Δ9 Tetrahydrocannabinol (Δ9 THC) solution metered dose inhaler

Abstract

The present invention provides therapeutic formulations for solutions of Δ9-tetrahydrocannabinol (Δ9 THC) to be delivered by metered dose inhalers. The formulations, which utilize non-CFC propellants, provide a stable aerosol-deliverable source of Δ9 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.

Description

DESCRIPTION

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is generally related to the therapeutic use of Δ 9 Tetrahydrocannabinol (Δ 9 THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of Δ 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.

2. Background Description

“Medical Marijuana” is a timely and controversial subject that is currently receiving widespread public attention. While marijuana is usually thought of as an illegal “recreational” drug, it also has a long history as a medicine. 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 (1). Table 1 summarizes the findings of several studies (references 2-18) that have documented therapeutically beneficial medicinal uses of the major active component of marijuana, Δ 9 tetrahydrocannabinol (Δ 9 THC).

TABLE 1
The Use of Δ 9 THC for the Treatment of Assorted Clinical Conditions
Condition
and Number	Administration
of Patients	Route and Dose	Findings	Reference
AIDS-associated	Oral placebo,	Long term THC	Beal et al.,
anorexia and	2.5 mg THC once	treatment was	1997
cachexia; 94	or twice daily	well tolerated;
patients; 12	increasing to 20	THC improved
months	mg daily	appetite and
		only tended to
		increase weight
		compared to
		controls
AIDS-associated	Oral placebo or	57% and 69%	Beal et al.,
anorexia and	2.5 mg THC	of vehicle and	1995
cachexia; 139	twice daily	THC patients
patients; 42 days		were evaluable
		for efficacy.
		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	Oral THC, 15	Reduction in	McCabe et al.,
emesis due to	mg/m 2	chemotherapy-	1988
cancer		induced nausea
chemotherapy; 36		and vomiting in
patients who		64% of patients
had experienced		given THC
severe nausea		compared to
and vomiting		prochloperazine;
that was		side effects
refractory to		included
prochlorperazine		dysphoria;
or		authors
thiethylperazine		recommend
		initial THC
		dose of 5
		mg/m 2
Nausea and	Oral 5 or	72% of patients	Lucas and
emesis due to	15 mg/m 2 THC	exhibited a THC-	Laszlo, 1980
cancer	four times per day	induced partial
chemotherapy; 53		or complete
patients which		blockade of
were refractory		vomiting
to other
antiemetics
Nausea and	Oral 10 mg/m 2	THC more	Sallan et al.,
emesis due to	THC of	effective than	1980
cancer	prochloperazine	prochloperazine
chemotherapy; 84
patients
Nausea and	Oral 15 mg THC,	Equal antiemetic	Frytak et al.,
emesis due to	10 mg	effects between	1979
cancer	prochloperzine	THC and
chemotherapy;	or placebo	prochlorperazine,
116 patients		effects of each
		greater than
		placebo; consider-
		ably more
		CNS side effects
		with THC than
		prochlorperazine
Nausea and	Oral placebo or	93% patients had	Chang et al.,
emesis due to	10 mg/m 2	a reduction in	1979
cancer	THC every 3	nausea and
chemotherapy; 15	hours for a	vomiting, 53%
patients	total of 5	had an excellent
	doses, THC	response, 40%
	(17 mg) laced	had a fair
	cigarettes of	response; plasma
	placebo were	THC levels
	given if vomiting	7.1 ± 6.9
	occurred	(mean ± SD)
		ng/ml. Side
		effects
		included sedation,
		tachycardia, few
		other side effects
Pain due to	Oral placebo and	Pain relief,	Noyes, et al,
advanced cancer;	5, 10, 15 or	elevated mood,	1975
10 patients	20 mg THC	appetite
		stimulation,
		drowsiness,
		slurred
		speech, mental
		clouding
Pain due to	Placebo, 10 and	THC produced a	Noyes et al.
advanced cancer;	20 mg THC, and	similar degree	1975
34 patients	60 and 120	of analgesia,
	codeine	with greater
		potency than
		codeine.
		THC CNS side
		effects
		included sedation,
		mental clouding,
		ataxia,
		and disorientation
Spasticity related	Oral 10 or 15 mg	Improvement in	Brenneisen et
to multiple	THC, rectal dose	passive mobility	al., 1996
schlerosis; 2	of 5 or 10	and walking
patients	mg THC	ability
Spasticity related	Oral 2.5 to 15	Significant	Ungerleider et
to multiple	mg THC once or	subjective	al., 1987
schlerosis; 13	twice daily or	improvement in
patients	placebo	spasticity at 7.5
		mg THC and
		higher,
		no significant
		improvement
		in objective
		measurements
Spasticity related	Oral 5 to 15 mg	5 of 8 patients	Clifford, 1983
to multiple	THC	had mild
schlerosis; 8		subjective
patients, single		improvement in
blind		tremor. 2 of 8
		patients had both
		objective and
		subjective
		improvement
Spasticity related	Placebo, or	Decrease in	Petro and
to multiple	5 or 10 mg	spasticity	Ellenberger,
schlerosis; 9	THC	compared	1981
patients		to placebo
		treatment,
		minimal side
		effects
Spasticity and	Oral placebo,	THC and codeine	Maurer et al.,
pain due to	THC (5 mg), or	had analgesic	1990
spinal cord injury;	codeine (50 mg)	effect compared
1 patient		to the placebo
		treatment. THC
		had a beneficial
		effect
		on spasticity
		whereas codeine
		did not
Glaucoma, 6	Oral placebo	Pain relief	Merritt et
patients	or 5, 10, 15	elevated mood,	al, 1980
	and 20 mg THC	appetite
		stimulation,
		drowsiness,
		slurred speech,
		mental clouding
Ten subjects	Intravenous THC	Decreased intra	Cooler and
with normal	(0.022 or 0.044	ocular pressure	Gregg, 1977
intra ocular	mg/kg)	by a mean of 37%
pressure
Nausea and	Oral 10 mg/m 2	In 20 courses of	Sallan et al.,
emesis due to	THC or placebo	THC, 5 resulted	1975
cancer		in no vomiting,
chemotherapy;		9 resulted in a
refractory to		reduction of
other antiemetics		vomiting, 3
		resulted in no
		decrease in
		vomiting,
		and 2 were
		unevaluable. THC
		was significantly
		better than
		placebo
		in decreasing
		vomiting.

