Development of Propofol Hemisuccinate for the Treatment of Epilepsy

Epilepsy is a brain disorder that causes repeated seizures over time. The seizures can be disabling and, due to loss of muscle control, pose the risk of injuries from falling. An estimated 2 million Americans have epilepsy. A migraine is a common type of severe headache that causes nausea, vomiting and sensitivity to light. Migraines can run in families, and they affect women more often than men. Some migraines and epilepsy are not responsive to treatments. The drug propofol, used during surgery and medical procedures to sedate patients or put them to sleep, could be effective in treating or preventing migraines and seizures. The investigators are developing an inhaler device for patients whose conditions have not responded to routine therapy. Patients can use the inhaler to breathe in propofol just before or during a migraine or seizure.

Scientific Synopsis

The investigators are developing an inhaler system to treat intractable epilepsy and migraine. The system has two uses in epilepsy. In the first epilepsy application, the system is used by a patient experiencing a seizure aura to prevent a full-blown (motor) seizure. In the second epilepsy application, the system is used by a caregiver or by a bystander to treat a patient with epilepsy who is experiencing status epilepticus or seizure clusters in an out-of-hospital setting. The system also may be used to treat migraine: a patient experiencing a migraine aura or early migraine attack uses the system to abort the migraine symptoms and prevent the development of a full-blown headache.

The system administers a proprietary water-soluble prodrug form of propofol by nebulization into the deep lung. The investigators have conducted extensive proof-of-principle studies demonstrating that intrapulmonary propofol hemisuccinate (PHS) effectively protects against seizures in animal models. The team also has acquired preliminary data in an animal model of cortical spreading depression, supporting the use of PHS in the treatment of migraine. Finally, they have shown that intrapulmonary PHS does not cause pulmonary damage or inflammation.

The investigators plan to conduct human safety and efficacy studies of nebulized PHS in normal volunteers and in persons with epilepsy who experience seizure auras prior to a full-blown motor seizure. In these early clinical trials, PHS solution will be administered with an off-the-shelf nebulizer system. At a later stage in this project, the researchers anticipate developing a custom-designed, miniaturized, portable electronic nebulizer system that can be carried easily by patients. Following the development of the portable delivery system, the team may conduct studies in the treatment of status epilepticus seizure clusters or migraine.

Lead Collaborator

Regents of the University of California, Oakland
, California
Michael Rogawski, M.D.

Public Health Impact

Epilepsy and migraine are neurological disorders whose therapeutic approach is commonly preventive. Treatment of acute attacks is difficult and frequently dependent on assistance by a health care professional. The proposed research seeks to develop a portable drug inhaler that can be used to stop a developing seizure or a migraine headache.


BrIDGs scientists developed and validated analytical methods for the drug substance, synthesized GMP propofol hemmisuccinte, developed a suitable formulation for dosing, and conducted pharmacology and toxicology studies. Preclinical data did not warrant filing an Investigational New Drug (IND) application, since efficacy data could not be reproduced with the non-GMP drug product. The project was closed and BrIDGs support was concluded.

Project Details

  • Manufacture of Good Manufacturing Practice (GMP) active pharmaceutical ingredient
  • Formulation development
  • Pharmacokinetic studies
  • Manufacture of drug product
  • Dose range finding toxicology