US 201500 10638A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0010638A1 Sakuma et al. (43) Pub. Date: Jan. 8, 2015

(54) METHOD FOR IMPROVING WATER A613 L/40 (2006.01) SOLUBLITY OF SLIGHTLY SOLUBLE A63/67 (2006.01) SUBSTANCE A613 L/7048 (2006.01) A613 L/455 (2006.01) (71) Applicant: Kabushiki Kaisha Sangi, Tokyo (JP) B5D3/12 (2006.01) A613 L/18 (2006.01) (72) Inventors: Shuji Sakuma, Tokyo (JP); Keiichiro A613 L/10 (2006.01) Kikukawa, Tokyo (JP); Ryosuke (52) U.S. Cl. Miyasaka, Tokyo (JP) CPC ...... A61 K9/501 (2013.01); A61K 31/18 (2013.01); A61 K31/195 (2013.01); A61 K (21) Appl. No.: 14/380,442 31/426 (2013.01); A61 K3I/505 (2013.01); A6 IK3I/10 (2013.01); A61K 31/40 (2013.01); (22) PCT Filed: Feb. 21, 2013 A6 IK3I/167 (2013.01); A61 K3I/7048 (86). PCT No.: PCT/UP2013/001000 (2013.01); A61 K3I/4515 (2013.01); A61 K 9/5089 (2013.01); B05D3/12 (2013.01); B05D S371 (c)(1), 5/04 (2013.01) (2) Date: Aug. 22, 2014 USPC ...... 424/490; 514/592: 514/563; 514/370; 514/275: 514/712: 514/428: 514/626; 514/423; (30) Foreign Application Priority Data 514/29: 514/327; 427/212; 427/2.14 Mar. 2, 2012 (JP) ...... 2012-047399 (57) ABSTRACT It is an object of the present invention to provide a method for Publication Classification improving the solubility of a poorly-soluble substance, which is capable of increasing the solubility of substantially all (51) Int. Cl. poorly-soluble Substances. This is a method comprising coat A 6LX 9/50 (2006.01) ing the Surface of a poorly-soluble Substance particle with A 6LX3L/95 (2006.01) microparticles of a calcium compound Such as calcium phos A6 IK3I/426 (2006.01) phate or calcium carbonate, and at least one selected from a A 6LX3L/505 (2006.01) pH adjuster and a surfactant, by applying mechanical energy B05D 5/04 (2006.01) thereto. US 2015/OO 10638 A1 Jan. 8, 2015

METHOD FOR IMPROVING WATER mechanical energy thereto, and thus that the solubility of the SOLUBILITY OF SLIGHTLY SOLUBLE poorly-soluble Substance can be improved. SUBSTANCE 0008. In the case of a method using calcium compound microparticles, it is assumed that as soon as a poorly-soluble TECHNICAL FIELD Substance coated with the calcium compound microparticles is contacted with water, a part of crystals of the poorly-soluble 0001. The present invention relates to a method for substance would be removed together with the calcium com improving the aqueous solubility of a poorly-soluble Sub pound microparticles, and the Surface area of the poorly stance used in pharmaceutical products, veterinary pharma soluble substance would be thereby increased, and also that ceutical products, quasi-drugs, cosmetic products, food prod Small calcium compound microparticles, as well as the ucts, agricultural chemicals, and the like. poorly-soluble substance, would be in a state in which they are nearly dissolved in water, and the amount of the poorly BACKGROUND ART soluble substance dissolved would be thereby improved. 0002 Useful substances have often poor solubility in Accordingly, it is considered that, by coating the Surface of a water in the fields of pharmaceutical products, veterinary poorly-soluble Substance particle with calcium compound pharmaceutical products, quasi-drugs, cosmetic products, microparticles and also with a pH adjuster and/or a surfactant food products, agricultural chemicals, and the like. This according to a method comprising applying mechanical restricts the use of useful substances. Thus, it has been desired energy thereto, the force of allowing the calcium compound to develop a method for improving the solubility of poorly microparticles to compressively adhere to the surface of the soluble useful substances. poorly-soluble Substance can be increased, and when the 0003. Under such circumstances, the present inventors calcium compound microparticles are removed from the had proposed a method for improving the solubility of a poorly-soluble Substance, its removing action or dispersing poorly-soluble substance, wherein the surface of the poorly action can be maximized. soluble Substance particle is coated by applying mechanical 0009 Specifically, the present invention relates to: energy to allow the microparticles of a calcium compound (1) a method for producing a Substance with improved aque Such as calcium phosphate or calcium carbonate to penetrate ous solubility, comprising coating the Surface of a poorly into the poorly-soluble substance particle to improve the solu soluble Substance particle with calcium compound micropar bility (see Patent Document 1). ticles and at least one selected from a pH adjuster and a surfactant by applying mechanical energy, to produce the PRIOR ART DOCUMENTS Substance with improved aqueous solubility; (2) the method for producing a substance with improved Patent Documents aqueous solubility according to (1) above, wherein the cal cium compound is calcium phosphate or calcium carbonate; 0004 Patent Document 1: WO2011/039952 (3) the method for producing a substance with improved aqueous solubility according to (2) above, wherein the cal SUMMARY OF THE INVENTION cium phosphate is hydroxyapatite or tricalcium phosphate: (4) the method for producing a substance with improved Object to be Solved by the Invention aqueous solubility according to any one of (1) to (3) above, 0005. The above described method for improving the solu wherein at least 5% of the surface of the poorly-soluble sub bility of a poorly-soluble substance by coating the surface of stance particle is coated with the calcium compound micro the poorly-soluble substance particle with the microparticles particles; of a calcium compound Such as calcium phosphate or calcium (5) the method for producing a substance with improved carbonate can be an extremely useful means for increasing the aqueous solubility according to any one of (1) to (4) above, solubility of poorly-soluble substances. However, there has which is a method using at least a pH adjuster, wherein the pH been a case in which the desired solubility cannot necessarily adjuster is used so that the pH of an aqueous solution of the be obtained, depending on the type of a poorly-soluble Sub substance with improved aqueous solubility becomes pH 6 or Stance. more; (6) the method for producing a substance with improved 0006. It is an object of the present invention to provide a aqueous solubility according to any one of (1) to (4) above, method for improving the solubility of a poorly-soluble sub which is a method using at least a surfactant, wherein the stance, which is capable of increasing the Solubility of Sub amount of the surfactant used is 1% to 300% by mass with stantially all poorly-soluble Substances. respect to the poorly-soluble Substance; (7) the method for producing a substance with improved Means to Solve the Object aqueous solubility according to any one of (1) to (6) above, 0007. With regard to the aforementioned method proposed wherein the method of applying mechanical energy is a by the present inventors, the inventors have searched for method involving mechanical fusion; various additives and have further studied regarding modifi (8) the method for producing a substance with improved cation of the particles of poorly-soluble Substances, etc. As a aqueous solubility according to any one of (1) to (6) above, result, the inventors have found that the dispersibility of a wherein the method of applying mechanical energy is a poorly-soluble Substance can be improved by coating the method involving hybridization; surface of the poorly-soluble substance particle with micro (9) the method for producing a substance with improved particles of a calcium compound Such as calcium phosphate aqueous solubility according to any one of (1) to (8) above, or calcium carbonate, and particularly hydroxyapatite, and wherein the mean particle diameter of the calcium compound also with a pH adjuster and/or a surfactant, by applying microparticles is 100 um or less; US 2015/OO 10638 A1 Jan. 8, 2015

(10) the method for producing a substance with improved Accordingly, it is considered that the force of allowing the aqueous solubility according to (9) above, wherein the mean calcium compound microparticles to compressively adhere to particle diameter of the calcium compound microparticles is the surface of the poorly-soluble substance can be increased, 50 to 200 nm, and when the calcium compound microparticles are removed (11) the method for producing a substance with improved from the poorly-soluble Substance, its removing action or aqueous solubility according to any one of (1) to (5) and (7) to dispersing action can be maximized. (10) above, wherein the pH adjuster is at least one selected 0014 Moreover, in the case of a poorly-soluble substance from the group consisting of disodium hydrogen phosphate, exhibiting acidity, since calcium compound microparticles L-arginine, Sodium hydrogen carbonate, citric acid, and are dissolved in acid, the calcium compound microparticles Sodium dihydrogen phosphate; need to exhibit their dispersion force without being com (12) the method for producing a substance with improved pletely dissolved, with respect to a decrease in pH occurring aqueous solubility according to any one of (1) to (4) and (6) to upon the dissolution of the poorly-soluble substance. Further (10) above, wherein the surfactant is sodium dodecyl sulfate; more, the solubility of a weak electrolyte such as a poorly and soluble Substance is changed depending on the pH of a solu (13) the method for producing a substance with improved tion. Thus, the higher the pH of a weakly acidic compound, aqueous solubility according to any one of (1) to (12) above, the larger the ratio of an ionic form that can be obtained, and wherein the poorly-soluble Substance is a Substance acting as as a result, Solubility increases. Accordingly, in the case of a an active ingredient of any one of a pharmaceutical product, a poorly-soluble Substance exhibiting acidity, it is considered Veterinary pharmaceutical product, a quasi-drug, a cosmetic that the pH is increased by addition of a pH adjuster, so that product and an agricultural chemical, or a food additive. synergic effects between the improvement of dissolution by 0010 Furthermore, the present invention relates to: the calcium compound microparticles and the improvement (14) a Substance with improved aqueous solubility obtained of the solubility of the poorly-soluble substance itself can be by the method according to any one of (1) to (13) above: exhibited. Further, in the case of a poorly-soluble substance (15) a pharmaceutical product, a veterinary pharmaceutical exhibiting basicity, it is considered that the solubility of a product, a quasi-drug, a cosmetic product, an agricultural poorly-soluble substance is suppressed because the pH of the chemical or a food product, comprising the Substance with coating calcium compound microparticles is basic. In this improved aqueous solubility according to (14) above; and case, the pH of a local portion that is contacted with the (16) the pharmaceutical product, Veterinary pharmaceutical poorly-soluble substance is more important than the pH of a product, quasi-drug, cosmetic product, agricultural chemical solution as a whole, and it is considered that the effect of or food product according to (15) above, which is an aqueous improving aqueous solubility can be further increased by liquid composition. decreasing the pH of a solution contacted with the poorly soluble substance by addition of a pH adjuster. Still further, it Effect of the Invention is considered that a surfactant is capable of improving the dispersibility of a poorly-soluble substance in water and of 0011. According to the present invention, the solubility of promoting solubilization. all poorly-soluble Substances, which are used for pharmaceu 0015. In the method of the present invention in which a pH tical products, veterinary pharmaceutical products, quasi adjuster is used, with respect to a poorly-soluble Substance drugs, cosmetic products, food products, agricultural chemi exhibiting acidity (calcium-coated poorly-soluble Sub cals, and the like, can be increased. In addition, the present stance), a pH adjuster exhibiting stronger basicity can be invention is advantageous in terms of productivity and cost used, and with respect to a poorly-soluble substance exhibit performance, it is excellent in terms of safety for workers, and ing basicity (calcium-coated poorly-soluble Substance), a pH it is highly useful in industrial application. adjuster exhibiting stronger acidity can be used. It is prefer able to use a pH adjuster Such that the pH of an aqueous MODE OF CARRYING OUT THE INVENTION Solution of a substance with improved aqueous solubility 0012. The method for producing a substance with becomes pH 6 or more. That is to say, with respect to an acidic improved aqueous solubility of the present invention is not poorly-soluble Substance having a low pH value, it is prefer particularly limited, as long as it is a method which comprises able to add a pH adjuster to a solution such that the pH of an coating the Surface of a poorly-soluble Substance particle aqueous solution of the Substance with improved aqueous with calcium compound microparticles and at least one solubility becomes at least pH 6. On the other hand, with selected from a pH adjuster and a surfactant by applying respect to a basic poorly-soluble Substance as well, it is pref mechanical energy thereto. The term “dissolution' is used in erable to add a pH adjuster to a solution such that pH of an the present invention to not only include a state in which a aqueous solution of the Substance with improved aqueous Substance is completely dissolved in water, but also include a solubility does not become extremely low and that it becomes state in which a substance is uniformly dispersed in an aque pH 6 or more. A mechanism of further improving solubility ous medium and it seems a transparent liquid by visual obser by retaining pH 6 or more has not necessarily been elucidated. Vation, Such as a solubilized State as a result of micelle for It is assumed that if pH is less than 6, the dissolution of a mation or the like. It means a state in which the amount of a calcium compound would progress and it would affect the Substance dissolved can be measured by a test method gen removing action or dispersing action upon the removal of the erally used in the measurement of the dissolved amount of calcium compound from a poorly aqueous soluble Substance. Such a substance. 0016. Moreover, as described above, since the pH of a 0013. In the present invention, the surface of a poorly local portion that is contacted with a poorly-soluble Substance soluble Substance particle is coated with calcium compound is more important than the pH of a solution as a whole, when microparticles and also with a pH adjuster and/or surfactant an acidic Substance is dissolved, desired effects can be according to a method of applying mechanical energy thereto. obtained even though the pH is not extremely high. It is US 2015/OO 10638 A1 Jan. 8, 2015