When marijuana is used illegally as a recreational psychoactive drug, the active ingredient Δ 9 THC is usually delivered to the lungs as an impure non-pharmaceutical aerosol in the form of marijuana smoke. Aerosolized Δ 9 THC in the inhaled smoke is absorbed within seconds and delivered to the brain efficiently. Table 2 and references 19-20 describe the pharmacokinetics of the administration of Δ 9 THC. As can be seen, inhalation is the preferred route of delivery for Δ 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.

TABLE 2
Pharmacokinetics of Δ 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 to 20%	0.5 to 1 hour	120-480 min	(PDR, 1995)
oil in gelatin	10 mg
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

Currently, the sources of Δ 9 THC for patients who could benefit from the drug are very limited. An oral form of Δ 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 Δ 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). Alternatively, some cancer patients do manage to obtain and smoke marijuana in order to alleviate such conditions as nausea and vomiting due to chemotherapy. This is, however, technically illegal and is thus obviously a less than ideal treatment protocol. There is no currently available pharmaceutically acceptable aerosol form of Δ 9 THC.

It would be advantageous to have available a form of pharmaceutical grade Δ 9 THC that could be administered as an aerosol. This would provide a means for rapid uptake of the drug without resorting to the illegal practice of smoking marijuana. Also, the potential adverse side effects encountered by smoking marijuana would be avoided. Further, an aerosol preparation of pharmaceutically pure Δ 9 THC could be administered in known, controlled dosages.

In 1976, Olsen et al. described a chlorofluorocarbon (CFC) propelled MDI formulation of Δ 9 THC (21). However, Δ 9 THC is known to deteriorate during storage, and the stability of Δ 9 THC in this formulation is suspect. In addition, the ethanol content in this formulation was so high (˜23%) as to create an aerosol with droplets too large to be effectively inhaled (22). The Δ 9 THC CFC formulations were tested for use in treating asthma but were shown to be only moderately effective (23, 24). Moreover, CFC propellants have since been banned so that such a formulation is now useless. It would clearly be advantageous to develop a new aerosol formulation in which the Δ 9 THC is stable, the droplets are of a size that can be effectively inhaled, and which utilizes a non-CFC propellant.

SUMMARY OF THE INVENTION

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 Δ 9 THC. 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 Δ 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 Δ 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 Δ 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

FIG. 1 . Δ 9 THC MDI characterization summary before and after storage at 40° C. and 82% relative humidity (RH).

FIG. 2 . Generalized schematic drawings of a Δ 9 THC MDI.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION

The instant invention provides a series of non-ozone depleting pressurized metered dose inhaler formulations of Δ 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.

