Development of Hormonal Intravaginal Rings: Technology and Challenges

Intravaginal rings (IVRs) are minimally invasive polymeric devices specifically designed to be used for the sustained and prolonged release of various type of drugs such as hormones. One of the benefits of using topical drug delivery systems (e.g., IVRs) is the fact that systemic drug delivery may cause drug resistance due to elevated drug levels. Topical drug delivery also provides higher concentrations of the drug to the target site and has fewer side effects. In addition, when a drug is administered vaginally, the hepatic first-pass effect is avoided, resulting in higher absorption. Contraception and treatments for specific diseases such as endometriosis and hormone deficiencies can be improved by the administration of hormones via an IVR. This article aims to classify and compare various designs of commercially available and non-commercial hormonal IVRs and to analyze their performance. Current challenges affecting the development of IVRs are investigated, and proposed solutions are discussed. A comprehensive search of publications in MEDLINE/PubMed and of commercial product data of IVRs was performed, and the materials, designs, performance, and applications (e.g., contraception, endometriosis, estrogen deficiency and urogenital atrophy) of hormonal IVRs were thoroughly evaluated. Most hormonal IVRs administer female sex hormones, i.e., estrogen and progestogens. In terms of material, IVRs are divided into 3 main groups: silicone, polyurethane, and polyethylene-co-vinyl acetate IVRs. As regards their design, there are 4 major designs for IVRs which strongly affect their performance and the timing and rate of hormone release. Important challenges include reducing the burst release and maintaining the bioavailability of hormones at their site of action over a prolonged period of administration as well as lowering production costs. Hormonal IVRs are a promising method which could be used to facilitate combination therapies by administering multiple drugs in a single IVR while eliminating the side effects of conventional drug administration methods. IVRs could considerably improve womenʼs quality of life all over the world within a short period of time.

Pharmacists’ Perceptions, Barriers, and Potential Solutions to Implementing a Direct Pharmacy Access Policy in Indiana

This study assessed pharmacists’ perceptions, barriers, and potential solutions for implementing a policy allowing pharmacists to prescribe hormonal contraceptives in Indiana. A mixed-method survey ( n = 131, 22.3% response rate), using Likert-type scales, dichotomous responses (yes/no), and open-ended questions, was distributed to pharmacy preceptors in Indiana. Pharmacists felt prescribing contraceptives would be beneficial (79.1%) and were interested in providing this service (76.0%), but only 35.6% reported having the necessary resources. Participants with a PharmD were significantly more likely to feel the service would be beneficial (odds ratio [ OR] = 10.360, 95% confidence interval [CI: 1.679, 63.939]) and be interested in prescribing contraceptives ( OR = 9.069, 95% CI [1.456, 56.485]). Reimbursement (86.4%), training courses (84.7%), private counseling rooms (69.5%), and increasing technician responsibilities (52.5%) were identified as ways to ease implementation. Women had significantly greater odds of being more comfortable than men prescribing injections ( OR = 2.237, 95% CI [1.086, 4.605]), and intravaginal rings ( OR = 2.215, 95% CI [1.066, 4.604]), when controlling for age, degree, and setting. Qualitative findings reinforced quantitative findings.

Safety_and_Pharmacokinetics_of_Dapivirine_Delivery.7

Vaginal microbicides for the prevention of HIV transmission maybe an important option for protecting women from infection.Incorporation of dapivirine, a lead candidate nonnucleoside reversetranscriptase inhibitor, into intravaginal rings (IVRs) for sustainedmucosal delivery may increase microbicide product adherence andefficacy compared with conventional vaginal formulations. Twentyfourhealthy HIV-negative women 18–35 years of age were randomlyassigned (1:1:1) to dapivirine matrix IVR, dapivirine reservoir IVR,or placebo IVR. Dapivirine concentrations were measured in plasmaand vaginal fluid samples collected at sequential time points over the33-day study period (28 days of IVR use, 5 days of follow-up). Safetywas assessed by pelvic/colposcopic examinations, clinical laboratorytests, and adverse events. Both IVR types were safe and well toleratedwith similar adverse events observed in the placebo and dapivirinegroups. Dapivirine from both IVR types was successfully distributedthroughout the lower genital tract at concentrations over 4 logs greaterthan the EC50 against wild-type HIV-1 (LAI) in MT4 cells. Maximumconcentration (Cmax) and area under the concentration–time curve(AUC) values were significantly higher with the matrix than reservoirIVR. Mean plasma concentrations of dapivirine were ,2 ng/mL.These findings suggest that IVR delivery of microbicides is a viableoption meriting further study.Key Words: dapivirine, HIV, intravaginal ring, microbicide,pharmacokinetics, prevention

3466 Innovative 3D Printed Intravaginal Rings: Developing AnelleO PRO, the First Intravaginal Ring for Infertility

OBJECTIVES/SPECIFIC AIMS: The study aims to develop and test a biocompatible 3D-printed IVRs for the mechanical and release properties of a model drug, β-estradiol, then translate these methods to the target drug, progesterone. The goals include demonstrating decoupling of mechanical and release properties of the rings, release profiles driven by geometry and efficacy in sheep animal models to evaluate device safety. METHODS/STUDY POPULATION: A novel 3D-printing platform, continuous liquid interface production (CLIP), pioneered by Carbon, enables the fabrication of complex designs on a timescale that is amenable to manufacturing. The process utilizes computational-aided design (CAD), specifying shape and geometry, which is recreated via a photopolymerization process. IVRs are fabricated with CLIP using a biocompatible resin at a rate of approximately 15 min. per ring. Rings were fabricated and assessed for the release of a model drug, β-estradiol. The process was then translated to the target drug, progesterone. Rings were evaluated for radial compression and in vitro release in simulated vaginal fluid (SVF). RESULTS/ANTICIPATED RESULTS: Intravaginal rings (IVRs) were designed and fabricated to be geometrically complex in an effort to control release. Ring geometry and subsequent pore size was achieved through the use of unit cells. Several design parameters were explored including unit cell type, size, and band presence in two resins of differing mechanical properties. Through design, a wide range of radial compressive properties were achieved which spanned values covered by commercially available rings. The release of β-estradiol in SVF was found to span 57 – 115 days and resulted in near or complete release of the total loaded drug. Changing the internal geometric design of the ring was found to have minimal influence on the compression properties, thus the mechanical and release characteristics of the rings were largely decoupled. DISCUSSION/SIGNIFICANCE OF IMPACT: This is a novel approach to the design and fabrication of intravaginal rings for the treatment of infertility. The use of CAD and the decoupling of release from mechanical properties allows for us to move away from the one-size one-dose fits all approach to IVRs.