Parenteral cannabinoid formulations and uses thereof

Abstract

Provided herein is a non-toxic parenteral pharmaceutical formulation comprising at least one cannabinoid, typically cannabinol.Cannabinoids can be prepared from plant sources or synthetically.Methods for preparing such formulations and methods for using such formulations are also disclosed.Methods of such use include, but are not limited to, intravenous administration of the formulations of the present invention for the treatment of perioperative pain.The formulations of the present invention can provide the potential for the replacement or dosage reduction of opioids for acute and chronic pain management.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 128,447, filed December 21, 2020, entitled "PARENTERAL CANNABINOID FORMULATIONS AND USES THEREOF," which is hereby incorporated by reference in its entirety. [Background technology]

[0002] background The global opioid crisis is well known, as reported in the media and scientific literature, with statistics from well-known health organizations, such as the World Health Organization, the US Centers for Disease Control, and the US Department of Health and Human Services. The literature and these organizations report that the initial use of opioids occurs for various reasons and sources, including voluntary use leading to dependence, but legitimate medical reasons are often the basis and justification for the initial opioid use. The first step of medically justified opioid use, which can lead to long-term dependence, is often by the use of parenterally administered opioids for perioperative and / or postoperative pain. Thus, medical, health, social, and medical organizations have been searching, mostly unsuccessfully, for alternative effective and safe treatments for perioperative pain management, including perioperative and / or postoperative pain management.

[0003] The present invention provides certain non-toxic parenteral formulations containing one or more cannabinoids for the treatment of peri-operative pain, among other medicinal indications.

[0004] Cannabinoid parenteral formulations have not been generally described in the scientific and patent literature. In general, much of the scientific literature describes cannabinoid formulations designed for direct injection into laboratory animals without any consideration of long-term safety and / or stability. One study simply used (-)-trans Δ 9-Indicated to contain the cannabinoid cannabidiol (CBD), with or without tetrahydrocannabinol.

[0005] More medically sophisticated parenterally administered cannabinoid formulations are described in U.S. Patent Application Publication No. 2019 / 0314296, which also includes a more detailed review of parenteral cannabinoid formulations developed prior to the filing date of this patent publication on June 17, 2017. The pharmaceutical formulations taught and claimed therein incorporate certain key elements: i) cannabinoids; ii) an isotonic agent; iii) a surfactant; iv) at least one antioxidant; Includes.

[0006] The isotonic agent is It is defined as the group consisting of polyethylene glycol, glycerol, saline and glucose and is used in an amount to provide an osmolality in the range of 100-500 mOsMol / Kg, more preferably 200-400 mOsMol / Kg, more preferably still 285-310 mOsMol / Kg, most preferably about 300 mOsMol / Kg. Most preferably the isotonicity agent is glycerol and is present in an amount of 5-50 mg / ml, more preferably 10-30 mg / ml, most preferably 20 mg / ml.

[0007] This US patent application publication describes other potential isotonicity agents for use in the described formulations such as, for example, sodium chloride (saline), dextrose (5%) and lactated Ringer's solution, having a pH of 7.0.

[0008] Although often used in parenteral pharmaceutical solutions, it is well known in the pharmaceutical arts that isotonic agents can be problematic and, in fact, toxic to the patient, especially if the patient is also receiving maintenance IV fluids. For example, the use of glucose and dextrose as IV fluids varies from country to country. Without the additional dextrose in parenteral drugs, which could worsen the effect of administration of IV fluids containing dextrose, One randomized trial in the perioperative setting showed that 72% of patients who received IV fluids containing dextrose developed transient hyperglycemia, while patients without dextrose remained euglycemic. Dextrose may need to be avoided, especially in this setting, because hyperglycemia is associated with worse outcomes after acute neurological injury. Hoorn, EJ Intravenous Fluids: Balancing Solutions. J Nephrol., 2020, January 28: 33(2): 387.

[0009] In addition, the use of saline (sodium chloride) has been shown to induce hyperchloremic metabolic acidosis, which may impair blood clotting. It is unknown whether the addition of saline, used as an isotonic agent in the formulations taught in U.S. Patent Publication No. 2019 / 0314296, is toxic to patients, particularly neonates, who are the target patient population for the formulations taught in this patent application publication. However, if neonates are also receiving IV fluids, the probability of saline-induced toxicity would likely increase substantially.

[0010] Therefore, the use of isotonicity agents in parenteral formulations, especially parenteral cannabinoid pharmaceutical formulations, can make such formulations toxic or at least pharmacologically problematic, especially when IV solutions are co-administered, which is not uncommon when IVs are required in addition to perioperative pain medication.

[0011] In addition, the referenced US Patent Publication does not contain a buffer. When administered via slow infusion, the pH of the administered drug may fluctuate, and perhaps at a pH of about 4.0, the patient may experience site irritation and additional pain. A buffered cannabinoid pharmaceutical formulation may be more tolerable to the patient.

[0012] Additionally, buffered cannabinoid parenteral formulations provide a known solution to the attending physician, especially when other fluids and / or parenteral therapeutic agents are being administered and may be affected by administration of the compositions of the present invention, especially by infusion. Summary of the Invention [Problem to be solved by the invention]

[0013] Thus, the present invention provides, among other uses, non-toxic, pharma- ceutically acceptable, stable parenteral cannabinoid formulations for the treatment of peri-operative pain. [Means for solving the problem]

[0014] overview One aspect of the present invention is i. at least one cannabinoid; ii. at least one surfactant; iii. at least one antioxidant; iv. at least one chelating agent; v. optionally, at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; The present invention provides a non-toxic parenteral pharmaceutical formulation comprising:

[0015] Another aspect of the present invention is a method for producing a i. at least one cannabinoid; ii. at least one surfactant; iii. at least one antioxidant; iv. at least one chelating agent; v. optionally, at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; and provided that no isotonicity agents are added to the formulation.

[0016] Each of the elements or components of the present invention is pharma- ceutical acceptable.

