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Saquinavir Loaded Acetalated Dextran Microconfetti – a Long Acting Protease Inhibitor Injectable

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Abstract

Purpose

Since the adoption of highly active antiretroviral therapy, HIV disease progression has slowed across the world; however, patients are often required to take multiple medications daily of poorly bioavailable drugs via the oral route, leading to gastrointestinal irritation. Recently, long acting antiretroviral injectables that deliver drug for months at a time have moved into late phase clinical trials. Unfortunately, these solid phase crystal formulations have inherent drawbacks in potential dose dumping and a greater likelihood for burst release of drug compared to polymeric formulations.

Methods

Using electrospinning, acetalated dextran scaffolds containing the protease inhibitor saquinavir were created. Grinding techniques were then used to process these scaffolds into injectables which are termed saquinavir microconfetti. Microconfetti was analyzed for in vitro and in vivo release kinetics.

Results

Highly saquinavir loaded acetalated dextran electrospun fibers were able to be formed and processed into saquinavir microconfetti while other polymers such as poly lactic-co-glycolic acid and polycaprolactone were unable to do so. Saquinavir microconfetti release kinetics were able to be tuned via drug loading and polymer degradation rates. In vivo, a single subcutaneous injection of saquinavir microconfetti released drug for greater than a week with large tissue retention.

Conclusions

Microconfetti is a uniquely tunable long acting injectable that would reduce the formation of adherence related HIV resistance. Our findings suggest that the injectable microconfetti delivery system could be used for long acting controlled release of saquinavir and other hydrophobic small molecule drugs.

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Abbreviations

Ace-DEX:

Acetalated dextran

FDA:

Food and drug administration

GI tract:

Gastrointestinal tract

HAART:

Highly active antiretroviral therapy

HIV:

Human immunodeficiency virus

MTB:

Mycobacterium tuberculosis

PCL:

Polycaprolactone

Pgp:

P-glycoprotein

PIs:

Protease inhibitors

PLGA:

Poly lactic-co-glycolic acid

RTV:

Ritonavir

SQV:

Saquinavir

SQV-MC:

Saquinavir microconfetti

WHO:

World health organization

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Acknowledgments and Disclosures

We would like to acknowledge the Chapel Hill Analytical and Nanofabrication Laboratory (CHANL) and Campus Microscopy and Imaging Facility (CMIF) for allowing us access to use the imaging equipment used within this manuscript. Additionally, we would like to acknowledge the University of North Carolina at Chapel Hill Center for AIDS Research (P30 AI50410).

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Author notes

  1. Kristy M. Ainslie

    Present address: Division of Molecular Pharmaceutics, Eshelman College of Pharmacy, University of North Carolina, 4211 Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina, 27599, USA

Authors and Affiliations

  1. Division of Molecular Pharmaceutics, Eshelman College of Pharmacy, University of North Carolina, 4211 Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina, 27599, USA

    Michael A. Collier & Eric M. Bachelder

  2. William G. Lowrie Department of Chemical and Biomolecular Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, 43210, USA

    Matthew D. Gallovic

  3. Division of Experimental Therapeutics, Eshelman College of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599, USA

    Craig D. Sykes & Angela Kashuba

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  1. Michael A. Collier
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Correspondence to Kristy M. Ainslie.

Electronic Supplementary Material

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Supplemental Figure 1

Scanning electron micrographs with scale bar indicating 5 μm for electrospun constructs from 71kDa acetalated dextran (Ace-DEX) encapsulating saquinavir (SQV) at a) 10, b) 20, c) 30, and d) 40% wt/wt, and 500kDa Ace-DEX encapsulating SQV at e) 50% wt/wt. (DOCX 715 kb)

Supplemental Figure 2

Scanning electron micrograph with scale bar indicating 10 μm of 71kDa acetalated dextran microconfetti (Ace-DEX-MC) using a mortar and pestle for processing. (DOCX 158 kb)

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Collier, M.A., Gallovic, M.D., Bachelder, E.M. et al. Saquinavir Loaded Acetalated Dextran Microconfetti – a Long Acting Protease Inhibitor Injectable. Pharm Res 33, 1998–2009 (2016). https://doi.org/10.1007/s11095-016-1936-y

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  • DOI: https://doi.org/10.1007/s11095-016-1936-y

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