Stable injectable cannabidiol formulation

Abstract

An injectable cannabidiol formulation for non-IV parenteral administration comprising, consisting essentially of, or consisting of: (i) an effective amount of at least one triglyceride oil and (ii) an effective amount of at least one C1-C3 alkyl ester of a C6-C22 fatty acid; and (b) an effective amount of cannabidiol; the formulation is free of water and ethanol, has a viscosity of less than about 35 cP, and is phase-stable and chemically stable. The formulation may further comprise at least one other pharmaceutically acceptable excipient. Kits containing the formulation are also described.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 397,237, filed August 11, 2022, the entire contents of which are hereby incorporated by reference.

[0002]

[0003] Field

[0004] The present invention relates generally to pharmaceutical formulations containing cannabinoids, and more particularly to injectable pharmaceutical formulations containing cannabidiol. [Background technology]

[0003]

[0005] Background of the Invention

[0006] Cannabinoids include phytocannabinoids, which are compounds found naturally in the plant Cannabis sativa. Synthetic cannabinoids also exist and can be made by known methods. The primary cannabinoid components of Cannabis sativa include cannabidiol and tetrahydrocannabinol (THC). THC is known to increase pulse rate, cause conjunctival redness, and provide psychotropic (mood-altering) effects such as a feeling of euphoria. In contrast, cannabidiol is non-intoxicating, a characteristic that makes it desirable for use as a medicine or pharmaceutical ingredient. Known uses of cannabidiol include treating epilepsy, chronic pain, anxiety, insomnia, and inflammation.

[0004]

[0007] Cannabinoids, including cannabidiol, are susceptible to inactivation via first-pass metabolism when taken orally. This first-pass metabolism results in low active blood concentrations and a systemic bioavailability of less than 10%. Parenteral administration of cannabinoids can avoid this first-pass metabolism and is expected to increase bioavailability. Examples of parenteral administration include injection into a vein (intravenous, IV), into a muscle (intramuscular, IM), into the space around the spinal cord (intrathecal, IT), into a body cavity called the peritoneum (intraperitoneal, IP), and under the skin (subcutaneous, SC).

[0005]

[0008] Cannabidiol is known to be unstable in the presence of oxygen and moisture, presenting problems in formulating stable cannabidiol formulations due to the decomposition of cannabidiol into other compounds, such as THC. Another problem relates to the insolubility of cannabidiol in water. Therefore, desirable properties of parenteral formulations containing cannabidiol include cannabidiol stability, meaning that cannabidiol does not decompose or convert to other compounds (such as THC) and maintains efficacy and function over time; and phase stability, meaning that the ingredients are completely soluble in the solvent or solvent system, providing consistent dosing and results. Other desirable properties include a high enough concentration of cannabidiol to achieve injection volumes low enough to be practical and minimize patient discomfort; safety and non-toxicity during repeated and long-term administration when treating chronic conditions; and low enough viscosity to provide ease of administration.

[0006]

[0009] Cannabinoid-containing parenteral formulations are described in Rosenkrantz H, Thompson GR, Braude MC. Oral and parenteral formulations of marijuana constituents. J Pharm Sci. 1972 Jul;61(7):1106-12. doi: 10.1002 / jps.2600610715. PMID: No. 4625586; U.S. Patent Application Publication No. 2007 / 0060638 to Olmstead et al.; WO 2008 / 019146A2 to Kottayil et al.; WO 2008 / 144475 to McAllister et al.; U.S. Patent Application Publication No. 2013 / 0209483 to McAllister; WO 2016 / 147186 to Sinai; U.S. Patent Application Publication No. 2019 / 0314296A1 to Wright et al.; WO 2019 / 094625A1 to Wasyl et al.; U.S. Patent Application Publication No. 20210393784A1 to Kingsley et al.; and WO 2019140325A1 to Witowski. Nevertheless, there remains a need to provide new injectable cannabidiol formulations to meet market demand and that have one or more of the above desirable properties. Summary of the Invention [Means for solving the problem]

[0007]

[0010] Summary of the Invention

[0011] The inventors have found that alkyl esters of certain fatty acids, when combined with triglyceride oils, are effective in dissolving and stabilizing cannabidiol and providing a formulation having a sufficiently low viscosity and a sufficiently high cannabidiol concentration to provide a cannabidiol formulation suitable for parenteral administration other than by IV injection.

[0008]

[0012] According to a first aspect, the present invention provides an injectable cannabidiol formulation for non-IV parenteral administration comprising, consisting essentially of, or consisting of: (i) an effective amount of at least one triglyceride oil; and (ii) an effective amount of at least one C1-C3 alkyl ester of a C6-C22 fatty acid; and (b) an effective amount of cannabidiol; the formulation is water and ethanol free, has a viscosity of less than about 35 cP and is phase stable and chemically stable.

[0009]

[0013] The at least one C1-C3 alkyl ester of a C6-C22 fatty acid can be selected from the group consisting of methyl octanoate, ethyl octanoate, isopropyl myristate, ethyl caprate, methyl oleate, and ethyl oleate. In some embodiments, the C1-C3 alkyl ester of a C6-C22 fatty acid is selected from the group consisting of methyl octanoate and ethyl octanoate.

[0010]

[0014] The at least one triglyceride oil can be at least one medium chain triglyceride. In some embodiments, the at least one medium chain triglyceride comprises esters of fatty acids in the following amounts: (i) 0-2% w / w of esters of C6 fatty acids, 50-65% w / w of esters of C8 fatty acids, 30-45% w / w of esters of C10 fatty acids, <2% w / w of esters of C12 fatty acids, <1% w / w of esters of C14 fatty acids, and <1% w / w of esters of C16 or longer chain fatty acids, and is commercially available under the trade name Miglyol 812N.

