Cannabidiol composition for use in the treatment of cardiac conditions

Abstract

A pharmaceutical composition containing an effective amount of cannabidiol (CBD) for use in the treatment or prevention of cardiac conditions, as well as related methods and uses. [Solution] Cardiac conditions include heart failure, acute myocarditis, toxicity caused by anticancer therapy, acute pericarditis, cardiac sarcoidosis, inflammatory cardiomyopathy, and atherosclerosis, as well as related uses and methods. This disclosure shows that CBD is effective in (i) reducing cardiac hypertrophy; (ii) reducing cardiac fibrosis; (iii) reducing BNP levels; (iv) reducing cytokine IL1β levels; (v) reducing cytokine IL6 levels; (vi) reducing CD69 levels; (vii) increasing cytokine IL10 levels; and (viii) combinations thereof. The compositions are preferably adapted for parenteral administration.

Description

Technical Field

[0001]

[0001] This application claims priority from U.S. Provisional Patent Application No. 62 / 926,066, filed on October 25, 2019, the entire content of which is incorporated herein by reference.

[0002]

[0002] Field

[0003] The present invention generally relates to pharmaceutical compositions containing cannabidiol (CBD) and to the treatment or prevention of diseases and disorders using such compositions.

Background Art

[0003]

[0004] [[ID= vingt]] Background

[0005] Chronic heart failure (CHF) affects more than 26 million people worldwide. More than 6 million adults in Canada and the United States suffer from chronic heart failure, which remains the leading cause of death and hospitalization, and the associated medical costs exceed $30 billion per year in the United States alone.

[0004]

[0006] People with heart failure (HF) are troubled by shortness of breath, palpitations, edema, and reduced exercise capacity. Such people often struggle with simple daily activities and are frequently hospitalized. For many people, these symptoms significantly reduce the quality of life.

[0005]

[0007] Heart failure occurs when the heart is unable to pump enough blood to meet the body's needs. There are two types of heart failure: heart failure with reduced ejection fraction (HFrEF, also called systolic heart failure) and heart failure with preserved ejection fraction (HFpEF, formerly called diastolic heart failure). In heart failure with reduced ejection fraction (HFrEF), there is a decrease in left ventricular systolic function, meaning that insufficient blood is pumped into circulation with each contraction of the heart. In heart failure with preserved ejection fraction (HFpEF), the problem is primarily limited left ventricular filling during diastole. The lesion stiffens the left ventricle, preventing it from relaxing normally. As a result, it cannot fill normally, and pressure begins to increase in the left heart chamber and lungs. This increased pressure in the lungs causes shortness of breath.

[0006]

[0008] HFpEF is a complex syndrome. Its pathophysiological mechanisms are still not fully understood, which is one reason why there is currently no effective treatment. However, several conditions are recognized as frequently associated with HFpEF. Among these, the most important are the components of metabolic syndromes (impaired glucose tolerance, obesity, hypertension, and dyslipidemia). Obesity is particularly important, as it leads to a systemic inflammatory state and causes cardiac inflammation, which is associated with fibrosis and decreased ventricular compliance (relaxation). Hypertension (HTN) is also a major precursor to HFpEF, leading to increased thickness of the left ventricular (LV) muscle (LV hypertrophy) and decreased LV compliance. This inability of the left ventricle to fill normally is also called left ventricular diastolic dysfunction (LVDD). Some consider HTN to be the most significant risk factor for the development of LVDD.

[0007]

[0009] The publication incorporated herein by reference, Glezeva et al., “Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target,” (Heart Fail Rev (2014) 19:681-694; DOI 10.1007 / s10741-013-9405-8), argues that inflammation is an early and fundamental factor in ventricular remodeling in HTN. This document describes studies showing that it is a contributing factor and a cause of LVDD. The studies suggest that inflammation is caused by elevated levels of endothelial adhesion molecules as well as increased production and release of inflammatory cytokines and chemokines in the tissue. The latter promotes the infiltration of activated inflammatory cells, particularly monocytes, into cardiac tissue. Increased monocyte infiltration is linked to HTN and HFp This is observed in the early and late stages of EF. Upon entering tissue, monocytes are thought to differentiate into macrophages, promoting cardiac inflammation, tissue damage, and myocardial fibrosis. This mechanism is considered to be part of the progression to HFpEF. The authors conclude that myocardial inflammation plays a role in the pathophysiology of HFpEF and suggest that therapeutic approaches that intervene in the inflammatory pathway should be used in addition to antihypertensive therapy in at-risk patients or patients with LVDD and / or HFpEF. The authors conclude that more large-scale randomized clinical trials in patients with HFpEF are needed, along with a better understanding of the persistent inflammatory response in HTN and LVDD.

[0008]

[0010] In addition to hypertension, there are several other risk factors associated with the development of HFpEF. One of the main risk factors is diabetes, a common risk factor for atherosclerosis of the coronary arteries, which is a typical cause of heart attacks as well as heart failure. Other major risk factors are obesity and aging. Interestingly, aging, diabetes, and obesity are all conditions associated with increased systemic inflammation. Adipocytes are the main producers of inflammatory cytokines that circulate to other tissues. The combination of hypertension, diabetes, and obesity is very common in HFpEF, and each contributes to the inflammatory environment that many people consider to be the cause of this syndrome.

[0009]

[0011] Cannabinoids are compounds found naturally in the plant Cannabis sativa. The main cannabinoid components are cannabidiol (CBD) and tetrahydrocannabinol (THC). THC is known to increase heart rate, cause conjunctival redness, and produce antipsychotic (mood-altering) effects such as euphoria. In contrast to THC, CBD is non-addictive. Therefore, CBD is more commonly used as a pharmaceutical ingredient to treat a wide range of conditions, including epilepsy, chronic pain, anxiety, and insomnia. The anti-inflammatory effects of CBD have been mentioned in several publications. See, for example, International Publication No. 2014 / 117999Al (Chronic Inflammation and Inflammatory Diseases), International Publication No. 2017 / 191630Al (Hepatitis), U.S. Patent No. 9,549,906 (Ocular Inflammation), and International Publication No. 2018148152 (Neuroinflammation).

[0010]

[0012] Cannabidiol (CBD) is fat-soluble and virtually insoluble in water. Furthermore, it is prone to inactivation in the liver due to first-pass metabolism. This high first-pass metabolism results in low effective blood levels and an overall bioavailability of less than 10% when taken orally. [Overview of the Initiative] [Problems that the invention aims to solve]

[0011]

[0013] CB optimizes and maintains drug blood levels by avoiding first-pass hepatic metabolism. There remains a need to provide improved compositions containing D. There also remains a need to better understand the pathophysiological mechanisms of cardiac conditions, including heart failure, and to provide new therapies for their treatment and / or prevention. [Means for solving the problem]

[0012]

[0014] overview

[0015] The inventors have found that parenterally administered CBD, for example subcutaneously, can treat heart failure in vivo. In a non-ischemic (hypertension-induced) mouse model, we found that CBD was effective in reducing cardiac hypertrophy and cardiomyopathy, and beneficially regulating the levels of molecular markers for remodeling and inflammation. Surprisingly, these effects were observed at very low doses. We also found that CBD was effective in preventing cell enlargement (hypertrophy) in an in vitro model of cardiomyocyte hypertrophy using H9c2 cells. Furthermore, we conducted studies demonstrating that CBD is effective in reducing the expression of CD69 (a marker of inflammation) by human lymphocytes and monocytes in vitro. These findings and published texts The findings presented support the beneficial role of CBD in the treatment or prevention of cardiac conditions including heart failure (e.g., HFpEF), acute myocarditis, toxicity caused by certain anticancer therapies (e.g., doxorbin, checkpoint inhibitors), acute pericarditis, cardiac sarcoidosis, certain dilated cardiomyopathy (inflammatory cardiomyopathy), and atherosclerosis (coronary artery disease). Each of these cardiac conditions has inflammation as a prominent component and includes varying degrees of hypertrophy or fibrosis.

