Enhancement of pharmacokinetic and pharmacological behavior of ocular dorzolamide after factorial optimization of self-assembled nanostructures

Abstract

Dorzolamide hydrochloride is frequently administered for the control of the intra-ocular pressure associated with glaucoma. The aim of this study is to develop and optimize self-assembled nanostructures of dorzolamide hydrochloride and L-α-Phosphatidylcholine to improve the pharmacokinetic parameters and extend the drug pharmacological action. Self-assembled nanostructures were prepared using a modified thin-film hydration technique. The formulae compositions were designed based on response surface statistical design. The prepared self-assembled nanostructures were characterized by testing their drug content, particle size, polydispersity index, zeta potential, partition coefficient, release half-life and extent. The optimized formulae having the highest drug content, zeta potential, partition coefficient, release half-life and extent with the lowest particle size and polydispersity index were subjected to further investigations including investigation of their physicochemical, morphological characteristics, in vivo pharmacokinetic and pharmacodynamic profiles. The optimized formulae were prepared at pH 8.7 (F5 and F6) and composed of L-α-Phosphatidylcholine and drug mixed in a ratio of 1:1 and 2:1 w/w, respectively. They showed significantly higher Cmax, [Formula: see text] and [Formula: see text] at the aqueous humor with extended control over the intra-ocular pressure, when compared to the marketed product; Trusopt®. The study introduced novel and promising self-assembled formulae able to permeate higher drug amount through the cornea and achieve sustained pharmacological effect at the site of action.

Fig 1

The electrostatic interactions between the drug and phosphatidylcholine at low (A), medium (B) and high (C) pH values.

Fig 2

Response surface plots for the effects of pH and P/D ratio on the drug content (A), particle size (B), polydispersity index (C), zeta potential (D), partition coefficient (E), release T_50% (F) and release extent (G) of Dorzolamide self-assembled nanostructures.

Fig 3

Release profiles of the drug from the formulae prepared at low (A), medium (B) and high (C) pH values.

Fig 4

In vitro characterization of the optimized formulae using DSC (A), X-ray diffraction (B) and TEM (C and D).

Fig 5

Pharmacokinetic and pharmacological behavior of the optimized formulae (A and C) and their correlation to the in vitro release profiles (B and D).