Azelaic acid esters in the treatment or prevention of dyslipidemia and related diseases

Abstract

A pharmaceutical composition comprising C1-C4 alkyl ester azelates, e.g., diethyl azelate (DBA), dimethyl azelate (DMA), di-isopropyl azelate (DiPA), di-isobutyl azelate (DiBuA), and di-2-pentyl azelate (D2PA), and in particular, a method for improving abnormal lipid levels and treating or preventing diseases of dyslipidemia and / or related conditions, comprising administering such pharmaceutical composition to a subject.

Description

Technology Field

[0001] Related applications

[0002]

[0001] This patent application claims priority to U.S. Provisional Patent Application No. 62 / 978,785, filed February 19, 2020, titled “AZELAIC ACID ESTERS IN THE TREATMENT OR PREVENTION OF DYSLIPIDEMIA AND ASSOCIATED CONDITIONS” (inventors Robert T. STREEPER and Elzbieta IZBICKA). The entire contents of said patent application are incorporated herein by reference. Background Technology

[0003]

[0002] In particular, pharmaceutical compositions and methods are provided for improving abnormal lipid levels and treating or preventing diseases of dyslipidemia and / or related conditions, including diseases of lipid signaling, which include administering such pharmaceutical compositions to a subject. Such pharmaceutical compositions include C1-C4 alkyl ester azelates, for example, diethyl azelate (DEA), dimethyl azelate (DMA), di-isopropyl azelate (DiPA), di-isobutyl azelate (DiBuA), or di-2-pentyl azelate (D2PA).

[0004]

[0003] Dyslipidemia is a disorder of lipoprotein metabolism, lipid transport and elimination, and / or excess or insufficient consumption. This disorder may manifest as abnormal or abnormal blood total cholesterol levels or concentrations, low-density lipoprotein (LDL) levels or concentrations, triglyceride levels or concentrations, and / or high-density lipoprotein (HDL) levels or concentrations. While the above terms describe a broad range of conditions, the most common forms of dyslipidemia include one or more of the following: elevated levels of low-density lipoprotein (LDL), or "bad cholesterol"; low levels of high-density lipoprotein (HDL), or "good cholesterol"; elevated levels of triglycerides; high cholesterol, referring to high LDL and triglyceride levels; an elevated LDL-to-HDL (LDL / HDL) ratio, and / or an elevated non-cholesterol HDL-to-HDL (non-cholesterol HDL / HDL) ratio.

[0005]

[0004] Dyslipidemia, such as hypertriglyceridemia, hyperlipidemia, and hypercholesterolemia, has also been shown to be associated with and / or cause pancreatitis, hepatomegaly, hypertension, overweight, and obesity. Numerous studies have also documented a causal relationship between elevated or abnormal serum cholesterol levels and cardiovascular diseases, e.g., atherosclerosis, arteriosclerosis, coronary heart disease, stroke, ischemic heart disease, and other comorbidities. A strong association between dyslipidemia and insulin resistance has also been observed, and both are major components of metabolic syndrome, a set of metabolic factors including impaired fasting glucose or type II diabetes, which increase the risk of core obesity, dyslipidemia, hypertension, and, in turn, other metabolic disorders including cardiovascular disease, fatty liver disease, non-alcoholic steatohepatitis (NASH), and alcoholic steatohepatitis (ASH).

[0006]

[0005] Western diets combined with a sedentary lifestyle have been shown to cause chronic metabolic inflammation (8, 9), insulin resistance, and obesity. A diet consisting of about 50% carbohydrates with high levels of fructose has been shown to induce insulin resistance in healthy, non-obese men within 2 to 7 days (10). The harmful health effects of dietary fructose are similar to those of ethanol (11). The diabetic effects of acute (12) or chronic (13) ethanol consumption are strongly correlated with the development of insulin resistance in a dose-dependent manner (14, 15).

[0007]

[0006] Despite the high prevalence and concordance of dyslipidemia in the context of insulin resistance, prediabetes, type II diabetes, metabolic syndrome, and other comorbidities associated with metabolic syndrome, therapies and regimens designed to reduce insulin resistance and / or treat prediabetes or type II diabetes often do not satisfactorily address concomitant abnormal lipid levels or / or treat any other comorbidities associated with abnormal lipid levels, such as concomitant dyslipidemia or cardiovascular diseases, e.g., atherosclerosis, arteriosclerosis, coronary heart disease, stroke, ischemic heart disease. Similarly, subjects with overweight or obesity often experience abnormal lipid levels and / or dyslipidemia with or without insulin resistance, prediabetes, and / or type II diabetes, yet they are nevertheless at risk of having or acquiring many of these comorbid metabolic and cardiovascular diseases or conditions. Therefore, lipid-lowering and / or lipid-improving therapies and treatments are desirable in these overweight or obese subjects, either independently of or in lieu of any treatment for insulin resistance, prediabetes, or type II diabetes.

[0008]

[0007] Current clinical treatment of dyslipidemia reflects the results of numerous basic science studies on lipids, lipid metabolism, and the effects of different lipids on the cellular components of arteries, inflammatory cells, and platelets. In general, low-density lipids activate intracellular pathways to increase local and systemic inflammation, monocyte adhesion, endothelial dysfunction and apoptosis, and smooth muscle cell proliferation, leading to foam cell formation. Therefore, dyslipidemia can be viewed in certain respects not only as an inflammatory disorder but also as a disorder that is associated with or can exacerbate inflammatory diseases.

[0009]

[0008] Various strategies are currently used for the management of dyslipidemia, both independently and in the context of other related diseases or conditions such as insulin resistance and type II diabetes. Regarding the treatment of dyslipidemia, strategies include dietary changes aimed at reducing the consumption of foods high in cholesterol and fat, as well as the prescription of one or more drugs aimed at improving elevated cholesterol, LDL, and / or triglyceride levels. These drugs include statins such as atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, and rosuvastatin; fibrates such as clofibrate, gemfibrozil, and fenofibrate; niacin; and leptin or leptin agonists including metreleptin.

[0010]

[0009] Similar to strategies for treating dyslipidemia, insulin resistance and type II diabetes are often managed by first taking dietary changes aimed at increasing physical activity and reducing calorie (primarily carbohydrate) intake. If these measures do not sufficiently lower blood glucose and / or A1c levels, medications designed to affect blood glucose and / or A1c levels are typically used. Various formulations of insulin, the most commonly used medication, are used to lower blood glucose. The biguanide drug metformin may also be prescribed, which inhibits glucose production and release by the liver. By blocking the glucose supply, metformin increases insulin sensitivity. Other therapies include insulin sensitizers, such as thiazolidinediones including pioglitazone and rosiglutozone; and glucagon-like peptide-1 (GLP-1) agonists, such as exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and semaglutide; This includes the administration of amylin agonists, e.g., pramlintide; leptin or leptin agonists, e.g., metreleptin; sodium-glucose co-transporter 2 (SGLT2) inhibitors, e.g., canagliflozin, dapagliflozin, empagliflozin, and ertuglifozin.

[0011]

[0010] Azelates, such as C1-C4 alkyl ester azelates including diethyl azelate (DEA), are naturally occurring metabolic products in humans and other mammals [17, 18]. Azelates are also present in grain-derived products, including grains and alcoholic beverages

[19] , and in fermented foods due to the bacterial breakdown of acylglycerol fatty acids and the esterification of the resulting medium-chain fatty acids

[20] . The fermentation of olives by Lactobacilli to make them edible has been practiced in the Mediterranean basin for at least 6,000 years

[21] . Lactobacilli break down the bitter alkaloids contained in olive fruit, converting them into edible olives

[22] . Additionally, Lactobacilli ferment some of the oleic acid contained in olives into azelaic acid and azelates. Olive skins also contain a significant amount of azelaic acid. Fermented soybean products, which have been produced by humans for over 3,000 years

[23] , can help prevent or mitigate the progression of T2D

[24] . Azelaic acid and azelate ethyl esters are also present in douchi, a fermented black bean product

[25] .

[0012]

[0011] Although not currently used as drugs, azelates and similar fatty acid esters are used as food additives, lubricants, and plasticizers. DEA is approved as a flavor additive in the European Union [26, 27], and diethylhexyl azelate is approved in the United States for food contact packaging. Diethyl sebacate, a closely related ester that differs from DEA in that sebacate is one methylene unit longer than azelaic acid, is on the U.S. Food and Drug Administration (FDA) list of generally recognized as safe (GRAS) compounds

[28] and the list of inactive ingredients

[29] .

[0013]

[0012] A method for improving one or more abnormal lipid levels in a subject is provided, comprising administering to a subject an effective amount of a C1-C4 alkyl ester azelate to improve one or more abnormal lipid levels, in some embodiments which may be combined with one or more other embodiments or embodiments. In some embodiments, the method comprises administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate selected from the group consisting of diethyl azelate (DEA); dimethyl azelate (DMA), di-isopropyl azelate (DiPA), di-isobutyl azelate (DiBuA), and di-2-pentyl azelate (D2PA). In some embodiments, the method comprises administering a pharmaceutical composition comprising DEA.

[0014]

[0013] In some embodiments that may be combined with one or more other aspects or embodiments, a method is provided for lowering elevated LDL levels in a subject, raising reduced HDL levels, lowering elevated triglyceride levels, lowering elevated cholesterol / HDL, lowering elevated LDL / HDL, lowering elevated LDL / triglyceride, or lowering elevated non-cholesterol HDL / HDL, said method comprising administering to a subject a pharmaceutical composition comprising an effective amount of a C1-C4 alkyl ester azelate. In some embodiments, said method comprises administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, said method comprises administering a pharmaceutical composition comprising DEA.

[0015]

[0014] A method for treating or preventing dyslipidemia or a disease or condition associated with dyslipidemia in a subject is provided, comprising administering to a subject a pharmaceutical composition containing a C1-C4 alkyl ester azelate in an amount effective for treating or preventing dyslipidemia or a disease or condition associated with dyslipidemia in a subject, in some embodiments which may be combined with one or more other embodiments or embodiments. In some embodiments, dyslipidemia comprises at least one of elevated LDL levels, decreased HDL levels, elevated triglyceride levels, elevated cholesterol / HDL, elevated LDL / HDL, elevated LDL / triglyceride, and elevated non-cholesterol HDL / HDL. In some embodiments, the method comprises administering a pharmaceutical composition containing a C1-C4 alkyl ester azelate selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, the method comprises administering a pharmaceutical composition containing DEA.

[0016]

[0015] In some embodiments which may be combined with one or more other embodiments or examples, a method for treating or preventing dyslipidemia or a disease or condition associated with dyslipidemia in a subject is provided, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a C1-C4 alkyl ester azelate, wherein the disease or condition associated with dyslipidemia includes one or more of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight, and obesity. In some embodiments, the method comprises administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, this method includes administering a pharmaceutical composition containing DEA.

[0017]

[0016] In some embodiments that may be combined with one or more other embodiments or examples, the method provided herein is about 0.1 mg / kilogram / day (mg / kg / day) to about 10 mg / kg / day, about 0.2 mg / kg / day to about 9.5 mg / kg / day, about 0.3 mg / kg / day to about 9 mg / kg / day, 0.4 mg / kg / day to about 8.5 mg / kg / day, about 0.5 mg / kg / day to about 8 mg / kg / day, about 0.6 mg / kg / day to about 7.5 mg / kg / day, about 0.7 mg / kg / day to about 7.0 mg / kg / day, about 0.8 mg / kg / day to about 6.5 mg / kg / day, about 0.9 mg / kg / day to about 6.0 mg / kg / day, about 1.0 mg / kg / day to about 5.5 mg / kg / day, about 1.0 mg / kg / day to about 5.0 mg / kg / day, about 0.1 mg / kg / day to about 5.0 mg / kg / day, about 0.25 mg / kg / day to about 5.0 mg / kg / day, about 0.1 mg / kg / day to about 4.0 mg / kg / day, about 0.25 mg / kg / day to about 4.0 mg / kg / day, about 0.5 mg / kg / day to about 4.0 mg / kg / day, about 0.75 to about 4.0 mg / kg / day, or about 0.25 mg / kg / day to about 3.0 mg / kg / day, about 0.25 mg / kg / day to about 2.5 mg / kg / day, about 0.25 mg / kg / day to about 2.0 mg / kg / day, about 0.25 mg / kg / day to about 1.5 mg / kg / day, or about It includes administering C1-C4 alkyl ester azelate to a subject at a dosage ranging from 0.25 mg / kg / day to about 1.5 mg / kg / day. In some embodiments, C1-C4 alkyl ester azelate is administered orally at this dosage range.

