US 2002O150616A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0150616A1 VANDECRUYS (43) Pub. Date: Oct. 17, 2002 (54) PHARMACEUTICAL COMPOSITIONS (86) PCT No.: PCT/EP98/03189 COMPRISING CYCLODEXTRINS (30) Foreign Application Priority Data (76) Inventor: ROGER PETRUS GEREBERN VANDECRUYS, WESTERLO (BE) Jun. 5, 1997 (GB)......................................... 97.11643.8 Correspondence Address: Publication Classification AUDLEY A CAMPORCERO ONE JOHNSON & JOHNSON PLAZA (51) Int. Cl." ....................................................... A61K 9/20 NEW BRUNSWICK, NJ 089337003 (52) U.S. Cl. ............................................ 424/464; 424/465 (*) Notice: This is a publication of a continued pros (57) ABSTRACT ecution application (CPA) filed under 37 CFR 1.53(d). The invention provides a novel pharmaceutical composition comprising a no more than Sparingly water-Soluble drug (21) Appl. No.: 09/445,297 compound, a cyclodextrin, a physiologically tolerable water Soluble acid, and a physiologically tolerable water-Soluble (22) PCT Filed: May 27, 1998 organic polymer. Patent Application Publication Oct. 17, 2002. Sheet 1 of 3 US 2002/0150616 A1 Figure 1 30 20 110 1 OO 8 O 12 Time, hours treatment (i) treatment (ii) treatment (iii) Patent Application Publication Oct. 17, 2002. Sheet 2 of 3 US 2002/0150616A1 Figure 2 3O 120 1 O 1 OO 90 8O 7O 60 5O 40 30 2O O Time, hours -A- treatment (i) -O- treatment (iv) -- treatment (v) Patent Application Publication Oct. 17, 2002 Sheet 3 of 3 US 2002/0150616A1 Figure 3 m formula 2CA) m m formula 20B) formula 2(C) US 2002/O150616 A1 Oct. 17, 2002 PHARMACEUTICAL COMPOSITIONS 0007 Thus viewed from one aspect the invention pro COMPRISING CYCLODEXTRINS vides a pharmaceutical composition comprising a no more than sparingly water-Soluble drug compound, a cyclodex 0001. This invention relates to novel pharmaceutical compositions, in particular compositions and dosage forms trin, a physiologically tolerable water-Soluble acid, and a providing improved drug release and uptake on administra physiologically tolerable water-Soluble organic polymer. tion into externally voiding body cavities (e.g. the gi tract) 0008 Viewed from a further aspect the invention pro or on topical administration, especially for acid Solubilized vides the use of a no more than sparingly water-Soluble drug drug compounds. compound, a cyclodextrin, a physiologically tolerable water 0002 Many drug compounds, while possessing desired Soluble acid, and a physiologically tolerable water-Soluble therapeutic properties, are used inefficiently due to their poor organic polymer for the manufacture of a pharmaceutical water Solubilities. Thus for example where Such compounds composition according to the invention for use in a method are administered orally, only a Small fraction of the drug is of therapy or diagnosis of the human or non-human animal taken up into the blood during transit of the gi tract. AS a (e.g. mammalian, reptilian or avian) body. result, to achieve adequate drug uptake it may be necessary 0009 Viewed from a still further aspect the invention to administer high doses of the drug compound, to prolong provides a method of therapy or diagnosis of the human or the period of drug administration or to make frequent non-human animal (e.g. mammalian, reptilian or avian) administrations of the drug compound. Indeed, the poor body which comprises administering to Said body a thera Solubility and hence poor bioavailability of a drug may peutically or diagnostically effective dose of a pharmaceu cause an alternative drug, perhaps one with undesired side tical composition, the improvement comprising using as Said effects or one which requires invasive administration (e.g. composition a composition according to the present inven by injection or infusion), to be used in place of the poorly tion. Soluble drug. 0010. The compositions of the invention may if desired 0003. One approach to poor solubility is to derivatise the be acqueous, but in general will preferably be Substantially drug molecule to introduce water Solubilizing groups, e.g. water-free, e.g. containing up to 3% by weight, preferably ionic groupS. Such as carboxyl groups or non-ionic groups less than 1% by weight water, and most preferably less than Such as polyhydroxyalkyl groups, So as to produce a more 0.5% water, but may be mixed with water immediately soluble derivative. This approach however is not always before administration or may be coated and dispersed in an Successful as it may not be possible to maintain adequately aqueous medium whereby the coating is only broken down high therapeutic efficacy and adequately low toxicity or after administration. Such acqueous compositions are deemed other Side effects. Thus one example of a poorly water to fall within the scope of the invention. Depending on the soluble drug which has not been Superseded by a solubilized Selection of components, the compositions of the invention derivative is the antifungal