Verma Hitesh, Garg Rajeev
IKG Punjab Technical University, Kapurthala, India, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India, Overseas R & D Centre, Overseas HealthCare Pvt Ltd., Phillaur, Punjab, India.
IKG Punjab Technical University, Kapurthala, India, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India, Institute of Pharmaceutical Sciences, IET Bhaddal Technical Campus, Ropar, Punjab, India.
Magnes Res. 2021 May 1;34(2):43-63. doi: 10.1684/mrh.2021.0487.
The objective of the present research is to develop and optimize a chewable tablet containing synergistic combination of magnesium orotate dihydrate (MOD), cholecalciferol (CHOL) and menaquinone-7 (MK-7) as per product development guidelines of ICH Q8 (R2). The effects of critical variables on quality attributes of chewable tablets were evaluated using 30 runs based design of experiment (DoE) after risk assessment. Optimized formulation was found to be the one that was prepared with moderate granulation time of 7.23 min and contained 14 mg/tablet binder, 31 mg/tablet disintegrant and 11.377 mg/tablet lubricant. Prepared tablets were evaluated for prescribed pharmacopoeial and regulatory quality checks. Optimized formulation was found to have very low disintegration time of 6.06 min and 87.39% dissolution of MOD within 15 min in acidic media (0.1 N HCl), which ensure that the developed formulation behaves as a solution following oral administration. Stability studies under accelerated conditions revealed that the developed formulation can retain its quality characteristics throughout its shelf life. Pharmacokinetics study of chewable tablets in male Wistar rats shows that the time to reach maximum plasma or serum concentration (T) was 3 h for MOD and 6 h for both CHOL and MK-7. Maximum plasma or serum concentration (C) of MOD, CHOL and MK-7 was found to be 7.233 ± 1.159, 8.182 ± 0.783 and 8.331 ± 0.863 μg/mL [mean ± standard deviation (SD)], respectively. The area under the curve (AUC -) for MOD, CHOL and MK-7 was 80.692 ± 11.197, 124.325 ± 17.101 and 126.568 ± 12.064 μg.mL.h (mean ± SD), respectively. Comparison of pharmacokinetic data of chewable tablets with a mixture of pure drugs proves that the developed formulation can efficiently deliver all the three nutrients in blood and is capable to elicit desired pharmacological response.
本研究的目的是根据国际人用药品注册技术协调会（ICH）Q8（R2）的产品开发指南，开发并优化一种含有二水合乳清酸镁（MOD）、胆钙化醇（CHOL）和甲基萘醌-7（MK-7）协同组合的咀嚼片。在风险评估后，使用基于30次运行的实验设计（DoE）评估了关键变量对咀嚼片质量属性的影响。发现优化后的配方是在7.23分钟的适度制粒时间下制备的，每片含有14毫克粘合剂、31毫克崩解剂和11.377毫克润滑剂。对制备的片剂进行了规定的药典和监管质量检查。发现优化后的配方崩解时间非常短，仅为6.06分钟，且在酸性介质（0.1N HCl）中15分钟内MOD的溶出率为87.39%，这确保了所开发的制剂在口服后表现为溶液状态。加速条件下的稳定性研究表明，所开发的制剂在其整个货架期内都能保持其质量特性。咀嚼片在雄性Wistar大鼠中的药代动力学研究表明，MOD达到最大血浆或血清浓度（T）的时间为3小时，CHOL和MK-7均为6小时。发现MOD、CHOL和MK-7的最大血浆或血清浓度（C）分别为7.233±1.159、8.182±0.783和8.331±0.863μg/mL[平均值±标准差（SD）]。咀嚼片与纯药物混合物的药代动力学数据比较证明，所开发的制剂能够有效地将所有三种营养素输送到血液中，并能够引发所需的药理反应。