[0018]

[0017] In some embodiments that may be combined with one or more other aspects or embodiments, the method provided herein is about 0.1 mg / kg / day, about 0.2 mg / kg / day, about 0.3 mg / kg / day, about 0.4 mg / kg / day, about 0.5 mg / kg / day, about 0.6 mg / kg / day, about 0.7 mg / kg / day, about 0.8 mg / kg / day, about 0.9 mg / kg / day, about 1.0 mg / kg / day, about 1.1 mg / kg / day, about 1.2 mg / kg / day, about 1.3 mg / kg / day, 1.4 mg / kg / day, about 1.5 mg / kg / day, about 1.6 mg / kg / day, about 1.7 mg / kg / day, about 1.8 mg / kg / day, about 1.9 mg / kg / day, about 2.0 mg / kg / day, about 2.1 mg / kg / day, approx. 2.2 mg / kg / day, approx. 2.3 mg / kg / day, approx. 2.4 mg / kg / day, approx. 2.5 mg / kg / day, approx. 2.6 mg / kg / day, approx. 2.7 mg / kg / day, approx. 2.8 mg / kg / day, approx. 2.9 mg / kg / day, approx. 3.0 mg / kg / day, approx. 3.1 mg / kg / day, approx. 3.2 mg / kg / day, approx. 3.3 mg / kg / day, approx. 3.4 mg / kg / day, approx. 3.5 mg / kg / day, approx. 3.6 mg / kg / day, approx. 3.7 mg / kg / day, approx. 3.8 mg / kg / day, approx. 3.9 mg / kg / day, approx. 4.0 mg / kg / day, approx. 4.1 mg / kg / day, approx. 4.2 mg / kg / day, approx. 4.3 mg / kg / day, approx. 4.4 mg / kg / day, approx. 4.5 mg / kg / day, approx. 4.6 mg / kg / day, approx. 4.7 mg / kg / day, approx. 4.8 mg / kg / day, approx. 4.9 mg / kg / day, 5.0 mg / kg / day, approx. 5.1 mg / kg / day, approx. 5.2 mg / kg / day, approx. 5.3 mg / kg / day, approx. 5.4 mg / kg / day, approx. 5.5 mg / kg / day, approx. 5.6 mg / kg / day, approx. 5.7 mg / kg / day, approx. 5.8 mg / kg / day, approx. 5.9 mg / kg / day, approx. 6.0 mg / kg / day, approx. 6.1 mg / kg / day, approx. 6.2 mg / kg / day, approx. 6.3 mg / kg / day, approx. 6.4 mg / kg / day, approx. 6.5 mg / kg / day, approx. 6.6 mg / kg / day, approx. 6.7 mg / kg / day, approx. 6.8 mg / kg / day, approx. 6.9 mg / kg / day, 7.0 mg / kg / day, approx. 7.1 mg / kg / day, approx. 7.2 mg / kg / day, approx. 7.3 mg / kg / day, approx. 7.4 mg / kg / day, approx. 7.5 mg / kg / day, approx. 7.6 mg / kg / day, approx. 7.7 mg / kg / day, approx. 7.8 mg / kg / day, approx. 7.9 mg / kg / day, 8.0 mg / kg / day, approx. 8.1 mg / kg / day, approx. 8.2 mg / kg / day, approx. 8.3 mg / kg / day, approx. 8.4 mg / kg / day, approx. 8.5 mg / kg / day, approx. 8.6 It comprises administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate to a subject at a dosage of mg / kg / day, about 8.7 mg / kg / day, about 8.8 mg / kg / day, about 8.9 mg / kg / day, 9.0 mg / kg / day, about 9.1 mg / kg / day, about 9.2 mg / kg / day, about 9.3 mg / kg / day, about 9.4 mg / kg / day, about 9.5 mg / kg / day, about 9.6 mg / kg / day, about 9.7 mg / kg / day, about 9.8 mg / kg / day, about 9.9 mg / kg / day, or about 10.0 mg / kg / day. In some embodiments, the C1-C4 alkyl ester azelate is administered orally at these dosages.

[0019]

[0018] In some embodiments that may be combined with one or more other embodiments or examples, the method provided herein is about 0.1 mg / kg / day to about 10 mg / kg / day, about 0.2 mg / kg / day to about 9.5 mg / kg / day, about 0.3 mg / kg / day to about 9 mg / kg / day, 0.4 mg / kg / day to about 8.5 mg / kg / day, about 0.5 mg / kg / day to about 8 mg / kg / day, about 0.6 mg / kg / day to about 7.5 mg / kg / day, about 0.7 mg / kg / day to about 7.0 mg / kg / day, about 0.8 mg / kg / day to about 6.5 mg / kg / day, about 0.9 mg / kg / day to about 6.0 mg / kg / day, about 1.0 mg / kg / day to about 5.5 mg / kg / day, about 1.0 mg / kg / day to About 5.0 mg / kg / day, about 0.1 mg / kg / day to about 5.0 mg / kg / day, about 0.25 mg / kg / day to about 5.0 mg / kg / day, about 0.1 mg / kg / day to about 4.0 mg / kg / day, about 0.25 mg / kg / day to about 4.0 mg / kg / day, about 0.5 mg / kg / day to about 4.0 mg / kg / day, about 0.75 to about 4.0 mg / kg / day, or about 0.25 mg / kg / day to about 3.0 mg / kg / day, about 0.25 mg / kg / day to about 2.5 mg / kg / day, about 0.25 mg / kg / day to about 2.0 mg / kg / day, about 0.25 mg / kg / day to about 1.5 mg / kg / day, or about 0.25 mg / kg / day It comprises administering a pharmaceutical composition containing DEA to a subject at a dosage ranging from about 1.5 mg / kg / day. In some embodiments, the pharmaceutical composition comprises DEA administered orally at this dosage range.

[0020]

[0019] In some embodiments that may be combined with one or more other aspects or embodiments, the method provided herein is about 0.1 mg / kg / day, about 0.2 mg / kg / day, about 0.3 mg / kg / day, about 0.4 mg / kg / day, about 0.5 mg / kg / day, about 0.6 mg / kg / day, about 0.7 mg / kg / day, about 0.8 mg / kg / day, about 0.9 mg / kg / day, about 1.0 mg / kg / day, about 1.1 mg / kg / day, about 1.2 mg / kg / day, about 1.3 mg / kg / day, 1.4 mg / kg / day, about 1.5 mg / kg / day, about 1.6 mg / kg / day, about 1.7 mg / kg / day, about 1.8 mg / kg / day, about 1.9 mg / kg / day, about 2.0 mg / kg / day, about 2.1 mg / kg / day, approx. 2.2 mg / kg / day, approx. 2.3 mg / kg / day, approx. 2.4 mg / kg / day, approx. 2.5 mg / kg / day, approx. 2.6 mg / kg / day, approx. 2.7 mg / kg / day, approx. 2.8 mg / kg / day, approx. 2.9 mg / kg / day, approx. 3.0 mg / kg / day, approx. 3.1 mg / kg / day, approx. 3.2 mg / kg / day, approx. 3.3 mg / kg / day, approx. 3.4 mg / kg / day, approx. 3.5 mg / kg / day, approx. 3.6 mg / kg / day, approx. 3.7 mg / kg / day, approx. 3.8 mg / kg / day, approx. 3.9 mg / kg / day, approx. 4.0 mg / kg / day, approx. 4.1 mg / kg / day, approx. 4.2 mg / kg / day, approx. 4.3 mg / kg / day, approx. 4.4 mg / kg / day, approx. 4.5 mg / kg / day, approx. 4.6 mg / kg / day, approx. 4.7 mg / kg / day, approx. 4.8 mg / kg / day, approx. 4.9 mg / kg / day, 5.0 mg / kg / day, approx. 5.1 mg / kg / day, approx. 5.2 mg / kg / day, approx. 5.3 mg / kg / day, approx. 5.4 mg / kg / day, approx. 5.5 mg / kg / day, approx. 5.6 mg / kg / day, approx. 5.7 mg / kg / day, approx. 5.8 mg / kg / day, approx. 5.9 mg / kg / day, approx. 6.0 mg / kg / day, approx. 6.1 mg / kg / day, approx. 6.2 mg / kg / day, approx. 6.3 mg / kg / day, approx. 6.4 mg / kg / day, approx. 6.5 mg / kg / day, approx. 6.6 mg / kg / day, approx. 6.7 mg / kg / day, approx. 6.8 mg / kg / day, approx. 6.9 mg / kg / day, 7.0 mg / kg / day, approx. 7.1 mg / kg / day, approx. 7.2 mg / kg / day, approx. 7.3 mg / kg / day, approx. 7.4 mg / kg / day, approx. 7.5 mg / kg / day, approx. 7.6 mg / kg / day, approx. 7.7 mg / kg / day, approx. 7.8 mg / kg / day, approx. 7.9 mg / kg / day, 8.0 mg / kg / day, approx. 8.1 mg / kg / day, approx. 8.2 mg / kg / day, approx. 8.3 mg / kg / day, approx. 8.4 mg / kg / day, approx. 8.5 mg / kg / day, approx. 8.6 It comprises administering to a subject a pharmaceutical composition comprising DEA at a dose of mg / kg / day, about 8.7 mg / kg / day, about 8.8 mg / kg / day, about 8.9 mg / kg / day, 9.0 mg / kg / day, about 9.1 mg / kg / day, about 9.2 mg / kg / day, about 9.3 mg / kg / day, about 9.4 mg / kg / day, about 9.5 mg / kg / day, about 9.6 mg / kg / day, about 9.7 mg / kg / day, about 9.8 mg / kg / day, about 9.9 mg / kg / day, or about 10.0 mg / kg / day. In some embodiments, the pharmaceutical composition comprises DEA administered orally at these doses.

[0021]

[0020] In some embodiments that may be combined with one or more other aspects or embodiments, the method provided herein comprises administering a pharmaceutical composition containing DEA to a subject at a dosage of about 0.1 mg / kg / day, about 0.25 mg / kg / day, about 0.5 mg / kg / day, about 1 mg / kg / day, about 2 mg / kg / day, or about 4 mg / kg / day. In some embodiments, the pharmaceutical composition comprises DEA administered orally at such dosages.

[0022]

[0021] In some embodiments that may be combined with one or more other aspects or embodiments, the method provided herein comprises administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate to a subject, wherein the subject has at least one of insulin resistance, prediabetes, type II diabetes, overweight, or obesity, is suspected of having such, or is suspected of having a predisposition to acquire such. In some embodiments, the subject has prediabetes. In some embodiments, the subject has type II diabetes. In some embodiments, the subject is overweight. In some embodiments, the subject is obese.

[0023]

[0022] In some embodiments that may be combined with one or more other aspects or embodiments, the method provided herein comprises administering a pharmaceutical composition containing DEA to a subject, wherein the subject has at least one of insulin resistance, prediabetes, type II diabetes, overweight, or obesity, is suspected of having such, or is suspected of having a predisposition to acquire such. In some embodiments, the subject has prediabetes. In some embodiments, the subject has type II diabetes. In some embodiments, the subject is overweight. In some embodiments, the subject is obese.

[0024]

[0023] In some embodiments that may be combined with one or more other embodiments or examples, the method provided herein comprises administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate to a subject, wherein the subject has a body mass index (BMI) of less than 25 to 30 or a BMI of 30 or more.

[0025]

[0024] In some embodiments that may be combined with one or more other embodiments or examples, the method provided herein comprises administering a pharmaceutical composition containing DEA to a subject, wherein the subject has a BMI of less than 25 to 30 or a BMI of 30 or more.

[0026]

[0025] In some embodiments that may be combined with one or more other aspects or embodiments, the method provided herein comprises administering to a subject a pharmaceutical composition comprising a C1-C4 alkyl ester azelate formulated for buccal delivery. In some embodiments, the C1-C4 alkyl ester azelate formulated for buccal delivery comprises DEA.

[0027]

[0026] In some embodiments that may be combined with one or more other aspects or embodiments, the method provided herein comprises administering to a subject a pharmaceutical composition comprising a C1-C4 alkyl ester azelate formulated for gastric delivery. In some embodiments, the C1-C4 alkyl ester azelate formulated for gastric delivery comprises DEA.

[0028]

[0027] In some embodiments that may be combined with one or more other aspects or embodiments, the method provided herein further comprises administering a second active ingredient in addition to the C1-C4 alkyl ester azelate. In some embodiments, the second active ingredient is administered separately from the pharmaceutical composition comprising the C1-C4 alkyl ester azelate. In some embodiments, the second active ingredient is co-administered with the pharmaceutical composition comprising the C1-C4 alkyl ester azelate. In some embodiments, the second active ingredient is a C1-C4 alkyl ester azelate other than DEA, biguanide, metformin, buformin, phenformin, thiazolidinedione, pioglitazone, rosiglitazone, corticosteroid, prednisone, insulin, lipase inhibitor, orlistat, glucagon-like peptide-1 (GLP-1) agonist, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitor, statin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, lusovastatin, simvastatin, fibrate, gemfibrozil, fenofibrate, niacin, leptin, leptin agonist, metreleptin, amylin agonist, pramlintide, and one or more of combinations thereof. In some embodiments, insulin is formulated as a rapid-acting formulation, an intermediate-acting formulation, a long-acting formulation, or a combination thereof.

[0029]

[0028] In some embodiments that may be combined with one or more other aspects or embodiments, the method provided herein comprises administering a pharmaceutical composition consisting essentially of DEA as an active ingredient.

[0030]

[0029] In some embodiments that may be combined with one or more other embodiments or examples, the method provided herein comprises administering a pharmaceutical composition composed of DEA as an active ingredient.

[0031]

[0030] In some embodiments that may be combined with one or more other aspects or embodiments, a pharmaceutical composition comprising a C1-C4 alkyl ester azelate for buccal delivery of doses ranging from about 0.25 mg / kg to about 2.0 mg / kg, about 0.5 to about 2.0 mg / kg, or about 0.5 to about 1.0 mg / kg is provided. In some embodiments, the C1-C4 alkyl ester azelate is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, the C1-C4 alkyl ester azelate is DEA.

[0032]

[0031] In some embodiments which may be combined with one or more other aspects or embodiments, a pharmaceutical composition is provided comprising a C1-C4 alkyl ester azelate for buccal delivery of doses ranging from about 0.25 mg / mg to about 2.0 mg / kg, about 0.5 to about 2.0 mg / kg, or about 0.5 to about 1.0 mg / kg, said doses being effective in improving one or more abnormal lipid levels when administered to a subject. In some embodiments, such a C1-C4 alkyl ester azelate is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, such a C1-C4 alkyl ester azelate is DEA.

