CA2344637A1 - .delta.9 tetrahydrocannabinol (.delta.9 thc) solution metered dose inhalers and methods of use - Google Patents
.delta.9 tetrahydrocannabinol (.delta.9 thc) solution metered dose inhalers and methods of use Download PDFInfo
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- CA2344637A1 CA2344637A1 CA002344637A CA2344637A CA2344637A1 CA 2344637 A1 CA2344637 A1 CA 2344637A1 CA 002344637 A CA002344637 A CA 002344637A CA 2344637 A CA2344637 A CA 2344637A CA 2344637 A1 CA2344637 A1 CA 2344637A1
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- tetrahydrocannabinol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The present invention provides therapeutic formulations for solutions of .DELTA.9-tetrahydrocannabinol to be delivered by metered dose inhalers (100) , (102). The formulations, which utilize non-CFC propellants, provide a stable aerosol-deliverable source of .DELTA.9-tetrahydrocannabinol for the treatmen t 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
WO OOI24362 PCTIUS99l24486 D9 TETRAHYDROCANNABINOL ( L19 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 ~4 Tetrah~~drocannabinol (~9 THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of t19 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.
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 { I ). Table I summarizes the findings of several studies (references 2-I 8) that have documented therapeutically beneficial medicinal uses of the major active component of marijuana, ~9 tetrahydrocannabinol (09 THC ).
WO 00!24362 PCTlUS99124486 TATtLE 1. The Use of A9THC
for the Treatment of Assorted Clinical Conditions Condition and Administration Findings Reference l~Iumber of Route and Dose Patients AIDS-associatedOral placebo, Long term THC Beal et 2.5 mg THC ai., anorexia and once or twice treatment was 1997 cachexia; daily well-94 patients; increasing to tolerated; THC
20 mg daily 12 months improved appetite and only tended to increase weight compared to controls AIDS-associatedOral placebo or 57% and 69% of Beal et 2.5 mg vehicle ai., anorexia and THC twice daily and THC patients1995 cachexia; were 139 patients; evaluable for efficacy.
42 days Appetite increased 38%
over baseline for THC
group compared to only 8% for the placebo group. THC also decreased nausea.
No significant changes were found between the groups for weight change.
Nausea and emesisOral THC, I 5mglm=Reduction in McCabe due et al., to cancer chemotherapy-induced1988 chemotherapy; nausea and vomiting in 36 patLents 64% of patients who had given experienced THC compared severe to nausea and vomiting prochioperazine;
side that was refractory effects included to prochlorperazine dysphoria; authors or thiethylperazine recommend initial THC
dose of 5 mglm=
wo oona362 ~ PcTn~s99na4s6 TABLE 1. The Use of A'THC
for the Treatment of Assorted Clinical Conditions Nausea and emesisOral 5 or 15 mg/m'72% of patients Lucas and due THC
to cancer four rimes per exhibited a THC-Laszlo, day 1980 chemotherapy; induced partial or 53 patients complete blockade which were of refractory to vomiting other antiernetics Nausea and emesisOral 10 mg/m' THC more effectiveSallan due THC of et al., to cancer prochloperazine than prochloperazine1980 chemotherapy;
84 patients , Nausea and emesisOral 15 mg THC, Equal antiemeticFrytak due l Omg effects et al., to cancer prochloperzine between THC and 1979 or placebo chemotherapy; prochlorperaZine, effects 116 patients of each greater than placebo; considerably more CNS side effects with THC than prochlorperazine Nausea and emesisOral placebo or 93% patients Chang et due 10 mgltn= had a ai., to cancer THC every 3 hoursreduction in 1979 for a nausea and chemotherapy; total of 5 doses,vomiting, 53%
THC ( 17 had an 15 patients mg) laced cigarettesexcellent response, of 40%
placebo were givenhad a fair response;
if vomiting occurredplasma THC levels 7.It6.9 (mean t SD) nglml. Side effects included sedation, tachycardia, few other side effects Pain due to Oral placebo and Pain relief, Noyes, advanced 5, 10, 15 elevated et al, cancer:, 10 or 20mg THC mood, appetite 1975 patients stimulation, drowsiness, slurred speech, mental clouding WO 00/14362 PCT/US99/2448b TAIBLE 1. The Use of L~,'THC
for the Treatment of Assorted Clinical Conditions Pain due to advancedPlacebo, 10 and THC produced Noyes et 20mg a similar al.
cancer; 34 patientsTHC; and 60 and degree of analgesia,1975 codeine with greater potency than codeine.
