Department of Formulation Design and Pharmaceutical Technology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka 569-1094, Japan.
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
Mol Pharm. 2023 Aug 7;20(8):4071-4085. doi: 10.1021/acs.molpharmaceut.3c00226. Epub 2023 Jul 27.
Coamorphous formulation is a useful approach for enhancing the solubility of poorly water-soluble drugs via intermolecular interactions. In this study, a hydrogen-bonding-based coamorphous system was developed to improve drug solubility, but it barely changed the apparent permeability () of the drug. This study aimed to design a novel coamorphous salt using ionic interactions to improve drug permeability and absorption. Telmisartan (TMS), with an acidic group, was used to form a coamorphous salt with basic amlodipine (AML). Evaluation of the physicochemical properties confirmed the formation of a coamorphous salt via ionic interactions between the amine group of AML and the carboxyl group of TMS at a molar ratio of 1:1. The coamorphous salt of TMS/AML enhanced the partitioning of both drugs into octanol, indicating increased lipophilicity owing to the interaction between TMS and AML. The coamorphous salt dramatically enhanced TMS solubility (99.8 times that of untreated TMS) and decreased AML solubility owing to the interaction between TMS and AML. Although the coamorphous salt showed a decreased in the permeation study in the presence of a thicker unstirred water layer (UWL) without stirring, increased in the presence of a thinner UWL with stirring. The oral absorption of TMS from the coamorphous salt increased by up to 4.1 times compared to that of untreated TMS, whereas that of AML remained unchanged. Although the coamorphous salt with increased lipophilicity has a disadvantage in terms of diffusion through the UWL, the UWL is thin in human/animal bodies owing to the peristaltic action of the digestive tract. Dissociation of the coamorphous salt on the membrane surface could contribute to the partitioning of the neutral form of drugs to the membrane cells compared with untreated drugs. As a result, coamorphous salt formation has the advantage of improving the membrane permeation and oral absorption of TMS, owing to the enhanced solubility and supply of membrane-permeable free TMS on the surface of the membrane.
共晶型制剂是一种通过分子间相互作用提高疏水性药物溶解度的有效方法。本研究通过氢键构建了一种共晶体系，以提高药物的溶解度，但对药物的表观渗透系数（）几乎没有影响。本研究旨在设计一种新型共晶盐，利用离子相互作用提高药物的渗透性和吸收性。具有酸性基团的替米沙坦（TMS）与碱性氨氯地平（AML）形成共晶盐。物理化学性质评价证实，AML 的胺基与 TMS 的羧基以 1:1 的摩尔比通过离子相互作用形成共晶盐。TMS/AML 共晶盐增强了两种药物在辛醇中的分配，表明由于 TMS 和 AML 之间的相互作用，亲脂性增加。由于 TMS 和 AML 之间的相互作用，TMS 溶解度显著提高（未处理 TMS 的 99.8 倍），AML 溶解度降低。尽管在存在较厚未搅动水层（UWL）且不搅拌的情况下，共晶盐在渗透研究中显示出较低的，但在存在较薄 UWL 且搅拌的情况下， 增加。与未处理的 TMS 相比，TMS 从共晶盐中的口服吸收增加了 4.1 倍，而 AML 则保持不变。尽管具有较高亲脂性的共晶盐在通过 UWL 扩散方面存在劣势，但由于消化道的蠕动作用，人体/动物体内的 UWL 很薄。与未处理的药物相比，共晶盐在膜表面的解离可能有助于药物中性形式的分配到膜细胞中。因此，共晶盐的形成有利于提高 TMS 的膜渗透和口服吸收，这是由于膜表面可透过的游离 TMS 的溶解度和供应增加。
