CA2341035A1 - Pulmonary delivery of liposomal-encapsulated cannabinoids - Google Patents

Abstract

A liposomal composition containing a cannabinoid or cannabimimetic agent and methods of systemic delivery by contacting pulmonary tissue of a mammal with the liposomal composition to achieve a prolonged psychoactive effect.

Description

PULMONARY DELIVERY OF LIPOS~-ENCAPSULATED C?INI~i7~rBINOIDS
FIELD OF THE INVENTION
The present invention is related to the field of liposome-encapsulation of hydrophilic and hydrophobic agents.
More specifically, the present invention relates to the field of liposome-encapsulate=d cannabinoids.
BACKGROUND OF THE INVENTION
Since ivs discovery over 12,000 years ago, cannabis is one of the most widely used drugs throughout the world. See, Adams, et al., 1996. Ada'ict:ion 91: 1585-1614. Although the cannabis plant contains more than 400 chemical compounds, the main constituents of cannabis responsible for the psychoactive properties are the 09- tetrahydrocannabinol (09-THC} and ee-t:etrahydroc:annabinol (~B-THC) . Although both O9-THC and De-THC are active compounds extracted from the plant, D9-THC composed o.f 90% of the active ingredient of the cannabis plant. Specific cannabinoid receptors (i.e., CB1 and CB2) have recently been identified and cloned and their distribution throughout the entire CNS and body has been mapped. See, Herkenham, et al., 1991. Brain Res. 547:267-274; Jansen, et al., 1992. Brain Res. 575: 93-102; Gerard, et al., 1991. Biochem. J. 279: 129-134. In addition, a cannabinoid antagonist with a high affinity for the cannabinoid receptor has also been characterised. See, Cook, et al., 1998.
J. Pharmacol. Exp. The.r. 285: 1150-1156. The establishment of a cannabinoid receptor, antagonist, and endogenous ligand SUBSTITUTE SHEET (RULE 26) with biosynthesis and degradation pathways suggests the presence of a distinct n.eurochemical system for cannabinoids.
Despite substantial advances in the knowledge of cannabinoid pharmacology, its beneficial therapeutic effects are mostly anecdotal, with a lack of quantitative scientific evidence. However, over the past several decades, many potential clinical applications for Dg-THC have been suggested. These include, but are not limited to, (i) the management of patients with glaucoma (see, Ungerleider, et al., 1985. Int. J. Addict. 20: 691-699); pain (see, Noyes, et al., 1974. Comp. Psychic try. 15: 531-535); seizure (see, Consroe, et al., 1975. ~TAMA 234: 306-307): appetite stimulation for HIV patients (see, Plasse, et al., 1991.
Pharmacol. Biochem. Behav. 90: 695-700); multiple sclerosis (see, Greenberg, et al.,. 1!394. Clin. Pharmacol. Ther. 55:
324-328); and anti-emetic <sffect for patients receiving, e.g., chemotherapy (see,. Ungerleider, et al., 1982. Cancer 50: 636-645). Similarly, however, quantitative results for these claims are lacking.
The lack of quantit:at:ive results is primarily due to the fact that cannabinoids (e. g., O9-THC and ~a-THC) are highly lipophilic compounds with no suitable route of administration apart from smoking the cannabis leaf or resin.
Unfortunately, a large number of unnecessary toxic chemicals present in the cannabis plant will also be absorbed into the circulation after smoking. Furthermore, the quality control is generally not available and the D9-THC, OB-THC, and 11-OH-THC content of the carnabis leaf are highly variable, thus making it difficult to predict the bioavailability of 09-THC, SUBS",CITUTE SHEET (RULE 26) WO 01/03668 PCT/CA00l00805 De-THC, and 7.1-OH-THC, following smoking of the crude cannabis leaf. Therefore, the evaluation of the pharmacodynamic effects (i.e., the correlation between plasma cannabinoid ~~oncentrations and observed clinical effects) has been extremely difficult. Although oral 49-THC (Dronabinol'~) has been available for many years, its absorption is slow and its bioavailability is poor (i.e., 3-6g of total dose), with unpredictable absorption and high hepatic first-pass clearance effect. See, Ohlsson, et al., 1980. Clin.
Pharmacol. Ther. 28: 409-416. Moreover, no detectable D9-THC
was found in the plasma following rectal application of several suppository formulations using carbowax, witepsol, sesame oil, cocoa butter', and Cetomacrogol. See, Perlin, et al., 1985. J. Pharm. Sci. 74: 171-174.
Therefore, at present, there remains an, as yet, unfulfilled need for the development of a drug delivery system for cannabinoids, including ~9-THC, Dg-THC, and 11-OH-THC, which can provide a~ rapid increase and sustained therapeutic plasma cannabinoid concentration to achieve and maintain a desired clinical effect.
SU1~1ARY OF TBE INVENTIOIvI
The invention features a liposomal composition containing a cannabinoid or cannabimimetic agent and methods of systemic delivery by contacting pulmonary tissue of a mammal with the liposomal composition to achieve a prolonged psychoactive effect. The compositions and methods of treatment involve the u:>e of unilamellar and multilamellar liposomes as a vehicle t:o provide systemic delivery of cannabinoids, for example, O9-tetrahydrocannabinol (D9-THC), SUBSTITUTE SHEET {RULE 26) OB-tetrahydrocannabinol, (~a-THC); and 11-hydroxy-tetrahydrocannabinol (11-OH-THC), via administration to the pulmonary system.
Liposomal composit.ic>ns contain a cannabinoid or cannabimimetic agent, and the composition is in a form that is suitable for pulmonary administration. The liposomes of the composition are .relatively uniform in size. For example, the range of size of liposomes in the composition is preferably within 25v, more preferably within 200, more preferably within 150, more preferably within 100, and most preferably within 5s of they mean size of the liposomes. For example, at least 85s (more preferably 90$, more preferably 95~, and most preferably 99-100x) of the liposomes in the composition are with a defined size range, e.g., between 300-400 nm in size. In another example, the liposomes are within 450-550 nm in size. In yet. another example, the size range of the liposomes is between 700-800 nm.
As utilized herein, t:he term cannabinoid is defined as a pharmacologically-active agent producing psychoactive effects which may either be derived directly from the flowering tops of the pistillate hemp plant (e. g., Cannabis sativa var.
indica) or is chemically-synthesized in the laboratory. See, Stedman, Medical Dictionary, pg. 111, Williams &
Wilkins,Baltimore, MD (1987). Cannabinoids synthesized by the hemp plant include, but are not limited to, cannabinol, cannabidiol, cannabinolic acid, cannabigerol, cannabicyclol, and several isomers of tet:rachydrocannabinol (THC). See, Goodman and Gilman, The Pharmacological Basis of Therapeutics, 6t'' Ed., pp. 560-563, MacMillan Publishing, New :30 York, NY (I983) .