THC CNS
side effects included sedation, mental clouding, ataxia, and disorientation Spasticity relatedOral 10 or l5mg Improvement in Srenneisen to THC; passive et multiple schlerosis;rectal dose of mobility and al., 1996 5 or lOmg walking 2 patients THC ability Spasticity relatedOral 2.5 to I Significant subjectiveUngerleider to Smg THC et multiple schlerosis;once or twice improvement in al,, 1987 daily or 13 patients placebo spasticity at 7.5mg THC
and higher, no significant improvement in objective measurements Spasticity relatedOral 5 to I Smg 5 of 8 patients Clifford, to THC had mild 1983 multiple schlerosis; subjective improvement 8 patients, single in tremor. 2 blind of 8 patients had both objective and subjective improvement Spasticity relatedPlacebo, or Decrease in spasticityPetro and to multiple schlerosis;5 or l Omg THC compared to placeboEllenberger, 9 patients treatment, minimal1981 side effects Spasticity and Oral placebo, THC and codeine Maurer pain due had et al., to spinal cord THC (5 mg), or analgesic effect1990 injury;
1 patient codeine (50 mg) compared to the placebo treatment. THC
had a beneHeial effect on spasticity whereas codeine did not TABLE 1. The Use of A9THC
for the Treatment of Assorted Clinical Conditions Glaucoma, 6 Oral placebo or Pain relief, Merritt patients elevated et al, 5, I0, ~I S and mood, appetite 1980 20 mg THC
stimulation, drowsiness, slurred speech, mental clouding Ten subjects Intravenous THC Decreased infraCooler wish ocular and normal infra (0.022 or 0.044 pressure by Gregg, ocular mg/kg) a mean of 1977 pressure 37%
Nausea and emesisOral 10 mg/m'- In 20 courses Sallan due THC or of THC, 5 et al., to cancer placebo resulted in 19?5 no vomiting, chemotherapy; 9 resulted in a reduction refractory to of vomiting, other 3 resulted antiemetics 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 d,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 D9 THC. When compared to oral deliver)r, 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 ~''THC
Given Orally, Intravenously or by Smoking Route Dose ! Dose Onset of Peak PlasmaReferences in Pharmacol Levels Plasma ogicai Action Oral, 2.5, i0 to 0.5 to I20-480 (PDR, 1995) 5, or 20% 1 hour min sesame 10 mg oil in gelatin capsules Oral, 20 mg 4 to 120-180 60-90 min (Ohlsson, in 12% min et al., cookies 1980) Intre 5 mg 100% 10 min 3 min (Ohlsson, et al., venous, 1980) bolus Smoking 13 mg 8 to 10 min 3 min (Ohlsson, 24% et al., (THC lost 1980) to side stream smoke and pyrolysis Currently, the sources of L19 THC for patients who could benefit from the drug a~-e very limited. An oral form of l~4 THC (MA1RINOL} is marketed as a treatment for nausea arid vomiting related to cancer chemotherapy, and as an appetite stimulant in patients suffering from AIDS wasting syndrome. In MARINOL, pharmaceutical grade L19 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 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 D9 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 povtential adverse side effects encountered by smoking marijuana would be avoided. Further, an aerosol preparation of~pharmaceutically pure O9 THC could be administered in known, controlled dosages.
In 1976, Olsen et al. described a chlorofluorocarbon (CFC) propelled MDI
formulation of O9 THC (2I }. However, ~9 THC is known to deteriorate during storage, and the stability of t19 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 D9 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 d,° 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 L19 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 t19 THC. The propellant is present in the range of approximately 78 to I00% by WO OOJ2436Z PCTlUS99J24486 weight, and more particularly the propellant is present in the range of approximately 8S to 100% by weight. An organic solvent such as ethanol can be used to assist in solubilizing the 09 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 vctill he required. The pharmaceutically effective concentration of ~Q 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
Figure 1. 09 THC MDI characterization summary before and after storage at 40°C and 82% relative humidity (RH).
Figure 2. Generalized schematic drawings of a O9 THC MDI.
INVENTION
'The instant invention provides a series of non-ozone depleting pressurized metered dose inhaler formulations of L19 THC. In preferred embodiments of the invention, the formulations contain the pharmaceutically acceptable, non-ozone depleting hydrofluoroatkane propellants HFA 134a (1,1,1,2-tetrahydrofluoroethane) 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 ~9 THC. However, higher _g_ 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 1 S % solvent. Within this range of percentages, pharmaceutically useful concentrations of ~9 THC can be achieved and droplet size is still small enough (<5.8~,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 D9 THC
and droplet size. Any ratio of propellant to solvent that results in appropriate sized droplets and adequate dissolution of the L1,9 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" (ar 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. °.Chis 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 10i.~,m in size.
_g_ WO 00/243b2 PCTlUS99/24486 TABLE 3.
Apparent Solubility of 09 THC
in Ethanol/HFA
Propellant Blends FormulationMass (g) Mass (g) Apparent Comments of of d' THC FormulationSolubiiity in Sample Sampled Mean (fSD) L19 'fHC 0.000240 0.1071 0.224% w/w Excess A9 THC
in added 100% HFA 00.063) to propellant blend (in i34a pressurized MDI).
Solubility sample removed using puff absorber. ns5 O' THC in 0.00144 0.0914 1.585% w/w As above 5%
Ethanol (t0.321 ) / 95%
HFA 134a A9 THC in 0.00363 0.1036 3.511% w/w As above 10% Ethanol 00249) I
90% HFA
134a D' THC in 0.00536 0.1098 4.883% w/w As above I 5% Ethanol (t0.224) /
85% HFA
134a O' THC in 0.00021 0.1451 0.147% w/w As above 100i~o HFA (t0.008) A9 THC in 0.00134 0.0979 1.339% w/w As above 5%
Ethanol (f0,169) / 95%
D9 THC in 0.00454 0.1267 3.240% w/w As above 10% Ethanol 00.161 ) /
90% HFA
INHALERS AND METHODS OF USE
DESCRIPTION
BACKGROUND OF THE INVENTION
Field of the Invention The invention is generally related to~the therapeutic use of ~4 Tetrah~~drocannabinol (~9 THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of t19 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.
