=37 nm, the value of D50=78 nm, and the value of D90=162 nm.
(2) A Process of Water-Washing
300 mg of the dough was weighed into a 50-mL falcon tube and then added 10 mL of purified water. After dispersed by a vortex, centrifugal separation was carried out by using a table-top centrifugal separator (number of rotation: 6000 rpm, for 10 minutes). Thereafter, the supernatant solution was discarded. Then, the centrifugal separation was carried out again after 10 mL of purified water was added to the residue. Such a set of operation was repeated until the electric conductivity of the final supernatant solution became 10 μs/cm or less, whereby producing a wet cake (this contained about 30 mg of curcumin). The Wet cake was added 5 mL of a mixed solution of 0.1% SDS (sodium dodecylsulfate) and 0.1% hydrogenated soy bean lecithin, and then was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. Then, the solution dispersed above was added 45 mL of purified water, and was again subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. The particle diameter distribution of the synthetic curcumin nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=255 nm, the value of Dav)=102 nm, the value of D50=192 nm, and the value of D90=431 nm.
(3) A Process of Drying
The wet cake obtained by the same procedure as the water-washing process was dried under vacuum (conditions: 30 degrees C. or lower, 1 hPa and 18 hours) to obtain 28 mg of dry powder. The dry powder obtained using above method was added 5 mL of a mixed solution of 0.1% SDS (sodium dodecylsulfate) and 0.1% hydrogenated soy bean lecithin and then was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. Then, the solution dispersed above was added 45 mL of purified water, and was again subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. The particle diameter distribution of the synthetic curcumin powder measured by the foregoing particle diameterdistribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=3048 nm, the value of D10=133 nm, the value of D50=507 nm, and the value of D90=9376 nm.
Table 1 shows the particle diameter distributions of the products obtained in each process of Example 1, Example 2 and Comparative Example 1.








TABLE 1








Particle diameter distribution (nm)











After milling
After water-washing
After drying




















Dav
D10
D50
D90
Dav
D10
D50 
D90
Dav
D10
D50
D90






















Example 1
202
78
162
338
—
—
—
—
223
99
185
336


Example 2
379
155
298
603
—
—
—
—
463
147
359
802


Comparative 
96
37
78
162
255
102
192
431
3048
133
507
9376


Example 1





















As shown in Table 1, without the process of drying, finer nano-powder was obtained by the conventional milling method used the salt, while with the process of drying, the powder obtained by milling method used the salt tended to agglomerate more easily. On the other hand, in the milling methods of Examples 1 and 2 used D-mannitol, even with the process of drying, nano-powder having the particle diameter distribution not significantly changed from the particle diameter distribution of the powder immediately after the milling could be obtained. This means that the particles in the powder become difficult to agglomerate after drying by milling with D-mannitol.
Example 3
Preparation of Powder Containing 10% by Weight of Rutin
(1) Processes of Mixing and Milling
10 g of rutin powder (manufactured by Wako Pure Chemical Industries, Ltd.), 80 g of D-(−)-mannitol used in Example 1, 10 g of the sucrose fatty acid ester used in Example 1, 2.0 g of sodium carboxymethyl cellulose used in Example 1 and 10 g of purified water were introduced into a 500-mL trimix kneader (manufactured by Inoue MFG., Inc.), and then were mixed and kneaded under the same conditions as Example 1. The particle diameter distribution of the rutin powder measured by the particle diameter distribution measurement instrument used in Example 1 before the process of mixing was as follows: the average particle diameter (Dav)=8949 nm, the value of D10=1972 nm, the value of D50=5007 nm, and the value of D90=21450 nm. A part of the dough (30 mg) after the mixing and kneading was weighed into a 50-mL glass vial and then added 3 mL of 10% mannitol solution. Then, the solution obtained above was subjected to a dispersion treatment by using the bath-type ultrasonic disperser used in Example 1 for 0.5 to 1 minutes. The particle diameter distribution of rutin nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment of the kneaded product was as follows: the average particle diameter (Dav)=277 nm, the value of D10=136 nm, the value of D50=226 nm, and the value of D90=410 nm.
(2) A Process of Drying
The dough (10 g) obtained in the foregoing process was dried in a vacuum dryer (type of VOS-300VD, EYELA) 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 solution and then was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 0.5 to 1 minutes. The particle diameter distribution of the rutin nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=321 nm, the value of D10=140 nm, the value of D50=265 nm, and the value of D90=492 nm.
Example 4
Preparation of Kneaded Product Containing 45% by Weight of Fexofenadine Hydrochloride
(1) Processes of Mixing and Milling
20 g of fexofenadine hydrochloride powder (manufactured by Sumitomo Chemical Co., Ltd.), 20 g of D-(−)-mannitol used in Example 1, 2 g of hydroxypropyl cellulose (trade name of SSL, manufactured by Nippon Soda Co., Ltd.) and 13.3 g of 10% polyvinyl alcohol (trade name of Poval 217C, manufactured by Kuraray Co., Ltd.) were introduced into the trimix kneader used in Example 1 and then were mixed and kneaded under the same conditions as Example 1. The particle diameter distribution of the fexofenadine hydrochloride powder measured by the particle diameter distribution measurement instrument used in Example 1 before the process of mixing was as follows: the average particle diameter (Dav)=45660 nm, the value of D10=3225 nm, the value of D50=27320 nm, and the value of D90=139600 nm. A part of the dough (15 mg) after the mixing and kneading was weighed into a 50-mL glass vial and then added 5 mL of a 0.4% aqueous sodium chloride solution. Then, the solution obtained above was subjected to a dispersion treatment by using the bath-type ultrasonic disperser used in Example 1 for 0.5 to 1 minutes. The particle diameter distribution of fexofenadine hydrochloride nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment of the kneaded product was as follows: the average particle diameter (Dav)=316 nm, the value of D10=142 nm, the value of D50=250 nm, and the value of D90=489 nm.
(2) A Process of Drying
The dough (20 g) obtained in the foregoing process was dried in the vacuum dryer used in Example 3 to obtain 15.5 g of dry powder. A part of the obtained dry powder (15 mg) was mixed with 5 mL of a 0.4% aqueous sodium chloride solution and then was subjected to a dispersion treatment by using a probe-type ultrasonic disperser (probe-type 419 with Amp. of 25 for 1 minute, S4000 type, Astrason). The particle diameter distribution of the fexofenadine hydrochloride nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=230 nm, the value of D10=129 nm, the value of D50=198 nm, and the value of D90=309 nm.
Example 5
Experiment 2
Preparation of Fluorometholone-Containing Ophthalmic Formulation
(1) Processes of Mixing and Milling
8 g of fluorometholone powder (manufactured by Sicor Biotech UAB), 32 g of D-(−)-mannitol used in Example 1, 40 g of milled salt (trade name of Tomita Salt K-30, manufactured by Tomita Pharmaceutical Co., Ltd.) and 14 g of glycerin (manufactured by Wako Pure Chemical Industries, Ltd.) were introduced into the trimix kneader used in Example 1 and then were mixed and kneaded under the same conditions as Example 1. The particle diameter distribution of the fluorometholone powder measured by the particle diameter distribution measurement instrument used in Example 1 before the process of mixing was as follows: the average particle diameter (Dav)=3148 nm, the value of D10=1389 nm, the value of D50=2636 nm, and the value of D90=5709 nm. A part of the dough (60 mg) after the mixing and kneading was weighed into a 50-mL glass vial and then added 5 mL of a mixed solution of 0.1% SDS and 0.1% hydrogenated soy bean lecithin. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. The particle diameter distribution of fluorometholone nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=136 nm, the value of D10=68 nm, the value of D50=114 nm, and the value of D90=202 nm.
(2) A Process of Dispersion
4.5 g of the dough obtained in the foregoing process was added 36 g of 1.0% HCO60, 36 g of 1.0% HEC and 36 g of 0.01% benzarconium chloride and then was subjected to a dispersion treatment by using a probe-type ultrasonic disperser (probe-type 406HWS with Amp. of 30 for 4 minutes, 54000 type, Astrason). Then, 36 g of a mixture solution comprising 6% disodium phosphate dodecahydrate, 0.6% sodium dihydrogen phosphate dihydrate and 0.1% EDTA.2Na, and 36 g of 1.0% methyl cellulose was added thereinto and then purified water was further added thereinto in order to preapre 360 g of the mixture. Then, the solution obtained above was subjected to a dispersion treatment by using the probe-type ultrasonic disperser (probe-type 406HWS with Amp. of 30 for 1 minute, 54000 type, Astrason). Thus prepared formulation had the quality of passing through a 0.2 μm membrane filter almost thoroughly (passing rate of 90% or higher by HPLC analysis) and was with the particle diameter thereof coincident very well with that of the dough. Meanwhile, the osmotic pressure rate of the prepared formulation was about 1 (0.3 Osmol/kg H2O), so the formulation could be used as an ophthalmic formulation as it was.
Example 6
Experiment 3
Preparation of Clarithromycin-Containing Drug
(1) Processes of Mixing and Milling
10 g of clarithromycin powder (manufactured by Assia Chemical Industries Ltd.), 60 g of D-(−)-mannitol used in Example 1, 10 g of the milled salt used in Example 5, 3 g of polyvinyl pyrrolidone, 5.0 g of hydrogenated soy bean lecithin (manufactured by H. Holstein GmbH) and 20 g of glycerin were introduced into the trimix kneader used in Example 1, and then were mixed and kneaded under the same conditions as Example 1. The particle diameter distribution of the clarithromycin powder measured by the particle diameter distribution measurement instrument used in Example 1 before the process of mixing was as follows: the average particle diameter (Dav)=10160 nm, the value of D10=2277 nm, the value of D50=6872 nm, and the value of D90=22850 nm. A part of the dough (100 mg) after the mixing and kneading was weighed into a 50-mL glass vial and then added 3 mL of 0.1% HCO60. The solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 3 minutes. The particle diameter distribution of clarithromycin nano-powder measured by the foregoing particle diameter distribution measurement instrument after the dispersion treatment was as follows: the average particle diameter (Dav)=145 nm, the value of D10=81 nm, the value of D50=125 nm, and the value of D90=197 nm.
(2) A Process of Dispersion
1.3 g of the obtained dough was added 65 g of 0.1% HCO60 and 13 g of 2.0% hypromellose and then was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 10 minutes. Then, purified water was added thereinto in order to prepare 130 g of the mixture, which was then further subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 minute. Thus prepared formulation had the quality of passing through a 0.2-μm membrane filter almost thoroughly (passing rate of 90% or higher by HPLC analysis) and was with the particle diameter thereof coincident very well with that of the dough. Meanwhile, the osmotic pressure rate of the prepared formulation was about 1 (0.3 Osmol/kg H2O), so the formulation could be used as an ophthalmic formulation as it was.
As shown above, when the organic compound is milled by using a carbohydrate compound such as mannitol, an organic compound nano-powder or a suspension containing the powder can be produced in so simple process without the water-washing process, so that recovery loss of the powder can be avoided. In addition, because the water-washing process is not necessary, the particles of the organic compound are difficult to agglomerate. As a result, the diameter of the particles in the dough obtained immediately after milling may be kept.
Table 2 shows granular carbohydrate compounds used in following experiments. The term “Dav” means an average particle diameter (Dav). In the table, the term “D10” means the particle diameter (D10 value) of the particle at the position of 10% when counted from the smallest size zero (minimum) to 100% (maximum) of the particle diameter in a particle diameter distribution. The term “D50” means a certain particle diameter (D50 value) when amount of a larger side becomes equal to amount of a smaller side of the particle diameters divided into two a powder from the certain particle diameter. The term “D90” means the particle diameter (D90 value) of the particle at the position of 90% when counted from the smallest size zero (minimum) to 100% (maximum) of the particle diameter in the particle diameter distribution. The same definitions shall apply to following tables.










