Polyurethane Intravaginal Ring for Controlled Delivery of Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor of HIV-1

Gupta, Kavita M.; Pearce, Serena M.; Poursaid, Azadeh; Aliyar, Hyder A.; Tresco, Patrick A.; Mitchnik, Mark A.; Kiser, Patrick F.

doi:10.1002/jps.21331

Cited by 90 publications

(95 citation statements)

References 42 publications

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“…The upper loading of 14 wt% API was selected, as it is approximately the maximum amount at which PYD2 is soluble in the hydrophobic PU; since the API release rate increases linearly with API loading until maximum solubility is attained in the polymer (given that dissolution into the vaginal fluid is not rate limiting), loading-dependent release was expected over the loadings evaluated (7,14). Placebo IVRs were also made as controls.…”

Section: Methodsmentioning

confidence: 99%

Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings

Johnson

Srinivasan²,

Albright

et al. 2012

Antimicrob Agents Chemother

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The potent antiretroviral pyrimidinediones IQP-0528 (PYD1) and IQP-0532 (PYD2) were formulated in polyurethane intravaginal rings (IVRs) as prophylactic drug delivery systems to prevent the sexual transmission of HIV-1. To aid in the selection of a pyrimidinedione candidate and the optimal loading of the drug in the IVR delivery system, four pyrimidinedione IVR formulations (PYD1 at 0.5 wt% [PYD1 0.5wt% ], PYD1 1wt% , PYD2 4wt% , and PYD2 14wt% ) were evaluated in pigtail macaques over 28 days for safety and pyrimidinedione vaginal biodistribution. Kinetic analysis of vaginal proinflammatory cytokines, native microflora, and drug levels suggested that all formulations were safe, but only the high-loaded PYD2 14wt% IVR demonstrated consistently high pyrimidinedione vaginal fluid and tissue levels over the 28-day study. This formulation delivered drug in excess of 10 g/ml to vaginal fluid and 1 g/g to vaginal tissue, a level over 1,000 times the in vitro 50% effective concentration. The in vitro release of PYD1 and PYD2 under nonsink conditions correlated well with in vivo release, both in amount and in kinetic profile, and therefore may serve as a more biologically relevant means of evaluating release in vitro than typically employed sink conditions. Lastly, the pyrimidinediones in the IVR formulation were chemically stable after 90 days of storage at elevated temperature, and the potent nanomolar-level antiviral activity of both molecules was retained after in vitro release. Altogether, these results point to the successful IVR formulation and vaginal biodistribution of the pyrimidinediones and demonstrate the usefulness of the pigtail macaque model in evaluating and screening antiretroviral IVR formulations prior to preclinical and clinical evaluation.

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Section: Methodsmentioning

confidence: 99%

Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings

Johnson

Srinivasan²,

Albright

et al. 2012

Antimicrob Agents Chemother

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“…The gel (200 l) was placed on the donor compartment by using a positive-displacement pipette. The donor and receptor compartments were separated by a 13-mm-pore-size nylon membrane (Millipore, Billerica, MA) prewetted by soaking in the receptor solution for 1 h. Three different sink conditions were evaluated: 2% Solutol HS-15 in 100 mM acetate buffer (pH 4.2), liposomes (prepared from soy lecithin) (17) in acetate buffer (pH 4.2), and 50:50 isopropyl alcohol-phosphate buffer (IPA-PBS; pH 7.0, 100 mM). The receptor solution was circulated at a flow rate of 0.18 ml/min and collected at 2, 4, 6, 8, and 24 h for IQP-0528 content analysis using HPLC (n ϭ 5).…”

Section: Methodsmentioning

confidence: 99%

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Mahalingam

Simmons

Ugaonkar

et al. 2011

Antimicrob Agents Chemother

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Pyrimidinediones, a novel class of compounds, have previously been shown to possess antiviral activity at nanomolar concentrations. One member of this class of compounds, IQP-0528, was selected as the lead molecule for formulation development owing to its stability at physiologically relevant conditions, wide therapeutic window, and antiviral activity in the nanomolar range. Here, we report the development of two vaginal gels-3.0% hydroxyethyl cellulose (HEC) formulation and a 0.65% Carbopol formulation-for the sustained delivery of IQP-0528. Stability studies under accelerated conditions confirmed the chemical stability of IQP-0528 and mechanical stability of the gel formulation for 3 months. In vitro release studies revealed that diffusion-controlled release of IQP-0528 occurred over 6 h, with an initial lag time of approximately 1 h. Based on the drug release profile, the 3.0% HEC gel was selected as the lead formulation for safety and activity evaluations. The in vitro and ex vivo safety evaluations showed no significant loss in cell viability or significant inflammatory response after treatment with a 3.0% HEC gel containing 0.25% IQP-0528. In an in vitro HIV-1 entry inhibition assay, the lead formulation showed an 50% effective concentration of 0.14 g/ml for gel in culture media, which corresponds to ϳ0.001 M IQP-0528. The antiviral activity was further confirmed by using polarized cervical explants, in which the formulation showed complete protection against HIV infection. In summary, these results are encouraging and warrant further evaluation of IQP-0528 gel formulations in in vivo models, as well as the development of alternative formulations for the delivery of IQP-0528 as a microbicide.

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“…More recently, efforts have been aimed at developing sustained or controlled release, coitally independent vaginal dosage forms intended to provide protection over at least a 24 h period, irrespective of whether intercourse is imminent (Klasse et al, 2008). For example, vaginal ring devices, similar to those already used for contraception and estrogen replacement therapy Malcolm, 2008) ated for the controlled release of dapivirine over several weeks or months (Gupta et al, 2009). Reservoir-type silicone elastomer vaginal rings have been shown to provide in vitro release of dapivirine at a mean rate equivalent to 136 g/day over a period of 71 days (Malcolm et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Freeze-dried, mucoadhesive system for vaginal delivery of the HIV microbicide, dapivirine: Optimisation by an artificial neural network

Woolfson

Umrethia

Kett

et al. 2010

International Journal of Pharmaceutics

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b s t r a c tDapivirine mucoadhesive gels and freeze-dried tablets were prepared using a 3 × 3 × 2 factorial design. An artificial neural network (ANN) with multi-layer perception was used to investigate the effect of hydroxypropyl-methylcellulose (HPMC): polyvinylpyrrolidone (PVP) ratio (X1), mucoadhesive concentration (X2) and delivery system (gel or freeze-dried mucoadhesive tablet, X3) on response variables; cumulative release of dapivirine at 24 h (Q 24 ), mucoadhesive force (F max ) and zero-rate viscosity. Optimisation was performed by minimising the error between the experimental and predicted values of responses by ANN. The method was validated using check point analysis by preparing six formulations of gels and their corresponding freeze-dried tablets randomly selected from within the design space of contour plots. Experimental and predicted values of response variables were not significantly different (p > 0.05, two-sided paired t-test). For gels, Q 24 values were higher than their corresponding freeze-dried tablets. F max values for freeze-dried tablets were significantly different (2-4 times greater, p > 0.05, twosided paired t-test) compared to equivalent gels. Freeze-dried tablets having lower values for X1 and higher values for X2 components offered the best compromise between effective dapivirine release, mucoadhesion and viscosity such that increased vaginal residence time was likely to be achieved.

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Polyurethane Intravaginal Ring for Controlled Delivery of Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor of HIV-1

Cited by 90 publications

References 42 publications

Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings

Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Freeze-dried, mucoadhesive system for vaginal delivery of the HIV microbicide, dapivirine: Optimisation by an artificial neural network

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