Rao V M, Lin M, Larive C K, Southard M Z
Chemical and Petroleum Engineering Department, The University of Kansas, Lawrence 66045, USA.
J Pharm Sci. 1997 Oct;86(10):1132-7. doi: 10.1021/js9604974.
The in vivo dissolution of many poorly soluble drugs is enhanced by the action of surfactants secreted into the upper gastrointestinal (GI) tract. These substances may act by solubilizing individual drug molecules into two separate liquid phases: the free aqueous phase and a micellar phase in which the drug is incorporated into a complex of two or more surfactant molecules. This complex process, micellar solubilization, was the subject of this in vitro study, wherein griseofulvin (gris) dissolution was observed in flowing surfactant solutions. Aqueous solutions of sodium dodecyl sulfate (SDS), an anionic surfactant, were pumped over a gris tablet embedded in a laminar flow device to simulate flow in the human upper GI tract. SDS solutions were well above the critical micellar concentration (cmc approximately 6-7 mM), and flow rates ranged from 4 to 7 mL/min. Gris solubility in premicellar (4 mM), near-micellar (6 mM), and micellar (>6 mM) SDS solutions was also determined. The measured solubility of gris increased linearly with SDS concentrations above the cmc. Drug solubility in SDS concentrations below the cmc was also higher than that in water. Gris diffusion coefficients were measured using pulsed-field gradient NMR spectroscopy. To determine the controlling mechanism for surfactant-enhanced dissolution, a mathematical model was developed. The model solution, an equation for drug dissolution rate, was compared with experimental data to demonstrate that drug transport away from the solid surface is the slow step in the process. Measured gris diffusion coefficients and solubility values were used as constants in the mathematical model solution and were combined to calculate an effective gris diffusion coefficient. Using these experimentally determined properties, model-calculated dissolution rates were within 7% of the measured values. As hypothesized, dissolution rates were found to be directly proportional to the transport properties of the system (effective drug diffusion coefficient and fluid flow rate) as well as to the drug solubility. To further verify transport-limited dissolution, the measured dissolution rates were found to be proportional to the surrounding medium flow rate to the 1/3 power, as predicted by the model dissolution rate equation.
许多难溶性药物在体内的溶出会因分泌至上消化道（GI）的表面活性剂的作用而增强。这些物质可能通过将单个药物分子溶解到两个不同的液相中来发挥作用：游离水相和胶束相，药物在胶束相中被并入两个或更多表面活性剂分子的复合物中。这个复杂的过程，即胶束增溶，是本体外研究的主题，其中在流动的表面活性剂溶液中观察了灰黄霉素（gris）的溶出。将阴离子表面活性剂十二烷基硫酸钠（SDS）的水溶液泵过嵌入层流装置中的gris片剂，以模拟人体上消化道中的流动。SDS溶液远高于临界胶束浓度（cmc约为6 - 7 mM），流速范围为4至7 mL/min。还测定了gris在亚胶束（4 mM）、近胶束（6 mM）和胶束（>6 mM）SDS溶液中的溶解度。测得的gris溶解度在cmc以上随SDS浓度呈线性增加。在低于cmc的SDS浓度下药物的溶解度也高于在水中的溶解度。使用脉冲场梯度核磁共振光谱法测量了gris扩散系数。为了确定表面活性剂增强溶出的控制机制，建立了一个数学模型。将模型解，即药物溶出速率方程，与实验数据进行比较，以证明药物从固体表面的转运是该过程中的慢步骤。测得的gris扩散系数和溶解度值用作数学模型解中的常数，并结合起来计算有效的gris扩散系数。利用这些实验确定的性质，模型计算的溶出速率在测量值的7%以内。正如所假设的，发现溶出速率与系统的转运性质（有效药物扩散系数和流体流速）以及药物溶解度成正比。为了进一步验证转运受限的溶出，发现测得的溶出速率与周围介质流速的1/3次方成正比，这是模型溶出速率方程所预测的。
