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Design and Characterization of Injectable Poly(Lactic-Co-Glycolic Acid) Pastes for Sustained and Local Drug Release

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Abstract

Purpose

We describe the preparation of injectable polymeric paste (IPP) formulations for local and sustained release of drugs. Furthermore, we include the characterization and possible applications of such pastes. Particular attention is paid to characteristics relevant to the successful clinical formulation development, such as viscosity, injectability, degradation, drug release, sterilization, stability performance and pharmacokinetics.

Methods

Paste injectability was characterized using measured viscosity and the Hagen-Poiseuille equation to determine injection forces. Drug degradation, release and formulation stability experiments were performed in vitro and drug levels were quantified using HPLC-UV methods. Pharmacokinetic evaluation of sustained-release lidocaine IPPs used five groups of six rats receiving increasing doses subcutaneously. An anti-cancer formulation was evaluated in a subcutaneous tumor xenograft mouse model.

Results

The viscosity and injectability of IPPs could be controlled by changing the polymeric composition. IPPs demonstrated good long-term stability and tunable drug-release with low systemic exposure in vivo in rats. Preliminary data in a subcutaneous tumor model points to a sustained anticancer effect.

Conclusions

These IPPs are tunable platforms for local and sustained delivery of drugs and have potential for further clinical development to treat a number of diseases.

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Abbreviations

AUC:

Area under the curve

Cl:

Clearance

Cmax :

Maximum observed concentration

DMSO:

Dimethyl sulfoxide

FDA:

Food and drug administration

IPP:

Injectable polymeric paste

LNCaP:

Androgen-sensitive human prostate adenocarcinoma cells

mPEG:

Methoxy polyethylene glycol

MRT:

Mean residence time

NMP:

N-methyl-2-pyrrolidone

PBS:

Phosphate buffered saline

PCL:

Poly(caprolactone)

PDLLA-MePEG:

Poly(DL-lactide)co-methoxyPEG)

PEG:

Polyethylene glycol

PGA:

Poly(glycolic acid)

PLA:

Poly(lactic acid)

PLGA:

Poly(lactic-co-glycolic acid)

RP-HPLC-UV:

Reversed phase high-performance liquid chromatography with ultraviolet detection

RT:

Retention time

t1/2 :

Terminal half-life

UPLC-MS/MS:

Ultra performance liquid chromatography - tandem mass spectrometry

λz:

Terminal rate constant

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Acknowledgements & Disclosures

We would like to thank Hans Adomat for performing the UHPLC/MS analysis for the rat PK study. We would like to state that the University of British Columbia has submitted a patent application on the injectable polymer paste formulation, listing Martin Gleave, John K. Jackson, Veronika Schmitt and Claudia Kesch as co-inventors. The technology has been outlicensed to Sustained Therapeutics, an early-stage biotech company founded by Dr. Gleave.

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Author notes

  1. Veronika Schmitt and Claudia Kesch contributed equally to this work.

Authors and Affiliations

  1. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

    Veronika Schmitt, Claudia Kesch, Samir Bidnur, Eliana Beraldi, Virginia Yago, Mary Bowden & Martin E. Gleave

  2. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

    Veronika Schmitt & John K. Jackson

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  1. Veronika Schmitt
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  2. Claudia Kesch
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Correspondence to Martin E. Gleave.

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Schmitt, V., Kesch, C., Jackson, J.K. et al. Design and Characterization of Injectable Poly(Lactic-Co-Glycolic Acid) Pastes for Sustained and Local Drug Release. Pharm Res 37, 36 (2020). https://doi.org/10.1007/s11095-019-2730-4

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