Solubilization and stability of bumetanide in vehicles for intranasal administration, a pilot study.

The solubility of bumetanide in vehicles of various polarities, suitable for intranasal administration in acute situations, has been investigated. The solubility at 4 degrees C in glycofurol and polyethylene glycol 200 was high (167 and 143 mg/mL, respectively), decreasing exponentially with addition of phosphate buffer or coconut oil. Vehicles containing coconut oil and glycofurol did not seem to improve the solubility relative to mixtures between glycofurol and buffer. Adequate solubility (approximately 50 mg/mL) was achieved in vehicles containing about 80% cosolvent. The stability of bumetanide was studied at 5 degrees C and 57 degrees C. No degradation was observed at low temperature. At high temperature, bumetanide decomposes in nonaqueous vehicles with half-lifes ranging from 69 to 400 days, but sufficient stability may be obtained by adjustment of pH to 7.4. It may be concluded that it is possible to prepare a clinically relevant formulation for intranasal delivery of bumetanide.

Intranasal administration of different liquid formulations of bumetanide to rabbits.

The bioavailability of bumetanide in rabbits after intranasal administration of eight formulations intended for use in acute situations has been studied. The vehicles tested were combinations of phosphate buffer, pH 7.4, glycofurol 75. polyethylene glycol 200 and coconut oil. A mixture of 51% glycofurol in polyethylene glycol 200 was administered containing doses of 1 and 8 mg bumetanide respectively. For all other formulations the lower dose level only was studied. The tmax obtained ranged from 3 to 10 min. The vehicles resulting in the highest rate of absorption were 60% glycofurol in coconut oil and pure glycofurol. The observed bioavailability for the different formulations ranged from 16 to 37% for the time period 0-120 min. The bioavailability was also calculated omitting the initial peak seen after i.v. injection, which may be undesirable. Using this method bioavailabilities of 33-82, for the time interval 5-120 min was found. The study also demonstrated that the total amount of bumetanide absorbed increased proportionally to the dose administered. The rate of absorption of bumetanide from all formulations tested may be relevant for the treatment of acute oedematous states. The tmax obtained after intranasal administration was shorter than reported for other non-parenteral routes of administration.