EP1109533A1 - Administration pulmonaire de cannabinoides encapsules dans des liposomes - Google Patents

Administration pulmonaire de cannabinoides encapsules dans des liposomes

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Publication number
EP1109533A1
EP1109533A1 EP00945490A EP00945490A EP1109533A1 EP 1109533 A1 EP1109533 A1 EP 1109533A1 EP 00945490 A EP00945490 A EP 00945490A EP 00945490 A EP00945490 A EP 00945490A EP 1109533 A1 EP1109533 A1 EP 1109533A1
Authority
EP
European Patent Office
Prior art keywords
composition
cannabinoid
thc
tetrahydrocannabinol
liposomes
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00945490A
Other languages
German (de)
English (en)
Inventor
Orlando Hung
Jiri Zamecnik
Pang N. Shek
Peter Tikuisis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Minister of National Defence of Canada
UK Government
Original Assignee
Minister of National Defence of Canada
UK Government
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Minister of National Defence of Canada, UK Government filed Critical Minister of National Defence of Canada
Publication of EP1109533A1 publication Critical patent/EP1109533A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • 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-encapsulated cannabinoids .
  • cannabis Since its discovery over 12,000 years ago, cannabis is one of the most widely used drugs throughout the world. See, Adams, et al . , 1996. Addiction 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 ⁇ 9 - tetrahydrocannabinol ( ⁇ 9 - THC) and ⁇ 8 -tetrahydrocannabinol ( ⁇ 8 -THC) . Although both ⁇ 9 - THC and ⁇ 8 -THC are active compounds extracted from the plant, ⁇ 9 -THC composed of 90% of the active ingredient of the cannabis plant.
  • cannabinoid receptors i.e., CB1 and CB2
  • CB1 and CB2 cannabinoid receptors
  • cannabinoids e.g., ⁇ 9 -THC and ⁇ 8 -THC
  • cannabinoids e.g., ⁇ 9 -THC and ⁇ 8 -THC
  • cannabinoids are highly lipophilic compounds with no suitable route of administration apart from smoking the cannabis leaf or resin.
  • a large number of unnecessary toxic chemicals present in the cannabis plant will also be absorbed into the circulation after smoking.
  • the quality control is generally not available and the ⁇ 9 -THC, ⁇ 8 -THC, and 11-OH- THC content of the cannabis leaf are highly variable, thus making it difficult to predict the bioavailability of ⁇ 9 -THC, ⁇ 8 -THC, and 11-OH-THC, following smoking of the crude cannabis leaf. Therefore, the evaluation of the pharmacodynamic effects ( i .
  • the invention features a Iiposomal composition containing a cannabinoid or cannabimimetic agent and methods of systemic delivery by contacting pulmonary tissue of a mammal with the Iiposomal composition to achieve a prolonged psychoactive effect.
  • the compositions and methods of treatment involve the use of unilamellar and multilamellar liposomes as a vehicle to provide systemic delivery of cannabinoids, for example, ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) , ⁇ -tetrahydrocannabinol, ( ⁇ 8 -THC) ; and 11-hydroxy- tetrahydrocannabinol (11-OH-THC) , via administration to the pulmonary system.
  • cannabinoids for example, ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) , ⁇ -tetrahydrocannabinol, ( ⁇ 8 -THC) ;
  • Liposomal compositions 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.
  • the range of size of liposomes in the composition is preferably within 25%, more preferably within 20%, more preferably within 15%, more preferably within 10%, and most preferably within 5% of the mean size of the liposomes.
  • at least 85% (more preferably 90%, more preferably 95%, and most preferably 99-100%) of the liposomes in the composition are with a defined size range, e.g., between 300- 400 nm in size.
  • the liposomes are within 450-550 nm in size.
  • the size range of the liposomes is between 700-800 nm.
  • 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 sa tiva var. indica ) or is chemically-synthesized in the laboratory. See, Stedman, Medical Dictionary, pg. Ill, 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 tetrachydrocannabinol (THC) .
  • THC tetrachydrocannabinol
  • the cannabinoid to be delivered is selected from the group consisting of cannabinol, cannabidiol, ⁇ 9 - tetrahydrocannabinol, ⁇ 8 -tetrahydrocannabinol, 11-hydroxy- tetrahydrocannabinol, ll-hydroxy- ⁇ 9 -tetrahydrocannabinol, levonantradol, ⁇ 11_ tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol, amandamide, and nabilone.
  • a cannabimimetic agent is a composition characterized as having at least 50% of the psychoactive effect of ⁇ 8 - tetrahydrocannabinol .
  • the mimetic may differ from ⁇ 8 - 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 0.01% to 10% by weight.
