Cross-linked valerolactone copolymer implants with tailorable biodegradation, loading and in vitro release of paclitaxel

https://doi.org/10.1016/j.ejps.2021.105808Get rights and content

Highlights

  • Disc-shaped implants were formed from cross-linked δ-valerolactone-based copolymers.

  • Incorporation of a PEGylated cross linkable δ-valerolactone copolymer alters the physico-chemical properties of the discs.

  • The discs caused no adverse effects following 1 month implantation in vivo.

  • Facile post-loading resulted in high drug loading and sustained release in vitro.

  • The discs tailorable drug loading and in vitro release increases their functionality.

Abstract

Implantable drug delivery systems, formed from degradable and non-degradable polymers, can offer several advantages over traditional dosage forms for sustained drug delivery. The majority of degradable implant systems developed to date are composed of poly(lactide-co-glycolide) (PLGA). However, PLGA-based systems are not suitable for the delivery of all drugs. Each drug is unique in terms of physico-chemical properties, and polymer-drug compatibility plays a significant role in determining a drug formulation's performance. In this study, two novel cross-linkable δ-valerolactone-based copolymers were synthesized and used to prepare cross-linked disc-shaped implants. The manipulation of the composition of the discs and conditions used during drug loading were found to influence various aspects of the delivery system performance including the degree of swelling, degradation, drug-loading and in vitro release. The polymeric discs resulted in no adverse effects following subcutaneous implantation in naïve rats. These studies support further development of cross-linkable valerolactone matrices as implantable formulations for sustained drug delivery.

Introduction

Since the 1960′s, there has been significant research into the development of implantable drug delivery systems (IDDSs) (Folkman and Long, 1964). IDDSs, formed from degradable and non-degradable polymers can offer several advantages over traditional dosage forms. They can enable localized distribution of drug which can reduce systemic drug exposure and distribution to non-target tissues resulting in improvements in the drug safety profile (Santos et al., 2014). They can provide sustained drug release enabling a reduction in the dosing frequency and an improvement in patient compliance (Santos et al., 2014; Kleiner et al., 2014; Danckwerts and Fassihi, 1991; Bollinger et al., 2020).

The first non-degradable implant system, Norplant®, received FDA approval in 1990. However, limitations associated with this delivery system, including a high incidence of complications upon implant removal, led to its discontinuation in the US market in 2002 (Siegel Watkins, 2010). A number of other IDDSs composed of non-degradable polymeric materials have reached the market, including; Nexplanon®, Probuphine®, Vantas®, Iluvien®, Retisert® and Yutiq® (Kleiner et al., 2014). In order to eliminate the need for implant removal beyond the period of drug release, systems have also been designed from biodegradable materials. The majority of the biodegradable implant systems developed to date have been formed from polyesters, with poly(lactide-co-glycolide) (PLGA) being the material most commonly employed (Kleiner et al., 2014; Nkanga et al., 2020; Kamali et al., 2020; Zhang and Fassihi, 2020; Kelley et al., 2020). Clinically approved examples of PLGA-based products include: Zoladex®, Ozurdex® and Scenesse® (Kang-Mieler et al., 2020).

However, PLGA-based systems are not suitable for delivery of all drugs given that each drug is unique in terms of its physico-chemical properties. Polymer-drug compatibility and interactions play a significant role in determining a drug formulation's performance (Park et al., 2019). There are also limitations associated with some PLGA-based systems including burst release of drug which can lead to release of up to a quarter of the loaded drug within an initial 24 h period (Yoo and Won, 2020). There are also reports of minor biocompatibility issues with some PLGA-based systems (Park et al., 2019; Xue et al., 2014). For example, during clinical trials of Scenesse®, in the placebo arm, 10% of patients developed implant site reactions following administration of the non-drug loaded PLGA system (Clinuvel, 2019).

