关节腔注射用盐酸青藤碱原位液晶的制备及体内外评价

Preparation and evaluation of intra-articular injectable sinomenine hydrochloride-loaded in situ liquid crystals

本文以植烷三醇(phytantriol,PT)、乙醇(ethanol,ET)和水三组分体系制备原位立方液晶(in situ cubic liquid crystal,ISV_2),采用三元相图法优选出各向同性溶液,以可注射性、p H值、相转化最少吸水量、相转化时间作为指标优化处方;在ISV_2处方基础上加入维生素E醋酸酯(vitamin E acetate,Vit EA)制备原位六角相液晶(in situ hexagonal liquid crystal,ISH_2),以体外释药行为作为考察指标优化Vit EA的添加量;采用小角度X射线散射对ISV_2和ISH_2吸水相转化后的液晶结构进行表征;对ISV_2和ISH_2的流变学性质进行研究;采用动态透析法对ISV_2和ISH_2体外释药行为进行比较;以佐剂性关节炎大鼠作为模型动物,盐酸青藤碱(sinomenine hydrochloride,SMH)作为模型药物,考察ISH_2关节局部药动学。优选出的ISV_2(PT/ET/水,64∶16∶20,w/w/w;载药量为6 mg·g^(-1))可用于注射,p H值为5.20,相转化最少吸水量为63.33μL,相转化时间为4.21 s,体外可缓释SMH长达144 h。优选出的ISH_2(PT/Vit EA/ET/水,60.8∶3.2∶16∶20,w/w/w/w;载药量为6 mg·g^(-1))可用于注射,p H值为5.51,体外可缓释SMH长达240 h。大鼠关节腔局部药动学研究结果显示,ISH_2组与溶液组相比,其t_(1/2α)、t_(1/2β)、t_(max)和MRT_(0-∞)明显延长,ISH_2组的AUC_(0-∞)是溶液组的6.01倍。本研究制备的ISH_2关节腔给药后可在关节局部缓释药物,延长药物驻留时间,提高药物利用度,具有较好的应用前景。

Phytantriol（PT）, ethanol（ET） and water were used to prepare in situ cubic liquid crystal（ISV2）. The pseudo-ternary phase diagram of PT-ET-water was constructed and isotropic solution formulations were chosen for further optimization. The physicochemical properties of isotropic solution formulations were evaluated to optimize the composition of ISV2. In situ hexagonal liquid crystals（ISH2） were prepared based on the composition of ISV2 with the addition of vitamin E acetate（Vit EA） and the amount of Vit EA was optimized by in vitro release behavior. The phase structures of liquid crystalline gels formed by ISV2 and ISH2 in excess water were confirmed by crossed polarized light microscopy and small angle X-ray scattering, respectively. Rheological properties of ISV2 and ISH2 were studied by a DHR-2 rheometer. In vitro drug release studies were conducted by using a dialysis membrane diffusion method. Pharmacokinetics was investigated by determination of sinomenine hydrochloride（SMH） concentration in synovial membrane after intra-articular injection of SMH-loaded ISH2 in adjuvant-induced arthritis rats. The optimal ISV2（PT/ET/water, 64∶16∶20, w/w/w） loaded with 6 mg·g^-1 of SMH showed a suitable p H, injectable and formed a cubic liquid crystalline gel in situ with minimum water absorption in the shortest time. The optimal ISV2 was able to sustain the drug release for 144 h. The optimal ISH2 system was prepared by addition of 5% Vit EA into PT in the optimal ISV2 system. This ISH2（PT/Vit EA/ET/water, 60.8∶3.2∶16∶20, w/w/w/w） was an injectable isotropic solution with suitable p H. The new ISH2 was able to sustain the drug release for more than 240 h. Local pharmacokinetics study indicated that the retention time and AUC（0-∞） of ISH2 group were increased significantly compared with that of SMH solution group and the AUC（0-∞） of ISH2 group was 6.01 times higher than that of SMH solution group. The developed ISH2 was suitable for intra-articular injection that may apply to patients in the treatment of rheumatoid arthritis.