目的 探究炮制对草乌Aconiti Kusnezoffii Radix（AKR）中6种乌头类生物碱（aconitine alkaloids，AAs）经皮吸收的影响，并研制含生草乌和制草乌Aconiti Kusnezoffii Radix Cocta（AKRC）提取物的压敏胶分散型贴片，考察其药效差异。方法 分别从生、制草乌中提取AAs，质量分数分别为59.3%和59.1%。提取出的AAs由乌头碱、新乌头碱、次乌头碱、苯甲酰乌头原碱（BAC）、苯甲酰新乌头原碱（BMA）和苯甲酰次乌头原碱（BHA）6种生物碱组成。经过炮制，BAC、BMA和BHA的质量分数分别由3.8%、9.2%、0.4%提高至22.7%、32.9%、2.1%，而乌头碱、新乌头碱、次乌头碱的质量分数分别由19.6%、24.3%、2.0%降低至0.5%、0.6%、0.3%。采用溶剂挥发法分别制备含有生、制草乌提取物的透皮贴片。在体外透皮实验中，考察了生、制草乌中AAs的经皮渗透性的差异，并优化贴片处方。最后，采用弗氏完全佐剂诱导的大鼠慢性炎症模型和醋酸诱导的小鼠扭体模型评价含生、制草乌最佳贴片的抗炎镇痛活性。结果 BMA在6种AAs中表现出最强的经皮渗透性。经过炮制，制草乌提取物中的BMA质量分数由9.2%增加到了32.9%。因此制草乌供给液中BMA的Q₂₄由（2.53±0.31）μg/cm²提高到了（5.51±0.69）μg/cm²（P<0.05）。油酸的渗透增强效果最大，渗透增强比分别为4.57（生草乌）和9.93（制草乌）。最佳配方为生或制草乌提取物（10%）、油酸（10%）、DURO-TAK^® 87-4098（压敏胶基质）和Scotchpak^TM 9707（背衬层）。最优制草乌贴片的AAs累积渗透量约为最优生草乌贴片的2倍。最佳制草乌透皮贴片较最佳生草乌贴片能显著降低大鼠类风湿性关节炎模型后爪肿胀度和小鼠扭体模型的扭体次数。结论 炮制草乌可提高其中AAs的皮肤渗透量，从而提高草乌透皮贴片的镇痛和抗炎作用，为采用炮制方法提高含草乌透皮贴片功效提供科学依据。

Objective To investigate the effect of processing on the transdermal absorption of six aconitine alkaloids (AAs) from Aconiti Kusnezoffii Radix (AKR), and develop drug-in-adhesive patches containing AKR and Aconiti Kusnezoffii Radix Cocta (AKRC) extract, so as to investigate the differences of their efficacy. Methods AAs was severally extracted from AKR and AKRC, and the content of AAs were 59.3% and 59.1%, respectively. The extracted AAs were composed of aconitine, mesaconitine, hypaconitine, benzoylaconine (BAC), benzoylmesaconine (BMA) and benzoylhypaconine (BHA). After processing, the content of BAC, BMA and BHA increased from 3.8%, 9.2% and 0.4% to 22.7%, 32.9% and 2.1%, respectively, while the content of aconitine, mesaconitine, and hypaconitine decreased from 19.6%, 24.3% and 2.0% to 0.5%, 0.6% and 0.3%, respectively. Then transdermal patches containing AKR and AKRC extract were prepared by the solvent evaporation technique, respectively. The difference of transdermal permeability of AAs in the AKR and AKRC was investigated and the formulation of the transdermal patch was optimized based on the in vitro skin permeation experiment. Finally, the anti-inflammatory and analgesic activity of AKR and AKRC optimal patches were evaluated using complete Freund's adjuvant (CFA)-induced chronic inflammation model of rat and acetic acid-induced writhing model of mice. Results BMA exhibited the strongest percutaneous permeability in AAs. After processing, the content of BMA in the AKRC extract increased from 9.2% to 32.9%. Therefore, the Q₂₄ of BMA in the donor solution of AKRC was increased from (2.53 ±0.31) μg/cm² to (5.51 ±0.69) μg/cm² (P < 0.05). Oleic acid showed the maximum permeation enhancement effect with the enhancement ratio values of 4.57 (AKR) and 9.93 (AKRC). The optimal formulation consisted of AKR or AKRC extract (10% of the matrix), oleic acid (10% of the matrix), DURO-TAK^® 87-4098 (pressure sensitive adhesive matrix) and Scotchpak™ 9707 (backing layer). Moreover, the cumulative amounts of AAs permeated per unit area in the optimal AKRC extract patch was about 2 times the optimal AKR extract patch. The optimal transdermal patches containing AKRC extract significantly reduced the swelling degree of hind paws and the number of writhing in rheumatoid arthritis rat model and writhing model of mice than the optimal AKR extract patch. Conclusion The processing of AKR could improve the skin permeation amount of the AAs, thus improving the analgesic and anti-inflammatory effects of the transdermal patch containing AKR extract, which provides scientific basis for improving the efficacy of the transdermal patch containing AKR extract by processing method.

R283.6

国家自然科学基金资助项目（81373367）；国家中医药管理局项目（201507004-03）