Azelaic acid esters in the treatment or prevention of lipid metabolism disorders and related conditions

Abstract

Provided are pharmaceutical compositions comprising azelaic acid C1-C4 alkyl esters, such as diethyl azelate (DEA), dimethyl azelate (DMA), di-isopropyl azelate (DiPA), di-isobutyl azelate (DiBuA), and di-2-pentyl azelate (D2PA), and methods for improving abnormalities in lipid levels to treat or prevent disorders of dyslipidemia and / or conditions associated with dyslipidemia, comprising, inter alia, administering such pharmaceutical compositions to a subject.

Description

Background Art

[0001]

[0002] In particular, there is provided a pharmaceutical composition for treating or preventing dyslipidemia and / or a disease or condition associated with dyslipidemia, including improving abnormal lipid levels and treating lipid signaling diseases, and a method including the step of administering such a pharmaceutical composition to a subject. Such pharmaceutical compositions include azelaic acid C1-C4 alkyl esters such as diethyl azelate (DEA), dimethyl azelate (DMA), di-isopropyl azelate (DiPA), di-isobutyl azelate (DiBuA) or di-2-pentyl azelate (D2PA).

[0002]

[0003] Dyslipidemia refers to disorders of lipoprotein metabolism, lipid transport and clearance, and / or overeating or undereating. These disorders can manifest as abnormalities or irregularities in total blood cholesterol levels or concentrations, low density lipoprotein (LDL) levels or concentrations, triglyceride levels or concentrations, and / or high density lipoprotein (HDL) levels or concentrations. This term describes a wide range of conditions, but the most common forms of dyslipidemia are: an increase in the level of low density lipoprotein (LDL), i.e., "bad cholesterol"; a low level of high density lipoprotein (HDL), i.e., "good cholesterol"; an increase in triglyceride levels; high cholesterol, referred to as high LDL and triglyceride levels; an increase in the LDL to HDL (LDL / HDL) ratio, and / or an increase in the non-cholesterol HDL to HDL (non-cholesterol HDL / HDL) ratio, including one or more of these.

[0003]

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

[0004]

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

[0005]

[0006] In the context of insulin resistance, prediabetes, type II diabetes, metabolic syndrome, and other co-existing diseases associated with metabolic syndrome, despite the high prevalence and co-occurrence rate of dyslipidemia, treatments and therapies designed to reduce insulin resistance and / or treat prediabetes or type II diabetes often cannot adequately address the concurrent abnormal lipid levels and / or often do not adequately treat any of the other co-existing diseases associated with abnormal lipid levels such as concurrent dyslipidemia, or heart diseases such as 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 concurrent insulin resistance, prediabetes and / or type II diabetes, and nevertheless are at risk of having or acquiring a number of these co-existing metabolic diseases or conditions and cardiovascular diseases or conditions. Thus, independent of or in lieu of any treatment for insulin resistance, prediabetes or type II diabetes, lipid-lowering and / or lipid-improving therapies and treatments are desirable for such overweight or obese subjects.

[0006]

[0007] Current clinical treatments for dyslipidemia are the result of large-scale basic basic science research on lipids, lipid metabolism, and the effects of various lipids on the cellular components of arteries, inflammatory cells, and platelets. Generally, low-density lipids activate intracellular pathways that increase local and systemic inflammation, monocyte adhesion, endothelial cell dysfunction and apoptosis, and smooth muscle cell proliferation, leading to foam cell formation. Thus, dyslipidemia can be viewed, in certain respects, as an inflammatory disorder and a disorder that may be associated with or exacerbate inflammatory conditions.

[0007]

[0008] Independently of other related diseases or conditions such as insulin resistance and type II diabetes, and in both of those situations, various strategies are currently being used for the control of dyslipidemia. With regard to treating dyslipidemia, the strategies include dietary modifications aimed at reducing the intake of high-cholesterol and high-fat diets, and the prescription of one or more medicaments aimed at improving elevated cholesterol, LDL, and / or triglyceride levels. Such medicaments 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.

[0008]

[0009] Insulin resistance and type II diabetes are often first managed, as with dyslipidemia treatment strategies, by making dietary modifications aimed at increasing physical activity and reducing calorie (mainly carbohydrate) intake. If these measures do not sufficiently lower blood sugar and / or A1c levels, medicaments designed to affect blood sugar and / or A1c levels are typically used. Insulin, the most commonly used drug, is used in various formulations to lower blood glucose. Metformin, a biguanide drug that inhibits glucose production and release by the liver, may also be prescribed. Metformin increases insulin sensitivity by blocking glucose supply. Other treatments include insulin sensitizers such as thiazolidinediones including pioglitazone and rosiglitazone; glucagon-like peptide-1 (GLP-1) agonists such as exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and semaglutide; amylin agonists such as pramlintide; leptin or leptin agonists such as metreleptin; and the administration of sodium-glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin, dapagliflozin, empagliflozin, and ertuglifozin.

[0009]

[0010] Azelaic acid esters such as diethyl azelate (DEA), including C1-C4 alkyl esters of azelaic acid, are metabolic natural products in humans and other mammals [17, 18]. Azelaic acid esters are also present in grains, grain-derived products including alcoholic beverages

[19] , and fermented foods by bacterial decomposition of acylglycerol fatty acids and esterification of the resulting medium-chain fatty acids

[20] . Fermentation of olives by lactic acid bacteria for human consumption has been carried out in the Mediterranean region for at least 6,000 years

[21] . Lactic acid bacteria destroy the bitter alkaloids contained in olive fruits, converting the olive fruits into table olives

[22] . Furthermore, lactic acid bacteria ferment part of the oleic acid contained in olives into azelaic acid and azelaic acid esters. Olive skins also contain a significant amount of azelaic acid. Fermented soybean products produced by humans for more than 3,000 years

[23] can help prevent or weaken the progression of T2D

[24] . Azelaic acid and ethyl azelate are also present in tempeh, a fermented soybean product

[25] .

[0010]

[0011] Azelaic acid esters and similar fatty acid esters are not currently used as drugs, but 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 for food-contact packaging in the United States. Diethyl sebacate, a closely related ester that differs from DEA in that it has one more methylene unit than azelaic acid, is on the list of generally recognized as safe (GRAS) compounds

[28] , and the inactive ingredient list of the US Food and Drug Administration (FDA)

[29] .

Summary of the Invention

[0011]

[0012] In some embodiments, which may be combined with one or more other embodiments or aspects, there is provided a method of improving one or more lipid level abnormalities in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an azelaic acid C1-C4 alkyl ester effective to improve one or more lipid level abnormalities in the subject. In some embodiments, such method comprises administering a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester 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, such method comprises administering a pharmaceutical composition comprising DEA.

[0012]

[0013] In some embodiments, which may be combined with one or more other embodiments or aspects, there is provided a method of reducing elevated LDL levels, increasing decreased HDL levels, reducing elevated triglyceride levels, reducing elevated cholesterol / HDL, reducing elevated LDL / HDL, reducing elevated LDL / triglyceride, or reducing elevated non-cholesterol HDL / HDL in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester. In some embodiments, such method comprises administering a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, such method comprises administering a pharmaceutical composition comprising DEA.

[0013]

[0014] In some embodiments, which may be combined with one or more other embodiments or implementations, a method for treating or preventing dyslipidemia, or a disease or condition associated with dyslipidemia, in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of azelaic acid C1-C4 alkyl ester to treat or prevent dyslipidemia, or a disease or condition associated with dyslipidemia, in the subject. In some embodiments, the dyslipidemia comprises at least one of the following: 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, such a method comprises administering a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, such a method comprises administering a pharmaceutical composition comprising DEA.

[0014]

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

[0015]

[0016] In some embodiments, which may be combined with one or more other embodiments or implementations, the methods provided herein administer to a subject an azelaic acid C1-C4 alkyl ester in a dosage range of from about 0.1 milligrams per kilogram per day (mg / kg / day) to about 10 mg / kg / day, from about 0.2 mg / kg / day to about 9.5 mg / kg / day, from about 0.3 mg / kg / day to about 9 mg / kg / day, from 0.4 mg / kg / day to about 8.5 mg / kg / day, from about 0.5 mg / kg / day to about 8 mg / kg / day, from about 0.6 mg / kg / day to about 7.5 mg / kg / day, from about 0.7 mg / kg / day to about 7.0 mg / kg / day, from about 0.8 mg / kg / day to about 6.5 mg / kg / day, from about 0.9 mg / kg / day to about 6.0 mg / kg / day, from about 1.0 mg / kg / day to about 5.5 mg / kg / day, from about 1.0 mg / kg / day to about 5.0 mg / kg / day, from about 0.1 mg / kg / day to about 5.0 mg / kg / day, from about 0.25 mg / kg / day to about 5.0 mg / kg / day, from about 0.1 mg / kg / day to about 4.0 mg / kg / day, from about 0.25 mg / kg / day to about 4.0 mg / kg / day, from about 0.5 mg / kg / day to about 4.0 mg / kg / day, from about 0.75 to about 4.0 mg / kg / day, or from about 0.25 mg / kg / day to about 3.0 mg / kg / day, from about 0.25 mg / kg / day to about 2.5 mg / kg / day, from about 0.25 mg / kg / day to about 2.0 mg / kg / day, from about 0.25 mg / kg / day to about 1.5 mg / kg / day, or from about 0.25 mg / kg / day to about 1.5 mg / kg / day. In some embodiments, the azelaic acid C1-C4 alkyl ester is orally administered in such dosage ranges.

[0016]

[0017] In some embodiments, which may be combined with one or more other embodiments or implementations, the methods provided herein administer to a subject from 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, about 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, about 2.3 mg / kg / day, about 2.4 mg / kg / day, about 2.5 mg / kg / day, about 2.6 mg / kg / day, about 2.7 mg / kg / day, about 2.8 mg / kg / day, about 2.9 mg / kg / day, about 3.0 mg / kg / day, about 3.1 mg / kg / day, about 3.2 mg / kg / day, about 3.3 mg / kg / day, about 3.4 mg / kg / day, about 3.5 mg / kg / day, about 3.6 mg / kg / day, about 3.7 mg / kg / day, about 3.8 mg / kg / day, about 3.9 mg / kg / day, about 4.0 mg / kg / day, about 4.1 mg / kg / day, about 4.2 mg / kg / day, about 4.3 mg / kg / day, about 4.4 mg / kg / day, about 4.5 mg / kg / day, about 4.6 mg / kg / day, about 4.7 mg / kg / day, about 4.8 mg / kg / day, about 4.9 mg / kg / day, 5.0 mg / kg / day, about 5.1 mg / kg / day, about 5.2 mg / kg / day, about 5.3 mg / kg / day, about 5.4 mg / kg / day, about 5.5 mg / kg / day, about 5.6 mg / kg / day, about 5.7 mg / kg / day, about 5.8 mg / kg / day, about 5.9 mg / kg / day, about 6.0 mg / kg / day, about 6.1 mg / kg / day, about 6.2 mg / kg / day, about 6.3 mg / kg / day, about 6.4 mg / kg / day, about 6.5 mg / kg / day, about 6.6 mg / kg / day, about 6.7 mg / kg / day, about 6.8 mg / kg / day, about 6.9 mg / kg / day, 7.0 mg / kg / day, about 7.1 mg / kg / day, about 7.2 mg / kg / day, about 7.3 mg / kg / day, about 7.4 mg / kg / day, about 7.5 mg / kg / day, about 7.6 mg / kg / day, about 7.7 mg / kg / day, about 7.8 mg / kg / day, about 7.administering a pharmaceutical composition comprising azelaic acid C1-C4 alkyl ester at a dosage of 9 mg / kg / day, 8.0 mg / kg / day, about 8.1 mg / kg / day, about 8.2 mg / kg / day, about 8.3 mg / kg / day, about 8.4 mg / kg / day, about 8.5 mg / kg / day, about 8.6 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 azelaic acid C1-C4 alkyl ester is administered orally at such dosages.

