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Preparation and Evaluation of Paclitaxel Solid Dispersion by Supercritical Antisolvent Process

초임계유체를 이용한 파클리탁셀고체분산체의 제조 및 평가

  • Published : 2008.08.20

Abstract

Paclitaxel is a taxane diterpene amide, which was first extracted from the stem bark of the western yew, Taxus brevifolia. This natural product has proven to be useful in the treatment of a variety of human neoplastic disorders, including ovarian cancer, breast and lung cancer. Paclitaxel is a highly hydrophobic drug that is poorly soluble in water. It is mainly given by intravenous administration. Therefore, The pharmaceutical formulation of paclitaxel ($Taxol^{(R)}$; Bristol-Myers Squibb) contains 50% $Cremophor^{(R)}$ EL and 50% dehydrated ethanol. However the ethanol/Cremophor EL vehicle required to solubilize paclitaxel in $Taxol^{(R)}$ has a pharmacological and pharmaceutical problems. To overcome these problems, new formulations for paclitaxel that do not require solubilization by $Cremophor^{(R)}$ EL are currently being developed. Therefore this study utilized a supercritical fluid antisolvent (SAS) process for cremophor-free formulation. To select hydrophilic polymers that require solubilization for paclitaxel, we evaluated polymers and the ratio of paclitaxel/polymers. HP-${\beta}$-CD was used as a hydrophilic polymer in the preparation of the paclitaxel solid dispersion. Although solubility of paclitaxel by polymers was increased, physical stability of solution after paclitaxel/polymer powder soluble in saline was unstable. To overcome this problem, we investigated the use of surfactants. At 1/20/40 of paclitaxel/hydrophilic polymer/ surfactant weight ratio, about 10 mg/mL of paclitaxel can be solubilized in this system. Compared with the solubility of paclitaxel in water ($1\;{\mu}g/mL$), the paclitaxel solid dispersion prepared by SAS process increased the solubility of paclitaxel by near 10,000 folds. The physicochemical properties was also evaluated. The particle size distribution, melting point and amophorization and shape of the powder particles were fully characterized by particle size distribution analyzer, DSC, SEM and XRD. In summary, through the SAS process, uniform nano-scale paclitaxel solid dispersion powders were obtained with excellent results compared with $Taxol^{(R)}$ for the physicochemical properties, solubility and pharmacokinetic behavior.

