BACKGROUND

Propofol (2,6-diisopropylphenol) is a low molecular weight phenol derivative that is widely used as a hypnotic or sedative agent for intravenous administration in the induction and maintenance of anesthesia or sedation in humans and animals. Among its useful characteristics as an anesthetic drug are administration via the intravenous route, rapid onset and offset of anesthesia, rapid clearance, and a side-effect profile that makes it preferable to other injectable anesthetics, such as barbiturates. Additional clinical uses for propofol, including, but not limited to, treatment of migraine, nausea, pain and anxiety, have been proposed (Vasileiou, 2009).

In addition to its sedative and anesthetic effects, propofol has a range of other biological and medical applications. For example, it has been reported to be an anti-emetic, McCollum J S C et al., Anesthesia 43 (1988) 239, an anti-epileptic, Chilvers C R, Laurie P S, Anesthesia 45 (1990) 995, and an anti-pruritic, Borgeat et al., Anesthesiology 76 (1992) 510. See also, Vasileiou, 2009 (proposing additional clinical uses for propofol, including, but not limited to, treatment of migraine, nausea, pain and anxiety).

Anti-emetic and anti-pruritic effects are typically observed at subhypnotic doses, i.e., at doses that achieve propofol plasma concentrations lower than those required for sedation or anesthesia. Antiepileptic activity, on the other hand, is observed over a wider range of plasma concentrations. Borgeat et al., Anesthesiology 80 (1994) 642. Short-term intravenous administration of subanesthetic doses of propofol also has been reported to be remarkably effective in the treatment of intractable migraine and nonmigrainous headache. Krusz J C, et al., Headache, 40 (2000) 224-230. It has further been speculated that propofol may be useful as an anxiolytic, Kurt et al., Pol. J. Pharmacol. 55 (2003) 973-7, neuroprotectant, Velly et al., Anesthesiology 99 (2003) 368-75, muscle relaxant, O'Shea et al., J. Neurosci. 24 (2004) 2322-7, and, due to its antioxidant properties in biological systems, may further be useful in the treatment of inflammatory conditions, especially inflammatory conditions with a respiratory component, and in the treatment of neuronal damage related to neurodegeneration or trauma. Such conditions are believed to be associated with the generation of reactive oxygen species and therefore amenable to treatment with antioxidants. See, e.g., U.S. Pat. No. 6,254,853 to Hendler et al.

Propofol typically is formulated for clinical use as a oil-in-water emulsion. The formulation has a limited shelf-life and has been shown to be sensitive to bacterial or fungal contamination, which has led to instances of postsurgical infections. Bennett S N et al., N Engl J Med 333 (1995) 147. Due to the dense, white color of the formulation, bacterial or fungal contamination cannot be detected by visual inspection of the vial in the first instance.

Not only is propofol poorly water soluble, but it also causes pain at the injection site, which must often be alleviated by using a local anesthetic. Dolin S J, Drugs and pharmacology. In: N. Padfield, Ed., Total Intravenous Anaesthesia. Butterworth Heinemann, Oxford 2000. Due to its formulation in a lipid emulsion, its intravenous administration also is associated with undesirable hypertriglyceridemia in patients, especially in patients receiving prolonged infusions. Fulton B and Sorkin E M, Drugs 50 (1995) 636. Its formulation as a lipid emulsion further makes it difficult to co-administer other IV drugs. Any physical changes to the formulation, such as a change in lipid droplet size, can lead to changes in the pharmacological properties of the drug and cause side effects, such as lung embolisms.

It has further been reported that the use of propofol in anesthesia induction is associated with a significant incidence of apnea, which appears to be dependent on dose, rate of injection, and premedication. Reyes, J G, Glass, P S A, Lubarsky D A, Nonbarbiturate intravenous anesthetics. In: R. D. Miller et al., Eds, Anesthesia. 5.sup.th Ed. Churchill Livingstone, Pa., 2000. Respiratory consequences of administering anesthetic induction doses of propofol, including a reduction in tidal volume and apnea, occur in up to 83% of patients. Bryson et al., Drugs 50 (1995) at 520. Induction doses of propofol also are known to have a marked hypotensive effect, which is dose- and plasma concentration-dependent [Reyes et al., supra]. The hypotension associated with peak plasma levels after rapid bolus injection of propofol sometimes requires the use of controlled infusion pumps or the breaking-up of the induction bolus dose into several smaller incremental doses. Further, the short duration of unconsciousness caused by bolus induction doses renders propofol suitable for only brief medical procedures. For all the above reasons, propofol for induction and/or maintenance of anesthesia must normally be administered in an in-patient setting under the supervision of an anesthesiologist, and is often considered inappropriate for use by non-anesthesiologists in an ambulatory or day case setting.