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 { I ). Table I summarizes the findings of several studies (references 2-I 8) that have documented therapeutically beneficial medicinal uses of the major active component of marijuana, ~9 tetrahydrocannabinol (09 THC ).
WO 00!24362 PCTlUS99124486 TATtLE 1. The Use of A9THC
for the Treatment of Assorted Clinical Conditions Condition and Administration Findings Reference l~Iumber of Route and Dose Patients AIDS-associatedOral placebo, Long term THC Beal et 2.5 mg THC ai., anorexia and once or twice treatment was 1997 cachexia; daily well-94 patients; increasing to tolerated; THC
20 mg daily 12 months improved appetite and only tended to increase weight compared to controls AIDS-associatedOral placebo or 57% and 69% of Beal et 2.5 mg vehicle ai., anorexia and THC twice daily and THC patients1995 cachexia; were 139 patients; evaluable for efficacy.
42 days Appetite increased 38%
over baseline for THC
group compared to only 8% for the placebo group. THC also decreased nausea.
No significant changes were found between the groups for weight change.
Nausea and emesisOral THC, I 5mglm=Reduction in McCabe due et al., to cancer chemotherapy-induced1988 chemotherapy; nausea and vomiting in 36 patLents 64% of patients who had given experienced THC compared severe to nausea and vomiting prochioperazine;
side that was refractory effects included to prochlorperazine dysphoria; authors or thiethylperazine recommend initial THC
dose of 5 mglm=
wo oona362 ~ PcTn~s99na4s6 TABLE 1. The Use of A'THC
for the Treatment of Assorted Clinical Conditions Nausea and emesisOral 5 or 15 mg/m'72% of patients Lucas and due THC
to cancer four rimes per exhibited a THC-Laszlo, day 1980 chemotherapy; induced partial or 53 patients complete blockade which were of refractory to vomiting other antiernetics Nausea and emesisOral 10 mg/m' THC more effectiveSallan due THC of et al., to cancer prochloperazine than prochloperazine1980 chemotherapy;
84 patients , Nausea and emesisOral 15 mg THC, Equal antiemeticFrytak due l Omg effects et al., to cancer prochloperzine between THC and 1979 or placebo chemotherapy; prochlorperaZine, effects 116 patients of each greater than placebo; considerably more CNS side effects with THC than prochlorperazine Nausea and emesisOral placebo or 93% patients Chang et due 10 mgltn= had a ai., to cancer THC every 3 hoursreduction in 1979 for a nausea and chemotherapy; total of 5 doses,vomiting, 53%
THC ( 17 had an 15 patients mg) laced cigarettesexcellent response, of 40%
placebo were givenhad a fair response;
if vomiting occurredplasma THC levels 7.It6.9 (mean t SD) nglml. Side effects included sedation, tachycardia, few other side effects Pain due to Oral placebo and Pain relief, Noyes, advanced 5, 10, 15 elevated et al, cancer:, 10 or 20mg THC mood, appetite 1975 patients stimulation, drowsiness, slurred speech, mental clouding WO 00/14362 PCT/US99/2448b TAIBLE 1. The Use of L~,'THC
for the Treatment of Assorted Clinical Conditions Pain due to advancedPlacebo, 10 and THC produced Noyes et 20mg a similar al.
cancer; 34 patientsTHC; and 60 and degree of analgesia,1975 codeine with greater potency than codeine.
THC CNS
side effects included sedation, mental clouding, ataxia, and disorientation Spasticity relatedOral 10 or l5mg Improvement in Srenneisen to THC; passive et multiple schlerosis;rectal dose of mobility and al., 1996 5 or lOmg walking 2 patients THC ability Spasticity relatedOral 2.5 to I Significant subjectiveUngerleider to Smg THC et multiple schlerosis;once or twice improvement in al,, 1987 daily or 13 patients placebo spasticity at 7.5mg THC
and higher, no significant improvement in objective measurements Spasticity relatedOral 5 to I Smg 5 of 8 patients Clifford, to THC had mild 1983 multiple schlerosis; subjective improvement 8 patients, single in tremor. 2 blind of 8 patients had both objective and subjective improvement Spasticity relatedPlacebo, or Decrease in spasticityPetro and to multiple schlerosis;5 or l Omg THC compared to placeboEllenberger, 9 patients treatment, minimal1981 side effects Spasticity and Oral placebo, THC and codeine Maurer pain due had et al., to spinal cord THC (5 mg), or analgesic effect1990 injury;
1 patient codeine (50 mg) compared to the placebo treatment. THC
had a beneHeial effect on spasticity whereas codeine did not TABLE 1. The Use of A9THC
for the Treatment of Assorted Clinical Conditions Glaucoma, 6 Oral placebo or Pain relief, Merritt patients elevated et al, 5, I0, ~I S and mood, appetite 1980 20 mg THC
stimulation, drowsiness, slurred speech, mental clouding Ten subjects Intravenous THC Decreased infraCooler wish ocular and normal infra (0.022 or 0.044 pressure by Gregg, ocular mg/kg) a mean of 1977 pressure 37%
Nausea and emesisOral 10 mg/m'- In 20 courses Sallan due THC or of THC, 5 et al., to cancer placebo resulted in 19?5 no vomiting, chemotherapy; 9 resulted in a reduction refractory to of vomiting, other 3 resulted antiemetics 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 d,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 D9 THC. When compared to oral deliver)r, 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 ~''THC
Given Orally, Intravenously or by Smoking Route Dose ! Dose Onset of Peak PlasmaReferences in Pharmacol Levels Plasma ogicai Action Oral, 2.5, i0 to 0.5 to I20-480 (PDR, 1995) 5, or 20% 1 hour min sesame 10 mg oil in gelatin capsules Oral, 20 mg 4 to 120-180 60-90 min (Ohlsson, in 12% min et al., cookies 1980) Intre 5 mg 100% 10 min 3 min (Ohlsson, et al., venous, 1980) bolus Smoking 13 mg 8 to 10 min 3 min (Ohlsson, 24% et al., (THC lost 1980) to side stream smoke and pyrolysis Currently, the sources of L19 THC for patients who could benefit from the drug a~-e very limited. An oral form of l~4 THC (MA1RINOL} is marketed as a treatment for nausea arid vomiting related to cancer chemotherapy, and as an appetite stimulant in patients suffering from AIDS wasting syndrome. In MARINOL, pharmaceutical grade L19 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 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 D9 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 povtential adverse side effects encountered by smoking marijuana would be avoided. Further, an aerosol preparation of~pharmaceutically pure O9 THC could be administered in known, controlled dosages.