TABLE 2









Melting 



Carbohydrate
Particle Size (μm)
point














compound
Dav 
D10
D50
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)


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
280
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
566
104
Wako Pure Chemical Industries, 








Ltd. (High grade)


Lactose
45
3
20
123
202
Kanto Chemical Co., Inc. 


monohydrate





(High grade)


Trehalose
25
7
20
50
203
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
Milling with D-Mannitol
Example 7
Preparation of a Curcumin Nano-Powder
100 mg of turmeric powder (70% or more purity of curcumin, or 90% or more purity of curcuminoid, manufactured by Bio Actives Japan Corp.), 325 mg of D-(−)-mannitol used in Example 1, 50 mg of sucrose fatty acid ester (trade name of DK Ester SS, manufactured by Dai-Ichi Kogyo Seiyaku Co., Ltd.), 9 mg of sodium carboxymethyl cellulose (trade name of Cellogen F-3H, manufactured by Dai-Ichi Kogyo Seiyaku Co., Ltd.) and 110 mg of purified water were served on a glass disk of a Hoover muller (manufactured by Imoto Machinery Co., Ltd.) and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the turmeric powder was finely milled. Hereinafter, the term “turmeric powder” will be also called as another term “curcumin” for the reason that curcumin is a major ingredient in the turmeric powder. 10 mg 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% sodium dodecylsulfate (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.01% hydrogenated soy bean lecithin (trade name of Phospholipon 90H, manufactured by Lipoid GmbH). Then, the solution obtained above was subjected to a dispersion treatment by using a bath-type ultrasonic disperser (type of US100 III, manufactured by AS ONE Corp., the same shall apply hereinafter) for 1 to 2 minutes. The particle diameter distribution of curcumin nano-powder measured by the same particle diameter distribution measurement instrument as used in Example 1 was as follows: Dav=384 nm, the value of D10=154 nm, the value of D50=280 nm, and the value of D90=569 nm.
Example 8
Preparation of a Mefenamic Acid Nano-Powder
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 7 except changing from 100 mg of turmeric powder to 100 mg of mefenamic acid powder (manufactured by Tokyo Chemical Industry Co., Ltd.). As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=247 nm, the value of D10=99 nm, the value of D50=198 nm, and the value of D90=403 nm.
Example 9
Preparation of an Acetaminophen Nano-Powder
An acetaminophen powder was milled under the same conditions as Example 7 except both changing from 100 mg of turmeric powder to 100 mg of acetaminophen powder (manufactured by Tokyo Chemical Industry Co., Ltd.) and changing from sucrose fatty acid ester to decaglyceryl monostearate (trade name of Decaglyn 1-SV, manufactured by Nikko Chemicals Co., Ltd.). Then, 100 mg of the dough obtained after milling was weighed and then subjected to a dispersion treatment under the same conditions as Example 7 except adding only 5 mL of 0.1% sodium dodecylsulfate (same as used in Example 7 and also used in following experiments) but no 0.01% hydrogenated soy bean lecithin (same as used in Example 7 and also used in following experiments). As a result, the particle diameter distribution of acetaminophen nano-powder obtained after above procedures was as follows: Dav=443 nm, the value of D10=92 nm, the value of D50=286 nm, and the value of D90=886 nm.
Example 10
Preparation of an Ibuprofen Nano-Powder
An ibuprofen powder was milled under the same conditions as Example 7 except both changing from 100 mg of turmeric powder to 100 mg of ibuprofen powder (manufactured by Tokyo Chemical Industry Co., Ltd.) and changing from sucrose fatty acid ester to hydrogenated soy bean lecithin. Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 7 except adding 10 mL of a mixed solution of 0.1% sodium dodecylsulfate and 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of ibuprofen nano-powder obtained after above procedures was as follows: Dav=286 nm, the value of D10=71 nm, the value of D50=122 nm, and the value of D90=257 nm.
Example 11
Preparation of an Amphotericin B Nano-Powder
An amphotericin B powder was milled under the same conditions as Example 7 except both changing from 100 mg of turmeric powder to 100 mg of amphotericin B powder (manufactured by Wako Pure Chemical Industries, Ltd.) and changing from sucrose fatty acid ester to hydrogenated soy bean lecithin. Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 7 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of amphotericin B nano-powder obtained after above procedures was as follows: Dav=242 nm, the value of D10=87 nm, the value of D50=195 nm, and the value of D90=397 nm.
Example 12
Preparation of a Diclofenac Sodium Nano-Powder
A diclofenac sodium powder was milled under the same conditions as Example 7 except both changing from 100 mg of turmeric powder to 100 mg of diclofenac sodium powder (manufactured by Tokyo Chemical Industry Co., Ltd.) and changing from sucrose fatty acid ester to decaglyceryl monostearate (same as used in Example 9 and also used in following experiments). Then, 100 mg of the dough obtained after milling was weighed and then subjected to a dispersion treatment under the same conditions as Example 7 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of diclofenac sodium nano-powder obtained after above procedures was as follows: Dav=303 nm, the value of D10=99 nm, the value of D50=228 nm, and the value of D90=536 nm.
Example 13 
Preparation of an Indomethacin Nano-Powder
An indomethacin powder was milled under the same conditions as Example 7 except changing from 100 mg of turmeric powder to 100 mg of indomethacin powder (manufactured by Wako Pure Chemical Industries, Ltd.). Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 7 except adding only 10 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=353 nm, the value of D10=155 nm, the value of D50=289 nm, and the value of D90=539 nm.
Example 14
Preparation of a Felbinac Nano-Powder
A felbinac powder was milled under the same conditions as Example 7 except changing from 100 mg of turmeric powder to 100 mg of felbinac powder (manufactured by Wako Pure Chemical Industries, Ltd.). Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 7 except adding 10 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of felbinac nano-powder obtained after above procedures was as follows: Dav=335 nm, the value of D10=170 nm, the value of D50=279 nm, and the value of D90=481 nm.
Example 15
Preparation of a Pranlukast Hydrate Nano-Powder
A pranlukast hydrate powder was milled under the same conditions as Example 7 except changing from 100 mg of turmeric powder to 100 mg of pranlukast hydrate powder (manufactured by Hallochem Pharma. Co., Ltd., China). Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 7 except adding only 10 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of pranlukast hydrate nano-powder obtained after above procedures was as follows: Dav=152 nm, the value of D10=85 nm, the value of D50=132 nm, and the value of D90=208 nm.
Example 16
Preparation of a Dexamethasone Nano-Powder
A dexamethasone powder was milled under the same conditions as Example 7 except changing from 100 mg of turmeric powder to 100 mg of dexamethasone powder (manufactured by Wako Pure Chemical Industries, Ltd.). Then, 20 mg of the dough obtained after milling was weighed and then subjected to a dispersion treatment under the same conditions as Example 7 except adding only 5 mL of 0.1% Polyoxyethylene Hydrogenated Castor Oil 60 (trade name of NIKKOL HCO-60, manufactured by Nikko Chemicals Co., Ltd.). As a result, the particle diameter distribution of dexamethasone nano-powder obtained after above procedures was as follows: Dav=179 nm, the value of D10=102 nm, the value of D50=155 nm, and the value of D90=240 nm.