[0013]

[0016] Therefore, according to the first aspect, the present invention relates to heart failure (e.g., HFpEF). ) Provide the use of an effective amount of CBD for treating or preventing a heart condition selected from the group consisting of acute myocarditis, toxicity caused by anti-cancer therapies (e.g., doxorubicin, checkpoint inhibitors), acute pericarditis, cardiac sarcoidosis, inflammatory cardiomyopathy, and atherosclerosis.

[0014]

[0017] In certain embodiments, the use of CBD is, in a subject, (a) reduce cardiac hypertrophy; (b) reduce cardiac fibrosis; (c) reduce the level of BNP; (d) reduce the level of cytokine IL1β; (e) reduce the level of IL6; (f) reduce the level of CD69; (g) increase the level of cytokine IL10; or (h) result in any combination of the above and is effective for.

[0015]

[0018] One of ordinary skill in the art will recognize that when a reduction in the blood level of BNP is observed, cardiac function, including cardiac dilation, is improved in heart failure subjects. Further, when the levels of cytokines IL1β, IL6, and CD69 are reduced or the level of cytokine IL10 is increased, this indicates a reduction in inflammation, which is known to underlie the above-described inflammatory heart conditions.

[0016]

[0019] In selected embodiments, CBD is used in a subject to result in at least 2, 3, 4, 5, 6, or all of the above (a)-(g ).

[0017]

[0020] According to a second aspect of the invention, CBD can be present in a parenteral composition, the composition The composition comprises, consists essentially of, or consists of an effective amount of CBD and an effective amount of at least one pharmaceutically acceptable solvent for solubilizing the CBD in the composition. Administering CBD parenterally will avoid first-pass liver metabolism and thus optimize and maintain drug blood levels. The composition is adapted to be administered by any parenteral route including intramuscular (IM), intravenous (IV), intraperitoneal (IP), and subcutaneous (SC) injection routes. Preferably, the composition is adapted to be administered by SC and IM injection.

[0018]

[0021] The present invention also contemplates using CBD in combination with one or more additional anti-inflammatory pharmaceutically active agents such as β-caryophyllene (BCP), methotrexate ( MTX), and cyclosporine (CsA). These other agents may be administered concomitantly or sequentially with CBD and, depending on the agent, may be administered with CBD in the same composition. BCP and CsA are agents that can be included in the same composition as CBD. In some embodiments, the pharmaceutically active agent in the composition consists of CBD. In other embodiments, the pharmaceutically active agent consists of CBD and BCP. Further, the present use, composition, and method may supplement existing therapies and methods for treating cardiac conditions and improving patient outcomes. aid.

[0019]

[0022] The at least one pharmaceutically acceptable solvent is selected from the group consisting of natural and synthetic medium-chain (C6– C12) triglycerides (MCTs), structured lipids, di(caprylyl / capric) propylene glycol, vegetable oils, N-methyl-2-pyrrolidone, polyoxyethylene castor oil derivatives, dimethylacetamide (DMA), ethanol, glycerin, PEG300, PEG400, polyoxyethylene 20 sorbitan monooleate, propylene glycol (PG), polyglycol mono- and diesters of 12-hydroxystearic acid, solvents sold in association with the trademark Kolliphor® and mixtures thereof These solvents are useful for solubilizing lipophilic compounds such as CBD, BCP, and CsA. On the other hand, other (hydrophilic) solvents would be used for non-lipophilic MTX.

[0020]

[0023] In some embodiments, at least one pharmaceutically acceptable solvent is The group consists of natural and synthetic medium-chain (C6-C12) triglycerides (MCTs). Furthermore, at least about 95% of the MCTs may consist of C8 triglycerides, C10 triglycerides, or mixtures thereof.

[0021]

[0024] A pharmacokinetically active drug exists in an "effective dose" as defined below. In embodiments where the active agent consists of CBD or CBD and BCP, the pharmaceutically active agent may be present in amounts of at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg / mL of composition. Alternatively or additionally, the pharmaceutically active agent may be present in amounts up to about 350, 300, 250, 200, or 150 mg / mL of composition. Typically, each pharmaceutically active agent is administered in amounts of about 0.1, 0.5, 1, 1.5, 2, 3, or 4 to about 30, 25, 20, 15, 10, 9, 8, 7, 6, or 5 mg per kg of body weight. Preferably, each pharmaceutically active agent is administered in amounts of about 0.1 to about 10 mg / kg body weight or about 1 to about 10 mg / kg body weight.

[0022]

[0025] In embodiments where the pharmaceutically active agents consist of CBD and BCP, CBD The weight ratio of CBD to BCP can vary, provided that each active ingredient is present in an effective amount. For example, the weight ratio of CBD to BCP may be approximately 1:4 to 4:1, approximately 1:2 to 2:1, or approximately 1:1.

[0023]

[0026] In some embodiments, the parenteral composition is substantially water-free. In one or another embodiment, the composition is substantially free of micelles.

[0024]

[0027] According to a third aspect, the present invention relates to heart failure (e.g., HFpEF), acute myocardial infarction. The present invention provides a method for treating and / or preventing cardiac conditions selected from the group consisting of inflammation, toxicity caused by anticancer therapies (e.g., doxorbin, checkpoint inhibitors), acute pericarditis, cardiac sarcoidosis, inflammatory cardiomyopathy, and atherosclerosis. The method is as follows: (i) Identifying subjects who have or are at risk of having the aforementioned cardiac conditions; and (ii) Administer an effective dose of CBD to the target population. Including CBD administration, (a) Does it reduce cardiac hypertrophy? (b) Does it reduce cardiac fibrosis? (c) Reduce the level of BNP; (d) Reduce the level of cytokine IL1? (e) Reduce the level of IL6; (f) Reduce the level of CD69; (g) Increase the level of cytokine IL10; or (h) results in any of the above combinations.

[0025]

[0028] In the selected embodiment, the administration of CBD is performed on the subject as described in (a) above. ~(g) brings about at least two, three, four, five, six or all of them.

[0026]

[0029] Preferably, administration is via a parenteral route that avoids first-pass hepatic metabolism. Therefore, CBD may be present in the parenteral composition according to a second aspect of the present invention.

[0027]

[0030] In the method according to the present invention, the composition is administered at least once, twice, or three times per week. It may be administered at least once or at least twice daily for 1, 2, 3, 4, 5, 6, 7, or 8 weeks or longer. When treating chronic conditions, the treatment period may be indefinite, and the amount of pharmaceutically active ingredient is expected to be adjusted to a dosage that avoids long-term toxicity. Depending on the frequency of administration, each dose of the parenteral composition may contain approximately 1, 2, 3, 4, or 5 to approximately 20, 15, or 10 mg of CBD (or CBD and BCP, respectively) per kg of body weight.

