Intranasal administration of carbamazepine-loaded carboxymethyl chitosan nanoparticles for drug delivery to the brain

Abstract

Epilepsy is considered as a common and diverse set of chronic neurological disorders and its symptoms can be controlled by antiepileptic drugs (AEDs). The presence of p-glycoprotein and multi-drug resistance transporters in the blood-brain barrier could prevent the entry of AEDs into the brain, causing drug resistant epilepsy. To overcome this problem, we propose using carboxymethyl chitosan nanoparticles as a carrier to deliver carbamazepine (CBZ) intra-nasally with the purpose to bypass the blood-brain barrier thus to enhance the brain drug concentration and the treatment efficacy. Results so far indicate that the developed CBZ-NPs have small particle size (218.76 ± 2.41 nm) with high drug loading (around 35%) and high entrapment efficiency (around 80%). The in vitro release profiles of CBZ from the NPs are in accordance with the Korsmeyer-peppas model. The in vivo results show that both encapsulation of CBZ in nanoparticles and the nasal route determined the enhancement of the drug bioavailability and brain targeting characteristics.

Keywords: Blood-brain barrier; Carbamazepine; Chitosan; Nanoparticles; Nasal drug delivery; Pharmacokinetics.

Graphical abstract

Fig. 1

Synthetic routes of CMC (1. O-CMC, 2. N-CMC).

Fig. 2

Estimation of degree of substitution of CMC by titration with sodium hydroxide.

Fig. 3

FT-IR spectroscopy of (A) chitosan and (B)CMC.

Fig. 4

¹H NMR spectrum of CMC.

Fig. 5

¹³C NMR spectrum of CMC.

Fig. 6

Microphotograph of CBZ-NPs by Transmission Electron Microscope (TEM).

Fig. 7

Release profiles of CBZ from the 3 batches of CBZ-NPs prepared under the optimal experimental condition in pH 7.4 PBS media at 37 °C, 300 rpm in water bath (n = 3) (–●–batch 1, –▲– batch 2, –■– batch 3).

Fig. 8

The mean concentration of CBZ (µg/ml) in mice plasma and brain after intranasal administration at dose of 2 mg/kg of CBZ-NPs (—■— plasma, —○—brain, n = 3 ± SD) and CBZ-SL (—▲—Plasma, —▽—Brain, n = 3 ± SD). Paired t-test: (* and #) significantly different from CBZ-SL, P < 0.05, (** and ##) very significantly different from CBZ-SL, P < 0.01.