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Osmotic pump tablets for delivery of antiretrovirals to the vaginal mucosa.

ABSTRACT: Vaginal pre-exposure prophylaxis has focused heavily on gel formulations. Low adherence linked with frequent dosing and short therapeutic duration has emerged as the major reason for inconsistent efficacy outcomes with gels in clinical trials. Osmotic pumps can achieve versatile drug release profiles however, have not been explored for vaginal delivery. In this report, we describe an osmotic pump tablet (OPT) that can deliver antiretrovirals for several days. We also describe configuring the OPT for pH sensitive delivery where the drug delivery system consistently delivers an antiretroviral at vaginal pH and then gives a burst release triggered by a coitally associated pH increase. We have investigated the vaginal OPT for multiple day delivery of a potent antiretroviral, IQP-0528 in a sheep model. To effectively register spatial drug distribution we also engineered a tool to precisely collect multiple vaginal fluid samples. In a 10-day duration post single application, high micromolar mucosal levels were obtained with peak concentration more than 6 logs higher than the EC50 of IQP-0528. Overall, our results show successful implementation of the osmotic pump technology for vaginal antiretroviral delivery.

SUBMITTER: Rastogi R

PROVIDER: S-EPMC3924427 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Osmotic pump tablets for delivery of antiretrovirals to the vaginal mucosa.

Rastogi Rachna R Teller Ryan S RS Mesquita Pedro M M PM Herold Betsy C BC Kiser Patrick F PF

Antiviral research 20130820 1

Vaginal pre-exposure prophylaxis has focused heavily on gel formulations. Low adherence linked with frequent dosing and short therapeutic duration has emerged as the major reason for inconsistent efficacy outcomes with gels in clinical trials. Osmotic pumps can achieve versatile drug release profiles however, have not been explored for vaginal delivery. In this report, we describe an osmotic pump tablet (OPT) that can deliver antiretrovirals for several days. We also describe configuring the OPT ...[more]

PMID: 23973812

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Project description:BACKGROUND:A newly developed multiple use applicator for vaginal tablets/vaginal inserts* was evaluated for its general suitability. There are no standard procedures described in guidelines or general accepted publications as to how this kind of product should be tested for suitability of purpose. METHODS:Due to the lack of existing standard procedures, three separate tests were designed and successful executed: (a) First, a patient acceptability evaluation was carried out as part of a phase III trial (registered in EudraCT on 9 Jan 2017, number 2017-000142-22 2. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number%3A2017-000142-22 ). (b) Secondly, a cleaning procedure for the applicator after simulated multiple use was developed and verified in order to prove a minimized risk of microbiological contamination of the device. A newly developed vaginal fluid to simulate multiple applications was applied for this trial. (c) Lastly, a third trial evaluated the mechanical stability and proper functionality of the applicator after multiple simulated uses. Even potential abrasion of material of the device was checked. RESULTS:Acceptable patient compliance of the new multiple use applicator was verified after 2 weeks of daily use. Furthermore, diary data assessments of patients participating in the Pharmacodynamic part of the trial were evaluated as well. Overall, patient acceptability of the new applicator was proven. The easy-to-use cleaning procedure for the applicator, which can even be carried out in a domestic environment, was developed and successfully verified for effectiveness, meeting all microbiological acceptance criteria for vaginal products of the European Pharmacopeia. The mechanical stability and proper functionality of the applicator after 50 simulated uses was also evaluated. All tested applicator batches (fresh and aged) passed the final evaluation, with no limitations in functionality. CONCLUSION:The tests developed and executed consider various compliance aspects of the newly developed applicator. Results of these individual tests met the expectations and/or the predefined acceptance criteria. All included trials performed produced results justifying and qualifying the applicator for the intended multiple-use. The procedures outlined may also be a guide as to how this kind of medical device can be tested for suitability. Trial registration Registered in EudraCT, number 2017-000142-22, start date 24 May 2017.

Project description:BackgroundOral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.ObjectiveMTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.Methods and findingsWe enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ?90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ?130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).ConclusionsCompared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy.Trial registrationClinicalTrials.gov NCT00592124.

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Osmotic pump tablets for delivery of antiretrovirals to the vaginal mucosa.

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Osmotic pump tablets for delivery of antiretrovirals to the vaginal mucosa.

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