WO2018163202A1

WO2018163202A1 - Stable dronabinol formulations

Info

Publication number: WO2018163202A1
Application number: PCT/IN2018/050117
Authority: WO
Inventors: Teresa BANDROWSKY; Laxman SHINDE; Yogesh RANE; Girish Kumar Jain
Original assignee: Alkem Laboratories Ltd
Current assignee: Alkem Laboratories Ltd
Priority date: 2017-03-10
Filing date: 2018-03-05
Publication date: 2018-09-13
Anticipated expiration: 2019-09-10

Abstract

The present invention relates to a stable pharmaceutical formulation comprising from about 0.1 to about 5% w/w dronabinol, at least about 40% w/w or more of water buffered to a pH from about 6 to about 7.5, from about 15 to about 65% w/w alcohol, from about 3 to about 10% w/w propylene glycol, from about 0.001 to about 1% w/w butylated hydroxyanisole, wherein the formulation does not use polyethylene glycol, and wherein the formulation is stable at 5 ºC., for at least 6 to 12 months and/or; 25 ºC /60% RH for at least 6 months; and/or 40 ºC/75% RH for at least 3 to 6 months.

Description

FIELD OF THE INVENTION

The present invention relates to formulations of cannabinoids such as dronabinol. BACKGROUND

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 aqueous-based formulations due to degradation and insolubility.

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.

We have surprisingly found that stable formulations of dronabinol can be made in spite of using at least about 40% w/w or more of water. Surprisingly the formulation of the invention also does not use preservatives or multiple co-solvents. It can be understood from prior art that making a stable formulation which contain more amount of water is difficult as the dronabinol precipitates out. However it is desirable to have more amounts of water and less amounts of co-solvent & avoid use of preservatives.

OBJECT AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide stable cannabinoids formulations, and more particularly to aqueous-based oral dronabinol formulations comprising water, alcohol and propylene glycol that are stable at 5 °C, and/or; 25 °C 160% RH and/or 40 °C/75%.

It is a further object of the present invention to provide stable dronabinol formulations comprising water, alcohol and propylene glycol that are stable at 5 °C, and/or; 25 °C /60% RH and/or 40 °C/75%.

It is a further object of the invention to provide stable formulations of dronabinol containing high content of water which are stable at 5 °C, and/or; 25 °C 160% RH and/or 40 °C/75%.

It is a further object of the invention to provide stable formulations of dronabinol containing more than 33% w/w of water which are stable at 5 °C, and/or; 25 °C /60% RH and/or 40 °C/75%.

It is a further object of the invention to provide stable formulations of dronabinol containing at least about 40% w/w or more of water which are stable at 5 °C, and/or; 25 °C /60% RH and/or 40 °C/75%.

It is a further object of the invention to provide a stable pharmaceutical formulations comprising from about 0.1 to about 5% w/w dronabinol, at least about 40% w/w or more of water, buffered to a pH from about 6 to about 7.5, from about 15 to about 65% w/w alcohol, from about 3 to about 10 % w/w propylene glycol, from about 0.001 to about 1% w/w butylated hydroxyanisole, wherein the formulation does not use polyethylene glycol, and wherein the formulation is stable at 5 °C, and/or; 25 °C /60% RH and/or 40 °C/75%.

It is a further object of the invention to provide stable oral formulations of dronabinol which are stable at 5 °C, and/or; 25 °C /60% RH and/or 40 °C/75%.

It is a further object of the invention to provide stable oral solutions comprising a cannabinoid, preferably, dronabinol from about 0.1 to 5% w/w, and the following ingredients: a) at least about 40% w/w or more of water, buffered to a pH of 6-7.5, b) about 50% w/w alcohol, c) about 3-10 % w/w propylene glycol, d) about 0.01% w/w butylated hydroxylanisole (BHA), wherein the formulation is stable at 5 °C, and/or; 25 °C /60% RH and/or 40 °C/75%.

