Design of ethylene vinyl acetate intravaginal rings releasing progesterone for contraception therapies during lactation

IGNACIO M. HELBLING; JUAN C.D. IBARRA; JULIO A. LUNA

Haikou

Simposio; 3rd Annual Symposium of Drug Delivery Systems (SDDS); 2013

BIT Life Sciences, Inc.

Purpose: To date, only one intravaginal ring, named Progering®, is commercialized for application in contraception therapies during lactation. This ring is made of silicone and release progesterone through the vaginal walls of about 10 mg day-1. However, some drawbacks are related to the use of silicone. For this reason, ethylene vinyl acetate copolymer (EVA) was studied as material support to replace silicone in rings fabrication. Methods: Ring-shaped matrices made of EVA and containing progesterone were fabricated by a hot-melt extrusion procedure. Swelling and degradation assays to characterize these matrices and the commercial ring Progering® were performed. The in vitro release of progesterone from EVA rings and from Progering® was studied and a mathematical model was employed to determine the effect of design parameters over release rate. Comparisons between the experimental data obtained and the theoretical prediction were realized, and the f1 and f2 factors were used to quantitatively measure the model prediction. In addition, the solubility of progesterone in several liquids and in EVA matrices were determined. Results: The solubility of progesterone in EVA matrices was Cs = 25.39 ± 3.01 mg cm-3. The hormone solubility in water was 0.007 mg cm-3. As ethanol content in the liquid media increases, the hormone solubility increases to reach a value of 128.12 mg cm-3 for pure ethanol. The liquid uptake by EVA rings was similar in both ultra filtered water and ethanol/water with an ethanol content of 15%. For these liquids, the maximum percentage of liquid uptake was less than 0.7%. As ethanol content in the liquid media increases, the maximum percentage of liquid uptake also increases, reaching a value of 11% for pure ethanol. The total polymer mass loss in the different ethanol/water mixture after 9 weeks was less than 0.8%. Thus, it can be concluded that EVA rings do not degrade in the liquid media analyzed under the experimental conditions established. In the in vitro release studies, a good agreement between the model prediction and the experimental data is observed, allowing to establish the validity of the model. The effect of design parameters over the release was studied. As expected, the increment in ring area and/or in the initial load of progesterone lead to a rise in the amount of hormone released. In addition, the increment in the initial load extends the lifetime of devices. The in vitro mean release rate of Progering® was about 11.77 ± 7.89 mg day-1, allowing to achieve proper plasma progesterone levels for a successful contraception therapy during lactation. An optimization of the initial hormone load in EVA rings was carried out, using the mathematical model as a tool. The in vitro mean release rate of optimized EVA rings was 12.05 ± 8.91 mg day-1. Conclusions: EVA rings could be designed to release progesterone at a proper rate to be successfully used in contraception therapy during lactation. The optimized EVA rings have initially several advantages over the commercial ring.