Parenteral cannabinoid formulations and their use

Abstract

To provide a non-toxic, pharmaceutically acceptable, and stable parenteral cannabinoid formulation for use in the management of perioperative pain. [Solution] A non-toxic parenteral pharmaceutical formulation is provided, comprising: i. at least one cannabinoid; ii. at least one surfactant; iii. at least one antioxidant; and iv. at least one chelating agent.

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 Art

[0002] Background The global opioid crisis is well - known as reported in the media and scientific literature using statistics from well - known health agencies such as the World Health Organization, the U.S. Centers for Disease Control, and the U.S. Department of Health and Human Services. The literature and these agencies report that initial opioid use occurs for a variety of reasons and sources, including self - use that can lead to dependence, but legitimate medical reasons are often the basis and justification for initial opioid use. The first step of medically justified opioid use, which can lead to long - term dependence, is often due to the use of opioids administered parenterally for peri - operative and / or post - operative pain. Thus, pharmaceutical, health, social, and medical groups have generally unsuccessfully investigated alternative effective and safe treatments for peri - operative pain management, including peri - operative and / or post - operative pain management.

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

[0004] Cannabinoid parenteral formulations are not generally described in the scientific and patent literature. Generally, many scientific papers describe cannabinoid formulations designed for direct injection into experimental animals without consideration for long - term safety and / or stability. One study simply described (-)-transΔ solubilized in "animal fat". 9- Indicates the inclusion of cannabidiol (CBD), a cannabinoid, with or without tetrahydrocannabinol.

[0005] A more medically sophisticated parenteral cannabinoid formulation is 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, June 17, 2017. The pharmaceutical formulations taught and claimed herein have certain key elements: i) Cannabinoids and; ii) with an isotonic agent; iii) Surfactants and; iv) at least one antioxidant, Includes.

[0006] Isotonic agents are The group is defined as consisting of polyethylene glycol, glycerol, physiological saline, and glucose, and is used in amounts that provide a gravimetric osmolality of about 300 mOsMol / Kg, more preferably in the range of 100 to 500 mOsMol / Kg, more preferably 200 to 400 mOsMol / Kg, and even more preferably 285 to 310 mOsMol / Kg. The most preferably isotonic agent is glycerol, and is present in an amount of 5 to 50 mg / ml, more preferably 10 to 30 mg / ml, and most preferably 20 mg / ml.

[0007] This U.S. patent application publication describes, for example, other potential isotonic agents for use in described formulations such as sodium chloride (physiological saline), dextrose (5%), and Ringer's lactate solution, which have a pH of 7.0.

[0008] Although often used in parenteral drug solutions, isotonic agents can present problems and, in fact, can be toxic to patients, especially if the patient is also receiving maintenance IV fluids, as is well known in the pharmaceutical technology field. For example, the use of glucose and dextrose as IV fluids varies from country to country. Without additional dextrose in parenteral drugs, the administration of IV fluids containing dextrose may worsen the effects of such fluids. One randomized trial in a perioperative setting showed that 72% of patients who received IV fluids containing dextrose developed transient hyperglycemia, while those who did not receive dextrose remained normal. Since hyperglycemia is associated with exacerbation of outcomes after acute neurological injury, dextrose may need to be avoided, especially in this context. 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 and may impair blood clotting. It is unknown whether the addition of saline as an isotonic agent in the formulation taught in U.S. Patent Publication No. 2019 / 0314296 is toxic to patients, particularly neonates, who are the target patient population of the formulation taught in this patent application publication. However, if neonates are also receiving IV fluids, the probability of saline-induced toxicity is likely to increase substantially.

[0010] Therefore, the use of isotonic agents in parenteral formulations, particularly in parenteral cannabinoid formulations, can make such formulations toxic, or at least pharmacokinetically problematic, especially when co-administered with IV solutions. Such co-administration is not uncommon when IV is required in addition to medication for perioperative pain.

[0011] In addition, the referenced U.S. patent application publication does not contain a buffer. When administered via slow infusion, the pH of the administered drug may fluctuate, possibly to around pH 4.0, which may cause site irritation and further pain in the patient. Buffered cannabinoid drug formulations would be more tolerable for the patient.

[0012] Furthermore, the buffered cannabinoid parenteral formulation provides the attending physician with a known solution, especially when other fluids and / or parenteral treatments are being administered and may be affected by the administration of the composition of the present invention, particularly by the intravenous fluid. [Overview of the project] [Problems that the invention aims to solve]

[0013] Therefore, the present invention provides a non-toxic, pharmaceutically acceptable, and stable parenteral cannabinoid formulation that is particularly used for the treatment of perioperative pain among its many uses. [Means for solving the problem]

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

[0015] Another aspect of the present invention is, i. with at least one cannabinoid; ii. with at least one surfactant; iii. with at least one antioxidant; iv. with at least one chelating agent; v. optionally, at least one buffering agent selected from the group consisting of hypotonic and hypertonic buffering agents, to provide a non-toxic parenteral pharmaceutical formulation, provided that no tonicity agent is added to the formulation.

[0016] Each element or component of the present invention is pharmaceutically acceptable.

[0017] An additional aspect provides 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 aspect provides the above formulation containing 0.3% or less of (-)-trans Δ 9 -tetrahydrocannabinol.

[0019] Another aspect provides the above formulation lacking (-)-trans Δ 9 -tetrahydrocannabinol.