It is a further object of the invention to provide stable oral solution of dronabinol comprising of about 0.54%) w/w dronabinol, about 42% w/w water, buffered to a pH of 6-7.5, about 50% w/w alcohol, about 5.7 % w/w propylene glycol, about 1.8% w/w sucralose, and about 0.015% w/w butylated hydroxyanisole (BHA), wherein said oral solution is stable at 5 °C, and/or; 25 °C /60% RH and/or 40 °C/75%..

It is a further object of the invention to provide stable dronabinol solutions wherein the solution does not use multiple co-solvents.

It is a further object of the invention to provide stable dronabinol solutions wherein the solution is free from preservatives.

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 dronabinol formulation that contains at least about 80% w/w and preferably at least about 90% w/w of the dronabinol in undegraded form after exposure of the formulation at 5 °C, for at least 6 to 12 months and/or; 25 °C /60% RH for at least 6 months; and/or 40 °C/75% RH for at least 3 to 6 months. The invention may be summarized as given below:

A. A stable pharmaceutical formulation comprising from about 0.1 to about 5% w/w dronabinol, at least about 40% w/w or more of water buffered to a pH from about 6 to about 7.5, from about 15 to about 65%) w/w alcohol, from about 3 to about 10 %> w/w propylene glycol, from about 0.001 to about 1%> w/w butylated hydroxyanisole, wherein the formulation does not use polyethylene glycol, and wherein the formulation is stable at 5 °C, for at least 6 to 12 months and/or; 25 °C /60% RH for at least 6 months ; and/or 40 °C/75% RH for at least 3 to 6 months.

B. A stable pharmaceutical formulation 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 stable pharmaceutical formulation as in B above, wherein the formulation is administered by oral route.

D. A stable pharmaceutical formulation as in C above, wherein the formulation is a solution.

E. A stable oral pharmaceutical solution comprising of about 0.54%> w/w dronabinol, about 42%> w/w water, buffered to a pH of 6-7.5, about 50%> w/w alcohol, about 5.7 %> w/w propylene glycol, about 1.8% w/w sucralose, and about 0.015%> w/w butylated hydroxyanisole, wherein the solution does not use polyethylene glycol, and wherein said oral solution is stable at 5 °C, for at least 6 to 12 months and/or; 25 °C /60% RH for at least 6 months ; and/or 40 °C/75% RH for at least 3 to 6 months.

F. A stable oral pharmaceutical solution according to E, wherein the solution uses only propylene glycol as a co-solvent.

G. A stable oral pharmaceutical solution according to E, wherein the solution is free from preservatives. 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 23°C. Issues associated with degradation and insolubility makes formulating dronabinol into a stable solution 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.

In prior art, cannabinoid formulations were considered unstable when the aqueous component of the carrier system exceeded 20% by volume. At high concentrations of water, the cannabinoid readily precipitates out of solution. Despite this fact, U.S. Pat. No. 9,345,771 describes a formulation with an aqueous component between 30-33% by weight that is stable at all conditions (room, cooled, or refrigerated temperatures) for eighteen months.

The proposed dronabinol formulation of the present invention represents a liquid formulation with the highest water content to date to achieve chemical stability at 5 °C, and/or; 25 °C /60% RH and/or 40 °C/75%.

The formulation of the invention comprises stable oral pharmaceutical formulations comprising from about 0.1 to about 5% w/w dronabinol, at least about 40% w/w or more of water, buffered to a pH from about 6 to about 7.5, from about 15 to about 65% w/w alcohol, from about 3 to about 10 % w/w propylene glycol, from about 0.001 to about 1% w/w butylated hydroxyanisole, wherein the formulations do not use polyethylene glycol. The dronabinol formulation is stable at 5 °C, for at least 6 to 12 months and/or; 25 °C /60% RH for at least 6 months; and/or 40 °C/75% RH for at least 3 to 6 months. The formulation may be stored in a refrigerator or at ambient temperatures and humidity.

