US 2007/0148240 Al  1  Jun.28,2007  ORAL FORMULATION CONTAINING  ITRACONAZOLE AND METHODS FOR  MANUFACTURING AND USING THE SAME  FIELD OF THE INVENTION  BACKGROUND OF THE INVENTION  [0001]  The present invention relates to an oral pharma› ceutical formulation which contains a core and a drug  coating layer. The core is preferred to be a round, spherical  core which comprises sucrose, lactose, starch, talc, or micro› crystalline cellulose or any combination thereof. The pre› ferred drug is an azole antifungal drug, including, but not  limited to, itraconazole, saperconazole, ketoconazole, and  fluconazole. The drug coating layer includes the drug and a  binder, but does not include an emulsion (such as polyox› ypropylene-polyoxyethylene block copolymers, polyoxy› ethylene-sorbitan-fatty acid esters, sodium lauryl sulfate, or  vitamin E polyethylene glycol succinate) and an absorbent  aid, which is an organic acid (such as DL-malic acid, citric  acid, ascorbic acid, and alginic acid). The present invention  also relates to a method for making and using the oral  pharmaceutical formulation.  [0002]  U.S. Pat. No. 4,267,179 discloses a number of  lH-imidazole and lH-1,2,4-triazole derivatives having anti› fungal and antibacterial properties. Specifically, a number of  heterocyclic derivatives of ( 4-phenyl-1-piperazinyl-ary› loxymethyl-1,3-dioxolan-2-yl) methyl-lH-imidazoles and  lH-1,2,4-triazoles are described. Among these azole com› pounds and their derivatives, itraconazole, saperconazole,  ketoconazole, and fluconazole are currently commercially  available. These commercially available azole compounds  are known for their broad spectrum of antimicrobial activity.  For example, they are found to be highly active against a  wide variety of fungi such as  Microsporum canis, Pity› rosporum ovale, Ctenomyces mentagrophytes, Trichophyton  rubrum, Phialophora verrucosa, Cryptococcus neoformans,  Candida tropicalis,  Candida albicans, Mucor  species,  Aspergillus fumigatus, Sporotricum schenckii  and  Saproleg› nia  species. They are also active against bacteria, such as  Erysipelotrix insidiosa, Staphylococcus hemolyticus  and  Streptococcus pyogenes.  [0003]  Itraconazole is currently commercially available  under the trade name Sporanoxfi in capsule or tablet form  from Janssen Pharmaceutica (Beerse, BE). The chemical  [0004]  Itraconazole is especially known for its act1V1ty  against a broad range of fungal inductions such as those  caused by  Trichophyton rubrum, Tricophyton mentagro› phytes, Epidermophyton jloccsum  and  Candida al bi cans.  [0005]  The chemical structure of saperconazole is dis› closed in U.S. Pat. No. 4,916,134 as (–)-cis-4-[ 4-[ 4-[ 4-[[2- (2,4-difluorophenyl)-2-(lH-1,2,4-triazol-1-ylmethyl)-1,3- dioxolan-4-yl ]methoxy ]phenyl]-1-piperazinyl ]phenyl]-2,4- dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one.  Saperconazole has antimicrobial activity, in particular  against fungi belonging to the genus  Aspergillus.  [0006]  Ketoconazole was the first of the azole antifungal  agents to become commercially available. The chemical  structure of ketoconazole is disclosed in U.S. Pat. No.  4,144,346 as cis-l-acetyl-4-[ 4-[[2-(2,4-dichlorophenyl)-2- (1 H-imidazole- l-ylmethyl)-1,3-dioxolan-4-yl ]methoxy]  phenyl]piperazine. Ketoconazole is an orally active, broad› spectrum antifungal agent. The compound, an imidazole  derivative structurally related to miconazole and clotrima› zole, impairs the synthesis of ergosterol, which is the prin› cipal sterol of fungal cell membranes.  [0007]  Fluconazole is a water-soluble triazole with greater  than 90% bioavailability after oral administration. The  chemical structure of fluconazole is disclosed in U.S. Pat.  No. 4,404,216 as 2-(2,4-difluorophenyl)-1,3-bis(lH-1,2,4- triazol-1-yl)propan-2-ol. Fluconazole is used extensively to  treat a wide range of  Candida  infections. In particular, it is  widely used in connection with therapy for oropharyngeal  candidiasis in patients with advanced HIV infection and  AIDS.  [0008]  The solubility and bioavailability of itraconazole  and saperconazole are low due to the fact that these com› pounds have a low solubility in water and a low pKa value.  For example, the solubility of itraconazole is less than 1  µg/ml  in water and the pKa value ofitraconazole is 3.7. The  solubility of itraconazole in ethanol is also low. However,  itraconazole is easily soluble in methylene chloride and also  structure of itraconazole is disclosed in U.S. Pat. No. 4,267,  179 as (–)-cis-4-[ 4-[ 4-[ 4-[[2-(2,4-dichlorophenyl)-2-(lH-1,  2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy ]phe- nyl ]-1-piperazinyl]phenyl ]-2,4-dihydro-2-(1- methylpropyl)-3H-1,2,4-triazol-3-one, having the formula  of: 