[0017] Additional embodiments provide the above formulation, wherein the cannabinoid is selected from the group consisting of at least one plant-derived cannabinoid and a synthetic cannabinoid.

[0018] A further embodiment has a (-)-trans Δ 9 - providing a formulation as above containing tetrahydrocannabinol.

[0019] Another embodiment is (-)-trans Δ 9 - providing a formulation as above that is devoid of tetrahydrocannabinol.

[0020] An additional embodiment provides the above formulation that is devoid of any form of tetrahydrocannabinol, also known as "THC."

[0021] A further embodiment provides the above formulation having a shelf life of at least 12 months without refrigeration.

[0022] An additional embodiment is a formulation of the present invention that can be terminally sterilized.

[0023] Another aspect is i. combining in a first container at least one surfactant with at least one antioxidant and at least one cannabinoid; ii. combining in a second container at least one identical or different second antioxidant and at least one chelating agent; and iii. mixing the contents of the first and second containers; and iv. optionally adding at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; The present invention provides a method for preparing the formulation of the present invention, comprising:

[0024] Another aspect is i. combining in a first container at least one surfactant with at least one antioxidant and at least one cannabinoid; ii. combining in a second container at least one of the same or different second antioxidants and at least one chelating agent; and iii. mixing the contents of the first and second containers; and iv. optionally adding at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; A method for preparing the formulation of the present invention is provided, comprising: provided that no isotonicity agents are added to the formulation.

[0025] Additional embodiments provide the above methods, wherein the cannabinoid is selected from the group consisting of plant-derived cannabinoids and synthetic cannabinoids.

[0026] Further embodiments include a formulation having 0.3% or less (-)-trans Δ 9 - containing tetrahydrocannabinol.

[0027] Another embodiment is where the formulation is (-)-trans Δ 9 - The method as described above, wherein the compound is devoid of tetrahydrocannabinol.

[0028] Additional embodiments provide the above methods, wherein the formulation is devoid of any form of tetrahydrocannabinol, also known as "THC."

[0029] A further aspect provides a method of treating a mammal in need of treatment comprising parenteral administration, typically intravenous administration, of a composition of the invention. Often the mammal being treated is a human.

[0030] More particularly, the present invention also provides a method of treating a mammal in need of treatment for pain selected from the group consisting of perioperative pain, postoperative pain, and combinations thereof, comprising parenteral administration, typically intravenous administration, of a formulation of the present invention.

[0031] Although aspects of the present disclosure are susceptible to various modifications and alternative forms, specific embodiments thereof are described in detail herein. It should be understood, however, that the detailed description is not intended to limit the disclosure to the particular forms exemplified, but rather that the present invention encompasses all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims. The headings used herein are for organizational purposes only and are not intended to limit the scope of the present disclosure. The language "may" used throughout this application is used in an authoritative sense and means "having the possibility" rather than the required sense of "must be". Similarly, the words "include", "including" and "includes" mean inclusive without limitation. Additionally, the singular forms "a", "an" and "the" used in this specification and the appended claims include singular and plural referents unless the content clearly dictates otherwise.

[0032] The scope of the present disclosure includes any feature or combination of features, or any concept thereof, disclosed herein (either explicitly or implicitly), whether or not it alleviates any of the problems addressed herein. New claims may therefore be drafted during prosecution of this application (or an application claiming priority thereto) to any such combination of features. In particular, with respect to the appended claims, features from the dependent claims may be combined with features of the independent claims, and features from each independent claim may be combined in any suitable manner, and not simply in the specific combinations recited in the appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Detailed Description definition The term "drug substance" means a substance or mixture of substances that is intended for use in the manufacture of a drug product, and when used in the manufacture of a drug, becomes the active ingredient in the drug product.

[0034] As used herein, the term "acute pain" means pain that begins suddenly, usually subsides over a short period of time (days, hours, minutes), and may occur following physical injury and / or surgery, and generally resolves once the injury / surgery has healed.

[0035] The term "antioxidant" has the meaning typically used in the pharmaceutical formulation art. Exemplary antioxidants are further described herein.

[0036] The term "buffer" refers to a weak acid or base, typically a base as used herein, used to maintain the acidity (pH) of a solution near a selected value after the addition of another acid or base. That is, the function of a buffer is to prevent rapid changes in pH when an acid or base is added to a solution. Exemplary buffers are further described herein.

[0037] The term "cannabinoid" refers to any of a group of closely related compounds, including, but not limited to, cannabichromene (CBC), cannabichromene acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabidiol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA), and other active components of cannabis, including each of the phytocannabinoids. Additional bioactive components include, but are not limited to, cannabidiol-C1 (CBD-C1); cannabidiol-C4 (CBD-C4); and cannabidiol-C6 (CBD-C6). and bioactive metabolites such as, but not limited to, 7-hydroxy CBD. Such compounds and components may be derived from cannabis or may be synthetically prepared.

[0038] The term "chelating agent" has the meaning typically used in the drug formulation art. Exemplary chelating agents are further described herein.

[0039] The term "chronic pain" means pain that persists past the normal healing time and lacks the acute warning functions of physiological nociceptive pain. Pain is usually considered chronic if it persists for more than 3-6 months or if it recurs.

[0040] The term "dosage form" refers to one or more vials, ampoules, syringes, infusion bags, or other pharma- ceutically acceptable containers filled with a pharmaceutical formulation solution of the present invention.

[0041] The term "peri-operative pain" refers to pain before, during, and / or after a surgical procedure.

[0042] The term "perioperative pain management" refers to measures taken before, during, and / or after a surgical procedure intended to reduce or eliminate postoperative pain before the patient is discharged from the hospital after surgery.

[0043] The term "pharmaceutical acceptable" means useful in preparing pharmaceutical compositions or formulations that are generally safe, non-toxic and not biologically or otherwise undesirable, and includes those that are acceptable for human pharmaceutical and veterinary use.

[0044] The term "surfactant" has the meaning that is typically used in the drug formulation art. As used herein, the term surfactant typically refers to the use of one or more surfactants, typically non-ionic surfactants. Exemplary surfactants are further described herein.

