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2 12/ 35 74Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 22 March 2012 (22.03.2012) 2 12/ 35 74 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/16 (2006.01) A61K 9/51 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 9/14 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP201 1/065959 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 14 September 201 1 (14.09.201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/382,653 14 September 2010 (14.09.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, NANOLOGICA AB [SE/SE]; P.O Box 8182, S-104 20 ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Stockholm (SE). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, (72) Inventors; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (75) Inventors/ Applicants (for US only): ZHOU, Chunfang SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, [CN/SE]; Frejgatan 22, S-11349 Stockholm (SE). XIA, GW, ML, MR, NE, SN, TD, TG). Xin [CN/SE]; Gubbkarrsvagen 21-09b, S-16840 Bromma (SE). GARCIA-BENNETT, Alfonso, E. [SE/SE]; War- Declarations under Rule 4.17 : gentinsgatan 6, S-l 1229 Stockholm (SE). — of inventorship (Rule 4.1 7(iv)) (74) Agents: GIAVARINI, Francesco et al; Zanoli & Gi- Published: avarini S.R.L, Via Melchiorre Gioia, 64, 1-20125 Milano (ΓΓ). — with international search report (Art. 21(3)) (54) Title: SUPER-SATURATING DELIVERY VEHICLES FOR POORLY WATER-SOLUBLE PHARMACEUTICAL AND COSMETIC ACTIVE INGREDIENTS 250 300 250 300 250 300 250 300 o Wavelength (nm) © Figure 1 © (57) Abstract: A pharmaceutical or cosmetic composition, comprising: a substantially poorly water-soluble pharmaceutical active ingredient; and a nanoporous folic acid material, wherein the active pharmaceutical ingredient is incorporated inside the Q nanoporous channels of the particles. SUPER- SATURATING DELIVERY VEHICLES FOR POORLY WATER-SOLUBLE PHARMACEUTICAL AND COSMETIC ACTIVE INGREDIENTS DESCRIPTION Field of the invention The present invention relates to a super-saturating drug delivery system which comprises nanoporous materials and poorly water-soluble bioactive pharmaceutical compounds, capable of functioning even in the presence of proton pump inhibitors. Wet impregnation techniques, rotary evaporation techniques, co-spray drying technique or freeze-drying techniques can be applied to prepare the super-saturating delivery system. The mechanism of enhancement of dissolution is based on nano-confinement of the poorly soluble pharmaceutical active material within an ordered porous material via suppression of crystallization. Background of the invention More than one third of the drugs listed in the US Pharmacopoeia and up to 40% new chemical entities discovered by pharmaceutical industry are poorly soluble or lipophilic compounds. The solubility of active pharmaceutical ingredients (APIs) is one of the most challenging issues in the improvement of many existing pharmaceutical formulations or the development of new chemical entities for commercialization, because the maximum achievable intraluminal drug concentration will limit the drug adsorption and bioavailability. Furthermore, improvements in bioavailability of APIs can yield to reduction in toxic secondary effects due to the use of less active, improvements in patient comfort due to the possibility of administering drugs without decreases in gastrointestinal pH, and improvements in patient compliance through a reduction of the number of doses required to achieve an adequate therapeutic level of the API. Therefore, the configuration of supersaturating drug delivery systems is a promising concept to obtain adequate oral bioavailability and improve overall pharmacokinetic properties. Additionally reduction in compound dose through better pharmacokinetic properties directly yields a reduction in costs of treatment. Much effort has been made to enhance the solubility of the poorly soluble drugs to increase the adsorption and bioavailability. One most common method is to reduce the drug particle size to increase surface area and curvature of particles which may improve the solubility and bioavailability of the drugs. The use of nanoparticles may further enhance the capacity to generate supersaturation [see: Matteucci ME,et al., Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Mol Pharm 4:782-793. (2007); Overhoff KA, et al. Effect of stabilizer on the maximum degree and extent of supersaturation and oral absorption of tacrolimus made by ultra-rapid freezing. Pharm Res 25:167-175. (2008)]. However, the nanoparticles with high surface energy