FORM2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION
(SECTION 10; RULE 13)
TITLE:
LIQUIDCOMPOSITIONS COMPRISINGCANNABINOIDS
ALKEM LABORATORIES LIMITED,
A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT: ALKEM HOUSE, SENAPATI BAPAT MARG, LOWER PAREL,MUMBAI-400013
THE FOLLOWINGSPECIFICATION DESCRIBESTHEINVENTION

FIELD OF THE INVENTION
The present invention relates to liquid compositions of cannabinoids. The cannabinoid compositions of the present invention are liquid pharmaceutical compositions, namely, solutions, emulsions, suspensions, spray, and drops, that are formulated with therapeutically effective amounts of cannabinoid and can be administered by nasal, oral, sublingual, parenteral route, preferably nasal route to treat disorders or disease states or alleviate or mitigate symptoms thereof that are treatable with cannabinoids.
BACKGROUND
Cannabinoids include naturally occurring active compounds in plants such as Cannabis sativa (hemp or marihuana). Synthetic cannabinoids have also been prepared. Exemplary cannabinoids include tetrahydrocannabinols, for example, delta-9-tetrahydrocannabinol (.DELTA..sup.9-THC or dronabinol), delta-9-tetrahydrocannabinol propyl analogue, cannabidiol, cannabidiol propyl analogue, cannabinol, cannabichromene, cannabichromene propyl analogue, nabilone and cannabigerol. A number of cannabinoids, more particularly tricyclic cannabinoids such as .DELTA..sup.9-THC, are psychoactive.
Delta-9-Tetrahydrocannabinol (also known as THC, dronabinol and D9THC) is a naturally occurring compound and is the primary active ingredient in the controlled substance marijuana. Marijuana refers to the dried flowers and leaves of Cannabis Sativa, the hemp plant. These parts of the plant contain several compounds called cannabinoids (including dronabinol), that may help patients with certain disease conditions. Dronabinol has been approved by the Food and Drug Administration (FDA) for the control of nausea and vomiting associated with chemotherapy and, more recently, for appetite stimulation of AIDS patients suffering from wasting syndrome. Synthetic dronabinol has been utilized as a pharmaceutically active ingredient, and cannabis-based medicines using botanical sources of cannabis rather than synthetic THC are also known in the art.
Lipophilic compounds that are unstable in the presence of oxygen and moisture, such as dronabinol, have proven difficult to formulate into stable liquid composition due to degradation and insolubility.

At least 35% ethanol and probably closer to 50% ethanol is likely to be required to achieve complete dissolution of lipophilic THC into aqueous medium but such relatively high levels of ethanol may irritate nasal mucosa. Specifically when the route of administration is intranasal. Ethanol, when used at high concentrations to deliver a drug to a mucosal surface, provokes a stinging sensation and is beyond the limit of tolerability.
U.S. Pat. No. 6,747,058 describes an aerosolizable formulation for delivery of delta-9-tetrahydrocannabinol in a semi-aqueous solvent, such as 35:10:55 alcohol:water:propylene glycol (v/v), which is said to produce a stable clear solution near the solubility point of the drug. When the water content of the described formulations approaches 20 parts by volume, droplets form. As the water content of dronabinol formulations increases and the amount of organic solvent such as ethanol content decreases the drug readily falls out of solution, thus inducing instability.
U.S. Pat. No. 9,345,771 describes liquid cannabinoid formulations contain between about 25% to about 35% w/w water; more preferably, between about 30% and about 33% w/w water, and most preferably, about 33% w/w water. The said invention describes the liquid cannabinoid formulations comprising dronabinol and, the following ingredients 25-33% w/w water, combination of propylene glycol & polyethylene glycol, alcohol, butylated hydroxyanisole, and preservative such as paraben.
U.S. Pat. No. 4,464,378 to describes preparing a nasal dosage form of .DELTA..sup.9-THC by suspending the drug in an aqueous system.
U.S. Patent Application Publication No. 2003/0003113 describes administration of addictive drugs including cannabinoids as part of a method of cessation therapy. Routes of delivery including transdermal, intranasal and sublingual administration are proposed.
U.S. Patent Application Publication No. 2007/0060639 describes Compositions and methods for intranasal delivery of tricyclic cannabinoids.

