Bioavailability and tolerability of intranasal diazepam in healthy adult volunteers.

Intranasal therapy has been proposed as an alternative for the management of seizure emergencies. The bioavailability, dose proportionality and tolerability of a supersaturated intranasal formulation of diazepam (DZP) solubilized in a glycofurol-water cosolvent system was investigated. Eight healthy volunteers were randomized into a single-blind, three-way crossover study to compare 5 and 10mg intranasal DZP doses of the investigational formulation with a 5mg dose of a DZP solution (DZP injectable, 5mg/mL) administered intravenously. Treatments were separated by a two-week washout period. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 48h post-dose and assayed by HPLC. Visual analog scales (VAS) were used to assess tolerability (1-tolerable; 10-extremely intolerable) and pain (1-no pain; 4-extreme pain) at predefined time points. Following the 5 and 10mg doses, the median t(max) were 20 and 30min and the mean C(max) were 134.3+/-62 and 247.6+/-61ng/mL. Estimated bioavailability was 75% for both doses. Pain scores of 2 and 2.3 were observed following the 5 and 10mg doses; tolerability scores were 4.4 and 4.7. Pain and tolerability scores returned to baseline within 10h. Our formulation provided reasonable bioavailability, but was not well tolerated.

Administration of Carbatrol to children with feeding tubes.

An extended-release formulation of carbamazepine (Carbatrol) might be suited for administration through feeding tubes because the capsules can be pulled apart to release the small granules. However, after encouraging several parents to use the new formulation, we were informed that the drug occluded some tubes. The purpose of this study was to determine if a protocol could be developed to administer Carbatrol without occlusion of the tubes. We administered the granules through feeding tubes to six children. Ten milliliters of water was used to flush the tube before administration. One capsule of Carbatrol was added to the 15 mL of liquid followed by an additional 10 mL water flush. For four children, 152 of 154 doses were administered without difficulty; however, two children were withdrawn from the study because of frequent tube occlusions. No adverse experiences occurred other than tube occlusion. The two children with frequent tube occlusions had long-standing problems with constipation or rigidity, which may have increased intra-abdominal pressure and slowed the rate of administration. We conclude that the use of Carbatrol granules for children with feeding tubes can be useful. However, some children are prone to frequent occlusion.