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AAPS PharmSci. Dec 2003; 5(4): 1–12.
Published online Oct 16, 2003. doi:  10.1208/ps050426
PMCID: PMC2750988

Amphiphilic star-like macromolecules as novel carriers for topical delivery of nonsteroidal anti-inflammatory drugs

Abstract

The objective of this study was to evaluate amphiphilic star-like macromolecules (ASMs) as a topical drug delivery system. Indomethacin, piroxicam, and ketoprofen were individually encapsulated into the ASMs using coprecipitation. The effects of the ASMs on percutaneous permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) across full thickness, hairless mouse skin were evaluated in vitro using modified Franz diffusion cells. In addition, solubility and in vitro release experiments were performed to characterize ASMs behavior in aqueous media. Poly(ethylene glycol) (PEG) and Pluronic P-85 were used as polymer controls to compare the role of PEG and amphiphilic behavior in the ASMs. In vitro release experiments indicated that ASMs can delay drug release (P[less than, with dot]05), whereas solubility measurements showed that ASMs can increase NSAIDs aqueous solubility (P[less than, with dot]05). Percutaneous permeation studies revealed that ASMs decreased both flux and Q24 of drugs compared with the control (P[less than, with dot]10). Skin pretreatment studies with ASM-containing solution before drug application demonstrated that pretreatment similarly influenced NSAID percutaneous permeation. In conclusion, ASMs likely slow drug permeation through 2 mechanisms, delayed drug diffusion from its core and skin dehydration by its shell. Thus, ASMs may be useful for delayed dermal delivery or prevention of compound permeation through the skin (eg, sunscreens, N,N-diethyl-m-toluamide [DEET]) from aqueous formulations.

Keywords: topical drug delivery, NSAIDs, polymeric micelle, permeation, drug release