International Patent Application Publication No. WO 2005/044093 describes use of .DELTA..sup.9-THC for treatment of multiple sclerosis, and mentions nasal administration as a possible method of delivery.
We have surprisingly found that stable liquid composition of dronabinol can be made in spite of using less % of ethanol. Surprisingly the composition of invention may not use polyethylene glycol and/or propylene glycol. It can be understood from prior art that making a stable liquid composition which contains a higher amounts of water and a lesser quantity of ethanol is difficult as the dronabinol precipitates out. However it is desirable to have higher amounts of water and lesser amounts of ethanol to avoid irritation of nasal mucosa.
OBJECT AND SUMMARY OF THE INVENTION
It is an object of the present invention to provide liquid compositions of cannabinoids and preferably dronabinol.
It is a further object of the invention to provide liquid compositions of dronabinol containing high content of water and less content of ethanol which are stable at room, and/or at refrigerated, and/or at 40 ºC temperatures.
It is a further object of the invention to provide liquid compositions of dronabinol containing at least about 50% w/w or more of water which are stable at room, and/or at refrigerated, and/or at 40 ºC temperatures.
It is a further object of the invention to provide liquid compositions of dronabinol containing more than 70% w/w of water which are stable at room, and/or at refrigerated, and/or at 40 °C temperatures.
It is a further object of the invention to provide liquid compositions of dronabinol containing less than 2% w/w of ethanol which are stable at room, and/or at refrigerated, and/or at 40 °C temperatures.

It is a further object of the invention to provide liquid compositions of dronabinol without using ethanol which are stable at room, and/or at refrigerated, and/or at 40 °C temperatures.
It is a further object of the invention to provide a liquid pharmaceutical composition comprising from about 0.1 to about 10% w/w dronabinol, at least about 50% w/w or more of water, from about 2 % w/w or less ethanol, from about 1 to about 40% w/w castor oil or derivatives thereof, wherein the liquid composition is stable at room, and/or at refrigerated and/or at 40 ºC temperatures.
All percentages of ingredients reported herein are expressed as weight by weight, unless otherwise indicated.
The term "stable" or "stability" as used herein with respect to dronabinol refers to a liquid pharmaceutical composition remains within at least about 80% of the dronabinol in undegraded form and having less than 2% cannabinol and less than 2% delta-8-THC after exposure of the formulation at 5 ºC., and/or; 25 ºC /60% RH; and/or 40 ºC/75% RH.
The invention may be summarized as given below:
A. A liquid pharmaceutical composition comprising from about 0.1 to about 10% w/w
dronabinol, at least about 50% w/w or more of water, from about 2 % w/w or less ethanol,
from about 1 to about 40% w/w castor oil or derivatives thereof, wherein the liquid composition
is stable at room, and/or at refrigerated and/or at 40 ºC temperatures.
B. A liquid pharmaceutical composition as in A above, wherein the formulation may be
administered by a delivery route selected from the group consisting of pulmonary, oral, nasal,
transmucosal such as buccal and sublingual, transdermal, intravenous and ophthalmic.
C. A liquid pharmaceutical composition as in B above, wherein the formulation is administered
by nasal route.
D. A liquid pharmaceutical composition as in A above, wherein the formulation is a solution.

DETAILED DESCRIPTION
Dronabinol is unstable in the presence of oxygen and moisture resulting in rapid degradation. Additionally, dronabinol demonstrates low solubility in water, 2.8 mg/L at 23ºC. Issues associated with degradation and insolubility makes formulating dronabinol into a stable liquid challenging.
U.S. Pat. No. 6,747,058 describes that when the water content of dronabinol formulation increases and ethanol content decreases beyond a certain level, the drug readily falls out of solution.
The proposed dronabinol composition of the present invention represents a liquid formulation with the high water content to achieve chemical stability at room and/or refrigerated, and/or at 40 ºC temperatures. A stable liquid pharmaceutical composition comprising from about 0.1 to about 10% w/w dronabinol, at least about 50% w/w or more of water, from about 2 % w/w or less ethanol, from about 1 to about 40 % w/w castor oil or derivatives thereof. The liquid composition of dronabinol is stable for at least 3 months at room, and/or, at refrigerated, and/or, at 40 ºC temperatures. The formulation may be stored in a refrigerator or at ambient temperatures and humidity. The active pharmaceutical ingredient may remain within at least 80% of the initial dronabinol content for a shelf-life of at least 1 year after manufacture. If current trends continue in the stability data, a shelf-life of at least 18 months to 2 years seems achievable.
Cannabinoids in general, and dronabinol specifically, are insoluble in water. The formulations of the present invention is liquid pharmaceutical composition of dronabinol using the high water content wherein said liquid composition is stable at room, and/or, at refrigerated, and/or at 40 ºC temperatures with higher amounts of water and less amount of ethanol.
Although certain sections of this specification provide specific focus on dronabinol, one skilled in the art will appreciate that the present invention is applicable to the class of pharmaceutically acceptable cannabinoids. For purposes of the present invention, the term "cannabinoid"

