Roy S D, Gutierrez M, Flynn G L, Cleary G W
Cygnus Therapeutic Systems, Redwood City, CA 94063, USA.
J Pharm Sci. 1996 May;85(5):491-5. doi: 10.1021/js950415w.
Transdermal delivery of fentanyl from various adhesive matrix formulations to achieve a steady-state skin flux was investigated. For this purpose, various pressure-sensitive adhesives selected from the three chemical classes of polymers (polyisobutylene (PIB), acrylate, and silicone adhesives) were characterized with respect to fentanyl's solubility, diffusion coefficient, and permeability coefficient. The solubility of fentanyl in various pressure-sensitive adhesives at 32 degrees C was determined by the drug absorption-desorption method. The solubilities of fentanyl in these adhesives were in the following order: acrylate > silicones > PIB. The permeability coefficient and diffusion coefficient of fentanyl in these adhesives were determined by the membrane diffusion method. The diffusion coefficient rank order was silicone-2920 > silicone-2675 > or = acrylate > PIB. The release profiles of fentanyl in the aqueous buffer from these adhesives with 2-4% drug loading was evaluated. The release rate of fentanyl from the acrylate polymer was significantly higher than those of silicone and PIB adhesives. The in vitro flux of fentanyl through cadaver skin from various adhesives with 2% drug loading was determined at 32 degrees C using modified Franz diffusion cells. The skin fluxes of fentanyl from silicone-2920 and PIB adhesives were 6.3 +/- 0.7 and 3.1 +/- 0.3 micrograms/cm2/h, respectively. On the other hand, the skin fluxes of fentanyl from acrylate and silicone-2675 adhesive matrices were about 1 microgram/cm2/h. The effect of drug loading on skin flux was investigated using PIB as a model adhesive. The drug released in the phosphate buffer (pH = 6.0) increased linearly as the drug loading in the PIB was increased from 1% to 4%; and as the drug loading exceeded 4%, an initial burst effect followed by a zero-order release was observed. The skin flux of fentanyl increased proportionally as the drug loading in the PIB adhesive was increased from 1 to 4%, and a plateau was reached beyond 4% drug loading. These results suggest that fentanyl concentration in the PIB adhesive might have reached saturation above 4% drug loading and that the optimum skin flux was accomplished from such a system because of attainment of maximum thermodynamic activity.
研究了从各种粘性基质制剂经皮递送芬太尼以实现稳态皮肤通量的情况。为此，从聚合物的三类化学类别（聚异丁烯（PIB）、丙烯酸酯和硅酮粘合剂）中选择的各种压敏粘合剂，就芬太尼的溶解度、扩散系数和渗透系数进行了表征。通过药物吸收 - 解吸法测定了32℃时芬太尼在各种压敏粘合剂中的溶解度。芬太尼在这些粘合剂中的溶解度顺序如下：丙烯酸酯＞硅酮＞PIB。通过膜扩散法测定了芬太尼在这些粘合剂中的渗透系数和扩散系数。扩散系数的排序为：硅酮 - 2920＞硅酮 - 2675≥丙烯酸酯＞PIB。评估了载药量为2 - 4%的这些粘合剂在水性缓冲液中芬太尼的释放曲线。芬太尼从丙烯酸酯聚合物中的释放速率显著高于硅酮和PIB粘合剂。使用改良的Franz扩散池在32℃下测定了载药量为2%的各种粘合剂中芬太尼经尸体皮肤的体外通量。来自硅酮 - 2920和PIB粘合剂的芬太尼皮肤通量分别为6.3±0.7和3.1±0.3微克/平方厘米/小时。另一方面，来自丙烯酸酯和硅酮 - 2675粘合剂基质的芬太尼皮肤通量约为1微克/平方厘米/小时。以PIB作为模型粘合剂研究了载药量对皮肤通量的影响。在磷酸盐缓冲液（pH = 6.0）中释放的药物随着PIB中载药量从1%增加到4%呈线性增加；当载药量超过4%时，观察到初始突释效应，随后是零级释放。随着PIB粘合剂中载药量从1%增加到4%，芬太尼的皮肤通量成比例增加，载药量超过4%时达到平稳状态。这些结果表明，PIB粘合剂中芬太尼浓度在载药量超过4%时可能已达到饱和，并且由于达到了最大热力学活性，从这样的系统中实现了最佳皮肤通量。
