BR112020016494A2 - PROLONGED RELEASE FORMULATIONS OF BEMPEDOIC ACID - Google Patents

Abstract

the present invention relates to extended release bempedoic acid compositions with improved bioavailability and pharmacokinetic characteristics, kits comprising said compositions and methods of using them. methods of releasing bempedoic acid are also described.

Description

Descriptive Report of the Invention Patent for “FORMULATIONS OF PROLONGED RELEASE OF BEMPEEDIC ACID”.

CROSS REFERENCE TO RELATED REQUESTS

[001] This application claims priority benefit for North American Provisional Application No. 62 / 710,417, filed on February 16, 2018 and North American Interim Application No. 62 / 774,083, filed on November 30 2018, each of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[002] Bempedoic acid (ETC-1002) behaves like a prodrug in vivo, where it is converted into an active species (ETC- 1002-CoA) by the endogenous activity of the acyl-coenzyme (CoA) synthase (ACS) of the liver. A specific ACS isozyme, very long chain acyl-CoA synthase (ACSVL1), is required to form the active species. Once activated, ETC-1002-CoA directly inhibits ATP-citrate lyase (ACL) and, through this action, measures the effects on lipid metabolism. With traditional formulations, a fraction of the well-pedoic acid within a dosage form becomes activated, with the remaining non-activated fraction of the administered dose being eliminated. This is partly because many Class II active pharmaceutical ingredients ("APIs") of the Biopharmaceutics Classification System (“BCS”) - such as bempedoic acid - have low solubility and high permeability. What is needed, then, is a means of increasing the exposure of the active drug in the liver without increasing the dose of bempedoic acid administered to patients.

SUMMARY OF THE INVENTION

[003] The inventors found that the prolonged release of bempedoic acid provides an increase in activation efficiency for the active species and improves the exposure of the activated drug in the liver.

[004] Aspects of the description comprise a pharmaceutical formulation comprising the components: (i) 50-70% bempedoic acid, (ii) a filler, (iii) a diluent or solubilizer and (iv) a binder, wherein the formulation is formulated for the prolonged release of bempedoic acid. In some respects, the filler is selected from the group consisting of, for example, microcrystalline cellulose, sodium carboxymethyl cellulose and a combination of microcrystalline cellulose and sodium carboxymethyl cellulose. In some respects, the diluent or solubilizer is selected from a group consisting of, for example, sodium lauryl sulfate and sodium starch glycolate. In some respects, the binder is, for example, hydroxylpropylmethylcellulose (HMPC). In some ways, the formulation is formulated as a solid. In some respects, the formulation is formulated for oral administration.

[005] In some respects, any formulation described above comprises bempedoic acid dispersed within a polymeric matrix. In some respects, any of the formulations described above are formulations that exhibit a drug release profile corresponding to a pattern in which, for example, after 2 hours, no more than 30% of the total mass of bempedoic acid is released in a individual. In some respects, any of the formulations described above are formulations that exhibit a drug release profile corresponding to a pattern in which, for example, after 4 hours, no more than 75% of the total mass of bempedoic acid is released. In some respects, any of the formulations described above are formulations that exhibit a drug release profile corresponding to a standard in which, for example, after 8 hours, no more than 90% of the total mass of bempedoic acid are released. In some respects, any of the formulations described

The above are formulations that provide a therapeutically effective concentration of bempedoic acid over a period of, for example, 24 hours when administered to a human subject.

[006] In some respects, in any of the formulations described above, the filler component is, for example, microcrystalline cellulose, or sodium carboxymethyl cellulose, or a combination of sodium carboxymethyl cellulose and microcrystalline cellulose. In some respects, the amount of filler component in the formulation is 5-50% w / w. In some respects, the binder component is about 0.1-1.5% w / w. In some respects, the formulations described above comprise, for example, 50-70% w / w bempedoic acid, 30% - 45% w / w filler, 1-5% w / w diluent or solubilizing component and 0.1-1.5% w / w of agglutinating component. In some respects, the formulations described above comprise, for example, 55-65% w / w of well-pedoic acid, 30-45% w / w of filler, 1-5% w / w diluent or solubilizing component and 0.1-1.5% w / w binder component. In some respects, the formulations described above comprise, for example, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210 or 220 mg of well pedoic acid.

[007] In some respects, the formulations described above dissolve at a zero order release rate for at least, for example, 8, 9, 10, 11 or 12 hours. In some respects, the formulations described above comprise bempedoic acid and a polymeric matrix and have a hardness of, for example, 2-30 kg. In some respects, the formulations described above are in the form of a sphere or have a thickness to diameter ratio that is effective in allowing erosion when dissolution is tested.

[008] In some respects, any of the formulations described

The above provides a therapeutically effective concentration of bempedoic acid over a 24 hour period when administered to a human subject. In some respects, the formulation provides a maximum blood plasma concentration (Cmax) of bempedoic acid of no more than, for example, 50 µg / mL, 60 µg / mL, 70 µg / mL or 80 µg / mL when administered to a patient. individual human being. In some aspects, the formulation provides a maximum blood plasma concentration (Cmax) of bempedoic acid in a range, for example, 45 µg / mL to 60 µg / mL, for example, 20, 21, 22, 23 or 24 hours after administration to a human individual.

[009] In some respects, any of the formulations described above are formulated, for example, gelatin capsules or tablets. In some aspects, the gelatin capsule comprises, for example, a powdered excipient.

[0010] In some respects, the description covers methods of administering a bempedoic acid formulation to a human individual in need, where the formulation comprises bempedoic acid and a polymeric matrix and where administration results in a blood plasma concentration maximum (Cmax) of bempedoic acid of not more than about, for example, 60 µg / mL, and where the concentration in blood plasma is in a range of about 45-57 µg / mL for 24 hours after administration . In a related aspect, the formulation is one of the formulations described above.

[0011] In some respects, the description covers methods of treating cardiovascular disease or reducing the risk of cardiovascular disease in an individual, the method comprising administering an effective amount of a pharmaceutical formulation to a human individual in need, where the formulation comprises the components of bempedoic acid and a polymer, and where the

formulation solution exhibits a drug release profile corresponding to a standard, for example, after 2 hours, no more than 30% of bempedoic acid is released; after 4 hours, no more than 75% of bempedoic acid is released; after 8 hours, no more than 90% of bempedoic acid is released. In some respects, the method provides a therapeutically effective concentration of bempedoic acid over a period of 24 hours to treat cardiovascular diseases or reduce the risk of cardiovascular disease when administered to the individual. In another related aspect, the administered formulation does not release more than 95% of bempedoic acid after 8 hours. In a related aspect, the formulation administered is one of the formulations described above.

[0012] [0012] In certain aspects of the methods described above, the polymer is hydroxypropylmethylcellulose (HPMC). In certain other aspects, the bempedoic acid in the administered formulation is, for example, about 30-80% by weight and the polymer is hydroxypropylmethylcellulose (HPMC) and is, for example, about 15-35% by weight.

[0013] In certain aspects of any of the methods described above, the method reduces total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) when administered to a human individual having, for example, hypercholesterolemia, mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver disease or kidney disease. In certain other aspects of any of the methods described above, the method decreases the level of very low density lipoprotein (VLDL) in the individual below that of a control subject receiving a placebo. In certain other aspects of any of the methods described above, the method decreases the size of the VLDL particles in the individual below that of a control subject receiving a placebo. In certain other aspects of any of the methods described above, the method decreases the ratio of apolipoprotein B

(ApoB) for apolipoprotein A-1 (ApoA1) in the subject below that of a control subject receiving placebo. In certain other aspects of any of the methods described above, the method decreases the level of low-density lipoprotein (LDL-C) cholesterol in the individual. In certain other aspects of any of the methods described above, the method decreases LDL-C levels by at least 5%, 10%, 15% or 20% compared to an individual not otherwise treated or an individual treated with placebo. In certain other aspects of any of the methods described above, the method decreases LDL-C levels by 5-40% compared to an untreated individual or a placebo-treated individual. In certain other aspects of any of the methods described above, the method decreases LDL-C levels in an individual at least as effectively as an equal dose of an immediate release bempedoic acid formulation. In certain other aspects of any of the methods described above, the method lowers LDL-C levels in an individual at least as effectively as a higher dose of an immediate release bempedoic acid formulation, where the highest dose high is 180 mg / day.

[0014] In addition, the extended release compositions described herein provide an efficient means for the systematic release of bempedoic acid. As a result, a lower dose and / or less frequent administration (compared to known well-pedoic acid formulations) is necessary to produce the same effect. In this way, unwanted side effects can be reduced, minimized or eliminated.

[0015] In one aspect, the description provides a pharmaceutical composition comprising a solid dosage form, a solid dosage form comprising bempedoic acid and a polymeric matrix. In one respect, the description provides a solid dosage form

of which is a capsule or pill.

[0016] In one aspect, the description provides an extended-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: bempedoic acid and a polymeric matrix. In one aspect, bempedoic acid is dispersed within a polymeric matrix.

[0017] In one aspect, the description provides a zero-order extended release composition comprising bempedoic acid and a polymeric matrix. In one aspect, the zero-order extended release composition comprises bempedoic acid dispersed within a polymeric matrix.

[0018] In one aspect, the description provides a pharmaceutical composition comprising a solid dosage form, where the solid dosage form has physical properties so that it exhibits a certain dissolution profile when the dissolution is tested using a United States Pharmacopoeia (USP).

[0019] In one aspect, the description provides methods of treating or reducing the risk of cardiovascular disease in an individual by administering the compositions described here, which can be prolonged-release formulations in some modalities or release formulations other modalities. In one aspect, the description provides methods of treating a metabolic syndrome in an individual by administering the compositions described herein. In one aspect, the description provides methods of treating non-alcoholic hepatic steatosis (NAFLD) disease in an individual by administering the compositions described herein. In one aspect, the description provides methods of treating non-alcoholic steatohepatitis (NASH) in an individual by administering the compositions described herein.

[0020] In some respects, the description covers a method of inhibiting the enzyme ATP-citrate lyase (ACL) in an individual, wherein the method comprises administering to the individual the pharmaceutical dosage form of any of the above formulations.

[0021] In some respects, the description covers a method of treating metabolic syndrome in an individual, in which the method comprises administering an effective amount of a pharmaceutical dosage form of any of the above formulations.

[0022] In some respects, the description covers a method of treating metabolic syndrome in an individual, in which the individual is obese, has hypercholesterolemia, has mixed dyslipidemia, has type 2 diabetes or any combination thereof, and wherein the method comprises administering an effective amount of a pharmaceutical dosage form of any of the foregoing formulations.

[0023] In some respects, the description covers a method of treating metabolic syndrome in an individual, in which the individual has hypercholesterolemia and in which the method comprises administering an effective amount of a pharmaceutical dosage form of any one of the above formulations.

[0024] In some respects, the description covers a method of treating metabolic syndrome in an individual, in which the metabolic syndrome is non-alcoholic hepatic steatosis disease (NAFLD) and in which the method comprises the administration of an effective amount of a pharmaceutical dosage form of any of the above formulations.

[0025] In some respects, the description covers a method of treating metabolic syndrome in an individual, in which the metabolic syndrome is non-alcoholic steatohepatitis (NASH) and in which the method comprises the administration of an effective amount of a pharmaceutical dosage form of any of the above formulations.

[0026] In addition, the extended release compositions described here provide an efficient means for the systemic release of bempedoic acid. As a result, a lower dose and / or less frequent administration (compared to known well-pedoic acid formulations) is necessary to produce the same effect. In this way, unwanted side effects can be reduced, minimized or eliminated.

[0027] In one aspect, the description provides a pharmaceutical composition comprising a solid dosage form, a solid dosage form comprising bempedoic acid and a polymeric matrix. In one aspect, the description provides a solid dosage form that is a capsule or a tablet.

[0028] In one aspect, the description provides an extended-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: bempedoic acid and a polymeric matrix. In one aspect, bempedoic acid is dispersed within a polymeric matrix.

[0029] In one aspect, the description provides a zero-order extended release composition comprising bempedoic acid and a polymeric matrix. In one aspect, the zero-order extended release composition comprises bempedoic acid dispersed within a polymeric matrix.

[0030] In one aspect, the description provides a pharmaceutical composition comprising a solid dosage form, wherein the solid dosage form has physical properties so that it exhibits a certain dissolution profile when tested dissolution using a Pharmacopoeia Apparatus of the United States (USP).

[0031] In one aspect, the description provides methods of treating or reducing the risk of cardiovascular disease in an individual by administering the compositions described herein, which can be prolonged-release formulations in some modalities or immediate-release formulations in other modalities. In one aspect, the description provides methods of treating a metabolic syndrome in an individual by administering the compositions described herein. In one aspect, the description provides methods of treating non-alcoholic hepatic steatosis (NAFLD) disease in an individual by administering the compositions described herein. In one aspect, the description provides methods of treating non-alcoholic steatohepatitis (NASH) in an individual by administering the compositions described herein.

[0032] In another aspect, the description provides methods of administration or methods of distribution of bempedoic acid by the administration of the compositions described above and described in more detail below.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0033] These and other characteristics, aspects and advantages of the present invention will be better understood with respect to the following description and attached drawings, where:

[0034] Figure 1A is a graph showing serum plasma concentrations of bempedoic acid (ETC-1002) in the liver of male Han Wistar rats after: 1. a single administration in a bolus of bempedoic acid (circles) and 2. multiple bolus administrations divided in bempedoic acid (squares).

[0035] Figure 1B is a graph showing the liver Acetyl-CoA concentrations in male Han Wistar rats after: 1. a single administration of bempedoic acid bolus (circles) and 2. multiple divided bolus administrations of bempedoic acid (squares).

[0036] Figure 1C is a graph showing the concentrations of the active species, ETC-1002-CoA in livers of male Han Wistar rats after: (1) a single administration in a bolus of bempedoic acid (circles) and (2 ) several divided administrations of bempedoic acid (squares).

[0037] Figure 2A is a graph showing the concentration versus times of bempedoic acid released from multiple formulations of bempedoic acid after testing in a USP dissolution assay.

[0038] Figure 2B is a graph showing the time-dependent concentration of bempedoic acid released from the CU07-101 and CU07-118 bempedoic acid formulations after testing in a USP dissolution test.

[0039] Figure 3 is a graph showing the average plasma concentration of bempedoic acid in human subjects after administration of an immediate release tablet comprising 180 mg of active ingredient of bempedoic acid.

[0040] Figure 4 is a graph showing the average plasma concentration of bempedoic acid in obese but otherwise healthy individuals after administration of a single dose of prolonged-release tablets comprising 50 mg, 100 mg and 200 mg of bempedoic acid.

[0041] Figure 5 is a graph showing the percentage change in LDL-C levels from baseline after 14 days of prolonged release tablet dosing comprising 100 mg of bempedoic acid.

[0042] Figure 6 summarizes the study project for the Immediate Release Study (IR) 1.

[0043] Figure 7 summarizes the study project of the Immediate Release Study (IR) 2.

