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Natural products as potential drug permeation enhancer in transdermal drug delivery system

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Abstract

Permeation enhancers are defined as substances that are capable of promoting penetration of drugs into skin and transdermal therapeutic systems offers a more reliable mean of administering drug through the skin. Skin is a natural barrier so it is necessary to employ enhancement strategies to improve topical bioavailability. This review explores that natural products have got potential to enhance the permeation of the drug through skin by reversibly reducing the skin barrier resistance. The use of natural products is the most reliable means of permeation enhancement of transdermally administered drugs and permits the delivery of broader classes of drugs through the stratum corneum. They are safe, non-toxic, pharmacologically inert, non-irritating, and non-allergenic to use as permeation enhancers. The present review initially highlights the current status of natural products on the basis of SAR studies which have shown significant enhancer activities.

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References

  1. Akimoto T, Aoyagi T, Minoshima J, Nagase Y (1997) Polymeric percutaneous drug penetration enhancer-synthesis and enhancing property of PEG/PDMS block copolymer with a cationic end group. J Control Release 49(13):229–241

    Article  CAS  Google Scholar 

  2. Akimoto T, Kawahara K, Nagase Y, Aoyagi T (2001) Polymeric transdermal drug penetration enhancer: the enhancing effect of oligodimethylsiloxane containing a glucopyranosyl end group. J Control Release 77(1–2):49–57

    Article  CAS  PubMed  Google Scholar 

  3. Amin S, Mir SR, Kohli K, Ali B, Ali M (2010) A study of the chemical composition of black cumin oil and its effect on penetration enhancement from transdermal formulation. Nat Prod Res 24(12):115–1151

    Article  Google Scholar 

  4. Aqil M, Ahad A, Sultana Y, Ali A (2007) Status of terpenes as skin permeation enhancers. Drug Discov Today 12:1061–1067

    Article  CAS  PubMed  Google Scholar 

  5. Arellano A, Santoyo S, Martin C, Ygartua P (2006) Enhancing effect of terpenes on the in vitro percutaneous absorption of diclofenac sodium. Int J Pharm 130:141–147

    Article  Google Scholar 

  6. Aungst B (1995) Fatty acids as skin permeation enhancers. In: Smith EW, Maibach HI (eds) Percutaneous penetration enhancers. CRC Press, Florida, pp 277–287

    Google Scholar 

  7. Aungst BJ, Rogers NJ, Shefter E (1986) Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amines. Int J Pharm 33:225–234

    Article  CAS  Google Scholar 

  8. Barry BW (1983) Dermatological formulation: percutaneous absorption, vol 18. Mercel Dekker, New York, pp 225–238

    Google Scholar 

  9. Barry BW (1987) Mode of action of penetration enhancers in human skin. J Control Release 6:85–97

    Article  CAS  Google Scholar 

  10. Barry BW (1991) Lipid-protein-partitioning theory of skin penetration enhancement. J Control Release 15:237–248

    Article  CAS  Google Scholar 

  11. Barry BW (1991) Modern methods of promoting drug absorption through the skin. Mol Asp Med 12:195–241

    Article  CAS  Google Scholar 

  12. Barry BW (1991) The LPP theory of skin penetration enhancement. In vitro percutaneous absorption: principles, fundamentals and applications. CRC Press, Florida, pp 165–185

    Google Scholar 

  13. Barry BW, Williams AC (1993) Terpenes as skin penetration enhancers. In: Walters KA, Hadgraft J (eds) Pharmaceutical skin penetration enhancement. Marcel Dekker, New York, pp 95–111

    Google Scholar 

  14. Ben-Shabat S, Baruch N, Sintov AC (2007) Conjugates of unsaturated fatty acids with propylene glycol as potentially less irritant skin penetration enhancers. Drug Dev Ind Pharm 33:1169–1175