SUBSTITiJTE SHEET (RULE 26) The cannabinoid to be delivered is selected from the group consisting of cannabinol, c:annabidiol, O9-tetrahydrocannabinol, d$-tetrahydrocannabinol, 11-hydroxy tetrahydrocannabinol, 11-hydroxy-~9-tetrahydrocannabinol, levonantradol, O11-tetrah,ydrocannabinol, tetrahydrocannabivarin, dronabinol, amandamide, and nabilone.
A cannabimimetic agent is a composition characterized as having at least 50g of the psychoactive effect of ~
tetrahydrocannabinol. fhe mimetic may differ from 08-tetrahydrocannabinol in structure, pattern of side group substitution, or both. The composition contains the active psychoactive ingredient, cannabinoid or a cannabimimetic agent, in an amount of between approximately O.Ola to 10$ by weight.
The composition may also contain a phospholipid, e.g., a phosphatidylcholine, a dipalmitoylphosphatidylcholine, a lysophosphatidylcholine, a phosphatidylserine, a phosphatidyl-ethanolam.ine, a phosphatidylglycerol, or a phosphatidylinositol. Cholesterol is also a component of the composition, and the approximate molar ratio of phospholipid to cholesterol is altered to achieve a desired pharmacokinetic effect. The rate of cannabinoid release from the composition is indii:ectly proportionate to the concentration of cholesterol in the composition, i.e., a higher percentage of cholesterol yields a composition with a slower pharmacokinetic: release profile compared to a composition with a lower percentage of cholesterol.
Increasing the amount oi= cholesterol in the composition results in production oi_ l:iposomes with a more rigid SUBSTITUTE SHEET (RULE 26) membrane. A more rigid membrane indicates a relatively more stable liposome. For e~;ample, the molar ratio of dipalmitoylphosphatyidy7_choline:cholesterol is 7:3, 6:4, or 9:1. Therefore, a composition formulated with an approximate molar ratio of dipalmitoylphosphatyidylcholine:cholesterol of 7:3 is systemically released over a longer period of time compared to formulations with a lower relative amount of cholesterol. The compositions contain at least 10$
cholesterol. To tailor the kinetics of drug release, the composition is formulated to contain at least 200, 250, 30~, 35~ or 40o cholesterol.. Preferably, the percentage of cholesterol in the composition does not exceed 45%. The composition contains l.iposomes, which are multilamellar, unilamellar, or a mixture of both multilamellar and unilamellar.
The invention also includes a method for delivery of a cannabinoid to the cer~t:ral nervous system of a mammal using the compositions descz:ibed above. Pulmonary tissue of a mammal is contacted with a liposomal composition containing a cannabinoid or cannabim:imetic agent. The compositions are administered orally, int ratracheally, intravenously, and by other standard clinical modes of administration. Mammals, e.g., humans, to be ti:e;sted include those who have been identified as suffering from or at risk of developing a disease or disorder seel~~cted from the group consisting of:
nausea, loss of appetite, glaucoma, seizure, multiple sclerosis, or pain.
Systemic delivery of t:he cannabinoid is multiphasic. By multiphasic is meant 1=he pharmacokinetic pattern of systemic absorption of a cannabinaid or active metabolite thereof has SUBS'CITUTE SHEET (RULE 26) WO 01!03668 PCTlCA00100805 at least two compartments. For example, a multiphasic delivery system resulta, in a fast pharmacokinetic compartment, mid-range pharmacokinetic compartment, and a sustained pharmacokinetic compartment. A first phase (or rapid compartment) is ~~haracterized by rapid systemic absorption of the cannabinaid or cannabinimimetic agent. The first phase ranges from 30 seconds to 30 minutes after pulmonary tissue is contacted with the cannabinoid composition. A second (or third) phase is characterized by sustained systemic absorption of the cannabinoid or cannabinimimetic agent. the second (or subsequent) phase ranges from 30 minutes to 2 days after pulmonary tissue is contacted with the canna.binoid or cannabinimimetic composition. For example, the method results in a sustained systemic concentration of a cannabinoid (e.g., as measured in plasma, or other tissue; such as brain) for 6 hours, 12 hours, 24 hours, and up to several days post-administration.
Thus, the invention provides a method of inducing a sustained psychoactive cannabinoid effect in the central nervous system of a mammal by contacting a pulmonary tissue of the mammal with a liposome-encapsulated cannabinoid or cannabimimetic agent.
The major advantage's of the present invention include:
(i) the rapid bioavailabil:ity and initial onset of the pharmacological effect of the cannabinoids from the immediate release of l.iposome-encapsulated cannabinoids (e. g., approximately 10-20 ~ of the total O9-THC dose); (ii) the continuous-release properties of the liposomes to provide a sustained pharmacological effect (e.g., approximately 80-90~
of the total. O9-THC dose); (iii) the non-invasiveness of the SUBSTITUTE SHEET (RULE 26) drug delivery method; (iv) a controlled purity of the administered cannabinoid;s; and (v) in comparison with the oral administration of c;snnabinoids, this system does not require a functioning bowel and is not be affected by hepatic first-pass elimination, which can significantly affect the bioavailability of cannabinoids.. Because of the non-invasive nature of this drug delivery system, it is particularly suitable for some patient populations, such as pediatric, elderly and ambulatory patients.
.LO The rate of drug release is regulated by altering: (i) the nature of the phospholipids utilized; (ii) the phospholipid:cholesterol ratio; (iii) the hydrophilic/lipophilic properties of the active ingredients;
and (iv) the method by which the liposomes are generated.
:L5 As illustrated by the disclosed pharmacokinetic and tissue distribution data, pulmonary administration of liposome-encapsulated ~:annabinoids i.s efficient, safe, and does not exhibit any s:igni.ficant adverse cardiopulmonary side effects. The effects of the cannabinoid formulation last 20 more than 24 hours fol:lowi.ng pulmonary administration of liposomal cannabinoid. Furthermore, the various experimental manipulations of the composition of the liposomes applied herein indicate that the plasma pharmacokinetic profile of cannabinoids can be tailored to provide a desired duration of 25 the drug's therapeutic effect.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a line graph which illustrates mean plasma ~G-THC concentration versus time profile.

