Quality by Design and Characterization of Nimodipine Novel Carriers for the Treatment of Hypertension: Assessment of the Pharmacokinetic Profile
Authors: Chettupalli Ananda , Amarachinta Padmanabha Rao , Kuchukuntla Mounika Reddy , Katta Sunand , Vobenaboina Vijay Kumar , Garige Baba Shanker Rao , Renukuntla Pranay , Samein Laith 
Published: February 2024

Background:

Nimodipine is a highly lipophilic anti-hypertensive drug having 13%
oral bioavailability (log P 3.41). Nimodipine is a prominent calcium channel blocker that must be
given intravenously for an extended period of time (1-2 weeks) in order to treat cerebral vasospasm.
It might be possible to substitute a sustained-release biodegradable formulation for the
ongoing intravenous infusion used in this traditional therapy.

Objectives:

The primary goal of this study was to formulate and evaluate the potentiality of ethosomes
to deliver nimodipine, a potent water-insoluble anti-hypertensive drug, through the deeper layers of the
skin. The greatest challenge for drug formulation is its poor oral bioavailability and solubility.

Methods:

Nimodipine-loaded ethosomal gel was developed for transdermal drug delivery to increase
solubility and skin penetration and to promote oral bioavailability. Central composite design
employing a thin-film hydration method was used to prepare and optimize ethosomes. A better
dispersion medium for nimodipine's preparation in ethosomes was selected based on the effect. The
design consisted of independent variables as lipid (X1), ethanol (X2), and sonication time (X3).
Concentrations were manipulated to examine the effects on three responses, namely the %entrapment
efficiency (Y1), vesicle size (Y2), and %cumulative drug release (Y3). Surface morphology
and other in vitro tests were used to identify ethosomes containing nimodipine. The preparation of
ethosomal gel formulations began with incorporating a single ethosomal formulation (F4) into various
concentrations of gelling agents. These studies performed physicochemical characterization,
compatibility testing, and in vitro drug release tests on ethosomal gels. In vivo studies involving hypertensive
rats were conducted after skin permeation, and ex vivo studies were performed. In order
to assess the drug's permeability and deposition, we employed the abdomen skin of rats.

Results:

The optimal process parameters resulted in ethosomes with 89.9 ± 0.19 percent entrapment
efficiency, a vesicle size of 102.37 ± 5.84 nm, and a cumulative drug release of 98.3 ±
0.13%. pH and drug content measurements were consistent with the homogeneous ethosomal
gels. Viscosity was found to increase with the spreadability. The ethosomal gel formulation (G2)
met the regulatory standards regarding appearance, spreadability, viscosity, and in vitro release
studies. Compared to pure nimodipine, ethosomal suspension (F4) and ethosomal gel (G2) formulations
had higher ex vivo permeation, steady-state flux, and drug retention. Rats' mean arterial
pressure (146.11 ± 0.84 mmHg) was significantly lower (p < 0.01) after after two hours of the
experiment than it had been (p < 0.001) (98.88 ± 0.63 mmHg) after six hours.

Conclusion:

To summarize, ethosomal gels have been found to be lipid carriers that enhance skin
permeation and extend the anti-hypertensive effect of nimodipine. Compared to plain gel, ex vivo
drug permeation through rat abdominal skin in ethosomal gel was enhanced. Gel-based ethosomal
transdermal drug delivery formulations of nimodipine can be used to achieve a faster rate and
extend the duration of drug delivery by more than 24 hours.