References

1. Roberts M, Cross S. Percutaneous absorption of topically applied NSAIDs and other compounds: role of solute properties, skin physiology and delivery systems. Inflammopharmacology. 1999;7:339–350. doi: 10.1007/s10787-999-0028-6. [PubMed] [Cross Ref]
2. Hadgraft J, Plessis J, Goosen C. The selection of NSAIDs for dermal delivery. Int J Pharm. 2000;207:31–37. doi: 10.1016/S0378-5173(00)00517-2. [PubMed] [Cross Ref]
3. Beetge E, Plessis J, Goosen C. The influence of the physicochemical characteristics and pharmacokinetic properties of selected NSAIDs on their transdermal absorption. Int J Pharm. 2000;193:261–264. doi: 10.1016/S0378-5173(99)00340-3. [PubMed] [Cross Ref]
4. Cordero J, Camacho M, Obach R, Domenench J, Vila L. In vitro based index of topical anti-inflammatory activity to compare a series of NSAIDs. Eur J Pharm Biopharm. 2001;51:135–142. doi: 10.1016/S0939-6411(00)00149-1. [PubMed] [Cross Ref]
5. Valenta C, Wanka M, Heidlas J. Evaluation of novel soyalecithin formulations for dermal use containing ketoprofen as a model drug. J Control Release. 2000;63:165–173. doi: 10.1016/S0168-3659(99)00199-6. [PubMed] [Cross Ref]
6. Rhee Y, Choi J, Park E, Chi S. Transdermal delivery of ketoprofen using microemulsions. Int J Pharm. 2001;228:161–170. doi: 10.1016/S0378-5173(01)00827-4. [PubMed] [Cross Ref]
7. Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Biopharm. 2001;14:101–114. [PubMed]
8. Kabanov A, Batrakova E, Alakhov V. Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J Control Release. 2002;82:189–212. doi: 10.1016/S0168-3659(02)00009-3. [PubMed] [Cross Ref]
9. Kataoka K, Haraha A, Nagasaki Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev. 2001;47:113–131. doi: 10.1016/S0169-409X(00)00124-1. [PubMed] [Cross Ref]
10. Liu H, Jiang A, Guo J, Uhrich K. Unimolecular micelles: synthesis and characterization of amphiphilic polymer systems. J Polym Sci [A1] 1999;37:703–712.
11. Liu M, Kono K, Frechet J. Water-soluble dendritic unimolecular micelles: their potential as drug delivery agents. J Control Release. 2000;65:121–131. doi: 10.1016/S0168-3659(99)00245-X. [PubMed] [Cross Ref]
12. Liu H, Farrell S, Uhrich K. Drug release characteristics of unimolecular polymeric micelles. J Control Release. 2000;68:167–174. doi: 10.1016/S0168-3659(00)00247-9. [PubMed] [Cross Ref]
13. Kwon G, Naito M, Yokoyama M, Okano T, Sakurai Y, Kataoka K. Block copolymer micelles for drug delivery: loading and release of doxorubicin. J Control Release. 1997;48:195–201. doi: 10.1016/S0168-3659(97)00039-4. [Cross Ref]
14. Jansen JF, Brabander-Van Den Berg E, Meijer E. Encapsulation of guest molecules into a dendritic box. Science. 1994;266:1226–1229. doi: 10.1126/science.266.5188.1226. [PubMed] [Cross Ref]
15. Cordero J, Alarcon N, Escribano E, Obach R, Domenech J. A comparative study of the transdermal penetration of a series of NSAIDs. J Pharm Sci. 1997;86:503–508. doi: 10.1021/js950346l. [PubMed] [Cross Ref]
16. Porzio S, Caselli G, Pellegrini L, Pallottini V, Clavenna G, Mellilo G. Efficacy of a new topical gel-spray formulation of ketoprofen lysine salt in the rat: percutaneous permeation in vitro and in vivo and pharmacological activity. Pharmacol Res. 1998;37:41–46. doi: 10.1006/phrs.1997.0260. [PubMed] [Cross Ref]
17. Fini G, Fazio G, Feroci G. Solubility and solubulization properties of NSAIDs. Int J Pharm. 1995;126:95–102. doi: 10.1016/0378-5173(95)04102-8. [Cross Ref]
18. Foldvari M. Non-invasive administration of drugs through the skin: challenges in delivery system design. Pharm Sci Technol Today. 2000;3:417–425. doi: 10.1016/S1461-5347(00)00317-5. [PubMed] [Cross Ref]
19. Touitou E, Meidan V, Horowitz E. Methods for quantitative determination of drug localized in the skin. J Control Release. 1998;56:7–21. doi: 10.1016/S0168-3659(98)00060-1. [PubMed] [Cross Ref]
