Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings

Malcolm, R. Karl; Woolfson, David; Russell, Julie A.; Tallon, Paul; McAuley, L.; Craig, Duncan Q.M.

doi:10.1016/s0168-3659(03)00178-0

Cited by 109 publications

(82 citation statements)

References 32 publications

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“…If the volume of the solvated molecule is sufficiently small relative to the pore size of the elastomer matrix, passive diffusion occurs. Accordingly, the silicone elastomer solubility of the drug, its initial loading in the ring, and its molecular volume are all key factors influencing release (25). The molecular size and log P values for the neutral forms of MVC (X) and CMPD167 (XH) are similar (Table 1).…”

Section: Discussionmentioning

confidence: 96%

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

Malcolm

Veazey

Geer

et al. 2012

Antimicrob Agents Chemother

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e Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 g/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ϳ10 6 -fold greater than the 50% inhibitory concentrations (IC 50 s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

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Section: Discussionmentioning

confidence: 96%

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

Malcolm

Veazey

Geer

et al. 2012

Antimicrob Agents Chemother

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“…The impact of biological matter adhesion on drug release has not been reported in literature but could potentially affect drug elution and the corresponding pharmacokinetics. However, since the diffusion coefficient of small-molecule APIs through mucus is comparable to that of IVR polymers (approximately 10 Ϫ7 cm 2 /s [10,17,26]), it is unlikely that a thin layer of biological material on the ring surface significantly impedes drug transport. This assumption holds true only for uncharged molecules such as the PYDs, as mucus is known to bind charged molecules and thereby hinder transport (9,10).…”

Section: Discussionmentioning

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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“…However, large degrees of variance were associated with this method (Suryanarayanan et al, 1992). The solubility of a drug in silicone oil has been used as a predictor for solubility within a silicone elastomer matrix (Malcolm et al, 2003a(Malcolm et al, ,b, 2004Woolfson et al, 2003); this method assumes that the solubility characteristics within the relatively low molecular weight oil are similar to those within the cross-linked elastomer. The use of differential scanning calorimetry (DSC) for the quantitative measurement of the solubility of solid drugs dispersed in polymeric matrices was first described by Theeuwes et al (1974).…”

Section: Introductionmentioning

confidence: 99%

High speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a solid or semi-solid matrix

Gramaglia¹,

Conway²,

Kett³

et al. 2005

International Journal of Pharmaceutics

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General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. AbstractConventional differential scanning calorimetry (DSC) techniques are commonly used to quantify the solubility of drugs within polymeric-controlled delivery systems. However, the nature of the DSC experiment, and in particular the relatively slow heating rates employed, limit its use to the measurement of drug solubility at the drug's melting temperature. Here, we describe the application of hyper-DSC (HDSC), a variant of DSC involving extremely rapid heating rates, to the calculation of the solubility of a model drug, metronidazole, in silicone elastomer, and demonstrate that the faster heating rates permit the solubility to be calculated under non-equilibrium conditions such that the solubility better approximates that at the temperature of use. At a heating rate of 400 • C/min (HDSC), metronidazole solubility was calculated to be 2.16 mg/g compared with 6.16 mg/g at 20 • C/min.

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Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings

Cited by 109 publications

References 32 publications

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

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

High speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a solid or semi-solid matrix

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