includes naturally occurring and non-natural derivatives of cannabinoids which can be obtained by derivation of natural cannabinoids and which are unstable like natural cannabinoids. In other words, the cannabinoid used in the formulations of the invention may be natural, semi-synthetic, or synthetic. The cannabinoid may be included in its free form, or in the form of a salt; an acid addition salt of an ester; an amide; an enantiomer; an isomer; a tautomer; a prodrug; a derivative of an active agent of the present invention; different isomeric forms (for example, enantiomers and diastereoisomers), both in pure form and in admixture, including racemic mixtures; enol forms. The term "cannabinoid" is also meant to encompass derivatives that are produced from another compound of similar structure by the replacement of, e.g., substitution of one atom, molecule or group by another such as 11-hydroxy-delta-8-tetrahydrocannabinol and 11-hydroxy-delta-9-tetrahydrocannabinol. The term "cannabinoid", as used in the present invention, further includes delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, nabilone, delta-9-tetrahydro cannabinotic acid, the non-psychotropic cannabinoid 3-dimethylnepty 11 carboxylic acid homologine 8. (J. Med. Chem. 35, 3135, 1992). The term cannabinoid also includes prodrugs of cannabinoids, as well as pharmaceutically acceptable salts and complexes of cannabinoids. An example of a suitable prodrug is THC-hemisuccinate.
In certain preferred embodiments of the present invention, the active ingredient (cannabinoid) comprises or consists essentially of Delta-9-tetrahydrocannabinol, also known as (and referred to herein as) dronabinol.
Dronabinol is in a class of medications called cannabinoids. It works by affecting the area of the brain that controls nausea, vomiting, and appetite.
Dronabinol is naturally-occurring and has been extracted from Cannabis sativa L. (marijuana). It has also been produced chemically as described in U.S. Pat. No. 3,668,224. Dronabinol is a light-yellow resinous oil that is sticky at room temperature, but hardens upon refrigeration. It turns to a flowable liquid when heated at higher temperatures. Dronabinol is insoluble in water. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7. Dronabinol is available in natural (extracted from plant) and synthetic forms. On the other hand, synthetic

dronabinol may be utilized and may be synthesized using the starting materials Olivetol and p-2,8-menthadien-2-ol (PMD).
The term "dronabinol" is further meant to encompass naturally occurring dronabinol, metabolites, synthetically derived dronabinol, and synthetically modified dronabinol.
In certain exemplary embodiments, the cannabinoid comprises dronabinol hemisuccinate ester (THC-HS).
In certain embodiments, the solvents are organic solvents such as dehydrated alcohol, ethanol, propanol, isopropanol, propylene glycol, and combinations thereof that are pharmaceutically acceptable based on the desired formulation. For purposes of this invention, the term "dehydrated alcohol" is used interchangeably with the term "absolute alcohol". The amount of dehydrated alcohol in a particular formulation will vary based on the intended formulation and the solubility of the cannabinoid. The amount of ethanol in the formulations of the present invention can range from about 2% w/w or less.
In certain embodiments, the formulation may contain co-solvent from about 1% to about 50% by weight propylene glycol (PG) and preferably from about 1% to about 30% by weight propylene glycol. Most preferably, the co-solvent will range from 1-20% by weight.
In certain preferred embodiments, polyethylene glycol (PEG) may use as a portion of the co-solvent for the cannabinoid, more preferably a low molecular weight polyethylene glycol is used, most preferably polyethylene glycol 400.
In certain embodiments, the formulation of the present invention may use both propylene glycol and polyethylene glycol. In certain embodiments, the formulation of the present invention may use only propylene glycol. In certain embodiments, the formulation of the present invention may use only polyethylene glycol. In certain embodiments, the formulation of the present invention may not use both propylene glycol and polyethylene glycol.