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 Δ 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 Δ 9 THC can be achieved and droplet size is still small enough (<5.8 μm) 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 Δ 9 THC and droplet size. Any ratio of propellant to solvent that results in appropriate sized droplets and adequate dissolution of the Δ 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.

Those skilled in the art will also recognize that the “respirable dose” (or mass of Δ 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 μm in size.

TABLE 3
Apparent Solubility of Δ 9 THC in Ethanol/HFA Propellant Blends
		Mass
	Mass	(g) of
	(g) of	Formu-
	Δ 9 THC	lation	Apparent
	in	Sam-	Solubility
Formulation	Sample	pled	Mean (±SD)	Comments
Δ 9 THC in	0.000240	0.1071	0.224% w/w	Excess Δ 9 THC
100% HFA			(±0.063)	added to propellant
134a				blend (in
				pressurized MDI).
				Solubility sample
				removed using puff
				absorber. n = 5
Δ 9 THC in 5%	0.00144	0.0914	1.585% w/w	As above
Ethanol/95%			(±0.321)
HFA 134a
Δ 9 THC in 10%	0.00363	0.1036	3.511% w/w	As above
Ethanol/90%			(±0.249)
HFA 134a
Δ 9 THC in 15%	0.00536	0.1098	4.883% w/w	As above
Ethanol/85%			(±0.224)
HFA 134a
Δ 9 THC in	0.00021	0.1451	0.147% w/w	As above
100% HFA 227			(±0.008)
Δ 9 THC in 5%	0.00134	0.0979	1.339% w/w	As above
Ethanol/95%			(±0.169)
HFA 227
Δ 9 THC in 10%	0.00454	0.1267	3.240% w/w	As above
Ethanol/90%			(±0.161)
HFA 227
Δ 9 THC in 15%	0.00623	0.1062	5.940% w/w	As above
Ethanol/85%			(±0.191)
HFA 227

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; reference #25) 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.

A major consideration in the formulation of any drug is its stability. Δ 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 Δ 9 THC in reproducible doses following accelerated storage testing. Apparently, the containment of Δ 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.

Further, lipophilic materials like Δ 9 THC are generally known to partition into the elastomers of the valves in MDI formulations. (Δ 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 emmited 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 Δ 9 THC for the formulation itself, rather than for the valve elastomers.

TABLE 4A
Formulation and aerosol characteristics of Δ 9 THC pressurized metered dose
inhalers in ethanol/hydrofluoroalkane (HFA) propellant blends
	Formulation (% w/w)
Inhaler	Δ 9 THC	Ethanol	Propellant	Description
1	0.13%	˜5%	95% HFA 134a	3/98 Pale Yellow Solution
2	0.13%	˜5%	95% HFA 227	3/98 Pale Yellow Solution
3	0.12%	˜5%	95% HFA 134a	3/98 Pale Yellow Solution
4	0.18%	˜5%	95% HFA 134a	3/98 Pale Yellow Solution
5	0.27%	˜5%	95% HFA 227	3/98 Pale Yellow Solution
6	0.25%	˜5%	95% HFA 134a	3/98 Pale Yellow Solution
7	0.57%	˜5%	95% HFA 134a	3/98 Yellow Solution
8	0.58%	˜5%	95% HFA 227	3/98 Yellow Solution
9	0.49%	˜5%	95% HFA 134a	3/98 Yellow Solution
10	1.02%	˜5%	95% HFA 134a	3/98 Yellow Solution
11	1.11%	˜5%	95% HFA 227	3/98 Yellow Solution
12	0.97%	˜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° C./82% RH**
SS* #2 after	1.00%	5.01%	95% HFA 134a	7/98 Yellow Solution
21 days at
40° C./82% RH**
SS* #3 Modified	1.02%	5.15%	93.8% HFA 134a	10/98 Yellow Solution
Actuator***
a Mean (Standard Deviation) of five determinations.
b Mass of Δ 9 THC aerosol particles <5.8 μm aerodynamic diameter
*SS: Stability Sample
**RH: relative humidity
***Approximate spray nozzle diameter = 0.2 mm.