[0028]

[0031] Those at risk of developing heart failure (HFpEF) include elderly individuals (for example) The subjects are those aged 60 and over, as well as those with hypertension, diabetes, and / or obesity. Regarding acute myocarditis, this is a post-viral condition, and the affected population can be younger individuals. Cardiac sarcoidosis is rare overall, but is more common in African Americans, typically in the 30-40 age group. It is characterized by the presence of granulomas in cardiac tissue, and diagnosis may require endocardial biopsy. Inflammatory cardiomyopathy often occurs in young adults and can lead to chronic heart failure. In some cases, it can be the final outcome of acute myocarditis. More and more cancer patients are taking medications (such as anthracyclines and checkpoint inhibitors), which can affect the heart and lead to inflammation-induced damage. In some cases, for example, after taking checkpoint inhibitors, the condition can rapidly worsen, leading to cardiogenic shock or death. Acute pericarditis is an acute inflammation of the pericardium and may involve various inflammatory injuries to the adjacent heart. It tends to occur in younger populations, but can occur at any age. Atherosclerotic heart disease is a common cause of myocardial infarction and is usually associated with coronary artery thrombosis. The pathogenesis of thrombosis is widely thought to arise, at least in part, from inflammatory processes in the arterial wall.

[0029]

[0032] Brief explanation of the drawing

[0033] The present invention can be better understood by referring to the following description together with the following drawings. . [Brief explanation of the drawing]

[0030] [Figure 1]

[0034] Includes selected confocal microscopy images showing the effects of different doses of CBD on the cell surface area of ​​H9c2 cells in an in vitro model of cardiomyocyte hypertrophy. [Figure 2]

[0035] This graph shows the effect of administering different doses of CBD on the cell surface area of ​​H9c2 cells in an in vitro model of cardiomyocyte hypertrophy. [Figure 3a]

[0036] This graph shows the reduction in mRNA expression levels of type B natriuretic peptide (BNP) (a remodeling biomarker) induced by CBD administered at different doses in an in vitro model of cardiomyocyte hypertrophy. [Figure 3b]

[0036] This graph shows the reduction in collagen mRNA expression levels by CBD administered at different doses in an in vitro model of cardiomyocyte hypertrophy. [Figure 4]

[0037] This graph shows the reduction of mitochondrial reactive oxygen species (MitoSOX), a marker of inflammation, by administering CBD at different doses in an in vitro model of cardiomyocyte hypertrophy. [Figure 5]

[0038] This describes the experimental design used to measure the effects of CBD administration in a mouse model of non-ischemic heart failure. [Figure 6A]

[0039] Figure 5 shows a representative slide of mouse cardiac tissue stained with Masson's trichrome, illustrating the reduction in fibrosis (reduction in blue staining) after CBD administration in the experiment. [Figure 6B]

[0039] A representative slide of mouse cardiac tissue stained with Masson's trichrome staining is shown, illustrating the reduction in fibrosis (reduction in blue staining) after CBD administration in the experiment shown in Figure 5. [Figure 6C]

[0039] A representative slide of mouse cardiac tissue stained with Masson's trichrome staining is shown, illustrating the reduction in fibrosis (reduction in blue staining) after CBD administration in the experiment shown in Figure 5. [Figure 6D]

[0039] A representative slide of mouse cardiac tissue stained with Masson's trichrome staining is shown, illustrating the reduction in fibrosis (reduction in blue staining) after CBD administration in the experiment shown in Figure 5. [Figure 7]

[0040] Figure 5 is a graph showing the reduction in fibrosis after CBD administration in the experiment. [Figure 8]

[0041] Figure 5 is a graph showing the reduction in muscle cell area (hypertrophy) after CBD administration in the experiment. [Figure 9]

[0042] Figure 5 is a graph showing the reduction in BNP mRNA expression levels after CBD administration in the experiment. [Figure 10a]

[0043] Figure 5 is a graph showing the level of mRNA expression of the inflammatory cytokine IL1β after CBD administration in the experiment. [Figure 10b]

[0043] This graph shows the level of mRNA expression of the inflammatory cytokine IL6 after CBD administration in the experiment shown in Figure 5. [Figure 10c]

[0043] Figure 5 is a graph showing the level of mRNA expression of the anti-inflammatory cytokine IL10 after CBD administration in the experiment. [Figure 11]

[0044] This graph shows the effect of CBD administration on CD69 expression in stimulated / activated monocytes and lymphocytes (leukocytes) in another experiment. [Modes for carrying out the invention]

[0031]

[0045] In the diagram, the "p-value" is, * Or #=≦0.05, ** Or ## = ≤ 0.01 and *** Alternatively, it is indicated as ### = ≤ 0.001. A lower "p-value" indicates a higher statistical significance between groups.

[0032]

[0046] Detailed explanation

[0047] definition

[0048] For clarity and to avoid ambiguity, certain terms are used as follows in this specification. It is defined as follows.

[0033]

[0049] The term "pharmaceutically active agent" refers to drugs, cells, DNA, RNA, oligonucleotides, etc. This means any composition (e.g., a drug, compound, or component) that contains rheotides, proteins, and peptides and is capable of providing a therapeutic effect to a subject (e.g., curing, alleviating, or preventing a disease or its symptoms).

[0034]

[0050] When a composition, for example, a compound or component, is described as having "X% purity" This means that one or more impurities may be present in amounts ranging from 100% to X% by weight based on the total weight of the composition. The purity of the components can be determined by high-performance liquid chromatography (HPLC) or other suitable means.

[0035]

[0051] The term "subject" refers to members of the animal kingdom, including humans and other mammals. .

[0036]

[0052] As used herein, the term “treatment” means the treatment of a condition, disorder, or progression of a disease. The term "prevention" means to stop or delay the onset of a condition, disorder, or disease. This term encompasses "improving the quality of life," "extending lifespan," and "improving clinical outcomes" for individuals who have or are at risk of developing a condition, disorder, or disease, and does not necessarily mean "curing" the condition, disorder, or disease.

[0037]

[0053] As used herein, "pharmaceutically acceptable excipients" means pharmaceutically active This refers to any substance that can be formulated together with or in combination with a sexual agent to achieve a desired function or multiple functions. To be "pharmaceutically acceptable," an excipient must be non-toxic, safe for humans and animals, and compatible with the other components in the composition, taking into account the parenteral administration mode. Those skilled in the art will recognize, based on the teachings herein and information in the public domain, which compounds or components are suitable as pharmaceutically acceptable excipients.

[0038]

[0054] "Pharmacologically acceptable solvents" are (either alone or with other pharmaceutically acceptable solvents) This refers to a pharmaceutically acceptable excipient that is effective in solubilizing at least one pharmaceutically active agent (whether in combination with other excipients) into the overall composition.

[0039]

[0055] The phrases "at least one," "one or more," and "and / or" are used in practice. These are non-restrictive expressions that are both associative and separable. For example, the expressions "at least one of A, B, and C," "at least one of A, B, or C," "one or more of A, B, and C," and "A, B, and / or C" each mean A only, B only, C only, A and B together, A and C together, B and C together, or A, B, and C together.

[0040]

[0056] The term "a" or "an" refers to one or more of those entities. Therefore, the terms "a" (or "an"), "one or more", and The phrase "at least one" may be used interchangeably in this specification. It should be noted that the term "or" is generally used to mean "and / or" unless explicitly indicated otherwise in the context.

[0041]

[0057] The term "includes" means "includes indefinitely." Therefore, the list of ingredients... Compositions containing may contain additional components not explicitly listed. Note that the terms “contains,” “includes,” and “possess” may be used interchangeably.