[0020] An additional aspect provides the above formulation lacking any form of tetrahydrocannabinol, also known as "THC".

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

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

[0023] Another aspect is i. mixing at least one surfactant with at least one antioxidant and at least one cannabinoid in a first container; ii. mixing at least one identical or different second antioxidant with at least one chelating agent in a second container; and iii. mixing the contents of the first and second containers; and iv. Depending on the circumstances, at least one buffer selected from the group consisting of hypotonic and hypertonic buffers may be added. The present invention provides a method for preparing a compound containing [the specified ingredient].

[0024] Another aspect is, i. Mixing at least one surfactant with at least one antioxidant and at least one cannabinoid in a first container; ii. Mixing at least one identical or different second antioxidant and at least one chelating agent in a second container; and iii. Mixing the contents of the first and second containers; and iv. Depending on the circumstances, at least one buffer selected from the group consisting of hypotonic and hypertonic buffers may be added. The present invention provides a method for preparing a compound containing the present invention, However, this is conditional on no isotonic agents being added to the formulation.

[0025] An additional embodiment provides the above method, wherein the cannabinoid is selected from the group consisting of plant-derived cannabinoids and synthetic cannabinoids.

[0026] A further embodiment is a compound containing 0.3% or less (-)-trans-Δ 9 - Provides the above method containing tetrahydrocannabinol.

[0027] Another aspect is that the compound is (-)-trans-Δ 9 - Provides the above method lacking tetrahydrocannabinol.

[0028] An additional embodiment provides the above method wherein the formulation lacks any form of tetrahydrocannabinol, also known as "THC".

[0029] Further embodiments provide methods for treating mammals in need of treatment, including parenteral administration, typically intravenous administration, of the compositions of the present invention. In many cases, the mammals being treated are humans.

[0030] More specifically, the present invention also provides a method for treating mammals that require treatment of pain selected from the group consisting of perioperative pain, postoperative pain, and combinations thereof, including parenteral administration, typically intravenous administration, of the formulations of the present invention.

[0031] While aspects of this disclosure are subject to various modifications and alternative forms, specific embodiments are described in detail herein. However, the detailed descriptions do not limit this disclosure to the individual forms exemplified; on the contrary, it should be understood that the present invention encompasses all modifications, equivalents, and alternatives that fall within the spirit and scope of this 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 this specification. The language “may be” used throughout this application is used in the sense of permission, meaning “possible” rather than “must be.” Similarly, the languages ​​“include,” “contains,” and “includes” mean to include without limitation. In addition, the singular forms “a,” “an,” and “the” used herein and in the appended claims refer to single and plural subjects unless the content otherwise clearly specifies.

[0032] The scope of this disclosure includes any feature or combination of features disclosed herein (either explicitly or implicitly), or any concept thereof, whether or not it mitigates any of the issues addressed herein. Therefore, new claims may be drafted in any such combination of features during the prosecution of this application (or an application claiming priority thereto). In particular, with respect to the appended claims, features from dependent claims may be combined with features from independent claims, and features from each independent claim may be combined in any good manner, and not merely in the specific combinations enumerated in the appended claims. [Modes for carrying out the invention]

[0033] Detailed description definition The term "active pharmaceutical ingredient" refers to a substance or mixture of substances intended for use in the manufacture of a drug product, and when used in the manufacture of a drug, it becomes the active ingredient in the drug product.

[0034] As used herein, the term "acute pain" means pain that begins suddenly, typically subsides within a short period (days, hours, or minutes), may occur following an injury and / or surgery, and generally disappears once the injury / surgical wound has healed.

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

[0036] The term “buffer” refers to a weak acid or base used to maintain the acidity (pH) of a solution at a value close to a selected value after the addition of another acid or base, typically the bases used herein. That is, the function of a buffer is to prevent a rapid change 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 the closely related group of compounds, including, for example, cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and tetrahydrocannabivaric acid (THCVA), as well as other active components of cannabis, including phytocannabinoids. Additional biologically active components include, for example, cannabidiol-C1 (CBD-C1); cannabidiol-C4 (CBD-C4); and cannabidiol-C6 (CBD-C6). and, not limited to, bioactive metabolites such as 7-hydroxyCBD. Such compounds and components may be derived from cannabis or prepared by synthesis.

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

[0039] The term "chronic pain" refers to pain that persists beyond the normal healing time and lacks the acute warning function of physiological nociception. Generally, pain is considered chronic if it lasts longer 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 pharmaceutically acceptable containers filled with the pharmaceutically acceptable formulation solution of the present invention.

[0041] The term "perioperative 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 in patients before they are discharged from the hospital after surgery.

[0043] The term "medically acceptable" means useful in preparing a pharmaceutical composition or formulation that is generally safe, non-toxic, and not inappropriate in a biological or otherwise sense, and that is acceptable for human medicinal and veterinary use.

[0044] The term "surfactant" has the meaning typically used in the field of drug formulation technology. As used herein, the term "surfactant" typically refers to the use of one or more surfactants, typically nonionic surfactants. Exemplary surfactants are further described herein.

[0045] The term “finally sterilized” means, for example, a physical method of sterilization at the point when the formulation of the present invention is placed in a container used to distribute such formulation for administration to mammals, typically humans. Such methods include, for example, dry heating, steam, radiation, and plasma, with steam being the most commonly used.