[0045] The term "terminally sterilized" refers to, for example and without limitation, physical methods of sterilization once the formulation of the present invention is placed into a container used to dispense such formulation for administration to a mammal, typically a human. Such methods include, for example, dry heat, steam, radiation and plasma, with steam typically being used.

[0046] The term "THC" refers to a compound called tetrahydrocannabinol, and can include, for example, THCA, THCV, Delta-8 THC, and Delta-9 THC.

[0047] The term "treatment" or its derivatives contemplates partial or complete inhibition of the target indication, often the treatment of pain, when the compositions of the invention are administered prophylactically or when such pharmaceutical formulations of the invention are administered after the onset of the indication, particularly pain.

[0048] explanation The following description and examples are included to demonstrate the embodiments of the present disclosure.It should be recognized by those skilled in the art that the pharmaceutical formulations, techniques and methods disclosed in the examples herein function in the practice of the disclosed embodiments.However, those skilled in the art in each technical field should recognize in light of this disclosure that modifications can be made to specific embodiments without departing from the spirit and scope of the disclosed embodiments and still obtain the same or similar results.

[0049] This specification includes references to "one aspect / embodiment" or "an aspect / embodiment." These phrases do not necessarily refer to the same embodiment, but embodiments including any combination of the features or elements disclosed herein are generally contemplated, unless expressly disclaimed herein. Particular pharmaceutical formulations, features, steps, elements or characteristics may be combined in any suitable manner consistent with the present disclosure.

[0050] As referenced above, little is known regarding the formulation of stable, non-toxic parenterally administered cannabidiol formulations. Therefore, the present invention provides i. at least one cannabinoid; ii. at least one surfactant; iii. at least one antioxidant; iv. at least one chelating agent; v. optionally, at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; The present invention provides a non-toxic parenteral pharmaceutical formulation comprising:

[0051] The present invention also provides i. at least one cannabinoid; ii. at least one surfactant; iii. at least one antioxidant; iv. at least one chelating agent; v. optionally, at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; and provided that such formulations do not contain isotonicity agents.

[0052] For clarity, each of the elements or components of the present invention is pharma- ceutically acceptable. For further clarity, at least one antioxidant is used twice during the preparation of the formulation of the present invention, as further described hereafter. In practice, the same or different antioxidants may be used. Thus, an additional aspect of the present invention is: i. at least one cannabinoid; ii. at least one surfactant; iii. at least two different antioxidants; iv. at least one chelating agent; v. optionally, at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; The present invention provides a non-toxic parenteral pharmaceutical formulation comprising:

[0053] The present invention further comprises: i. at least one cannabinoid; ii. at least one surfactant; iii. at least two different antioxidants; iv. at least one chelating agent; v. optionally, at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; and provided that such formulations do not contain isotonicity agents.

[0054] As a drug substance, the at least one cannabinoid may be selected from the group consisting of, for example, but not limited to, cannabichromene (CBC), cannabichromene acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabidiol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA), and other active components of cannabis including, for example, each of the phytocannabinoids. Additional bioactive components include, but are not limited to, cannabidiol-C1 (CBD-C1); cannabidiol-C4 (CBD-C4); and cannabidiol-C6 (CBD-C6). And bioactive metabolites, such as, but not limited to, 7-hydroxy CBD. Such compounds and components can be derived from synthetically prepared, semi-synthetically prepared cannabis, or as one or more metabolites of such cannabinoids.

[0055] The most commonly used cannabinoid in the formulations of the present invention is cannabidiol (CBD), preferably free of any other cannabinoids. Plant-derived CBD is acceptable for use in the formulations of the present invention, but purification methods for producing pure or nearly pure plant-derived CBD active pharmaceutical ingredients ("API") are still in the process of improvement. Therefore, synthetically prepared CBD is also acceptable for use in the formulations of the present invention.

[0056] Plant-derived cannabinoids, particularly CBD, are available from a variety of suppliers in the United States and internationally, which are readily identifiable through a simple internet search.

[0057] Synthetically prepared cannabidiol is a specialty chemical product and is available from limited manufacturers. For example, cannabidiol API is available from Purisys LLC (Athens, Georgia, USA) and is used in the formulations described herein. Such cannabidiol can be synthetically prepared, for example, but not limited to, following the teachings described in U.S. Pat. No. 10,059,683 (Noramco, Inc., Wilmington, Del., USA, assignee) and WO2020 / 051371 (Noramco, Inc., applicant). Typically, the CBD used in the formulations of the present invention is enantiomerically pure (-)-trans CBD form.

[0058] Additionally, the cannabidiol used in the formulations of the present invention contains no more than 0.3% (-)-trans Δ 9 -Containing tetrahydrocannabinol, preferably (-)-trans Δ 9 -tetrahydrocannabinol. In addition, the cannabidiol used in the formulations of the present invention typically contains 0.3% or less of any form of THC, and may be devoid of all forms of THC if possible. More specifically, the API used in the formulations of the present invention contains 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, or any portion thereof.

[0059] The concentration of total cannabinoids, particularly cannabidiol, used in the formulations of the present invention may vary, for example and without limitation, to include at least 0.5 mg of API per milliliter of final formulation solution. More particularly, such concentrations are from about 0.5 to about 50 mg / mL, more particularly about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, and about 50 mg / mL of the final solution, or any partial or full numerical range within the stated ranges.

