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. 2015;22(7):918-30.
doi: 10.3109/10717544.2013.878857. Epub 2014 Jan 27.

Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization

Brijesh M Shah  1 , Manju Misra  2 , Chamanlal J Shishoo  1 , Harish Padh  3
Affiliations

Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization

Brijesh M Shah et al. Drug Deliv. 2015.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to irreversible loss of neurons, cognition and formation of abnormal protein aggregates. Rivastigmine, a reversible cholinesterase inhibitor used for the treatment of AD, undergoes extensive first-pass metabolism, thus limiting its absolute bioavailability to only 36% after 3-mg dose. Due to extreme aqueous solubility, rivastigmine shows poor penetration and lesser concentration in the brain thus requiring frequent oral dosing. This investigation was aimed to formulate microemulsion (ME) and mucoadhesive microemulsions (MMEs) of rivastigmine for nose to brain delivery and to compare percentage drug diffused for both systems using in-vitro and ex-vivo study. Rivastigmine-loaded ME and MMEs were prepared by titration method and characterized for drug content, globule size distribution, zeta potential, pH, viscosity and nasal ciliotoxicity study. Rivastigmine-loaded ME system containing 8% w/w Capmul MCM EP, 44% w/w Labrasol:Transcutol-P (1:1) and 48% w/w distilled water was formulated, whereas 0.3% w/w chitosan (CH) and cetyl trimethyl ammonium bromide (as mucoadhesive agents) were used to formulate MMEs, respectively. ME and MMEs formulations were transparent with drug content, globule size and zeta potential in the range of 98.59% to 99.43%, 53.8 nm to 55.4 nm and -2.73 mV to 6.52 mV, respectively. MME containing 0.3% w/w CH followed Higuchi model (r(2) = 0.9773) and showed highest diffusion coefficient. It was free from nasal ciliotoxicity and stable for three months. However, the potential of developed CH-based MME for nose to brain delivery of rivastigmine can only be established after in-vivo and biodistribution study.

Keywords: Alzheimer’s disease; brain targeting; intranasal route; mucoadhesive agents; rivastigmine.

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Conflict of interest statement

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Figures

Figure 1.
Figure 1.
Solubility study data for RHT in oils, surfactants and cosurfactants, n = 3.
Figure 2.
Figure 2.
Falling liquid film technique for ex-vivo determination of mucoadhesive strength.
Figure 3.
Figure 3.
Pseudo-ternary phase diagram of Capmul MCM EP (oil), Smix (Labrasol:Transcutol-P, 1:1, 2:1, 3:1) and water.
Figure 4.
Figure 4.
Ternary compositions of Smix ratio 1:1 showing appearance of nine different oil to Smix ratio (9:1 to 1:9) to assess the clarity of the system (O – Oil, Sm – Smix, W – Water, G – Globule size, P – PDI).
Figure 5.
Figure 5.
Effect of various Smix concentrations (% w/w) on globule size (nm).
Figure 6.
Figure 6.
Size distribution of ME, CH-ME and CTAB-ME by dynamic light scattering.
Figure 7.
Figure 7.
Transmission electron microscopy image of CH-ME.
Figure 8.
Figure 8.
Contact angle images of (A) ME and (B) CH-ME.
Figure 9.
Figure 9.
In-vitro diffusion profile of RHT from ME, MMEs and DS in PBS (pH 6.4).
Figure 10.
Figure 10.
Ex-vivo diffusion profile of RHT from ME, MMEs and DS in PBS (pH 6.4).
Figure 11.
Figure 11.
Optical microscopic images of nasal mucosa. (A) Positive control – isopropyl alcohol, (B) negative control – PBS – pH 6.4 and (C) CH-ME treated mucosa.
See this image and copyright information in PMC

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