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AAPS PharmSciTech. 2004 September; 5(3): 82–89.
Published online 2004 August 18. doi:  10.1208/pt050348
PMCID: PMC2750270

Transdermal delivery of zidovudine (AZT): The effects of vehicles, enhancers, and polymer membranes on permeation across cadaver pig skin

Abstract

The purpose of this study was to investigate the effects of vehicles, enhancers, and polymer membranes on 3-azido-3-deoxythymidine (AZT) permeation across cadaver pig skin. Four binary vehicles (ethanol/water, isopropyl alcohol/water, polyethylene glycol 400/water, and ethanol/isopropyl myristate [IPM] were tested for AZT solubility and permeability across pig skin; ethanol/IPM (50/50, vol/vol) demonstrated the highest AZT flux (185.23 μ/cm2/h). Next, the addition of various concentrations of different enhancers (N-methyl-2-pyrrolidone [NMP], oleic acid, and lauric acid) to different volume ratios of ethanol/IPM was investigated for their effect on AZT solubility and permeability across pig skin. The use of 2 conbinations (ethanol/IPM [20/80] plus 10% NMP and ethanol/IPM [30/70] plus 10% NMP) resulted in increased AZT solubility (42.6 and 56.27 mg/mL, respectively) and also high AZT flux values (284.92 and 460.34 μg/cm2/h, respectively) without appreciable changes in lag times (6.25 and 7.49 hours, respectively) when compared with formulations using only ethanol/IPM at 20/80 and 30/70 volume ratios without addition of the enhancer NMP. Finally, AZT permeation across pig skin covered with a microporous polyethylene (PE) membrane was investigated. The addition of the PE membrane to the pig skin reduced AZT flux values to ~50% of that seen with pig skin alone. However, the AZT flux value attained with ethanol/IPM (30/70) plus 10% NMP was 215.30 μg/cm2/h, which was greater than the target flux (208 μg/cm2/h) needed to maintain the steady-state plasma concentration in humans. The results obtained from this study will be helpful in the development of an AZT transdermal drug delivery system.

Keywords: Zidovudine permeation, enhancer, binary vehicles, polymer membrane, transdermal delivery system

