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## ORAL FORMULATION CONTAINING ITRACONAZOLE AND METHODS FOR MANUFACTURING AND USING THE SAME 

[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. 

## BACKGROUND OF THE INVENTION 

[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 

## FIELD OF THE INVENTION 

<img src='content_image/923792.jpg'>

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: 

[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 