[0011]

[0015] The amount of the at least one triglyceride oil can be at least about 10% w / v and / or not more than about 50% w / v, with intermediate lower and upper limits also contemplated, such as at least about 12, 14, 16, 18, 20, 22, 24, 26, or 28% w / v and / or not more than about 48, 46, 44, 42, 40, 38, 36, 34, 32, or 30% w / v.

[0012]

[0016] The amount of C1-C3 alkyl ester of at least one C6-C22 fatty acid can be at least about 25% w / v and / or not more than about 70% w / v, with intermediate lower and upper limits also contemplated, such as at least about 27, 29, 31, 33, 35, 37, 39, 41, 43, or 45% w / v and / or not more than about 69, 67, 65, 63, 61, 59, 57, 55, 53, 51, 49, or 47% w / v.

[0013]

[0017] The ratio of (i) at least one triglyceride oil to (ii) at least one C1-C3 alkyl ester of a C6-C22 fatty acid can be from about 2:1 to about 1:7, or from about 1:1 to about 1:7, or from about 2:1 to about 1:6, or from about 1:1 to about 1:6. Intermediate ratios are also specifically contemplated, such as, for example, about 50:309, about 2000:1591, about 10:63, etc.

[0014]

[0018] The cannabidiol can have a purity of at least 98.5, 99, 99.5, or 99.8%, with higher levels of purity being preferred. Furthermore, the cannabidiol can be of natural origin or synthetically produced. Combinations of natural and synthetic cannabidiol are also specifically contemplated.

[0015]

[0019] Cannabidiol can be present in amounts from about 100 mg / mL. Cannabidiol can also be present in amounts up to about 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, or 350 mg / mL, with higher cannabidiol concentrations being preferred to reduce injection volume and facilitate ease of administration while reducing patient discomfort. The identity of the ingredients and their amounts in the solvent system will determine the actual amount of cannabidiol that can be fully dissolved. The inventors have found that cannabidiol can be dissolved in amounts of at least 750 mg / mL in methyl octanoate and / or ethyl octanoate. Therefore, the greater the amount of alkyl ester of fatty acid present, the greater the amount of cannabidiol that can be dissolved.

[0016]

[0020] The formulation can have a viscosity of less than about 30 cP, about 25 cP, or about 20 cP. Generally, decreasing the viscosity increases ease of administration.

[0017]

[0021] The formulation may further comprise, consist essentially of, or consist of an effective amount of at least one other lipophilic pharmaceutically acceptable excipient, which may be selected from the group consisting of preservatives, antioxidants, anesthetic compounds, viscosity modifiers, and pharmacokinetic modifiers.

[0018]

[0022] Examples of lipophilic antioxidants are those selected from the group consisting of propyl gallate, vitamin E, ascorbyl palmitate, butylhydroxytoluene (BHT), and butylhydroxyanisole (BHA). These compounds and other lipophilic antioxidants and preservatives are used to improve shelf life. In some embodiments, at least one lipophilic antioxidant is vitamin E and / or ascorbyl palmitate. The total amount of these antioxidants can be from about 0.01, 0.05, or 0.1% w / v to about 1.5, 1.0, 0.8, 0.7, 0.6, or 0.5% w / v or less.

[0019]

[0023] An example of a lipophilic anesthetic compound is benzyl alcohol, which can be present in an amount of about 0.5% w / v to about 1.5% w / v. Benzyl alcohol also functions as another lipophilic solvent.

[0020]

[0024] In some embodiments, the formulation is free of phosphatidylglycerol and / or salts thereof. In the same or other embodiments, the formulation is free of POPG-Na (2-oleoyl-1-palmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt). In the same or other embodiments, the formulation is free of fatty acids, such as C6 to C22 fatty acids. In some embodiments, the formulation is free of octanoic acid.

[0021]

[0025] In the same or other embodiments, the formulations of the present invention are free of other surfactants, polar lipids, and / or other solvents. These include surfactants selected from the group consisting of polyoxyethylene (20) sorbitan monooleate (also known as polysorbate 80 and Tween 80); macrogol hydroxystearic acid (a mixture of primarily mono- and diesters of 12-hydroxystearic acid and macrogol obtained by ethoxylation of 12-hydroxystearic acid (15 moles of ethylene oxide reacted per mole of 12-hydroxystearic acid; proprietary versions include Solutol™ HS 15, Crodasol™ HS, and Kolliphor™ HS 15); poloxamer (a triblock copolymer with a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene; proprietary products include Pluronics™); and glycocholic acid. Polar lipids that may be excluded include glycerol, such as phospholipids. Examples of solvents that may be excluded include phospholipids (GPLs), glycolipids, sphingolipids, glycerol monooleate, and glycerol monostearate. Solvents that may be excluded include amphiphilic liquid polymer solvents such as other aliphatic alcohols (e.g., methanol, propanol, etc.), C8-C22 cyclic alcohols, aromatic alcohols, sesame oil, propylene glycol, polyethylene glycols (e.g., PEG-100, PEG-200, PEG-300, PEG-400, PEG-600, PEG-800, PEG-1000, and PEG-2000), polyethoxylated glycerides, polyethylene glycol esters, N-(2-hydroxypropyl)methacrylamide (HPMA), and polyvinylpyrrolidone (PVP) (e.g., K12 or K17). In the same or other embodiments, the formulation is free of two, three, four, or five of the above compounds or ingredients.