References

  1. C. Spencer and D. Faulos, Paclitaxel ; A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of Cancer, Drugs, 48, 794-847 (1994) https://doi.org/10.2165/00003495-199448050-00009
  2. A. Mathew, M.R. Mejillano, J.P. Nath, R.H. Himes and V.J. Stella, Sythesis and evauation of same water soulble prodrugs and derivates of taxol with antitumer activity, J. Med. Chem., 35, 145-151 (1992) https://doi.org/10.1021/jm00079a019
  3. M. Schimitt Sody, S. Krasnici, B. Sauer, B. Schulze, M. Teifel, U. Michaelis, K. Maujoks and M. Dellian, Neovascular targeting therapy : paclitaxel encapsulated in cationic liposome improves antitumoral efficacy, Clin. Cancer Res., 6, 2335-2341 (2003)
  4. S.C. Kim, D.W. Kim, Y.H. Shin, J.S. Bang, H.S. Oh and S.W. Kim, In vivo evaluation of polytaxel formulation : toxicity and efficacy, J. Control. Release, 72, 191-202 (2001) https://doi.org/10.1016/S0168-3659(01)00275-9
  5. B.B. Lundberg, V. Risovic, M. Ramaswamy and K.M. Wasan, A lipophilic paclitaxel derivate incorporated in a lipid emulsion for parenteral administration, J. Control. Release, 86, 93-100 (2003) https://doi.org/10.1016/S0168-3659(02)00323-1
  6. A.O. Nornoo, D.W. Osborne and D.S. Chow, Cremophorfree intravenous microemulsion for paclitaxel I: Formulation, cytotoxicity and hemolysis, 349, 108-116 (2008) https://doi.org/10.1016/j.ijpharm.2007.07.042
  7. S. Alcaro, C.A. Ventura, D. Paolino, D. Battaglia, F. Ortuso, L. Cattel, G. Puglisi and M. Fresta, Preparation, characterization, molecular modeling and in vitro activity of paclitaxel-cyclodextrin complexes, Bioorg. Med. Chem. Letto, 12, 1637-1641 (2002) https://doi.org/10.1016/S0960-894X(02)00217-2
  8. M.K. Lee, S.J. Lim and C.K. Kim, Preparation, characterization and in vitro cytotoxicity of paclitaxel loaded sterically stabilized solid lipid nanoparticles, Biomaterials, 28, 2137-2146 (2007) https://doi.org/10.1016/j.biomaterials.2007.01.014
  9. Kang Y, Wu J, Yin G, Huang Z, Liao X, Yao Y, Ouyang P, Wang H and Yang Q. Characterization and biological evaluation of paclitaxel-loaded poly(l-lactic acid) microparticles prepared by supercritical CO2, Langmuir, 24, 7432-7441 (2008) https://doi.org/10.1021/la703900k
  10. Kang Y, Yin G, Ouyang P, Huang Z, Yao Y, Liao X, Chen A and Pu X. Preparation of PLLA/PLGA microparticles using solution enhanced dispersion by supercritical fluids (SEDS), J Colloid Interface Sci., 322, 87-94 (2008) https://doi.org/10.1016/j.jcis.2008.02.031
  11. Lee LY, Wang CH and Smith KA, Supercritical antisolvent production of biodegradable micro- and nanoparticles for controlled delivery of paclitaxel, J Colloid Release., 125, 96- 106 (2008) https://doi.org/10.1016/j.jconrel.2007.10.002
  12. S. Palakodaty and York, P. Phase, Behavioral effects on particle formation processes using supercritical fluids, Pharm, Res., 16, 976-985 (1997)
  13. Kim MS, Kwon YJ, Lee S, Lee TW and Hwang SJ, Preparation and Evaluation of Paclitaxel Nano- and Microparticle by Supercritical Antisolvent Precipitation Process, CRS 2004 Annual Meeting, 31st Annual Meeting & Exposition, June 12-16, 2004, Honolulu, Hawaii, United States of America
  14. S.D. Yeo, P.G. Debendetti, S.Y. Patro and T.M. Przybycien, Secondary structure characterization of microparticulate insulin powders, J. Pharm. Sci., 83, 1651-1656 (1994) https://doi.org/10.1002/jps.2600831203
  15. N. Elvassore, M. Baggio, P. Pallado and A. Bertucco, Production of different morphologies of biocompatible polymeric materials by supercritical $CO_2$ antisolvent technologies, Biotechnol. Bioeng., 73, 449-457 (2001) https://doi.org/10.1002/bit.1079
  16. P.M. Gallagher, M.P. Coffey, V.J. Krukonis and N. Klasutis, GAS antisolvent recrystallization :new process to recrystallize compounds in soluble and supercritical fluids, Am. Chem. Sypm. Ser., No 406 (1993)
  17. J.W. Tom and P.G. Debenedetti, Particle Formulation with Supercritical fluids-A Review, J. Aerosol. Sci., 22(5), 555-5 (1991) https://doi.org/10.1016/0021-8502(91)90013-8
  18. D.H. Won, M.S. Kim, S.B. Lee, J.S. Park and S.J. Hwang, Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process, Int. J. Pharm., 301, 199-208 (2005) https://doi.org/10.1016/j.ijpharm.2005.05.017
  19. Q. Xu, B. Han and H. Yan, Precipitation polymerization of methyl methacrylate in tetrahydrofuran with compressed CO2 as antisolvent, J. Appl. Polym. Sci., 8, 2427-2433 (2003)
  20. S.D. Yeo, G.B. Lim, P.G. Debenedetti and H. Bernstein, Formation of microparticulate protein powders using a supercritical fluid antisolvent, Biotechnol. Bioeng., 41, 341- 346 (1993) https://doi.org/10.1002/bit.260410308