|Title of Invention||
DELTA <9> TETRAHYDROCANNABINOL ( DELTA <9> THC) SOLUTION METERED DOSE INHALERS AND METHODS OF USE
|Abstract||The present invention provides therapeutic formulations for solutions of ?9 TETRAHYDROCANNABINOL (?9 THC) to be delivered by metered dose inhalers. The formulations, which utilize non-CFC propellants, provide a stable aerosol-deliverable source of ?9 THC for the treatment of various medical conditions, such as nausea and vomiting associated with chemotherapy, muscle spasticity; pain; anorexi associated with AIDS wasting syndrome; epilepsy; glaucoma; bronchial asthma; and mood disorders.|
|Full Text||?9 TETRAHYDROCANNABINOL ( ?9 THC) SOLUTION METERED DOSE INHALERS AND METHODS OF USE
DESCRIPTION BACKGROUND OF THE INVENTION
Field of the Invention
The invention is generally related to the therapeutic use of A9
Tetrahydrocannabinoi (?9 THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of ?9 THC to patients suffering from nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, epilepsy, glaucoma, bronchia] asthma, mood disorders, and the like.
"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 (I). 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. A9 tetrahydrocannabinoi (?9 THC ).
When marijuana is used illegally as a rccreauonai psychoactive drug, the active ingredient ?9 THC is usually delivered to the lungs as an impure non-pharmaceutical aerosol in the form of marijuana smoke. Aerosolized ?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 ?9 THC. As can be seen, inhalation is the preferred route of delivery for ?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
Currently, the sources of ?9 THC for patients who could benefit from the drug are very limited An oral form of ?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?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 ?9 THC.
It would be advantageous to have available a form of pharmaceutical grade A9 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 pharmaceuticaily pure ?9THC could be administered in known, controlled dosages.
In 1976. Oisen et al. described a chlorofluorocarbon (CFC) propelled MDI formulation of ?9THC (21). However. A" THC is known to deteriorate during storage, and the stability of ?9 THC in this formulation is suspect. In addition, the ethanoi content in this formulation was so high (-23%) as to create an aerosol with droplets too large to be effectiveiy inhaled (22). The ?9THC 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 ?9THC is stable, the droplets are of a size that can be effectively inhaled, and which utiiizes 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 ?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 ?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 ?9 THC in the propeilant 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 ?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 ACCOMPANYING DRAWINGS
Figure 1 ?9 THC MDI characterization summary before and after storage at 40°C and 82% relative humidity (RH)
Figure 2. Generalized schematic drawings of a ?9 THC MDI
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE
The instant invention provides a series of non-ozone depleting pressurized metered dose inhaler formulations of ?9THC In preferred embodiments of the invention, the formulations contain the pharmaceutically acceptable, non-ozone depleting hydrofluoroalkane propcllants HFA 134a (1,1,1,2-tetrahydrofluoroethane) and HFA 227 (1,1,1,2,3.3,3-heptafIuoropropane). or a mixture thereof.
When the propeilant is a hydrofluoroalkane it has been discovered that the propeilant may be used with or without a solvent such as ethanol Higher percentages of solvent generally allow higher levels of dissolution of ?9THC However, higher
percentages of solvent also cause droplet size to increase In preferred embodiments of the invention, the range of propellam 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 ?9 THC can be achieved and droplet size is still small enough ( Those skilled in the art will also recognize that the respirable dose" (or mass of ?9 THC in particles with aerodynamic diameters small enough to be delivered to and absorbed by the lungs) (Figure 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?m in size
A distinct advantage of the present formuiations 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 hpophilic 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. ?9 THC :s known to deteriorate upon storage so that the effective concentration decreases and the purity is vitiated. The stability of the formuiations of the present invention were tested according to accelerated storage testing protocols The results are given in Figure 1 and Tables 4A and 4B The formuiations of the present invention were shown to be stable with respect to the release of aerosolized ?9 THC in reproducible doses following accelerated storage testing Apparently, the containment of ?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, hpophilic materials like ?9 THC are generally known to partition into the elastomers of the valves in MDI formulations. (?9THC is highly hpophilic as reflected in its octanolwater partition coefficient of 6000 1) Over time, this partitioning results in a decrease in the emitted or delivered dose of a hpophilic drug Thus, this phemonemon also decreases the useful shelf-life of such preparations. However, the data presented in Figure 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 ?9THC for the formulation itself, rather than for the valve elastomers TABLE 4A. Formulation and aerosol characteristics of ?9 THC pressurized metcred dose inhalers in ethanol/hydrofluoroalkane (HFA) propellant blends.
