Development and Evaluation of a Novel Intranasal Spray for the Delivery of Amantadine

Abstract

The aim of this study was to develop and characterise an intranasal delivery system for amantadine (AMT). Optimal formulations (F) consisted of a thermosensitive polymer Pluronic ® 127 (P127) and either carboxy methyl cellulose (CMC) or chitosan (CS) which demonstrated gel-transition at nasal cavity temperatures (34 °C ± 1 °C). Rheologically, the loss tangent (Tan δ) confirmed a three-stage gelation phenomena at 34 °C ± 1 °C and nonNewtonian behaviour. Storage of FCMC and FCS at 4 °C for 8 weeks resulted in repeatable release profiles at 34 °C when sampled, with a Fickian mechanism earlier on but moving towards anomalous transport by week 8. Polymers (P127, CMC and CS) demonstrated no significant cellular toxicity to human nasal epithelial cells up to 4 mg/mL and up to 1 mM for AMT (IC50: 4.5 mM ± 0.05 mM). FCMC and FCS demonstrated slower release across an in-vitro human nasal airway model (43-44 % vs 79 % ± 4.58 % for AMT). Using a human nasal cast model, deposition into the olfactory regions (potential nose-to-brain) was demonstrated upon nozzle insertion (5 mm) whereas tilting of the head forward (15°) resulted in greater deposition in the bulk of the nasal cavity. KEYWORDSParkinson's disease; rheology; nasal; RPMI 2650; nose to brain; thermoresponsive; 3 INTRODUCTION Parkinson's disease (PD) is an ageing associated progressive neurological disorder and affects 1.5 % of the population over 65-years of age 1 , with age-adjusted prevalence rates thought to be around 150 per 100,000 with a suggested mean onset in the 70's 1 . Ageing is the largest single risk factor for the development of PD and the pathogenesis of PD is composed of a range of events leading towards neuronal apoptosis, primarily of degradation of dopamine neurones in the sustantia nigra. The mainstay of clinical drug therapy focuses on increases the levels of dopamine (DA) in the brain, with oral dosing of levodopa being the most commonly used to pharmacological intervention treatment to reverse the symptoms of PD. It is also common to use adjunct therapies in conjunction with levodopa, such as the weak NMDA-type receptor antagonist amantadine, which can aid in blocking dopamine reuptake.

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods

“…In comparison, chamber configurations can deliver a uniform density through larger membranes (diameter ≥24 mm), with a reduced reading variation (Srinivasan et al, 2015). Both excised mucosa and cell layers require an equilibrium time (∼30 min or 60 min (Röhm et al, 2017;Lungare et al, 2016;Wang et al, 2017;Li et al, 2006) before performing the permeation study, which then consists of taking aliquots from the basal compartment at regular intervals (Gonçalves et al, 2016). The deposition of a reproducible and uniform amount of drug on the tissue is thus crucial as it will directly influence the gradient concentration and could thus introduce variation in the permeability (Upadhyay et al, 2017).…”

“…For insert materials, polyethylene terephthalate or polyester (which can be sometimes coated with collagen) are preferred for RPMI 2650 culture (Lungare et al, 2016;Gonçalves et al, 2016). The culture media selected are minimal essential medium non-essential amino acids or Eagle's modified essential medium supplemented with 10% v/v foetal bovine serum and other additives (e.g.…”

“…A second method described the preparation of an agar/mucins mixture that was coated onto a glass plate and left for gelification (Lungare et al, 2016;Bertram and Bodmeier, 2006). The formulation is then deposited on the plate and the displacement factor is measured (Nakamura et al, 1996).…”

“…The displacement of the inserts on the agar/mucin gel was evaluated to assess potential bioadhesion. This method was also used to evaluate the mucoadhesion of nasal in situ gelling inserts containing salbutamol (Farid et al, 2013) or liquid formulation containing amantadine and a thermosensitive polymer (Lungare et al, 2016). This method therefore L. Salade, et al International Journal of Pharmaceutics 561 (2019) 47-65 makes it possible to measure easily the potential of a formulation to adhere and to compare different excipients with each other.…”

Amantadine and phenytoin: patent protected cases of drug repositioning

“…For the last indication, a special extended release formulation has been tested. Other new formulations of this old drug are underway [16].…”