    Article  CAS  PubMed  Google Scholar 

  15. Benson ACH (2005) Transdermal drug delivery: penetration enhancement techniques. Cur Drug Deliv 2:23–33

    Article  CAS  Google Scholar 

  16. Bhatia KS, Singh J (1998) Synergistic effect of ionto-ability through porcine skin. J Pharm Sci 87:462–469

    Article  CAS  PubMed  Google Scholar 

  17. Brain K, Hadgraft J, Al-Shatalebi M (1990) Membrane modification in activity of plant molluscicides. Planta Med 56:663

    Article  Google Scholar 

  18. Brown MB, Martin GP, Jones SA, Akomeah FK (2006) Dermal and transdermal drug delivery system: current and future prospects. Drug Deliv 13:175–187

    Article  CAS  PubMed  Google Scholar 

  19. Chi SC, Park ES, Kim H (1995) Effect of penetration enhancers on flurbiprofen permeation through rat skin. Int J Pharm 126:267

    Article  CAS  Google Scholar 

  20. Cho CW, Choi JS, Kim SJ, Shin SC (2009) Enhanced transdermal delivery of loratadine from the EVA matrix. Drug Deliv 16(4):230–235

    Article  CAS  PubMed  Google Scholar 

  21. Cho CW, Choi JS, Yang KH, Shin SC (2009) Enhanced transdermal absorption and pharmacokinetic evaluation of pranoprofen-ethylene-vinyl acetate matrix containing penetration enhancer in rats. Arch Pharm Res 32(5):747–753

    Article  CAS  PubMed  Google Scholar 

  22. Choi S, Jung SY, Kim CH, Kim HS, Rhim H, Kim SC, Nah SY (2001) Effect of ginsenosides on voltage-dependent Ca2+ channel subtypes in bovine chromaffin cells. J Ethnopharmacol 74:75–81

    Article  CAS  PubMed  Google Scholar 

  23. Cole L, Heard C (2007) Skin permeation enhancement potential of Aloe vera and a proposed mechanism of action based upon size exclusion and pull effect. Int J Pharm 333(1–2):10–16

    Article  CAS  PubMed  Google Scholar 

  24. Fang JY, Hwang TL, Fang CL, Chiu HC (2003) In vitro and in vivo evaluations of the efficacy and safety of skin permeation enhancers using flurbiprofen as a model drug. Int J Pharm 255:153–166

    Article  CAS  PubMed  Google Scholar 

  25. Francis G, Kerem Z, Makkar HP, Becker K (2002) The biological action of saponins in animal systems: a review. Br J Nutr 88:587–605

    Article  CAS  PubMed  Google Scholar 

  26. Gao S, Singh J (1997) Mechanism of transdermal transport of 5-fluorouracil by terpenes-carvone, 1, 8-cineole and thymol. Int J Pharm 154:67–77

    Article  CAS  Google Scholar 

  27. Ghafourian T, Zandasrar P, Hamishekar H, Nokhodchi A (2004) The effect of penetration enhancers on drug delivery through skin: a QSAR study. J Control Release 99:113–125

    Article  CAS  PubMed  Google Scholar 

  28. Godwin DA, Michniak BB (1999) Influence of drug lipophilicity on terpenes as transdermal penetration enhancers. Drug Dev Ind Pharm 25:905–915

    Article  CAS  PubMed  Google Scholar 

  29. Guy RH, Hadgraft J (1987) The effect of penetration enhancers on the kinetics of percutaneous absorption. J Control Release 5:43–51

    Article  CAS  Google Scholar 

  30. Guy RH, Hadgraft J (1989) Selection of dug candidates for transdermal drug delivery. In: Walters KA, Hadgraft J (eds) Transdermal drug delivery developmental issues and research initiatives. Marcel Dekker, New York, pp 59–81

    Google Scholar 

  31. Hadgraft J (2001) Skin, the final frontier. Int J Pharm 224:1–18

    Article  CAS  PubMed  Google Scholar 

  32. Heard CM, Kung D, Thomas CP (2006) Skin penetration enhancement of mefenamic acid by ethanol and 1, 8-cineole can be explained by the ‘pull’ effect. Int J Pharm 321:167–170