sufficient if a pH adjuster is used such that the pH of an preferable to adopt a method which comprises coating the aqueous solution of a Substance with improved aqueous solu surface of a poorly-soluble substance particle with a mixture bility becomes pH 8 or less. Accordingly, it is preferable to of calcium compound microparticles and a pH adjuster and/or use a pH adjuster Such that the pH of an aqueous solution of a surfactant by applying mechanical energy thereto (method a substance with improved aqueous solubility becomes pH 6 C). to 8. Herein, the pH of an aqueous solution indicates a pH 0021. The calcium compound is preferably a poorly value that is measured 60 minutes after the addition of a target soluble calcium compound that is hardly dissolved in water. substance to 50 mL of distilled water in an amount 2 times Examples of Such a compound include calcium phosphate, larger than the substance dissolved in 360 minutes. More calcium carbonate, calcium Sulfate, and calcium hydroxide. specifically, the pH of an aqueous solution indicates a pH Of these, calcium phosphate and calcium carbonate are pref value that is measured according to Dissolution test of erable. These calcium compounds may be used singly or in poorly-soluble substances in the below-mentioned the form of a mixture of two or more types. Examples. 0022. An example of the calcium phosphate is a calcium 0017. The method of the present invention in which a pH phosphate having a Ca/P ratio of 0.8 to 2.0, and preferably adjuster is used is effective for poorly-soluble substances having a Ca/P ratio of 1.0 to 2.0. Specific examples of such having any pH value. The present method is more effective in calcium phosphate include hydroxyapatite, tricalcium phos the case of using a poorly-soluble Substance, regarding which phate, tetracalcium phosphate, octacalcium phosphate, cal the pH of an aqueous solution containing the calcium-coated cium hydrogen phosphate, calcium pyrophosphate, and cal substance is less than 6 or more than 8. The present method is cium metaphosphate. Of these, hydroxyapatite and tricalcium particularly effective in the case of using a poorly-soluble phosphate are preferable. Moreover, the calcium phosphate Substance, regarding which the pH of an aqueous solution may be obtained from the nature, or may also be synthesized containing the calcium-coated Substance is less than 5 or by a known method such as a wet method or a dry method. more than 9. 0023 The hydroxyapatite is one type of calcium phos 0018. In addition, in the method of the present invention in phate, which is a main ingredient of the bone. In general, it is which a surfactant is used, the Surfactant is used at a percent shown as a stoichiometric composition represented by Cao age of preferably 1% to 300% by mass, and more preferably (PO)(OH). The hydroxyapatite is characterized in that it 10% to 200% by mass, based on the total mass of a poorly can exhibit properties as hydroxyapatite and can adopt an soluble Substance. As the amount of Such a surfactant added apatite structure even if it is a non-stoichiometric composition increases, the effect of improving dissolution becomes whose Ca/P molar ratio is not 1.67. In the present invention, higher. However, taking into consideration toxicity and the both hydroxyapatite as a stoichiometric composition and like, the Surfactant is used in an amount used in common hydroxyapatite as a non-stoichiometric composition can be practice. used. Hydroxyapatite having a Ca/P molar ratio of 1.4 to 1.8 0019 Moreover, in the present invention, it is preferable to is preferably used. use a pH adjuster in combination with a surfactant. Since the 0024. In general, as methods for synthesizing hydroxya effect of improving a dissolved amount by a pH adjuster is patite, there are various types of synthetic methods such as different from the effect of improving a dissolved amount by dry synthesis and wet synthesis. In the case of the wet syn a Surfactant in terms of action, the effect of improving Solu thesis for example, hydroxyapatite can be obtained by allow bility can be enhanced by each action. ing a calcium salt to react with phosphate in an aqueous 0020 Specific examples of the coating method of the solution. The Ca/P molar ratio of hydroxyapatite can be con present invention include: a method which comprises coating trolled by regulating the mixing ratio of a salt as a raw mate the surface of a poorly-soluble substance particle with cal rial or synthetic conditions. In the wet synthetic method for cium compound microparticles by applying mechanical example, if an aqueous solution is adjusted to be basic using energy thereto, and then coating the aforementioned Surface an ammonia water or the like during the synthesis, the Ca/P with a pH adjuster and/ora Surfactant by applying mechanical molar ratio can be controlled to be high. On the other hand, if energy thereto (method A); a method which comprises coat the aqueous solution is adjusted to be neutral or weakly acidic ing the Surface of a poorly-soluble Substance particle with a using dilute acid, the Ca/P molar ratio can be controlled to be pH adjuster and/or a surfactant by applying mechanical low. energy thereto, and then coating the aforementioned Surface 0025. The tricalcium phosphate may be either C.-Ca with calcium compound microparticles by applying (PO) or f3-Ca(PO). Of these, C.-Ca(PO) is preferable mechanical energy thereto (method B); and a method which because this is a more bioactive material. As a method for comprises coating the Surface of a poorly-soluble Substance producing tricalcium phosphate, in general, a calcium source particle with a mixture of calcium compound microparticles is mixed with a phosphoric acid source at a molar ratio of 3:2. and a pH adjuster and/or a Surfactant by applying mechanical and the mixture is then heated at 1200° C. or higher, so as to energy thereto (method C). In the present invention, since the obtain an O-type tricalcium phosphate. On the other hand, the particle of a poorly-soluble Substance is coated by applying aforementioned mixture is heated at 1000° C. or lower, so as mechanical energy, a part or the entire of calcium compound to obtain B-type tricalcium phosphate. A specific example of microparticles, a pH adjuster, and a surfactant is allowed to the tricalcium phosphate that can be used herein is the trical penetrate into the poorly-soluble Substance particle, and cium phosphate described in the Japanese Standards of Food thereby, the surface of the poorly-soluble substance particle Additives, which contains 98.0% to 103.0% of tricalcium can be coated. In the case of the above described method A phosphate Ca(PO) when it is dried. This tricalcium phos and method B, there is a case in which a Substance as a second phate described in the Japanese Standards of Food Additives layer would not reach the particle of the poorly-soluble sub is used as an anticaking agent for instant coffee, powdery milk stance and it would penetrate into a first layer. In the present products, condiments, powdered preparations, and the like, or invention, in order to obtain higher solubility, it is particularly as a calcium source for various types of food products. US 2015/OO 10638 A1 Jan. 8, 2015