[0060] An additional element of the formulation of the present invention is the addition of at least one pharma-ceutically acceptable surfactant, typically a non-ionic surfactant.Exemplary non-ionic surfactants include, for example, polyoxyethylene (20) sorbitan oleate, also called polysorbate 80 (Tween 80), which can be obtained from a number of suppliers, including but not limited to, for example, Sigma-Aldrich / MilliporeSigma (St. Louis, Missouri, USA); macrogol 15 hydroxystearate, which is a mixture of monoesters and diesters of 12-hydroxystearic acid, and macrogol obtained by ethoxylation of 12-hydroxystearic acid. The moles of ethylene oxide reacted per mole of 12-hydroxystearic acid is 15. Proprietary types of these surfactants include Solutol HS15 (MedChemExpress, Monmouth Junction, NJ, USA), Crodasol™ HS (Croda Inc., Newark, NJ, USA), and Kolliphor® HS15 (BASF, Florham Park, NJ, USA); and poloxamers, which are triblock copolymers of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene. Poloxamers are well known in the art and are available under the name "Pluronic" and are readily supplied by a variety of suppliers found via internet searches. In the formulations of the present invention, Kolliphor HS15 and / or Kolliphor ELP are often used in the formulations of the present invention.

[0061] Surfactant concentrations are used in the formulations of the present invention in the range of about 50 mg / mL to about 500 mg / mL. For example, if the desired cannabinoid concentration is about 10 mg / mL of the final formulation solution, the surfactant concentration is about 150 mg / mL of the final formulation solution. As the concentration of the cannabinoid increases, the surfactant concentration also increases. As a further example, if the desired cannabinoid concentration is about 50 mg / mL of the final formulation solution, the surfactant concentration is about 250 mg / mL of the final formulation solution. Those skilled in the art can further extrapolate the concentration of surfactants used in the formulations of the present invention based on the desired concentration of at least one desired cannabinoid, typically cannabidiol. Additional examples are shown in Table 1 below.

[0062] To be more specific, the surfactant concentration in the formulations of the present invention can be about 50 mg / mL, about 100 mg / mL, about 150 mg / mL, about 200 mg / mL, about 250 mg / mL, about 300 mg / mL, about 350 mg / mL, about 400 mg / mL, about 450 mg / mL, about 500 mg / mL, or any whole or partial number within the stated ranges in the final formulation solution.

[0063] Antioxidants play an important role in the stability of the formulation of the present invention.During the preparation of the formulation of the present invention, the same or different antioxidants are added in two separate process steps, as described in more detail herein below.Generally, the process includes a first container into which at least one cannabinoid, at least one surfactant and a first at least one antioxidant are mixed; a second container into which at least one chelating agent and at least one same or different antioxidant are mixed, and the mixing of materials from the first container and the second container is followed to provide a final formulation solution, referred to herein as final formulation, and any ingredient can still be added, as long as such ingredient or ingredients are not restricted from use herein.

[0064] In the first container, at least one antioxidant is added to reduce or eliminate the decomposition of at least one cannabinoid.Typically, without antioxidant in this step, cannabidiol can rapidly decompose into hydroxyquinone derivatives, which can contaminate the formulation solution and reduce the desired cannabidiol concentration in such solution formulation.The absence of purplish color in the formulation solution is a simple test for the absence of hydroxyquinone decomposition products.

[0065] The use of the same or different antioxidant(s) added to the second container further stabilizes the final formulation solution, generally in aqueous form, from oxidative degradation.

[0066] Pharmaceutically acceptable antioxidants are generally known to those of skill in the pharmaceutical arts and include, for example, but are not limited to, the following classes of antioxidants: natural antioxidants including, for example, tocopherol (vitamin E), sesamol, guaiac resin, and methionine; synthetic antioxidants including, for example, BHA, BHT, tertiary butyl hydroquinone; water soluble antioxidants including, for example, citric acid, tartaric acid, phosphoric acid, ascorbic acid (and their precursors listed below), sodium pyrosulfite, and thiol derivatives; and fat soluble antioxidants including, for example, BHA and BHT.

[0067] For the purpose of preparing the pharmaceutical formulation of the present invention, the antioxidant used is typically selected from the group consisting of water-soluble antioxidants. More specifically, ascorbic acid, which is used in the form of ascorbyl palmitate and hydrolyzes partially or completely to ascorbic acid depending on the composition in which ascorbyl acid is present, is typically used in the first container. The same or different antioxidant added to the second container can typically be ascorbic acid, ascorbyl palmitate, citric acid, or a combination thereof, although any suitable antioxidant can be used in either the first or second container.

[0068] The concentration of at least one pharma- ceutically acceptable antioxidant typically comprises a total of about 0.5 mg / mL of the final formulation solution to about 10 mg / mL of the final formulation solution, more typically about 1 mg / mL to about 5 mg / mL of the final formulation solution. More speci?c antioxidant concentrations are about 0.5 mg / mL, about 1.0 mg / mL, about 2.0 mg / mL, about 3.0 mg / mL, about 4.0 mg / mL, about 5.0 mg / mL, about 6.0 mg / mL, about 7.0 mg / mL, about 8.0 mg / mL, about 9.0 mg / mL, about 10.0 mg / mL, or any whole or partial number within the stated range of the final formulation solution. Such concentrations may be divided betWeen tWo preparation vessels, With the same or different antioxidants in each vessel, often to half the total concentration of antioxidants in each vessel.

[0069] At least one pharma- ceutically acceptable chelating agent represents an additional component of the cannabinoid formulation of the present invention.Exemplary chelating agents include, but are not limited to, eidetic acid (Spectrum Chemical Manufacturing Corp., New Brunswick, NJ, USA), Versene™ NA (Dow Chemical Company, Midland, MI, USA) and EDTA (ethylenediaminetetraacetic acid; commonly available as disodium and calcium EDTA) and the like.EDTA is readily available from a variety of sources, which can be found through a simple internet search.

[0070] The concentration of at least one chelating agent in the cannabinoid formulation of the present invention is typically used in the range of about 0.1 mg / mL to about 5 mg / mL of the final formulation solution. More specific chelating agent concentrations are about 0.1 mg / mL, 0.5 mg / mL, 1.0 mg / mL, 2.0 mg / mL, 3.0 mg / mL, 4.0 mg / mL, 5.0 mg / mL, or any whole or partial number within the stated range of the final formulation solution. Typically, the concentration of the chelating agent as used in the formulation of the present invention is about 0.5 mg / mL to about 3.0 mg / mL of the final formulation solution.