    Article  CAS  PubMed  Google Scholar 

  33. Hostettmann K, Marston A (1995) Chemistry and pharmacology of natural products: Saponins. Cambridge University Press, Cambridge, pp 234–284

    Google Scholar 

  34. Hsu LR, Huang YB, Wu PC, Tsai YH (1994) Percutaneous absorption of piroxicam from FAPG base through rat skin: effects of fatty acid added to FAPG base. Int J Pharm 106:1–6

    Article  CAS  Google Scholar 

  35. Ibrahim SA, Li SK (2010) Efficiency of fatty acids as chemical penetration enhancers: mechanisms and structure enhancement relationship. Pharm Res 27(1):115–125

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Jain R, Aqil M, Ahad A, Ali S, Khar RK (2008) Basil oil is a promising skin permeation enhancer for transdermal delivery of labetalol hydrochloride. Drug Dev Ind Pharm 34:384–389

    Article  CAS  PubMed  Google Scholar 

  37. Kang L, Yap CW, Lim PFC, Chen YZ, Ho PC, Chan YW, Wong GP, Chan SY (2007) Formulation development of transdermal dosage form: quantitative structure activity relationship model for predicting activity of terpenes that enhance drug penetration through human skin. J Control Release 120:211–219

    Article  CAS  PubMed  Google Scholar 

  38. Kanikkannan N, Babu RJ, Singh M (2006) Structure-activity relationship of chemical penetration enhancers. In: Smith EW, Maibach HI (eds) Percutaneous penetration enhancers, 2nd edn. CRC Press, Florida, pp 17–32

    Google Scholar 

  39. Kanikkannan N, Singh M (2002) Skin permeation enhancement effect and skin irritation of saturated fatty alcohols. Int J Pharm 248(1–2):219–228

    Article  CAS  PubMed  Google Scholar 

  40. Kim MJ, Doh HJ, Choi MK, Chung SJ, Shim CK, Kim DD, Kim JS, Yong CS, Choi HG (2008) Skin permeation enhancement of diclofenac by fatty acids. Drug Deliv 15(6):373–379

    Article  CAS  PubMed  Google Scholar 

  41. Kimura C, Nakanishi T, Tojo K (2007) Skin permeation of ketotifen applied from stick-type formulation. Eur J Pharm Biopharm 67:420–424

    Article  CAS  PubMed  Google Scholar 

  42. Klang V, Matsko N, Zimmermann NM, Vojnikovic E, Valenta C (2010) Enhancement of stability and skin permeation by sucrose stearate and cyclodextrins in progesterone nanoemulsions. Int J Pharm 393(1–2):153–161

    Article  Google Scholar 

  43. Kligman AM (1965) Topical pharmacology and toxicology of dimethylsulfoxide. J Am Med Assoc 193:796–804

    Article  CAS  Google Scholar 

  44. Komata Y, Inaoka M, Kaneko A, Fujie T (1992) In vitro percutaneous absorption of thiamine disulfide from a mixture of propylene glycol and fatty acid. J Pharm Sci 81:744–746

    Article  CAS  PubMed  Google Scholar 

  45. Kunta JR, Goskonda VR, Brotherton HO, Khan MA, Reddy IK (1997) Effect of menthol and related terpenes on the percutaneous absorption of propranolol across excised hairless mouse skin. J Pharm Sci 86:1369–1373

    Article  CAS  PubMed  Google Scholar 

  46. Melzig MF, Bader G, Loose R (2001) Investigations of the mechanism of membrane activity of selected triterpenoid saponins. Planta Med 67:43–48

    Article  CAS  PubMed  Google Scholar 

  47. Menin L, Panchichkina M, Keriel C, Olivares J, Braun U, Seppert EK, Saks VA (2001) Macro-compartmentation of total creatine in cardiomyocytes revisited. Mol Cell Biochem 220:149–159