In certain embodiments of the invention further solubilizing agents may be added in the formulation. Exemplary solubilizing agents include Capryol 90; Cremophor, Kolliphor EL; Kolliphor RH40; Labrafil M 1944 CS; Labrafil M 2125 CS; Lauroglycol 90; PEG MW>4000; Plurol Oleique CC 497; poloxamer 124; poloxamer 188; Softigen 701; Softigen 767; Tagat TO; Tween 80; triacetin; triethylcitrate; tributylcitrate; acetyl triethylcitrate; acetyl tributyl citrate; ethyl oleate; ethyl caprylate; ethyl butyrate; triacetin; 2-pyrrolidone; 2-piperidone; N-methylpyrrolidone; N-ethylpyrrolidone; N-hydroxyethyl pyrrolidone; N-octylpyrrolidone; N-laurylpyrrolidone; dimethylacetamide; Miglyol, lanolin, castor oil or derivatives thereof, petrolatum, mineral oil and mixtures thereof. In certain embodiments, the formulation of the present invention may use the polyoxyl 35 & 40 castor oils. In certain embodiments, the formulation of the present invention may use Kolliphor EL. The formulations of the present invention may use a solubilizing agent from about 0 % to about 100% of the inactive ingredients or from about 5% to about 85% by weight.
Other components such as preservatives, antioxidants, emulsifiers, surfactants, absorption enhancers, viscosity modifiers, bulking agents, diluents, coloring agents, flavoring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into any of the compositions described as part of the invention. The amount of each of these components which may be used will be optimized for each formulation, in order to obtain a stable product (dosage form) having the desired shelf-life. Generally speaking, in embodiments in which these components are included, suitable formulations may include from about 0.001% to about 20% w/w of a pharmaceutically acceptable preservative, antioxidant, surfactant, absorption enhancer, viscosity modifier, bulking agent, diluent, coloring agent, flavoring agent, pH modifier, sweetener or taste-masking agent.
In certain preferred embodiments, the formulation may contain amounts of one or more pharmaceutically acceptable anti-oxidants in an amount effective to stabilize the cannabinoid contained therein such that the cannabinoid does not degrade to an unacceptable extent and the formulation is deemed stable for at least eighteen months when placed under storage conditions selected from refrigerated or room temperature.

In further embodiments of the invention, an effective (stabilizing) amount of one or more pharmaceutically acceptable anti-oxidants may be added to the formulation. The term "anti-oxidant" is used herein to describe any compound or combination of compounds that prevents or slows down cannabinoid oxidation. Any of the known anti-oxidants may be used, including but not limited to anti-oxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, lecithin, Vitamin E tocopherol, sesamin, sesamol, sesamolin, alpha tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate and sodium metabisulphite, as well as chelating agents such as disodium EDTA, may also be used to stabilize the cannabinoid formulations of the present invention.
The preparation may also contain anti-oxidant synergists to prevent oxidative degradation. Any of the known anti-oxidant synergists may also be used in effective amounts, for example disodium edetate.
The amount of anti-oxidant which may be used will be optimized for each formulation, in order to obtain a stable product (dosage form) having the desired shelf-life. Generally speaking, in embodiments in which an anti-oxidant is included, suitable formulations may include from about 0.001% to about 20% w/w of a pharmaceutically acceptable anti-oxidant(s). In other preferred embodiments, BHA, or BHT or combinations thereof, is used as the anti-oxidant in an amount of from about 0.001 to about 1%, w/w, and in certain embodiments more preferably in the range from about 0.01% to about 0.1% w/w. The anti-oxidant preferably prevents the formation of degradants in the dosage form to unacceptable levels.
Preservatives have bactericidal and fungicidal properties. Parabens are widely used preservatives in the pharmaceutical industry because of their efficacy as preservatives in combination with their long history of safe use. Parabens work best when they are used in combination since various combinations of parabens allows for the use of lower levels while increasing preservative activity. Examples of parabens include methyl paraben and propyl paraben. The formulations of the present invention may contain methyl paraben and/or propyl paraben as a preservative.

