Liu P, Kurihara-Bergstrom T, Clarke F H, Gonnella N, Good W R
Pharmaceuticals Division, CIBA-GEIGY Corporation, Ardsley, New York 10502.
Pharm Res. 1992 Aug;9(8):1035-42. doi: 10.1023/a:1015854411498.
It has been reported previously that saturated terbutaline sulfate in aqueous isopropanol significantly enhances the terbutaline flux through human skin in vitro. This paper demonstrates that the effect of isopropanol on the permeant species in the formulation contributes to the flux enhancement. This demonstration is based on studies involving measurements of conductivity and pKa as well as NMR spectroscopy in isopropanol-water mixtures. Increasing isopropanol concentration inhibits the proton dissociation of terbutaline and results in the ion associations between the protonated terbutaline and its counterion, sulfate anion. The species present in the formulation include protonated terbutaline, the negatively charged terbutaline-sulfate (1:1) ion pair, and the neutral terbutaline-sulfate (2:1) ion triplet. The results of the studies provide the basis for a quantitative evaluation of the species equilibria in solutions of terbutaline sulfate. The saturated terbutaline sulfate in 60% isopropanol produces the maximum concentration of the neutral ion triplet. This result is almost parallel to the terbutaline skin flux, which maximized at 60-80% isopropanol.
先前已有报道称，在异丙醇水溶液中的饱和硫酸特布他林能显著提高特布他林在体外透过人体皮肤的通量。本文证明，异丙醇对制剂中渗透物种类的影响有助于通量的提高。这一证明基于对异丙醇 - 水混合物中的电导率、pKa以及核磁共振光谱的测量研究。异丙醇浓度的增加会抑制特布他林的质子解离，并导致质子化特布他林与其抗衡离子硫酸根阴离子之间的离子缔合。制剂中存在的物种包括质子化特布他林、带负电荷的硫酸特布他林（1:1）离子对以及中性的硫酸特布他林（2:1）离子三联体。这些研究结果为定量评估硫酸特布他林溶液中的物种平衡提供了依据。60%异丙醇中的饱和硫酸特布他林产生的中性离子三联体浓度最高。这一结果几乎与特布他林的皮肤通量平行，特布他林的皮肤通量在60 - 80%异丙醇时达到最大值。
