(M1030-01-03) Reverse Engineering of Nexplanon^® Contraceptive Implant: Physicochemical Properties and In Vitro Drug Release

Purpose: Nexplanon^® is a long-acting implant that releases etonogestrel to prevent pregnancy for up to three years. The implant is a non-biodegradable and flexible rod (4 cm in length and 2 mm in diameter) composed of a solid ethylene vinyl acetate (EVA) core imbedded with etonogestrel and barium sulfate. Surrounding the core is a rate-controlling EVA membrane (implant skin). The vinyl acetate content of EVA in implant core and skin is 28% and 15%, respectively. This study aimed to characterize implant physicochemical properties and to assess the in-vitro drug release of Nexplanon^®.

Methods: The implant structure of Nexplanon^® was examined using light microscope, scanning electron microscopy (SEM) and X-ray micro-computed tomography. Images of molten implants (at 150 °C) taken using a hot-stage polarized light microscope were analyzed using ImageJ™ software. In-vitro drug release from skin of implant, two ends of implant and entire implant were tested at 37 °C in a shaker at 150 rpm. To test skin or ends-only release, either ends or skin was sealed by etonogestrel-impermeable Loctite^® 4011 glue, respectively. Etonogestrel was assayed using a reverse-phase HPLC method with UV detection. Etonogestrel solubility and diffusivity in EVA free films were determined by permeation experiments at 37 °C using “time lag” method [1]. Drug supersaturation in core was calculated based on mass balance equations [(1), (2)]. Skin release and ends release were modeled using Fick’s law in cylindrical coordinates (3) [2] and Higuchi model (4) [3], respectively.

Results: The composition of Nexplanon^® is presented in Table 1. The cross section of Nexplanon^® consisted of a transparent concentric skin and an opaque circular core (Figure 1A). The skin thickness was 61.0 ± 2.7 µm (SD, n=8). The skin did not cover the ends (Figure 1D). The D90 of etonogestrel and barium sulfate was 11.9 µm and 0.8 µm, respectively (Figure 2C,D). Nexplanon^® is extruded at 145 °C [4]. At this temperature, etonogestrel solubility in EVA 28 is 5 wt.%, a 20-fold higher than the solubility at storage temperature (25 °C) [2]. Therefore, etonogestrel was supersaturated in Nexplanon^® after extrusion. Because EVA is insoluble in water, etonogestrel was released via diffusion mechanisms only. The diffusion kinetics are determined by drug solubility and diffusivity in EVA 28 (core) and EVA 15 (skin), which were summarized in Table 2. The cumulative release rate of skin and two ends corresponded to release rate of whole implant (Figure 3A).  Because of the drug supersaturation, there was an initial burst release through the skin that lasted for 15 days, followed by a steady state (Figure 3C). The degree of drug supersaturation in Nexplanon^® was determined to be 1.4. At steady state, skin release was limited by drug diffusion through the skin due to the lower solubility and diffusivity of EVA 15 (skin) compared to EVA 28 (core) (Table 2). The predicted release rate was about 65% higher than the measured value (Figure 3C). This deviation was attributed to the difference in crystallinity between Nexplanon^® skin and the EVA free films used for the solubility and diffusivity measurements. The predicted release rate from ends was about 40% lower than the measured values (top graph of Figure 3D). This deviation was attributed to (i) lower crystallinity of EVA 28 in the presence of barium sulfate and etonogestrel and (ii) formation of solution-filled pores as drug release progressed (Figure 2A and B). The initial deviation from Higuchi model (non-linear portion of bottom graph of Figure 3D) was attributed to (i) depletion of supersaturated drug and (ii) the solubilization of drug crystals presented on the ends (Figure 1E). Despite only making up 2.2% of implant surface area, the ends accounted for 32% of implant drug release at day 1 (Figure 3B).  As release progressed, the contribution of ends release became less significant (Figure 3B).

Conclusion: Etonogestrel (D90 of 11.9 µm) was supersaturated in Nexplanon^®. Burst release was attributed to depletion of supersaturated drug. The diffusion of etonogestrel through both skin and two ends contributed to drug release. Diffusion through the skin was the limiting factor for release. Following burst release through skin lasted for 15 days, skin release rate reached a steady state of 55 mcg/day. At steady state, the skin release rate predicted by Fick’s law was 65% higher than the measured values. The deviation was attributed to the difference in crystallinity between Nexplanon^® skin and the EVA free films used for solubility and diffusivity measurements. The ends release rate predicted by Higuchi model was 40% lower than the measured values. Due to different drug release mechanisms of skin and ends, the ends release accounted for 32% of implant drug release at day 1, despite the fact that it accounted for only 2.2% of implant surface area.  As drug release progressed, the contribution from ends became less significant due to the faster decrease in ends release rate as a function of time.

References: 1. Lee, E.K., et al., Transport of steroids in poly (etherurethane) and poly (ethylene vinyl acetate) membranes. Journal of membrane science, 1985. 24(2): p. 125-143.
2. Laarhoven, J.A.H.v., Physical-chemical aspects of a coaxial sustained release device based on Poly-EVA. 2005: Utrecht University.
3. Higuchi, T., Physical chemical analysis of percutaneous absorption process from creams and ointments. J Soc Cosmet Chem, 1960. 11: p. 85-97.
4. Veenstra, H. and W. De Graaff, X-ray visible drug delivery device. 2014, US 8,722,037 B2.
5. LABEL: NEXPLANON - etonogestrel implant. [cited 2024 04/06/24].

Acknowledgements: This work was supported by the Broad Agency Announcement (BAA) Contract # 75F40122C00019 from the U.S. Food and Drug Administration (FDA). The content reflects the views of the authors and should not be construed to present FDA’s views or policies.


Figure 1. (A) Light microscope image of Nexplanon® cross section, (B and C) SEM images of Nexplanon® skin, and (D and E) SEM images of Nexplanon® ends. In E, circles indicate etonogestrel and squares indicate barium sulfate.
Table 1. Nexplanon® composition [5].
Table 2. Solubility and diffusivity of etonogestrel in EVA 28 and EVA 15 at 37°C (SD, n=3).


Figure 2. SEM images of Nexplanon® cross section (A) prior to drug release and (B) after the complete drug release. (C) Polarized light microscope image of molten Nexplanon® at 150C and (D) particle size distribution of etonogestrel.


Figure 3. (A) In-vitro drug release of Nexplanon® from implant skin or ends only and whole implant (B) % of contribution of implant skin or two ends to drug release (C) models of skin release and (D) model of ends release (SD, n=3).