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A transmucosal Lorazepam spray for treatment of acute seizures: Summary

Lorazopem spray seizures

A transmucosal Lorazepam spray for treatment of acute seizures: Summary

The estimated annual incidence of prolonged epileptic seizures (status epilepticus) in the USA is about 150,000 cases and approximately 400,000 patients that suffer from repetitive seizures. These emergency conditions lead to 40,000 deaths in the USA every year. Control of status epilepticus and repetitive seizures usually requires hospitalization and emergency treatment by means of intravenous administration of anticonvulsant drugs. Any delay in effective treatment may lead to the possibility of increased mortality and morbidity.

The utilization of anticonvulsants for treatment of acute seizures by more convenient than parenteral or rectal routes of administration (buccal, nasal) is actively studied but to date no medications in such forms have been approved in North America. Since oral anticonvulsants (tablets, capsules, oral solutions) cannot provide fast onset of anti-seizure action, there is presently a large unmet need for a convenient, safe, and very rapid treatment of the seizure state; particularly in out-of-hospital settings.

The possibility of developing a very fast acting, rapid-onset formulation of an anticonvulsant which can be administered via a simple oral spray, will be highly accepted in the clinical epilepsy treatment community.

The rationale for earlier treatment of seizures is supported by evidence that the longer the seizures persist, the more difficult they are to stop and the higher the mortality.

A new Lorazepam oral transmucosal spray is proposed as a fast and effective treatment of acute seizures not only in the hospital but mainly in outpatient settings or in the home. This novel form of one of the most potent anticonvulsants may be a convenient alternative to injectable benzodiazepines to efficiently control epilepsy emergencies, particularly in out-of-hospital settings. The novel low volume spray can be used either by the patient himself or by any non-trained person even in the time of ongoing seizures.

We are developing a very fast acting dosage form of Lorazepam, based on the proprietary transmucosal delivery system which delivers the drug through the mucosa lining of the mouth directly into the blood stream. The fast absorption of Lorazepam into the blood stream escapes the gastrointestinal delay as well as the first pass metabolism in the liver and provides rapid and effective delivery of the medicine to the brain.

Since most epileptic seizures start in a community setting, a rapid, convenient and effective Lorazepam spray that can easily be administered by family members, caregivers, or paramedics is highly demanded. This oral spray could be used during a seizure, when a patient is clenching his/her mouth, since the spray can be applied directly to the gum or lip mucosa. Suggested doses for Lorazepam oral spray fall inside the approved dose limits for the injectable form of Lorazepam.

Highlights of proposed Lorazepam transmucosal spray

  • Formulation is based on approved pharmaceutical excipients only

  • Easy, convenient, non-invasive administration

  • Fast onset of action, comparable to injection

  • Suitable for self-administration

  • Can be administered in any setting

  • Easy and convenient control of delivered doses

  • Can be applied to mucosa of lips or gums even when teeth clenched in a seizure

  • May satisfies requirement of 505 (b)(2) regulatory pathway in the USA


Lorazepam oral spray is based on a proprietary patent pending technological approach. Our technology allowed for the incorporation of required amounts of active drug in minimal volume of the spray and while making transmucosal penetration and fast absorption possible.

Technological highlights

  • Based on a patent pending self-nanoemulsifying drug delivery system

  • The spray forms the drug loaded oil-in-water nanoemulsion upon contact with saliva

  • Extremely small droplets (about 50 nanometers) easily penetrate through the oral mucosa lining

  • Self-nanoemulsifying oral spray formulation eliminates drug precipitation after contact with saliva despite high drug loading

  • High drug loading – 0.5 mg of Lorazepam in a single actuation (50 microliters) allows easy and effective dose adjustment

  • Provides fast onset of action after intraoral administration

Lorazepam oral spray development is conducted in close collaboration with renowned epileptologist and neurophysiologist Dr. Peter Carlen, Toronto Western Research Institute (Toronto Western Hospital, University Health Network). The development has also been supported by Ontario Brain Institute grants.



transmucosal_Lorazepam spray_003

  • Melting point 166 -168oC

  • Practically insoluble in water

  • Sparingly soluble in chloroform, alcohol, propylene glycol, oils, diethyl ether

  • Highly soluble in polyethylene glycol, benzyl alcohol

  • Unstable in solutions in presence of water

Obstacles and challenges in formulation development

  • Due to extremely low water solubility the drug is completely precipitated from solutions in polar water miscible solvents after contact with saliva; showing delayed onset of anti-seizure activity when delivered intraorally

  • Low oil solubility impedes preparation of highly loaded emulsions

  • Most appropriate excipients are viscous and very difficult to spray

Formulation development progress

  • A proprietary combination of excipients and method of preparation allowed an increase in the solubility of Lorazepam by several times (patent pending)

  • The Lorazepam self-emulsifying composition forms a nanoemulsion with oil droplets smaller than 100 nm

  • A low viscosity formulation with good sprayability was developed

Example of Lorazepam oral spray nanoemulsion size distribution

 transmucosal_Lorazepam spray_005


Anti-seizures activity of Lorazepam in transmucosal self-nanoemulsifying compositions

Animal model: Murine timed intravenous PTZ model

  • Animals: CD-1 mice, weight 25-30 g

  • Seizure induction: rate controlled intravenous infusion of Pentamethylenetetrazole solution (timed PTZ iv model)

  • Seizure threshold evaluation (cumulative dose of PTZ)

  • Intraoral (transmucosal) delivery using a calibrated microliter syringe

  • Positive control – Lorazepam in a dose of 2.5 mg/kgadministered intraperitoneally 5 minutes before initiation of PTZ infusion

transmucosal_Lorazepam spray_001 transmucosal_Lorazepam spray_004

Preliminary results

  • Intraoral transmucosal Lorazepam in a self-nanoemulsifying drug delivery system (SNEDDS) can effectively protects against PTZ induced seizures contrary to similarly administered Lorazepam in injectable solution

  • SNEDDS loaded with Lorazepam, administered 3 or 5 minutes before start of PTZ infusion, showed anticonvulsant efficacy comparable with parenteral administration of Lorazepam injectable solution


 transmucosal_Lorazepam spray_002

The planned oral spray device is designed for precise delivery of small volumes (metered dose). It is available in a large array of closure sizes and has a wide selection of dispensing heads and adapters for oral applications.


  • Lorazepam transmucosal oral spray – a convenient and rapid acting anticonvulsant prototype that can be developed into a drug product for hospital and out-of-hospital settings

  • Since a large amount of Lorazepam preclinical and clinical data already exist human clinical trials in Canada can be initiated within 24 months.

  • Lorazepam oral spray development most likely will meet requirements of 505 (b)(2) regulatory pathway in the USA

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