[0017]

[0018] In some embodiments, which may be combined with one or more other embodiments or implementations, the methods provided herein involve administering to a subject a pharmaceutical composition comprising DEA at a dosage in the range of from about 0.1 mg / kg / day to about 10 mg / kg / day, from about 0.2 mg / kg / day to about 9.5 mg / kg / day, from about 0.3 mg / kg / day to about 9 mg / kg / day, from 0.4 mg / kg / day to about 8.5 mg / kg / day, from about 0.5 mg / kg / day to about 8 mg / kg / day, from about 0.6 mg / kg / day to about 7.5 mg / kg / day, from about 0.7 mg / kg / day to about 7.0 mg / kg / day, from about 0.8 mg / kg / day to about 6.5 mg / kg / day, from about 0.9 mg / kg / day to about 6.0 mg / kg / day, from about 1.0 mg / kg / day to about 5.5 mg / kg / day, from about 1.0 mg / kg / day to about 5.0 mg / kg / day, from about 0.1 mg / kg / day to about 5.0 mg / kg / day, from about 0.25 mg / kg / day to about 5.0 mg / kg / day, from about 0.1 mg / kg / day to about 4.0 mg / kg / day, from about 0.25 mg / kg / day to about 4.0 mg / kg / day, from about 0.5 mg / kg / day to about 4.0 mg / kg / day, from about 0.75 to about 4.0 mg / kg / day or from about 0.25 mg / kg / day to about 3.0 mg / kg / day, from about 0.25 mg / kg / day to about 2.5 mg / kg / day, from about 0.25 mg / kg / day to about 2.0 mg / kg / day, from about 0.25 mg / kg / day to about 1.5 mg / kg / day, or from about 0.25 mg / kg / day to about 1.5 mg / kg / day. In some embodiments, the pharmaceutical composition comprises DEA for oral administration at such dosage ranges.

[0018]

[0019] In some embodiments, which may be combined with one or more other embodiments or implementations, the methods provided herein involve administering to a subject from 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, about 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, about 2.3 mg / kg / day, about 2.4 mg / kg / day, about 2.5 mg / kg / day, about 2.6 mg / kg / day, about 2.7 mg / kg / day, about 2.8 mg / kg / day, about 2.9 mg / kg / day, about 3.0 mg / kg / day, about 3.1 mg / kg / day, about 3.2 mg / kg / day, about 3.3 mg / kg / day, about 3.4 mg / kg / day, about 3.5 mg / kg / day, about 3.6 mg / kg / day, about 3.7 mg / kg / day, about 3.8 mg / kg / day, about 3.9 mg / kg / day, about 4.0 mg / kg / day, about 4.1 mg / kg / day, about 4.2 mg / kg / day, about 4.3 mg / kg / day, about 4.4 mg / kg / day, about 4.5 mg / kg / day, about 4.6 mg / kg / day, about 4.7 mg / kg / day, about 4.8 mg / kg / day, about 4.9 mg / kg / day, 5.0 mg / kg / day, about 5.1 mg / kg / day, about 5.2 mg / kg / day, about 5.3 mg / kg / day, about 5.4 mg / kg / day, about 5.5 mg / kg / day, about 5.6 mg / kg / day, about 5.7 mg / kg / day, about 5.8 mg / kg / day, about 5.9 mg / kg / day, about 6.0 mg / kg / day, about 6.1 mg / kg / day, about 6.2 mg / kg / day, about 6.3 mg / kg / day, about 6.4 mg / kg / day, about 6.5 mg / kg / day, about 6.6 mg / kg / day, about 6.7 mg / kg / day, about 6.8 mg / kg / day, about 6.9 mg / kg / day, 7.0 mg / kg / day, about 7.1 mg / kg / day, about 7.2 mg / kg / day, about 7.3 mg / kg / day, about 7.4 mg / kg / day, about 7.5 mg / kg / day, about 7.6 mg / kg / day, about 7.7 mg / kg / day, about 7.8 mg / kg / day, about 7.administering a pharmaceutical composition comprising DEA at a dose of 9 mg / kg / day, 8.0 mg / kg / day, about 8.1 mg / kg / day, about 8.2 mg / kg / day, about 8.3 mg / kg / day, about 8.4 mg / kg / day, about 8.5 mg / kg / day, about 8.6 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 for oral administration at such a dose.

[0019]

[0020] In some aspects, which may be combined with one or more other aspects or embodiments, the methods provided herein comprise administering to a subject a pharmaceutical composition comprising DEA at a dose 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 for oral administration at such a dose.

[0020]

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

[0021]

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

[0022]

[0023] In some embodiments, which may be combined with one or more other embodiments or aspects, the methods provided herein include administering to a subject a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester, wherein the subject has a body mass index (BMI) of less than 25 to 30 or a BMI of 30 or more.

[0023]

[0024] In some embodiments, which may be combined with one or more other embodiments or aspects, the methods provided herein include administering to a subject a pharmaceutical composition comprising DEA, wherein the subject has a BMI of less than 25 to 30 or a BMI of 30 or more.

[0024]

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

[0025]

[0026] In some embodiments, which may be combined with one or more other aspects or embodiments, the methods provided herein include administering to a subject a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester formulated for intragastric delivery. In some embodiments, the azelaic acid C1-C4 alkyl ester formulated for intragastric delivery comprises DEA.

[0026]

[0027] In some embodiments, which may be combined with one or more other aspects or embodiments, the methods provided herein further include administering a second active ingredient in addition to the azelaic acid C1-C4 alkyl ester. In some embodiments, the second active ingredient is administered separately from the pharmaceutical composition comprising the azelaic acid C1-C4 alkyl ester. In some embodiments, the second active ingredient is co-administered with the pharmaceutical composition comprising the azelaic acid C1-C4 alkyl ester. In some embodiments, the second active ingredient comprises one or more of an azelaic acid C1-C4 alkyl ester 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, rosuvastatin, simvastatin, fibrate, gemfibrozil, fenofibrate, niacin, leptin, leptin agonist, metreleptin, amylin agonist, pramlintide, and combinations thereof. In some embodiments, the insulin is formulated as a short-acting formulation, intermediate-acting formulation, long-acting formulation, or combination thereof.

[0027]

[0028] In some embodiments, which may be combined with one or more other embodiments or implementations, the methods provided herein include administering, as an active ingredient, a pharmaceutical composition consisting essentially of DEA.

[0028]

[0029] In some embodiments, which may be combined with one or more other embodiments or implementations, the methods provided herein include administering, as an active ingredient, a pharmaceutical composition consisting of DEA.

[0029]

[0030] In some embodiments, which may be combined with one or more other embodiments or implementations, there is provided a pharmaceutical composition comprising a C1-C4 alkyl ester of azelaic acid for buccal delivery at a dose in the range of about 0.25 milligrams per kilogram (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. In some embodiments, such a C1-C4 alkyl ester of azelaic acid is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, such a C1-C4 alkyl ester of azelaic acid is DEA.

[0030]

[0031] In some embodiments, which may be combined with one or more other embodiments or implementations, there is provided a pharmaceutical composition comprising a C1-C4 alkyl ester of azelaic acid for buccal delivery at 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, wherein said dose is effective to improve one or more abnormal lipid levels when administered to a subject. In some embodiments, such a C1-C4 alkyl ester of azelaic acid is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, such a C1-C4 alkyl ester of azelaic acid is DEA.

[0031]

[0032] In some embodiments, which may be combined with one or more other embodiments or aspects, there is provided a pharmaceutical composition for oral delivery at a dosage 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, the dosage being effective to lower elevated LDL levels, raise decreased 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 when administered to a subject. In some embodiments, such azelaic acid C1-C4 alkyl esters are selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, such azelaic acid C1-C4 alkyl ester is DEA.

[0032]

[0033] In some embodiments, which may be combined with one or more other embodiments or aspects, there is provided a pharmaceutical composition for oral delivery at a dosage 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, the dosage being effective to treat or prevent dyslipidemia, or a disease or condition associated with dyslipidemia. In some embodiments, such azelaic acid C1-C4 alkyl esters are selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, such azelaic acid C1-C4 alkyl ester is DEA.

[0033]

[0034] In some embodiments, which may be combined with one or more other embodiments or implementations, a pharmaceutical composition for oral delivery at a dosage 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, comprising an azelaic acid C1-C4 alkyl ester, wherein the dosage is effective to treat or prevent dyslipidemia, or a disease or condition associated with dyslipidemia, and the disease or condition associated with dyslipidemia is selected from the group consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial combined hyperlipidemia, lipodystrophy, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight and obesity. In some embodiments, such azelaic acid C1-C4 alkyl esters are selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA.

Brief Description of the Drawings

[0034]

Figure 1

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 4A

Figure 4B

Figure 5A

Figure 5B

Figure 5C

Figure 5D

Figure 5E

Figure 6A

Figure 6B

Figure 6C

Figure 6D

Figure 6E

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Mode for Carrying Out the Invention

[0035]

[0053] In particular, it has now been discovered that administration of azelaic acid C1-C4 alkyl esters such as DEA induces beneficial changes ("improvements") in metabolic markers of dyslipidemia, insulin resistance, and diseases or conditions associated with dyslipidemia and / or insulin resistance, such as improvement of plasma lipid and glucose levels, and risk factors therefor. In particular, these beneficial changes correlating with the severity of the disease or condition in subjects having insulin resistance, prediabetes, diabetes, abnormal lipid levels, overweight and / or obesity are disclosed herein.

[0036]

[0054] Although not bound by any theory, these effects are thought to be achieved, at least in part, by modulation of plasma membrane fluidity using membrane-soluble molecules such as azelaic acid C1-C4 alkyl esters. A growing body of evidence suggests that even minor modifications in membrane structure and composition can affect host immune function, inflammatory signaling, and innate immune responses [68-70]. Reports have shown that the structure of the plasma membrane can be modified in various diseases [71, 72], and that diet itself can affect the structure of the plasma membrane. Dietary fats and sugars have been proposed 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 azelaic acid C1-C4 alkyl esters, such as DEA, diffuse into the plasma membrane [74, 75], increase membrane fluidity, and can trigger metabolic changes that translate into health benefits.