[0022]

[0026] The formulation is sterile and can be sterilized by methods known in the art.The formulation can be administered via subcutaneous (SC), intramuscular (IM), intraperitoneal (IP) and / or intrathecal (IT) injection, and can be provided in various formats, including as part of a kit.Accordingly, according to a second aspect, the present invention provides a kit comprising: (i) a container containing the formulation according to the first aspect; and (ii) instructions for using the formulation.The container can be part of a single-dose or multi-dose syringe, a vial, a cartridge or a pre-filled syringe. DETAILED DESCRIPTION OF THE INVENTION

[0023]

[0027] Detailed Description

[0028] definition

[0029] For clarity and to avoid ambiguity, certain terms are defined herein as follows.

[0024]

[0030] The term "solvent system" is used to refer to a mixture of components that work together to dissolve cannabidiol.

[0025]

[0031] "Single-phase" means that the solution is homogeneous and lacks a solid and a separate liquid phase.

[0026]

[0032] The term "room temperature" is used interchangeably with "ambient temperature" and means a temperature between 18°C and 25°C.

[0027]

[0033] As used herein, the term "pharmaceutically active agent" can be used as disclosed herein and refers to a drug or medication intended for use in a subject to treat or prevent a disease, illness, physical injury, or pathological condition; or to affect the physical condition, state, or function, or mental state. Drugs used include those described, for example, in the Rote Liste

[0034] or can be found in reference works such as the Merck Index. Examples that may be mentioned include, for example, cannabidiol.

[0028]

[0035] When a composition is described as having "X% purity," this means that one or more impurities may be present in an amount up to 100-X% by weight, based on the total weight of the composition. The purity of a component can be determined by high performance liquid chromatography (HPLC) or other suitable means.

[0029]

[0036] The term "subject" means any member of the animal kingdom, including humans and other mammals.

[0030]

[0037] As used herein, the terms "treat," "treatment," and similar phrases mean halting or slowing the progression of a condition, disorder, or disease. The terms "prevent," "prevention," and similar phrases mean preventing or delaying the onset of a condition, disorder, or disease. This term is intended to encompass "improving the quality of life," "prolonging the lifespan," and "improving the clinical outcome" of a subject suffering from or at risk of suffering from a condition, disorder, or disease, and does not necessarily mean, but does not exclude, "curing" the condition, disorder, or disease.

[0031]

[0038] "Pharmaceutically acceptable excipient," as used herein, means any substance that can be formulated with or present together with a pharmaceutically active agent to achieve a desired function and that is not biologically undesirable or otherwise undesirable in an injectable dosage form. For example, the excipient must be non-toxic when injected and compatible with other ingredients in the formulation. One of ordinary skill in the art, given the teachings of this specification and information available to the public, will know which compounds or components qualify as pharmaceutically acceptable excipients.

[0032]

[0039] The phrases "at least one," "one or more," and "and / or" are open-ended expressions in which both conjunctive and disjunctive expressions are valid. For example, the expressions "at least one of A, B, and C," "at least one of A, B, or C," "one or more of A, B, and C," "one or more of A, B, or C," and "A, B, and / or C" mean A only, B only, C only, A and B, A and C, B and C, or A, B, and C, respectively.

[0033]

[0040] The terms "a" or "an" mean "one or more." Thus, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein. It should also be noted that the term "or" is generally used in the sense of "and / or" unless the context clearly dictates otherwise.

[0034]

[0041] The term "comprising" means "including, but not limited to." Thus, a formulation containing listed ingredients may contain other ingredients not specifically listed. It should also be noted that the terms "comprising," "including," "containing," and "having" can be used interchangeably.

[0035]

[0042] The term "consisting of" means including the listed ingredients and other ingredients that may be present in the listed ingredients, such as natural or commercially available impurities or additives. Natural and commercially available impurities and additives will be apparent to those skilled in the art. For example, synthetic cannabidiol may contain up to about 0.5% w / w impurities, such as residual solvents and by-products of the manufacturing process.

[0036]

[0043] The formulations of the present invention are phase stable. As used herein, "phase stable" or similar expressions mean that the formulation forms a clear, single-phase solution both at the time of preparation and after storage in an airtight, sealed container at a temperature ranging from about 2°C to about 25°C for at least 12 months. The formulations of the present invention are also chemically stable, meaning that cannabidiol is not substantially converted to THC during storage under the same conditions and time frame. Conversion to THC of 10 ppm or less, based on the total formulation, is not considered to impair chemical stability.

[0037]

[0044] The term "consisting essentially of" means "including the listed ingredients and any other ingredients that do not materially affect the basic and novel characteristics of the invention." The "basic and novel characteristics" refer to the phase stability of the formulations of the invention and the suitability of the formulations as non-IV parenteral dosage forms (e.g., SC injection, IM injection, IP injection, IT injection, etc.) for the treatment or prevention of conditions, diseases, or disorders, as defined above.

[0038]

[0045] The terms "% w / w", "% wt.", "w / w%", "wt.%" and variations thereof mean the amount of a substance relative to the weight of that substance divided by the total weight of the formulation containing that substance and multiplied by 100.

[0039]

[0046] The terms "% w / v," "w / v%," and variations thereof, refer to the mass of a solute in grams divided by the volume in mL of the solution in which the solute is dissolved and multiplied by 100. For example, a formulation containing 10 grams of solvent per 25 mL of solvent-containing solution would have 40 w / v% solvent, calculated as follows: (10 ÷ 25) x 100 = 40 w / v%.

[0040]

[0047] The term "about" refers to variations in the expressed quantity that may occur through, for example, measuring and liquid handling procedures used to make the pharmaceutical formulation, differences in the manufacture, source, or purity of the ingredients used to make the formulation, and / or differences due to different equilibrium conditions or different reaction levels of the ingredients in the formulation due to the initial mixture. For clarity, the term "about" includes variations in the expressed value of no more than ±5% or no more than ±10%. Whether or not the value is modified by the term "about," the claims include equivalents to the value.

