Development, Production And Characterization Of Nanocrystals Of Poorly Soluble Drugs [desenvolvimento, Produção E Caracterização De Nanocristais De Fármacos Pouco Solúveis]

Poorly soluble drugs have low bioavailability, representing a major challenge for the pharmaceutical industry. Processing drugs into the nanosized range changes their physical properties, and these are being used in pharmaceutics to develop innovative formulations known as Nanocrystals. Use of nanocrystals to overcome the problem of low bioavailability, and their production using different techniques such as microfluidization or high pressure homogenization, was reviewed in this paper. Examples of drugs, cosmetics and nutraceutical ingredients were also discussed. These technologies are well established in the pharmaceutical industry and are approved by the Food and Drug Administration.35918481853Durán, N., Durán, M., Tasic, L., Marcato, P., (2010) Quim. Nova, 33, p. 151Merisko-Liversidge, E.M., Liversidge, G.G., (2008) Toxicol. Pathol., 36, p. 43Junghanns, J.U., Müller, R.H., (2008) Int. J. Nanomedicine, 3, p. 295Miao, X., Sun, C., Jiang, T., Zheng, L., Wang, T., Wang, S., (2011) J. Pharm. Sci., 14, p. 196Sun, W., Mao, S., Shi, Y., Li, L.C., Fang, L., (2011) J. Pharm. Sci., 100, p. 3365Sylvestre, J.P., Tang, M.C., Furtos, A., Leclair, G., Meunier, M., Leroux, J.C., (2011) J. Control. Release, 149, p. 273Deng, J., Huang, L., Liu, F., (2010) Int. J. Pharm., 390, p. 242Ning, X., Sun, J., Han, X., Wu, Y., Yan, Z., Han, J., He, Z., (2011) Drug Dev. Ind. Pharm., 37, p. 727Lou, H., Zhang, X., Gao, L., Feng, F., Wang, J., Wei, X., Yu, Z., Zhang, Q., (2009) Int. J. Pharm., 379, p. 181Sigfridsson, K., Lundqvist, A.J., Strimfors, M., (2009) Drug Dev. Ind. Pharm., 35, p. 1479Ganta, S., Paxton, J.W., Baguley, B.C., Garg, S., (2009) Int. J. Pharm., 367, p. 179Rabinow, B., Kipp, J., Papadopoulos, P., Wong, J., Glosson, J., Gass, J., Sun, C.S., Wood, K., (2007) Int. J. Pharm., 339, p. 251Rabinow, B., (2005) Discov. Med., 5, p. 74Marques, I., Lopes, C.M., Souto, E.B., (2009) Rev. Facul. Ciências da Saúde, 6, p. 60Müller, R. H.Becker, R.Kruss, B.Peters, K.U.P. 5858410, 1999Shegokar, R., Müller, R.H., (2011) Int. J. Pharm., 399, p. 129Müller, R.H., Gohla, S., Keck, C.M., (2011) Eur. J. Pharm. Biopharm., 78, p. 1Möschwitzer, J., Müller, R.H., (2004) International Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, , Nürnberg, GermanyVerma, S., Lan, Y., Gokhale, R., Burgess, D.J., (2009) Int. J. Pharm., 377, p. 185Keck, C.M., Müller, R.H., (2006) Eur. J. Pharm. Biopharm., 62, p. 3Chen, H., Khemtong, C., Yang, X., Chang, X., Gao, J., (2010) Drug Discov. Today, 16, p. 354Gülsün, T., Gürsoy, R.N., Öner, L., (2009) J. Pharm. Sci., 34, p. 55Xia, D., Cui, F., Piao, H., Cun, D., Piao, H., Jiang, Y., Ouyang, M., Quan, P., (2010) Pharm. Res., 27, p. 1965Petersen R. D.PCT/EP2007/009943, 2006Gao, Y., Li, Z., Sun, M., Guo, C., Yu, A., Xi, Y., Cui, J., Zhai, G., (2011) Drug Deliv, 18, p. 131Lou, H., Gao, L., Wei, X., Zhang, Z., Zheng, D., Zhang, D., Zhang, X., Zhang, Q., (2011) Colloids Surf. B, 87, p. 319Sahoo, N.G., Kakran, M., Shaal, L.A., Li, L., Müller, R.H., Pal, M., Tan, L.P., (2011) J. Pharm. Sci., 100, p. 2379Benita, S., Levy, M.Y., (1993) J. Pharm. Sci., 82, p. 1069Müller, R.H., Jacobs, C., Kayser, O., (2003) Em DissoCubes-A Novel Formulation for Poorly Soluble and Poorly Bioavailable Drugs;, , Rathbone M. J.Hadgraft, J.Roberts M. S., eds.Marcel Dekker: New YorkKuo, F., Subramanian, B., Kotyla, T., Wilson, T.A., Yoganathan, S., Nicolosi, R.J., (2008) Int. J. Pharm., 363, p. 206Muchow, M., Maincent, P., Müller, R.H., (2008) Drug Dev. Ind. Pharm., 34, p. 1394Wang, Y., Liu, Z., Zhang, D., Gao, X., Zhang, X., Duan, C., Jia, L., Zhang, Q., (2011) Colloids Surf. B, 83, p. 189Müller, R. H.Krause, K.Mäder, K.WO/2001/003670, 2001Martins, S., Tho, I., Ferreira, D.C., Souto, E.B., Brandl, M., (2011) Drug Dev. Ind. Pharm., 37, p. 815Teeranachaideekul, V., Junyaprasert, V.B., Souto, E.B., Müller, R.H., (2008) Int. J. Pharm., 354, p. 227Sahoo, N.G., Kakran, M., Shaal, L.A., Li, L., Müller, R.H., Pal, M., Tan, L.P., (2011) J. Pharm. Sci., 100, p. 2379Buttle, I.Dissertation, Freie Universität, Berlin, 2004Kipp, J. E. W.Joseph, C. T.Doty, M. J.Rebbeck, C. L.U.P. 6869617, 2001Bawa, R., (2010) Eur. J. Nanomedicine, 3, p. 34Merisko-Liversidge, E., Liversidge, G.G., Cooper, E.R., (2003) Eur. J. Pharm. Sci., 18, p. 113Shegokar, R., Singh, K.K., Müller, R.H., (2011) Int. J. Pharm., 416, p. 461Al Shaal, L., Müller, R.H., Shegokar, R., (2010) Pharmazie, 65, p. 877Han, X., Ghoroi, C., To, D., Chen, Y., Dave, R., (2011) Int. J. Pharm., 415, p. 185Gu, C.H., Grant, D.J., (2001) J. Pharm. Sci., 90, p. 1277Wang, Y., Li, X., Wang, L., Xu, Y., Cheng, X., Wei, P., (2011) Int. J. Nanomedicine, 6, p. 1497Li, W., Yang, Y., Tian, Y., Xu, X., Chen, Y., Mu, L., Zhang, Y., Fang, L., (2011) Int. J. Pharm., 408, p. 15