0026. The calcium carbonate may be derived from the num Sulfate, potassium aluminum Sulfate hydrate, oxyquino natural products such as coral, or may also be derived from line Sulfate, DL-malic acid, potassium dihydrogen phos synthetic products such as calcium oxide, calcium chloride, phate, calcium dihydrogen phosphate, and Sodium calcium peroxide, calcium acetate, etc. There can be used the dihydrogen phosphate monohydrate. precipitated calcium carbonate described in the Japanese 0029 Specific examples of the pH adjuster exhibiting Pharmacopoeia, Such as calcium carbonate containing 98.5% basicity include L-arginine, tetrasodium edetate, carrag or more of calcium carbonate CaCO when it is dried, or the eenan, Sodium carboxymethyl starch, carmellose Sodium, calcium carbonate described in the Japanese Standards of dried sodium sulfite, dried sodium carbonate, Xanthan gum, Food Additives, such as calcium carbonate which contains disodium 5'-guanylate, calcium citrate, sodium citrate 98.0% to 102.0% of calcium carbonate (CaCO, when it is hydrate, trisodium glycyrrhizinate, aluminum magnesium dried. These calcium carbonates are used as agents for silicate, diatomaceous earth, crystalline cellulose-carmellose improving antacid action in gastroduodenal ulcer orgastritis, Sodium, disodium Succinate hexahydrate, colloidal hydrous calcium fortifiers for various types of food products, and the aluminum silicate, sodium acetate hydrate, calcium bromide, like. DL-sodium tartrate, potassium hydroxide, calcium hydrox 0027. The type of the pH adjuster is not particularly lim ide, Sodium hydroxide, magnesium hydroxide, Sodium ited, as long as it is a powdery agent (microparticles). hydrogen carbonate, magnesium carbonate, Sodium thiosul Examples of the pH adjuster that can be used herein include fate hydrate, Sodium desoxycholate, Sodium copper chloro Substances used as a stabilizing agent, a stabilizer, a plasti phyllin, trometamol, Sodium propyl paraoxybenzoate, cizer, a lubricating agent, a lubricant, a solubilizing agent, a Sodium methyl paraoxybenzoate, potato starch, calcium pan solubilizer, a buffering agent, a Sweetener, a base agent, a tothenate, L-histidine, hydroxyethylcellulose, hypromellose, corrigent, a binder, a Suspending agent, a suspender, an anti tetrasodium pyrophosphate, heparin Sodium, bentonite, oxidant, a brightener, a coating agent, a Sustaining agent, a borax, sodium polyacrylate, anhydrous Sodium citrate, anhy moisturizer, a moisture controlling agent, a filer, an antifoam drous sodium pyrophosphate, anhydrous sodium monohy ing agent, an augmenting agent, an antistatic agent, a flavor drogen phosphate, anhydrous trisodium phosphate, meglu ing agent, an aromatic, a coloring agent, a Sugar-coated agent, mine, lauric acid diethanolamide, disodium an isotonizing agent, a softener, an emulsifier, a foaming 5'-ribonucleotide, sodium monohydrogen phosphate hep agent, a skin protective agent, an excipient, a disperser, a tahydrate, trisodium phosphate, sodium hydrogen phosphate disintegrator, a disintegration aid, a fragrance, a desiccant, an hydrate (disodium hydrogen phosphate), and dipotassium antiseptic, a preservative, a Soothing agent, a dissolving phosphate. agent, a dissolution aid, or a fluidizer. In Japan, those 0030. Moreover, a pH adjuster in a neutral range, which described in Japanese Pharmaceutical Excipients (JPE) are exhibits a buffering action to the neutral range of pH during preferable. the dissolution of a drug, can also be used. Specific examples 0028 Specific examples of the pH adjuster exhibiting of Such a pH adjuster in a neutral range include Sodium acidity include ascorbic acid, L-aspartic acid, aspartame, alg L-aspartate, ethylene carbonate, calcium disodium edetate, inic acid, isocyanuric acid, Sodium edetate, Zinc chloride, Sodium erythorbate, dried magnesium sulfate, Xanthan gum, ammonium chloride, magnesium chloride, cysteine hydro calcium gluconate hydrate, L-arginine L-glutamate, potas chloride, triethanolamine hydrochloride, histidine hydro sium L-glutamate, sodium L-glutamate, L-lysine chloride, meprylcaine hydrochloride, kaoline, casein, fruc L-glutamate, dihydroxy aluminum amino acetate, D-Sorbitol, tose, captan, carbazochrome sodium Sulfonate hydrate, Sodium thiosulfate hydrate, copper chlorophyll, Sugar acid carboxymethyl starch sodium, carmellose calcium, Xanthan calcium, white Sugar, and Veegum Neutral. gum, Xylitol, citric acid, Sodium dihydrogen citrate, disodium 0031. The type of the surfactant is not particularly limited, citrate, glycyrrhizic acid, dipotassium glycyrrhizinate, diso as long as it is a powdery agent (microparticles). In Japan, dium glycyrrhizinate, calcium glycyrrhizinate hydrate, those described in Japanese Pharmaceutical Excipients (JPE) L-glutamine, L-glutamic acid, croScarmellose Sodium, are preferable. Examples of the surfactant include N-cocoyl crospovidone, aluminum hydroxychloride, light anhydrous L-arginine ester ester-DL-pyrrolidonecarboxylate, N-co silicic acid-containing hydroxypropyl cellulose, crystalline coyl-N-methylaminoethyl sulfonate sodium, cholesterol, cellulose, crystalline sodium dihydrogen phosphate, gentisic self-emulsifying glyceryl monostearate. Sucrose fatty acid acid ethanolamide, N-cocoyl-arginine ethyl ester-DL-pyr ester, polyoxyl 40 stearate, cetanol, cetomacrogol 1000, rolidonecarboxylate. Succinic acid, monosodium Succinate, Sodium dodecylbenzenesulfonate, polyoxyethylene cetyl copoly Vidone, choline phosphate, sodium chondroitin Sul ether, polyoxyethylene (105) polyoxypropylene (5) glycol, fate, potassium dichloroisocyanurate, L-cysteine, tartaric polyoxyethylene (160) polyoxypropylene (30) glycol, glyc acid, D-tartaric acid, potassium hydrogen tartrate. Sucralose, eryl monostearate, Sorbitan monostearate, N-coconut oilfatty Sodium thiomalate, tyloxapol, dextran, corn starch, nicotina acid acyl-L-arginine-ethyl DL-pyrrolidonecarboxylate, mide, lactic acid, aluminum lactate, hydroxypropyl Starch, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, dietha hydroxypropyl cellulose, L-phenylalanine, monosodium nolamide laurate, and sodium lauroyl sarcosinate. fumarate, procaine hydrochloride, powdered cellulose, pec 0032. The size of the calcium compound microparticle or tin, boric acid, partially neutralized polyacrylate, polysorbate the microparticle of a pH adjuster and/or a surfactant, which 20, polysorbate 40, polysorbate 60, macrogol 600, macrogol are used in the present invention, is preferably Smaller than 1000, macrogol 1500, macrogol 1540, macrogol 6000, mac the particle diameter of a poorly-soluble substance. In addi rogol 20000, maltose hydrate, malonic acid, anhydrous citric tion, the Smaller the particle diameter, the larger the specific acid, anhydrous sodium dihydrogen phosphate, methane Surface area, and as a result, the rate of coating the poorly Sulfonic acid, DL-methionine, methyl cellulose, sodium soluble Substance can be enhanced. Thus, the particle diam N-lauroyl-L-glutamate, L-lysine monohydrochloride, eter is preferably as small as possible. Specifically, the present Sodium riboflavine phosphate, Zinc sulfate hydrate, alumi calcium compound microparticles are, for example, particles US 2015/0010638 A1 Jan. 8, 2015 having a mean particle diameter of preferably 100 lm or less, single layer provides sufficient effects, although the poorly more preferably 50 um or less, further preferably 10 um or soluble substance may also be coated with two or more layers. less, and particularly preferably 1 um or less. The lower limit 0.036 Furthermore, it is preferable to coat the poorly of the particle diameter is not particularly limited. It is gen soluble substance particle such that the outermost layer erally approximately 0.05 um for production reasons. The thereof is coated with a substance having high water absorb size of a calcium compound microparticle, or of the micro ability. For example, when a pH adjuster or a surfactant is not particle of a pH adjuster and/or a surfactant, to be penetrated a substance having high water absorbability, the above into the poorly-soluble substance particle serving as a core, is described method B or method C can be adopted. In the case more preferably /s or less, and further preferably /10 or less, of adopting the method C, it is preferable that the poorly with respect to the size of the poorly-soluble substance par soluble substance be coated with calcium compound micro ticle because the state of the penetrated calcium compound particles serving as an outermost layer. microparticle, or of the microparticle of a pH adjuster and/or 0037. The type of the poorly-soluble substance used in the surfactant, can be stably retained when the microparticle has present invention is not particularly limited, as long as it is a the aforementioned size. substance having a property that it is hardly dissolved in 0033. The method of finely grinding the calcium com water. It is a substance having a solubility (25°C.) of for pound and the like is not particularly limited and include a dry example, 10000 ppm or less, 5000 ppm or less, 3000 ppm or method and a wet method, and a general dry mill or wet mill less, and 1000 ppm or less. Examples of such a poorly-soluble can be used, for example. For instance, a bead mill, a sand substance include: a substance acting as an active ingredient mill, a high-speed impact mill, a high-pressure wet atomizing for pharmaceutical products, veterinary pharmaceutical unit, and the like can be used. Specific examples of the bead products, quasi-drugs, cosmetic products and agricultural mill and sand mill include: Visco Mill manufactured by chemicals; and a food additive. Synthetic or natural poly Aimex Co., Ltd.; Grain Mill manufactured by Asada Iron meric substances, which are generally referred to as resins or Works Co., Ltd.; Dyno-Mill manufactured by Sinmaru Enter rubbers, are not included in the present poorly-soluble sub prises Corp.; Anealler Mill manufactured by Mitsui Kozan K. stance. The size of the poorly-soluble substance is not par K.; Sand Mill manufactured by Inoue Manufacturing Co., ticularly limited. Its mean particle diameter is preferably 0.5 Ltd.; and Sand Mill manufactured by Kotobuki Engineering to 2000 um, more preferably 1 to 200 um, and further pref & Manufacturing Co., Ltd. An example of the high-speed erably 5 to 50 um. impact mill is Ultra-High-Pressure Homogenizer manufac 0038. The poorly-soluble drug used in the present inven tured by MIZUHO Industrial CO., LTD. Examples of the tion is a drug that is "sparingly soluble.” “slightly soluble.” high-pressure wet atomizing unit include: Nanomizer manu “very slightly soluble.” and “practically insoluble,” which are factured by Yoshida Kikai Co., Ltd.; Atomization Apparatus defined in the Japanese Pharmacopoeia. The present poorly manufactured by Sugino Machine Ltd.; and Atomization soluble drug may have any dosage form of an oral preparation Apparatus manufactured by Microfluidics. for internal application, an injection, a preparation for local 0034). In the present invention, as a method of coating a administration, etc. Examples of such a poorly-soluble drug poorly-soluble substance with such calcium compound include an antitumor agent, an antibiotic, an antipyretic anal microparticles or a pH adjuster and/or a surfactant, a method gesic, an antihyperlipidemic agent, an antibacterial agent, a of applying mechanical energy is applied. This is specifically sedative hypnotic, a tranquilizer, an antiepileptic agent, an a method comprising coating a poorly-soluble substance with antidepressant, a gastrointestinal agent, an allergic disease calcium compound microparticles and the like by applying therapeutic agent, an antihypertensive agent, a drug for arte mechanical energy such as physical compression, shearing riosclerosis, a blood circulation promoting agent, an antidia force or impact force to allow the microparticles and the like betic agent, a hormonal agent, a fat-soluble vitamin, an anti to penetrate into the poorly-soluble substance particle. androgen agent, a cardiotonic drug, a drug for arrhythmia, a Examples of this coating method include a mechanical fusion drug for diuresis, a local anesthetic, an anthelminthic, an method and a hybridization method. More specific examples antiarrhythmic agent, an anticoagulant, an antihistamic of such a coating method include: Mechanofusion System agent, an antimuscarinic agent, an antimycobacterial agent, (manufactured by Hosokawa Micron Group), Hybridization an immunosuppressive agent, an antithyroid agent, an antivi System (manufactured by Nara Machinery Co., Ltd.), Theta ral agent, an anxiolytic agent, an astringent, a f-adrenorecep Composer (manufactured by Tokuju Corp.), KRYPTRON tor blocker, an agent exerting inotropic action on cardiac (manufactured by Kawasaki Heavy Industries, Ltd.), Mecha muscle, a contrast medium, corticosteroid, a cough suppress nomill (manufactured by Okada Seiko Co., Ltd.), CF Mill ing agent, a diagnostic agent, a diagnostic imaging agent, a (manufactured by Ube Industries, Ltd.), COMPOSI (manu diuretic, a dopamine agonist, a hemostatic agent, a lipid factured by Nippon Coke & Engineering Co., Ltd.), Swing adjuster, a muscle relaxer, a parasympathetic drug, thyrocal Processor (manufactured by Dalton Co., Ltd.), SFP (manu citonin and biphosphonate, prostaglandin, a radiopharmaceu factured by Powrex Corp.), Cyclomix (manufactured by tical agent, sex hormone, a stimulant, an appetite suppressing Hosokawa Micron Group), Nanomech Reactor Simoloyer agent, a sympathetic agent, a thyroid drug, a vasodilator, and (J. TEC Ltd.), MAIC (Aveka, Inc.), and Rotating fluidized Xanthene. bed coater (RFBC) (International Publication WO2007/ 0039 Specific examples of the antitumor agent include 010396). HER2 inhibitors (heterocyclic compounds described in 0035 Moreover, with regard to the amounts of calcium WO01/77107 and the like), melphalan, taxol, dacarbazine, compound microparticles that coat the poorly-soluble Sub doxorubicin hydrochloride, bleomycin hydrochloride, car stance, the surface of the particle of the poorly-soluble sub mofur, methotrexate, enocitabine, etoposide, 5-fluorouracil, stance is coated at a percentage of preferably 5% or more, mitoxantrone, mesna, dimesna, aminoglutethimide, tamox more preferably 60% or more, further preferably 90% or ifen, acrolein, cisplatin, carboplatin, cyclophosphamide, more, and particularly preferably 100%. Coating with a lomustine, carmustine, cyclophosphamide, buSulphan, para US 2015/OO 10638 A1 Jan. 8, 2015 aminosalicylic acid, mercaptopurine, tegafur, azathioprine, cilexetil, urapidil, carvedilol, prazosin hydrochloride, vinblastine Sulfate, mitomycin C. ciclosporin, L-asparagi bunaZosin hydrochloride, doxazosin mesilate, reserpine, nase, and ubenimex. methyldopa, guanabenZ acetate, deserpidine, meptame, and 0040. Examples of the antibiotic include amikacin, meptamate. dibekacin, gentamycin, bacitracin, penicillin, cephalexin, tet 0051 Examples of the drug for arteriosclerosis include racycline, Streptomycin, nystatin, erythromycin, fradiomycin clofibrate, Simfibrate, elastase, Soysterol, and nicomol. Sulfate, chloramphenicol, cefimetazole, and tolnaftate. 0.052 Examples of the blood circulation promoting agent 0041. Examples of the antipyretic analgesic include aspi include tocopherol acetate, benzyl nicotinate, tolaZoline, rin, aspirin aluminum, aminopyrine, phenacetin, mefenamic Verapamil, caffeine, cyclandelate, acetylcholine, and toco acid, flufenamic acid, flufenamic acid aluminum, tolfenamic pherol nicotinate. acid, acemetacin, indomethacin, alclofenac, diclofenac, ibu 0053 Examples of the antidiabetic agent include tolbuta profen, ibuprofenpiconol, oxyphenbutaZone, phenylbuta mide, glibenclamide, gliclazide, troglitaZone, epalrestat, Zone, ketophenylbutaZone, clofeZone, tiaramide hydrochlo buformin, and metformin. ride, ketoprofen, diclofenac sodium, Sulindac, naproxen, 0054 Examples of the hormonal agent include dexam fenbufen, flurbiprofen, fenprofen, bufexamac, mepirizole, ethasone, dexamethasone acetate, betamethasone, perisoxal citrate, glafenine, bucolome, pentazocine, metiaz betamethasone Valerate, betamethasone dipropionate, inic acid, protizinic acid, pranoprofen, fenoprofen calcium, beclometaSone dipropionate, prednisolone, prednisolone val piroXicam, feprazone, fentiazac, bendazac, dimethylisopro erate, prednisolone acetate, methylprednisolone, methyl pylaZulene, glycyrrhetic acid, bufexamac, Salicylic acid, prednisolone acetate, hydrocortisone, hydrocortisone acetaminophen, methyl salicylate, glycol salicylate, buco acetate, hydrocortisone acetate propionate, amcinonide, tri lome, benzydamine, tialamide, tinoridine, ethenZamide, amcinolone, triamcinolone acetonide, fluocinolone tenoxicam, chlortenoxicam, clidanac, naproxen, glycyr acetonide, hexestrol, methimazole, estriol, estriol tripropi rhizin, glycyrrhetic acid, azulene, camphor, thymol. 1-men onate, clobetaSone acetate, clobetasol propionate, fluocinon thol, Sasapyrine, alclofenac, diclofenac, Suprofen, loxopro ide, testosterone propionate, testosterone enanthate, flu fen, diflunisal, tiaprofenic acid, oxaprozin, and felbinac. oxymesterone, drostanolone propionate, estradiol benzoate, 0042 Examples of the antihyperlipidemic agent include estradiol propionate, estradiol Valerate, ethinylestradiol. clinofibrate, clofibrate, fenofibrate, bezafibrate, mestranol, estriol benzoate diacetate, fluorometholone, cholestyramine, Soysterol, tocopherol nicotinate, nicomol. fludroxycortide, diflucortolone Valerate, halcinonide, proges niceritrol, probucol, simvastatin, colestimide, and elastase. terone, hydroxyprogesterone caproate, pregnanediol. 0043. Examples of the antibacterial agent include ofloxa medroxyprogesterone acetate, dimethisterone, norethister cin, ciprofloxacin hydrochloride, to Sufloxacintosilate, nor one, allylestrenol, gestonorone caproate, and oxendolone. floxacin, lomefloxacin hydrochloride, paZufloxacin, rokita 0055 Examples of the antiandrogen agent include oxen mycin, cefpodoxime proxetil, roXithromycin, midecamycin dolone, allylestrenol, chlormadinone acetate, gestonorone acetate, cefatrizine.josamycin propionate, and fosfomycin or caproate, osaterone acetate, flutamide, and bicalutamide. a salt thereof. 0056. Examples of the cardiotonic drug include digoxin, 0044 Examples of the sedative hypnotic include barbital, digotoxin, and ubidecarenone. amobarbital, amobarbital sodium, phenobarbital, phenobar 0057 Examples of the drug for arrhythmia include pin bital Sodium, secobarbital Sodium, pentobarbital calcium, dolol, nadolol, bopindolol malonate, arotinolol hydrochlo hexobarbital, triclofos, bromovalerylurea, glutethimide, ride, atenolol, lidocaine, propafenone hydrochloride, amio methaqualone, perlapine, nitrazepam, estazolam, flurazepam darone hydrochloride, disopyramide, and carteolol hydrochloride, flunitrazepam, and estazolam. hydrochloride. 0045 Examples of the tranquilizer include diazepam, 0.058 Examples of the drug for diuresis include polythi lorazepam, and oxazolam. azid, Spironolactone, chlortalidone, triamteren, hydrochlo 0046 Examples of the antiepileptic agent include pheny rothiazide, and furosemide. loin, phenobarbital, carbamazepine, primidone, phenace 0059 Examples of the local anesthetic include dibucaine mide, ethylphenacemide, ethotoin, phensuximide, hydrochloride, ethyl aminobenzoate, procaine hydrochlo nitrazepam, and clonazepam. ride, lidocaine, tetracaine hydrochloride, lidocaine hydro 0047. Examples of the antidepressant include imipramine, chloride, T-Cain, benzocaine, benzyl alcohol, pramoxine noxiptiline, and phenelzine. hydrochloride, quatacaine hydrochloride, butanicaine hydro 0048 Examples of the gastrointestinal agent include chloride, piperocaine hydrochloride, and chlorobutanol. aldioxa, irsogladine maleate, metoclopramide, cimetidine, 0060 Examples of the substance used in cosmetic prod famotidine, omeprazole, lanSoprazole, enprostil, gefarnate, ucts or quasi-drugs include methyl cinnamate, ethyl cin teprenone, Sulpiride, trepibutone, oxethazain, and Sucralfate. namate, dl-C-tocopherol acetate, C-tocopherol (vitamin E), 0049. Examples of the allergic disease therapeutic agent trichlorocarbanilide, eugenol, isoeugenol, ethyl methyl phe include clemastine fumarate, cyproheptadine hydrochloride, nylglycidate, geranyl acetate, piperonal, hexyl laurate, ion fexofenadine hydrochloride, ebastine, meduitazine, diphen one, cinnamyl acetate, decyl oleate, terpinyl acetate, triazine, hydramine, methdilazine, clemizole, and methoxyphe anilide, benzophenone, triazole, cinnamide, Sulfonated ben namine. Zoimidazole, carotene, piroctone olamine, minoxidil, phytos 0050 Examples of the antihypertensive agent include ala teside, tocopherol nicotinate, ethinyl estradiol, polyporuster cepril, nicardipine hydrochloride, delapril hydrochloride, one, ecdysteroids, and various types of perfumes. captopril, cilnidipine, felodipine, barnidipine hydrochloride, 0061 Examples of the substance used in food and drink efonidipine hydrochloride, amlodipine besylate, benidipine products include L-ascorbyl Stearate, benzoic acid, ionone, hydrochloride, nisoldipine, manidipine hydrochloride, isoeugenol, ergocalciferol (vitamin D), eugenol, butyl nitrendipine, nilvadipine, trandolapril, Valsartan, candesartan parahydroxybenzoate, isopropyl parahydroxybenzoate, US 2015/OO 10638 A1 Jan. 8, 2015