Comparative Example 2
Milling of a Curcumin Powder without Using D-Mannitol
The turmeric powder used in Example 7 was milled under the same conditions as Example 7 except adding no D-(−)-mannitol. Then, 2 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 7. As a result, the particle diameter distribution of curcumin powder obtained after above procedures was as follows: Dav=716 nm, the value of D10=131 nm, the value of D50=216 nm, and the value of D90=2983 nm. Thus, the Dav and the D90 of the particle diameter distribution were more than 500 nm and 1500 nm, respectively.
Comparative Example 3
Milling of a Mefenamic Acid Powder without Using D-Mannitol
The mefenamic acid powder used in Example 8 was milled under the same conditions as Example 8 except adding no D-(−)-mannitol. Then, 2 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 8. As a result, the particle diameter distribution of mefenamic acid powder obtained after above procedures was as follows: Dav=926 nm, the value of D10=155 nm, the value of D50=276 nm, and the value of D90=3673 nm. Thus, the Dav and the D90 of the particle diameter distribution were more than 500 nm and 1500 nm, respectively.
Comparative Example 4
Milling of an Acetaminophen Powder without Using D-Mannitol
The acetaminophen powder used in Example 9 was milled under the same conditions as Example 9 except adding no D-(−)-mannitol. Then, 20 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 9. As a result, the particle diameter distribution of acetaminophen powder obtained after above procedures was as follows: Dav=1124 nm, the value of D10=134 nm, the value of D50=400 nm, and the value of D90=2899 nm. Thus, the Dav and the D90 of the particle diameter distribution were more than 500 nm and 1500 nm, respectively.
Comparative Example 5
Milling of an Ibuprofen Powder without Using D-Mannitol
The ibuprofen powder used in Example 10 was milled under the same conditions as Example 10 except adding no D-(−)-mannitol. Then, 2 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 10. As a result, the particle diameter distribution of ibuprofen powder obtained after above procedures was as follows: Dav=2873 nm, the value of D10=403 nm, the value of D50=619 nm, and the value of D90=10421 nm. Thus, the Dav and the D90 of the particle diameter distribution were more than 500 nm and 1500 nm, respectively.
Comparative Example 6
Milling of an Amphotericin B Powder without Using D-Mannitol 
The amphotericin B powder used in Example 11 was milled under the same conditions as Example 11 except adding no D-(−)-mannitol. Then, 2 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 11. As a result, the particle diameter distribution of amphotericin B powder obtained after above procedures was as follows: Dav=750 nm, the value of D10=159 nm, the value of D50=314 nm, and the value of D90=841 nm Thus, the Dav of the particle diameter distribution was more than 500 nm.
Comparative Example 7
Milling of a Diclofenac Sodium Powder without Using D-Mannitol
The diclofenac sodium powder used in Example 12 was milled under the same conditions as Example 12 except adding no D-(−)-mannitol. Then, 20 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 12. As a result, the particle diameter distribution of diclofenac sodium powder obtained after above procedures was as follows: Dav=589 nm, the value of D10=78 nm, the value of D50=196 nm, and the value of D90=2364 nm. Thus, the Dav and the D90 of the particle diameter distribution were more than 500 nm and 1500 nm, respectively.
Comparative Example 8
Milling of an Indomethacin Powder without Using D-Mannitol
The indomethacin powder used in Example 13, 30 mg of polyvinylpyrrolidone (trade name of K25, manufactured by Wako Pure Chemical Industries, Ltd.), 50 mg of hydrogenated soy bean lecithin and 50 mg of glycerin (manufactured by Junsei Chemical Co., Ltd.) were served on a glass disk of a Hoover muller (same as used in Example 7 and also used in following experiments) without adding D-(−)-mannitol and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the indomethacin powder was milled 2 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 13. As a result, the particle diameter distribution of indomethacin powder obtained after above procedures was as follows: Dav=1346 nm, the value of D10=145 nm, the value of D50=219 nm, and the value of D90=4154 nm. Thus, the Dav and the D90 of the particle diameter distribution were more than 500 nm and 1500 nm, respectively.
Comparative Example 9
Milling of a Felbinac Powder without Using D-Mannitol
The felbinac powder used in Example 14, 30 mg of polyvinylpyrrolidone (same as used in Comparative Example 8 and also used in following experiments), 50 mg of hydrogenated soy bean lecithin and 50 mg of glycerin (same as used in Comparative Example 8 and also used in following experiments) were served on a glass disk of the foregoing Hoover muller without adding D-(−)-mannitol and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the felbinac powder was milled 2 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 14. As a result, the particle diameter distribution of felbinac powder obtained after above procedures was as follows: Dav=1457 nm, the value of D10=154 nm, the value of D50=309 nm, and the value of D90=5452 nm. Thus, the Dav and the D90 of the particle diameter distribution were more than 500 nm and 1500 nm, respectively.
Comparative Example 10
Milling of a Pranlukast Hydrate Powder without Using D-Mannitol
The pranlukast hydrate powder used in Example 15 (also used in following experiments), 30 mg of polyvinylpyrrolidone, 50 mg of hydrogenated soy bean lecithin and 75 mg of glycerin were served on a glass disk of the foregoing Hoover muller without adding D-(−)-mannitol and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the pranlukast hydrate powder was milled 2 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 15. As a result, the particle diameter distribution of pranlukast hydrate powder obtained after above procedures was as follows: Dav=1102 nm, the value of D10=129 nm, the value of D50=408 nm, and the value of D90=4226 nm. Thus, the Dav and the D90 of the particle diameter distribution were more than 500 nm and 1500 nm, respectively.
Comparative Example 11
Milling of a Dexamethasone Powder without Using D-Mannitol
The dexamethasone powder used in Example 16, 30 mg of polyvinylpyrrolidone, 50 mg of hydrogenated soy bean lecithin and 50 mg of glycerin were served on a glass disk of the foregoing Hoover muller without adding D-(−)-mannitol and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the dexamethasone powder was milled 4 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then subjected to a dispersion treatment under the same conditions as Example 16. As a result, the particle diameter distribution of dexamethasone powder obtained after above procedures was as follows: Dav=3704 nm, the value of D10=138 nm, the value of D50=852 nm, and the value of D90=12321 nm. Thus, the Dav and the D90 of the particle diameter distribution were more than 500 nm and 1500 nm, respectively.
Table 3 shows the particle diameter distributions of various organic compound powders prepared in Examples 7 to 16 and Comparative Examples 2 to 11 as compared with the particle diameter distributions of the powders before milling. The term “Cur” in the table means curcumin. The term “Mef” in the table means mefenamic acid. The term “Ace” in the table means acetaminophen. The term “Ibu” in the table means ibuprofen. The term “Amp” in the table means amphotericin B. The term “Dic” in the table means diclofenac sodium. The term “Ind” in the table means indomethacin. The term “Fel” in the table means felbinac. The term “Pra” in the table means pranlukast hydrate. The term “Dex” in the table means dexamethasone.









