目的 運(yùn)用微流控技術(shù)制備天麻素（GAS）多囊脂質(zhì)體（GAS-MVLs），考察GAS-MVLs在小鼠體內(nèi)藥動(dòng)學(xué)及腦靶向性。方法 以成形性為評(píng)價(jià)指標(biāo)，通過(guò)單因素實(shí)驗(yàn)篩選GAS-MVLs成形工藝；以包封率為指標(biāo)，以藥脂比（GAS∶卵磷脂）、醇脂比（膽固醇∶卵磷脂）、卵磷脂與三油酸甘油酯的質(zhì)量比、聚山梨酯80的質(zhì)量濃度為變量，正交試驗(yàn)優(yōu)化GAS-MVLs處方；對(duì)GAS-MVLs進(jìn)行包封率、粒徑、聚合物分散性指數(shù)（PDI）、形態(tài)進(jìn)行表征，進(jìn)行體外累積釋放率及初步穩(wěn)定性試驗(yàn)。采用HPLC法測(cè)定小鼠給予GAS、GAS-MVLs（30 mg·kg^-1）后5、15、30、60、90、120、150、180、240、300 min血漿及腦組織中GAS的濃度，以相對(duì)攝取率（Re）、靶向效率（Te）及腦內(nèi)峰濃度比（Ce）評(píng)價(jià)GAS-MVLs腦靶向性。結(jié)果 優(yōu)化處方為藥脂比為1∶2，醇脂比為1∶1，卵磷脂與三油酸甘油酯為1∶1.5，聚山梨酯80質(zhì)量濃度為6%。精密稱取處方量的卵磷脂、膽固醇、三油酸甘油酯溶于氯仿-乙醚（2∶1）混合溶劑為脂相，精密稱取GAS溶于水作為內(nèi)水相，內(nèi)水相與脂相體積比為2∶3，將內(nèi)水相加入到脂相中，在冰水浴下超聲3 min，形成初乳；以6%聚山梨酯80為外水相，與初乳從不同入口注入微流控裝置中，通過(guò)Y型芯片，設(shè)置總體積流量（18.78 mL·h^-1）和體積流量比（外水相∶初乳＝23∶1），經(jīng)氮?dú)馊コ袡C(jī)溶劑，得GAS-MVLs。GAS-MVLs平均粒徑為（2.09±0.14） μm，PDI為0.258±0.013，平均包封率為（34.47±0.39）%，分布均勻，形態(tài)圓整，結(jié)構(gòu)致密。GAS在溶出介質(zhì)中迅速溶解，6 h的釋放量接近90%；GAS-MVLs在前6 h釋放速度較快，隨后接近平衡，72 h最大累積釋放率在65%左右。穩(wěn)定性試驗(yàn)中GAS-MVLs的平均粒徑緩慢增大，包封率緩慢下降。藥動(dòng)學(xué)試驗(yàn)Re為5.70、Te為0.37、Ce為2.04。結(jié)論 采用微流控技術(shù)成功制備GAS-MVLs，可顯著提高GAS的腦內(nèi)富集程度。

Objective Microfluidic technology was used to prepare Gastrodin (GAS) multivesicular liposomes (GAS-MVLs), and to investigate the pharmacokinetic and brain targeting properties of GAS-MVLs in mice. Methods Using the formability as the evaluation index, a single-factor experiment was conducted to select the GAS-MVLs forming process; using the encapsulation rate as the index, the orthogonal experiment was conducted to optimize the GAS-MVLs formula with the variables of the ratio of GAS to lecithin, the ratio of cholesterol to lecithin, the ratio of lecithin to triolein, and the concentration of polyoxyethylene sorbitan monolaurate. The GAS-MVLs were characterized by encapsulation rate, particle size, polymer dispersion index (PDI), and morphology, and the in vitro cumulative release rate and initial stability were tested. The GAS concentration in the plasma and brain tissue of mice given GAS or GAS-MVLs (30 mg·kg^-1) at 5, 15, 30, 60, 90, 120, 150, 180, 240, and 300 min was determined by HPLC, and the brain targeting of GAS-MVLs was evaluated by relative uptake rate (Re), targeting efficiency (Te) and peak concentration ratio (Ce). Results The optimized formula was a ratio of GAS to lecithin of 1:2, a ratio of cholesterol to lecithin of 1:1, a ratio of lecithin to triolein of 1:2, and a concentration of polyoxyethylene sorbitan monolaurate of 6%. The egg yolk was prepared by dissolving the specified amount of lecithin, cholesterol, and triolein in a chloroform-ethanol (2:1) mixture as the lipid phase, and dissolving GAS in water as the internal aqueous phase. The internal aqueous phase was added to the lipid phase in a ratio of 2:3, and the mixture was sonicated for 3 minutes in an ice bath to form an emulsion. The external aqueous phase was prepared by adding 6% polyoxyethylene sorbitan monolaurate as the aqueous phase, and the emulsion and the external aqueous phase were injected from different inlets into a micro, by using a Y-type chip, the total volumetric flow rate (18.78 mL·h^-1) and the volume flow ratio (external aqueous phase : colloidal dispersion = 23 : 1) were set, and the organic solvent was removed by nitrogen, resulting in GAS-MVLs. The average particle size of GAS-MVLs was (2.09±0.14) μm, the PDI was (0.258±0.013), and the average encapsulation rate was (34.47±0.39)%. The distribution was uniform, the morphology was round and compact, and the structure was dense. GAS dissolved rapidly in the release medium, and the release amount after 6 hours was close to 90%. In the stability test, the average particle size of GAS-MVLs slowly increased, and the encapsulation rate slowly decreased. In the pharmacokinetics test, Re was 5.70, Te was 0.37, and Ce was 2.04. Conclusion The preparation of GAS-MVLs by microfluidic technology can significantly improve the degree of intracerebral enrichment of GAS, which lays the foundation for further development of GAS brain-targeted formulations.

R94

貴州省自然科學(xué)基金項(xiàng)目（貴州省科技基金-ZK［2021］-524）;貴州省衛(wèi)健委科技基金項(xiàng)目（GZWKJ2022-233）