Department of Pharmaceutics, Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacića 1, HR-10000 Zagreb, Croatia.
J Pharm Biomed Anal. 2010 May 1;52(1):9-18. doi: 10.1016/j.jpba.2009.11.013. Epub 2009 Nov 18.
Binary products of bupivacaine hydrochloride (BVP HCl), an amide type local anesthetic, with parent beta-cyclodextrin (beta-CD) and its soluble beta-cyclodextrin-epichlorohydrin polymer (EPI-beta-CD) were prepared and evaluated as a first phase in the development of a novel mucoadhesive formulation aimed for buccal delivery of this drug. The solid products were obtained by physical mixing, ball milling in high-energy mills, co-evaporation and lyophilisation, in order to rationally select the most effective preparation technique. The solid products obtained were carefully characterised by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and environmental scanning electron microscopy (ESEM). The impact of the preparation techniques on the physicochemical properties of plain drug was also studied. Results of solid-state analysis revealed more intense interactions of BVP HCl with EPI-beta-CD than with native beta-CD, accompanied by stronger reduction of drug crystallinity in the samples, probably favoured by the amorphous nature of the polymeric carrier. While summarising the results of DSC and XRPD analyses, it seems that ball milling of drug/cyclodextrin binary mixtures was particularly efficient in inducing solid-state interaction between the components and it can be considered as the method of choice for preparation of complexes of BVP HCl with beta-CD and EPI-beta-CD. In vitro dissolution properties in artificial saliva of ball-milled BVP HCl and corresponding CD complexes were investigated by simulating the conditions present at the surface of the buccal mucosa. The obtained results confirmed that complexation of BVP HCl with beta-CD and EPI-beta-CD is a suitable tool for properly tailoring the dissolution properties of the drug and it can be favourably exploited for the development of an effective buccal drug delivery system.
布比卡因盐酸盐（BVP HCl）是一种酰胺型局部麻醉剂，与母体β-环糊精（β-CD）及其可溶性β-环糊精-表氯醇聚合物（EPI-β-CD）的二元产物被制备并评价为开发旨在用于口腔递药的新型黏附制剂的第一阶段。通过物理混合、高能球磨、共蒸发和冻干来获得固体产物，以便合理选择最有效的制备技术。通过差示扫描量热法（DSC）、X 射线粉末衍射法（XRPD）、傅里叶变换红外光谱法（FTIR）和环境扫描电子显微镜（ESEM）对获得的固体产物进行了仔细的表征。还研究了制备技术对原料药物理化学性质的影响。固态分析的结果表明，BVP HCl 与 EPI-β-CD 的相互作用比与天然β-CD 的相互作用更强烈，同时样品中药物结晶度的降低更强，这可能是由于聚合物载体的无定形性质所致。在总结 DSC 和 XRPD 分析结果时，似乎药物/环糊精二元混合物的球磨特别有效地诱导了各成分之间的固态相互作用，因此可以认为是制备 BVP HCl 与β-CD 和 EPI-β-CD 配合物的首选方法。通过模拟口腔颊黏膜表面的条件，研究了人工唾液中球磨 BVP HCl 及其相应 CD 配合物的体外溶解性能。所得结果证实，BVP HCl 与β-CD 和 EPI-β-CD 的络合是适当调整药物溶解性能的合适工具，可有利地用于开发有效的口腔递药系统。