[0042]

[0058] The term "consists of" means "the listed components and among the listed components, natural This means "or contains additional components that may be present as commercially available impurities or additives." Natural and commercially available impurities and additives will be obvious to those skilled in the art. Synthetic cannabidiol (CBD) may contain impurities up to about 0.5% w / w, such as residual solvents and by-products of the manufacturing process. Therefore, a composition "consisting of synthetic CBD" means a composition having at least about 99.5% w / w CBD and up to about 0.5% by weight of impurities.

[0043]

[0059] The term "basically derived from" means "the listed components and the basic and novel aspects of the present invention." "Contains any additional components that do not substantially affect the properties." "Basic and novel properties" means the usefulness of the composition in the treatment or prevention of cardiac conditions as expressed herein. In embodiments in which CBD is used, "basic and novel properties" also means the stability and solubility of CBD in the composition and the suitability of the composition for parenteral administration.

[0044]

[0060] Unless otherwise specified, the terms "percent by weight," "%w / w," and "by weight" are used. "Percent," "weight %," "wt.%," and variations thereof refer to the amount of a substance obtained by dividing its weight by the total weight of the composition containing that substance and multiplying by 100.

[0045]

[0061] Unless otherwise specified, the terms "volume percentage", "vol.%", and "by volume" are used. "Percent," "volume %," "%v / v," and variations thereof refer to the amount of a substance obtained by dividing its volume by the total volume of the composition containing that substance and multiplying by 100.

[0046]

[0062] The term "approximately" refers, for example, to the measurement and liquid handling used in the manufacture of pharmaceutical compositions. This refers to variations in the expressed quantity that may occur due to differences in the manufacture, source, or purity of the components used in the production of the composition and / or differences in equilibrium conditions or different reaction levels of the components in the composition resulting from the initial mixture. For clarity, the term "about" includes variations of up to ±5% of the expressed value. Whether or not the value is modified by the term "about," the claim includes equivalents of the value.

[0047]

[0063] As used herein, the term “effective amount” means the public amount of the components related to the present invention. Based on the purpose and function of the knowledge, an effective amount means the quantity that will produce the desired effect. For example, an effective amount of a pharmaceutically active agent is the quantity that would be effective in providing the therapeutic effect described herein. An effective amount of a solvent is the quantity that would be effective in solubilizing the other or remaining components of the composition, either alone or in combination with other components. What constitutes an effective amount will be determined by a person skilled in the art through standard experiments, taking into account the teachings herein.

[0048]

[0064] Where used herein, the expression “substantially Y-free” means that “Y” is not present. This means that while not intentionally included, water may be present as an impurity or due to other factors. For example, in the case of a substantially water-free parenteral composition, the composition may contain small amounts of water due to the atmosphere and water present in the composition or its components exposed to the atmosphere. For simplicity, a "substantially Y-free" composition means that it does not contain Y, or contains up to 0.5% w / w of "Y" relative to the composition.

[0049]

[0065] The values ​​listed herein include, but are not explicitly listed, those stated. This includes all values ​​that satisfy the specified parameter. For example, a value less than 1.0% w / w includes less than 0.99% w / w, less than 0.98 wt.%, less than 0.97 wt.%, less than 0.90% w / w, less than 0.84% ​​w / w, less than 0.56% w / w, less than 0.01% w / w, etc. Therefore, the entire range disclosed herein should be understood to encompass all sub-ranges contained within it. For example, the stated range "1 to 10" should be considered to include all sub-ranges from the minimum value 1 to the maximum value 10 (including both ends), such as 1 to 6.3, or 5.5 to 10, or 2.7 to 6.1, etc.

[0050]

[0066] This specification does not specify whether any component is included or excluded herein. Even if not explicitly listed, the possibility of omitting that component is considered.

[0051]

[0067] The chemical structures described herein are in accordance with the conventional standards known in the art. It is described. Therefore, if an atom such as a carbon atom that is described appears to have an unfilled valence, its valence is considered to be filled by a hydrogen atom, even if the hydrogen atom is not necessarily clearly described. Some structures of the compounds herein contain carbon atoms that give rise to stereoisomerism. That is, any chiral carbon center may be either (R)-stereochemistry or (S)-stereochemistry. Isomers resulting from such asymmetry (e.g., total enantiomers and diastereomers) are within the scope of this specification, as will be understood by those skilled in the art, insofar as such isomers are known to have pharmacokinetic activity. It should be understood that such isomers are included. These isomers can be obtained in substantially pure form by conventional separation techniques and stereochemically controlled synthesis. Furthermore, alkenes may, where appropriate, include either the E configuration or the Z configuration. The configuration in question will provide the desired pharmacokinetic activity.

[0052]

[0068] Cannabidiol (CBD)

[0069] This composition contains (at least) cannabidiol (CBD) in a pharmaceutically active form. It is contained as a pharmaceutical. The terms cannabidiol and CBD are used interchangeably in this specification and refer to compounds having the following chemical structure. [ka]

[0053]

[0070] CBD may be of natural or synthetic origin and may be in crystalline or oily form. All commercial sources of CBD are useful in connection with the present invention.

[0054]

[0071] Preferably, the CBD is at least 99.5%, 99.6%, 99.7%. It has a purity of 99.8% or 99.9%.

[0055]

[0072] "Synthetic cannabinoids" have a cannabinoid-like structure and are chemical or It is a compound produced using biosynthetic means. Methods for producing synthetic cannabidiol are known in the art. For example, CBD from NORAMCO, INC., headquartered in Wilmington, Delaware, USA, is produced according to processes such as those described in U.S. Patent Application Publication 2017 / 0008868A1 (granted as U.S. Patent No. 10,059,683) and U.S. Patent Application Publication 2018 / 031,976A1, which are incorporated herein by reference. Synthetic CBD produced by other processes and manufacturers may also be used to produce this composition if it has the desired purity.

[0056]

[0073] Plant-derived CBD can be derived from various cannabis plants, including hemp. It can be refined using conventional methods.

[0057]

[0074] Terms: tetrahydrocannabinol, THC, delta-9-tetrahydrocannabinol Navinol and delta-9-THC are used interchangeably herein and refer to chemical compounds having the structures shown below. The term is used more broadly herein to include double bond isomers and their stereoisomers. [ka]

[0058]

[0075] Those skilled in the art will know that commercial sources of CBD may contain trace amounts of impurities, including THC. It will be recognized that, for example, synthetic CBD may contain small amounts of residual solvents (e.g., methanol, n-heptane, dichloromethane, and triethylamine) as well as by-products of production, such as oliveitol, monobromo-CBD, and delta-9-THC. Plant-derived CBD may contain small amounts of other cannabinoids (including THC), terpenes, and solvents or components used in the purification process.

[0059]

[0076] In some embodiments, the composition is "substantially THC-free". However, this means that THC is either absent or present in any amount less than 0.5% w / w relative to the composition. In these embodiments, THC may be present in amounts less than 0.4, 0.3, 0.2, or 0.1% w / w relative to the composition. In the same or other embodiments, THC may be present in amounts less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 ppm relative to the composition.

[0060]

[0077] In some embodiments, the concentration of CBD in the composition is about 10, 20, The concentration may range from 30, 40, 50, 60, 70, 80, or 90 to approximately 350, 300, 250, 200, 150, or 100 mg / mL of composition.

