US 2007/0148240 Al  3  Jun.28,2007  [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.  [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- [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.  [0036]  Optionally, a protective layer can be added to cover  the drug coating layer as shown in the following scheme:  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).  DETAILED DESCRIPTION OF THE  INVENTION  BRIEF DESCRIPTION OF THE DRAWINGS 