[0044] Figure 8 summarizes the study design of the Liberation Study

Immediate ration (IR) 3.

[0045] Figure 9 summarizes the study project of the Extended Liberation Study (SR).

DETAILED DESCRIPTION OF THE INVENTION Advantages and utility

[0046] In one aspect, the present description provides compositions and methods for prolonged release formulations of well pedoic acid.

[0047] Included are extended-release compositions comprising bempedoic acid and a polymeric matrix. The present description encompasses a variety of components to form an extended release formulation comprising bempedoic acid and a polymeric material. For example, the present description includes formulations for parenteral use, such as tablets or coated tablets loaded or not. In the case of empty coated tablets, the polymer may have sufficient porosity to allow fluid to enter one or more coated tablet chambers and lead to osmotic pressure release. An example of this technology is the extended-release coated tablet pump developed by Alza Corp as described, for example, in U.S. Patents 3,760,984, 3,845,770, 4,008,719, 4,036,227, 4,093,708,

4,111,202, 4,449,983, 4,455,143, 4,576,604, 4,673,405, 4,742,915 and

4,777,049.

[0048] The extended release technologies of the present description include delayed release and extended release formulations. These systems modify the temporal release of the drug release, allowing the active ingredient to be released by intermittent dosing (an example of delayed release) or by controlled or maintained dosing (an example of prolonged release) to a lower level. - therapeutic level of the active drug for a prolonged period. Length

Mills or delayed-release capsules can be configured for repeated action and are enteric-coated so that the programmed release is achieved by the slow diffusion of the active barrier coating. These extended release formulations can be a tablet loaded with a material, usually a polymer that is degraded in vivo in a controlled manner.

[0049] These compositions improve the bioavailability of the activated form of bempedoic acid and effectively extend the half-life of the drug administered. These compositions are useful for treating or reducing the risk of cardiovascular disease and other related comorbidities.

[0050] The advantages of the described extended-release bempedoic acid compositions approach are numerous. These bempedoic acid compositions not only maximize conversion to the active portion and optimize pharmacokinetic properties, for example, increased amount of the activated form of the drug in the liver, etc., the compositions can be used to reduce the dose per day. The extended release bempedoic acid compositions described here provide a therapeutically effective amount of bempedoic acid over a longer period of time (compared to immediate release formulations) and in concentrations within the therapeutic window over a period of time. longer time. Definitions

[0051] The terms used in the claims and specifications are defined as set out below, unless otherwise specified. The practice of the present invention includes the use of conventional pharmaceutical chemistry techniques that are within the experience in the art.

[0052] The term "cardiovascular disease" refers to diseases of the heart and circulatory system. These diseases are often associated with dyslipoproteinemias and / or dyslipidemias. Cardiovascular diseases for which the compositions of the present invention are useful to prevent or treat include, but are not limited to, arteriosclerosis; atherosclerosis; stroke; ischemia; endothelial dysfunctions, particularly those dysfunctions that affect the elasticity of blood vessels; peripheral vascular disease; coronary heart disease; myocardial infarction; brain infarction and restenosis.

[0053] In general, the term "prolonged release" refers to a dosage form designed to release a drug at a predetermined (but not necessarily constant) rate in order to maintain a desired range of drug concentration during a specific time period, for example, 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, etc., with minimal side effects. This can be achieved through a variety of formulations, as exemplified by the extended release formulations of bempedoic acid described here.

[0054] The term "dyslipidemias" refers to disorders that lead to or are manifested by aberrant levels of circulating lipids. As the blood lipid levels are very high, the compositions of the invention are administered to a patient to restore normal levels. Normal levels of lipids are reported in medical treaties known to those skilled in the art. For example, recommended blood levels of LDL, HDL, free triglycerides and other parameters related to lipid metabolism can be found on the websites of the American Heart Association and the National Cholesterol Education Program of the National Heart, Lung and Blood Institute.

[0055] Currently, the recommended level of HDL cholesterol in the blood is above 35 mg / dL; the recommended level of LDL cholesterol in the blood is less than 130 mg / dL; the recommended ratio of LDL: HDL cholesterol in the blood is less than 5: 1, ideally 3.5: 1; and the recommended level of free triglycerides in the blood is less than 200 mg / dL.

[0056] The term "metabolic syndrome" refers to a set of conditions - increased blood pressure, high blood sugar, excess body fat around the waist and abnormal cholesterol or triglyceride levels - which occur together , increasing the risk of heart disease, stroke and diabetes. These conditions are the co-occurrence of several known cardiovascular risk factors, including insulin resistance, obesity, atherogenic dyslipidemia and hypertension.

[0057] The term "non-alcoholic fatty liver disease (NA-FLD)" refers to a condition in which excess fat is stored in your liver. This accumulation of fat is not caused by the excessive use of alcohol.

[0058] Non-alcoholic hepatic steatosis (NAFLD) is characterized or diagnosed by the presence of fat in the liver (hepatic steatosis), either in the image or in liver histology after excluding secondary causes of fat accumulation in the liver (for example, significant consumption of alcohol, certain drugs and other medical conditions). NAFLD is further classified histologically into non-alcoholic liver steatosis (NAFL) and non-alcoholic steatohepatitis (NASH).

[0059] The term "simple fatty liver or non-alcoholic fatty liver (NAFL)" refers to a form of NAFLD in which you have fat in your liver, but little or no inflammation or damage to liver cells. NAFL is characterized by hepatic steatosis without evidence of hepatocellular lesion in the form of ballooning of hepatocytes.

[0060] The term "non-alcoholic steatohepatitis (NASH)" refers to a form of NAFLD in which you have hepatitis - inflammation of the liver - and damage to liver cells, in addition to fat in your liver. Inflammation and damage to liver cells can cause fibrosis or scarring of the liver. NASH is characterized by the presence of hepatic steatosis and inflammation with hepatocyte damage (ballooning) with or without fibrosis.

[0061] The term "individual" refers to any mammal, including humans, and thus includes mammals, such as those animals of veterinary and research interest that include, but are not limited to: apes, cattle, horses, dogs, cats and rodents The term "individual" is interchangeable with the term "patient".

[0062] The term "mammal", when used herein, includes human and non-human mammals, for example, non-human primates, canines, felines, murines, cattle, horses and pigs.

[0063] The term "administering" or "administering" a drug and / or therapy to an individual (and grammatical equivalents of this phrase) refers to the direct or indirect administration, which may be administration to an individual by a medical professional, self-administration and / or indirect administration, which can be the act of prescribing or inducing someone to prescribe a drug and / or therapy to an individual.

[0064] The term "treating" or "treating" a disorder or disease refers to taking measures to alleviate the symptoms of the disorder or disease, or otherwise obtaining some beneficial or desired results for an individual, including clinical results. Any benefit or desired clinical results may include, but are not limited to, alleviating or improving one or more symptoms of cancer or conditional survival and reducing tumor burden or tumor volume; decrease in the extent of the disease; delay or slowdown of tumor progression or disease progression; improvement, palliation or stabilization of the tumor and / or the disease state; or other beneficial results.

[0065] The term "improvement" refers to any therapeutically beneficial outcome in the treatment of a disease state, for example, a disease state of the cardiovascular system, including prophylaxis, decreased severity or progression or remission.

[0066] The term "in situ '' or" in vitro "refers to processes that occur in a living cell growing separate from a living organism, for example, growing in tissue culture.

[0067] The term "in vivo" refers to processes that occur in a living organism.

[0068] The term "sufficient amount" means an amount sufficient to produce a desired effect.

[0069] The term "bempedoic acid" or "ETC-1002" refers to 8-hydroxy-2,2,14,14 tetramethylpentadecanedioic acid:

[0070] The term "activated bempedoic acid" or "activated ETC-1002" refers to acid (9R) -1 - [(2R, 3S, 4R, 5R) -5- (6- amino-9H-purin-9-yl) -4-hydroxy-3- (phosphonooxy) tetrahydro-2-furanyl] -3,5,9,26-tetrahydroxy-8,8,20,20,32 , 32-hexamethyl-10,14,19-trioxo-2,4,6-trioxa-18-thia-11,15-diaza-3,5-diphosphatitriacontan-33-oico:

[0071] The term "zero order release rate" refers to a substantially constant release rate, so that a drug

maco dissolves in the fluid of the environment of use at a substantially constant rate. A zero order release rate can vary by up to about 25% and preferably no more than about 10% of your average release rate.

[0072] The term "a therapeutically effective concentration" or "a therapeutically effective amount" means an amount of the drug that is effective in ameliorating a symptom of a disease, for example, an amount that treats at least one symptom of cardiovascular disease or means an amount of the drug that statistically significantly reduces the risk of cardiovascular disease in the individual.

[0073] The term "phosphate buffer" means any buffer solution containing disodium hydrogen phosphate and sodium chloride. Some of these buffer solutions contain potassium cations in addition to or in place of sodium cations. Regardless, someone skilled in the art is well aware of the inorganic compounds and compatible organic compounds that can be added to these solutions (commercially available or otherwise prepared in a standard manner in the laboratory), as minor modifications / additions can be made (such as addition of relatively small amounts of Ca2 +, Fe3 + and / or ethylene diaminetetraacetic acid (ETDA), for example), as needed, as long as the solution's ability to maintain a reasonably constant pH is not altered. The person skilled in the art may refer, for example, to Conover, W. J. Chem. Educ., 1998, 75 (2), 153, which is incorporated herein by reference in its entirety.

[0074] The term "Cmax" refers to the overall observed maximum blood plasma concentration of an analysand, such as a drug or prodrug.

[0075] The pharmacokinetic parameters described here include:

area under the plasma-time concentration curve (AUC0-t and AUC0-∞, both with quantity * time / volume units); AUCτ, ss; maximum blood plasma concentration (Cmax); time of maximum blood plasma concentration (Tmax); and terminal elimination half-life (T1 / 2). The maximum concentration time (Tmax) is determined as the time corresponding to Cmax. The area under the plasma-time concentration curve until the time corresponding to the last measurable concentration (AUC0-t) is calculated by numerical integration using the linear trapezoidal rule as follows: where Ci is the plasma concentrations of the drug at the corresponding sampling time point ti en is the number of time points up to and including the last quantifiable concentration.

[0076] The terminal half-life (T1 / 2) is calculated using the following equation: where λ is the terminal elimination rate constant.

[0077] The area under the plasma-time concentration curve from time zero to infinity is calculated according to the following equation: where Clast is the last measurable concentration.

[0078] The term "Tmax" refers to the time at which the plasma concentration of an analysand, such as a drug or prodrug, reaches the maximum blood plasma concentration.

[0079] The term "AUCτ, ss" refers to the area under the concentration-time curve during a steady-state dosing interval.

where units are defined as quantity * time / volume.

[0080] The term "therapeutic window" is the range of doses of a drug / API that induces a therapeutic response without causing any significant adverse effect on patients. Generally, the therapeutic window is a relationship between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC).

[0081] The term "polycellulose" means a polymer made of cellulose, having a weighted average molecular weight of 500 Da to 5,000,000 Da, optionally cross-linked and including cellulose derivatives. Such derivatives include "functionalized" cellulose polymers that result from the reaction or crosslinking of cellulose polymers with one or more organic functional groups. The functional group (s) is / are pending (s) and, although it can (s) change the physicochemical properties of the cellulose polymer, it (s) does not fundamentally ( 1) the structure of the saccharide nucleus that repeats the chemical motif, or (2) where (that is, the carbon numbers in the respective saccharides to which the O-glycosidic bond is attached) and how (alpha / beta) the saccharides are covalently linked. The person skilled in the art is well aware of such functional groups and methods of preparing these derivatives. Someone skilled in the art can consult Handbook of Polymers for Pharmaceutical Technologies: Biodegradable Polymers, Vol. 3, Vijay Kumar Thakur and Manju Kumari Thakur, Wiley, 2015, which is incorporated herein by reference in its entirety.

[0082] The term "weighted average molecular weight" refers to Pm or a molecular weight that takes into account the molecular weight of a chain when determining contributions to the average molecular weight. Pm is determined by analytical methods that are sensitive to the molecular size of polymer chains, rather than just

the chain count. Analytical techniques, such as dynamic light scattering, provide Pm. Pm is calculated by: Mw = Pm where Mi is the molecular weight of a chain and Ni is the number of chains of that molecular weight.

[0083] It should be noted that, as used in the specification and the appended claims, the singular forms "one", "one" and "o (a)" include plural referents, unless the context clearly dictates otherwise. Pharmaceutical Compositions

[0084] Here, long-term pharmaceutical dosage forms are described comprising a solid oral dosage form. In some embodiments, the solid oral dosage form comprises bempedoic acid and a polymeric matrix. In some modalities, the solid oral dosage form comprises felicic acid dispersed within a polymeric material.

[0085] In some respects, the description provides an extended-release pharmaceutical dosage form comprising a solid oral dosage form comprising bempedoic acid and a polymeric matrix, wherein the polymer is hydroxypropylmethylcellulose (HPMC). In some respects, the solid oral dosage form comprises bempedoic acid dispersed in HPMC. In some respects, bempedoic acid is not dispersed within the polymer. In some respects, bempedoic acid is not dispersed in HPMC.

[0086] In one aspect, the description provides an extended-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises: bempedoic acid and a polymeric matrix, and in that the solid oral dosage form provides a concentrated therapeutic form

effective traction of bempedoic acid in a period of 12 hours, in a period of 14 hours, in a period of 16 hours, in a period of 18 hours, in a period of 20 hours, in a period of 22 hours, in a period 24 hours, over a 36 hour period, or over a 48 hour period when administered to an individual.

[0087] In one aspect, the description provides a solid oral dosage form which is a gelatin capsule. In one aspect, the solid oral dosage form is a hard shell capsule containing spheronized powder particles. In one aspect, the solid oral dosage form which is a soft shell capsule. In one aspect, the solid oral dosage form is a gelatin capsule further comprising a powdered excipient. In one aspect, the solid oral dosage form is a gelatin capsule further comprising an excipient in a suspension. In one aspect, the solid oral dosage form is a gelatin capsule further comprising one or more plasticizers, such as glycerin or sorbitol. In one aspect, the solid oral dosage form is a gelatin capsule further comprising one or more of: coloring agents, preservatives, disintegrants, lubricants and surface treatment agents.

[0088] In one aspect, the description provides a solid oral dosage form that is a tablet. In one aspect, the description provides a solid oral dosage form that is a rhombus.

[0089] In one aspect, the description provides a solid oral dosage form which is a gelatin capsule. In one aspect, the disclosure provides a solid oral dosage form which is a capsule containing a solid composition comprising felicic acid and one or more excipients. Bempedoic Acid - Structure and Synthesis

[0090] The structure of bempedoic acid (also known as

ETC-1002 or 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is:

[0091] ETC-1002 and the processes for the synthesis of ETC-1002 are described in U.S. Patent No. 7,335,799. Details of this process can be found in published US Patent No. US2005 / 0043278A1, in paragraphs [0247] -

[0343] of the specification, which is incorporated herein by reference in its entirety.