There are a wide range of acute and chronic conditions that could benefit from treatment with drugs formulated in IDDSs (Kumar and Pillai, 2018). Given the range of drugs, and their distinct physico-chemical properties, there is a need to expand the number of biocompatible materials that are available to prepare these delivery systems. We have developed and characterized two novel cross linkable δ-valerolactone based copolymers: poly(δ-valerolactone-co-allyl-δ-valerolactone) (PVL-co-PAVL) and PAVL-b-PVL-poly(ethylene glycol)-PVL-b-PAVL (PEG-(PVL-b-PAVL)2). Cross-linked disc-shaped implants were prepared from PVL-co-PAVL as well as blends of PVL-co-PAVL and PEG-(PVL-b-PAVL)2. The extent of swelling was evaluated in aqueous media and organic solvents. Degradation was assessed in vitro in a lipase solution and biocompatibility was assessed in vivo following subcutaneous implantation in naïve Sprague-Dawley rats. The hydrophobic drug, paclitaxel (PTX) was post-loaded into discs using a swelling-equilibrium method and in vitro release of PTX was evaluated. Overall, the polymeric discs resulted in no adverse effects in vivo and manipulation of the composition of the discs was found to yield tailorable swelling, degradation kinetics, drug-loading and in vitro drug release.

Section snippets

Materials

δ-Valerolactone (VL, technical grade) from Sigma Aldrich and α-allyl-δ-valerolactone (AVL) provided by Pendant Biosciences (Toronto, Canada) were distilled over CaH2 under reduced pressure and stored under argon before use. Poly(ethylene glycol) (PEG, average Mn 20 kg/mol), 1,5,7-triazabicyclo[4.4.0]dec‑5-ene (TBD, 98%), benzyl alcohol (Bz-OH, 99.8%), 2,2-dimethoxy-2-phenylacetophenone (DMPA, 99%), 1,6-hexanedithiol (HDT, 96%), Pseudomonas cepacia lipase (≥30 U/mg), sodium dodecyl sulphate

Synthesis and characterization of copolymers

In a previous report we described the synthesis and characterization of PVL-co-PAVL copolymers of different molecular weights and the formation of cross-linked cylinders from these materials (Le Devedec et al., 2018). In the current study, the PVL-co-PAVL copolymer (Mn=32.0 kg/mol) was mixed with a PEGylated block copolymer as a means to alter the physico-chemical properties (i.e., degradation rate, swelling), drug loading and release kinetics of the cross-linked discs.

Results for the DP,

Conclusion

Discs formed from PVL-co-PAVL and PEG-(PVL-b-PAVL)2 (including PEG-(PVL-b-PAVL)2/PVL-co-PAVL blends) represent two novel cross-linkable non-PLGA systems that enable facile post-loading of drug and provide sustained drug release. PEG-(PVL-b-PAVL)2/PVL-co-PAVL blends exhibit tailorable properties including degradation, drug loading and in vitro drug release. Implanting these materials in vivo did not result in any discernible adverse effects. Drug loading and release properties of the PVL-co-PAVL

CRediT authorship contribution statement

Jack Bufton: Data curation, Investigation, Methodology, Validation, Visualization, Writing - original draft. Sungmin Jung: Investigation, Methodology, Resources, Supervision, Writing - original draft. James C. Evans: Supervision, Project administration, Writing - original draft, Writing - review & editing. Zeqing Bao: Investigation, Writing - original draft. Dean Aguiar: Conceptualization, Resources, Writing - review & editing. Christine Allen: Conceptualization, Funding acquisition, Project

Acknowledgments

This research was funded by a grant to C.A. from the Natural Sciences and Engineering Research Council of Canada (Grant no. 503143) and support from Pendant Biosciences Inc. (Toronto, ON and Nashville, TN). J.B. also acknowledges a Dean's Scholarship from the Leslie Dan Faculty of Pharmacy at the University of Toronto. The authors also acknowledge fruitful discussions with Dr. Eric Elmquist and Dr. David Stevens (Pendant Biosciences Inc.) throughout the duration of the research and the helpful

References (58)

  • L.W. Kleiner et al.

