Kim D D, Chien Y W
Controlled Drug-Delivery Research Center, Rutgers, State University of New Jersey, College of Pharmacy, Piscataway 08854, USA.
J Pharm Sci. 1995 Sep;84(9):1061-6. doi: 10.1002/jps.2600840906.
The stability of dideoxynucleoside-type anti-HIV drugs in solution when in contact with hairless rat skin was investigated in order to study the feasibility of their transdermal delivery. The freshly excised dorsal region of hairless rat skin was mounted on Valia-Chien skin permeation cells, and both epidermis (donor) and dermis (receptor) were extracted with isotonic phosphate buffer (pH 7.4) at 37 degrees C for 24 h. Zalcitabine (DDC), didanosine (DDI), and zidovudine (AZT) were found to be stable in the extract of the epidermis at 37 degrees C for at least 30 h. However, DDC and DDI degraded in the extract of the dermis following first-order kinetics at both 25 and 37 degrees C, while AZT was stable at 37 degrees C for at least 30 h. The degradation mechanism(s) of DDC and DDI was (were) studied by analyzing HPLC chromatograms and by evaluating the drug stability in the extract which was filtered to remove any microbes. An unidentified peak produced by DDC in the dermis extract did not appear when the drug was added to the filtered extract, which suggested a bacterial degradation of DDC. On the other hand, DDI was unstable even in the filtered extract and produced a degradation product which corresponded to hypoxanthine, which suggested that a cutaneous enzyme is also involved in the degradation of DDI. DDC was stabilized by the addition of 0.01% (w/v) of an antibacterial agent, such as thimerosal or gentamicin, in the receptor solution, while DDI was stabilized by 0.01% (w/v) purine nucleoside phosphorylase inhibitor, i.e., p-chloromercuribenzoic acid. These results show the importance of stability studies when designing skin permeation experiments using hairless rat since compounds with similar chemical structures can have different stability profiles when in contact with hairless rat skin.
为了研究双脱氧核苷类抗艾滋病病毒药物经皮给药的可行性，对其在溶液中与无毛大鼠皮肤接触时的稳定性进行了研究。将刚切除的无毛大鼠背部皮肤安装在Valia-Chien皮肤渗透细胞上，表皮（供体）和真皮（受体）均在37℃下用等渗磷酸盐缓冲液（pH 7.4）提取24小时。发现扎西他滨（DDC）、去羟肌苷（DDI）和齐多夫定（AZT）在37℃下在表皮提取物中至少30小时内是稳定的。然而，DDC和DDI在25℃和37℃下在真皮提取物中均遵循一级动力学降解，而AZT在37℃下至少30小时内是稳定的。通过分析高效液相色谱图以及评估过滤以去除任何微生物的提取物中的药物稳定性，研究了DDC和DDI的降解机制。当将药物添加到过滤后的提取物中时，真皮提取物中由DDC产生的一个未鉴定峰未出现，这表明DDC存在细菌降解。另一方面，DDI即使在过滤后的提取物中也不稳定，并产生了一种与次黄嘌呤相对应的降解产物，这表明一种皮肤酶也参与了DDI的降解。在受体溶液中添加0.01%（w/v）的抗菌剂（如硫柳汞或庆大霉素）可使DDC稳定，而添加0.01%（w/v）的嘌呤核苷磷酸化酶抑制剂即对氯汞苯甲酸可使DDI稳定。这些结果表明，在设计使用无毛大鼠的皮肤渗透实验时，稳定性研究非常重要，因为具有相似化学结构的化合物与无毛大鼠皮肤接触时可能具有不同的稳定性特征。
