Compositions comprising cannabinoids

Details Compositions comprising cannabinoids Compositions comprising cannabinoids

2000-06-16

2002-05-07

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C424S455000, C424S488000, C424S489000

Reexamination Certificate

active

06383513

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical compositions for nasal delivery of cannabinoids and pharmaceutically acceptable salts and prodrugs thereof. The present invention also relates to the delivery of cannabinoids across the nasal mucosa of animals, especially humans, for the treatment of conditions such as pain, nausea and to stimulate appetite.
It is known that the active ingredients of cannabis, in the form of cannabinoids, can be useful in medical practice. The material delta-9-tetrahydrocannabinol (THC) is useful in the treatment of AIDS (J. Pain. Symptom Manage. 1995, 10, 89-97) when given orally. The drug is called Dronabinol and is formulated in sesame oil for oral delivery. The material is available commercially as the product Marinola® sold by Roxane in the USA.
Dronabinol (9-delta THC or THC) exhibits complex effects on the central nervous system (CNS), including central sympathomimetic activity. Dronabinol has been shown to have a marked appetite stimulant effect and has been used in the treatment of AIDS-related anorexia. Dronabinol also demonstrates effects on mood, cognition, memory and perception. Furthermore, the drug has anti-emetic properties and is used for the control of nausea and vomiting associated with cancer chemotherapy. These effects appear to be dose related. After oral administration, Dronabinol has an onset of action of approximately 0.5 to 1 hour and a peak effect at 2-4 hours. The duration of action for psychoactive effects is 4-6 hours, but the appetite stimulant effect may continue for 24 hours or longer after administration. Dronabinol is almost completely absorbed (90-95%) after single oral doses. However, due to a combined effect of first pass hepatic metabolism and high lipid solubility only 10-20% of the administered dose reaches the systemic circulation.
Studies on the use of THC in pain have been described in Pharm. J. 259, 104, 1997 and in Pharm. Sci. 3, 546, 1997. Nabilone, a synthetic cannabinoid has been reported to be an anti-emetic and anxiolytic, and also useful for treating pain of various etiologies such as multiple sclerosis (MS), peripheral neuropathy and spinal injuries (Lancet, 1995, 345, 579, Pharm. J. 259, 104, 1997). It is also known that inhaling cannabis by smoking can lead to a more rapid onset of action than oral ingestion.
A nasal formulation for the improved delivery of cannabinoids would be advantageous. Absorption of drugs from the nasal route tends to be rapid due to the large surface area available and the extensive blood supply. In addition, the drug is delivered directly to the systemic circulation and there is no loss due to “first pass” metabolism in the liver.
The nasal route is known to provide advantages for the delivery of drugs, and for some drugs the pharmacokinetic profile following nasal administration is similar to that found after intravenous administration. However, THC is in the form of an oily liquid which is highly lipid soluble and only sparingly soluble in water. Hence, the person skilled in the art would consider it impossible to produce a simple nasal solution or other simple gel or suspension formulation that could produce sufficient nasal absorption and therapeutic plasma levels.
The nasal administration of cannabinoids and their analogues has been described in U.S. Pat. No. 4,464,378. It was suggested that the drugs would be administered as simple nasal sprays, ointments, gels or suspensions, though no examples of formulations produced with THC were described. As explained above, the person skilled in the art would not expect such simple formulations of THC to be successful due to the low water solubility.
SUMMARY OF THE INVENTION
We have found surprisingly that cannabinoids and especially THC can be formulated successfully into a nasal product by using a biphasic delivery system and that such a biphasic delivery system provides improved nasal absorption and therapeutically relevant plasma levels. We have also found surprisingly that cannabinoids and especially THC can be delivered successfully via the nasal route by formulating into a microsphere system and particularly an albumin microsphere system.
According to a first aspect of the present invention there is provided a composition for the nasal delivery of a cannabinoid comprising a cannabinoid in a biphasic delivery system.
According to a second aspect of the present invention there is provided a composition for the nasal delivery of a cannabinoid comprising a cannabinoid in a microsphere delivery system.
By the term “cannabinoid” we include, inter alia, delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol, cannabidol, olivetol, cannabinol, cannabigerol, nabilone, delta-9-tetrahydro cannabinotic acid. The non-psychotropic cannabinoid 3-dimethylnepty 11 carboxylic acid homologine 8, delta-8-tetrahydrocannabinol, (J. Med. Chem. 35, 3135, 1992) as well as the prodrugs and pharmaceutically acceptable salts of cannabinoids are also suitable for the present invention and are included in the term “cannabinoid”. A suitable prodrug is THC-hemisuccinate.
By a “biphasic delivery system” we are referring to a pharmaceutical composition comprising two phases of which one phase contains the dissolved, dispersed, solubilised or dissoluted drug and the other phase provides the carrier for the composition, for example the outer (surrounding) water phase in an emulsion system or the matrix of a microcapsule or microsphere system.
By “improved nasal absorption” we mean more than 10%, preferably more than 20% and most preferably more than 30% bioavailability of the drug after nasal administration. By the term bioavailability, we mean the absorption of the drug as measured by the area under the plasma level versus time profile following nasal administration as compared to the same parameter when the drug is given by intravenous injection; the values for the area being corrected for the dose of the drug if necessary.
DETAILED DESCRIPTION OF THE INVENTION
Biphasic delivery systems may be in the form of emulsion systems, such as an oil-in-water (O/W) emulsion, aqueous systems containing a solubilising or dispersing agent or microsphere systems where the phase containing the drug can be encapsulated by or dispersed on the surface of the microspheres.
An oil-in-water emulsion can be prepared using a combination of a pharmaceutically acceptable oil and emulsifier. The drug is dissolved in the oil phase which is then mixed with an aqueous phase typically containing a stabiliser under vigorous mixing, milling or homogenisation. Such emulsification methods are well described by Idson, Pharmaceutical Emulsions, Ch. 6, Pharmaceutical Dosage Forms, Disperse Systems. Vol. 1. Ed. Lieberman et al. Dekker, New York, 1988.
Preferred oils are vegetable oils such as soybean oil, olive oil, cotton seed oil, peanut oil, sesame oil and castor oil, with sesame oil and castor oil being preferred.
Vitamin E (tocopherol) can also be used as the oil phase. This material is also an antioxidant and can help to stabilise the chosen cannabinoid which tend to be prone to oxidation.
By the term Vitamin E (tocopherol) we include the &agr;-, &bgr;-, &ggr;- and &dgr;-forms of tocopherol that differ by the number and position of methyl groups on the chromanol ring as well as the various isomers of these compounds. Pharmaceutically acceptable derivatives of tocopherol are also included, such as the esters of tocopherol, e.g. the linoleate, nicotinate, acetate or acid succinate ester.
The United States Pharmacopoeia describes Vitamin E as a form of &agr;-tocopherol. This includes d- or d, 1-&agr;-tocopherol, d- or d, 1-&agr;-tocopherol acetate and d- or d, 1-&agr;-tocopherol succinate. The term Vitamin E is also used as a generic description for all tocopherol and tocotrienol derivatives that exhibit Vitamin E activity. Thus, the term tocopherols is synonymous with Vitamin E, but also for methyl tocols.
A preferred Vitamin E composition for use in the emulsions of the present invention is &agr;-tocopherol as described in the United States Pharmacopoeia,

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