(W1030-07-42) Buffering for Contraception: A QbD-Guided 3D Printed Vaginal Film for On-Demand, Hormone-Free Protection

Purpose: This study addresses the need for a more accessible, user-friendly, and cost-effective non-hormonal contraceptive method. Inspired by the FDA-approved acid-buffering gel Phexxi®, which relies on a disposable applicator and plunger, we aimed to develop a 3D printed, hormone-free vaginal film capable of self-insertion without an applicator system. The objective was to create a film that rapidly modulates vaginal pH upon semen exposure, thereby achieving on-demand contraception without hormonal intervention. A Quality by Design (QbD) approach was employed to systematically optimize formulation and fabrication parameters.

Methods: The goal was to fabricate a 3D printed vaginal film containing fixed doses of three active agents, lactic acid (1.8%), citric acid (1.0%), and potassium bitartrate (0.4%) - matching the active concentrations present in 5 g of Phexxi^® - within a target film weight of approximately 750 mg (Figure 1). A physical mixture comprising these actives and polyethylene oxide (PEO N10) as the film-forming polymer was initially prepared and fabricated using a direct extrusion 3D printer (BIO X, Cellink). However, early formulations were brittle, prompting the exploration of plasticizers to improve mechanical properties. Polyethylene glycol (PEG 1500 and PEG 400) and triethyl citrate (TEC) at 3–5% concentrations were evaluated, but failed to yield films with adequate flexibility and strength. Sorbitol at 5% w/w demonstrated superior plasticization, resulting in films with improved elasticity and structural integrity. Subsequently, a fixed formulation containing lactic acid, citric acid, potassium bitartrate, PEO N10, and sorbitol was used to optimize the 3D printing parameters. A Box-Behnken design was implemented using Design-Expert^® software to evaluate the effects of four independent variables: sorbitol content (% w/w), printing speed (mm/s), extrusion pressure (kPa), and nozzle temperature (°C) on key performance attributes of the films. The dependent variables included disintegration time (seconds), film elasticity (measured as deformation at break, mm), and printability (coded as “1” for successful film formation and “0” for failed prints). The optimized formulation was further characterized for mechanical strength via puncture testing using a texture analyzer (TA.XT2i), and analyzed by Fourier-transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (¹H-NMR) to assess potential interactions between formulation components. In vitro pH modulation efficacy was assessed by measuring pH reduction in simulated semen fluid following film exposure. The optimized film was also subjected to accelerated stability testing under ICH conditions (40 °C/75% RH) to evaluate its physical and functional stability over time.

Results: The target active doses equivalent to Phexxi^® was successfully incorporated into a 750 mg 3D printed vaginal film. A Box-Behnken design with four independent variables: sorbitol content (5–15%), printing temperature (80–100 °C), pressure (300–700 kPa), and speed (2–5 mm/s),  generated 25 runs, of which 16 were successfully printed. Failed runs (n=9) resulted in non-printable masses and were excluded from analysis. Response surface models indicated that printing temperature and speed significantly influenced disintegration time (p < 0.05); lower temperatures and higher speeds yielded faster disintegration due to reduced polymer fusion and thinner film profiles, respectively. Elasticity was significantly impacted by printing temperature (p < 0.05), with lower temperatures producing more flexible films, likely due to reduced thermal degradation or migration of plasticizers and excipients, resulting in better matrix integrity. Printability was primarily governed by extrusion pressure (p < 0.05); excessive pressure led to premature mass extrusion. Sorbitol enhanced disintegration at higher concentrations and improved elasticity at lower levels, suggesting dual functionality as a disintegrant and plasticizer (Figure 2). The optimized film disintegrated within 1 minute 40 seconds, exhibited 39.5 mm elasticity, and was chemically stable as confirmed by FTIR and ¹H-NMR analyses (Figure 3). In vitro, the film reduced the pH of simulated semen from 7.2 to 3.5 within 2 minutes, demonstrating effective acid-buffering capacity for contraceptive action.

Conclusion: This study demonstrates the successful development of a 3D printed, hormone-free vaginal film that provides on-demand contraceptive protection through rapid pH modulation. Guided by a QbD framework, the optimized film incorporated clinically relevant acid concentrations equivalent to Phexxi^® and achieved desirable mechanical, disintegration, and printability attributes. In vitro results confirmed the film’s ability to quickly restore vaginal acidity upon semen exposure, effectively creating conditions that immobilize sperm. The film highlights its potential as a user-friendly, applicator-free alternative to gel-based non-hormonal contraceptives.

References: US11992472B2 - Compositions and methods for enhancing the efficacy of contraceptive microbicides - Google Patents


Figure 1. Demonstration of vaginal film fabrication and its mechanism of action.


Figure 2. Response surface 3D plots; (a) Effect of sorbitol (% w/w) and temperature on disintegration time, (b) Effect of printing speed and temperature on disintegration time, (c) Effect of sorbitol (% w/w) and temperature on elasticity, (d) Effect of printing pressure and speed on printability.


Figure 3. (a) NMR spectra of physical mixture and 3D printed film, (b) FTIR spectra