Direct and enhanced delivery of nanoliposomes of anti schizophrenic agent to the brain through nasal route

Abstract

The problem of inadequate oral bioavailability of Quetiapine Fumarate, a lipophilic drug used for schizophrenia, due to hepatic metabolism and repulsion by brain barrier was attempted in this study. Combination of two approaches, viz. Quetiapine inclusion into the liposomal carrier for better diffusion and administration through nasal route to avoid hepatic metabolism and barrier elimination was applied. Thin film hydration followed by sonication method was employed in liposome preparation and the formulation was optimized using 3² full factorial design. The number of sonication cycles (X₁) of 2 min and 80% amplitude and molar ratio of constructional components such as cholesterol to egg phosphatidylcholine (X₂) as independent variables and a % of entrapment efficiency (Y₁) and cumulative in vitro drug release (Y₂) at 6 h as dependent variables was selected. Batch F7 prepared by 2 cycles of sonication and 1:3 M ratio of cholesterol:egg phosphatidylcholine was optimized as a consequence of substantial entrapment efficiency of 75.63 ± 3.77%, and 99.92 ± 1.88% drug release and 32.33 ± 1.53% drug diffusion, which was optimum among all other batches at 6 h. Diffusion study was done for all the batches of liposomal formulation by using sheep nasal mucosa and good amount with better diffusion rate was measured which proved liposomal dispersion a virtuous delivery system for brain drug delivery through nasal route. Results of in vivo, ciliotoxicity and gamma scintigraphy studies on mice supported the above inference.

Keywords: Blood brain barrier; Dispersion; Liposomes; Nasal route; Quetiapine Fumarate.

Figure 1

Analytical determination of QTF. A. Uv overlay absorption spectra of different dilutions of QTF; B. HPLC chromatogram of QTF.

Figure 2

FTIR of. A. QTF pure; B. Mixture of QTF with excipient; C. Cholesterol; D. EPC.

Figure 3

Microscopic images of liposomal formulation. A. Light microscope with magnification of 15 × 100; B. SEM (Scale: 1 cm = 100 nm); C. TEM (Scale: 1 cm = 100 nm).

Figure 4

Zetasizer graph of optimized batch F7. A. Average particle size and size distribution measurement; B. Zeta potential determination.

Figure 5

%Diffusion of liposomal dispersion (batches F1–F9) across sheep nasal mucosa with respect to time (n = 3).

Figure 6

%Entrapment efficiency of all the batches (F1–F9) (n = 3).

Figure 7

%Cumulative drug release of QTF with respect to time (n = 3).

Figure 8

Gamma scintigraphy results after nasal administration of. A. QTF liposome (Posterior (A) and anterior (a)); B. QTF solution in mice (Posterior (B) and anterior (b)).

Figure 9

Amount of QTF in brain homogenate (ng/ml) containing liposome and simple dispersion (n = 3).

Figure 10

Photomicrographs of sheep nasal mucosa. A. Control; B. Nasal mucosa after diffusion study of liposomal formulation of QTF; C. Nasal mucosa treated with IPA.