TABLE 4B
Formulation and aerosol characteristics
of Δ 9 THC pressurized metered dose inhalers in
ethanol/hydrofluoroalkane (HFA) propellant blends
	Aerosol Characterization
			Fine
	Metered Dose	Emitted Dose	Particle Dose
Inhaler	(mg) a	(mg) a	(mg) 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	1.06 (0.03)	0.92 (0.04)	0.23 (0.02)
28 days at
40° C./82% RH**
SS* #2 after	1.02 (0.05)	0.90 (0.05)	0.21 (0.02)
21 days at
40° C./82% RH**
SS* #3 Modified	ND	ND	0.40 (n = 1)
Actuator***
a Mean (Standard Deviation) of five determinations.
b Mass of Δ 9 THC aerosol particles with <5.8 μm aerodynamic diameter
*SS: Stability Sample
**RH: relative humidity
ND: not determined
***Approximate spray nozzle diameter = 0.2 mm

The final concentration of Δ 9 THC in a given formulation may be varied by adjusting the ratio of propellant to solvent and thus the solubility of the Δ 9 THC. Higher percentages of solvent (e.g. ethanol) generally allow a higher amount of Δ 9 THC to be dissolved. For example, in preferred embodiments of the invention, the apparent solubility of Δ 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 Δ 9 THC in a given metered volume may be selected by changing the formulation.

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 0.4mm. The “fine particle dose” or “respirable dose” of the formulations of the present invention was shown to be unaffected by storage.

The Δ 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 Δ 9 THC may be synthesized (e.g. esters and salts) and thus used in the practice of this invention.

The desired final concentration of Δ 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 Δ 9 THC in a patient's serum can be readily and reliably monitored by gas chromatography/mass spectrophotometry (GC/MS).

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 Δ 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 Δ 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 Δ 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.

Δ 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 Δ 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 Burns and Marshak, which is herein incorporated by reference, can be used to prevent overdose or unauthorized consumption of Δ 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 Δ 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 Δ 9 THC.

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.

REFERENCES

1. Workshop on the medical utility of marijuana. National Institutes of Health, August 1997.

2. 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. (1997) Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain. Symptom Manage . 14:7-14.

3. Beal, J. A., Olson, R., Laubenstein, L., Morales, J. O., Bellman, B., Yangco, B., Lefkowitz, L., Plasse, T. F. and Shepard, K. V. (1995) Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS J Pain. Symptom Manage . 10:89-97.

4. McCabe, M., Smith, F. P., MacDonald, J. S., Wooley, P. V., Goldberg, D. and Schein, P. S. (1988) Efficacy of tetrahydrocannabinol in patients refractory to standard antiemetic therapy. Invest. New Drugs 6:243-246.

5. Lucas, V. S. and Laszlo, J. (1980) Δ 9 -THC for refractory vomiting induced by cancer chemotherapy. JAMA 243:1241-1243.

6. Sallan, S. E., Cronin, C., Zelen, M. and Zinberg, N. E. (1980) Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of Δ 9 THC and prochlorperazine. N Engl. J Med . 302:135-138. p 0 7. Frytak, S., Moertel, C. G., O'Fallon, J. R., Rubin, J., Creagan, E. T., O'C.onnell, M. J., Schutt, A. J. and Schwartau, N. W. (1979) Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy: a comparison with prochlorperazine and a placebo. Ann. Inter. Med . 91:825-830.

8. Chang, A. E., Shiling, D. J., Stillman, R. C., Goldgerg, N. H., Seipp, C.A., Barofdky, I., Simon, R. M. and Rosenberg SA (1979) Δ 9 THC as an antiemitic in cancer patients receiving high-dose methotrexate. Ann. Internal. Med . 91:819-824.

9. Sallan, S. E., Zinberg, N. E. and Frei, I. E. (1975) Antiemetic effect of Δ 9 THC in patients receiving cancer chemotherapy. New Engl. J. Med . 293:795-797.

10. Noyes, J. R., Brunk, S. F., Baram, D. A. and Canter, A. (1975) The analgesic properties of Δ 9 THC and codeine. J. Clin. Pharmacol . 15:139-143.

11. Noyes, R., Jr., Brunk, S. F., Baram, D. A. and Canter, A. (1975) Analgesic effect of Δ 9 -tetrahydrocannabinol. J. Clin. Pharmacol . 15:139-143.

12. Brenneisen, R., Egli, A., Elosohlly, M. A., Henn, V. and Spiess, Y. (1996) The effect of orally and rectally administered Δ 9 THC on spasticity: a pilot study with 2 patients. Int. J. Clin. J. Pharmocol. Ther . 34:446-452.

13. Ungerleider, J. T., Andyrsiak, T. F. L., Ellison, G. W. and Myers, L. W. (1987) Δ 9 THC in the treatment of spasticity associated with multiple sclerosis. Adv. Alcohol Subst. Abuse 7:39-50.

