Hameed Hajra Afeera, Khan Shahzeb, Shahid Muhammad, Ullah Riaz, Bari Ahmed, Ali Syed Saeed, Hussain Zahid, Sohail Muhammad, Khan Shafi Ullah, Htar Thet Thet
Department of Pharmacy, University of Malakand, Chakdara, Khyber Pakhtunkhwa 18800, Pakistan.
Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.
Drug Des Devel Ther. 2020 Jan 7;14:27-41. doi: 10.2147/DDDT.S232111. eCollection 2020.
Naproxen (NP) is a non-steroidal anti-inflammatory drug with poor aqueous solubility and low oral bioavailability, which may lead to therapeutic failure. NP causes crucial GIT irritation, bleeding, and peptic and duodenal ulcers.
This study aimed to engineer and characterize polymer hybrid enteric microspheres using an integrated (experimental and molecular modelling) approach with further development to solid dosage form with modified drug release kinetics and improved bioavailability.
NP loaded polymer hybrid enteric microspheres (PHE-Ms) were fabricated by using a modified solvent evaporation technique coupled with molecular modelling (MM) approach. The PHE-Ms were characterized by particle size, distribution, morphology, crystallinity, EE, drug-polymer compatibility, and DSC. The optimized NP loaded PHE-Ms were further subjected to downstream procedures including tablet dosage form development, stability studies and comparative in vitro-in vivo evaluation.
The hydrophobic polymer EUD-L100 and hydrophilic polymer HPMC-E5 delayed and modified drug release at intestinal pH while imparting retardation of NP release at gastric pH to diminish the gastric side effects. The crystallinity of the NP loaded PHE-Ms was established through DSC and P (XRD). The particle size for the developed formulations of PEH-Ms (M1-M5) was in the range from 29.06 ±7.3-74.31 ± 17.7 μm with Span index values of 0.491-0.69, respectively. The produced NP hybrid microspheres demonstrated retarded drug release at pH 1.2 and improved dissolution at pH 6.8. The in vitro drug release patterns were fitted to various release kinetic models and the best-followed model was the Higuchi model with a release exponent "n" value > 0.5. Stability studies at different storage conditions confirmed stability of the NP loaded PHE-Ms based tablets (<0.05). The molecular modelling (MM) study resulted in adequate binding energy of co-polymer complex SLS-Eudragit-HPMC-Naproxen (-3.9 kcal/mol). In contrast to the NP (unprocessed) and marketed formulations, a significant increase in the C of PHE-MT1 (44.41±4.43) was observed.
The current study concludes that developing NP loaded PHE-Ms based tablets could effectively reduce GIT consequences with restored therapeutic effects. The modified release pattern could improve the dissolution rate and enhancement of oral bioavailability. The MM study strengthens the polymer-drug relationship in microspheres.
萘普生（NP）是一种非甾体抗炎药，其水溶性差且口服生物利用度低，这可能导致治疗失败。NP会引起严重的胃肠道刺激、出血以及胃和十二指肠溃疡。
本研究旨在采用综合（实验和分子建模）方法设计并表征聚合物混合肠溶微球，并进一步开发具有改良药物释放动力学和提高生物利用度的固体剂型。
采用改良溶剂蒸发技术结合分子建模（MM）方法制备载NP聚合物混合肠溶微球（PHE-Ms）。通过粒径、分布、形态、结晶度、包封率、药物-聚合物相容性和差示扫描量热法对PHE-Ms进行表征。对优化后的载NP PHE-Ms进一步进行下游工艺，包括片剂剂型开发、稳定性研究和体外-体内比较评价。
疏水性聚合物EUD-L100和亲水性聚合物HPMC-E5在肠道pH值下延迟并改变药物释放，同时在胃pH值下延缓NP释放，以减少胃部副作用。通过差示扫描量热法（DSC）和粉末X射线衍射（P（XRD））确定了载NP PHE-Ms的结晶度。所开发的PEH-Ms（M1-M5）制剂的粒径范围为29.06±7.3 - 74.31±17.7μm，跨度指数值分别为0.491 - 0.69。所制备的NP混合微球在pH 1.2时表现出药物释放延迟，在pH 6.8时溶解改善。体外药物释放模式符合各种释放动力学模型，最佳拟合模型为Higuchi模型，释放指数“n”值>0.5。不同储存条件下的稳定性研究证实了载NP PHE-Ms基片剂的稳定性（<0.05）。分子建模（MM）研究得出共聚物复合物SLS-丙烯酸树脂-HPMC-萘普生的结合能足够（-3.9 kcal/mol）。与NP（未加工）和市售制剂相比，观察到PHE-MT1的曲线下面积（AUC）显著增加（44.41±4.43）。
本研究得出结论，开发载NP PHE-Ms基片剂可有效减少胃肠道不良后果并恢复治疗效果。改良的释放模式可提高溶解速率并增强口服生物利用度。MM研究加强了微球中聚合物与药物的关系。