B-carotene, citronellyl formate, cholecalciferol (vitamin D). quinclorac, quizalofop ethyl, rimsulfuron, Siduron, simazine, cinnamyl acetate, phenethyl acetate, ethyl cinnamate, dibu terbuthylazine, terbutryn, thiazopyr, tralkoxydim, and tri tylhydroxytoluene, allyl hexanoate, propyl gallate, methyl etazine. B-methyl ketone, folic acid, riboflavine tetrabutyrate, leci 0.066 Examples of the poorly-soluble plant growth regu thin, and dl-C-tocopherol. latory Substance include 6-benzylaminopurine, cyclanilide, 0062) Examples of the agricultural chemical include flumetralin, forchlorfenuron, inabenfide, 2-(1-naphtyl)aceta poorly-soluble agricultural chemical active ingredients hav mide, paclobutraZol, n-phenylphthalamidic acid, thidiaZuron, ing insecticidal action, germicidal action, herbicidal action, and uniconazole. plant growth regulatory and other actions, such as a Substance 0067. The substance with improved aqueous solubility having a solubility in water (25°C.) of 1000 ppm or less. obtained by the production method of the present invention 0063 Specifically, examples of the poorly-soluble insec can be used by mixing it into pharmaceutical products, vet ticidal Substance include abamectin, acrinathrin, amitraz, erinary pharmaceutical products, quasi-drugs, cosmetic azadirachtin, azamethiphos, azinphos-methyl, azocyclotin, products, agricultural chemicals, food products, and the like. ethofenproX, ethylthiometon, chlorpyrifos methyl, benSultap, The forms of the pharmaceutical products, veterinary phar bifenthrin, bromopropylate, buprofezin, carbaryl, chlor maceutical products, quasi-drugs, cosmetic products, agri fenapyr, chlorfenson, chlorfluaZuron, clofentezine, couma cultural chemicals, and food products are not particularly phos, diazinon, cycroprothrin, cyfluthrin, B-cyfluthrin, cyper limited. The forms may be either solid compositions such as methrin, C-cypermethrin, 0-cypermethrin, deltamethrin, a tablet, granule or powder, or aqueous liquid compositions diafehthiuron, dicofol, diflubenzuron, carbosulfan, endosul containing water. As a result of the improvement of solubility fan, esfenvalerate, etoxazole, fenazaquin, fenbutatin oxide, according to the present invention, a Substance, which has not fenoxycarb, fenpyroximate, fipronil, fluaZuron, flucycloXu sufficiently exhibited effects due to its poor solubility, can ron, flufenoxuron, flubendiamide, fenthion, halofenozide, exhibit the effects. hexaflumuron, hexythiazox, hydramethylnon, metaflumi Zone, lufenuron, methiocarb, methoxychlor, milbemycin, EXAMPLES novaluron, pentachlorophenol, pyridaben, rotenone, Sulflura mid, tebufenozide, tebufenpyrad, tebupirimfos, teflubenzu 1. Preparation of Coating Agent ron, tetrachlorvinphos, tetradifon, thiodicarb, benfuracarb, tralomethrin, tolfenpyrad, triflumuron, trimethacarb, A. Preparation of Hydroxyapatite Microparticles furathiocarb, and bendiocarb. 0068 A phosphoric acid aqueous solution in a 30 wt % 0064. Examples of the poorly-soluble germicidal sub concentration was added dropwise to a calcium hydroxide stance include azoxystrobin, isoprothiolane, benalaxyl, suspension under stirring, until the Ca/P ratio became 1.67. benomyl, bitertanol, bromuconazole, captafol, captan, car The thus generated gelatinous Substance was left at a room propamide, carbendazim, chinomethionate, chlorothalonil. temperature for 1 day, so as to age it. Thereafter, this gelati chloZolinate, cyprodinil, dichlofluanid, diclofen, diclomez nous Substance was filtrated with a glass filter, and the ine, dicloran, diclocymet, diethofencarb, dimethomorph, remaining substance was then dried in the air at 100°C. The diniconazole, dithianon, tiadinil, epoxiconazole, famoxa resultant was ground with a mixer, so as to obtain hydroxya done, fenarimol, fenbuconazole, fenfuram, fenpiclonil, fen patite. tin, fluaZinam, fludioxonil, fluoroimide, fluguinconazole, 0069. Such hydroxyapatite was suspended in water to pre flusulfamide, flutolanil, folpet, hexachlorobenzene, hexa pare a 20% suspension. This Suspension was then ground conazole, imibenconazole, ipconazole, iprodione, kresoxim employing Dino Mill (ECM-PILOT, manufactured by Willy methyl, manzeb, maneb, mepanipyrim, mepronil, metcona A. Baechofen AG Machinenfabrik Basel) using 0.3-mm zir Zole, metiram, nickel bis(dimethyldithiocarbamate), conia beads. Particle size distribution was measured every 30 nuarimol, oxine copper, OXolinic acid, pencycuron, phthalide, minutes, and the grinding was terminated at the time point in procymidone, propineb, quintoZene, Sulfur, tebuconazole, which almost no change was observed in terms of particle tecloftalam, tecnaZene, thifluZamide, thiophanete-methyl, size, thereby obtaining hydroxyapatite microparticles. thiram, tolclofos-methyl, tolylfluanide, triadimefon, triadi menol, triazoxide, triforine, triticonazole, VincloZolin, Zineb, B. Preparation of pH Adjuster and Surfactant and Ziram. 0070 A pH adjuster and a surfactant were each crushed in 0065. Examples of the poorly-soluble herbicidal sub a mortar, and they were then passed through a 150-lum mesh stance include azafenidin, thenylchlor, bifenox, Sulfentra Zone, pyraflufen-ethyl, flumiclorac-pentyl, flumioxazin, sieve. The resultants were used in experiments. aclonifen, atrazine, indanofan, benSulfuron methyl, ben 2. Preparation of Substance with Improved Aqueous Zofenap, bromobutide, bromofenoxim, chlomethoxyfen, Solubility chlorbromuron, chlorimuron ethyl, chlornitrofen, chlortolu ron, chlorthal-dimethyl, clomeprop, dymron, desmedipham, (0071 A. Coating of Poorly-Soluble Substance with dichlobenil, diflufenican, dimefuron, dinitramine, diuron, Hydroxyapatite Microparticles Using Mechanofusion Sys ethametSulfuron methyl, traiziflam, fenoxaprop-ethyl, flam tem prop-methyl, flaZaSulfuron, flumetSulam, fluthiacet-methyl, (0072. Using Mechanofusion System AMS-MINI-GMP flupoxam, fluridone, flurtamone, oxaziclomefone, isoprotu (manufactured by Hosokawa Micron Group), a poorly ron, isoxaben, isoxapyrifop, lactofen, lenacil, linuron, mefen soluble Substance was coated with hydroxyapatite micropar acet, methabenzthiazuron, metobenzuron, naproanilide, ticles. neburon, norflurazon, ory Zalin, oxadiazon, oxyfluorfen, 0073. A poorly-soluble substance and hydroxyapatite phenmedipham, prodiamine, prometryn, propazine, propyZa microparticles were placed into a Mechanofusion System mide, pyrazolynate, pyrazosulfuron-ethyl, pyributicarb, Device while changing the ratio between the poorly-soluble US 2015/OO 10638 A1 Jan. 8, 2015

