WO2007073112A1

WO2007073112A1 - A composition comprising azole antifungal drug and a preparation process thereof

Info

Publication number: WO2007073112A1
Application number: PCT/KR2006/005648
Authority: WO
Inventors: Yil Woong Yi; Hye Jeong Yoon; Min Hyo Seo; Myung Seob Shim
Original assignee: Samyang Corp
Current assignee: Samyang Corp
Priority date: 2005-12-23
Filing date: 2006-12-22
Publication date: 2007-06-28
Anticipated expiration: 2008-06-23
Also published as: KR100858508B1; KR20070067764A

Abstract

The present invention relates to a composition for oral administration comprising azole antifungal drug as an active ingredient, specifically to an azole antifungal drug composition comprising azole antifungal drug, nonionic surfactant, polylactic acid derivative containing carboxylic acid terminal group, and metal salt of polylactic acid derivative containing carboxylic acid terminal group, characterized in forming colloidal dispersion system in aqueous solution, and a preparation process thereof. The azole antifungal drug composition of the present invention improves the solubility of a poorly water-soluble drug in water, and increases the bioavailability in oral administration. Also, according to the preparation process of the present invention, the composition is prepared at a low temperature of 50 °C or below, and so can avoid stability problem influenced by high temperature during the preparation process.

Description

A COMPOSITION COMPRISING AZOLE ANTIFUNGAL DRUG AND A PREPARATION PROCESS THEREOF

[1] TECHNICAL FIELD

[2]

[3] The present invention relates to a pharmaceutical composition comprising azole antifungal drug as an active ingredient, specifically to an azole antifungal drug composition comprising azole antifungal drug, nonionic surfactant, polylactic acid derivative containing carboxylic acid terminal group, and metal salt of polylactic acid derivative containing carboxylic acid terminal group, characterized in forming colloidal dispersion system in aqueous solution, and a preparation process thereof.

[4]

[5] BACKGROUND ART

[6]

[7] Antifungals can be classified into azoles such as itraconazole, fluconazole, ke- toconazole, etc.; polyenes such as amphotericin B, etc.; allylamines such as terbinafine, butenafine, etc.; echinocandins such as caspofungin, micafugin, etc.; morpholines such as amorolfine, etc.; pyrimidines such as flucytosine, etc.; and other antifungals, according to reaction mechanism and chemical structure.

[8] Azole antifungal drugs among the above antifungals show the antifungal activity by inhibiting synthesis of ergosterol in fungal cell membranes, and are known as therapeutic agent effective for systemic fungal infections and superficial mycoses. Although azole antifungal drugs show broad spectrum of antifungal activity, they are insoluble in water when orally administered, and so there have been many attempts to solve the problem.

[9] General methods for solubilizing water-insoluble drugs in water include a method for solubilizing a drug in a cosolvent system of water-miscible organic solvent and water; a method for forming salts of an insoluble drug; a method for forming soluble complex of an insoluble drug; a micellizing method by adding surfactants; a method for forming prodrug by adding hydrophilic group to an insoluble drug; a method for increasing solubility by forming micronized particles of an insoluble drug; a method for forming solid dispersion with a water-soluble polymer; or a method for forming i nclusion complex of an insoluble drug (Mark Gibson, ed., 'Pharmaceutical Pre- formulation and Formulation', IHS Health Group, Colorado, USA, 2001).

[ 10] WO 2002/42283 and USP No. 6,448,401 disclose a skill of improving solubility by forming prodrug through adding hydrophilic groups to azoles. WO 2002/66465 discloses pharmacologically acceptable salts of triazole compound having antifungal activity. USP No. 6,204,415 discloses derivatives and salts of azole compounds having improved solubility. [11] USP No. 6,673,373 discloses an azole antifungal drug composition comprising an emulsifier, a binder, and an absorbent aid. WO 95/22973 discloses an azole antifungal drug composition wherein the solubility is increased by dispersing azoles in water with use of an oil component. [12] WO 98/57967 discloses azole antifungal drug formulations wherein the solubility of azoles is increased by decreasing the particle size of azoles and increasing the degree of crystallinity of azoles. [13] KRP No. 159,730 discloses an azole composition having improved solubility by adding an organic acid to ketoconazole. [14] WO 85/02767 and WO 95/08993 disclose a method of increasing the solubility of drug by forming inclusion complex of insoluble azoles with cyclodextrin derivatives.