    Evolution of implantable and insertable drug delivery systems

    J. Control. Release

    (2014)
  • A. Kumar et al.

    Chapter 13 - implantable drug delivery systems: an overview

  • R.T. Liggins et al.

    Solid-state characterization of paclitaxel

    J. Pharm. Sci.

    (1997)
  • C.I. Nkanga et al.

    Clinically established biodegradable long acting injectables: an industry perspective

    Adv. Drug Deliv. Rev.

    (2020)
  • K. Park et al.

    Injectable, long-acting PLGA formulations: analyzing PLGA and understanding microparticle formation

    J. Control. Release

    (2019)
  • N.A. Peppas et al.

    A Simple equation for the description of solute release. III. Coupling of diffusion and relaxation

    Int. J. Pharm.

    (1989)
  • K.A. Rubinson et al.

    Deep hydration: poly(ethylene glycol) Mw 2000–8000 Da probed by vibrational spectrometry and small-angle neutron scattering and assignment of ΔG° to individual water layers

    Polymer (Guildf)

    (2013)
  • J. Shen et al.

    In vitro-in vivo correlation for complex non-oral drug products: where do we stand?

    J. Control. Release

    (2015)
  • Z.G. Tang et al.

    Surface properties and biocompatibility of solvent-cast poly[ε-caprolactone] films

    Biomaterials

    (2004)
  • N.G. Welch et al.

    Antifibrotic strategies for medical devices

    Adv. Drug Deliv. Rev.

    (2020)
  • K. Balani et al.

    Physical, Thermal, and Mechanical Properties of Polymers

    Biosurfaces: A Materials Science and Engineering Perspective

    (2014)
  • N.R.F. Beeley et al.

    Fabrication, implantation, elution, and retrieval of a steroid-loaded polycaprolactone subretinal implant

    J. Biomed. Mater. Res. A

    (2005)
  • F. Behar-Cohen

    Recent advances in slow and sustained drug release for retina drug delivery

    Expert Opin. Drug Deliv.

    (2019)
  • B. Bochove et al.

    Photo-crosslinked synthetic biodegradable polymer networks for biomedical applications

    J. Biomater. Sci. Polym. Ed.

    (2019)
  • M.L. Bruschi

    Mathematical models of drug release

    Strategies to Modify the Drug Release from Pharmaceutical Systems

    (2015)
  • C.R. Chen et al.

    ProteinVolume: calculating molecular van Der Waals and void volumes in proteins

    BMC Bioinformat.

    (2015)
  • Clinuvel

    SCENESSE® [(Afamelanotide) Implant, For Subcutaneous Use]

    (2019)
  • M.M. Crowley et al.

    Pharmaceutical applications of hot-melt extrusion: Part II

    Drug Dev. Ind. Pharm.

    (2007)
  • M. Danckwerts et al.

    Implantable controlled release drug delivery systems: a review

    Drug Dev. Ind. Pharm.

    (1991)
  • Cited by (4)

    • Poly(δ-valerolactone-co-allyl-δ-valerolactone) cross-linked microparticles: Formulation, characterization and biocompatibility

      2021, Journal of Pharmaceutical Sciences
      Citation Excerpt :

      In the current study, there was only one treatment group so the effects of the polymer and drug cannot be distinguished. However, our group previously showed that drug-free PVL-co-PAVL disc-shaped implants were not toxic based on hematological analysis, bodyweight measurements, and clinical chemistry following subcutaneous implantation in rats for 28 days.5 The lack of toxicity at the site of administration at the study endpoint in conjunction with increasing bodyweight throughout the study provides further evidence for the biocompatibility of the PVL-co-PAVL MPs.

    1

    J. Bufton and S. Jung contributed equally to this work.

    View full text