14. Clifford, D. B. (1983) Tetrahydrocannabinol for tremor in multiple sclerosis. Ann. Neurol . 13:669-171.

15. Petro, D. J. and Ellenberger, C. (1981) Treatment of human spasticity with delta 9-tetrahydrocannabinol. J. Clin. Pharmacol . 21:413S-416S.

16. Maurer, M., Henn, V., Dittrich, A. and Hofinan, A. (1990) Delta 9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur. Arch. Psychiatry Neurol. Sci . 240:1-4.

17. Merritt, J., Crawford, W., Alexander, P., Anduze, A. and Gelbart, S. (1980) Effects of marihuana on intra ocular and blood pressure in glaucoma. Opht . 87:222-228.

18. Cooler, P. and Gregg, J. M. (1977) Effect of delta 9-Δ 9 THC on intra ocular pressure in humans. South. Med J . 70:951-954.

19. PDR (1995) Physician's Desk Reference (49) Montvalek, New Jersey: Medical Economics Data Production Co., pp.2787.

20. Ohlsson, A., Lindgren, J. E., Wahlen, A., Agurall, S., Hollister, L. E. and Gillespie, H. K. (1980) Plasma Δ 9 THC concentrations and effects after oral and intravenous administration and smoking. Clin. Pharmacol. Ther . 28:409-416.

21. Olsen, J. L., Lodge, J. W., Shapiro, B. J. and Tashkin, D. P. (1976) An inhalation aerosol of Δ 9 -tetrahydrocannabinol. J. Pharmacy and Pharmacol . 28:86.

22. Dalby, R. N. and Byron, P. R. (1988) Comparison of output particle size distributions from pressurized aerosols formulated as solutions or suspensions. Pharm. Res . 5:36-39.

23. Tashkin, D. P., Reiss, S., Shapiro, B. J., Calvarese, B., Olsen, J. L. and Lidgek, J. W. (1977) Bronchial effects of aerosolized Δ 9 - tetrahydrocannabinol in healthy and asthmatic subjects. Amer. Rev. of Resp. Disease . 115:57-65.

24. Williams, S. J., Hartley, J. P. R. and Graham, J. D. P. (1976) Bronchodilator effect of delta-9-THC administered by aerosol to asthmatic patients. Thorax . 31:720-723.

25. European Patent 0,372,777 (Riker Laboratories). Medicinal aerosol formulations.

Claims

1. A pharmaceutical composition consisting essentially of 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), Δ9-tetrahydrocannabinol, and up to 15 percent by weight of an organic solvent, said Δ9-tetrahydrocannabinol and said organic solvent being dissolved in said HFA 227 to form a stable composition, wherein said Δ9-tetrahydrocannabinol is present in said composition in concentrations ranging from 0.147% w/w (±0.008) to 5.940% w/w (±0.191).

2. The pharmaceutical composition of claim 1 wherein said Δ9-tetrahydrocannabinol is present in pharmaceutically pure form.

3. The pharmaceutical composition of claim 1 wherein the concentration of Δ9-tetrahydrocannabniol is sufficient to achieve serum concentration levels in a patient of 10-100 ng/ml fifteen minutes following inhalation.

4. The pharmaceutical composition of claim 1 wherein said organic solvent is ethanol.

5. The pharmaceutical composition of claim 1 wherein said organic solvent is 0% w/w of said stable composition.

6. The pharmaceutical composition of claim 1 wherein said stable composition is surfactant free.

7. A pharmaceutical composition consisting essentially of 1,1,1,2-tetrafluoroethane (HFA 134a), Δ9-tetrahydrocannabinol, and up to 15 percent by weight of an organic solvent, said Δ9-tetrahydrocannabinol and said organic solvent being dissolved in said HFA 134a to form a stable composition, wherein said Δ9-tetrahydrocannabinol is present in said composition in concentrations ranging from 0.224% w/w (±0.063) to 4.883% w/w (±0.224).

8. The pharmaceutical composition of claim 7 wherein said Δ9-tetrahydrocannabinol is present in pharmaceutically pure form.

9. The pharmaceutical composition of claim 7 wherein the concentration of Δ9-tetrahydrocannabniol is sufficient to achieve serum concentration levels in a patient of 10-100 ng/ml fifteen minutes following inhalation.

10. The pharmaceutical composition of claim 7 wherein said organic solvent is ethanol.

11. The pharmaceutical composition of claim 7 wherein said organic solvent is 0% w/w of said stable composition.

12. The pharmaceutical composition of claim 7 wherein said stable composition is surfactant free.