Substance and the hydroxyapatite microparticles. They were 3. Dissolution Test of Poorly-Soluble Substances placed in the device to a total amount of 90 g/once, and 0078. A poorly-soluble substance coated with calcium thereafter, a coating treatment was carried out. During the compound microparticles (a Substance with improved aque coating treatment, the jacket portion of the device was cooled ous solubility) and a test solution (50 mL) were placed in a with alcohol, so that the temperature of the portion became 50-mL screw cap centrifuge tube made of glass. From initia 20° C. or lower. Moreover, in order to prevent the rotation tion of the test, the mixed solution was stirred with a stirrer load from exceeding 2.0 A, the coating treatment was carried having a length of 15 mm. The rotation number of the stirrer out at a rotation number of 1,250 to 4,000 rpm for 15 to 60 was 120 rpm, and all of the tests were conducted in a thermo minutes. In the case of products, which could be subjected to stat at 37+0.5°C. Two types oftest solutions, namely, distilled a coating treatment at a rotation number of 4,000 rpm, the water and 2nd fluid for disintegration test (pH 6.8) of the coating treatment was carried out for 15 minutes. On the other Japanese Pharmacopoeia were used. As such 2nd fluid for hand, in the case of products whose rotation load exceeded disintegration test of the Japanese Pharmacopoeia, a solution 2.0 A, and consequently, the rotation number became 4,000 prepared by diluting the 10-fold concentration solution of rpm or less, a coating treatment time was increased due to the Kanto Kagaku Co., Ltd. with distilled water was used. With rotation number. Thus, a coating treatment was carried out at regard to the amount of a Substance with improved aqueous the fewest rotation number (1,250 rpm) for 60 minutes as the solubility used in the dissolution test, a preliminary test was longest coating treatment time. carried out on each Substance with improved aqueous solu 0.074 The coated substance was recovered, and thereafter, bility several times according to the above described method, ground pH adjuster and/or Surfactant were added to the recov and the amount of the Substance with improved aqueous ered Substance in an amount of /100 to 3 times the amount of solubility used in the dissolution test was defined as an the poorly-soluble substance. The obtained mixture was sub amount approximately two times the amount of the Substance jected to Mechanofusion Device again, so as to produce a with improved aqueous solubility dissolved for 360 minutes. final pharmaceutical preparation. Thereby, there was 0079 A comparative test was carried out in the same man obtained a pharmaceutical preparation, in which the outer ner as that described above, with the exception that, instead of most layer of a pharmaceutical preparation formed by coating a Substance with improved aqueous solubility coated with a poorly-soluble Substance with hydroxyapatite micropar hydroxyapatite microparticles and with a pH adjuster and/or ticles was coated with a pH adjuster and/or a surfactant. a surfactant, a poorly-soluble Substance or the like was used in B. Coating of Poorly-Soluble Substance with Hydroxyapa the same amount as the Substance with improved aqueous tite Microparticles According to Hybridization System solubility. 0075. Using Hybridization System NHS-1 (manufactured 0080 1 mL of the solution was sampled in an Eppendorf by Nara Machinery Co., Ltd.), a poorly-soluble substance centrifuge tube, 1, 3, 10, 30, 60, 180 and 360 minutes after was coated with calcium compound microparticles. initiation of the test. The thus sampled solution was centri 0076. A mixture that had previously been prepared by fuged at 12,000 rpm for 5 minutes. Thereafter, the substance mixing a poorly-soluble Substance with hydroxyapatite with improved aqueous solubility and hydroxyapatite micro microparticles was placed in the Hybridization System, while particles, which had not been dissolved in the solution, were changing the ratio between the poorly-soluble Substance and removed. In the case of the comparative test, the poorly the hydroxyapatite microparticles. They were placed in the soluble substance or the like, which had not been dissolved in system to a total amount of 100 g/once, and thereafter, a the Solution, was removed. An aliquot of this Supernatant was coating treatment was carried out at 3,000 rpm for 5 minutes. immediately frozen. The frozen sample was freeze-dried, and 0077. The resultant was recovered, and thereafter, ground it was then used as a sample in the measurement of the amount pH adjuster and/or surfactant were added thereto in an of the substance with improved aqueous solubility, which had amount of /100 to 3 times the amount of the poorly-soluble been dissolved in the test solution. The dissolved poorly Substance. The obtained mixture was again Subjected to soluble Substance was measured mainly using a dual wave Hybridization System, so as to produce a final pharmaceutical length absorption photometer. preparation. Thereby, there was obtained a pharmaceutical 3-1. Dissolved Amounts of Poorly-Soluble Substances after preparation, in which the outermost layer of a pharmaceutical Dissolution Test for 360 Minutes preparation formed by coating a poorly-soluble Substance with hydroxyapatite microparticles was coated with a pH 1. Tolbutamide adjuster and/or a Surfactant. 0081 TABLE 1.

Coating agent Dissolved Coating Particle Coating amount method Ingredient diameter Additive rate Dissolution test medium (ig/ml) Example 1-1 Mechanofusion Hydroxyapatite 100 nm. Disodium 100% Distilled water 7101.4 System hydrogenphosphate Second disintegration S2SO.4 1,10 test medium Example 1-2 Mechanofusion Hydroxyapatite 100 nm. Disodium 100% Distilled water 85O2.0 System hydrogenphosphate Second disintegration 6098.6 1.5 test medium Example 1-3 Mechanofusion Hydroxyapatite 50 mm Disodium 100% Distilled water 8792.7 System hydrogenphosphate Second disintegration 7883.4 1.5 test medium US 2015/OO 10638 A1 Jan. 8, 2015

TABLE 1-continued Coating agent Dissolved Coating Particle Coating amount method Ingredient diameter Additive rate Dissolution test medium (g/ml) Example 1-4 Mechanofusion Hydroxyapatite 100 nm. L-Arginine 1/5 00% Distilled water 8391.2 System Second disintegration S766.8 est medium Example 1-5 Mechanofusion Hydroxyapatite 100 nm. SDS1.5 00% Distilled water 8678.O System Second disintegration 6319.3 est medium Example 1-6 Mechanofusion Hydroxyapatite 100 nm. Disodium 00% Distilled water 7498.7 System hydrogenphosphate Second disintegration S685.3 1.10 SDS1,10 est medium Comparative Mechanofusion Hydroxyapatite 100 nm. Not used 00% Distilled water 2S84.O Example 1-1 System Second disintegration 4913.4 est medium Comparative Mechanofusion Not used Disodium 00% Distilled water 133.3 Example 1-2 System hydrogenphosphate Second disintegration S32.1 1.5 est medium Comparative Mechanofusion Not used L-Arginine 1/5 00% Distilled water 768.4 Example 1-3 System Second disintegration 1792.4 est medium Comparative Mechanofusion Not used SDS1.5 00% Distilled water 302.5 Example 1-4 System Second disintegration 1862.3 est medium Comparative Tolbutamide Distilled water 68.6 Example 1-5 Second disintegration 2429.1 est medium

2. Bezafibrate 0082 TABLE 2

Dissolved Coating Coating agent Coating amount method Ingredien Grinding Additive rate Dissolution test medium (Lig/ml) Example 2-1 Hybridization Hydroxyapatite 100 nm Disodium 100% Distilled water 7426.9 System hydrogenpnosphate Second disintegration 7012.8 1,100 est medium Example 2-2 Hybridization Hydroxyapatite 100 nm Disodium 100% Distilled water 13498.4 System hydrogenpnosphate Second disintegration 11743.6 1,10 est medium Example 2-3 Hybridization Hydroxyapatite 10 m Disodium 100% Distilled water 91.93.2 System hydrogenpnosphate Second disintegration 9046.5 1.5 est medium Example 2-4 Hybridization Hydroxyapatite 100 nm Disodium 100% Distilled water 147412 System hydrogenpnosphate Second disintegration 12127.5 1.5 est medium Example 2-5 Hybridization Hydroxyapatite 100 nm Disodium 50% Distilled water 13702.5 System hydrogenpnosphate Second disintegration 11171.8 1.5 est medium Example 2-6 Hybridization Hydroxyapatite 100 nm Disodium 10% Distilled water 11856.2 System hydrogenpnosphate Second disintegration 10572.2 1.5 est medium Example 2-7 Hybridization Hydroxyapatite 50 mm Disodium 100% Distilled water 12101.2 System hydrogenpnosphate Second disintegration 11116.2 1.5 est medium Example 2-8 Hybridization Hydroxyapatite 100 nm Disodium 100% Distilled water 8363.0 System hydrogenpnosphate Second disintegration 3876.7 3. est medium Example 2-9 Hybridization Hydroxyapatite 100 nm L-Arginine 1.5 10% Distilled water 16703.3 System Second disintegration 12298.4 est medium Example 2-10 Hybridization Hydroxyapatite 100 nm Sodium 100% Distilled water 19659.9 System hydrogencarbonate Second disintegration 15898.4 1.5 est medium Example 2-11 Hybridization Hydroxyapatite 100 nm SDS1.5 100% Distilled water 18239.1 System Second disintegration 15137.5 est medium US 2015/OO 10638 A1 Jan. 8, 2015 10

TABLE 2-continued

Dissolved Coating Coating agent Coating amount method Ingredient Grinding Additive rate Dissolution test medium (Lig/ml) Comparative Hybridization Hydroxyapatite 100 nm. Not used 100% Distilled water 3440.3 Example 2-1 System Second disintegration 6538.0 est medium Comparative Mixing Hydroxyapatite 100 nm. Not used 100% Distilled water 101.2 Example 2-2 Second disintegration 2254.3 est medium Comparative Hybridization Not used Disodium 100% Distilled water 1813 Example 2-3 System hydrogenphosphate Second disintegration 1180.0 1.5 est medium Comparative Hybridization Not used Sodium 100% Distilled water 944.1 Example 2-4 System hydrogencarbonate Second disintegration 41543 1.5 est medium Comparative Hybridization Not used SDS1.5 100% Distilled water 1012.O Example 2-5 System Second disintegration 9984.8 est medium Comparative Bezafibrate Distilled water 13.2 Example 2-6 Second disintegration 3096.6 est medium

3. Famotidine 0083 TABLE 3

Dissolved Coating Coating agent Coating amount method Ingredient Grinding Additive rate Dissolution test medium (ig/ml) Example 3-1 Mechanofusion Hydroxyapatite 100 nm. Citric 100% Distilled water 11365.1 System acid 15 Second disintegration 10710.8 estmedium Example 3-2 Mechanofusion Hydroxyapatite 100 nm. SDS1.5 100% Distilled water 2380.6 System Second disintegration 4929.7 estmedium Comparative Mechanofusion Hydroxyapatite 100 nm Not used 100% Distilled water 1671.5 Example 3-1 System Second disintegration 26984 estmedium Comparative Mechanofusion Not used Citric 100% Distilled water 956.5 Example 3-2 System acid 15 Second disintegration 1468.1 estmedium Comparative Mechanofusion Not used SDS1.5 100% Distilled water 1580.0 Example 3-3 System Second disintegration 1809.2 estmedium Comparative Famotidine Distilled water 1497.4 Example 3-4 Second disintegration 2410.4 estmedium

4. Trimethoprim 0084 TABLE 4

Dissolved Coating Coating agent Coating amount

method Ingredient Grinding Additive rate Dissolution test medium (ig/ml)

Example 4-1 Hybridization Hydroxyapatite 100 nm. Citric 100% Distilled water 10144.4 System acid 15 Second disintegration 13265.3 test medium Comparative Hybridization Hydroxyapatite 100 nm Not used 100% Distilled water 1212.6 Example 4-1 System Second disintegration 2S32.6 test medium US 2015/OO 10638 A1 Jan. 8, 2015 11