[0061]

[0078] β-caryophyllene (BCP)

[0079] The compositions according to the present invention (optionally) include β-caryophyllene (BCP) and / or its derivatives may be included as additional active pharmaceutical ingredients. BCP is also called trans-(1R,9S)-8-methylene-4,11,11-trimethylbicyclo[7.2.0]undeca-4-ene or [1R-(1R,4E,9S)]-4,11,11-trimethyl-8-methylene-bicyclo[7.2.0]undeca-4-ene and its derivatives. BCP is naturally present in plant extracts of plants including Cannabis sativa. It is a natural bicyclic sesquiterpene compound. It is a component of many essential oils, especially clove (Syzygium aromaticum) oil, and is "generally safe." "Recognized as such" (GRAS).

[0062]

[0080] The anti-inflammatory activity of CBD is likely to be synergistically increased by the addition of BCP. It is predicted or expected that caryophyllene is the only terpene known to interact with the endogenous cannabinoid system (at the CB2 receptor). β-caryophyllene selectively binds to the CB2 receptor and is a functional CB2 agonist. Furthermore, β-caryophyllene has been identified as a functional non-psychoactive CB2 receptor ligand in food products and as a macrocyclic anti-inflammatory cannabinoid in cannabis (Proc Natl Acad Sci USA. 2008 Jul. 1; 105 (26): 9099-104. doi: 10.1073 / pnas.0803601105. Epub 2008 Jun. 23. β-caryophyllene is also a dietary cannabinoid).

[0063]

[0081] The weight ratios of BCP and its derivatives to CBD are approximately 1:10, 1:9, and 1:8. The ratios may be 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, or other ratios within these ranges. The concentration of BCP in the composition may range from about 10, 20, 30, 40, 50, 60, 70, 80 or 90 to about 350, 300, 250, 200, 150 or 100 mg / mL of composition. In one embodiment, the composition contains about 100 mg of CBD and 100 mg of BCP per 1 mL of composition.

[0064]

[0082] The commercial source of BCP includes products available from Sigma Aldrich, the product specifications of which are included in Appendix A (CAS No. 87-44-5). Such products contain impurities such as major and trace amounts of C15H24 terpenes at least 95% w / w and up to 5% w / w of manufacturing by-products. Therefore, Sigma Aldrich's BCP is, It has a purity of at least 95%. Other embodiments of the present invention may use BCP with higher purity, for example, other commercial sources of BCP with a purity of at least 96, 97, 98, 99, or 99.5%.

[0065]

[0083] The BCP and its derivatives used in this composition are of synthetic or natural origin. It is possible.

[0066]

[0084] As used herein, BCP "derivative" refers to C15H24 trace terpene It refers to hydrocarbons and contains trace amounts of terpenes present in Sigma-Aldrich products.

[0067]

[0085] Pharmacologically acceptable solvents

[0086] A pharmaceutically acceptable solvent is used to solubilize the active pharmaceutical product in this composition. These are used. Preferably, they must be suitable for parenteral administration via subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), and intravenous (IV) routes. For lipid-soluble drugs such as CBD and BCP, these solvents are hydrophobic or lipophilic.

[0068]

[0087] Examples of hydrophobic or lipophilic solvents include medium-chain (C6-C12) triglycerides. MCT (MCT), long-chain (C14-C20) triglycerides, structural lipids, di(caprylic / capric acid) propylene glycol, vegetable oil, N-methyl-2-pyrrolidone (NMP; Pharmasolve), polyoxyethylene castor oil derivative, dimethylacetamide (DMA), ethanol Solvents sold in association with Kolliphor®, glycerin, PEG300, PEG400, polyoxyethylene 20-sorbitan monooleate, propylene glycol (PG), polyglycol mono- and diesters of 12-hydroxystearic acid There are natural and synthetic solvents containing media and mixtures thereof.

[0069]

[0088] "Medium-chain triglycerides" have three C6-C12 fatty acid chains and three lipids This refers to glycerol esters whose fatty acid chains are the same or may be different. Medium-chain triglycerides are represented by the following formula: [ka]

[0070]

[0089] In the formula, each x is independently 4, 6, 8, or 10. When x is 4, the chain This is called a C6 fatty acid. When x is 6, the chain is called a C8 fatty acid. When x is 8, the chain is called a C10 fatty acid. When x is 10, the chain is called a C12 fatty acid. In various embodiments, within one molecule of triglyceride, each x is the same integer; two x are the same integer and one x is a different integer; or each x is a different integer.

[0071]

[0090] Preferably, the composition contains medium-chain triglycerides (MCTs), and more preferably... Or, it includes those in which C8 and C10 fatty acids constitute at least 95% of the composition. Medium-chain triglycerides may be synthetic or natural (e.g., produced from fractionated oils such as coconut oil and / or palm kernel oil).

[0072]

[0091] In various embodiments, medium-chain triglycerides are (i) three C8 fatty acids (ii) three C10 fatty acids; (iii) two C8 fatty acids and one C10 fatty acid; (iv) two C10 fatty acids and one C8 fatty acid; (v) two C8 fatty acids and one C6 fatty acid; (vi) two C10 fatty acids and one C6 fatty acid; (vii) one C8 fatty acid, one C10 fatty acid and one C6 fatty acid; or (viii) esters of any other combination of C6, C8, C10 and C12 fatty acids. In one embodiment, the medium-chain triglyceride comprises two C8 fatty acids and one C10 fatty acid. In one embodiment, the medium-chain triglyceride comprises two C10 fatty acids and one C8 fatty acid.

[0073]

[0092] Those skilled in the art will know that a mixture of medium-chain triglycerides can be used to prepare medium-chain triglycerides. It will be recognized that these can result from any process used (e.g., fractionation, hydrogenation). For example, substantially all medium-chain triglycerides obtained from fractionated coconut oil may contain C8 and / or C10 fatty acids. However, some medium-chain triglycerides may contain C6 and / or C12 fatty acids.

[0074]

[0093] In one embodiment, the medium-chain triglyceride is (i) 0-2% w / w C6 (ii) C6 fatty acids, 65-80% w / w C8 fatty acids, 20-35% w / w C10 fatty acids and 0-2% w / w C12 fatty acids; (ii) 0-2% w / w C6 fatty acids, 50-65% w / w C8 fatty acids, 30-45% w / w C10 fatty acids and 0-2% w / w C12 fatty acids; (iii) 0-2% w / w C6 fatty acids, 45-65% w / (iv) an ester of 0-2% w / w C6 fatty acid, 45-55% w / w C8 fatty acid, 0-3% w / w C12 fatty acid, and 0-5% w / w linoleic acid; or (iv) an ester of 0-2% w / w C6 fatty acid, 45-55% w / w C8 fatty acid, 30-40% w / w C10 fatty acid, 0-3% w / w C12 fatty acid, and 10-20% w / w succinic acid. In one embodiment, the medium-chain triglyceride contains 0-2% w / w C6 fatty acid, 50-65% w / w C8 fatty acid, 30-45% w / w C10 fatty acid, and 0-2% w / w C12 fatty acid, and is marketed as MIGLYOL® 812 (IOI Oleo GmbH, Herrengraben 31, 20459 Hamburg, Germany). The weight percentage is based on the total fatty acid content of the triglycerides. In one embodiment, the medium-chain triglycerides may contain up to 2% w / w of C14 fatty acids.

[0075]

[0094] The carrier may contain one, two, three, or four or more different medium-chain triglycerides. In one embodiment, the carrier comprises a medium-chain triglyceride containing an ester of two C8 fatty acids and one C10 fatty acid. In one embodiment, the carrier comprises a medium-chain triglyceride containing an ester of one C8 fatty acid and two C10 fatty acids. In one embodiment, the carrier comprises two different medium-chain triglycerides, the first medium-chain triglyceride containing an ester of two C8 fatty acids and one C10 fatty acid, and the second medium-chain triglyceride containing an ester of one C8 fatty acid and two C10 fatty acids. In one embodiment, the carrier comprises a medium-chain It contains medium-chain triglycerides, based on the total fatty acid content of triglycerides, including 0-2% w / w C6 fatty acids, 50-65% w / w C8 fatty acids, 30-45% w / w C10 fatty acids, and 0-2% w / w C12 fatty acids.