By use of this method, formulations of intravenous injection and oral solution of itraconazole an insoluble azole drug, were marketed under the brand name of Sporanox

®

[15] WO 00/76520 discloses a skill for increasing solubility by using fused mixture of insoluble antifungals and phosphoric acid.

[16] AU the above methods improve the solubility of insoluble azole antifungal drugs, but have limits for attaining effective bioavailability through oral administration. Also, the above methods require complex preparation processes consisting of many steps, or include a process to influence the drug stability by exposure to high temperature.

[17]

[ 18] DITAILED DESCRIPTION OF THE INVENTION

[19]

[20] TECHNICAL SUBJECT

[21]

[22] The present inventors have conducted numerous studies to develop an azole antifungal drug composition which has improved solubility and stability to obtain effective bioavailability. As a result, the inventors confirmed that in case of using an azole antifungal drug together with a nonionic surfactant, a polylactic acid derivative containing carboxylic acid terminal group , and a metal salt of polylactic acid derivative containing carboxylic acid terminal group, the azole antifungal composition can form a stable colloidal dispersion system in aqueous media, thereby they completed the present invention.

[23] Therefore, the objective of the present invention is to provide an azole antifungal drug composition having remarkably increased bioavailability by improving the solubility and stability of azole antifungal drugs in water. [24] [25] BRIEF DESCRIPTION OF THE DRAWINGS

[26]

[27] Fig. 1 is a graph showing the blood plasma concentration-time profiles of the drug

(itraconazole) after single oral administration of the composition according to one embodiment of the present invention and the marketed Sporanox solution to rats.

[28] Fig. 2 is a graph showing the blood plasma concentration-time profiles of the drug metabolite (hydroxy itraconazole) after single oral administration of the composition according to one embodiment of the present invention and the marketed Sporanox^® solution are administered to rats.

[29] Fig. 3 is a graph showing the blood plasma concentration-time profiles of the drug

(itraconazole) after single oral administration of the composition according to one embodiment of the present invention and the marketed Sporanox^® solution to Beagle dogs.

[30] Fig. 4 is a graph showing showing the blood plasma concentration-time profiles of the drug metabolite (hydroxy itraconazole) after single oral administration of the composition according to one embodiment of the present invention and the marketed

(5)

Sporanox solution are administered to Beagle dogs. [31] Fig. 5 is a graph showing the blood plasma concentration-time profiles of the drug

(itraconazole) after daily oral administrations of the composition according to one embodiment of the present invention and the marketed Sporanox solution to Beagle dogs for a week. [32] Fig. 6 is a graph showing the blood plasma concentration-time profiles of the drug metabolite (hydroxy itraconazole) after daily oral administrations of the composition according to one embodiment of the present invention and the marketed Sporanox solution to Beagle dogs for a week. [33]

[34] MODE FOR CARRYING OUT THE INVENTION

[35] [36] The present invention relates to an azole antifungal drug composition comprising azole antifungal drug, nonionic surfactant, polylactic acid derivative containing carboxylic acid terminal group, and metal salt of polylactic acid derivative containing carboxylic acid terminal group. [37] Also, the present invention relates to a preparation process of an azole antifungal drug composition comprising two steps of: [38] dissolving an azole antifungal drug composition comprising azole antifungal drug, nonionic surfactant, polylactic acid derivative containing carboxylic acid terminal group, and metal salt of polylactic acid derivative containing carboxylic acid terminal group in an organic solvent to obtain a solution (1^st step); and

[39] spraying the solution obtained in 1^st step to form dried solid particles (2ⁿ step).

[40] Preferably, the present invention relates to a preparation process of azole antifungal drug composition comprising three steps of:

[41] dissolving an azole antifungal drug composition comprising azole antifungal drug, nonionic surfactant, polylactic acid derivative containing carboxylic acid terminal group, and metal salt of polylactic acid derivative containing carboxylic acid terminal group in an organic solvent to obtain a solution (1^st step);

[42] adding sweeteners to the fluidized bed granulator (2^nd step); and

[43] spraying the solution obtained in 1^st step with fluidizing the sweeteners of 2ⁿ step using dried air current to form dried solid particles (3^rd step).