[0041]

[0048] As used herein, the term "effective amount" refers to an amount that would produce a desired effect based on the purpose and function of the component in the context of the invention disclosed herein. Implicit in "desired effect" is the absence of toxicity. For example, an effective amount of a pharmaceutically active agent is an amount that would be effective to provide a therapeutic effect while avoiding toxicity, such as may occur over long-term administration. An effective amount of a solvent is an amount that would be effective to dissolve other or remaining components of the formulation, either alone or together with other components. What constitutes an effective amount can be determined by one of ordinary skill in the art through routine experimentation given the teachings herein.

[0042]

[0049] As used herein, the phrase "free of Y" means that "Y" is not intentionally added, but may be present as an impurity or due to other factors. For example, in the case of a formulation of the invention that is free of water, the formulation may contain trace amounts of water due to the formulation or its components being exposed to water in the atmosphere or containing water as an impurity. For clarity, a "free of Y" formulation does not contain Y or contains no more than 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, or 0.5% w / v based on the total formulation.

[0043]

[0050] Values recited herein are intended to include all values meeting the stated parameters, including values not specifically recited. For example, a value less than 1.0 is intended to include less than 0.99, less than 0.98, less than 0.97, less than 0.90, less than 0.84, less than 0.56, less than 0.01, etc. Accordingly, all ranges disclosed herein should be understood to include all subranges subsumed therein. For example, a stated range of "1 to 10" should be considered to include all subranges between the minimum value of 1 and the maximum value of 10 (inclusive), such as 1 to 6.3, 5.5 to 10, 2.7 to 6.1, etc.

[0044]

[0051] This specification contemplates the possibility that any component may be omitted, even if the component is not specifically specified as being included or excluded herein.

[0045]

[0052] Solvent System

[0053] The formulations of the present invention utilize a solvent system for dissolving at least 100 mg of cannabidiol per mL of formulation while achieving a viscosity of 35 centipoise (cP) or less. The solvent system comprises an effective amount of at least one triglyceride oil and an effective amount of at least one C1-C3 alkyl ester of a C6-C22 fatty acid. The greater the ratio of C1-C3 alkyl ester of a C6-C22 fatty acid to triglyceride oil, the lower the viscosity of the final formulation and, further, the greater the amount of cannabidiol that can be completely dissolved.

[0046]

[0054] triglyceride oil

[0055] Triglyceride oils are lipid molecules with three fatty acids attached to a glycerol backbone.

[0047]

[0056] Medium-chain fatty acids (MCFAs), along with the more abundant long-chain fatty acids (LCFAs), are natural compounds present in both animal and plant tissues that are involved in cellular metabolism. MCFAs are monocarboxylic acids with hydrocarbon chain lengths of 6 to 12 total carbon atoms. Although abundant in nature, MCFAs occur in much lower amounts in plant and animal materials than LCFAs, which have hydrocarbon chain lengths of 14 to 22 total carbon atoms. The lipophilicity of MCFAs and LCFAs, measured as the partitioning of the free acid between water and heptane, gradually increases with increasing carbon atom chain length.

[0048]

[0057] Triglyceride oils are liquid at room temperature. As with simple fatty acids, the length of the fatty acid group determines the name of the triglyceride, e.g., short-chain triglyceride (SCT), medium-chain triglyceride (MCT), and long-chain triglyceride (LCT).

[0049]

[0058] Preferably, the at least one triglyceride oil is one or more medium chain triglycerides (MCTs). "Medium chain triglyceride" refers to an ester of glycerol having three C6 to C12 fatty acid chains, which may be the same or different. Medium chain triglycerides are represented by the following formula: [ka]

[0059] In the formula, each R 1 , R 2 , and R 3 and R each represent a fatty acid molecule having 6 to 12 carbon atoms. A fatty acid molecule having 6 carbons is referred to as a C6 fatty acid. A fatty acid molecule having 8 carbons is referred to as a C8 fatty acid. Similarly, a fatty acid molecule having 10 carbons is referred to as a C10 fatty acid. In various embodiments, each R group is the same. In other embodiments, two are the same and one is different. In still other embodiments, they are all different.

[0050]

[0060] Medium chain triglycerides may be synthetic as known in the art or natural (eg, produced from fractionated oils such as coconut oil and / or palm kernel oil).

[0051]

[0061] In various embodiments, the medium chain triglycerides comprise esters of (i) three C8 fatty acids; (ii) three C10 fatty acids; (iii) two C8 fatty acids and one C10 fatty acid; (iv) two C10 fatty acids and one C8 fatty acid; (v) two C8 fatty acids and one C6 fatty acid; (vi) two C10 fatty acids and one C6 fatty acid; (vii) one C8 fatty acid, one C10 fatty acid and one C6 fatty acid; or (viii) any other combination of C6, C8, C10, and C12 fatty acids.

[0052]

[0062] Those skilled in the art will recognize that a mixture of medium-chain triglycerides may result from any process (e.g., fractionation, hydrogenation) used to prepare medium-chain triglycerides. MCTs may contain one, two, three, four, or more different medium-chain triglycerides. For example, substantially all of the medium-chain triglycerides obtained from fractionated coconut oil may contain C8 and / or C10 fatty acids; however, there may be some medium-chain triglycerides containing C6 and / or C12 fatty acids. In one embodiment, MCTs contain two different medium-chain triglycerides, where the first medium-chain triglyceride contains an ester of two C8 fatty acids and one C10 fatty acid, and the second medium-chain triglyceride contains an ester of one C8 fatty acid and two C10 fatty acids.