[0092] When used herein, the term "bempedoic acid" also encompasses pharmaceutically acceptable salts of the compound. Such pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, citric, tartaric, methanesulfonic, fumaric, malic, maleic and mandelic acids, mucate, N-oxide, sulfate, acetate, phosphate dibasic, monobasic phosphate, acetate trihydrate, bi (heptafluorobutyrate), bi (methylcarbamate), bi (pentafluoropropionate), bi (pyridine-3-carboxylate), bi (trifluoroacetate), bitartarate, hydrochloride and pentahydrate sulfate benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, fatigue, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, stolate, esilate, fumarate, gluceptate, gluconate, glutamate, glycolylsanilate, hydrochloride, hexylresin hydrochloride, hydroxinaftoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, p oligalacuronate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, trietiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, propionate sodium and zinc salts and the like. Polymer matrix

Hydrophilic & hydrophobic components

[0093] According to the present description, a main component of the matrix for the extended release formulations can be a hydrophilic polymer. Hydrophilic polymers are well suited for the controlled oral administration of drugs because they can produce a desirable drug profile and are economical. However, bempedoic acid is hydrophobic and the absorption process in the body depends to some extent on the lipophilic nature of a dosage form. Consequently, a desired release profile can be obtained by including hydrophilic and hydrophobic components and / or excipients in dosage form, the exact nature of which is determined on a case-by-case basis.

[0094] The extended release pharmaceutical composition matrix includes a polymer as a major component. Synthetic and natural polymers and / or their derivatives and / or combinations thereof can be used in compositions within the scope of this description.

[0095] Polysaccharides can be used as a polymer in the oral extended release formulations of the present description. Such formulations can include cellulose (polymer) derivatives, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), ethylcellulose and methylcellulose (MC). Each cellulose derivative has different degrees and different properties in terms of molecular weight, viscosity, solubility, hydration, etc. Consequently, different polymers and their respective different derivatives can be used to formulate controlled release systems by dissolution and controlled diffusion of the present description. Polymers that follow diffusion control are generally insoluble in water, although some are not. Polymers commonly used for controlled diffusion systems (reservoir and monolithic systems)

include cellulose (for example, ethyl cellulose), collagen, nylon, polyl (alkylcyanoacrylate), polyethylene, poly (ethylene-co-vinylacetate), polyl (hydroxyethyl methacrylate), poly (hydroxypropylethyl methacrylate), poly (methyl methacrylate), polyurethane and silicone rubber.

[0096] In addition to the dissolution release kinetics, the polymer glass transition temperature (Tg) is a very important polymer property. Tg affects properties such as fluidity, compactability, flexibility, permeability, etc.

[0097] Plasticizers can optionally be included in the polymer mixtures of the present description. Examples of plasticizers are glycerin, glyceryl triacetate (triacetin), poly (ethylene glycol) (PEG) and propylene glycol. Plasticizers are also commonly used in film coating to help the polymer (s) achieve the desired film quality. Since plasticizers reduce the rigidity of polymer molecules, they are useful for increasing the diffusion rate of bempedoic acid through the dosage form. Synthetic / natural polymers and derivatives

[0098] The so-called "natural polymers" are polymeric substances that are found in nature and can be extracted. They are often water-soluble materials. Examples of naturally occurring polymers include polysaccharides, such as cellulose, polynucleotides, such as RNA or DNA, and polyamides, such as proteins.

[0099] Synthetic polymers are derived from petroleum oil and made by scientists and engineers. Examples of synthetic polymers include (poly) vinyl, acrylates, nylon, polyethylene, polyester and Teflon.

[00100] In some respects, the present description provides a polymeric matrix in which the polymer is a synthetic polymer and is selected from the group consisting of: poly (vinyl) alcohol (PVA), poly acid (acrylic), poly (ethylene oxide) (PEOs), poloxamers, pluronics and polymethacrylates.

[00101] In some respects, the present description provides a polymeric matrix in which the polymer is a combination of two synthetic polymers and the two polymers are selected from the group consisting of: Carbopol, Eudragit, Avicel PH- 101, HPMC 606, Avicel CL-611 and Aqualon.

[00102] In some respects, the present description provides a polymeric matrix in which the polymer is selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), HPC (hydroxypropylcellulose), hydroxyethylcellulose (HEC), EC (ethylcellulose) ), MC (methylcellulose), Alginate Na, Carboxymethylcellulose Na, Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611, microcrystalline cellulose and Aqualon. In some respects, the present description provides a polymeric matrix in which the polymer is a combination of two polymers and the two polymers are selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), HPC (hydroxypropylcellulose), hydroxyethylcellulose (HEC ), EC (ethyl cellulose), MC (methyl cellulose), Alginate Na, Carboxymethyl cellulose Na, Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611, microcrystalline cellulose and Aqualon. In some respects, the present description provides a polymeric matrix in which the polymer is a combination of three polymers and the three polymers are selected from the group consisting of: hydroxypropylmethylcellulose (HPMC), HPC (hydroxypropylcellulose), hydro - xethylcellulose (HEC), EC (ethylcellulose), MC (methylcellulose), Alginate Na, Carboxymethylcellulose Na, Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611, microcrystalline cellulose and Aqualon.

[00103] In some respects, the present description provides a polymeric matrix in which the polymer is a combination of four or more synthetic polymers selected from any of the polymers named here.

[00104] In any of the aspects described here, the present description provides a polymeric matrix in which the polymer is a synthetic polymer and the matrix includes a plasticizer. In some respects, the plasticizer may be one or more of the plasticizers named herein. Plasticizers are well known in the art and, as a result, someone skilled in the art can consult a reference text described here and choose any of the plasticizers listed within. Examples of plasticizers include, but are not limited to: glycerin, glyceryl triacetate (triacetin), poly (ethylene glycol) (PEG), propylene glycol and combinations thereof.

[00105] In some respects, the present description provides a polymeric matrix in which the polymer is selected from the group consisting of: polycellulose, microcrystalline cellulose, polyvinyl acetate, polyvinylpyrrolidone, polyacrylate, an insensitive ammonium polymer to pH and its mixtures.

[00106] In some respects, the present description provides a polymeric matrix in which the polymer is selected from the group consisting of: (poly) cellulose (for example, ethyl cellulose), collagen, nylon, polyl (alkylcyanoacrylate), polyethylene, poly (ethylene-co-vinylacetate), poly (hydroxyethyl methacrylate), poly (hydroxypropylethyl methacrylate), poly (methyl methacrylate), polyurethane and silicone rubber.

[00107] In some respects, the present description provides a polymeric matrix in which the polymer is microcrystalline cellulose. In some respects, the present description provides a polymeric matrix in which the polymer is a mixture of microcrystalline cellulose and polycellulose. In some respects, the present description provides a polymeric matrix in which the polymer is a mixture of microcrystalline cellulose and hydroxypropylmethylcellulose (HPMC). In some respects, the present description provides a polymeric matrix in which the polymer is hydroxypropylmethylcellulose (HPMC). In some respects, the present description provides a polymeric matrix in which the polymer is a polycellulose.

Porosity & permeability

[00108] The production of API tablets and solid granulation has an effect on the density of the dosage form, porosity and hardness, disintegration and particle size. Increases in density and hardness of the solid will result in a decrease in permeability and penetrability of the solvent.

[00109] In some respects, the present description provides a polymeric matrix that is not porous, but amorphous. In some aspects, the present description provides a polymeric matrix that has a relatively low porosity. Porosity can be calculated by: where ͼ is the matrix porosity, T is tortuosity, C 0 is the total amount of drug present per unit volume in the matrix, C is the solubility of the drug in the release medium, at the moment, t, M is the amount of drug released per unit area, and Ds is the diffusion coefficient of the drug in the release medium.

[00110] In some respects, the present description provides a polymer matrix with an average particle size of 10-200 µm. In some respects, the present description provides a polymeric matrix with an average particle size of 20-180 µm. In some respects, the present description provides a polymeric matrix with an average particle size of 20-150 µm. In some respects, the present description provides a polymeric matrix with an average particle size of 40-100 µm.

[00111] In some respects, the present description provides a polymeric matrix with an average pore size of 10-200 nm, 20-180 nm, 20-150 nm or 40-100 nm. Synthesis examples

[00112] In some respects, the present description provides a polymeric matrix in which the polymer is a derivative of a synthetic polymer.

natural or natural. Someone skilled in the art can synthesize the monomer compound with organic synthesis techniques, as long as the reactive organic functional group of the monomer also does not polymerize simultaneously (thermally). Another way for someone skilled in the art to prepare a derivative of a synthetic polymer is to polymerize (in a controlled polymerization reaction) the desired polymer, that is, starting material, or in the case of a natural polymer, to obtain a polymer starting material natural commercial desired from companies such as Sigma Aldrich, TCI Chemicals, Strem, etc. and then perform one or more reactions of organic synthesis to the polymer to functionalize it with the desired pending groups. The reaction can be initiated with organic functional groups of the polymer that are potentially reactive, that is, those of a nucleophilic or electrophilic nature. Someone skilled in the art is careful not to react with the functional groups that covalently bond each of the monomer units of the polymer, since the reaction of these groups would degrade the polymer and decrease the average molecular weight of the polymer chains. However, in the case of natural polymers, it is often the case that such a chain split occurs and the person skilled in the art will try to mitigate such adverse reaction conditions.

[00113] An example of the first approach employs an acrylate polymer. An acrylate monomer can be functionalized through the carboxylate through esterification or amidation reactions with a desired nucleophilic functional group becoming the pendent group. For example, acrylic acid can be functionalized with a 3000 Da polyethylene glycol through Steglich's esterification reaction conditions. The resulting ethylene glycol ester can be polymerized under thermal conditions with AIBN "azoisobutylnitrile" (optionally with another monomeric compound such as methyl methacrylate to produce a copolymer) in a controlled manner to make a polymer with the desired Tg and other physical properties .

[00114] Another example of synthesis of a polymer derivative applies to the natural polymer and includes the preparation of the derivative by functionalizing the natural polymer with organic functional groups. For example, the natural cellulose polymer can react through hydroxyl functional groups with propylene oxide and methyl chloride with sodium hydroxide reagent. The product formed is a cellulose polymer (polycellulose) with ether functional groups (methyl and isopropyl) in a certain percentage of the previous hydroxy functional groups. In some respects, the percentage of functional ether groups is 0.1-50%, preferably 0.1-45%, preferably 0.1-30%, preferably 0.1-15% , preferably from 0.1-10%, preferably from 0.1-9%, preferably from 0.1-8%, preferably from 0.1-7%, preferably from 0.1-6%, preferably from 0.1-5%, preferably 0.1-4%, preferably 0.1-3%, preferably 0.1-2%, preferably 0.1-1%, or more preferably 0.1-0.5%.

[00115] Such derivation reactions and preparations are well within the reach of the person skilled in the art. Textbooks like Bio-degradable Polymers in Pharmacy and Medicine. Classification, Chemical Structure, Principles of Biodegradation and Use, Jan Gajdziok Roman Gonec David Vetchy, Verlag, 2016; Cellulose and Cellulose Derivatives: Synthesis, Modification and Applications, Ibrahim H. Mondal, Nova Science Publishers Incorp., 2015 and Biomedical Polymers: Synthesis and Processing, Vinod B. Damodaran, Divya Bhatnagar, N. Sanjeeva Murthy, Springer, 2016, which are hereby incorporated by reference in their entirety, are available to the person versed for reference. Excipients Components for a solid dosage form

[00116] The dissolution rate of a pure drug can be changed when mixed with various excipients during the process of manufacturing solid dosage forms.

[00117] Someone skilled in the art can commercially buy certain compounds and materials to use as excipients or better, they can derive known compounds and starting material. Such methods of synthesis (and the use of these excipients in the formulation of solid dosage forms) are well known in the art and found in the primary reference texts here, as well as in Handbo-ok of Pharmaceutical Excipients, 4th ed. Rowe RC, Sheskey PJ, Weller PJ, ed. London, UK: AphA and Pharmaceutical Press, 2003, which is incorporated herein by reference in its entirety.

[00118] In some respects, the present description provides a solid dosage form comprising bempedoic acid and a polymeric matrix, wherein the solid dosage form further comprises a surfactant. In some respects, the present description provides a solid dosage form comprising bempedoic acid and a polymeric matrix, wherein the solid dosage form further comprises an anionic surfactant. In some respects, the present description provides a solid dosage form comprising bempedoic acid and a polymeric matrix, in which the solid dosage form further comprises an anionic surfactant, in which the anionic surfactant is sodium lauryl sulfate.

[00119] In some respects, the present description provides a solid dosage form comprising bempedoic acid and a polymeric matrix, wherein the solid dosage form further comprises microcrystalline cellulose and sodium lauryl sulfate.

[00120] Other compounds suitable for use as excipients for the solid oral dosage forms described here are also found in the primary textbooks referenced here, as

Remington, The Science and Practice of Pharmacy. Easton, Pa: Mack Pub. Co. 21st Ed. Excipient classes

[00121] Excipients can be added to fulfill certain pharmaceutical functions, such as diluents (fillers), dyes, binders, granulating agents, disintegrants and lubricants.

[00122] In some respects, the present description provides a solid dosage form comprising bempedoic acid and a polymeric matrix, wherein the solid dosage form further comprises a binder, filler, diluent, dye, granulating agent, a disintegrant, a lubricant, or any combination thereof.

[00123] In some respects, the present description provides a solid dosage form comprising bempedoic acid, a polymeric matrix and a binder, a filler, a diluent, a dye, a granulating agent, a disintegrant, a lubricant or any combination thereof. In some respects, the present description provides a solid dosage form comprising bempedoic acid, a polymeric matrix and a binder and lubricant. In some aspects, the present description provides a solid dosage form comprising bempedoic acid, a polymeric matrix and a binder and a lubricant, wherein the lubricant is a surfactant. In some respects, the present description provides a solid dosage form comprising bempedoic acid, a polymeric matrix and a binder and a lubricant, wherein the lubricant is sodium lauryl sulfate. Solid dosage forms

[00124] The pharmaceutical dosage forms may include a variety of solid forms, for example, the pharmaceutical product may be a pill, for example, a tablet, a buccal dosage form similar to a tablet being a tablet or lozenge, for example example, a sublingual or oral disintegrating gum, tablet or lozenge, a thin film, etc.

[00125] Genetically, solid oral dosage forms of prolonged release can be categorized into three basic categories: tablets / pills based on matrix, multiparticulate solids and solid osmotic dosage forms. The present description provides an extended-release pharmaceutical dosage form comprising a solid oral dosage form, wherein the solid oral dosage form comprises bempedoic acid and a polymer. In some ways, the polymer is in the form of a polymeric matrix. In other respects, the polymer is a pure, dry powder. The currently described solid oral dosage form can be formulated in a dosage form of any of the categories mentioned above.