[44]

[45] Hereinafter, the present invention will be described in detail .

[46] Azole antifungal drug used in the present invention is selected from the group consisting of itraconazole, fluconazole, voriconazole, posaconazole, ketoconazole, clotrimazole, econazole, miconazole, and thioconazole.

[47] Nonionic surfactant used in the present invention is selected from the group consisting of poloxamer, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene fatty acid ester, sorbitan ester, polysorbate, and mixture thereof.

[48] Among the above surfactants, particularly, poloxamer, i.e., copolymer of polyoxyethylene and polyoxypropylene, is preferable. The safety of poloxamer in human body was proven, and poloxamers have been marketed with the several brand names, such as Pluronic™ F-68(M.W.: 8,350), Pluronic™ F-108(M.W.: 14,500) or Pluronic™ F-127(M.W.: 12,500) of BASF.

[49] In the azole antifungal drug composition according to the present invention, nonionic surfactant is preferably used in an amount of 1 to 10 parts by weight to azole antifungal drug of 1 part by weight, more preferably 2 to 8 parts by weight to azole antifungal drug of 1 part by weight. If the amount of nonionic surfactant is less than 1 part by weight, the colloidal dispersion system cannot be formed. And, if the amount is more than 10 parts by weight, the amount is unsuitable for single dosage.

[50] Polylactic acid derivative containing carboxylic acid terminal group used in the present invention preferably has the number average molecular weight of 500 to 2,500 daltons, more preferably, 800 to 2,000 daltons. Here, if the number average molecular weight is lower than 500 daltons, the colloidal dispersion system cannot be formed. And, if the number average molecular weight is higher than 2,500 daltons, precipitation occurs.

[51] Said polylactic acid derivative containing carboxylic acid terminal group is prepared by a method described in WO 03/33952, and is preferably selected from the group consisting of D,L-polylactic acid, L-polylactic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and 1 ,4-dioxan-2-one.

[52] Among the above polylactic acid derivatives containing carboxylic acid terminal group, particularly, D,L-polylactic acid containing carboxylic acid terminal group is preferable. D,L-polylactic acid is hydrolyzed in human body to be excreted. Its safety was proven, and so it is widely used as drug carriers and surgical biomaterials.

[53] In the azole antifungal drug composition according to the present invention, the polylactic acid derivative containing carboxylic acid terminal group is used in an amount of 0.5 to 5 parts by weight to azole antifungal drug of 1 part by weight, more preferably, 1 to 3 parts by weight to azole antifungal drug of 1 part by weight. Here, if the amount of polylactic acid derivative is less than 0.5 part by weight, the colloidal dispersion system cannot be formed. And, if the amount is more than 5 parts by weight, the amount of the formulation is not suitable for single dosage.

[54] The metal salt of polylactic acid derivative containing carboxylic acid terminal group used in the present invention preferably has the number average molecular weight of 500 to 2,500 daltons, more preferably, 800 to 2,000 daltons. Here, if the number average molecular weight is lower than 500 daltons, the colloidal dispersion system cannot be formed. And, if the number average molecular weight is higher than 2,500 daltons, precipitation occurs.

[55] Said metal salt of polylactic acid derivative containing carboxylic acid terminal group is prepared by the method described in WO 03/33952, and is preferably selected from the group consisting of sodium salt, potassium salt, magnesium salt and calcium salt of D,L-polylactic acid, L-polylactic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, or copolymer of D,L-lactic acid and l,4-dioxan-2-one.

[56] Among the above metal salts of polylactic acid derivative containing carboxylic acid terminal group, particularly, the sodium salt of D,L-polylactic acid containing carboxylic acid terminal group is preferable. D,L-polylactic acid is hydrolyzed in human body to be excreted. Its safety was proven, and so it is widely used as drug carriers and surgical biomaterials.

