Victoria Hutter3, Khaled Alzahabi1, Lucas Silva1, Angelo Consalvo2, Paul Shields2, Joanne Kelsall3, Ewelina Hoffman3, Victoria Hutter3.
1Nanopharm Ltd, An Aptar Pharma Company, Cwmbran, UK.
2Enteris BioPharma, Inc., Boonton, USA.
3ImmuONE, Stevenage, UK.
Summary
Leuprolide, a gonadotropin-releasing hormone (GnRH) agonist, is used to manage hormone-related conditions such as prostate cancer, endometriosis, and central precocious puberty [1,2]. Due to poor oral bioavailability resulting from first-pass metabolism in the liver, it is typically administered by injection [3]. While effective, injectable formulations are associated with adverse effects [4]. Intranasal (IN) delivery offers a non-invasive alternative with the potential for quicker systemic absorption [5].
This study evaluated the in vitro performance of spray-dried intranasal leuprolide formulations incorporating different permeation enhancers. Three formulations containing β-cyclodextrin, hydroxypropyl methylcellulose (HPMC), or a combination of HPMC and mannitol were compared to unprocessed leuprolide. Permeability and cytotoxicity were assessed using RPMI-2650 nasal epithelial cells. Cytotoxicity was evaluated via metabolic activity and membrane integrity assays, while permeability was measured using air–liquid interface cultures and HPLC.
All formulations, applied in solution, were well tolerated, with no significant cytotoxicity or loss of cell membrane integrity. Spray-dried formulations demonstrated significantly enhanced permeability compared to pure leuprolide (p<0.05). The β-cyclodextrin formulation showed the greatest improvement, increasing apparent permeability 5.1-fold. Formulations with HPMC and HPMC/mannitol increased permeability by 4.5- and 3.7-fold, respectively.
These findings highlight the potential of spray-dried leuprolide formulations with permeation enhancers to provide effective intranasal delivery. Further in vivo studies are needed to confirm these results and support development of a needle-free alternative to injectable leuprolide therapies.