Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer's disease

Abstract

With the increasing aging population and progressive nature of the disease, Alzheimer's disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of β-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor, is a more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing the first-pass metabolism exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver them efficiently to the brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to the brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in acute scopolamine-induced amnesia and chronic colchicine induced cognitive dysfunction animal models, and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modeling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax = 5 min), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F = 118.65 ± 23.54; AUC = 35,921.75 ± 9559.46), increased half-life (30.92 ± 8.38 min), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax = 15 min; Cmax = 56.29 ± 27.05; F = 4.39 ± 1.82; AUC = 1663.79 ± 813.54; t1/2 = 13.48 ± 5.79; Kel (1/min) = 0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine as well as colchicine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modeling demonstrated a strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation.

Keywords: Amnesia; Nanoformulation; Neurodegeneration; Nose to brain delivery; PK-PD modeling.

Fig. 1

Experimental protocol for acute and chronic models of dementia followed in the study

Fig. 2

In vitro characterization of rivastigmine PLGA nanoparticles. (a) Zeta potential; (b) particle size measurements; (c) SEM and (d) TEM images of rivastigmine loaded nanoparticles; (e) typical HPLC chromatogram of rivastigmine in nanoparticles formulation; (f) in vitro release profile

Fig. 3

Plasma concentration–time curve of different formulation administered through intranasal or oral route in scopolamine induced amnesia rats (n = 4)

Fig. 4

Pharmacokinetic features of different rivastigmine formulations. Maximum concentration (Cmax), area under the curve (AUC), elimination rate constant (Kel), half-life (t 1/2), clearance (Cl_F_obs), Mean residence time (MRT), absolute bioavailability (%F), volume of distribution (Vz_F_obs) of rivastigmine, and its formulations in scopolamine-induced rats. Data represented as mean ± SD, ANOVA followed by post-hoc test *a = p < 0.05 vs. ORSM; *b = p < 0.05 vs. INRSM; *c = p < 0.05 vs. INRNP

Fig. 5

Influence of different formulations of rivastigmine on locomotor activity in scopolamine induced amnesia in rats

Fig. 6

Influence of different formulations of rivastigmine in scopolamine induced amnesia on MWM task parameters: EL, escape latency; RT, residence time; and PST, peripheral swim time. Data represented as mean ± SD, ANOVA followed by post-hoc tests *a = p < 0.05 vs. NC; *b = p < 0.05 vs. SCP; *c = p < 0.05 vs. SCP + ORSM; *d = p < 0.05 vs. SCP + INRL

Fig. 7

Effect of different rivastigmine formulations administered through different routes of administration in scopolamine induced amnesia on parameters of passive avoidance task. (A) AT (acquisition time), LT (latency time to enter into darker compartment), D (time spent in the darker compartment), L (time spent in the brighter compartment), and (B) number of crossings. Data represented as mean ± SD, ANOVA followed by post-hoc tests *a = p < 0.05 vs. normal control; *b = p < 0.05 vs. SCP; *c = p < 0.05 vs. SCP + ORSM

Fig. 8

Influence of different rivastigmine formulations on % AChE inhibition in scopolamine induced amnesic rats. (A) At different time intervals with plasma samples. (B) At 15 min with plasma samples. (C) At 15 min with whole-brain homogenate. Data represented as mean ± SD, ANOVA followed by post-hoc tests. *a = p < 0.05 vs. normal control; *b = p < 0.05 vs. SCP; *c = p < 0.05 vs. SCP + ORSM; *d = p < 0.05 vs. SCP + INRNP; e = p < 0.05 vs. SCP + INRNP)

Fig. 9

Influence of different rivastigmine formulations on locomotor activity in colchicine-induced dementia in rats

Fig. 10

Influence of different rivastigmine formulations in colchicine induced dementia rats assessed by Morris water maze task parameters, (A) escape latency and (B) residence time. Data represented as mean ± SD, ANOVA followed by post-hoc tests. *a = p < 0.05 vs. SC; *b = p < 0.05 vs. ACSF; *c = p < 0.05 vs. COL; *d = p < 0.05 vs. COL + ORSM; *e = p < 0.05 vs. COL + INRSM

Fig. 11

Influence of different rivastigmine formulations on (A) latency time to enter the dark chamber, (B) time spent in darker chamber, and (C) number of crossings on different retention test days during PAT in colchicine-induced dementia rats. Data represented as mean ± SD, ANOVA followed by post-hoc tests. *a = p < 0.05 vs. SC; *b = p < 0.05 vs. ACSF; *c = p < 0.05 vs. COL; *d = p < 0.05 vs. COL + ORSM; *e = p < 0.05 vs. COL + INRSM

Fig. 12

Influence of different rivastigmine formulations on % AChE inhibition in colchicine induced dementic rats. (A) At different time intervals with plasma samples. (B) At 15 min with plasma samples. (C) At 15 min with whole-brain homogenate. Data represented as mean ± SD, ANOVA followed by post-hoc tests (*a = p < 0.05 vs. SC; *b = p < 0.05 vs. ACSF; *c = p < 0.05 vs. COL;*d = p < 0.05 vs. COL + ORSM; *e = p < 0.05 vs. COL + INRSM)

Fig. 13

Predicted and observed models of rivastigmine-loaded liposomes following intranasal administration in scopolamine induced rats. (a) PK model predicted plasma concentration vs. time relationship. (b) PD model predicted plasma concentration vs. AChE inhibition. (c) PK-PD model predicted time vs. plasma AChE inhibition. (d) PK-PD model predicted hysteresis curve