[57] In the azole antifungal drug composition according to the present invention, the metal salt of polylactic acid derivative containing carboxylic acid terminal group is preferably used in an amount of 1 to 20 parts by weight to azole antifungal drug of 1 part by weight, more preferably, 5 to 15 parts by weight to azole antifungal drug of 1 part by weight. Here, if the amount of metal salt is less than 1 part by weight, the colloidal dispersion system cannot be formed. And, if the amount is more than 20 parts by weight, the amount of the formulation is unsuitable for single dosage. [58] Preferably, polylactic acid derivative containing carboxylic acid terminal group of the present invention or its metal salt comprises the compound of the following formula (I):

[59] [Formula I]

[60] RO-CHZ-[A] -[B] -COOM n m

[61] wherein

[62] A is -COO-CHZ-,

[63] B is -COO-CHY-, -COO-CH CH CH CH CH - or -COO-CH CH OCH ,

2 2 2 2 2 2 2 2

[64] R is hydrogen, acetyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl,

[65] Z and Y each are independently hydrogen, methyl or phenyl,

[66] M is H, Na, K, or Li,

[67] n is an integer of 1 to 30, and

[68] m is an integer of O to 20.

[69]

[70] More preferably, polylactic acid derivative containing carboxylic acid terminal group of the present invention comprises the compound of the following formula (II):

[71] [Formula II]

[72] RO-CHZ-[COO-CHX] -[COO-CHY'] -COO-CHZ-COOM p q

[73] wherein

[74] X is methyl,

[75] Y' is hydrogen or phenyl,

[76] P is an integer of O to 25,

[77] q is an integer of O to 25,

[78] wherein p+q is an integer of 5 to 25,

[79] R, Z and M each are the same as defined in said formula (I).

[80]

[81] Also, preferably, polylactic acid derivative of the present invention comprises the compound of the following formulae (JR) to (V): [82] [Formula III]

[83] RO-PAD-COO-W-M'

[84] wherein

[85]

COOH C CH₂COOM _C(m

W-M' is ^CH2C00H or -CH-CH₂OX⁾M _^ [86] PAD is D,L-lactic acid, D-polylactic acid, polymandelic acid, copolymer of

D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and l,4-dioxan-2-one,

[87] R and M are the same as defined in said formula (I).

[88] [Formula IV]

[89] S-O-PAD-COO-Q

[90] wherein

_{s ig} (CHa)₃-COOI ^

[91] L iS -NR₁- Or -O-,

[92] R is hydrogen or C alkyl,

[93] Q is C alkyl, or benzyl,

1-4

[94] a is an integer of 0 to 4,

[95] b is an integer of 1 to 10,

[96] M is the same as defined in said formula (I),

[97] PAD is the same as defined in said formula (HI).

[98] [Formula V]

CH₂-O-R' _or

[99] wherein

[100] R' is -PAD-O-C(O)-CH₂CH₂-C(O)-OM,

[101] M is the same as defined in said formula (T),

[102] PAD is the same as defined in said formula (HI),

[103] a is an integer of 1 to 4.

[104]

[105] The azole antifungal drug composition of the present invention may preferably comprise one or more sweeteners. The sweeteners are one or more selected from the group consisting of sucrose, dextrose, fructose, sorbitol, mannitol, maltitol, sucralose, acesulfame potassium, aspartame, saccharin, ammonium glycyrrhizinate, sodium chloride and mixture thereof.

[106] In the azole antifungal drug composition according to the present invention, the sweeteners are used in an amount of 0.1 to 50 parts by weight to azole antifungal drug of 1 part by weight, more preferably, 1 to 40 parts by weight.

[107] The azole antifungal drug composition according to the present invention may additionally comprise pharmaceutically acceptable flavoring agents or colorants.

[108]

[109] The azole antifungal drug composition of the present invention is prepared by the following method.

[110] First, azole antifungal drug, nonionic surfactant, polylactic acid derivative containing carboxylic acid terminal group, and metal salt of polylactic acid derivative containing carboxylic acid terminal group, preferably, pharmaceutically acceptable flavouring agents or colorants, are dissolved in an organic solvent by a certain ratio to prepare a solution. The above organic solvent is selected from the group consisting of methylene chloride, chloroform, acetonitrile, methanol and ethanol. Methylene chloride is the most preferable solvent. The above solution is sprayed into fluidized bed granulator at a predetermined speed to prepare the azole antifungal drug composition of the present invention in the form of dried powder.