[0076]

[0095] Triglycerides can be prepared by methods known in the art and are commercially available as MIGLYOL® 810, 812, 818, 829 (IOI Oleo GmbH, Herrengraben 31, 20459 Hamburg, Germany), NEOBEE® 1053, 895, M-5 (Stepan Company, Northfield, IL), and Labrafac (Gattefosse). Vigon International, Inc. has developed C8 and We also sell MCT containing a mixture of C8 and C10 triglycerides in a ratio of approximately 55:45 to 65:35.

[0077]

[0096] In another embodiment, the pharmaceutically acceptable solvent is the chain length of C8 and C10. This is a propylene glycol diester of saturated vegetable fatty acids containing (caprylic acid and capric acid). An example of such a commercially available carrier is MIGLYOL® 840 (IOI Oleo GmbH, Herrengraben 31, 20459 Hamburg, Germany.

[0078]

[0097] Other pharmaceutically acceptable solvents include, but are not limited to, those marketed in association with trademark Solutol HS 15, Kolliphors® (formerly Cremophors®), Labrasol, Labrafil, and Gelucire.

[0079]

[0098] Solutol HS 15 is composed of a mixture of lipophilic and hydrophilic compounds (approximately 70% lipophilic consists of polyglycol mono- and diesters of 12-hydroxystearic acid, and approximately 30% hydrophilic consists of polyethylene glycol). Solutol HS 15 is produced by reacting 12-hydroxystearic acid with 15 moles of ethylene oxide. It is synthesized by [this].

[0080]

[0099] Kolliphors (trademark) (formerly Cremophors (trademark)) is also used in solvents. This can be achieved. These are complex mixtures of various hydrophobic and hydrophilic components. Kolliphor® EL is produced by reacting 35 moles of ethylene oxide with 1 mole of castor oil. It is obtained by reacting 40 moles of ethylene oxide with 1 mole of hydrogenated castor oil, and

[0081] [000100] Labrasol is a mixture of mono-, di-, and triglycerides and mono- and di- fatty acid esters of PEG400. Labrasol is synthesized by alcohol decomposition / esterification reaction using medium-chain triglycerides derived from coconut oil and PEG400, with caprylic / capric acid as the main fatty acid.

[0082] [000101] Labrafil M-1944 CS is a mixture of mono-, di-, and triglycerides and mono- and di- fatty acid esters of PEG300. Labrafil M-1944 CS is synthesized by an alcoholic hydrolysis / esterification reaction using apricot kernel oil and PEG300, with oleic acid (58-80%) being the main fatty acid.

[0083] [000102] Labrafil M-2125 CS is a mixture of mono-, di-, and triglycerides and mono- and di- fatty acid esters of PEG300. Labrafil M-2125 CS is synthesized by an alcoholic hydrolysis / esterification reaction using corn oil and PEG300, with linoleic acid (50-65%) being the main fatty acid.

[0084] [000103] Gelucire 44 / 14 is a mixture of mono-, di-, and triglycerides and mono- and di- fatty acid esters of PEG1500. Gelucire 44 / 14 is synthesized by alcohol decomposition / esterification reaction using palm kernel oil and PEG1500, with lauric acid as the main fatty acid.

[0085] [000104] Those skilled in the art will understand how to formulate compositions for SC, IM and IV administration based on published literature such as Strickley, “Solubilizing Excipients in Oral and Injectable Formulations” (Pharmaceutical Research, Vol. 21, No. 2, February 2004 (Copyright 2004)), which is incorporated herein by reference in whole. Components such as preservatives, emulsifiers, isotonic agents, salts, buffers, and diluents may also be used.

[0086] [000105] In a preferred embodiment, the composition comprises an effective amount of CBD dissolved in MCT or an effective amount of CBD and BCP respectively, and is substantially free of water and micelles.

[0087] [000106] Method of administration [000107] This composition is intended for parenteral administration, for example, by intravenous (IV), subcutaneous (SC), intraperitoneal (IP) and intramuscular (IM) injection. The following examples demonstrate that this composition may be useful in reducing leukocyte-mediated inflammation, cardiac fibrosis and / or cardiac hypertrophy.

[0088] [000108] The composition may be administered at least once a week or at least once every 6, 5, 4, 3, or 2 days. The composition may also be administered at least once a day or at least twice a day. Each dose contains at least about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 mg of the pharmaceutically active agent per kg of body weight. The duration of treatment may be 6, 5, 4, 3, or 2 months or 8, 7, 6, 5, or 4 weeks. In the case of chronic conditions (e.g., heart failure), it is conceivable that very low doses may be administered indefinitely, with the dosage selected to avoid long-term toxicity. In one embodiment, 1 mg / kg body weight may be administered indefinitely at least once a week or at least once every 1, 2, 3, 4, or 5 days. [Examples]

[0089] [000109] Example [000110] Example 1 - CBD reduces angiotensin II-mediated hypertrophy in H9c2 cells in vitro. [000111] In vitro, a study was conducted using the cardiomyocyte cell line H9c2 to measure the effects of CBD in a model of cardiomyocyte hypertrophy. In this study, H9c2 cells grown in culture medium were divided into four groups. Group 1 was untreated ("control"). Groups 2, 3, and 4 were treated with angiotensin II added to the culture medium ("Ang") to a final concentration of 1.0 μM. Hypertrophy was induced by adding angiotensin II. Group 3 was treated with CBD to a concentration of 0.1 μM ("Ang + CBD 0.1 μM"). Finally, Group 4 was treated with CBD to a concentration of 1 μM ("Ang + CBD 1 μM").

[0090] [000112] Figure 1 shows representative confocal microscopy images of H9c2 cells from each group. Images were obtained using a model with the same parameters, and cell staining to measure the surface area per cell was achieved using calcein fluorescent dye. As can be seen in this figure, the cells of group 2 had a significantly larger cell surface area than the cells of group 1. The cells of groups 3 and 4 had a significantly smaller cell surface area than those of group 2. The results are summarized in Figure 2, where each group contains at least three independent replicates.

[0091] [000113] Thus, the study demonstrated that CBD exerts an effect on cardiac cells and is effective in reducing the degree of hypertrophy caused by angiotensin II administration to H9c2 cells in vitro.

[0092] [000114] The experiment was repeated using H9c2 cells grown in culture medium divided into seven groups. One group received no treatment ("CTRL"). Angiotensin II was added to the culture medium of groups 2, 4, 5, 6, and 7 ("ANG") to a final concentration of 1.0 μM. Angiotensin II was added to induce hypertrophy. CBD was added to group 3 to a concentration of 0.1 μM as an additional control group ("CBD0.1μM"). CBD was added to the following groups: (a) to the fourth group ("ANG+CBD0.001μM") to achieve a concentration of 0.001μM, (b) to the fifth group ("ANG+CBD0.01μM") to achieve a concentration of 0.01μM, (c) to the sixth group ("ANG+CBD0.1μM") to achieve a concentration of 0.1μM, and finally (d) to the seventh group ("ANG+CBD1μM") to achieve a concentration of 1μM.