  • the composition may also contain a phospholipid, e . g.
  • a phosphatidylcholine a dipalmitoylphosphatidylcholine, a lysophosphatidylcholine, a phosphatidylserine, a phosphatidyl-ethanolamine, 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 indirectly 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 of cholesterol in the composition results in production of liposomes with a more rigid membrane.
  • a more rigid membrane indicates a relatively more stable liposome.
  • the molar ratio of dipalmitoylphosphatyidylcholine : 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.
  • the composition is formulated to contain at least 20%, 25%, 30%, 35% or 40% cholesterol.
  • the percentage of cholesterol in the composition does not exceed 45%.
  • the composition contains liposomes, 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 central nervous system of a mammal using the compositions described above.
  • Pulmonary tissue of a mammal is contacted with a Iiposomal composition containing a cannabinoid or cannabimimetic agent.
  • the compositions are administered orally, intratracheally, intravenously, and by other standard clinical modes of administration.
  • Mammals, e . g. , humans, to be treated include those who have been 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.
  • Systemic delivery of the cannabinoid is multiphasic.
  • multiphasic is meant the pharmacokinetic pattern of systemic absorption of a cannabinoid or active metabolite thereof has at least two compartments.
  • a multiphasic delivery system results, in a fast pharmacokinetic compartment, mid-range pharmacokinetic compartment, and a sustained pharmacokinetic compartment.
  • a first phase (or rapid compartment) is characterized by rapid systemic absorption of the cannabinoid 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 cannabinoid or cannabinimimetic composition.
  • the method results in a sustained systemic concentration of a cannabinoid (e . g. , as measured in plasma, or other tissues such as brain) for 6 hours, 12 hours, 24 hours, and up to several days post-administration.
  • a cannabinoid e . g. , as measured in plasma, or other tissues such as brain
  • 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 advantages of the present invention include: ( i ) the rapid bioavailability and initial onset of the pharmacological effect of the cannabinoids from the immediate release of liposome-encapsulated cannabinoids ( e . g. , approximately 10-20 % of the total ⁇ 9 -THC dose); ( ii ) the continuous-release properties of the liposomes to provide a sustained pharmacological effect ( e . g.
  • 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.
  • 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.
  • pulmonary administration of liposome-encapsulated cannabinoids is efficient, safe, and does not exhibit any significant adverse cardiopulmonary side effects.
  • the effects of the cannabinoid formulation last more than 24 hours following pulmonary administration of
  • Iiposomal cannabinoid Iiposomal 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 the drug's therapeutic effect.
  • FIG. 1 is a line graph which illustrates mean plasma ⁇ 9 - THC concentration versus time profile.
  • FIG. 2 is a line graph which illustrates mean plasma ⁇ 9 - THC concentration verses time profiles for Composition 1.
  • FIG. 3 is a line graph which illustrates mean plasma ⁇ 9 - THC concentration verses time profiles for Composition 2.
  • FIG. 4 is a line graph whichillustrates mean plasma ⁇ 9 - THC concentration verses time profiles for Composition 3.
  • FIG. 5 is a line graph which illustrates mean plasma ⁇ 9 - THC concentration verses time profiles for Composition 4.
  • FIG. 6 is a line graph which illustrates a comparison of the predicted plasma ⁇ 9 -THC concentration profiles various Composition trials (Compositions 1-16) .
  • FIG. 7 is a line graph which illustrates lung ⁇ 9 -THC concentrations versus time profiles.
  • FIG. 8 is a line graph which illustrates brain ⁇ 9 -THC concentrations versus time profiles.
  • FIG. 9 is a line graph which illustrates mean plasma ⁇ 8 - THC concentration verses time profile.
  • FIG. 10 is a line graph which illustrates mean plasma 11-OH-THC concentration versus time profile.
  • Liposomes are used as a vehicle to deliver cannabinoids (e . g. , tetrachydrocannabinol) and other cannabimimetic agents to improve the pharmacokinetic profiles of the cannabinoid and cannabimimetic agents.
  • Liposomes are microscopic vesicles composed of one or more aqueous compartments alternating with phospholipid bilayers.
  • the liposomes 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 the pulmonary system.
  • the methods provide a systemic drug effect for humans.