In 1976, Olsen et al. described a chlorofluorocarbon (CFC) propelled MDI
formulation of O9 THC (2I }. However, ~9 THC is known to deteriorate during storage, and the stability of t19 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 D9 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 d,° 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 L19 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 t19 THC. The propellant is present in the range of approximately 78 to I00% by WO OOJ2436Z PCTlUS99J24486 weight, and more particularly the propellant is present in the range of approximately 8S to 100% by weight. An organic solvent such as ethanol can be used to assist in solubilizing the 09 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 vctill he required. The pharmaceutically effective concentration of ~Q 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
Figure 1. 09 THC MDI characterization summary before and after storage at 40°C and 82% relative humidity (RH).
Figure 2. Generalized schematic drawings of a O9 THC MDI.
INVENTION
'The instant invention provides a series of non-ozone depleting pressurized metered dose inhaler formulations of L19 THC. In preferred embodiments of the invention, the formulations contain the pharmaceutically acceptable, non-ozone depleting hydrofluoroatkane propellants HFA 134a (1,1,1,2-tetrahydrofluoroethane) 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 ~9 THC. However, higher _g_ 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 1 S % solvent. Within this range of percentages, pharmaceutically useful concentrations of ~9 THC can be achieved and droplet size is still small enough (<5.8~,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 D9 THC
and droplet size. Any ratio of propellant to solvent that results in appropriate sized droplets and adequate dissolution of the L1,9 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" (ar 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. °.Chis 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 10i.~,m in size.
_g_ WO 00/243b2 PCTlUS99/24486 TABLE 3.
Apparent Solubility of 09 THC
in Ethanol/HFA
Propellant Blends FormulationMass (g) Mass (g) Apparent Comments of of d' THC FormulationSolubiiity in Sample Sampled Mean (fSD) L19 'fHC 0.000240 0.1071 0.224% w/w Excess A9 THC
in added 100% HFA 00.063) to propellant blend (in i34a pressurized MDI).
Solubility sample removed using puff absorber. ns5 O' THC in 0.00144 0.0914 1.585% w/w As above 5%
Ethanol (t0.321 ) / 95%
HFA 134a A9 THC in 0.00363 0.1036 3.511% w/w As above 10% Ethanol 00249) I
90% HFA
134a D' THC in 0.00536 0.1098 4.883% w/w As above I 5% Ethanol (t0.224) /
85% HFA
134a O' THC in 0.00021 0.1451 0.147% w/w As above 100i~o HFA (t0.008) A9 THC in 0.00134 0.0979 1.339% w/w As above 5%
Ethanol (f0,169) / 95%
D9 THC in 0.00454 0.1267 3.240% w/w As above 10% Ethanol 00.161 ) /
90% HFA
4' Tl-IC 0.00623 0.1062 5.940% w/w As above in I S% Ethanol 00. 191 ) /
85% HFA
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 134alethanol 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. L19 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 Figure l and Tables 4A and 4B. The formulations 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 D9 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 L19 THC are generally known to partition into the elastomers of the valves in MDI formulations. (D,9 THC is highly iipophilic as reflected in its octanol:water partition coefficient of 6000:1 ). Over time, this partitioning results in a decrease in the emitted or delivered dose of a lipophiiic drug.
Thus, dus 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 WU~ OOI24362 PCTNS99I24486 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 D' THC for the formulation itself, rather than for the valve elastomers.
TABLE 4A. Formulation and aerosol characteristics of t~,' THC pressurized metered dose inhalers in ethanoVhydrofluoroalkane (HFA) propellant blends.
