醋甲唑胺眼用混悬剂的家兔房水药动学

Ocular pharmacokinetics of methazolamide ophthalmic suspension in rabbit aqueous humor

醋甲唑胺是一种碳酸酐酶抑制剂类的抗青光眼药物,其口服制剂被广泛应用于临床。为减少其全身不良反应,研究开发可局部给药的醋甲唑胺眼用混悬剂,并以醋甲唑胺口服片剂为对照,采用微透析技术研究其在家兔房水中的药动学。将药物在一定条件下球磨后,以一定浓度的卡波普940(处方1)或卡波普974(处方2)为助悬剂可以制得符合中国药典要求的均一、稳定的眼用混悬剂。家兔眼内药动学结果显示:处方1(含0.4%卡波普940)的药动学参数为:AUC=(109838.3±28081.26)ng·min/mL,cmax=(1535.60±125.75)ng/mL,tmax=(50±8.66)min;处方2(含0.45%卡波普974)的药动学参数为:AUC=(116803.1±21015.71)ng·min/mL,cmax=(1399.78±136.45)ng/mL,tmax=(30±0.00)min;市售醋甲唑胺片(尼目克司)的房水药动学参数为:AUC=(59197.07±10020.72)ng·min/mL,cmax=(313.96±6.57)ng/mL,tmax=(85±17.32)min。处方1和处方2的AUC分别是市售片剂的1.86倍和1.97倍(P<0.05)。结果表明,醋甲唑胺的眼用混悬剂可以显著提高药物在眼内的生物利用度,达到了局部用药制剂的设计要求。

Methazolamide （ MTZ） is a carbonic anhydrase inhibitor widely used in oral administration in the treatment of glaucoma. Topical formulations of MTZ ophthalmic suspension were developed to avoid the systemic sideeffects. Micronized drug obtained by ball milling was suspended in the solutions of Carbopol 940 （ Formulation 1） or Carbopol 974 （ Formulation 2） of appropriate concentrations to develop uniform and stable MTZ ophthalmic suspension. The pharmacokinetic profiles of the ophthalmic suspensions in rabbit aqueous humor were investigated by the microdialysis technique using orally administered MTZ tablets as the control. It was shown in aqueous humor that the pharmacokinetic parameters （ AUC,cmax,and tmax） of Formulation 1 （ with 0. 4% Carbopol 940） were estimated to be （ 109 838. 3 ± 28 081. 26） ng· min /mL,（ 1 535. 60 ± 125. 75） ng /mL,and （ 50 ± 8. 66） min,respectively; those of Formulation 2 （ with 0. 45% Carbopol 974） （ 116 803. 1 ± 21 015. 71） ng · min /mL, （ 1 399. 78 ± 136. 45） ng /mL,and （ 30 ± 0. 00） min,respectively; those of MTZ tablets （ 59 197. 07 ± 10 020. 72） ng· min /mL,（ 313. 96 ± 6. 57） ng /mL,and （ 85 ± 17. 32） min,respectively. In addition,AUCs of Formulation 1 and Formulation 2 were 1. 86 and 1. 97 times higher than that of the control group,respectively （ P〈0.05） . These results indicate that the ophthalmic suspensions increased the bioavailability of MTZ in the eye aqueous humor,which is of significance in the development of topical dosage form of MTZ.