[Ill] Alternatively, the composition of the present invention may preferably comprise one or more sweeteners. When the sweeteners are added to the composition, one or more sweeteners are placed in the bottom of fluidized bed granulator (e.g., GPCG-I of Glatt Co.); the above solution is connected to the fluidized bed granulator for being sprayed into the fluidized bed granulator through a metering pump; and a predetermined process condition is confirmed in advance. While the sweetener is fluidized with dried air current by operating fluidized bed granulator, the solution comprising the drug is sprayed at a predetermined speed to prepare the azole antifungal drug composition of the present invention in the form of dried powder.

[112] The composition of the present invention may be prepared and administered as oral formulations such as solution, tablet, capsule, etc., or as external preparations such as spray solution.

[113]

[114] Below, the present invention is specifically described by examples, but the scope of the present invention is not limited by them in any manner.

[115]

[116] Example 1

[117] lOOg of itraconazole as azole antifungal drug, 300g of poloxamer 188 (Pluronic F-

68, BASF) as nonionic surfactant, lOOg of PLA-COOH as polylactic acid derivative containing carboxylic acid terminal group, l,500g of (PLA-COONa) as sodium salt of polylactic acid derivative containing carboxylic acid terminal group, and 1Og of cherry flavor were dissolved in 5 L of methylene chloride to obtain a solution.

[118] 1,50Og of sucrose, 5Og of sucralose, lOOg of acesulfame potassium, and 50g of sodium chloride were added as sweeteners to the bottom of fluidized bed granulator (GPCG-I of Glatt Co.), and the above solution was connected to the fluidized bed granulator for being sprayed into the fluidized bed granulator through a metering pump.

[119] While the sweeteners were fluidized with dried air current (40°C) by operating fluidized bed granulator, the solution was sprayed at a speed of lOmL/min to prepare a composition comprising itraconazole in the form of dried powder.

[120]

[121] Each ingredient and content of the composition was shown in Table 1. [122] [Table 1]

[123] [124] Example 2 [125] A composition comprising ketoconazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 2.

[126] [Table 2]

[127]

[128] Example 3

[129] A composition comprising itraconazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 3. [130] [Table 3]

[131] [132] Example 4 [133] A composition comprising fluconazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 4. [134] [Table 4]

[135] [136] Example 5 [137] A composition comprising itraconazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 5.

[138] [Table 5]

[139]

[140] Example 6 [141] A composition comprising clotrimazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 6.

[142] [Table 6]

[143] [144] Example 7 [145] A composition comprising itraconazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 7.

[146] [Table 7]

*polyoxyethylene castor oil

[147] [148] Comparative Example 1 [149] A composition comprising itraconazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 8.

[150] [Table 8]

[151] [152] Comparative Example 2 [153] A composition comprising itraconazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 9. [154] [Table 9]

[155]

[156] Comparative Example 3

[157] A composition comprising itraconazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 10. [158] [Table 10]

[ 160] Comparative Example 4

[161] A composition comprising itraconazole in the form of dried powder was prepared by the same method as Example 1 by using the ingredients in Table 11. [162] [Table 11]

[163] [164] Experimental Example 1: Determination of solubility [165] Each composition prepared in Examples 1-7 and Comparative Examples 1-4 containing approximately 500mg of azole antifungal drug was put into 2OmL volumetric flasks. Separately, approximately 500mg of each azole antifungal drug, i.e., itraconazole, ketoconazole, fluconazole and clotrimazole, was put into 2OmL volumetric flasks. Then, distilled water was added thereto to make the total volume to 2OmL. The drugs in volumetric flasks were dissolved by using shaking water bath at 25 °C for 24 hours with stirring at lOOrpm. After the water bath was stood for 30 min, each 1OmL of the solutions was taken, and centrifuged for 30 min at 5,000rpm. The su- pernatants were filtered with 0.45 D PVFD filter, and the filtrates were centrifuged again at 15,000 rpm. The supernatants were taken therefrom and the drug contents were determined with HPLC. The result was shown in Table 12.