[0037]

[0055] FIG. 18 illustrates a non-limiting example of such dynamics, where, as a function of membrane fluidity, percent protein function (% protein function) is illustrated graphically. Molecules such as azelaic acid C1-C4 alkyl esters, such as DEA, that can diffuse into the plasma membrane affect (e.g., increase) membrane fluidity, thereby affecting in vivo the function of membrane proteins and receptors (e.g., improving them). These effects on membrane fluidity are thought to depend on the relative ratios of the various lipid species present within the membrane, and there is thought to be an optimal fluidity or range of fluidities that optimizes / maximizes the function of membrane proteins or membrane receptors in vivo. In particular, there is also thought to be an innate feedback regulatory physiological mechanism (Adaptive Membrane Fluidity Modulation System: “AMFMS”) that regulates membrane fluidity through changes in membrane lipids, lipid metabolism, and blood lipid levels, including changes in triglycerides and cholesterol. Drugs that can affect or modulate such lipid levels and / or lipid metabolism may affect the AMFMS. Thus, plasma lipid levels can then serve as biomarkers that inform modulation of the AMFMS response and / or as biomarkers that identify drugs effective in modulating the AMFMS such that a therapeutic benefit is achieved.

[0038]

[0056] Accordingly, drugs and therapeutic compounds or molecules that modulate or are designed to modulate the physicochemical characteristics of membranes serve as viable candidates for the treatment of a variety of human diseases, including dyslipidemias, insulin resistance, and diseases or conditions associated therewith, caused or exacerbated by lipid level abnormalities and / or blood glucose level abnormalities. Such diseases or conditions include, for example, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial combined hyperlipidemia, lipodystrophy, adipose tissue atrophy, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, prediabetes, type II diabetes, insulin resistance, overweight, and obesity.

[0039]

[0057] In some embodiments, provided are pharmaceutical compositions and methods for improving another lipid level abnormality in a subject, comprising the step of administering such a pharmaceutical composition to the subject, wherein such a pharmaceutical composition comprises a C1-C4 alkyl ester of azelaic acid, such as DEA. In embodiments, for reducing elevated LDL levels; increasing decreased (i.e., "low") HDL levels; reducing elevated triglyceride levels; reducing elevated cholesterol / HDL; reducing elevated LDL / HDL; reducing elevated LDL / triglyceride; or reducing elevated non-cholesterol HDL / HDL levels, or combinations thereof, in a subject in need thereof, pharmaceutical compositions and methods are provided. In embodiments, provided is a method for treating or preventing dyslipidemia, or a disease or condition associated with dyslipidemia, comprising the step of administering to the subject a pharmaceutical composition comprising a C1-C4 alkyl ester of azelaic acid, such as DEA.

[0040]

[0058] As used herein, the present disclosure demonstrates, inter alia, that diseases or conditions associated with abnormal blood lipid levels and / or abnormal blood glucose levels, including, but not limited to, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial combined hyperlipidemia, lipodystrophy, adipose tissue atrophy, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, prediabetes, type II diabetes, insulin resistance, overweight, and obesity, are susceptible to treatment or prevention by administering an azelaic acid C1-C4 alkyl ester, such as DEA, to a subject in need of such treatment or prevention.

[0041]

[0060] In some embodiments, there is provided a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester, and a method for preventing, ameliorating, or treating a disease or condition associated with abnormal lipid metabolism or insulin resistance, the method comprising administering such an azelaic acid C1-C4 alkyl ester to a subject. In some embodiments, there is provided a pharmaceutical composition comprising DEA for preventing, ameliorating, or treating a disease or condition associated with abnormal lipid metabolism or insulin resistance.

[0042]

[0061] In some embodiments, there is provided a method for preventing, ameliorating, or treating a disease or condition associated with abnormal lipid metabolism or insulin resistance, the method comprising administering an azelaic acid C1-C4 alkyl ester to a subject. In some embodiments, the azelaic acid C1-C4 alkyl ester comprises DEA.

[0043]

[0062] As used interchangeably throughout, the term "abnormal lipid metabolism" or "abnormal lipid metabolisms" refers to a group of conditions or disorders characterized by abnormal lipid levels in the blood of a subject.

[0044]

[0063] "Abnormal lipid levels" compared to normal lipid levels are as follows: Elevated LDL 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 refers to one or more of. "Abnormal lipid levels" also refers to blood lipid component concentration levels or blood lipid component concentration ranges.

[0045]

[0064] Throughout, "lipid level", "lipid range", "lipid component level" and "lipid component range", or the corresponding plurals, which are used interchangeably, refer to the concentration or concentration range of lipid components in blood, plasma and / or serum, measured by methods conventional to those skilled in the art. Such lipid levels, lipid component levels, lipid ranges and / or lipid component ranges are measured, for example, in milligrams per deciliter (mg / dL).

[0046]

[0065] Throughout, "lipid component(s)" or "lipid component(s)", which are used interchangeably, refer to, for example, total cholesterol, LDL, HDL, VLDL, triglycerides and calculated LDL.

[0047]

[0066] Throughout, "normal lipid level", "healthy lipid level", "normal lipid range", "healthy lipid range" or the corresponding plurals, which are used interchangeably, refer to the concentration of lipid components in blood and / or serum recognized as being within a healthy range by health agencies and / or the medical community, such as the National Institutes of Health and the World Health Organization.

[0048]

[0067] In embodiments, normal lipid levels are as follows:

Table 0

[0049]

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

[0050]

[0069] "Improve", "improving", or "improvement" refers to, for example, bringing the level of one or more analytes, 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, and / or one or more ratios of the levels of the analytes closer to normal levels compared to previous abnormal levels. In some embodiments, such "improvement" and / or "improving" is achieved as a result of administering a pharmaceutical composition comprising azelaic acid C1-C4 alkyl esters. In some embodiments, such "improvement" and / or "improving" is achieved as a result of administering a pharmaceutical composition comprising azelaic acid C1-C4 alkyl esters selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, such "improvement" and / or "improving" is achieved as a result of administering a pharmaceutical composition comprising DEA.

[0051]

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

[0052]

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

[0053]

[0072] "Prediabetes" refers to a condition associated with one or more early diabetes conditions, including impaired glucose utilization, abnormal or defective fasting glucose levels, impaired glucose tolerance, impaired insulin sensitivity, and insulin resistance. In an embodiment, "prediabetes" can be defined by a hemoglobin A1c measurement of about 6.0% or more.

[0054]

[0073] "Insulin-resistant" or "insulin resistance" refers to a state in which insulin-sensitive cells become resistant to the action of insulin (a hormone that regulates the uptake of glucose into cells), and / or the amount of insulin produced is insufficient to maintain normal glucose levels. The cells have a reduced ability to respond to the action of insulin when promoting the transport of blood-derived sugar glucose to muscles and other tissues (i.e., reduced sensitivity to insulin). Eventually, the pancreas produces a considerably larger amount of insulin than normal, and the cells remain resistant. As long as sufficient insulin is produced to overcome this resistance, the blood glucose level remains normal. Once the pancreas can no longer maintain an elevated blood glucose level, it will eventually result in diabetes such as type II diabetes. Insulin resistance ranges from normal values (insulin sensitivity) to insulin resistance (IR).

[0055]

[0074] "Overweight" refers to a condition in a subject defined by excessive body fat. In embodiments, overweight is characterized in a subject by a BMI in the range of 25 to less than 30, and / or, in the case of females, generally between about 33% and about 39%, and in the case of males, generally between about 19% and about 25% body fat percentage.

[0056]

[0075] "Obesity" refers to a condition in a subject defined by excessive body fat. In embodiments, obesity is characterized in a subject by a BMI of 30 or greater, and / or, in the case of females, generally greater than about 39%, and in the case of males, generally greater than about 25% body fat percentage.

[0057]

[0076] As used herein, the term "disease" reflects an abnormal condition of the body or a part thereof of a human or animal that impairs normal function, and is typically intended to be generally synonymous with and used interchangeably with the terms "disorder" and "condition" (i.e., medical condition) in that characteristic signs and symptoms are recognized and the lifespan or quality of life of the human or animal is reduced.

[0058]

[0077] As used herein, the term "about" is intended to mean that the numerical value modified by about is such that it is appropriate to indicate such value as a variable within the range of error. In the absence of a specific error range, such as a standard deviation relative to an average value shown in a data chart or table, the term "about" is understood to mean a range encompassing the recited value, and similarly, a range that would be included by rounding up or down the numerical value, taking significant figures into account.

[0059]

[0078] When a numerical range of values is disclosed, such range is intended to include the numbers themselves, as well as any sub-ranges therebetween. This range may include integers between and including the end values, or may be continuous.

[0060]

[0079] The term "combination therapy" means the administration of two or more therapeutic agents for treating a therapeutic condition or disorder described in the present disclosure. Such administration can include co-administering these therapeutic agents substantially simultaneously in a single dosage form having a fixed ratio of active ingredients, or in multiple individual dosage forms for each active ingredient, etc. Further, such administration can also include using each type of therapeutic agent sequentially. In any case, the treatment regimen results in a beneficial effect of the combination drug when treating the condition or disorder described herein.

[0061]

[0080] The phrases "therapeutically effective amount" or "effective amount" are intended to specify the amount of an active ingredient used to achieve a clinical or therapeutic outcome, improvement, or benefit in a subject. A "therapeutically effective amount" or "effective amount" is an amount that produces some degree of improvement, alleviation, reduction, decrease, or stabilization in at least one clinical symptom in a subject. One of ordinary skill in the art understands that the therapeutic effect need not be complete, nor need it result in a cure, so long as some degree of benefit is provided to the subject.

[0062]

[0081] In some embodiments, a "therapeutically effective amount" or "effective amount" is an amount effective to improve one or more abnormal lipid levels in a subject when administered to the subject.

[0063]

[0082] In some embodiments, a "therapeutically effective amount" or "effective amount" is an amount effective to lower elevated LDL levels, raise decreased 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 in a subject when administered to the subject.

[0064]

[0083] In some embodiments, a "therapeutically effective amount" or "effective amount" is an amount effective to treat or prevent lipid metabolism disorders, or diseases or conditions associated with lipid metabolism disorders.

[0065]

[0084] In some embodiments, a "therapeutically effective amount" or "effective amount" is an amount effective to treat or prevent one or more diseases or conditions associated with lipid metabolism disorders selected from the group consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial combined hyperlipidemia, lipodystrophy, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight and obesity, when administered to a subject. Treatment of the diseases, conditions or disorders therein. This amount will achieve the purpose of reducing or eliminating the effects of the diseases, conditions or disorders.

[0066]

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

[0067]

[0086] "Associated with" refers to a disease, condition or clinical finding or outcome that occurs simultaneously with, causes, is a comorbidity of, is a risk factor for, is a biomarker for, and / or indicates a predisposition to acquire another disease, condition or clinical finding or outcome.

