Brain Targeted Transcranial Administration of Diazepam and Shortening of Sleep Latency in Healthy Human Volunteers

Application of medicated oils on scalp had been practiced for centuries in the Ayurvedic system of medicine in diseases associated with the central nervous system. It is possible that the effectiveness of the therapy may be a result of targeted delivery of active compounds to the brain transcranially. Evidence also comes from two previous studies with positive results on brain targeted transcranial delivery of methadone base and diazepam on rat models. Possibility of transcranial drug delivery was investigated in healthy human volunteers using electroencephalography techniques by assessing the ability of transcranially administered diazepam in bringing about β activity in the electroencephalographic wave patterns and shortening of the sleep latency period. Non polar drug molecules dissolved in a non-aqueous sesame oil based vehicle is a significant feature in the transcranial dosage design. The study was under taken in two phases. In the Phase-I study scalp application of a single dose of 2 mg/3 ml of the oil was employed and in the Phase-II study repeat application of three doses 24 h apart were employed. Sleep latency changes were monitored with Multiple Sleep Latency Tests with 5 naps employing the standard electroencephalography, electroocculography and electromyography electrodes. Sleep onset was identified with the first epoch of any sleep stage non rapid eye movement 1, 2, 3, 4 or rapid eye movement using electroencephalography, electroocculography and electromyography criteria. In both phases of the study there was significant reduction in the sleep latencies. It was much more pronounced in the Phase-II study. None of the subjects however displayed beta activity in the electroencephalography. Sleep latency reduction following scalp application in both the phases are suggestive of transcranial migration of diazepam molecules to the receptor sites of the nerve tissue of the brain eliciting its pharmacological effect of sedation. Transcranial brain targeted dosage design is therefore feasible.