[166] [167] Experimental Example 2: Particle size analysis [168] Each composition prepared in Examples 1-7 and Comparative Examples 1-4 containing approximately lOOmg of azole antifungal drug was dissolved in 1OmL of distilled water, and colloid particle sizes were measured by dynamic light scattering (DLS). The result was shown in T able 12.

[169] [170] [Table 12]

[171] [172] Experimental Example 3: Pharmacokinetic profiles after single oral administration (Rat)

[173] 180~230g (6-8 weeks) of male Sprague-Dawley rats were purchased from Charles River Laboratories, and bred at the animal laboratory keeping constant temperature and humidity for 7 days or longer. General conditions of the animals were observed, and healthy animals by appearance were selected for the experiment. For 24 hrs before oral administration, the animals were fasted, and were fed after 2 hrs post-administration.

[174] The composition of Example 1 was diluted in distilled water to make the drug content to lOmg/mL. For comparison, the marketed formulation, Sporanox^® solution, was used as control.

[175] The above samples were orally administered by using oral sonde at a dose of 10mg/kg. Blood samples were taken from tail vein at designated time points of 0.5, 1, 2, 3, 6, 9 and 24 hrs after drug administration. The samples were centrifuged and the drug concentration in blood plasma was analyzed by HPLC. The concentration of hydroxy itraconazole in blood plasma was also analyzed because hydroxy itraconazole, one of the metabolites of itraconazole, has been known to have equivalent activity to itraconazole. The results were shown in Fig. 1 and Fig. 2. The Area Under the Blood Plasma Concentration-time Curve (AUC) was shown in Table 13.

[176]

[177] [Table 13] Area Under the Blood Plasma Concentration-time Curve (AUC )

0-24h itraconazole (^βS ^• h/mL) hydroxy itraconazole(μg ^• h/mL)

Example 1 4 .0 5.9

Marketed 3 .6 5.1 Formulation

[178] [179] Experimental Example 4: Pharmacokinetic profiles after single oral administration (Dog)

[180] Male Beagle dogs (11 weeks) were purchased from Woo Jung BSC, Inc. ( Korea ), and bred at the animal laboratory keeping constant temperature and humidity for 7 days or longer. From hematology and blood chemistry tests, only suitable animals were selected. For 12 hrs before oral administration, the animals were fasted, and were fed after 3 hrs post-administration.

[181] The composition of Example 1 was diluted in distilled water to make the drug content to lOmg/mL. For comparison, the marketed formulation, Sporanox^® solution, was used as control.

[182] The above samples were orally administered by using oral sonde at a dose of 7.5mg/kg. Blood samples were taken from cephalic vein at designated time points of 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hrs after drug administration. The samples were centrifuged and the concentrations of drug and active metabolite in blood plasma were analyzed by LC-MS/MS. The results were shown in Fig. 3 and Fig. 4. The Area Under the Blood Plasma Concentration-time Curve (AUC) was shown in Table 14.

[183] [184] [Table 14] Area Under the Blood Plasma Concentration-time Curve (AUC )

0-72h

[186] Experimental Example 5: Pharmacokinetic profiles after repeated oral administrations (Dog)

[187] Beagle Dogs used in the above Experimental Example 4 took a rest for 7 days, and then were repeatedly orally administered. [188] The composition of Example 1 was diluted in distilled water to make the drug content to lOmg/mL. For comparison, the marketed formulation, Sporanox^® solution, was used as control.

[189] The above samples were orally administered once a day by using oral sonde at a dose of 7.5mg/kg/day for 7 days. Blood samples were taken from cephalic vein right before the administration and after 1 hr post-administration. The samples were centrifuged and the concentrations of drug and active metabolite in blood plasma were analyzed by LC-MS/MS. The results each were shown in Fig. 5 and Fig. 6. The Area Under the Blood Plasma Concentration-time Curve (AUC) was shown in Table 15.