Cannabinoids in general, and dronabinol specifically, are insoluble in water. The formulations of the present invention is an aqueous - based 1 pharmaceutical formulation of dronabinol using the high water content wherein said oral pharmaceutical formulation is stable at 5 °C, and/or; 25 °C /60% RH and/or 40 °C/75%. Additionally the composition is free from any preservative.

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 1 l-hydroxy-delta-8- tetrahydrocannabinol and 1 l-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- hemi succinate.

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 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.

In certain exemplary embodiments, the cannabinoid comprises dronabinol hemisuccinate ester (THC-HS).

Cannabinoids such as dronabinol may be used alone or in combination with other cannabinoids or cannabis-derived molecules (synthetic or natural) or other medications in the formulations of the present invention. The formulations and methods of the invention may further include one or more additional therapeutically active agents, such as, for example, non-narcotic analgesics such as acetaminophen or aspirin, opioid or opiate analgesics, non-steroidal anti-inflammatory drugs (NSAIDs, for example, non-selective cyclooxygenase inhibitors and COX-2 inhibitors), anti-emetics (for example, 5- hydroxytryptamine3 (5-HT3) inhibitors such as ondansetron, granisetron, tropisetron, palonosetron, dolasetron, and mirtazapine) and steroids (for example megestrol acetate, oxandrolone, oxymetholone, and dexamethasone). In certain embodiments of the invention, a second therapeutically active drug including but not limited to the above-mentioned drugs, is incorporated into the oral cannabinoid dosage form. In yet other embodiments, the second therapeutically active drug is separately administered to the patient in conjunction with the oral cannabinoid dosage form.

The therapeutic compounds that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration. Thus, a regimen may call for sequential administration of the therapeutic compounds with spaced-apart administration of the separate, active agents. The time period between the multiple administration steps may range from, for example, a few minutes to several hours to days, depending upon the properties of each therapeutic compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the therapeutic compound, as well as depending upon the effect of food ingestion and the age and condition of the subject. Orcadian variation of the target molecule concentration may also determine the optimal dose interval.

The therapeutic compounds of the combined therapy whether administered simultaneously, substantially simultaneously, or sequentially, may involve a regimen calling for administration of one therapeutic compound by oral route and another therapeutic compound by an oral route, a percutaneous route, an intravenous route, an intramuscular route, or by direct absorption through mucous membrane tissues. Whether the therapeutic compounds of the combined therapy are administered orally, rectally, topically, buccally, sublingually, or parenterally (for example, subcutaneous, intramuscular, intravenous and intradermal injections, or infusion techniques), separately or together, each such therapeutic compound will be contained in a suitable pharmaceutical formulation of pharmaceutically-acceptable excipients, diluents or other formulations components.

The formulations of the invention may be administered by a delivery route selected from the group consisting of: pulmonary, oral, nasal, transmucosal (eg. buccal and sublingual), transdermal, intravenous and ophthalmic. The formulations of the present invention are preferably administered orally, e.g. via oral solution or sublingually. However, one skilled in the art will appreciate that the stabilized aqueous-based cannabinoid formulations of the present invention are not limited to administration by these routes, and can be administered via the nasogastric route, an intramuscular route, or by direct absorption through mucous membrane tissues, 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 stable formulation of the present invention comprises therapeutic compound or mixture of therapeutic compounds, preferably dronabinol, water buffered to a pH from about 6 to about 7.5, a solvent which is preferably alcohol, a co-solvent such as propylene glycol, an antioxidant such as butylated hydroxyanisole, wherein the formulation does not use polyethylene glycol, and wherein the formulation is stable at 5 °C, for at least 6 to 12 months and/or; 25 °C /60% RH for at least 6 months; and/or 40 °C/75% RH for at least 3 to 6 months. Other components such as preservatives, antioxidants, 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.

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 dehydrated alcohol in the formulations of the present invention can range from about 10% to about 90%; from about 15% to about 65%; and about 15% to about 50% by weight.