  • the sustained release property of the Iiposomal product is regulated by the lipid and other excipient composition of the Iiposomal 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: cholesterol ratio ( i . e . , the higher the ratio, the faster the rate of release) ; ( iii ) the hydrophilic/lipophilic properties of the active ingredients; and ( iv) the method utilized in the production of the of liposomes.
  • Plasma cannabinoid concentrations were determined using a gas chromatography-mass spectrometry technique (GC-MS; see, e . g. , Wilkins, et al . , 1995. J. Anal . Toxicol . 19: 483-491).
  • GC-MS gas chromatography-mass spectrometry technique
  • the sample was then analyzed by GC/MS (Finnigan Voyager) using Negative Ion Chemical lonization (methane CI gas) in SIM mode (m/z 410 and m/z 413) .
  • the quantitation was performed using a 5-point calibration curve ( i . e . , blank plasma "spiked” with 0.1, 0.5, 5, 10, 100 ng/ l of ⁇ 9 -THC) .
  • Three QC samples i . e . , blank plasma aliquots "spiked” with 0.5, 5 and 50 ng/ml of ⁇ 9 -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, ⁇ 8 - tetrahydrocannabinol ( ⁇ 8 -THC) , and 11-hydroxy- tetrahydrocannabinol (11-OH-THC), using different internal standards.
  • cannabinoids including, but not limited to, ⁇ 8 - tetrahydrocannabinol ( ⁇ 8 -THC) , and 11-hydroxy- tetrahydrocannabinol (11-OH-THC)
  • 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.
  • DPPC dipalymitoylphosphatidylcholine
  • the selected lipids 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 dried 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/in ⁇ .
  • 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.
  • liposome encapsulation 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 the appropriate active ingredient, lipids, and other excipient composition.
  • the pharmacologically-active cannabinoid ingredients include, but are not limited to, ⁇ 9 - THC, ⁇ 8 -THC, and 11-OH-THC.
  • Lipid components include, but are not limited to, phospholipids and cholesterol.
  • the excipients include, but are not limited to, tocopherol, antioxidants, viscosity-inducing agents, and/or preservatives.
  • tocopherol antioxidants
  • viscosity-inducing agents and/or preservatives.
  • compositions are merely illustrative of the compositions of present invention, and are not to be regarded as limiting.
  • ⁇ 9 -THC, ⁇ 8 -THC, and 11-OH-THC were encapsulated into both uni- and multi-lamellar liposomes.
  • Arterial blood samples (1 ml, each) were drawn at nominal times of 5, 10 15, 20, 25, and 30 minutes, and at 1, 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 ⁇ 9 -THC concentration verses time profile is illustrated in Table 2 ( see, I.V.) and also in FIG. 1.
  • Table 3 illustrates in tabular form the Mean ⁇ SD of ⁇ 9 - THC dosage ( ⁇ g/-kg) and pharmacokinetic parameters for 2 compartments based on the regressions of the individual animal data within each trial.
  • composition 15 and 16 were excluded due to low sample numbers
  • Dosage I.V. vs Composition 1, 2, 3, and 4
  • ai Composition 1 verses 4
  • a 2 Composition 1 verses 2 and I.V.
  • 2 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.
  • ⁇ i Composition 2 verses 1, 4, and, I.V.
  • New Zealand White rabbits (4 to 6 per composition tested) were used to study the ⁇ 9 -THC concentration-time profiles following pulmonary administration of several compositions (Compositions 1, 2, 3, and 4) of liposome- encapsulated ⁇ 9 -THC.
  • compositions 1, 2, 3, and 4 of liposome- encapsulated ⁇ 9 -THC.
  • the central ear artery of the rabbit was cannulated using a #22 catheter for blood sampling.
  • tracheal intubation was performed using a #1 laryngoscope.
  • 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 , 4, 6, and 8 hours post-administration. Venous blood samples were also collected at 24 hours post-administration.
  • the mean plasma ⁇ 9 -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 FIG. 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 to the plasma ⁇ 9 -THC measured beyond 300 minutes following pulmonary ⁇ 9 -THC administration.
  • the “mid” and “fast” compartments correspond to ⁇ 9 -THC concentrations measured from 30 to 300 minutes inclusive, and within 30 minutes after ⁇ 9 -THC administration, respectively.
  • Application of the compartmental fitting procedure resulted in the predicted profiles superimposed on FIG. 1 to FIG. 5.
  • the mean ( ⁇ SD) ⁇ 9 -THC dosage ( ⁇ g/kg) and pharmacokinetic parameters based upon the regression, are summarized in Table 3.
