Development and characterization of thermosensitive pluronic-based metronidazole in situ gelling formulations for vaginal application
The purpose of this study was to develop pluronic-based in situ gelling formulations of metronidazole (MTZ) for treatment of bacterial vaginosis, aimed at prolonging the residence time, controlling drug release, enhancing efficacy, decreasing recurrence, and increasing patient compliance. The in situ gel formulations were prepared using different concentrations of pluronic F-127 (PF-127) alone and in combination with pluronic F-68 (PF-68). The prepared formulations were evaluated for their gelation temperature (Tgel), in vitro drug release, rheological properties, mucoadhesion properties and tolerability by vaginal mucosa in tissue levels. The Tgel decreased with increasing PF-127 concentration. The Tgel was modulated by addition of PF-68 to be within the acceptable range of 25-37 °C. With increasing pluronic concentration, the in vitro drug release decreased, viscosity and mucoadhesive force increased. Histopathological examination of rabbit vaginas from the control and treated groups revealed normal histology of the vagina and cervix. Based on the in vitro evaluation of prepared formulations, the in situ gelling liquid formulated with PF-127/PF-68 (20/10 %, m/m) was selected for further clinical evaluation.
J. Y. Chang, Y.-K. Oh, H. G. Choi, Y. B. Kim and C.-K. Kim, Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions, Int. J. Pharm.241 (2002) 155-163; DOI: 10.1016/S0378-5173(02)00232-6.
Y. Qiu and K. Park, Environment-sensitive hydrogels for drug delivery, Adv. Drug Deliv. Rev.53 (2001) 321-339; DOI: 10.1016/S0169-409X(01)00203-4.
C. K. Mauck, D. Katz, E. P. Sandefer, M. D. Nasution, M. Henderson, G. A. Digenis, I. Su, R. Page and K. Barnhart, Vaginal distribution of Replens and K-Y jelly using three imaging techniques, Contraception77 (2008) 195-204; DOI: 10.1016/j.contraception.2007.11.016.
I. R. Schmolka, Artificial skin. I. Preparation and properties of pluronic F-127 gels for the treatment of burns, J. Biomed. Mater. Res.6 (1972) 571-582; DOI: 10.1002/jbm.820060609.
H. G. Choi, J. H. Jung, J. M. Ryu, S. J. Yoon, Y. K. Oh and C. K. Kim, Development of in situ-gelling and mucoadhesive acetaminophen liquid suppository, Int. J. Pharm.165 (1998) 33-44; DOI: 10.1016/S0378-5173(97)00386-4.
A. A. Koffi, F. Agnely, G. Ponchel and J. L. Grossiord, Modulation of the rheological and mucoadhesive properties of thermosensitive poloxamer based hydrogels intended for the rectal administration of quinine, Eur. J. Pharm. Sci.27 (2006) 328-335; DOI: 10.1016/j.ejps.2005.11.001.
H. S. Ch'ng, H. Park, P. Kelly and J. R. Robinson, Bioadhesive polymers as platforms for oral controlled drug delivery. II. Synthesis and evaluation of some swelling water insoluble bioadhesive polymers, J. Pharm. Sci.74 (1985) 339-405.
D. Woolfson, M. L. Umrethia, V. L. Kett and R. K. Malcolm, Freeze-dried, mucoadhesive system for vaginal delivery of the HIV microbicide, dapivirine: Optimisation by an artificial neural network, Int. J. Pharm.388 (2010); DOI: 10.1016/j.ijpharm.2009.12.042.
A. D. Woolfson, M. L. Umrethia, V. L. Kett and R. K. Malcolm, Freeze-dried, mucoadhesive system for vaginal delivery of the HIV microbicide, dapivirine: Optimisation by an artificial neural network, Int. J. Pharm.388 (2010)136.143; DOI: 10.1016/j.ijpharm.2009.12.042.
J. Y. Chang, Y.-K. Oh, H. S. Kong, E. J. Kim, D. D. Jang, K. T. Nam and C.-K. Kin, Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels on vaginitis, J. Control Release82 (2002) 39-50; DOI: 10.1016/S0168-3659(02)00086-X.
E. Y. Kim, Z. G. Gao, J. S. Park, H. Li and K. Han, rhEGF/HP-β-CD complex in poloxamer gel for ophthalmic delivery, Int. J. Pharm.233 (2002) 159-167; DOI: 10.1016/S0378-5173(01)00933-4.
A. L. Rashad, W. L. Toffler, N. Wolf, K. Thoraburg, E. P. Kirk, G. Ellis and W. E. Whitehead, Vaginal P02 in healthy women and in women infected with Trichomoniasis vaginalis: Potential implications for metronidazole therapy, Am. J. Obestet. Gynecol.166 (1992) 620-624.
K. Edsman, J. Carlfors and R. Petersson, Rheological evaluation of poloxamer as an in situ gel for ophthalmic use, Eur. J. Pharm. Sci.6 (1998) 105-112; DOI: 10.1016/S0928-0987(97)00075-4.
H. Qi, L. Li, C. Huang, W. Li and C. Wu, Optimization and physicochemical characterization of thermosensitive poloxamer gel containing puerarin for ophthalmic use, Chem. Pharm. Bull.54 (2006) 1500-1507; DOI 10.1248/cpb.54.1500.
A. Cabana, A. Ait-Kadi and J. Juhasz, Study of the gelation process of polyethylene oxide-poly-propylene oxide-polyethylene oxide copolymer (poloxamer 407) aqueous solutions, J. Colloid Interface Sci.190 (1997) 307-312; DOI: 10.1006/jcis.1997.4880.
N. Jain, V. Aswal, P. Goyal and P. Bahadur, Micellar structure of an ethylene oxide-propylene oxide block copolymer: a small-angle neutron scattering study, J. Phys. Chem.102 (1998) 8452-8460; DOI: 10.1021/jp982568o.
I. R. Schmolka, A review of block polymer surfactants, J. Am. Oil Chem. Soc.54 (1977) 110-116; DOI: 10.1007/BF02894385.
C. Charrueau, C. Tuleu, V. Astre, J.-L. Grossiord and J.-L. Chaumeil, Poloxamer 407 as a thermogelling and adhesive polymer for rectal administration of short-chain fatty acids, Drug Dev. Ind. Pharm.27 (2001) 351-357; DOI: 10.1081/DDC-100103735.
P. Alexandridis and T. A. Hatton, Poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer surfactants in aqueous solutions and at interfaces: thermodynamic, structure, dynamic and modeling, Colloid Surface A96 (1995) 1-46; DOI: 10.1016/0927-7757(94)03028-X.
O. M. Shaaban, G. N. Fetih, N. H. Abdellah, S. Ismail, M. A. Ibrahim and S. A. Ibrahim, A pilot randomized trial for treatment of bacterial vaginosis using in-situ forming metronidazole vaginal gel, J. Obstet. Gynecol. Res.37 (2011) 874-881; DOI: 10.1111/j.1447-0756.2010.01457.x.