(T1430-02-09) Development of a Hollow Vaginal Drug-Eluting Device Using Stereolithography 3D Printing for the Treatment of Recurrent Vulvovaginal Candidiasis

Purpose: Vulvovaginal candidiasis is a condition caused by the polymorphic opportunistic fungus Candida albicans, which involves the first-line treatment with antifungal agents comprising azole groups. An intravaginal drug-eluting device is an alternate approach to conventional therapies that transcend multiple daily administrations and systemic side effects associated with oral medications and offers effective drug concentrations at the target site for a sustained period. This study reports, for the first time, the development of a novel hollow vaginal device by exploiting stereolithography (SLA) 3D printing technology to achieve localized and extended delivery. A shape memory material (elastic resin) was used in fabricating the hollow device and was incorporated with an antifungal agent formulated into a lipid-based solid dispersion system to improve its solubility and dissolution, and for ease of injection into a hollow device.

Methods: Blender Software was used to design the 3D structure and exported as STL. file to SLA Formlabs Form 3 printer (Figure. 1). Five drug loadings (3% w/w, 6% w/w, 9% w/w, 11% w/w, and 14% w/w) of lipid-based solid dispersion were prepared by melting drug and lipid together and injected the molten mixture into hollow devices. Differential Scanning Calorimetry (DSC) was performed to determine the amorphous conversion of the drug in the lipid matrix. The drug-lipid mixtures were quantified using High-Performance Liquid Chromatography (HPLC) to determine the drug loading. The formulations were investigated using Fourier Transform Infrared (FTIR) spectroscopy to confirm the absence of any chemical interactions between the drug and excipients. Subsequently, all the formulations were exposed to accelerated stability storage conditions (40±2.0°C and 75±5% RH) for one month to see if the formulations were stable over time. Further, the devices (11% drug loading) were subjected to dissolution testing in an orbital shaking incubator and studied for drug release for seven days. Lastly, the amount of drug released from the device at each time point was studied for Minimum Inhibitory Concentration (MIC) to report its efficacy against C. albicans.

Results: All the devices were fabricated with a smooth surface finish, showed excellent resistance to stretching forces, and could recoil to their original shape immediately after the external forces were withdrawn. This attribute of the device owes to its easy insertion, retention, and removal from the vagina. The DSC thermogram showed the complete disappearance of the drug peak in the formulation, which might be due to the amorphous conversion of the crystalline drug during the melting process (Figure. 2). The drug content was in accordance with the theoretical drug loadings, implying no loss of drug during the preparation process. The FTIR spectra showed that drug-excipient interactions in the lipid-based solid dispersion (drug-lipid) were absent (Figure. 2). The drug-lipid mixtures (3%, 6%, 9%, 11%, and 14%) that were subjected to accelerated stability testing, were analyzed using DSC. The results revealed that the mixture with 14% drug loading underwent recrystallization after being exposed to accelerated stability conditions. In-vitro dissolution testing showed a sustained drug release from the device (11% drug loading) over seven days, and the amount of drug released from hollow devices was well above the MIC values against C. albicans, implying its efficacy against the infection (Figure. 3).

Conclusion: For the first time, novel hollow vaginal devices were developed using SLA 3D printing, achieving sustained and localized drug delivery to the vagina, and it showed efficacy against C. albicans, proving the possibility of treating fungal infections. Though there are several once-a-day products in the market for treating vaginal candidiasis (e.g., Monistat one, vagistat-1-vaginal, etc.), they have several disadvantages like difficulty in administration, interference with vaginal flushes (menstrual discharge and vaginal discharges) and sexual intercourse. The drug-loaded hollow vaginal device could overcome the disadvantages associated with conventional dosage forms and improves patient compliance and treatment efficacy. Furthermore, SLA 3D fabrication technology made possible the development of personalized and complex geometries easily and cost-effectively. The hollow vaginal devices could easily be adapted for treating various other vaginal conditions (versatile) just by changing the drug.

References: 1. Xu X, Goyanes A, Trenfield SJ, Diaz-Gomez L, Alvarez-Lorenzo C, Gaisford S, et al. Stereolithography (SLA) 3D printing of a bladder device for intravesical drug delivery. Mater Sci Eng C. 2021 Jan 1;120:111773.
2.Nonprescription Management of Vulvovaginal Candidiasis [Internet]. [cited 2022 Nov 28]. Available from: https://www.uspharmacist.com/article/nonprescription-management-of-vulvovaginal-candidiasis

3D design of the hollow vaginal device

A) DSC thermograms of pure drug, lipid, physical mixture, and drug-lipid formulation (bottom-top) B) FTIR spectra of pure drug, lipid, physical mixture, and drug-lipid formulation (bottom-top).

Drug release from 11% hollow device A) Cumulative drug release B) Daily drug release Vs MIC (0.63 mcg/mL)