[00126] In one aspect, the present description provides a solid oral dosage form comprising bempedoic acid and a polymeric matrix.

[00127] In one aspect, the present description provides a solid oral dosage form, wherein the solid dosage form is a tablet.

[00128] In one aspect, the present description provides a solid oral dosage form, wherein the solid dosage form is a gelatin capsule. In one aspect, the present description provides a solid oral dosage form, wherein the solid dosage form is a gelatin capsule further comprising a powdered excipient.

[00129] In one aspect, the present description provides a solid oral dosage form, wherein the dosage form is not controlled by diffusion, but by controlled dissolution.

Formulation properties

[00130] In some respects, the present description provides a solid dosage form comprising bempedoic acid, wherein the dosage form provides an extended release of well pedoic acid over a period of at least 2-8 hours after administration oral, or produces a certain release profile for bemedic acid, for example, a Cmax plateau prolonged for at least one hour for bempedoic acid (or its metabolite, activated bempedoic acid) after oral administration of bempedoic acid. Weight ranges & amounts of composition

[00131] In one aspect, the description provides a solid oral dosage form in which bempedoic acid is 30-50% by weight, 35-55% by weight, 40-60% by weight, 45 -65% by weight, 50-70% by weight, 55-75% by weight or 60-80% by weight.

[00132] In some respects, the present description provides the administration of a prolonged release formulation of well pedoic acid, in which the dosage is 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 220 mg / day, 230 mg / day, 240 mg / day or 250 mg / day.

[00133] In some respects, the present description provides administration of a prolonged release formulation of well pedoic acid, where the dosage is 45-55 mg / day, 55-65 mg / day, 65-75 mg / day, 75-85 mg / day, 85-95 mg / day, 95-105 mg / day, 105-115 mg / day, 115-125 mg / day, 125-135 mg / day, 135-145 mg / day, 145-155 mg / day, 155-165 mg / day, 165-175 mg / day, 175-185 mg / day, 185-195 mg / day, 195-205 mg / day, 205-215 mg / 215-225 mg / day, 225-235 mg / day, 235-245 mg / day or 245-255 mg / day.

[00134] In one aspect, the description provides a dosage form

solid oral gem in which HMPC is 0-10% by weight, 0-5% by weight, 0-4% by weight, 0-3% by weight, 0-2% by weight or 0-1% by weight.

[00135] In one aspect, the description provides a solid oral dosage form comprising: bempedoic acid 40-60% by weight and HPMC is 0-3% by weight, or bempedoic acid is 60-80 % by weight and HPMC 0-5% by weight.

[00136] In one aspect, the description provides a solid oral dosage form in which the pharmaceutical dosage form comprises: 60.0% w / w bempedoic acid; 37.3% w / w microcrystalline cellulose; 0.7% w / w hydroxypropylmethylcellulose; and 2% w / w sodium lauryl sulfate.

[00137] In one aspect, the description provides a solid oral dosage form in which the pharmaceutical dosage form comprises: 60.0% w / w bempedoic acid; 9.3% w / w microcrystalline cellulose; 28.0% w / w microcrystalline cellulose / sodium carboxymethyl cellulose; 0.7% w / w of hydroxypropylmethylcellulose 2.0% w / w of sodium lauryl sulfate.

[00138] In one aspect, the description provides a solid oral dosage form in which the pharmaceutical dosage form comprises: 60.0% w / w bempedoic acid; 33.7% w / w microcrystalline cellulose; 3.7% w / w sodium carboxymethyl cellulose;

0.7% w / w of hydroxypropylmethylcellulose; and 2.0% w / w sodium lauryl sulfate.

[00139] In some respects, the present description provides a pharmaceutical composition in which the composition comprises at least 40% and no more than 80% bempedoic acid, at least 45% and no more than 80% bempedoic acid in w / w, at least 50% and no more than 80% bempedoic acid in w / w, at least 55% and no more than 80% bempedoic acid in w / w, at least 60% and no more than 80 % bempedoic acid w / w, at least 65% and no more than 80% bempedoic acid in w / w, at least 70% and no more than 80% bempedoic acid in w / w, at least 75% and no more than 80% bempedoic acid w / w.

[00140] In some respects, the present description provides a pharmaceutical composition in which the composition comprises at least 5% and no more than 50% of the w / w polymer, at least 10% and no more than 50% of the polymer in w / w, at least 15% and not more than 50% of the w / w polymer, at least 20% and not more than 50% of the w / w polymer, at least 25% and no more than 50 % w / w polymer, at least 30% and no more than 50% w / w polymer, at least 35% and no more than 50% w / w polymer, at least 40% and no more than 50% w / w polymer, at least 45 and no more than 50% w / w polymer.

[00141] In some respects, the present description provides a pharmaceutical composition in which the polymer component is hydroxypropylmethylcellulose (HPMC) and is at least 0.1% and not more than 10% of the HPMC in w / w, at least minus 0.5% and not more than 10% of HPMC in w / w, at least 1% and not more than 10% of HPMC in w / w, at least 5% and not more than 10% of HPMC in p / p.

[00142] In some respects, the present description provides a pharmaceutical composition in which the polymer is microcrystalline cellulose and is at least 1% and no more than 60% of the microcrystalline cellulose in w / w, at least 5% and no more than 60 % of microcrystalline cellulose in w / w, at least 10% and not more than 60% of microcrystalline cellulose in w / w, at least 15% and not more than 60% of microcrystalline cellulose in w / w, at least 20% and not more than 60% of the microcrystalline cellulose in w / w, at least 25% and not more than 60% of the microcrystalline cellulose in w / w, at least 30% and not more than 60 % w / w microcrystalline cellulose, at least 35% and no more than 60% w / w microcrystalline cellulose, at least 40% and no more than 60% w / w microcrystalline cellulose, at least 45% and not more than 60% of the microcrystalline cellulose in w / w, at least 50% and not more than 60% of the microcrystalline cellulose in% w / w, at least 55% and not more than 60% of the microcrystalline cellulose talina in w / w.

[00143] In some respects, the present description provides a pharmaceutical composition in which the polymer is sodium carboxymethyl cellulose and is at least 1% and no more than 50% of the sodium carboxymethyl cellulose in w / w, at least 5% and no more than 50% of the sodium carboxymethylcellulose in w / w, at least 10% and not more than 50% of the sodium carboxymethylcellulose in w / w, at least 15% and not more than 50% of the sodium carboxymethylcellulose in w / w, at least 20% and no more than 50% of the sodium carboxymethyl cellulose in w / w, at least 25% and no more than 50% of the sodium carboxymethyl cellulose in w / w, at least 30% and no more than 50% w / w sodium carboxymethyl cellulose, at least 35% and no more than 50% w / w sodium carboxymethyl cellulose, at least 40% and no more than 50% w / w sodium carboxymethyl cellulose P.

[00144] In some respects, the present description provides a pharmaceutical composition comprising sodium lauryl sulfate and is at least 0.1% and no more than 10% of sodium lauryl sulfate in w / w, at least 0.5% and not more than 10% of sodium lauryl sulphate in w / w, at least 1% and not more than 10% of sodium lauryl sulphate in w / w, at least 5% and no more than 10% of lauryl sulphate of sodium in w / w.

[00145] In some respects, the present description provides a pharmaceutical composition comprising sodium starch glycolate and is at least 0.1% and no more than 10% of the sodium starch glycolate in w / w, at least 0, 5% and no more than 10% w / w sodium starch glycolate, at least 1% and no more than 10% w / w sodium starch glycolate, at least 5% and no more than 10 % of sodium starch glycolate in w / w.

[00146] In some respects, the present description provides a pharmaceutical composition comprising a ratio of bempedoic acid to polymer of about 4 to 1.

[00147] In some respects, the present description provides a pharmaceutical composition that comprises a ratio of bempedoic acid to polymer of about 3 to 2.

[00148] In some respects, the present description provides a pharmaceutical composition comprising a ratio of bempedoic acid to polymer of about 2 to 1.

[00149] In some respects, the present description provides a solid dosage form, in which the average particle size is 1-200 µm. In some respects, the present description provides a solid dosage form, in which the average particle size is 1-150 µm. In some respects, the present

[00150] the description provides a solid dosage form, in which the average particle size is 1-125 µm. In some respects, the present description provides a solid dosage form, in which the average particle size is 10-100 µm. In some respects, the present description provides a solid dosage form, in which the average particle size is 20-100 µm. In some respects, the present description provides a solid dosage form, in which the average particle size is 40-100 µm. In some respects, the present description provides a solid dosage form, in which the average particle size is 50-100 µm. In some respects, the present description provides a solid dosage form, in which the average particle size is 80-100 µm. Threshold & Saturation

[00151] Side effects related to toxicity often result after administration, when the rate of increase and / or the actual plasma concentrations of bempedoic acid exceed the maximum tolerable concentration limit (TCM). At the same time, in order to achieve a therapeutic effect, concentrations must be kept above a minimum effective concentration (ECM).

[00152] In some respects, the present description provides a solid dosage form in which, when dosed as recommended, the resulting maximum serum concentration is measured over the dose range.

[00153] In some respects, the present description provides a solid dosage form in which, when dosed as recommended, the resulting minimum serum concentration (MEC) is measured over the dose interval (ie the period between dosages repeated).

[00154] In some respects, the present description provides a solid dosage form, in which the concentration of bempedoic acid is maintained between MEC and MTC for: at least 8 hours and no more than 48 hours; at least 12 hours and no more than 48 hours; or at least 24 hours and no more than 36 hours after administration.

[00155] In some respects, the present description provides a solid dosage form, wherein the solid oral dosage form provides a therapeutically effective concentration of bempedoic acid over a period of 24 hours when administered to an individual . In some aspects, the present description provides a solid dosage form, wherein the solid oral dosage form provides a therapeutically effective concentration of bempedoic acid over a period of 36 hours when administered to an individual. In some respects, the present description provides a solid dosage form, wherein the solid oral dosage form provides a therapeutically effective concentration of bempedoic acid over a period of 48 hours when administered to an individual. Unit dose

[00156] A unit dosage form is a term that is generally understood by the person skilled in the art. A unit dosage form is a pharmaceutical drug marketed for a specific use. The drug includes the active ingredient (s) and any inactive components, most often in the form of polymers and pharmaceutically acceptable vehicles or excipients.

[00157] In some respects, the extended release composition is formulated in a (1) unit dosage form that is effective for at least twelve (12) hours, eighteen (18), twenty-four (24), thirty (30), thirty-six (36) or forty-eight (48) hours.

[00158] In some respects, the extended release composition is formulated in at least two (2) separately separate unit dosage forms with different release profiles. Pharmacodynamics

[00159] API formulations administered orally must be absorbed before becoming bioavailable, circulating systematically. For most drugs / APIs, pre-elimination

systemic occurs in sites of the gastrointestinal tract and significantly affects the absorption of the drug / API. The degradation of drugs administered orally occurs, to some extent, with hydrolysis in the stomach and upper gastrointestinal tract or by digestion of enzymes in the intestine. In addition, drugs are metabolised by microorganisms in the intestine and by enzymes in the liver (ie, the first-pass effect). These degradation processes can affect the variable or insufficient absorption of the drug. In general, it is observed that the higher the absorption efficiency of the drug / API, the greater the bioavailability of the API. Bioavailability measures include values for Cmax, Tmax and AUC, among others. The concentrations of well pedoic acid in blood plasma in an individual can be determined by clinical trials, well known to the skilled person, to determine the values of pharmacokinetic parameters and to determine the correlation between tolerability and the clinical effect and plasma concentrations of bempedoic acid.

[00160] In some respects, the present description provides a solid dosage form, in which the solid dosage form provides the bempedoic acid with a Cmax of at least 8 µg / L.

[00161] In some respects, the present description provides a solid dosage form, wherein the solid dosage form provides for bempedoic acid an AUC of at least 0.6 ng * hr / ml per mg of bempedoic acid.

[00162] In some respects, the present description provides a solid dosage form, wherein the solid dosage form provides for bempedoic acid a T1 / 2 of at least 24 hours.

[00163] In some respects, the present description provides a solid dosage form, wherein the solid dosage form provides for activated bempedoic acid a Cmax of at least 10 µg / L.

[00164] In some respects, the present description provides a solid dosage form, wherein the solid dosage form provides for 60 µg / mL, 57 µg / mL, 55 µg / mL, 53 µg / mL for activated bempedoic acid. mL, 50 µg / mL, 47 µg / mL, 45 µg / mL or 40 µg / mL.

[00165] In some respects, the present description provides a solid dosage form, wherein the solid dosage form provides for activated bempedoic acid an AUC of at least 0.8 ng * hr / ml per mg of bempedoic acid.

[00166] In some respects, the present description provides a solid dosage form, wherein the solid dosage form provides bempedoic acid activated for at least 28 hours.

[00167] In some respects, the present description provides a solid dosage form, where the solid dosage form provides an AUC of 1.1 ng * hr / mL per mg of bempedoic acid after oral administration of a single 180 mg bempedoic acid capsule.

[00168] In some respects, the present description provides a solid dosage form, wherein the solid dosage form provides an AUC of at least 50 µg * hr / L per mg of bempedoic acid activated after oral administration of a single 180 mg capsic acid capsule. Zero order release

[00169] The ideal release of an API from a certain dosage form maintains therapeutic levels in the blood and tissues of the drug for an extended period of time, usually over 8 hours. This maintained concentration is typically achieved by obtaining a zero order release rate from the API of the dosage form. Zero order release is an API release of the dosage form that is independent of the amount of drug in the delivery system (that is, a constant release rate).

[00170] In one aspect, the description provides a dosage form

solid oral pharmaceutical gem that has a zero order release rate for at least 12 hours when dissolution is tested using United States Pharmacopoeia Apparatus 2 (50 rpm paddles) in 50 mM phosphate buffer at 20 ° C, the form solid oral pharmaceutical dosage comprising: bempedoic acid and a polymeric matrix, in which the pharmaceutical dosage form has a hardness of 2-30 kg and is in the form of a sphere or has a thickness to effective diameter ratio to allow erosion and penetration control sufficient to control surface erosion when dissolution is tested.

[00171] In one aspect, the description provides a solid oral pharmaceutical dosage form that has a zero order release rate for at least 6 hours, for at least 8 hours, for at least 10 hours, for at least 12 hours, for at least 14 hours, for at least 16 hours, for at least 18 hours, for at least 20 hours, for at least 22 hours, for at least 24 hours, or for at least 36 hours. In some respects, each solid oral pharmaceutical dosage form corresponding to the period of 6-36 hours of time for zero order release when dissolution tested using United States Pharmacopoeia Apparatus 2 (50 rpm paddles) in phosphate buffer 50 mM at 20 ° C maintains a zero order release rate during that time. Dissolution & pH

[00172] Solid dosage forms can release the API according to the mechanisms of erosion (dissolution) and / or diffusion, depending on the nature of the polymeric matrix and the chemical-physical properties of the API.