Inhaler Formulation Description (% wlw) A' THC EthanolPropellant 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% ~S% 95% HFA 134a 3198 Pale Yellow Solution 7 0.57% ~5% 95% HFA 134a 3/98 Yellow Solution 8 0.58% w5% 95% HFA 227 3198 Yellow Solution 9 0.49% ~5% 95% HFA 134a 3/98 Yellow Solution 10 1.02% ~5% 95% HFA I34a 3/98 Yellow Solution Y 1 1.11% ~5% 9S% HFA 227 3/98 Yellow Solution 1.2 0.97% ~5% 95% HFA 134a 3/98 Yellow Solution SS* #I 1.07% 4.94% 94.0% HFA 6198 Yellow Solution Initial 134a WC! 0012362 PCTIUS99/24486 SS* #i afterI.07% 4.94% 94.0% HFA 134a7/98 Yellow Solution 28 days at 40C/82%
R',H*
SS* #2 after1.00% 5.01% 95% HFA 134a 7198 Yellow Solution 21 days at 40C/82%
RH*
S S* #3 1.02% 5.15% 93.8% HFA 134a10198 Yellow Modified Solution Actuator*
a Mean (Standard Deviation) of five determinations.
b Mass of L19 THC aerosol particles <5.8 ~.m aerodynamic diameter * SS: Stability Sample * * RH: relative humidity * * * Aproximate spray nozzle diameter = 0.2 mm.
TALE 4E. Formulation and aerosol characteristics of ~9 THC pressurized metered dose inhalers in ethanoUhydrofluoroalkane (HFA) prapellant blends.
Inhaler Aerosol Characterization Metered Dose Emitted Dose Fine {mg)" (mg)a Particle Dose (mg) a,b 11 1.72 {0.25) 1.32 (0.17) ND
- i2_. - __ ~-0.94 (0.23) 0.97 (0.10) 0.38 (0.02) -13~
WO 00/4362 PCT/US99I2448b 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 40C/82%
~**
SS* #2 after 1.02 (0.05) 0.90 (0.05) 0.21 (0.02) 21 days at 40C/82%
~**
SS* #3 Modified ND ND 0.40 (n=1) Actuator* * ~' 8 Mean (Standard Deviation) of five determinations.
b Mass of ~9 THC aerosol particles with <5.8 ~tm aerodynamic diameter *SS: Stability Sample ** RH: relative humidity ND: not determined *** A.pproximate spray nozzle diameter = U.2 mm The final concentration of 09 THC in a given formulation may be varied by adjusting the ratio of propellant to solvent and thus the solubility of the O9 THC.
Higher percentages of solvent (e.g. ethanol) generally allow a higher amount of 09 THC to be dissolved. I~or example, in preferred embodiments of the invention, the apparent solubility of l19 THC ranged from 0.147% wlw to 5.94% wlw as the propellant composition varied from 100% HFA 227 to 85% HFA 227 and I S%
ethanol. Thus, the dose of L~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 Figure 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 WO 00124362 PCTlUS99124486 unaffected by storage.
The D9 THC of the present invention is pharmaceutically pure. That is, its form is the nonionized resinous drug substance (6aR-traps)-ba,7,8, I Oa-tetrahydro-6,6,9-trime~thyl-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 ,~9 THC may be synthesized (e.g. esters and salts) and thus used in the practice of this invention.
The desired final concentration of L~9 THC in a patient's serum will vary from patient to patient depending on, far 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 10-100ng1m1 at 15 minutes following inhalation. The level of L19 THC in a patient's serum can be readily and reliably monitored by gas chromatographylmass 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 L19 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 D9 THC by inhalation prescribed 3-S 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 ~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.
t~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 WO OO/Z43b2 PCT/US99/24486 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 far 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 A° 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.
Patent 5,284,133 to Burns and Marshak, which is herein incorporated by reference, can be used to prevent overdose or unauthorized consumption of D,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 ~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 09 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., Leflcowitz, 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 ofdronahinol for acquired immunodeficiency syndrome-associated anorexia. .I. Pain. Symptom Manage. 14:7-i 4.
WO 00!24362 PCTIUS99I24486 3. Beat, 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 antiernetic therapy. Invest. New Drugs 6:243-246.
5. Lucas, V.S. and Laszlo, J. (1980) L19 -THC fox 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 comparision of D9 THC and prochlorperazine. N. E'ngl. J. Med 302:135-138.
7. Frytak, S., Moertel, C.G., O'FaIlon, J.R,, Rubin, J., Creagan, E.T., O'Connetl, M.J., Schut~~, A.J. and Schwartau, N.W. (1979) Delta-9-tetrahydrocannabinol as an antiernetic 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, L, Simon, R,M. and Rosenberg SA (1979) A9 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, LE. {1975) Antiemetic effect of 09 THC
in patients receiving cancer chemotherapy. New Engl. J. Med 293:795-?97.
10. Noyes, J.R., Brunk, S.F., Baram, D.A. and Canter, A. (1975) The analgesic WO 00/24362 PCTNS99I?~W86 properties of L19 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 ~9 -tetrahydrocannabinol. J. ~ Cdin. Pharmacol. 15:139-143.
85% HFA
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 134alethanol 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. L19 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 Figure l and Tables 4A and 4B. The formulations 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 D9 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 L19 THC are generally known to partition into the elastomers of the valves in MDI formulations. (D,9 THC is highly iipophilic as reflected in its octanol:water partition coefficient of 6000:1 ). Over time, this partitioning results in a decrease in the emitted or delivered dose of a lipophiiic drug.