Ibuprofen nanocrystals developed by 22 factorial design experiment: A new approach for poorly water-soluble drugs

The reduction of the particle size of drugs of pharmaceutical interest down to the nano-sized range has dramatically changed their physicochemical properties. The greatest disadvantage of nanocrystals is their inherent instability, due to the risk of crystal growth. Thus, the selection of an appropriate stabilizer is crucial to obtain long-term physicochemically stable nanocrystals. High pressure homogenization has enormous advantages, including the possibility of scaling up, lack of organic solvents and the production of small particles diameter with low polydispersity index. The sequential use of high shear homogenization followed by high pressure homogenization, can modulate nanoparticles’ size for different administration routes. The present study focuses on the optimization of the production process of two formulations composed of different surfactants produced by High Shear Homogenization followed by hot High Pressure Homogenization. To build up the surface response charts, a 22 full factorial design experiment, based on 2 independent variables, was used to develop optimized formulations. The effects of the production process on the mean particle size and polydispersity index were evaluated. The best ibuprofen nanocrystal formulations were obtained using 0.20% Tween 80 and 1.20% PVP K30 (F1) and 0.20% Tween 80 and 1.20% Span 80 (F2). The estimation of the long-term stability of the aqueous suspensions of ibuprofen nanocrystals was studied using the LUMISizer. The calculated instability index suggests that F1 was more stable when stored at 4 °C and 22 °C, whereas F2 was shown to be more stable when freshly prepared. Keywords: Factorial design, Nanocrystals, High pressure homogenization, Physicochemical stability, Ibuprofen, Surfactant