百草伤膏凝胶贴膏的制备及其对骨关节炎的药效学评价

Preparation of Baicaoshanggao Plaster and its pharmacodynamic evaluation on osteoarthritis

关键词:  百草伤膏  凝胶贴膏  体外经皮渗透  骨关节炎  安全性

Key words:  Baicaoshanggao  gel plaster  in vitro transdermal permeation  osteoarthritis  Safety

摘要:

目的 将传统医疗机构制剂百草伤膏（Baicaoshanggao，BCSG）改良为现代凝胶贴膏制剂，并对其处方工艺、体外释放、经皮渗透、安全性及抗骨关节炎作用进行评价。方法 采用低温交联-高速搅拌技术制备百草伤膏凝胶贴膏（Baicaoshanggao Plaster，BCTG）；通过单因素结合Box-Behnken响应面设计，以外观形状、赋形性、初黏力、持黏力、剥离强度、黏着力为综合评分指标对BCTG处方工艺进行优化；以丁香酚、反式茴香脑、龙脑、乌头总碱（乌头碱、次乌头碱、新乌头碱）、樟脑和对甲氧基肉桂酸乙酯为指标成分，采用桨碟法和Franz扩散池法分别考察BCTG的体外释放和体外经皮渗透；采用改良Hulth法构建大鼠骨关节炎模型评价BCTG的安全性和抗骨关节炎作用。结果 本研究成功制备了BCTG，筛选的最优基质处方为23.642 g甘油、6.314 g NP-700、45 mg甘羟铝、0.933 g醇浸膏、3 mL乙醇、27.946 g水、1.8 mg EDTA-2Na、33 mg酒石酸和1.166 g水浸膏。BCTG指标成分丁香酚、反式茴香脑、龙脑、乌头总碱（乌头碱、次乌头碱、新乌头碱）、樟脑和对甲氧基肉桂酸乙酯在22 h的累计释放量分别为55.34、18.04、158.52、455.64、2185.44和2.73 μg·cm-2，累积透过量分别为37.47、12.27、111.75、317.86、1131.82和2.07 μg·cm-2。相较BCSG，BCTG对皮肤损伤较低，表现出更高的生物相容性和安全性。行为学、炎症因子表达以及HE染色结果证明BCTG具有良好的抗骨关节炎作用，其疗效与BCSG相近。结论 BCTG具有良好的体外经皮渗透性和抗骨关节炎作用，且皮肤外用安全可靠，为传统贴膏向现代剂型凝胶贴膏转型与开发提供思路。

Abstract:

OBJECTIVE This study aims to modernize the traditional preparations in medical institutions, Baicaoshanggao (BCSG), into a contemporary gel paste formulation, and to assess its formulation process, in vitro release, transdermal penetration, safety, and anti-osteoarthritic effects. METHODS Baicaoshanggao Plaster (BCTG) was developed using low-temperature cross-linking and high-speed mixing technology. The BCTG formulation was optimized through single-factor investigation and Box-Behnken response surface design, focusing on appearance, excipient, initial adhesion, adhesion holding force, peel strength, and overall adhesion as evaluation criteria. The in vitro release and transdermal penetration of BCTG were examined using the paddle over disk method and Franz diffusion cell method, respectively, with eugenol, trans anethole, borneol, total aconitine (aconitine, hypaconitine, mesaconitine), camphor, and Ethyl 4-methoxycinnamate as marker compounds. The safety and anti-osteoarthritic efficacy of BCTG were evaluated in rat osteoarthritis model established using the modified Hulth technique. RESULTS The study successfully formulated BCTG, with the optimal matrix composition being 23.642 g glycerol, 6.314 g NP-700, 45 mg dihydroxyaluminium aminoacetate, 0.933 g alcohol extract, 3 mL ethanol, 27.946 g water, 1.8 mg EDTA-2Na, 33 mg tartaric acid, and 1.166 g aqueous extract. The cumulative release of the index components from BCTG reached 55.34, 18.04, 158.52, 455.64, 2185.44, and 2.73 μg·cm-2, respectively, with corresponding cumulative permeation amounts of 37.47, 12.27, 111.75, 317.86, 1131.82, and 2.07 μg·cm-2 over 22 hours. BCTG exhibited reduced skin irritation and enhanced biocompatibility and safety compared to BCSG. Behavioral assessments, inflammatory factor expression, and HE staining confirmed the potent anti-osteoarthritic effects of BCTG, comparable to BCSG. CONCLUSION BCTG demonstrates favorable in vitro transdermal permeability and anti-osteoarthritic properties, ensuring safety and reliability for topical application. This research provides insights into the transformation and development of traditional plasters into modern gel plaster formulations.