Kwak Seong Shin, Lee Eun Seok, Yoon Ho Yub, Kim Chang Hyun, Goo Yoon Tae, Kang Myung Joo, Lee Sangkil, Lee Bong Sang, Jeon Hong Ryeol, Oh Chang Hyun, Choi Young Wook
College of Pharmacy, Chung-Ang University, Heuksuk-ro, Dongjak-gu, Seoul 06974, Republic of Korea,
College of Pharmacy, Dankook University, Dandae-ro, Dongnam-gu, CheonanChungnam 31116, Republic of Korea.
Drug Des Devel Ther. 2018 Oct 9;12:3377-3392. doi: 10.2147/DDDT.S178456. eCollection 2018.
To develop an immediate release-type tablet containing varenicline salicylate (VRC-S), a smoking cessation agent, formulation and stability studies were performed. The in vitro dissolution and in vivo pharmacokinetic (PK) behavior of the tablets were compared with those of the commercial product (Champix) as a reference.
The characteristics of the powder were investigated by particle morphology, size distribution, solubility, hygroscopicity, differential scanning calorimetry, and powder X-ray diffraction. Based on the drug-excipient compatibility test, different VRC-S tablets were prepared with the selected excipients through direct compression or wet granulation method and subjected to a dissolution test. The stability of the most promising VRC-S tablet (F4) was evaluated under accelerated conditions (40°C and 75% relative humidity). Further, the dissolution and human pharmacokinetic profiles of the F4 tablet and Champix were compared.
VRC-S showed a positively skewed unimodal size distribution with a specific surface area of 2.02 m/g, single endothermic peak of 225.2°C in differential scanning calorimetry, crystalline internal structure in powder X-ray diffraction, aqueous solubility of 244.7 mg/mL, and hygroscopicity of 0.256 mg/g. The wet granulation method was preferred for tablet preparation and employed the following excipients: microcrystalline cellulose and anhydrous dibasic calcium phosphate as diluents, croscarmellose sodium as a disintegrant, and colloidal silicon dioxide and magnesium stearate as lubricants. The F4 tablet was stable for 6 months under accelerated conditions. The dissolution of VRC was pH independent, revealing values of 76.49 and 68.38 at pH 1.2 and pH 6.8, respectively. After the oral administration of F4 tablet and Champix to healthy human volunteers, pharmacokinetic parameters, including time to reach the maximum plasma concentration (T), maximum plasma concentration (C), and area under the curve from 0 to infinity (AUC), were compared. The values of 90% CI were 0.972-1.035 for C and 0.982-1.075 for AUC, which was indicative of the bioequivalence of both products.
VRC-S-containing F4 tablet might be a good candidate for smoking cessation treatment.
为研发一种含有戒烟药物水杨酸伐尼克兰（VRC-S）的速释型片剂，进行了制剂和稳定性研究。将该片剂的体外溶出度和体内药代动力学（PK）行为与市售产品（畅沛）进行比较作为参考。
通过颗粒形态、粒度分布、溶解度、吸湿性、差示扫描量热法和粉末X射线衍射研究粉末的特性。基于药物-辅料相容性试验，选用辅料通过直接压片或湿法制粒法制备不同的VRC-S片剂，并进行溶出度试验。对最有前景的VRC-S片剂（F4）在加速条件（40°C和75%相对湿度）下进行稳定性评价。此外，比较了F4片剂和畅沛的溶出度和人体药代动力学特征。
VRC-S呈现正偏态单峰粒度分布，比表面积为2.02 m/g，差示扫描量热法中单一吸热峰温度为225.°C，粉末X射线衍射显示为晶体内部结构，水溶解度为244.7 mg/mL，吸湿性为0.256 mg/g。湿法制粒法更适合片剂制备，使用的辅料如下：微晶纤维素和无水磷酸氢钙作为稀释剂，交联羧甲基纤维素钠作为崩解剂，胶态二氧化硅和硬脂酸镁作为润滑剂。F4片剂在加速条件下6个月稳定。VRC的溶出度与pH无关，在pH 1.2和pH 6.8时的溶出度分别为76.49和68.38。将F4片剂和畅沛口服给予健康人体志愿者后，比较了药代动力学参数，包括达最大血药浓度时间（T）、最大血药浓度（C）和0至无穷大曲线下面积（AUC）。C值的90%置信区间为0.972-1.035，AUC值的90%置信区间为0.982-1.075，表明两种产品生物等效。
含VRC-S的F4片剂可能是戒烟治疗的良好候选药物。
