title: A silicone elastomer vaginal ring for HIV prevention containing two microbicides with different mechanisms of action.
abstract: Vaginal rings are currently being developed for the long-term (at least 30 days) continuous delivery of microbicides against human immunodeficiency virus (HIV). Research to date has mostly focused on devices containing a single antiretroviral compound, exemplified by the 25mg dapivirine ring currently being evaluated in a Phase III clinical study. However, there is a strong clinical rationale for combining antiretrovirals with different mechanisms of action in a bid to increase breadth of protection and limit the emergence of resistant strains. Here we report the development of a combination antiretroviral silicone elastomer matrix-type vaginal ring for simultaneous controlled release of dapivirine, a non-nucleoside reverse transcriptase inhibitor, and maraviroc, a CCR5-targeted HIV-1 entry inhibitor. Vaginal rings loaded with 25mg dapivirine and various quantities of maraviroc (50-400mg) were manufactured and in vitro release assessed. The 25mg dapivirine and 100mg maraviroc formulation was selected for further study. A 24-month pharmaceutical stability evaluation was conducted, indicating good product stability in terms of in vitro release, content assay, mechanical properties and related substances. This combination ring product has now progressed to Phase I clinical testing.
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fetherston
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Boyd
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: Clare F
authors.initials: CF
authors.lastname: McCoy
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: Marcella C
authors.initials: MC
authors.lastname: McBride
authors.affiliation: International Partnership for Microbicides, Silver Spring, MD 20910, USA.
authors.forename: Karen-Leigh
authors.initials: KL
authors.lastname: Edwards
authors.affiliation: International Partnership for Microbicides, Silver Spring, MD 20910, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ampofo
authors.affiliation: School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland, UK. Electronic address: k.malcolm@qub.ac.uk.
authors.forename: R Karl
authors.initials: RK
authors.lastname: Malcolm
mesh_terms: D065100:CCR5 Receptor Antagonists / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003274:Contraceptive Devices, Female; D003510:Cyclohexanes / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000032:analysis / Q000737:chemistry; D004338:Drug Combinations; D016503:Drug Delivery Systems; D004355:Drug Stability; D004356:Drug Storage; D015658:HIV Infections / Q000517:prevention & control; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006358:Hot Temperature / Q000009:adverse effects; D000077592:Maraviroc; D055595:Mechanical Phenomena; D011743:Pyrimidines / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D012826:Silicone Elastomers / Q000737:chemistry*; D012995:Solubility; D014230:Triazoles / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*
chemical_list: D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D012826:Silicone Elastomers; D014230:Triazoles; D054303:HIV Reverse Transcriptase; D000077592:Maraviroc; C481671:Dapivirine