Meloxicam transdermal delivery: effect of eutectic point on the rate and extent of skin permeation

Document Type: Original Article

Authors

1 Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran

3 Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

4 Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Objective(s):Drug delivery through the skin can transfer therapeutic levels of drugs for pharmacological effects. Analgesics such as NSAIDs have gastrointestinal side effects and topical dosage forms of these drugs are mainly preferred, especially for local pains. Meloxicam is one of NSAIDs with no topical form in the market. In this research, we attempted to quantify the skin permeation of a meloxicam topical preparation and to show how permeation would be increased by using thymol as an enhancer. The effect of eutectic point of drug and thymol mixture on rate and extent of skin permeation was also studied.
Materials and Methods: Different mixtures of thymol and meloxicam (2:8, 4:6, 5:5, 6:4, 8:2) were prepared and their melting point were obtained by differential scanning calorimetry. Then drug permeation was measured using diffusion cells and the Guinea pig skin.
Results: Mixtures in ratios 5:5 and 4:6 of meloxicam / thymol showed a new endotherm at 149 and 140°C in DSC thermograms. The permeability of meloxicam from the creams containing 6:4, 5:5 and 4:6 ratios of meloxicam to thymol were 4.71, 15.2, 22.06 µg/cm2 respectively. This was significantly different from the cream of pure meloxicam (3.76 µg/cm2).
Conclusion: This study set out to determine that thymol plays as a skin permeation enhancer and increases the meloxicam skin absorption and this enhancement is significant at the eutectic point of drug-enhancer mixture.

Keywords


1. El-Kattan AF, Asbill CS, Kim N, Michniak BB. The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities. Int J Pharm 2001; 215:229-240.

2. Cui LL, Hou XM, Jiang J, Li GD, Liang YY, Xin X. Comparative enhancing effects of electret with chemical enhancers on transdermal delivery of meloxicam in vitro. J Phys Conf Ser 2008; 142:12-15.

3. Karande P, Mitragotri S. Enhancement of transdermal drug delivery via synergistic action of chemicals. Biochim Biophys Acta 2009;1788:2362-2373.

4. Naik A, Kalia YN, Guy RH. Transdermal drug delivery: overcoming the skin’s barrier function. Pharm Sci Technol Today 2000; 3:318-326.

5. Ah Y-C, Choi J-K, Choi Y-K, Ki H-M, Bae J-H. A novel transdermal patch incorporating meloxicam:In vitro and in vivo characterization. Int J Pharm 2010; 385:12-19.

6. Cordero JA, Alarcon L, Escribano E, Obach R, Domenech J. A comparative study of the transdermal penetration of a series of nonsteroidal antiinflammatory drugs. J Pharm Sci 1997; 86:503-508.

7. Bae JW, Kim MJ, Jang CG, Lee SY. Determination of meloxicam in human plasma using a HPLC method with UV detection and its application to a pharmacokinetic study. J Chromatogr B 2007; 859:69-73.

8. Duangjit S, Opanasopit P, Rojanarata T, Ngawhirunpat T. Characterization and in vitro skin permeation of meloxicam-loaded liposomes versus transfersomes. J Drug Deliv 2011; 2011:418316.

9. Martin RM, Biswas P, Mann RD. The incidence of adverse events and risk factors for upper gastrointestinal disorders associated with meloxicam use amongst 19 087 patients in general practice in England: cohort study. Br J Clin Pharmacol 2000; 50:35-42.

10. Ruiz Martinez MA, López-Viota Gallardo J, de Benavides MM, de Dios García López-Duran J, Gallardo

Enhanced transdermal delivery of meloxicam by thymol Mohammadi-Samani et al Lara V. Rheological behavior of gels and meloxicam release. Int J Pharm 2007; 333:17-23.

11. Mahrous GM. Proniosomes as a drug carrier for transdermal delivery of meloxicam. Bull Pharm Sci 2010; 3:131-140.

12. El Maghraby GM. Transdermal delivery of hydrocortisone from eucalyptus oil microemulsion: Effects of cosurfactants. Int J Pharm 2008; 355:285-292.