In certain embodiments, the formulation contains co-solvent from about 1% to about 50% by weight propylene glycol and preferably from about 1% to about 10% by weight propylene glycol. Most preferably, the co-solvent will range from 3-10% by weight. In certain embodiments, the formulation of the present invention avoid the use of multiple cosolvent. In certain embodiments, the formulation uses only propylene glycol as a cosolvent.

In certain embodiments of the invention further solubilizing agents may be added in the formulation. Exemplary solubilizing agents include Capryol 90; Cremophor 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; tributyl citrate; 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, petrolatum, mineral oil and mixtures thereof. The formulations of the present invention may comprise a solubilizing agent from about 0 % to about 100%) of the inactive ingredients or from about 5% to about 85% by weight. In certain preferred embodiments, the formulation contains 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 antioxidants 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 antioxidants 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 metabi sulphite, 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 antioxidant 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 oral formulations of the present invention are free from any preservative. The formulations of the invention may additionally include physiologically acceptable components such as sodium chloride and like materials conventionally used to achieve isotonicity with typical body fluids.

In certain embodiments, the formulations of the present invention contain at least about 40% w/w or more of water buffered to a pH of 6-7.5. Agents which buffer the pH to maintain a physiologically compatible pH range 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 100 mM concentration of a buffer may be present in the formulations, more preferably from about 5 mM to about 50 mM concentration of a buffer may be present in the formulations The concentration of buffer is such that a pH of the formulation is from about 5 to about 10; preferably from about 6 to about 8; more preferably from about 6.5 to about 7.5 and most preferably about 7. Due to solubility properties of suitable buffers, phosphate is preferable. In certain preferred embodiments the current formulation contains a mixture of sodium phosphate monobasic anhydrous, and sodium phosphate dibasic heptahydrate to form a buffering system with a 10 mM concentration and a pH of 7.

In some embodiments, the invention is directed to stable dronabinol formulations that contain sucrose, fructose, sucralose, sorbitol, xylitol, saccharin, saccharin sodium, or combinations thereof as a sweetening agent. In certain exemplary embodiments, the oral dronabinol formulations contain a pharmaceutically acceptable sweetener such as sucralose in an amount from about 0.01% to about 10% by weight. Other exemplary embodiments may include sweeteners such as xylitol from about 1% to about 25%, saccharin from about 0.01%) to about 5%), and saccharin sodium from about 0.01% to about 5% by weight of the formulation. The composition of the invention may be formulated by blending the dronabinol which has been dissolved in the solvent such as ethanol with the excipient solution. The excipient solution may contain excipients such as ethanol, propylene glycol, sucralose, and BHA. It is degassed with nitrogen prior to adding the dissolved dronabinol. Then a pre-made buffer solution with a pH ranging from 6 to 7.5, such as for example, a sodium phosphate buffer is blended into the formulation. The final oral dronabinol formulation is then filtered and 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.

Example 1

An exemplary formulation of the cannabinoid formulation of the present invention is as follows:

Table 1

Manufacturing procedure for aqueous - based oral dronabinol formulation A container is flushed with nitrogen gas for about 15-20 minutes. The container is air tight and remains under an inert atmosphere for the duration of the experiment. An excipient solution is prepared by dissolving sucralose in a portion of dehydrated ethanol. Once a clear solution is obtained, propylene glycol and butylated hydroxyanisole are added. The excipient solution is sparged with nitrogen for 20-30 minutes. A calculated amount of dronabinol is added to the excipient solution. A pre-made buffer solution with a pH of about 7 is blended into the formulation. The solution is sparged with nitrogen for 20-30 minutes. Then water and the remaining dehydrated alcohol are added. The solution is stirred for 30 minutes. The formulation is filtered and stored in an amber glass bottle.

Stability Data

Table 2 includes stability data for the oral dronabinol formulation prepared in Table 1. The oral dronabinol formulation of the present invention was stored at 5 degrees C. and 25 degrees C, and assay and impurities were measured for up to twelve months. As can be seen from the results, the oral dronabinol formulation of the present invention remains within 80% of the dronabinol at all temperatures.