SUBSTITUTE SHEET (RULE 26) WO 01103668 PCTlCA00/00805 FIG. 2 is a line graph which illustrates mean plasma ~~-THC concentration verses. time profiles for Composition 1.
FIG. 3 is a line graph which illustrates mean plasma 0~-THC concentration verses, time profiles for Composition 2.
FIG. 4 is a line graph whichillustrates mean plasma D9-THC concentration verses. time profiles for Composition 3.
FIG. 5 is a line graph which illustrates mean plasma ~'3-THC concentration verses time profiles for Composition 4.
FIG. 6 is a line graph which illustrates a comparison of the predicted plasma ~''-'THC concentration profiles various Composition trials (Compositions 1-1.6).
FIG. 7 .is a line graph which illustrates lung D9-THC
concentrations versus time profiles.
FIG. 8 :is a line graph which illustrates brain O9-THC
concentrations versus time profiles.
FIG. 9 :is a line graph which illustrates mean plasma 0~-THC concentration verses time profile.
FIG. 10 is a line graph which illustrates mean plasma 11-OH-THC concentration versus time profile.
;ZO DETAILED DESCRIPTION OF THE INVENTION
Liposomes are used as a vehicle to deliver cannabinoids (e. g., tetrachydrocannabinol) and other cannabimimetic agents to improve the pharmaco kinetic profiles of the cannabinoid and cannabimimetic agents. Liposomes are microscopic vesicles composed of one or more aqueous compartments alternating with phospholipid bilayers. The liposomes SUBS7.'1TUTE SHEET (RULE 26) described herein are formulated to provide a controlled, sustained release system. The rate of drug release by the liposome is primarily determined by its physicochemical properties. Liposomes are tailored by the modification of size, composition, and surface charge to provide the desired rate of drug delivery.
The primary advantages of the present invention include, but are not limited to: (i) the rapid onset of drug effect;
(ii) the slow release properties of the liposomes to provide a sustained drug effect: and (iii) the non-invasive method of drug delivery through th:e pulmonary system. The methods provide a systemic drug effect for humans.
The sustained release property of the liposomal product is regulated by the lipid and other excipient composition of the liposomal products. The methods described herein permit accurate and reproducible: prediction of the overall rate of drug release, based upon the specific composition of the liposome formulation. The rate of drug release is primarily dependent upon: (i) the nature of the specific phospholipids (e.g., hydrogenated (-H) or unhydrogenated (-G)); (ii) the phospholipid:cholestero7_ ratio (i.e., the higher the ratio, the faster the rate of i:elease); (iii) the hydrophilic/lipophilic properties of the active ingredients;
and (iv) the method uti~_ized in the production of the of liposomes.
I. Quantitation of Cannabinoids by Gas Chromatography-Mass Spectrometry Plasma cannabinoi.d concentrations were determined using a gas chromatography-mass spectrometry technique (GC-MS; see, to SUBSTITUTE SHEET (RULE 26) e.g., Wilkins, et al., '.995. J. Anal. Toxicol. 19: 483-491).
For O9-THC, a measured volume of plasma (approximately 0.4 -1.0 ml), with labelled-t1''--THC added as an internal standard, was deproteinized by the addition of 2-volumes of acetonitrile, and centrifuged at 2500 r.p.m. The majority of the acetonitrile was removed from the supernatant by a stream of nitrogen gas. The remaining aqueous layer was then extracted with 3-volume; o:f hexane:ethylacetate (9:1 v/v).
The organic layer was di:ied under a stream of nitrogen gas and derivatized with 50 ml of trifluoroacetic anhydride in 50 ml of chloroform for 30 minutes at 45°C. The sample was then analyzed by GC/MS (Finnigan Voyager) using Negative Ion Chemical Ionization (met:hane CI gas) in SIM mode (m/z 410 and m/z 413). The quantitat:ion was performed using a 5-point calibration curve .(i.e.,. blank plasma "spiked" with 0.1, 0.5, 5, 10, 100 ng/ml of O9-THC:). Three QC samples (i.e., blank plasma aliquots "spiked" with 0.5, 5 and 50 ng/ml of O9-THC) were analyzed with every batch of 45 samples. This assay method was also used to determine the plasma concentrations of other cannabinoids, including, but not limited to, De-tetrahydrocannabinol (de-THC), and 11-hydroxy-tetrahydrocannabinol (11.-OH-THC), using different internal standards.
II. Preparation of Liposomal Cannabinoids The lipids used for the preparation of liposomes to entrap cannabinoids primarily consisted of dipalymitoylphosphatidylcholine (DPPC) and cholesterol in a molar ratio of 9:1, 7:.3, or 6:4, however, other bilayer-forming lipids may also be utilized for the same purpose.