[00173] The erosion (dissolution) of many API formulations, and of well-known pediatric acid formulations in particular, are prone to the "discharge" of the dose. In other words, once the dosage form

gem was solvated beyond a certain limit, a significant amount of the API leaks out of the compositions on an uncontrolled subject. The effect of the pH of the local media on the release of the API is greater in systems that are under erosion control. In mediums of relatively high and low pH, API formulations are susceptible to hydrolysis or degradation, so that the dosage form becomes sufficiently solvated so that erosion and discharge are more likely to occur.

[00174] The solid oral dosage forms of extended release bempedoic acid described here are also characterized (at least in part) by their physical characteristics, that is, the physical properties of the dosage form that provide a certain profile of dis - bempedoic acid solution.

[00175] Described herein are prolonged release pharmaceutical dosage forms comprising a solid oral dosage form, in which the solid oral dosage form comprises well pedoic acid and a polymeric matrix and in which the oral dosage form solid does not pour bempedoic acid for 24 hours after administration. In one aspect, the description provides a solid oral dosage form that does not pour more than 10% bempedoic acid into a pH 8 medium after 30 minutes.

[00176] Erosion of the solid dosage form and absorption of the absorption of the dissolution medium can be determined, among other ways, gravimetrically under the same conditions used for the dissolution test. The basic calculations are shown below. Dissolution Medium Capture (%) (Net Weight - Remaining Dry Weight) Remaining Dry Weight Remaining Mass (%) (Remaining Dry Weight) Original Dry Weight

[00177] The rotary disk system of USP Wood Apparatus or USP Dissolution Apparatus 2 (United States Pharmacopoeia 34 / National Form 29, 2011, General Chapter <711> Dissolution, here incorporated by reference in its entirety, see also Chapter 35, pages 679-687 in Remington, JP (1995). Remington, The Science and Practice of Pharmacy. Easton, Pa: Mack Pub. Co. 21st Ed., Also incorporated herein by reference in its entirety) is used by people skilled in determining the dissolution profile or dissolution rate for prolonged release dosage forms. Briefly, the device has three parts: the steel punch, a matrix and a base plate. The base of the matrix is attached to the base plate and the screws fixed to the base plate are inserted into the matrix. The hole punch is inserted into the die cavity, thereby compressing the internal material. The pellet and matrix assembly are then inserted with the pellet side up, at the bottom of the dissolution vessel (1 liter). It is important that the bottom of the vase is flat. The paddles of the USP 2 Apparatus shake the material and care is taken so that no air bubbles form on the surface of the pellet and that there is no change in temperature (37 ° C).

[00178] The dissolution apparatus can be USP Type I, II, IV and VII, that is, rotating basket, rotating paddle, flow cell and alternative support. In the dissolution medium, someone skilled in the art can select certain parameters based on API stability, assay sensitivity, sinking condition in which the final drug concentration is at least three times less than a saturated concentration is needed, etc. It is worth noting that the current USP dissolution tests exert minimal mechanical strength in the solid dosage form.

[00179] In one aspect, the description provides an extended release pharmaceutical dosage form that comprises a

solid oral dosage form, in which the solid oral dosage form comprises: Bempedoic acid dispersed within a polymeric matrix, in which the solid oral dosage form when dissolution tested using the United States Pharmacopoeia Apparatus 2 (50 rpm paddles) in 50 mM phosphate buffer at 20 ° C exhibits a drug release profile substantially corresponding to the following pattern: after 2 hours, no more than 30% of the total mass of bempedoic acid is released ; after 4 hours, no more than 75% of the total mass of bempedoic acid is released; and after 8 hours, no more than 90% of the total mass of bempedoic acid is released.

[00180] In some respects, the present description provides a solid dosage form, in which the solid oral dosage form comprises: Bempedoic acid dispersed within a polymeric matrix, in which the solid oral dosage form when dissolution was tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20 ° C exhibits a drug release profile substantially corresponding to the following standard: after 1 hour, no more than 8% of the total mass of well-pedoic acid are released, or no more than 10% of the total mass of well-pedic acid is released, or no more than 6% of the total mass of well-pedic acid is released, or no more than 4% of the total mass of acid bempedoic acid are released, or no more than 3% of the total mass of bempedoic acid is released.

[00181] In some respects, the present description provides a solid dosage form, in which the solid oral dosage form comprises: Bempedoic acid dispersed within a polymeric matrix

ca, in which the solid oral dosage form when dissolution was tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20 ° C exhibits a drug release profile substantially corresponding to the following standard: after 2 hours, no more than 30% of the total mass of bempedoic acid is released, or no more than 25% of the total mass of bempedoic acid is released, or no more than 20% of the total mass of bempedoic acid is released, either no more than 15% of the total mass of bempedoic acid is released, or no more than 13% of the total mass of bempedoic acid is released.

[00182] In some respects, the present description provides a solid dosage form, in which the solid oral dosage form comprises: Bempedoic acid dispersed within a polymeric matrix, in which the solid oral dosage form when the dissolution was tested using United States Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20 ° C exhibits a drug release profile substantially corresponding to the following standard: after 3 hours, no more than 50% of the total mass of bempedoic acid are released, or no more than 45% of the total mass of bempedoic acid is released, or no more than 40% of the total mass of bempedoic acid is released, or no more than 35% of the total mass of acid bempedoic acid are released, or no more than 33% of the total mass of bempedoic acid is released.

[00183] In some respects, the present description provides a solid dosage form, in which the solid oral dosage form comprises: Bempedoic acid dispersed within a polymeric matrix, in which the solid oral dosage form when the dissolution was tested using US Pharmacopoeia Apparatus 2

(50 rpm paddles) in 50 mM phosphate buffer at 20 ° C exhibits a drug release profile substantially corresponding to the following pattern: after 4 hours, no more than 75% of the total mass of bempedoic acid is released, or no more than 65% of the total mass of bempedoic acid is released, or no more than 60% of the total mass of bempedoic acid is released, or no more than 55% of the total mass of bempedoic acid is released, or no more than 53 % of the total mass of bempedoic acid is released.

[00184] In some respects, the present description provides a solid dosage form, in which the solid oral dosage form comprises: Bempedoic acid dispersed within a polymeric matrix, in which the solid oral dosage form when the dissolution was tested using United States Pharmacopoeia Apparatus 2 (50 rpm paddles) in 50 mM phosphate buffer at 20 ° C exhibits a drug release profile substantially corresponding to the following pattern: after 8 hours, no more than 90% of the total mass of bempedoic acid are released, or no more than 85% of the total mass of bempedoic acid is released, or no more than 80% of the total mass of bempedoic acid is released, or no more than 78% of the total mass of bempedoic acid is released , or not more than 75% of the total mass of bempedoic acid is released.

[00185] In some respects, the extended release composition does not release more than 3 mg of bempedoic acid over a given period of 5 minutes up to 8 hours after administration, over a period of 15 minutes until 8 hours after administration, for a period of 30 minutes to 8 hours after administration, or for a period of time from 1 hour to 8 hours after administration. Formulation preparation

[00186] There are numerous references that tell someone skilled in the art how to make the extended release pharmaceutical compositions (and solid oral dosage forms) described here, for example, see the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosa- ge Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), (current edition), all incorporated herein by reference in its entirety. Briefly, in the preparation of prolonged release formulations in an oral dosage form, many excipients and pharmaceutical media commercially available are employed. For example, suitable carrier vehicles and added additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, starches, sugars, thinners, granulating agents, lubricants, binders, disintegrating agents and similar, many of which are described in the section above entitled "Excipients." Specific excipients may include, for example, sucrose, mannitol, polyethylene glycol, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium lauryl sulfate, chromophor, tweens, spans, pluronic, microcrystalline cellulose, calcium phosphate, talc, fumed silica, hydroxypropylmethylcellulose, wax and fatty acids, etc.

[00187] As mentioned above, solid oral dosage forms fall into: matrix-based tablets / pills, multiparticulate solids and osmotic solids categories. Many different or separate processes can be used for all or any of the three approaches, however, there are some preferred or usual processes for each.

[00188] The formulation processes for making tablets or pills based on matrix are based on controlled systems of diffusion and dissolution (i.e., erosion of the matrix). The release of the drug from hydrophilic matrix systems involves both diffusion and dissolution, since the size of the matrix decreases as more drug / API is released, the amount of drug / API released is also decreased, ie , resulting in a non-zero release order. Typical lipophilic matrix systems are often observed to be under diffusion control only. The solid dosage forms described herein can comprise a hydrophilic matrix or a lipophilic matrix.

[00189] Someone skilled in the art can use a variety of granulation processes to formulate the solid matrix-based dosage forms described herein. These include dry mixing (direct compression), roller compaction, wet granulation, fluid bed granulation, foam granulation and melt extrusion granulation, all useful for preparing matrix tablets.

[00190] For this purpose, the processes for preparing the solid dosage form include a generic process, such as manufacturing by the wet granulation technique. For example, bempedoic acid and polymer (s) are mixed using a solvent, such as methanol, as the granulation fluid. The remaining excipients are dissolved in a portion of granulation fluid and this mixture is mixed with wet slowly added to the bempedoic acid with continuous mixing in the mixer. The granulation fluid is added until a wet mixture is produced, whose wet mass mixture is then forced through a predetermined screen in oven trays. The mixture is dried for 18 to 24 hours at 24 ° C to 40 ° C in a forced air oven. The dried granules are then sieved. Then, a lubricant such as magnesium stearate is granulated in the mixture and placed in grinding jars. Grinding involves mixing in an open mill for about 10-30 minutes. Then, the composition is then pressed and perhaps coated with another excipient.

[00191] Considerations for which process to use include drug loading, fluidity and compactability. For example, both wet granulation and fluid bed granulation may not be ideal for moisture sensitive drugs, while melt extrusion granulation may not be suitable for thermally unstable drugs.

[00192] On the other hand, solid multiparticulate dosage forms comprise the drug / API and layered granules or microspheres. Fluid bed granulation, extrusion and spheronization, hot melt extrusion granulation, spray freezing or roller compaction are some common methods used to micronize and coat particles of such dosage forms. The formation of granules can be carried out by crosslinking the non-covalent alginate layer with calcium cations to form alginate granules.

[00193] Finally, osmotic tablets in solid dosage form, such as the solid dosage forms developed by Alza Corporation, normally contain four components: a drug / API compartment, the dilation compartment containing an osmotically salt active, a membrane (s) and microscopic orifice (s) for release. The drug / API and the expansion compartments are made by the granulation processes described for matrix-based systems above. The osmotic tablet works by forming a kind of “pull-push” osmotic pump with the drug / API and swelling compartments. Both compartments are compressed into a two-layer tablet and one membrane (s) containing holes (made with laser perforations) are coated (see above for spray drying processes and the Remington reference) on the tablet. . The membrane allows water-free diffusion, but not drugs. When the tablet is exposed to water or any fluid in the body, water flows into the tablet due to the osmotic pressure difference. For processes for preparing osmotic tablets, see, for example, US Patent Nos. 8,629,179 and 8,163,798, and Remington's Pharmaceutical Sciences (Arthur Osol, editor; current edition).

[00194] The most significant advantage for osmotic systems is that the dosage form, to some extent, is independent of pH and provides a constant release rate over an extended period of time, even when the dosage form moves through from non-homogeneous micro-environments (with respect to pH, salinity, ion concentration, etc.) from various sections of the GI tract. Santus and Baker, "Osmotic drug delivery: a review of the patent literature", Journal of Controlled Release 35 (1995) pp. 1-21, incorporated in its entirety by reference here, is a good review of such systems. In addition, US patents issued to ALZA Corporation, describe how to make and use osmotic dosage forms, each of which are incorporated in their entirety here: US Patent Nos. 3,845,770; 3,916,899; 3,995,631; 4,008,719;

4,111,202; 4,160,020; 4,327,725; 4,519,801; 4,578,075; 4,681,583;

5,019,397; and 5,156,850.

[00195] Some exemplary swelling polymers for osmotic systems include, but are not limited to, 1 million to 15 million average molecular weight L polyoxide (alkylene), as represented by poly (ethylene oxide) and poly (alkaline carboxymethyl cellulose) from 500,000 to 3,500,000 average numerical molecular weight (alkali: sodium, potassium or lithium), acid carboxypolymer, acrylic acid cross-linked with polyalkylene ethers or divinyl glycol, cross-linked homopolymers and acid copolymers acrylic, including divinylglycol and / or C10-C30 alkyl acrylate cross-linked with allyl pentaerythritol as copolymer, an acrylic polymer cross-linked with a polyalyl sucrose, average numerical molecular weight - 250,000 to

4,000,000; acrylic acid polymers, polyacrylamides; water-expandable indenomaleic anhydride cross-linked polymers; numerical average molecular weight of polyacrylic acid -80,000 to 200,000; acrylate polymer polysaccharides composed of condensed glucose units, for example, crosslinked diester polyglurane; and similar. Some hydrogel-forming polymers include those described in United States Patent No. 3,865,108, United States Patent 4,002,173, United States Patent No. 4,207,893, and in Handbook of Common Polymers, Scott and Roff, Chemical Rubber Co., Cleveland, OH. Suitable osmotic agent solutes include, but are not limited to: sodium chloride, potassium chloride, lithium chloride, magnesium sulphate, magnesium chloride, potassium sulphate, sodium sulphate, lithium sulphate, acid phosphate potassium, mannitol, urea, inositol, magnesium succinate, tartaric acid, rafmoose, sucrose, glucose, lactose, sorbitol, inorganic salts, organic salts and carbohydrates. The solvents suitable for the manufacture of the components of the dosage form comprise inert or aqueous organic solvents that do not harm the materials used in the system. Solvents include, but are not limited to: aqueous buffer solvents, for example, phosphate buffer, alcohols, ketones, ethers, ethers, aliphatic hydrocarbons, halogenated, cycloaliphatic, aromatic solvents, heterocyclic solvents and mixtures thereof . Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n -hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbohydrate tetrachloride nitroethane, nitropropane tetrachloride, ethyl ether, isopropyl ether, ether isopropyl ether, ether isopropyl ether.

hexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts, such as sodium chloride, calcium chloride and the like, and mixtures thereof, such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol.

[00196] Finally, techniques for drilling the holes in the outer membrane, including mechanical and laser drilling, are described in US Patent Nos. 3,916,899 and U.S. Patent No.

4,088,864, both of which are incorporated in their entirety here.

[00197] Therefore, the description provides an extended release pharmaceutical dosage form comprising a solid oral osmotic dosage form comprising felicic acid and a polymeric matrix. In some aspects, the description provides an extended-release pharmaceutical dosage form comprising a solid oral osmotic dosage form comprising bempedoic acid and a polymeric matrix, in which the polymer is selected from a group consisting of hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose and sodium carboxymethylcellulose. Usage methods

[00198] Here, methods of treating cardiovascular disease or reducing the risk of cardiovascular disease in an individual are described by administering a prolonged release composition comprising bempedoic acid and a polymeric matrix.