[0033]

[0032] In some embodiments which may be combined with one or more other embodiments or examples, a pharmaceutical composition is provided comprising a C1-C4 alkyl ester azelate for buccal delivery of a dose in the range of about 0.25 mg / mg to about 2.0 mg / kg, about 0.5 to about 2.0 mg / kg, or about 0.5 to about 1.0 mg / kg, said doses being effective when administered to a subject for lowering elevated LDL levels, raising reduced HDL levels, lowering elevated triglyceride levels, lowering elevated cholesterol / HDL, lowering elevated LDL / HDL, lowering elevated LDL / triglyceride, or lowering elevated non-cholesterol HDL / HDL. In some embodiments, such a C1-C4 alkyl ester azelate is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, this C1-C4 alkyl ester azelate is DEA.

[0034]

[0033] In some embodiments which may be combined with one or more other embodiments or examples, a pharmaceutical composition is provided comprising a C1-C4 alkyl ester azelate for buccal delivery of doses ranging from about 0.25 mg / mg to about 2.0 mg / kg, about 0.5 to about 2.0 mg / kg, or about 0.5 to about 1.0 mg / kg, said doses being effective for treating or preventing dyslipidemia, or diseases or conditions associated with dyslipidemia. In some embodiments, the C1-C4 alkyl ester azelate is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, the C1-C4 alkyl ester azelate is DEA.

[0035]

[0034] In some embodiments that may be combined with one or more other embodiments or examples, a pharmaceutical composition is provided comprising a C1-C4 alkyl ester azelate for buccal delivery of a dose in the range of about 0.25 mg / mg to about 2.0 mg / kg, about 0.5 to about 2.0 mg / kg, or about 0.5 to about 1.0 mg / kg, said doses being effective for treating or preventing dyslipidemia, or diseases or conditions associated with dyslipidemia, said disease or condition associated with dyslipidemia being selected from the group consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight, and obesity. In some embodiments, these C1-C4 alkyl ester azelates are selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. Brief explanation of the drawing

[0036]

[0035] Fig. 1 This shows the stratification by glucose markers of the study cohort of 17 subjects described in Example 1. Stratification by declining hemoglobin A1c levels, filled circles; corresponding fasting plasma glucose levels, empty squares.

[0036] Fig. 2 This presents the effect of DEA on fasting plasma glucose in the subject described in Example 1. Fig. 2a : Glucose levels in subgroups of subjects with ≥100 mg / dL and <100 mg / dL prior to treatment. Fig. 2b : Correlation between changes in glucose levels observed after treatment, hemoglobin A1c levels, and fasting plasma glucose levels before treatment (left and right panels, respectively).

[0037] Fig. 3This presents the effect of DEA treatment on glucose levels in an oral glucose tolerance test (OGTT) on an empty stomach for subjects described in Example 1. Fig. 3a : Comparison of DEA effects at 180 minutes in high and low A1c subgroups. The horizontal line at 100 mg / dL marks the boundary between normal and abnormal glucose ranges. Fig. 3b : Depiction of OGTT glucose profiles of three prediabetic subjects shown in Fig. 1. Day 0 (the day before the start of DEA treatment therapy), dotted line; Day 21 (the last day of DEA treatment therapy), solid line.

[0038] Fig. 4 It presents the correlation between the A1c level study subjects described in Example 1 and the effect of DEA treatment on fasting insulin. Fig. 4a : Fasting insulin in a cohort stratified into high and low A1c subgroups by A1c levels. The horizontal line at 25 μU / mL marks the boundary between the normal and abnormal insulin ranges. Fig. 4b : Insulin profiles in three prediabetic subjects shown in Fig. 1 over a 180-minute time course. Day 0 (the day before the start of DEA treatment therapy), dotted line; Day 21 (the last day of DEA treatment therapy), solid line.

[0039] Fig. 5 This presents the effect of DEA treatment on a single lipid marker for the subject described in Example 1. Fig. 5a : Total cholesterol. Fig. 5b : LDL cholesterol. Fig. 5c : HDL cholesterol. Fig. 5d : Non-cholesterol HDL. Fig. 5e : Triglycerides. For all of Figures 5a through 5e, the cohorts were stratified into high and low A1c subgroups based on A1c levels. Horizontal dashed lines indicate the boundaries between the normal and abnormal ranges for the measured endpoints.

[0040] Fig. 6 This presents the effect of DEA treatment on the ratio of lipid markers for the subject described in Example 1. Fig. 6a : Total Cholesterol / HDL, Fig. 6b: LDL / HDL, Fig. 6c : LDL / triglyceride, Fig. 6d : Non-cholesterol HDL / HDL, Fig. 6e : Triglycerides / HDL. In all cases, the cohort was stratified into high and low A1c subgroups based on A1c levels. Horizontal dashed lines indicate the boundaries between the normal and abnormal ranges for the measured endpoints.

[0041] Fig. 7 This presents the effect of DEA treatment on lipid markers in the cohort of subjects described in Example 1. Left column: All subjects. Middle column: Low A1c subgroup. Right column: High A1c subjects. The average percentage change at the endpoint level is presented in grayscale, and numerical values ​​for all endpoints are provided. Darker ranges (greater than "10" to "30") correspond to increased values ​​after processing, and brighter ranges (less than "0" to "-10") correspond to decreased values.

[0042] Fig. 8 This presents the effect of DEA administration via buccal delivery on lipid levels as a function of DEA dose (mg / kg) as described in Example 2. HDL = High-density lipoprotein; Calc LDL = Calculated low-density lipoprotein.

[0043] Fig. 9 This presents the effect of DEA administration via buccal delivery on the total cholesterol / high-density lipoprotein (TC / HDL) ratio as a function of the directed DEA dosage as described in Example 2.

[0044] Fig. 10 This presents the effect of DEA administration via buccal delivery on plasma glucose concentration measured at an indicated time point after intake of a standard glucose dose in an OGTT as a function of the indicated DEA dosage as described in Example 2.

[0045] Fig. 11This presents the effect of DEA administration via buccal delivery on plasma glucose concentrations measured at indicated time points after intake of a standard glucose dose in an OGTT under fasting conditions as a function of the indicated DEA dose as described in Example 2. Glucose administration provided at T=0. The first glucose measurement was performed at T=0, and subsequent glucose measurements were performed at t=1, t=2, and t=4 hours.

[0046] Fig. 12 This presents the effect of DEA administration via buccal delivery on plasma glucose concentration measured 1 hour after intake of a standard glucose dose in OGTT as a function of the indicated DEA dosage as described in Example 2.

[0047] Fig. 13 This presents the effect of DEA administration via buccal delivery on plasma glucose concentration measured 2 hours after intake of a standard glucose dose in OGTT as a function of the indicated DEA dosage as described in Example 2.

[0048] Fig. 14 This presents the effect of DEA administration via buccal delivery on plasma glucose concentration measured 4 hours after intake of a standard glucose dose in OGTT as a function of the indicated DEA dosage as described in Example 2.

[0049] Fig. 15 It provides a comparison of indicated lipid measurements upon administration of DEA via buccal delivery (upper panel) or gastric delivery (lower panel) as described in Example 2. HDL = High-density lipoprotein; Calc LDL = Calculated low-density lipoprotein; TC / HDL = Total cholesterol / high-density lipoprotein ratio.

[0050] Fig. 16 It provides a comparison of the effects of buccal delivery (upper panel) versus gastric delivery (lower panel) of an indicated DEA dose on plasma glucose concentrations measured at indicated time points after intake of a standard glucose dose in an OGTT, as described in Example 2.

[0051] Fig. 17This provides a comparison of the effects of the indicated doses of DEA administered via buccal or gastric delivery as described in Example 2. Upper panel: Measured lipid levels (HDL = High-density lipoprotein; Calc LDL = Calculated low-density lipoprotein; TC / HDL = Total cholesterol / High-density lipoprotein ratio). Lower panel: Plasma glucose concentrations measured at the indicated time points after intake of a standard glucose dose in the OGTT.

[0052] Fig. 18 It does not wish to be bound by any theory and provides a graphical representation of the influence of the proposed membrane fluidity degree ("soft" to "hard") on the percentage of membrane protein function (100% protein function constitutes "maximum" function). Specific details for implementing the invention

[0037]

[0053] Now, in particular, it has been found that the administration of C1-C4 alkyl ester azelates, such as DEA, induces beneficial changes (“improvements”) in metabolic markers and risk factors for dyslipidemia, insulin resistance, and diseases or conditions associated with dyslipidemia and / or insulin resistance, e.g., improvements in plasma lipid levels and glucose levels. These beneficial changes are disclosed herein as being correlated with the severity of the disease or condition, particularly in subjects with insulin resistance, prediabetes, diabetes, abnormal lipid levels, overweight, and / or obesity.

[0038]

[0054] Without being bound by any theory, these effects are believed to be achieved at least partially by regulating plasma membrane fluidity using membrane-soluble molecules such as C1-C4 alkyl ester azelates. Increasing evidence suggests that even minor changes in membrane structure and composition affect host immune function, inflammatory signaling, and innate immune responses [68-70]. Reports indicate that the structure of the plasma membrane can be altered in various diseases [71, 72], and that diet itself can influence plasma membrane structure. Dietary fats and sugars have been suggested to induce changes in the plasma membrane that lead to pathological insulin signaling and reduced tissue glucose uptake associated with type II diabetes

[73] . Lipophilic molecules such as C1-C4 alkyl ester azelates, such as DEA, diffuse into the plasma membrane [74, 75], increase membrane fluidity, and can trigger metabolic changes that translate into health benefits.

[0039]

[0055] Non-limiting examples of this dynamics are Fig. 18This is exemplified in [document], where the percentage of protein function ("protein function %) as a function of membrane fluidity is illustrated in a graph. Molecules capable of diffusing into the plasma membrane, such as C1-C4 alkyl ester azelates like DEA, can influence membrane fluidity (e.g., increase it) and thereby affect membrane protein and receptor function in vivo (e.g., improve it). These effects on membrane fluidity are believed to depend on the relative ratios of various lipid species present within the membrane, and it is believed that there exists an optimal range of fluidity or fluidity that optimizes / maximizes membrane protein or receptor function in vivo. Furthermore, innate feedback-regulated physiological mechanisms are believed to exist that regulate membrane fluidity through changes in membrane lipids, lipid metabolism, and blood lipid levels, particularly including changes in triglycerides and cholesterol (referred to as "Adaptive Membrane Fluidity Regulating Systems" ("AMFMS")). Agents capable of influencing or regulating these lipid levels and / or lipid metabolism can affect AMFMS. Therefore, plasma lipid levels, in turn, [influence] the AMFMS response It can serve as a biomarker to identify agents effective in regulating AMFMS in a manner that implies regulation and / or achieves therapeutic benefits.

[0040]

[0056] Therefore, drugs and therapeutic compounds or molecules designed to modify or modulate membrane physicochemical properties are considered to serve as viable candidates for the treatment of various human diseases, including dyslipidemia, insulin resistance, and related diseases or conditions, which are caused or exacerbated by abnormal lipid levels and / or abnormal blood glucose levels. These diseases or conditions include, for example, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, lipoatrophy, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, pancreatitis, prediabetes, type II diabetes, insulin resistance, overweight, and obesity.

[0041]

[0057] In some embodiments, a pharmaceutical composition and method for improving one or more abnormal lipid levels in a subject are provided, comprising administering a pharmaceutical composition to a subject, wherein the pharmaceutical composition comprises a C1-C4 alkyl ester azelate such as DEA. In embodiments, lowering elevated LDL levels; raising reduced (i.e., "low") HDL levels; lowering elevated triglyceride levels; lowering elevated cholesterol / HDL; lowering elevated LDL / HDL; lowering elevated LDL / triglycerides; lowering elevated non-cholesterol HDL / HDL levels; or in subjects requiring a combination of the above, lowering elevated LDL levels; raising reduced (i.e., "low") HDL levels; lowering elevated triglyceride levels; lowering elevated cholesterol / HDL; lowering elevated LDL / HDL; lowering elevated LDL / triglycerides; lowering elevated non-cholesterol HDL / HDL levels; Alternatively, pharmaceutical compositions and methods for combinations of the above-mentioned ones are provided. In an embodiment, a method for treating or preventing dyslipidemia, or diseases or conditions associated with dyslipidemia, is provided, comprising administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate such as DEA to a subject.

[0042]

[0058]

[0059] The disclosure of the present invention demonstrates that diseases or conditions associated with abnormal blood lipid levels and / or abnormal blood glucose levels, including hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, lipodystrophy, lipoatrophy, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, pancreatitis, prediabetes, type II diabetes, insulin resistance, overweight, and obesity, can be treated or prevented by administering a C1-C4 alkyl ester azelate, e.g., DEA, to subjects requiring treatment or prevention thereof.

[0043]

[0060] In some embodiments, a pharmaceutical composition comprising a C1-C4 alkyl ester azelate and a method for preventing, improving, or treating a disease or condition associated with dyslipidemia or insulin resistance are provided, comprising administering the C1-C4 alkyl ester azelate to a subject. In some embodiments, a pharmaceutical composition comprising DEA for preventing, improving, or treating a disease or condition associated with dyslipidemia or insulin resistance is provided.