[0068]

[0087] The term "comprising" is intended to mean that a composition and method include the recited elements but do not exclude others. As applied to the compositions of the present embodiments, the term "consisting essentially of" means that a composition can contain the additional elements so long as the additional elements do not substantially alter the composition. As applied to a composition, the term "substantially altered" refers to an increase or decrease in the therapeutic effectiveness of the composition as compared to the effectiveness of a composition consisting of the recited elements. In other words, "consisting essentially of" is meant to exclude other constituents that are essential for the composition when used to define the composition. Thus, a composition consisting essentially of the components defined herein does not exclude trace contaminants resulting from isolation and purification methods, as well as pharmaceutically acceptable carriers. "Consisting of" is meant to exclude elements of other components in excess of trace amounts, and essential method steps for administering the compositions of the present invention. Embodiments defined by each of these transitional terms are within the scope of the present invention.

[0069] Pharmaceutical Compositions and Treatments

[0088] Provided herein is a pharmaceutical composition comprising one or more of certain compounds disclosed herein, such as azelaic acid C1-C4 alkyl esters, optionally formulated or, if not, optionally combined with one or more pharmaceutically acceptable carriers therefor and optionally containing one or more other therapeutic components. In some embodiments, the pharmaceutical composition comprises an azelaic acid C1-C4 alkyl ester selected from the group consisting of DEA, DMA, DiPA, DiBuA, and D2PA, each of which can be prepared from azelaic acid and the respective alcohol (e.g., methyl, ethyl, propyl, isobutyl, 1-, 2- and 3-pentyl, and cyclohexyl) using standard acid-catalyzed esterification. An aliphatic acid contains an alkyl group attached to the carboxyl group.

[0070]

[0089] In an embodiment, the pharmaceutical composition contains 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., 2015), and in the EU, it is a flavoring additive (AFC 2005) approved in gram amounts.

[0071]

[0090] In an embodiment, the pharmaceutical composition contains a second active ingredient, and the second active ingredient is an alkyl ester of azelaic acid C1 - C4 (different from DEA if DEA is already contained in the pharmaceutical composition), biguanide, metformin, buformin, fenformin, 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, rosuvastatin, simvastatin, fibrate, gemfibrozil, fenofibrate, niacin, leptin, leptin agonist, metreleptin, amylin agonist, pramlintide, and one or more of their combinations.

[0072]

[0091] Other second active ingredients include, without limitation, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, AKA incretin enhancers (including alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin), sulfonylureas and related agents (including glibenclamide, gliclazide, glimepiride, glipizide, tolbutamide and nateglinide, repaglinide), acarbose, sodium-glucose cotransporter 2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin) and natural products (including nopal (prickly pear), fenugreek, karela (bitter melon), gymnema, ota ne ninjin, torandora, chromium and alpha-lipoic acid and hydroxycitric acid, etc.).

[0073]

[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 dosage.

[0074]

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

[0075]

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

[0076]

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

[0077]

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

[0078]

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

[0079]

[0098] In some embodiments, the HMG-CoA reductase inhibitor includes statins, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0080]

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

[0081]

[0100] In some embodiments, the pharmaceutical composition is enteric-coated. The pharmaceutical composition of this embodiment can be configured to provide immediate release, sustained release, continuous release, and controlled release of C1-C4 alkyl esters of azelaic acid such as DEA. In some embodiments, the pharmaceutical composition is configured to provide sustained release of C1-C4 alkyl esters of azelaic acid such as DEA. In some embodiments, the pharmaceutical composition is configured to provide any combination of immediate release, sustained release, continuous release, and controlled release of C1-C4 alkyl esters of azelaic acid such as DEA. The various release profiles of the foregoing embodiments can be achieved by any conventional method known in the art. In some embodiments, the pharmaceutical composition is administered once a day. In some embodiments, the pharmaceutical composition is administered twice a day or three times a day.

[0082]

[0101] A carrier (s) is "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not harmful to the subject. Suitable formulations depend on the chosen route of administration. Any well-known techniques, carriers, and excipients understood in the art can be used, for example, those disclosed in Remington’s Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein can be manufactured by any method known in the art, such as by conventional mixing, dissolving, granulating, enteric coating, microencapsulating, emulsifying, encapsulating, entrapping, or compressing processes.

[0083]

[0102] The pharmaceutical composition is suitable for enteral (including oral, intraoral, intragastric, and rectal), parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, and topical (including skin, intraoral, sublingual, ocular, intranasal, and intraocular) administration or delivery. However, the most suitable route of administration or delivery may depend, for example, on the condition and disorder of the recipient.

[0084]

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

[0085]

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

[0086]

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

[0087]

[0106] The pharmaceutical composition may conveniently be provided in unit dosage form and may be prepared by any method well known in the pharmaceutical arts. Usually, these methods include the step of mixing azelaic acid C1-C4 alkyl esters such as DEA and optionally any co-administered active ingredient disclosed herein with a carrier that constitutes one or more accessory ingredients. Generally, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired composition.

[0088]

[0107] A pharmaceutical composition comprising either an azelaic acid C1-C4 alkyl ester such as DEA, or an optional secondary active ingredient suitable for oral, buccal or gastric administration or delivery, can be provided as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient(s) as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient(s) may also be provided as a bolus, a lozenge or a paste. In the case of buccal or sublingual administration or delivery, the composition may take the form of a conventionally formulated tablet, lozenge, pastille or gel. Such compositions may contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth. With regard to gastric administration or delivery, the composition may take the form of a gelatin capsule such as a hard gelatin capsule. An example of a gelatin capsule for gastric administration or delivery of an azelaic acid C1-C4 alkyl ester such as DEA is a size 00 gelatin capsule (PureCaps, Philmont, NY, USA).

[0089]

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

[0090]

[0109] For example, all pharmaceutical compositions for oral, buccal or gastric administration or delivery can be in a dosage suitable for such administration or delivery. Push-fit capsules can contain the active ingredient in a mixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. 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. Further, stabilizers may be added. The core of the dragees is provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the coating agent of the tablets or dragees to distinguish or characterize various combinations of the dosage of the active compound.

[0091]

[0110] Examples of fillers or diluents for use in oral pharmaceutical preparations such as capsules and tablets include, without limitation, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressed sugar, microcrystalline cellulose (MCC), powdered cellulose, corn starch, pregelatinized starch, dextrate, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers (such as polyethylene oxide and hydroxypropylmethylcellulose). Fillers may have complexed solvent molecules, such as when the lactose used is lactose monohydrate. Fillers may also be proprietary, such as in the case of PROSOLV® (available from JRS Pharma). PROSOLV® is a proprietary, optionally, high-density silicified microcrystalline cellulose consisting of 98% microcrystalline cellulose and 2% colloidal silicon dioxide. The silicification of microcrystalline cellulose is achieved by a patented process, resulting in a tight association between the colloidal silicon dioxide and the microcrystalline cellulose. PROSOLV® is supplied in various grades based on particle size and is a white or almost white, fine powder or granular powder that is substantially insoluble in water, acetone, ethanol, toluene, and dilute acids, and also in a 50 g / L solution of sodium hydroxide.

[0092]

[0111] Examples of disintegrants used in pharmaceutical compositions such as capsules and tablets include, without limitation, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, povidone, crospovidone (polyvinylpolypyrrolidone), methyl cellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.

[0093]

[0112] Furthermore, a flow promoter and a lubricant can be used in an oral pharmaceutical composition to ensure a uniform blend of the excipients during 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 flow promoters include, but are not limited to, silicon dioxide (SiO2), talc, corn starch, and poloxamer. Poloxamer (or LUTROL® available from BASF Corporation) is an A-B-A block copolymer, where segment A is a hydrophilic polyethylene glycol homopolymer and segment B is a hydrophobic polypropylene glycol homopolymer.

[0094]

[0113] Examples of tablet binders include, but are not limited to, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, copovidone, methylcellulose, liquid glucose, maltodextrin, polymethacrylate, povidone, pregelatinized starch, sodium alginate, starch, sucrose, tragacanth, and zein.

[0095] Treatment method

[0114] Azelaic acid C1-C4 alkyl esters, such as DEA, have been particularly discovered to have beneficial effects, especially when administered to a subject, on improving blood lipid levels, blood glucose levels, blood insulin levels, and blood A1c levels. Such benefits have been observed, for example, in subjects having one or more diseases among certain metabolic disorders related states such as overweight, obesity, insulin-resistance, prediabetes and / or type II diabetes, as well as other sequelae related to metabolic syndrome and lipid imbalance. This is important because at least abnormal lipids and lipid levels are important for maintaining metabolic homeostasis and adapting to the stress imposed by nutrient fluctuations during the feeding and fasting cycles, but there is a risk that they may contribute to certain diseases or conditions such as cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, etc., or act as risk factors for them, as reported. Furthermore, since lipid metabolism and immune response are highly integrated, the accumulation of harmful lipids or the generation of lipid signaling intermediates may interfere with immune regulation in multiple tissues, triggering a dangerous cycle of dysregulated immunometabolism, and the development of numerous conditions and disorders related to lipid metabolism disorders and metabolic syndrome. Without wishing to be bound by any theory, azelaic acid C1-C4 alkyl esters, such as DEA, exert the beneficial effects disclosed herein by modulating membrane fluidity and / or by modulating immunoregulatory signaling intermediates and mechanisms so as to promote and / or normalize metabolic homeostasis and immune homeostasis, thereby preventing, ameliorating, or treating diseases or conditions affected by metabolic disorders and inflammatory disorders.

[0096]

[0115] Conditions and disorders associated with lipid metabolism disorders and metabolic syndrome include, for example: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial combined hyperlipidemia, lipodystrophy, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight and obesity. Accordingly, a subject having one or more of lipid metabolism disorders, metabolic syndrome, or a condition or disease associated with lipid metabolism disorders or metabolic syndrome, suspected of having these, or having a predisposition to acquire these is suitable for treatment using the methods provided herein and throughout.

[0097]

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

[0098]

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

[0099]

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

[0100]

[0119] In some embodiments, the method comprises oral administration of an azelaic acid C1-C4 alkyl ester such as DEA. In some embodiments, oral administration provides buccal or gastric delivery of an azelaic acid C1-C4 alkyl ester such as DEA. Such oral administration can be effected, for example, by tablets, capsules, elixirs, etc., as described throughout this specification. In some embodiments, the administration step is effected parenterally. In some embodiments, parenteral administration is effected intramuscularly or subcutaneously. In some embodiments, a combination of enteral and parenteral administration may be used.

[0101]

[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 the level of one or more lipids and / or insulin resistance, blood glucose level, and blood A1c rate in a subject. A suitable or effective amount of the single - dose size can also be a dose that, when administered one or more times over a suitable period, can cause a measurable change in insulin resistance in a subject compared to a measure of insulin resistance established prior to the start of treatment. The dose can vary depending on the condition of the subject being treated, including whether the subject has overt diabetes, the severity of dyslipidemia, a disease or condition associated with dyslipidemia, and / or any other relevant or non - relevant health factors experienced by a particular patient.