  • pulmonary administration is a non- invasive method of ⁇ 9 -THC delivery and appeared to be well- tolerated by the rabbits; and ( ii) Pulmonary delivery of liposome-encapsulated ⁇ 9 -THC provides a rapid onset of drug effect with a peak ⁇ 9 -THC concentration occurred within 5 minutes after administration (comparable to intravenous administration; see, Table 2) and a sustained plasma ⁇ 9 -THC concentration to provide a prolonged ⁇ 9 -THC drug effect.
  • Liposome-Encapsulated ⁇ 9 -THC A total of 25 New Zealand White rabbits were used to study the tissue ⁇ 9 -THC concentrations following pulmonary administration of liposome-encapsulated ⁇ 9 -THC (Composition 2) . Under similar experimental conditions as described supra , the central ear artery of the rabbit was cannulated using a #22 catheter for blood sampling. Under deep anaesthesia, tracheal intubation was performed, and 0.5 ml volume of liposome preparation (Composition 2; 150 ⁇ g of ⁇ 9 - THC) was instilled into the trachea through the endotracheal tube.
  • Composition 2 150 ⁇ g of ⁇ 9 - THC
  • the organs were weighed and finely minced. One gram of the tissue (either brain or lung) was then homogenized. To facilitate extraction of the ⁇ 9 -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 was separated. The ⁇ 9 -THC concentration of the supernatant was then determined using the GC/MS as described, supra .
  • the lung and brain ⁇ 9 -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 for both the "fast” and “slow” compartments for the brain are 0.28 and 13.9 hours, respectively; whereas the half-times for both the "fast” and “slow” compartments for the lungs are 0.09 and 31.4 hours, respectively.
  • the mean ( ⁇ SD) ⁇ 9 -THC concentration present in the lungs at 24 hours was found to be 1.5 ⁇ 0.8 ng/gm of tissue.
  • ⁇ 9 -THC The retention of ⁇ 9 -THC within the lung tissues 24 hours after intratracheal administration is likely due to the liposomal encapsulation, which delayed the clearance of ⁇ 9 -THC from the lungs. See, Tan, et al . , 1996. Drug Delivery 3 : 251-254. Although the endogenous lipase present in the lung parenchyma would continuously break down the liposomes present in the lungs and release the entrapped ⁇ 9 -THC for systemic absorption, the highly lipid- soluble ⁇ 9 -THC was distributed extensively in the body immediately after absorption.
  • the small amount of ⁇ 9 -THC present within the brain may indicate a long-lasting ⁇ 9 -THC drug effect within the CNS following pulmonary administration of liposomal ⁇ 9 -THC.
  • the plasma ⁇ 8 -THC concentrations were determined by the GC-Mass spectrometry as described, supra .
  • the mean plasma ⁇ 8 -THC 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 ⁇ 8 -THC.
  • the pharmacokinetic parameters were consistent with those derived from other studies described herein.
  • the results indicate that the drug concentrations of ⁇ 8 -THC exceeded 1 ng/ml well- beyond 1 hour post pulmonary administration. For example, the ⁇ 8 -THC concentrations were still measurable in blood samples after 24 hours following pulmonary administration.
  • 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 post-administration. Two venous blood samples were also collected at approximately 24 hours.
  • the plasma 11-OH-THC concentrations were then determined by the GC-Mass spectrometry, as described supra .
  • the mean plasma 11-OH-THC concentration verses time profile is shown in FIG. 10 and illustrated in tabular form in Table 2 (Composition 16) .
  • a two-compartment model was then used to fit the mean results of the 11-OH-THC.
  • the estimated pharmacokinetic parameters were not markedly different from those results obtained for the ⁇ 8 -THC.
  • the 11-OH-THC concentration verses time profile indicates that the drug 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 post pulmonary administration.

Abstract

L'invention concerne une composition liposomale contenant un agent cannabinoïde ou cannabimimétique. L'invention concerne également des méthodes d'administration systémique, par contact du tissu pulmonaire d'un mammifère avec la composition liposomale, afin d'obtenir un effet psychoactif prolongé.
EP00945490A 1999-07-08 2000-07-07 Administration pulmonaire de cannabinoides encapsules dans des liposomes Withdrawn EP1109533A1 (fr)

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US14279099P 1999-07-08 1999-07-08
US142790P 1999-07-08
PCT/CA2000/000805 WO2001003668A1 (fr) 1999-07-08 2000-07-07 Administration pulmonaire de cannabinoides encapsules dans des liposomes

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JP (1) JP2003504321A (fr)
AU (1) AU5958200A (fr)
CA (1) CA2341035A1 (fr)
WO (1) WO2001003668A1 (fr)

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US20050079136A1 (en) * 2001-07-10 2005-04-14 Woolfe Austen John Aerosol formulations of delta tetrahydrocannabinol
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