[0044]

[0061] In some embodiments, a method for preventing, improving, or treating a disease or condition associated with dyslipidemia or insulin resistance is provided, comprising administering a C1-C4 alkyl ester azelate to a subject. In some embodiments, the C1-C4 alkyl ester azelate comprises DEA.

[0045]

[0062] "Dyslipidemia" or "dyslipidemias," used interchangeably throughout, refers to a group of diseases or disorders characterized by abnormal lipid levels in the subject's blood.

[0046]

[0063] "Abnormal lipid levels" refers to one or more of the following: elevated LDL levels relative to normal lipid levels; elevated very low-density lipoprotein (VLDL) levels; decreased (i.e., "low") HDL levels; elevated triglyceride levels; elevated cholesterol / HDL; elevated LDL / HDL; elevated LDL / triglyceride; and elevated non-cholesterol HDL / HDL levels. "Abnormal lipid levels" also refers to levels or ranges of blood lipid component concentrations.

[0047]

[0064] "Lipid level," "lipid range," "lipid component level," and "lipid component range," or their corresponding plural forms, used interchangeably throughout, refer to the concentration or range of concentration of lipid components in blood, plasma, and / or serum as measured by routine methods to those skilled in the art. Such lipid levels, lipid component levels, lipid ranges, and / or lipid component ranges, etc., are measured, for example, in milligrams per deciliter (mg / dL).

[0048]

[0065] "Lipid component" or "lipid components" used interchangeably throughout refers, for example, total cholesterol, LDL, HDL, VLDL, triglycerides, and calculated LDL.

[0049]

[0066] "Normal lipid levels," "healthy lipid levels," "normal lipid range," "healthy lipid range," or the corresponding plural forms, used interchangeably throughout, refer to blood and / or serum lipid component concentrations recognized as within healthy limits by medical institutions and / or the medical community, such as, for example, the National Institutes of Health and the World Health Organization.

[0050]

[0067] In an embodiment, the normal lipid levels are as follows:

[0051]

[0052]

[0068] "Abnormal lipid level," "abnormal lipid range," "abnormal lipid levels," or "abnormal lipid ranges," used interchangeably throughout, each refer to a measured concentration or range of concentration of one or more lipid components that correspond to or do not fall within a normal (healthy) lipid level or normal (healthy) lipid range.

[0053]

[0069] “Improving,” “to improve,” or “improvement” refers to bringing the levels of one or more analytes and / or one or more ratios of analyte levels, such as glucose, A1c, LDL, VLDL, triglycerides, HDL, calculated cholesterol, cholesterol / HDL ratio, LDL / HDL ratio, LDL / triglyceride ratio, or non-cholesterol HDL / HDL ratio, to a normal level relative to a previous abnormal level. In some embodiments, such “improving” and / or “improvement” is achieved as a result of administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate. In some embodiments, such “improving” and / or “improvement” is achieved as a result of administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, such "improving" and / or "improvement" is achieved as a result of administering a pharmaceutical composition containing DEA.

[0054]

[0070] "Diabetes" refers to a group of metabolic diseases characterized by high blood sugar (glucose) levels resulting from defects in insulin secretion or action, or both.

[0055]

[0071] "Type 2 diabetes" or "T2D" refers to one of the two major types of diabetes in which, at least in the early stages of the disease, the beta cells of the pancreas produce insulin, but the body cannot use it effectively because the body's cells are resistant to the action of insulin. In the later stages of the disease, beta cells may stop producing insulin. Type 2 diabetes is also known as insulin-resistant diabetes, non-insulin-dependent diabetes, and adult-onset diabetes.

[0056]

[0072] “Prediabetes” refers to one or more early diabetes-related conditions including impaired glucose utilization, abnormal or impaired fasting glucose levels, impaired glucose tolerance, impaired insulin sensitivity, and insulin tolerance. In an embodiment, “prediabetes” may be defined by a hemoglobin A1c measurement of about 6.0% or higher.

[0057]

[0073] "Insulin-resistant" or "insulin intolerance" refers to a condition in which insulin-sensitive cells become resistant to the effects of insulin (a hormone that regulates glucose uptake into cells) and / or the amount of insulin produced is insufficient to maintain normal glucose levels. Cells have a reduced ability to respond to the action of insulin in facilitating the transport of glucose from the blood to muscles and other tissues (i.e., sensitivity to insulin decreases). Eventually, the pancreas produces much more insulin than normal, and the cells continue to develop resistance. As long as enough insulin is produced to overcome this resistance, blood glucose levels remain normal. When the pancreas can no longer sustain this, blood glucose levels rise, ultimately leading to diabetes, such as Type 2 diabetes. Insulin resistance falls within the range of normal (insulin-sensitive) to insulin resistance (IR).

[0058]

[0074] "Overweight" refers to a condition defined by an excess amount of body fat in a subject. In an embodiment, overweight is characterized by a BMI in the range of 25 to less than 30 and / or a body fat percentage of generally about 33% to about 39% for women and generally about 19% to about 25% for men.

[0059]

[0075] "Obesity" refers to a condition defined by an excess amount of body fat in a subject. In an embodiment, obesity is characterized by a BMI of 30 or higher in a subject, and / or a body fat percentage generally exceeding about 39% for women and generally exceeding about 25% for men.

[0060]

[0076] The term “disease” as used herein is intended to be generally synonymous with and used interchangeably with the terms “disorder” and “disease” (as in medical disease) in that they both reflect an abnormal condition of one of the human or animal body or parts thereof that impairs normal function, typically manifested by distinguishing signs and symptoms, and reduce the duration or quality of life of the human or animal.

[0061]

[0077] As used herein, the term "approximately" is intended to limit the numerical value it modifies, representing a value as a variable within an error range. Where a specific error range, such as the standard deviation for the mean value provided in a chart or data table, is not mentioned, the term "approximately" should be understood to mean the range that includes the mentioned value and the range that would also be included by rounding up or down to that value, taking into account the valid figures.

[0062]

[0078] When a numerical range of values ​​is initiated, such range is intended to include the numeric values ​​themselves and any sub-ranges between them. This range may be integers or continuous, including the final values.

[0063]

[0079] The term “combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic disease or disorder described in the disclosure of the present invention. Such administration may include the co-administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single dosage form having a fixed non-active ingredient or in multiple individual dosage forms for each active ingredient. Additionally, such administration may also include the use of each type of therapeutic agent in a sequential manner. In either case, the therapeutic therapy will provide the beneficial effects of the drug combinations in treating the disease or disorder described herein.

[0064]

[0080] The terms “therapeutic effective dose” or “effective dose” are intended to limit the amount of active ingredient used to achieve a clinical or therapeutic outcome, improvement, or benefit in a subject. “Therapeutic effective dose” or “effective dose” is an amount that provides some improvement, relief, alleviation, reduction, or stabilization of at least one clinical symptom in a subject. Those skilled in the art will understand that the therapeutic effect does not need to be complete or curative as long as some benefit is provided to the subject.

[0065]

[0081] In some embodiments, the “therapeutic effective dose” or “effective dose” is an amount effective in improving one or more abnormal lipid levels in a subject when administered to the subject.

[0066]

[0082] In some embodiments, the “therapeutic effective dose” or “effective dose” is an amount effective when administered to a subject to lower elevated LDL levels, raise reduced HDL levels, lower elevated triglyceride levels, lower elevated cholesterol / HDL, lower elevated LDL / HDL, lower elevated LDL / triglyceride, or lower elevated non-cholesterol HDL / HDL.

[0067]

[0083] In some embodiments, the “therapeutic effective amount” or “effective amount” is an amount effective for treating or preventing dyslipidemia or diseases or conditions associated with dyslipidemia.

[0068]

[0084] In some embodiments, the “therapeutic effective dose” or “effective dose” is an amount effective for treating or preventing one or more diseases or disorders associated with dyslipidemia selected from the group consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight, and obesity, wherein the treatment of the disease, disorder, or disorder. This amount will achieve the goal of reducing the effects of the disease, disorder, or disorder or eliminating them.

[0069]

[0085] References to "treatment" of a subject include prevention or avoidance. The term "subject" means all mammals, including humans. Examples of patients include humans, cattle, dogs, cats, goats, sheep, pigs, and rabbits. In some embodiments, the subject is a human.

[0070]

[0086] "Related to" refers to a disease, condition, or clinical finding or outcome that is consistent with and / or is the cause of; is and / or is a comorbidity of; is and / or a risk factor for; is and / or a biomarker for; or indicates a predisposition to acquire.

[0071]

[0087] The term "comprising" is intended to mean that the composition and method include the cited elements but do not exclude other elements. The term "consisting essentially of," applied to the composition of the embodiments of the present invention, means that the composition may contain additional elements unless the additional elements substantially alter the composition. The term "substantially altered," applied to the composition, refers to an increase or decrease in the therapeutic effect of the composition compared to the effect of the composition composed of the cited elements. That is, when used to define the composition, "consisting essentially of" will mean excluding other components that have any essential significance to the composition. Accordingly, a composition composed of components as defined herein as essential will not exclude trace contaminants and pharmaceutically acceptable carriers from the separation and purification methods. "Consisting of" will mean excluding substantial method steps for administering the composition of the present invention and exceeding trace elements of other components. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0072] Pharmaceutical compositions and treatments

[0073]

[0088] Pharmaceutical compositions are provided herein comprising one or more of the specific compounds disclosed herein, such as C1-C4 alkyl ester azelates, which may be optionally formulated with or otherwise combined with one or more pharmaceutically acceptable carriers and may also optionally comprise one or more other therapeutic components. In some embodiments, the pharmaceutical composition comprises a C1-C4 alkyl ester azelate selected from the group consisting of DEA, DMA, DiPA, DiBuA, and D2PA, each of which may be prepared from an azelaic acid and its respective alcohol (e.g., methyl, ethyl, propyl, isobutyl, 1-, 2-, and 3-pentyl, and cyclohexyl) using standard acid-catalyzed esterification. The aliphatic acid contains an alkyl group bonded to a carboxyl group.

[0074]

[0089] In an embodiment, the pharmaceutical composition comprises DEA. Diethyl azelate can be found in some common foods (Yu 2001; Plough, Zhangxia et al. 2002; Kim and Chung 2008; Fan, Fan et al. It is an approved flavor additive in gram amounts in the EU (AFC 2005).

[0075]

[0090] In an embodiment, the pharmaceutical composition comprises a C1-C4 alkyl ester azelate (different from DEA if DEA is already included in the pharmaceutical composition), biguanide, metformin, buformin, phenformin, thiazolidinedione, pioglitazone, rosiglitazone, corticosteroid, prednisone, insulin, lipase inhibitor, orlistat, glucagon-like peptide-1 (GLP-1) agonist, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semabiglutide, HMG-CoA reductase inhibitor, statin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rusovastatin, simvastatin, fibrate, gemfibrozil, fenofibrate, niacin, leptin, leptin agonist, It includes a second active ingredient that may include one or more of metreleptin, amylin agonists, pramlintide, and combinations thereof.

[0076]

[0091] Other second active ingredients include alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, AKA incretin enhancers (including alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin), sulfonylureas and related agents (including glibenclamide, gliclazide, glimeprid, glipizide, tolbutamide, and nateglinide and repaglinide), acarbose, sodium-glucose co-transporter 2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin), and natural products, e.g., nopal (prickly pear cactus), fenugreek, karela (bitter melon), gymnema, ginseng, Includes, but is not limited to, tronadola, chromium, alpha-lipoic acid, and hydroxycitric acid.

[0077]

[0092] If the compound is not used due to toxicity or other harmful side effects, the dosage may be substantially reduced compared to the originally approved dose.

[0078]

[0093] In some embodiments, the thiazolidinedione includes pioglitazone, rosiglitazone, or a combination thereof.

[0079]

[0094] In some embodiments, the corticosteroid includes prednisone.

[0080]

[0095] In some embodiments, insulin is formulated as a rapid-acting formulation, an intermediate-acting formulation, a long-acting formulation, or a combination thereof.

[0081]

[0096] In some embodiments, the lipase inhibitor includes orlistat.

[0082]

[0097] In some embodiments, GLP-1 agonists include exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, semaglutide formulated for oral administration (e.g., RYBELSUS® semaglutide tablets) and combinations thereof.

[0083]

[0098] In some embodiments, HMG-CoA reductase inhibitors include statins, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rusovastatin, and simvastatin.

[0084]

[0099] In some embodiments, the pharmaceutical composition consists essentially of DEA as an active ingredient. In some embodiments, the pharmaceutical composition consists of DEA as an active ingredient.

[0085]

[0100] In some embodiments, the pharmaceutical composition is enteric-coated. The pharmaceutical composition of an embodiment of the present invention may be configured for immediate release, extended release, sustained release, and controlled release of a C1-C4 alkyl ester azelate such as DEA. In some embodiments, the pharmaceutical composition is configured for the extended release of a C1-C4 alkyl ester azelate such as DEA. In some embodiments, the pharmaceutical composition is configured for any combination of immediate release, extended release, sustained release, and controlled release of a C1-C4 alkyl ester azelate such as DEA. Various release profiles of the foregoing embodiments may be achieved through any conventional method known in the art. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered two or three times daily.

[0086]

[0101] Carrier(s) are "allowed" in the sense that they are compatible with other components of the formulation and are not harmful to the subject. The appropriate formulation depends on the selected route of administration. Any well-known technology, carrier, and excipient as understood in the art, e.g. those disclosed in the literature [Remington's Pharmaceutical Sciences], may be used. The pharmaceutical compositions disclosed herein may be prepared in any manner known in the art, such as by conventional mixing, dissolving, granulation, sugar-coating, lavigating, emulsifying, encapsulating, capturing, or compression processes.

