Density Mediated Drug Release From Dapivirine Vaginal Rings Produced by Additive Manufacturing

Background: Droplet deposition modelling (DDM) is a form of 3D printing that fuses droplets of molten polymer to create each layer, providing exquisite levels of control over an object‘s design and morphology. Such manipulation allows properties including density, geometry and surface area to be manipulated in ways that have been unthinkable using conventional thermoplastic processing techniques. Here we utilise the DDM process and compare this to injection moulding to produce dapivirine (DPV) loaded vaginal rings using a pharmaceutically relevant, life science grade thermoplastic polyurethane.Methods: Vaginal rings (54.0 mm outer diameter, 4.0 mm cross sectional diameter) were fabricated by injection molding or Arburg Plastic Freeforming - a proprietary DDM process, using a hydrophobic TPU loaded with 10% w/w dapivirine. Using the DDM process, rings of 100, 50 and 10% matrix density were produced. Rings were evaluated for in vitro drug release over 29 days in an aqueous release media and assessed for thermal characteristics. Results: Daily DPV release from all ring designs ranged between 387 - 8666 μg (Day 1) and 193 - 992 μg on Day 29. DDM printed VRs with 10% infill density (68 mg DPV load) exhibited a seven fold increase in DPV release rate compared to injection molded rings containing 190 mg DPV. For DDM printed rings, there was very significant correlation between decreasing ring density and increasing DPV release rate as a percentage of total drug loading. Thermal analysis showed that the DPV melt endotherm was absent from TPU + 10% w/w DPV, suggesting that DPV was fully solubilised within the TPU at the experimental conditions.Conclusions: DDM printing on an Arburg Freeformer has been shown to create vaginal rings with a range of densities and has provided a new potential to either increase the release rate of poorly water soluble compounds or reduce the loading required to maintain a desired release rate

Packing polymorphism of dapivirine and its impact on the performance of a dapivirine-releasing silicone elastomer vaginal ring

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Matrix and reservoir-type multipurpose vaginal rings for controlled release of dapivirine and levonorgestrel

A matrix-type silicone elastomer vaginal ring providing 28-day continuous release of dapivirine (DPV) - a lead candidate human immunodeficiency virus type 1 (HIV-1) microbicide compound - has recently demonstrated moderate levels of protection in two Phase III clinical studies. Here, next-generation matrix and reservoir-type silicone elastomer vaginal rings are reported for the first time offering simultaneous and continuous in vitro release of DPV and the contraceptive progestin levonorgestrel (LNG) over a period of between 60 and 180days. For matrix-type vaginal rings comprising initial drug loadings of 100, 150 or 200mg DPV and 0, 16 or 32mg LNG, Day 1 daily DPV release values were between 4132 and 6113μg while Day 60 values ranged from 284 to 454μg. Daily LNG release ranged from 129 to 684μg on Day 1 and 2-91μg on Day 60. Core-type rings comprising one or two drug-loaded cores provided extended duration of in vitro release out to 180days, and maintained daily drug release rates within much narrower windows (either 75-131μg/day or 37-66μg/day for DPV, and either 96-150μg/day or 37-57μg/day for LNG, depending on core ring configuration and ignoring initial lag release effect for LNG) compared with matrix-type rings. The data support the continued development of these devices as multi-purpose prevention technologies (MPTs) for HIV prevention and long-acting contraception.</p

Development of a Multi-layered Vaginal Tablet Containing Dapivirine, Levonorgestrel and Acyclovir for use as a Multipurpose Prevention Technology

Multipurpose prevention technologies (MPTs) are preferably single dosage forms designed to simultaneously address multiple sexual and reproductive health needs, such as unintended pregnancy, HIV infection and other sexually transmitted infections (STIs). This manuscript describes the development of a range of multilayered vaginal tablets, with both immediate and sustained release layers capable of delivering the antiretroviral drug dapivirine, the contraceptive hormone levonorgestrel, and the anti-herpes simplex virus drug acyclovir at independent release rates from a single dosage form. Depending on the design of the tablet in relation to the type (immediate or sustained release) or number of layers, the dose of each drug could be individually controlled. For example one tablet design was able to provide immediate release of all three drugs, while another tablet design was able to provide immediate release of both acyclovir and levonorgestrel, while providing sustained release of Dapivirnie for up to 8 hours. A third tablet design was able to provide immediate release of both acyclovir and levonorgestrel, a large initial burst of Dapivirine, followed by sustained release of Dapivirine for up to 8 hours. All of the tablets passed the test for friability with a percent friability of less than 1%. The hardness of all tablet designs were between 115 and 153 Newtons, while their drug content met the European Pharmacopeia 2.9.40 Uniformity of Dosage units acceptance value at level 1 and 2. Finally, the accelerated stability of all three actives was significantly enhanced in comparison to a mixed drug control.ye

Dapivirine and levonorgestrel vaginal rings

A matrix-type silicone elastomer vaginal ring providing 28-day continuous release of dapivirine (DPV) ⿿ a lead candidate human immunodeficiency virus type 1 (HIV-1) microbicide compound ⿿ has recently demonstrated moderate levels of protection in two Phase III clinical studies. Here, next-generation matrix and reservoir-type silicone elastomer vaginal rings are reported for the first time offering simultaneous and continuous in vitro release of DPV and the contraceptive progestin levonorgestrel (LNG) over a period of between 60 and 180 days. For matrix-type vaginal rings comprising initial drug loadings of 100, 150 or 200 mg DPV and 0, 16 or 32 mg LNG, Day 1 daily DPV release values were between 4132 and 6113 μg while Day 60 values ranged from 284 to 454 μg. Daily LNG release ranged from 129 to 684 μg on Day 1 and 2⿿91 μg on Day 60. Core-type rings comprising one or two drug-loaded cores provided extended duration of in vitro release out to 180 days, and maintained daily drug release rates within much narrower windows (either 75⿿131 μg/day or 37⿿66 μg/day for DPV, and either 96⿿150 μg/day or 37⿿57 μg/day for LNG, depending on core ring configuration and ignoring initial lag release effect for LNG) compared with matrix-type rings. The data support the continued development of these devices as multi-purpose prevention technologies (MPTs) for HIV prevention and long-acting contraception.ye

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .)

Packing polymorphism of dapivirine and its impact on the performance of a dapivirine-releasing silicone elastomer vaginal ring

A silicone elastomer vaginal ring providing sustained release over 28 days of the antiretroviral 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 behaviour; 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

Future strategies in microbicide development

The reduction in human immunodeficiency virus (HIV) infection in women demonstrated by pericoital use of tenofovir gel has encouraged the continued development of microbicides. Novel approaches include new ways to deliver tenofovir, as well as products that contain different antiretroviral drugs, either as single agents or as combinations of antiretroviral drugs. Indeed, emphasis has renewed on the development of multipurpose prevention technologies, products designed to address multiple sexually transmitted infections. Dual-purpose contraceptive antiretroviral products are also being designed to prevent HIV and pregnancy. Since consistent and correct use of these products will be critical to their effectiveness, the active pharmaceutical ingredients must be delivered in acceptable vaginal dosage forms, such as gels, films and sustained-release vaginal rings. The development of different dosage forms will help ensure that women can find a method to protect themselves from HIV, pregnancy, and potentially other sexually transmitted infections