SUBS'CITUTE SHEET (RULE 26) WO 01/036b8 PCT/CA00/00805 The selected lipid~> were dissolved in a minimal volume of chloroform in a round-bottomed glass vessel, followed by the addition of a defined amount of cannabinoids (Sigma-Aldrich Canada, Ltd.; Oakville, ON, Canada). Chloroform was then evaporated under a stream of helium gas at 40°C, and the glass vessel was placed under vacuum overnight to remove any residual solvent. The clr:ied lipid-cannabinoid mixture was then hydrated at 51°C :in phosphate-buffered saline (0.15 M, pH 7.2) and kept at this: temperature with periodic vortexing for the next 30 minutes. The liposomes with entrapped cannabinoid were extruded a total of 10-times with an extruder (Lipex Biomolecules; Vancouver, BC) fitted with doubly-stacked polycarbonate filters of 400 nm or 1000 nm pore size, using a helium pressure of 100-200 lb/in2.
Liposomal vesicle size was determined with a Coulter N4SD
particle-size analyzer (see Table 1). Unlike other methods of liposome manufacture (which method yields a heterogeneous population of liposomes which vary widely in size), extrusion yields a population of liposomes that are relatively uniform in size. Uniformity of size allows more reproducible pharmacokinetics than other methods in the art.
The materials and procedures for liposome encapsulation are well-known. Many other liposome manufacturing techniques can be used to make the final liposomal product containing :25 the appropriate active ingredient, lipids, and other excipient composition. The pharmacologically-active cannabinoid :ingredients include, but are not limited to, THC, De-THC, and 11-OH--TIC. Lipid components include, but are not limited to, phospholipids and cholesterol. The :30 excipients include, but are not limited to, tocopherol, SUBSTITUTE SHEET (RULE 26) antioxidants, viscosity-inducing agents, and/or preservatives. For disclosure of preferred methodology for liposome preparation in the present invention, see, United States Patens No. 5,451,408, incorporated herein by reference in its entirety.
Table 1 CompositiCholesterol/O Cannabinoid Filter Particle on NumberPPC Molar Concentration Size size (nm) Ratio 1 0.11 O9-THC 0.3 400 nm 366 21 mg/mI

