Abstract
Objective Acute decompensated heart failure is often treated with a
combination of loop and thiazide-like diuretics. Of these thiazide-like
diuretics, two common choices are intravenous chlorothiazide or oral metolazone.
Metolazone is more potent and has a longer duration of action, but since it is
an oral formulation, it has a longer on-set time as compared to chlorothiazide.
In addition, metolazone is poorly water-soluble, thereby rendering intravenous
formulation more challenging. To address these issues, we proposed the
formulation of a solvent-free metolazone emulsion for intravenous
administration.
Methods An oil-in-water emulsion containing 1 mg/mL of
metolazone was formulated by homogenizing soybean oil and l-lecithin in
water in the presence of optimized concentrations of glycerin with tween 80 or
poloxamer 188 as surfactant. The emulsion was characterized on the basis of
particle size, zeta potential, morphology and metolazone release kinetics. The
diuretic effect of the metolazone emulsion was evaluated in rats.
Results The 1 mg/mL metolazone emulsion prepared with
5% tween 80 displayed the best physical stability. The emulsion
exhibited a hydrodynamic diameter of 157.13±1.52 nm. About
93% of metolazone was released from the formulation within 2 h.
The 2 mg/kg and 4 mg/kg dose of the metolazone
emulsion increased urine output in the rats by 68.9 and 134%,
respectively, as compared to control rats. Furthermore, the
4 mg/kg dose exhibited a 168.8%, 25.8%, and
150.9% increase in sodium, potassium, and chloride, respectively.
Conclusion This metolazone emulsion was capable of increasing urine volume
output and demonstrated both natriuretic and kaliuretic properties.
Key words
Metolazone - emulsion - intravenous - acute decompensated heart failure - diuretic