TABLE 4-continued

Dissolved Coating Coating agent Coating amount method Ingredient Grinding Additive rate Dissolution test medium (ig/ml) Comparative Hybridization Not used Citric 100% Distilled water 806.9 Example 4-2 System acid 15 Second disintegration 1985.O test medium Comparative Trimethoprim Distilled water 656.3 Example 4-3 Second disintegration 1321.9 test medium

5. Probucol 0085 TABLE 5

Dissolved Coating Coating agent Coating amount method Ingredient Grinding Additive rate Dissolution test medium (g/ml) Example 5-1 Mechanofusion Hydroxyapatite 100 nm. Disodium 100% Distilled water S61.5 System hydrogenphosphate Second disintegration 332.4 1.5 test medium Comparative Mechanofusion Hydroxyapatite 100 nm. Disodium 100% Distilled water 289.1 Example 5-1 System and hydrogenphosphate Second disintegration 1806 Mixing(* 1.5 test medium Comparative Probucol Distilled water 9.7 Example 5-2 Second disintegration 28.0 test medium Probucol was coated with hydroxyapatite using Mechanofusion System, and disodium hydrogen phosphate was then mixed therein,

6. Sulpiride 0086 TABLE 6

Dissolved Coating Coating agent Coating amount method Ingredien Grinding Additive rate Dissolution test medium (ig/ml) Example 6-1 Mechanofusion Hydroxyapatite 00 nm. Citric 00% Distilled water 12814.7 System acid 1,100 Second disintegration 18099.7 estmedium Example 6-2 Mechanofusion Hydroxyapatite 00 nm. Citric 00% Distilled water 352934 System acid 15 Second disintegration 38O81.1 estmedium Example 6-3 Mechanofusion Hydroxyapatite 00 nm. Citric 00% Distilled water 18186.7 System acid 3.1 Second disintegration 23748.5 estmedium Example 6-4 Mechanofusion Hydroxyapatite 00 nm SDS1,100 00% Distilled water 66956 System Second disintegration 9735.7 estmedium Example 6-5 Mechanofusion Hydroxyapatite 00 nm. SDS1.5 00% Distilled water 6923.O System Second disintegration 13619.7 estmedium Example 6-6 Mechanofusion Hydroxyapatite 00 nm. SDS3.1 00% Distilled water 22631.4 System Second disintegration 27321.3 estmedium Comparative Mechanofusion Hydroxyapatite 00 nm Not used 00% Distilled water 1144.8 Example 6-1 System Second disintegration 6459.8 estmedium Comparative Mechanofusion Not used Citric 00% Distilled water 1733.0 Example 6-2 System acid 15 Second disintegration 57OO.O estmedium Comparative Mechanofusion Not used SDS1.5 00% Distilled water 242SO Example 6-3 System Second disintegration 3746.2 estmedium US 2015/OO 10638 A1 Jan. 8, 2015 12

TABLE 6-continued

Dissolved Coating Coating agent Coating amount method Ingredient Grinding Additive rate Dissolution test medium (ig/ml) Comparative Sulpiride Distilled water 715.8 Example 6-4 Second disintegration 6866.1 test medium

7. Lidocaine 0087 TABLE 7

Dissolved Coating Coating agent Coating amount method Ingredient Grinding Additive rate Dissolution test medium (ig/ml) Example 7-1 Mechanofusion Hydroxyapatite 100 nm. Citric 100% Distilled water 299344 System acid 15 Second disintegration 35102.5 test medium Comparative Mechanofusion Hydroxyapatite 100 nm Not used 100% Distilled water 4528.8 Example 7-1 System Second disintegration 876O.O test medium Comparative Mechanofusion Not used Citric 100% Distilled water 3582.6 Example 7-2 System acid 15 Second disintegration 636O1 test medium Comparative Lidocaine Distilled water 3248.6 Example 7-3 Second disintegration S469.0 test medium

8. Alacepril 0088 TABLE 8

Dissolved Coating Coating agent Coating amount method Ingredient Grinding Additive rate Dissolution test medium (g/ml) Example 8-1 Mechanofusion Hydroxyapatite 100 nm. Disodium 100% Distilled water 26119.0 System hydrogenphosphate Second disintegration 27527.2 1.5 test medium Example 8-2 Mechanofusion Hydroxyapatite 100 nm. Disodium 100% Distilled water 31636.7 System hydrogenphosphate Second disintegration 32384.9 1.f4 test medium Comparative Alacepril Distilled water 996.S Example 8-1 Second disintegration 2S48.2 test medium

9. Erythromycin 0089 TABLE 9

Dissolved Coating Coating agent Coating amount method Ingredient Grinding Additive rate Dissolution test medium (ig/ml) Example 9-1 Mechanofusion Hydroxyapatite 100 nm. Citric 100% Distilled water 25648.9 System acid 15 Second disintegration 21844.7 test medium Comparative Erythromycin Distilled water 846.1 Example 9-1 Second disintegration 6044.7 test medium US 2015/OO 10638 A1 Jan. 8, 2015

10. Haloperidol 0090 TABLE 10

Dissolved Coating Coating agent Coating amount method Ingredient Grinding Additive rate Dissolution test medium (g/ml) Example 10-1 Hybridization Hydroxyapatite 100 nm. Citric 100% Distilled water 562.7 System acid 15 Second disintegration 148.6 test medium Comparative Haloperidol Distilled water 13.1 Example 10-1 Second disintegration 48.9 test medium

3-2. Dissolution Time and Dissolved Amount 1. Tolbutamide 0091 Dissolution Test Using Water Dissolved Amount (ug/ml) TABLE 11

Elution time (min

Example No. Coating ingredient 1 3 10 30 60 18O 360 Example 1-1 Disodium hydrogenphosphate 67.046 6852.3 6925.9 74.41.6 7339.2 6735.4 7101.4 110 + 100 nm HAP Example 1-2 Disodium hydrogenphosphate 7087.3 7936.O 8375.1 82O1.9 8391.2 83444 85O2.O 1.5 + 100 nm HAP Example 1-3 Disodium hydrogenphosphate 7057.9 7SO7.7 8O36.S 81 60.2 832O.O 8514.3 8792.7 1.5 + 50 nm HAP Example 1-4. L-Arginine 1/5 + 100 nm HAP 8646.2 8646.7 7654.3 8O85.7 8281.3 82O6.4 8391.2 Example 1-5 SDS1.5 + 100 nm HAP 4349.4 6817.6 76SO.9 7769.1 8061.2 8096.9 8678.O Example 1-6 Disodium hydrogenphosphate S711.7 7004.1 7327.2 779S4 7188.8 7314.1 7498.7 110+ SDS1 10 + 100 nm HAP Comparative 100 nm HAP 2114.6 2421.2 2592.4 25919 2559.S. 2574.2 2S84.O Example 1-1 Comparative Disodium hydrogenphosphate 105.7 1221 12O6 131.8 135.8 131.9 133.3 Example 1-2 1/5 Comparative L-Arginine 1.5 27.47 139.6 1352.9 1451.8 963.8 838.6 768.4 Example 1-3 Comparative SDS1/5 591.6 265.6 384.1 248.7 402.5 271.1 302.5 Example 1-4 Comparative — 48.8 49.3 51.3 56.6 50.5 S2.9 68.6 Example 1-5

Dissolution Test Using 2nd Fluid for Disintegration Test Dis Solved Amount (ug/ml) TABLE 12

Elution time (min Example No. Coating ingredient 1 3 10 30 60 18O 360 Example 1-1 Disodium hydrogenphosphate 3565.5 4545.7 5122.9 5020.9 5111.2 5291.2 5250.4 110 + 100 nm HAP Example 1-2 Disodium hydrogenphosphate 4286.1 5122.4 6100.4 6192.9 6005.6 6125.2 6098.6 1.5 + 100 nm HAP Example 1-3 Disodium hydrogenphosphate 7990.5 6127.2 7111.8 7786.1 8171.6 7721.9 7883.4 1.5 + 50 nm HAP Example 1-4. L-Arginine 1/5+100 nm HAP 3475.7 5015.5 6141.8 6110.3 5602.3 5749.3 5766.8 Example 1-5 SDS1.5 + 100 nm HAP 2S30.3 4384.8 S171.2 S493.5 S496.8 SS63.4 6319.3 Example 1-6 Disodium hydrogenphosphate 2975.1 4814.9 55.13.8 5579.8 5461.1 5639.1 5685.3 1.5 + SDS1.5 + 100 nm HAP Comparative 100 nm HAP 3603.O 3915.4 4265.2 4428.8 4554S 4907.2 4913.4 Example 1-1 Comparative Disodium hydrogenphosphate 525.4 475.1 495.7 S22.9 447.3 480.8 S32.1 Example 1-2 1/5 US 2015/OO 10638 A1 Jan. 8, 2015 14

TABLE 12-continued

Elution time (min

Example No. Coating ingredient 1 3 10 30 60 18O 360 Comparative L-Arginine 1.5 4.1 53.7 96.O.2 1084.2 1289.6 2249.2 1792.4 Example 1-3 Comparative SDS1/5 1426.8 1493.2 1584.9 2048.7 1803.4 1732.1 1862.3 Example 1-4 1OOO1 Comparative — 637.3 1597.2 2041.9 2141.1 2449.4 2432.9 2429.1 Example 1-5

2. Bezafibrate 0092 Dissolution Test Using Water Dissolved Amount (ug/ml) TABLE 13

Elution time (min

Example No. Coating ingredien 1 3 10 30 60 18O 360 Example 2-1 Disodium hydrogenphosphate 4.737.3 S876.1. 6713.O 7541.3 7586.6 7418.3 7426.9 100 +100 nm HAP Example 2-2 Disodium hydrogenphosphate 13217.O 15062.8 15145.3 15844.6 15564.2 15120.3 13498.4 10+100 nm HAP Example 2-3 Disodium hydrogenphosphate 4636.4 8858.2 9102.6 906O.9 8963.1 9137.1 91.93.2 /5 + 10 Im HAP Example 2-4 Disodium hydrogenphosphate 17967.4 15876.7 16846.8 16067.0 16028.1 15617.9 14741.2 S + 100 nm HAP Example 2-5 Disodium hydrogenphosphate 6256.9 10918.7 13350.3 1361O.S 13443.7 12776.S 13702.5 S + 100 nm HAP 50% Example 2-6 Disodium hydrogenphosphate 8323.2 10646.9 13714.O 12353.8 12176.9 12438.6 11856.2 S + 100 nm HAP 10% Example 2-7 Disodium hydrogenphosphate 11379.8 12048.4 12414.6 12314.5 12269.4 12228.2 12101.2 S + 50 nm HAP Example 2-8 Disodium hydrogenphosphate 12228.2 6O70.3 6648.1 6950.O 7682.6 7745.1 8363.0 31 + 100 nm HAP Example 2-9 L-Arginine 1/5 + 100 nm HAP 10840.7 14993.9 18099.3 18051.1 1802O.O 17792.8 16703.3 Example 2-10 Sodium hydrogencarbonate 9297.8 10413.7 12546.4 14638.3 185O2.6 19699.7 19659.9 S + 100 nm HAP Example 2-11 SDS1.5 + 100 nm HAP 9SO4.9 13499.3 17515.4 16393.7 163O3S 18451.5 18239.1 Comparative OO mm HAP 2758.S 2941.9 31 61.9 3336.4 3289.S. 3392.2 3440.3 Example 2-1 Comparative 00 nm HAP(Mixing) 55.5 78.O 813 86.O 86.1 97.1 101.2 Example 2-2 Comparative Disodium hydrogenphosphate 137.9 146.5 166.3 169.4 1719 178.7 1813 Example 2-3 5 Comparative Sodium hydrogencarbonate 53.0 119.7 491.6 587.0 734.1 868.4 944.1 Example 2-4 5 Comparative SDS1,5 975.4 993.9 1027.4 900.6 957.8 1096.S 1012.O Example 2-5 Comparative 10.4 11.6 10.9 11.9 12.3 12.9 13.2 Example 2-6