[0053]

[0063] In one embodiment, the medium chain triglycerides comprise: (i) 0-2% w / w of C6 fatty acids, 65-80% w / w of C8 fatty acids, 20-35% w / w of C10 fatty acids, and 0-2% w / w of C12 fatty acids; (ii) 0-2% w / w of C6 fatty acids, 50-65% w / w of C8 fatty acids, 30-45% w / w of C10 fatty acids, and 0-2% w / w of C12 fatty acids; or (iii) 0-2% w / w of C6 fatty acids, 45-65% w / w of C8 fatty acids, 30-45% w / w of C10 fatty acids, 0-3% w / w of C12 fatty acids, and 0-5% w / w of linoleic acid esters. In one embodiment, the medium-chain triglyceride comprises 0-2% w / w C6 fatty acids, 50-65% w / w C8 fatty acids, 30-45% w / w C10 fatty acids, 0-2% w / w C12 fatty acids, <1% w / w C14 fatty acids, and <1% w / w C16 or longer chain fatty acids, and is commercially available as MIGLYOL® 812N. The weight percentages listed in this paragraph are based on the weight of the total fatty acid content of the triglyceride. Other commercially available MCTs that can be used are those sold under the trade names MIGLYOL® 810, 818, and 829 (from the supplier IOI Oleochemical GmbH, Germany).

[0054]

[0064] Preferably, the formulation comprises MCTs containing a mixture of C8 and C10 triglycerides in a ratio of about 55:45 to about 65:35 (C8:C10).

[0055]

[0065] Still other triglyceride oils that can be used are triglyceride oils containing omega-3 and omega-6 fatty acids. Omega-3 fatty acids include (C18) alpha-linolenic acid (ALA), (C20) eicosapentaenoic acid (EPA), and (C22) docosahexaenoic acid (DHA). Omega-6 fatty acids include (C18) linolenic acid (LA) and (C20) arachidonic acid (AA).

[0056]

[0066] In one embodiment, the formulation is free of unmodified fatty acids, such as, for example, C6 to C22 fatty acids. An exemplary C6 to C22 fatty acid is octanoic acid.

[0057]

[0067] C1-C3 alkyl esters of C6-C22 fatty acids

[0068] C1-C3 alkyl esters of C6-C22 fatty acids that are liquid at room temperature are used as cosolvents in the cosolvent systems of the present invention. The inventors have found that these compounds are useful for dissolving larger amounts of cannabidiol than triglycerides, and when incorporated into the formulations of the present invention, further help reduce the viscosity of the final formulation while preventing the conversion of cannabidiol to other compounds such as THC. Examples of C1-C3 alkyl esters of fatty acids that can be used include the methyl and ethyl esters of octanoic acid (i.e., methyl octanoate and ethyl octanoate, respectively).

[0058]

[0069] Other C1-C3 alkyl esters of C6-C22 fatty acids that can be used are C1-C3 alkyl esters of omega-3 and omega-6 fatty acids. Omega-3 fatty acids include (C18) alpha-linolenic acid (ALA), (C20) eicosapentaenoic acid (EPA), and (C22) docosahexaenoic acid (DHA). Omega-6 fatty acids include (C18) linolenic acid (LA) and (C20) arachidonic acid (AA).

[0059]

[0070] Cannabidiol

[0071] The formulations of the present invention contain an effective amount of cannabidiol, a compound having the following chemical structure: [ka]

[0060]

[0072] Cannabidiol can be of natural or synthetic origin. Methods for producing synthetic cannabidiol are known in the art. For example, cannabidiol from PURISYS, LLC (headquartered in Athens, Georgia, USA) is produced according to processes such as those described in U.S. Patent Application Publication No. 2017 / 0008868A1 (granted as U.S. Patent No. 10,059,683) and U.S. Patent Application Publication No. 20180319763A1 (granted as U.S. Patent No. 10,844,035), which are incorporated herein by reference. Synthetic cannabidiol produced by other processes and manufacturers can also be used to produce the formulations of the present invention. Plant-sourced cannabidiol can be extracted from various cannabis plants, including hemp, and purified using conventional means. The cannabidiol that can be used to produce the formulations of the present invention can be in crystalline or oil form before dissolving in a solvent system. All commercial sources of cannabidiol are useful in the context of the present invention.

[0061]

[0073] Preferably the cannabidiol has a purity of at least 99.5%, 99.6%, 99.7%, 99.8% or 99.9%. As the formulations of the present invention contain compounds / ingredients other than cannabidiol, any impurities present in the cannabidiol will be present in much smaller amounts in the overall formulation.

[0062]

[0074] Impurities that may be present in synthetic cannabidiol include residual solvents (e.g., methanol, n-heptane, dichloromethane, and triethylamine) and / or manufacturing by-products or residues, such as olivetol, monobromo-cannabidiol, and delta-9-THC. Plant-sourced cannabidiol may contain small amounts of other cannabinoids (e.g., cannabidivarin (CBDV) and the butyl analog of cannabidiol (cannabidibutol)), terpenes, and solvents or ingredients used in the purification process, as well as pesticide residues.

[0063]

[0075] The terms tetrahydrocannabinol, THC, delta-9-tetrahydrocannabinol and delta-9-THC are used interchangeably herein to refer to the chemical compound having the structure shown below. [ka]

[0064]

[0076] The term "THC" is used broadly herein to include double bond isomers and their stereoisomers.