    Article  CAS  PubMed  Google Scholar 

  48. Merfort I, Heilmann J, Hagedorn-Leweke U, Lippold BC (1994) In vivo skin permeation studies of chamomile flavones. Pharmazie 49(7):509–511

    CAS  PubMed  Google Scholar 

  49. Moghimipour E, Sajadi Tabassi SA, Ramazani M, Lobenberg R (2002) Enhanced permeability of gentamicin sulfate through shed snake-skin and liposomal membranes by different enhancers. IJBMS 6(1):9–20

    Google Scholar 

  50. Mohammadi-Samani S, Jamshidzadeh A, Montaseri H, Rangbar-Zahedani M, Kianrad R (2010) The effects of some permeability enhancers on the percutaneous absorption of lidocaine. Pak J Pharm Sci 23(1):83–86

    CAS  PubMed  Google Scholar 

  51. Morimoto K, Tojima H, Haruta T, Suzuki M, Kakemi M (1996) Enhancing effect of unsaturated fatty acids with various structures on the permeation of indomethacin through rat skin. J Pharm Pharmacol 48:1133–1137

    Article  CAS  PubMed  Google Scholar 

  52. Namba T, Sekiya K, Kadota S, Hattori M, Katayama K, Koizumi T (1992) Studies on the baths with crude drug: the effects of Senkyu extract as skin penetration enhancer. Yakugaku Zasshi 112(9):638–644

    CAS  PubMed  Google Scholar 

  53. Namba T, Sekiya K, Toshinal A, Kadota S, Hatanaka T, Katayama K, Koizumi T (1995) Study on baths with crude drug. II: the effects of Coptidis rhizoma extracts as skin permeation enhancer. Yakugaku Zasshi 115(8):618–625

    CAS  PubMed  Google Scholar 

  54. Nokhodchi A, Nazemiyeh H, Ghafourian T, Hassan-Zahed D, Valizadeh H, Bahary LA (2002) The effect of glycyrrhizin on the release rate and the skin permeation of diclofenac sodium from topical formulations. Farmao 57(11):883–888

    Article  CAS  Google Scholar 

  55. Ogiso T, Shintani M (1990) Mechanism for the enhancement effect of fatty acids on the percutaneous absorption of propranolol. J Pharm Sci 79:1065–1071

    Article  CAS  PubMed  Google Scholar 

  56. Oh HJ, Oh YK, Kim CK (2001) Effects of vehicles and enhancers on transdermal delivery of melatonin. Int J Pharm 212:63–71

    Article  CAS  PubMed  Google Scholar 

  57. Okamoto H, Ohyabu M, Hashida M (1987) Enhanced penetration of mitomycin C through hairless mouse and rat skin by enhancers with terpene moieties. J Pharm Pharmacol 39:531–534

    Article  CAS  PubMed  Google Scholar 

  58. Pfister WR, Hsieh DS (1990) Permeation enhancers compatible with transdermal drug delivery system. Part II: system design considerations. Med Device Technol 1:28–33

    CAS  PubMed  Google Scholar 

  59. Plock A, Sokolowska-Kohler W, Presber W (2001) Application of flow cytometry and microscopical methods to characterize the effect of herbal drugs on leishmania spp. Exp Parasitol 97:141–153

    Article  CAS  PubMed  Google Scholar 

  60. Rhee YS, Choi JS, Park ES (2001) Transdermal delivery of ketoprofen using microemulsions. Int J Pharm 228:161–170

    Article  CAS  PubMed  Google Scholar 

  61. Sapra B, Jain S, Tiwary AK (2008) Transdermal delivery of carvedilol containing glycyrrhizin and chitosan as permeation enhancers: biochemical, biophysical, microscopic and pharmacodynamic evaluation. Drug Deliv 15(7):443–454

    Article  CAS  PubMed  Google Scholar 

  62. Sapra B, Jain S, Tiwary AK (2009) Effect of Asparagus racemosus extract on transdermal delivery of carvedilol: a mechanistic study. Pharm Sci Tech 10(1):199–210

