Greimel Alexander, Bernkop-Schnürch Andreas, Del Curto Maria Dorly, D'Antonio Mauro
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innsbruck, Austria.
Drug Dev Ind Pharm. 2007 Jan;33(1):71-7. doi: 10.1080/03639040600712953.
The purpose of the present study was to investigate the permeation characteristics of the beta sheet breaker peptide AS 602704 (BSB) on excised bovine nasal mucosa using an Ussing chamber model. The influence of various absorption enhancers such as sodium cholate, sodium dodecyl sulfate (SDS), cetrimidum, sodium caprate, Na(2)EDTA, polycarbophil (PCP), the thiomer conjugate polycarbophil-cysteine (PCP-Cys), and poly-l-arginine (poly-l-arg; 100 kDa) was evaluated. Additionally, the influence of temperature and pH on the transport rate as well as the stability of the peptide drug against enzymatic degradation were investigated in vitro. The effective permeability coefficient (P(eff)) of BSB in Krebs-Ringer-buffer (KRB) pH 7.4 was (1.89 +/- 0.44)* 10-5, while in the presence of sodium caprate (0.5%) a P(eff) of (9.58 +/- 1.82)*10-5 was achieved. Rank order of enhancement ratio was sodium caprate > SDS > sodium cholate > Na(2)EDTA > poly-L-arg = PCP-Cys. In case of cetrimidum and PCP even a decrease in the absorption of BSB was determined. Na2EDTA reduced the enzymatic degradation of BSB when exposed to a nasal tissue homogenate by more than the half. An increased lipophilicity of BSB because of a more acidic milieu (pH 5.5) did not lead to an increased transcellular transport. Permeation studies carried out at 4 degrees C compared to 37 degrees C demonstrated a temperature dependent permeation behaviour suggesting an additional active carrier mediated transport. The results obtained within these studies should facilitate the development of a nasal delivery system for AS 602704 for the treatment of Alzheimer's disease.
本研究的目的是使用尤斯灌流室模型研究β-折叠破坏肽AS 602704（BSB）在离体牛鼻黏膜上的渗透特性。评估了各种吸收促进剂的影响，如胆酸钠、十二烷基硫酸钠（SDS）、西曲溴铵、癸酸钠、乙二胺四乙酸二钠（Na₂EDTA）、聚卡波非（PCP）、硫醇聚合物聚卡波非-半胱氨酸（PCP-Cys）和聚-L-精氨酸（聚-L-精；100 kDa）。此外，还体外研究了温度和pH对转运速率的影响以及肽药物对酶降解的稳定性。BSB在pH 7.4的 Krebs-Ringer缓冲液（KRB）中的有效渗透系数（P eff）为（1.89±0.44）×10⁻⁵，而在存在0.5%癸酸钠的情况下，P eff达到（9.58±1.82）×10⁻⁵。增强比的排序为癸酸钠>SDS>胆酸钠>Na₂EDTA>聚-L-精氨酸 = PCP-Cys。对于西曲溴铵和PCP，甚至确定BSB的吸收减少。当暴露于鼻组织匀浆时，Na₂EDTA使BSB的酶降解减少了一半以上。由于更酸性的环境（pH 5.5）导致BSB亲脂性增加，但并未导致跨细胞转运增加。与37℃相比，在4℃进行的渗透研究表明存在温度依赖性渗透行为，提示存在额外的主动载体介导的转运。这些研究中获得的结果应有助于开发用于治疗阿尔茨海默病的AS 602704鼻递送系统。
