Title:  Intraconazole exhibiting an improved solubility, a method of preparing the same and a pharmaceutical composition for oral administration comprising the same

United States Patent:  6,346,533

Assignee:  Dong-A Pharmaceutical Co., Ltd. (Seoul, KR)

Filed:  December 14, 1999

PCT NO:  PCT/KR98/00164

102(e) Date:  December 14, 1999

PCT PUB. Date:  December 23, 1998

Foreign Application Priority Data:  Jun 16, 1997[KR] (97-24938)

The particle diameter of itraconazole, insoluble drug, is reduced and crystallinity thereof is changed from crystalline into amorphous, increasing water solubility and a dissolution rate thereof. The improved itraconazole is applied to an oral adminstration drug.

DETAILED DESCRIPTION OF THE INVENTION

For absorbing a solid drug into a systemic circulation via epithelial cells, the solid drug should be soluble in water. Because a water-insoluble drug is slowly dissolved from a solid formulation, the drug dissolution step is rate-limiting step in absorbing the drug. Thus, the potency of the drug and on set time, the potency duration time depend on the dissolution rate of the drug.

The concentration of a drug in blood depends on the absorption and elimination rates thereof. Therefore, as the dissolution rate of the drug decreases, the absorption rate of the drug is reduced. As a result, although the total amount of drug absorbed into a human body is constant, time for reaching effective concentration thereof in blood is getting longer and maximum concentration thereof in blood decreases. Therefore, bioavailability and solubility of water-insoluble drugs decreases.

In order to solve these disadvantages and increase bioavailability and solubility, it is required to increase the dissolution rate of the water-insoluble drugs. For that purpose, particle size of the drug is reduced, or polymorphism, complex form, amorphous form, solid solution, co-melting mixture, conjugated compound, solvated compound of the drug and general drug additives are used.

The present invention provides an improved itraconazole having reduced particle size and modified crystalline characteristics from crystalline into amorphous. The improved itraconazole exhibits good water solubility, thereby increasing the bioavailability.

A method of preparing the improved itraconazole will be now illustrated in more detail.

Itraconazole is dissolved in an organic solvent and dissolution-induced dried to obtain powder of itraconazole. An amount of itraconazole in the organic solvent is 2 to 6 wt % and preferably, 4 wt %. It is preferred that the organic solvent is methylene chloride which is a good solvent for itraconazole. The dissolution-induced drying step is performed with a spray drier, a centrifugal granulator or fluid-bed granulator. In the dissolution-induced drying step, a carrier, for example, lactose or other pharmaceutical excipients may be used. The pharmaceutical excipients may be include a binder, a disintergrant, an agent for increasing viscosity, a lubricant, a stabilizer, a surfactant, a preservative, an electrolyte, a composite and a complex compound or another active material.

In the preparing step, it is important to control a dissolution-induced drying rate. If dissolution-induced drying rate is extremely slow, the solvent is too fast evaporated so that a large amount of drug is loss. Contrarily, if dissolution-induced drying rate is fast, microparticles are entangled with another, prior to evaporation, enlarging the particle size. It is preferred that the dissolution-induced drying rate is controlled to be slow initially and then controlled to gradually increase.

The particle size depends on an atomizing air pressure as well as the dissolution-induced drying rate. Low atomizing air pressure results in the formulation of larger droplets and increased tendency toward agglomeration. High atomizing air pressure could conceivably carry the risk of dissolution-induced drying of the drug solution, but this was found not to be a problem. Consequently, atomizing air pressure may be set at nearly maximum level.

The physical changes of itraconazole may be confirmed by differential scanning calorimeter (DSC) and x-ray crystallography.

Itraconazole prepared by method of the present invention has a particle diameter of about 0.5 to about 10 .mu.m and an average particle diameter of about 3.7 .mu.m. The itraconazole may include a trace of particles with diameter of below 0.5 .mu.m.

The itraconazole of the present invention may be used as an active ingredient for a pharmaceutical composition for oral administration.

The pharmaceutical composition further includes vehicle such as lactose as carrier, or other pharmaceutical excipients.

The pharmaceutical excipients may be include a binder, a disintegrant, an agent for increasing viscosity, a lubricant, a stabilizer, a surfactant, a preservative, an electrolyte, a composite and a complex compound or another active material.

Itraconazole of the present invention is applied to various types of a drug for oral administration. The various type of the drug are a tablet, a capsule, a granule and a fine-granule. One tablet or one capsule may include 50 mg to 100 mg of itraconazole.

Claim 1 of 7 Claims

What is claimed is:

1. A method of preparing itraconazole in an amorphous form, comprising the steps of:

dissolving itraconazole in an organic solvent; and

dissolution-induced drying the mixture with a spray drier, fluid-bed granulator, or a centrifugal granulator, at a drying rate controlled to be slow initially and then gradually increase, under high atomizing air pressure to obtain itraconazole in an amorphous form exhibiting an improved bioavailability, and having a particle diameter of 0.5 to 10 .mu.m.

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