[0046] The term "THC" refers to compounds known as tetrahydrocannabinol, which may include, for example, THCA, THCV, Delta-8 THC, and Delta-9 THC.

[0047] The term “treatment” or its derivatives refers to the partial or complete inhibition, often of pain, of a targeted indication, when the composition of the present invention is administered protectively or when such pharmaceutical formulations of the present invention are administered after the onset of an indication, particularly pain.

[0048] explanation The following descriptions and examples are included to demonstrate 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 practice of the disclosed embodiments. However, those skilled in the art in each field should recognize that modifications may be made to specific embodiments in light of the present disclosure without departing from the spirit and scope of the disclosed embodiments, and similar or comparable results may still be obtained.

[0049] This specification includes references to “one aspect / embodiment” or “a certain aspect / embodiment.” These terms do not necessarily refer to the same embodiment, but embodiments including any combination of features or elements disclosed herein are generally intended unless expressly disclaimed herein. Special pharmaceutical formulations, features, processes, elements or characteristics may be combined in any appropriate manner consistent with this disclosure.

[0050] As previously referenced, little is known about the formulation of stable, non-toxic, parenterally administered cannabidiol compounds. Therefore, the present invention aims to provide a solution. i. with at least one cannabinoid; ii. with at least one surfactant; iii. with at least one antioxidant; iv. with at least one chelating agent; v. Depending on the circumstances, at least one buffer selected from the group consisting of hypotonic and hypertonic buffers, The present invention provides a non-toxic parenteral pharmaceutical formulation that includes [the specified ingredient].

[0051] The present invention also, i. with at least one cannabinoid; ii. with at least one surfactant; iii. with at least one antioxidant; iv. with at least one chelating agent; v. Depending on the circumstances, at least one buffer selected from the group consisting of hypotonic and hypertonic buffers, We provide non-toxic parenteral pharmaceutical formulations that include, However, this is conditional on the formulation not containing an isotonic agent.

[0052] For clarity, each element or component of the present invention is pharmaceutically acceptable. For further clarity, at least one antioxidant is used twice during the preparation of the formulations of the present invention, as further described herein. In practice, the same or different antioxidants may be used. Therefore, additional aspects of the present invention are as follows: i. with at least one cannabinoid; ii. with at least one surfactant; iii. with at least two different antioxidants; iv. with at least one chelating agent; v. Depending on the circumstances, at least one buffer selected from the group consisting of hypotonic and hypertonic buffers, The present invention provides a non-toxic parenteral pharmaceutical formulation that includes [the specified ingredient].

[0053] The present invention further, i. with at least one cannabinoid; ii. with at least one surfactant; iii. with at least two different antioxidants; iv. with at least one chelating agent; v. Depending on the circumstances, at least one buffer selected from the group consisting of hypotonic and hypertonic buffers, We provide non-toxic parenteral pharmaceutical formulations that include, However, this is conditional on the formulation not containing an isotonic agent.

[0054] As the active pharmaceutical ingredient, at least one cannabinoid may be selected from the group consisting of other active components of cannabis, including, for example, cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and tetrahydrocannabivaric acid (THCVA), as well as other active components of cannabis, such as phytocannabinoids. Additional bioactive components include, for example, cannabidiol-C1 (CBD-C1); cannabidiol-C4 (CBD-C4); and cannabidiol-C6 (CBD-C6), and, for example, bioactive metabolites such as 7-hydroxyCBD. Such compounds and components may be derived from synthetically prepared or semi-synthetically prepared cannabis, or as one or more metabolites of such cannabinoids.

[0055] In the formulations of the present invention, the most commonly used cannabinoid is cannabidiol (CBD), and preferably, it does not contain any other cannabinoids. While plant-derived CBD is acceptable for use in the formulations of the present invention, purification methods for producing pure or nearly pure plant-derived CBD active pharmaceutical ingredients ("APIs") are still under development. Therefore, synthetically prepared CDB is also acceptable for use in the formulations of the present invention.

[0056] Plant-derived cannabinoids, particularly CBD, are readily available from various US and international suppliers, easily identifiable through a simple internet search.

[0057] Synthetically prepared cannabidiols are specialty chemical products and are available from limited manufacturers. For example, cannabidiol APIs are available from Purisys LLC (Athens, Georgia, USA) and are used in the formulations described herein. Such cannabidiols may be synthetically prepared, for example, in accordance with the teachings described in U.S. Patent No. 10,059,683 (Noramco, Inc., Wilmington, Delaware, USA, assignee) and W02020 / 051371 (Noramco, Inc., applicant). Typically, the CBD used in the formulations of the present invention is in enantiomerically pure (-)-trans CBD form.

[0058] Furthermore, the cannabidiol used in the formulation of the present invention is (-)-trans-Δ at a concentration of 0.3% or less. 9 - Contains tetrahydrocannabinol, and if possible, (-)-trans-Δ 9 -Tetrahydrocannabinol may be omitted. 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, if possible, be free of all forms of THC. 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 part thereof.

[0059] The concentration of total cannabinoids, particularly cannabidiol, used in the formulations of the present invention may vary, for example, in a range containing at least 0.5 mg of API per milliliter of the final formulation solution, for example, not limited to this range. More specifically, such concentrations may range from about 0.5 to about 50 mg / mL, more specifically 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 part or all of the numbers within the stated range.

