Tang Wei-Lun, Tang Wei-Hsin, Chen Weihsu Claire, Diako Charles, Ross Carolyn F, Li Shyh-Dar
Faculty of Pharmaceutical Sciences, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
School of Food Science, Washington State University , Pullman, Washington 99164, United States.
Mol Pharm. 2017 Jun 5;14(6):1969-1979. doi: 10.1021/acs.molpharmaceut.7b00077. Epub 2017 May 9.
Mefloquine (Mef), a poorly soluble and highly bitter drug, has been used for malaria prophylaxis and treatment. The dosage form for Mef is mostly available as adult tablets, and thus children under the age of 5 suffer from poor medication adherence. We have developed a stable, rapidly dissolvable, and palatable pediatric formulation for Mef using liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol with a mean diameter of ∼110 nm. Mef was actively loaded into the liposomes via an ammonium sulfate gradient using the solvent-assisted loading technology (SALT) developed in our lab. Complete loading of Mef inside the liposomal core was achieved at a high drug-to-lipid ratio (D/L) of 0.1-0.2 (w/w), and the final drug content in the formulation was ∼8 mg/mL, well above the solubility of Mef (<0.6 mg/mL in simulated fluids). The strong bitterness of Mef was masked by the liposomal encapsulation as measured by an electronic tongue. Incubating the Mef-liposomes (Mef-Lipo) in the simulated gastric fluid (pH 1.2) and the simulated intestinal fluid containing 3 mM sodium taurocholate (pH 6.8) induced changes in liposome size and the polydispersity, resulting in drug release (∼40% in 2 h). However, no drug release from the Mef-Lipo was measured in the bile salt-free intestinal fluid or simulated saliva (0% in 3 h). These data suggest that drug release from the Mef-Lipo was mediated by a low pH and the presence of a surfactant. Pancreatic lipase did not degrade DSPC in the Mef-Lipo after 8 h of incubation nor induce Mef release from the liposomes, indicating that lipid digestion played a minor role for drug release from the Mef-Lipo. In order to improve long-term room temperature storage, the Mef-Lipo was lyophilized to obtain a solid formulation, which was completely dissolvable in water in 10 s and displayed similar in vitro profiles of release as the liquid form. The lyophilized Mef-Lipo was stable at room temperature for >3 months. In mice, orally delivered liquid and lyophilized Mef-Lipo displayed comparable absorption with bioavailability (BA) of 81-86%, while the absorption of the standard Mef suspension was significantly lower with BA of 70% and 20% decreased maximal plasma concentration and area under the curve. Our data suggest that the Mef-Lipo was a stable, palatable, and bioavailable formulation that might be suitable for pediatric use.
甲氟喹（Mef）是一种难溶性且苦味极强的药物，一直用于疟疾的预防和治疗。Mef的剂型大多为成人片剂，因此5岁以下儿童用药依从性较差。我们使用由1,2 - 二硬脂酰 - sn - 甘油 - 3 - 磷酸胆碱（DSPC）和胆固醇组成的平均直径约为110 nm的脂质体，开发了一种稳定、快速溶解且口感良好的Mef儿科制剂。利用我们实验室开发的溶剂辅助负载技术（SALT），通过硫酸铵梯度将Mef主动负载到脂质体中。在0.1 - 0.2（w/w）的高药物 - 脂质比（D/L）下，Mef在脂质体核心内实现了完全负载，制剂中的最终药物含量约为8 mg/mL，远高于Mef的溶解度（在模拟流体中<0.6 mg/mL）。通过电子舌测量发现，脂质体包封掩盖了Mef的强烈苦味。将Mef - 脂质体（Mef - Lipo）在模拟胃液（pH 1.2）和含有3 mM牛磺胆酸钠的模拟肠液（pH 6.8）中孵育，会导致脂质体大小和多分散性发生变化，从而引起药物释放（2小时内约40%）。然而，在无胆盐的肠液或模拟唾液中未检测到Mef - Lipo有药物释放（3小时内为0%）。这些数据表明，Mef - Lipo的药物释放是由低pH值和表面活性剂的存在介导的。孵育8小时后，胰脂肪酶并未降解Mef - Lipo中的DSPC，也未诱导Mef从脂质体中释放，这表明脂质消化在Mef - Lipo的药物释放中起次要作用。为了改善长期室温储存条件，将Mef - Lipo冻干以获得固体剂型，该剂型在10秒内可完全溶解于水中，并且在体外显示出与液体剂型相似的释放曲线。冻干的Mef - Lipo在室温下可稳定保存>3个月。在小鼠中，口服给药的液体和冻干的Mef - Lipo表现出相当的吸收，生物利用度（BA）为81 - 86%，而标准Mef悬浮液的吸收显著较低，BA为70%，最大血浆浓度降低20%，曲线下面积也降低。我们的数据表明，Mef - Lipo是一种稳定、口感良好且生物可利用的制剂，可能适用于儿科使用。
