Madan Jyotsana R, Pawar Kiran T, Dua Kamal
Department of Pharmaceutics, Sinhgad Technical Education Society's, Smt. Kashibai Navale College of Pharmacy, Pune, Maharashtra, India.
Faculty of Medicine and Health, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
Int J Pharm Investig. 2015 Apr-Jun;5(2):114-20. doi: 10.4103/2230-973X.153390.
Low aqueous solubility is a major problem faced during formulation development of new drug molecules. Lurasidone HCl (LRD) is an antipsychotic agent specially used in the treatments of schizophrenia and is a good example of the problems associated with low aqueous solubility. Lurasidone is practically insoluble in water, has poor bioavailability and slow onset of action and therefore cannot be given in emergency clinical situations like schizophrenia. Hence, purpose of this research was to provide a fast dissolving oral dosage form of Lurasidone. This dosage form can provide quick onset of action by using the concept of mixed hydrotropy. Initially, solubility of LRD was determined individually in nicotinamide, sodium citrate, urea and sodium benzoate at concentration of 10, 20, 30 and 40% w/v solutions using purified water as a solvent. Highest solubility was obtained in 40% sodium benzoate solution. In order to decrease the individual hydrotrope concentration mixed hydrotropic agents were used. Highest solubility was obtained in 15:20:5 ratio of Nicotinamide + sodium benzoate + sodium citrate. This optimized combination was utilized in the preparation of solid dispersions by using distilled water as a solvent. Solid dispersions were evaluated for X-ray diffraction, differential scanning calorimetry and Fourier-transform infrared to show no drug-hydrotropes interaction has occurred. This solid dispersion was compressed to form fast dissolving tablets. Dissolution studies of prepared tablets were done using USP Type II apparatus. The batch L3 tablets show 88% cumulative drug release within 14 min and in vitro dispersion time was 32 min. It was concluded that the concept of mixed hydrotropic solid dispersion is novel, safe and cost-effective technique for enhancing the bioavailability of poorly water-soluble drugs. The miraculous enhancement in solubility and bioavailability of Lurasidone is clear indication of the potential of mixed hydrotropy to be used in future for other poorly water-soluble drugs in which low bioavailability is a major concern.
低水溶性是新药分子制剂开发过程中面临的一个主要问题。盐酸鲁拉西酮（LRD）是一种专门用于治疗精神分裂症的抗精神病药物，是与低水溶性相关问题的一个典型例子。鲁拉西酮几乎不溶于水，生物利用度差，起效缓慢，因此在精神分裂症等紧急临床情况下不能使用。因此，本研究的目的是提供一种鲁拉西酮的快速溶解口服剂型。这种剂型可以通过混合助溶的概念实现快速起效。最初，以纯化水为溶剂，分别在浓度为10%、20%、30%和40% w/v的烟酰胺、柠檬酸钠、尿素和苯甲酸钠溶液中测定LRD的溶解度。在40%苯甲酸钠溶液中获得了最高溶解度。为了降低单一助溶剂的浓度，使用了混合助溶剂。在烟酰胺+苯甲酸钠+柠檬酸钠的比例为15:20:5时获得了最高溶解度。以蒸馏水为溶剂，将这种优化组合用于制备固体分散体。对固体分散体进行X射线衍射、差示扫描量热法和傅里叶变换红外光谱分析，结果表明未发生药物与助溶剂的相互作用。将这种固体分散体压制成快速溶解片。使用美国药典II型装置对制备的片剂进行溶出度研究。L3批次片剂在14分钟内累积药物释放率为88%，体外分散时间为32分钟。得出的结论是，混合助溶固体分散体的概念是一种新颖、安全且具有成本效益的技术，可用于提高难溶性药物的生物利用度。鲁拉西酮溶解度和生物利用度的显著提高清楚地表明了混合助溶在未来用于其他生物利用度低的难溶性药物的潜力。
