University of Lille, College of Pharmacy, 3 Rue du Prof. Laguesse, 59006 Lille, France; INSERM U 1008, 3 Rue du Prof. Laguesse, 59006 Lille, France.
University of Lille, College of Pharmacy, 3 Rue du Prof. Laguesse, 59006 Lille, France; INSERM U 995, 3 Rue du Prof. Laguesse, 59006 Lille, France.
Int J Pharm. 2015 Jan 15;478(1):31-38. doi: 10.1016/j.ijpharm.2014.10.071. Epub 2014 Nov 4.
Coated pellets offer a great potential as controlled drug delivery systems. However, constant drug release rates are difficult to achieve with this type of dosage forms if the drug is freely water-soluble. This is because diffusional mass transport generally plays a major role and with time the drug concentration within the system decreases, resulting in decreased concentration gradients, which are the driving forces for drug release. Thus, generally "curve-shaped" release profiles with monotonically decreasing slopes are observed. This type of release kinetics might be inappropriate for an efficient and safe drug treatment. Despite the great practical importance of this potentially crucial formulation challenge, surprisingly little is yet known on how to effectively address it. In this study, a novel approach is presented based on sequential layers of drug and polymer (initially free of drug) to provide a non-homogeneous initial drug distribution, combined with lag-time effects, and partial initial drug diffusion towards the pellet's core. Sugar and microcrystalline cellulose beads were used as starter cores, metoprolol succinate as freely soluble drug, ethylcellulose, and poly(vinyl acetate) as release rate controlling polymers. The type, number, thickness, and sequence of the drug and polymer layers were varied. Interestingly, a rather simple four layer system (two drug and two polymer layers) allowed providing about constant drug release during 8h. Compared to previously proposed coated pellets aiming at constant release of freely water-soluble drugs based on non-homogeneous initial drug distribution, the total coating level in this study was very much reduced: to only about 20%. Hence, the suggested formulation approach is relatively simple and can help overcoming a potentially major hurdle in practice. Its applicability has also been demonstrated for another type of drug: propranolol hydrochloride.
包衣丸剂具有很大的潜力，可用作控释药物传递系统。然而，如果药物是自由水溶性的，则这种剂型很难实现恒定的药物释放率。这是因为扩散质量传递通常起着主要作用，随着时间的推移，系统内的药物浓度降低，导致浓度梯度降低，这是药物释放的驱动力。因此，通常观察到“曲线形”的释放曲线，其斜率单调下降。这种类型的释放动力学可能不适合有效的和安全的药物治疗。尽管这种潜在关键制剂挑战具有巨大的实际重要性，但令人惊讶的是，对于如何有效地解决这一问题，人们知之甚少。在这项研究中，提出了一种新的方法，基于药物和聚合物（最初不含药物）的顺序层，提供非均匀的初始药物分布，结合滞后时间效应，并在初始时向丸芯部分扩散药物。糖和微晶纤维素珠用作起始核心，琥珀酸美托洛尔作为自由水溶性药物，乙基纤维素和聚醋酸乙烯酯作为释放速率控制聚合物。改变药物和聚合物层的类型、数量、厚度和顺序。有趣的是，一个相当简单的四层系统（两层药物和两层聚合物）可以在 8 小时内提供相对恒定的药物释放。与以前提出的基于非均匀初始药物分布旨在恒定释放自由水溶性药物的包衣丸剂相比，本研究中的总涂层水平大大降低：仅约 20%。因此，所提出的配方方法相对简单，可以帮助克服实践中的一个潜在的主要障碍。其适用性也已在另一种药物：盐酸普萘洛尔中得到证明。