2 0.92 ~9-THC 0.3 400 nm 368 42 mg/ml 3 0.66 ~9-THC 0.3 400 nm 378 214 mg/ml 4 0.66 ~9-THC 0.3 1000 nm 888 32 mg/ml 0.42 08-THC 0.3 900 nm 634 31 - mg/ml 16 0.42 11-OH-THC 900 nm 539 134 0.3 mg/ml SUBSTITUTE SHEET (RULE 2b) The following compositions are merely illustrative of the compositions of pre~;ent invention, and are not to be regarded as limiting. 4~9-THC, ~e-THC, and 11-OH-THC were encapsulated into both uni- and multi-lamellar liposomes.
III. Cannabinoid Compositions for Inhalation Cosrrposition 1 ( for each 10 ml ) 09-THC 3.0 mg Dipalmitoyl phosphatidylcholine 949.7 mg Cholesterol 55.3 mg Phosphate-Buffered Saline q.s 10 ml Extruded through 400 n:m filter Co~osition 2 (for each 10 ml):
O9-THC 3.0 mg Dipalmitoyl phosphatidylcholine 815.8 mg Cholesterol 184.2 mg Phosphate-Buffered Saline q.s 10 ml Extruded through 400 nm filter Composition 3 (for each 10 ml):
119-THC 3.0 mg Dipalmitoyl phosphatidylcholine 740.1 mg Cholesterol 259.9 mg Phosphate Buffered Saline q.s 10 ml Extruded through 400 nm fil_ter Co~osition 4 ( for each 10 ml ) ~9-THC 3.0 mg Dipalmitoyl phosphatid:ylchaline 740.1 mg Cholesterol 259.9 mg SUBSTITUTE SHEET (RULE 26) Phosphate Buffered Saline q.s 10 ml Extruded thraugh 1000 nm filter Carmposition 5 ( for each 5 ml ) D9-THC 1.5 mg Soy lecithin (hydrogenatesd) 250.0 mg Phosphate Buffered Sali.nes q.s 5 ml Extruded through 400 nm i=filter Composition 6 (for each 5 ml):
O9-THC 1.5 mg Soy lecithin (hydrogenated) 225.0 mg Cholesterol 25 mg Phosphate Buffered Saline q.s 5 ml Extruded through 400 nm f:ilter Composition 7 ( for each '.i m:l ) 09-THC 1.5 mg Soy lecithin (unhydrogenated) 250.0 mg Phosphate Buffered Saline q.s 5 ml Extruded through 400 nm. filter Composition 8 (for each _'> ml):
D9-THC 1.5 mg Soy lecithin (unhydrogenated) 225.0 mg Cholesterol 25 mg Phosphate Buffered Saline q.s 5 ml Extruded through 400 nm filter Cormg~osition 9 ( for each 5 ml ) D9-THC 1.5 mg Phospholipon 80 (hydrogenated) 250.0 mg SiJBSTITUTE SHEET (RULE 26) WO 01/03668 PCTlCA00100805 Phosphate Buffered Saline q.s 5 ml Extruded through 400 nm filter Camposition 10 ( for each 5 ml ) D9-THC 1.5 mg Phospholipon BO (hydroge~nat:ed) 225.0 mg Cholesterol 25 mg Phosphate Buffered Saline q.s 5 ml Extruded through 400 nm filter Composition 11 (for each 10 ml):
D9-THC 3 mg Dipalmitoyl Phosphatidylcholine 1000 mg Phosphate Buffered Saline q.s 10 ml Extruded through 400 nm filter Composition I2 (for each 3U ml):
O9-THC 200.0 mg Dipalmitoylphosphatidylcholine 2834.1 mg Cholesterol 166.2 mg Lactose 4500 mg Phosphate Buffered Saline q.s 30 ml Extruded through 400 nm filter Composition 13 (for each. 30 ml) L19-THC 200.0 mg Dipalmitoyl phosphatidylcholine 2447.4 mg Cholesterol 552.6 mg Lactose 4500 mg Phosphate Buffered Saline q.s 30 ml Extruded through 400 nm filter SUBS'CfTUTE SHEET (RULE 26) Composition 14 (for each 30 ml):
09-THC 200.0 mg Dipalmitoyl phosphatidyl.choline 2220.3 mg Cholesterol 779.7 mg Lactose 4500 mg Phosphate Buffered Saline q.s 30 ml Extruded through 400 nm filter Cou~osition IS (for each. 5 ml):
Oe-tetrahydrocannabinol 1.5 mg Dipalmitoyl phosphatidylcholine 907.92 mg Cholesterol 92.08 mg Phosphate Buffered Saline q.s 5 ml Extruded through 400 nm filter Composition 16 (for each 5 ml):
11-hydroxy-tetrahydroc,3nnabinol 1.5 mg Dipalmitoyl phosphatidylcholine 407.92 mg Cholesterol 92.08 mg Phosphate Buffered Saline q.s 5 ml Extruded through 400 nm filter IV. Pharmacokinetics and Tissue Distribution of hiposomal To allow for a comparison of the bioavailabilities and pharmacokinetic parameters of pulmonary delivery of different liposomal ~9-THC preparations, a comparative study with intravenous administration was conducted in rabbits.
1. Phsrmacakinetics of Intravenous d9-THC

SUBSTITUTE SHEET (RULE 26) Five New Zealand White rabbits were used to study the plasma O9-THC concentration-time profiles following intravenous administratian of A9-THC (100 ~g/ml) in alcohol,.
Anesthesia was induced by intramuscular injection of ketamine and was maintained by halothane in a mixture of nitrous oxide and oxygen. Under anae;~thesia, the central ear artery was cannulated using a #22 catheter for blood sampling. A9-THC :in alcohol (100 fig) was then administered intravenously to the marginal ear vein of the' contra lateral ear. Arterial blood samples (1 ml, each) were drawn at nominal times of 5, 10 15, 20, 25, and 30 minutes, and at l, 2, 4, 6, and 8 hours post-administration of ~9-THC. Venous samples were also collected at 24 hours post-administration. The plasma was separated immediately following the blood collection and stored at -20°C until analyzed. Plasma ~9-THC concentrations were determined using a gas chromatography-mass spectrometry technique as described, .supra. The mean plasma 0'-THC
concentratian verses time profile is illustrated in Table 2 (see, I.V.) and also in FIG. 1.