[0093] [000115] In these H9c2 cell populations, dose-dependent reductions were observed in mRNA levels of BNP (cardiac remodeling biomarker) (see Figure 3a) and collagen (see Figure 3b). BNP was significantly reduced in the ANG + CBD 1 μM group compared to the ANG group (Figure 3a), and collagen was significantly reduced in the angiotensin-treated CBD groups at concentrations of 0.1 and 1 μM compared to the ANG group (Figure 3b). Mitochondrial reactive oxygen species (ROS), markers of inflammation, were also reduced to control levels (see Figure 4).

[0094] [000116] These experiments demonstrate that CBD exerts an anti-hypertrophic effect on cardiac cells, which is reflected at the molecular level by significantly reducing mitochondrial ROS, a remodeling biomarker and mediator of inflammation.

[0095] [000117] Example 2 - CBD reduces fibrosis, myocyte area, remodeling parameters and inflammatory cytokines and increases anti-inflammatory cytokines in a mouse model of cardiac inflammation and heart failure. [000118] A study was conducted to evaluate the ability of CBD to treat or prevent heart failure in a mouse model of non-ischemic heart failure (HF) shown in Figure 5.

[0096] [000119] Male C57BL / 6 laboratory mice aged 3-4 weeks were used in the experiment. The mice were divided into four groups. Group 1 (control) received nothing. Group 2 (angiotensin) mice were given water containing 0.1 mg / ml of N(γ)-nitro-L-arginine methyl ester (L_NAME) and 1% sodium chloride (NaCl) as needed for one week. Subsequently, 0.7 mg / kg / week of angiotensin II was administered subcutaneously using an osmotic pump for four weeks. Groups 3 and 4 were subjected to the same protocol as group 2, but Group 3 (ANG + CBD 1 mg / kg) and Group 4 (ANG + CBD 10 mg / kg) received synthetic CBD in amounts of 1 mg / kg and 10 mg / kg, respectively, subcutaneously once every three days for the same four-week period. The CBD composition used in this experiment consisted of CBD dissolved in PEG400.

[0097] [000120] After 4 weeks of treatment, cardiac tissue was evaluated for fibrosis, myocyte hypertrophy, remodeling, and changes in inflammatory biomarkers.

[0098] [000121] Several changes, including increased fibrosis and increased myocyte area (hypertrophy), were observed in the hearts of mice from groups 2, 3, and 4 compared to group 1. Figures 6A, 6B, 6C, and 6D show representative slides of cardiac tissue taken from each of the four groups. Cardiac tissue was stained with Masson's trichrome, and the mice from groups 2, 3, and 4 were stained compared to group 1 (control). The study showed an increased level of fibrotic tissue in the second group (evidence of which is blue staining), and a decrease in the level of fibrosis in the third and fourth groups of mice compared to the second group. This information is represented graphically in Figure 7. Myocyte area was also measured in all four groups, and the results are shown in Figure 8. Figures 7 and 8 show that both 1 mg / kg and 10 mg / kg of CBD were effective in reducing cardiac fibrosis and myocyte area in a mouse model of heart failure. Each group contained at least three independent replicates.

[0099] [000122] Figure 9 shows the levels of mRNA expression of type B natriuretic peptide (BNP) in the cardiac tissue of all four mouse groups, as measured by qPCR. Both the 1 mg / kg CBD group and the 10 mg / kg CBD group showed a significant reduction in BNP expression in the heart compared to the ANG group. Each group contained at least three independent replicates. BNP is a remodeling marker and a clinical marker of myocardial stretching (pressure overload), and it is positively correlated with cardiac dysfunction and heart failure (see, e.g., Glezeva et al.). There is clinical evidence that reducing BNP levels to less than 100 pg / mL in patients with chronic heart failure (CHF) reduces the risk of CHF-related death or hospitalization (Jourdain et al., 2007: https: / / www.ncbi.nlm.nih.gov / pubmed / ?term=17448376). Therefore, this reduction in BNP may also indicate that CBD may be beneficial in the treatment and / or prevention of heart failure.

[0100] [000123] Furthermore, mRNA expression of the inflammatory cytokine IL1β tended to decrease to control levels (Figure 10a), and mRNA expression of the inflammatory cytokine IL6 was significantly reduced at both 1 mg / kg body weight doses of CBD (Figure 10b). mRNA expression of IL10 was significantly increased at a dose of 1 mg / kg body weight of CBD (Figure 10c). Each group contained at least three independent replicates. IL10 is an anti-inflammatory cytokine and is also known as a human cytokine inhibitor capable of inhibiting the synthesis of inflammatory cytokines. There is evidence suggesting that IL-10 plays a role in vascular protection; in animal models, IL-10 deficiency has been shown to cause COX-2 / thromboxane A2-dependent vascular endothelial and cardiac dysfunction (Gautam Sikka et al., 'Interleukin 10 Knockout Frail Mice Develop Cardiac and Vascular Dysfunction with Increased Age', Experimental Gerontology 48, no. 2 (February 2013): 128, https: / / doi.org / 10.1016 / j.exger.2012.11.001).

[0101] [000124] In summary, the inventors observed dose-dependent reductions in remodeling and inflammatory parameters resulting from CBD administration in a mouse model of non-ischemic HF. Regarding remodeling, significant reductions in fibrosis, myocyte hypertrophy, and BNP gene expression were observed. Inflammatory parameters improved, namely CBD administration reduced the levels of inflammatory cytokines IL1 and IL6 and significantly increased the level of the anti-inflammatory cytokine IL10. These findings support the beneficial role of CBD in the treatment or prevention of heart failure and other conditions such as the development or progression of coronary artery disease lesions, acute myocarditis, inflammatory cardiomyopathy, cardiac sarcoidosis, acute pericarditis, myocardial damage resulting from the administration of certain anticancer drugs, and in some cases coronary artery disease lesions, by reducing cardiac inflammation and associated hypertrophy and fibrosis.

[0102] [000125] Example 3 - CBD reduces the activation of human lymphocytes and monocytes. [000126] Further tests were conducted to measure the effect of CBD on the expression of CD69 (a marker of leukocyte activation) in human lymphocytes and monocytes activated in vitro by ionomycin (1 μg / mL) and phorbol myristate acetate (PMA, 50 ng / mL).

[0103] [000127] Mononuclear cells derived from healthy human donors are obtained by Ficoll-Pacque HE Healthcare Cells were isolated using the gradient method. They were washed with RPMI medium containing 10% FCS and 1% penicillin / streptomycin, and then placed in 1 × 10⁶ well trays. 6 cells / mL The cells were placed and stimulated with 1 μg / ml ionomycin and 50 ng / ml PMA for 4 hours. CBD was added 15 minutes before using DMSO as the vehicle. After stimulation, the cells were washed again and resuspended in 150 μL of staining buffer (PBS + 1% BSA). An optimized protocol for surface marker staining was used. CD69 was added to the cells, and then incubated in the dark at room temperature for 15 minutes. After this, the cells were washed twice with PBS + 1% BSA and resuspended in 150 μL of buffer. The cells were kept at 4°C before being placed in the FACSCanto® II site. Cells were analyzed using a meter. Cell populations were measured using FSC / SSC. The number of events was at least 2000 per gate. Data were saved as FCS3.0 files. Data were analyzed using FlowJo X. Doublets were distinguished by the FSC-A / FSC-W exclusion gate. Lymphocyte and monocyte gating was determined using FSC-A / SSC-A. The frequency and expression of CD69-FITC were analyzed using its FITC channel.

