Laboratory of Pharmaceutical Technology, Ghent University, B-9000 Ghent, Belgium.
J Pharm Sci. 2011 Jul;100(7):2858-70. doi: 10.1002/jps.22480. Epub 2011 Jan 19.
Sustained-release matrix tablets were developed by injection moulding using metoprolol tartrate (MPT) and ethylcellulose (EC) as sustained-release agent. Dibutyl sebacate was selected as plasticiser. The influence of matrix composition, plasticiser concentration, and drug load on drug release was evaluated. The influence of plasticiser addition was assessed on processability and drug release: Dibutyl sebacate was added to a dichloromethane/EC solution and subsequently spray-dried, or was mixed as a liquid with EC powder. Hydrated tablets were evaluated by frequency sweep and creep rheological tests to correlate the results with drug release. Xanthan gum (XG) was added to the formulation because drug release was too slow (<50%, 24 h) from EC/MPT matrices (70%/30%, w/w). Increasing XG concentrations provided faster MPT release rates characterised by zero-order release kinetics, no burst release was observed. Lower plasticiser concentrations and higher drug loads increased drug release substantially. The plasticiser addition method did not affect drug release. Matrix composition, drug load, and plasticiser level affected the rheological properties of the swollen matrix tablets. X-ray diffraction demonstrated the formation of solid dispersions. Formulations composed of XG/EC (ratio 1:1.5) and 30% (w/w) MPT had a low relative bioavailability compared with the commercial product Lopressor®, which significantly improved at higher MPT concentration (50%, w/w).
采用酒石酸美托洛尔（MPT）和乙基纤维素（EC）作为缓控释剂，通过注塑成型制备了缓控释骨架片。选择癸二酸二丁酯作为增塑剂。考察了骨架组成、增塑剂浓度和药物载量对药物释放的影响。评估了增塑剂添加对可加工性和药物释放的影响：癸二酸二丁酯加入二氯甲烷/EC 溶液中，然后喷雾干燥，或作为液体与 EC 粉末混合。通过频率扫描和蠕变流变试验对水合片剂进行评估，以将结果与药物释放相关联。由于 EC/MPT 基质（70%/30%，w/w）的药物释放太慢（<50%，24 h），因此向配方中添加黄原胶（XG）。增加 XG 浓度可提供更快的 MPT 释放率，其特征为零级释放动力学，未观察到突释。较低的增塑剂浓度和较高的药物载量可大大增加药物释放。增塑剂添加方法不影响药物释放。基质组成、药物载量和增塑剂水平影响溶胀基质片的流变性能。X 射线衍射表明形成了固体分散体。与商品 Lopressor®相比，由 XG/EC（比例为 1:1.5）和 30%（w/w）MPT 组成的配方的相对生物利用度较低，当 MPT 浓度（50%，w/w）较高时，显著提高。