[0071] When the phrase "or any whole or part number within a stated range" is used herein, the phrase is intended to teach each specific whole or part number not expressly stated herein. Typical dosages of chelating agents should not exceed 50 mg / kg body weight, and typically should not exceed 3 g / day. These guidelines should be considered when formulating the compositions of the present invention to avoid toxicity from the chelating agent component of the compositions of the present invention.

[0072] As previously referenced, injection sites, especially of IV solutions administered over a period of time, can cause injection site irritation and pain. A common reason for such irritation and pain is the pH of the administered solution. In addition, the pH of the intravenous ("IV") administered formulations of the present invention can interfere with other administered medications, especially IV administered medications. Therefore, the buffered cannabinoid formulations of the present invention, especially when administered as an infusion, can reduce injection site irritation and pain and provide the attending physician with a known and consistent pKa of the formulations of the present invention. Furthermore, the buffered solutions can: They differ from isotonic saline in three properties: lower sodium and chloride content, which makes them closer to normal plasma levels; the presence of other ions such as potassium, calcium or magnesium, which may have an effect on factors such as potassium or lactate levels or may play a role in liver disease; and the content of anions such as lactate, acetate and gluconate, which may be metabolized to bicarbonate by tissue cells and exert an additional buffering effect. Cochrane Database Syst Rev. 2016 Jun;2016(6): CD012247.

[0073] In the formulations of the present invention, the concern with the addition of at least one optional hypotonic or hypertonic buffer is the maintenance of solution pH at a given point rather than the targeted isotonic osmolality of the final formulation solution.

[0074] Therefore, an optional element of the formulation of the present invention is at least one hypotonic or hypertonic buffer. Such buffers are well known in the art of pharmaceutical formulation development and include, for example, but not limited to, at least one buffer, typically citric acid, in a hypertonic or hypotonic (non-isotonic) amount. However, other pharma-ceutical acceptable buffers are known and used in liquid / aqueous pharmaceutical formulations. They include, for example, bicarbonate buffers, carboxylate buffers, phosphate buffers, zwitterion buffers, TRIS buffers, and the like, in addition to citric acid.

[0075] Exemplary buffers and respective pKa's provided for each such buffer: Buffer pKa pH range Maleic acid 1.9, 6.2 2~3 Tartaric acid 2.9, 4.2 2.5~4 Lactic acid 3.8 3~4.5 Citric acid 3.1, 4.8, 6.4 3~7 Acetic acid 4.75 4~6 Sodium bicarbonate (range) 4.2-10.3 4-9 Sodium phosphate 2.2, 7.2, 12.4 8~8

[0076] Each such buffer, which is prepared to be hypotonic or hypertonic (non-isotonic) when used with the formulations of the invention, is used in an amount required to stabilize the formulations of the invention at a pH between about pH 4.5 and about pH 6.0, more typically pH 5.0 and pH 5.5.

[0077] Non-isotonic amounts of, for example, citric acid, are prepared by adding a certain amount of citric acid to water, typically deionized water, or to an aqueous solution such as the formulation of the present invention. For example, hypotonic or hypertonic solutions of citric acid can be easily prepared at various concentrations. The amount used to buffer the formulation of the present invention will be determined by the strength of the buffer and the desired final buffered pH. Other buffers are similarly prepared and are well known to those skilled in the art.

[0078] A further aspect of the present invention is i. combining in a first container at least one surfactant with at least one antioxidant and at least one cannabinoid; ii. combining in a second container at least one same or different second antioxidant and at least one chelating agent; and iii. mixing the contents of the first and second containers; and iv. optionally adding at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; The present invention provides a method for preparing the formulation of the present invention, comprising:

[0079] and, i. combining in a first container at least one surfactant with at least one antioxidant and at least one cannabinoid; ii. combining in a second container at least one identical or different second antioxidant and at least one chelating agent; and iii. mixing the contents of the first and second containers; and iv. optionally adding at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers; Including, provided that no isotonicity agents are added to the formulation.

[0080] It may also be possible to prepare the formulations of the present invention in a one-pot process.

[0081] The following are non-limiting exemplary preparations of the formulations of the present invention using two containers for the preparation of i) a cannabinoid, particularly synthetically prepared cannabidiol, a surfactant and an antioxidant; and ii) an antioxidant and a chelating agent, followed by mixing the solutions of the two containers. [Table 1]

[0082] 1. Kolliphor HS15 was heated to approximately 40°C (so that it became clear and melted for weighing). 2. Excess water was heated to approximately 60°C formulation for injection: 1. 150 mg / mL (15% w / v) Kolliphor HS 15 was dispensed into Container A (at approximately 60° C.), making sure that no solidification of the Kolliphor HS 15 occurred. 2 mg / mL (0.2% w / v) citric acid was added and stirred until dissolved. 2. 10 mg / mL CBD was slowly added to the center of container A, ensuring that no CBD clumps formed on the sides of the container, and stirred until the CBD was dissolved.

[0083] in parallel 3. 2.0 mg / mL (0.02% w / w) ascorbic acid was added to vessel B, which had been preheated to approximately 60° C. 25% of the final volume of preheated water, typically “Water for Injection” or “WFI”, was added and stirred. 4. To container B, 1.0 mg / mL (0.01% w / v) calcium disodium EDTA was added, mixed until completely dissolved, and then placed back in the over oven at approximately 60°C.

[0084] Once container A contains a clear solution with no CBD crystals present, 5. The contents of vessel B were added to vessel A as a slow addition with constant stirring to prevent solidification. 6. Container B was rinsed with approximately 25% more WFI and the contents were added to container A. 7. Water was added to the desired volume (based on the concentration of each component) and mixed to avoid introducing bubbles and air. 8. The combined solution was allowed to stir for about 10 minutes (at about 60° C.) and then allowed to cool to ambient temperature.

[0085] The resulting pharmaceutical formulation was used in the stability study shown at the beginning of Example 1.