[00199] The pharmaceutical compositions useful according to the present invention are given to an individual, administration is preferably in a "therapeutically effective amount" / "therapeutically effective concentration" (meaning the same) or a "prophylactically amount effective "(as appropriate, although prophylaxis may be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered and the rate and time of administration will depend on the nature and severity of the disease to be treated. and the prescription of treatment, for example, decisions about dosage, etc., are the responsibility of general practitioners and other doctors and usually take into account the disorder to be treated, the condition of the individual patient, the release site, the method of administration and other factors known to physicians Exemplary therapeutically effective amounts are 50, 100, 200, 300, 400 or 500 mg per day, more preferably 50, 100 or 200 mg per day, even more preferably 90 or 180 mg per day. Exemplary prophylactically effective amounts are 50, 100, 200, 300, 400 or 500 mg per day, more preferably 50, 100 or 200 mg per day, even more preferably 90 or 180 mg per day.

[00200] In one aspect, the description provides a method of treating cardiovascular disease or reducing the risk of cardiovascular disease in an individual, the method comprising: administering an effective amount of a solid oral dosage form to an individual in need of it, in which the solid oral dosage form comprises bempedoic acid and a polymer, and in which the solid oral dosage form when the dissolution was tested using the United States Pharmacopoeia Apparatus 2 ( 50 rpm paddles) in 50 mM phosphate buffer exhibits a drug release profile substantially corresponding to the following pattern: after 2 hours, no more than 30% of bempedoic acid is released; after 4 hours, no more than 75% of bempedoic acid is released; after 8 hours, no more than 90% of bempedoic acid is released; and wherein the solid oral dosage form provides a therapeutically effective concentration of bempedoic acid over a 24 hour period to treat cardiovascular disease or to reduce the risk of cardiovascular disease when administered to the individual.

[00201] In one aspect, the description provides a method in which the solid oral dosage form does not release more than 95% of bempedoic acid after 8 hours when dissolved in 50 mM phosphate buffer with a pH of 8.5 to 20 ° C.

[00202] In one aspect, the description provides a method of inhibiting the enzyme ATP-citrate lyase (ACL) in an individual, the method comprising administering to the individual the pharmaceutical dosage form of any one described herein.

[00203] In one aspect, the description provides a method in which the solid oral dosage form comprises from 5 mg to 500 mg of bempedoic acid. In one aspect, the description provides a method in which the solid oral dosage form comprises from 5 mg to 100 mg of bempedoic acid. In one aspect, the description provides a method in which the solid oral dosage form comprises from 5 mg to 50 mg of bempedoic acid. In one aspect, the description provides a method in which the solid oral dosage form comprises from 180 mg to 240 mg of bempedoic acid. In one aspect, the description provides a method in which the solid oral dosage form comprises from 200 mg to 240 mg of bempedoic acid.

[00204] In one aspect, the description provides a method in which the polymer is microcrystalline cellulose. In one aspect, the description provides a method in which the polymer is a mixture of microcrystalline cellulose and polycellulose. In one aspect, the description provides a method in which the polymer is a mixture of microcrystalline cellulose and hydroxypropylmethyl cellulose (HPMC). In one aspect, the description provides a method in which the polymer is hydroxypropylmethyl cellulose (HPMC). In one aspect, the description provides a method in which the polymer is a polycellulose. Cardiovascular disease and release of bempedoic acid Clinical end points

[00205] In one aspect, the description provides methods for decreasing the level of a lipid, lipoprotein or cholesterol in the blood in an individual. In some respects, the reduction is determined by comparing the levels of an analysand measured from a sample obtained from the subject before and after the administration of the drug. In some respects, the reduction is based on results of clinical trial results comparing combined populations, one receiving drug and the other receiving a placebo. In one aspect, the description provides methods of lowering low density lipoprotein (LDL-C) cholesterol in an individual.

[00206] In one aspect, the description provides methods for reducing total cholesterol (TC) in an individual. In one aspect, the description provides methods in which the method reduces total cholesterol (TC) and low density lipoprotein (LDL-C) cholesterol in an individual. In one aspect, the description provides methods for reducing total cholesterol (CT) when administered to a human subject with hypercholesterolemia, mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver disease or kidney disease. In one aspect, the description provides methods for reducing total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) when administered to a human subject with hypercholesterolemia, mixed dyslipidemia, type II diabetes mellitus, obesity , chronic liver disease or kidney disease.

[00207] In one aspect, the description provides methods for decreasing the level of very low density lipoprotein (VLDL) in an individual.

[00208] In one aspect, the description provides methods for decreasing the size of the VLDL particles in an individual.

[00209] In one aspect, the description provides methods for decreasing the level of apolipoprotein B (ApoB) in an individual. In one aspect, the description provides methods for decreasing the level of apolipoprotein A-1 (ApoA1) in an individual.

[00210] In one aspect, the description provides methods for decreasing the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in an individual below. In one aspect, the description provides methods for not changing the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in an individual.

[00211] In one aspect, the description provides methods in which the individual has hypercholesterolemia. In one aspect, the description provides methods in which the individual has mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver disease, kidney disease or any combination thereof.

[00212] In one aspect, the description provides methods in which the individual is a mammal. In one aspect, the description provides methods in which the individual is human. Therapeutic window

[00213] The therapeutic window can also generally be expressed as a relationship between the minimum effective concentrations (MEC, also known as minimum inhibitory concentration (MIC)) to the minimum toxic concentration (MTC) (of the drug / API). An important goal of drug release is to maintain plasma drug levels between ECM and ECM to provide the most beneficial and risk-free therapeutic effects. If the concentration of the drug exceeds the TCM, then the toxic effects will be observed, on the other hand, if the concentration of the drug is not able to overcome the TCM, the treatment suffers therapeutic failure.

[00214] The therapeutic index (TI) describes a relationship between the doses of a drug that causes lethal or toxic effects with the dose that causes therapeutic effects. It can be calculated by: Therapeutic index (TI) = LD50 / ED50 where LD50 is the minimum amount of drug that causes adverse effects in 50% of the population. LD50 can also be replaced by a toxic dose (TD50). ED50 is the amount of a drug that can produce the desired therapeutic effects in 50% of the population.

[00215] In some respects, the present description provides methods in which the concentration of bempedoic acid is between MEC and MTC for a period of time from 20 minutes to 8 hours after administration. In some respects, the present description provides methods in which the concentration of bempedoic acid is between the ECM and the ECM for a period of time: 20 minutes to 9 hours, 20 minutes to 10 hours, 20 minutes to 12 hours, 20 minutes at 14 hours, 20 minutes at 16 hours, 20 minutes at 18 hours, 20 minutes at 20 hours, 20 minutes at 24 hours, 20 minutes at 36 hours or 20 minutes at 48 hours after administration.

[00216] In some respects, the present description provides methods in which the pharmaceutical dosage form provides an AUC for bempedoic acid in the rat of 7.5 mg / kg or 30 mg / kg of bempedoic acid capsule. In some respects, the present description provides methods in which the pharmaceutical dosage form provides an AUC for mouse 661 ng * hr / ml activated bempedoic acid per mg of bempedoic acid after oral administration of a single 7-well bempedoic acid capsule, 5 mg / kg or 30 mg / kg.

[00217] In some respects, the present description provides methods in which the pharmaceutical dosage form, when administered in a 180 mg unit dose of bempedoic acid to a Spra- rat

1 kg male-Dawley, results in a maximum blood plasma concentration (Cmax) of bempedoic acid in the rat of no more than 60 µg / mL and is in a range of 45 µg / mL -59 µg / mL for 24 hours after administration.

[00218] In some respects, the present description provides methods in which the pharmaceutical dosage form provides a Tmax in the rat for more than 8 hours after oral administration of a single 50, 100, 200 or 180 mg bempedoic acid tablet.

[00219] In some respects, the present description provides a method of administering bempedoic acid, the method comprising: administering to an individual an effective amount of a pharmaceutical dosage form comprising a solid oral dosage form for a individual in need, where the solid oral dosage form comprises bempedoic acid and a polymer, and when, when tested in a standard pharmacokinetic assay, for example, rat, said administration results in a maximum blood plasma concentration (Cmax ) of no more than 60 µg / mL and, in which it is in a range of 45 µg / mL-60 µg / mL for 24 hours after administration.

[00220] In some respects, the present description provides methods in which bempedoic acid is delivered at a rate such that it is independent of the amount of bempedoic acid in the dosage form. In such aspects, the method provides zero-order liberation of bempedoic acid. In some respects, the present description provides methods in which bempedoic acid is released at an almost constant rate (meaning deviation from the average release rate of no more than +/- 10% over the life of the release effective dosage form) for at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours , at least 18 hours, at least 20 hours, at least 22 hours, at least 24 hours, but not more than 36 hours (that is, covering periods of 2 to 36 hours).

[00221] In some respects, the methods described can be practiced by administering a pharmaceutical dosage form of bempedoic acid described herein. Combination therapy and dosage forms

[00222] In some respects, the present description provides methods and compositions in which the extended release pharmaceutical compositions further comprise therapeutically effective amounts of Ezetimibe. In such aspects, the formulations do not need to provide prolonged release of Ezetimibe, but provide prolonged release of bempedoic acid according to this description.

[00223] In some respects, the present description provides methods and compositions in which the sustained release pharmaceutical compositions further comprise therapeutically effective amounts of a statin. In such aspects, the formulations do not need to provide a prolonged release of a statin, but they do provide a prolonged release of bempedoic acid according to this description.

[00224] In some respects, the present description provides methods in which the prolonged release pharmaceutical composition is administered in combination with other lipid-lowering treatments, simultaneously or sequentially, depending on the clinical situation of the cardiovascular condition being treated.

[00225] In some respects, the present description provides methods and compositions in which the sustained release pharmaceutical compositions further comprise therapeutically effective amounts of an antibody that reduces the subtilisin / quexin type 9 protein convertase (PCSK9 inhibitor) ). In some respects, the present description provides methods and compositions in which the extended release pharmaceutical compositions further comprise therapeutically effective amounts of a bile acid scavenger.

[00226] In some respects, the present description provides methods and compositions in which the extended-release pharmaceutical compositions further comprise therapeutically effective amounts of a biguanide (e.g., metformin) or adenosine monophosphate-activated protein kinase activators (AMPK), or alfaglycosidase inhibitors, or amylin analogs, or dipeptidyl peptidase 4 inhibitors, or incretin mimetics, or meglinitides, or sulphylureas, or non-sulfonylureas, or sodium glucose transporter 2 inhibitors (SGLT2), or thiozolidinediones, or glucagon-like peptide-1 (GLP-1) and / or combinations thereof.

[00227] In some respects, the present description provides methods and compositions in which the extended release pharmaceutical compositions further comprise therapeutically effective amounts of a farnesoid X receptor (FXR) and / or bile acid receptor agonists, or agonist of the peroxisome proliferator activated receptor (PPAR) alpha, or PPAR gamma agonist, or delta PPAR agonist or PPAR alpha / gamma agonist, alpha / delta PPAR agonist or PPAR pan agonist, or cysteine or phosphodiesterase-4 (PDE-4) inhibitors, or inhibitors of the apoptosis signal regulating kinase 1 (ASK-1), or chemokine receptor inhibitors, including CCR2 / CCR5 inhibitors or combinations thereof.

[00228] In some respects, the present description provides methods and compositions in which the sustained release pharmaceutical compositions further comprise therapeutically effective amounts of a compound that reduces the levels of (inhibitor) alanine aminotransferase, alkaline phosphatase, bilirubin total or triglycerides or Cytokeratin-18. Administration schedule

[00229] In some respects, the present description provides methods in which the extended release pharmaceutical composition is administered twice daily, once daily or once every two days. Treatment of metabolic syndrome with bempedoic acid Metabolic syndromes / disorders

[00230] Metabolic syndromes and / or metabolic disorders are associated with conditions such as increased adiposity, insulin resistance, dyslipidemia, fatty liver, inflammation and atherosclerosis. These abnormalities are linked in some degree to the atherogenesis process. Although bempedoic acid may improve metabolic dysregulation pathways related to some of these abnormalities, it is not clear whether therapeutic efficacy is limited by pharmacodynamic parameters.

[00231] Here, the inventors describe that targeting ACL and AMPK enzymes with a prolonged release formulation of bempedoic acid increases the formation efficiency, residence life and therapeutic effectiveness of activated bempedoic acid, which in turn provides significantly more value therapeutic in the treatment of diseases and disorders of the metabolic syndrome, such as NAFLD, NASH, hepatic steatosis, inflammation, fibrosis or any combination thereof.

[00232] In one aspect, the description provides methods of treating a metabolic syndrome and / or a metabolic disorder in an individual, the method comprising administering to the individual an effective amount of any of the prolonged release formulations / forms dosage described here. In one aspect, the description provides methods of treating liver steatosis in an individual, the method comprising administering to the individual an effective amount of any of the prolonged release formulations / dosage forms described herein. In one aspect, the description provides methods of treating inflammation or fibrosis in an individual, the method comprising administering to the individual an effective amount of any of the prolonged release formulations / dosage forms described herein.

[00233] In one aspect, the description provides methods of treating a metabolic syndrome, metabolic disorder, hepatic steatosis, inflammation, fibrosis or any combination thereof in an individual diagnosed or measured by liver biopsy pathology or methodologies of image described here. Non-alcoholic fatty liver disease (NAFLD)

[00234] If the rate of lipid release to the liver and lipogenesis back into the liver are not matched by the rates of - fatty acid oxidation and VLDL secretion, then hepatocytes will increase the formation of lipid droplets and NAFLD will occur . NAFLD is the hepatic manifestation of the metabolic syndrome due to its strong association with obesity, dyslipidemia and type 2 diabetes (see, for example, Asrih, M., and FR Jornayvaz. 2015. Molecular and Cellular Endocrinology. 418: 55-65). NAFLD encompasses a spectrum of disorders from simple steatosis to steatohepatitis.

[00235] NAFLD is largely asymptomatic in the early stages. The standard for the diagnosis of NAFLD is a liver biopsy. The non-invasive diagnosis of NAFLD includes methods that use imaging modalities, plasma markers and scoring algorithms. The image is made with ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), transient elastography or FibroScan®. Plasma markers used to assess liver function include alanine and aspartate transaminases (ALT and AST, respectively), albumin, platelet count, glucose, insulin, TG and cholesterol (see, for example, Machado, MV and H Cortez-Pinto, 2013.

Journal of Hepatology. 58: 1007-1019; Pacana, T., and AJ Sanyal. 2015. F1000Prime Rep. 7: 28). There are also many classification algorithms that use these plasma measurements, in addition to age, sex, body mass index, insulin and blood glucose resistance, hypertension and the results of imaging tools.

[00236] Here are described prolonged release formulations comprising bempedoic acid effective in the treatment of NAFLD, NASH and / or NAFL.

