S. Knapp, R. Janusziewicz, S.R. Benhabbour
AnelleO,
United States
Keywords: infertility, assisted reproductive technology, progesterone, intravaginal rings, women’s health, 3D printing
Summary:
Infertility is a growing global concern that affects upwards of 13-15% of couples. Assisted reproductive technology (ART) utilizes progesterone supplementation as a cornerstone of treatment. Progesterone (PRO) improves the success rate of implantation and gestations, preventing miscarriages, and in some cases preventing preterm birth. Although the value of PRO supplementation is clear, options are limited for patients. FDA approved options either have low bioavailability, such as the oral Prometrium, or require multiple messy applications every day, such as the vaginal gel Crinone or the vaginal insert Endometrin. Clinicians will prescribe a daily or twice daily intramuscular injection (IM) that cannot be self-administered and leads to patient discomfort. While vaginal routes of administration are preferred, no form exists that allows for sustained delivery of progesterone. Intravaginal rings (IVRs) are long-acting devices notable for high patient compliance and have been FDA approved for a variety of indications, however there does not exist a commercially available IVR for progesterone supplementation. Herein, we introduce the use of 3D printed IVRs for the sustained release of PRO over a 28-day cycle, eliminating repeated daily, messy, or painful applications. A state-of-the-art 3D printing method, digital light synthesis (DLS), was combined with a novel drug loading process to enable rapid, iterative device development. A variety of preliminary IVR designs, solid and geometrically complex, were developed and in vitro release properties were explored in simulated vaginal fluid. A solid placebo IVR was used in an ovine model to determine safety and tolerability of the 3D printed material. A solid progesterone loaded IVR was investigated in vivo to assess safety and pharmacokinetics over 35 days. Preliminary IVR designs demonstrated the ability to release PRO from 3D printed IVRs for > 100 days in vitro, with release rate gated both by total loaded amount and IVR design. Solid IVRs were well tolerated in sheep, both placebo and loaded device, but plasma levels were below the target therapeutic concentrations. With these data and the unique ability for rapid device iteration development led by 3D printing technology, ANLO101 was developed. ANLO101 is an IVR design that maintains volume while increasing surface area, leading to an increased PRO release rate. ANLO101 was similarly investigated via in vitro and in vivo models for PRO release. ANLO101 reached target PRO release in vitro (≥11 mg/day) and target plasma concentrations in vivo (6-9 ng/mL). We report for the first time sustained progesterone delivery of 28 days with ANLO101, presenting a promising, self-administered, and patient-focused treatment option for infertility.