Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.789183
Title: Microencapsulated human albumin nanoparticles for drug delivery to the lungs
Author: Patel, Ayasha Vali
ISNI:       0000 0004 8500 0666
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Abstract:
Albumin nanoparticles are attractive candidates for optimising drug delivery to the lungs by modifying local biodistribution. However, there has been little exploration of the loading of therapeutic agents into albumin-based nanoformulations for inhaled delivery. The aim of this work was to develop respirable microparticles containing albumin nanoparticles for drug delivery to the lungs. Human serum albumin (HSA) nanoparticle suspensions were developed using a modified desolvation method. The solubility of four anti-tuberculosis benzothiazinone (BTZ) drug candidates (IR 20, IF 274, FG 2, AR 112; 0.38-134 μg/mL) was enhanced 2 to 140-fold by 50 mg/mL (1 mL) albumin. Tryptophan 213 residue quenching studies indicated moderate drug binding strength to Sudlow's site I. Nanoparticle manufacture was optimised to provide 37-60% drug encapsulation efficiency in HSA particles (169 nm, zeta potential -31 mV). Drug release was < 8% over 48 h in aqueous medium, but 66-88% was released by 48 h after the addition of proteases at concentrations representative of the enzyme levels found in lung lining fluid. Dissolution profiles reflected Logistic release kinetics for IR 20 and Weibull release kinetics for FG 2 (R2= 0.988 and 0.975, respectively) and antimycobacterial activity in an M. tuberculosis infected macrophage model was enhanced compared to delivery in DMSO or albumin solution. Pilot spray-drying studies demonstrated that incorporation of albumin nanoparticles into respirable carrier particles was possible. The spray-dried powders developed in this work were suitably sized for lung deposition (~4 μm) and albumin nanoparticles were recoverable after the spray-drying process with good re-dispersibility and size uniformity. An albumin nanoparticle content in the spray-dried mannitol formulation of 40% was selected as the most promising. HSA nanoparticles containing roflumilast, a selective phosphodiesterase 4 inhibitor, were incorporated in the dry powder formulation with little effect on the aerodynamic properties of the powders produced. Roflumilast release from the spray-dried microcarriers was found to be the same as from the suspension form (< 20% at 48 hours) without the presence of trypsin, and a rapid release rate for the first 4 hours with the presence of trypsin, followed by a slower rate for the remaining 48 hours (total ~80% drug release). Dose deposition in human lungs was modelled using the PreciseInhale® system, indicating that aerosol administration of a single capsule containing 10 mg of the dry powder formulation would deliver roughly 6 μg roflumilast. This work demonstrates opportunities for developing human serum albumin nanoparticle-based microcarriers as a platform for inhaled drug delivery.
Supervisor: Forbes, Benjamin John ; Dailey, Lea Ann Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.789183  DOI: Not available
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