[0087]

[0102] Pharmaceutical compositions include those suitable for intestinal (including oral, buccal, gastric and rectal), parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, and local (including skin, buccal, sublingual, ocular, intranasal, and intraocular) administration or delivery, but the most suitable route of administration or delivery may depend, for example, on the recipient's disease and disability.

[0088]

[0103] In an embodiment, the pharmaceutical composition is formulated for oral administration or delivery.

[0089]

[0104] In an embodiment, the pharmaceutical composition is formulated for buccal administration or delivery.

[0090]

[0105] In an embodiment, the pharmaceutical composition is formulated for gastric administration or delivery.

[0091]

[0106] The pharmaceutical composition may be conveniently provided in a unit dosage form and may be prepared by any method widely known in the pharmaceutical field. Typically, such a method comprises the step of mixing a C1-C4 alkyl ester azelate, e.g., DEA, and optionally any co-administered active ingredient disclosed herein with a carrier constituting one or more auxiliary ingredients. Generally, the pharmaceutical composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, molding the product into a desired composition.

[0092]

[0107] For example, a pharmaceutical composition of a C1-C4 alkyl ester azelate, e.g., DEA, and any optional secondary active ingredient suitable for oral, buccal, or gastric administration or delivery may be provided as individual units, such as capsules, cases, or tablets, each containing a predetermined amount of the active ingredient(s); as a powder or granule; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient(s) may also be provided as a bolus, soft pill, or paste. For buccal or sublingual administration or delivery, the composition may take the form of a tablet, lozenge, pill, or gel formulated in a conventional manner. Such compositions may contain the active ingredient as a flavor base, such as sucrose and acacia or tragacanth. For gastric administration or delivery, the composition may take the form of a gelatin capsule, e.g., a hard gelatin capsule. For example, an example of a gelatin capsule for gastric administration or delivery of a C1-C4 alkyl ester azelate such as DEA is a gelatin capsule size 00 (PureCaps USA, Philmont, NY).

[0093]

[0108] For example, pharmaceutical formulations that may be used for oral, buccal, or gastric administration or delivery include tablets, capsules made of gelatin which may be hard gelatin capsules, as well as soft sealed capsules made of gelatin and a plasticizer, e.g., glycerol or sorbitol. Tablets may optionally be manufactured by compression or molding with one or more accessory components. Compressed tablets may be manufactured by compressing an active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersant. Molded tablets may be manufactured by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and may be formulated to provide slow release or controlled release of the active ingredient contained therein.

[0094]

[0109] For example, any pharmaceutical composition for oral, buccal, or gastric administration or delivery may be present in a dosage suitable for such administration or delivery. Push-fit capsules may contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer may be added. A suitable coating is provided on the tablet core. For this purpose, a concentrated sugar solution may be used that may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar coating for identification or to characterize different combinations of active compound dosages.

[0095]

[0110] Examples of fillers or diluents for use in oral pharmaceutical formulations, such as capsules and tablets, include, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressed sugars, microcrystalline cellulose (MCC), powdered cellulose, corn starch, pregelatinized starch, dextrate, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tert-basic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer, e.g., polyethylene oxide, and hydroxypropyl methylcellulose. The filler may have complexed solvent molecules, such as when the lactose used is lactose monohydrate. The filler may also be the filler PROSOLV ® It may be exclusive, as in the case of (available from JRS Pharma). PROSOLV ® PROSOLV is a proprietary, selectively high-density silicified microcrystalline cellulose composed of 98% microcrystalline cellulose and 2% colloidal silicon dioxide. The silicification of the microcrystalline cellulose is achieved by a patented process, resulting in close association between the colloidal silicon dioxide and the microcrystalline cellulose. ® It is available in different grades depending on particle size, is a white or nearly white fine or granular powder, and is substantially insoluble in water, acetone, ethanol, toluene, dilute acid, and a 50 g / L sodium hydroxide solution.

[0096]

[0111] Examples of disintegrants for use in pharmaceutical compositions such as capsules and tablets include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, povidone, crospovidone (polyvinylpolypyrrolidone), methyl cellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.

[0097]

[0112] Additionally, lubricants and lubricants may be used in oral pharmaceutical compositions to ensure a uniform blend of excipients upon mixing. Examples of lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. Examples of lubricants include, but are not limited to, silicon dioxide (SiO2), talc, corn starch, and poloxamer. Poloxamer (or LUTROL available from BASF Corporation) ® ) is an ABA block copolymer in which segment A is a hydrophilic polyethylene glycol homopolymer and segment B is a hydrophobic polypropylene glycol homopolymer.

[0098]

[0113] Examples of purification binders include, but are not limited to, acacia, alginic acid, carbomer, sodium carboxymethyl cellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, copolyvidon, methyl cellulose, liquid glucose, maltodextrin, polymethacrylate, povidone, pregelatinized starch, sodium alginate, starch, sucrose, tragacanth, and zein.

[0099] Treatment methods

[0100]

[0114] In particular, C1-C4 alkyl ester azelates, such as DEA, have been found to have beneficial effects when administered to subjects, particularly in improving blood lipid levels, blood glucose levels, blood insulin levels, and blood A1c levels. These benefits have been observed in subjects with one or more diseases associated with specific metabolic disorders, such as overweight, obesity, insulin resistance, prediabetes, and / or type II diabetes, as well as subjects with metabolic syndrome and other sequelae associated with lipid imbalances. This is significant because, while abnormal lipids and lipid levels are important for maintaining metabolic homeostasis and adapting to stress imposed by nutritional fluctuations during feeding and fasting cycles, they have also been reported to contribute to or act as risk factors for specific diseases or conditions such as cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, and pancreatitis. Furthermore, as lipid metabolism and immune responses become highly integrated, the accumulation of harmful lipids or the generation of lipid signaling intermediates disrupts immune regulation in many tissues, leading to a vicious cycle of immune-metabolic disorders and the development of various diseases and disorders associated with dyslipidemia and metabolic syndrome. While not to be limited to any theory, it is believed that C1-C4 alkyl ester azelates, such as DEA, exert the beneficial effects disclosed herein by preventing, improving, or treating diseases or conditions affected by metabolic and inflammatory abnormalities through the regulation of membrane fluidity and / or the modulation of immune-modulating signaling intermediates and mechanisms in a manner that promotes and / or normalizes metabolic and immune homeostasis.

[0101]

[0115] Diseases and disorders associated with dyslipidemia and metabolic syndrome include, for example, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight, and obesity. Accordingly, subjects who have dyslipidemia, metabolic syndrome, or one or more diseases or conditions associated with dyslipidemia or metabolic syndrome, are suspected of having them, or have a predisposition to acquire them, may be treated using the methods provided at this institution and throughout.

[0102]

[0116] In some embodiments, a method for improving one or more abnormal lipid levels in a subject is provided, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a C1-C4 alkyl ester azelate to improve one or more abnormal lipid levels. In some embodiments, the C1-C4 alkyl ester azelate is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, the C1-C4 alkyl ester azelate is DEA.

[0103]

[0117] In some embodiments, a method is provided for lowering elevated LDL levels in a subject, raising reduced HDL levels, lowering elevated triglyceride levels, lowering elevated cholesterol / HDL, lowering elevated LDL / HDL, lowering elevated LDL / triglyceride, or lowering elevated non-cholesterol HDL / HDL, said method comprising administering to a subject an effective amount of a pharmaceutical composition comprising a C1-C4 alkyl ester azelate. In some embodiments, the C1-C4 alkyl ester azelate is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, the C1-C4 alkyl ester azelate is DEA.

[0104]

[0118] In some embodiments, a method for treating or preventing dyslipidemia or a disease or condition associated with dyslipidemia in a subject is provided, comprising administering to a subject a pharmaceutical composition containing an amount of C1-C4 alkyl ester azelate effective for treating or preventing dyslipidemia or a disease or condition associated with dyslipidemia in the subject. In some embodiments, the C1-C4 alkyl ester azelate is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, the C1-C4 alkyl ester azelate is DEA.

[0105]

[0119] In some embodiments, the method comprises oral administration of a C1-C4 alkyl ester azelate such as DEA. In some embodiments, oral administration provides buccal or gastric delivery of a C1-C4 alkyl ester azelate such as DEA. Such oral administration may be achieved, for example, via tablets, capsules, elixirs, etc., as described herein and in its entirety. In some embodiments, the administration step is performed parenterally. In some embodiments, parenteral administration is performed intramuscularly or subcutaneously. In some embodiments, a combination of intestinal and parenteral administration may be used.

[0106]

[0120] A suitable or effective single dose size is a dose that, when administered one or more times over a suitable period, can cause a measurable improvement in one or more lipid levels and / or insulin resistance, blood glucose levels, or the subject's blood A1c percentage. A suitable or effective single dose size may also be a dose that, when administered one or more times over a suitable period, can cause a measurable change in insulin resistance in the subject compared to the measure of insulin resistance established prior to the initiation of treatment. The dose may vary depending on the condition of the subject being treated, including the severity of dyslipidemia, diseases or conditions associated with dyslipidemia, whether the subject has overt diabetes, and / or any other relevant or unrelated health factors experienced by the specific patient.

[0107]

[0121] In some embodiments, the method provided herein is about 0.1 mg / kg / day, about 0.2 mg / kg / day, about 0.3 mg / kg / day, about 0.4 mg / kg / day, about 0.5 mg / kg / day, about 0.6 mg / kg / day, about 0.7 mg / kg / day, about 0.8 mg / kg / day, about 0.9 mg / kg / day, about 1.0 mg / kg / day, about 1.1 mg / kg / day, about 1.2 mg / kg / day, about 1.3 mg / kg / day, 1.4 mg / kg / day, about 1.5 mg / kg / day, about 1.6 mg / kg / day, about 1.7 mg / kg / day, about 1.8 mg / kg / day, about 1.9 mg / kg / day, about 2.0 mg / kg / day, about 2.1 mg / kg / day, about 2.2 mg / kg / day, approx. 2.3 mg / kg / day, approx. 2.4 mg / kg / day, approx. 2.5 mg / kg / day, approx. 2.6 mg / kg / day, approx. 2.7 mg / kg / day, approx. 2.8 mg / kg / day, approx. 2.9 mg / kg / day, approx. 3.0 mg / kg / day, approx. 3.1 mg / kg / day, approx. 3.2 mg / kg / day, approx. 3.3 mg / kg / day, approx. 3.4 mg / kg / day, approx. 3.5 mg / kg / day, approx. 3.6 mg / kg / day, approx. 3.7 mg / kg / day, approx. 3.8 mg / kg / day, approx. 3.9 mg / kg / day, approx. 4.0 mg / kg / day, approx. 4.1 mg / kg / day, approx. 4.2 mg / kg / day, approx. 4.3 mg / kg / day, approx. 4.4 mg / kg / day, approx. 4.5 mg / kg / day, approx. 4.6 mg / kg / day, approx. 4.7 mg / kg / day, approx. 4.8 mg / kg / day, approx. 4.9 mg / kg / day, 5.0 mg / kg / day, approx. 5.1 mg / kg / day, approx. 5.2 mg / kg / day, approx. 5.3 mg / kg / day, approx. 5.4 mg / kg / day, approx. 5.5 mg / kg / day, approx. 5.6 mg / kg / day, approx. 5.7 mg / kg / day, approx. 5.8 mg / kg / day, approx. 5.9 mg / kg / day, approx. 6.0 mg / kg / day, approx. 6.1 mg / kg / day, approx. 6.2 mg / kg / day, approx. 6.3 mg / kg / day, approx. 6.4 mg / kg / day, approx. 6.5 mg / kg / day, approx. 6.6 mg / kg / day, approx. 6.7 mg / kg / day, approx. 6.8 mg / kg / day, approx. 6.9 mg / kg / day, 7.0 mg / kg / day, approx. 7.1 mg / kg / day, approx. 7.2 mg / kg / day, approx. 7.3 mg / kg / day, approx. 7.4 mg / kg / day, approx. 7.5 mg / kg / day, approx. 7.6 mg / kg / day, approx. 7.7 mg / kg / day, approx. 7.8 mg / kg / day, approx. 7.9 mg / kg / day, 8.0 mg / kg / day, approx. 8.1 mg / kg / day, approx. 8.2 mg / kg / day, approx. 8.3 mg / kg / day, approx. 8.4 mg / kg / day, approx. 8.5 mg / kg / day, approx. 8.6 mg / kg / day, approx. 8.7 mg / kg / day, approx. 8.8 It comprises administering a pharmaceutical composition comprising a C1-C4 alkyl ester azelate in a dosage of mg / kg / day, about 8.9 mg / kg / day, 9.0 mg / kg / day, about 9.1 mg / kg / day, about 9.2 mg / kg / day, about 9.3 mg / kg / day, about 9.4 mg / kg / day, about 9.5 mg / kg / day, about 9.6 mg / kg / day, about 9.7 mg / kg / day, about 9.8 mg / kg / day, about 9.9 mg / kg / day, or about 10.0 mg / kg / day. In some embodiments, the C1-C4 alkyl ester azelate administered in this dosage range is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, the C1-C4 alkyl ester azelate administered in this dosage range is DEA.

