Delta9 Tetrahydrocannabinol (delta9 Thc) Solution Metered Dose Inhaler

*US06509005B1*  
(12)United States Patent(10)Patent No: US 6,509,005 B1
 Peart et al.(45)Date of Patent:Jan. 21, 2003

(54)Δ9 Tetrahydrocannabinol (Δ9 THC) solution metered dose inhaler 
(75)Inventors: Joanne Peart, Richmond, Virginia (US); Peter R. Byron, Richmond, Virginia (US); Aron H. Lichtman, Richmond, Virginia (US); and Billy R. Martin, Richmond, Virginia (US)
(73) Assignee: Virginia Commonwealth University, Richmond, Virginia  
Type:U.S.
( * )Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. 
(21)Appl. No.: 09/273,766 
(22)Filed: Mar. 22, 1999 
  Related U.S. Application Data
(60)Provisional Application No. 60/105850 Filed on Oct. 27, 1998
     
(51)Int. Cl.7A61L 9/04; A01N 43/16; A61K 31/35 
(52)U.S. Cl.424/45; 514/454 
(58)Field of Search 424/45; 424/46; 424/43; 514/454 

        
(56)References Cited
 
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* cited by examiner
(74)Primary Examiner —Dameron L. Jones
 Assistant Examiner — Lauren Q. Wells
 Attorney, Agent, or Firm — Whitham, Curtis & Christofferson, P.C.; Michael J. Rafa
 Exemplary claim number — 1
 Art Unit — 1619

(57)

Abstract

[00001]  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.
12 Claims, 1 Drawing Sheet, and 2 Figures


CROSS REFERENCE TO RELATED APPLICATION

   [00002]  This application is a continuation-in-part of U.S. provisional application Ser. No. 60/105,850 filed Oct. 27, 1998, and the complete contents of that application are incorporated herein by reference.
   [00003]  Funding for the research which led to this invention was provided in part by the United States Government in grant # DA 02396 from the National Institutes of Health and the government may have certain rights in this invention.

DESCRIPTION

BACKGROUND OF THE INVENTION

   [00004]  1. Field of the Invention
   [00005]  The invention is generally related to the therapeutic use of Δ9 Tetrahydrocannabinol (Δ9 THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of Δ9 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.
   [00006]  2. Background Description
   [00007]  “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, Δ9 tetrahydrocannabinol (Δ9 THC).
[TABLE-US-00001]
 TABLE 1
 
 The Use of Δ9THC 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/m2 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/m2 
 Nausea and Oral 5 or 72% of patients Lucas and
 emesis due to 15 mg/m2 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/m2 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/m2 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/m2 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. 
 
   [00008]  When marijuana is used illegally as a recreational psychoactive drug, the active ingredient Δ9 THC is usually delivered to the lungs as an impure non-pharmaceutical aerosol in the form of marijuana smoke. Aerosolized Δ9 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 Δ9 THC. As can be seen, inhalation is the preferred route of delivery for Δ9 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-US-00002]
 TABLE 2
 
 Pharmacokinetics of Δ9 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     
 
   [00009]  Currently, the sources of Δ9 THC for patients who could benefit from the drug are very limited. An oral form of Δ9 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 Δ9 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 Δ9 THC.
   [00010]  It would be advantageous to have available a form of pharmaceutical grade Δ9 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 Δ9 THC could be administered in known, controlled dosages.
   [00011]  In 1976, Olsen et al. described a chlorofluorocarbon (CFC) propelled MDI formulation of Δ9 THC (21). However, Δ9 THC is known to deteriorate during storage, and the stability of Δ9 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 Δ9 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 Δ9 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

   [00012]  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 Δ9 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 Δ9 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 Δ9 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 Δ9 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

   [00013]  FIG. 1. Δ9 THC MDI characterization summary before and after storage at 40° C. and 82% relative humidity (RH).
   [00014]  FIG. 2. Generalized schematic drawings of a Δ9 THC MDI.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION

   [00015]  The instant invention provides a series of non-ozone depleting pressurized metered dose inhaler formulations of Δ9 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.
   [00016]  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 Δ9 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 Δ9 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 Δ9 THC and droplet size. Any ratio of propellant to solvent that results in appropriate sized droplets and adequate dissolution of the Δ9 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.
   [00017]  Those skilled in the art will also recognize that the “respirable dose” (or mass of Δ9 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-US-00003]
 TABLE 3
 
 Apparent Solubility of Δ9THC in Ethanol/HFA Propellant Blends
   Mass  
  Mass (g) of  
  (g) of Formu-  
  Δ9THC lation Apparent 
  in Sam- Solubility 
 Formulation Sample pled Mean (±SD) Comments
 
 Δ9THC in 0.000240 0.1071 0.224% w/w Excess Δ9THC
 100% HFA   (±0.063) added to propellant
 134a    blend (in
     pressurized MDI).
     Solubility sample
     removed using puff
     absorber. n = 5
 Δ9THC in 5% 0.00144 0.0914 1.585% w/w As above
 Ethanol/95%   (±0.321) 
 HFA 134a    
 Δ9THC in 10% 0.00363 0.1036 3.511% w/w As above
 Ethanol/90%   (±0.249) 
 HFA 134a    
 Δ9THC in 15% 0.00536 0.1098 4.883% w/w As above
 Ethanol/85%   (±0.224) 
 HFA 134a    
 Δ9THC in 0.00021 0.1451 0.147% w/w As above
 100% HFA 227   (±0.008) 
 Δ9THC in 5% 0.00134 0.0979 1.339% w/w As above
 Ethanol/95%   (±0.169) 
 HFA 227    
 Δ9THC in 10% 0.00454 0.1267 3.240% w/w As above
 Ethanol/90%   (±0.161) 
 HFA 227    
 Δ9THC in 15% 0.00623 0.1062 5.940% w/w As above
 Ethanol/85%   (±0.191) 
 HFA 227    
 
   [00018]  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.
   [00019]  A major consideration in the formulation of any drug is its stability. Δ9 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 Δ9 THC in reproducible doses following accelerated storage testing. Apparently, the containment of Δ9 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.
   [00020]  Further, lipophilic materials like Δ9 THC are generally known to partition into the elastomers of the valves in MDI formulations. (Δ9 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 Δ9 THC for the formulation itself, rather than for the valve elastomers.
[TABLE-US-00004]
 TABLE 4A
 
 Formulation and aerosol characteristics of Δ9 THC pressurized metered dose
 inhalers in ethanol/hydrofluoroalkane (HFA) propellant blends
  Formulation (% w/w) 
 Inhaler Δ9 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***    
 
 aMean (Standard Deviation) of five determinations.
 bMass of Δ9 THC aerosol particles <5.8 μm aerodynamic diameter
 *SS: Stability Sample
 **RH: relative humidity
 ***Approximate spray nozzle diameter = 0.2 mm.
[TABLE-US-00005]
 TABLE 4B
 
 Formulation and aerosol characteristics
 of Δ9 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***   
 
 aMean (Standard Deviation) of five determinations.
 bMass of Δ9 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
   [00021]  The final concentration of Δ9 THC in a given formulation may be varied by adjusting the ratio of propellant to solvent and thus the solubility of the Δ9 THC. Higher percentages of solvent (e.g. ethanol) generally allow a higher amount of Δ9 THC to be dissolved. For example, in preferred embodiments of the invention, the apparent solubility of Δ9 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 Δ9 THC in a given metered volume may be selected by changing the formulation.
   [00022]  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.
   [00023]  The Δ9 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 Δ9 THC may be synthesized (e.g. esters and salts) and thus used in the practice of this invention.
   [00024]  The desired final concentration of Δ9 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 Δ9 THC in a patient's serum can be readily and reliably monitored by gas chromatography/mass spectrophotometry (GC/MS).
   [00025]  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 Δ9 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 Δ9 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 Δ9 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.
   [00026]  Δ9 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.
   [00027]  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 Δ9 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 Δ9 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 Δ9 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 Δ9 THC.
   [00028]  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

