Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-11-19
2003-01-21
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S474000, C424S475000, C514S254070
Reexamination Certificate
active
06509038
ABSTRACT:
The present invention is concerned with novel pharmaceutical compositions of itraconazole which can be administered to a mammal suffering from a fungal infection, whereby a single such dosage form can be administered once daily, and in addition at any time of the day independently of the food taken in by said mammal. These novel compositions comprise innovative particles obtainable by melt-extruding a mixture comprising itraconazole and an appropriate water-soluble polymer and subsequently milling said melt-extruded mixture.
The development of pharmaceutical compositions having good bioavailability of itraconazole, a compound that is practically insoluble in aqueous media, remains one of the main challenges of pharmaceutical development of this compound.
The term “practically insoluble” or “insoluble” is to be understood as defined in the United States Pharmacopeia, i.e. a “very slightly soluble” compound requiring from 1000 to 10,000 parts of solvent for 1 part of solute; a “practically insoluble” or “insoluble” compound requiring more than 10,000 parts of solvent for 1 part of solute. The solvent referred to herein is water.
Itraconazole or (±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1yl-methyl)-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 broadspectrum antifungal compound developed for oral, parenteral and topical use and is disclosed in U.S. Pat. No. 4,267,179. Its difluoro analog, saperconazole or (±)-cis-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methoxypropyl)-3H-1,2,4-triazol-3-one, has improved activity against Aspergillus spp. and is disclosed in U.S. Pat. No. 4,916,134. Both itraconazole and saperconazole consist of a mixture of four diastereoisomers, the preparation and utility of which is disclosed in WO 93/19061: the diastereoisomers of itraconazole and saperconazole are designated [2R-[2&agr;,4&agr;,4(R*)]], [2R-[2&agr;,4&agr;,4(S*)]], [2S-[2&agr;,4&agr;,4(S*)]] and [2S-[2&agr;,4&agr;,4(R*)]]. The term “itraconazole” as used hereinafter 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 or four of its stereoisomers. The preferred itraconazole compound is the (±)-(2R* , 4S*) or (cis) forms of the free base form, having the Chemical Abstracts Registry Number [84625-61-6]. 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 organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
In WO 94/05263, published on Mar. 17, 1994, there are disclosed beads or pellets having a 25-30 mesh sugar core (600-710 &mgr;m) coated with an antifungal, more particularly itraconazole (or saperconazole) and a hydrophilic polymer, more particularly, hydroxypropyl methylcellulose. Finished with a sealing film coat, such cores are referred to as beads or pellets. The beads are filled into capsules suitable for oral administration. The itraconazole is present in the drug-coating and is released readily from the surface of said coated beads, which leads to improved bioavailability of itraconazole (or saperconazole) over the then known oral dosage forms of itraconazole.
The preparation of coated beads as described in WO 94/05263 requires special techniques and special equipment in a purpose-built plant. Indeed, the beads described in the prior art are prepared in a quite complex manner requiring a lot of manipulation steps. First, a drug coating solution is prepared by dissolving into a suitable solvent system appropriate amounts of the antifungal agent and a hydrophilic polymer, preferably hydroxypropyl methylcellulose (HPMC). A suitable solvent system comprises a mixture of methylene chloride and an alcohol. Said mixture should comprise at least 50% by weight of methylene chloride acting as a solvent for the drug substance. As hydroxypropyl methylcellulose does not dissolve completely in methylene chloride, at least 10% alcohol has to be added. Subsequently, the 25-30 mesh sugar cores are drug-coated in a fluidized bed granulator equipped with a bottom spray insert. Not only should the spraying rate be regulated carefully, but also temperature control in the fluidized bed granulator is crucial. Hence, this process requires a lot of control in order to obtain a good quality product reproducibly. Moreover, this technique adequately, but still only partially solves the issue of residual organic solvents, such as methylene chloride and methanol or ethanol being present in the coating. In order to remove any solvents which might remain in the drug-coated intermediate product, an extra drying step is required. Subsequently a seal coating is applied and this adds yet another two steps to the production process as it involves another drying step, too.
About 460 mg beads, equivalent to about 100 mg itraconazole, are filled into a hard-gelatin capsule (size 0) and two of these capsules are administered once daily to a patient suffering from a fungal infection. The capsules are commercially available in many countries under the Trademark Sporanox™. In order to achieve the desired antifungal effect, it is essential that the two capsules are ingested at the end of a meal. This may seriously limit how easily the patients can comply with their prescribed therapy; for example, some patients are not able to eat normally or swallow medica-ments easily because of illness, nausea or because of fungal infection of the esophagus. It would therefore be highly desirable to have pharmaceutical dosage forms which can be administered to a patient—or for that matter, to any mammal—at any time of the day independently of food taken in, i.e. dosage forms which can be administered to patients (mammals) in a fasted state. Dosage forms with a high drug content, one unit of which contains the required daily dose of the active ingredient instead of two such units, are another desirable goal in the pharmaceutical development of itraconazole.
At this stage, it may be remarked that therapeutically effective plasma levels of itraconazole can be maintained easily for at least 24 hours as its half-life is sufficiently long. The condition is that the itraconazole must reach the plasma. The absorption of dissolved itraconazole from the stomach is in itself not a problem. Thus, there is no need for a sustained release dosage form of itraconazole, an immediate release form will do just as well. In other words, the main problem with the administration of itraconazole in therapeutically effective amounts is in the first place concerned with ensuring that a sufficient amount of itraconazole remains in solution sufficiently long enough to allow it to get into the circulation, and that it does not convert into a form that is not readily bioavailable, in particular into crystalline itraconazole (which forms, for example, when itraconazole precipitates in an aqueous medium).
The present invention provides pharmaceutical compositions of itraconazole and a water-soluble polymer which can be administered to a mammal, in particular a human, suffering from a fungal infection, whereby a single such dosage form can be administered on
Baert Lieven Elvire Colette
Thoné Dany
Verreck Geert
Janssen Pharmaceutica N.V.
Travers Russell
Wang Shengjun
Woodcock & Washburn LLP
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