U.S. patent application number 10/759280 was filed with the patent office on 2004-12-23 for delta9 tetrahydrocannabinol (delta9 thc) solution metered dose inhalers and methods of use.
Invention is credited to Byron, Peter R., Lichtman, Aron H., Martin, Billy R., Peart, Joanne.
Application Number | 20040258622 10/759280 |
Document ID | / |
Family ID | 26803013 |
Filed Date | 2004-12-23 |
United States Patent
Application |
20040258622 |
Kind Code |
A1 |
Peart, Joanne ; et
al. |
December 23, 2004 |
Delta9 tetrahydrocannabinol (delta9 THC) solution metered dose
inhalers and methods of use
Abstract
The present invention provides therapeutic formulations for
solutions of .DELTA..sup.9-tetrahydrocannabinol (.DELTA..sup.9 THC)
to be delivered by metered dose inhalers. The formulations, which
use non-CFC propellants, provide a stable aerosol-deliverable
source of .DELTA..sup.9 THC for the treatment of various medical
conditions, such as: nausea and vomiting associated with
chemotherapy-muscle spasticity; pain; anorexia associated with AIDS
wasting syndrome, epilepsy; glaucoma; bronchial asthma; and mood
disorders.
Inventors: |
Peart, Joanne; (Richmond,
VA) ; Byron, Peter R.; (Richmond, VA) ;
Lichtman, Aron H.; (Richmond, VA) ; Martin, Billy
R.; (Richmond, VA) |
Correspondence
Address: |
WHITHAM, CURTIS & CHRISTOFFERSON, P.C.
11491 SUNSET HILLS ROAD
SUITE 340
RESTON
VA
20190
US
|
Family ID: |
26803013 |
Appl. No.: |
10/759280 |
Filed: |
January 20, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10759280 |
Jan 20, 2004 |
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09944221 |
Sep 4, 2001 |
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6713048 |
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09944221 |
Sep 4, 2001 |
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09273766 |
Mar 22, 1999 |
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6509005 |
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60105850 |
Oct 27, 1998 |
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Current U.S.
Class: |
424/45 ;
514/453 |
Current CPC
Class: |
A61K 9/008 20130101;
A61P 21/02 20180101; A61P 1/08 20180101; A61P 25/00 20180101; A61P
1/14 20180101; A61P 25/04 20180101; A61P 25/06 20180101; A61K
31/352 20130101; A61P 43/00 20180101 |
Class at
Publication: |
424/045 ;
514/453 |
International
Class: |
A61L 009/04; A61K
031/353 |
Goverment Interests
[0002] Funding for the research which led to this invention was
provided in part by the United States Government in grant# DA 02396
and DA-07027 from the National Institutes of Health and the
government may have certain rights in this invention.
Claims
1-22. (Cancelled).
23. A method of administering a pharmaceutically effective dose of
aerosolized tetrahydrocannabinol to a patient, comprising the steps
of: providing a solution comprising a pharmaceutically acceptable
form of said tetrahydrocannabinol in a hydrofluoroalkane, said
solution having not more than 15% of a pharmaceutically acceptable
solvent; aerosolizing said solution to provide respirable droplets
comprising said tetrahydrocannabinol, wherein at least 20% of the
mass of said respirable droplets comprise droplets having an
aerodynamic diameter of less than 5.8 .mu.m; administering a
pharmaceutically effective dose of said respirable droplets to said
patient's lungs.
24. The method of claim 23 wherein said tetrahydrocannabinol is
present in pharmaceutically pure form.
25. The method of claim 23 wherein said tetrahydrocannabinol is a
pharmaceutically acceptable salt of said tetrahydrocannabinol.
26. The method of claim 23 wherein said pharmaceutically acceptable
solvent comprises ethanol.
27. The method of claim 23 wherein said solution consists
essentially of said hydrofluoroalkane and said
tetrahydrocannabinol.
28. The method of claim 23 wherein said solution is surfactant
free.
29. The method of claim 23 wherein said tetrahydrocannabinol is
present in said solution at a concentration sufficient to achieve
serum concentration levels in said patient of 10-100 ng/ml fifteen
minutes following inhalation.
30. The method of claim 23 wherein said pharmaceutically effective
dose is sufficient to treat nausea.
31. The method of claim 23 wherein said pharmaceutically effective
dose is sufficient to treat vomiting.
32. The method of claim 23 wherein said pharmaceutically effective
dose is sufficient to reduce pain.
33. The method of claim 23 wherein said pharmaceutically effective
dose is sufficient to relieve muscle spasticity.
34. The method of claim 23 wherein said pharmaceutically effective
dose is sufficient to relieve migraine headaches.
35. The method of claim 23 wherein said pharmaceutically effective
dose is sufficient to relieve movement disorders.
36. The method of claim 23 wherein said pharmaceutically effective
dose is sufficient to increase appetite in patients suffering from
cachexia.
37. A method of administering a pharmaceutically effective dose of
medical marijuana to a patient, comprising the steps of: providing
a solution comprising a pharmaceutically acceptable form of said
medical marijuana in a hydrofluoroalkane, said solution having not
more than 15% of a pharmaceutically acceptable solvent;
aerosolizing said solution to provide respirable droplets
comprising said medical marijuana, wherein at least 20% of the mass
of the respirable droplets comprise droplets having an aerodynamic
diameter of less than 5.8 .mu.m; administering a pharmaceutically
effective dose of said respirable droplets to said patient's
lungs.
38. The method of claim 37 wherein said pharmaceutically acceptable
solvent comprises ethanol.
39. The method of claim 37 wherein said solution consists
essentially of said hydrofluoroalkane and said medical
marijuana.
40. The method of claim 37 wherein said solution is surfactant
free.
41. The method of claim 37 wherein said medical marijuana is
present in said solution at a concentration sufficient to achieve
serum concentration levels in said patient of 10-100 ng/ml fifteen
minutes following inhalation.
42. The method of claim 37 wherein said pharmaceutically effective
dose is sufficient to treat a condition selected from the group
consisting of nausea, vomiting, pain, muscle spasticity, migraine
headaches, movement disorders, and loss of appetite due to
cachexia.
43. A pharmaceutical composition comprising a hydrofluoroalkane,
.DELTA..sup.9-tetrahydrocannabinol, and up to 15 percent by weight
of an organic solvent, said A9-tetrahydrocannabinol and said
organic solvent being dissolved in said hydrofluoroalkane to form a
stable composition, wherein said .DELTA..sup.9-tetrahydrocannabinol
is present in said composition in concentrations ranging from
0.147% w/w (.+-.0.008) to 5.940% w/w (.+-.0.191).
44. The pharmaceutical composition of claim 43 wherein said
.DELTA..sup.9-tetrahydrocannabinol is present in pharmaceutically
pure form.
45. The method of claim 43 wherein said
.DELTA..sup.9-tetrahydrocannabinol is a pharmaceutically acceptable
salt of said .DELTA..sup.9-tetrahydrocan- nabinol.
46. The pharmaceutical composition of claim 43 wherein said organic
solvent comprises ethanol.
47. The pharmaceutical composition of claim 43 wherein said
solution consists essentially of said hydrofluoroalkane and said
.DELTA..sup.9-tetrahydrocannabinol.
48. The pharmaceutical composition of claim 43 wherein said stable
composition is surfactant free.
49. The pharmaceutical composition of claim 43 wherein said
.DELTA..sup.9-tetrahydrocannabniol is present in said stable
composition at a concentration sufficient to achieve serum
concentration levels in a patient of 10-100 ng/ml fifteen minutes
following inhalation.
50. A pharmaceutical composition comprising a hydrofluoroalkane, a
tetrahydrocannabinol, and up to 15 percent by weight of an organic
solvent, said tetrahydrocannabinol and said organic solvent being
dissolved in said hydrofluoroalkane to form a stable composition,
wherein said tetrahydrocannabinol is present in said composition in
concentrations ranging from 0.147% w/w (.+-.0.008) to 5.940% w/w
(.+-.0.191).
51. The pharmaceutical composition of claim 50 wherein said
tetrahydrocannabinol is present in pharmaceutically pure form.
52. The method of claim 50 wherein said tetrahydrocannabinol is a
pharmaceutically acceptable salt of said tetrahydrocannabinol.
53. The pharmaceutical composition of claim 50 wherein said organic
solvent comprises ethanol.
54. The pharmaceutical composition of claim 50 wherein said
solution consists essentially of said hydrofluoroalkane and said
tetrahydrocannabinol.
55. The pharmaceutical composition of claim 50 wherein said stable
composition is surfactant free.
56. The pharmaceutical composition of claim 50 wherein said
tetrahydrocannabinol is present in said stable composition at a
concentration sufficient to achieve serum concentration levels in a
patient of 10-100 ng/ml fifteen minutes following inhalation.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of pending U.S.
Ser. No. 09/273,766 which claims priority of U.S. provisional
application Ser. No. 60/105,850 filed Oct. 27, 1998, and the
complete contents of those applications are incorporated herein by
reference.
DESCRIPTION
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The invention is generally related to the therapeutic use of
.DELTA..sup.9 Tetrahydrocannabinol (.DELTA..sup.9 THC). In
particular, the invention provides a metered dose inhaler (MDI) for
the aerosol administration of .DELTA..sup.9 THC to patients
suffering from nausea and vomiting associated with cancer
chemotherapy, muscle spasticity, pain, anorexia associated with
AIDS wasting syndrome, epilepsy, glaucoma, bronchial asthma, mood
disorders, and the like.
[0005] 2. Background Description
[0006] In 1997, the National Institutes of Health (NIH) released a
review of the scientific data concerning potential therapeutic uses
for marijuana. In that review, the NIH found that marijuana may
indeed have beneficial medicinal effects and recommended that
researchers develop alternative dosage forms for the drug, such as
a "smoke free" inhaled delivery system. Workshop on the medical
utility of marijuana, National Institutes of Health, August 1997.
Studies have documented therapeutically beneficial medicinal uses
of the major active component of marijuana, .DELTA..sup.9
tetrahydrocannabinol (.DELTA..sup.9 THC). Beal, J. A., Olson, R.,
Lefkowitz, L., Laubenstein, L., Bellman, P., Yangco, B., Morales,
J. O., Murphy, R., Powderly, W., Plasse, T. F., Mosdell, K. W. and
Shepard, K. W., Long-term efficacy and safety of dronabinol for
acquired immunodeficiency syndrome-associated anorexia, J Pain.