TABLE 3









Paticle diameter distribution (nm)











Organic
Before milling
After milling

















compound
Dav
D10
D50
D90
Dav
D10
D50
D90



















Example 7
Cur
16640
930 
12150 
35870 
384
154
280
569


Example 8
Mef
16130
770 
13290 
35550 
247
99
198
403


Example 9
Ace
109940
41240
103460
188510
443
92
286
886


Example 10
Ibu
79030
23100
69440
149660
286
71
122
257


Example 11
Amp
19660
510
12520
51740 
242
87
195
397


Example 12
Dic
77780
23400 
68380
152090
303
99
228
536


Example 13
Ind
12400
630
8670 
30820 
353
155
289
539


Example 14
Fel
190720
46270
166710
356860
335
170
279
481


Example 15
Pra
9500 
1050
6150 
23660
152
85
132
208


Example 16
Dex
2690
280
2580
5360
179
102
155
240


Comparative 
Cur
16640
930 
12150
35870
716
131
216 
2983


Example 2











Comparative 
Mef
16130
770 
13290 
35550 
926
155
276
3673


Example 3











Comparative 
Ace
109940
41240
103460
188510 
1124
134
400
2899


Example 4











Comparative
Ibu
79030
23100
69440
149660 
2873
403
619
10421


Example 5











Comparative
Amp
19660
510 
12520 
51740
750
159
314
841


Example 6











Comparative
Dic
77780
23400 
68380
152090 
589
78
196 
2364


Example 7











Comparative 
Ind
12400
630
8670
30820
1346
145
219 
4154


Example 8











Comparative
Fel
190720
46270
166710
356860
1457
154
309
5452


Example 9











Comparative
Pra
9500 
1050
6150 
23660 
1102
129
408
4226


Example 10











Comparative 
Dex
2690
280
2580 
5360
3704
138
852
12321


Example 11









As shown in Table 3, organic compound nano-powder consisting of the particles with so small particle diameter was prepared when organic compound powder was milled with using D-mannitol as one of carbohydrate compounds. On the other hand, organic compound nano-powder consisting of the particles with Dav of 500 nm or less and D90 of 1500 nm or less were unable to prepare when the organic compound powder was milled without using D-mannitol. According to above results, it is considered that the carbohydrate compound contributes to increase the efficiency of milling the organic compound.
Experiment 5
Milling with Xylitol
Example 17
Preparation of a Curcumin Nano-Powder
100 mg of turmeric powder (same as used in Example 7 and also used in following experiments), 325 mg of xylitol, 50 mg of sucrose fatty acid ester (same as used in Example 7 and also used in following experiments), 9 mg of sodium carboxymethyl cellulose (same as used in Example 7 and also used in following experiments) and 110 mg of purified water were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the turmeric powder was finely milled 10 mg 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% sodium dodecylsulfate and 0.01% hydrogenated soy bean lecithin. Then, the solution obtained above was subjected to a dispersion treatment by using a bath-type ultrasonic disperser (same as used in Example 7 and also used in following experiments) for 1 to 2 minutes. As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=283 nm, the value of D10=138 nm, the value of D50=234 nm, and the value of D90=418 nm.
Example 18
Preparation of a Mefenamic Acid Nano-Powder
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 17 except changing from 100 mg of turmeric powder to 100 mg of mefenamic acid powder (same as used in Example 8 and also used in following experiments). As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=241 nm, the value of D10=98 nm, the value of D50=191 nm, and the value of D90=398 nm.
Example 19
Preparation of an Ibuprofen Nano-Powder 
An ibuprofen powder was milled under the same conditions as Example 17 except changing from 100 mg of turmeric powder to 100 mg of ibuprofen powder (same as used in Example 10 and also used in following experiments). Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 17 except adding 10 mL of a mixed solution of 0.1% sodium dodecylsulfate and 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of ibuprofen nano-powder obtained after above procedures was as follows: Dav=321 nm, the value of D10=150 nm, the value of D50=265 nm, and the value of D90=477 nm.
Example 20
Preparation of an Amphotericin B Nano-Powder
An amphotericin B powder was milled under the same conditions as Example 17 except both changing from 100 mg of turmeric powder to 100 mg of amphotericin B powder (same as used in Example 11 and also used in following experiments) and changing from sucrose fatty acid ester to hydrogenated soy bean lecithin. Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 17 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of amphotericin B nano-powder obtained after above procedures was as follows: Dav=343 nm, the value of D10=107 nm, the value of D50=170 nm, and the value of D90=326 nm.
Example 21
Preparation of a Diclofenac Sodium Nano-Powder
A diclofenac sodium powder was milled under the same conditions as Example 17 except both changing from 100 mg of turmeric powder to 100 mg of diclofenac sodium powder (same as used in Example 12 and also used in following experiments) and changing from sucrose fatty acid ester to decaglyceryl monostearate (same as used in Example 9 and also used in following experiments). Then, 100 mg of the dough obtained after milling was weighed and then subjected to a dispersion treatment under the same conditions as Example 17 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of diclofenac sodium nano-powder obtained after above procedures was as follows: Dav=200 nm, the value of D10=58 nm, the value of D50=178 nm, and the value of D90=300 nm.
Table 4 shows the particle diameter distributions of various organic compound powders prepared in Examples 17 to 21 as compared with the particle diameter distributions of the powders before milling.









TABLE 4









Particle diameter distribution (nm)












Before milling
After milling

















Organic compound
Dav
D10
D50
D90
Dav
D10
D50
D90



















Example 17 
Cur
16640
930 
12150
35870 
283
138
234 
418


Example 18
Mef
16130
770 
13290
35550
241
98
191 
398


Example 19
Ibu
79030 
23100
69440
149660
321
150
265
477


Example 20
Amp
19660
510 
12520
51740 
343 
107
170
326


Example 21
Dic
77780 
23400
68380
152090
200
58 
178 
300









As shown in Table 4, organic compound nano-powder consisting of the particles with so small particle diameter was prepared when organic compound powder was milled with using xylitol as one of carbohydrate compounds.
Experiment 6
Milling with Glucose
Example 22
Preparation of a Curcumin Nano-Powder
100 mg of turmeric powder, 325 mg of glucose, 50 mg of sucrose fatty acid ester, 9 mg of sodium carboxymethyl cellulose and 110 mg of purified water were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the turmeric powder was finely milled 10 mg 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% 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 ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=345 nm, the value of D10=96 nm, the value of D50=242 nm, and the value of D90=648 nm.
Example 23
Preparation of a Mefenamic Acid Nano-Powder
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 22 except changing from 100 mg of turmeric powder to 100 mg of mefenamic acid powder. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=224 nm, the value of D10=85 nm, the value of D50=193 nm, and the value of D90=339 nm.
Example 24
Preparation of an Ibuprofen Nano-Powder
An ibuprofen powder was milled under the same conditions as Example 22 except both changing from 100 mg of turmeric powder to 100 mg of ibuprofen powder and changing from sucrose fatty acid ester to hydrogenated soy bean lecithin. Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 22 except adding 10 mL of a mixed solution of 0.1% sodium dodecylsulfate and 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of ibuprofen nano-powder obtained after above procedures was as follows: Dav=327 nm, the value of D10=156 nm, the value of D50=266 nm, and the value of D90=489 nm.
Example 25
Preparation of a Diclofenac Sodium Nano-Powder
A diclofenac sodium powder was milled under the same conditions as Example 22 except both changing from 100 mg of turmeric powder to 100 mg of diclofenac sodium powder and changing from sucrose fatty acid ester to decaglyceryl monostearate. Then, 100 mg of the dough obtained after milling was weighed and then subjected to a dispersion treatment under the same conditions as Example 22 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of diclofenac sodium nano-powder obtained after above procedures was as follows: Dav=244 nm, the value of D10=78 nm, the value of D50=130 nm, and the value of D90=266 nm.
Table 5 shows the particle diameter distributions of various organic compound powders prepared in Examples 22 to 25 as compared with the particle diameter distributions of the powders before milling.









TABLE 5









Particle diameter distibution (nm)












Before milling
After milling

















Organic compound
Dav
D10
D50
D90
Dav 
D10
D50
D90



















Example 22
Cur
16640
930 
12150 
35870
345
96
242 
648


Example 23
Mef
16130
770 
13290
35550
224
85 
193
339


Example 24
Ibu
79030
23100
69440
149660
327
156 
266
489


Example 25
Dic
77780
23400
68380
152090
244
78
130
266









As shown in Table 5, organic compound nano-powder consisting of the particles with so small particle diameter was prepared when organic compound powder was milled with using glucose as one of carbohydrate compounds.
Experiment 7
Milling with Fructose
Example 26
Preparation of a Curcumin Nano-Powder 
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 disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the turmeric powder was finely milled 10 mg 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% 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 ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=181 nm, the value of D10=82 nm, the value of D50=144 nm, and the value of D90=286 nm.
Example 27
Preparation of a Mefenamic Acid Nano-Powder
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 26 except changing from 100 mg of turmeric powder to 100 mg of mefenamic acid powder. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=205 nm, the value of D10=84 nm, the value of D50=165 nm, and the value of D90=328 nm.
Example 28
Preparation of an Acetaminophen Nano-Powder
The acetaminophen powder was milled under the same conditions as Example 26 except both changing from 100 mg of turmeric powder to 100 mg of acetaminophen powder (same as used in Example 9 and also used in following experiments) and changing from sucrose fatty acid ester to decaglyceryl monostearate. Then, 100 mg of the dough obtained after milling was weighed and then subjected to a dispersion treatment under the same conditions as Example 26 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of acetaminophen nano-powder obtained after above procedures was as follows: Dav=186 nm, the value of D10=82 nm, the value of D50=148 nm, and the value of D90=296 nm.
Example 29
Preparation of an Ibuprofen Nano-Powder
An ibuprofen powder was milled under the same conditions as Example 26 except changing from 100 mg of turmeric powder to 100 mg of ibuprofen powder. Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 26 except adding 10 mL of a mixed solution of 0.1% sodium dodecylsulfate and 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of ibuprofen nano-powder obtained after above procedures was as follows: Dav=434 nm, the value of D10=176 nm, the value of D50=335 nm, and the value of D90=711 nm.
Example 30
Preparation of an Amphotericin B Nano-Powder
An amphotericin B powder was milled under the same conditions as Example 26 except both changing from 100 mg of turmeric powder to 100 mg of amphotericin B powder and changing from sucrose fatty acid ester to hydrogenated soy bean lecithin. Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 26 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of amphotericin B nano-powder obtained after above procedures was as follows: Dav=376 nm, the value of D10=132 nm, the value of D50=298 nm, and the value of D90=625 nm.
Table 6 shows the particle diameter distributions of various organic compound powders prepared in Examples 26 to 30 as compared with the particle diameter distributions of the powders before milling.









TABLE 6









Particle diameter distribution (nm)











Organic
Before milling
After milling

















compound
Dav
D10
D50
D90
Dav 
D10
D50
D90



















Example 26
Cur
16640
930 
12150
35870 
181
82 
144 
286


Example 27 
Mef
16130
770 
13290
35550
205
84 
165 
328


Example 28
Ace
109940
41240
103460
188510
186
82 
148 
296


Example 29
Ibu
79030
23100
69440
149660
434 
176 
335 
711


Example 30
Amp
19660
510 
12520
51740 
376 
132
298 
625









As shown in Table 6, organic compound nano-powder 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.
Experiment 8
Milling with Trehalose
Example 31
Preparation of a Curcumin Nano-Powder
100 mg of turmeric powder, 325 mg of trehalose, 50 mg of sucrose fatty acid ester, 9 mg of sodium carboxymethyl cellulose and 110 mg of purified water were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the turmeric powder was finely milled 10 mg 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% 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 ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=263 nm, the value of D10=86 nm, the value of D50=211 nm, and the value of D90=444 nm.
Example 32
Preparation of a Mefenamic Acid Nano-Powder
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 31 except changing from 100 mg of turmeric powder to 100 mg of mefenamic acid powder. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=193 nm, the value of D10=105 nm, the value of D50=167 nm, and the value of D90=264 nm.
Example 33
Preparation of an Acetaminophen Nano-Powder
The acetaminophen powder was milled under the same conditions as Example 31 except both changing from 100 mg of turmeric powder to 100 mg of acetaminophen powder and changing from sucrose fatty acid ester to decaglyceryl monostearate. Then, 100 mg of the dough obtained after milling was weighed and then subjected to a dispersion treatment under the same conditions as Example 31 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of acetaminophen nano-powder obtained after above procedures was as follows: Dav=238 nm, the value of D10=87 nm, the value of D50=196 nm, and the value of D90=381 nm.
Example 34
Preparation of an Amphotericin B Nano-Powder
An amphotericin B powder was milled under the same conditions as Example 31 except both changing from 100 mg of turmeric powder to 100 mg of amphotericin B powder and changing from sucrose fatty acid ester to hydrogenated soy bean lecithin. Then, the dough obtained after milling was subjected to a dispersion treatment under the same conditions as Example 31 except adding only 5 mL of 0.1% sodium dodecylsulfate but no 0.01% hydrogenated soy bean lecithin. As a result, the particle diameter distribution of amphotericin B nano-powder obtained after above procedures was as follows: Dav=162 nm, the value of D10=83 nm, the value of D50=137 nm, and the value of D90=229 nm.
Table 7 shows the particle diameter distributions of various organic compound powders prepared in Examples 31 to 34 as compared with the particle diameter distributions of the powders before milling.









