(M1030-01-04) Development of Customizable Swelling Vaginal Rings for Targeted Infection Treatment via 3D Printing

Purpose: The female reproductive system is subject to a multitude of hormonal changes that can impact women's health. To address the issue of decreased patient compliance with locally delivered semisolid formulations, there is a need to develop vaginal inserts that can provide sustained release of medications. Recent advances in 3D printing technology have made it possible to create vaginal inserts for drug delivery. The use of 3D printing technology in developing vaginal rings has emerged as a promising approach in the field of women's health. Vaginal rings are a popular method of delivering drugs for contraception, hormone therapy, and other conditions. 3D printing can be used to create customized vaginal rings with specific shapes, sizes, and compositions, leading to improved drug delivery and therapeutic outcomes. The purpose of the current research involve: 1) development of novel polymeric matrix with sustained release profile of about 8hrs 2)3d printing of novel polymeric combination into vaginal ring 3) drug loading into vaginal rings for treatment of vaginal candidiasis and bacterial vaginosis.  The objective of current research was to develop a novel polymeric matrix which was selected from the screening of different ratios of polymers Poly-ethylene-oxide (PEO) and Poly(2-ethyl-2-oxazoline) (PETOx).

Methods: The drug miconazole was molecularly dispersed within polymers using a method called hot melt extrusion (HME), which yielded filaments suitable for 3D printing. For the designing of the ring, online software Tinkercad was used and once the design was finalized it was obtained in a stereolithographic format(.stl). The solid-state characterization of MZ extrudates of PETOx: PEO and MZ alone was performed by Q200 modulated DSC instrument the probe or assembly used in the study is HDP/M3PB (three-point bend test assembly) (Fig 1b). For processing the design template to 3D printer MakerBot, it was imported into the MakerBot software using cloud and hence, it was exported for printing. The evaluation of differences in swellability was performed via understanding of different swellability assessment factors. The following were calculated: (a)swellability index (b) radial change in swellability by using the texture analyzer using the compression mode. A mucoadhesion study was conducted on a hydrogel composed of mucin and PVA to mimic vaginal mucosa. For understanding the release patterns of 3D printed MZ vaginal rings, the in vitro release was performed in 6 well plates on an orbital shaker at 50 rpm. The media used for analysis was simulated vaginal fluid with 1% SLS for maintaining the sink conditions and the samples were withdrawn at predetermined timepoints of 0.5,1,2,4,6,8 h. HeLa cells were used to carry out in vitro biocompatibility studies on the excipients used in the miconazole vaginal rings. The overall methodology for preparation and characterization studies for MZ rings is shown in Fig 1a.

Results: The HME of polymers was performed at 170°C. According to the preliminary studies of DSC, the drug has a melting point at around 80°C, and the polymers have peaks at 60°C and 75°C, respectively. The extrusion was performed at 170°C, wherein the minimum extrusion for PETOx is 170°C. Therefore, the maximum extrusion temperature was performed at 170°C, considering that the high temperatures for 7M M.W. of PEO will aid in proper mixing of both polymers and drug. The batches were extruded with varying ratios of PEO: PETOx 25:75,50:50,75:25 and 25:75 respectively. The filaments with only PEO were not printable. We observed that for sustained released and maximum swelling index, more than 25% of PEO was essential in the matrix. Consequently, with swelling 50:50 and 25:75 was explored further for in vitro dissolution studies. The swelling patterns of rings were unique, wherein both from inner and outer sides provided the erosion fronts. The insight into the swelling patterns aids in understanding the drug release patterns wherein the swelling increased maximum until 4h, with drug release < 50%(Fig.2). We observed 1183±34.23% swelling at 4h which was dependent on concentration of PEO(Fig.1c). The adhesive strength of formulation was found to be 0.1960±0.05 N, owing to 1:1 proportion of PETOx: PEO. The maximum radius increase was at 4h, which further decreases, and erosion takes place completely within 8h. Once, the gelling and erosion were maximum, the drug release >80% at 8h which was diffusion and erosion controlled for 50:50 proportion.

Conclusion: Depending on the in vitro biocompatibility studies, the swellability studies and mucoadhesion testing, PEO: PETOx provided a novel swellable polymeric matrix for developing customizable vaginal inserts.

Figure 1. (1a) The methodological schematic representation of the different studies performed while preparation of miconazole loaded vaginal rings (1b) Results showing the polymeric matrix optimization for developing 3D printed vaginal rings with graph showing solid state characterization and mechanical properties screening for hot-melt extruded filaments.
(1c) Swellability Characterization of MZ loaded 3d printed vaginal rings (A) swellability index assessment for different formulation batches, indicating the maximum and minimum swelling of different polymeric proportions (B) % Radius Increase studies performed using digital imagining and ImageJ software showing maximum radius increase until 6h.

Figure 2. In-vitro dissolution studies for MZ loaded 3D printed vaginal rings depicting MZ release of 82.21901±0.822% release within 8h for PETOx: PEO (50:50) and 59.9605± 0.599% release for PETOx: PEO (25:75)