Thermoplastic polyurethane-based intravaginal rings for prophylaxis and treatment of (recurrent) bacterial vaginosis

G Verstraete; L Vandenbussche; S Kasmi; L Nuhn; D Brouckaert; J Van Renterghem; W Grymonpré; V Vanhoorne; T Coenye; B G De Geest; T De Beer; J P Remon; C Vervaet

doi:10.1016/j.ijpharm.2017.06.076

Thermoplastic polyurethane-based intravaginal rings for prophylaxis and treatment of (recurrent) bacterial vaginosis

Int J Pharm. 2017 Aug 30;529(1-2):218-226. doi: 10.1016/j.ijpharm.2017.06.076. Epub 2017 Jun 27.

Authors

G Verstraete¹, L Vandenbussche¹, S Kasmi¹, L Nuhn¹, D Brouckaert², J Van Renterghem², W Grymonpré¹, V Vanhoorne¹, T Coenye³, B G De Geest¹, T De Beer², J P Remon¹, C Vervaet⁴

Affiliations

¹ Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
² Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium.
³ Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.
⁴ Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium. Electronic address: Chris.Vervaet@Ugent.be.

PMID: 28663088
DOI: 10.1016/j.ijpharm.2017.06.076

Abstract

The aim of the present study was to develop thermoplastic polyurethane (TPU)-based intravaginal rings (IVRs) for prophylaxis and treatment of bacterial vaginosis via hot melt extrusion/injection molding. Therefore, different TPU grades were processed in combination with lactic acid or metronidazole, targeting a sustained lactic acid release over a 28day-period and sustained metronidazole release over 4-7days. Hot melt extrusion of lactic acid/TPU combinations required a lower extrusion temperature due to the plasticizing properties of lactic acid, evidenced by the lower glass transition temperature (T_g) and cross-over point (T_tanδ₌₁) values. NIR-chemical imaging data showed a homogenous distribution of lactic acid in TPU matrices at drug loads up to 30% (w/w). The addition of metronidazole did not lower processing temperatures, as the active pharmaceutical ingredient remained crystalline in the TPU matrix. Hydrophobic TPUs with a low ratio between the soft and hard segments (SS/HS ratio) in the polymer structure were suitable carriers for the lactic acid-eluting device over a 28-day period, while hydrophilic TPUs were needed to achieve the required release rate of metronidazole-eluting IVRs. IVRs manufactured with a TPU grade having a higher SS/HS ratio and lactic acid/TPU ratio exhibited a more elastic behavior. The addition of 25% (w/w) metronidazole did not affect the mechanical properties of the IVRs. Hydrophilic TPUs were most prone to biofilm formation by Candida albicans and Staphylococcus aureus, but the incorporation of metronidazole in the device prevented biofilm formation. Based on the drug eluting performance and mechanical tests, a mixture of lactic acid and Tecoflex™ EG-93A (20/80, w/w) and a combination of metronidazole and Tecophilic™ SP-93A-100 (25/75, w/w) were selected to design IVRs for the prophylaxis and treatment of bacterial vaginosis, respectively. Slug mucosal irritation tests predicted low irritation potency for both devices.

Keywords: Bacterial vaginosis; Hot melt extrusion; Intravaginal rings; Lactic acid; Metronidazole; Thermoplastic polyurethanes.

MeSH terms

Administration, Intravaginal
Drug Delivery Systems*
Drug Liberation
Female
Humans
Lactic Acid / chemistry*
Metronidazole / pharmacology*
Polyurethanes / chemistry*
Vaginosis, Bacterial / drug therapy*

Substances

Polyurethanes
Metronidazole
Lactic Acid