TABLE 7









Particle diameter distribution (nm)











Organic
Before milling
After milling

















compound
Dav
D10
D50
D90
Dav 
D10
D50
D90



















Example 31 
Cur
16640
930
12150
35870 
263
86
211 
444


Example 32 
Mef
16130
770
13290
35550
193
105
167 
264


Example 33 
Ace
109940
41240
103460
188510
238
87
196
381


Example 34 
Amp
19660
510
12520
51740 
162
83
137 
229









As shown in Table 7, organic compound nano-powder consisting of the particles with so small particle diameter was prepared when organic compound powder was milled with using trehalose as one of carbohydrate compounds.
Experiment 9
Milling with Various Carbohydrate Compounds
(1) Milling of a Curcumin Powder
Example 35
Carbohydrate Compound: D-Mannitol
Example 35 is same one as Example 7. The particle diameter distribution of curcumin nano-powder obtained in Example 35 was as follows: Dav=384 nm, the value of D10=154 nm, the value of D50=280 nm, and the value of D90=569 nm.
Example 36
Carbohydrate Compound: Maltitol
A curcumin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 35 except using maltitol as the carbohydrate compound. As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=199 nm, the value of D10=95 nm, the value of D50=176 nm, and the value of D90=286 nm.
Example 37
Carbohydrate Compound: Erythritol
A curcumin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 35 except using erythritol as the carbohydrate compound. As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=275 nm, the value of D10=98 nm, the value of D50=201 nm, and the value of D90=483 nm.
Example 38
Carbohydrate Compound: Xylitol
Example 38 is same one as Example 17. The particle diameter distribution of curcumin nano-powder obtained in Example 38 was as follows: Dav=283 nm, the value of D10=138 nm, the value of D50=234 nm, and the value of D90=418 nm.
Example 39
Carbohydrate Compound: Glucose
Example 39 is same one as Example 22. The particle diameter distribution of curcumin nano-powder obtained in Example 39 was as follows: Dav=345 nm, the value of D10=96 nm, the value of D50=242 nm, and the value of D90=648 nm.
Example 40
Carbohydrate Compound: Fructose 
Example 40 is same one as Example 26. The particle diameter distribution of curcumin nano-powder obtained in Example 40 was as follows: Dav=181 nm, the value of D10=82 nm, the value of D50=144 nm, and the value of D90=286 nm.
Example 41
Carbohydrate Compound: Lactose Monohydrate
A curcumin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 35 except using lactose monohydrate as the carbohydrate compound. As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=320 nm, the value of D10=102 nm, the value of D50=232 nm, and the value of D90=574 nm.
Example 42
Carbohydrate Compound: Trehalose
Example 42 is same one as Example 31. The particle diameter distribution of curcumin nano-powder obtained in Example 42 was as follows: Dav=263 nm, the value of D10=86 nm, the value of D50=211 nm, and the value of D90=444 nm.
Example 43
Carbohydrate Compound: Cellobiose
A curcumin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 35 except using cellobiose as the carbohydrate compound. As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=273 nm, the value of D10=41 nm, the value of D50=241 nm, and the value of D90=435 nm.
(2) Milling of a Mefenamic Acid Powder
Example 44
Carbohydrate Compound: D-Mannitol 
Example 44 is same one as Example 8. The particle diameter distribution of mefenamic acid nano-powder obtained in Example 44 was as follows: Dav=247 nm, the value of D10=99 nm, the value of D50=198 nm, and the value of D90=403 nm.
Example 45
Carbohydrate Compound: Maltitol
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 44 except using maltitol as the carbohydrate compound. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=209 nm, the value of D10=115 nm, the value of D50=185 nm, and the value of D90=284 nm.
Example 46
Carbohydrate Compound: Erythritol
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 44 except using erythritol as the carbohydrate compound. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=185 nm, the value of D10=119 nm, the value of D50=164 nm, and the value of D90=230 nm.
Example 47
Carbohydrate Compound: Xylitol
Example 47 is same one as Example 18. The particle diameter distribution of mefenamic acid nano-powder obtained in Example 47 was as follows: Dav=241 nm, the value of D10=98 nm, the value of D50=191 nm, and the value of D90=398 nm.
Example 48
Carbohydrate Compound: Glucose 
Example 48 is same one as Example 23. The particle diameter distribution of mefenamic acid nano-powder obtained in Example 48 was as follows: Dav=224 nm, the value of D10=85 nm, the value of D50=193 nm, and the value of D90=339 nm.
Example 49
Carbohydrate Compound: Fructose
Example 49 is same one as Example 27. The particle diameter distribution of mefenamic acid nano-powder obtained in Example 49 was as follows: Dav=205 nm, the value of D10=84 nm, the value of D50=165 nm, and the value of D90=328 nm.
Example 50
Carbohydrate Compound: Lactose Monohydrate
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 44 except using lactose monohydrate as the carbohydrate compound. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=261 nm, the value of D10=114 nm, the value of D50=207 nm, and the value of D90=417 nm.
Example 51
Carbohydrate Compound: Trehalose
Example 51 is same one as Example 32. The particle diameter distribution of mefenamic acid nano-powder obtained in Example 51 was as follows: Dav=193 nm, the value of D10=105 nm, the value of D50=167 nm, and the value of D90=264 nm.
Example 52
Carbohydrate Compound: Cellobiose
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 44 except using cellobiose as the carbohydrate compound. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=271 nm, the value of D10=122 nm, the value of D50=217 nm, and the value of D90=424 nm.
Example 53
Carbohydrate Compound: Inositol
A mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 44 except using inositol as the carbohydrate compound. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=223 nm, the value of D10=101 nm, the value of D50=183 nm, and the value of D90=341 nm.
Tables 8 and 9 show the particle diameter distributions of various organic compound powders prepared in Examples 35 to 43 and Examples 44 to 53, respectively as compared with the particle diameter distributions of the powders before milling. The term “Man” in the tables means D-mannitol. The term “Mal” in the tables means maltitol. The term “Ery” in the tables means erythritol. The term “Xyl” in the tables means xylitol. The term “Glu” in the tables means glucose. The term “Fru” in the tables means fructose. The term “Lac” in the tables means lactose. The term “Tre” in the tables means trehalose. The term “Cel” in the tables means cellobiose. The term “Ino” in the tables means inositol. These definitions shall apply to following tables.









TABLE 8








Carbo-




hydrate
Particle diameter distribution (nm)











com-
Before milling
After milling

















pound
Dav
D10
D50
D90
Dav
D10
D50
D90



















Exam-
Man
16640
930
12150
35870
384
154
280
569


ple 35











Exam-
Mal




199
95
176
286


ple 36











Exam-
Ery




275
98
201
483


ple 37











Exam-
Xyl




283
138
234
418


ple 38











Exam-
Glu




345
96
242
648


ple 39











Exam-
Fru




181
82
144
286


ple 40











Exam-
Lac




320
102
232
574


ple 41











Exam-
Tre




263
86
211
444


ple 42











Exam-
Cel




273
41
241
435


ple 43


















TABLE 9








Carbo-




hydrate
Particle diameter distribution (nm)











com-
Before milling
After milling

















pound
Dav
D10
D50
D90
Dav
D10
D50
D90



















Exam-
Man
16130
770
13290
35550
247
99
198
403


ple 44











Exam-
Mal




209
115
185
284


ple 45











Exam-
Ery




185
119
164
230


ple 46











Exam-
Xyl




241
98
191
398


ple 47











Exam-
Glu




224
85
193
339


ple 48











Exam-
Fru




205
84
165
328


ple 49











Exam-
Lac




261
114
207
417


ple 50











Exam-
Tre




193
105
167
264


ple 51











Exam-
Cel




271
122
217
424


ple 52











Exam-
Ino




223
101
183
341


ple 53









As shown in Tables 8 and 9, organic compound nano-powder consisting of the particles with so small particle diameter was prepared even when organic compound powder was milled with using the sugar alcohol like mannitol, maltitol, erythritol or xylitol; the monosaccharide like inositol, glucose or fructose; or the disaccharide like lactose, trehalose or cellobiose.
Experiment 10
Milling with a Mixture of Carbohydrate Compounds
(1) Milling of a Curcumin Powder
Example 54
Mixture Group: D-Mannitol and Sorbitol
100 mg of turmeric powder, a mixed carbohydrate compound of 162.5 mg of D-(−)-mannitol and 162.5 mg of sorbitol (mass ratio=1:1), 50 mg of sucrose fatty acid ester, 9 mg of sodium carboxymethyl cellulose and 110 mg of purified water were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the turmeric powder was finely milled 10 mg 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% 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 ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=421 nm, the value of D10=80 nm, the value of D50=199 nm, and the value of D90=685 nm.
Example 55
Mixture Group: D-Mannitol and Xylitol
A curcumin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 54 except using a mixed carbohydrate compound of 162.5 mg of D-(−)-mannitol and 162.5 mg of xylitol (mass ratio=1:1) instead of the mixed carbohydrate compound of 162.5 mg of D-(−)-mannitol and 162.5 mg of sorbitol (mass ratio=1:1). As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=237 nm, the value of D10=98 nm, the value of D50=183 nm, and the value of D90=394 nm.
Example 56
Mixture Group: D-Mannitol and Dextrin
A curcumin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 54 except using a mixed carbohydrate compound of 162.5 mg of D-(−)-mannitol and 162.5 mg of dextrin (mass ratio=1:1) instead of the mixed carbohydrate compound of 162.5 mg of D-(−)-mannitol and 162.5 mg of sorbitol (mass ratio=1:1). As a result, the particle diameter distribution of curcumin nano-powder obtained after above procedures was as follows: Dav=254 nm, the value of D10=83 nm, the value of D50=189 nm, and the value of D90=454 nm.
(1) Milling of a Mefenamic Acid Powder
Example 57
Mixture Group: D-Mannitol and Sorbitol
The processes of milling and dispersion treatment were performed under the same conditions as Example 54 except using a mefenamic acid powder instead of the curcumin powder. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=365 nm, the value of D10=127 nm, the value of D50=239 nm, and the value of D90=518 nm.
Example 58
Mixture Group: D-Mannitol and Xylitol
The processes of milling and dispersion treatment were performed under the same conditions as Example 55 except using a mefenamic acid powder instead of the curcumin powder. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=226 nm, the value of D10=105 nm, the value of D50=182 nm, and the value of D90=350 nm.
Example 59
Mixture Group: D-Mannitol and Dextrin 
The processes of milling and dispersion treatment were performed under the same conditions as Example 56 except using a mefenamic acid powder instead of the curcumin powder. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=238 nm, the value of D10=123 nm, the value of D50=193 nm, and the value of D90=351 nm.
Tables 10 and 11 show the particle diameter distributions of various organic compound powders prepared in Examples 54 to 56 and Examples 57 to 59, respectively as compared with the particle diameter distributions of the powders before milling. The term “Sor” in the tables means sorbitol. The term “Dext” in the tables means dextrin.