[0060] An additional element of the formulation of the present invention is the addition of at least one pharmaceutically acceptable surfactant, typically a nonionic surfactant. Examples of nonionic surfactants include, but are not limited to, polyoxyethylene (20) sorbitan oleate, also known as polysorbate 80 (Tween 80), which is available from numerous suppliers, including, for example, Sigma-Aldrich / MilliporeSigma (St. Louis, Missouri, USA); macrogol 15 hydroxystearic acid, which is primarily a mixture of monoesters and diesters of 12-hydroxystearic acid, and macrogol obtained by ethoxylation of 12-hydroxystearic acid. The number of moles of ethylene oxide reacted per mole of 12-hydroxystearic acid is 15. The proprietary types of these surfactants include Solutol HS15 (MedChemExpress, Monmouth Junction, New Jersey, USA), Crodasol® HS (Croda Inc., Newark, New Jersey, USA), and Kolliphor® HS15 (BASF, Florham Park, New Jersey, USA); and poloxamers, which are triblock copolymers of a central hydrophobic chain of polyoxypropylene with two hydrophilic chains of polyoxyethylene adjacent to each other. Poloxamers are well known in the art and are available under the name "Pluronic," readily available from various suppliers found through 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] The surfactant concentration used in the formulation of the present invention ranges from approximately 50 mg / mL to approximately 500 mg / mL. For example, if the desired cannabinoid concentration is approximately 10 mg / mL of the final formulation solution, the surfactant concentration is approximately 150 mg / mL of the final formulation solution. As the cannabinoid concentration increases, the surfactant concentration also increases. As a further example, if the desired cannabinoid concentration is approximately 50 mg / mL of the final formulation solution, the surfactant concentration is approximately 250 mg / mL of the final formulation solution. Those skilled in the art can further extrapolate the surfactant concentration used in the formulation 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] For more specificity, the surfactant concentration in the formulation of the present invention may be approximately 50 mg / mL, approximately 100 mg / mL, approximately 150 mg / mL, approximately 200 mg / mL, approximately 250 mg / mL, approximately 300 mg / mL, approximately 350 mg / mL, approximately 400 mg / mL, approximately 450 mg / mL, approximately 500 mg / mL, or any all or part of the stated range of the final formulation solution.

[0063] Antioxidants play an important role in the stability of the formulations of the present invention. During the preparation of the formulations of the present invention, the same or different antioxidants are added in two separate process steps, as described in more detail below herein. 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; and a second container into which at least one chelating agent and at least one of the same or different antioxidants are mixed, the mixing of the materials from the first and second containers thereafter to provide a final formulation solution, which is referred to herein as the final formulation, although any additional raw materials are still possible, unless such raw materials or multiple raw materials are limited from use herein.

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

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

[0066] Medicinally acceptable antioxidants are generally known to those skilled in the pharmaceutical art and include, for example, non-limitingly, antioxidants of the following classifications: natural antioxidants, such as tocopherol (vitamin E), sesamol, guaiac resin, and methionine; synthetic antioxidants, such as BHA, BHT, and tertiary butylhydroquinone; water-soluble antioxidants, such as citric acid, tartaric acid, phosphoric acid, ascorbic acid (and their precursors listed below), sodium pyrosulfite, and thiol derivatives; and lipid-soluble antioxidants, such as BHA and BHT.

[0067] For the purpose of preparing the pharmaceutical formulations of the present invention, the antioxidants used are typically selected from the group consisting of water-soluble antioxidants. More specifically, ascorbic acid, used in the form of ascorbyl palmitate and hydrolyzing part or all of it to ascorbic acid depending on the composition in which ascorbic acid is present, is typically used in the first container. The same or different antioxidants added to the second container are typically ascorbic acid, ascorbyl palmitate, citric acid, or a combination thereof, but any suitable antioxidant may be used in either the first or second container.

[0068] The concentration of at least one pharmaceutically acceptable antioxidant typically amounts to approximately 0.5 mg / mL to approximately 10 mg / mL of the final formulation solution, more typically 1 mg / mL to approximately 5 mg / mL of the final formulation solution. More specific antioxidant concentrations are approximately 0.5 mg / mL, 1.0 mg / mL, 2.0 mg / mL, 3.0 mg / mL, 4.0 mg / mL, 5.0 mg / mL, 6.0 mg / mL, 7.0 mg / mL, 8.0 mg / mL, 9.0 mg / mL, 10.0 mg / mL, or any all or some of the figures within the stated range of the final formulation solution. Such concentrations may be divided between two preparation containers, often to half the total concentration of antioxidants in each container, using the same or different antioxidants in each container.

[0069] At least one pharmaceutically acceptable chelating agent represents an additional element of the cannabinoid formulation of the present invention. Examples of chelating agents include, but are not limited to, eideic acid (Spectrum Chemical Manufacturing Corp., New Brunswick, New Jersey, USA), Versene® NA (Dow Chemical Company, Midland, Michigan, USA), and EDTA (ethylenediaminetetraacetic acid; typically available as disodium EDTA and calcium EDTA) and similar agents. EDTA is readily available from various sources 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 all or some of the numbers within the stated range of the final formulation solution. Typically, the concentration of the chelating agent 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] Where the phrase "or any all or part of the numbers within the stated range" is used herein, the phrase is intended to teach each specific all or part of the numbers not explicitly stated herein. Typical doses of chelating agents should not exceed 50 mg / kg body weight and typically not exceed 3 g / day. These guidance should be considered when formulating the formulations of the present invention to avoid toxicity from the chelating agent elements of the formulations of the present invention.

