.DELTA.9 Tetrahydrocannabinol (.DELTA.9 THC) solution metered dose inhaler

DESCRIPTION

BACKGROUND OF THE INVENTION

1. Field of the Invention

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.

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, .DELTA..sup.9 tetrahydrocannabinol (.DELTA..sup.9 THC).

TABLE 1 The Use of .DELTA..sup.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.sup.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.sup.2 Nausea and Oral 5 or 72% of patients Lucas and emesis due to 15 mg/m.sup.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.sup.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.sup.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.sup.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 .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. Table 2 and references 19-20 describe the pharmacokinetics of the administration of .DELTA..sup.9 THC. 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.

TABLE 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 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 .DELTA..sup.9 THC for patients who could benefit from the drug are very 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). 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 .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 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 .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 (21). 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 (22). The .DELTA..sup.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 .DELTA..sup.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 .DELTA..sup.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 .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

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

FIG. 2. Generalized schematic drawings of a .DELTA..sup.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 .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.

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.

Those skilled in the art will also 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 .mu.m in size.

TABLE 3 Apparent Solubility of .DELTA..sup.9 THC in Ethanol/HFA Propellant Blends Mass Mass (g) of (g) of Formu- .DELTA..sup.9 THC lation Apparent in Sam- Solubility Formulation Sample pled Mean (.+-.SD) Comments .DELTA..sup.9 THC in 0.000240 0.1071 0.224% w/w Excess .DELTA..sup.9 THC 100% HFA (.+-.0.063) added to propellant 134a 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 10% 0.00363 0.1036 3.511% w/w As above Ethanol/90% (.+-.0.249) HFA 134a .DELTA..sup.9 THC in 15% 0.00536 0.1098 4.883% w/w As above Ethanol/85% (.+-.0.224) 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 10% 0.00454 0.1267 3.240% w/w As above Ethanol/90% (.+-.0.161) HFA 227 .DELTA..sup.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. .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.

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 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 .DELTA..sup.9 THC for the formulation itself, rather than for the valve elastomers.

TABLE 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% 95% HFA 134a 7/98 Yellow Solution 21 days at 40.degree. C./82% RH** SS* #3 Modified 1.02% 5.15% 93.8% HFA 134a 10/98 Yellow Solution Actuator*** .sup.a Mean (Standard Deviation) of five determinations. .sup.b Mass 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.

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

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.

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 .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) and thus used in the practice of this invention.

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).

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.

.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 Burns 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.

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.

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