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
16640
930 
12150 
35870
421
80
199 
685


Example 55
Man + Xyl





237
98
183 
394


Example 56
Man + Dext





254
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
770 
13290 
35550 
365
127
239
518


Example 58
Man + Xyl





226
105 
182
350


Example 59
Man + Dext





238
123 
193
351









As shown in Tables 10 and 11, with regard to the milling capacity of the carbohydrate compound, the mixture system of mannitol and xylitol or the mixture system of mannitol and dextrin was more advantageous than the mixture system of mannitol and sorbitol.
Experiment 11
Milling with a Mixture of Carbohydrate Compound and Salt
Various organic compounds were milled with a mixture of carbohydrate compound and salt.
(1) Preparation of an Indomethacin Nano-Powder
Example 60
An indomethacin powder was milled with using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and a hydrogenated soy bean lecithin under following conditions.
100 mg of indomethacin powder, 600 mg of D-(−)-mannitol, 100 mg of sodium chloride (trade name of Tomita salt K30, manufactured by Tomita Pharmaceutical Co., Ltd.), 30 mg of polyvinylpyrrolidone, 50 mg of hydrogenated soy bean lecithin and 200 mg of glycerin were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the indomethacin powder was finely milled 10 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 10 mL of 0.1% sodium dodecylsulfate. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=283 nm, the value of D10=104 nm, the value of D50=204 nm, and the value of D90=500 nm.
Example 61
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 60 except using only a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and no hydrogenated soy bean lecithin. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=253 nm, the value of D10=98 nm, the value of D50=189 nm, and the value of D90=432 nm.
Example 62
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 60 except using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=340 nm, the value of D10=171 nm, the value of D50=296 nm, and the value of D90=474 nm.
Example 63
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 61 except using only a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride) and no hydrogenated soy bean lecithin. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=255 nm, the value of D10=100 nm, the value of D50=199 nm, and the value of D90=419 nm.
(2) Preparation of a Felbinac Nano-Powder
Example 64
A felbinac powder was milled with using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and a hydrogenated soy bean lecithin under following conditions.
100 mg of felbinac powder (same as used in Example 14 and also used in following experiments), 600 mg of D-(−)-mannitol, 100 mg of sodium chloride (same as used in Example 60 and also used in following experiments), 30 mg of polyvinylpyrrolidone, 50 mg of hydrogenated soy bean lecithin and 200 mg of glycerin were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the felbinac powder was finely milled. 10 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 10 mL of 0.1% sodium dodecylsulfate. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of felbinac nano-powder obtained after above procedures was as follows: Dav=246 nm, the value of D10=137 nm, the value of D50=212 nm, and the value of D90=330 nm.
Example 65
A felbinac powder was milled and then subjected to a dispersion treatment under the same conditions as Example 64 except using only a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and no hydrogenated soy bean lecithin. As a result, the particle diameter distribution of felbinac nano-powder obtained after above procedures was as follows: Dav=228 nm, the value of D10=105 nm, the value of D50=186 nm, and the value of D90=349 nm.
Example 66
A felbinac powder was milled and then subjected to a dispersion treatment under the same conditions as Example 64 except using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distribution of felbinac nano-powder obtained after above procedures was as follows: Dav=211 nm, the value of D10=115 nm, the value of D50=181 nm, and the value of D90=292 nm.
Example 67
A felbinac powder was milled and then subjected to a dispersion treatment under the same conditions as Example 65 except using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distribution of felbinac nano-powder obtained after above procedures was as follows: Dav=228 nm, the value of D10=126 nm, the value of D50=199 nm, and the value of D90=305 nm.
(3) Preparation of a Pranlukast Hydrate Nano-Powder
Example 68
A pranlukast hydrate powder was milled with using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and a hydrogenated soy bean lecithin under following conditions.
100 mg of pranlukast hydrate powder, 600 mg of D-(−)-mannitol, 100 mg of sodium chloride, 30 mg of polyvinylpyrrolidone, 50 mg of hydrogenated soy bean lecithin and 200 mg of glycerin were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the pranlukast hydrate powder was finely milled. 10 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 10 mL of 0.1% sodium dodecylsulfate. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of pranlukast hydrate nano-powder obtained after above procedures was as follows: Dav=151 nm, the value of D10=60 nm, the value of D50=116 nm, and the value of D90=253 nm.
Example 69
A pranlukast hydrate powder was milled and then subjected to a dispersion treatment under the same conditions as Example 68 except using only a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and no hydrogenated soy bean lecithin. As a result, the particle diameter distribution of pranlukast hydrate nano-powder obtained after above procedures was as follows: Dav=195 nm, the value of D10=56 nm, the value of D50=152 nm, and the value of D90=345 nm.
Example 70 
A pranlukast hydrate powder was milled and then subjected to a dispersion treatment under the same conditions as Example 68 except using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distribution of pranlukast hydrate nano-powder obtained after above procedures was as follows: Dav=192 nm, the value of D10=90 nm, the value of D50=158 nm, and the value of D90=295 nm.
Example 71
A pranlukast hydrate powder was milled and then subjected to a dispersion treatment under the same conditions as Example 69 except using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distribution of pranlukast hydrate nano-powder obtained after above procedures was as follows: Dav=204 nm, the value of D10=81 nm, the value of D50=166 nm, and the value of D90=326 nm.
(4) Preparation of a Dexamethasone Nano-Powder
Example 72
A dexamethasone powder was milled with using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and a hydrogenated soy bean lecithin under following conditions.
100 mg of dexamethasone powder, 600 mg of D-(−)-mannitol, 100 mg of sodium chloride, 30 mg of polyvinylpyrrolidone, 50 mg of hydrogenated soy bean lecithin and 200 mg of glycerin were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the dexamethasone powder was finely milled. 20 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 5 mL of Polyoxyethylene Hydrogenated Castor Oil 60 (NIKKOL HCO-60, manufactured by Nikko Chemicals Co., Ltd.). Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of dexamethasone nano-powder obtained after above procedures was as follows: Dav=217 nm, the value of D10=74 nm, the value of D50=158 nm, and the value of D90=389 nm.
Example 73
A dexamethasone powder was milled and then subjected to a dispersion treatment under the same conditions as Example 72 except using only a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and no hydrogenated soy bean lecithin. As a result, the particle diameter distribution of dexamethasone nano-powder obtained after above procedures was as follows: Dav=168 nm, the value of D10=82 nm, the value of D50=149 nm, and the value of D90=240 nm.
Example 74
A dexamethasone powder was milled and then subjected to a dispersion treatment under the same conditions as Example 72 except using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distribution of dexamethasone nano-powder obtained after above procedures was as follows: Dav=205 nm, the value of D10=75 nm, the value of D50=166 nm, and the value of D90=336 nm.
Example 75
A dexamethasone powder was milled and then subjected to a dispersion treatment under the same conditions as Example 73 except using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distribution of dexamethasone nano-powder obtained after above procedures was as follows: Dav=185 nm, the value of D10=108 nm, the value of D50=162 nm, and the value of D90=243 nm.
(5) Preparation of a Fenofibrate Nano-Powder
Example 76
A fenofibrate powder was milled with using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and a hydrogenated soy bean lecithin under following conditions.
100 mg of fenofibrate powder (manufactured by Sigma-Aldrich Corporation, Dav: 48170 nm, the value of D10: 3520 nm, the value of D50: 33720 nm, and the value of D90: 115590 nm), 600 mg of D-(−)-mannitol, 100 mg of sodium chloride, 30 mg of polyvinylpyrrolidone, 50 mg of hydrogenated soy bean lecithin and 200 mg of glycerin were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the fenofibrate powder was finely milled 10 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 10 mL of 0.1% sodium dodecylsulfate. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of fenofibrate nano-powder obtained after above procedures was as follows: Dav=320 nm, the value of D10=149 nm, the value of D50=265 nm, and the value of D90=474 nm.
Example 77
A fenofibrate powder was milled and then subjected to a dispersion treatment under the same conditions as Example 76 except using only a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=6:1 and no hydrogenated soy bean lecithin. As a result, the particle diameter distribution of fenofibrate nano-powder obtained after above procedures was as follows: Dav=269 nm, the value of D10=132 nm, the value of D50=223 nm, and the value of D90=397 nm.
Example 78
A fenofibrate powder was milled and then subjected to a dispersion treatment under the same conditions as Example 76 except using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distribution of fenofibrate nano-powder obtained after above procedures was as follows: Dav=368 nm, the value of D10=182 nm, the value of D50=298 nm, and the value of D90=547 nm.
Example 79
A fenofibrate powder was milled and then subjected to a dispersion treatment under the same conditions as Example 77 except using a mixture of carbohydrate compound and salt which was in a mass ratio of D-mannitol:sodium chloride=1:1 (350 mg of D-(−)-mannitol and 350 mg of sodium chloride). As a result, the particle diameter distribution of fenofibrate nano-powder obtained after above procedures was as follows: Dav=311 nm, the value of D10=172 nm, the value of D50=264 nm, and the value of D90=427 nm.
Table 12 shows the particle diameter distributions of various organic compound powders prepared in Examples 60 to 79. The term “Fen” in the table means fenofibrate.