agentitraconazole. may be liquid, Solid or Semi-Solid-e.g. gel-like. Preferably the compositions are non-freeflowing at ambient tempera 0004 Attempts have therefore been made to enhance the ture (e.g. 21 C.), other than as free flowing particulates. uptake of drugs. Such as itraconazole by increasing the Thus the compositions at ambient temperature are preferably Surface area of the drug compound exposed to Saliva or gastric fluid, and hence promote dissolution of the drug Solids or Semi-Solids or, leSS preferably, highly viscous compound, by thinly coating the drug compound onto essen fluids. tially inert carrier particles, e.g. Sugar beads. This however 0011. In the compositions of the invention the drug has the drawback that the volume of solid composition compound, acid, cyclodextrin and organic polymer are inti required to administer a given quantity of the drug com mately admixed. pound is quite high Since the carrier contributes Significantly to the overall administration Volume. Since administration 0012. Thus where the composition is particulate, the acid, of large Volume capsules or tablets, or of large quantities of drug compound, cyclodextrin and organic polymer are Smaller Volume capsules or tablets, provides difficulties for mixed together within the particles (e.g. at the molecular level following solvent removal from a solution of these the patient, the drawbacks of this approach are obvious. components). Granulate mixtures where individual particles 0005 Yet another approach has been to administer the do not contain all four components, or have cores of one or drug compound in the form of a Solution of the drug more components coated with other components are not compound and a drug complexing agent Such as a cyclo preferred. This intimate admixture is important Since the dextrin. This approach has limitations also in that the dosage effects of the components are complimentary at the micro Volume is constrained by the Solubilizing power of the Scopic level during dissolution of the compositions of the complexing agent, readily unitized Solid dosage forms can invention. not be used, and there is no gradual release of the drug compound for biological uptake. 0013 Preferably, all components are dispersed so as to form a System that is chemically and physically uniform or 0006. However, we have now found that by combining homogenous throughout, or consists of one phase as defined Such drug compounds with a cyclo-dextrin, a water-Soluble in thermodynamics, Such a dispersion will be called a glass acid and a water-Soluble organic polymer, an administration thermoplastic phase or System hereinafter. The components form may be produced which Surprisingly improves the of the glass thermoplastic System are readily bioavalaible to biological uptake of the drug compound, in particular a form the organisms to which they are administered. This advan which can Surprisingly improve the time profile for the drug tage can probably be explained by the ease with which Said content of the plasma of the patient (i.e. the pharmacokinetic glass thermoplastic System can form liquid Solutions when profile defined by Such parameters as AUC, t lax C lax etc.). contacted with a body liquid Such as gastric juice. The ease US 2002/O150616 A1 Oct. 17, 2002 of dissolution may be attributed at least in part to the fact that ably is in the range of 0.125 to 3, in particular 0.3 to 2, more the energy required for dissolution of the components from particularly 0.3 to 1, and the MS is in the range of 0.125 to a glass thermoplastic System is less than that required for the 10, in particular 0.3 to 3 and more particularly 0.3 to 1.5. dissolution of components from a crystalline or microcryS 0020. Of particular utility in the present invention are the talline Solid phase. B-cyclodextrin ethers, e.g. dimethyl-3-cyclodextrin as 0.014. As the cyclodextrin in the compositions of the described in Drugs of the Future, Vol. 9, No. 8, p. 577-578 invention, there may be used any of the physiologically by M. Nogradi (1984) and polyethers, e.g. hydroxypropyl tolerable water-soluble substituted or unsubstituted cyclo B-cyclodextrin and hydroxyethyl-f-cyclodextrin. Such alkyl dextrins or physiologically tolerable derivatives thereof, e.g. ethers may for example be methyl ethers with a degree of Cl-, 3- or Y-cyclodextrins or derivatives thereof, in particular substitution of about 0.125 to 3, e.g. about 0.3 to 2. Such a derivatives wherein one or more of the hydroxy groups are hydroxypropyl cyclodextrin may for example be formed Substituted, e.g. by alkyl, hydroxyalkyl, carboxyalkyl, alky from the reaction between B-cyclodextrin and propylene lcarbonyl, carboxyalkoxyalkyl, alkylcarbonyloxyalkyl, oxide and may have a MS value of about 0.125 to 10, e.g. alkoxycarbonylalkyl or hydroxy-(mono or polyalkoxy)alkyl about 0.3 to 3. groups, wherein each alkyl or alkylene moiety preferably 0021 Especially suitable cyclodextrins are f3-CD, 2,6- contains up to six carbons.