[0072] As previously referenced, injection sites, especially those of IV solutions administered over a period of time, can experience 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") formulation of the present invention can interfere with other administered drugs, particularly those administered IV. Therefore, the buffered cannabinoid formulation of the present invention can reduce injection site irritation and pain, especially when administered as an infusion, and can provide the physician with a known constant pKa of the formulation of the present invention. Furthermore, the buffered solution, It differs from isotonic saline in three characteristics: lower sodium and chlorine content, which brings them closer to normal plasma levels; the presence of other ions such as potassium, calcium, or magnesium, which may affect 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 can 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 adding at least one optional hypotonic or hypertonic buffer is the maintenance of the solution pH at a predetermined point rather than the target 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, non-limitingly, at least one buffer in hypertonic or hypotonic (non-isotonic) amounts, typically citric acid. However, other pharmaceutically acceptable buffers are known and used in liquid / aqueous pharmaceutical formulations. These include, for example, bicarbonate buffers, carboxylic acid buffers, phosphate buffers, amphoteric ion buffers, TRIS buffers, and the like, in addition to citric acid.

[0075] An example buffer and each pKa presented 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 of these buffers, prepared to be hypotonic or hypertonic (non-isotonic) when used with the formulation of the present invention, is used in an amount required to stabilize the formulation of the present invention at a pH between approximately 4.5 and approximately 6.0, more typically between pH 5.0 and pH 5.5.

[0077] For example, non-isotonic amounts of citric acid can be prepared by adding a specific amount of citric acid to water, typically deionized water, or an aqueous solution such as the formulation of the present invention. For example, hypotonic or hypertonic solutions of citric acid can be readily 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 can be prepared similarly and are well known to those skilled in the art.

[0078] Further aspects of the present invention include: i. Mixing at least one surfactant with at least one antioxidant and at least one cannabinoid in a first container; ii. Mixing at least one identical or different second antioxidant and at least one chelating agent in a second container; and iii. Mixing the contents of the first and second containers; and iv. Depending on the circumstances, at least one buffer selected from the group consisting of hypotonic and hypertonic buffers may be added. The present invention provides a method for preparing a compound containing [the specified ingredient].

[0079] and, i. Mixing at least one surfactant with at least one antioxidant and at least one cannabinoid in a first container; ii. Mixing at least one identical or different second antioxidant and at least one chelating agent in a second container; and iii. Mixing the contents of the first and second containers; and iv. Depending on the circumstances, at least one buffer selected from the group consisting of hypotonic and hypertonic buffers may be added. Includes, However, this is conditional on no isotonic agents being added to the formulation.

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

[0081] The following are non-limiting and exemplary preparations of the formulations of the present invention, which involve using two containers for the preparation of i) cannabinoids, particularly synthetically prepared cannabidiol, surfactants, and antioxidants; and ii) antioxidants and chelating agents, and then mixing the solutions in the two containers. [Table 1]

[0082] 1. Kolliphor HS15 was heated to approximately 40°C (so that it would become transparent and melt for measurement). 2. Excess water was heated to approximately 60°C in the formulation for injection: 1.150 mg / mL (15% w / v) of Kolliphor HS15 was distributed into container A (at approximately 60°C) to ensure that the Kolliphor HS15 did not solidify. 2 mg / mL (0.2% w / v) of citric acid was added and stirred until dissolved. 2.10 mg / mL of CBD was gently added to the center of container A, ensuring that no clumps of CBD formed on the sides of the container, and then stirred until the CBD was dissolved.

[0083] in parallel 3.20 mg / mL (0.02% w / w) of ascorbic acid was added to container 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. 1.0 mg / mL (0.01% w / v) of EDTA calcium disodium was added to container B, mixed until completely dissolved, and then returned to the oven at approximately 60°C (in the over).

[0084] If container A contains a clear solution in which no CBD crystals are present, 5. The contents of container B were added to container A gradually while being stirred at a constant rate to prevent solidification. 6. Container B was rinsed with approximately 25% more WFI, and its contents were added to container A. 7. Water was added to the specified volume (based on the concentration of each element) and mixed without introducing bubbles or air. 8. The mixed solution was stirred for approximately 10 minutes (at approximately 60°C), and then allowed to cool to ambient temperature.

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

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

[0087] Preparation 2: • Preparation in container A HS15 must be transparent and warm when dispensing.

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

[0089] Adding citric acid to warm Kolliphor HS15 should prevent the solution from turning purple when CBD is added.

[0090] Overheating CBD can cause it to decompose, so the CBD in Kolliphor HS15 should not be heated.

[0091] • Preparation in container B All excipients (EDTA, ascorbic acid) are readily soluble in water.

[0092] The aqueous phase is kept at a high temperature as previously referenced, thereby preventing the solidification of the CBD-containing Kolliphor HS15 when it is added to container A.

[0093] The entire process must be maintained within the temperature range specified earlier.

[0094] Ascorbic acid preparations should typically not be prepared in advance.

[0095] • Mixing of phases The addition of the contents of container B to container A must be done slowly, and the mixer speed must be adjusted so as not to generate additional foam in the mixture.

