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In vivo evaluation of different formulation strategies for sustained release injectables of a poorly soluble HIV protease inhibitor

Wuyts, Koen; Meeus, Joke; Muees, Joke; Scurr, David J.; Amssoms, Katie; Annaert, Pieter; Davies, Martyn C.; Roberts, Clive J.; Van den Mooter, Guy

Authors

Koen Wuyts

Joke Meeus

Joke Muees

DAVID SCURR david.scurr@nottingham.ac.uk
Senior Research Fellow in Surface Analysis

Katie Amssoms

Pieter Annaert

Martyn C. Davies

Guy Van den Mooter



Abstract

At present no scientific rationale exists for selecting a particular enabling strategy to formulate a poorly water-soluble drug, although this is crucial as it will influence the in vivo performance of the resulting formulation. This study provides an insight into this complicated decision making process for a poorly soluble human immunodeficiency virus (HIV) protease inhibitor based upon in vivo test results. A formulation strategy based on the molecular dispersion of this active pharmaceutical ingredient (API) into a biphasic matrix consisting of water-insoluble poly(lactic-co-glycolic acid) (PLGA) and water-soluble polyvinylpyrrolidone (PVP) was evaluated. The long-term in vivo performance of this strategy was compared to that of other solubility enhancing approaches by evaluating the exposure in male Beagle dogs. Solid dispersions, based on a PLGA/PVP matrix, were compared to solid dispersions in a pure water-insoluble PLGA matrix. Additionally these solid dispersion strategies were compared to the strategy of particle size reduction by means of an API microsuspension. The in vivo performance of the various formulations over a period of 28 days after intramuscular injection was evaluated by the observed initial burst release, plasma concentration-time profiles, time at which maximum plasma levels were reached (tmax,obs) and the estimated bioavailability. Compared to the other formulation strategies assessed, it was concluded that the addition of PVP in a PLGA matrix resulted in vivo in a more sustained release as well as a higher amount of drug released from the polymeric matrix. This was explained based on the structure of these binary PLGA/PVP matrices where the pore network originating from rapidly dissolving PVP plays a crucial role. Moreover, the results suggest that the release of this type of formulations could be delayed by increasing the amount of PLGA in the formulation.

Journal Article Type Article
Publication Date 2015-02
Journal Journal of Controlled Release
Print ISSN 0168-3659
Electronic ISSN 1873-4995
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 199
Pages 1-9
APA6 Citation Wuyts, K., Meeus, J., Muees, J., Scurr, D. J., Amssoms, K., Annaert, P., …Van den Mooter, G. (2015). In vivo evaluation of different formulation strategies for sustained release injectables of a poorly soluble HIV protease inhibitor. Journal of Controlled Release, 199, 1-9. https://doi.org/10.1016/j.jconrel.2014.11.020
DOI https://doi.org/10.1016/j.jconrel.2014.11.020
Keywords Solid dispersions; PLGA; Microspheres; Controlled release; In vivo
Publisher URL http://www.sciencedirect.com/science/article/pii/S0168365914007688
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0
Additional Information This article is maintained by: Elsevier; Article Title: In vivo evaluation of different formulation strategies for sustained release injectables of a poorly soluble HIV protease inhibitor; Journal Title: Journal of Controlled Release; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jconrel.2014.11.020; Content Type: article; Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0





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