Pharmacokinetics of UC781-loaded intravaginal ring segments in rabbits: a comparison of polymer matrices

Clark, Meredith R.; Kiser, Patrick F.; Loxley, Andrew; McConville, Christopher; Malcolm, R. Karl; Friend, David R.

doi:10.1007/s13346-011-0032-4

Cited by 16 publications

(13 citation statements)

References 27 publications

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“…This observation, along with the undetectable ACV and TFV levels in rabbit vaginal secretions, point to a superiority of the sheep model in the present study. The rabbit model has been used previously to test the IVIVC and plasma levels of hormonal contraceptives from silicone devices (9) and was employed recently to compare polymer matrices and drug loadings in terms of in vivo release of an antiviral agent delivered from IVR segments (10). The sheep model has been developed as a costeffective large-mammal animal model for study of the human reproductive system.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous Delivery of Tenofovir and Acyclovir via an Intravaginal Ring

Moss

Malone

Smith

et al. 2012

Antimicrob Agents Chemother

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Vaginal microbicides may play an important role in protecting women from HIV infection. A strong synergy between HSV and HIV has been observed, and epidemiological studies demonstrate that HSV infection increases the risk of HIV acquisition. Incorporation of the antiretroviral tenofovir (TFV) along with the antiherpetic acyclovir (ACV) into combination intravaginal rings (IVRs) for sustained mucosal delivery of both compounds could lead to increased microbicide product adherence and efficacy compared with conventional vaginal formulations. A novel, dual-protection "pod IVR" platform developed in-house and delivering ACV and TFV was evaluated in rabbit and sheep models. The devices were safe and exhibited sustained release of both drugs independently and at controlled rates over the 28-day studies. Daily release rates were estimated based on residual drug content of the used devices: rabbits, 343 ؎ 335 g day ؊1 (ACV) and 321 ؎ 207 g day ؊1 (TFV); sheep, 174 ؎ 14 g day ؊1 (ACV) and 185 ؎ 34 g day ؊1 (TFV). Mean drug levels in sheep vaginal samples were as follows: secretions, 5.25 ؎ 7.31 g ml ؊1 (ACV) and 20.6 ؎ 16.2 g ml ؊1 (TFV); cervicovaginal lavage fluid, 118 ؎ 113 ng ml ؊1 (ACV) and 191 ؎ 125 ng ml ؊1 (TFV); tissue, 173 ng g ؊1 (ACV) and 93 ng g ؊1 (TFV). An in vitro-in vivo correlation was established for both drugs and will allow the development of future formulations delivering target levels for prophylaxis and therapy. These data suggest that the IVR based on the pod design has potential in the prevention of transmission of HIV-1 and other sexually transmitted pathogens. Significant progress has been achieved in providing increased access to HIV/AIDS services in several low-and middleincome countries (44). Despite these encouraging findings, women in the developing world remain disproportionately at risk of HIV infection. Seventy-six percent of new HIV infections in sub-Saharan Africa occur in women aged 15 to 24 years (42). The proportion is as high as 90% in South Africa (38). In the absence of a preventative vaccine, effective prophylactic biomedical technologies are urgently required. Campaigns aimed at encouraging monogamy and condom use have had limited success in areas where marriage has been identified as the major risk factor for HIV acquisition in women (3,15,16,21,25).Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2), the serotype most commonly associated with genital herpes, are responsible for two intersecting epidemics, where the disease caused by one virus facilitates the transmission of and pathogenesis by the other. A strong synergy between HSV and HIV has been observed, and epidemiological studies demonstrate that HSV infection increases the risk of HIV-1 acquisition (33,34,43). A meta-analysis found that prevalent HSV-2 infection is associated with a threefold-increased risk of HIV acquisition among both men and women. These results suggest that, in areas of high HSV-2 prevalence, a substantial proportion of HIV infection is linked to HSV-2 infection (...

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Section: Discussionmentioning

confidence: 99%

Simultaneous Delivery of Tenofovir and Acyclovir via an Intravaginal Ring

Moss

Malone

Smith

et al. 2012

Antimicrob Agents Chemother

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“…24 Both exhibit sustained release over 30 days in vitro . Three different matrix IVRs (polyurethane, ethylene vinyl acetate, and silicone) containing the antiretroviral drug UC781 were evaluated in vitro and in a rabbit model, 25 and ethylene-vinyl acetate (EVA) matrix IVRs delivering UC781 in combination with the contraceptive hormone levonorgestrel were investigated in vitro . 26 Degradation of UC781 during the fabrication process, however, has made further development difficult.…”

Section: Introductionmentioning

confidence: 99%

An Intravaginal Ring for the Simultaneous Delivery of Multiple Drugs

Baum

Butkyavichene

Gilman

et al. 2012

Journal of Pharmaceutical Sciences

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130

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Intravaginal delivery of microbicide combinations is a promising approach for the prevention of sexually transmitted infections, but requires a method of providing simultaneous, independent release of multiple agents into the vaginal compartment. A novel intravaginal ring (IVR) platform has been developed for simultaneous delivery of the reverse-transcriptase inhibitor tenofovir (TFV) and the guanosine analogue antiviral acyclovir (ACV) with independent control of release rate for each drug. The IVR is based on a pod design, with up to 10 individual polymer-coated drug cores embedded in the ring releasing through preformed delivery channels. The release rate from each pod is controlled independently of the others by the drug properties, polymer coating, and size and number of delivery channels. Pseudo-zero-order in vitro release of TFV (144 ± 10 µg day) and ACV (120 ± 19 µg day−1) from an IVR containing both drugs was sustained for 28 days. The mechanical properties of the pod IVR were evaluated and compared with the commercially available Estring® (Pfizer, NY, NY). The pod-IVR design enables the vaginal delivery of multiple microbicides with differing physicochemical properties, and is an attractive approach for the sustained intravaginal delivery of relatively hydrophilic drugs that are difficult to deliver using conventional matrix IVR technology.

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“…3) and in vivo. 34 Second, UC781 chemical stability was remarkably increased by creating a UC781 solid solution in PU that demonstrated at least 1 month stability under accelerated stress conditions (40 • C/75% RH and 60 • C, Fig. 5) in contrast to an aqueous solution where the UC781 half-life was on the order of 3 days.…”

Section: Discussionmentioning

confidence: 99%

“…34 For the comparison of in vitro and in vivo release of UC781 from prototype ring segments, we report the analysis of retrieved PU ring segments from this study. Female New Zealand albino white rabbits aged 5-8 months (∼2.5 kg) were used to test ring segments.…”

Section: In Vivo Uc781 Release In Rabbitsmentioning

confidence: 99%