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 1.02% 5.15% 93.S% HFA 134a 10/98 Yellow Modified Solution
Mean (Standard Deviation) of five determinations
Mass of ?9 THC aerosol particles *SS" Stability Sample ** RH relative humidity
**' Aproximate spray nozzle diameter = 02 mm.
TABLE 4B. Formulation and aerosol characteristics of ?9THC pressurized metercd dose inhalers in cthanol/hydrofluoroalkane (HFA) pronellant blends.
Inhaler Aerosol Characterization Metered Dose Emitted Dose Fine (mg)2 (mg)1 Particle Dose (mg)
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%
SS* #2 after 1.02(0 05) 0.90(0.05) 0 21 (0 02) 21 days at 40°C/S2% RH*
SS* #3 Modified ND- ND 0 40 (n=I) Actuator***
a Mean (Standard Deviation) of five determinations.
b Mass of ?9THC aerosol particles with *SS- Stability Sample *• RH. relative humidity ND. not
determined * * * Approximate spray nozzle diameier = 02 mm
The final concentration of ?9 THC in a given formulation may be varied by adjusting the ratio of propellant to solvent and thus the solubility of the ?9 THC Higher percentages of solvent (e g ethanol) generally allow a higher amount of THC to be dissolved. For example, in preferred embodiments of the invention, the apparent solubility of ?9 THC ranged from 0.147% w/w to 5.94% w/was the propellant composition varied from 100% HFA 227 to 85% HFA 227 and 15% ethanol Thus, the dose of ?9 THC in a given metered volume may be selected by changing the formulation
Further, as stated above, the "fine particle dose" or "lespirable dose' of a drug dispensed with an MDI is a function of the spray nozzle diameter. In Figure I and Tables 4A and 4B, the spray nozzle diameter is 0 4mm. The "fine particle dose'1 or "respirable dose" of the formulations of the present invention was shown to be
unaffected by storage
The ?9 THC of the present invention is pharmaceutically pure. That is its form is the nonionized resinous drug substance (6aR.-trans)-6a.7,S,10a-tetrahydro-6.6.9-trimethyl-3-pentyl-6H-dibenzo[b,d]-pyran-l-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 ?9 THC may be synthesized (e g. esters and salts) and thus used in the practice of this invention
The desired final concentration of ?9 THC in a patient's serum will vary from patient to patient depending on, for example, the nature and seventy 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 10-100ng/ml at 15 minutes following inhalation. The level of ?9THC 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 ?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 ?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 sptnal cord injury may have ?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.
?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 an 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 optoids as well as nonsteroidal anti-inflammatory agents.
The containers lor 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 an. 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 ?9THC 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. Patent 5.284.133 to Bums and Marshak. which is herein incorporated by reference, can be used to prevent overdose or unauthorized consumption of ?9 THC Figure 2 provides a generalized drawing of an MDI containing the composition of this invention and provides the advantage of delivering metered quantities of ?9THC on a repetitive basis The MDI includes a container 100 for holding the composition and a valve delivery mechanism 102 for delivery of aerosolized ?9 THC.