In addition the formulations may additionally include physiologically acceptable components such as sodium chloride and like materials conventionally used to achieve isotonicity with typical body fluids based on the intended route of administration. Agents which buffer the pH to maintain a physiologically compatible pH range for the intended route of administration and to enhance the solubility and stability of the active agent present, and the like may also be included in certain embodiments of the present invention.
Suitable buffers include, but are not limited to acetate, bicarbonate, citrate, phosphate, pharmaceutically acceptable salts thereof and combinations or mixtures thereof. When one or more buffers are utilized in the formulations of the invention, they may be combined, e.g., with a pharmaceutically acceptable vehicle and may be present in the final formulation, e.g., in an amount ranging from about 0.01% to about 20% by weight, more preferably from about 0.01% to about 10% by weight. Therefore, from about 5 mM to about 200 mM concentration of a buffer may be present in the formulations. The concentration of buffer may also be different in the formulations.
In certain embodiments, the present invention may comprise a sweetening agent. Suitable sweetening agents include, but are not limited to, sucralose, sucrose, aspartame, saccharin, dextrose, mannitol, xylitol, ethyl maltol, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, acesulfame K, and combinations thereof. If the formulations contain a sweetener, the formulations preferably contain from about 0.001% to about 5% by weight.
In certain embodiments, the present invention may comprise a flavoring agents. Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry grape flavors, combinations thereof, and the like. The formulation may also contain phenylethyl alcohol as a flavoring agent.
In certain embodiments, the present invention may comprise viscosity modifiers including, for example, cellulose or cellulose derivatives such as ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, caboxymethylcellulose, sodium hydroxypropylmethylcellulose, methylcellulose, methylethylcellulose, sodium carboxymethylcellulose, Aerosil, cetostearyl

alcohol, Gelucires 33/01, 39/01 and 43/01, glyceryl behenate, glyceryl palmitostearate, Softisans 100, 142, 378 and 649, stearyl alcohol carbomer, xanthan gum, maltodextrin, acacia, tragacanth, povidone and polyvinyl alcohol.
In certain embodiments, the present invention may comprise absorption enhancers. Absorption enhancers for use in accordance with certain embodiments of the present invention include, for example, Gelucire 44/14; Gelucire 50/13; Tagat TO; Tween 80; isopropyl myristate, polysorbates, sorbitan esters, poloxamer block copolymers, castor oil or derivatives thereof, PEG-35 castor oil, PEG-40 hydrogenated castor oil, caprylocaproyl macrogol-8 glycerides, PEG-8 caprylic/capric glycerides, sodium lauryl sulfate, dioctyl sulfosuccinate, polyethylene lauryl ether, ethoxydiglycol, propylene glycol mono-di-caprylate, glycerol monocaprylate, glyceryl fatty acids (C8-C18) ethoxylated, oleic acid, linoleic acid, glyceryl caprylate/caprate, glyceryl monooleate, glyceryl monolaurate, caprylic/capric triglycerides, ethoxylated nonylphenols, PEG-(8-50) stearates, olive oil PEG-6 esters, triolein PEG-6 esters, lecithin, d-alpha tocopheryl polyethylene glycol 1000 succinate, polycarbonate, sodium glycocholate, sodium taurocholate, cyclodextrins, citric acid, sodium citrate, triacetin, combinations thereof, and the like. In certain preferred embodiments, the absorption enhancer is triacetin. In certain preferred embodiments wherein an absorption enhancer is included in the formulation, the absorption enhancer is included in an amount of from about 0.001% to about 40% by weight of the formulation, preferably in an amount of about 0.01% to about 5% by weight of the formulation.
In certain embodiments, the present invention may comprise surfactants. Surfactants include any one or mixture of surfactants. The surfactants may belong to non-ionic, anionic or cationic surfactants: Glycol Distearate, Sorbitan Trioleate, Propylene Glycol Isostearate, Glycol Stearate, Sorbitan Sesquioleate, Lecithin, Sorbitan Oleate, Sorbitan Monostearate NF, Sorbitan Stearate, Sorbitan Isostearate, Steareth-2, Oleth-2, Glyceryl Laurate, Ceteth-2, PEG-30 Dipolyhydroxystearate, Glyceryl Stearate SE, Sorbitan Stearate (and) Sucrose Cocoate, PEG-4 Dilaurate, Methyl Glucose Sesquistearate, Lecithin HLB (variable) PEG-8 Dioleate, Sorbitan Laurate, Sorbitan Laurate, PEG-40 Sorbitan Peroleate, a polyoxyl glyceride, such as Labrafil.RTM. M1944CS, Laureth-4, PEG-7 Glyceryl Cocoate, PEG-20 Almond Glycerides,