[0108]

[0122] In some embodiments, the C1-C4 alkyl ester azelate, e.g., DEA, in the pharmaceutical composition is about 1 mg / kg / day. The dose range for adult humans is generally 3 mg to 2 g per day. The dosage may be calculated based on the subject's body mass. For example, based on an average body mass of about 120 to about 180 kg, the dose range for adult humans may be 50 mg to 0.5 g per day; based on an average body mass of about 80 to about 120 kg, the dose range for adult humans may be 10 mg to 1 g per day, or 5 mg to 0.15 g per day; and based on an average body mass of about 60 to about 80 kg, the dose range for adult humans may be 25 mg to 0.3 g per day. Depending on the method of administration, the pharmaceutical composition may contain, for example, about 0.1% by weight to about 99% by weight of DEA. Where the pharmaceutical composition comprises dosage units, each unit may contain, for example, about 10 to 2000 mg, or about 10 to 1000 mg, more typically 5 mg to 150 mg of the active ingredient in a single or divided dose. Those skilled in the art may recognize flexibility in administration based on the needs of individual patients, and dosages may be outside these ranges based on responses observed in tests such as glucose tolerance tests and assessments of baseline lipid levels (e.g., lipid levels measured before the start of treatment). Therefore, these ranges should be understood as merely exemplary. In some embodiments, dosages are selected based on diagnostic screening as part of an ongoing therapy regimen, thus enabling adjustment of dosage as needed for each individual subject.

[0109]

[0123] The above method may further include administering a second active ingredient. In some embodiments, administering the second active ingredient is separate from administering a pharmaceutical composition containing a C1-C4 alkyl ester azelate, e.g., DEA. In some embodiments, the second active ingredient is co-administered with a pharmaceutical composition containing a C1-C4 alkyl ester azelate, e.g., DEA. In some embodiments, the second active ingredient is present in a pharmaceutical composition containing a C1-C4 alkyl ester azelate, e.g., DEA. The second active ingredient above is a C1-C4 alkyl ester azelate other than DEA, biguanide, metformin, buformin, phenformin, thiazolidinedione, pioglitazone, rosiglitazone, corticosteroid, prednisone, insulin, lipase inhibitor, orlistat, glucagon-like peptide-1 (GLP-1) agonist, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitor, statin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, lusovastatin, simvastatin, fibrate, gemfibrozil, fenofibrate, niacin, leptin, leptin agonist, metreleptin, amylin agonist, pramlintide, and their It can be selected from combinations.

[0110]

[0124] In some embodiments, the disclosure of the present invention provides for the use of a pharmaceutical composition comprising a C1-C4 alkyl ester azelate to treat or prevent dyslipidemia or a disease or condition associated with dyslipidemia in a subject.

[0111]

[0125] In some embodiments, the disclosure of the present invention provides for the use of a pharmaceutical composition comprising a C1-C4 alkyl ester azelate to improve one or more abnormal lipid levels when administered to a subject.

[0112]

[0126] In some embodiments, the disclosure of the present invention provides for the use of C1-C4 alkyl ester azelates in the manufacture of drugs for treating or preventing dyslipidemia or diseases or conditions associated with dyslipidemia in subjects.

[0113]

[0127] In some embodiments, the disclosure of the present invention provides the use of a C1-C4 alkyl ester azelate in the manufacture of a drug for improving one or more abnormal lipid levels when administered to a subject.

[0114]

[0128] In some embodiments, the disclosure of the present invention provides a drug comprising a C1-C4 alkyl ester azelate for the treatment or prevention of dyslipidemia or a disease or condition associated with dyslipidemia in a subject.

[0115]

[0129] In some embodiments, the disclosure of the present invention provides a drug comprising a C1-C4 alkyl ester azelate for improving one or more abnormal lipid levels when administered to a subject.

[0116]

[0130] In an embodiment, the agent is a C1-C4 alkyl ester azelate other than DEA, biguanide, metformin, buformin, phenformin, thiazolidinedione, pioglitazone, rosiglitazone, corticosteroid, prednisone, insulin, lipase inhibitor, orlistat, glucagon-like peptide-1 (GLP-1) agonist, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitor, statin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rusovastatin, simvastatin, fibrate, gemfibrozil, fenofibrate, niacin, leptin, leptin agonist, metreleptin, amylin agonist, pramlintide, and combinations thereof. It further includes a second active ingredient comprising one or more of the following.

[0117]

[0131] The following examples are provided to illustrate embodiments of the disclosure of the present invention. These examples are merely illustrative and are not intended to limit the scope of the disclosure of the present invention. Also, parts and percentages are by weight unless otherwise indicated. As used herein, "room temperature" refers to a temperature of about 20°C to about 25°C.

[0118] Examples

[0119] Example 1

[0120]

[0001] The evaluation of the effects of alkyl azelates, e.g., DEA, on specific markers of insulin resistance and dyslipidemia, including plasma glucose, insulin levels, and / or lipid levels, when administered orally to overweight or obese adult male volunteers

[30] is described in this example. The cohort ranged from normal to prediabetic subjects based on the level of glycated hemoglobin A1c (A1c), a blood marker considered a long-term gauge of blood glucose control

[31] . The American Diabetes Association defines prediabetes as A1c levels of 5.7%–6.4%, but also states that patients with A1c levels just below the 5.7% threshold are at risk of developing diabetes

[32] . The results of the study demonstrate that alkyl azelates such as DEA can significantly improve lipid levels and, consequently, significantly improve dyslipidemia or diseases or conditions associated with dyslipidemia, such as in the context of insulin resistance.

[0121]

[0002] abbreviation

[0122] A1c= Hemoglobin A1c

[0123] AFLD = Alcoholic Fatty Liver Disease

[0124] BMI = Body Mass Index

[0125] CHL = Cholesterol

[0126] DEA = Diethyl azelate

[0127] GC-MS = Gas Chromatography-Mass Spectrometry

[0128] HDL = High-density lipoprotein

[0129] LDL = low-density lipoprotein

[0130] NAFLD = Non-alcoholic fatty liver disease

[0131] NASH = Non-alcoholic fatty liver disease

[0132] ncHDL = Non-cholesterol high-density lipoprotein

[0133] OGTT = Fasting Oral Glucose Tolerance Test

[0134] T2D = Type 2 diabetes

[0135] TRG = Triglyceride

[0136]

[0003] Materials and Methods

[0137]

[0004] Diethyl azelate was synthesized from azelaic acid and ethyl alcohol by fractional distillation following a standard acid-catalyzed esterification reaction, and DEA was produced with 99% purity as determined by chromatography-mass spectrometry (GC-MS).

[0138]

[0005] Other azelaic acid esters are synthesized from azelaic acid and their respective alcohols (e.g., methyl, propyl, isobutyl, 1-, 2-, and 3-pentyl) using fractional distillation after standard acid-catalyzed esterification to produce DMA, DiPA, DiBuA, di-(1-pentyl) azelate (D1PA), (D2PA), or di-(3-pentyl) azelate (D3PA).

[0139]

[0006] Human research was conducted with the approval of the Institutional Review Board of IntegReview (Austin, TX, USA). Written informed consent was obtained from research subjects in accordance with the advance consent protocol EP20160001. The Board was constituted and operated in accordance with the ethical rules of the Declaration of Helsinki and the requirements set forth in U.S. Federal Regulation 21 CFR Part 56.

[0140]

[0007] Seventeen subjects were recruited by sampling a large group at risk of T2D (based on convenience sampling; statistical method to derive representative data

[33] ) to measure changes in glucose, lipid, and insulin measurements after OGTT after treating the subjects for 21 days.

[0141]

[0008] The object is 27.2 to 43.6 kg / m² 2 The subjects were overweight to obese men with a body mass index (BMI) in the range of 5.0–6.2%, glycated hemoglobin A1c (HbA1c), and insulin levels of 8.8–52 μU / mL. The study was conducted by Clinical Trials of Texas, Inc. in San Antonio, Texas. The cohort represented a group at risk of developing T2D. This study was limited to male participants to control for variability in insulin sensitivity associated with the menstrual cycle

[34] . Subjects received 21 daily oral doses ("q1d") of 1 mg / kg DEA. The OGTT, in which 75 grams of glucose with a total volume of 300 mL was orally administered to the subjects, was performed again on days 0 and 21. Glucose measurements were taken at -30, -5, and 0 minutes, insulin measurements were taken at -30 and 0 minutes, and both glucose and insulin measurements were taken at 30, 60, 90, 120, and 180 minutes, where "0 minutes" is the time when the glucose solution was administered. The 180-minute time point was selected to obtain early insight into possible signals of drug action

[35] . Blood lipid levels (triglycerides, cholesterol, HDL, non-cholesterol HDL, and LDL) were measured again on days 0 and 21 prior to the start of treatment. The error of the test was <5%

[36] .

[0142]

[0009] The results of various marker measurements on days 0 and 21 were compared using both the paired Students T-test and the Wilcoxon signed-rank test. The results of both calculations are provided; first, from the paired Students T-test p The p-values ​​were followed by the p-values ​​from the Wilcoxon signed-rank test. Results generated by other methods were validated using generalized estimation equations and bootstrapping. Fasting glucose was calculated as the mean of the -30, -5, and 0-minute measurements, and fasting insulin was calculated as the mean of the -30 and 0-minute measurements. Spearman's correlation coefficient was calculated for the relationship between A1c and pre-treatment fasting plasma glucose versus post-treatment fasting plasma glucose. The area under the curve (AUC) was calculated over the 180-minute time range of the OGTT. All analyses were performed using the open-language engine R 3.4.4. Statistical significance was at the α = 0.05 level.

[0143]

[0010] result

[0144]

[0145]

[0013] Daily oral DEA was well tolerated by all study subjects; only one subject experienced transient mild diarrhea during the first week of treatment. No other adverse effects were reported. The specific effects of DEA on the investigated endpoints are summarized in Table 1 and presented in detail below.

[0146]

[0147]

[0014] glucose

[0148]

[0015] Levels of glycated hemoglobin A1c ("A1c"), which are considered a measure of average blood glucose levels in subjects over the 2 or 3 months prior to measurement, are often measured to evaluate the effects of oral antidiabetic drugs on glucose regulation, and drug activity becomes apparent within the first 4 to 6 months

[37] . Although a measurable effect on A1c was not expected in this short-term study, it was used to measure A1c levels prior to treatment and to assess the relative status of insulin resistance in subjects.

[0149]

[0016] When cohorts are classified by descending A1c values ​​( Fig. 1 Three subjects with A1c values ​​of 6.2, 6.1, and 6.0% were classified as prediabetes, and six subjects with A1c values ​​of 5.6–5.7% were classified as having an increased risk for T2D. This subgroup of nine subjects with A1c ≥5.6% is referred to herein as 'high A1c'. The remaining eight subjects with A1c values ​​of 5.0–5.4%, who have a lower risk for T2D, were referred to as "low A1c". Stratification by fasting plasma glucose levels indicated that nine subjects had levels greater than 100 mg / dL ('high glucose') and eight subjects had levels below the threshold of 100 mg / mL ('low glucose').

[0150]

[0017] To measure the effect of DEA on blood glucose, we relied on the evaluation of fasting plasma glucose levels, a commonly used measure to indicate that a subject may have diabetes. Levels below 100 mg / dL are considered clinically normal

[38] , while a range of 100 to 125 mg / dL indicates prediabetes

[39] . At a threshold of 100 mg / dL, the human body begins to have an impaired insulin response to glucose shock

[40] . We used an OGTT, which involves orally ingesting a standard dose of glucose and collecting a blood sample at a specific time after ingestion. Subsequently, plasma blood glucose measurements were obtained as a means to understand the pharmacodynamic effects of DEA.

[0151]

[0018] When analyzing the entire cohort of 17 subjects as a group, fasting glucose increased slightly but not significantly by 0.11 mg / dL after treatment ( p = 0.962; p = 0.96). However, fasting glucose decreased in subjects of both the high glucose and high A1c groups. For individuals with HbA1c ≥ 5.6%, the mean decrease was 4.25 mg / dL (p = 0.128; p = 0.22). The greatest decrease occurred in 8 subjects with fasting glucose ≥ 100 mg / dL, with an average decrease of 6.06 mg / dL (p=0.033; p=0.06). Fig. 2a (Reference). The decrease in fasting glucose after treatment had a moderate correlation with pre-treatment A1c and ( p = -0.551), there was a strong correlation with fasting plasma glucose pretreatment ( p = -0.755)( Fig. 2b ).

[0152]

[0019] Controlling postprandial glucose levels is of interest for drug development, given that even transient hyperglycemia has long-term effects on cardiovascular and renal diseases, neuropathy and retinopathy [42, 43]. Fig. 3a This presents the effect of DEA on glucose at 180 minutes in high A1c and low A1c subject groups. In a subset of 12 subjects, DEA reduced glucose levels at 180 minutes by 2.4% to 31.5% with an average decrease of 21.7% compared to average glucose levels before OGTT at 21 days (p < 0.001; median decrease 25.3%). For the entire cohort, the average decrease at 180 minutes was not significant due to a single outlier (subject #1) showing a 58.6% increase (9.14%; p = 0.136; 0.057). This particular subject had an average fasting insulin of 77.45 μU / mL and may be leptin resistant, which could interfere with the mechanism of action of DEA

[44] (unpublished data). Excluding that subject, the remaining 16 subjects showed a 13.5% decrease in plasma glucose at 180 minutes after treatment (p = 0.002; 0.003).

[0153]

[0020] The effect of DEA can be evaluated by analyzing three individual cases of prediabetes. Fig. 3b As shown in [figure], the glucose processing profile of Subject #1 (A1c 6.2%) increased after treatment, but fasting and 180-minute glucose levels decreased from 123.8 to 116.3 mg / dL and from 200.0 to 184.5 mg / dL, respectively. Subjects #2 (A1c 6.1%) and #3 (A1c 6.0%) experienced an improvement in glucose clearance rates at 180 minutes (from 88.3 to 69 mg / dL and from 146 to 119 mg / dL, respectively).