[0065]

[0077] The formulations of the present invention are THC-free, meaning that THC is absent or present in any amount less than 0.5% w / w, preferably less than 0.4% w / w, even more preferably less than 0.3% w / w, and even more preferably less than 0.2% w / w, based on the weight of the formulation. It may be desirable to reduce the level of THC to as low a level as possible to avoid psychotropic or intoxicating effects. Embodiments of the formulations of the present invention are THC-free or have a concentration of THC of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 ppm based on the total formulation.

[0066]

[0078] The concentration of cannabidiol in the formulations of the present invention may be about 100, 150 or 200 mg / mL. Additionally or alternatively, the concentration of cannabidiol in the formulations of the present invention may be up to about 350, 300 or 250 mg / mL.

[0067]

[0079] Other ingredients

[0080] The formulations of the present invention may contain other pharmaceutically acceptable additives and pharmaceutically active agents, provided that these ingredients do not destroy the basic and novel characteristics of the present invention.

[0068]

[0081] For example, the formulations of the present invention may employ an effective amount of at least one lipophilic antioxidant to prevent oxidation and degradation of the compound during storage. The at least one antioxidant may be selected from the group consisting of vitamin E (also known as α-tocopherol), carotenoids (xanthophylls and carotenes), propyl gallate, lecithin, ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), and monothioglycerol tert-butylhydroquinone (TBHQ). What constitutes an "effective amount" depends on the identity of the compound. Generally, the total amount of antioxidant is greater than about 0.01% w / v and less than about 1.5% w / v. In some embodiments, the amount is greater than about 0.1% w / v and less than about 1% w / v.

[0069]

[0082] Other additives contemplated for use in the practice of the present disclosure are those available to those skilled in the art, such as those found in the United States Pharmacopeia - National Formulary Vol. XVII, US Pharmacopeia Convention, Inc., Rockville, Md. (1989). [Example]

[0070]

[0083] Example

[0084] Specific examples will now be described and the following abbreviations will be used:

[0071]

[0085] List of abbreviations ℃ - Celsius temperature cP - centipoise mL - milliliter Pre-TS - Pre-Terminal Sterilization Procedures QS-moderate amount RH - Relative Humidity T-Time TS-Terminal sterilization wk(s) - week

[0072]

[0086] In the following examples, the raw materials in Table A were used.

[0073]

[0087] [Table 1]

[0074]

[0088] Example 1

[0089] Formulations 1-8 were prepared and are summarized in Table 1 below. The amounts shown are the amounts of raw materials used. Effective concentrations can be calculated with reference to Table A. All formulations were formulated to provide 250 mg cannabidiol / mL of formulation ("label claim").

[0075]

[0090] [Table 2]

[0076]

[0091] Formulations 1 and 2 are not in accordance with the present invention and do not contain alkyl esters of fatty acids, let alone C1-C3 alkyl esters of C6-C22 fatty acids. Instead, they contain a cosolvent (octanoic acid) and the surfactant / emulsifier POPG-Na. Formulations 3-8 contain either a C1 alkyl ester of a C8 fatty acid (methyl octanoate) or a C2 alkyl ester of a C8 fatty acid (ethyl octanoate), but do not contain POPG-Na.

[0077]

[0092] Samples of each formulation were prepared using the method described below in Example 2, filled into clear glass vials, and the glass vials were manually stoppered and sealed.

[0078]

[0093] Table 2 shows the amount of cannabidiol and THC in samples of Formulations 1-8 at time = 0, i.e. immediately after preparation.

[0079]

[0094] [Table 3]

[0080]

[0095] The amount of cannabidiol shown above is expressed as a % of the label claim, which is 250 mg / mL.

[0081]

[0096] The viscosities of samples of Formulations 1-8 were measured at room temperature at time=0 and the results are shown in Table 3 below.

[0082]

[0097] [Table 4]

[0083]

[0098] Other samples of Formulations 1-8 were stored at approximately 5°C (between 2°C and 8°C) at 60±5% relative humidity for two weeks. The cannabidiol and THC content of these other samples was measured and is shown in Table 4 below.

[0084]

[0099] [Table 5]

[0085] [000100] Additional samples of Formulations 1-8 were stored at about 25°C (± about 2°C) at 60±5% relative humidity for two weeks. These samples were evaluated for their cannabidiol and THC content at room temperature and the results are summarized in Table 5.

[0086] [000101] [Table 6]

[0087] [000102] The results shown in Tables 4 and 5 indicate that THC was not detected in Formulations 3-8 after 2 weeks of storage at temperatures ranging from 2° C. to 27° C. However, Formulations 1 and 2 showed THC formation both initially and after storage under the same conditions.

[0088] [000103] Other samples of Formulations 1-8 were stored at 5°C (±3°C) or 25°C (±2°C) and 60±5% relative humidity for 4 weeks. The viscosities of these other samples measured at room temperature at time = 4 weeks are summarized in Table 6.

[0089] [000104] [Table 7]

[0090] [000105] Tables 3 and 6 show that the viscosity remained substantially constant over the four week period, with all formulations having a viscosity less than 35 cP and therefore deemed suitable for injection according to the present invention, except for Formulation 2, which had a viscosity greater than 35 cP and was not deemed suitable for injection according to the present invention.

[0091] [000106] Formulations 1-8 were clear and single-phase when prepared and remained so throughout the experiments described above.

[0092] [000107] Taken together, these results demonstrate that formulations with acceptable viscosity, chemical stability, phase stability and concentration of cannabidiol can be formulated using the ingredients of Formulations 3-8 in the amounts specified in Table 1. These results also demonstrate that the chemical stability of cannabidiol is compromised when methyl octanoate or ethyl octanoate are replaced with their fatty acid counterparts, i.e., octanoic acid, in combination with 2% w / v POPG-Na.