Symptom Manage. 14.7-14 (1997); Beal, J. A., Olson, R.,
Laubenstein, L., Morales, J. O., Beliman, B., Yangco, B.,
Lefkowitz, L., Plasse, T. F. and Shepard, K. V. Dronabinol as a
treatment for anorexia associated with weight loss in patients with
AIDS, J Pain. Symptom Manage, 10. 89-97 (1995); McCabe, M., Smith,
F. P., MacDonald, J. S., Wooley, P. V., Goldberg, D. and Schein, P.
S., Efficacy of tetrahydrocannabinol in patients refractory to
standard antiemetic therapy, Invest. New Drugs 6:243-246 (1988);
Lucas, V. S. and Laszlo, J. .DELTA..sup.9-THC for refractory
vomiting induced by cancer chemotherapy, JAMA 243:1241-1243 (1980);
Sallan, S. E., Cronin, C., Zelen, M. and Zinberg, N. E.,
Antiemetics in patients receiving chemotherapy for cancer: a
randomized comparison of .DELTA..sup.9 THC and prochlorperazine, N.
Engl. J Med., 302:135-138 (1980); Frytak, S., Moertel, C. G.,
O'Fallon, JR., Rubin, J., Creagan, E. T., O'Connell, M. J., Schutt,
A. J. and Schwartau, N. W., Delta-9-tetrahydrocannabinol as an
antiemetic for patients receiving cancer chemotherapy: a comparison
with prochlorperazine and a placebo, Ann. Inter. Med 91:825-830
(1979); Chang, A. E., Shiling, D. J., Stillman, R. C., Goldgerg, N.
H., Seipp, C. A., Barofdky, I., Simon, R. M. and Rosenberg SA,
.DELTA..sup.9 THC as an antiemitic in cancer patients receiving
high-dose methotrexate. Ann. Internal Med. 91:819-824 (1979);
Sallan, S. E., Zinberg, N. E. and Frei, I. E., Antiemetic effect of
.DELTA..sup.9 THC in patients receiving cancer chemotherapy, New
Engl. J. Med. 293:795-797 (1975); Noyes, J R., Brunk, S. F., Baram,
D. A. and Canter, A., The analgesic properties of .DELTA..sup.9 THC
and codeine. J. Clin. Pharmacol 15:139-143 (1975); Noyes, R., Jr.,
Brunk, S. F., Baram, D. A. and Canter, A., Analgesic effect of
.DELTA..sup.9 tetrahydrocannabinol, Clin. Pharmacol & Ther
18:84-89 (1975); Brenneisen, R., Egli, A., Elosohlly, M. A., Henn,
V. and Spiess, Y., The effect of orally and rectally administered
.DELTA..sup.9 THC on spasticity: a pilot study with 2 patients,
Int. J. Clin. J Pharmocol Ther. 34:446-452 (1996); Ungerleider, J.
T., Andyrsiak, T.F.L., Ellison, G. W. and Myers, L. W.,
.DELTA..sup.9 THC in the treatment of spasticity associated with
multiple sclerosis, Adv. Alcohol Subst. Abuse 7:39-50 (1987);
Clifford, D. B., Tetra-hydrocannabinol for tremor in multiple
sclerosis, Ann. Neurol 13:669-171 (1983); Petro, D. J. and
Ellenberger, C., Treatment of human spasticity with delta
9-tetrahydrocannabinol, J. Clin. Pharmacol 21:413S-4165 (1981);
Maurer, M., Henn, V., Dittrich, A. and Hofman, A., Delta
9-tetrahydrocannabinol shows antispastic and analgesic effects in a
single case double-blind trial, Eur. Arch. Psychiatry Neurol Sci.
240:1-4 (1990); Merritt, J., Crawford, W., Alexander, P., Anduze,
A. and Gelbart, S., Effects of marihuana on intra ocular and blood
pressure in glaucoma, Opht. 87:222-228 (1980); Cooler, P. and
Gregg, J. M., Effect of delta 9-.DELTA..sup.9 THC on intra ocular
pressure in humans. South. Med J 70:951-954 (1977). Table 1
summarizes the findings of these studies.
1TABLE 1 The Use of .DELTA..sup.9 THC for the Treatment of Assorted
Clinical Conditions Condition and Administration Number of Patients
Route and Dose Findings Reference AIDS-associated anorexia Oral
placebo, 2.5 mg Long term THC treatment Beal et al., 1997 and
cachexia; THC once or twice was well-tolerated; THC 94 patients;
daily increasing to 20 mg improved appetite and only 12 months
daily tended to increase weight compared to controls
AIDS-associated anorexia Oral placebo or 2.5 mg 57% and 69% of
vehicle Beal et al., 1995 and cachexia; THC twice daily and THC
patients were 139 patients; evaluable for efficacy. 42 days
Appetite increased 38% over baseline for THC group compared to only
8% for the placebo group. THC also decreased nausea. No significant
changes were found between the groups for weight change. Nausea and
emesis due to Oral THC, 15 mg/m.sup.2 Reduction in McCabe et al.,
1988 Cancer chemotherapy; chemotherapy-induced 36 patients who had
nausea and vomiting in experienced severe 64% of patients given THC
nausea and vomiting that compared to was refractory to
prochloperazine; side prochlorperazine or effects included
dysphoria; thiethylperazine authors recommend initial THC dose of 5
mg/m.sup.2 Nausea and emesis due to Oral 5 or 15 mg/m.sup.2 72% of
patients exhibited a Lucas and Laszlo, Cancer chemotherapy; THC
four times per THC-induced partial or 1980 53 patients which were
day complete blockade of refractory to other vomiting antiemetics
Nausea and emesis due to Oral 10 mg/m.sup.2 THC THC more effective
than Sallan et al., 1980 cancer chemotherapy; of prochloperazine
prochloperazine 84 patients Nausea and emesis due to Oral 15 mg
THC, Equal antiemetic effects Frytak et al., 1979 Cancer
chemotherapy; 10 mg prochloperzine between THC and 116 patients or
placebo prochlorperazine, effects of each greater than placebo;
considerably more CNS side effects with THC than prochlorperazine
Nausea and emesis due to Oral placebo or 10 mg/m.sup.2 93% patients
had a Chang et al., 1979 Cancer chemotherapy; THC every 3 reduction
in nausea and 15 patients hours for a total of 5 vomiting, 53% had
an doses, THC (17 mg) excellent response, 40% laced cigarettes of
had a fair response; plasma placebo were given if THC levels 7.1
.+-. 6.9 (mean .+-. SD) ng/ml. vomiting occurred Side effects
tachycardia, few other side effects Pain due to advanced Oral
placebo and 5, Pain relief, elevated mood, Noyes, et al., 1975
cancer; 10 patients 10, 15 or 20 mg THC appetite stimulation,
drowsiness, slurred speech, mental clouding Pain due to advanced
Placebo, 10 and 20 mg THC produced a similar Noyes et al., 1975
cancer; 34 patients THC, and 60 and degree of analgesia, with 120
codeine greater potency than codeine. THC CNS side effects included
sedation, mental clouding, ataxia, and disorientation Spasticity
related to Oral 10 or 15 mg Improvement in passive Brenneisen et
al., multiple sclerosis; 2 THC, rectal dose of 5 mobility and
walking 1996 patients or 10 mg THC ability Spasticity related to
Oral 2.5 to 15 mg Significant subjective Ungerleider et al.,
multiple sclerosis; 13 THC once or twice improvement in spasticity
1987 patients daily or placebo at 7.5 mg THC and higher, no
significant improvement in objective measurements Spasticity
related to Oral 5 to 15 mg THC 5 of 8 patients had mild Clifford,
1983 multiple sclerosis; 8 subjective improvement in patients,
single blind tremor. 2 of 8 patients had both objective and
subjective improvement Spasticity related to Placebo, or 5 or 10 mg
Decrease in spasticity Petro and multiple sclerosis; 9 THC compared
to placebo Ellenberger, 1981 patients treatment, minimal side
effects Spasticity and pain due to Oral placebo, THC (5 mg), THC
and codeine had Maurer et al., 1990 spinal cord injury; 1 or
codeine (50 mg) analgesic effect compared patient to the placebo
treatment. THC had a beneficial effect on spasticity whereas
codeine did not Glaucoma, 6 patients Oral placebo or 5, 10, Pain
relief, elevated mood, Merritt et al, 1980 15 and 20 mg THC
appetite stimulation, drowsiness, slurred speech, mental clouding
Ten subjects with normal Intravenous THC Decreased intra ocular
Cooler and Gregg, intra ocular pressure (0.022 or 0.044 mg/kg)
presser by mean of 37% 1977 Nausea and emesis due to Oral 10
mg/m.sup.2 THC In 20 courses of THC, 5 Sallan et al., 1975 cancer
chemotherapy; or placebo resulted in no vomiting, 9 refractory to
other resulted in a reduction of antiemetics vomiting, 3 resulted
in no decrease in vomiting, and 2 were unevaluable. THC was
significantly better than placebo in decreasing vomiting
[0007] The year after the 1997 NIH study, the House of Lords made a
recommendation to the British government
(House-of-Lords-Select-Committee- -on-Science-and-Technology, 1998)
to reschedule marijuana. Similarly, there have been efforts to
decriminalize marijuana in the United States.
[0008] When marijuana is used as a recreational psychoactive drug,
the active ingredient .DELTA..sup.9 THC is usually delivered to the
lungs as an impure non-pharmaceutical aerosol in the form of
marijuana smoke. Aerosolized .DELTA..sup.9 THC in the inhaled smoke
is absorbed within seconds and delivered to the brain efficiently.
The pharmacokinetics of the administration of .DELTA..sup.9 THC is
described in PDR Physician's Desk Reference (49) Montvalek, New
Jersey: Medical Economics Data Production Co. (1995), pp.2787;
Ohlsson, A., Lindgren J. E., Wahlen, A., Agurall, S., Hollister, L.