TABLE 12












hydrogenated
Particle diameter distribution (nm)















Organic 
Carbohydrate

Carbohydrate:
soy bean
Before milling
After milling





















compound
compound
Salt
Salt
lecithin
Dav
D10
D50
D90
Dav
D10
D50
D90























Example 60
Ind
Man
NaCl 
6:1
Exist
12400
630
8670
30820
283
104
204 
500


Example 61




No




253
98
189 
432


Example 62



1:1
Exist




340
171
296 
474


Example 63




No




255
100
199 
419


Example 64
Fel
Man
NaCl
6:1
Exist
190720 
46270 
166710
356860
246
137
212 
330


Example 65




No




228
105
186 
349


Example 66



1:1
Exsist




211
115
181 
292


Example 67




No




228
126
199 
305


Example 68
Pra
Man
NaCl
6:1
Exist
9500
1050
6150
23660
151
60
116 
253


Example 69




No




195
56
152 
345


Example 70



1:1
Exist




192
90
158 
295


Example 71




No




204
81
166 
326


Example 72
Dex
Man
NaCl
6:1
Exist
2690
280
2580
5360
217
74
158 
389


Example 73




No




168
82
149 
240


Example 74



1:1
Exist




205
75
166 
336


Example 75




No




185
108
162 
243


Example 76
Fen
Man
NaCl
6:1
Exist
48170
3520
33720 
115590
320
149
265 
474


Example 77




No




269
132
223 
397


Example 78



1:1
Exist




368
182
298 
547


Example 79




No




311
172
264 
427









As shown in Table 12, the diameter distributions of nano-powders obtained after milling various organic compounds were almost same one in spite of changing the mass ratio of the carbohydrate compound and the salt, or the presence or absence of lecithin.
Experiment 12
Milling without Anti-Agglomeration Agent
Various organic compounds were milled with carbohydrate compound and polyol, further with salt optionally.
(1) Preparation of an Indomethacin Nano-Powder
Example 80
100 mg of indomethacin powder, 600 mg of D-(−)-mannitol, 100 mg of sodium chloride and 200 mg of glycerin were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the indomethacin powder was finely milled. 10 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 10 mL of 0.1% sodium dodecylsulfate. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=335 nm, the value of D10=115 nm, the value of D50=237 nm, and the value of D90=609 nm.
Example 81
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 80 except using 350 mg of D-(−)-mannitol and 350 mg of sodium chloride. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=243 nm, the value of D10=132 nm, the value of D50=209 nm, and the value of D90=332 nm.
Example 82
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 80 except using 700 mg of D-(−)-mannitol and no sodium chloride. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=283 nm, the value of D10=128 nm, the value of D50=231 nm, and the value of D90=433 nm.
(1) Preparation of a Felbinac Nano-Powder
Example 83
100 mg of felbinac powder, 600 mg of D-(−)-mannitol, 100 mg of sodium chloride and 200 mg of glycerin were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the felbinac powder was finely milled. 10 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 10 mL of 0.1% sodium dodecylsulfate. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of felbinac nano-powder obtained after above procedures was as follows: Dav=415 nm, the value of D10=236 nm, the value of D50=360 nm, and the value of D90=588 nm.
Example 84
A felbinac powder was milled and then subjected to a dispersion treatment under the same conditions as Example 83 except using 350 mg of D-(−)-mannitol and 350 mg of sodium chloride. As a result, the particle diameter distribution of felbinac nano-powder obtained after above procedures was as follows: Dav=479 nm, the value of D10=257 nm, the value of D50=414 nm, and the value of D90=690 nm.
Example 85 
A felbinac powder was milled and then subjected to a dispersion treatment under the same conditions as Example 83 except using 700 mg of D-(−)-mannitol and no sodium chloride. As a result, the particle diameter distribution of felbinac nano-powder obtained after above procedures was as follows: Dav=488 nm, the value of D10=242 nm, the value of D50=410 nm, and the value of D90=744 nm.
(3) Preparation of a Pranlukast Hydrate Nano-Powder
Example 86
100 mg of pranlukast hydrate powder, 600 mg of D-(−)-mannitol, 100 mg of sodium chloride and 200 mg of glycerin were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the pranlukast hydrate powder was finely milled 10 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 10 mL of 0.1% Polyoxyethylene Hydrogenated Castor Oil 60. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of pranlukast hydrate nano-powder obtained after above procedures was as follows: Dav=286 nm, the value of D10=95 nm, the value of D50=171 nm, and the value of D90=327 nm.
Example 87
A pranlukast hydrate powder was milled and then subjected to a dispersion treatment under the same conditions as Example 86 except using 350 mg of D-(−)-mannitol and 350 mg of sodium chloride. As a result, the particle diameter distribution of pranlukast hydrate nano-powder obtained after above procedures was as follows: Dav=190 nm, the value of D10=93 nm, the value of D50=158 nm, and the value of D90=282 nm.
Example 88
A pranlukast hydrate powder was milled and then subjected to a dispersion treatment under the same conditions as Example 86 except using 700 mg of D-(−)-mannitol and no sodium chloride. As a result, the particle diameter distribution of pranlukast hydrate nano-powder obtained after above procedures was as follows: Dav=188 nm, the value of D10=100 nm, the value of D50=159 nm, and the value of D90=265 nm.
(4) Preparation of a Dexamethasone Nano-Powder
Example 89
100 mg of dexamethasone powder, 600 mg of D-(−)-mannitol, 100 mg of sodium chloride and 200 mg of glycerin were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the dexamethasone powder was finely milled 20 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 5 mL of 0.1% Polyoxyethylene Hydrogenated Castor Oil 60. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of dexamethasone nano-powder obtained after above procedures was as follows: Dav=221 nm, the value of D10=114 nm, the value of D50=185 nm, and the value of D90=318 nm.
Example 90
A dexamethasone powder was milled and then subjected to a dispersion treatment under the same conditions as Example 89 except using 350 mg of D-(−)-mannitol and 350 mg of sodium chloride. As a result, the particle diameter distribution of dexamethasone nano-powder obtained after above procedures was as follows: Dav=227 nm, the value of D10=133 nm, the value of D50=198 nm, and the value of D90=295 nm.
Example 91
A dexamethasone powder was milled and then subjected to a dispersion treatment under the same conditions as Example 89 except using 700 mg of D-(−)-mannitol and no sodium chloride. As a result, the particle diameter distribution of dexamethasone nano-powder obtained after above procedures was as follows: Dav=270 nm, the value of D10=125 nm, the value of D50=225 nm, and the value of D90=401 nm.
Table 13 shows the particle diameter distributions of various organic compound powders prepared in Examples 80 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
D50
D90






















Example 80
Ind
Man
NaCl
6:1
12400
630
8670
30820
335
115
237
609


Example 81



1:1




243
132 
209
332


Example 82



1:0




283
128 
231
433


Example 83
Fel
Man
NaCl
6:1
190720 
46270
166710
356860
415
236
360
588


Example 84



1:1




479
257 
414
690


Example 85



1:0




488
242
410
744


Example 86
Pra
Man
NaCl
6:1
9500
1050
6150 
23660 
286
95
171
327


Example 87



1:1




190
93
158
282


Example 88



1:0




188
100
159
265


Example 89
Dex
Man
NaCl
6:1
2690
280
2580
5360 
221
114
185
318


Example 90



1:1




227
133
198
295


Example 91



1:0




270
125 
225
401









As shown clearly from Table 13, it was achieved to mill the organic compound to nanoscale even without adding any anti-agglomeration agents like lecithin and polyvinylpyrrolidone at the process of milling.
Experiment 13
Milling with Using Various Polyols
An indomethacin powder was milled with adding carbohydrate compound and polyols other than glycerin.
(1) Milling with Ethylene Glycol as Polyol
Example 92
100 mg of indomethacin powder, 700 mg of xylitol and 200 mg of ethylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.) were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the indomethacin powder was finely milled. 10 mg of the dough obtained after milling was weighed into a 50-mL glass vial and then added 10 mL of 0.1% sodium dodecylsulfate. Then, the solution obtained above was subjected to a dispersion treatment by using the foregoing bath-type ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=487 nm, the value of D10=121 nm, the value of D50=204 nm, and the value of D90=498 nm.
Example 93
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 92 except using fructose instead of xylitol. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=261 nm, the value of D10=142 nm, the value of D50=227 nm, and the value of D90=353 nm.
Example 94
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 92 except using trehalose instead of xylitol. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=420 nm, the value of D10=130 nm, the value of D50=309 nm, and the value of D90=749 nm.
(2) Milling with Propylene Glycol as Polyol
Example 95
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 92 except using propylene glycol (manufactured by Wako Pure Chemical Industries, Ltd. and also used in following experiments) instead of ethylene glycol. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=217 nm, the value of D10=125 nm, the value of D50=189 nm, and the value of D90=284 nm.
Example 96
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 95 except using fructose instead of xylitol. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=316 nm, the value of D10=118 nm, the value of D50=222 nm, and the value of D90=497 nm.
Example 97
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 95 except using trehalose instead of xylitol. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=365 nm, the value of D10=158 nm, the value of D50=283 nm, and the value of D90=598 nm.
(3) Milling with Polyethylene Glycol as Polyol
Example 98
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 92 except using polyethylene glycol 400 (manufactured by Wako Pure Chemical Industries, Ltd. and also used in following experiments) instead of ethylene glycol. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=456 nm, the value of D10=136 nm, the value of D50=278 nm, and the value of D90=726 nm.
Example 99
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 98 except using fructose instead of xylitol. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=368 nm, the value of D10=145 nm, the value of D50=281 nm, and the value of D90=616 nm.
Example 100
An indomethacin powder was milled and then subjected to a dispersion treatment under the same conditions as Example 98 except using trehalose instead of xylitol. As a result, the particle diameter distribution of indomethacin nano-powder obtained after above procedures was as follows: Dav=454 nm, the value of D10=151 nm, the value of D50=351 nm, and the value of D90=776 nm.
Table 14 shows the particle diameter distributions of indomethacin powders prepared in Examples 92 to 100.