[0086] In general, the formulations of the present invention are prepared as follows:

[0087] Preparation 2: Container A preparation HS15 should be clear and warm when dispensed.

[0088] Vessel A should be set to process conditions of about 50° C. to about 70° C. The melting point of CBD is about 65° C. to about 71° C. The particle size of the CBD API affects dissolution and slight variations in heating conditions may be required for complete dissolution of the CBD API.

[0089] The addition of citric acid to the warm Kolliphor HS15 should prevent the solution from turning purple upon addition of CBD.

[0090] The CBD in Kolliphor HS15 should not be overheated as this can cause the CBD to decompose.

[0091] Container B preparation All excipients (EDTA, ascorbic acid) are readily soluble in water.

[0092] The water phase is kept elevated at the temperature referenced above so that solidification of the Kolliphor HS15 containing CBD does not occur when it is added to Container A.

[0093] The entire process must be maintained within the temperature ranges set forth above.

[0094] Preparations of ascorbic acid typically should not be made in advance.

[0095] Phase mixing The addition of the contents of Container B to Container A should be performed slowly and the mixer speed should be adjusted so as not to create additional foam within the blend.

[0096] Using a mixer or glass rod ensures that any Kolliphor HS15 hydrates away from the sides of the container and dissolves the desired concentration of each formulation component into solution.

[0097] The solution may become cloudy when water is added; this is because the micelles formed become larger and are visible to the naked eye at higher temperatures.

[0098] Once the final formulation solution is brought to final volume, the solution becomes less cloudy and typically becomes completely clear upon reaching ambient temperature, so water is added to the formulation as desired or prescribed to meet the concentration requirements set forth herein for each component of the formulation of the present invention.

[0099] Filling and Finishing Reducing bioburden Sterile filtration using approximately 0.2 micron PVDF filters or other methods known to those skilled in the art are acceptable; the tubing should be platinum hardened to prevent CBD adsorption to the tubing.

[0100] Typically, any bubbles are dissipated prior to filling the formulations of the present invention into vials or other final containers, which must be done by weight, taking advantage of the specific gravity of the formulation, followed by a sparge of an inert gas to remove any dissolved oxygen.

[0101] The above allows for the preparation of the formulations of the present invention with various concentrations of each component, adjusting the particular component as the concentration of the cannabinoid, typically cannabidiol, is increased. Non-limiting examples of such adjustments of the concentrations of particular exemplary components are shown in Table 1 below. [Table 2]

[0102] The ratios in the table result in a clear solution upon QS with Water for Injection.

[0103] There is no minimum CBD concentration, but for example, at 250 mg / mL, the ratio of surfactant to cannabidiol is from about 0.1 to about 20 mg / mL while maintaining stability.

[0104] After considerable scientific development efforts, the present invention provides non-toxic formulations administered via at least one parenteral (intravenous (IV), intramuscular (IM) and intraperitoneal (IP)) administration means. For such administration means, a variety of dosage forms are available. Thus, the present invention provides dosage forms including, for example and without limitation, one or more vials, ampoules, syringes, infusion bags or other pharma- ceutically acceptable containers filled with the formulations of the present invention. Such dosage forms may be single or multiple use dosage forms.

[0105] For the purpose of long shelf life and stability, such dosage forms may be prepared with an inert gas headspace to help prevent oxidation and / or degradation of the API, typically indicated by discoloration of the formulation of the present invention. Such inert gases can typically include nitrogen and argon. Furthermore, longer headspace vials finished with such inert gas may provide additional long-term stability of the formulation of the present invention. For further protection, the glass or plastic dosage forms referenced above may be colored tan or dark to ensure resistance to any photodegradation.

[0106] In the formulations of the present invention, a given dosage form or bulk formulation can typically be maintained at ambient temperature. Such dosage forms or bulk formulations can also be stored under non-frozen refrigerated conditions. The formulations of the present invention can also be freeze-dried, which typically requires the addition of a pharma- ceutically acceptable bulking agent, such as mannitol, lactose, sucrose, dextran, glycerin and / or trehalose. In lyophilized products, the bulking agent also provides cryoprotection to the product. The concentration of the bulking agent added often depends on the nature and amount of other raw materials in the formulation. Such concentrations are known to those skilled in the art.

[0107] The pharmaceutical formulations of the present invention are stable for a period of at least 6 months to at least 2 years, or any whole or part number within this range or beyond this range. More specifically, the formulations of the present invention in bulk form, or more specifically in a dosage form ready for administration of the formulations of the present invention, are generally stable without refrigeration for about 6 months, about 1 year, about 1.5 years, about 2 years, or any whole or part number within the range of about 6 months to about 2 years. Typically, it is desirable that the present invention is stable and usable for a period of at least 2 years after the formulations of the present invention are prepared and filled into one or more suitable containers.

[0108] Another aspect of the invention provides formulations of the invention that can be terminally sterilized. Such sterilization can be completed by any method now known or developed in the future that can provide a sterile formulation of the invention when the sterile formulation of the invention is placed into a container, typically a container used to distribute such formulation for administration to a mammal, typically a human. Such methods include, for example, dry heat, steam, radiation and plasma, with steam typically being used.

[0109] Alternatively, other methods known to those skilled in the art of sterile pharmaceutical formulation may be used, such as, for example and without limitation, preparation of the formulations of the invention under aseptic manufacturing conditions as designed utilizing gases such as ethylene oxide, glutaraldehyde, propylene oxide, hydrogen peroxide and chlorine dioxide, sterile filtration, and appropriate pore size / surface chemistry to remove bacteria and other microorganisms via size exclusion, entrapment, electrostatic attraction and other modalities.

[0110] Additionally, the formulations of the present invention may be formulated with other drugs, fluids or other components typically used for parenteral administration.

