Gardyne Stephen J, Mucalo Michael R, Rathbone Michael J
Waikato Pathways College, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand.
Chemistry Department, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand.
Results Pharma Sci. 2011 Nov 25;1(1):80-7. doi: 10.1016/j.rinphs.2011.11.002. eCollection 2011 May.
Eight bioactive drug compounds (abamectin, amoxicillin, dexamethasone, dexamethasone valerate, ketoprofen, melatonin, oestradiol 17β, and oestradiol benzoate) were combined via melt extrusion and disc pressing processes with a polycaprolactone (PCL) matrix and were then evaluated and compared via membrane diffusion and Hanson dissolution studies. This investigation was to determine the potential of this matrix to act as a controlled release drug delivery vehicle for a number of drugs not previously combined with PCL in a melt extrusion mix. The inclusion of the progesterone/PCL system, for which the drug release behaviour has been well studied before was intended for comparison with the PCL systems incorporating drugs that have received little research attention in the past. Initial studies centred on an evaluation of the permeation ability of the bioactive drugs dissolved in aqueous cyclodextrin solutions through a poly(ε-caprolactone) (PCL) membrane using Valia-Chien side-by-side cells. Permeation rates were mostly low and found to range from 0 to 122 μg h(-1) with only ketoprofen, melatonin, and progesterone displaying rates exceeding 20 μg h(-1). Hanson dissolution release profiles in aqueous alcohol were subsequently measured for the 9 melt extruded PCL/drug combinations and led to Hanson release rates of 0-556 μg cm(-2) h(-0.5) with dexamethasone, dexamethasone valerate, ketoprofen, melatonin, and progesterone giving values exceeding 100 μg cm(-2) h(-0.5). A number of drugs such as the dexamethasones probably performed better than they did in the permeability rate measurements because of the less polar aqueous alcoholic solvent used. In searching for useful correlations between the drug physicochemical properties and release rate, only a moderate correlation (R (2)=0.5675) between Hanson dissolution release rate and permeation rate was found. This suggests that the release rate and the permeation are both controlled by the rate of drug diffusion through the PCL with release rate involving an additional dissolution process (of the drug) before permeation occurs accounting for the moderate correlation. In general, of the eight drugs considered, it was clear that the oestradiol-based drugs, abamectin, and amoxicillin were generally not suited to drug delivery via PCL under the conditions used. However, ketoprofen was found to be very suitable as a drug candidate for melt extrusion with PCL with dexamethasone valerate, dexamethasone, and melatonin also showing potential as candidates though to a much lesser extent.
八种生物活性药物化合物（阿维菌素、阿莫西林、地塞米松、戊酸地塞米松、酮洛芬、褪黑素、17β-雌二醇和苯甲酸雌二醇）通过熔融挤出和压片工艺与聚己内酯（PCL）基质混合，然后通过膜扩散和汉森溶解研究进行评估和比较。本研究旨在确定该基质作为多种此前未在熔融挤出混合物中与PCL结合的药物的控释给药载体的潜力。纳入此前已对药物释放行为进行充分研究的孕酮/PCL系统，旨在与过去很少受到研究关注的含药PCL系统进行比较。初步研究集中在使用Valia-Chien并列细胞评估溶解在环糊精水溶液中的生物活性药物通过聚（ε-己内酯）（PCL）膜的渗透能力。渗透速率大多较低，范围为0至122μg h⁻¹，只有酮洛芬、褪黑素和孕酮的速率超过20μg h⁻¹。随后对9种熔融挤出的PCL/药物组合在水醇中的汉森溶解释放曲线进行了测量，地塞米松、戊酸地塞米松、酮洛芬、褪黑素和孕酮的汉森释放速率为0至556μg cm⁻² h⁻⁰·⁵，其值超过100μg cm⁻² h⁻⁰·⁵。由于使用的水醇溶剂极性较小，一些药物如地塞米松类药物在溶解释放速率测量中的表现可能比在渗透速率测量中更好。在寻找药物理化性质与释放速率之间的有用相关性时，发现汉森溶解释放速率与渗透速率之间只有中等相关性（R² = 0.5675）。这表明释放速率和渗透均受药物通过PCL的扩散速率控制，释放速率在渗透发生之前涉及额外的（药物）溶解过程，这解释了中等相关性。总体而言，在所考虑的八种药物中，很明显在所用条件下，基于雌二醇的药物、阿维菌素和阿莫西林通常不适合通过PCL进行药物递送。然而，发现酮洛芬非常适合作为与PCL熔融挤出的药物候选物，戊酸地塞米松、地塞米松和褪黑素也显示出作为候选物的潜力，尽管程度要小得多。