[0093] [000108] Example 2 - Effect of terminal sterilization on stability [000109] Experiments were conducted to determine the effect of terminal sterilization procedures on the stability of formulations according to the present invention. Formulations 9-12, having a label claim of 250 mg / mL cannabidiol, were prepared and are summarized in Table 7.

[0094] [000110] [Table 8]

[0095] [000111] As shown above, formulations 9 to 12 contain the same ingredients in the same amounts as formulations 3, 7, 4 and 8, respectively.

[0096] [000112] 500 mL batches of each formulation were prepared as follows: 1. Selected amounts by weight of methyl or ethyl octanoate and Miglyol 812N were dispensed into the main formulation container. 2. The selected amount by weight of cannabidiol was added to the formulation vessel while stirring using a magnetic stir bar until completely dissolved. 3. A selected amount by weight of benzyl alcohol was added with stirring to obtain a homogeneous solution. 4. This solution was then transferred to a 500 mL volumetric flask and the QS amount of methyl octanoate or ethyl octanoate was added to bring the volume to 500 mL. 5. The flask was stoppered and mixed by inverting at least 20 times. 6. 2 mL aliquots of each formulation were dispensed into 3 mL Type I clear glass vials. The vials were then stoppered with gray Flurotec 4588 / 40 13 mm stoppers, washed with WFI, and sealed with 13 mm Flip Off TruEdge™ 6-Bridge seals. A total of 135 filled, labeled, and sealed vials were prepared. In steps 1-4 above, the amounts of ingredients were selected to achieve the final concentrations outlined in Table 7 above.

[0097] [000113] Bulk samples of the four formulations were visually inspected for their appearance and analyzed for their cannabidiol content, delta-9 THC content, and viscosity. Vialed samples of all four formulations were removed for pre-terminal sterilization (pre-TS) analytical testing. The remaining vialed samples were subjected to autoclave sterilization with steam at 121°C for 35 minutes ("overkill cycle") ("terminal sterilization" or "TS"). Separate vialed samples were subjected to different conditions in the stability tester as follows: a.5℃±3℃ and 60%RH±5%RH, b. 25°C ± 2°C and 60% RH ± 5% RH or c. 40°C ± 2°C and 75% RH ± 5% RH Samples were taken at T=0, T=1 wk, T=2 wks, and T=4 wks, visually inspected for their appearance, and analyzed for their cannabidiol content, delta-9 THC content, and viscosity. The results are summarized in Tables 8, 9, 10, and 11.

[0098] [000114] [Table 9]

[0099] [000115] [Table 10]

[0100] [000116] [Table 11]

[0101] [000117] [Table 12]

[0102] [000118] All sample solutions appeared as clear oils (single phase) with moderate viscosity. The reason for the color differences is unknown.

[0103] [000119] These results indicate that the production of delta-9 THC from cannabidiol did not occur when esters of octanoic acid, i.e., methyl octanoate and ethyl octanoate, were used and POPG-Na and octanoic acid were omitted. In other words, by omitting POPG-Na and octanoic acid from the formulation and replacing octanoic acid with esters of octanoic acid, the production of delta-9 THC from cannabidiol was reduced or eliminated. Furthermore, these results indicate that terminal sterilization did not compromise the chemical and physical stability of the formulation.

[0104] [000120] Other embodiments [000121] The following other embodiments are in accordance with the present invention.

[0105] [000122] [Table 13]

[0106] [000123] Item List [000124] The following is a non-exhaustive list of items provided by the present invention.

[0107] [000125] Item 1.i. A solvent system comprising: (i) an effective amount of at least one triglyceride oil and (ii) an effective amount of at least one C1-C3 alkyl ester of a C6-C22 fatty acid; and ii. An injectable cannabidiol formulation for non-IV parenteral administration comprising, consisting essentially of, or consisting of an effective amount of cannabidiol; The formulation is an injectable cannabidiol formulation that is water and ethanol free, has a viscosity of less than about 35 cP, and is phase stable and chemically stable.

[0108] [000126] Item 2. The formulation of Item 1, wherein the at least one C1 to C3 alkyl ester of a C6 to C22 fatty acid is selected from the group consisting of methyl octanoate, ethyl octanoate, isopropyl myristate, ethyl caprate, methyl oleate, ethyl oleate, and combinations thereof.

[0109] [000127] Item 3. The formulation of Item 2, wherein the at least one C1 to C3 alkyl ester of a C6 to C22 fatty acid is selected from the group consisting of methyl octanoate, ethyl octanoate, and combinations thereof.

[0110] [000128] Item 4. The formulation of any one of items 1-3, wherein the at least one triglyceride oil is at least one medium chain triglyceride.

[0111] [000129] Item 5. The formulation of item 4, wherein the at least one medium chain triglyceride comprises esters of fatty acids in the following amounts: 0-2% w / w of esters of C6 fatty acids, 50-65% w / w of esters of C8 fatty acids, 30-45% w / w of esters of C10 fatty acids, <2% w / w of esters of C12 fatty acids, <1% w / w of esters of C14 fatty acids, and <1% w / w of esters of C16 or longer chain fatty acids.

[0112] [000130] Item 6. The formulation of any one of items 1-5, wherein the amount of the at least one triglyceride oil is at least about 10% w / v.

[0113] [000131] Item 7. The formulation of any one of items 1-6, wherein the amount of the at least one triglyceride oil is about 50% w / v or less.

[0114] [000132] Item 8. The formulation of any one of items 1-7, wherein the amount of the at least one C1-C3 alkyl ester of a C6-C22 fatty acid is at least about 25% w / v.