[0111] Also provided are cannabinol pharmaceutical formulations of the present invention prepared on or in a patch for transdermal delivery of such pharmaceutical formulations. A wide range of patches are known in the art, including, for example, reservoir and rate-controlling membrane patches, matrix patches, drug substance in adhesive patches, electroporation, iontophoresis, sonophoresis and microneedle patches. Therefore, also provided are methods of delivering pharmaceutical formulations of the present invention via one or more pharma- ceutical acceptable patch delivery systems. However, the patch technology of the present invention may not be an option for sufficient delivery of pharmaceutical formulations of the present invention, which requires additional research and development to achieve the desired dosage strength. Such patches may be used to treat disease conditions treatable by parenteral formulations as provided herein, and may be used as a single treatment or continuously, before, with, or following one or more parenteral administrations of parenteral pharmaceutical formulations as provided herein.

[0112] The present invention further provides a method of treating a mammal, typically a human, in need of treatment comprising parenteral administration, typically intravenous administration, of the formulations of the present invention. The pharmaceutical and / or medicinal uses of the formulations of the present invention are not limited by the examples, as many potential medical disorders may be treated via parenteral administration of the formulations of the present invention, often via IV administration.

[0113] One such use includes, for example and without limitation, parenteral administration, typically IV administration, of the inventive formulations to treat pain selected from the group consisting of perioperative pain, postoperative pain, and combinations thereof, or in other words, for perioperative and / or postoperative pain management. Such pain, and the need for treatment therewith, may be assessed on any one of a variety of pain scales used by the medical community as mild, mild-moderate, moderate, moderate-severe, severe, or other pain as described by the patient in need of treatment.

[0114] Pain assessment scales are used in routine clinical practice to measure pain intensity. Commonly used measurement scales include the Visual Analog Scale (VAS), Graphic Rating Scale (GRS), Simple Descriptor Scale (SDS), Numerical Rating Scale (NRS), and Faces Rating Scale (FRS). All of these scales have been validated as official measures of pain intensity. The three most commonly used scales in the United States are the numeric, verbal, and facial scales.

[0115] The inventive combinations, when administered and monitored by appropriate, typically medical personnel, can be used in hospitals, clinics, homes, military or other settings to treat, for example, acute or chronic pain, including, for example, neuropathic pain and / or pain associated with certain forms of cancer, whether perioperative or other pain.Furthermore, it is contemplated that the inventive combinations can be used to treat pain as described in the Pain Matrix (also known as the Neuromatrix), including, for example, pain associated with a variety of different pain syndromes, including, but not limited to, conditions such as fibromyalgia, phantom limb pain, postherpetic neuralgia, complex regional pain syndrome (CRPS), diabetic nerve injury, and central pain associated with stroke or spinal cord injury.Methods of using the inventive combinations further include, for example, pain in soft and bone tissues, pain associated with trauma, and generally any form of pain for which opioid drugs are currently used, whether administered orally or via parenteral administration.The inventive combinations may also be used in particular instances for the treatment of severe depression and intractable headaches, especially when administered as infusions. The compositions of the present invention can also be used to treat Dravet syndrome, Lennox-Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, intractable epilepsy, schizophrenia, juvenile convulsions, West syndrome, tuberous sclerosis, brain tumors, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and autism. More specifically, the use of the pharmaceutical compositions of the present invention for epilepsy is typically used in emergency use. Other disease conditions that can potentially be treated by the compositions of the present invention include inflammatory diseases, including cardiac inflammatory diseases such as pericarditis and endocarditis, hypertension and other disease conditions treated by vasorelaxants, arrhythmias, congestive heart failure, arterial plaque (and its reduction), reducing glucose absorption from arterial walls, inhibiting endotoxin production, stroke (before, during, and after stroke occurrence, generally by providing brain protection and brain recovery; treating ischemic and hemorrhagic stroke). The compositions of the present invention may also be used generally as antioxidants.

[0116] The formulations of the present invention may be prepared in a variety of dosage forms, including, for example, vials, ampoules, syringes, infusion bags, or other pharma- ceutically acceptable containers. Such dosage forms may be filled with one of a variety of dosage concentrations of the cannabinoid, typically cannabidiol, used in the formulations of the present invention. For example and without limitation, such dosage forms may be filled with a formulation of the present invention that includes at least 0.5 mg of a cannabinoid, typically cannabidiol, per milliliter of final formulation solution. More particularly, such concentrations range from about 0.5 mg / mL to about 50 mg / mL of the final formulation solution, more particularly about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, and about 50 mg / mL, or any part or all of the numbers within the stated ranges.

[0117] Certain dosage forms, such as syringes, containing the formulations of the present invention can be administered or injected directly into a bolus or infusion bag containing any one of a number of pharma- ceutically acceptable fluids that can be administered to a patient. Such fluids may include, for example, but are not limited to, nutrients, hydration fluids, and / or treatments for pain, other ailments, and / or any other medical purpose. As a precaution, a small amount of the formulations of the present invention must be premixed with the other such fluid or fluids to ensure compatibility of the mixture before administration. The formulations of the present invention can be present in other pharma-ceutically acceptable containers that can be used to prepare the final form for bolus or infusion administration, often for slow infusion over a period of time.

[0118] In using the compositions of the present invention to treat a mammal in need of treatment for perioperative and / or postoperative pain, such compositions are typically administered one to two times preoperatively and one or two additional times postoperatively. The actual number of doses, dosage concentrations, and timing of administration are typically left to the discretion of the attending physician, associate physician, medical professional, and the like. Thus, the dosage, number of doses, and timing of such administration are not intended to be limited by the present disclosure.

[0119] Dosages of the formulations of the present invention should be calculated on a mg / kg basis with respect to the amount of API, typically cannabidiol, and such dosages should be in the range of about 0.1 mg / kg to about 10 mg / kg. More specifically, such dosages include, for example, 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10.0 mg / kg, amounts greater than 10.0 mg / Kg, or any whole or partial number within the stated range. The final determination of such dosages should be left to the discretion of the attending physician or other competent medical personnel.

[0120] Although specific embodiments have been described above, these embodiments do not limit the scope of the present disclosure even if only one embodiment is described with respect to a particular feature. The examples of features provided in this disclosure are intended to be illustrative rather than limiting, unless otherwise stated. This disclosure is intended to cover alternatives, modifications, and / or equivalents as would be apparent to one skilled in the art having the benefit of this disclosure.

