Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

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Abstract

The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginally-administered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women. Currently, the lead candidate microbicide is a 28-day silicone elastomer vaginal ring releasing dapivirine (Ring-004), an experimental non-nucleoside reverse transcriptase inhibitor. The ring was tested in two pivotal Phase III clinical studies in 2016 and is currently undergoing review by the European Medicines Agency. Recently, we described a new type of silicone elastomer vaginal ring offering sustained release of the protein molecule 5P12-RANTES, a potent experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. Building on our previous work, here we report the preclinical development of a new combination vaginal ring that offers sustained release of both 5P12-RANTES and dapivirine, in which the 5P12-RANTES is incorporated into an exposed core within the ring body and the dapivirine in the sheath. In this way, in vitro release of dapivirine matches closely that for Ring-004. Also, we report the pharmacokinetic testing of this combination ring formulation in sheep, where vaginal concentrations of both drugs are maintained over 28 days at levels potentially useful for preventing HIV infection in women.

Introduction

The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginally-administered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women (Malcolm et al., 2015, Notario-Pérez et al., 2017, Thurman et al., 2013, Traore et al., 2018). In 2016, the results of two parallel Phase III clinical studies conducted across multiple sites in Africa were reported for the lead candidate microbicide product, a matrix-type silicone elastomer vaginal ring offering 28-day continuous release of the non-nucleoside reverse transcriptase inhibitor dapivirine (Baeten et al., 2016, Chen et al., 2018). Both clinical studies found that the monthly dapivirine ring helped reduce women’s HIV risk by approximately 30% overall and was well-tolerated with long-term use. HIV risk was cut by 45% among participants who used the ring at least some of the time, and by more than 60% among women 25 years of age or older. As of early 2019, the developer of the ring, The International Partnership for Microbicides (IPM), is pursuing approvals from regulatory authorities to license the product in countries where women face the highest risk of HIV infection.

Since their conception back in the late 1960s, vaginal rings have relied primarily upon a permeation-controlled drug release mechanism, involving simple molecular diffusion of dissolved drug molecules driven by the drug concentration gradient established between the ring and the vaginal fluid/tissue (Malcolm et al., 2003). For the various silicone elastomer vaginal ring products that have reached market (Estring®, Femring®, Progering®, Fertiring® and Annovera®) and the dapivirine ring, the drug material is incorporated into the ring matrix or the ring core significantly above its solubility limit at room temperature, such that a sizeable fraction of the drug is present as a dispersed solid in the silicone elastomer. By comparison, for the marketed thermoplastic vaginal ring products Nuvaring® and Ornibel®, the drugs are incorporated into the rings such that they are fully dissolved in the polymeric matrix at room temperature and control of release is achieved using a thermoplastic rate-controlling membrane.

For all of these marketed rings, the reliance on a simple drug permeation mechanism, coupled with the hydrophobic nature of the polymers used for vaginal ring fabrication (e.g. silicone elastomer, ethylene-vinyl acetate copolymer, and thermoplastic urethanes), has generally limited vaginal rings to release of highly potent, relatively hydrophobic, small molecule drugs (McBride et al., 2019). However, recent advances in vaginal ring technology are extending the type of molecules that can be effectively released, as discussed in detail in a recent review article (Malcolm et al., 2015). Recently, we reported a new ‘exposed-core’ vaginal ring design offering sustained releasing of 5P12-RANTES, a protein-based antiretroviral molecule that targets the CCR5 co-receptor involved in the HIV entry process (McBride et al., 2019).

