(L-453) Thermoresponsive Local Drug Release System in Endometriosis

Endometriosis is a debilitating condition affecting 10% of reproductive-age women worldwide. It is a chronic inflammatory condition characterised by the growth of endometrial tissues outside the uterine cavity causing pain and infertility. The current treatment regimens include hormonal therapies having several systemic side effects due to high dosing and long-term use. Surgical procedures for treatment are invasive and require to add-back hormonal therapy, which further increases the cost of treatment and has a high chance of reoccurrence. Therefore, a cost-effective cytoreductive strategy with reduced adverse effects is required to treat the disease. Recently, aromatase inhibitors have been investigated to target increased estrogen synthesis by ectopic endometrial tissues and effectively prevent lesions’ growth. Letrozole, the most potent aromatase inhibitor, effectively reduces endometrial lesions and symptoms when administered 2.5mg/day orally¹. However, it is found to cause osteoporosis and systemic estrogen imbalance on oral administration. Therefore, there is a need for an efficient site-specific drug delivery strategy to minimise systemic side effects. To achieve this, we developed and characterised a thermoresponsive mucoadhesive gel loaded with letrozole-loaded particles to be administrated at the lesion site. The developed gel is biodegradable. After installation, it solidifies and adheres to the uterine wall and provides sustained drug delivery to the local site.

1) Drug carriers: Nanoparticles consisting of liposomes and lipid particles of soya phosphatidylcholine (SPC) and triglycerol monostearate (TG) were formed using thin film hydration and homogenisation method respectively. Nanoparticles were prepared as drug carriers to encapsulate the hydrophobic drug letrozole to be incorporated in a hydrophilic gel vehicle. Nanoparticles were characterised via transmission electron microscopy, dynamic light scattering and reverse phase high liquid chromatography (HPCL). The drug release profile was obtained using the dialysis membrane method. MTT assay for biocompatibility and confocal microscopy for cellular uptake was performed in human endometrial stromal cells (HESC). 2) In-situ gel as a delivery vehicle: In-situ gel formulated with two components mucoadhesive polymer, gellan and thermo-sensitive polymer, poloxamer. The gel composition was formulated to be liquid at room temperature and to gel at 37°C to be ideal for intra-uterine administration using a small diameter catheter. The gel was characterised for gelling time and temperature using the invert vial method and rheology studies. The gel stability was checked in PBS, and injectability was tested using a 23 gauge needle using the universal testing machine.

1) SPC-TG mixed spherical liposomes were developed of hydrodynamic size ~150nm, with a polydispersity index (PDI) of 0.31 and encapsulation efficiency (EE) of ~80% based on HPLC. SPC spherical lipid particles were of hydrodynamic size ~165nm, PDI of 0.275 with 65% EE. In in-vitro tests, both nanoparticles showed a two-fold increase in uptake by the HESC. 2) Different concentrations of poloxamer-gellan polymer were optimized so as to achieve gelling in 5 mins on installation at the local site so that it does not get washed by body fluids.  The optimum combination gelled within 5 mins, as tested by the invert vial method and rheology data. The selected gel composition shows a maximum injection force of less than 8N making it suitable for intrauterine delivery.

Lipid-based drug carriers were formed and incorporated in thermoresponsive gel. Preliminary results show the formulation to be ideal for administration using a small-diameter catheter for uterine delivery. Further studies are underway to check in-vivo drug release profile and reduction in progression markers in endometriosis animal model. Once developed, it will be an easy, patient-compliant, cost-effective drug delivery method for endometriosis treatment and can be explored for other uterine conditions.