[0121] It should be understood that the pharmaceutical formulations of the present invention are limited only to the ranges and / or limits set forth herein, and are not limited to variations within such ranges. It should also be understood that the techniques used herein are for the purpose of describing specific embodiments only, and are not intended to be limiting.

[0122] Further refinements and alternative embodiments of various aspects of the embodiments described in this disclosure will be apparent to those skilled in the art upon consideration of this disclosure. Elements and materials may be substituted for those illustrated and described herein, parts and steps may be reversed, and certain features of the embodiments may be used independently, all as would be apparent to one skilled in the art after having the benefit of this specification. Changes may be made in the elements described herein without departing from the spirit and scope of the appended claims.

[0123] Working Example Example 1: Stability of parenteral formulations The pharmaceutical formulation of Preparation 1 was subjected to stability testing. The materials, methods, data and analysis are as follows: analysis: HPLC analysis method: An Agilent 1200 series HPLC system consisting of a quaternary gradient pump, autosampler, column oven, and single wavelength detector (UV-visible) was used to analyze CBD. The detector wavelength was set at 220 nm. Chromatographic separation was performed on a Hichrom C18 reversed phase column ((150×4.5 mm), 4.7 μm) at a temperature of 35° C. The mobile phase was a mixture of acetonitrile:0.25% acetic acid:methanol (75:20:5, v / v), filtered and flowing at a rate of 1 mL / min. Data were collected and analyzed.

[0124] Preparation of calibration standards: A stock solution of CBD (1.0 mg / mL) was prepared by dissolving 50 mg of CBD in 50 mL of HPLC grade methanol using a 50 mL volumetric flask. Calibration standard solutions of 25, 50, 100, and 250 μg / mL of CBD were then prepared by diluting the stock solution with HPLC grade methanol.

[0125] Samples were prepared at a concentration of 0.1 mg / mL in methanol and injected into the system. [Table 3] [Table 4] [Table 5]

[0126] Review the data: This stability study was performed on one batch of 10 mg / mL CBD intravenous formulation. The development batch used was manufactured at the proposed clinical scale of a 1 L manufacturing lot. The batch was aliquoted to provide sufficient samples at different storage conditions and time points. A placebo was also set up in parallel with this study if required at the time points.

[0127] EMA Guidance for Clinical Trials The shelf life and storage conditions of the IMP must be defined based on the stability profile of the active substance and the data available in the IMP. Extrapolation may be used, provided that stability studies are performed in parallel and throughout the clinical trials. Shelf life extrapolation may be performed under the following conditions: Results for long-term and accelerated storage conditions are available; No trends in stability behavior are observed. If any are observed, justification must be provided.

[0128] Depending on the data available, a 4-fold extrapolation of the real-time data may be acceptable up to a shelf-life of 12 months, and for shelf-lives longer than 12 months, an extrapolation of x+12 months may be acceptable.

[0129] Overall, there were minor changes in the CBD content or pH of the samples throughout the 6 week testing period to date. These results at 6 weeks at storage conditions of 40°C ± 2°C / 75% RH ± 5% RH are within specifications. There was no change in the physical appearance or color of the samples. At the time of manufacture the solutions were sterile filtered using 0.22 micron PVDF filters. There was no indication of crystallization of CBD in the solutions as reflected in the assay results. All analytical results are within analytical variability.

[0130] All other results are within the scope of the specification.

[0131] At accelerated storage conditions of 40°C and 75% RH for 6 weeks, the batch data meets specifications and shows no change over time.

[0132] Manufacturing can be done in one vessel using a heated jacketed mixer vessel. Pre-warmed Kolliphor HS15 is weighed into the heated mixer vessel. Cannabinoids are aliquoted and added to the HS15 in the mixer vessel with stirring. Antioxidants are added to the vessel and mixing continues until dissolved. Using the liquid feeder, pre-warmed aqueous phase containing antioxidants, buffers and chelating agents is aliquoted and mixed together in the mixer vessel. Once mixed, the jacketed vessel is set to cool to room temperature. A bioburden reduction filter is run at the outlet valve prior to aseptic filling and nitrogen flush finishing of the product.

Claims

1. i. at least one cannabinoid; ii. macrogol(15)-hydroxystearate surfactant; iii. Citric acid antioxidant; iv. at least one chelating agent; A non-toxic parenteral pharmaceutical formulation comprising: The formulation does not include an isotonicity agent; A formulation, wherein the formulation is devoid of any form of tetrahydrocannabinol.

2. 2. The formulation of claim 1, wherein the at least one cannabinoid is cannabidiol.

3. 3. The formulation of claim 2, wherein the at least one cannabinoid is synthetically prepared.

4. 10. The formulation of claim 1, wherein the chelating agent comprises at least one form of EDTA.

5. 5. The formulation of claim 4, wherein the form of EDTA is selected from the group consisting of disodium EDTA and calcium EDTA.

6. 10. The formulation of claim 1, further comprising at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers.

7. 7. The formulation of claim 6, wherein the buffering agent comprises sodium bicarbonate.

8. i. at least one cannabinoid; ii. macrogol(15)-hydroxystearate surfactant; iii. Citric acid antioxidant; iv. at least one chelating agent; A non-toxic parenteral pharmaceutical formulation comprising: A formulation, wherein the formulation does not include an isotonicity agent.

9. 9. The formulation of claim 8, further comprising at least one buffer selected from the group consisting of hypotonic buffers and hypertonic buffers.

10. 9. The formulation of claim 8, wherein the at least one cannabinoid is synthetically prepared cannabidiol.

11. A formulation according to any one of claims 1 to 10, having a shelf life of at least 12 months without refrigeration.

12. The formulation of any one of claims 1 to 10, wherein the formulation is terminally sterilized.

13. A formulation according to any of claims 1 to 10 prepared on or in a pharma- ceutical acceptable patch for transdermal delivery.