There is now considerable interest in developing second generation ring products that bring additional clinical benefits. These products could contain combinations of microbicides (to increase the breadth of protection against HIV by targeting different steps in the HIV replication cycle and/or to reduce the possibility of emergence of resistant strains of the virus) or different combinations of antiretrovirals, contraceptives agents and/or other agents to treat other sexually transmitted diseases (so-called multi-purpose prevention technologies; MPTs) (Abdool Karim et al., 2014a, Abdool Karim et al., 2014b, Boonstra et al., 2014, Brady and Manning, 2013, Fernández-Romero et al., 2015, Friend et al., 2013, Guilamo-Ramos et al., 2018, Malcolm et al., 2014). Combination vaginal rings containing dapivirine and either maraviroc or darunavir have previously been reported (Chen et al., 2015, Fetherston et al., 2013a, Fetherston et al., 2013b, Murphy et al., 2018, Murphy et al., 2014). Maraviroc is an established antiretroviral used in HIV treatment that inhibits entry of HIV into host cells by targeting the CCR5 receptor (Chen et al., 2015, Fetherston et al., 2013a, Fetherston et al., 2013b); darunavir is a protease inhibitor already used in combination with other antiretrovirals in the treatment of HIV infection (Mallolas, n.d.). Other combination microbicide vaginal rings have also been reported, including dapivirine and tenofovir (Johnson et al., 2010), tenofovir disoproxil fumarate and maraviroc (Moss et al., 2016), MIV-150 and zinc acetate (plus other drugs) (Ugaonkar et al., 2015), and tenofovir, nevirapine, and saquinavir (plus other drugs) (Moss et al., 2013).

In this paper, we report for the first time an exposed core-type vaginal ring device offering simultaneous release of dapivirine and 5P12-RANTES, as demonstrated through in vitro data and a pharmacokinetic study in sheep.

Section snippets

Ethics

The study was carried out in compliance with applicable sections of the United Kingdom Animals (Scientific Procedures) Act 1986, Amendment Regulations 2012. The study complied with the applicable sections of the Codes of Practice for the Housing and Care of Animals used in Scientific Procedures and the Humane Killing of Animals under Schedule 1 of the Act.

Materials

5P12-RANTES (molecular weight: 7904.8 g/mol) solution (cGMP grade; 6.4 mg/mL in 1.7 mM acetic acid; pH 4.0) was supplied to Queen’s

Results and discussion

All ring variants were manufactured successfully, with no gross defects observed and the strong chemical bond between the silicone core and sheath components was not affected by the core excipients.

The force required to compress the rings through 5 mm was ∼0.12 N, and no significant differences in compressional force were observed between the various formulations (Fig. 2). Following the cyclical compression test, all ring devices showed recovery to 100% of the original OD, indicating that the

Conclusions

This easy-to-manufacture combination microbicide vaginal ring, containing lyophilized 5P12-RANTES loaded into an excipient-modified silicone elastomer core and dapivirine incorporated into the silicone elastomer sheath, provided in vitro and in vivo sustained release of both antiretrovirals. Given their different mechanisms of action, this ring device may provide increased protection from HIV infection and limit the emergence of resistant HIV strains. The ring design may also be useful for

Acknowledgments

This study was partly funded by a research project entitled 'Chemokine-Based Microbicides: A Pathway from a First-in-Human Study toward Phase 2/3 and Licensure', funded by the Wellcome Trust, UK (Grant ID Number: 104252), and by a Confidence in Concept Grant awarded to Queen's University Belfast by the Medical Research Council (MRC) UK. The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the MRC. Dapivirine was supplied by the

Conflict of interest

The authors declare no competing financial interest.

References (35)

  • C.F. McCoy et al.

    Mechanical testing methods for drug-releasing vaginal rings

    Int. J. Pharm.

    (2019)
  • D.J. Murphy et al.

    Impact of ring size and drug loading on the pharmacokinetics of a combination dapivirine-darunavir vaginal ring in cynomolgus macaques

    Int. J. Pharm.

    (2018)
  • P. Spence et al.

    Post-use assay of vaginal rings (VRs) as a potential measure of clinical trial adherence

    J. Pharm. Biomed. Anal.

    (2016)
  • S.R. Ugaonkar et al.

    A novel intravaginal ring to prevent HIV-1, HSV-2, HPV, and unintended pregnancy

    J. Controlled Release

    (2015)
  • Q. Abdool Karim et al.

    Microbicides and their potential as a catalyst for multipurpose sexual and reproductive health technologies

    BJOG

    (2014)
  • S. Abdool Karim et al.

    The need for multipurpose prevention technologies in sub-Saharan Africa

    BJOG

    (2014)
  • J.M. Baeten et al.

    Use of a vaginal ring containing dapivirine for HIV-1 prevention in women

    N. Engl. J. Med.

    (2016)
  • Cited by (0)

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