目的 制備坎地沙坦（CD）-雷公藤紅素（CEL）共載還原敏感膠束，并對其進行制劑學(xué)評價。方法 以合成的具有還原敏感性的透明質(zhì)酸-胱氨-CD（HCCD）作為聚合物材料，透明質(zhì)酸-1,6-己二胺-CD（HHCD）作為非還原敏感對照，單因素法進行制備方法、溶劑、CEL與HCCD質(zhì)量比的篩選，制備HHCD、HCCD、HHCD/CEL、HCCD/CEL 4種聚合物膠束。采用芘-丙酮法測定樣品的臨界膠束濃度；應(yīng)用電位粒徑測定儀分析各膠束粒徑、聚合物分散性指數(shù)（PDI）、Zeta電位； HPLC法檢測載藥量、包封率；透射電鏡法觀察形態(tài)；進行各膠束儲存穩(wěn)定性、血漿穩(wěn)定性、凍干粉復(fù)溶穩(wěn)定性考察及溶血情況考察；考察0、10 μmol·L^-1、10、20 mmol·L^-1谷胱甘肽（GSH）對膠束粒徑的影響；考察在含0、10 μmol·L^-1、10、20 mmol·L^-1 GSH的釋放介質(zhì)中HHCD/CEL、HCCD/CEL體外釋放行為。結(jié)果 制備的HHCD、HCCD的臨界膠束濃度值約為4.5 μg·mL^-1，4種膠束的粒徑在200 nm左右，PDI均小于0.2，且分布較為均勻； 4種聚合物膠束的電位分別為-24.7、-29.2、-25.9、-32.1 mV； 4種膠束的載藥量和包封率分別在8.9%和73%以上； 4種膠束的形態(tài)均呈類球形，穩(wěn)定性良好，不發(fā)生溶血； HHCD/CEL膠束在濃度為0、10 μmol·L^-1、10、20 mmol·L^-1的GSH條件下粒徑均無明顯變化，而HCCD/CEL膠束在GSH的濃度為10、20 mmol·L^-1時粒徑發(fā)生明顯的變化；在GSH濃度為0、10 μmol·L^-1時，2種聚合物膠束中的藥物在48 h內(nèi)的釋放量均在21%左右。在GSH的濃度為10 mmol·L^-1時，HCCD/CEL中的2種藥物在24 h內(nèi)累積釋放量分別為40%、50%左右；在GSH濃度為20 mmol·L^-1時，HCCD/CEL中的藥物CD、CEL在24 h時累積釋放量達到70%左右，48 h時達到80%左右。結(jié)論 制備的還原敏感性膠束HCCD/CEL具有良好的穩(wěn)定性、還原敏感性。

Objective To prepare redox-sensitive prodrug micelles co-loaded with candesartan (CD) and celastrol (CEL) and evaluate their pharmaceutical properties. Methods The synthesized hyaluronic acid-cystamine-candesartan (HCCD) with reductive sensitivity was used as the polymer material, and hyaluronic acid-1,6-hexanediamine-candesartan (HHCD) was used as the non-reductive sensitive control. The preparation method, solvent, and the mass ratio of CEL to HCCD were screened by the single-factor method to prepare four types of polymer micelles: HHCD, HCCD, HHCD/CEL, and HCCD/CEL. The critical micelle concentration (CMC) of the samples was determined by the pyrene-acetone method. The particle size, polydispersity index (PDI), and Zeta potential of each micelle were analyzed by a particle size analyzer. The drug loading and encapsulation efficiency were detected by HPLC. The morphology was observed by transmission electron microscopy. The storage stability, plasma stability, and reconstitution stability of the freeze-dried powder of each micelle were investigated, as well as the hemolysis situation. The effects of 0, 10 μmol·L^-1, 10, and 20 mmol·L^-1 glutathione (GSH) on the particle size of the micelles were investigated. The in vitro release behaviors of HHCD/CEL and HCCD/CEL in release media containing 0, 10 μmol·L^-1, 10, and 20 mmol·L^-1 GSH were also investigated. Results The CMC values of HHCD and HCCD were approximately 4.5 μg·mL^-1. The particle sizes of the four types of micelles were around 200 nm, and the PDI was less than 0.2, with a relatively uniform distribution. The potentials of the four types of micelles were -24.7, -29.2, -25.9, and -32.1 mV, respectively. The drug loading and encapsulation efficiency of the four types of micelles were above 8.9% and 73%, respectively. The morphologies of the four types of micelles were all spherical-like, with good stability and no hemolysis. The particle size of HHCD/CEL micelles did not change significantly under GSH concentrations of 0, 10 μmol·L^-1, 10, and 20 mmol·L^-1, while the particle size of HCCD/CEL micelles changed significantly at GSH concentrations of 10 and 20 mmol·L^-1. At GSH concentrations of 0 and 10 μmol·L^-1, the cumulative release of the two drugs in the two types of micelles within 48 h was approximately 21%. At a GSH concentration of 10 mmol·L^-1, the cumulative release of the two drugs in HCCD/CEL within 24 h was approximately 40% and 50%, respectively. At a GSH concentration of 20 mmol·L^-1, the cumulative release of CD and CEL in HCCD/CEL reached approximately 70% and 80% within 24 h and 48 h, respectively. Conclusion The prepared reductive-sensitive micelles HCCD/CEL have good stability and reductive sensitivity.

河南省科技攻關(guān)項目（232102311178， 252102311282）；河南省高等學(xué)校重點科研項目（24A350002， 25B350003）；開封市科技攻關(guān)項目（2403002）