Dissolution Test Using 2nd Fluid for Disintegration Test Dis Solved Amount (ug/ml) TABLE 1.4

Elution time (min

Example No. Coating ingredient 1 3 10 30 60 18O 360 Example 2-1 Disodium hydrogenphosphate 4211.O SS87.1 7230.7 6592.2 7278.1 6956.S. 7012.8 1100 + 100 nm HAP Example 2-2 Disodium hydrogenphosphate 12093.S 13293.2 13272.6 13367.0 131978 12777.9 11743.6 110 + 100 nm HAP Example 2-3 Disodium hydrogenphosphate 6016.8 82.71.S 88.33.7 8695.7 8957.4 8830.8 9046.5 1/5 + 10 Im HAP Example 2-4 Disodium hydrogenphosphate 13713.6 14009.3 1422.S.S 14026.1 13727.0 12809.1 12127.5 1.5 + 100 nm HAP Example 2-5 Disodium hydrogenphosphate 6606.4 98.20.1 10783.S. 1076O.S 11134.4 11360.2 11171.8 1.5 + 100 nm HAP 50% US 2015/OO 10638 A1 Jan. 8, 2015 15

TABLE 14-continued

Elution time (min

Example No. Coating ingredient 1 3 30 60 18O 360 Example 2-6 Disodium hydrogenphosphate 8198.1 10217.0 1 1683.7 10868.4 10727.5 10904.3 10572.2 S + 100 nm HAP 10% Example 2-7 Disodium hydrogenphosphate 10298.O. 10901.O 11256.1 11263.8 108O8.5 11082.6 11116.2 S + 50 nm HAP Example 2-8 Disodium hydrogenphosphate 87.08.1 S416.7 4150.6 3734.3 3328.8 3876.7 31 + 100 nm HAP Example 2-9 L-Arginine 1/5 + 100 nm HAP 9.SSO.O 11264.S 13296.1 12841.7 131236 12817.2 12298.4 Example 2-10 Sodium hydrogencarbonate 8616.7 10460.1 12709.6 12239.0 12363.7 153O8.2 15898.4 S + 100 nm HAP Example 2-11 SDS1.5 + 100 nm HAP 94.09.O 11134.8 14379.2 15139.0 14282.8 15137.5 Comparative OO mm HAP 4840.4 S42O.O Sf73.4 S840.2 5976.7 6538.0 Example 2-1 Comparative 00 nm HAP (Mixing) 1754.3 1864.8 2229.6 2267.6 2224.5 2282.7 2254.3 Example 2-2 Comparative Disodium hydrogenphosphate 850.7 920.8 1108.1 1152.0 1174.O 1170.1 118O.O Example 2-3 5 Comparative Sodium hydrogencarbonate 706.8 1036.8 2704.9 3285.6 3458.7 3753.2 41543 Example 2-4 5 Comparative SDS1,5 S724.4 839 O.S 8781.7 9118.3 9124.5 8958.0 9984.8 Example 2-5 Comparative 805.1 2552.5 2866.S 2942.6 2965.5 3096.6 Example 2-6

3. Famotidine 0093 Dissolution Test Using Water Dissolved Amount (ug/ml) TABLE 1.5

Elution time (min

Example No. Coating ingredient 1 3 10 30 60 18O 360 Example 3-1 Citric acid 1/5 7688.1 10183.6 11246.S 11673.1 11584.S 11519.7 11365.1 100 nm HAP Example 3-2 SDS1/5 905.7 1412.1 2018.2 2294.1 2470.4 2SSS. 6 2380.6 100 nm HAP Comparative 100 nm HAP 1080.2 1269.9 1616.6 1834.6 1819.8 1778.1. 1671.5 Example 3-1 Comparative Citric acid 1/5 402.2 363.O 415.4 915.3 850.3 983.5 956.5 Example 3-2 Comparative SDS1/5 777.7 10111 1646.6 1606.8 1712.6 1761.2 1580.0 Example 3-3 Comparative — 1162.9 15O2.6 1416.8 1566.8 1S65.8 1509.8 1497.4 Example 3-4

Dissolution Test Using 2nd Fluid for Disintegration Test Dis Solved Amount (ug/ml) TABLE 16

Elution time (min

Example No. Coating ingredient 1 3 10 30 60 18O 360 Example 3-1 Citric acid 1/5 6106.9 8806.8 995S.O 106SS-3 10742.8 10784.9 10710.8 100 nm HAP Example 3-2 SDS1/5 1084.6 3248.8 42O8.1 4902.O 4960.1 SO2O.2 4929.7 100 nm HAP Comparative 100 nm HAP 1943.5 24O9.8 2648.0 2658.9 2690.2 2657.9 2698.4 Example 3-1 Comparative Citric acid 1/5 1696.9 276.1.1 1745.7 1787.6 1S68.8 1592.7 1468.1 Example 3-2 Comparative SDS1/5 1161.5 1500.7 1775.2 1895.9 1818.2 1845.2 1809.2 Example 3-3 Comparative — 1980.2 2286.6 2541.7 2600.9 2667.9 2SO9.7 2410.4 Example 3-4 US 2015/OO 10638 A1 Jan. 8, 2015 16

4. Trimethoprim 0094) Dissolution Test Using Water Dissolved Amount (ug/ml) TABLE 17

Elution time (min

Example No. Coating ingredient 1 3 10 30 60 18O 360 Example 4-1 Citric acid 1/5 10546.6 11358.O. 10853.1 106121 11559.S. 10403.0 10144.4 100 nm HAP Comparative 100 nm HAP 1085.3 1186.4 1208.2 1196.1 1209.9 1225.9 1212.6 Example 4-1 Comparative Citric acid 1/5 867.5 1036.6 756.3 812.1 907.9 750.2 806.9 Example 4-2 Comparative — 3S4.6 531.O 68S.O 677.9 671.8 672.O 656.3 Example 4-3

Dissolution Test Using 2nd Fluid for Disintegration Test Dis Solved Amount (ug/ml) TABLE 1.8

Elution time (min Example No. Coating ingredient 1 3 10 30 60 18O 360 Example 4-1 Citric acid 1/5 10960.3 12969.8 13896.O 14411.1 13778.2 13081.S 13265.3 100 nm HAP Comparative 100 nm HAP 2389.3 2S32.8 2756.7 2698.8 2606.8. 2532.8 2S32.6 Example 4-1 Comparative Citric acid 1/5 1880.1 21926 2596.1 2264.9 23.61.8 2600.2 1985.O Example 4-2 Comparative — 807.8 11604 1291.7 1344.O 1324.8 1296.5 1321.9 Example 4-3

5. Probucol 0095 Dissolution Test Using Water Dissolved Amount (ug/ml) TABLE 19

Elution time (min

Example No. Coating ingredient 1 3 10 30 60 18O 360 Example 5-1 Disodium hydrogenphosphate 88.9 115.1 339.7 SSO.8 462.S. 649.3 S61.5 15100 nm HAP Comparative Disodium hydrogenphosphate 223.1 211.3 244.8 254.8 257.8 277.7 289.1 Example 5-1 1/5 100 nm HAP Comparative — 0.7 2.7 3.7 6.1 7.6 8.3 9.7 Example 5-2

Dissolution Test Using 2nd Fluid for Disintegration Test Dis Solved Amount (ug/ml) TABLE 20

Elution time (min

Example No. Coating ingredient 1 3 10 30 60 18O 360 Example 5-1 Disodium hydrogenphosphate 35.9 55.8 180.1 163.7 379.4 616.5 332.4 15100 nm HAP Comparative Disodium hydrogenphosphate 111.1 132.8 142.1 157.1 158.5 173.8 180.6 Example 5-1 1/5 100 nm HAP Comparative — 4.7 14.9 19.9 212 21.8 26.8. 28.0 Example 5-2 US 2015/OO 10638 A1 Jan. 8, 2015 17

6. Sulpiride 0096 Dissolution Test Using Water Dissolved Amount (ug/ml) TABLE 21 Example Coating Elution time (min

No. ingredient 3 10 30 120 360 Example 6-1 Citric acid 1,100 12877.9 125972 12425.1 126O7.0 12814.7 100 nm HAP Example 6-2 Citric acid 1.5 2995O1 3462O.2 34483.9 3551.4.1 35293.4 100 nm HAP Example 6-3 Citric acid 3/1 11590.8 10562.6 11248.7 11693.6 18186.7 100 nm HAP Example 6-4 SDS1,100 69706 6946.6 6985.9 6336.5 6695.6 100 nm HAP Example 6-5 SDS1,5 6494.7 6917.6 71856 6998.4 6923.0 100 nm HAP Example 6-6 SDS3.1 22841.O 22791.6 22667.0 22421.8 22631.4 100 nm HAP Comparative 100 nm HAP 1146.0 1204.8 1084.8 1173.1 1144.8 Example 6-1 Comparative Citric acid 1.5 2028.2 17SO4 2O69.3 2060.1 1733.O Example 6-2 Comparative SDS1,5 24O2.6 2416.2 2390.2 2421.4 2425.O Example 6-3 Comparative 555.2 772.8 8O3.2 724.9 715.8 Example 6-4

Dissolution Test Using 2nd Fluid for Disintegration Test Dis Solved Amount (ug/ml) TABLE 22 Example Coating Elution time (min

No. ingredient 3 10 30 120 360

Example 6-1 Citric acid 1,100 18433.8 18076.0 19386.8 18655.3 18099.7 100 nm HAP Example 6-2 Citric acid 1.5 32715.2 35731.4 36896.7 38452.6 38O81.1 100 nm HAP Example 6-3 Citric acid 3/1 1907.O.S 14546.7 11739.1 19157.5 23748.5 100 nm HAP Example 6-4 SDS1,100 9999.1 98.21.7 9667.8 1.01286 9735.7 100 nm HAP Example 6-5 SDS1,5 97811 11062.O 13110.6 13485.1 13619.7 100 nm HAP Example 6-6 SDS3.1 23446.O 245414 25241.3 30004.4 27321.3 100 nm HAP Comparative 100 nm HAP SS38.8 SO98.O 59444 617O.O 6459.8 Example 6-1 Comparative Citric acid 1.5 S804.0 S445.8 S640.1 SS23.4 S7OO.O Example 6-2 Comparative SDS1,5 32O3.O 3992.3 3928.O 3997.8 3746.2 Example 6-3 Comparative 5873.2 6995.7 6751.4 72.06.2 6866.1 Example 6-4

7. Lidocaine 0097 Dissolution Test Using Water Dissolved Amount (ug/ml) TABLE 23

Example Coating Elution time (min

No. ingredient 3 10 30 18O 360

Example 7-1 Citric acid 1.5 25916.O 28885.7 26856.3 27951.2 299344 100 nm HAP US 2015/OO 10638 A1 Jan. 8, 2015

TABLE 23-continued Example Coating Elution time (min

No. ingredient 3 10 30 18O 360 Comparative 100 nm HAP 2545.8 2849.5 3764.3 4090.5 4528.8 Example 7-1 Comparative Citric acid 1.5 2253.5 2419.1 28SO.8 3225.2 3582.6 Example 7-2 Comparative 1681.4 2204.3 2246.2 2919.3 3248.6 Example 7-3

Dissolution Test Using 2nd Fluid for Disintegration Test Dis Solved Amount (ug/ml) TABLE 24 Example Coating Elution time (min

No. ingredient 3 10 30 18O 360 Example 7-1 Citric acid 1.5 2S130.2 2S237.1 26434.S 27018.1 35.102.5 100 nm HAP Comparative 100 nm HAP 886O1 9028.3 8977.9 876S.O 876O.O Example 7-1 Comparative Citric acid 1.5 2400.8 4230.3 S1909 SS66.3 636O1 Example 7-2 Comparative 1873.3 2931.4 40398 S485.O S469.0 Example 7-3

8. Alacepril 0098 Dissolution Test Using Water Dissolved Amount (ug/ml) TABLE 25 Example Coating Elution time (min

No. ingredient 3 10 30 120 360 Example 8-1 Disodium 28634.4 23227.2 23692.2 24879.0 26119.0 hydrogenphosphate 15100 nm HAP Example 8-2 Disodium 34213.2 27170.9 28093.S 29257.2 31636.7 hydrogenphosphate 1f4 100 nm HAP Comparative 526.2 805.6 93.1.2 994.9 996.S Example 8-1