Thus, dus 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 WU~ OOI24362 PCTNS99I24486 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 D' THC for the formulation itself, rather than for the valve elastomers.
TABLE 4A. Formulation and aerosol characteristics of t~,' THC pressurized metered dose inhalers in ethanoVhydrofluoroalkane (HFA) propellant blends.
Inhaler Formulation Description (% wlw) A' THC EthanolPropellant 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% ~S% 95% HFA 134a 3198 Pale Yellow Solution 7 0.57% ~5% 95% HFA 134a 3/98 Yellow Solution 8 0.58% w5% 95% HFA 227 3198 Yellow Solution 9 0.49% ~5% 95% HFA 134a 3/98 Yellow Solution 10 1.02% ~5% 95% HFA I34a 3/98 Yellow Solution Y 1 1.11% ~5% 9S% HFA 227 3/98 Yellow Solution 1.2 0.97% ~5% 95% HFA 134a 3/98 Yellow Solution SS* #I 1.07% 4.94% 94.0% HFA 6198 Yellow Solution Initial 134a WC! 0012362 PCTIUS99/24486 SS* #i afterI.07% 4.94% 94.0% HFA 134a7/98 Yellow Solution 28 days at 40C/82%
R',H*
SS* #2 after1.00% 5.01% 95% HFA 134a 7198 Yellow Solution 21 days at 40C/82%
RH*
S S* #3 1.02% 5.15% 93.8% HFA 134a10198 Yellow Modified Solution Actuator*
a Mean (Standard Deviation) of five determinations.
b Mass of L19 THC aerosol particles <5.8 ~.m aerodynamic diameter * SS: Stability Sample * * RH: relative humidity * * * Aproximate spray nozzle diameter = 0.2 mm.
TALE 4E. Formulation and aerosol characteristics of ~9 THC pressurized metered dose inhalers in ethanoUhydrofluoroalkane (HFA) prapellant blends.
Inhaler Aerosol Characterization Metered Dose Emitted Dose Fine {mg)" (mg)a Particle Dose (mg) a,b 11 1.72 {0.25) 1.32 (0.17) ND
- i2_. - __ ~-0.94 (0.23) 0.97 (0.10) 0.38 (0.02) -13~
WO 00/4362 PCT/US99I2448b 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 40C/82%
~**
SS* #2 after 1.02 (0.05) 0.90 (0.05) 0.21 (0.02) 21 days at 40C/82%
~**
SS* #3 Modified ND ND 0.40 (n=1) Actuator* * ~' 8 Mean (Standard Deviation) of five determinations.
b Mass of ~9 THC aerosol particles with <5.8 ~tm aerodynamic diameter *SS: Stability Sample ** RH: relative humidity ND: not determined *** A.pproximate spray nozzle diameter = U.2 mm The final concentration of 09 THC in a given formulation may be varied by adjusting the ratio of propellant to solvent and thus the solubility of the O9 THC.
Higher percentages of solvent (e.g. ethanol) generally allow a higher amount of 09 THC to be dissolved. I~or example, in preferred embodiments of the invention, the apparent solubility of l19 THC ranged from 0.147% wlw to 5.94% wlw as the propellant composition varied from 100% HFA 227 to 85% HFA 227 and I S%
ethanol. Thus, the dose of L~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 Figure 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 WO 00124362 PCTlUS99124486 unaffected by storage.
The D9 THC of the present invention is pharmaceutically pure. That is, its form is the nonionized resinous drug substance (6aR-traps)-ba,7,8, I Oa-tetrahydro-6,6,9-trime~thyl-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 ,~9 THC may be synthesized (e.g. esters and salts) and thus used in the practice of this invention.
The desired final concentration of L~9 THC in a patient's serum will vary from patient to patient depending on, far 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 10-100ng1m1 at 15 minutes following inhalation. The level of L19 THC in a patient's serum can be readily and reliably monitored by gas chromatographylmass 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 L19 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 D9 THC by inhalation prescribed 3-S 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 ~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.
t~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 WO OO/Z43b2 PCT/US99/24486 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 far 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 A° 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.
Patent 5,284,133 to Burns and Marshak, which is herein incorporated by reference, can be used to prevent overdose or unauthorized consumption of D,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 ~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 09 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., Leflcowitz, 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 ofdronahinol for acquired immunodeficiency syndrome-associated anorexia. .I. Pain. Symptom Manage. 14:7-i 4.
WO 00!24362 PCTIUS99I24486 3. Beat, 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 antiernetic therapy. Invest. New Drugs 6:243-246.
5. Lucas, V.S. and Laszlo, J. (1980) L19 -THC fox 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 comparision of D9 THC and prochlorperazine. N. E'ngl. J. Med 302:135-138.
7. Frytak, S., Moertel, C.G., O'FaIlon, J.R,, Rubin, J., Creagan, E.T., O'Connetl, M.J., Schut~~, A.J. and Schwartau, N.W. (1979) Delta-9-tetrahydrocannabinol as an antiernetic 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, L, Simon, R,M. and Rosenberg SA (1979) A9 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, LE. {1975) Antiemetic effect of 09 THC
in patients receiving cancer chemotherapy. New Engl. J. Med 293:795-?97.