[00029]  1. Workshop on the medical utility of marijuana. National Institutes of Health, August 1997.
[00030]  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.
[00031]  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.
[00032]  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.
[00033]  5. Lucas, V. S. and Laszlo, J. (1980) Δ9-THC for refractory vomiting induced by cancer chemotherapy. JAMA 243:1241-1243.
[00034]  6. Sallan, S. E., Cronin, C., Zelen, M. and Zinberg, N. E. (1980) Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of Δ9 THC and prochlorperazine. N Engl. J Med. 302:135-138. p07. 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.
[00035]  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) Δ9 THC as an antiemitic in cancer patients receiving high-dose methotrexate. Ann. Internal. Med. 91:819-824.
[00036]  9. Sallan, S. E., Zinberg, N. E. and Frei, I. E. (1975) Antiemetic effect of Δ9 THC in patients receiving cancer chemotherapy. New Engl. J. Med. 293:795-797.
[00037]  10. Noyes, J. R., Brunk, S. F., Baram, D. A. and Canter, A. (1975) The analgesic properties of Δ9 THC and codeine. J. Clin. Pharmacol. 15:139-143.
[00038]  11. Noyes, R., Jr., Brunk, S. F., Baram, D. A. and Canter, A. (1975) Analgesic effect of Δ9-tetrahydrocannabinol. J. Clin. Pharmacol. 15:139-143.
[00039]  12. Brenneisen, R., Egli, A., Elosohlly, M. A., Henn, V. and Spiess, Y. (1996) The effect of orally and rectally administered Δ9 THC on spasticity: a pilot study with 2 patients. Int. J. Clin. J. Pharmocol. Ther. 34:446-452.
[00040]  13. Ungerleider, J. T., Andyrsiak, T. F. L., Ellison, G. W. and Myers, L. W. (1987) Δ9 THC in the treatment of spasticity associated with multiple sclerosis. Adv. Alcohol Subst. Abuse 7:39-50.
[00041]  14. Clifford, D. B. (1983) Tetrahydrocannabinol for tremor in multiple sclerosis. Ann. Neurol. 13:669-171.
[00042]  15. Petro, D. J. and Ellenberger, C. (1981) Treatment of human spasticity with delta 9-tetrahydrocannabinol. J. Clin. Pharmacol. 21:413S-416S.
[00043]  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.
[00044]  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.
[00045]  18. Cooler, P. and Gregg, J. M. (1977) Effect of delta 9-Δ9 THC on intra ocular pressure in humans. South. Med J. 70:951-954.
[00046]  19. PDR (1995) Physician's Desk Reference (49) Montvalek, New Jersey: Medical Economics Data Production Co., pp.2787.
[00047]  20. Ohlsson, A., Lindgren, J. E., Wahlen, A., Agurall, S., Hollister, L. E. and Gillespie, H. K. (1980) Plasma Δ9 THC concentrations and effects after oral and intravenous administration and smoking. Clin. Pharmacol. Ther. 28:409-416.
[00048]  21. Olsen, J. L., Lodge, J. W., Shapiro, B. J. and Tashkin, D. P. (1976) An inhalation aerosol of Δ9-tetrahydrocannabinol. J. Pharmacy and Pharmacol. 28:86.
[00049]  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.
[00050]  23. Tashkin, D. P., Reiss, S., Shapiro, B. J., Calvarese, B., Olsen, J. L. and Lidgek, J. W. (1977) Bronchial effects of aerosolized Δ9- tetrahydrocannabinol in healthy and asthmatic subjects. Amer. Rev. of Resp. Disease. 115:57-65.
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[00052]  25. European Patent 0,372,777 (Riker Laboratories). Medicinal aerosol formulations.
(57)

We claim:

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.
*****

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