Dissolution Test Using 2nd Fluid for Disintegration Test Dis Solved Amount (ug/ml) TABLE 26

Example Coating Elution time (min)

No. ingredient 3 10 30 120 360

Example 8-1 Disodium hydrogenphosphate 26630.5 27702.2 30248.5 30328.3 27527.2 15100 nm HAP Example 8-2 Disodium hydrogenphosphate 30525.2 30598.9 34879.5 343.27.3 32384.9 1f4 100 nm HAP Comparative — 2311.1 2S14.7 2S25.O 2S88.4 2S48.2 Example 8-1 US 2015/OO 10638 A1 Jan. 8, 2015 19

9. Erythromycin 0099 Dissolution Test Using Water Dissolved Amount (ug/ml) TABLE 27 Example Coating Elution time (min

No. ingredient 3 10 30 120 360 Example 9-1 Citric acid 1.5 20911.S 22571.1 22154.7 23818.3 25648.9 100 nm HAP Comparative 63S.O 861.6 944.7 927.7 846.1 Example 9-1

Dissolution Test Using 2nd Fluid for Disintegration Test Dis Solved Amount (ug/ml) TABLE 28 Example Coating Elution time (min

No. ingredient 3 10 30 120 360 Example 9-1 Citric acid 1.5 15564.O 166OS.S 17082.5 18728.2 21844.7 100 nm HAP Comparative 2S56.3 4984.2 S103.6 S904.1 6044.7 Example 9-1

10. Haloperidol Dissolution Test Using 2nd Fluid for Disintegration Test Dis solved Amount (ug/ml) 01.00 Dissolution Test Using Water Dissolved Amount (ug/ml)01.00 9. TABLE 30 Example Coating Elution time (min TABLE 29 No. ingredient 3 10 30 120 360 Example Coating Elution time (min) Example 10-1 Citric acid 15 214.1 303.5 352.6 583.5 148.6 100 nm HAP No. ingredient 3 10 30 12O 360 Comparative 23.9 35.6 45.2 SO.1 48.9 Example 10-1 Example 10-1 Citric acid 1.5 1OOO.9 814.7 560-4 S92.4 S 62.7 100 nm HAP 0101. In addition, the pH of an aqueous solution after the C omparative 8.2 10.O 113 12.8 13.1 passage of 60 minutes pin each ofC the above described Example 10-1 Examples, in which distilled water was used, is shown below. 0102 The pH values of poorly-soluble substances and poorlyoorly-soluble Substances coated with coating2 a.2agents TABLE 31 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 1-1 Tolbutamide 6.7 100 mm 00 Disodium hydrogenphosphate f10 Example 1-2 Tolbutamide 6.8 100 mm 00 Disodium hydrogenphosphate 5 Example 1-3 Tolbutamide 6.7 50 mm 00 Disodium hydrogenphosphate 5 Example 1-4 Tolbutamide 6.9 100 mm OO L-Arginine 1/5 Example 1-5 Tolbutamide 100 mm 00 — SDS1.5 Example 1-6 Tolbutamide 100 mm 00 Disodium SDS1,10 Comparative Tolbutamide 6.6 100 mm 00 hydrogenphosphate — Example 1-1 f10 Comparative Tolbutamide 6.4 — Disodium Example 1-2 hydrogenphosphate 5 US 2015/OO 10638 A1 Jan. 8, 2015 20

TABLE 31-continued Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Comparative Tolbutamide 6.2 — L-Arginine 1/5 Example 1-3 Comparative Tolbutamide SDS1,5 Example 1-4 Comparative Tolbutamide 4.3 Example 1-5

TABLE 32 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 2-1 Bezafibra 6.3 100 mm 100 Disodium hydrogenpnosphate f100 Example 2-2 Bezafibra 6.4 100 mm 100 Disodium hydrogenpnosphate f10 Example 2-3 Bezafibra 6.2 10 m 100 Disodium hydrogenpnosphate 5 Example 2-4 Bezafibra 6.4 100 mm 100 Disodium hydrogenpnosphate 5 Example 2-5 Bezafibra 6.4 100 mm 50 Disodium hydrogenpnosphate 5 Example 2-6 Bezafibra 6.2 100 mm 10 Disodium hydrogenpnosphate 5 Example 2-7 Bezafibra 6.4 50mm 100 Disodium hydrogenpnosphate 5 Example 2-8 Bezafibra 7.8 100 mm 100 Disodium hydrogenpnosphate 3.1 Example 2-9 Bezafibra 6.7 100 mm 10 L-Arginine 1/5 Example 2-10 Bezafibra 7.1 100 mm 100 Sodium hydrogencarbonate 5 Example 2-11 Bezafibra 100 mm 100 — SDS1,5 Comparative Bezafibra 6.0 100 mm 100 — Example 2-1 Comparative Bezafibra 5.8 100 mm 100 — Example 2-2 Mixing Comparative Bezafibra 6.2 — Disodium Example 2-3 hydrogenphosphate 1.5 Comparative Bezafibra 6.5 — Sodium Example 2-4 hydrogencarbonate 1.5 Comparative Bezafibra SDS1,5 Example 2-5 Comparative Bezafibra 4.3 Example 2-6

TABLE 33 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 3-1 Famotidine 6.3 100 mm 100 Citric acid 1.5 Example 3-2 Famotidine 100 mm 100 — SDS1,5 US 2015/OO 10638 A1 Jan. 8, 2015 21

TABLE 33-continued

Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance

Comparative Famotidine 9.3 100 mm 100 — Example 3-1 Comparative Famotidine 5.5 — Citric acid 1.5 Example 3-2 Comparative Famotidine SDS1,5 Example 3-3 Comparative Famotidine 8.4 Example 3-4

TABLE 34 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 4-1 Trimethoprim 6.3 100 mm 100 Citric acid 1.5 Comparative Trimethoprim 9.1 100 mm 100 — Example 4-1 Comparative Trimethoprim 5.9 — Citric acid 1.5 Example 4-2 Comparative Trimethoprim 8.4 Example 4-3

TABLE 35 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 5-1 Probucol 9.1 100 nm. 100 Disodium hydrogenphosphate 1/5 Comparative Probucol 9.2 100 nm. 100 Disodium Example 5-1 hydrogenphosphate 1/5 Comparative Probucol 5.4 Fxample 5-2

TABLE 36 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 6-1 Sulpiride 8.9 100 nm. 100 Citric acid 1,100 — Example 6-2 Sulpiride 7.1 100 nm. 100 Citric acid 1.5 Example 6-3 Sulpiride 6.2 100 nm. 100 Citric acid 3.1 Example 6-4 Sulpiride 100 nm. 100 — SDS1,100 Example 6-5 Sulpiride 100 nm. 100 — SDS1.5 Example 6-6 Sulpiride 100 nm. 100 — SDS3.1 Comparative Sulpiride 9.5 100 nm. 100 — Example 6-1 Comparative Sulpiride 6.6 — Citric acid 1.5 Example 6-2 Comparative Sulpiride SDS1.5 Example 6-3 Comparative Sulpiride 9.3 Example 6-4 US 2015/OO 10638 A1 Jan. 8, 2015

TABLE 37 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 7-1 Lidocaine 7.4 100 nm. 100 Citric acid 1.5 Comparative Lidocaine 9.8 100 nm. 100 — Example 7-1 Comparative Lidocaine 6.8 — Citric acid 1.5 Example 7-2 Comparative Lidocaine 9.7 Example 7-3

TABLE 38 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 8-1 Alacepril 5.9 100 nm. 100 Disodium hydrogenphosphate 1/5 Example 8-2 Alacepril 6.2 100 nm. 100 Disodium hydrogenphosphate 1f4 Comparative Alacepril 2.9 Example 8-1

TABLE 39 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 9-1 Erythromycin 6.2 100 ml 100 Citric acid 1.5 Comparative Erythromycin 9.6 Example 9-1

TABLE 40 Particle Coating Poorly- pH at 60 diameter rate by pH adjustor Surfactant soluble minutes after of HAP HAP ratio to poorly- ratio to poorly Substance dissolution (Lm) (%) soluble substance soluble substance Example 10-1 Haloperidol S.6 100 mm 100 Citric acid 1.5 Comparative Haloperidol 8.1 Example 10-1

INDUSTRIAL APPLICABILITY 2. The method for producing a substance with improved aqueous solubility according to claim 1, wherein the calcium 0103) The substance with improved aqueous solubility compound is calcium phosphate or calcium carbonate. produced by the present invention can be used for pharma 3. The method for producing a substance with improved ceutical products, veterinary pharmaceutical products, quasi aqueous solubility according to claim 2, wherein the calcium drugs, cosmetic products, food products, agricultural chemi phosphate is hydroxyapatite or tricalcium phosphate. cals, and the like. 4. The method for producing a substance with improved aqueous solubility according to claim 1, wherein at least 5% of the surface of the poorly-soluble substance particle is 1. A method for producing a Substance with improved coated with the calcium compound microparticles. aqueous solubility, comprising coating the Surface of a 5. The method for producing a substance with improved poorly-soluble Substance particle with calcium compound aqueous solubility according to claim 1, which is a method microparticles and at least one of a pH adjuster or a surfactant using at least a pH adjuster, wherein the pH adjuster is used so by applying mechanical energy, to produce the Substance that the pH of an aqueous solution of the substance with with improved aqueous solubility. improved aqueous solubility becomes pH 6 or more. US 2015/OO 10638 A1 Jan. 8, 2015

6. The method for producing a substance with improved of any one of a pharmaceutical product, a veterinary pharma aqueous solubility according to claim 1, which is a method ceutical product a quasi-drug, a cosmetic product and an using at least a surfactant, wherein the amount of the Surfac agricultural chemical, or a food additive. tant used is 1% to 300% by mass with respect to the poorly 14. A substance with improved aqueous solubility pro soluble substance. duced by the method according to claim 1. 7. The method for producing a substance with improved 15. A pharmaceutical product, a veterinary pharmaceutical aqueous solubility according to claim 1, wherein the method product, a quasi-drug, a cosmetic product, an agricultural of applying mechanical energy is a method involving chemical, or a food product, comprising the Substance with mechanical fusion. improved aqueous solubility according to claim 14. 8. The method for producing a substance with improved 16. The pharmaceutical product, veterinary pharmaceuti aqueous solubility according to claim 1, wherein the method cal product, quasi-drug, cosmetic product, agricultural of applying mechanical energy is a method involving hybrid chemical or food product according to claim 15, which is an ization. aqueous liquid composition. 9. The method for producing a substance with improved 17. The method for producing a substance with improved aqueous solubility according to claim 1, wherein the mean aqueous solubility according to claim 2, which is a method particle diameter of the calcium compound microparticles is using at least a surfactant, wherein the amount of the Surfac 100 um or less. tant used is 1% to 300% by mass with respect to the poorly 10. The method for producing a substance with unproved soluble substance. aqueous solubility according to claim 9, wherein the mean 18. The method for producing a substance with improved particle diameter of the calcium compound microparticles is aqueous solubility according to claim 3, which is a method 50 to 200 nm. using at least a surfactant, wherein the amount of the Surfac 11. The method for producing a substance with improved tant used is 1% to 300% by mass with respect to the poorly aqueous solubility according to claim 1, wherein the pH soluble substance. adjuster is at least one selected from the group consisting of 19. The method for producing a substance with improved disodium hydrogen phosphate, L-arginine, sodium hydrogen aqueous solubility according to claim 4, which is a method carbonate, citric acid, and Sodium dihydrogen phosphate. using at least a surfactant, wherein the amount of the Surfac 12. The method for producing a substance with improved tant used is 1% to 300% by mass with respect to the poorly aqueous solubility according to claim 1, wherein the Surfac soluble substance. tant is sodium dodecyl sulfate. 20. The method for producing a substance with improved 13. The method for producing a substance with improved aqueous solubility according to claim 6, wherein the Surfac aqueous solubility according to claim 1, wherein the poorly tant is sodium dodecyl Sulfate. soluble Substance is a Substance acting as an active ingredient k k k k k