Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-06-27
2003-12-16
Venkat, Jyothsna (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S456000, C424S461000, C424S490000, C427S213000
Reexamination Certificate
active
06663901
ABSTRACT:
The present invention is concerned with novel pellets of itraconazole, a process for preparing said pellets, and oral dosage forms comprising a therapeutically effective amount of such pellets.
The development of efficaceous pharmaceutical compositions of azole antifungals such as itraconazole is hampered considerably by the fact that said antifungals are only very sparingly soluble in water. The solubility and bioavailability of said compounds can be increased by complexation with cyclodextrins or derivatives thereof as described in WO-85/02767 and U.S. Pat. No. 4,764,604.
In WO-94/05263, published on Mar. 17, 1994, there are disclosed beads having a 25-30 mesh sugar core (600-710 &mgr;m) coated with an azole antifungal, more particularly itraconazole (or saperconazole), and a polymer, more particularly, hydroxypropyl methylcellulose. Finished with a sealing film coat, such drug coated cores are referred to as beads. About 460 mg beads, equivalent to about 100 mg itraconazole, are filled into a hard-gelatin capsule (size 0) suitable for oral administration. The capsules are commercially available in many countries under the Trademark Sporanox™. The azole antifungal is easily released from the surface of the coated beads, which leads to improved bioavailability over previously known oral dosage forms of azole antifungals.
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 appropriate amounts of the antifungal agent and a hydrophilic polymer, preferably hydroxypropyl methylcellulose (HPMC), into a suitable solvent system. 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. Further, this technique requires the adequate resolution of 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 may remain in the drug-coated intermediate product, a drying step in vacuo is required. Subsequently, a seal coating is applied to the dried drug coated cores.
WO-94/05263 explains that the size of the cores is of considerable importance. On the one hand, if the cores are too large, there is less surface area available for applying the drug coating layer, which results in thicker coating layers. This raises problems in the manufacturing process as an intensive drying step is needed to reduce residual solvent levels in the coating layer. The intense drying conditions may adversely affect drug dissolution from the pellets and should therefore be controlled extremely well during the manufacturing process. On the other hand, small cores have a larger total surface available for coating resulting in thinner coating layers. Consequently a far less intensive drying step can be used to decrease residual solvents levels. Cores which were too small, e.g. 500-600 &mgr;m (30-35 mesh) cores, however, had the disadvantage of showing considerable tendency to agglomerate during the coating process. Therefore, it was concluded that 600-710 &mgr;m (25-30 mesh) cores represented the optimum size where neither agglomeration nor an intensive drying step constrained the process.
It would be highly desirable to have access to pharmaceutical dosage forms comprising drug coated cores wherein the cores are relatively large, 710-1180 &mgr;m (25-16 mesh), in particular 710-1000 &mgr;m (25-18 mesh) and especially 710-850 &mgr;m (25-20 mesh), and wherein the residual solvent levels in said drug coated cores are within the limits set out by the International Conference on Harmonisation (ICH) [ICH Topic Q3C Impurities.: Residual Solvents (CPMP/ICH/283/95) in force as of March 1998]. Therein, dichloromethane and methanol are both considered to be Class 2 solvents whose presence in pharmaceutical products should be limited; their respective Permitted Daily Exposure (PDE) is 6 mg/day and 30 mg/day; their respective concentration limits in pharmaceutical dosage forms are 600 ppm and 3000 ppm.
As mentioned previously, attaining these low residual solvent levels in beads with a relatively large core and a relatively thick drug/polymer coating layer is difficult. As the drug coat grows thicker, it takes longer for the residual solvent to diffuse outwardly. The rate of diffusion of a solute being proportional to its concentration gradient, it follows that lowering pressure should help to reduce the residual solvent levels.
However, the lower pressure at the same time dimishes the efficiency of heat transfer to the drug coated beads when conventional heating techniques are used, and thus, the evaporation of the residual solvents is slowed down. The present invention provides a method of efficiently conveying heat to the drug coated cores in a low pressure environment, thus enabling one to obtain drug coated cores that satisfy the above-mentioned guidelines issued by ICH. The method for the first time allows one to obtain relatively large beads complying with the newest international limits on residual solvents in pharmaceutical products.
Itraconazole or (±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-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 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 of its stereoisomers. The preferred itraconazole compound is the (±)-(cis) form of the free base form. 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-hydroxy-propanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxy-butanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
It may be remarked that th
De Conde Valentin Florent Victor
Gilis Paul Marie Victor
Vandecruys Roger Petrus Gerebern
Janssen Pharmaceutical N.V.
Venkat Jyothsna
Woodcock & Washburn LLP
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