[0102]

[0121] In some embodiments, the methods provided herein are 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, about 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, about 2.3 mg / kg / day, about 2.4 mg / kg / day, about 2.5 mg / kg / day, about 2.6 mg / kg / day, about 2.7 mg / kg / day, about 2.8 mg / kg / day, about 2.9 mg / kg / day, about 3.0 mg / kg / day, about 3.1 mg / kg / day, about 3.2 mg / kg / day, about 3.3 mg / kg / day, about 3.4 mg / kg / day, about 3.5 mg / kg / day, about 3.6 mg / kg / day, about 3.7 mg / kg / day, about 3.8 mg / kg / day, about 3.9 mg / kg / day, about 4.0 mg / kg / day, about 4.1 mg / kg / day, about 4.2 mg / kg / day, about 4.3 mg / kg / day, about 4.4 mg / kg / day, about 4.5 mg / kg / day, about 4.6 mg / kg / day, about 4.7 mg / kg / day, about 4.8 mg / kg / day, about 4.9 mg / kg / day, 5.0 mg / kg / day, about 5.1 mg / kg / day, about 5.2 mg / kg / day, about 5.3 mg / kg / day, about 5.4 mg / kg / day, about 5.5 mg / kg / day, about 5.6 mg / kg / day, about 5.7 mg / kg / day, about 5.8 mg / kg / day, about 5.9 mg / kg / day, about 6.0 mg / kg / day, about 6.1 mg / kg / day, about 6.2 mg / kg / day, about 6.3 mg / kg / day, about 6.4 mg / kg / day, about 6.5 mg / kg / day, about 6.6 mg / kg / day, about 6.7 mg / kg / day, about 6.8 mg / kg / day, about 6.9 mg / kg / day, 7.0 mg / kg / day, about 7.1 mg / kg / day, about 7.2 mg / kg / day, about 7.3 mg / kg / day, about 7.4 mg / kg / day, about 7.5 mg / kg / day, about 7.6 mg / kg / day, about 7.7 mg / kg / day, about 7.8 mg / kg / day, about 7.9 mg / kg / day, 8.0 mg / kg / day, about 8.1 mg / kg / day, about 8.Administering a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester at a dosage of 2 mg / kg / day, about 8.3 mg / kg / day, about 8.4 mg / kg / day, about 8.5 mg / kg / day, about 8.6 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 azelaic acid C1-C4 alkyl ester administered in such dosage ranges is selected from the group consisting of DEA; DMA; DiPA; DiBuA; and D2PA. In some embodiments, the azelaic acid C1-C4 alkyl ester administered in such dosage ranges is DEA.

[0103]

[0122] In some embodiments, the azelaic acid C1-C4 alkyl ester such as DEA in the pharmaceutical composition is about 1 mg / kg / day. The dosage range for adult humans is generally 3 mg to 2 g per day. The dosage can be calculated based on the weight of the subject. For example, based on an average weight of about 120 to about 180 kg, the dosage range for adult humans can be 50 mg to 0.5 g per day, and based on an average weight of about 80 to about 120 kg, the dosage range for adult humans can be 10 mg to 1 g or 5 mg to 0.15 g per day, and based on an average weight of about 60 to about 80 kg, the dosage range for adult humans can be 25 mg to 0.3 g per day. The pharmaceutical composition can contain, for example, about 0.1% to about 99% by weight of DEA, depending on the administration method. When the pharmaceutical composition contains dosage units, each unit can contain the active ingredient in a single dose or divided doses, for example, about 10 to 2000 mg, or about 10 to 1000 mg, more typically 5 mg to 150 mg. Those skilled in the art can recognize flexible dosing based on the needs of individual patients, and the dosage can be outside the above ranges based on the response observed in tests such as glucose tolerance tests and the evaluation of baseline lipid levels (e.g., lipid levels measured before the start of treatment). Therefore, it should be understood that these ranges are merely illustrative. In some embodiments, the dosage is selected based on diagnostic screening as part of an ongoing treatment regimen, thus allowing adjustment of the dosage for each individual subject as needed.

[0104]

[0123] The method may further include the step of administering a second active ingredient. In some embodiments, the step of administering the second active ingredient is separate from the step of administering a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester such as DEA. In some embodiments, the second active ingredient is co-administered with a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester such as DEA. In some embodiments, the second active ingredient is present in a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester such as DEA. Such second active ingredients can be selected from azelaic acid C1-C4 alkyl esters other than DEA, biguanides, metformin, buformin, phenformin, thiazolidinediones, pioglitazone, rosiglitazone, corticosteroids, prednisone, insulin, lipase inhibitors, orlistat, glucagon-like peptide-1 (GLP-1) agonists, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitors, statins, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, fibrates, gemfibrozil, fenofibrate, niacin, leptin, leptin agonists, metreleptin, amylin agonists, pramlintide, and combinations thereof.

[0105]

[0124] In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester for treating or preventing dyslipidemia, or a condition or disease associated with dyslipidemia, in a subject.

[0106]

[0125] In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising an azelaic acid C1-C4 alkyl ester for improving an abnormality in one or more lipid levels when administered to a subject.

[0107]

[0126] In some embodiments, the present disclosure provides the use of azelaic acid C1-C4 alkyl esters in the manufacture of a medicament for treating or preventing dyslipidemia, or a condition or disease associated with dyslipidemia, in a subject.

[0108]

[0127] In some embodiments, the present disclosure provides the use of azelaic acid C1-C4 alkyl esters in the manufacture of a medicament for improving an abnormality in one or more lipid levels when administered to a subject.

[0109]

[0128] In some embodiments, the present disclosure provides a medicament comprising an azelaic acid C1-C4 alkyl ester for treating or preventing dyslipidemia, or a condition or disease associated with dyslipidemia, in a subject.

[0110]

[0129] In some embodiments, the present disclosure provides a medicament comprising an azelaic acid C1-C4 alkyl ester for improving an abnormality in one or more lipid levels when administered to a subject.

[0111]

[0130] In an embodiment, the medicament further comprises a second active ingredient selected from one or more of the following: azelaic acid C1-C4 alkyl esters other than DEA, biguanides, metformin, buformin, phenformin, thiazolidinediones, pioglitazone, rosiglitazone, corticosteroids, prednisone, insulin, lipase inhibitors, orlistat, glucagon-like peptide-1 (GLP-1) agonists, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitors, statins, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, fibrates, gemfibrozil, fenofibrate, niacin, leptin, leptin agonists, metreleptin, amylin agonists, pramlintide, and combinations thereof.

[0112]

[0131] The following examples are provided to illustrate embodiments of the present disclosure. These examples are merely intended to be illustrative and are not intended to limit the scope of the present disclosure. Similarly, 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.

Example

[0113] Example 1

[0001] In this example, the effect of alkyl azelates such as DEA on certain markers of insulin resistance and lipid metabolism disorders, including plasma glucose, insulin levels and / or lipid levels, when orally administered to overweight or obese adult male volunteers, is described. This cohort ranged from normal subjects to prediabetic subjects based on the level of glycated hemoglobin A1c (A1c), a blood marker considered to be a long-term reference for blood glucose control

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

[32] . The results of this study demonstrate that alkyl azelates such as DEA can significantly improve lipid levels, i.e., lipid metabolism disorders, or diseases or conditions associated with lipid metabolism disorders, in situations of insulin resistance.

[0114]

[0002] Abbreviations A1c = Glycated hemoglobin A1c AFLD = Alcoholic fatty liver disease BMI = Body mass index CHL = Cholesterol DEA = Diethyl azelate GC-MS = Gas chromatography - mass spectrometry HDL = High - density lipoprotein LDL = Low - density lipoprotein NAFLD = Non - alcoholic fatty liver disease NASH = Non - alcoholic steatohepatitis ncHDL = non-cholesterol high density lipoprotein OGTT = Oral Glucose Tolerance Test T2D = Type 2 Diabetes TRG = Triglyceride

[0115]

[0003] Substances and Methods:

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

[0116]

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

[0117]

[0006] The human study was conducted with the approval of the Institutional Review Board at IntegReview (Austin, TX, USA). Written consent was obtained from the subjects in accordance with the informed consent protocol EP20160001. The board was constituted and operated in accordance with the ethical principles of the Declaration of Helsinki and the requirements described in Title 21 CFR Part 56 of the US Code of Federal Regulations.

[0118]

[0007] By sampling a large population at risk of T2D (following a convenience sample; statistical method for extracting representative data

[33] ), 17 subjects were recruited and the changes in the measured values of glucose, lipids and insulin were measured after OGTT after these subjects were treated for 21 days.

[0119]

[0008] The subjects had a body mass index of 27.2 - 43.6 kg / m 2Overweight to obese men with a body mass index (BMI) in the range of, glycated hemoglobin A1c (HbA1c) of 5.0 - 6.2%, and insulin levels of 8.8 - 52 μU / mL were included. This study was conducted by a clinical trial at Texas, Inc. (San Antonio, TX). This cohort represents a population at risk of developing type 2 diabetes (T2D). This trial was limited to male participants to control for fluctuations in insulin sensitivity related to the menstrual cycle

[34] . Subjects took an oral dose of 1 mg / kg of DEA per day (“q1d”) for 21 days. An oral glucose tolerance test (OGTT) with 75 grams of glucose in 300 mL total volume was administered orally to the subjects again on day 0 and day 21, with glucose measurements at -30, -5, and 0 minutes, insulin measurements at -30 and 0 minutes, and both glucose and insulin measurements at 30, 60, 90, 120, and 180 minutes (“0 minutes” is the time when the glucose solution was administered). An 180-minute time point was selected to obtain early insights into possible signals of drug action

[35] . Blood lipid levels (triglycerides, cholesterol, HDL, non-cholesterol HDL, and LDL) were measured before the start of treatment on day 0 and again on day 21. The assay error was set at <5%

[36] .

[0120]

[0009] The results of various marker measurements on day 0 and day 21 were compared using both the paired Student's t-test and the Wilcoxon signed-rank test. Both calculation results; first the p-value from the paired Student's t-test, then the p-value from the Wilcoxon signed-rank test are presented. Generalized estimating equations and bootstrapping were used to confirm the results generated by other methods. Fasting glucose was calculated as the mean of the measurements at -30, -5, and 0 minutes, and fasting insulin was calculated as the mean of the measurements at -30 and 0 minutes. The Spearman correlation coefficient regarding the relationship between A1c and fasting plasma glucose before treatment and fasting plasma glucose after treatment was calculated. The area under the curve (AUC) was calculated over the 180-minute period of the OGTT. All analyses were performed using the open-source R 3.4.4 engine. Statistical significance was set at the α = 0.05 level.

[0121]

[0010] Results

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

[0122]

Table 1

[0123]

[0014] Glucose

[0015] To evaluate the effect of oral antidiabetic agents on glucose control, the level of glycated hemoglobin A1c (“A1c”), which is considered a measure of mean blood glucose levels in subjects, is often measured over a 2 - or 3 - month period prior to measurement, and the drug activity becomes apparent within the first 4 - 6 months

[37] . A measurable effect on A1c was not expected in such a short - term study, but the pre - treatment A1c levels were measured in subjects and used to evaluate the relative state of insulin resistance.

[0124]

[0016] This cohort was stratified by descending A1c values (Figure 1), and 3 subjects with A1c of 6.2, 6.1 and 6.0% were classified as prediabetic, and 6 subjects with A1c of 5.6 - 5.7% were considered to have an increased risk of T2D. This subgroup of 9 subjects with A1c ≥ 5.6% is referred to herein as “high A1c”. The remaining 8 subjects with A1c of 5.0 - 5.4% and a low risk of T2D were referred to as “low A1c”. Stratification by fasting plasma glucose levels showed that 9 subjects ( “high glucose”) were ≥ 100 mg / dL, and 8 subjects were below the 100 mg / mL threshold ( “low glucose”).

