Dorkoosh F A, Verhoef J C, Borchard G, Rafiee-Tehrani M, Junginger H E
Department of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
J Control Release. 2001 Apr 28;71(3):307-18. doi: 10.1016/s0168-3659(01)00232-2.
Novel drug delivery systems were developed for peroral administration of peptide and protein drugs for site specific mechanical fixation at the gut wall and with specific release patterns. These so-called shuttle systems were designed by using superporous hydrogels (SPH) and SPH composite (SPHC) as the conveyor of a core which contained the model compound N-alpha-benzoyl-L-arginine ethylester (BAEE). Two different types of shuttle systems were evaluated: (a) core inside the shuttle system, and (b) core attached to the surface of shuttle system. Each of these systems was made of two parts: (1) the conveyor system made of SPHC which is used for keeping the dosage form at specific site(s) of the GI tract by mechanical interaction of the dosage form with the intestinal membranes, and (2) the core containing the active ingredient and incorporated in the conveyor system. The effect of formulation composition of the core on the release profile of BAEE was investigated by changing the type and amount of excipients in the formulations. In addition, the effect of various enteric-coat layers on the release profile and dissolving of the dosage form was investigated. The systems were also characterized for trypsin inactivation and Ca(2+) binding. The release profile of BAEE from the core formulation consisting of PEG 6000 microparticles or small tablets showed the desired burst release. When these core formulations were incorporated into the conveyor system made of SPH and SPHC, a suitable time-controlled release profile was obtained. Changing the type, concentration and thickness of the enteric-coat layer influenced the starting time of BAEE release from the dosage form, which indicates the necessary lag time for dissolving of the dosage form at any desired specific site of drug absorption in the intestine. Both SPH and SPHC were found to partly inhibit the activity of trypsin, due to two mechanisms: Ca(2+) binding and entrapment of the enzyme in these polymers. In conclusion, the presently developed delivery systems demonstrate suitable in vitro characteristics with an appropriate time-controlled release profile, making these systems very promising for effective peroral delivery of peptide and protein drugs.
新型药物递送系统被开发用于肽和蛋白质药物的口服给药，以实现肠道壁的位点特异性机械固定并具有特定的释放模式。这些所谓的穿梭系统是通过使用超多孔水凝胶（SPH）和SPH复合材料（SPHC）作为包含模型化合物N-α-苯甲酰-L-精氨酸乙酯（BAEE）的核心的输送载体而设计的。评估了两种不同类型的穿梭系统：（a）穿梭系统内部的核心，以及（b）附着在穿梭系统表面的核心。这些系统中的每一个都由两部分组成：（1）由SPHC制成的输送系统，其通过剂型与肠膜的机械相互作用用于将剂型保持在胃肠道的特定部位，以及（2）包含活性成分并掺入输送系统中的核心。通过改变制剂中辅料的类型和用量，研究了核心制剂组成对BAEE释放曲线的影响。此外，研究了各种肠溶衣层对剂型释放曲线和溶解的影响。还对这些系统进行了胰蛋白酶失活和Ca(2+)结合的表征。由聚乙二醇6000微粒或小片组成的核心制剂中BAEE的释放曲线显示出所需的突释。当将这些核心制剂掺入由SPH和SPHC制成的输送系统中时，获得了合适的时间控制释放曲线。改变肠溶衣层的类型、浓度和厚度会影响BAEE从剂型中释放的起始时间，这表明剂型在肠道中任何所需的特定药物吸收部位溶解所需的必要滞后时间。发现SPH和SPHC均部分抑制胰蛋白酶的活性，这归因于两种机制：Ca(2+)结合和酶在这些聚合物中的截留。总之，目前开发的递送系统表现出合适的体外特性以及适当的时间控制释放曲线，使得这些系统对于肽和蛋白质药物的有效口服递送非常有前景。
