van der Merwe S M, Verhoef J C, Kotzé A F, Junginger H E
Department of Pharmaceutics, School of Pharmacy, Potchefstroom University for Christian Higher Education, Potchefstroom, South Africa.
Eur J Pharm Biopharm. 2004 Jan;57(1):85-91. doi: 10.1016/s0939-6411(03)00152-8.
In this study, minitablet and granule formulations were developed as solid oral dosage forms for the delivery of peptide drugs with the absorption enhancer N-trimethyl chitosan chloride (TMC). Minitablets were deemed suitable as a dosage form due to their ability, as components of multiple unit dosage forms (MUDFs), to disperse from each other, before disintegration, effectively increasing the area in which the polymer can assert its absorption-enhancing effect. The polymer should be released from the dosage forms prior to the release of the peptide, which was, together with achieving maximum release of both ingredients, the main focus of this study. Desmopressin (1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (DDAVP) was used as model peptide drug. The optimized minitablet formulation consisted of two types of granules, namely DDAVP and TMC granules. DDAVP granules, containing tetraglycerol pentastearate (TGPS), were specifically aimed at delaying the release of the peptide from the dosage form. Burst release of TMC was attempted with TMC granules. Both these granule types were included in the granule formulation. Release profiles for both the optimized minitablet formulation as well as the granule formulation showed that the release of DDAVP was effectively delayed from the formulation compared to the formulation where no attempt at delaying the release was made. In comparison, more TMC was released, and at a faster rate, from the granule formulation than the optimized minitablet formulations. Both the optimized minitablet formulation and the granule formulation show suitable release profiles for the delivery of peptide drugs with TMC as absorption enhancer in solid oral dosage forms.
在本研究中，开发了微型片和颗粒剂配方作为固体口服剂型，用于递送含有吸收促进剂N-三甲基壳聚糖氯化物（TMC）的肽类药物。微型片被认为是一种合适的剂型，因为作为多单元剂型（MUDFs）的组成部分，它们在崩解前能够相互分散，有效地增加了聚合物发挥其吸收增强作用的面积。聚合物应在肽释放之前从剂型中释放出来，这与实现两种成分的最大释放一起，是本研究的主要重点。去氨加压素（1-(3-巯基丙酸)-8-D-精氨酸加压素单乙酸盐（DDAVP））被用作模型肽类药物。优化后的微型片配方由两种类型的颗粒组成，即DDAVP颗粒和TMC颗粒。含有五硬脂酸四甘油酯（TGPS）的DDAVP颗粒专门用于延迟肽从剂型中的释放。尝试通过TMC颗粒实现TMC的突释。这两种颗粒类型都包含在颗粒剂配方中。优化后的微型片配方和颗粒剂配方的释放曲线表明，与未尝试延迟释放的配方相比，DDAVP从该配方中的释放得到了有效延迟。相比之下，颗粒剂配方中释放的TMC比优化后的微型片配方更多，且释放速度更快。优化后的微型片配方和颗粒剂配方都显示出适合以TMC作为吸收促进剂的固体口服剂型递送肽类药物的释放曲线。