[0154]

[0021] insulin

[0155]

[0022] In prediabetic conditions and furthermore in T2D, the body responds inadequately to insulin, leading to insulin resistance. Subjects with insulin resistance exhibit elevated blood glucose and insulin levels. In the study of the present invention, fasting insulin levels in the high A1c and low A1c groups were mostly within the normal range of <25 μU / mL before and after treatment ( Fig. 4a ), differences between groups were not significant. Outliers were the high A1c group, in which the average fasting insulin before treatment increased from 77.45 μU / mL to 96.15 μU / mL after treatment ( Fig. 4b It was a single subject (#1) of the reference. The remaining 16 subjects experienced a 13.4% decrease in fasting insulin ( p = 0.007; 0.009).

[0156]

[0023] In a subset of 8 subjects (#2-4, 8-11, and 13) from both high and low (≥5.3%) A1c groups, DEA treatment significantly reduced mean fasting insulin by 37.8% ( p =0.004, p =0.008) reduced (median reduction of 42.5%). Obvious nonresponders, including the outlier (Subject #1), otherwise had normal pre-treatment levels of fasting insulin, plasma glucose, and / or lipid markers. Considering all 17 subjects, the reduction was 0.7 μU / mL ( p =0.916; p =0.963). In the high fasting plasma glucose group, the decrease was 2.97 μU / mL ( p =0.752; p =0.855) and in the high A1c group, the decrease was 0.84 μU / mL ( p =0.916; p =0.963)

[0157]

[0024] Treatment effect on individual insulin profiles in 3 prediabetic subjects ( Fig. 4b ) is their glucose reaction ( Fig. 3bIt is similar to ) and suggests that in cases like Subject #1, who has advanced prediabetes, the dosage and / or duration of treatment should be further optimized.

[0158]

[0025] The area under the median insulin curve (AUC) decreased by 1663.5 in the high A1c group but increased by 3380.25 in the low A1c group. Neither change was statistically significant. Glucose and insulin responses to DEA were correlated for the entire cohort. Overall, DEA increased the correlation between AUC for glucose and insulin from 0.229 before treatment to 0.523 after treatment (data not presented).

[0159]

[0026] Geological panel

[0160]

[0027] When lipid data were analyzed for the entire cohort, DEA did not show a statistically significant effect on any endpoint considered alone: ​​total cholesterol, LDL, HDL, non-cholesterol HDL, and triglycerides (see Table 1). However, the pharmacological effect of DEA is prominent between the high A1c group and the low A1c group ( Figures 5a-5e In two subjects of the high A1c group, abnormal total cholesterol (>200 mg / dL) decreased or returned to normal levels. Moderate total cholesterol decreased by 1 mg / dL in the high A1c group but increased by 9 mg / dL in the low A1c group ( Fig. 5a LDL tended to decrease to normal values ​​of <100 mg / dL in the high A1c group, but to a lesser extent in the low A1c group (Fig. 5b). HDL and non-cholesterol HDL were within the normal range (>40 mg / dL and <130 mg / dL) in all subjects and were not significantly affected by treatment. Figs. 5c and 5dElevated triglycerides decreased to normal levels after treatment in 8 subjects, including 2 subjects in the high A1c group who had abnormal triglycerides >150 mg prior to treatment ( Fig. 5e ).

[0161]

[0028] In contrast, substantial differences were observed in lipid ratios. Total cholesterol remained largely unaffected by DEA treatment, but the total cholesterol / HDL ratio decreased significantly by 5.36% ( p = 0.025; p =0.041). This decrease was mainly led by the high A1c group, showing a 7.99% decrease ( p = 0.017; p =0.068); also Fig. 6a Refer to ). Likewise, LDL / HDL decreased by 6.46% in all 17 subjects ( p = 0.011; p =0.02). Among high A1c subjects, this reduction was 9.8% ( p = 0.008; p =0.02); also Fig. 6b Refer to [link]. Although the LDL / triglyceride and triglyceride / HDL ratios did not differ significantly between the high A1c and low A1c groups, some individuals experienced clear improvement ( Figs. 6c and 6e The focus of interest was the treatment effect on the triglyceride / HDL ratio

[39] , a predictor of cardiovascular disease, which increased by 15% in the low A1c group (from 3.9 to 4.6 after treatment) but decreased by 11% in the high A1c group (from 3.4 to 3.0). Significant improvement was also observed in the non-cholesterol HDL / HDL ratio

[45] , a predictor of the development of non-alcoholic fatty liver disease (NAFLD), which decreased by 6.6% in the entire cohort ( p = 0.025; p= 0.057) decreased by 9.8% in the high A1c group ( p =0.025; p =0.074); also Fig. 6d Refer to .

[0162]

[0029] Fig. 7 This illustrates lipid panel results for the entire cohort and both the low and high A1c groups. Large differences between the A1c subgroups were evident for HDL / LDL, total cholesterol / HDL, and triglycerides. Overall, the lipid panel differences between the high A1c and low A1c groups suggested an adaptive response to DEA.

[0163]

[0030] Data mining of the results disclosed in Example 1 using various statistical analysis methods confirmed the statistical significance of the effects of DEA on markers of dyslipidemia and insulin resistance (e.g., plasma lipid levels, plasma lipid ratios, and plasma glucose levels as disclosed herein). In the case of fasting plasma glucose, the effects of DEA were significant in subjects with prediabetes and subjects at high risk for T2D (e.g., the high A1c subgroup and the high fasting plasma glucose (FPG) group). Obvious non-responders did not possess clinical indicators of T2D or prediabetes and would therefore not be considered a group requiring antidiabetic therapy. The inconsistent response in the study group suggests that normal subjects did not benefit from DEA, while subjects with signs of dyslipidemia or insulin resistance responded to DEA treatment and showed improvement in their clinical indices. Individuals with higher insulin resistance experienced significantly greater improvement with DEA ​​treatment. Subjects classified as at risk of T2D or in the prediabetic range demonstrated improvement in plasma glucose as well as insulin levels. These results suggest that with DEA ​​treatment, the pancreas functions less vigorously in insulin production and is less likely to become 'burned out' as seen in late T2D

[46] .

[0164]

[0031] A comparison of the specific effects of metformin and DEA as presented herein showed many similarities and benefits of DEA compared to metformin, as provided in Table 2 below.

[0165]

[0166]

[0032] For example, in a 28-day study of 16 subjects with type II diabetes, metformin reduced fasting glucose but did not affect insulin levels

[47] . In a meta-analysis of 4,750 prediabetic subjects in a randomized trial of at least 8 weeks, metformin reduced fasting glucose (-4.5%), fasting insulin (-14.4%), and LDL (-5.6%), and increased HDL (5.0%) compared to placebo or no treatment

[48] . In the 21-day study presented herein, fasting plasma glucose was reduced by 5.9% and fasting insulin by 38%. In a 15-year study, metformin reduced the incidence of diabetes by 17% compared to placebo, and the subset that received the most benefit included subjects with higher baseline plasma glucose or A1c

[49] . The data presented herein indicate that DEA may be significantly more effective in treating or preventing not only more advanced diabetic pathology but also dyslipidemia and related conditions or diseases.

[0167]

[0033] As presented herein, the administration of metformin

[51] or DEA did not cause hypoglycemia. The effect of DEA on lipid levels presented herein was at least qualitatively similar to that of metformin and superior in many respects

[47] . For example, DEA significantly improved the LDL / HDL ratio, and the 9.8% reduction achieved in just 3 weeks was similar to the 11.7% reduction reported after 1 year of treatment with metformin in statin-naive subjects

[52] . Furthermore, oral administration of DEA was well tolerated, whereas metformin caused serious gastrointestinal side effects in 1 in 4 users and 5% of patients could not tolerate metformin at all

[53] .

[0168]

[0034] Metformin has been proposed as a treatment for obesity by inducing weight loss

[54] , reducing the risk of cardiovascular disease

[55] and cancer

[56] , and promoting life extension[57, 58]. The results presented herein, which are superior to those reported for metformin by many measures, also demonstrate the utility of DEA in these indications and other related diseases or conditions.

[0169]

[0035] Unlike the glucose and insulin effects of DEA in subjects with higher insulin resistance, significant improvements in diagnostic lipid ratios of cholesterol / HDL, LDL / HDL

[59] , and non-cholesterol HDL / HDL

[60] were observed in the entire cohort of the subject study. These subjects were overweight or obese and were therefore at risk of metabolic syndrome-related diseases and conditions, including metaflammation

[61] , NAFLD and NASH

[62] , type 2 diabetes, cardiovascular disease, stroke, coronary artery disease, atherosclerosis, and cancer.

[0170]

[0036] There are currently no approved drugs to treat NAFLD or NASH, and lipid-based complications of metabolic syndrome are currently treated with statins

[63] . Except for a reduced LDL / HDL ratio for DEA (9.8%, 21-day study disclosed herein) versus statins (26.7%, 18-24-month study disclosed herein], no overlap was found in statistically significant endpoints for DEA administration and statins disclosed herein. However, statins have been reported to increase the risk of hyperglycemia and type II diabetes, particularly with a high-carbohydrate diet

[66] , and their side effects include severe muscle conditions; rhabdomyolysis further exacerbated by metabolic syndrome

[67] . Therefore, a population of subjects who cannot tolerate statins may benefit from DEA treatment, which can lower the risk of progressive disease initiated and induced by dyslipidemia.

[0171]

[0037] Example 2

[0172]

[0038] Evaluation of the effects of alkyl azelates such as DEA on specific markers of insulin resistance and dyslipidemia, namely plasma glucose, insulin levels and / or lipid levels

[30] when administered via buccal or gastric delivery to male subjects with diet-induced insulin resistance and diabetes mellitus with a BMI of approximately 27 is described in this example.

[0173]

[0039] Materials and Methods

[0174]

[0040] Diethyl azelate was synthesized from azelaic acid and ethyl alcohol by fractional distillation following a standard acid-catalyzed esterification reaction to produce DEA with 99% purity as determined by chromatography-mass spectrometry (GC-MS). The 99% distilled DEA distillate product was administered in unformulated, unencapsulated forms (i.e., "as is") for buccal delivery as shown below.

[0175]

[0041] For gastric delivery, 99% DEA distillate was placed in a hard gelatin capsule, size 00 (PureCaps USA, Philmont, NY) and administered by swallowing it with a glass of water.

[0176]

[0042] Other azelaic acid esters are synthesized from azelaic acid and their respective alcohols (methyl, propyl, isobutyl, 1-, 2-, and 3-pentyl, and cyclohexyl) using fractional distillation after standard acid-catalyzed esterification to produce DMA, DIPA, DiBuA, D1PA, D2PA, and D3PA.

[0177]

[0043] Fasting blood glucose levels were measured using UniStrip blood glucose test strips (UniStrip Technologies LLC, Charlotte, NC) and a OneTouchUltra 2 blood glucose meter (LifeScan OneTouch, Tampa, FL).

[0178]

[0044] Glycated hemoglobin A1c (A1c) blood levels are A1C Now according to the manufacturer's instructions + Measurements were taken using a sample dilution kit, test cartridge, and monitor (Polymer Technology Systems, Inc., Indianapolis, IN).

[0179]

[0045] Fasting blood levels of cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured using Lipid Panel PTS test strips and the CardioChek PA test system (Polymer Technology Systems, Inc., Indianapolis, IN) according to the manufacturer's instructions.

[0180]

[0046] result

[0181]

[0047] Fig. 8 This presents the effect of buccal DEA delivery on the measured concentrations (mg / dL) of total cholesterol, high-density lipoprotein (HDL), triglycerides, and calculated LDL (Calc LDL) as a function of DEA doses provided at 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg. The results demonstrate that total cholesterol, triglycerides, and calculated LDL were all lowered in response to buccal delivery at all administered DEA doses compared to the levels observed when DEA was not administered (i.e., "0" mg / kg DEA). More pronounced lowering effects on these lipids were observed at 0.5 mg / kg, 1 mg / kg, and 2 mg / kg DEA doses, with the greatest lowering effect observed at the 0.5 mg / kg DEA dose. The results also demonstrate that HDL levels increased at all tested DEA doses compared to the levels observed when DEA was not administered (i.e., "0" mg / kg DEA). Overall, these results demonstrate that buccal delivery of DEA leads to improvements in lipid profiles / lipid levels for all measured lipids.

[0182]

[0048] Fig. 9 This presents the effect of buccal DEA delivery on the total measured cholesterol / high-density lipoprotein (TC / HDL) ratio as a function of DEA dose, provided at 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg. The results demonstrate a lowered (i.e., improved) TC / HDL ratio with buccal delivery of DEA at all tested DEA amounts compared to the TC / HDL ratio measured without DEA administration, with greater TC / HDL ratio-lowering effects observed at 0.5 mg / kg, 1 mg / kg, and 2 mg / kg DEA doses. The TC / HDL ratio was lowered most significantly at the 0.5 mg / kg DEA dose.

[0183]

[0049] Fig. 10This presents the buccal delivery effects of 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg of DEA on plasma glucose concentrations (mg / dL) measured in the OGTT environment (i.e., "dL") at 0, 1, 2, and 4 hours after the intake of 75 g of glucose in a volume of 300 mL. The results demonstrate that buccal administration of DEA lowered (improved) plasma glucose levels in the OGTT environment, with the most significant reduction (improvement) observed at DEA doses of 0.5 mg / kg and 1 mg / kg.

