Penetration enhancer-containing spanlastics (PECSs) for transdermal delivery of haloperidol: in vitro characterization, ex vivo permeation and in vivo biodistribution studies

Abstract

Haloperidol (Hal) is one of the widely used antipsychotic drugs. When orally administered, it suffers from low bioavailability due to hepatic first pass metabolism. This study aimed at developing Hal-loaded penetration enhancer-containing spanlastics (PECSs) to increase transdermal permeation of Hal with sustained release. PECSs were successfully prepared using ethanol injection method showing reasonable values of percentage entrapment efficiency, particle size, polydispersity index and zeta potential. The statistical analysis of the ex vivo permeation parameters led to the choice of F1L - made of Span^® 60 and Tween^® 80 at the weight ratio of 4:1 along with 1% w/v Labrasol^® - as the selected formula (SF). SF was formulated into a hydrogel by using 2.5% w/v of HPMC K4M. The hydrogel exhibited good in vitro characteristics. Also, it retained its physical and chemical stability for one month in the refrigerator. The radiolabeling of SF showed a maximum yield by mixing of 100 µl of diluted formula with 50 µl saline having 200 MBq of ^99mTc and containing 13.6 mg of reducing agent (NaBH₄) and volume completed to 300 µl by saline at pH 10 for 10 min as reaction time. The biodistribution study showed that the transdermal ^99mTc-SF hydrogel exhibited a more sustained release pattern and longer circulation duration with pulsatile behavior in the blood and higher brain levels than the oral ^99mTc-SF dispersion. So, transdermal hydrogel of SF may be considered a promising sustained release formula for Hal maintenance therapy with reduced dose size and less frequent administration than oral formula.

Keywords: Haloperidol; Penetration enhancer-containing spanlastics; biodistribution; technetium-99m; transdermal ex vivo permeation.

Figure 1.

(a) and (b): Permeation plots of Hal from different spanlastics and penetration enhancer containing spanlastics compared to drug solution and (c)Transmission electron microscope image of selected formula.

Figure 2.

(a) Release profiles of Hal from SF, SF-hydrogel and Hal solution, (b) SF-hydrogel rheological characterization and (c) Effect of storage on Hal release of from SF-hydrogel.

Figure 3.

Effect of different variables (a) amount of dil-SF, (b) amount of reducing agent (NaBH4), (c) pH and (d) reaction time – on percent radioactive yield of ^99mTc-SF.

Figure 4.

Percentage radioactivity (%R/g) in different body organs and blood at different time points after transdermal application of ^99mTc-SF-hydrogel or oral administration of ^99mTc-SF.

Figure 5.

Brain/blood ratio of radioactive complex after transdermal application of ^99mTc-SF-hydrogel or oral administration of ^99mTc-SF.