Cataleptogenic Effect of Haloperidol Formulated in Water-Soluble Calixarene-Based Nanoparticles

Abstract

In this study, a water-soluble form of haloperidol was obtained by coaggregation with calix[4]resorcinol bearing viologen groups on the upper rim and decyl chains on the lower rim to form vesicular nanoparticles. The formation of nanoparticles is achieved by the spontaneous loading of haloperidol into the hydrophobic domains of aggregates based on this macrocycle. The mucoadhesive and thermosensitive properties of calix[4]resorcinol-haloperidol nanoparticles were established by UV-, fluorescence and CD spectroscopy data. Pharmacological studies have revealed low in vivo toxicity of pure calix[4]resorcinol (LD₅₀ is 540 ± 75 mg/kg for mice and 510 ± 63 mg/kg for rats) and the absence of its effect on the motor activity and psycho-emotional state of mice, which opens up a possibility for its use in the design of effective drug delivery systems. Haloperidol formulated with calix[4]resorcinol exhibits a cataleptogenic effect in rats both when administered intranasally and intraperitoneally. The effect of the intranasal administration of haloperidol with macrocycle in the first 120 min is comparable to the effect of commercial haloperidol, but the duration of catalepsy was shorter by 2.9 and 2.3 times (p < 0.05) at 180 and 240 min, respectively, than that of the control. There was a statistically significant reduction in the cataleptogenic activity at 10 and 30 min after the intraperitoneal injection of haloperidol with calix[4]resorcinol, then there was an increase in the activity by 1.8 times (p < 0.05) at 60 min, and after 120, 180 and 240 min the effect of this haloperidol formulation was at the level of the control sample.

Keywords: TEM; calixarene; catalepsy; haloperidol; mucoadhesion; nanoparticles; open field; self-assembly; toxicity in vivo.

Figure 1

Molecular structures of calix[4]resorcinol VC10 (a) and Hal (b).

Figure 2

UV-Vis absorption spectra of 0.15 mM VC10, 0.15 mM VC10–0.15 mM Hal in H₂O, and 0.15 mM Hal in EtOH.

Figure 3

¹H-NMR spectra of 2 mM VC10 and the binary 2 mM VC10–2 mM Hal system in D₂O.

Figure 4

Particle size distribution by number in aqueous solutions of VC10–Hal (1:1) at different concentrations.

Figure 5

Transmission electron micrographs of VC10–Hal (a) and the histogram showing the average particle size obtained from the TEM images using ImageJ software (b).

Figure 6

Turbidimetric titration of 1 mg/mL PGM with 1 mg/mL solution of VC10–Hal (1:1).

Figure 7

UV circular dichroism spectra of the PGM, PGM–VC10 (a) and PGM–[VC10–Hal] (b) systems in aqueous solution. The concentration of PGM was constant (1 mg/mL) [VC10–Hal] = 1:1.

Figure 8

Duration of catalepsy after intranasal administration (s). * p < 0.05—Statistically significant difference compared to the haloperidol group. # 0.05 < p < 0.1—Significance trend compared to haloperidol group.

Figure 9

Duration of catalepsy after intraperitoneal administration (s). * p < 0.05—Statistically significant difference compared to the haloperidol group. # 0.05 < p < 0.1—Significance trend compared to haloperidol group.