[0184]

[0050] Fig. 11 This presents the buccal delivery effects of 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg of DEA on plasma glucose concentrations (mg / dL) in the context of OGTT (i.e., "during"). The results demonstrate that buccal administration of DEA lowered (improved) plasma glucose levels in the context of fasting OGTT, with the most significant reduction (improvement) observed at DEA doses of 0.5 mg / kg and 1 mg / kg.

[0185]

[0051] Fig. 12 This presents the buccal delivery effects of 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg of DEA on plasma glucose concentrations (mg / dL) in the OGTT environment (i.e., "dL") measured 1 hour after the intake of 75 g of glucose in a 300 mL volume. The results demonstrate that buccal administration of DEA lowered (improved) plasma glucose levels in the OGTT environment at all DEA doses, with more significant reductions (improvements) observed at 0.5 mg / kg, 1 mg / kg, and 4 mg / kg DEA doses, and the most significant reduction (improvement) observed at 0.5 mg / kg DEA dose.

[0186]

[0052] Fig. 13This presents the buccal delivery effects of 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg DEA on plasma glucose concentrations (mg / dL) in the OGTT environment (i.e., "dL") measured 2 hours after the intake of 75 g of glucose in a 300 mL volume. The results demonstrate that buccal administration of DEA lowered (improved) plasma glucose levels in the OGTT environment at all DEA doses, with more significant reductions (improvements) observed at 0.5 mg / kg, 1 mg / kg, and 4 mg / kg DEA doses, and the most significant reductions (improvements) observed at 0.5 mg / kg and 1 mg / kg DEA doses.

[0187]

[0053] Fig. 14 This presents the buccal delivery effects of 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg of DEA on plasma glucose concentrations (mg / dL) in the OGTT environment (i.e., "dL") measured 4 hours after the intake of 75 g of glucose in a 300 mL volume. The results demonstrate that buccal administration of DEA lowered (improved) plasma glucose levels in the OGTT environment at DEA doses of 0.5 mg / kg, 1 mg / kg, and 4 mg / kg, with the most significant reduction (improvement) observed at DEA doses of 0.5 mg / kg, 1 mg / kg, and 4 mg / kg.

[0188]

[0054] Fig. 15This presents the effects of buccal DEA delivery (upper panel) and gastric delivery (lower panel) on total cholesterol (TC) levels, high-density lipoprotein (HDL) levels, triglyceride levels, calculated low-density lipoprotein (Calc LDL) levels, and the TC / HDL ratio measured at the prescribed DEA dosage (leftmost column; DEA dosage in mg / kg). The results demonstrate lowered (i.e., improved) measured TC, triglyceride, and Calc LDL levels, as well as the TC / HCl ratio, at all DEA dosages tested in both buccal and gastric delivery compared to no DEA administration ("0" mg / kg DEA). The results also demonstrate elevated (i.e., improved) HCL levels at all DEA dosages in both buccal and gastric delivery compared to no DEA administration ("0" mg / kg DEA). More significant improvements in the indicated lipid levels and ratios were observed, for example, at a dose of 1 mg / kg DEA for buccal delivery and 0.25 mg / kg DEA for gastric delivery.

[0189]

[0055] Fig. 16 This presents the effects of buccal DEA delivery (upper panel) and gastric delivery (lower panel) on plasma glucose levels (mg / dL) measured as indicated in the OGTT environment (i.e., "during") at 0, 1, 2, and 4 hours after the intake of 75 g of glucose in a 300 mL volume. The results demonstrate reduced (i.e., improved) plasma glucose levels with both buccal and gastric delivery of DEA at most tested DEA doses and time points after glucose intake, compared to no DEA administration ("0" mg / kg DEA). More significant improvements in plasma glucose levels were observed, for example, at a dose of 0.5 mg / kg DEA for buccal delivery and 0.25 mg / kg DEA for gastric delivery.

[0190]

[0056] Fig. 17It provides a comparison of indicated measurements of lipid levels (upper panel) and plasma glucose levels (lower panel) at indicated DEA doses via buccal delivery and gastric delivery (left column), as well as an evaluation of the statistical association between the delivery modes for each measurement as determined by Student's paired two-tailed T-test and homoskedastic analysis T-test. The results indicate that, for example, buccal delivery of DEA resulted in statistically significantly greater improvements in total cholesterol and the total cholesterol / high-density lipoprotein (TC / HDL) ratio compared to the improvements observed with gastric delivery of DEA. The results also indicate that, for example, buccal delivery of DEA resulted in significantly greater improvements in plasma glucose levels at 0 and 4 hours after ingesting 75 grams of glucose in a 300 mL volume in the OGTT setting.

[0191]

[0057] References

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

Claims

Claim 1 A pharmaceutical composition for buccal delivery comprising a C1-C4 alkyl ester azelate to treat or prevent dyslipidemia or a disease or condition associated with dyslipidemia in a subject, wherein the disease or condition associated with dyslipidemia comprises one or more of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, and pancreatitis. Claim 2 A pharmaceutical composition according to claim 1, comprising treatment or prevention that improves one or more abnormal lipid levels in a subject. Claim 3 A pharmaceutical composition according to claim 2, wherein the improvement comprises lowering elevated low-density lipoprotein (LDL) levels in a subject, raising reduced high-density lipoprotein (HDL) levels, lowering elevated triglyceride levels, lowering elevated total cholesterol to HDL ratio (cholesterol / HDL), lowering elevated LDL-to-HDL ratio (LDL / HDL), lowering elevated LDL-to-triglyceride ratio (LDL / triglyceride), or lowering elevated non-cholesterol HDL-to-HDL ratio (non-cholesterol HDL / HDL). Claim 4 A pharmaceutical composition according to claim 1, comprising at least one of an elevated LDL level, a decreased HDL level, an elevated triglyceride level, an elevated cholesterol / HDL, an elevated LDL / HDL, an elevated LDL / triglyceride, and an elevated non-cholesterol HDL / HDL. Claim 5 A pharmaceutical composition according to claim 1, wherein the C1-C4 alkyl ester azelate is selected from the group consisting of dimethyl azelate (DEA), dimethyl azelate (DMA), di-isopropyl azelate (DiPA), di-isobutyl azelate (DiBuA), and di-2-pentyl azelate (D2PA). Claim 6 A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a C1-C4 alkyl ester azelate in a dosage range of about 0.1 mg / kg / day to about 10 mg / kg / day. Claim 7 In claim 1, the pharmaceutical composition comprises DEA. Claim 8 A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a dosage of DEA of about 0.1 mg / kg / day, about 0.25 mg / kg / day, about 0.5 mg / kg / day, about 1 mg / kg / day, about 2 mg / kg / day, or about 4 mg / kg / day. Claim 9 A pharmaceutical composition according to claim 1, wherein the subject has at least one of insulin resistance, prediabetes, type II diabetes, overweight, or obesity; is suspected of having such; or is suspected of having a predisposition to acquire such. Claim 10 A pharmaceutical composition according to claim 1, wherein the subject has a body mass index (BMI) of less than 25 to 30 or a BMI of 30 or more. Claim 11 A pharmaceutical composition according to claim 1, wherein the second active ingredient is administered separately from or co-administered with the pharmaceutical composition containing DEA. Claim 12 A pharmaceutical composition according to claim 1, wherein a second active ingredient present in the pharmaceutical composition containing DEA is additionally administered. Claim 13 In paragraph 12, the second active ingredient is a C1-C4 alkyl ester azelate other than DEA, biguanide, metformin, buformin, phenformin, thiazolidinedione, pioglitazone, rosiglitazone, corticosteroid, prednisone, insulin, lipase inhibitor, orlistat, glucagon-like peptide-1 (GLP-1) agonist, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitor, statin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, lusovastatin, simvastatin, fibrate, gemfibrozil, fenofibrate, niacin, leptin, leptin agonist, metreleptin, amylin agonist, pramlintide, A pharmaceutical composition comprising one or more of the above and combinations thereof. Claim 14 A pharmaceutical composition in which insulin is formulated as a rapid-acting formulation, an intermediate-acting formulation, a long-acting formulation, or a combination thereof, as per paragraph 13. Claim 15 A pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition consists essentially of DEA as an active ingredient. Claim 16 A pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition comprises DEA as an active ingredient. Claim 17 A pharmaceutical composition according to any one of claims 1 to 14, wherein the subject has insulin resistance or type II diabetes. Claim 18 A pharmaceutical composition comprising DEA and a buccally permissible carrier, for use in a method for treating or preventing dyslipidemia or a disease or condition associated with dyslipidemia in a subject, wherein the method comprises administering an effective amount of the pharmaceutical composition comprising DEA to a subject at a dosage ranging from about 0.1 mg / kg / day to about 10 mg / kg / day, and wherein the disease or condition associated with dyslipidemia comprises one or more of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, and pancreatitis. Claim 19 A pharmaceutical composition according to claim 18, comprising the treatment or prevention of improving one or more abnormal lipid levels in a subject. Claim 20 A pharmaceutical composition according to claim 19, wherein the improvement comprises lowering elevated LDL levels in a subject, raising reduced HDL levels, lowering elevated triglyceride levels, lowering elevated cholesterol / HDL, lowering elevated LDL / HDL, lowering elevated LDL / triglyceride, or lowering elevated non-cholesterol HDL / HDL. Claim 21 A pharmaceutical composition according to claim 18, wherein the second active ingredient is administered separately from or co-administered with the pharmaceutical composition containing DEA. Claim 22 A pharmaceutical composition in which a second active ingredient present in a pharmaceutical composition containing DEA is additionally administered, as described in paragraph 18. Claim 23 In claim 21, the second active ingredient is a C1-C4 alkyl ester azelate other than DEA, biguanide, metformin, buformin, phenformin, thiazolidinedione, pioglitazone, rosiglitazone, corticosteroid, prednisone, insulin, lipase inhibitor, orlistat, glucagon-like peptide-1 (GLP-1) agonist, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitor, statin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, lusovastatin, simvastatin, fibrate, gemfibrozil, fenofibrate, niacin, leptin, leptin agonist, metreleptin, amylin agonist, pramlintide, A pharmaceutical composition comprising one or more of the above and combinations thereof. Claim 24 A pharmaceutical composition in which insulin is formulated as a rapid-acting formulation, an intermediate-acting formulation, a long-acting formulation, or a combination thereof, as per paragraph 23. Claim 25 In claim 18, a pharmaceutical composition having a BMI of less than 25 to 30 or a BMI of 30 or more. Claim 26 A pharmaceutical composition for treating or preventing dyslipidemia or diseases or conditions associated with dyslipidemia, comprising a C1-C4 alkyl ester azelate for buccal or gastric delivery, wherein the C1-C4 alkyl ester azelate is present in a dose ranging from about 0.25 mg / mg to about 2.0 mg / kg, and the diseases or conditions associated with dyslipidemia include one or more of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, and pancreatitis. Claim 27 A pharmaceutical composition according to claim 26, wherein the C1-C4 alkyl ester azelate is selected from the group consisting of DEA, DMA, DiPA, DiBuA, and D2PA. Claim 28 A pharmaceutical composition according to claim 26, wherein the C1-C4 alkyl ester azelate is DEA. Claim 29 In paragraph 26, a pharmaceutical composition effective in improving one or more abnormal lipid levels when a dose is administered to a subject. Claim 30 A pharmaceutical composition according to claim 26 that is effective in lowering elevated LDL levels, raising reduced HDL levels, lowering elevated triglyceride levels, lowering elevated cholesterol / HDL, lowering elevated LDL / HDL, lowering elevated LDL / triglyceride, or lowering elevated non-cholesterol HDL / HDL when the dose is administered to a subject. Claim 31 A pharmaceutical composition effective in treating or preventing dyslipidemia, or diseases or conditions associated with dyslipidemia, when administered to a subject in a dose according to claim 26. Claim 32 A pharmaceutical composition according to any one of claims 26 to 31, wherein the disease or condition associated with dyslipidemia is selected from the group consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, and pancreatitis. Claim 33 A pharmaceutical composition comprising a C1-C4 alkyl ester azelate for improving one or more abnormal lipid levels when administered to a subject. Claim 34 A pharmaceutical composition according to claim 33, comprising, when administered to a subject, improving one or more abnormal lipid levels, lowering elevated LDL levels, raising reduced HDL levels, lowering elevated triglyceride levels, lowering elevated cholesterol / HDL, lowering elevated LDL / HDL, lowering elevated LDL / triglyceride, or lowering elevated non-cholesterol HDL / HDL. Claim 35 A pharmaceutical composition according to claim 33 or 34, wherein the pharmaceutical composition is used to treat or prevent dyslipidemia or a disease or condition associated with dyslipidemia, and the disease or condition associated with dyslipidemia comprises one or more of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial mixed hyperlipidemia, steatosis, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, hepatomegaly, and pancreatitis. Claim 36 In paragraph 33 or 34, a pharmaceutical composition comprising DEA. Claim 37 In paragraph 36, a pharmaceutical composition in which DEA ​​is formulated for buccal or gastric delivery. Claim 38 A pharmaceutical composition according to claim 36, wherein DEA is administered at a dose ranging from about 0.25 mg / mg to about 2.0 mg / kg. Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete Claim 48 delete Claim 49 delete Claim 50 delete Claim 51 delete Claim 52 delete Claim 53 delete Claim 54 delete Claim 55 delete Claim 56 delete Claim 57 delete

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