10. Noyes, J.R., Brunk, S.F., Baram, D.A. and Canter, A. (1975) The analgesic WO 00/24362 PCTNS99I?~W86 properties of L19 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 ~9 -tetrahydrocannabinol. J. ~ Cdin. 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 I)' 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) d~
THC in the treatment of spasticity associated with multiple sclerosis. Adv.
Alcohol Subst. Abuse 7:39-50.
THC in the treatment of spasticity associated with multiple sclerosis. Adv.
Alcohol Subst. Abuse 7:39-50.
14. Clifford, D.B. (I983) Tetrahydrocannabinol for tremor in multiple sclerosis. Ann.
Neurol. 13:669-171.
I5. Petro, D.J. and Ellenberger, C. (1981) Treatment of human spasticity with delta 9 -tetrahydrocannabinol. J. Clin. PharmacoL 21:4135-416S.
16. Maurer, M., Henn, V., Dittrich, A. and Hofman, 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 Geibart, S.
{1980) Effects of marihuana on infra ocular and bland pressure in glaucoma. Opht.
87:222-228.
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20. Ohlsson, A., Lindgren, J:E., Wahlen, A., Agurall, S., Hollister, L.E. and Gillespie, H.K. (1980) Plasma A~ 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 d9- tetrahydrocannabinol. J. Pharmacy and Pharmacol. 28:86.
22. Dolby, 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 09- tetrahydrocannabinoI 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-!~-THC administered by aerosol to asthmatic patients. Thorax. 31:720-723.
25. European Patent 0,372,777 (Riker Laboratories). Medicinal aerosol formulations.
Claims (23)
1. An aerosol-dispensable pharmaceutical composition, comprising:
a hydrofluoroalkane propellant; and .DELTA.9- tetrahydrocannabinol present in a pharmaceutically acceptable form and at a pharmaceutically effective concentration dissolved in said hydrofluoroalkane propellant.
a hydrofluoroalkane propellant; and .DELTA.9- tetrahydrocannabinol present in a pharmaceutically acceptable form and at a pharmaceutically effective concentration dissolved in said hydrofluoroalkane propellant.
2. The aerosol dispensable pharmaceutical composition of claim 1 wherein said .DELTA.9- tetrahydrocannabinol is dissolved in said hydrofluoroalkane propellant without the use of a solubilizing agent selected from the group consisting of solvents and surfactants.
3. The aerosol-dispensable pharmaceutical composition of claim 1 wherein said hydrofluoroalkane is selected from the group consisting of: HFA 134a and HFA
227.
227.
4. The aerosol-dispensable pharmaceutical composition of claim 3 wherein said hydrofluoroalkane is present in an amount in excess of 85% by weight.
5. The aerosol-dispensable pharmaceutical composition of claim 1 further comprising an organic solvent.
6. The aerosol-dispensable pharmaceutical composition of claim 5 wherein said organic; solvent is ethanol present in an amount ranging up to 15% by weight.
7. The aerosol-dispensable pharmaceutical composition of claim 1 wherein said pharmaceutically effective concentration of .DELTA.9-tetrahydrocannabinol ranges from 0.05 to 10% by weight.
8. The aerosol-dispensable pharmaceutical composition of claim 1 wherein said pharmaceutically effective concentration of .DELTA.9-tetrahydrocannabinol ranges from 0.1 to 6% by weight.
9. The aerosol-dispensable pharmaceutical compositon of claim 1 wherein .DELTA.9-tetrahydrocannabinol is present in pure form.
10. A solvent free pharmaceutical composition consisting essentially of 1,1,1,2,3,3,3-hydrofluoropropane (HFA 227) and .DELTA.9- tetrahydrocannabinol.
11. A solvent free pharmaceutical composition consisting essentially of 1,1,1,2-hydrofluroethane (HFA 134a) and .DELTA.9- tetrahydrocannabinol.
12. A method of treating a patient in need thereof with an aerosolized pharmaceutically acceptable form of .DELTA.9- tetrahydrocannabinol, comprising the step of:
administering an aerosolized dose of a pharmaceutically acceptable form of .DELTA.9-tetrahydrocannabinol as respirable droplets to a patient's lung from a composition comprised of a hydrofluoroalkane propellant and said pharmaceutically acceptable form of .DELTA.9- tetrahydrocannabinol.
administering an aerosolized dose of a pharmaceutically acceptable form of .DELTA.9-tetrahydrocannabinol as respirable droplets to a patient's lung from a composition comprised of a hydrofluoroalkane propellant and said pharmaceutically acceptable form of .DELTA.9- tetrahydrocannabinol.
13. The method of claim 12 wherein said composition comprises a pharmaceutically acceptable solvent.
14. The method of claim 12 wherein said composition is solvent-free.
15. The method of claim 12 wherein said aerosolized dose is sufficient to reduce nausea.
16. The method of claim 12 wherein said aerosolized dose is sufficient to reduce vomiting.
17. The method of claim 12 wherein said aerosolized dose is sufficient to reduce pain.
18. The method of claim 12 wherein said aerosolized dose is sufficient to relieve muscle spasticity.
19. The method of claim 12 wherein said aerosolized dose is sufficient to relieve migraine headaches.
20. The method of claim 12 wherein said aerosolized dose is sufficient to relieve movement disorders.
21. The method of claim 12 wherein said aerosolized dose is sufficient to increase appetite in patients suffering from cachexia.