Table 2

Example 2

Exemplary Formulations of the invention and Stability Data Table 3 contains one additional exemplary formulation of the dronabinol formulation of the present invention while Table 4 shows stability data of the said formulation.

Table 3

j Name %w/w basis

] Dronabinol 0.50

] Ethanol 50.000

j Propylene Glycol 7.490

Water (Buffered) 40.000

j BHA 0.010

j Sucralose 2.000 j

j Total Weight Percent (% w/w) ldo.ood j

Manufacturing procedure for aqueous - based oral dronabinol formulation:

Manufacturing process is similar to the process described in example 1

Stability Data

Table 4 includes stability data for the dronabinol formulation of the present invention. The dronabinol formulation of the present invention was stored at 5 degrees C, 25 degrees C, and 40 degrees C. and assay and impurities were measured for 6 months. As can be seen from the results, the dronabinol formulation of the present invention remains within 80% of the dronabinol at all temperatures.

Table 4

Example 3

Exemplary Formulations of the invention and Stability Data

Table 5 contains one additional exemplary formulation of the dronabinol formulation of the present invention while Table 6 shows stability data of the said formulation.

Table 5

Manufacturing procedure for aqueous - based oral dronabinol formulation:

Manufacturing process is similar to the process described in example 1

Stability Data

Table 6 includes stability data for the dronabinol formulation of the present invention. The dronabinol formulation of the present invention was stored at 5 degrees C, 25 degrees C, and 40 degrees C. and assay and impurities were measured for 6 months. As can be seen from the results, the dronabinol formulation of the present invention remains within 90% of the dronabinol at all temperatures and total impurities were less than 4%.

Table 6

Example 4

Exemplary Formulations of the invention and Stability Data

Table 7 contains one additional exemplary formulation of the dronabinol formulation of the present invention while Table 8 shows stability data of the said formulation.

Table 7

Manufacturing procedure for aqueous - based oral dronabinol solution:

Manufacturing process is similar to the process described in example 1

Stability Data

Table 8 includes stability data for the dronabinol formulation of the present invention. The dronabinol formulation of the present invention was stored at 5 degrees C, 25 degrees C, and 40 degrees C. and assay and impurities were measured for 12 months. As can be seen from the results, the oral dronabinol solution of the present invention remains within 90% of the dronabinol at all temperatures.

Table 8

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

We claim:

1. A stable pharmaceutical formulation comprising from about 0.1 to about 5% w/w dronabinol, at least about 40% w/w or more of water buffered to a pH from about 6 to about 7.5, from about 15 to about 65% w/w alcohol, from about 3 to about 10 % w/w propylene glycol, from about 0.001 to about 1% w/w butylated hydroxyanisole, wherein the formulation does not use polyethylene glycol, and wherein the formulation is stable at 5 °C, for at least 6 to 12 months and/or; 25 °C /60% RH for at least 6 months ; and/or 40 °C/75% RH for at least 3 to 6 months.

2. A stable pharmaceutical formulation as in claim 1, 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.

3. A stable pharmaceutical formulation as in claim 2, wherein the formulation is administered by oral route.

4. A stable pharmaceutical formulation as in claim 3, wherein the formulation is a solution.

5. A stable oral pharmaceutical solution comprising of about 0.54% w/w dronabinol, about 42% w/w water, buffered to a pH of 6-7.5, about 50% w/w alcohol, about 5.7 % w/w propylene glycol, about 1.8% w/w sucralose, and about 0.015% w/w butylated hydroxyanisole, wherein the solution does not use polyethylene glycol, and wherein said oral solution is stable at 5 °C, for at least 6 to 12 months and/or; 25 °C /60% RH for at least 6 months ; and/or 40 °C/75% RH for at least 3 to 6 months.

6. A stable oral pharmaceutical solution as in claim 5, wherein the solution uses only propylene glycol as a co-solvent.

7. A stable oral pharmaceutical solution as in claim 5, wherein the solution is free from preservatives.