E. and Gillespie, H. K., Plasma .DELTA..sup.9 THC concentrations
and effects after oral and intravenous administration and smoking,
Clin. Phamacol Ther. 28:409-416 (1980), summarized in Table 2
below. As can be seen, inhalation is the preferred route of
delivery for .DELTA..sup.9 THC. When compared to oral delivery,
inhalation provides a more rapid onset of pharmacological action
and peak plasma levels. The effects achieved via inhalation are
comparable to those achieved when the drug is administered
intravenously, but inhalation is a much less invasive
technique.
2TABLE 2 Pharmacokinetics of .DELTA..sup.9 THC Given Orally,
Intravenously or by Smoking Onset of % Dose in Pharmacological Peak
Plasma Route Dose Plasma Action Levels References Oral, sesame 2.5,
5, or 10 mg 10 to 20% 0.5 to 1 hour 120-480 min (PDR, 1995) oil in
gelatin capsules Oral, in 20 mg 4 to 12% 120-180 min 60-90 min
(Ohlsson, et cookies al., 1980) Intravenous, 5 mg 100% 10 min 3 min
(Ohlsson, et bolus al., 1980) Smoking 13 mg 8 to 24% 10 min 3 min
(Ohlsson, et (THC lost to al., 1980) side stream smoke and
pyrolysis
[0009] Currently, the sources of .DELTA..sup.9 THC for patients who
could benefit from the drug are limited. An oral form of
.DELTA..sup.9 THC (MARINOL) is marketed as a treatment for nausea
and vomiting related to cancer chemotherapy, and as an appetite
stimulant in patients suffering from AIDS wasting syndrome. In
MARINOL, pharmaceutical grade .DELTA..sup.9 THC is dissolved in
sesame oil, encapsulated in gelatin capsules and delivered orally.
However, when the drug is taken orally, the absorption is slower
and more variable than when inhaled, with an onset of action
between 30 minutes and 2 hours (Table 2). Drawbacks of MARINOL
include its slow onset of action and extensive first-pass
metabolism (Mattes, R. D. Shaw, L. M., Edling-Owens, J., Engelman,
K., Elsohly, M. A., Bypassing the first-pass effect for the
therapeutic use of cannabinoids, Pharmacol Biochem Behav,
44:745-747 (1993); Ohlsson, Lindgren, Whlen, Agurell, Hollister,
Gillespie, Plasma delta-9-hydrocannabinol concentration and
clinical effects after oral and intravenous administration and
smoking, Clin Pharmacol Ther (1980), supra; PDR, 2000; Perlin, E.,
Smith, C. G., Nichols, A. I., Almirez, R., Flora, K. P., Cradock,
J. C., Peck, C. C., Disposition and bioavailability of various
formulations of tetrahydrocannabinol in the rhesus monkey, J Pharm
Sci, 74:171-174 (1985)). There is also the difficulty of taking an
oral medication during nausea and vomiting.
[0010] In contrast, inhalation of marijuana smoke (as some cancer
patients do to alleviate nausea and vomiting due to chemotherapy)
results in the rapid delivery of a systemic dose of .DELTA..sup.9
THC while avoiding the first-pass metabolism. Barnett C., Chiang,
C., Perez-Reyes, M., Owens, S., Kinetic study of smoking marijuana,
J Pharmacokin Biopharm, 10, 495-506 (1982); Chiang, C. W., Barnett,
G., Marijuana effect and delta-9-tetrahydrocannabinol plasma level,
Clin Pharmacolo Ther, 36,234-238 (1984); Cone, E., Huestis, M.,
Relating blood concentrations of tetrahydrocannabinol and
metabolites to pharmacologic effects and time of marihuana usage,
Ther Drug Mon, 15:527-532 (1993); Huestis, M. A., Sampson, A. H.,
Holicky, B. J., Henningfield, J. E., Cone, E. J., Characterization
of the absorption phase of marijuana smoking, Clin Pharmacol Ther,
52:31-41 (1992); Johansson, E., Ohlsson, A., Lindgren, J. E.,
Agurell, S., Gillespie, H., Hollister, L. E., Single-dose kinetics
of deuterium-labelled cannabinol in man after intravenous
administration and smoking, Biomed Environ Mass Spectrom,
14:495-499 (1987); Ohlsson, A., Lindgren, J. E., Wahlen, A.,
Agurell, S., Hollister, L. E., Gillespie, H. K., Plasma delta-9
tetrahydrocannabinol concentrations and clinical effects after oral
and intravenous administration and smoking, Clin Pharmacol Ther,
28:409-16 (1980). Thus a patient would be expected to have better
control by using the smoking route than from an orally administered
gel capsule. However, inhalation of marijuana smoke exposes the
user to mutagens, carcinogens, and other harmful by-products of
pyrolysis. Hiller, F. C., Wilson, F.J.J., Mazumder, M. K., Wilson,
J. D., Bone, R. C., Concentration and particle size distribution in
smoke from marijuana cigarettes with different
.DELTA..sup.9-tetrahydrocannabinol content, Fundam Appl Toxicol,
4:451-454 (1984); Matthias, P., Tashkin, D. P., Marques-Magallanes,
J. A., Wilkins, J. N., Simmons, M. S., Effects of Varying Marijuana
Potency on Deposition of Tar and .DELTA..sup.9-THC in the Lung
During Smoking, Pharmacol Biochem Behav, 58:1145-1150 (1997). In
heavy users, marijuana smoke causes bronchial irritation and
impaired airway conductance (Henderson, R., Tennant, F., Guerney,
R., Respiratory manifestations of hashish smoking, Arch Otol,
95:248-251 (1972); Tashkin, D., Shapiro, B., Lee, Y., Harper, C.,
Subacute effects of heavy marihuana smoking on pulmonary function
in healthy men, N Eng J Med, 294:125-129 (1976)), as well as
depressed alveloar macrophage bactericidal activity (Huber, G. L.,
Simmons, G. A., McCarthy, C. R., Cutting, M. B., Laguarda, R.,
Pereira, W., Depressant effect of marihuana smoke on
antibactericidal activity of pulmonary alveolar macrophages, Chest,
68:769-73 (1975)). Another concern is the presence of numerous
untested chemicals in the smoke. In addition to .DELTA..sup.9 THC,
marijuana contains at least 60 cannabinoids and over 400 total
chemical constituents (Ross, S., Elsohyl, M., Constituents of
Cannabis sativa L., XXVIII, A review of the natural constituents:
1980-1984, Zagazig J Pharm Sci, 4:1-10 (1995); Turner, C., Bouwsma,
O., Billets, S., Elsohly, M., Constituents of Cannabis sativa L.
XCIII--Electron voltage selected ion monitoring study in
cannabinoids, Biomed Mass Spectrom, 7:247-256 (1980)), increasing
the likelihood of multiple drug interactions. Further, marijuana
remains illegal in most jurisdictions. Inhalation of marijuana
smoke is thus not a particularly desirable treatment.
[0011] The Institute of Medicine (IOM) recently reviewed the
scientific evidence for the potential of marijuana and its
cannabinoid constituents to act as therapeutic agents. Joy, J.,
Watson Jr., S., Benson, J. E., Marijuana and Medicine: Assessing
the Science Base (Washington, D. C.: National Academy Press, 1999).
This report concluded that there is a potential for cannabinoid
drugs, mainly .DELTA..sup.9 THC, for alleviation of pain, control
of nausea and vomiting, and stimulation of appetite. However, they
pointed out that marijuana is a "crude .DELTA..sup.9--THC delivery
system" that delivers harmful chemicals along with the delivery of
.DELTA..sup.9 THC, and recommended instead the development of a
rapid-onset, reliable, and safe delivery .DELTA..sup.9 THC system.
The House of Lords Select Committee on Science and Technology
(Ninth Report) made similar suggestions to the British Government
(House-of-Lords-Select-Committee-on-Science-and-Technology, 1998).
Although the scheduling of cannabis has not been changed by the
British or U.S. governments, the U.S. FDA has rescheduled MARINOL
to a Schedule 3 drug, thus increasing the feasibility of developing
other delivery forms of the drug.
[0012] There is no currently available pharmaceutically acceptable
aerosol form of .DELTA..sup.9 THC. It would be advantageous to have
available a form of pharmaceutical grade .DELTA..sup.9 THC that
could be administered as an aerosol. This would provide a means for
rapid uptake of the drug. Also, the potential adverse side effects
encountered by smoking marijuana would be avoided. Further, an
aerosol preparation of pharmaceutically pure .DELTA..sup.9 THC
could be administered in known, controlled dosages. In 1976, Olsen
et al. described a chlorofluorocarbon (CFC) propelled MDI
formulation of .DELTA..sup.9 THC. Olsen, J. L., Lodge, J. W.,
Shapiro, B. J. and Tashkin, D. P., An inhalation aerosol of
.DELTA..sup.9-tetrahydrocannabinol. J Pharmacy and pharmacol.,
28:86 (1976). However, .DELTA..sup.9 THC is known to deteriorate
during storage, and the stability of .DELTA..sup.9 THC in this
formulation is suspect. In addition, the ethanol content in this
formulation was so high (.about.23%) as to create an aerosol with
droplets too large to be effectively inhaled. Dalby, R. N. and
Byron, P. R., Comparison of output particle size distributions from
pressurized aerosols formulated as solutions or suspensions, Pharm.
Res. 5:36-39 (1988). The .DELTA..sup.9 THC CFC formulations were
tested for use in treating asthma but were shown to be only
moderately effective. Tashkin, D. P., Reiss, S., Shapiro, B. J.,
Calvarese, B., Olsen, J. L. and Lidgek, J. W., Bronchial effects of
aerosolized .DELTA..sup.9-tetrahydrocannabinol in healthy and
asthmatic subjects, Amer. Rev. of Resp. Disease. 115:57-65 (1977);
Williams, S. J., Hartley, J. P. R. and Graham, J.D.P.,
Bronchodilator effect of delta-9-THC administered by aerosol to
asthmatic patients. Thorax. 31:720-723 (1976). Moreover, CFC
propellants have since been banned so that a CFC propellant
alternative would be particularly useful. It would clearly be
advantageous to develop new aerosol formulations using a non-CFC
propellant and having other advantageous features.
[0013] To date, much of the .DELTA..sup.9-THC aerosol exposure in
humans concentrates on the bronchodilation effects of
.DELTA..sup.9-THC. Tashkin et al. (1977) used a .DELTA..sup.9-THC
MDI to deliver aerosolized .DELTA..sup.9-THC to healthy and
asthmatic patients in an effort to assess bronchodilation as well
as possible side effects due to systemic absorption. Tashkin, D.
