Kandimalla K, Kanikkannan N, Andega S, Singh M
College of Pharmacy, Florida A and M University, Tallahassee 32307, USA.
J Pharm Pharmacol. 1999 Jul;51(7):783-90. doi: 10.1211/0022357991773140.
Transdermal delivery of melatonin would be advantageous in the treatment of sleep disorders considering the short biological half-life of melatonin and its variable bioavailability via the oral route. This study looked at suitable penetration enhancers for the transdermal permeation of melatonin. The permeation of melatonin was enhanced by all saturated and unsaturated fatty acids across both rat and porcine skin. There was a parabolic relationship between the carbon chain length of saturated fatty acids and the enhancement of melatonin permeation across rat and porcine skin. For rat skin, the maximum flux was observed with undecanoic acid (45.33 microg cm(-2) h(-1)) which enhanced the flux of melatonin 8.6 times compared with the control, whereas lauric acid produced the maximum flux of melatonin (24.98 microg cm(-2) h(-1); 4-7 times) across porcine skin. An increase in the number of double bonds in cis-9-octadecanoic acid increased the flux of melatonin across rat skin. In contrast, with porcine skin, the flux of melatonin decreased as the number of double bonds increased, although the flux values were not statistically significant. Treatment of rats with undecanoic acid, oleic acid and linolenic acid for 3 h using Hill top chamber enhanced the transepidermal water loss significantly. The maximum transepidermal water loss was observed with undecanoic acid and linolenic acid among saturated and unsaturated fatty acids, respectively. Nonanoic acid and myristic acid did not cause a significant change in the transepidermal water loss. The enhancement effect of saturated fatty acids on the permeation of melatonin was dependent on the chain-length of the fatty acid in both rat and porcine skin. While an increase in the number of double bonds in the fatty acid increased the flux of melatonin in rat skin, no significant difference in the flux was observed with porcine skin. The permeation enhancement of melatonin by saturated and unsaturated fatty acids across rat skin was significantly higher than that of porcine skin. A positive correlation was observed between the permeation enhancement effect of the fatty acids across rat skin in-vitro and the transepidermal water loss in rats in-vivo, suggesting that there is a similarity in the mechanism by which fatty acids enhance the permeation of melatonin and in the enhancement of transepidermal water loss. We conclude that saturated fatty acids such as undecanoic acid or lauric acid which showed maximum permeation across rat and porcine skin, respectively, may be used as potential penetration enhancers in the development of a transdermal delivery system for melatonin.
考虑到褪黑素的生物半衰期较短且口服途径的生物利用度可变，经皮递送褪黑素在治疗睡眠障碍方面具有优势。本研究考察了适合褪黑素经皮渗透的渗透促进剂。所有饱和脂肪酸和不饱和脂肪酸均能增强褪黑素在大鼠和猪皮肤中的渗透。饱和脂肪酸的碳链长度与褪黑素在大鼠和猪皮肤中的渗透增强之间呈抛物线关系。对于大鼠皮肤，观察到十一烷酸的通量最大（45.33微克·厘米⁻²·小时⁻¹），与对照组相比，其使褪黑素通量提高了8.6倍，而月桂酸在猪皮肤中产生了最大的褪黑素通量（24.98微克·厘米⁻²·小时⁻¹；4 - 7倍）。顺 - 9 - 十八碳烯酸双键数量的增加提高了褪黑素在大鼠皮肤中的通量。相反，对于猪皮肤，随着双键数量增加，褪黑素通量降低，尽管通量值无统计学显著差异。使用顶空扩散池用十一烷酸、油酸和亚麻酸处理大鼠3小时，显著增加了经皮水分流失。在饱和脂肪酸和不饱和脂肪酸中，分别观察到十一烷酸和亚麻酸导致的经皮水分流失最大。壬酸和肉豆蔻酸未引起经皮水分流失的显著变化。饱和脂肪酸对褪黑素渗透的增强作用在大鼠和猪皮肤中均取决于脂肪酸的链长。虽然脂肪酸双键数量的增加提高了大鼠皮肤中褪黑素的通量，但在猪皮肤中通量未观察到显著差异。饱和脂肪酸和不饱和脂肪酸对褪黑素在大鼠皮肤中的渗透增强显著高于猪皮肤。观察到脂肪酸在体外对大鼠皮肤的渗透增强作用与体内大鼠经皮水分流失之间存在正相关，表明脂肪酸增强褪黑素渗透的机制与增强经皮水分流失的机制具有相似性。我们得出结论，分别在大鼠和猪皮肤中显示出最大渗透的饱和脂肪酸，如十一烷酸或月桂酸，可作为开发褪黑素经皮递送系统的潜在渗透促进剂。
