Transdermal administration remains an active research and development area as an alternative route for long-acting drug delivery. It avoids major drawbacks of conventional oral (gastrointestinal side effects, low drug bioavailability, and need for multiple dosing) or parenteral routes (invasiveness, pain, and psychological stress and bio-hazardous waste generated from needles), thereby increasing patient appeal and compliance. This review focuses on the current state of long-acting transdermal drug delivery, including adhesive patches, microneedles, and molecularly imprinted polymeric systems. Each subsection describes an approach including key considerations in formulation development, design, and process parameters with schematics. An overview of commercially available conventional (adhesive) patches for long-acting drug delivery (longer than 24 h), the reservoir- and matrix-type systems under preclinical evaluation, as well as the advanced transdermal formulations, such as the core-shell, nanoformulations-incorporated and stimuli-responsive microneedles, and 3D-printed and molecularly imprinted polymers that are in development, is also provided. Finally, we elaborated on translational aspects, challenges in patch formulation development, and future directions for the clinical advancement of new long-acting transdermal products.
HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery systems. To fill the gap in the HIV prevention product pipeline, CONRAD has developed a topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG), two potent and synergistic antiretrovirals, as a simple, low-cost, and discreet option that can be self-administered vaginally and/or rectally, before and after coitus. In this review, we have described the development path of the TAF/EVG insert up to its current point in clinical testing, highlighting findings from acceptability, preclinical safety, pharmacokinetics, and efficacy evaluations and early clinical studies. In summary, the TAF/EVG inserts are stable, easy to manufacture, low-cost, acceptable, and show highly promising preclinical and clinical results for on-demand topical pre- or post-exposure HIV prevention.
Background On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally. Methods MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant. Results TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively). Discussion Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420. Discussion Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420.
IntroductionEnd-user perspectives are vital to the design of new biomedical HIV prevention products. Conjoint analysis can support the integration of end-user perspectives by examining their preferences of potential pre-exposure prophylaxis (PrEP) products. The Microbicides Trial Network (MTN) 035 protocol examined three placebo rectal dosage forms (insert, enema and suppository) that could deliver PrEP prior to receptive anal sex (RAS).MethodsBetween April 2019 and July 2020, we enrolled 217 HIV-negative, cisgender men who have sex with men (MSM; n = 172; 79.3%) and transgender people (n = 47; 20.7%) ages 18-35 into a randomized cross-over trial across Malawi, Peru, South Africa, Thailand and the United States. Participants used each product prior to RAS over 4-week periods. Participants completed a conjoint experiment where they selected between random profiles using seven features (dosage form, timing of use before sex, side effects, duration of protection, effectiveness, frequency of use and need for a prescription).ResultsEffectiveness was the strongest determinant of choice (30.4%), followed by modality (18.0%), potential side effects (17.2%), frequency of use (10.8%), duration of protection (10.4%), timing of use before sex (7.4%) and need for a prescription (5.9%). Relative utility scores indicated that the most desirable combination of attributes was a product with 95% efficacy, used 30 minutes before sex, offering a 3- to 5-day protection window, used weekly, having no side effects, in the form of an enema and available over-the-counter.ConclusionsChoice in next-generation PrEP products is highly desired by MSM and transgender people, as no one-size-fits-all approach satisfies all the preferences. MTN-035 participants weighed product features differently, recognizing the need for diverse, behaviourally congruent biomedical options that fit the needs of intended end-users.