[0125]

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

[38] , while the range between 100 and 125 mg / dL is an indicator of prediabetes

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

[40] . An oral glucose tolerance test (OGTT) was used in which a standard dose of glucose was ingested orally and a blood sample was taken at specified times after ingestion. Next, to understand the pharmaceutical effect of DEA, measured values of plasma glucose were obtained.

[0126]

[0018] When the entire cohort of 17 subjects was analyzed as one group, fasting glucose after treatment increased slightly, by 0.11 mg / dL (p = 0.962; not significantly different from p = 0.96). However, fasting glucose decreased in subjects in both the high glucose group and the high A1c group. In subjects with HbA1c ≥ 5.6%, the average 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, and in these subjects, fasting glucose decreased by an average of 6.06 mg / dL (p = 0.033; p = 0.06) (see Figure 2A). The decrease in fasting glucose after treatment was moderately correlated with pre-treatment A1c (p = -0.551) and strongly correlated with pre-treatment fasting plasma glucose (p = -0.755) (Figure 2B).

[0127]

[0019] Modulation of postprandial glucose levels is of interest [42, 43] for drug development

[41] , considering that even transient hyperglycemia has long-term effects on cardiovascular and renal diseases, neuropathy and retinopathy. Figure 3A shows the effect of DEA on glucose at 180 minutes in the high A1c and low A1c subject groups. In a subgroup of 12 subjects, DEA decreased the glucose level by 2.4% - 31.5% at 180 minutes compared to the mean glucose level before the OGTT on day 21, with a mean decrease of 21.7% (p < 0.001; median decrease 25.3%). For the entire cohort, the mean decrease at 180 minutes was not significant (9.14%; p = 0.136; 0.057) due to one outlier (subject number 1) that showed a 58.6% increase. This particular subject had a mean fasting insulin of 77.45 μU / mL and may have leptin resistance

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

[0128]

[0020] The effect of DEA can be understood by the analysis of three individual cases of prediabetes. As shown in Figure 3B, the glucose processing profile of subject number 1 (A1c 6.2%) increased after treatment, but the 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. Subject number 2 (A1c 6.1%) and subject number 3 (A1c 6.0%) experienced an improvement in glucose clearance rate at 180 minutes (from 88.3 mg / dL to 69 mg / dL and from 146 mg / dL to 119 mg / dL, respectively).

[0129]

[0021] Insulin

[0022] In prediabetes and even in T2D, the body fails to respond appropriately to insulin, resulting in insulin resistance. Subjects with insulin resistance exhibit high blood glucose and insulin levels. In the studies by the present inventors, fasting insulin was within the almost normal range of <25 μU / mL before and after treatment in both the high A1c and low A1c groups (Figure 4A), and there was no significant difference between the groups. The outlier was one subject (subject number 1) in the high A1c group (see also Figure 4B), and their mean fasting insulin before treatment increased from 77.45 μU / mL to 96.15 μU / mL after treatment. The remaining 16 subjects experienced a decrease in fasting insulin of 13.4% (p = 0.007; 0.009).

[0130]

[0023] In a subgroup of 8 subjects (subject numbers 2 - 4, 8 - 11, and 13) from both the high A1c group and the low (≥5.3%) A1c group, DEA treatment significantly (p = 0.004, p = 0.008) decreased mean fasting insulin by 37.8% (median decrease rate of 42.5%). Clear non - responders, including the outlier (subject number 1), had pre - treatment levels of either fasting insulin, plasma glucose, and / or lipid markers that were normal. Considering all 17 subjects, the decrease 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).

[0131]

[0024] The effect of treatment on the individual insulin profiles in 3 prediabetic subjects (Figure 4B) was similar to their glucose response (Figure 3B), suggesting that in cases such as subject number 1 with progressive prediabetes, it may be necessary to further optimize the dose and / or duration of treatment.

[0132]

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

[0133]

[0026] Lipid panel

[0027] When lipid data were analyzed across the entire cohort, DEA had no statistically significant effect on any of the endpoints considered alone: total cholesterol, LDL, HDL, non-cholesterol HDL, and triglycerides (see Table 1). However, the pharmacological effect of DEA becomes prominent between the high A1c group and the low A1c group (Figs. 5A - 5E). Abnormal total cholesterol (>200 mg / dL) in two subjects in the high A1c group decreased or returned to normal levels. The median 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 the normal value of <100 mg / dL in the high A1c group, but not so much 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 5D). In the high A1c group, high triglycerides decreased to normal levels after treatment in eight subjects, including two subjects with abnormal triglycerides >150 mg before treatment (Fig. 5E).

[0134] In contrast, no substantial differences were observed in lipid ratios. Total cholesterol remained largely unaffected by DEA treatment, while the total cholesterol / HDL ratio significantly decreased by 5.36% (p = 0.025; p = 0.041). This decrease was mainly driven by the high A1c group, which showed a 7.99% decrease (p = 0.017; p = 0.068); see also Figure 6A. Similarly, LDL / HDL decreased by 6.46% in all 17 subjects (p = 0.011; p = 0.02). Among the high A1c subjects, this decrease was 9.8% (p = 0.008; p = 0.02); see also Figure 6B. There were no significant differences in the LDL / triglyceride and triglyceride / HDL ratios between the high A1c and low A1c groups, although some individuals experienced clear improvement (Figures 6C and 6E). Of interest is the effect of treatment on the triglyceride / HDL ratio, which is a predictor of cardiovascular disease

[39] , and this increased by 15% in the low A1c (from 3.9 to 4.6 after treatment), while it decreased by 11% in the high A1c group (from 3.4 to 3.0). A significant improvement was also observed in the non-cholesterol HDL / HDL ratio, which is a predictor of the development of non-alcoholic fatty liver disease (NAFLD)

[45] , and this ratio decreased by 6.6% (p = 0.025; p = 0.057) in the overall cohort and by 9.8% (p = 0.025; p = 0.074) in the high A1c group; see also Figure 6D.

[0135] Figure 7 illustrates the results of the lipid panel for the overall cohort and both the low A1c and high A1c groups. For HDL / LDL, total cholesterol / HDL, and triglycerides, large differences between the A1c subgroups were evident. Collectively, the differences in the lipid panel between the high A1c and low A1c groups suggested an adaptive response to DEA.

[0136]

[0030] Using several statistical analysis methods, the data mining of the results disclosed in this Example 1 confirmed the statistical significance of the effect of DEA on markers of lipid metabolism disorders and insulin resistance (e.g., plasma lipid levels, plasma lipid ratios, and plasma glucose levels disclosed herein). Regarding fasting plasma glucose, the effect of DEA was significant in prediabetic subjects and subjects at high risk of T2D (e.g., the high A1c subgroup and the high fasting plasma glucose (FPG) group). Clear non-responders did not have clinical indicators of T2D or prediabetes and were therefore not considered a population in need of antidiabetic therapy. The inconsistent responses in this test group suggest that normal subjects do not benefit from DEA and that subjects with signs of lipid metabolism disorders or insulin resistance show improvement in clinical treatment indices in response to DEA treatment. Individuals with higher insulin resistance experienced even greater improvement during DEA treatment. Subjects classified in the range of T2D risk or prediabetes also demonstrated improvement in insulin levels as well as plasma glucose. These results suggest that during DEA treatment, the pancreas does not function as strongly in insulin production and is unlikely to be "exhausted" as observed in late-stage T2D

[46] .

[0137]

[0031] As presented herein, when comparing certain effects of metformin and DEA, as presented in Table 2 below, it became clear that DEA has numerous similarities and advantages over metformin.

[0138]

Table 2

[0139]

[0032] For example, in a 28-day study, metformin decreased fasting glucose but had no effect on insulin levels in 16 subjects with type II diabetes

[47] . In a meta-analysis of 4,750 prediabetic subjects in randomized trials of at least 8 weeks, metformin decreased 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 decreased by 5.9% and fasting insulin decreased by 38%. In a 15-year study, metformin decreased the incidence of diabetes by 17% compared to placebo, and the subgroup that benefited most included subjects with higher baseline plasma glucose or A1c

[49] . The data presented herein indicate that DEA may be even more effective in treating or preventing further progression of diabetic lesions, as well as dyslipidemia and conditions or diseases associated with dyslipidemia.

[0140]

[0033] Neither metformin

[51] nor the DEA administration presented herein caused hypoglycemia. The effects of DEA on lipid levels presented herein were at least qualitatively similar to metformin and were superior to metformin in many respects

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

[52] . Furthermore, oral administration of DEA was well tolerated, while metformin caused severe gastrointestinal side effects in 1 out of 4 users, and 5% of patients were unable to tolerate metformin at all

[53] .

[0141]

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

[54] , reducing the risks of cardiovascular disease

[55] and cancer

[56] , and promoting life extension [57, 58]. The results presented herein, which are superior by a number of measures to those reported using metformin, demonstrate that DEA is useful in these indications and, similarly, in other diseases or conditions associated with these indications.

[0142]

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

[59] and non-cholesterol HDL / HDL

[60] across the entire cohort of subjects under study. These subjects were either overweight or obese and were thus at risk for conditions and diseases associated with metabolic syndrome, including tissue chronic inflammation (metaflammation)

[61] , NAFLD and NASH

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

[0143]

[0036] Currently, there are no approved drugs for treating NAFLD or NASH, and lipid-based complications of metabolic syndrome are currently treated with statins

[63] . There was no statistical overlap in significant endpoints between DEA administration as disclosed herein and statins, except for the decrease in the LDL / HDL ratio for DEA (9.8%, 21-day study as disclosed herein) compared to statins (26.7%, 18 - 24-month study

[64] ). However, statins have been reported to increase the risk of hyperglycemia and type II diabetes

[65] , especially when consuming a high-carbohydrate diet

[66] , and their adverse effects include rhabdomyolysis, a severe muscle condition that is exacerbated by metabolic syndrome

[67] . Thus, populations of subjects who cannot tolerate statins can benefit from DEA treatment, which can reduce the risk of progressive diseases initiated and driven by lipid metabolism disorders.

[0144]

[0037] Example 2

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

[30] , were described in a male subject with a BMI of approximately 27, having diet-induced insulin resistance and diabetes, when administered either by oral or gastric delivery.

[0145]

[0039] Substances and methods:

[0040] Diethyl azelate was synthesized from azelaic acid and ethyl alcohol using standard acid-catalyzed esterification followed by fractional distillation, yielding DEA with a purity of up to 99% as determined by gas chromatography-mass spectrometry (GC-MS). The distilled 99% DEA distillation product was administered in the non-formulated, non-encapsulated form for oral delivery as shown below (i.e., "as is").

[0146]

[0041] Regarding gastric delivery, the 99% DEA distillation product was placed in size 00 hard gelatin capsules (PureCaps, USA, Philmont, NY) and administered for gastric delivery by swallowing while drinking water.