[0096] Using a mixer or glass rod ensures that all Kolliphor HS15 is hydrated away from the sides of the container and that each compounding element is dissolved in the solution at the desired concentration.

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

[0098] Once the final formulation solution is in its final volume, the solution becomes less turbid and typically becomes completely clear upon reaching ambient temperature. Therefore, water is added to the formulation as desired or predetermined to meet the concentration requirements specified herein for each element of the formulation of the present invention.

[0099] Filling and finishing Reduction of biological load Aseptic filtration using a PVDF filter of approximately 0.2 microns or other methods known to those skilled in the art is acceptable; the tubing must be made of hardened platinum to prevent CBD adsorption to the tubing.

[0100] Typically, any bubbles are dissipated before filling the formulation of the present invention into vials or other final containers. Filling into vials or other such containers must be carried out by weight, utilizing the specific gravity of the formulation, followed by sparging with an inert gas to remove any dissolved oxygen.

[0101] The foregoing allows for the preparation of formulations of the present invention using various concentrations of each element, and as the concentration of cannabinoids, typically cannabidiol, increases, specific elements are modified. Non-limiting examples of such modifications of the concentration of specific exemplary elements are shown in Table 1 below. [Table 2]

[0102] The ratios in the table result in a clear solution when using sterile water for injection.

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

[0104] Following considerable scientific development efforts, the present invention provides a non-toxic formulation administered via at least one parenteral (intravenous (IV), intramuscular (IM), and intraperitoneal (IP)) administration method. Various dosage forms are available for such administration methods. Accordingly, the present invention provides, for example, a dosage form comprising one or more vials, ampoules, syringes, infusion bags, or other pharmaceutically acceptable containers filled with the formulation of the present invention. Such dosage forms may be single-use or repeat-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, as typically indicated by discoloration of the formulation of the present invention. Typical examples of such inert gases include nitrogen and argon. Furthermore, longer headspace vials finished with such inert gases may provide additional long-term stability of the formulation of the present invention. For further protection, the previously referenced glass or plastic dosage forms may be colored yellowish-brown 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 may also be stored under non-freezing refrigerated conditions. The formulations of the present invention may also be freeze-dried, which typically requires the addition of pharmaceutically acceptable fillers such as mannitol, lactose, sucrose, dextran, glycerin, and / or trehalose. In the freeze-dried product, the fillers also provide freeze protection to the product. The concentration of the filler added often depends on the properties and amounts of the 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 number of all or part of this range or beyond. More specifically, the formulations of the present invention in bulk form, or more particularly, in ready-to-administer dosage forms, are generally stable without refrigeration for about 6 months, about 1 year, about 1.5 years, about 2 years, or any number of all or part of this range from about 6 months to about 2 years. Typically, it is desirable that the formulations of the present invention be stable and usable for at least 2 years after preparation and filling into one or more suitable containers.

[0108] Another aspect of the present invention provides a formulation of the present invention that can be ultimately sterilized. Such sterilization can be completed by any currently known or future-developed method that can provide a sterilized formulation of the present invention when the sterilized formulation of the present invention is placed in a container, typically used to distribute such formulation for administration to mammals, typically humans. Such methods include, for example, dry heating, steam, radiation, and plasma, with steam being typically used.

[0109] Alternatively, other methods known to those skilled in the art in sterile pharmaceutical formulations may be used, such as, for example, the preparation of the formulations of the present invention under sterile manufacturing conditions, such as those designed to utilize appropriate pore size / surface chemistry to remove bacteria and other microorganisms via gases such as ethylene oxide, glutaraldehyde, propylene oxide, hydrogen peroxide, and chlorine dioxide, as well as sterilization filtration, and size exclusion, capture, electrostatic attraction, and other modalities.

[0110] Furthermore, the formulations of the present invention can be compounded 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-controlled membrane patches, matrix patches, active pharmaceutical ingredients in adhesive patches, electroporation, iontophoresis, sonophoresis, and microneedle patches. Therefore, also provided are methods for delivering the pharmaceutical formulations of the present invention via one or more pharmaceutically acceptable patch delivery systems. However, the patch technology of the present invention may not be an adequate option for the delivery of the pharmaceutical formulations of the present invention, requiring additional research and development to achieve the desired dosage strength. Such patches may be used to treat disease conditions treatable by the parenteral formulations described herein, and may be used as a single treatment or sequentially, before, with, or following one or more parenteral administrations of the parenteral pharmaceutical formulations described herein.

[0112] The present invention further provides a method for treating mammals, typically humans, that require treatment including parenteral administration, typically intravenous administration, of the formulation of the present invention. The pharmacokinetic and / or pharmaceutically appropriate use of the formulation of the present invention is not limited by examples, as a number of potential medical conditions can be treated via parenteral administration, often via intravenous administration, of the formulation of the present invention.

[0113] One such use involves, for example, non-limiting, parenteral administration, typically IV administration, of the formulation of the present invention for treating 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 thereof, may be assessed as mild, mild to moderate, moderate, moderate to severe, severe, or other pain as described by the patient requiring treatment, on any one of the various pain scales used by the medical community.

[0114] Pain assessment scales are used in daily clinical practice to measure pain intensity. Commonly used 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 proven as official measures of pain intensity. The three most commonly used scales in the United States are numerical, verbal, and facial expression scales.