20. Gwak H, Chun I. Effects of vehicles and penetration enhancers on the in vitro percutaneous absorption of tenoxicam through hairless mouse skin. Int J Pharm. 2002;236:57–64. doi: 10.1016/S0378-5173(02)00009-1. [PubMed] [Cross Ref]
21. Sintov A, Behar-Canetti C, Friedman Y, Tamarkin D. Percutaneous penetration and skin metabolism of ethylsalicylatecontaining agent, TU-2100: in vitro and in vivo evaluation in guinea pigs. J Control Release. 2002;79:113–122. doi: 10.1016/S0168-3659(01)00531-4. [PubMed] [Cross Ref]
22. Qui H, McCall J, Jun H. Formulation of topical insect repellent N,N-diethyl-m-toluamide (DEET): vehicle effects on DEET in vitro skin permeation. Int J Pharm. 1998;163:167–176. doi: 10.1016/S0378-5173(97)00379-7. [Cross Ref]
23. Walters K. Fundamentals of Percutaenous Penetration. In: Brain K. R., Walters K, editors. Perspectives in Percutaneous Penetration (PPP) 7th International Conference, La Grand Motte, France, April 2000. Cardiff: Publisher: STS Publishing Ltd.; 2000.
24. El-Kattan A, Asbill C, Michniak B. The effect of terpene enhancer lipophilicity on the percutaneous permeation of hydrocortisone formulated in HPMC gel systems. Int J Pharm. 2000;198:179–189. doi: 10.1016/S0378-5173(00)00330-6. [PubMed] [Cross Ref]
25. Bach M, Lippold B. Percutaneous penetration enhancement and its quantifications. Eur J Pharm Biopharm. 1998;46:1–13. doi: 10.1016/S0939-6411(97)00149-5. [PubMed] [Cross Ref]
26. Shah V, Elkin J, Williams R. Role of In Vitro Release Measurenent in Semisolid Dosage Forms. In: Bronaugh R, Maibach H, editors. Percutaneous Absorption: Drug-Cosmetics-Mechanism-Methodology. New York, NY: Marcel Dekker; 1999. pp. 555–569.
27. Kemppainen B. W, Reifenrath W. G. Methods for Skin Absorption. Boca Raton, FL: CRC Press; 1990.
28. Goosen C, Plessis J, Muller D, Rensburg L. Correlation between physicochemical characteristics, pharmacokinetic properties and transdermal absorption of NSAIDs. Int J Pharm. 1998;163:203–209. doi: 10.1016/S0378-5173(97)00359-1. [Cross Ref]
29. Linse P. Micellization of poly(ethylene oxide)-poly(propylene oxide) block copolymers in aqueous solution. Macromolecules. 1993;26:4437–4449. doi: 10.1021/ma00069a007. [Cross Ref]
30. Walters K, Brain K. Dermatological Formulations and Transdermal Systems. In: Walters K, editor. Dermatological and Transdermal Formulations. New York, NY: Marcel Dekker; 2002. pp. 401–499.
31. Fares H, Zatz J. Measurement of drug release from topical gels using two types of apparatus. J Pharm Technol. 1995;1:52–56.
32. Smith E, Surber C, Maibach H. Topical Dermatological Vehicles: A Holistic Approach. In: Bronaugh R, Maibach H, editors. Percutaneous Absorption: Drugs-Cosmetics-Mechanisms-Methodology. New York, NY: Marcel Dekker; 1999. pp. 779–785.
33. Bunge A. Release rates from topical formulations containing drugs in suspension. J Control Release. 1998;52:141–148. doi: 10.1016/S0168-3659(97)00211-3. [PubMed] [Cross Ref]
34. Criag D. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm. 2002;231:131–144. doi: 10.1016/S0378-5173(01)00891-2. [PubMed] [Cross Ref]
35. Wissing S, Muller R. Solid lipid nanoparticles as carrier for sunscreens: in vitro release and in vivo skin penetration. J Control Release. 2002;81:213–218. doi: 10.1016/S0168-3659(02)00056-1. [PubMed] [Cross Ref]
36. Soppimath K, Aminabhavi T, Kulkarni A, Rudzinski W. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release. 2001;70:1–20. doi: 10.1016/S0168-3659(00)00339-4. [PubMed] [Cross Ref]
37. Higaki K, Asai M, Suyama T, Nakayama K, Ogawara K, Kimura T. Estimation of intradermal disposition kinetics od drugs: II. Factors determining penetration of drugs from viable skin to muscular layer. Int J Pharm. 2002;239:129–141. doi: 10.1016/S0378-5173(02)00084-4. [PubMed] [Cross Ref]
38. Shin S, Cho C, Oh I. Enhanced efficacy by percutaneous absorption of piroxicam from the poloxamer gel in rats. Int J Pharm. 2000;193:213–218. doi: 10.1016/S0378-5173(99)00339-7. [PubMed] [Cross Ref]