[0147]

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

[0148]

[0043] Fasting blood glucose levels were measured using UniStrip blood glucose test strips (UniStrip Technologies LLC, Charlotte, NC) and OneTouch Ultra2 blood glucose meter (LifeScan OneTouch, Tampa, FL).

[0149]

[0044] Blood levels of glycated hemoglobin A1c (A1c) were measured using the A1C Now+ sample dilution kit, test cartridge, and monitor (Polymer Technology Systems, Inc., Indianapolis, IN) in accordance with the manufacturer's instructions.

[0150]

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

[0151]

[0046] Results

[0047] Figure 8 shows the effect of oral DEA delivery on the measured concentrations (mg / dL) of total cholesterol, high density lipoprotein (HDL), triglycerides and calculated LDL (LDL calculated) as a function of DEA dosages 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 all decreased in response to oral delivery at all administered DEA dosages compared to the levels observed when no DEA was administered (i.e., "0" mg / kg of DEA). A more pronounced decreasing effect on these lipids was observed at DEA dosages of 0.5 mg / kg, 1 mg / kg and 2 mg / kg, with the greatest decreasing effect observed at a DEA dosage of 0.5 mg / kg. The results also demonstrate that HDL levels increased at all tested DEA dosages compared to the levels observed when no DEA was administered (i.e., "0" mg / kg of DEA). Collectively, these results demonstrate that oral delivery of DEA results in an improvement in the lipid profile / lipid levels for all of the measured lipids.

[0152]

[0048] Figure 9 shows the effect of oral DEA delivery on the measured total cholesterol concentration / high density lipoprotein concentration (TC / HDL) ratio as a function of DEA dosages provided at 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg and 4 mg / kg. The results demonstrate that the TC / HDL ratio at the time of oral delivery of DEA decreased (i.e., improved) compared to the TC / HDL ratio (ration) measured without DEA administration at all tested DEA amounts, and a further decreasing effect on the TC / HDL ratio was observed when using DEA dosages of 0.5 mg / kg, 1 mg / kg and 2 mg / kg. This TC / HDL ratio decreased most when using a DEA dosage of 0.5 mg / kg.

[0153]

[0049] Figure 10 shows the effect of oral delivery of DEA at 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg on plasma glucose concentration (mg / dL) in the situation of OGTT (i.e., "during the period") measured 0 hour, 1 hour, 2 hours, and 4 hours after ingesting 75 grams of glucose in a volume of 300 mL. The results demonstrate that in the situation of OGTT, oral administration of DEA decreased (improved) the plasma glucose level, and the most significant decrease (improvement) was observed at DEA doses of 0.5 mg / kg and 1 mg / kg.

[0154]

[0050] Figure 11 shows the effect of oral delivery of DEA at 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg on plasma glucose concentration (mg / dL) in the situation of OGTT (i.e., "during the period"). The results demonstrate that in the situation of fasting OGTT, oral administration of DEA decreased (improved) the plasma glucose level, and the most significant decrease (improvement) was observed at DEA doses of 0.5 mg / kg and 1 mg / kg.

[0155]

[0051] Figure 12 shows the effect of oral delivery of DEA at 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg on plasma glucose concentration (mg / dL) in the situation of OGTT (i.e., "during the period") measured 1 hour after ingesting 75 grams of glucose in a volume of 300 mL. The results demonstrate that at all DEA doses, in the situation of OGTT, oral administration of DEA decreased (improved) the plasma glucose level, and a more significant decrease (improvement) was observed at DEA doses of 0.5 mg / kg, 1 mg / kg, and 4 mg / kg, and the most significant decrease (improvement) was observed at a DEA dose of 0.5 mg / kg.

[0156]

[0052] Figure 13 shows the effect of oral delivery of DEA at 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg and 4 mg / kg on plasma glucose concentration (mg / dL) in the situation of OGTT measured 2 hours after ingestion of 75 grams of glucose in a volume of 300 mL (i.e., "during the period"). The results demonstrate that in the situation of OGTT, at all doses of DEA administered, oral administration of DEA decreased (improved) the plasma glucose level, and a more significant decrease (improvement) was observed at DEA doses of 0.5 mg / kg, 1 mg / kg and 4 mg / kg, and the most significant decrease (improvement) was observed at DEA doses of 0.5 mg / kg and 1 mg / kg.

[0157]

[0053] Figure 14 shows the effect of oral delivery of DEA at 0 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg and 4 mg / kg on plasma glucose concentration (mg / dL) in the situation of OGTT measured 4 hours after ingestion of 75 grams of glucose in a volume of 300 mL (i.e., "during the period"). The results demonstrate that in the situation of OGTT at DEA doses of 0.5 mg / kg, 1 mg / kg and 4 mg / kg, oral administration of DEA decreased (improved) the plasma glucose level, and a more significant decrease (improvement) was observed at DEA doses of 0.5 mg / kg, 1 mg / kg and 4 mg / kg.

[0158]

[0054] Figure 15 shows the effects of buccal DEA delivery (upper panel) and gastric delivery (lower panel) on total cholesterol (TC) level, high density lipoprotein (HDL) level, triglyceride level, calculated low density lipoprotein (LDL calculated) level, and TC / HDL ratio measured at indicated DEA doses (leftmost column; DEA dose in mg / kg units). This result demonstrates that for both buccal and gastric delivery of DEA, at all tested DEA doses, the levels of measured TC, triglyceride, and LDL calculated, as well as the TC / HCL ratio, were decreased (i.e., improved) compared to when no DEA was administered (DEA of "0" mg / kg). This result also demonstrates that for both buccal and gastric delivery of DEA, at all DEA doses, the HDL level was increased (i.e., improved) compared to when no DEA was administered (DEA of "0" mg / kg). A more significant improvement in the lipid levels and ratios shown was observed, for example, at a DEA dose of 1 mg / kg during buccal delivery and at a DEA dose of 0.25 mg / kg during gastric delivery.

[0159]

[0055] Figure 16 shows the effects of buccal DEA delivery (upper panel) and gastric delivery (lower panel) on plasma glucose levels (mg / dL) measured at indicated times during an oral glucose tolerance test (OGTT) (i.e., "during period") after ingestion of 75 grams of glucose in a 300 mL volume at 0, 1, 2, and 4 hours. This result demonstrates that for both buccal and gastric delivery of DEA, at most tested DEA doses and at time points after glucose ingestion, the plasma glucose levels were decreased (i.e., improved) compared to when no DEA was administered (DEA of "0" mg / kg). A more significant improvement in plasma glucose levels was observed, for example, at a DEA dose of 0.5 mg / kg during buccal delivery and at a DEA dose of 0.25 mg / kg during gastric delivery.

[0160]

[0056] Figure 17 presents a comparison of the indicated measured values of lipid levels (upper panel) and plasma glucose levels (lower panel) at the indicated DEA doses by oral and gastric delivery (left column), and an evaluation of the statistical relevance of differences between delivery modes for each measurement, determined by Student's paired two-sided T-test, analysis of variance T (T-test). The results show, for example, that oral delivery of DEA resulted in a statistically significantly greater improvement in total cholesterol and total cholesterol / high density lipoprotein (TC / HDL) ratio compared to the improvement observed with gastric delivery of DEA. This result also shows that, in the context of an OGTT, for example, oral delivery of DEA resulted in a significantly greater improvement in plasma glucose levels at 0 and 4 hours after ingestion of 75 grams of glucose in a volume of 300 mL.

[0161]