[0115] The formulations of the present invention may be used, when administered and monitored appropriately, typically by a healthcare professional, in hospitals, clinics, homes, military, or other settings, to treat acute or chronic pain, including, for example, neuropathic pain and / or pain associated with certain forms of cancer, regardless of whether it is perioperative pain or other pain. Furthermore, the formulations of the present invention are intended to be used to treat pain described within the pain matrix (also known as the neuromatrix), which includes, for example, non-limitingly, pain associated with various different pain syndromes, such as fibromyalgia, phantom limb pain, postherpetic neuralgia, complex regional pain syndrome (CRPS), diabetic neuropathy, and central pain associated with stroke or spinal cord injury. Methods using the formulations of the present invention further include, for example, pain in soft tissue and bone tissue, pain associated with trauma, and any form of pain for which opioid drugs are currently used, whether orally or parenterally. The formulations of the present invention may also be used in special cases for the treatment of severe depression and refractory headaches, particularly when administered as an intravenous fluid. The formulations of the present invention may also be used to treat Dravet syndrome, Lennox-Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile convulsions, West syndrome, tuberous sclerosis, brain tumors, cannabis use disorder, post-traumatic stress disorder, anxiety disorders, early psychosis, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and autism. More specifically, the use of the pharmaceutical formulations of the present invention for epilepsy is typically for emergency use. Other disease conditions that may be potentially treated with the formulations of the present invention include inflammatory diseases, including cardiac inflammatory diseases such as pericarditis and endocarditis, hypertension and other disease conditions treated with vasodilators, arrhythmias, congestive heart failure, arterial plaque (and its reduction), reduction of glucose absorption from the arterial wall, inhibition of endotoxin production, and stroke (generally by providing cerebral protection and cerebral recovery before, during, and after stroke; treatment of ischemic and hemorrhagic strokes). The formulations of the present invention can also generally be used as antioxidants.

[0116] The formulations of the present invention can be prepared in various dosage forms, including, for example, vials, ampoules, syringes, infusion bags, and other pharmaceutically acceptable containers. Such dosage forms can be filled with one of the various dosing concentrations of the cannabinoid, typically cannabidiol, used in the formulations of the present invention. For example, non-limitingly, such dosage forms are filled with the formulations of the present invention containing at least 0.5 mg of the cannabinoid, typically cannabidiol, per milliliter of the final formulation solution. More specifically, such concentrations range from about 0.5 mg / mL to about 50 mg / mL of the final formulation solution, more specifically 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 figures within the stated range.

[0117] Certain dosage forms containing the formulation of the present invention, such as syringes, can be administered or infused directly into a bolus or infusion bag containing any one of several pharmaceutically acceptable fluids that can be administered to a patient. Such fluids may, for example, not limited to, nutrients, hydrations, and / or treatment agents for pain, other illnesses, and / or any other medical purposes. As a precaution, small amounts of the formulation of the present invention must be pre-mixed with other such fluids or multiple fluids to ensure compatibility of the mixture before administration. The formulation of the present invention may be present in other pharmaceutically acceptable containers that can be used for bolus or infusion administration, often to prepare a final form for slow infusion over a period of time.

[0118] In the use of the formulations of the present invention for treating mammals requiring treatment for perioperative and / or postoperative pain, such formulations are typically administered one to two times preoperatively and one or two more times postoperatively. The actual number of doses, dose concentrations, and timing of administration are typically left to the discretion of the attending physician, associate physician, healthcare professional, and similar person. Therefore, the dosage, number of doses, and timing of such administration are not limited by this disclosure.

[0119] The dosage of the formulation of the present invention must be calculated on a mg / kg basis for the amount of API, typically cannabidiol, and such dosages must be in the range of about 0.1 mg / kg to about 10 mg / kg. More specifically, such dosages include, for example, amounts exceeding 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, or any all or part of the figures within the stated range. The final determination of such dosages must be left to the discretion of the attending physician or other appropriate healthcare professional.

[0120] While specific embodiments are described earlier, these embodiments do not limit the scope of the disclosure, even if only one embodiment describes a particular feature. Examples of features provided in this disclosure are illustrative, not restrictive, unless otherwise stated. This disclosure covers alternatives, improvements, and / or equivalents that would be obvious to those skilled in the art who are interested in the disclosure.

[0121] It should be understood that the pharmaceutical formulations of the present invention are limited only to the scope and / or limitations shown herein, and not to variations within such scope. It should also be understood that the techniques used herein are intended only to describe specific embodiments and are not intended to be limiting.

[0122] Further improvements and alternative embodiments of various aspects of the embodiments described herein will become apparent to those skilled in the art by considering this disclosure. Elements and materials may be replaced with those illustrated and described herein, parts and processes may be reversed, and certain features of embodiments may be used independently, all of which will become apparent to those skilled in the art after benefiting from this disclosure. In elements described herein, modifications may be made without departing from the spirit and scope of the appended claims.

[0123] Examples Example 1: Stability of parenteral formulation 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 quarterly radiant pump, autosampler, column oven, and single-wavelength detector (UV-Vis), was used to analyze CBD. The detector wavelength was set to 220 nm. Chromatographic separation was performed at 35°C using a Hichrom C18 reverse-phase column ((150 × 4.5 mm), 4.7 μm). The mobile phase was a filtered mixture of acetonitrile:0.25% acetic acid:methanol (75:20:5, v / v) flowing at a rate of 1 mL / min. Data were collected and analyzed.

