Abstract：
In part I, we reported Hansen solubility parameters (HSP, HSPiP program), experimental solubility at varied temperatures for TOTA delivery. Here, we studied dose volume selection, stability, pH, osmolality, dispersion, clarity, and viscosity of the explored combinations (I-VI). Ex vivo permeation and deposition studies were performed to observe relative diffusion rate from the injected site in rat skin. Confocal laser scanning microscopy (CLSM) study was conducted to support ex vivo findings. Moreover, GastroPlus predicted in vivo parameters in humans and the impact of various critical factors on pharmacokinetic parameters (PK). Immediate release product (IR) contained 60% of PEG400 whereas controlled release formulation (CR) contained PEG400 (60%), water (10%) and d-limonene (30%) to deliver 2 mg of TOTA. GastroPlus predicted the plasma drug concentration of weakly basic TOTA as function of pH (from pH 2.0 to 9). The cumulative drug permeation and drug deposition were found to be in the order as B-VI˃ C-VI˃A-VI across rat skin. This finding was further supported with CLSM. Moreover, IR and CR were predicted to achieve Cmax of 0.0038 µg/ mL and 0.00023 µg/mL, respectively, after sub-Q delivery. Added limonene in CR extended the plasma drug concentration over period of 12 h as predicted in GastroPlus. Parameters sensitivity analysis (PSA) assessment predicted that sub-Q blood flow rate is the only factor affecting PK parameters in IR formulation whereas this was insignificant for CR. Thus, sub-Q delivery CR would be promising alternative with ease of delivery to children and aged patient.
摘要：
在第一部分,我们报道了汉森溶解度参数(HSP，HSPiP计划)，在不同温度下用于TOTA递送的实验溶解度。这里,我们研究了剂量体积的选择，稳定性,pH值,渗透压,色散，清晰度,和所研究的组合(I-VI)的粘度。进行离体渗透和沉积研究以观察大鼠皮肤中注射部位的相对扩散速率。进行共聚焦激光扫描显微镜(CLSM)研究以支持离体发现。此外，GastroPlus预测了人体的体内参数以及各种关键因素对药代动力学参数（PK）的影响。立即释放产品（IR）含有60％的PEG400，而控释制剂（CR）含有PEG400（60％），水(10%)和d-柠檬烯(30%)递送2mg的TOTA。GastroPlus预测了弱碱性TOTA的血浆药物浓度随pH（从pH2.0到9）的变化。发现大鼠皮肤的累积药物渗透和药物沉积顺序为B-VIC-VIA-VI。CLSM进一步支持了这一发现。此外，IR和CR预计达到0.0038µg/mL和0.00023µg/mL的Cmax，分别,Sub-Q交货后。如GastroPlus中所预测的,在CR中添加柠檬烯延长了12小时的血浆药物浓度。参数敏感性分析（PSA）评估预测，低于Q的血液流速是影响IR配方中PK参数的唯一因素，而这对于CR而言微不足道。因此，亚Q分娩CR将是很有希望的替代方案，易于对儿童和老年患者进行分娩。