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Chien YW, Wearley LL. Aids and chemotherapy. Drugs of Today. 1989;25:19–25.
2. Merigan TC, Skowron G. Safety and tolerance of dideoxycytidine as a single agent. Results of early-phase studies in patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. Study Group of the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. Am J Med. 1990;88(suppl 5B):S11–S15. doi: 10.1016/0002-9343(90)90415-A. [PubMed] [Cross Ref]
3. Kieburtz KD, Siedlin M, Lambert JS, et al. Extended follow-up of peripheral neuropathy in patients with AIDS and AIDS-related complex treated with dideoxyinosine. J Acquir Immune Defic Syndr. 1992;5:60–64. [PubMed]
4. Seki T, Kawaguchi T, Sugibayashi K, Juni K, Morimoto Y. Percutaneous absorption of azidothymidine in rats. Int J Pharm. 1989;57:73–75. doi: 10.1016/0378-5173(89)90265-2. [Cross Ref]
5. Seki T, Toeda C, Kawaguchi T, Juni K, Sugubayashi K, Morimoto Y. Enhanced transdermal delivery of zidovudine in rats and human skin. Chem Pharm Bull (Tokyo) 1990;38:3086–3089. [PubMed]
6. Seki T, Kawaguchi T, Juni K. Enhanced delivery of zidovudine through rat and human skin via ester prodrugs. Pharm Res. 1990;7:948–952. doi: 10.1023/A:1015902024664. [PubMed] [Cross Ref]
7. Kararli TT, Kirchhoff CF, Penzotti SC. Enhancement of transdermal transport of azidothymidine (AZT) with novel terpene and terpene-like enhancers: In vivo-in vitro correlations. J Control Release. 1995;34:43–51. doi: 10.1016/0168-3659(94)00128-H. [Cross Ref]
8. Kim DD, Chien YW. Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 2. The effect of vehicle and enhancer on skin permeation. J Pharm Sci. 1996;85:214–219. doi: 10.1021/js950141c. [PubMed] [Cross Ref]
9. Jin Y, Seki T, Juni K. Transdermal absorption of zidovudine from ethanol-isopropyl myristate mixed system and influence of probenecid on it in rats. Drug Dev Ind Pharm. 1996;22:1217–1221. doi: 10.3109/03639049609063240. [Cross Ref]
10. Jin Y, Seki T, Morimoto Y, Juni K. Effect of application volume of ethanol-isopropyl myristate mixed solvent system on permeation of zidovudine and probenecid through rat skin. Drug Dev Ind Pharm. 2000;26:193–198. doi: 10.1081/DDC-100100344. [PubMed] [Cross Ref]
11. Thomas NS, Panchagnula R. Transdermal delivery of zidovudine: effect of vehicles on permeation across rat skin and their mechanism of action. Eur J Pharm Sci. 2003;18:71–79. doi: 10.1016/S0928-0987(02)00242-7. [PubMed] [Cross Ref]
12. Bond JR, Barry BW. Damaging effect of acetone on the permeability barrier of hairless mouse skin compared with that of human skin. Int J Pharm. 1988;41:91–93. doi: 10.1016/0378-5173(88)90140-8. [Cross Ref]
13. Bond JR, Barry BW. Hairless mouse skin is limited as a model for assessing the effects of penetration enhancers in human skin. J Invest Dermatol. 1988;90:810–813. doi: 10.1111/1523-1747.ep12462031. [PubMed] [Cross Ref]
14. Catz P, Friend DR. Transdermal delivery of levonorgestrel. VIII. Effect of enhancers on rat skin, hairless mouse skin, hairless guinea pig skin, and human skin. Int J Pharm. 1990;58:93–102. doi: 10.1016/0378-5173(90)90245-Y. [Cross Ref]
15. Sato K, Sugibayashi K, Morimoto Y. Species differences in percutaneous absorption of nicorandil. J Pharm Sci. 1991;80:104–107. doi: 10.1002/jps.2600800203. [PubMed] [Cross Ref]
16. Fang JY, Wu PC, Huang YB, Tsai YH. In vitro permeation study of capsaicin and its synthetic derivatives from ointment bases using various skin types. Int J Pharm. 1995;126:119–128. doi: 10.1016/0378-5173(95)04105-2. [Cross Ref]
17. Wu PC, Huang YB, Fang JY, Tsai YH. In vitro percutaneous absorption of captopril. Int J Pharm. 1997;148:41–46. doi: 10.1016/S0378-5173(96)04826-0. [Cross Ref]
18. Rastogi SK, Singh J. Passive and iontophoretic transport enhancement of insulin through porcine epidermis by depilatories: permeability and Fourier transform infrared spectroscopy studies. AAPS PharmSciTech. 2003;4(3):E29–E29. doi: 10.1208/pt040329. [PMC free article] [PubMed] [Cross Ref]
19. Kenneth CJ, editor. Solution and solubioity. New York, NY: Marcel Dekker; 1986. pp. 37–49.
20. Higuchi T, Connors KA. Phase solubility techniques. Adv Anal Chem Instrum. 1965;4:117–212.
21. Harrison SM, Barry BW, Dugard PH. Effects of freezing on human skin permeability. J Pharm Pharmacol. 1984;36:261–262. [PubMed]
22. Dick IP, Scott RC. Pig ear skin as an in-vitro model for human skin permeability. J Pharm Pharmacol. 1992;44:640–645. [PubMed]
23. Lieb LM, Nash RA, Matias JR, Orentreich N. A new in vitro method for transepidermal water loss: A possible method for moisturizer evaluation. J Soc Cosmet Chem. 1988;39:107–119.
24. Klecker RW, Collins JM, Yarchoan R, et al. Plasma and cerebrospinal fluid pharmacokinetics of 3-azido-3-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther. 1987;41:407–412. doi: 10.1038/clpt.1987.49. [PubMed] [Cross Ref]
25. Goldberg-Cettina M, Liu P, Nightingale J, Kurihara-Bergstrom T. Enhanced transdermal delivery of estradiol in vitro using binary vehicles of isopropyl myristate and short-chain alkanols. Int J Pharm. 1995;114:237–245. doi: 10.1016/0378-5173(94)00253-2. [Cross Ref]
26. Shinha VR, Maninder PK. Permeation enhancers for transdermal drug delivery. Drug Dev Ind Pharm. 2000;26:1131–1140. doi: 10.1081/DDC-100100984. [PubMed] [Cross Ref]
27. Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001;14:101–114. doi: 10.1016/S0928-0987(01)00167-1. [PubMed] [Cross Ref]

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