[0124] Preparation of calibration standards: A stock CBD solution (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. Subsequently, calibration standard solutions of CBD at 25, 50, 100, and 250 μg / mL were prepared by diluting the stock solution with HPLC-grade methanol.

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

[0126] Data review: This stability test was performed on one batch of the 10 mg / mL CBD intravenous formulation. The development batch used was manufactured at the proposed clinical scale from a 1 L production lot. The batch was aliquoted to provide sufficient samples under different storage conditions and time points. A placebo was also administered in parallel with this test, where required at time points.

[0127] EMA guidance for clinical trials The shelf life and storage conditions of IMPs 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 testing is performed in parallel with clinical trials and throughout the entire period. Extrapolation of shelf life may be performed under the following conditions: • Results under long-term and accelerated storage conditions are available; • No trends are observed in the stability behavior. If any trends are observed, the evidence must be provided.

[0128] Depending on the available data, extrapolation of real-time data by a factor of four may be permitted up to a storage life of 12 months, and for storage lives longer than 12 months, extrapolation of x + 12 months may be permitted.

[0129] In summary, throughout the 6-week testing period to date, there were minor changes in the CBD content or pH of the samples. These results at 6 weeks under storage conditions of 40°C±2°C / 75%RH±5%RH are within the specified range. There were no changes in the physical appearance or color of the samples. At the time of preparation, the solution was aseptically filtered using a 0.22 micron PVDF filter. As reflected in the assay results, there were no signs of CBD crystallization in the solution. All analytical results are within the range of analytical variability.

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

[0131] Under accelerated storage conditions of 40°C and 75%RH for the sixth week, the batch data conformed to the specifications and showed no changes over time.

[0132] The manufacturing process can be carried out in a single container using a heated jacketed mixer container. Preheated Kolliphor HS15 is weighed into the heated mixer container. The cannabinoids are separated and added to the HS15 in the mixer container while stirring. The antioxidants are added to the container and mixing continues until dissolved. Using a liquid supply device, a preheated aqueous phase containing the antioxidants, buffers, and chelating agents is separated and mixed together in the mixer container. Once mixed, the jacketed container is set to cool to room temperature. Prior to aseptic filling of the product and nitrogen flush finishing, a bioburden reduction filter is performed at the outlet valve.

Claims

1. (i) cannabidiol (CBD) and; (ii) Macrogol (15) hydroxystearate and; (iii) Citric acid and; (iv) Chelating agents; (v) Second antioxidant, A pharmaceutical compound containing the following ingredients.

2. The formulation according to claim 1, wherein the formulation does not contain an isotonic agent.

3. The formulation according to claim 1, wherein the CBD is enantiomerically pure (-)-CBD.

4. The formulation according to claim 1, wherein the CBD is prepared synthetically.

5. The formulation according to claim 1, wherein the chelating agent is EDTA, or a salt thereof selected from the group consisting of EDTA disodium and EDTA calcium disodium.

6. The formulation according to claim 1, wherein the second antioxidant is selected from the group consisting of tocopherol, sesamol, methionine, BHA, BHT, tertiary butylhydroquinone, ascorbyl palmitate, tartaric acid, phosphoric acid, ascorbic acid, and sodium pyrosulfite.

7. The formulation according to claim 1, wherein the formulation comprises 50 mg / mL to 500 mg / mL of macrogol (15) hydroxystearate.

8. The formulation according to claim 1, wherein the formulation contains 0.5 mg / mL to 10 mg / mL of citric acid.

9. The formulation according to claim 1, wherein the formulation comprises 0.1 mg / mL to 5 mg / mL of a chelating agent.

10. The formulation according to claim 1, wherein the formulation comprises a second antioxidant in an amount of 0.5 mg / mL to 10 mg / mL.

11. (i) 10 mg / mL of cannabidiol (CBD) and; (ii) 150 mg / mL of macrogol (15) hydroxystearate; (iii) 2 mg / mL of citric acid; (iv) EDTA at 1 mg / mL; (v) 2 mg / mL ascorbic acid, A pharmaceutical compound containing the following ingredients.

12. The formulation according to claim 11, wherein the formulation is stable for a period of at least six months when stored at 25°C and 60% relative humidity.

13. The formulation according to claim 11, wherein the formulation is in the form of parenteral administration.

14. (i) cannabidiol (CBD) and; (ii) Macrogol (15) hydroxystearate and; (iii) Citric acid and; (iv) Chelating agents; (v) Second antioxidant, Drugs for treating acute or chronic pain, including

15. The drug according to claim 14, wherein the acute or chronic pain is perioperative pain or postoperative pain.

16. The drug according to claim 14, wherein the drug is for intravenous administration.

17. (a) heating macrogol (15) hydroxystearate; (b) Mixing the heated macrogol (15) hydroxystearate with citric acid to form a first mixture; (c) Adding cannabidiol (CBD) to the first mixture; (d) Forming a second mixture in water containing a second antioxidant and a chelating agent; (e) Mixing the first mixture and the second mixture to form a pharmaceutical compound, A method for manufacturing a pharmaceutical formulation containing [a specific ingredient / component].

18. The method according to claim 17, wherein the macrogol (15) hydroxystearate is heated to 40°C.

19. The method according to claim 17, wherein the mixing and adding steps are performed in a container heated to 50 to 70°C.