Transdermal Delivery of Gabapentin: Effect of Cosolvent and Microemulsion on Permeation through the Rat Skin

Chika J. Mbah, Charles O. Nnadi

Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria.

DOI: 10.4236/pp.2014.55057                

Abstract

The objective of the present study was to examine the influence of cosolvent system and micro-emulsion formulation on in-vitro skin permeation of gabapentin, furthermore, to characterize the physicochemical properties of drug-loaded oil-in-water (o/w) and water-in-oil (w/o) cremophor 40-based microemulsions in comparison to the blank counterparts. The cosolvent system prepared by homogenous mixing is composed of ethanol-water and propylene glycol-water mixture (90:10, 80:20, 70:30 v/v) respectively. The microemulsion consisted of coconut oil, water and mixture of cremophor 40 (surfactant) and ethanol (cosurfactant) and was prepared by aqueous phase titration method. Physicochemical properties of microemulsions were determined using reported procedures. Transdermal flux for gabapentin was studied in-vitro using modified Franz diffusion cells. The physicochemical properties of drug-loaded microemulsions and their blank counterparts were generally alike, however, slight variation in pH and viscosity was observed probably due to the intrinsic properties of the drug. The ethanol-water system (70:30 v/v) gave higher flux for gabapentin when compared to propylene glycol-water system (70:30 v/v). The w/o microemulsion formulations resulted in, higher flux for gabapentin when compared to o/w formulations. FTIR spectra of the untreated stratum corneum, when compared to cosolvent system and microemulsion treated stratum corneum, suggest the mechanism of permeation to be disruption of lipid bilayers and keratin denaturation of the stratum corneum. The results show that incorporation of gabapentin into microemulsions did not change the microemulsion type. The in vitro permeation data obtained from experimental work suggest that the cosolvent system (ethanol-water 70:30 v/v) and w/o microemulsion formulations respectively, can be successfully used as potential vehicles in developing transdermal therapeutic systems for gabapentin.