39. Touitou E, Godin B, Karl Y, Bujanover S, Becker Y. Oleic acid, a skin penetration enhancer, affects Langerhans cells and corneocytes. J Control Release. 2002;80:1–7. doi: 10.1016/S0168-3659(02)00004-4. [PubMed] [Cross Ref]
40. Kalia Y, Guy R. Modeling transdermal drug release. Adv Drug Deliv Rev. 2001;48:159–172. doi: 10.1016/S0169-409X(01)00113-2. [PubMed] [Cross Ref]
41. Moser K, Krivet K, Kalia Y, Guy R. Enhanced skin permeation of a lipophilic drug using supersaturated formulations. J Control Release. 2001;73:245–253. doi: 10.1016/S0168-3659(01)00290-5. [PubMed] [Cross Ref]
42. Yokoyama M. Novel Passive Targetable Drug Delivery With Polymeric Micelles. In: Okano T, editor. Biorelated Polymers and Gels. San Diego, CA: Academic Press; 1998. pp. 193–229.
43. Xing L, Mattice W. Strong solubilization of small molecules by triblock-copolymer micelles in selective solvents. Macromolecules. 1997;30:1711–1717. doi: 10.1021/ma961175p. [Cross Ref]
44. Alexandridis P. Amphiphilic copolymers and their application. Curr Opinions Colloid Interface Sci. 1996;1:490–501.
45. Sridevi S, Diwan PR. Optimized transdermal delivery of ketoprofen using pH and hydroxypropyl-beta-cyclodextrin as coenhancers. Eur J Pharm Biopharm. 2002;54:151–154. doi: 10.1016/S0939-6411(02)00056-5. [PubMed] [Cross Ref]
46. Yang L, Alexandridis P. Physicochemical aspects of drug delivery and release from polymer-based colloids. Curr Opinions Colloid Interface Sci. 2000;5:132–143. doi: 10.1016/S1359-0294(00)00046-7. [Cross Ref]
47. Kozlov M, Melik-Nubarov N, Batrakova E, Kabanov A. Relationship between pluronic block copolymers structure, critical micellization concentration and partitioning coefficients of low molecular mass solutes. Macromolecules. 2000;33:3305–3313. doi: 10.1021/ma991634x. [Cross Ref]
48. Yu B, Okano T, Kataoka K, Kwon G. Polymeric micelles for drug delivery: solubilization and haemolytic activity of amphotericin B. J Control Release. 1998;53:131–136. doi: 10.1016/S0168-3659(97)00245-9. [PubMed] [Cross Ref]
49. Trubetosky V. Polymeric micelles as carriers of diagnostic agents. Adv Drug Deliv Rev. 1999;37:81–88. doi: 10.1016/S0169-409X(98)00100-8. [PubMed] [Cross Ref]
50. Jenning V, Scafer-Korting M, Gohla S. Vitamin A-loaded solid lipid nanoparticles for topical use: drug release properties. J Control Release. 2000;66:115–126. doi: 10.1016/S0168-3659(99)00223-0. [PubMed] [Cross Ref]
51. Tsai J, Hung P, Shen H. Molecular weight dependence of PEG penetration across acetone-disrupted permeability barrier. Arch Dermatol Res. 2001;293:302–307. doi: 10.1007/s004030100229. [PubMed] [Cross Ref]
52. Lotem M, Hubert A, Layass O, Goldenhersh M. Skin toxic effects of polyethylene glycol coated liposomal doxorubicin. Arch Dermatol Res. 2000;136:1475–1480. doi: 10.1001/archderm.136.12.1475. [PubMed] [Cross Ref]
53. Ito M, O'Conner D. Skin pretreatment and the use of transdermal clonidine. Am J Med. 1991;91:42S–49S. doi: 10.1016/0002-9343(91)90062-3. [PubMed] [Cross Ref]
54. Ogiso T, Ninaka N, Iwaki M. Mechanism for enhancement effect of lipid disperse system on percutaneous absorption. J Pharm Sci. 1996;85:57–60. doi: 10.1021/js950178x. [PubMed] [Cross Ref]
55. Pugh W, Roberts M, Hadgraft J. Epidermal permeability-penetrant structure relationships: 3. The effect of hydrogen bonding interactions and molecular size on diffusion across the stratum corneum. Int J Pharm. 1996;138:149–165. doi: 10.1016/0378-5173(96)04533-4. [Cross Ref]
56. Bergh J, Bouwstra J, Junginger H, Wertz P. Elasticity of vesicles affects mouse skin structure and permeability. J Control Release. 1999;62:367–379. doi: 10.1016/S0168-3659(99)00168-6. [PubMed] [Cross Ref]
57. Foldvari M, Gesztes A, Mezei M. Dermal drug delivery by liposome encapsulation: clinical and electronic microscopic studies. J Microencapsul. 2001;7:479–489. doi: 10.3109/02652049009040470. [PubMed] [Cross Ref]

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