Effects of hydroxypropyl-β-cyclodextrin grafted polyethylenimine (HP-β-CD-PEI) including HP-β-CD-PEI 600 , HP-β-CD-PEI 1800 , HP-β-CD-PEI 10000 on the pulmonary absorption of insulin, calcitonin, 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate dextrans (FDs) with various molecular weights (FD4, FD10 and FD70) were examined by an pulmonary absorption study in rats. Pulmonary absorptions of these poorly absorbable drugs were significantly enhanced by HP-β-CD-PEI 1800 and HP-β-CD-PEI 10000 , and HP-β-CD-PEI 1800 with the concentration of 5% (w/v) provided maximal absorption enhancing effect on pulmonary absorption of these model drugs. The toxicity study demonstrated that HP-β-CD-PEI did not induce any toxic action to rat pulmonary membranes. In addition, zeta potential of insulin solution changed to positive by addition of various HP-β-CD-PEI, meanwhile, the degree of positive charge was linearly correlated with absorption enhancing effect of HP-β-CD-PEI, suggesting that positive charge of HP-β-CD-PEI might be related to their absorption enhancing mechanisms for enhancing pulmonary absorption of insulin in rats. In conclusion, HP-β-CD-PEI is a potential and safe absorption enhancer for improving absorption of hydrophilic macromolecules especially peptide and protein drugs by pulmonary delivery.
Yang Gao,Ya Sun,Guangli Liao,Hailong Zhang,Qingzhi Long
Objective This study aims to investigate the potential of DSPE-PEG polymers (DSPE-PEG-OH and DSPE-PEG-SH) on improving absorption of poorly absorbable macromolecules via intrapulmonary administration and underlying mechanism.Methods In situ pulmonary absorption experiments were performed to investigate the absorption of model compounds after intrapulmonary administration to rats. The local membrane damage induced by these DSPE-PEG polymers were evaluated based on morphological observation of lung tissues and measurement of biological toxic markers in bronchoalveolar lavage fluid (BALF) postintrapulmonary delivery of DSPE-PEG polymers to rats. The underlying enhancement mechanism of these polymers was explored by investigating their effects on the pulmonary membrane fluidity and gene expression of tight junction associated proteins with fluorescence polarization and western blotting, respectively.Results Intrapulmonary delivery of these DSPE-PEG polymers significantly enhanced absorptions of poorly absorbed model drugs and did not induce serious damage to the pulmonary membranes of rats. Mechanistic studies demonstrated unaffected pulmonary membrane fluidity and up-regulated expression levels of tight junction-associated proteins by DSPE-PEG polymers, thus indicating that paracellular pathways might be included in the underlying mechanisms by which DSPE-PEG polymers exerted their enhancing actions on drug absorption.Conclusions These findings suggested that these DSPE-PEG polymers are potential for promoting absorptions of poorly absorbable macromolecules with no evidence of damage to the local pulmonary membranes of rats.Novelty statementIn this study, DSPE-PEG-OH and DSPE-PEG-SH polymers, two DSPE-PEG2000 conjugates with different terminal groups demonstrated significant promoting effects on the absorption of poorly absorbed macromolecular drugs after intrapulmonary delivery to rats, and did not induce serious damage to the pulmonary membranes of rats. These DSPE-PEG polymers could statistically downregulate expression levels of tight junction-associated proteins (ZO-1 and occludin), indicating the underlying mechanism by which these polymers exerted their absorption enhancing actions through pulmonary epithelial paracellular pathways. Thus, this study exhibited prospective potential of these DSPE-PEG polymers in developing into dosage forms with the aim to improve the poor bioavailability of some poorly absorbed macromolecular drugs.
Zhang Hailong,Huang Xiaoyan,Mi Jie,Huo Yayu,Wang Guan,Xing Jianfeng,Gao Yang
ObjectivesThis study aims to evaluate the absorption-enhancing effects of Gelucire 44/14 on the pulmonary absorption of different poorly absorbable drugs and relative mechanism of action.MethodsAbsorption-enhancing effect of Gelucire 44/14 were examined by an in-vivo pulmonary absorption experiment in rats, and the membrane toxicity of Gelucire 44/14 was evaluated by measuring levels of protein and dehydrogenase (LDH) in the bronchoalveolar lavage fluid (BALF) and morphological observation.Key findingsPulmonary absorptions of fluorescein isothiocyanate-dextrans, insulin and calcitonin were enhanced by Gelucire 44/14 (0.1–2.0%, w/v) in a concentration-dependent manner, and the maximal absorption-enhancing effect was obtained when the concentration of Gelucire 44/14 increased to 2.0% (w/v). Furthermore, Gelucire 44/14 neither increase the levels of protein and LDH in BALF nor change morphology of lung compared with control group. In addition, a well correlation between the absorption-enhancing effect and surface tension of insulin solution in the presence of Gelucire 44/14 was observed, suggesting Gelucire 44/14-mediated decrease in the surface tension of the gas-liquid interface in alveolar tissue was possible one of the improving mechanisms of Gelucire 44/14.ConclusionGelucire 44/14 was a potential and safe absorption enhancer for improving the absorption of poorly absorbable drugs including insulin and calcitonin by pulmonary delivery.
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