非洛地平-美托洛尔复方经皮给药系统设计及其降压有效性评价

Development of transdermal drug delivery system of felodipine-metoprolol and evaluation of its antihypertensive effects

目的：设计制备非洛地平．美托洛尔复方经皮给药系统，评价其对自发性高血压大鼠的降压作用。方法：50只3月龄自发性高血压大鼠随机分为5组进行长期给药治疗试验：空白贴剂对照组、非洛地平（FEL）-美托洛尔（MET）口服混悬液组（FEL1mg·kg^-1，MET10mg·kg^-1，qd）及FEL-MET透皮贴剂低、中、高剂量组[剂量分别为：FEL1mg·kg^-1，MET10mg·kg^-1；FEL3mg·kg^-1，MET30mg·kg^-1；FEL9mg·kg^-1，MET90mg·kg^-1，每隔2d给药1次]，共持续44d。另设同月龄正常血压Wistar大鼠为正常对照组。以无创性尾套法测定给药后大鼠血压和心率，评价经皮给药系统的降压作用。结果：FEL—MET透皮贴剂降压作用起效快、持续时间长，无耐药趋势，强度具有剂量依赖性。FEL—MET透皮贴剂低、中、高剂量分别使收缩压下降27．3～39．2mmHg（14．78％～21．22％），34．2～49．7mmHg（18．59％～27．01％）和50．8～68．6mmHg（27．34％～36．92％）；使舒张压下降19．8～32．6mmHg（12．90％～21．24％），22．7～34．9mmHg（15．30％～23．52％）和33．7～52．8mmHg（22．74％～35．63％）；降压效果显著优于FEL和MET长期口服联用（P〈0．05）。结论：FEL-MET经皮给药系统降压效果确切，作用平稳，持效时间长，使用方便，安全性高，适于高血压的长期药物治疗。

Objective ： To prepare transdermal drug delivery system （TDDS） of felodipine （ FEL）-metoprolol（MET） and evaluate its antihypertensive effects on spontaneously hypertensive rats（SHR）. Methods： 50 3-month-old SHRs were randomly divided into 5 groups of 10 ：FEL 1 mg·kg^-1-MET 10 mg·kg^-1 po once a day; placebo against drugs-carrying transdermal patch at the concentrations of FEL 1 mg·kg^-1-MET l0 mg·kg^-1, FEL 3 mg·kg^-1-MET 30 mg·kg^-1 , and FEL 9 mg·kg^-1-MET 90 mg·kg^-1 once every two days for 44 days. Normotensive rats（NTR） were used as normal control. The antihypertensive effects of felodipine-metoprolol TDDS were investiga- ted by using Medlab bio-signal operating system to determine tail arterial blood pressure（BP） and heart rate（HR） indirectly in SHRs. Results： Significant reduction （ P 〈 0.05 ） in BP for the transdermal patch in the long-term therapeutic experiment was rapid in onset and could last a long time. The antihypertensive activities of the TDDS were dose-dependent and significantly better （ P 〈 0.05 ） than those of long-term po felodipine-metoprolol in SHRs. The reduction in SBP for transdermal patch at low, medium, and high doses was 27.3 -39.2 mmHg（ 14.78% - 21.22%）, 34.2-49.7 mmHg （18.59% -27.01%） and 50.8-68.6 mmHg （27.34% -36.92%）, respectively; and that in DBP was 19.8 -32.6 mmHg （12.90% -21.24% ）, 22.7 -34.9 mmHg（15. 30% -23.52% ） and 33.7 -52.8 mmHg（ 22. 74% -35.63% ）, respectively. No drug resistance occurred. Conclusion： The felodipine-metoprolol TDDS could steadily maintain perfect BP control for quite a long time, minimize administration frequency and therefore improve patient compliance. for patients with hypertension. Thus it is effective and well tolerated as a long-term therapy