Details

Autor(en) / Beteiligte

• Bayard, F.J.C.
• Thielemans, W.
• Pritchard, D.I.
• Paine, S.W.
• Young, S.S.
• Bäckman, P.
• Ewing, P.
• Bosquillon, C.

Titel

Polyethylene glycol-drug ester conjugates for prolonged retention of small inhaled drugs in the lung

Ist Teil von

• Journal of controlled release, 2013-10, Vol.171 (2), p.234-240

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• Typically, inhaled drugs are rapidly absorbed into the bloodstream, which results in systemic side effects and a brief residence time in the lungs. PEGylation was evaluated as a novel strategy for prolonging the retention of small inhaled molecules in the pulmonary tissue. Hydrolysable ester conjugates of PEG1000, PEG2000, mPEG2000, PEG3400 and prednisolone, a model drug cleared from the lungs within a few minutes, were synthesised and thoroughly characterised. The conjugates were stable in buffers with hydrolysis half-lives ranging from 1h to 70h, depending on the pH and level of substitution. With the exception of PEG3400-prednisolone, conjugates did not induce a significant lactate dehydrogenase (LDH) release from Calu-3 cells after a 20h exposure. Following nebulisation to isolated perfused rat lungs (IPRL), the PEG2000 and mPEG2000 conjugates reduced the maximum prednisolone concentration in the perfusate (Cmax) by 3.0 and 2.2 fold, respectively. Moreover, while prednisolone was undetectable in the perfusion solution beyond 20min when the free drug was administered, prednisolone concentrations were still quantifiable after 40min following delivery of the conjugates. This study is the first to demonstrate hydrolysable PEG drug ester conjugates are a promising approach for optimising the pharmacokinetic profile of small drugs delivered by inhalation. [Display omitted]