P., Reiss, S., Shapiro, B. J., Calvarese, B., Olsen, J. L., Lodge,
J. W., Bronchial effects of aerosolized
delta-9-tetrahydrocannabinol in healthy and asthmatic subjects, Am
Rev Respir Dis, 115:57-65 (1977). In healthy patients,
bronchodilation was seen, as well as substantial systemic side
effects (increased heart rate and subjective reports of being
`high`) at higher doses. However, in some asthmatic patients;
bronchoconstriction occurred. Tashkin et al. suggested that large
particle size of the .DELTA..sup.9-THC aerosol may have caused the
local irritant effects. Vachon et al. (1976) reported the use of a
nebulized .DELTA..sup.9-THC micro-aerosol to achieve
bronchodilation without systemic effects, however, the propylene
glycol vehicle had irritant effects. Vachon, J., Robins, A.,
Gaensler, E. A., Airways, response to aerosolized
delta-9-tetrahydrocannabinol: preliminary report, in The
therapeutic potential of marijuana, eds. Cohen, S., Stillman, R.
C., pp. 111-121 (New York: Plenum Medical Book Co., 1976). Williams
et al. (1976) also used a low concentration of .DELTA..sup.9-THC
for bronchodilation without systemic side effects or detectable
levels of .DELTA..sup.9-THC in the blood. Williams, S. J., Hartley,
J. P., Graham, J. D., Bronchodilator effect of delta
1-tetrahydrocannabinol administered by aerosol of asthmatic
patients, Thorax, 6:720-723 (1976). It would clearly be
advantageous to develop new aerosol formulations in which the
.DELTA..sup.9 THC is stable, the droplets are of a size that can be
effectively inhaled, and which use a non-CFC propellant.
[0014] Such objectives have been long desired but difficult to
achieve, because of problems such as the difficulty of working with
.DELTA..sup.9 THC, large dosage amounts required for .DELTA..sup.9
THC, and properties of .DELTA..sup.9 THC that make it unlike, and
not interchangeable with, most other drugs. For example,
.DELTA..sup.9 THC resembles rubber-cement, rather than a powder
like most drugs, and thus presents formulation difficulties.
Scientists working with THC found that they had to go to great
lengths to combat its instability, based on its instability to
light, oxygen, acids, bases, metal ions, etc. Thus, after the
initial interest in the 1970s in THC/CFC aerosols, scientists
generally settled into an acceptance of the unworkability of a THC
aerosol. The initial promise of a THC aerosol according to J. L.
Olsen, J. W. Lodge, B. J. Shapiro and D. P. Tashkin (1975) never
materialized, and in the past few decades it has been
conventionally thought that THC is not suited for
aerosol-dispensing, and especially not for MDI-dispensing.
[0015] Thus, a pharmaceutically effective THC aerosol that
overcomes the above-mentioned limitations of the prior art,
especially an MDI-dispensible aerosol would be much desired.
SUMMARY OF THE INVENTION
[0016] The present inventors have now discovered, surprisingly,
that THC dissolves well in HFA and that an aerosol-dispensable
THC/HFA pharmaceutical composition--i.e., a sufficiently stable
composition and at the high doses which are required for THC--may
be formulated. The present invention exploits these surprising
discoveries. It is an object of the present invention to provide a
stable aerosol-dispensable pharmaceutical composition comprising a
non-CFC propellant and a pharmaceutically effective concentration
of .DELTA..sup.9 THC, and .DELTA..sup.9 THC derivatives (e.g.,
cannabinoids such as .DELTA..sup.8-tetrahydrocannabinol, 11-hydroxy
.DELTA..sup.9-tetrahydroca- nnabinol, cannabinol, cannabidol,
nabilone, levonantradol, (-)-HU-210, Win 55212-2, Anandamide,
Methandamide, CP 55940, O-1057, SR141716A, etc.). More
particularly, it is an object of the present invention to provide a
stable aerosol-dispensable pharmaceutical composition comprising a
hydrofluoroalkane propellant (for example, HFA 227 or HFA 134a) and
.DELTA..sup.9 THC. The propellant is present in the range of
approximately 78 to 100% by weight, and more particularly the
propellant is present in the range of approximately 85 to 100% by
weight. An organic solvent such as ethanol can be used to assist in
solubilizing the .DELTA..sup.9 THC in the propellant but is not
required. If a solvent is used, preferably less than 20% by weight
will be required, and most preferably less than 15% by weight will
be required. The pharmaceutically effective concentration of
.DELTA..sup.9 THC is preferably in the range of 0.05 to 10% by
weight, and most preferably in the range of 0.1 to 6% by weight.
The pharmaceutical composition of the present invention can be used
to treat a variety of medical conditions including nausea and
vomiting associated with cancer chemotherapy, muscle spasticity,
pain, anorexia associated with AIDS wasting syndrome, anorexia
associated with cancer chemotherapy, epilepsy, glaucoma, bronchial
asthma, mood disorders, migraine headaches.
DETAILED DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a .DELTA..sup.9 THC MDI characterization summary
before and after storage at 40.degree. C. and 82% relative humidity
(RH).
[0018] FIG. 2 are generalized schematic drawings of a .DELTA..sup.9
THC MDI.
[0019] FIGS. 3A-3D are graphs reflecting cannabinoid activity
parameters (locomotor activity, % immobility, % MPE, temperature)
for mice exposed to .DELTA..sup.9-THC aerosol according to the
invention.
[0020] FIGS. 4A-D are graphs showing the effect of pretreatment
with SR 141716A on the behavioral effects of inhaled
.DELTA..sup.9-THC according to the invention for mice.
[0021] FIG. 5 is a graph of % MPE versus SR 141716A dose, showing
the dose-response relationship of SR 141716A in antagonizing the
antinociceptive effects following exposure to aerosolized
.DELTA..sup.9-THC according to the invention.
[0022] FIG. 6A is the chemical structure for HFA 134a; FIG. 6B is
the chemical structure for HFA 227.
[0023] FIG. 7A is the chemical formula for .DELTA..sup.9 THC and
FIGS. 7B-7N are chemical formulae for compounds according to the
present invention, including .DELTA..sup.8 THC (FIG. 7B), 11
hydroxy .DELTA..sup.9-THC (FIG. 7C), cannabinol (CBN) (FIG. 7D),
cannabidiol (CBD) (FIG. 7E), nabilone (FIG. 7F), levonantradol
(FIG. 7G), (-)-HU-210 (FIG. 7H), Win 55212-2 (FIG. 7I) Anandamide
(FIG. 7J), Methandamide (FIG. 7K), CP 55940 (FIG. 7L), 0-1057 (FIG.
7M) and SR141716A (FIG. 7N).
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION
[0024] The instant invention provides non-ozone depleting
pressurized metered dose inhaler formulations of .DELTA..sup.9 THC.
In preferred embodiments of the invention, the formulations contain
the pharmaceutically acceptable, non-ozone depleting
hydrofluoroalkane propellants HFA 134a (1,1,1,2-tetrafluoroethane)
and HFA 227 (1,1,1,2,3,3,3-heptafluoropropane), or a mixture
thereof.
[0025] When the propellant is a hydrofluoroalkane, it has been
discovered that the propellant may be used with or without a
solvent such as ethanol. Higher percentages of solvent generally
allow higher levels of dissolution of .DELTA..sup.9 THC. However,
higher percentages of solvent also cause droplet size to increase.
In preferred embodiments of the invention, the range of propellant
compositions, as shown in Table 3, may be from 100% propellant and
0% solvent to 85% propellant and 15% solvent. Within this range of
percentages, pharmaceutically useful concentrations of
.DELTA..sup.9 THC can be achieved and droplet size is still small
enough (<5.8 .mu.m) to provide excellent aerosol delivery of the
drug. While these ratios reflect preferred embodiments of the
invention, it will be recognized by those of skill in the art that
the exact ratio of propellant to solvent (e.g. ethanol) may vary
according to the desired final concentration of .DELTA..sup.9 THC
and droplet size. Any ratio of propellant to solvent that results
in appropriate sized droplets and adequate dissolution of the
.DELTA..sup.9 THC may be used in the practice of this invention,
and this will generally be in the range of from 100 to 80%
propellant and 0 to 20% solvent. It is expected that a wide variety
of solvents, such as ethanol, propanol, propylene glycol, glycerol,
polyethylene glycol, etc. may be used in the preparation of
formulations contemplated by this invention.
[0026] Those skilled in the art also will recognize that the
"respirable dose" (or mass of .DELTA..sup.9 THC in particles with
aerodynamic diameters small enough to be delivered to and absorbed
by the lungs) (FIG. 1) may be increased by choosing MDI spray
nozzles of different design and smaller orifice diameters.
Respirable doses may also be increased by extending the mouthpiece
of the MDI in such a way as to create an integral or separate
aerosol spacer or reservoir attached to the mouthpiece of the MDI.
This promotes an increase in droplet evaporation and hence in the
percentage of the dose in smaller "respirable" particles or
droplets. Generally, the optimal size of a respirable droplet is
less than 10 micrometers (.mu.m) in size. The size of a droplet in
an aerosol may be measured by cascade impaction and is
characterized by the mass median aerodynamic diameter (MMAD) (the
value for which 50% of the particles are larger or smaller). Using
THC aerosols according to the present invention, an MMAD of 2.5
.mu.m or better may be provided.