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.-I T1 ., ri U ~ ~ aCl SUBSTITUTE SHEET (RULE 26) Table 3 illustrates in tabular form the Mean t SD of A9-THC dosage (fig/-kg) and pharmacokinetic parameters for 2 compartments based on the regressions of the individual animal data within each trial. A = intercept (ng/-ml; a =
reciprocal of the time constant (h-'); AUC = area under the plasma drug concentration curve (ng~h-ml-1) ; Kel = drug elimination rate constant (h-1): C1 = total systemic clearance (ml-min-l~kg-1) ; Vd = volume of distribution (L-kg-1) ; T1 = time to a drug concentration level of 1 ng/ml; and bioavailability :LO (kg-h-L-1) . Significant differences between trials (Composition 15 and 16 were excluded due to low sample numbers) were in Dosage (I.V. vs Composition 1, 2, 3, and 4), al (Composition 1 verses 4); A2 (Composition 1 verses 2 and I.V.); a2 (Composition 1 verses 4; I.V. verses Composition 3 and 4); Kel (Composition 1 verses 4); AUC (Composition 1 verses 2); Vd (Composition 2 verses 1 and I.V.), and zl (Composition 2 verses 1, 4, and, I.V.). For detailed explanation of the parameters, see, Klassen, Distribution, excretion, and absorption of toxicants. in: Toxicology: The Basic Science of Poisons, pp. 33-63, Klassen and Amdur (eds), Macmillan, NY (1986).
2. Phaz~acokiaet~cs of Inhaled Liposoms-Eacapsulsted 49-'f$~.' New Zealand White rabbits (4 to 6 per composition tested) were used to study the A9-THC concentration-time profiles following pulmonary administration of several compositions (Compositions l, 2, 3, and 9) of liposome-encapsul.ated D9-THC. Under similar experimental conditions as utilized in the intravenous study, the central ear artery SUBSTITUTE SHEET (RULE 26) of the rabbit was cannulated using a #22 catheter for blood sampling. Under deep anaesthesia, tracheal intubation was performed using a #1 .Laryngoscope. 09-THC (150 fig) in 0.5 ml of liposome preparation (Composition l, 2, 3, and 9) was instilled into the trachea through the endotracheal tube.
Arterial blood samples (1 ml, each) were then drawn at nominal times of 5, 10 15, 20, 25, and 30 minutes, and at 1, 2, 9, 6, and 8 hours post-administration. Venous blood samples were also collected at 24 hours post-administration.
The mean plasma 49-THC: concentration verses time profiles for Compositions 1, 2, 3, and 4 are shown in tabular form in Table 2, and also illustrated in FIGS. 2, 3, 4, and 5, respectively.
The data shown in :EIG. 1 through FIG. 5 indicates that the mean drug clearance data can segregates into a 3-compartment pharmacokinetic model of systemic drug absorption. The "slow" compartment corresponds primarily t.o the plasma ~9-THC measured beyond 300 minutes following pulmonary O9-THC administration. The "mid" and "fast"
compartments correspond to 09-THC concentrations measured from 30 to 300 minute; :inclusive, and within 30 minutes after O9-THC administration, respectively. Application of the compartmental fitting procedure resulted in the predicted profiles superimposed on FIG. 1 to FIG. 5. The mean (~ SD) D9-THC dosage (~g/kg) and pharmacokinetic parameters based upon the regression, area summarized in Table 3. The clearance of Composition 2 (i.e., a 7:3 ratio of DPPC:Cholesterol) appeared to be considerably slower than the other compositions.