[0115] [000133] Item 9. The formulation of any one of items 1-8, wherein the amount of the at least one C1-C3 alkyl ester of a C6-C22 fatty acid is about 65% w / v or less.

[0116] [000134] Item 10. The formulation of any one of items 1-9, wherein the ratio of (i) the at least one triglyceride oil to (ii) the at least one C1-C3 alkyl ester of a C6-C22 fatty acid is from about 2:1 to about 1:7, or from about 1:1 to about 1:7, or from about 2:1 to about 1:6, or from about 1:1 to about 1:6.

[0117] [000135] Item 11. The formulation of any one of items 1 to 10, wherein the cannabidiol has a purity of at least 98.5, 99, 99.5, or 99.8%.

[0118] [000136] Item 12. The formulation of any one of items 1-11, wherein the cannabidiol is present in an amount of at least about 100 mg / mL and no more than about 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, or 350 mg / mL.

[0119] [000137] Item 13. The formulation of any one of items 1 to 12, wherein the formulation has a viscosity of less than about 30 cP, about 25 cP, or about 20 cP.

[0120] [000138] Item 14. The formulation of any one of items 1 to 13, further comprising, consisting essentially of, or consisting of at least one other pharmaceutically acceptable excipient.

[0121] [000139] Item 15. The formulation of item 14, wherein the at least one other pharmaceutically acceptable excipient is selected from the group consisting of other lipophilic solvents, preservatives, antioxidants, anesthetic compounds, viscosity modifiers, and pK modifiers.

[0122] [000140] Item 16. The formulation of Items 14 or 15, wherein the benzyl alcohol is present in an amount of about 0.5% w / v to about 1.5% w / v.

[0123] [000141] Item 17. The formulation of any one of items 14-16, wherein an effective amount of at least one lipophilic antioxidant is present and is selected from the group consisting of propyl gallate, vitamin E, ascorbyl palmitate, butylhydroxytoluene (BHT), and butylhydroxyanisole (BHA).

[0124] [000142] Item 18. The formulation of any one of items 1-17, wherein the solvent system consists of (i) an effective amount of at least one triglyceride oil; and (ii) an effective amount of at least one C1-C3 alkyl ester of a C6-C22 fatty acid; and (optionally) an effective amount of benzyl alcohol.

[0125] [000143] Item 19. The formulation of item 18, wherein the solvent system consists of (i) an effective amount of at least one medium chain triglyceride oil; and (ii) an effective amount of at least one of methyl octanoate and ethyl octanoate; and (optionally) an effective amount of benzyl alcohol.

[0126] [000144] Item 20. The formulation of any one of items 1 to 19, wherein the formulation is free of POPG-Na.

[0127] [000145] Item 21. The formulation of any one of items 1 to 19, wherein the formulation is free of phosphatidylglycerol and / or salts thereof.

[0128] [000146] Item 22. The formulation of any one of items 1 to 21, wherein the formulation is free of octanoic acid.

[0129] [000147] Item 23. The formulation of any one of items 1 to 21, wherein the formulation is free of C6 to C22 fatty acids.

[0130] [000148] Item 24. The formulation of any one of items 1 to 21, wherein the formulation is free of fatty acids.

[0131] [000149] Item 25. A kit comprising: (i) a container containing the formulation of any one of items 1 to 24; and (ii) instructions for use of the formulation.

[0132] [000150] Item 26. The kit of item 25, wherein the container is part of a single-dose or multi-dose syringe, vial, cartridge, or pre-filled syringe.

[0133] [000151] The embodiments described above are examples only and are not intended to limit the scope of the invention as described herein and defined by the claims that follow.

Claims

1. a. (i) an effective amount of at least one triglyceride oil; and (ii) a solvent system comprising an effective amount of at least one C1-C3 alkyl ester of a C6-C22 fatty acid; b. An effective amount of cannabidiol having a purity of at least 98.5%, 99%, 99.5%, or 99.8%; and c. At least one antioxidant An injectable cannabidiol preparation for non-IV parenteral administration, comprising: The aforementioned formulation is an injectable cannabidiol preparation that is free of water and ethanol, has a viscosity of less than approximately 35 cP, is phase-stable, and is chemically stable.

2. The formulation according to claim 1, wherein the C1-C3 alkyl ester of at least one C6-C22 fatty acid is selected from the group consisting of methyl octanoate, ethyl octanoate, isopropyl myristate, ethyl caprate, methyl oleate, and ethyl oleate.

3. The formulation according to claim 2, wherein the C1-C3 alkyl ester of at least one C6-C22 fatty acid is selected from the group consisting of methyl octanoate and ethyl octanoate.

4. The formulation according to claim 1, wherein the at least one triglyceride oil is at least one medium-chain triglyceride.

5. The formulation according to claim 1, wherein the amount of the at least one triglyceride oil is at least about 10% w / v and about 50% w / v.

6. The formulation according to claim 1, wherein the amount of the C1-C3 alkyl ester of at least one C6-C22 fatty acid is at least about 25% w / v and about 65% w / v or less.

7. The formulation according to claim 1, wherein the ratio of (i) at least one triglyceride oil to (ii) at least one C1-C3 alkyl ester of a C6-C22 fatty acid is about 2:1 to about 1:7 or about 1:1 to about 1:7 or about 2:1 to about 1:6 or about 1:1 to about 1:

6.

8. The formulation according to claim 1, wherein the cannabidiol is present in an amount of at least about 100 mg / mL and about 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL or 350 mg / mL or less.

9. The formulation according to claim 1, wherein the formulation has a viscosity of about 30 cP, about 25 cP, or less than about 20 cP.

10. The formulation according to any one of claims 1 to 9, wherein an effective amount of benzyl alcohol is present.

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