3TABLE 3 Apparent Solubility of .DELTA..sup.9 THC in Ethanol/HFA
Propellant Blends Mass (g) of Mass (g) of Apparent .DELTA..sup.9
THC in Formulation Solubility Formulation Sample Sampled Mean
(.+-.SD) Comments .DELTA..sup.9 THC in 0.000240 0.1071 0.224% w/w
Excess .DELTA..sup.9 THC 100% HFA 134a (.+-.0.063) added to
propellant blend (in pressurized MDI). Solubility sample removed
using puff absorber n = 5 .DELTA..sup.9 THC in 5% 0.00144 0.0914
1.585% w/w As above Ethanol/95% (.+-.0.321) HFA 134a .DELTA..sup.9
THC in 0.00363 0.1036 3.511% w/w As above 10% (.+-.0.249)
Ethanol/90% HFA 134a .DELTA..sup.9 THC in 0.00536 0.1098 4.883% w/w
As above 15% (.+-.0.224) Ethanol/85% HFA 134a .DELTA..sup.9 THC in
0.00021 0.1451 0.147% w/w As above 100% HFA 227 (.+-.0.008)
.DELTA..sup.9 THC in 5% 0.00134 0.0979 1.339% w/w As above
Ethanol/95% (.+-.0.169) HFA 227 .DELTA..sup.9 THC in 0.00454 0.1267
3.240% w/w As above 10% (.+-.0.161) Ethanol/90% HFA 227
.DELTA..sup.9 THC in 0.00623 0.1062 5.940% w/w As above 15%
(.+-.0.191) Ethanol/85% HFA 227
[0027] A distinct advantage of the present formulations is that,
surprisingly, the use of surface active agents or "surfactants" as
valve lubricants and solubilizers is not necessary. This is in
contrast to the invention of Purewal and Greenleaf (European Patent
0,372,777 (Riker Laboratories), Medicinal aerosol formulations)
which provides HFA 134a/ethanol mixtures to produce stable
formulations of pharmaceuticals in the presence of lipophilic
surface active agents. Lipophilic surface active agents are
incorporated in that invention in order to suspend undissolved
material and to ensure adequate valve lubrication of the MDI.
Without adequate valve lubrication, the useful life of the MDI and
its ability to deliver an accurate dose of drug are severely
attenuated. However, probably due to the inherent lubricity of the
formulations of the present invention, the use of such surface
active agents is unnecessary. This simplifies the composition and
thus is an advantage with respect to cost and the elimination of
potentially deleterious interactions between components of the
formulations and the agents.
[0028] A major consideration in the formulation of any drug is its
stability. .DELTA..sup.9 THC is known to deteriorate upon storage
so that the effective concentration decreases and the purity is
vitiated. The stability of the formulations of the present
invention were tested according to accelerated storage testing
protocols. The results are given in FIG. 1 and Tables 4A and 4B.
The formulations of the present invention were shown to be stable
with respect to the release of aerosolized .DELTA..sup.9 THC in
reproducible doses following accelerated storage testing.
Apparently, the containment of .DELTA..sup.9 THC in solution in the
non-aqueous formulations of the present invention is excellent with
respect to chemical degradation, making possible the construction
of a multidose inhaler with a good shelf life prognosis.
[0029] Further, lipophilic materials like .DELTA..sup.9 THC are
generally known to partition into the elastomers of the valves in
MDI formulations. (.DELTA..sup.9 THC is highly lipophilic as
reflected in its octanol: water partition coefficient of 6000: 1).
Over time, this partitioning results in a decrease in the emitted
or delivered dose of a lipophilic drug. Thus, this phenomenon also
decreases the useful shelf-life of such preparations. However, the
data presented in FIG. 1 and Table 4 show that this is not the case
with the formulations of the present invention. The emitted or
delivered doses were constant over the time period tested. This may
be due to the somewhat surprising preference of .DELTA..sup.9 THC
for the formulation itself, rather than for the valve
elastomers.
4TABLE 4A Formulation and aerosol characteristics of .DELTA..sup.9
THC pressurized metered dose inhalers in ethanol/hydrofluoroalkane
(HFA) propellant blends. Formulation (%(w/w) Inhaler .DELTA..sup.9
THC Ethanol Propellant Description 1 0.13% .about.5% 95% HFA 134a
3/98 Pale Yellow Solution 2 0.13% .about.5% 95% HFA 227 3/98 Pale
Yellow Solution 3 0.12% .about.5% 95% HFA 134a 3/98 Pale Yellow
Solution 4 0.18% .about.5% 95% HFA 134a 3/98 Pale Yellow Solution 5
0.27% .about.5% 95% HFA 227 3/98 Pale Yellow Solution 6 0.25%
.about.5% 95% HFA 134a 3/98 Pale Yellow Solution 7 0.57% .about.5%
95% HFA 134a 3/98 Yellow Solution 8 0.58% .about.5% 95% HFA 227
3/98 Yellow Solution 9 0.49% .about.5% 95% HFA 134a 3/98 Yellow
Solution 10 1.02% .about.5% 95% HFA 134a 3/98 Yellow Solution 11
1.11% .about.5% 95% HFA 227 3/98 Yellow Solution 12 0.97% .about.5%
95% HFA 134a 3/98 Yellow Solution SS* #1 Initial 1.07% 4.94% 94.0%
HFA 134a 6/98 Yellow Solution SS* #1 after 1.07% 4.94% 94.0% HFA
134a 7/98 Yellow Solution 28 days at 40.degree. C./82% RH** SS* #2
after 1.00% 5.01% 94% HFA 134a 7/98 Yellow Solution 21 days at
40.degree. C./82% RH** SS* #3 1.02% 5.15% 93.8% HFA 134a 10/98
Yellow Solution Modified Actuator*** .sup.aMean (Standard
Deviation) of five determinations. .sup.bMass of .DELTA..sup.9 THC
aerosol particles <5.8 .mu.m aerodynamic diameter *SS: Stability
Sample **RH: relative humidity ***Approximate spray nozzle diameter
= 0.2 mm.
[0030]
5TABLE 4B Formulation and aerosol characteristics of .DELTA..sup.9
THC pressurized metered dose inhalers in ethanol/hydrofluoroalkane
(HFA) propellant blends. Aerosol Characterization Metered Dose
Emitted Dose Fine Particle Inhaler (mg).sup.a (mg).sup.a Dose
(mg).sup.a,b 11 1.72 (0.25) 1.32 (0.17) ND 12 0.94 (0.23) 0.97
(0.10) 0.38 (0.02) SS* #1 Initial 1.10 (0.07) 0.90 (0.03) 0.22
(0.03) SS* #1 after 28 days at 1.06 (0.03) 0.92 (0.04) 0.23 (0.02)
40.degree. C./82% RH** SS* #2 after 21 days at 1.02 (0.05) 0.90
(0.05) 0.21 (0.02) 40.degree. C./82% RH** SS* #3 Modified ND ND
0.40 (n = 1) Actuator*** .sup.aMean (Standard Deviation) of five
determinations. .sup.bMass of .DELTA..sup.9 THC aerosol particles
<5.8 .mu.m aerodynamic diameter *SS: Stability Sample **RH:
relative humidity ***Approximate spray nozzle diameter = 0.2 mm ND:
not determined
[0031] The final concentration of .DELTA..sup.9 THC in a given
formulation may be varied by adjusting the ratio of propellant to
solvent and thus the solubility of the .DELTA..sup.9 THC. Higher
percentages of solvent (e.g. ethanol) generally allow a higher
amount of .DELTA..sup.9 THC to be dissolved. For example, in
preferred embodiments of the invention, the apparent solubility of
.DELTA..sup.9 THC ranged from 0.147% w/w to 5.94% w/w as the
propellant composition varied from 100% HFA 227 to 85% HFA 227 and
15% ethanol. Thus, the dose of .DELTA..sup.9 THC in a given metered
volume may be selected by changing the formulation.
[0032] Further, as stated above, the "fine particle dose" or
"respirable dose" of a drug dispensed with an MDI is a function of
the spray nozzle diameter. In FIG. 1 and Tables 4A and 4B, the
spray nozzle diameter is 0.4 mm. The "fine particle dose" or
"respirable dose" of the formulations of the present invention was
shown to be unaffected by storage.
[0033] The .DELTA..sup.9 THC of the present invention is
pharmaceutically pure. That is, its form is the nonionized resinous
drug substance
(6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d-
]-pyran-1-ol. Although its preferred embodiment in this invention
is not a salt or ester, it will be readily understood by those of
skill in the art that other appropriate forms of .DELTA..sup.9 THC
may be synthesized (e.g. esters and salts such as those described
in, for example, U.S. Pat. No. 5,847,128 and PCT WO 01/03690,
hereby incorporated in their entirety by reference) and thus used
in the practice of this invention.
[0034] The desired final concentration of .DELTA..sup.9 THC in a
patient's serum will vary from patient to patient depending on, for
example, the nature and severity of the condition being treated,
and the patient's overall condition, weight, gender and response to
the drug, etc. But the desired range will generally be 10-100 ng/ml
at 15 minutes following inhalation. The level of .DELTA..sup.9 THC
in a patient's serum can be readily and reliably monitored by gas
chromatography/mass spectrophotometry (GC/MS).
[0035] The exact treatment protocol to be used may vary from
patient to patient depending on the circumstances. For example, in
a preferred embodiment of the invention, a patient receiving
chemotherapy may have one dose of .DELTA..sup.9 THC prescribed via
inhalation, to be administered 15 minutes before chemotherapy and
4-8 times daily following chemotherapy. In another preferred
embodiment, a patient suffering from anorexia associated with AIDS
wasting syndrome may have .DELTA..sup.9 THC by inhalation
prescribed 3-5 times daily, 30 minutes before each meal or snack.
In other preferred embodiments, a patient suffering form cancer
pain, or spasticity related to either multiple sclerosis or spinal
cord injury may have .DELTA..sup.9 THC by inhalation prescribed 3-6
times daily. Those skilled in the art will readily recognize that
the treatment protocol may be crafted so as to address the
particular needs of each individual patient on a case by case
basis.
[0036] .DELTA..sup.9 THC may be used alone or in combination with
other medications. Those skilled in the art will readily recognize
that, for example, in the case of AIDS wasting syndrome, the
patient will likely also be taking drugs that combat the AIDS
virus. Similarly, those skilled in the art will readily recognize
that patients receiving chemotherapy for cancer may also receive
other antiemetics, and cancer patients seeking to relieve pain are
likely to receive opioids as well as nonsteroidal anti-inflammatory
agents. The containers for the formulations of the instant
invention may be any that are suitable for the efficacious delivery
of aerosol inhalants. Several containers and their method of usage
are known to those of skill in the art. For example, MDIs can be
used with various dose metering chambers, various plastic actuators
and mouthpieces, and various aerosol holding chambers (e.g. spacer
and reservoir devices), so that appropriate doses of .DELTA..sup.9
THC reach and deposit in the lung and are thereafter absorbed into
the bloodstream. In addition, a lock mechanism such as that shown
in U.S. Pat. No. 5,284,133 to Bums and Marshak, which is herein
incorporated by reference, can be used to prevent overdose or
unauthorized consumption of .DELTA..sup.9 THC. FIG. 2 provides a
generalized drawing of an MDI containing the composition of this
invention and provides the advantage of delivering metered
quantities of .DELTA..sup.9 THC on a repetitive basis. The MDI
includes a container 100 for holding the composition and a valve
delivery mechanism 102 for delivery of aerosolized .DELTA..sup.9
THC.