SUBSTITUTE SHEET (RULE 26) An additional parameter was also introduced that is particularly relevant too the present invention. This is the computed time to a drug concentration level of 1 ng/ml (il) which is close to the minimum effective concentration. Its value was determined it:e:ratively by solving the fitted drug clearance equation with concentration equal to 1 ng/ml.
There was a significant: :increase in the value of T1 for Composition 2, as compared to other compositions administered through the lungs (excepit for Composition 3) as well as following intravenous A9--THC administration, suggesting that Composition c: possesse~> a potentially prolonged therapeutic value. FIG. 6 shows a comparison of the predicted plasma ~9-THC concentration profi.lc:s of all the various Composition trials where the clearance of Composition 2 is seen to be considerably longer than any of the other compositions. This is consistent with the significantly higher value of T1 found for Composition 2 among all trials (see, Table 3).
The results disclosed herein have demonstrated that pulmonary administration of liposome-encapsulated D9-THC has several distinct advantages over I.V.-based administration.
These advantages include, but are not limited to:
(i) Intravenous admi.n:istration of D9-THC dissolved in alcohol (D9-THC is highly lipophilic and is not soluble in water) is invasive and painful upon injection. In fact, 2 of the 5 rabbits had evidence of thrombophlebitis at the site of I.V. injection site 24 hours after the I.V. administration of D9-THC. In contrast, pulmonary administration is a non-invasive method of A9-To~iC delivery and appeared to be well-tolerated by the rabbits; and SUBST'ITLJTE SHEET (RULE 26) (ii) Pulmonary delivery of liposome-encapsulated D9-THC
provides a rapid onset o:E drug effect with a peak 09-THC
concentration occurred within 5 minutes after administration (comparable t:o intravenous administration; see, Table 2) and a sustained plasma D9-THC: concentration to provide a prolonged O9-THC drug effect.
3. Tissue Concentrations of A9-THC Following Pulmonary Administration of Liposome-Encapsulated O9-THC
A total of 25 New Zealand White rabbits were used to study the tissue t19-THC concentrations following pulmonary administratian of lipo~some-encapsulated D9-THC (Composition 2). Under similar experimental conditions as described supra, the central ear artery of the rabbit was cannulated using a #22 catheter far blood sampling. Under deep anaesthesia, tracheal i.n1=ubation was performed, and 0.5 ml volume of liposome preparation (Composition 2; 150 ~g of THC) was instilled into t=he trachea through the endotracheal.
tube. Immediately after the instillation of the liposomal ~9-THC, 5 rabbits were sacrificed and the lungs and brains of these animals were immediately removed and excess blood was removed by dry, sterile: gauze. The D9-THC concentrations of the lungs and brains werE: determined, and these values were considered as the baseline. Similarly, 5 rabbits were sacrificed at 1, 4, 12, and 24 hours following pulmonary administration of lipo~;omal ~.9-THC and the lungs and brain were removed to determine: the tissue O9-THC concentrations.
In addition, for these rabbits, arterial blood samples (1 ml.
each) were collected where applicable at 5, 10, 15, 20, 25, SUBST'ITLfTE SHEET (RULE 26) WO 01/03b68 PCTICA00/00805 and 30 minutes post-administration, and also at 1, 2, 4, 6, 8 hour intervals. Venous blood samples were collected at 18 and 24 hours.
The organs were weighed and finely minced. One gram of the tissue (either brain or lung) was then homogenized. To facilitate extraction ~~f the A9-THC from the tissue, an equal volume of acetonitrile was added to the homogenate and vortexed. Following centrifugation at 9000 x g for 20 minutes in a refrigerated (4°C) centrifuge, the supernatant :LO was separated. The O9-THC concentration of the supernatant was then determined using the GC/MS as described, supra.
The lung and brain D9-THC concentrations versus time profiles are shown in FIG. 7 and FIG. 8, respectively. This data is described by a 2-compartment model. The half-times :L5 for both the "fast" and "slow" compartments for the brain axe 0.28 and 13.9 hours, respectively; whereas the half-times for both the "fast" and "s:low" compartments for the lungs are 0.09 and 31.4 hours, respectively. Although no D9-THC was detected in the plasma at 24 hours following pulmonary :?0 administration of lipoaomal O9-THC, the mean (~ SD) D9-THC
concentration present :in the lungs at 24 hours was found to be 1.5 t 0.8 ng/gm of tissue. The retention of 09-THC within the lung tissues 24 hours after intratracheal administration is likely due to the liposomal encapsulation, which delayed :?5 the clearance of D9-THC: f-_rom the lungs . See, Tan, et a1. , 1996. Drug Delivery 3: 251-254. Although the endogenous lipase present in the lung parenchyma would continuously break down the liposomE~s present in the lungs and release the entrapped 09-THC for systemic absorption, the highly lipid-SUBSTITUTE SHEET (RULE 26) WO 01/03668 PCTlCA00/00805 soluble 09-THC was distributed extensively in the body immediately after absorption.
Although there is O9-THC retained within the lung tissues, this rapid redistribution of the D9-THC together with the dilution effect from the large plasma volume may account for the undetectable D9-THC in the plasma at 29 hours. This is in direct contrast to those values obtained for the brain, which decreased significantly after 1 hour.
The time constant of 20 hours, suggests that it would take 54.3 hours for THC in t_he brain to decrease to a concentration of less than 0.1 ng/gm of tissue. Although no pharmacodynamic effects 'were measured during the study, the small amount of 09-THC present within the brain (0.5 f 0.1 ng/gm of tissue 24 hours after the pulmonary administration) J.5 may indicate a long-lasting ~9-THC drug effect within the CNS
following pulmonary administration of liposomal 09-THC.
V. Pharmacokinetics of I~iposo~me-Encapsulated D8-T8C
Two New Zealand White rabbits were used to study the ~8-THC concentration versus time profiles following pulmonary c'0 administration of liposome-encapsulated 08-THC. Under similar experimental conditions as described for liposome-encapsulated 09-THC, supra, the central ear artery of the rabbit was cannulated for blood sampling. Under deep anaesthesia, tracheal i.ntubation was performed, and 08-THC
25 (150 fig) in 0.5 ml of liposome preparation (Composition 15) was instilled into the trachea. Arterial blood samples (1 ml, each) were then drawn at nominal times of 5, 10 15, 20, 25, 30, 60, and 90 minute's, and at 2, 4, 6, 8, and 10 hours.