castor oil or derivatives thereof, PEG-25 Hydrogenated Castor Oil, Stearamide MEA, Glyceryl Stearate (and) PEG-100 Stearate, Polysorbate 85, PEG-7 Olivate, Cetearyl Glucoside, Stearamide MEA, PEG-8 Oleate, Polyglyceryl-3 Methyglucose Distearate, Oleth-10, Oleth-10/Polyoxyl 10 Oleyl Ether NF, Ceteth-10, PEG-8 Laurate, Cocamide MEA, Polysorbate 60 NF, Polysorbate 60, Polysorbate 80, Isosteareth-20, PEG-60 Almond Glycerides, PEG-20 Methyl Glucose Sesquistearate, Ceteareth-20, Oleth-20, Steareth-20, Steareth-20, Steareth-21, Steareth-21, Ceteth-20, Steareth-100.
The formulations of the present invention are preferably administered by nasal route. However, one skilled in the art will appreciate that the liquid formulations of the present invention are not limited to administration by these routes, and can be administered via the oral route, via the nasogastric route, an intramuscular route, or by direct absorption through mucous membrane tissues (e.g., rectally), pulmonary, intravenous; transdermal, and ophthalmic administration as well as vaginal, rectal, parenteral or transmucosal (e.g., buccal or sublingual) administration. Thus, the dosage form can be converted from a solution to a suspension, emulsion, suppository, spray, aerosol, gel, drops, syrup, elixir, or other dosage form, as desired.
The formulation of the present invention can be administered by metered dosing for inhalation to nasal mucosa and/or lung by atomizing spray or aerosol. Metered dosing can be achieved by manual pump or compressed propellant gas or other means. Dosing can be controlled such that only a limited dose or limited number of doses can be administered during any 24 hour period, this can be achieved mechanically or by electronic interlock.
The liquid composition is formulated by blending the dronabinol with the excipients. The excipient solution is sparged with nitrogen for 15-30 minutes. The formulation is then filled into pharmaceutically acceptable single-dose or multi-dose containers.
The following examples illustrate various aspects of the present invention, and are set forth to assist in understanding the invention. These examples should not be construed as specifically limiting the invention described herein. Variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those

skilled in the art, and changes in formulation or minor changes in experimental design, are considered to fall within the scope of the invention.

Examples 1 and 2 containing 12.5 mg/mL of Dronabinol
Example 1 Example 2
Ingredients % w/w % w/w
Dronabinol 1.34 1.40
Dehydrated Alcohol 40.00 50.00
Propylene Glycol 10.54 10.28
PEG 400 19.80 0
Water 28.00 38.00
Sucralose 0.05 0.05
Butylated Hydroxyanisole
(BHA) 0.02 0.02
Phenylethyl Alcohol 0.25 0.25
Total 100.00 100.00
Manufacturing Procedure for Cannabinoid Formulations
The dronabinol was melted under reduced pressure at 70°C. The melted dronabinol was quickly transferred to a flask and mixed with dehydrated alcohol or Kolliphor EL. The contents were mixed at 35°C ±5°C until the dronabinol was completely dissolved while being sparged with nitrogen. An excipient solution was prepared by adding the remaining organic solvents. Butylated hydroxyanisole (BHA), preservatives and sucralose were added to this solution and mixed until dissolved. The excipient solution was mixed while sparging with nitrogen for about fifteen minutes prior to being combined with the dissolved dronabinol. Then water was slowly added and mixed for about fifteen minutes while sparging with nitrogen. The pH is adjusted with dilute acid to give a final solution. The final solution was filtered and filled into pharmaceutically acceptable single-dose or multi-dose containers.

