School of Life Sciences, University of Applied Sciences Northwest Switzerland, Hofackerstrasse 30, 4132 Muttenz, Switzerland; Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
School of Life Sciences, University of Applied Sciences Northwest Switzerland, Hofackerstrasse 30, 4132 Muttenz, Switzerland.
J Pharm Sci. 2024 Aug;113(8):2524-2541. doi: 10.1016/j.xphs.2024.05.020. Epub 2024 May 23.
The objective of this study was to investigate the mechanisms underlying drug release from a controlled colonic release (CCR) tablet formulation based on a xyloglucan polysaccharide matrix and identify the factors that control the rate of release for the purpose of fundamentally substantiating the concept and demonstrating its robustness for colonic drug delivery. Previous work demonstrated in vitro limited release of 5-aminosalicylic acid (5-ASA) and caffeine from these tablets in small intestinal environment and significant acceleration of release by xyloglucanase, an enzyme of the colonic microbiome. Targeted colonic drug delivery was verified in an animal study in vivo. In the present work, interaction of the xyloglucan matrix tablets with aqueous dissolution media containing xyloglucanase was found to lead to the spontaneous formation of a hydrated highly viscous gummy layer at the surface of the matrix which had a reduced drug content compared to the underlying regions and persisted with a nearly constant thickness that was inversely correlated to the enzyme concentration throughout the duration of the release process. Enzymatic hydrolysis of xyloglucan was determined to take place at the surface of the matrix leading to matrix erosion and a relation for the rate of enzymatic reaction as a function of bulk enzyme concentration and the concentration of dissolved xyloglucan in the gummy layer was derived. A mathematical model was developed encompassing aqueous medium ingress, matrix metamorphosis due to xyloglucan dissolution and matrix swelling, enzymatic hydrolysis of the polysaccharide and concomitant drug release due to matrix erosion and simultaneous drug diffusion. The model was fitted to data of reducing sugar equivalents in the medium reflecting matrix erosion and released drug amount. Enzymatic reaction parameters and reasonable values of medium ingress velocity, xyloglucan dissolution rate constant and drug diffusion coefficient were deduced that provided an adequate approximation of the data. Erosion was shown to be the overwhelmingly dominant drug release mechanism while the role of diffusion marginally increased at low enzyme concentration and high drug solubility. Changing enzyme concentration had a rather weak effect on matrix erosion and drug release rate as demonstrated by model simulations supported by experimental data, while xyloglucan dissolution was slow and had a stronger effect on the rate of the process. Therefore, reproducible colonic drug delivery not critically influenced by inter- and intra-individual variation of microbial enzyme activity may be projected.
本研究的目的是探讨基于木葡聚糖多糖基质的控释结肠释放（CCR）片剂制剂中药物释放的机制，并确定控制释放速率的因素，以期从根本上证实该概念，并展示其用于结肠药物递送的稳健性。先前的工作表明，在小肠环境中，这些片剂中 5-氨基水杨酸（5-ASA）和咖啡因的体外释放有限，并且木葡聚糖酶（结肠微生物组的一种酶）的加速释放。在体内动物研究中验证了靶向结肠药物递送。在本工作中，发现木葡聚糖基质片剂与含有木葡聚糖酶的水性溶解介质的相互作用导致在基质表面自发形成水合的高粘性胶状层，与底层区域相比，该层的药物含量降低，并且保持几乎恒定的厚度，该厚度与酶浓度呈反比，在整个释放过程中。确定木葡聚糖的酶水解发生在基质的表面，导致基质侵蚀，并推导出作为基质中酶浓度和溶解木葡聚糖浓度的函数的酶反应速率的关系。开发了一个数学模型，该模型涵盖了水相介质的进入、由于木葡聚糖溶解和基质溶胀引起的基质变形、多糖的酶水解以及由于基质侵蚀和同时药物扩散引起的药物释放。该模型拟合了反映基质侵蚀和释放药物量的介质中还原糖当量的数据。推导了酶反应参数和合理的值，例如介质进入速度、木葡聚糖溶解速率常数和药物扩散系数，这些参数提供了对数据的充分近似。结果表明，侵蚀是药物释放的主要机制，而扩散的作用在低酶浓度和高药物溶解度下略有增加。通过模型模拟和实验数据的支持，表明改变酶浓度对基质侵蚀和药物释放速率的影响较弱，而木葡聚糖的溶解速度较慢，对过程的速率有更强的影响。因此，可能会预测到不受微生物酶活性的个体间和个体内差异的影响的可重现的结肠药物递送。
