Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

Abstract

Allopregnanolone, a positive modulator of GABAA receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED50, 5.6 mg/kg), picrotoxin (ED50, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a Tmax of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (Cmax, 16,000 ng/mg) whereas much lower levels (Cmax, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

“…Allopregnanolone’s predicted water solubility is very low (only 0.00136 mg/mL), but with sulfobutylether-β-cyclodextrin, the solubilizing agent in Zulresso, it was possible to obtain a concentrated solution (5 mg/mL) for intravenous perfusion [ 41 ]. An adaptation of this formulation for intranasal administration, an aqueous solution containing 0.9% NaCl and a large amount of sulfobutylether-β-cyclodextrin (40%), reached a drug concentration of 16 mg/mL, and has been shown to provide rapid seizure protection [ 14 ].…”

Allopregnanolone: An overview on its synthesis and effects

“…ALLO treatment in AD, the dosing and treatment regimen appears to be crucial 237,238,240 . By contrast, intranasal delivery of this neuroactive steroid has been proposed as an excellent therapeutic strategy against seizures 241 . In this context, it is important to highlight that neuroactive steroids represent an important target for the treatment of focal epileptic disorders 242 .…”

“…237,238,240 By contrast, intranasal delivery of this neuroactive steroid has been proposed as an excellent therapeutic strategy against seizures. 241 In this context, it is important to highlight that neuroactive steroids represent an important target for the treatment of focal epileptic disorders. 242 Indeed, alteration of ALLO synthesis modulate status epilepticus dynamics.…”

Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?

“…This behavior obtains efficacious therapeutic effects against acute repetitive seizures by nasal administration of benzodiazepines [ 70 ]. However, it has been evidenced that the nasally administered neuroactive steroid allopregnanolone is faster in producing the same central effects of nasally administered benzodiazepines, with the further advantage of not producing peripheral unwanted effects [ 71 ]. A nasal formulation for allopregnanolone was obtained by its dissolution in saline solution in the presence of SBE-β-CD, which, upon administration to mice, induced a direct nose-to-brain delivery of the drug, whose higher brain levels were detected in the olfactory bulbs.…”

“…A nasal formulation for allopregnanolone was obtained by its dissolution in saline solution in the presence of SBE-β-CD, which, upon administration to mice, induced a direct nose-to-brain delivery of the drug, whose higher brain levels were detected in the olfactory bulbs. Interestingly, the olfactory bulb axons project directly to regions of the brain involved with the seizure protection of antiepileptic drugs [ 71 ].…”