[0037] In vivo Experimentation
[0038] A .DELTA..sup.9 THC MDI was formulated and the physical
properties of the aerosolized drug characterized. The mass of drug
metered by the metering valve was determined following a single
actuation (metered dose). The mass of drug delivered (emitted dose)
was determined. The mass of particles with an aerodynamic diameter
less than 4.7 .mu.m was determined.
[0039] Whether inhalation exposure to .DELTA..sup.9 THC aerosol
would elicit pharmacological effects indicative of cannabinoid
activity in mice (Compton, D. R., Rice, K. C., De Costa, B. R.,
Rzdan, R. K., Melvin, L. S., Johnson, M. R., Martin, B. R.,
Cannabinoid structure-activity relationships: Correlation of
receptor binding and in vivo activities, J Pharmacol Exp Ther, 265:
218-226 (1993); Little et al., 1988) was determined. To assess
whether these effects were mediated through a cannabinoid receptor
mechanism of action, the specific CB.sub.1 receptor antagonist SR
141716A (Rinalidi-Carmona et al., 1994) was used. Blood and brain
levels of .DELTA..sup.9 THC were quantified to provide direct
evidence that the drug was absorbed following inhalation exposure.
The resulting blood and brain .DELTA..sup.9 THC concentrations
following inhalation exposure were compared to those found
following intravenous .DELTA..sup.9 THC administration using doses
of drug that elicited similar antinociceptive effects.
[0040] Male ICR mice, weighing approximately 30 g, obtained from
Harlan Laboratories (Indianapolis, Ind.) were provided a light
cycle of approximately 6 a.m. to 6 p.m., and the temperature
remained approximately 23.degree. C. The mice were placed in the
lab and allowed to accommodate to the surroundings the evening
prior to testing. Animals were allowed food (Harlan Teklab,
Madison, Wis.) and water ad libitum.
[0041] SR 141716A and .DELTA..sup.9 THC were obtained from the
National Institute on Drug Abuse (Bethesda, Md.). For systemic
injections, SR 141716A and .DELTA..sup.9 THC were dissolved in
vehicle, 1:1:18 (ethanol:alkamuls EL-620 (formerly Emulphor EL-620,
Rhone-Poluence):saline). Each MDI consisted of a clean, dry, 20 ml
plastic coated glass bottle (Wheaton Glass, Milville, N.J.) with a
100 .mu.l inverted metering valve (BK 357, Bespak, Inc., Cary,
N.C.). The MDI vehicle consisted of hydrofluoroalkane (HFA) 134a
(DuPont, Wilmington, Del.) and ethanol (Aaper Alcohol and Chemical
Co., Shelbyville, KY). The .DELTA..sup.9 THC MDIs were prepared
using the methods of Byron, 1994 with a formulation that provided a
theoretical ex-valve dose of 1 mg .DELTA..sup.9 THC per 100 .mu.l
actuation. Byron, P. R., Dosing reproducibility from experimental
albuterol suspension metered-dose inhalers, Pharm Res, 11, 580-4
(1994).
[0042] Appearance, metered dose reproducibility, emitted dose and
particle size distribution of the .DELTA..sup.9 THC MDI were
investigated, before and after storage in an environment maintained
at 40.degree. C. and 82% relative humidity for a 28 day period. The
mass of drug metered by the metering valve (metered dose, n 10) was
determined by collecting single actuations directly from the valve
in a puff absorber, using the methods of Byron, 1994. The mass of
drug delivered (emitted dose, n=10) was investigated at 28.3 1
min.sup.-1 using the USP Dosage Sampling Apparatus (USP, Physical
Tests and Determinations, <601>, Aerosols, metered-dose
inhalers, and dry powder inhalers, in United States Pharmacopeia,
(USP 24), pp. 1895-1912 (Philadelphia, Va.: National Publishing,
2000). Particle size analysis of .DELTA..sup.9-THC MDI was
determined by drawing the samples through an Andersen Cascade
Impactor (Andersen Samplers Inc., Atlanta, Ga.) at a volumetric
flow rate of 28.3 liter/minute following United States
Pharmacopeial guidelines (n=5; USP, 2000). The fine particle dose
(n=5), defined as the mass of particles with an aerodynamic
diameter less than 4.7 .mu.m, was then determined.
[0043] THC was analyzed by LC-UV detection at 280 nm using a 75:25
acetonitrile: 1% acetic acid mobile phase for .DELTA..sup.9-THC
detection. A standard reverse phase C18 column was used. A
calibration curve was constructed for each assay based on linear
regression of the. .DELTA..sup.9-THC standard peak areas.
[0044] The exposure chamber was a modified, inverted, 1-liter
separation funnel, housed under a fume hood, which allowed four
mice to be simultaneously exposed to the aerosol. Air was drawn
through the chamber at a rate of approximately 60 ml/minute and
filtered through glass wool (Corning Inc., Corning, N.Y.) and
charcoal traps (SKC Inc., Eighty Four, PA) upon exiting the
exposure chamber. Each actuation of .DELTA..sup.9-THC or vehicle
was delivered once per 5 s and the entire exposure period was 10
min. Mice were exposed to 20, 40 or 60 actuations of aerosolized
.DELTA..sup.9-THC or 60 actuations of vehicle.
[0045] Mice were placed in separate clear chambers (16.5
cm.times.25.5 cm.times.11.5 cm high) and assessed for hypomotility
using a Digiscan Animal Activity Monitor (Omnitech Electronics
Inc., Columbus, Ohio) in which the total number of photocell-light
beam interruptions was counted. Antinociception was assessed in the
tail-flick test (D'Amour, F. E., Smith, D. L., A method for
determining loss of pain sensation, J Pharm Exp Ther, 72:74-79
(1941)) with heat intensity adjusted to give baseline latencies
ranging from 2.0-4.0 seconds. A cut-off time of 10 seconds was used
to limit tissue damage. Percent maximum possible effect (% MPE) was
determined according to the following formula:
%MPE=[(test latency-baseline latency)/(cut-off-baseline
latency)]*100
[0046] A ring-test procedure was used to assess catalepsy. The
percent of time during a five minute observation period that mice
remained motionless, except for movements related to respiration,
while stationed on a 5.7 cm diameter ring stand 23 cm above the
laboratory bench, was assessed. Body temperature was assessed by
inserting a thermometer probe (Traceable Digital, Control Co.,
Friendswood, Tex.) 2.5 cm into the rectum. Subjects were assessed
for baseline tail-flick latency and rectal temperature prior to
drug or vehicle administration. In the antagonism studies, mice
were given an i.p. injection of SR 141716A or vehicle five-minutes
prior to inhalation exposure of aerosols from 60 actuations of
either a vehicle or a .DELTA..sup.9-THC MDI. Locomotor activity,
tail-flick latency, catalepsy, and hypothermia were assessed 5, 20,
40, and 60 minutes, respectively, after aerosol exposure. An
additional group of animals was given an i.v. injection of
.DELTA..sup.9-THC (0.3, 1, 3, or 10 mg/kg) or vehicle into a
lateral tail vein and assessed in the tail-flick test 20 minutes
later. All injections were given in a volume of 0.1 ml per 10 g
animal weight.
[0047] Blood and brain levels of .DELTA..sup.9-THC were determined
as follows. Extraction and LC-MS quantification of
.DELTA..sup.9-THC from whole blood and brain tissue were modified
from Lichtman, A. H., Poklis, J. L., Wilson, D. M., Martin, B. R.,
The pharmacological activity of inhalation exposure to marijuana
smoke in mice, Drug Alc Depend, 63:107-116(2001). Particularly, THC
and .sub.2H.sup.3-THC were extracted from brain material which
contains a high degree of lipids. Acetonitrile was added to the
pelletized solids and stored in a freezer overnight to separate the
acetonitrile layer (which contained THC/.sub.2H.sup.3-THC) from the
aqueous layers. The following day the acetonitrile layer was
removed. In the Lichtman et al., study, 2 ml of 9:1 NaOH was added
and the sample was vortexed. Four ml of 9:1 hexane:ethyl acetate
was added and the sample was vortexed and spun at 30 rpm for 30
minutes. The vials were then centrifuged at 4,000 rpm at 30 rpm for
10 minutes. The organic layer was removed and evaporated. Upon
drying, a derivatizing agent was added and the sample was vortexed,
and each sample analyzed by GC/MS. In the present experimentation,
the acetonitrile was instead evaporated to dryness under nitrogen.
The material was then resolubilized in 0.1 ml methanol. LC-MS
identification was used to quantify
.DELTA..sup.9-THC/.sub.2H.sup.3-THC in blood and brain matrices. In
the present experimentation, calibration standards were prepared
from blank mouse whole blood and homogenized brain (2:1,
water:brain, v:w). Fifty ng of .sup.2H.sub.3-THC (Radian
Corporation, Austin, Tex.) was added to the blood sample, brain
homogenate, and calibrators as an internal standard. Following an
equilibration period, 2.5 ml of cold acetonitrile (HPLC grade,
Fisher Scientific, Raleigh, N.C.) was added drop-wise while
vortexing. The samples were then centrifuged (Precision
Vari-Hi-Speed Centricone, Precision Scientific Co., Chicago, Ill.)
at 2500 rpm for 15 minutes to pelletize solids, then stored in the
freezer (-20.degree. C.) overnight, allowing the acetonitrile layer
to separate from the aqueous layers. The acetonitrile layer was
then removed and evaporated to dryness under nitrogen. The
.DELTA..sup.9-THC/.sup.2H.sub.3-THC was then resolubilized in 0.1
ml methanol (HPLC grade, Fisher Scientific).