[00237] In one aspect, the description provides methods of treating NAFLD in an individual, the method comprising administering to the individual an effective amount of any of the prolonged release formulations / dosage forms described herein . Non-alcoholic steatohepatitis (NASH)

[00238] NAFLD progresses to a very serious disease called non-alcoholic steatohepatitis (NASH). This disease is characterized by increased inflammation and fibrosis. NASH histologically presents as simple steatosis with hepatocyte ballooning, monocyte infiltration and collagen deposition (see, for example, Yeh, M. M. and E. M. Brunt. 2014. Gastroenterology. 147: 754-764). The increase in fibrosis and inflammation seen with NASH greatly increases the risk of liver cancer.

[00239] In one aspect, the description provides methods of treating NASH in an individual, the method comprising administering to the individual an effective amount of any of the prolonged release formulations / dosage forms described herein .

[00240] In one aspect, the description provides methods of treating NAFLD, NAFL and / or NASH, in which the individual is obese, has hypercholesterolemia, has mixed dyslipidemia, has type 2 diabetes or any combination of themselves.

EXAMPLES

[00241] Below are examples of specific modalities for carrying out the present invention. The examples are offered for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to the numbers used (eg quantities, temperatures, etc.), but some experimental errors and deviations must, of course, be allowed.

[00242] The practice of the present invention will employ, unless otherwise conventional methods of pharmaceutical chemistry and pharmacology, within experience in the art. Such techniques are fully explained in the literature. see, for example, Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Example 1 - Experimental conditions and protocol for pharmacokinetic studies (PK) in animals Animals & administration

[00243] Male Han Wistar rats [Crl: WI (Han)] were purchased from Charles River and were acclimated to the study conditions for four days prior to the administration of the initial dose. Certified rodent diet # 2016C (Envigo RMS, Inc.) was provided ad libitum. Fresh water was provided daily, ad libitum. Animals were assigned to 1 of 3 groups, where group 1 received ETC-1002 (30 mg / kg) as an oral dose in a single cake, group 2 received ETC-1002 (30 mg / kg) over 4 separate doses of 7.5 mg / kg) approximately 4 hours apart, and group three received no dose (Table 1). The animals were identified by means of individual cage cards and microchip identification devices implantable in the right dorsal lumbar region. Dosing, Collection & Analysis

[00244] Individual doses were calculated based on body weights recorded the day before the dose was administered and the oral dose was administered by oral gavage. Blood samples were collected at the pre-dose and approximately 2, 4, 6, 8, 10, 12,14,20 and 24 hours after the dose according to the schedule in Table 2 through a jugular vein by syringe and needle (approximately 0.3 mL) or by cardiac puncture under appropriate anesthesia. The blood was transferred to tubes without anticoagulant (serum separating tubes).

[00245] The blood was allowed to clot at room temperature before centrifugation to obtain serum. Centrifugation started within 1 hour after collection. The serum was placed in the appropriate tubes and kept on dry ice before storage at approximately -70 ° C. Liver samples were collected from three animals / group / time point approximately 2, 6, 10,14,20 and 24 hours after the dose (Table 2). The liver was harvested as quickly as possible using pre-cooled forceps. Then, the tissue and the forceps were immediately frozen by immersion in liquid nitrogen. After freezing, the tissues were wrapped in aluminum foil and kept on dry ice before storage at approximately - 70 ° C.

[00246] Serum was then analyzed for ETC-1002 levels using validated LC-MS / MS methods, and ETC-1002- CoA (activated wellpedoic acid) and acetyl-CoA levels were determined in liver samples after extraction of homogenates in MeOH - formic acid. A standard acetyl-CoA concentration curve was generated in control liver homogenates and unknown sample concentrations were calculated using a linear curve fitting model. ETC1002-CoA levels are expressed as changes in the peak area (acetyl-CoA µg equivalents).

Study Design Table 1. Level of Concentration Volume Number of Dose Dose of Animals Article Target Routine Target Target Group Males Test Dose (mg / kg) (mg / mL) (mL / kg) 1 18 Oral 30 3 10 ETC -1002 2 18 Orala 7.5 3 2.5 ETC-1002 3 3 NA NA NA NA NA NA: Not applicable, designed for control collections. a: The animals were dosed four times for 12 hours (approximately 4 hours separately) for a total of 30 mg / kg (3 mg / mL and 10 mL / kg). Table 2. Animals without Group Time Points (Hours Post-dose) Jugulara Cardiac Puncture 1-3 Pre-dose 2 4-6 4b 6 c 7-9 8 10 10-12 12d 14 13-15 - 20 16-18 - 24 a: All collections were based on the first daily dose for Group 2. b: For Group 2, samples were collected before the second dose. c: For Group 2, samples were collected before the third dose. d: For Group 2, samples were collected before the fourth dose. Formulation

[00247] ETC-1002 formulations were prepared in the appropriate volume of 0.5% CMC (pH 7-8) and were stirred throughout the course of dosing. Specific information about dose preparation is in Table 3.

Table 3. Volume Concentration of Weight Concentration of Vehicle Article Target Dose Dose Total Test (mg / mL) Calculated Groups (mg) (mL) (mg / mL) 1e2 390.025 130 3 3.00 Example 2: Cake PK Study unique in animals - exemplary immediate release bempedoic acid formulation

[00248] Existing orally administered formulations are rapidly absorbed in the small intestine (see, for example, Bilen et al., Curr Atheroscler Rep., 2016; 18 (10): 61). The purpose of this example is to establish a baseline pharmacodynamic profile for an exemplary immediate release bempedoic acid formulation. The experimental procedures employed are described in “Example 1 - Experimental conditions and protocol for pharmacokinetic studies (PK) in animals”, above. Results

[00249] PK single cake measurements were: Tmax = 2 hours, Cmax = 97.1 µg / mL and AUC0-24h = 1244.0 µg.hr / mL. Serum levels of bempedoic acid provided a maximum peak concentration close to 100,000 ng / mL (100 µg / mL) within 1 hour after administration. In addition, single bolus administration provided hepatic concentrations of ETC-1002-CoA below 250 ng / gm over a 20 hour period. Example 3: PK study of multiple administration divided into animals to simulate the prolonged release of bempedoic acid formulation

[00250] Multiple divided administrations were employed to simulate the prolonged release of bempedoic acid in vivo. The effect of the absorption of bempedoic acid on the properties of PK is tested here in the light of biological metabolism. The aim of this study is to determine the pharmacodynamic profile for a representative formulation of prolonged release bempedoic acid. The procedures to be followed are described in “Example 1 - Experimental conditions and protocols for studies on pharmacokinetics (PK) in animals”, described above. Results

[00251] Multiple PK measurements divided were: Tmax = 10 hours, Cmax = 55.5 µg / mL and an AUC0-24hr = 661 µg.hr / mL. Split multiple administration provided serum levels of bempedoic acid at a maximum concentration of about 60,000 ng / mL over 10 hours after administration. In addition, administration of multiple split cakes showed an increase of approximately 28% in AUC0-24, SS and an increase of approximately 24% in AUC0-24hr in liver ETC-1002-CoA. Example 4: Comparison of PK Study of Extended Release vs. Bempedoic Acid Formulation. immediate release in rats

[00252] The purpose of this example is to provide support for proof of concept for prolonged release formulations of wellic acid (ETC-1002) that have increased PK activities, showing that a reduced absorption rate provides a pharmaceutical profile - improved kinetic in the liver and plasma. An improved PK profile is defined as having a higher ETC-1002-CoA AUC0-24h in the liver with Cmax or AUC0-24h serum ETC-1002 equal or reduced, or an equal amount of AUC0-24h ETC-1002 -CoA in the liver with Cmax or AUC0-24h of serum ETC-1002 reduced for any dosage level. Results

[00253] Significant differences in serum pharmacokinetics have been observed between single bolus and multiple administrations of divided pediatric acid. Surprisingly, the simulation of the extended release with the administration of multiple fractionated cakes

caused a slow rise in the serum concentration of bempedoic acid, regardless of rapid absorption. This in contrast to the administration of a single bolus, which provided a characteristic short Tmax in serum levels of bempedoic acid almost immediately followed by an abrupt drop in the following 22 hours (Figure 1A).

[00254] Hepatic acetyl-CoA was suppressed in both groups throughout the 24-hour study period (Figure 1B). However, the administration of multiple division, that is, simulated prolonged release, showed a more significant decrease in the activity of acetyl-CoA of the liver, despite reaching a lower maximum serum exposure (47%, Figure 1B).

[00255] In addition, the simulated prolonged release achieved greater hepatic exposure of ETC-1002-CoA compared to the single bolus. Interestingly, the ratio of hepatic exposure of ETC-1002- CoA to serum exposure of ETC-1002 was greater for prolonged simulated release more than 2 times (Figure 1C). These findings support the conclusion that the conversion efficiency of the prodrug was increased by the altered rate of absorption of well pedoic acid in the intestine. Example 5: Prolonged-release formulations of well-pedoic acid and their respective dissolution data

[00256] Various formulations comprising bempedoic acid and a hydrophilic cellulosic polymeric matrix, hydroxypropylmethylcellulose (HPMC), were prepared and tested in USP dissolution tests. The formulations were constructed as spheres of solid microparticles. Each formulation was sieved.

[00257] The individual batches were formulated distinctly to include the compounds described in Tables 4-13 below. Table 4.

CU07-089 Ingredient Chemical Name mg / dose s% w / w% w / w / batch ETC-1002 Bempedoic Acid 200.0 60.0% 36.5% 217.0 AvicelPH-101 Microcrystalline Cellulose 124.3 37 .3% 22.7% 134.9

HPMC 606 Hydroxypropyl Methylcellulose 2.4 0.7% 0.4% 2.6 Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0% 1.2% 7.1 Treated Water Water - - 39.1% 232 .5 Total 333.3 100% 100% 594.1

Table 5. CU07-101 Ingredient Chemical Name mg / dose s% w / w% w / w / batch ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0 AvicelPH-101 Microcrystalline Cellulose 31 , 1 9.3% 6.2% 33.7

AvicelCL-611 Microcrystalline Cellulose- 93.3 28.0% 18.7% 101.2 na / Sodium Carboxymethyl Cellulose

HPMC 606 Hydroxypropyl Methylcellulose 2.4 0.7% 0.5% 2.6 Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0% 1.3% 7.1 Treated Water Water 33.3% 180.5 Total 333.3 100% 100% 542.1

Table 6. CU07-103 Ingredient Chemical Name mg / dose s% w / w% w / w / batch ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0 AvicelCL-611 Microcrystalline Cellulose 124.3 37.3% 24.9% 134.9 na / Sodium Carboxymethyl Cellulose

HPMC 606 Hydroxypropyl Methylcellulose 2.4 0.7% 0.5% 2.6

Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0% 1.3% 7.1 Treated Water Water - - 33.3% 180.5 Total 333.3 100% 100% 542.1

Table 7. CU07-105 Ingredient Chemical Name mg / dose s% w / w% w / w / batch ETC-1002 Bempedoic Acid 250.0 75.0% 53.5% 271.2 AvicelPH-101 Microcrystalline Cellulose 74 , 4 22.3% 15.9% 80.7

HPMC 606 Hydroxypropyl Methylcellulose 2.4 0.7% 0.5% 2.6

Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0% 1.4% 7.1 Treated Water Water - - 28.7% 145.5 Total 333.3 100% 100% 507.1

Table 8. CU07-107 Ingredient Chemical Name mg / dos s% w / w% w / w / batch ETC-1002 Bempedoic Acid 200.0 and 60.0% 33.2% 217.0 AvicelPH-101 111, 0 33.3% 18.4% 120.4 Microcrystalline cellulose

HPMC 606 2.4 0.7% 0.4% 2.6 Hydroxypropyl Methylcellulose

Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0% 1.1% 7.1

Explotab Sodium Starch Glycolate 13.4 4.0% 2.2% 14.5 Treated Water Water - - 44.7% 292.5 Total 333.3 100% 100% 654.1

Table 9. CU07-109

Ingredient Chemical Name mg / dose s% w / w% w / w g / batch

ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0

AvicelCL-611 Microcrystalline Cellulose 126.7 38.0% 25.4% 137.5 na / Sodium Carboxymethyl Cellulose Sodium Lauryl Sulfate 6.5 Sodium Lauryl Sulfate 6.5 2.0% 1.3% 7.1

Treated Water Water - - 33.3% 180.5

Total 333.3 100% 100% 542.1

Table 10. CU07-111 Ingredient Chemical Name mg / dose s% w / w% w / w / batch ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0 AvicelPH-101 Microcrystalline Cellulose 110 .2 33.1% 22.1% 119.6

Aqualon Sodium Carboxymethylcellulose 16.5 5.0% 3.3% 17.9 Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0% 1.3% 7.1 Treated Water Water - - 33.3% 180 .5 Total 333.3 100% 100% 542.1

Table 11. CU07-117 Ingredient Chemical Name mg / dose s% w / w% w / w / batch ETC-1002 Bempedoic Acid 200.0 60.0% 42.4% 217.0 AvicelPH-101 Microcrystalline Cellulose 103 , 9 31,2% 22,0% 112,7 Aqualon Sodium Carboxymethylcellulose 22,9 6,9% 4,8% 24,8 Sodium Lauryl Sulfate Lauryl Sodium Sulfate 6,5 2,0% 1,4% 7.1 Treated Water Water - - 29.4% 150.5 Total 333.3 100% 100% 512.1

Table 12. CU07-115 Ingredient Chemical Name mg / dose s% w / w% w / w / batch ETC-1002 Bempedoic Acid 200.0 60.0% 43.2% 217.0 AvicelPH-101 Microcrystalline Cellulose 97 .6 29.3% 21.1% 105.9

Aqualon Sodium Carboxymethyl Cellulose 29.1 8.7% 6.3% 31.6 Sodium Lauryl Sulfate Lauryl Sodium Sulfate 6.5 2.0% 1.4% 7.1 Treated Water Water - - 28.0% 140 .5 Total 333.3 100% 100% 502.1

Table 13. CU07-118 Ingredient Chemical Name mg / dose s% w / w% w / w / batch ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0 AvicelPH-101 Microcrystalline Cellulose 112 , 2 33.7% 22.4% 121.7 Aqualon Carboxymethylcellulose Sodium 12.2 3.7% 2.4% 13.2

HPMC 606 Hydroxypropyl Methylcellulose 2.4 0.7% 0.5% 2.6 Lauryl Sodium Lauryl Sulfate 6.5 2.0% 1.3% 7.1 Sodium Water Treated Water - - 33.3% 180 .5 Total 333.3 100.0% 100.0% 542.1 Dissolution Test

[00258] A USP dissolution experiment evaluates the rate and extent to which a compound forms a solution under carefully controlled conditions. The dissolution test helps to evaluate the performance of a drug. For a detailed description of the Apparatus settings and experimental procedures, refer to the United States Pharmacopeial Convention, USP 35 NF30, 2012: U S. Pharmacopoeia National Formulary, The United States pharmacopeia, 2011, Chapter 711, 5642-5648.