While the invention has been described tn 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
1 Workshop on the medical utility of marijuana National Institutes of Health. August
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23 Tashkin. D.P , Reiss. S , Shapiro, B J . Calvarese. B . OKen. J L and Lidgek. J.W
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25. European Patent 0.372,777 (Riker Laboratories) Medicinal aerosol formulations
1 A pharmaceutical composition consisting essentially of 1,1,1,2,3,3,3
heptafluoropropane (HFA 227), - tetrahydrocannabinol, and up to 15 percent by
weight of an organic solvent, said - tetrahydrocannabinol and said organic solvent
being dissolved in said HFA 227 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)
2 The pharmaceutical composition as claimed in claim 1 wherein said -
tetrahydrocannabinol is present in pharmaceutically pure form
3. The pharmaceutical composition as claimed in claim 1 wherein the concentration of -tetrahydrocannabinol is sufficient to achieve serum concentration levels in a patient of 10-100 ng/ml fifteen minutes following inhalation
4 The pharmaceutical composition as claimed in claim 1 wherein said organic solvent is
5 The pharmaceutical composition as claimed in claim 1 wherein said organic solvent is
0% w/w of said stable composition
6 The pharmaceutical composition as claimed in claim 1 wherein said stable
composition is surfactant free
7 A pharmaceutical composition consisting essentially of 1,1,1,2 - tetrafluoroethane
(HFA 134a), - tetrahydrocannabinol, and up to 15 percent by weight of an organic
solvent, said - tetrahydrocannabinol and said organic solvent being dissolved in said
HFA 134a to form a stable composition, wherein said - 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 as claimed in claim 7 wherein said -tetrahydrocannabinol is present in pharmaceutically pure form
9 The pharmaceutical composition as claimed in claim 7 wherein the concentration of A9-tetrahydrocannabinol is sufficient to achieve serum concentration levels in a patient of 10-100 ng/ml fifteen minutes following inhalation
10. The pharmaceutical composition as claimed in claim 7 wherein said organic solvent is
11. The pharmaceutical composition as claimed in claim 7 wherein said organic solvent is
0% w/w of said stable composition
12 The pharmaceutical composition as claimed in claim 7 wherein said stable composition is surfactant free
13. A composition comprising hydrofluoroalkane propellant and pharmaceutically acceptable form of A9- tetrahydrocannabinol and having not more than 15% of pharmaceutically acceptable solvent adapted to be administered as aerosollsed dose of pharmaceutically acceptable form of A9- tetrahydrocannabinol as respirable droplets to a patient lung wherein at least 20% of mass of respirable droplets have aerodynamic diameter of less than 5 8 un
14 A composition as claimed in claim 13 adapted to achieve brain levels of THC that substantially the same as blood levels of THC in the patient
15. The composition as claimed in claim 13 wherein said solution comprises less than 15% w/w of a solvent selected from the group consisting of ethanol, propanol, propylene, glycol, glycerol and polyethylene glycol
16. The composition as claimed in claim 15 wherein said solvent comprises ethanol.
17. A composition as claimed in claim 13 adapted to be administered as aerosolised dose sufficient to reduce nausea.
18 A composition as claimed in claim 13 adapted to be administered as aerosolised dose
sufficient to reduce vomiting.
19 A composition as claimed in claim 13 adapted to be administered as aerosolised dose
sufficient to reduce pain.
20 A composition as claimed in claim 13 adapted to be administered as aerosolised dose
sufficient to relieve muscle spasticity
21 A composition as claimed in claim 13 adapted to be administered as aerosolised dose
sufficient to relieve migraine headaches.
22 A composition as claimed in claim 13 adapted to be administered as aerosolised dose
sufficient to relieve movement disorders
23 A composition as claimed in claim 13 adapted to be administered as aerosolised dose
sufficient to increase appetite in patients suffering from cachexia
24 A composition as claimed in claim 13 wherein said pharmaceutically acceptable from
of A9- tetrahydrocannabinol is pure - tetrahydrocannabinol and said hydrofluroalkane
is selected from the group consisting of HFA 134a and HFA 227
The present invention provides therapeutic formulations for solutions of ?9 TETRAHYDROCANNABINOL (?9 THC) to be delivered by metered dose inhalers. The formulations, which utilize non-CFC propellants, provide a stable aerosol-deliverable source of ?9 THC for the treatment of various medical conditions, such as nausea and vomiting associated with chemotherapy, muscle spasticity; pain; anorexi associated with AIDS wasting syndrome; epilepsy; glaucoma; bronchial asthma; and mood disorders.
|Indian Patent Application Number||IN/PCT/2001/00385/KOL|
|PG Journal Number||09/2007|
|Date of Filing||02-Apr-2001|
|Name of Patentee||VIRGINIA COMMONWEALTH UNIVERSITY|
|Applicant Address||1101E, MARSHALL STREET, RICHMOND, VIRGINIA -23298 UNITED STATES OF AMERICA|
|PCT International Classification Number||A61K 31/35|
|PCT International Application Number||PCT/US99/24486|
|PCT International Filing date||1999-10-20|