TABLE 14











Particle diameter distribution (nm)













Organic

Carbohydrate
Before milling
After milling



















compound
Polyol
compound
Dav
D10
D50
D90
Dav
D10
D50
D90





















Example 92
Ind
Ethylene
Xyl
12400
630
8670
30820
487
121
204
498


Example 93

glycol
Fru




261
142
227
353


Example 94


Tre




420
130
309
749


Example 95

Propylene
Xyl




217
125
189
284


Example 96

glycol
Fru




316
118
222
497


Example 97


Tre




365
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









As shown clearly from Table 14, it was achieved to mill the organic compound to nanoscale even with using polyols other than glycerin.
Experiment 14
Investigation of the Additive Ratio of Carbohydrate Compound
A mefenamic acid powder was milled with using a variety of the additive ratios of a carbohydrate compound relative to an organic compound.
Comparative Example 12
A mefenamic acid powder was milled without adding D-mannitol under following conditions.
100 mg of mefenamic acid powder used at Example 8 in EXPERIMENT 4, 0 mg of D-(−)-mannitol, 50 mg of sucrose fatty acid ester, 9 mg of sodium carboxymethyl cellulose and 110 mg of purified water were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the mefenamic acid powder was finely milled. 2 mg 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% 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 ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of mefenamic acid powder obtained after above procedures was as follows: Dav=926 nm, the value of D10=155 nm, the value of D50=276 nm, and the value of D90=3673 nm.
Comparative Example 13
A mefenamic acid powder was milled under the condition using D-mannitol of 0.1 times by mass relative to the mefenamic acid powder. Specifically, the mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Comparative Example 12 except both milling with adding 10 mg of D-(−)-mannitol and weighing 4 mg of the dough obtained after milling into the foregoing glass vial. As a result, the particle diameter distribution of mefenamic acid powder obtained after above procedures was as follows: Dav=1013 nm, the value of D10=212 nm, the value of D50=467 nm, and the value of D90=1722 nm.
Example 101
A mefenamic acid powder was milled under the condition using D-mannitol of 0.3 times by mass relative to the mefenamic acid powder. Specifically, the mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Comparative Example 12 except both milling with adding 33 mg of D-(−)-mannitol and weighing 5 mg of the dough obtained after milling into the foregoing glass vial. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=326 nm, the value of D10=150 nm, the value of D50=265 nm, and the value of D90=495 nm.
Example 102
A mefenamic acid powder was milled under the condition using D-mannitol of 0.5 times by mass relative to the mefenamic acid powder. Specifically, the mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Comparative Example 12 except both milling with adding 50 mg of D-(−)-mannitol and weighing 7 mg of the dough obtained after milling into the foregoing glass vial. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=382 nm, the value of D10=169 nm, the value of D50=316 nm, and the value of D90=573 nm.
Example 103
A mefenamic acid powder was milled under the condition using D-mannitol of 1.0 time by mass relative to the mefenamic acid powder. Specifically, the mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Comparative Example 12 except both milling with adding 100 mg of D-(−)-mannitol and weighing 10 mg of the dough obtained after milling into the foregoing glass vial. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=267 nm, the value of D10=125 nm, the value of D50=217 nm, and the value of D90=404 nm.
Example 104
A mefenamic acid powder was milled under the condition using D-mannitol of about 3.3 times by mass relative to the mefenamic acid powder. Specifically, the mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Comparative Example 12 except both milling with adding 325 mg of D-(−)-mannitol and weighing 10 mg of the dough obtained after milling into the foregoing glass vial. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=247 nm, the value of D10=99 nm, the value of D50=198 nm, and the value of D90=403 nm.
Example 105
A mefenamic acid powder was milled under the condition using D-mannitol of 30 times by mass relative to the mefenamic acid powder. Specifically, 10 mg of mefenamic acid powder, 300 mg of D-(−)-mannitol, 5 mg of sucrose fatty acid ester, 1 mg of sodium carboxymethyl cellulose and 200 mg of purified water were served on a glass disk of the foregoing Hoover muller and then kneaded by repeating five times to rotate the disk in 20 turns per time. Above-served contents formed a kind of dough during kneading and whereby the mefenamic acid powder was finely milled. 100 mg 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% 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 ultrasonic disperser for 1 to 2 minutes. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=271 nm, the value of D10=126 nm, the value of D50=227 nm, and the value of D90=403 nm.
Example 106
A mefenamic acid powder was milled under the condition using D-mannitol of 50 times by mass relative to the mefenamic acid powder. Specifically, the mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 105 except both milling with adding 500 mg of D-(−)-mannitol and weighing 150 mg of the dough obtained after milling into the foregoing glass vial. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=245 nm, the value of D10=117 nm, the value of D50=207 nm, and the value of D90=358 nm.
Example 107
A mefenamic acid powder was milled under the condition using D-mannitol of 100 times by mass relative to the mefenamic acid powder. Specifically, the mefenamic acid powder was milled and then subjected to a dispersion treatment under the same conditions as Example 105 except both milling with adding 1000 mg of D-(−)-mannitol and 250 mg of purified water and weighing 300 mg of the dough obtained after milling into the foregoing glass vial. As a result, the particle diameter distribution of mefenamic acid nano-powder obtained after above procedures was as follows: Dav=264 nm, the value of D10=132 nm, the value of D50=217 nm, and the value of D90=386 nm.
Table 15 shows the particle diameter distributions of mefenamic acid powders prepared in Comparative Examples 12, 13 and Examples 101 to 107.


















TABLE 15










Additive 













ratio of a 






















carbohydrate
Particle diameter distibution (nm)













Organic
Carbohydrate
compound
Before milling
After milling



















compound
compound
(times)
Dav
D10
D50
D90
Dav
D10
D50 
D90





















Comparative
Mef
Man
0
16130
770
13290
35550
926
155
276
3673


Example 12













Comparative


0.1




1013
212
467
1722


Example 13













Example 101


0.3




326
150
265
495


Example 102


0.5




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









As shown clearly from Table 15, the organic compound nano-powder with an average particle diameter of 500 nm or less and a 90%-diameter of less than 1500 nm was successfully produced when an organic compound powder was milled under the condition using the carbohydrate compound with the additive ratio of 0.3 times or more by mass relative to the organic compound powder.
INDUSTRIAL APPLICABILITY
The present invention can be used in such fields as a drug, a health food and a cosmetic.

## Claims

1. A method for producing an organic compound nano-powder comprising:
mixing a granular organic compound, a granular sugar compound comprising at least any one of a granular sugar and a granular sugar alcohol and with amount of 0.3 times or more by mass relative to amount of the organic compound, and liquid in which the organic compound is insoluble or poorly soluble in a kneader;
wet-milling the organic compound using the granular sugar compound as a grinding medium after the mixing so that an average particle diameter thereof becomes 500 nm or less and a 90%-diameter thereof becomes less than 1500 nm; and
wherein the wet-milling of the organic compound is carried out while kneading the mixture obtained after the mixing in a kneader.

2. The method for producing an organic compound nano-powder according to claim 1, wherein the granular sugar compound is in an amount of 0.5 to 30 times by mass relative to amount of the organic compound.

3. The method for producing an organic compound nano-powder according to claim 1, wherein the mixing is carried out with adding a physiologically acceptable polyol as liquid in which the organic compound is insoluble or poorly soluble.

4. The method for producing an organic compound nano-powder according to claim 1, wherein a drying is carried out after the milling.

5. The method for producing an organic compound nano-powder according to claim 1, wherein the granular sugar compound is one or more kinds selected from the group consisting of mannitol, maltitol, xylitol, erythritol, glucose, fructose, inositol, lactose, trehalose, cellobiose and dextrin.

6. The method for producing an organic compound nano-powder according to claim 1, wherein a physiologically acceptable salt is further mixed in the process of the mixing.

7. The method for producing an organic compound nano-powder according to claim 6, wherein the physiologically acceptable salt is sodium chloride.

8. The method for producing an organic compound nano-powder according to claim 1, wherein the organic compound is one or more kinds selected from the group consisting of clarithromycin, fexofenadine hydrochloride, fluorometholone, curcuminoid, curcumin, rutin, mefenamic acid, acetaminophen, ibuprofen, amphotericin B, diclofenac sodium, indomethacin, felbinac, pranlukast hydrate, dexamethasone and fenofibrate.

9. The method for producing an organic compound nano-powder according to claim 1, wherein the mass ratio of the granular sugar compound to the liquid is 1.75-to-1 or more.

10. The method for producing an organic compound nano-powder according to claim 1, wherein the granular sugar compound comprises an average particle diameter of 10-631 microns.