22. The method of claim 12 wherein said pharmaceutically acceptable form of .DELTA.9-tetrahydrocannabinol is pure .DELTA.9-tetrahydrocannabinol and said hydrofluoroalkane is selected from the group consisting of HFA 134a and HFA 227.
23. A metered dose inhaler, comprising, a housing;
a metering valve connected to said housing; and, an aerosol-dispensable pharmaceutical composition which includes a hydrofluoroalkane propellant and .DELTA.9-tetrahydrocannabinol present in a pharmaceutically effective concentration dissolved in said hydrofluoroalkane propellant.
a metering valve connected to said housing; and, an aerosol-dispensable pharmaceutical composition which includes a hydrofluoroalkane propellant and .DELTA.9-tetrahydrocannabinol present in a pharmaceutically effective concentration dissolved in said hydrofluoroalkane propellant.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10585098P | 1998-10-27 | 1998-10-27 | |
| US60/105,850 | 1998-10-27 | ||
| US09/273,766 | 1999-03-22 | ||
| US09/273,766 US6509005B1 (en) | 1998-10-27 | 1999-03-22 | Δ9 Tetrahydrocannabinol (Δ9 THC) solution metered dose inhaler |
| PCT/US1999/024486 WO2000024362A2 (en) | 1998-10-27 | 1999-10-20 | Δ9 tetrahydrocannabinol (δ9 thc) solution metered dose inhalers and methods of use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2344637A1 true CA2344637A1 (en) | 2000-05-04 |
Family
ID=26803013
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002344637A Abandoned CA2344637A1 (en) | 1998-10-27 | 1999-10-20 | .delta.9 tetrahydrocannabinol (.delta.9 thc) solution metered dose inhalers and methods of use |
Country Status (14)
| Country | Link |
|---|---|
| US (3) | US6509005B1 (en) |
| EP (1) | EP1124551B1 (en) |
| JP (1) | JP2002528399A (en) |
| KR (1) | KR100636854B1 (en) |
| CN (1) | CN1214789C (en) |
| AT (1) | ATE391501T1 (en) |
| AU (1) | AU764119B2 (en) |
| BR (1) | BR9915095A (en) |
| CA (1) | CA2344637A1 (en) |
| DE (1) | DE69938505T2 (en) |
| ES (1) | ES2308855T3 (en) |
| HK (1) | HK1042846B (en) |
| MX (1) | MXPA01004188A (en) |
| WO (1) | WO2000024362A2 (en) |
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- 1999-10-20 KR KR1020017004513A patent/KR100636854B1/en not_active IP Right Cessation
- 1999-10-20 JP JP2000577974A patent/JP2002528399A/en active Pending
- 1999-10-20 CN CN99812654.3A patent/CN1214789C/en not_active Expired - Fee Related
- 1999-10-20 MX MXPA01004188A patent/MXPA01004188A/en not_active IP Right Cessation
- 1999-10-20 AT AT99965726T patent/ATE391501T1/en not_active IP Right Cessation
- 1999-10-20 EP EP99965726A patent/EP1124551B1/en not_active Expired - Lifetime
- 1999-10-20 DE DE69938505T patent/DE69938505T2/en not_active Expired - Fee Related
- 1999-10-20 CA CA002344637A patent/CA2344637A1/en not_active Abandoned
- 1999-10-20 ES ES99965726T patent/ES2308855T3/en not_active Expired - Lifetime
- 1999-10-20 BR BR9915095-6A patent/BR9915095A/en not_active Application Discontinuation
-
2001
- 2001-09-04 US US09/944,221 patent/US6713048B2/en not_active Expired - Lifetime
-
2002
- 2002-05-28 HK HK02103979.7A patent/HK1042846B/en not_active IP Right Cessation
-
2004
- 2004-01-20 US US10/759,280 patent/US20040258622A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002528399A (en) | 2002-09-03 |
| US6509005B1 (en) | 2003-01-21 |
| WO2000024362A2 (en) | 2000-05-04 |
| KR100636854B1 (en) | 2006-10-20 |
| US20040258622A1 (en) | 2004-12-23 |
| DE69938505T2 (en) | 2009-07-09 |
| WO2000024362A3 (en) | 2000-08-24 |
| HK1042846B (en) | 2006-01-20 |
| US20020031480A1 (en) | 2002-03-14 |
| EP1124551A2 (en) | 2001-08-22 |
| KR20010075610A (en) | 2001-08-09 |
| AU764119B2 (en) | 2003-08-07 |
| ATE391501T1 (en) | 2008-04-15 |
| US6713048B2 (en) | 2004-03-30 |
| BR9915095A (en) | 2002-01-15 |
| ES2308855T3 (en) | 2008-12-01 |
| AU2143000A (en) | 2000-05-15 |
| DE69938505D1 (en) | 2008-05-21 |
| HK1042846A1 (en) | 2002-08-30 |
| MXPA01004188A (en) | 2002-06-04 |
| CN1324236A (en) | 2001-11-28 |
| EP1124551B1 (en) | 2008-04-09 |
| CN1214789C (en) | 2005-08-17 |
| EP1124551A4 (en) | 2004-10-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |