Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer's Disease Treatment

Abstract

Direct nose-to-brain delivery has been raised as a non-invasive powerful strategy to deliver drugs to the brain bypassing the blood-brain barrier (BBB). This study aimed at preparing and characterizing an innovative composite formulation, associating the liposome and hydrogel approaches, suitable for intranasal administration. Thermosensitive gel formulations were obtained based on a mixture of two hydrophilic polymers (Poloxamer 407, P407 and Poloxamer 188, P188) for a controlled delivery through nasal route via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer's disease. The osmolarity and the gelation temperature (T° sol-gel) of formulations, defined in a ternary diagram, were investigated by rheometry and visual determination. Regarding the issue of assays, a mixture composed of P407/P188 (15/1%, w/w) was selected for intranasal administration in terms of T° sol-gel and for the compatibility with the olfactory mucosal (280 ± 20 mOsmol, pH 6). Liposomes of API were prepared by the thin film hydration method. Mucoadhesion studies were performed by using mucin disc, and they showed the good natural mucoadhesive characteristics of in situ gel formulations, which increased when liposomes were added. The study demonstrated successful pharmacotechnical development of a promising API-loaded liposomes in a thermosensitive hydrogel intended for nasal Alzheimer's disease treatment.

Keywords: nanocomposite; nose-to-brain delivery; thermosensitive hydrogel.

Figure 1

Ternary mix of Poloxamers 407/188 / H2O, sol-gel transition temperature (a), osmolarity (b). (a): low T°sol-gel transition, acceptable T°sol-gel transition, high T°sol-gel transition; (b): acceptable osmolarity, High osmolarity.

Figure 2

Rheology determination of gelation temperature of gel 15/1 with and without liposomes. Black continuous line G’ storage modulus of Gel 15/1, black broken line G’’ loss modulus of gel 15/1, grey continuous line G’ storage modulus of Gel 15/1 with liposome, grey broken line G’’ loss modulus of gel15/1 with liposome.

Figure 3

Shear stress-viscosity vs. deformation at 34 °C of gel 15/1 with and without liposomes (Shear-viscosity results). Black cercle: Gel 15/1, grey empty cercle: Gel 15/1 with liposome 60 mM, grey full cercle: gel 15/1 with liposome 120 mM.

Figure 4

Strain sweep of gel with and without liposome.Storage (G’) and loss (G’’) moduli as a function of the oscillation stress. Black full circle: G’ storage modulus of Gel 15/1, grey full triangle: G’ storage modulus of Gel 15/1 with liposome 60 mM, grey full square: G’ storage modulus of Gel 15/1 with liposome 120 mM, Black empty circle: G’’ loss modulus of Gel 15/1, grey empty triangle: G’’ loss modulus of Gel 15/1 with liposome 60 mM, grey empty square: G’’ loss modulus of Gel 15/1 with liposome 120 mM.

Figure 5

Mucoadhesion studies. Each point represents mean ± standard deviation (n = 4); *versus 15/1% p < 0.01; **versus 15/1% p < 0.001. detachment Force (mN), adhesion work (mN.mm).

Figure 6

Active pharmaceutical ingredient (API) release in simulated nasal fluid. Each point represents mean ± standard deviation (n = 3). Solution API 1 mg/mL, API-loaded liposomes , Gel with API 1mg/mL, API-loaded Liposomes in gel.