Oral itraconazole formulations and methods of making the same

Details Oral itraconazole formulations and methods of making the same Oral itraconazole formulations and methods of making the same

2001-08-20

2003-12-16

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S489000, C424S497000, C424S502000, C424S494000, C424S495000, C424S464000, C424S465000, C424S451000, C424S456000, C424S439000

Reexamination Certificate

active

06663897

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns methods of making oral itraconazole formulations, the oral dosage forms so made, and methods of use thereof.
BACKGROUND OF THE INVENTION
Itraconazole (also known as (±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-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) is a triazole antifungal compound with a piperazine portion. See generally Merck Index Reg. No. 5262 (12
th
ed. 1996). Itraconazole is disclosed in U.S. Pat. No. 4,267,179 to Heeres et al.
Itraconazole has an extremely low solubility in water. Indeed, its water and 0.1 N Hydrochloric acid solubilities are less than 1 microgram and 6 micrograms per milliliter respectively. Its pKa value is 3.7 and it remains largely un-ionized in human gastric secretions. Itraconazole is a classic example of a class 4 compound—one with low solubility and low permeability—based on the Biopharmaceutics Classification System and considerable effort has been devoted to developing oral formulations of itraconazole.
PCT Application WO 94/05263 to Gillis et al. (assigned to Janssen Pharmaceutica) describes 25-30 mesh beads having a core coated with itraconazole or saperconazole, which beads may be used to produce dosage forms of these drugs. To prepare the beads, the drug coating solution is dissolved into a suitable solvent system which is then combined with the beads. However, the only solvent system described is one comprising methylene chloride and an alcohol (see page 4, line 4 therein).
PCT Application WO 98/42318 to Vandecruys et al., (assigned to Janssen Pharmaceutica) describes 30-60 mesh beads having a core coated with itraconazole or saperconazole, which beads may likewise be used to produce dosage forms of these drugs. To prepare the beads the drug coating solution is, again, dissolved into a suitable solvent system. Again the only solvent system described is one comprising methylene chloride and an alcohol, and it is stated that the methylene chloride should comprise at least 50% by weight of the solvent system (see page 8, lines 32-34 therein).
Itraconazole is currently available as an oral formulation as SPORANOX™ itraconazole capsules. The capsules contain 100 mg of itraconazole coated on sugar spheres. See generally Physician's Desk Reference, page 1457 (54th ed. 2000). These capsules are currently believed to contain residual levels of methylene chloride and original SPORANOX® capsules were reformulated (per Summary Basis of Approval of the product) to the USP limit for methylene chloride which is 500 micrograms per day. See, e.g. USP 24 NF19, pages 1877-1878. Current SPORANOX® technology produces a product having approx. 60% less bio-availability under fasted conditions. See generally Physician's Desk Reference.
PCT Application WO 00/56726 to Erkoboni et al. (assigned to FMC Corp.) takes a different approach from the foregoing. Erkoboni describes a “hot melt” technique in which a normally solid hydrophobic vehicle is melted to dissolve itraconazole therein, and then the molten product granulated to produce granular particles that may be milled to appropriate size for the preparation of solid dosage forms. Structurally, the granular particles are solid solutions of the active agent rather than coated particles. A problem with hot melt procedures is the potential for thermal degradation of the active ingredient at elevated temperatures during manufacture. Operation of the granulator at higher temperatures, rapid cooling of the granulate, and discharging hot granulate through liquid nitrogen as described in the above patent requires special equipment for handling in the pharmaceutical industry. Dissolution testing of the itraconazole granulates thus made has shown only 51% dissolution of the drug in 60 minutes and thus offers no advantage for making an immediate release dosage form.
Accordingly, there remains a need for new ways to produce intraconazole oral dosage forms that utilize coated particles, but do not require the use of methylene chloride during the manufacture thereof.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a method of manufacturing an itraconazole (or other water-soluble antifungal agent) oral dosage form that is substantially free of residual methylene chloride. The method comprises the steps of: (a) providing a working solution comprising or consisting essentially of an alcohol, a strong acid, itraconazole, a water-soluble polymer, and water, with the itraconazole and the strong acid preferably present in the working solution in a ratio of 1 Mole itraconazole to 1 or 1.2 to 2.5 or 3 Moles strong acid; (b) providing particles formed from a pharmaceutically acceptable core material; (c) combining the working solution with the particles to produce itraconazole-coated particles; (d) drying the itraconazole-coated particles; and (e) forming the dried itraconazole-coated particles into an itraconazole oral dosage form that is substantially free of residual methylene chloride (e.g., contains less than 200 ppm methylene chloride, less than 100 ppm methylene chloride, less than 50 ppm methylene chloride, less than 20 ppm methylene chloride, or even less than 10 ppm methylene chloride).
In one embodiment of the foregoing, the dried itraconazole-coated particles preferably comprise, by weight from 5 to 40 percent itraconazole; from 10 to 50 percent particle core material; and from 10 to 80 percent water-soluble polymer.
A second aspect of the present invention is a pharmaceutically acceptable particle comprising (a) a central rounded or spherical core comprised of a core material; and (b) a coating film formed on the core, the coating film comprising a water-soluble polymer and itraconazole. The particle preferably comprises, by weight, from 5 to 40 percent itraconazole; from 10 to 50 percent particle core material; and from 10 to 80 percent water-soluble polymer; and with the particle substantially free of methylene chloride (e.g., containing less than 200 ppm methylene chloride, less than 100 ppm methylene chloride, or even less than 50 ppm methylene chloride).
A third aspect of the present invention is an itraconazole oral dosage form that is substantially free of residual methylene chloride, the formulation comprising an effective antifungal amount of particles as described above. Typically, such a dosage form contains from 50 to 300 milligrams of itraconazole.
A further aspect of the present invention is a method of treating a fungal infection in a subject in need thereof, comprising orally administering to the subject an oral dosage form as described above in an antifungal-infective amount.
In a preferred embodiment of the foregoing, the stabilized formulation provides about ten fold increased solubility under pH 5.0 dissolution conditions and there by results in enhanced bio-availability of the active ingredient under fasted conditions. The in-situ salt formation of the active compound prevents its recrystallization from its acidic aqueous solutions.
The foregoing and other objects and aspects of the present invention is explained in greater detail in the specification set forth below.
Detailed Description of the Preferred Embodiments
Itraconazole as used herein is to be interpreted broadly and comprises the free base form and the pharmaceutically acceptable addition salts of itraconazole, or of one of its stereoisomers, or of a mixture of two or three of its stereoisomers. A preferred itraconazole compound is the (±)-(cis) form of the free base form and a mixture of four cis diastereo isomers. The acid addition forms may be obtained by reaction of the base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid and the like; or strong organic acids such as, for example, methanesulphonic, ethanesulphonic, benzenesulphonic, 4-methylben

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