Packing Polymorphism of Dapivirine and Its Impact on the Performance of a Dapivirine-Releasing Silicone Elastomer Vaginal Ring

Abstract

A silicone elastomer vaginal ring providing sustained release over 28 days of the anti-retroviral microbicide dapivirine has recently completed phase III clinical testing and showed moderate protection against HIV acquisition. In support of the product licensure program, we report the impact of dapivirine packing polymorphism on the thermal and solubility characteristics of dapivirine and on the in vitro performance of the 25 mg dapivirine ring product. This is the first time that polymorphism has been reported for a drug-releasing vaginal ring product. Thermal, particle size, powder X-ray diffraction, and thermodynamic solubility analyses of dapivirine polymorphic forms I and IV, both of which are persistent at room temperature and with form I being the thermodynamically stable form, were conducted for both micronized and non-micronized materials. No significant differences in solubility between DPV forms I and IV were observed in media commonly used for in vitro release testing. Matrix-type silicone elastomer vaginal rings were manufactured and the impact of dapivirine polymorphism on key in vitro parameters (compression and tensile behavior; content assay; in vitro release; residual content assay) was investigated. The data demonstrate that dapivirine packing polymorphism has no significant impact on in vitro performance of the 25 mg dapivirine vaginal ring.

Intravaginal rings for continuous low-dose administration of cervical ripening agents

“…However, for other VRs -most notably the dapivirine-releasing silicone elastomer VR for prevention of sexual transmission of the human immunodeficiency virus (HIV)in vitro testing of dapivirine release using SVF correlated closely with in vivo release, based on residual drug analysis content post-use (Baeten et al, 2016;Malcolm et al, 2016;McCoy et al, 2017;Nel et al, 2016a).…”

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

“…In vitro release testing of the rings was conducted over 28 days using both a 1:1 mixture of isopropanol and water (IPA/H2O) and SVF. Both media have been widely used for in vitro release testing of vaginal rings (Boyd et al, 2016;Fetherston et al, 2013b;Malcolm et al, 2016;McCoy et al, 2017;Murphy et al, 2014). Isopropanol/water has been used extensively for in vitro release testing throughout product development of the dapivirine ring, primarly due to its ability to provide sink conditions for the very poorly-water soluble dapivirine and its discriminatory power for the key critical quality attributes of the drug product (McCoy et al, 2017;Woolfson et al, 2010).…”

“…Both media have been widely used for in vitro release testing of vaginal rings (Boyd et al, 2016;Fetherston et al, 2013b;Malcolm et al, 2016;McCoy et al, 2017;Murphy et al, 2014). Isopropanol/water has been used extensively for in vitro release testing throughout product development of the dapivirine ring, primarly due to its ability to provide sink conditions for the very poorly-water soluble dapivirine and its discriminatory power for the key critical quality attributes of the drug product (McCoy et al, 2017;Woolfson et al, 2010). Similar high isopropanol content buffer mixtures are routinely used for USP compendial dissolution testing of oral tablets containing the poorly water soluble anti-malarial drug atovaquone, and a medium containing 5% methanol is also recommended for the injectable suspension of triptorelin pamoate (U.S. Food and Drug Administration, 2018; https://www.accessdata.fda.gov/scripts/cder/dissolution/ (accessed 06/01/18)).…”

“…SVF is intended to simulate the chemical composition of vaginal fluid, with a particular emphasis on modelling pH and osmolarity; it is not intended to mimic the viscosity of vaginal fluid (Owen and Katz, 1999). However, although SVF is considered more physiologically relevant, its low solvating power creates many challenges in its use as an in vitro release medium for poorly water-soluble drugs like dapivirine (McCoy et al, 2017). In this study, we have performed in vitro release testing using both IPA/water and SVF media so as to explore both sink and non-sink condition models.…”

Synthesis of Novel Reactive Disperse Silicon-Containing Dyes and Their Coloring Properties on Silicone Rubbers

“…Silicone rubbers have been extensively used in medical [ 1 , 2 , 3 , 4 ], aviation and aerospace fields [ 5 , 6 , 7 ], electric wires and cables [ 8 , 9 , 10 , 11 ], electronics and electric appliances [ 12 , 13 ], and automobiles and machines [ 14 , 15 ] due to their sound biosafety, high air permeability, excellent physical and mechanical properties, radiation-resistance, high temperature-resistance, low temperature flexibility, and weather resistance [ 16 , 17 , 18 , 19 , 20 ]. Many of their applications involve different colors of the silicone rubbers, and their common coloring technologies include internal coloring, external coloring, and color inserting [ 21 ].…”