Figueiras Ana, Hombach Juliane, Veiga Francisco, Bernkop-Schnürch Andreas
Department of Pharmaceutical Technology, University of Coimbra, Coimbra, Portugal.
Eur J Pharm Biopharm. 2009 Feb;71(2):339-45. doi: 10.1016/j.ejpb.2008.08.016. Epub 2008 Aug 29.
In this work the enhancing effect of cyclodextrins on the buccal permeation of a hydrophobic model drug, omeprazole was studied. First, the influence of the complexation with cyclodextrins in the absence and in the presence of an alkali agent, L-arginine, on the drug stability was checked at neutral conditions since omeprazole alone is only stable in basic conditions. In vitro transbuccal permeation of omeprazole non-complexed and complexed with beta- and methyl-beta-cyclodextrin and in presence of L-arginine was examined using freshly obtained porcine buccal mucosa. Tissue viability after incubation with sample solutions was assessed using a MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) biochemical assay and histological evaluation. The toxicity of the sample solutions on buccal mucosa was evaluated by measuring lactate dehydrogenase activity. The present results show that complexation with cyclodextrins increases drug stability at neutral conditions; furthermore, L-arginine contributed to higher drug stability. Permeation studies indicate an increase on drug permeation in complexed form of 1.1- and 1.7-fold for beta-cyclodextrin and methyl-beta-cyclodextrin, respectively. The presence of L-arginine increases drug permeation 1.4-fold in omeprazole complexed with beta-cyclodextrin and 2.4-fold in the inclusion complex formed with methyl-beta-cyclodextrin. The cell viability of the buccal mucosa after a 3 h incubation period, with all sample solutions, remained around 70% and lactate dehydrogenase assay showed that studied cyclodextrins, even in the presence of an alkali agent are not cytotoxic for porcine buccal mucosa. Histological evaluation of the tissue demonstrated that the buccal epithelium remains viable after 3 h of incubation with sample solutions.
在本研究中，考察了环糊精对疏水性模型药物奥美拉唑经颊渗透的增强作用。首先，由于奥美拉唑仅在碱性条件下稳定，因此在中性条件下，研究了在不存在和存在碱性试剂L-精氨酸的情况下，环糊精络合对药物稳定性的影响。使用新鲜获取的猪颊黏膜，考察了未络合的奥美拉唑以及与β-环糊精和甲基-β-环糊精络合且存在L-精氨酸时的体外经颊渗透。使用MTT（3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐）生化分析和组织学评估来评价样品溶液孵育后组织的活力。通过测量乳酸脱氢酶活性来评估样品溶液对颊黏膜的毒性。目前的结果表明，与环糊精络合可提高中性条件下的药物稳定性；此外，L-精氨酸有助于提高药物稳定性。渗透研究表明，与β-环糊精和甲基-β-环糊精络合形式的药物渗透率分别提高了1.1倍和1.7倍。L-精氨酸的存在使与β-环糊精络合的奥美拉唑的药物渗透率提高了1.4倍，与甲基-β-环糊精形成的包合物的药物渗透率提高了2.4倍。所有样品溶液孵育3小时后，颊黏膜的细胞活力保持在70%左右，乳酸脱氢酶分析表明，所研究的环糊精即使在存在碱性试剂的情况下对猪颊黏膜也无细胞毒性。组织学评估表明，样品溶液孵育3小时后颊上皮仍保持活力。