Examples 3, 4, 5 and 6 containing 25 mg/mL of Dronabinol

Example 3 Example 4 Example 5 Example 6
Ingredients % w/w % w/w % w/w % w/w
Dronabinol 2.60 2.59 2.65 2.75
Dehydrated Alcohol 31.34 34.00 40.00 50.00
Propylene Glycol 20.00 20.00 8.98 16.93
PEG 400 19.96 17.10 18.05 0
Water 26.00 26.21 30.00 30.00
Sucralose 0.05 0.05 0.05 0.05
Butylated Hydroxyanisole (BHA) 0.02 0.02 0.02 0.02
Methyl Paraben 0.02 0.02 0 0
Propyl Paraben 0.02 0.02 0 0
Phenylethyl Alcohol 0 0 0.25 0.25
Total 100.00 100.00 100.00 100.00
Manufacturing Procedure: Manufacturing process is similar to the process described in examples 1 and 2
Examples 7 and 8 containing 40% w/w Water and Kolliphor EL. Dronabinol Concentration: 25 mg / ml

Example 7 Example 8
Ingredients % w/w % w/w
Dronabinol 2.42 2.38
Dehydrated Alcohol 2.00 2.00
Propylene Glycol 22.51 18.93
PEG 400 18.00 19.00
Water 40.00 42.62
Kolliphor EL 15.00 15.00
Sucralose 0.05 0.05
Butylated Hydroxyanisole
(BHA) 0.02 0.02
Total 100.00 100.00
Manufacturing Procedure: Manufacturing process is similar to the process described in examples 1 and 2

Examples 9, 10, and 11 containing 75% w/w or more Water and Kolliphor EL Dronabinol Concentration: 25 mg / ml

Ingredients % w/w % w/w % w/w
Dronabinol 2.45 2.45 2.50
Dehydrated Alcohol 2.00 2.00 2.00
Propylene Glycol 3.00 0.00 0.00
PEG 400 2.00 0.00 0.00
Water 75.44 80.00 85.00
Kolliphor EL 15.00 15.33 10.50
Sucralose 0.05 0.00 0.00
Butylated Hydroxyanisole
(BHA) 0.02 0.02 0.00
Methyl Paraben 0.02 0.00 0.00
Propyl Paraben 0.02 0.00 0.00
Phenylethyl Alcohol 0.00 0.20 0.00
Total 100.00 100.00 100.00
Manufacturing Procedure: Manufacturing process is similar to the process described in examples 1 and 2
Examples 12, 13, and 14: Alcohol free compositions. Dronabinol Concentration: 25 mg / ml, 50 mg/ml, and 100 mg/ml respectively

Example 12 Example 13 Example 14
Ingredients % w/w % w/w % w/w
Dronabinol 2.45 4.70 8.90
PEG 400 7.60 9.98 5.78
Water 74.63 60.00 50.00
Kolliphor EL 15.00 25.00 35.00
Sucralose 0.05 0.05 0.05
Butylated Hydroxyanisole
(BHA) 0.02 0.02 0.02
Phenylethyl Alcohol 0.25 0.25 0.25
Total 100.00 100.00 100.00

Manufacturing Procedure: Manufacturing process is similar to the process described in examples 1 and 2
The present invention has been described by reference to some of its preferred embodiments. This description is, however, in no way meant to limit the scope of the invention. Other embodiments that do not depart from the spirit of the invention should be similarly encompassed and addressed by the aforementioned description.

Claims for patent application No. 201821029411 (Liquid Compositions Comprising Cabbabinoids)
We claim:
1. The liquid pharmaceutical composition comprising from about 0.1 to about 10% w/w
dronabinol, at least about 50% w/w or more of water, from about 2 % w/w or less ethanol, from
about 1 to about 40% w/w castor oil or derivatives thereof, wherein the liquid composition is stable
at room, and/or at refrigerated and/or at 40 °C temperatures.
2. A liquid pharmaceutical composition of claim 1, wherein the formulation may be administered by a delivery route selected from the group comprising pulmonary, oral, nasal, transmucosal such as buccal and sublingual, transdennal, intravenous and ophthalmic.
3. A liquid pharmaceutical composition of claim 1, wherein the formulation is administered by nasal route.
4. A liquid pharmaceutical composition of claim 1, wherein the formulation is a solution.