Devarakonda Bharathi, Otto Daniel P, Judefeind Anja, Hill Ronald A, de Villiers Melgardt M
School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA.
Int J Pharm. 2007 Dec 10;345(1-2):142-53. doi: 10.1016/j.ijpharm.2007.05.039. Epub 2007 May 24.
The complexation of the practically insoluble drug furosemide (acidic pK(a) 3.22) with lower generation PAMAM dendrimers showed a significant release dependence on the ionization state of the drug. UV and FTIR studies suggested that the drug was localized in the interior of the dendrimer. The dendrimer amine, amide and ester groups, demonstrated pH-dependent ionization as did the drug carboxylic acid group and it was proven that the most efficient drug complexation was achieved in slightly acidic conditions (pH 4.0-6.0). At this pH, amide groups in the dendrimer cavities were at least partially ionized to expose a positive charge whilst the furosemide carboxylic acid ionized to great extent (pH>pK(a)) resulting in electrostatic complexation. Conversely, higher release rates were observed in acidic conditions (pH 1.2) where furosemide was virtually unionized, emphasizing the importance of the drug ionization state in the determination of drug release. Despite the complex interactions between the dendrimer and drug and its effects on release kinetics, the dendrimers resulted in higher solubility of the drug and contributed significantly to the array of available techniques to increase the solubility of poorly water-soluble drugs that are very abundant in industry today. Complexation with low generation PAMAM dendrimers (<generation 4) could provide opportunities to both increase drug solubility and tuning of the release profile for practically insoluble drugs.
几乎不溶的药物呋塞米（酸性pK(a) 3.22）与低代数聚酰胺-胺（PAMAM）树枝状大分子的络合显示出药物释放对其电离状态有显著依赖性。紫外和傅里叶变换红外光谱（FTIR）研究表明，药物定位于树枝状大分子内部。树枝状大分子的胺基、酰胺基和酯基与药物的羧酸基团一样表现出pH依赖性电离，并且已证明在微酸性条件（pH 4.0 - 6.0）下可实现最有效的药物络合。在此pH值下，树枝状大分子空腔中的酰胺基至少部分电离以暴露正电荷，而呋塞米羧酸则大量电离（pH > pK(a)），从而导致静电络合。相反，在酸性条件（pH 1.2）下观察到更高的释放速率，此时呋塞米几乎未电离，这强调了药物电离状态在药物释放测定中的重要性。尽管树枝状大分子与药物之间存在复杂的相互作用及其对释放动力学的影响，但树枝状大分子提高了药物的溶解度，并对当今工业中大量存在的水溶性差的药物增加溶解度的一系列现有技术做出了重大贡献。与低代数PAMAM树枝状大分子（<第4代）络合可为提高几乎不溶药物的溶解度和调节释放曲线提供机会。
