Abstract
Following recent marketing approval of the dapivirine-releasing vaginal ring (DapiRing®) for human immunodeficiency virus (HIV) prevention, focus has turned to next-generation multipurpose prevention technology ring products containing dapivirine and a contraceptive progestin for unintended pregnancy. However, hormonal contraceptives are associated with numerous side effects and contraindications, and women are increasingly interested in using hormone-free contraceptive products. Copper and zinc have well documented spermicidal activity, and various copper intrauterine devices are marketed and widely used by women. However, to date, there has been only limited research evaluating the contraceptive potential of vaginal rings containing copper or zinc. The aim of this PhD project is to develop a monthly multipurpose prevention technology vaginal ring that can provide sustained/control release of dapivirine, copper ions and zinc ions to simultaneously prevent HIV-1 infection and unintended pregnancy.Different combinations of vaginal rings or rods were successfully made by high temperature (50, 85 or 115°C) injection molding. Copper and zinc compounds had very limited impact on the thermal properties and in vitro release of dapivirine. Thus, the same 25 mg loading of dapivirine as in the marketed DapiRing® product was loaded in the vaginal ring formulations in the PhD project. The priorities of formulation development were to select suitable copper and zinc compounds to provide sustained copper and zinc ions release. Four different types of both copper and zinc substances were investigated in the study—65 nm copper nanopowder, 780 nm copper nanopowder, copper sulphate pentahydrate and copper sulphate anhydrous, 60– 70 nm zinc nanopowder, 790 nm zinc nanopowder, zinc acetate dihydrate and zinc sulphate monohydrate. Hydroxypropyl methylcellulose was selected as an excipient to increase copper and zinc ion release from vaginal rings by comparing the performances with other three types of excipients—gelatin, polyvinylpyrrolidone and sucrose.
Different formulations have been tested for (1) compatibility and thermal stability of actives, excipients and silicone elastomer by differential scanning calorimetry and thermogravimetric analysis; (2) in vitro release of dapivirine, Cu2+ ion and Zn2+ ion and (3) swelling by immersing vaginal rings in the release medium; and (4) mechanical performance (Shore M hardness, compression and elongation). A matrix-type LSR-4350 vaginal ring containing 25 mg dapivirine, 10% w/w copper sulphate anhydrous, 10% w/w zinc sulphate monohydrate and 10% w/w hydroxypropyl methylcellulose was selected as the lead candidate formulation. This ring device was evaluated for stability under long-term and accelerated conditions over three months. Results revealed that the ring performance was not significantly different before and after stability testing. Some minor differences in mechanical performance were observed, but these were attributed to post-curing effects; the mechanical properties of the ring were entirely similar to those for marketed vaginal rings. However, swelling and in vitro cytotoxicity studies indicated that further formulation optimization might be required to address device swelling and potential toxicity.
The experimental results obtained are encouraging and support the continued development of a matrix-type LSR-4350 vaginal ring containing 25 mg dapivirine, 10% w/w copper sulphate anhydrous, 10% w/w zinc sulphate monohydrate and 10% w/w hydroxypropyl methylcellulose as a novel multipurpose prevention technology strategy.
Date of Award | Dec 2024 |
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Original language | English |
Awarding Institution |
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Supervisor | Karl Malcolm (Supervisor) & Peter Boyd (Supervisor) |
Keywords
- HIV
- contraception
- non-hormone
- vaginal ring
- silicone elastomer
- dapivirine
- Copper
- zinc
- Multipurpose prevention technology