    Article  CAS  Google Scholar 

  63. Seeman P (1974) Ultra-structure of membrane lesions in immune lysis, osmotic lysis and drug-induced lysis. Fed Proc 33:2116–2124

    CAS  PubMed  Google Scholar 

  64. Seeman P, Cheng D, Iles GH (1973) Structure of membrane holes in osmotic and saponin hemolysis. J Cell Biol 56:519–527

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Southwell D, Barry BW (1983) Penetration enhancers for human skin: mode of action of 2-pyrrolidone and dimethylformamide on partition and diffusion of model compounds water, n-alcohol and caffeine. J Invest Dermatol 80(6):507–514

    Article  CAS  PubMed  Google Scholar 

  66. Thakur RA, Wang Y, Michniak BB (2006) Essential oils and terpenes. In: Smith EW, Maibach HI (eds) Percutaneous penetration enhancers, 2nd edn. CRC Press, Boca Raton, pp 159–173

    Google Scholar 

  67. Vaddi HK, Ho PC, Chan SY (2000) 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

    Article  Google Scholar 

  68. Wang Y, Thakur R, Fan Q, Michniak B (2005) Transdermal iontophoresis: combination strategies to improve transdermal iontophoretic drug delivery. Eur J Pharm Biopharm 60(2):179–191

    Article  CAS  PubMed  Google Scholar 

  69. William AC, Barry BW (2004) Penetration enhancers. Adv Drug Deliv Rev 56:603–618

    Article  Google Scholar 

  70. Williams AC, Barry BW (1991) The enhancement index concept applied to terpene penetration enhancer for human skin and model lipophilic (oestradiol) and hydrophilic (5 fluorouracil) drugs. Int J Pharm 74:157–168

    Article  CAS  Google Scholar 

  71. Woldemichael GM, Wink M (2001) Identification and biological activities of triterpenoid saponins from Chenopodium quinoa. J Agric Food Chem 49:2327–2332

    Article  CAS  PubMed  Google Scholar 

  72. Yamane MA, Williams AC, Barry BW (1995) Effect of terpenes and oleic acid as skin penetratin enhancers toward 5-Fluorouracil as assessed with time; permeation partitioning and differential scanning calorimetry. Int J Pharm 116:237–251

    Article  CAS  Google Scholar 

  73. Yamane MA, Williams AC, Barry BW (1995) Terpenes penetration enhancers in propylene glycol/water co-solvent system effectiveness and mechanism of action. J Pharm Pharmacol 47:978–989

    Article  CAS  PubMed  Google Scholar 

  74. Yamasaki Y, Ito K, Enomoto Y, Sutko JL (1987) Alterations by saponins of passive Ca2+ permeability and Na+–Ca2+ exchange activity of canine cardiac sarcolemmal vesicles. Biochem Biophys Acta 897:481–487

    Article  CAS  PubMed  Google Scholar 

  75. Deng S, May BH, Zhang AL, Lu C, Xue CC (2013) Topical herbal medicine combined with pharmacotherapy for psoriasis: a systematic review and meta-analysis. Arch Dermatol Res 305:179–189

    Article  CAS  PubMed  Google Scholar 

  76. Kage M, Tokudome Y, Hashimoto F (2013) Permeation of hyaluronan tetrasaccharides through hairless mouse skin: an in vitro and in vivo study. Arch Dermatol Res 305:69–77

    Article  CAS  PubMed  Google Scholar 

  77. Kataoka S, Hattori K, Date A, Tamura H (2013) Human keratinocyte caspase-14 expression is altered in human epidermal 3D models by dexamethasone and by natural products used in cosmetics. Arch Dermatol Res. doi:10.1007/s00403-013-1359-0

    PubMed  Google Scholar 

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Patil, U.K., Saraogi, R. Natural products as potential drug permeation enhancer in transdermal drug delivery system. Arch Dermatol Res 306, 419–426 (2014). https://doi.org/10.1007/s00403-014-1445-y

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