[0104] [000128] Figure 11 shows that administration of CBD at doses of 5 μg / mL or higher (per 1 mL of cell culture medium containing RPMI with 10% fetal bovine serum and 1% penicillin / streptomycin) reduced the level of CD69 expression by both monocytes and lymphocytes. Thus, this experiment shows that CBD can reduce leukocyte activation in vitro and may be expected to reduce inflammation, one of the underlying pathologies of heart failure.

[0105] [000129] Industrial applicability [000130] Experiments described herein demonstrate that CBD is useful in treating or preventing cardiac conditions selected from the group consisting of heart failure (e.g., HFpEF), acute myocarditis, toxicity caused by anticancer therapy (e.g., doxorbin, checkpoint inhibitors), acute pericarditis, cardiac sarcoidosis, inflammatory cardiomyopathy, and atherosclerosis, by reducing cardiac inflammation and associated hypertrophy and fibrosis.

[0106] [000131] Acute inflammation is the body's immune system's defense response to danger signals, including infected and damaged cells, in order to eliminate infection and repair damaged tissue. Inflammation leads to increased blood flow and vascular permeability so that immune cells can approach the site of infection or injury. After tissue repair and the removal of danger signals, it is essential to switch off the initial inflammatory and repair responses. This is usually the result of accumulated inflammatory cells undergoing apoptosis (programmed cell death) and being taken up by macrophages through efferocytosis, a process that induces an anti-inflammatory response and stops inflammation. If this switch cannot be turned off, chronic inflammation persists, which is seen in many diseases, including heart failure.

[0107] [000132] As mentioned above, factors that make people more susceptible to heart failure include aging, diabetes, and obesity. These conditions are associated with increased low-level background inflammation. While not bound by theory, chronic inflammation is thought to arise, in particular, from malfunctions in the efferocytosis of apoptotic cells, leading to increased cell death of cardiomyocytes (cardiac muscle cells), increased fibrosis (accumulation of scar tissue), and a decline in cardiac function due to the weakening and hardening of the myocardium resulting from these mechanisms.

[0108] [000133] Acute myocarditis is the leading cause of sudden cardiac death in people under 35 years of age. It is characterized by inflammation within the heart muscle (myocardium). There are many causes of it, but the most common is viral infection. In most patients, the immune system is effective in clearing the virus within 5-7 days, the inflammation subsides, and the individual makes a full recovery. However, in some patients, the inflammation within the heart persists—perhaps as an autoimmune process—leading to a decline in cardiac function along with symptoms and signs of heart failure. In some cases, this can become progressive and lead to chronic dilated cardiomyopathy, which is the most common reason for heart transplantation.

[0109] [000134] The embodiments described above are merely illustrative and will be described in detail herein, as follows This does not limit the scope of the present invention as defined by the claims.

[0110] [Table 1]

Claims

1. The use of an effective dose of CBD for the treatment or prevention of cardiac conditions selected from the group consisting of heart failure, acute myocarditis, toxicity caused by anticancer therapy, acute pericarditis, cardiac sarcoidosis, inflammatory cardiomyopathy, and atherosclerosis, wherein the CBD is used in the subject, (a) Does it reduce cardiac hypertrophy? (b) Does it reduce cardiac fibrosis? (c) Reduce the level of BNP; (d) Reduce the level of the cytokine IL1β; (e) Reduce the level of cytokine IL-6; (f) Reduce the level of CD69; (g) Increase the level of cytokine IL-10; or (h) results in any of the above combinations Effective for use.

2. The use according to claim 1, wherein at least two of (a) to (g) are met.

3. The use according to claim 2, wherein at least three of (a) to (g) are met.

4. The use according to claim 3, wherein at least four of (a) to (g) are met.

5. The use according to claim 4, wherein at least five of (a) to (g) apply.

6. The use according to claim 5, wherein at least six of (a) to (g) apply.

7. The use described in claim 6, wherein all of (a) to (g) apply.

8. The use according to any one of claims 1 to 7, wherein the CBD is present in a parenteral composition, and the parenteral composition further comprises an effective amount of at least one solvent for solubilizing the CBD in the composition.

9. The use according to claim 8, wherein the parenteral composition is adapted for subcutaneous or intramuscular administration.

10. The use of the composition according to claim 8 or 9, wherein the composition does not contain micelles.

11. The use according to any one of claims 8 to 10, wherein the composition is substantially water-free.

12. The use according to any one of claims 8 to 11, wherein the composition further comprises an effective amount of at least one additional pharmaceutically active agent.

13. The use according to claim 12, wherein the at least one additional pharmaceutically active agent is β-caryophyllene.

14. The use according to any one of claims 8 to 13, wherein the solvent is selected from the group consisting of natural and synthetic medium-chain (C6-C12) triglycerides (MCTs).

15. The use according to claim 14, wherein at least about 95% of the MCT consists of C8 triglycerides, C10 triglycerides, or a mixture thereof.

16. The use according to any one of claims 8 to 15, wherein the CBD is present in an amount up to approximately 350 mg / mL of the composition.

17. The use according to any one of claims 8 to 16, wherein the CBD is present in an amount of about 10 mg / mL of the composition.

18. The use according to any one of claims 1 to 17, wherein the heart failure is heart failure with preserved ejection fraction (HFpEF).

19. The use according to any one of claims 1 to 18, wherein the myocarditis is acute myocarditis.

20. A method for treating or preventing at least one cardiac condition selected from the group consisting of heart failure, acute myocarditis, toxicity caused by anticancer therapy, acute pericarditis, cardiac sarcoidosis, inflammatory cardiomyopathy, and atherosclerosis, (a) Identifying subjects who have or are at risk of having the aforementioned cardiac condition; and (b) Administer an effective amount of CBD to the subject. The administration of CBD includes, in the subject, (a) Does it reduce cardiac hypertrophy? (b) Does it reduce cardiac fibrosis? (c) Reduce the level of BNP; (d) Reduce the level of the cytokine IL1β; (e) Reduce the level of cytokine IL-6; (f) Reduce the level of CD69; (g) Increase the level of cytokine IL-10; or (h) A method that results in any of the above combinations.

21. The method according to claim 20, wherein the administration of CBD results in at least two of (a) to (g).

22. The method according to claim 21, wherein the administration of CBD results in at least three of (a) to (g).

23. The method according to claim 22, wherein the administration of CBD results in at least four of (a) to (g).

24. The method according to claim 23, wherein the administration of CBD results in at least five of (a) to (g).

25. The method according to claim 24, wherein the administration of CBD results in at least six of (a) to (g).

26. The method according to claim 25, wherein the administration of CBD results in all of (a) to (g).

27. The method according to claim 26, wherein the heart failure is heart failure with preserved ejection fraction (HFpEF).

28. The method according to any one of claims 20 to 27, wherein the myocarditis is acute myocarditis.

29. The method according to any one of claims 20 to 28, wherein the CBD is administered parenterally.

30. The method according to any one of claims 20 to 29, wherein the CBD is present in the parenteral composition according to any one of claims 8 to 17.

31. The method according to any one of claims 20 to 30, wherein the CBD is administered at least once a week.

32. The method according to claim 31, wherein the CBD is administered two or three times a week.

33. The method according to claim 32, wherein the CBD is administered at least once a day.

34. The method according to claim 33, wherein the CBD is administered at least twice a day.

35. The method according to any one of claims 20 to 34, wherein each administration consists of administering approximately 1 mg to approximately 20 mg of CBD per kg of body weight.

36. Parenteral composition according to any one of claims 8 to 17.

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