[190] [191] [Table 15] Area Under the Blood Plasma Concentration-time Curve (AUC )

0-168h

[192] [193] INDUSTRIAL APPLICABILITY [194] [195] The composition for oral administration of azole antifungal drug of the present invention improves the solubility of a poorly water-soluble drug in water, and increases the bioavailability when orally administered. Also, according to the preparation process of the present invention, the composition is prepared at a low temperature of 50°C or below, and so can avoid stability problem influenced by high temperature during the preparation process.

Claims

[1] 1. An azole antifungal drug composition comprising azole antifungal drug, nonionic surfactant, polylactic acid derivative containing carboxylic acid terminal group, and metal salt of polylactic acid derivative containing carboxylic acid terminal group.

[2] 2. The azole antifungal drug composition according to claim 1, comprising 1 to

10 parts by weight of nonionic surfactant, 0.5 to 5 parts by weight of polylactic acid derivative containing carboxylic acid terminal group, and 1 to 20 parts by weight of metal salt of polylactic acid derivative containing carboxylic acid terminal group, to azole antifungal drug of 1 part by weight.

[3] 3. The azole antifungal drug composition according to claim 1, wherein the azole antifungal drug is selected from the group consisting of itraconazole, fluconazole, voriconazole, posaconazole, ketoconazole, clotrimazole, econazole, miconazole and thioconazole.

[4] 4. The azole antifungal drug composition according to claim 1, wherein the nonionic surfactant is selected from the group consisting of poloxamer, poly- oxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene fatty acid ester, sorbitan ester, polysorbate and mixture thereof.

[5] 5. The azole antifungal drug composition according to claim 1, characterized in that the nonionic surfactant is poloxamer.

[6] 6. The azole antifungal drug composition according to claim 1, characterized in that the polylactic acid derivative containing carboxylic acid terminal group has 500 to 2,500 daltons of number average molecular weight.

[7] 7. The azole antifungal drug composition according to claim 1, wherein the polylactic acid derivative containing carboxylic acid terminal group is selected from the group consisting of D,L-polylactic acid, L-polylactic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and l,4-dioxan-2-one.

[8] 8. The azole antifungal drug composition according to claim 1, wherein the metal salt of polylactic acid derivative containing carboxylic acid terminal group has 500 to 2,500 daltons of number average molecular weight.

[9] 9. The azole antifungal drug composition according to claim 1, wherein the metal salt of polylactic acid derivative containing carboxylic acid terminal group is selected from the group consisting of sodium salt, potassium salt, magnesium salt and calcium salt of D,L-polylactic acid, L-polylactic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and l,4-dioxan-2-one.

[10] 10. The azole antifungal drug composition according to claim 1, additionally comprising sweeteners.

[11] 11. The azole antifungal drug composition according to claim 10, the sweeteners are one or more selected from the group consisting of sucrose, dextrose, fructose, sorbitol, mannitol, maltitol, sucralose, acesulfame potassium, aspartame, saccharin, ammonium glycyrrhizinate, sodium chloride and mixture thereof.

[12] 12. The azole antifungal drug composition according to claim 1, additionally comprising pharmaceutically acceptable flavoring agents or colorants.

[13] 13. A preparation process of azole antifungal drug composition comprising two steps of: dissolving azole antifungal drug, nonionic surfactant, polylactic acid derivative containing carboxylic acid terminal group, and metal salt of polylactic acid derivative containing carboxylic acid terminal group in an organic solvent to obtain a solution (1^st step); and spraying the solution obtained in 1^st step to form dried solid particles (2ⁿ step).

[14] 14. A preparation process of azole antifungal drug composition comprising three steps of: dissolving azole antifungal drug, nonionic surfactant, polylactic acid derivative containing carboxylic acid terminal group, and metal salt of polylactic acid derivative containing carboxylic acid terminal group in an organic solvent to obtain a solution (1^st step); adding sweeteners to the fluidized bed granulator (2ⁿ step); and spraying the solution obtained in 1^st step with fluidizing the sweeteners of 2^nd step using dried air current to form dried solid particles (3^r step).

[15] 15. The process according to claim 13 or 14, wherein the organic solvent is selected from the group consisting of methylene chloride, chloroform, ace- tonitrile, methanol and ethanol.