Abstract
Tiaprofenic acid is a potent analgesic and nonsteroidal anti-inflammatory drug (NSAID) and like any other nonsteroidal anti-inflammatory drug, oral administration of the conventional dosage forms of tiaprofenic acid invariably causes gastrointestinal side effects. In an effort to eliminate these side effects while enhancing the drug concentration at the target tissue, an epidermal application of tiaprofenic acid seems to be an effective alternative drug delivery modality. This study attempts to demonstrate the influence of different terpenes (d-limonene, menthol and nerolidol) in various combinations of preparations on the percutaneous penetration of tiaprofenic acid from Carbopol® 940 based gel formulations (1%) in an ex vivo experiment using Franz-type diffusion cells. The enhancement effect of terpenes on skin absorption of tiaprofenic acid was further evaluated by an in vivo method in rats. Amongst the terpenes used, d-limonene was the most outstanding penetration enhancer that was reference to penetration of tiaprofenic acid through rat skin ex vivo. In vivo penetration study shows that the AUC0–48h was increased by about 10 fold by the addition of 5% d-limonene to the formulation. Histological studies show that d-limonene causes disruption on the skin surface and is responsible for enhanced penetration of tiaprofenic acid. Since tiaprofenic acid is known to cause gastrointestinal disturbances following systemic administration, topical formulations of tiaprofenic acid in gel form including 5% d-limonene could be suggested as an alternative.
Similar content being viewed by others
References
Amnuaikit, C., Ikeuchi, I., Ogawara, K., Higaki, K., and Kimura, T., Skin permeation of propranolol from polymeric film containing terpene enhancers for transdermal use. Int. J. Pharm., 289, 167–178 (2005).
Aqil, M., Ahad, A., Sultana, Y., and Ali, A., Status of terpenes as skin penetration enhancers. Drug Discov. Today, 12, 1061–1067 (2007).
Chang, J. S., Tsai, Y. H., Wu, P. C., and Huang, Y. B., The effect of mixed-solvent and terpenes on percutaneous absorption of meloxicam gel. Drug Dev. Ind. Pharm., 33, 984–989 (2007).
Davies, N. M., Clinical pharmacokinetics of tiaprofenic acid and its enantiomers. Clin. Pharmacokinet., 31, 331–347 (1996).
Delbeke, F. T., Baert, K., and De Backer, P., Disposition of human drug preparations in the horse. VI. tiaprofenic acid. J. Chromatogr. B Biomed. Sci. Appl., 704, 207–214 (1997).
El-Kattan, A. F., Asbill, C. S., Kim, N., and Michniak, B. B., Effect of formulation variables on the percutaneous permeation of ketoprofen from gel formulations. Drug Deliv., 7, 147–153 (2000).
El-Kattan, A. F., Asbill, C. S., Kim, N., and Michniak, B. B., The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities. Int. J. Pharm., 215, 229–240 (2001).
Gungor, S. and Bergisadi, N., Effect of penetration enhancers on in vitro percutaneous penetration of nimesulide through rat skin. Pharmazie, 59, 39–41 (2004).
Gupta, S. K., Bansal, P., Bhardwaj, R. K., Jaiswal, J., and Velpandian, T., Comparison of analgesic and anti-inflammatory activity of meloxicam gel with diclofenac and piroxicam gels in animal models: pharmacokinetic parameters after topical application. Skin Pharmacol. Appl. Skin Physiol., 15, 105–111 (2002).
Hadgraft, J., Whitefield, M., and Rosher, P. H., Skin penetration of topical formulations of ibuprofen 5%: An in vitro comparative study. Skin Pharmacol. Appl. Skin Physiol., 16, 137–142 (2003).
Hooper, L., Brown, T. J., Elliott, R., Payne, K., Roberts, C., and Symmons, D., The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by nonsteroidal anti-inflammatory drugs: systematic review. BMJ, 329, 948 (2004).
Jantharaprapap, R. and Stagni, G., Effects of penetration enhancers on in vitro permeability of meloxicam gels. Int. J. Pharm., 343, 26–33 (2007).
Kang, L., Yap, C. W., Lim, P. F. C., Chen, Y. Z., Ho, P. C., Chan, Y. W., Wong, G. P., and Chan, S. Y., Formulation development of transdermal dosage forms: Quantitative structure-activity relationship model for predicting activities of terpenes that enhance drug penetration through human skin. J. Control. Release, 120, 211–219 (2007).
Krishnaiah, Y. S. R., Al-Saidan, S. M., and Jayaram, B., Effect of nerolidol, carvone and anethole on the in vitro transdermal delivery of selegiline hydrochloride. Pharmazie, 61, 46–53 (2006).
Moghimi, H., Willams, A., and Barry, B., A lamellar matrix model for stratum corneum intercellular lipids. V. Effects of terpene penetration enhancers on the structure and thermal behaviour of the matrix. Int. J. Pharm., 146, 41–54 (1997).
Okyar, A., Yildiz, A., Cinar, C., Aksu, B., Ozsoy, Y., and Baktir, G., Effect of terpenes as penetration enhancers on percutaneous penetration of tiaprofenic acid through pig skin. Acta Pharmaceutica Sciencia, 50, 247–256 (2008).
Ota, Y., Hamada, A., Nakano, M., and Saito, H., Evaluation of percutaneous absorption of midazolam by terpenes. Drug Metab. Pharmacokinet., 18, 261–266 (2003).
Ozsoy, Y., Gungor, S., and Cevher, E., Vehicle effects on in vitro release of tiaprofenic acid from different topical formulations. Farmaco, 59, 563–566 (2004).
Sapra, B., Jain, S., and Tiwary, A. K., Percutaneous permeation enhancement by terpenes: mechanistic view. AAPS J., 10, 120–132 (2008).
Shah, V. P., Midha, K. K., Dighe, S., McGilveray, I. J., Skelly, J. P., Yacobi, A., Layloff, T., Viswanathan, C. T., Cook, C. E., McDowall, R. D., Pittmann, K. A., and Spector, S., Analytical methods validation: Bioavailability, bioequivalence and pharmacokinetic studies. Eur. J. Drug Metab. Pharmacokinet., 16, 249–255 (1991).
Sift Carter, R., Ebner, D., Brenner, D., and Bruppacher, R., Use of topical NSAIDs in patients receiving systemic NSAID treatment: a pharmacy-based study in Germany. J. Clin. Epidemiol., 50, 217–218 (1997).
Tas, C., Ozkan, Y., Okyar, A., and Savaser, A., In vitro and ex vivo permeation studies of etodolac from hydrophilic gels and effect of terpenes as enhancers. Drug Deliv., 14, 453–459 (2007).
Vaddi, H. K., Ho, P. C., and Chan, S. Y., Terpenes in propylene glycol as skin-penetration enhancers: permeation and partition of haloperidol, fourier transform infrared spectroscopy, and differential scanning calorimetry. J. Pharm. Sci., 91, 1639–1651 (2002).
Williams, A. C. and Barry, B. W., Penetration enhancers. Adv. Drug Deliv. Rev., 56, 603–618 (2004).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Okyar, A., Nuriyev, M., Yildiz, A. et al. The effect of terpenes on percutaneous absorption of tiaprofenic acid gel. Arch. Pharm. Res. 33, 1781–1788 (2010). https://doi.org/10.1007/s12272-010-1110-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-010-1110-8