13. Stott PW, Williams AC, Barry BW. Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen. J Control Release 1998; 50:297-308.

14. Liu Y, Ye X, Feng X, Zhou G, Rong Z, Fang C,et al. Menthol facilitates the skin analgesic effect of tetracaine gel. Int J Pharm 2005; 305:31-36.

15. Kaplun-Frischoff Y, Touitou E. Testosterone skin permeation enhancement by menthol through formation of eutectic with drug and interaction with skin lipids. J Pharm Sci 1997; 86:1394-1399.

16. Narishetty ST, Panchagnula R. Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action. J Control Release 2004; 95:367-379.

17. Sinha VR, Kaur MP. Permeation enhancers for transdermal drug delivery. Drug Dev Ind Pharm 2000; 26:1131-1140.

18. Benson HAE. Transdermal drug delivery: penetration enhancement techniques. Curr Drug Deliv 2005; 2:23-33.

19. Fiala S, Brown MB, Jones SA. Dynamic in-situ eutectic formation for topical drug delivery. J Pharm Pharmacol 2011; 63:1428-1436.

20. Bandarkar FS, Vavia PR. A stability indicating HPLC method for the determination of meloxicam in bulk and commercial formulations. Trop J Pharm Res 2009; 8:257-264.

21. Mahmood K, Ashraf M. A simple, specific and precise HPLC method for the measurement of meloxicam in biological fluids. Pak J Sci 2008; 60:85-89.

22. Mahmood K, Khan B, Ashraf M, Haq I. Specific and simple hplc assay of ecofriendly meloxicam in pharmaceutical formulations. J Pharm Sci Res 2010; 2:878-883.

23. Awasthi SS, Kumar TG, Manisha P, Preeti Y, Kumar SS. Development of meloxicam formulations utilizing ternary complexation for solubility enhancement. Pak J Pharm Sci 2011; 24:533-538.

24. Gao S, Singh J.In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes. J Control Release 1998; 51:193-199.

25. El-Kattan AF, Asbill CS, Michniak BB. The effect of terpene enhancer lipophilicity on the percutaneous permeation of hydrocortisone formulated in HPMC gel systems. Int J Pharm 2000; 198:179-189.

26. Gohel MC, Nagori SA. Resolving issues of content uniformity and low permeability using eutectic blend of camphor and menthol. Ind J Pharm Sci 2009; 71:622-629.

27. Stott PW, Williams AC, Barry BW. Mechanistic study into the enhanced transdermal permeation of a model β-blocker, propranolol, by fatty acids: a melting point depression effect. Int J Pharm 2001; 219:161-176.

28. Yener G, Dal Ö, Üner M. Effect of vehicles on release of meloxicam from various topical formulations. Open Drug Deliv J 2009; 3:19-23.

29. Jantharaprapap R, Stagni G. Effects of penetration enhancers on in vitro permeability of meloxicam gels. Int J Pharm 2007; 343:26-33.

30. Fiala S, Jones SA, Brown MB. A fundamental investigation into the effects of eutectic formation on transmembrane transport. Int J Pharm 2010; 393:68-73.

31. Yong CS, Oh Y-K, Jung SH, Rhee J-D, Kim H-D, Kim C-K,et al. Preparation of ibuprofen-loaded liquid suppository using eutectic mixture system with menthol. Eur J Pharm Sci 2004; 23:347-353.

32. Shokri J, Nokhodchi A, Dashbolaghi A, Hassan-Zadeh D, Ghafourian T, Barzegar Jalali M. The effect of surfactants on the skin penetration of diazepam. Int J Pharm 2001; 228:99-107.

33. dos Anjos JLV, Alonso A. Terpenes increase the partitioning and molecular dynamics of an amphipathic spin label in stratum corneum membranes. Int J Pharm 2008; 350:103-112.

34. Yuan X. Enhanced transdermal drug delivery of NSAIDs using eutectic formation and a two-phase liquid system. 2003. PhD thesis, Graduate Faculty of The University of Georgia.