[0048] LC-MS identification was used for quantification of
.DELTA..sup.9-THC and .sup.2H.sub.3-THC in blood and brain matrices
using an 85:15 methanol: 1% glacial acetic acid (0.1% formic acid)
mobile phase. A guard column was used inline with the standard
reverse phase C18 column. The mass spectrometer was run in
APCI+mode. Ions analyzed in single ion monitoring mode were 315 for
.DELTA..sup.9-THC and 318 for .sup.2H.sub.3-THC. A calibration
curve was constructed for each assay based on linear regression
using the peak-area ratios of .DELTA..sup.9-THC to
.sup.2H.sub.3-THC of the extracted calibration samples.
[0049] The statistical analysis of the data was as follows. Data
are represented by means.+-.standard error (s.e.). Statistical
analysis of the data was performed using Student t-tests (for the
physiochemical comparisons of the aerosol), or ANOVA (for
pharmacological studies), with significance set at p<0.05. Post
hoc tests for significant ANOVAs included either Dunnett's test or
Tukey/Kramer post-hoc analysis. All ED.sub.50 values were
determined using least squares linear regression analysis and
calculation of 95% confidence limits (Bliss, C. I., Statistics in
Biology (New York: McGraw-Hill, 1967) and were based on the number
of actuations of the MDI (i.e., 1 mg/actuation). The Emax for
depression of locomotor activity was calculated by double
reciprocal plot. The Emax value for percent imobility was assigned
the mean from the group that was exposed to 60 mg
.DELTA..sup.9-THC. The Emax values for antinociception and
hypothermia were 100% MPE and 6.degree. C. respectively. The
ED.sub.50 of SR 141716A in antagonizing the antinociceptive effects
of .DELTA..sup.9-THC was determined through least squares linear
regression analysis and calculation of 95% confidence limits
(Bliss, 1967). A sample size of 6-8 mice was used in each
group.
[0050] Results. THC MDI Physiochemical Characteristics
[0051] As shown in Table 5 below, the physiochemical
characteristics of the aerosolized .DELTA..sup.9-THC were
unaffected following storage at 40.degree. C. with 82% relative
humidity for 28 days. The mass of drug metered by the metering
valve following a single actuation was reproducible and unaffected
by the accelerated stability storage (p>0.1). There was little
variance in the emitted dose and no significant effect of storage
(p>0.1). The fine particle dose represented 23.0.+-.0.8% before
and 23.6.+-.0.8% after accelerated stability testing of the emitted
dose and exhibited no deterioration in .DELTA..sup.9-THC content
(p>0.1).
6TABLE 5 Physiochemical characteristics of the .DELTA..sup.9-THC
MDI before and after accelerated stability testing (mean .+-.
s.e.). after 28 days initial 40.degree. C./82% Dose n evaluation
relative humidity Metered dose 10 1.10 .+-. 0.02 1.06 .+-. 0.01
Emitted dose 10 0.90 .+-. 0.01 0.92 .+-. 0.01 Fine particle dose 5
0.21 .+-. 0.01 0.22 .+-. 0.01
[0052] Behavioral Evaluation
[0053] Having thus determined that the tested MDI delivered a
.DELTA..sup.9-THC aerosol with particles of a sufficiently small
mass for lung absorption, further experimentation was conducted to
determine whether inhalation exposure to this aerosol could elicit
systemic pharmacological effects in mice. Mice exposed to the
.DELTA..sup.9-THC aerosol exhibited cannabinoid activity in each of
the four parameters tested (FIGS. 3A-D). Significant effects were
found for locomotor inhibition F(3,28)=5.9, p<0.05) (FIG. 3A),
antinociception (F(3,28)=7.8, p<0.05) (FIG. 3B), ring immobility
(F(3,28)=10.0, p<0.05) (FIG. 3C), and hypothermia (F(3,28)=26.4,
p<0.5) (FIG. 3D). The groups exposed to 40 and 60 actuations of
.DELTA..sup.9-THC aerosol significantly differed from vehicle
aerosol exposure (Dunnett's test, p<0.05). ED.sub.50 (95% CL)
values were 32 (26-41) mg delivered for locomotor depression, 30
(20-44) mg delivered for antinociception, 30 (22-39) mg delivered
for ring immobility, and 33 (25-44) mg of drug delivered for
hypothermia.
[0054] FIGS. 4A-D show the effect of pretreatment with the specific
CD.sub.1 receptor antagonist, SR 141716A on the behavioral effects
of inhaled .DELTA..sup.9-THC. Two-way ANOVA revealed that SR
141716A (10 mg/kg) significantly blocked .DELTA..sup.9-THC-induced
hypomotility (F(1,28)=7.4, p<0.05), antinociception
(F(1,28)=25.2, p<0.05), catalepsy (F(1,28)=7.4, p<0.05), and
hypothermia (F(1,28)=28.9, p<0.05). The groups given a vehicle
pretreatment and exposed to the .DELTA..sup.9-THC aerosol differed
from all other groups for each measure (Tukey test, p<0.05).
[0055] The dose-response relationship of SR 141716A in antagonizing
the antinociceptive effects following exposure to 60 mg of
aerosolized .DELTA..sup.9-THC is shown in FIG. 5. SR 141716A
significantly blocked the antinociception, F(5,30)=21.6, p<0.05,
with an AD.sub.50 (95% C. L.) of 0.8 (0.7-1.1) mg/kg.
[0056] Table 6 shows the blood and brain .DELTA..sup.9-THC
concentrations, 20 min after either inhalation exposure to
.DELTA..sup.9-THC aerosol or intraveneous injection of
.DELTA..sup.9-THC. Increasing the amount of drug delivered resulted
in increasing concentrations of .DELTA..sup.9-THC in both matrices.
The blood levels of .DELTA..sup.9-THC following aerosol exposure
20, 40, or 60 mg delivered increased in a dose dependent fashion
and were comparable to the blood levels produced by intravenous
injection of 3 and 10 mg/kg .DELTA..sup.9-THC. Brain levels of
.DELTA..sup.9-THC following those exposures were similar to that of
1 and 3 mg/kg intravenous injection of .DELTA..sup.9-THC. There was
dissociation in .DELTA..sup.9-THC blood and brain concentrations
between the inhalation and intravenous routes of administration, an
interesting result because other drugs such as methamphetamine,
heroin and phencyclidine have been observed to lead to similar
brain:blood plasma ratios between the two routes of administration.
For the present experimentation, whereas brain levels were 200-300%
higher than blood levels following i.v. injection of
.DELTA..sup.9-THC, the brain levels of .DELTA..sup.9-THC were
roughly equivalent to the blood levels of .DELTA..sup.9-THC
following inhalation.
7TABLE 6 Antinociceptive effect and blood and brain concentrations
of .DELTA..sup.9-THC 20 min after treatment ng .DELTA..sup.9-THC/
ng .DELTA..sup.9-THC/ % MPE g blood g brain route of (mean .+-.
(mean .+-. (mean .+-. administration THC dose S.E.) S.E.) S.E.)
inhalation 20 actuations 37 .+-. 11* 409 .+-. 86 340 .+-. 36 40
actuations 58 .+-. 14* 788 .+-. 273 791 .+-. 94 60 actuations 78
.+-. 11* 1132 .+-. 240 890 .+-. 151 intravenous 1 mg/kg 31 .+-. 8
102 .+-. 6 307 .+-. 28 3 mg/kg 70 .+-. 14 365 .+-. 39 854 .+-. 42
10 mg/kg 67 .+-. 11 1324 .+-. 38 3307 .+-. 190 *From FIG. 3B
[0057] Comparison of MDI antinociceptive potency with blood and
brain concentrations of .DELTA..sup.9-THC resulted in a high
correlation (r.sup.2=0.997 and r.sup.2=0.889 for blood and brain,
respectively). Additionally, comparison of blood and brain levels
of .DELTA..sup.9-THC at antinociceptive EC.sub.50 doses for
inhalation and i.v. injection of .DELTA..sup.9-THC as well as
comparison of potency ratios between the two routes of
administration revealed no significant differences in the different
matrices (Table 7).
8TABLE 7 Comparison of .DELTA..sup.9-THC blood and brain
concentrations at antinociceptive ED.sub.50 doses Route of Blood
Brain Administration ED.sub.50 (95% C.L.) ED.sub.50 (95% C.L.)
ED.sub.50 (95% C.L.) inhalation 30 (20-44) 591 (403-866)* 506
(333-769)* actuations intravenous 2.4 (1.4-4.2) 230 (102-521) 604
(270-1350) mg/kg *Potency ratios (95% C.L.) in blood, 1.8
(0.5-4.2), and in brain, 0.6 (0.2-1.5), were not significantly
different
[0058] The HFA 134a-ethanol formulated MDI delivered a respirable
.DELTA..sup.9-THC aerosol in an accurate and reproducible fashion.
Preliminary accelerated stability testing revealed that no
significant degradation of the .DELTA..sup.9-THC occurred following
storage in extreme conditions. Mice exposed to the aerosol
exhibited a full spectrum of pharmacological effects indicative of
cannabinoid activity (Compton et al., 1993; Little, P. J., Compton,
DR., Johnson, M. R., Melvin, L. S., Martin, B. R., Pharmacology and
stereoselectivity of structurally novel cannabinoids in mice, J
Pharmacol Exp Ther, 247:1046-1051 (1988)) including hypoactivity,
antinociception, catalepsy, and hypothermia. Each of these
responses was dose-dependent and antagonized by SR 141716A,
indicating a CB.sub.1 receptor mechanism of action. The hypothermic
effects of .DELTA..sup.9-THC were not completely antagonized.
SR141716A's low ED.sub.50 (i.e., 0.8 mg/kg) in antagonizing the
antinociceptive effects of inhaled .DELTA..sup.9-THC is in
agreement with those of previous reports including exposure to
marijuana smoke (0.6 mg/kg; Lichtman et al., 2001), injection of
.DELTA..sup.9-THC (0.4 mg/kg; Compton, D., Aceto, M., Lowe, J.,
Martin, B., In vivo characterization of a specific cannabinoid
receptor antagonist (SR141716A): inhibition of
delta-9-tetrahydrocannabinol-induced responses and apparent agonist
activity, J Pharmacol Exp Ther, 277, 586-594 (1996)), or injection
of the synthetic cannabinoid WIN 55,212-2 (1.6 mg/kg;
Rinaldi-Carmona, M., Barth, F., Heaulme, M., Shire, D., Calandra,
B., Congy, C., Martinez, S., Maruani, J., Neliat, G., Caput, D.,
Ferrara, P., Soubrie, P., Breliere, J. C., Le Fur, G., SR141716A, a
potent and selective antagonist of the brain cannabinoid receptor,
FEBS Lett, 350:240-244 (1994)).
