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[0024] The present invention also provides a method for making the oral pharmaceutical formulation which contains the following steps: (1) obtaining cores; (2) collecting the cores having a diameter of 18-20 mesh by passing the cores through a 18 inches sieve and 20 inches sieve respectively; (3) dissolving an azole antifungal drug and a binder in organic solvents to form a drug coating layer; and (4) spraying the drug coating layer onto the cores having a diameter of 18-20 mesh. 

[0025] The cores are obtained by (1) dissolving polyvinyl pyrrolidone in isopropanol to produce a binder solution; and (2) spraying the binder solution onto sucrose to form the cores. Optionally, starch and talc can be added to the cores simultaneously when the binder solution is sprayed onto the sucrose. 

[0026] Finally, the present invention provides a method for treating patients with fungal infection by orally admin› istering the oral pharmaceutical formulation as shown above to the patients having fungal infection. 

## BRIEF DESCRIPTION OF THE DRAWINGS 

[0027] FIG. 1 shows the% dissolution of infra Example 1 ( ♦, solid diamond), and Sporanoxfi by Janssen pharmaceu› tica (Beerse BE)( ■, solid square) in 0.1 N HCl at various time points. 

[0028] FIG. 2 shows the Mean (–S.E, standard error) plasma concentration profiles of itraconazole (ng/ml) in human after oral administrations of infra Examples 1 ( ■, solid square), and Sporanoxfi by Janssen Pharmaceutica (Beerse, BE) ( □, open square). 

[0029] FIG. 3 shows the% dissolution of infra Example 2 ( ♦, solid diamond), Example 3 ( ■, solid square), Example 4 (fl, open triangle), and Example 5 (._, solid triangle) in 0.1 N HCl at various time points. 

[0030] FIG. 4 shows the Mean (–S.E, standard error) plasma concentration profiles of itraconazole (ng/ml) in human after oral administrations of infra Examples 5 ( ■, solid square), and Sporanoxfi in capsule or tablet form from Janssen Pharmaceutica (Beerse, BE)( □, open square). The amount of itraconazole used in Example 5 was similar to that used in Sporanoxfi. 

[0031] FIG. 5 shows the Mean (–S.E, standard error) plasma concentration profiles of itraconazole (ng/ml) in human after oral administrations of infra Examples 5 ( ■, solid square), and Sporanoxfi in capsule or tablet form from Janssen Pharmaceutica (Beerse, BE) ( □, open square), where the amount of itraconazole used in Example 5 was reduced in half (i.e., 50% dosage). 

[0032] Azole antifungal or antibacterial agents, such as itraconazole, saperconazole, ketoconazole, or fluconazole, are extremely low in solubility and bioavailability. There› fore, these agents are difficult to administer orally. Although these agents are frequently prescribed for the treatment of fungal or bacterial infections, they are generally available in topical preparations or in oral formulations with limited bioavailability. 

[0033] Due to limited bioavailability, it is generally rec› ommended that these drugs be taken after meals to improve their bioavailability because these azole antimicrobial agents have a high binding rate with plasma proteins. For example, itraconazole has a binding rate with plasma pro- 

## DETAILED DESCRIPTION OF THE INVENTION 

teins of 99.8%, which is also evidenced by the fact that the concentration of itraconazole in blood is about 60% of that in plasma. 

[0034] The low solubility and bioavailability of itracona› zole are also demonstrated by the fact that once itraconazole has been taken by the patients, it takes about 3-4 hours for the drug to reach a peak concentration in plasma. The plasma itraconazole has a half life of about 1 to 1.5 days. Also, itraconazole is primarily metabolized in the liver. However, only one of the metabolites of itraconazole, hydroxy-itra› conazole, has been demonstrated in vitro to have antifungal activity. About 3-18% of the itraconazole in its original form is excreted in feces. About or less than 0.03% of the itraconazole in its original form is secreted in urine. About 35% of the itraconazole metabolites are secreted in urine within a week after the uptake of the drug. 

[0035] The present invention is designed to improve the solubility and bioavailability of the itraconazole for use in oral administration. The pharmaceutical formulation is designed as shown in the following diagram: 

Where 1 represents a granular core, and 2 represents a drug coating layer. The core is about 18-20-mesh in diameter. The term "mesh" is used in accordance with the pharmaceutical industrial standards to mean the size of the sugar spheres based on the number of sieve openings per surface unit. According to the standards used in the pharmaceutical industry, cores are measured and labeled based on the size sieve they fall through. For the 18-20 mesh cores, the cores should fall through a 18 mesh sieve but stays on top of the 20 mesh sieve. The 18-20 mesh cores generally have diam› eters in the range of 840-1000 µm. The drug coating layer contains the azole antifungal drug (such as itraconazole) and a binder. The drug coating layer is further characterized as containing no emulsion agent (such as polyoxypropylene› polyoxyethylene block copolymers, polyoxyethylene-sorbi› tan-fatty acid esters, sodium lauryl sulfate, or vitamin E polyethylene glycol succinate). In addition, the drug coating layer does not contain an absorbent aid (such as DL-malic acid, citric acid, ascorbic acid, and alginic acid). 

[0036] Optionally, a protective layer can be added to cover the drug coating layer as shown in the following scheme: 

[0037] The protective layer is designated as 3 as shown in the above scheme. The preferred material to be used in the protective layer is polyethylene glycol, having a molecular weight ranged from 6000 to 20,000. 

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