Keywords

Transdermal Delivery, Cosolvent System, Microemulsion, Gabapentin

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Pribosky, J., Takayamak, K., Nagai, T., Waitzova, D. and Elis, J. (1987) Evaluation of In-Vitro and In-Situ Transdermal Absorption of Drugs in Pig and Rat Skin. Chemical and Pharmaceutical Bulletin (Tokyo), 35, 4915-4920.
[2]	Yamane, M.A., Williams, A.C. and Barry, B.W. (1995) Terpenes Penetration Enhancers in Propylene Glycol/Water Cosolvent Systems: Effectiveness and Mechanisms of Actions. Journal of Pharmacy and Pharmacology, 47, 978-989. http://dx.doi.org/10.1111/j.2042-7158.1995.tb03282.x
[3]	Stott, P.W., Williams, A.C. and Barry, B.W. (2001) Mechanisstic Study into the Enhanced Transdermal Permeation of a Model Β-Blocker, Propranolol, by Fatty Acids: A Melting Point Depression Effect. International Journal of Pharmaceutics, 219, 161-176. http://dx.doi.org/10.1016/S0378-5173(01)00645-7
[4]	Narishetty, S.T.K. and Panchagnula, R. (2004) Transdermal Delivery of Zidovudine: Effects of Terpenes and Their Mechanism of Action. Journal of Controlled Release, 95, 367-379. http://dx.doi.org/10.1016/j.jconrel.2003.11.022
[5]	Lee, P.J., Lenger, R. and Shestri, V.P. (2003) Novel Microemulsion Enhancer Formulation for Simultaneous Transdermal Delivery of Hydrophilic and Hydrophobic Drugs. Pharmaceutical Research, 20, 264-269. http://dx.doi.org/10.1023/A:1022283423116
[6]	Chen, H., Chang, X., Weng, T., Zhao, X., Sao, H. Yang, Y., Xu, H. and Yang, X. (2004) A Study of Microemulsion Systems for Transdermal Delivery of Triptolide. Journal of Controlled Release, 98, 427-436. http://dx.doi.org/10.1016/j.jconrel.2004.06.001
[7]	Yuan, Y., Li, S., Mo, F. and Zhong, D. (2006) Investigation of Microemulsion System for Transdermal Delivery of Meloxicam. International Journal of Pharmaceutics, 321, 117-123. http://dx.doi.org/10.1016/j.ijpharm.2006.06.021
[8]	Sintov, A.C. and Botner, S. (2006) Transdermal Drug Delivery Using Microemulsion and Aqueous Systems: Influence of Skin Storage Conditions on the in Vitro Permeability of Diclofenac from Aqueous Vehicle Systems. International Journal of Pharmaceutics, 311, 55-62. http://dx.doi.org/10.1016/j.ijpharm.2005.12.019
[9]	Baboota, S., Shakeel, F., Ahuja, A., Ali, J. and Shafiq, S. (2007) Design Development and Evaluation of Novel Nanoemulsion Formulation for Transdermal Potential of Celecoxib. Acta Pharmaceutica, 8, 316-332.
[10]	Shafiq, S., Shakeel, F., Talegaonkar, S., Ahmed, F.J., Khar, R.K. and Ali, M. (2007) Development and Bioavailability Assessement of Ramipril Nanoemulsion Formulation. European Journal of Pharmaceutics and Biopharmaceutics, 66, 227-242. http://dx.doi.org/10.1016/j.ejpb.2006.10.014
[11]	Shakeel, F., Baboota, S., Ahuja, A., Ali, J., Aqui, I.M. and Shafiq, S. (2007) Nanoemulsions as Vehicles for Transdermal Delivery of Aceclofenac. AAPS PharmSciTech, 8, E104. http://dx.doi.org/10.1208/pt0804104
[12]	Bemer, B., Otte, J.H., Mazzenga, G.C., Steffens, R.J. and Ebert, C.D. (1989) Ethanol:Water Mutually Enhanced Transdermal Therapeutic System I: Nitroglycerin Solution Properties and Membrane Transport. Journal of Pharmaceutical Sciences, 78, 314-318. http://dx.doi.org/10.1002/jps.2600780411
[13]	Kurihara-Bergstrom, T., Knutson, K., DeNoble, L.J. and Goates, C.Y. (1990) Percutaneous Absorption Enhancement of an Ionic Molecules by Ethanol-Water System in Human Skin. Pharmaceutical Research, 7, 762. http://dx.doi.org/10.1023/A:1015879925147
[14]	Krishnaiah, Y.S.R., Satyanavayana, V. and Karthikeyan, R.S. (2002) Effect of Solvent System on the in-Vitro Permeability of Nicardipine Hydrochloride through Excised Rat Epidermis. Journal of Pharmacy & Pharmaceutical Sciences, 5, 123-130.
[15]	Touitou, E., Dyan, N., Bergelson, L., Sodin, B. and Eliaz, M. (2000) Ethosomes Novel Vesicular Carriers for Enhanced Delivery: Characterization and Skin Penetration Properties. Journal of Controlled Release, 65, 403-418. http://dx.doi.org/10.1016/S0168-3659(99)00222-9
[16]	Jain, S., Tiwary, A.K., Sapra, B. and Jain, N.K. (2007) Formulation and Evaluation of Ethosomes for Transdermal Delivery of Lamivudine. AAPS PharmSciTech: An Official Journal of American Association pf Pharmaceutical Scientists, 8, E111.
[17]	Toniton, E. (1986) Transdermal Delivery of Anxiolytics: In Vitro Skin Permeation of Midazolam Maleate and Diazepam. International Journal of Pharmaceutics, 33, 37-43. http://dx.doi.org/10.1016/0378-5173(86)90036-0
[18]	Obata, Y., Tagayamak, K., Maitan, Y., Machide, Y. and Naga, T. (1993) Effect of Ethanol on Skin Permeation of Nonionized and Ionized Diclofenac. International Journal of Pharmaceutics, 89, 191-198. http://dx.doi.org/10.1016/0378-5173(93)90243-9
[19]	LaGrow, B. (2005) Physicians’ Desk Reference. 59th Edition, Thomson PDR, New Jersey, 2590.
[20]	Boonme, P., Krauel, K., Graf, A., Rades, T. and Junyaprasert, V.B. (2006) Characterization of Microemulsion Structure in the Pseudoternary Phase Diagram of Isopropyl Palmitate/Water/Brij 97:1-Butanol. AAPS PharmSciTech: An Official Journal of American Association pf Pharmaceutical Scientists, 7, E99-E104.
[21]	Mbah, C.J. and Nnadi, C.O. (2010) The in Vitro Permeability of Valsartan through Excised Rat Skin. Bio-Research, 8, 598-601. http://dx.doi.org/10.4314/br.v8i1.62540
[22]	Songkro, S., Purwo, Y., Becket, G. and Rades, T. (2003) Investigation of Newborn Pig Skin as an in Vitro Animal Model for Transdermal Drug Delivery. STP Pharma Sciences, 13, 133-139.
[23]	Bhatia, K.S., Gao, S. and Singh, J. (1997) Effects of Penetration Enhancers and Iontophoresis on FTIR Spectroscopy and LHRH Permeability through Porcine Skin. Journal of Controlled Release, 47, 81-89. http://dx.doi.org/10.1016/S0168-3659(96)01618-5
[24]	Walker, R.B. and Smith, E.W. (1996) The Role of Percutaneous Penetration Enhancers. Advanced Drug Delivery Reviews, 18, 295-301. http://dx.doi.org/10.1016/0169-409X(95)00078-L
[25]	Paul, B.K. and Monlik, S.P. (1997) Microemulsions: An Overview. Journal of Dispersion Science and Technology, 18, 301-367. http://dx.doi.org/10.1080/01932699708943740
[26]	Lawrence, M.J. and Rees, G.D. (2000) Microemulsion-Based Media as Novel Drug Delivery Systems. Advanced Drug Delivery Reviews, 45, 89-121. http://dx.doi.org/10.1016/S0169-409X(00)00103-4
[27]	Golden, G.M., Guzek, D.B., Harris, R.R., Mekie, J.E. and Pous, R.D. (1986) Lipid Thermotropic Transition in Human Stratum Corneum. Journal of Investigative Dermatology, 86, 255-259. http://dx.doi.org/10.1111/1523-1747.ep12285373
[28]	Soates, C.Y. and Knutson, K. (1994) Enhanced Permeation of Polar Compounds through Human Epidermis. Permeability and Membrane Structural Changes in the Presence of Short Chain Alcohols. Biochimica et Biophysica Acta, 1195, 169-179.
[29]	Barry, B.W. (1991) Lipid-Protein Partitioning of Skin Penetration Enhancement. Journal of Controlled Release, 15, 237-248. http://dx.doi.org/10.1016/0168-3659(91)90115-T
[30]	Roberts, M.S. and Walker, M. (1993) Penetration Enhancement by Stratum Corneum Modification. In: Pharmaceutical Skin Penetration Enhancement, Marcel Dekker, New York, 1-30.
[31]	Wester, R.C. and Maibach, H.I. (1995) Effect of Oily Vehicles on Skin Hydration and Penetration Rate. In: Percutaneous Penetration Enhancers, CRC Press, Boca Raton, 21-28.
[32]	Benson, H.A.E. (2005) Transdermal Drug Delivery: Penetration Enhancement Techniques. Current Drug Delivery, 2, 23-33. http://dx.doi.org/10.2174/1567201052772915