[0059] Unlike parenteral methods of delivery in which a known
amount of drug is injected, determining the absorbed dose of an
inhaled drug is difficult to quantify. Although a large mass of
drug was actuated into the inhalation chamber, the majority of drug
mass is lost because it either deposits on the exposure apparatus
or escapes with exhausted air out of the apparatus. Additionally,
physiological properties, such as tidal volume and respiratory
rate, influence drug inhalation. Finally, because mice are obligate
nasal breathers, many particles do not reach the lungs. Therefore,
for the above experimentation, dose was indirectly assessed by
comparing the concentration of .DELTA..sup.9-THC in whole blood and
brain after inhalation and i.v. routes of adminstration. For both
routes of administration, the concentrations of drug increased in
both matrices with increasing doses. Inhalation exposure of each
respective dose of aerosolized .DELTA..sup.9-THC resulted in
equivalent concentrations of the parent compound in blood and
brain. On the other hand, i.v. administration resulted in
.DELTA..sup.9-THC brain levels that were approximately two to three
fold higher than those found in blood. The EC.sub.50 values for
inhalation exposure and i.v. injection in the above experimentation
were not significantly different in either matrix. Consequently,
exposure to the .DELTA..sup.9-THC aerosol produced dose-dependent
increases of .DELTA..sup.9-THC in blood and brain levels, and the
levels necessary to produce cannabinoid behavioral effects were
similar to i.v. injection.
[0060] In applying the results of the above experimentation on mice
to other animals, it will be taken into account that mice are
obligate nose-breathers with an extensive nasal infra-architecture,
such that substantial nasal deposition may have hindered alveoli
deposition. Schlesinger (1985) reported upper respiratory tract
deposition of particle sizes between 2-3 .mu.m ranged from 20-40%.
Schlesinger, R. B., Comparative deposition of inhaled aerosols in
experimental animals and humans: a review, J Toxicol Environ
Health, 15:197-214 (1985). Using empirical modeling, Asgharian et
al. (1995) calculated that less than 15% of particles with a mass
median aerodynamic diameter of 2-3 .mu.m could reach the alveolar
regions of rats compared to a 40% value in humans, and this
percentage would be expected to be even lower in mice because of
the smaller respiratory tract and general anatomical differences
between rats and mice. Asgharian, B., Wood, R., Schlesinger, R. B.,
Empirical modeling of particle deposition in the alveolar region of
the lungs: A basis for interspecies extrapolation, Fund Appl
Toxicol, 27, 232-238 (1995). Consequently, a considerable amount of
the exposed dose is likely to have been deposited in the upper
respiratory tract of the mice. In addition, such impacted particles
could be moved to the throat, via ciliary action, and swallowed,
resulting in gastrointestinal absorption. However, such absorption
would not be expected to be as rapid as alveolar absorption. Hence,
this delayed absorption might act to maintain .DELTA..sup.9-THC
blood and brain levels for a prolonged period of time. Despite the
extensive filtering done by mice, the fine particle dose generated
by the MDI (i.e., 0.22 mg per actuation) was sufficient to result
in the rapid elicitation of pharmacological behavior suggesting
that the behavioral effects were due to absorption in either the
lungs or the upper respiratory tract and not due to
gastrointestinal absorption. Nonetheless, nasal filtering is of
little concern in humans and the fact that locomotor depression
occurred within 5 minutes of exposure and antinociception occurred
at 20 minutes is consistent with the notion that a sufficient
amount of the aerosol reached the lungs.
[0061] The results of Tables 5-7 and FIGS. 3A-5 are particularly
significant because of the difficulties of exploiting properties
of, and effectively delivering, .DELTA..sup.9-THC. For example,
cannabinoid activity in mice has been reported following exposure
to marijuana smoke; however, placebo smoke mimicked marijuana in
hypothermia and locomotor inhibition assays. Lichtman et al., 2001.
Moreover, in the Lichtman et al. study, SR 141716A only effectively
antagonized the antinociceptive response, raising concerns that
exposure to the other chemicals in burned marijuana besides
.DELTA..sup.9-THC, as well as possible effects of a hypoxic state,
were of consequence there. These other chemicals may have unwanted
and unexpected interactions with other drugs. Thus, delivering
.DELTA..sup.9-THC without all the other chemicals of marijuana is
highly advantageous. However, such .DELTA..sup.9-THC delivery has
not been easily provided. The behavioral effects of a
.DELTA..sup.9-THC aerosol generated by a nebulizer have been
reported, A. H. Lichtman, J. Peart, J. L. Poklis, D. T. Bridgen, R.
Z. Razdan, D. M. Wilson, A. Poklis, Y. Meng, P. R. Byron, B. R.
Martin, "Pharmacological evaluation of aerosolized cannabinoids in
mice," Eur. J. Pharmacol. 399:141-149 (2000). While this method for
exposing mice to a .DELTA..sup.9-THC aerosol removed the
confounding influence of smoke, the only cannabinoid behavior
observed was a moderate degree of antinociception. Although
separation of the potentially therapeutic effects, such as
antinociception, from the other pharmacological effects of
.DELTA..sup.9-THC is a desirable goal, the modest cannabinoid
effect was attributed to the relatively low blood levels of
.DELTA..sup.9-THC. A 10-minute exposure to the nebulized aerosol
resulted in a drug blood concentration of approximately 100 ng
.DELTA..sup.9-THC/ml blood, whereas the .DELTA..sup.9-THC blood
levels of mice following a 10 minute exposure to 20 actuations of
the MDI aerosol was around 400 ng/g blood. (Table 8.) Another
problem with using the nebulizer to deliver aerosolized
.DELTA..sup.9-THC is the vehicle for dissolution of
.DELTA..sup.9-THC, with some surfactants (such as Emulphor) not
having FDA approval for inhalation exposure in humans.
9TABLE 8 .DELTA..sup.9-THC blood levels in mice .DELTA..sup.9-THC
blood level Administration (ng .DELTA..sup.9-THC/ml blood)
Nebulized aerosol* 100 MDI aerosol** (20 actuations) 400 *Emulphor
as the surfactant **Ethanol cosolvent; HFA 134a propellant
[0062] Other advantages of .DELTA..sup.9-THC delivery according to
the present invention also are seen. The present invention delivers
a systemic dose of .DELTA..sup.9-THC via the lungs. The development
of a .DELTA..sup.9-THC MDI, which leads to a rapid onset of action,
consistent blood levels, and by-passing the first-pass metabolism
in the liver, suggests the viability of the .DELTA..sup.9-THC
aerosol as a replacement for oral .DELTA..sup.9-THC.
[0063] In sum, the experimentation discussed above with regard to
Tables 5-7 and FIGS. 3A-5 show, inter alia, that a
.DELTA..sup.9-THC MDI was formulated that can be used to provide a
systemic dose of .DELTA..sup.9-THC via the lungs, and that a
.DELTA..sup.9 THC MDI is capable of producing the full
constellation of cannabinoid effects in mice. Physiochemical
characteristics of the aerosol were assessed before and after
accelerated stability testing. Following this characterization,
mice were exposed to the aerosol and evaluated for pharmacological
effects indicative of cannabinoid activity, including hypomotility,
antinociception, catalepsy, and hypothermia. The CB .sub.1 receptor
antagonist SR 141716A was used to determine whether the
pharmacological effects were mediated by the cannabinoid receptor.
The fine particle does of .DELTA..sup.9 THC was 0.22.+-.0.03 mg
(mean.+-.S.D.) or 25% of the emitted dose. In addition, the
physiochemical properties of the aerosol were unaffected by
accelerated stability testing. A 10-minute exposure to aerosolized
.DELTA..sup.9 THC elicited hypomotility, antinociception,
catalepsy, and hypothermia. Additionally, .DELTA..sup.9 THC
concentrations in blood and brain at the antinociceptive ED.sub.50
dose were similar for both inhalation and intravenous routes of
administration. Finally, pretreatment with 10 mg/kg (i.p.) of SR
141716A significantly antagonized all of the .DELTA..sup.9
THC-induced effects. These results indicate that an MDI is a viable
method to deliver a systemic dose of .DELTA..sup.9 THC that elicits
a full spectrum of cannabinoid pharmacological effects in mice that
is mediated via a CB.sub.1 receptor mechanism of action.
[0064] The experimental findings set forth herein suggest that an
aerosolized form of .DELTA..sup.9-THC for medicinal use may be
provided. Dosages for mice have been provided, and typically human
doses are about 100 times lower than mouse doses on a mg/kg basis.
The demonstration that a .DELTA..sup.9-THC aerosol, generated by a
MDI, is relatively stable and produces systemic pharmacological
effects in mice has clinical applications in the treatment of many
disorders, including pain management as well as the indications for
orally-available .DELTA..sup.9-THC. The availability of a highly
reproducible .DELTA..sup.9-THC aerosol, without exposure to
potentially harmful chemicals and carcinogens present in marijuana
smoke, is particularly advantageous for the treatment of human
patients.
[0065] While in the present invention use of .DELTA..sup.9 THC (see
FIG. 7A) is particularly preferred, it will be appreciated that in
place of .DELTA..sup.9 THC may be used .DELTA..sup.9 THC
derivatives and substitutes, e.g., .DELTA..sup.8 THC (FIG. 7B), 11
hydroxy .DELTA..sup.9-THC (FIG. 7C), cannabinol (CBN) (FIG. 7D),
cannabidiol (CBD) (FIG. 7E); synthetic cannabinoids (such as
nabilone (FIG. 7F), levonantradol (FIG. 7G), (-)--HU-210 (FIG. 7H),
Win 55212-2 (FIG. 7I)); Anandamide (FIG. 7J), Methandamine (FIG.
7K), CP 55940 (FIG. 7L), 0-1057 (FIG. 7M), SR141716A (FIG. FIG.
7N).
[0066] While the invention has been described in terms of its
preferred embodiments, those skilled in the art will recognize that
the invention can be practiced with modification within the spirit
and scope of the appended claims.
* * * * *