are easily aggregated, more costly than porous particles described in the present invention and may possess additional toxicological profiles. The amorphous form of a drug has the highest apparent solubility, so amorphous-based dosage forms are a popular formulation strategy for poorly water-soluble drugs. Spray-drying of drug compounds has been somewhat successful in processing amorphous formulations of drug compounds. However, amorphous drugs are thermodynamically unstable and often lead to re-crystallization in the presence of small amounts of moisture. It is a major issue to avoid recrystallization during storage. Scientific and economic efforts have been made to avoid recrystallization of the drugs adding to the overall cost of treatments. One or more polymers (e.g., polyvinylpyrrolidone (PVP), polyethyleneglycols (PEG), polymethacrylates, cellulose derivatives, inulin, etc.) and/or (polymeric) surfactants (e.g., Inutecl SP1, Gelucirel, poloxamer 407, etc.) have been used to disperse amorphous drug particles [see: Serajuddin AT. Solid dispersion of poorly water-soluble drugs: Early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 88:1058-1066; Leuner C, Dressman J . Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm 50:47-60. (2000); Vasconcelos T, et al. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today 12:1068-1075 (2007)]. However, the incorporation of surfactants in formulation of poorly water-soluble drugs may cause irritation and side effects after oral administration in some cases, and they are liable to additional stability issues. Recently, ordered nano (meso-)porous materials (e.g. silica) have been studied as carrier for the delivery of poorly water-soluble drugs [see: Salonen J, et al. Mesoporous silicon microparticles for oral drug delivery: Loading and release of five model drugs. J Control Release 108:362-374 (2005); Kaukonen AM, et al. Enhanced in vitro permeation of furosemide loaded into thermally carbonized mesoporous silicon (TCPSi) microparticles. Eur J Pharm Biopharm 66:348-356 (2007); Shen S.C. Mesoporous materials excipients for poorly aqueous soluble ingredients, International Publication Number WO 2010/050897 Al]. Ordered nanoporous materials exhibits a 2-dimensionally or 3-dimensional ordered array of cylindrical or cage type pores (in the range of 2-50nm) separated by thin silica walls. Bioactive drugs can be molecularly dispersed in these pores up to a certain loading (ca. 10- 50% by weight). The influx diffusion of water to the pore surfaces provides for a rapid release of poorly water-soluble drugs if the drug compound is loaded in an amorphous state. It has been shown that the release of the weak base itraconazole from mesoporous materials gave rise to supersaturation in simulated gastric fluid; a subsequent pH shift to simulated intestinal fluid caused only limited precipitation and supersaturated concentrations were maintained for at least 4 h [see: Mellaerts R, et al. Enhanced release of itraconazole from ordered mesoporous SBA-15 silica materials. Chem Commun 13:1375-1377 (2007); Mellaerts R, et al. Ordered mesoporous silica induces pH-independent supersaturation of the basic low solubility compound itraconazole resulting in enhanced transepithelial transport. Int J Pharm 357:169-179 (2008); Mellaerts R, et al. Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica. Eur J Pharm Biopharm 69:223-230 (2008)]. Ordered nanoporous materials have been attracting much attention because of the regular and adjustable pore size, different pore structures, high surface area and pore volume, high concentrations of silanol groups which make the channels like wet environment. Much work has been made to enhance the solubility of poorly water-soluble drugs on SBA-15 with the bigger pore size. Herein the present invention discloses methods that provide for enhancements in poorly water-soluble drugs loaded in the mesoporous material with the smaller pore size showing higher apparent solubility, where additionally 2d-hexagonal pore structure show improvements over 3d-cubic pore structures. In addition, the super-saturating state produced from the nanoporous materials with smaller pore size could maintain longer time than the samples with bigger pore size. Therefore, it is necessary to apply the mesoporous materials with the smaller pore size and 2-D pore structure to deliver poorly water-soluble drugs. Recently, one mesoporous materials named nanoporous folic acid materials ( M-1) have been developed by using the folic acid as template [see: Garcia-Bennett A.E.
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