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[0132] 75. Walter A, Gutknecht J. Permeability of small nonelectrolytes through lipid bilayer membranes. J Membr Biol. 1986;90(3):207-17. Epub 1986 / 01 / 01. doi: 10.1007 / bf01870127. PubMed PMID: 3735402. [Related Applications] This patent application claims priority to U.S. Provisional Patent Application No. 62 / 978,785, filed on February 19, 2020, entitled "AZELAIC ACID ESTERS IN THE TREATMENT OR PREVENTION OF DYSLIPIDEMIA AND ASSOCIATED CONDITIONS", naming inventors Robert T. STREEPER and Elzbieta IZBICKA. The entire content of the above patent application is incorporated herein by reference. [Supplementary Note] The present invention includes the following embodiments. 1. A method for treating or preventing lipid metabolism disorder, or a disease or condition associated with lipid metabolism disorder, in a subject, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of azelaic acid C 1 ~C 4 alkyl ester for treating or preventing the lipid metabolism disorder, or the disease or condition associated with lipid metabolism disorder, in the subject. 2. The method according to embodiment 1, wherein the treating or preventing comprises improving an abnormality in one or more lipid levels in the subject. 3. The improvement comprises, in the subject, reducing an elevated low density lipoprotein (LDL) level, increasing a decreased high density lipoprotein (HDL) level, reducing an elevated triglyceride level, reducing an elevated total cholesterol to HDL ratio (cholesterol / HDL), reducing an elevated LDL to HDL ratio (LDL / HDL), reducing an elevated LDL to triglyceride ratio (LDL / triglyceride), or reducing an elevated non-cholesterol HDL to HDL ratio (non-cholesterol HDL / HDL), according to the method of embodiment 1 or 2. 4. The lipid metabolism disorder is as follows: elevated LDL level, decreased HDL level, elevated triglyceride level, elevated cholesterol / HDL, elevated LDL / HDL, elevated LDL / triglyceride and elevated non-cholesterol HDL / HDL The method according to any one of embodiments 1 to 3, comprising at least one of the above. 5. The lipid metabolism disorder, or the disease or condition associated with the lipid metabolism disorder, is as follows: Hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial combined hyperlipidemia, lipodystrophy, cardiovascular disease, hypertension, stroke, atherosclerotic arteriosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight and obesity The method according to any one of Embodiments 1 to 4, comprising one or more of the above. 6. The pharmaceutical composition is a C azelaic acid 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) 1 ~C 4 The method according to any one of Embodiments 1 to 5, comprising an alkyl ester. 7. The pharmaceutical composition contains the C azelaic acid alkyl ester in a dose range of about 0.1 mg / kg / day to about 10 mg / kg / day 1 ~C 4 The method according to any one of Embodiments 1 to 6, comprising an alkyl ester. 8. The method according to any one of Embodiments 1 to 7, wherein the pharmaceutical composition contains DEA. 9. The method according to any one of Embodiments 1 to 8, wherein the pharmaceutical composition contains DEA in a dose 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. 10. The method according to Embodiment 1, wherein the subject has at least one of insulin resistance, prediabetes, type II diabetes, overweight or obesity, is suspected of having these, or is suspected of having a predisposition to acquire these. 11. The method according to Embodiment 1, wherein the subject has a body mass index (BMI) of less than 30 and between 25, or a BMI of 30 or more. 12. The pharmaceutical composition is the C azelaic acid 1 ~C 4 The method according to any one of Embodiments 1 to 11, formulated for buccal delivery of the alkyl ester. 13. The pharmaceutical composition is the C azelaic acid 1 ~C 4 The method according to any one of Embodiments 1 to 11, formulated for intragastric delivery of the alkyl ester. 14. The method according to any one of Embodiments 1 to 11, wherein the step of administering is by parenteral administration. 15. The method according to any one of Embodiments 1 to 11, wherein the step of administering is by enteral administration. 16. The method according to any one of embodiments 1 to 11, wherein the administering step is performed orally, intramuscularly, subcutaneously, intravenously, or a combination thereof. 17. The method further comprising the step of administering a second active ingredient, wherein the second active ingredient is azelaic acid C 1 ~C 4 alkyl ester is administered separately from the pharmaceutical composition containing it, or is co-administered with the pharmaceutical composition containing azelaic acid C 1~C 4 alkyl ester, the method according to any one of embodiments 1 to 16. 18. The method further comprising the step of administering a second active ingredient present in the pharmaceutical composition containing azelaic acid C 1 ~C 4 alkyl ester, the method according to any one of embodiments 1 to 17. 19. The second active ingredient is as follows: Azelaic acid C other than DEA 1 ~C 4 alkyl ester, biguanide, metformin, buformin, fenformin, 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, rosuvastatin, simvastatin, fibrate, gemfibrozil, fenofibrate, niacin, leptin, leptin agonist, metreleptin, amylin agonist, pramlintide, and combinations thereof The method according to any one of embodiments 1 to 18, comprising one or more of. 20. The method according to embodiment 19, wherein the insulin is formulated as a short-acting preparation, an intermediate-acting preparation, a long-acting preparation, or a combination thereof. 21. The method according to any one of embodiments 1 to 20, wherein the pharmaceutical composition consists essentially of DEA as an active ingredient. 22. The method according to any one of embodiments 1 to 20, wherein the pharmaceutical composition consists of DEA as an active ingredient. 23. The method according to any one of embodiments 1 to 22, wherein the subject has insulin resistance or type II diabetes. 24. A method for treating or preventing lipid metabolism disorders, or diseases or conditions associated with lipid metabolism disorders, in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising DEA in a dosage range of about 0.1 mg / kg / day to about 10 mg / kg / day. 25. The method according to embodiment 24, wherein the treating or preventing comprises improving an abnormality in one or more lipid levels in the subject. 26. The method according to embodiment 24 or 25, wherein the improving comprises reducing an elevated LDL level, increasing a decreased HDL level, reducing an elevated triglyceride level, reducing an elevated cholesterol / HDL, reducing an elevated LDL / HDL, reducing an elevated LDL / triglyceride, or reducing an elevated non-cholesterol HDL / HDL in the subject. 27. The method according to any one of embodiments 24 to 26, further comprising administering a second active ingredient, wherein the second active ingredient is administered either separately from the pharmaceutical composition comprising DEA or co-administered with the pharmaceutical composition comprising DEA. 28. The method according to any one of embodiments 24 to 27, further comprising administering a second active ingredient present in the pharmaceutical composition comprising DEA. 29. The second active ingredient is as follows: azelainic acid C other than DEA 1 ~C 4 alkyl esters, biguanides, metformin, buformin, phenformin, thiazolidinediones, pioglitazone, rosiglitazone, corticosteroids, prednisone, insulin, lipase inhibitors, orlistat, glucagon-like peptide-1 (GLP-1) agonists, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitors, statins, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, fibrates, gemfibrozil, fenofibrate, niacin, leptin, leptin agonists, metreleptin, amylin agonists, pramlintide, and combinations thereof The method according to any one of embodiments 24 to 28, comprising one or more of the above. 30. The method according to any one of embodiments 24 to 29, wherein the insulin is formulated as a short-acting preparation, an intermediate-acting preparation, a long-acting preparation, or a combination thereof. 31. The method according to any one of embodiments 24 to 30, wherein the subject has a BMI of less than 30 and greater than or equal to 25, or has a BMI of 30 or more. 32. The method according to any one of embodiments 24 to 31, wherein the pharmaceutical composition is formulated for oral delivery of the DEA. 33. The method according to any one of embodiments 24 to 31, wherein the pharmaceutical composition is formulated for gastric delivery of the DEA. 34. The method according to any one of embodiments 24 to 31, wherein the step of administering is performed by parenteral administration. 35. The method according to any one of embodiments 24 to 31, wherein the step of administering is performed by enteral administration. 36. The method according to any one of embodiments 24 to 31, wherein the step of administering is performed intramuscularly, subcutaneously, intravenously, or in combination thereof. 37. Azelaic acid C for either oral delivery or gastric delivery 1 ~C 4 alkyl ester, wherein the azelaic acid C 1 ~C 4 alkyl ester is in a dose range of about 0.25 mg / mg to about 2.0 mg / kg, a pharmaceutical composition. 38. The azelaic acid C 1 ~C 4 alkyl ester is selected from the group consisting of DEA, DMA, DiPA, DiBuA, and D2PA, the pharmaceutical composition according to embodiment 37. 39. The azelaic acid C 1 ~C 4 alkyl ester is DEA, the pharmaceutical composition according to embodiment 37 or 38. 40. The pharmaceutical composition according to any one of embodiments 37 to 39, wherein the dose is effective to improve one or more abnormal lipid levels when administered to a subject. 41. The pharmaceutical composition according to any one of embodiments 37 to 40, wherein the dose is effective to lower elevated LDL levels, raise decreased 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 when administered to a subject. 42. The pharmaceutical composition according to any one of embodiments 37 to 41, wherein the dosage is effective for treating or preventing dyslipidemia or a disease or condition associated with dyslipidemia when administered to a subject. 43. The pharmaceutical composition according to any one of embodiments 37 to 42, wherein the disease or condition associated with dyslipidemia is selected from the group consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial combined hyperlipidemia, lipodystrophy, cardiovascular disease, hypertension, stroke, atherosclerotic arteriosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight, and obesity. 44. Use of an azelaic acid C 1 ~C 4 alkyl ester-containing pharmaceutical composition for improving abnormalities in one or more lipid levels when administered to a subject. 45. The use according to embodiment 44, wherein improving abnormalities in one or more lipid levels when administered to a subject includes reducing elevated LDL levels, increasing reduced HDL levels, reducing elevated triglyceride levels, reducing elevated cholesterol / HDL, reducing elevated LDL / HDL, reducing elevated LDL / triglyceride, or reducing elevated non-cholesterol HDL / HDL. 46. The use according to embodiment 44 or 45, including treating or preventing dyslipidemia or a condition or disease associated with dyslipidemia. 47. The use according to any one of embodiments 44 to 46, wherein the disease or condition associated with dyslipidemia is selected from the group consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial combined hyperlipidemia, lipodystrophy, cardiovascular disease, hypertension, stroke, atherosclerotic arteriosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight, and obesity. 48. The use according to any one of embodiments 44 to 47, wherein the pharmaceutical composition contains DEA. 49. The use according to any one of embodiments 44 to 48, wherein the DEA is formulated for oral delivery or gastric delivery. 50. Use according to any one of embodiments 44 to 49, wherein the DEA is administered at a dose in the range of about 0.25 mg / mg to about 2.0 mg / kg. 51. Use of an azelaic acid C 1 ~C 4 alkyl ester in the manufacture of a medicament for treating or preventing dyslipidemia, or a condition or disease associated with dyslipidemia, in a subject. 52. Use according to embodiment 51, wherein said treating or preventing comprises improving an abnormality in one or more lipid levels when administered to said subject. 53. Use according to embodiment 51 or 52, wherein said treating or preventing comprises, when administered to said subject, reducing an elevated LDL level, increasing a decreased HDL level, reducing an elevated triglyceride level, reducing an elevated cholesterol / HDL, reducing an elevated LDL / HDL, reducing an elevated LDL / triglyceride, or reducing an elevated non-cholesterol HDL / HDL. 54. The disease or condition associated with dyslipidemia is as follows: Hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, familial combined hyperlipidemia, lipodystrophy, cardiovascular disease, hypertension, stroke, atherosclerosis, arteriosclerosis, coronary artery disease, NASH, ASH, fatty liver disease, NAFLD, liver hypertrophy, pancreatitis, metabolic syndrome, insulin resistance, prediabetes, type II diabetes, overweight and obesity Use according to any one of embodiments 51 to 53, comprising one or more of the above. 55. The azelaic acid C 1 ~C 4 alkyl ester contains DEA, use according to any one of embodiments 51 to 54. 56. Use according to any one of embodiments 51 to 55, wherein the DEA is formulated for oral or intragastric delivery. 57. Use according to any one of embodiments 51 to 56, wherein the DEA is administered at a dose in the range of about 0.25 mg / mg to about 2.0 mg / kg.

Claims

1. A pharmaceutical composition for oral delivery for treating or preventing lipid metabolism disorders, comprising an azelaic acid C １ to C ４ alkyl ester in an amount effective to treat or prevent said lipid metabolism disorder in a subject.

2. The pharmaceutical composition according to claim 1, wherein the azelaic acid C1-C4 alkyl ester is selected from the group consisting of diethyl azelate (DEA), dimethyl azelate (DMA), di-isopropyl azelate (DiPA), and di-isobutyl azelate (DiBuA).

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition contains DEA.

4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising a second active ingredient.

5. The second active ingredient is as follows: Azelaic acid C other than DEA １ ~C ４ alkyl esters, biguanides, metformin, buformin, phenformin, thiazolidinediones, pioglitazone, rosiglitazone, corticosteroids, prednisone, insulin, lipase inhibitors, orlistat, glucagon-like peptide-1 (GLP-1) agonists, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitors, statins, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, fibrates, gemfibrozil, fenofibrate, niacin, leptin, leptin agonists, metreleptin, amylin agonists, pramlintide, and combinations thereof The pharmaceutical composition according to claim 4, comprising one or more of the following.

6. The pharmaceutical composition according to claim 5, wherein the insulin is formulated as a short-acting preparation, an intermediate-acting preparation, a long-acting preparation, or a combination thereof.

7. The pharmaceutical composition according to any one of claims 1 to 3, consisting essentially of DEA as an active ingredient.

8. The pharmaceutical composition according to any one of claims 1 to 3, consisting of DEA as an active ingredient.

9. A pharmaceutical composition for oral delivery for treating or preventing lipid metabolism disorders in a subject, comprising an effective amount of DEA of 0.1 mg / kg / day to 10 mg / kg / day.

10. The pharmaceutical composition according to claim 9, further comprising a second active ingredient.

11. The second active ingredient is as follows: Azelaic acid C other than DEA １ to C ４ alkyl esters, biguanides, metformin, buformin, fenformin, thiazolidinediones, pioglitazone, rosiglitazone, corticosteroids, prednisone, insulin, lipase inhibitors, orlistat, glucagon-like peptide-1 (GLP-1) agonists, exendin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, HMG-CoA reductase inhibitors, statins, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, fibrates, gemfibrozil, fenofibrate, niacin, leptin, leptin agonists, metreleptin, amylin agonists, pramlintide and combinations thereof The pharmaceutical composition according to claim 10, comprising one or more of the following.

12. The pharmaceutical composition according to claim 11, wherein the insulin is formulated as a short-acting preparation, an intermediate-acting preparation, a long-acting preparation, or a combination thereof.

13. A pharmaceutical composition for oral delivery for improving abnormalities in one or more lipid levels when administered to a subject, comprising an azelaic acid C1-C4 alkyl ester.

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