为了溶解溶解性差的活性药物成分,多年来实施了各种战略,包括使用纳米载体,如环糊精和脂质体。然而,提高药物的表观溶解度并不总是转化为提高生物利用度。这项工作旨在研究与环糊精的复合和掺入脂质体对药物体外渗透性的影响程度,并找到渗透过程的机理描述。为此,我们研究了羟丙基-β-环糊精(HP-β-CD)和磷脂酰胆碱脂质体三种化学上不同的化合物(阿替洛尔,酮洛芬和氢化可的松)。我们通过UV局部光谱和高级数据拟合来研究制剂的药物扩散,以提取参数,例如扩散率和边界/游离药物分数。然后,我们将该信息与用新型PermeaPad®屏障获得的体外药物渗透性相关联。结果表明,HP-β-CD的浓度增加导致难溶性的unionized酮洛芬的增溶,以及氢化可的松。然而,这种表观溶解度的净增量与测得的通量增加不成比例。另一方面,使经验自由药物浓度的通量正常化,即,自由分数,给出了有意义的绝对渗透系数。脂质体制剂获得的结果与环糊精的发现一致。总之,我们证明了我们的方法在所检查的使能制剂中计算游离药物分数的充分性和有用性,支持已建立的药物扩散/渗透理论的有效性,即无限制的药物部分是药物跨膜渗透的主要驱动因素。
In order to solubilize poorly soluble active pharmaceutical ingredients, various strategies have been implemented over the years, including the use of nanocarriers, such as
cyclodextrins and liposomes. However, improving a drug\'s apparent solubility does not always translate to enhanced bioavailability. This work aimed to investigate to which extent complexation with
cyclodextrins and incorporation into liposomes influence drug in vitro permeability and to find a mechanistic description of the permeation process. For this purpose, we investigated hydroxypropyl-β-cyclodextrin (HP-β-CD) and phosphatidylcholine liposomes formulations of three chemically diverse compounds (atenolol, ketoprofen and hydrocortisone). We studied drug diffusion of the formulations by UV-localized spectroscopy and advanced data fitting to extract parameters such as diffusivity and bound-/free drug fractions. We then correlated this information with in vitro drug permeability obtained with the novel PermeaPadⓇ barrier. The results showed that increased concentration of HP-β-CD leads to increased solubilization of the poorly soluble unionized ketoprofen, as well as hydrocortisone. However, this net increment of apparent solubility was not proportional to the increased flux measured. On the other hand, normalising the flux over the empirical free drug concentration, i.e., the free fraction, gave a meaningful absolute permeability coefficient. The results achieved for the liposomal formulation were consistent with the finding on
cyclodextrins. In conclusion, we proved the adequacy and usefulness of our method for calculating free drug fractions in the examined enabling formulations, supporting the validity of the established drug diffusion/permeation theory that the unbounded drug fraction is the main driver for drug permeation across a membrane.