In addition to its use in induction and maintenance of anesthesia, propofol has been used successfully as a sedative to accompany either local or regional anesthesia in conscious patients. Its sedative properties also have been exploited in diagnostic procedures that have an unsettling effect on conscious patients, such as colonoscopy or imaging procedures. Propofol also has been used as a sedative in children undergoing diagnostic imaging procedures or radiotherapy. A recent development is that of patient-controlled sedation with propofol. This technique is preferred by patients and is as effective as anesthesiologist-administered sedation.

Compared with the widely used sedative midazolam or other such agents, propofol provided similar or better sedative effects when the quality of sedation and/or the amount of time that patients were at adequate levels of sedation were measured. See Fulton B and Sorkin E M, Drugs 50 (1995) 636. The faster recovery and similar or less amnesia associated with propofol makes it an attractive alternative to other sedatives, particularly for patients requiring only short sedation. However, because of the potential for hyperlipidemia associated with the current propofol formulation, and the development of tolerance to its sedative effects, the usefulness of propofol for patients requiring longer sedation is less well established.

Due to its very low oral bioavailability, propofol in its commercially available formulations is generally recognized as not suitable for other than parenteral administration, and must generally be injected or infused intravenously. While propofol is administered intravenously in a clinical setting, it has been suggested that it could be delivered for certain indications via other non-oral routes, such as via inhalation using a nebulizer, transmucosally through the epithelia of the upper alimentary tract, or rectally in the form of a suppository. See, e.g. Cozanitis, D. A., et al., Acta Anaesthesiol. Scand. 35 (1991) 575-7; see also U.S. Pat. Nos. 5,496,537 and 5,288,597]. However, the poor bioavailability of propofol when administered by any other than the intravenous route has hampered the development of such treatments.

SUMMARY

In some aspects, the presently disclosed subject matter provides a method for buccally, sublingually, or intranasally administering a prodrug of propofol, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment thereof in an amount sufficient to deliver a therapeutically effective amount of propofol to the subject.

In other aspects, the prodrug of propofol is a compound of Formula (I):



wherein each Z is independently selected from the group consisting of hydrogen, an alkali metal, and an amine. In particular aspects, the alkali metal is sodium.

In yet more particular aspects, the prodrug of propofol is administered intranasally in a form selected from the group consisting of a nasal spray, a nasal drop, a powder, a granule, a cachet, a tablet, an aerosol, a paste, a cream, a gel, an ointment, a salve, a foam, a paste, a lotion, a cream, an oil suspension, an emulsion, a solution, a patch, and a stick. In other aspects, the prodrug of propofol is administered sublingually in a form selected from the group consisting of a tablet, a capsule, a lozenge, a sublingual spray, a mouth wash, a solution, a suspension, an emulsion, a powder, a granule, a thin film, a gel, and the like. In yet other aspects, the prodrug of propofol is administered buccally in a form selected from the group consisting of a tablet, a capsule, a lozenge, a buccal spray, a mouth wash, a solution, a suspension, an emulsion, a powder, a granule, a thin film, a gel, and the like.

In certain aspects, the subject is afflicted with a condition selected from the group consisting of a migraine, nausea, emesis, pain, analgesia, pruritis, epilepsy, headache, and anxiety. In particular aspects, the headache is a cluster headache.

In other aspects, the presently disclosed subject matter provides a pharmaceutical composition for buccally, sublingually, or intranasally administering a prodrug of propofol, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment thereof in an amount sufficient to deliver a therapeutically effective amount of propofol to the subject.

Certain aspects of the presently disclosed subject matter having been stated hereinabove, which are addressed in whole or in part by the presently disclosed subject matter, other aspects will become evident as the description proceeds when taken in connection with the accompanying Examples and Figures as best described herein below.