SUBSTITUTE SHEET (RULE 26) Two venous blood samples were also collected at approximately 24 hours post-administration. The plasma De-THC
concentrations were determined by the GC-Mass spectrometry as described, supra.
The mean plasma Of'-'.CHC concentration verses time profile is shown in FIG. 9 and illustrated in tabular form in Table 2 (Composition 15). A two-compartment model was used to fit the mean results of the .ee-THC. The pharmacokinetic parameters were consistent with those derived from other :LO studies described herein. Furthermore, the results indicate that the drug concentrations of De-THC exceeded 1 ng/ml well.-beyond 1 hour post pulmonary administration. For example, the D8-THC concentrations were still measurable in blood samples after 24 hours following pulmonary administration.
:l5 VI. Pharmacokinetics of Liposo~e-Encapsulated 11-OH-THC
Two New Zealand White rabbits were also used to study the 11-OH-THC concentr~ition-time profiles following pulmonary administration of lipoaome-encapsulated 11-OH-THC. Under similar experimental conditions to those utilized for :?0 liposome-encapsulated AB--THC and Og-THC, as described supra, the central ear artery o:f the rabbit was cannulated for blood sampling. Under deep anaesthesia, tracheal intubation was performed and 11-OH-THC: (150 pg) in 0.5 ml of liposome preparation (Composition 16) was instilled into the trachea.
25 Arterial blood samples ('1 ml, each) were drawn at nominal times of 5, 10 15, 20, 25, 30, 60, and 90 minutes, and at 2, 4, 6, 8, and 10 hours goat-administration. Two venous blood samples were also collected at approximately 24 hours. The SUBSTITUTE SHEET (RULE 26) plasma 11-OH-THC concentrations were then determined by the GC-Mass spectrometry, as described supra. The mean plasma 11-OH-THC concentratior. verses time profile is shown in FIG.
and illustrated in tabular form in Table 2 (Composition 5 16). A two-compartment model was then used to fit the mean results of the 11-OH-THC. Similarly, the estimated pharmacokinet.ic parameters were not markedly different from those results obtained for the OB-THC. The 11-OH-THC
concentration verses times profile indicates that the drug 10 concentrations of 11-OH-THC exceeded 1 ng/ml well beyond 1 hour post pulmonary administration. Moreover, the 11-OH-THC
concentrations were also measurable in the blood samples greater than 24 hours po:>t pulmonary administration.
Equivalents Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims which follow. In particular, it is contemplated by the inventor that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scopes of the invention as defined by the claims. Other embodiments are within the following claims.
SUBST'ITLJTE SHEET (RULE 26)

Claims (25)

WHAT IS CLAIMED IS:

1. A liposomal composition comprising a cannabinoid or cannabimimetic agent, said composition being suitable for pulmonary administration.

2. The composition of claim 1, wherein the range of size of liposomes in said composition is within 25% of the mean size of said liposomes.

3. The composition of claim 1, wherein the size of liposomes in said composition is uniform.

4. The composition of claim 1, wherein said cannabinoid is selected from the group consisting of cannabinol, cannabidiol, .DELTA.9-tetrahydrocannabinol, .DELTA.8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-.DELTA.9-tetrahydrocannabinol, levonantradol, .DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol, amandamide, and nabilone.

5. The composition of claim 1, wherein said cannabinoid is .DELTA.9-tetrahydrocannabinol.

6. The composition of claim 1, wherein said cannabinoid is .DELTA.8-tetrahydrocannabinol.

7. The composition of claim 1, wherein said cannabinoid is 11-hydroxy-tetrahydrocannabinol.

8. The composition of claim 1, wherein said composition comprises said cannabinoid or cannabimimetic agent in an amount of between approximately 0.01% to 10% by weight.

9. The composition of claim 1, wherein said composition comprises phospholipid selected from the group consisting of a phosphatidylcholine, a dipalmitoylphosphatidylcholine, a lysophosphatidylcholine, a phosphatidylserine, a phosphatidyl-ethanolamine, a phosphatidylglycerol, and a phosphatidylinositol.

10. The composition of claim 9, wherein said composition further comprises cholesterol.

11. The composition of claim 10, wherein the approximate molar ratio of dipalmitoylphosphatyidylcholine:cholesterol is selected from the group consisting of 7:3, 6:4, and 9:1.

12. The composition of claim 10, wherein the approximate molar ratio of dipalmitoylphosphatyidylcholine:cholesterol is 7:3.

13. The composition of claim 1, wherein said composition comprises multilamellar liposomes.

14. The composition of claim 1, wherein said composition comprises unilamellar liposomes.

15. A composition of claim 1, wherein said compositions comprises multivesicular liposomes.

16. A method for delivery of a cannabinoid to the central nervous system of a mammal, comprising contacting a pulmonary tissue of said mammal with a liposomal composition comprising a cannabinoid or cannabimimetic agent.

17. The method of claim 16, wherein said delivery is multiphasic.

18. The method of claim 17, wherein a first phase is characterized by rapid systemic absorption of said cannabinoid or cannabinimimetic agent.

19. The method of claim 18, wherein said first phase ranges from 30 seconds to 30 minutes after said pulmonary tissue is contacted with said cannabinoid or cannabinimimetic agent.

20. The method of claim 17, wherein a second phase is characterized by sustained systemic absorption of said cannabinoid or cannabinimimetic agent.

21. The method of claim 20, wherein said second phase ranges from 30 minutes to 2 days after said pulmonary tissue is contacted with said cannabinoid or cannabinimimetic agent.

22. The method of claim 16, wherein said cannabinoid is selected from the group consisting of: cannabinol, cannabidiol, .DELTA.9-tetrahydrocannabinol, .DELTA.8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-.DELTA.9-tetrahydrocannabinol, levonantradol, .DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol, amandamide, and nabilone.

23. A method of claim 16, wherein said composition comprises said cannabinoid or cannabimimetic agent in an amount of between approximately 0.01 to 10% by weight.

24. The method of claim. 16, wherein said mammal is identified as suffering from or at risk of developing a disease or disorder selected from the group consisting of:
nausea, loss of appetite, glaucoma, seizure, multiple sclerosis, or pain.

25. A method of inducing a sustained psychoactive cannabinoid effect in the central nervous system of a mammal, comprising contacting a pulmonary tissue of said mammal with a liposome-encapsulated cannabinoid or cannabimimetic agent.