[00259] The physical properties of the dosage form, such as: single dose wettability, permeability, swelling, disintegration and disintegration affect the dissolution of pharmaceutical dosage forms.

[00260] The results of the dissolution test are described below in Table 14 and shown in Figures 2A and Figure 2B, respectively. Table 14 - Results of the Dissolution Test Time (minutes) Batch # 0 15 60 120 180 240 360 480 600 720 CU07-089 0 26 38 46 53 62 70 76 80 CU07-101 0 44 62 72 79 89 94 97 99 CU07- 103 0 50 68 78 85 94 98 100 102 CU07-105 0 31 46 56 64 75 83 88 93 CU07-107 0 38 54 64 72 82 88 93 96 CU07-109 0 56 74 84 90 95 98 100 101 CU07-111 0 54 71 80 86 92 95 97 99 CU07-117 0 69 86 93 96 98 99 99 100 CU07-115 0 77 93 97 98 99 99 99 99 CU07-118 0 44 62 72 79 88 93 96 99 IR tablet 0 84 94 98 99 99 99 99 99 99 - The numerical values are expressed as the percentage released in the solution of the initial total amount of bempedoic acid in the formulation

tion. * The CU07-105 and CU07-107 batches have relatively low yields in the desired 16/30 sieve cut range. Batteries CU07-117 and CU07-115 exhibited sticky behavior during the manufacturing process and also have relatively low overall yields. The 720 min time point is the infinite time point. Example 6: Drug compositions for immediate release (IR) and prolonged release (SR) formulations of wellic acid

[00261] This example describes the product compositions and formulations for immediate release and prolonged release of masoyamic acid.

[00262] Table 15 describes the composition of the immediate release (IR) formulation of bempedoic acid.

COMPOSITION OF THE IMMEDIATE RELEASE FORMULATION OF

BEMPEDOIC ACID Table 15 - Composition of 180 mg bempedoic acid tablets Component Function Quantity Nuclear tablet: (mg / tablet) Active Bempedoic acid 180.0 Microcrystalline cellulose Load 64.0 Lactose Load 30.0 Disintegrating sodium starch glycolate 23, 0 Hydroxy Propyl Agglutinating Cellulose 16.0 Lubricating Magnesium Stearate 9.0 Sliding Colloidal Silicon Dioxide 5.0 3 Solvent Purified Water N / A Nucleated Tablet Weight 327.0 mg Film Coating Suspension: Purified Water3 Solvent N / A OPADRY® White (85F18422) Dye 10.0 Total Tablet Weight 337.0 mg Abbreviations: IND = New investigational drug; LDL-C = low density lipoprotein cholesterol a Removed during processing.

[00263] Table 16 describes the drug in the IR formulation of bempedoic acid and placebo tablets. Table 16 - Investigational Medicinal Products (IMP) for Immediate Release Formulation of Well-Acid Tablets and Placebo Product Name: Investigational Medicinal Product Bempedoic Acid Placebo to Combine Bempedoic Acid Dosage Form: Film-coated tablets per film Single dose: 180 mg Not applicable Container / Closure: 9-count blister card with child-proof closures 9-count blister card with child-proof closures Routine of Administration: Oral, daily, approximately to Oral, daily , approximately at the same time, with or without food time, with or without food Physical Description: Tablet coated with oval film, Tablet coated with oval film, white to white to off-white, with off-white engraving, with "ABC" engraving on an "ABC" on one side and "000" on the face of the faces and "000" on the opposite side Manufacturer (Load / Finish): Patheon Patheon 2100 S yntex Court 2100 Syntex Court Mississauga, Ontario Mississauga, Ontario L5N7K9 L5N 7K9 Canada Canada

[00264] Table 17 describes the composition of the SR formulation of bempedoic acid.

COMPOSITION OF THE PROLONGED RELEASE FORMULATION

OF BEMPEDOIC ACID Table 17 - Composition for Extended Release Formulation of Bempedoic Acid Capsule Component Chemical Name Function s% w / pa mg / Capsule 50 mg 100 mg 200 mg ETC-1002 Bempedoic Acid Ingredient Far- 60.0% 50.0 100.0 200.0 maceutical Avicel PH-101 Microcrystalline Cellulose Load 33.7% 28.1 56.1 112.2 Aqualon Carboxymethylcellulose Sodium Load 3.7% 3.1 6.1 12.2

Sodium Lauryl Sulfate Lauryl Sulfate Dil- 2.0% 1.6 3.3 6.5 uente / solubilizador HPMC 606 Hydroxypropyl Methylcellulose Binder 0.7% 0.6 1.2 2.4 Purified Water - Solvent - - - - Totalc Filling Weight 100.0% 83.4 166.7 333.3 Capsule Shell: Two pieces, white, opaque, capsule shell Shell of the capsule - 1 N / A 1 (Size (Size # 0) # 3) a Values have been rounded to the nearest decimal place displayed. Totals are determined from exact values and may not be representative of the individual rounded values shown. b Water and HPMC 606 will be added as a pre-mixed solution. c Water is a processing aid and is not included in the final formulation. Therefore, “Total” does not include water. d The shell of the capsule is composed of titanium dioxide (E171) (2.9079%) as an opacifier and gelatin (sufficient amount for 100%).

DESCRIPTION OF FORMULATION BALL BALLS PROLONGED RELEASE OF BEMPEDOIC ACID

[00265] Extended release bempedoic acid (SR) capsules are white opaque hard gelatin capsules filled with spheres made of bempedoic acid and excipients. Two capsule sizes and doses are available for the NASH study:  "Size 3" for 50 mg bempedoic acid SR capsule  "Size 0" for 200 mg bempedoic acid SR capsule Example 7 - Administration of Representative prolonged release bempedoic acid formulation for humans

[00266] The primary objective is to evaluate the LDL-C reduction efficacy of a representative solid prolonged-release oral dosage form of bempedoic acid (tablet) versus placebo administered daily for 6 weeks in patients with elevated LDL-C.

[00267] The secondary objectives are to evaluate:

1. The effect of a prolonged-release formulation of bempedoic acid versus placebo on non-high density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (ApoB), highly sensitive C-reactive protein (hs- CRP), TG and HDL-C.

2. The effect of the prolonged-release solid oral dosage form (tablet) of bempedoic acid (180 mg) on the percentage of patients who reached LDL-C levels <70 mg / dL.

3. The effect of the prolonged-release solid oral dosage form (tablet) of bempedoic acid (180 mg) versus placebo on the percentage of patients who achieved LDL-C reduction> 50%

4. The safety and tolerability of the prolonged-release solid oral dosage form of bempedoic acid (180 mg) versus placebo.

[00268] The primary end point being used to assess the objectives of this study is the percentage change from baseline to Week 6 in LDL-C levels. Secondary end points also include percentage changes from baseline to week 6 at non-HDL-C, TC, ApoB, hs-CRP, TG and HDL-C levels, percentage change from baseline to Week 6 in Percentage of patients with LDL-C <70 mg / dL at Week 6 and percentage of patients with LDL-C reduction of> 50% from baseline to Week 6. Drug Administration - Patient Treatment

[00269] During the treatment period, patients are rarely

designed to receive IMP from solid dosage forms of extended release bempedoic acid or placebo once daily. Each daily IMP quota was made up of a tablet of well pedoic acid in a blister pack. The blister pack of placebo contains the corresponding pairing placebo for the solid dosage forms of bempedoic acid. Patients are instructed to ingest IMP orally once daily with or without food. On clinical visit days, patients are instructed to delay IMP intake until all study procedures are completed. Example 8: Single dose study of immediate release formulation of bempedoic acid in healthy individuals (Study of IR 1)

[00270] This example describes a single dose study that assessed the safety, tolerability and pharmacokinetics of bempedoic acid in healthy individuals. Figure 6 summarizes the design of this study.

[00271] A main objective of this study was to evaluate and characterize the pharmacokinetic profile (PK) of bempedoic acid and its metabolite after the administration of single, staggered, oral doses to healthy individuals.

[00272] This was a single-center, randomized, double-blind, placebo-controlled, staggered, single-dose, crossover study. The crossover project involved 2 cohorts of 9 individuals each. Each cohort climbed cautiously through 3 single dose groups. Each dose group comprised 6 randomized subjects and received bempedoic acid and 3 randomized subjects and received placebo. The randomization scheme ensured that individuals received a total of 2 separate doses of active drug and a single administration of placebo. Dosage groups were separated by an elimination period of not less than 10 days between administration of the study medication. Dose escalation depended on acceptable safety, tolerance and pharmacokinetic data and followed clearly defined stopping rules, including an exposure limit. The exposure limit of AUC0-24 to bempedoic acid of 200 µg.hr / mL in this study was greater than the estimated therapeutic exposure of 36 to 72 µg.h / mL, providing an opportunity to fully explore the upper limit of the dose range in the more controlled phase of drug development. Results

[00273] Table 18 shows pharmacokinetic parameters (PK) measured and dose corrected after the single dose of immediate release (IR) formulation of bempedoic acid in healthy individuals. Table 18 - PK parameters measured and dose corrected after a single dose of immediate release formulation of Bempedoic acid from the IR study mL) a Cmax (µg / mL) at 50 3-3.5 hours 46 2.95 100 128 7.38 200 334 16.3 a Parameters were corrected per dose for a dose of 50, 100 or 200 mg, respectively. Example 9: Study of multiple ascending doses of immediate release formulation of bempedoic acid in individuals with mild dyslipidemia (Study of RI 2)

[00274] This example describes a study of multiple ascending doses of bempedoic acid in individuals with mild dyslipidemia. Figure 7 summarizes the design of this study.

[00275] The main objectives of this study evaluated and characterized the pharmacokinetic profile (PK) and the pharmacodynamic end points.

cos (PD), such as the level of low density lipoprotein cholesterol (LDL-C), of bempedoic acid and its metabolite after the administration of multiple ascending doses of bempedoic acid to individuals with mild dyslipidemia.

[00276] This was a single-center, randomized, double-blind (open sponsor), placebo-controlled, crescent, multi-dose study with 4 ascending cohorts followed by an optional 5th cohort. The first 4 cohorts included 8 male and female individuals each (6 active / 2 placebos) with a slightly elevated LDL-C level treated for 14 days in the Clinical Unit. Dose escalation in the first 4 cohorts depended on acceptable safety, tolerance and PK data and will follow clearly defined stopping rules, including a predefined exposure limit for AUC0-24 of 200 µg.h / mL for the sum of acid bempedoico and its metabolite ESP15228. As long as the safety profile of the first 4 cohorts was acceptable, an optional 5th cohort of 24 male and female free-living individuals (18 active / 6 placebos) with slightly elevated LDL-C and triglyceride levels treated by 28 days has been completed.

[00277] Bempedoic acid capsules (20 mg) or placebo capsules were used for this study.

[00278] Multiple oral doses of 20, 60, 100 and 120 mg were administered to fasting subjects in Cohorts 1 to 4 and did not exceed the predefined exposure limit for AUC0-24 of 200 µg.h / mL for the sum of bempedoic acid and its metabolite ESP15228. Results

[00279] Table 19 shows pharmacokinetic parameters (PK) measured and dose-corrected after the single dose of the immediate release (IR) formulation of bempedoic acid in healthy individuals. Table 19 - Mean Percentage Change of Baseline LS in LDL-C After Single Dose of Bempedoic Acid Immediate Release Formulation of the IR Study 2 IR Study 2 Treatment Comparison Time Point Average Treatment Group LS (SE) PBO difference p-value Day 15 Placebo 10.6 (4.5) 20 mg 3.5 (5.0) -7.1 0.2974 60 mg -11.2 (5.1) -21 , 8 0,0035 100 mg -16.5 (5.1) -27.1 0.0003 120 mg -15.0 (5.0) -25.6 0.0004 Example 10: Multiple ascending dose study of formulation of immediate release of bempedoic acid in healthy individuals (IR Study 3)

[00280] This example describes a study of multiple ascending doses of bempedoic acid in doses above 120 mg / day in healthy subjects. Figure 8 summarizes the design of this study.

[00281] The main objectives of this study evaluated and characterized the pharmacokinetic profile (PK) and the pharmacodynamic end points (PD), such as low density lipoprotein cholesterol level (LDL-C), bempedoic acid and its metabolite following the administration of multiple ascending doses of bempedoic acid to healthy subjects.

[00282] This was a single-center, randomized, double-blind (sponsored), placebo-controlled, ascending, multiple-dose study with approximately 4 ascending cohorts, each of which included 8 healthy male or female subjects (6 active / 2 placebos) treated for 14 days in the Clinical Unit. Dose escalation in the next cohort depended on acceptable safety, tolerance and PK data and followed clearly defined interruption rules, including a predefined exposure limit for AUC0-24 average of 400 µg.h / mL for the sum of bempedoic acid and its metabolite ESP15228.

[00283] 20 mg bempedoic acid capsules or placebo capsules were used for this study. Multiple oral doses of 140, 180, 220 and 260 mg / day were administered to fasting subjects and did not exceed the predefined exposure limit for AUC0-24 average of 400 µg.h / mL for the sum of bempedoic acid and its metabolite ESP15228 . Results

[00284] Table 20 shows the average steady-state PK parameters of the immediate release formulation of bempedoic acid. Table 20 - PK Parameters in Steady State Average Formulation of Immediate Release of Bempedoic Acid from the IR Study 3rd Parameter Cmax values (µg / mL) 21.6 AUC, SS (hr * µg / mL) b 307 Fluctuation of Peak to Depression (µg / mL) 13.1 a Determined from 180 mg dose data assuming linear kinetics. bMediana.

[00285] Table 21 shows the percentage change of the LDL-C Baseline Least Squares Average after the single dose of the immediate release formulation of bempedoic acid from the IR Study 3. Table 21 - Average Percentage Change of LS of the LDL-C Baseline After a Single Dose of the Immediate Release Formulation of the IR Study 3 IR Study 3 Treatment Comparison Time Point Treatment Group Mean LS (SE) PBO Difference p value Day 15 Placebo 4, 4 (5.4) 140 mg -21.3 (5.4) -25.7 0.0012

180 mg -27.1 (5.4) -31.5 0.0001 220 mg -36.1 (5.4) -40.5 <0.0001 Example 11: Single and repeated dose study of release formulation dose of bempedoic acid in otherwise healthy overweight / obese individuals (SR study)

[00286] This example describes a single and repeated dose study of prolonged release formulation of bempedoic acid carried out in overweight / obese individuals, however, otherwise healthy. Figure 9 summarizes the design of this study.

[00287] The formulations of the prolonged release tablets of bempedoic acid used in this study can be found in Tables 13 and 17.

[00288] The main objectives of this study were to evaluate the end points of pharmacokinetics, safety, tolerability and pharmacodynamics, such as LDL-C, of prolonged release therapy of welledic acid in overweight / obese individuals, however, in another healthy way.

[00289] Period 1 evaluated PK in a single dose, safety and tolerability. Period 1 was randomized, however, it was not blinded or controlled by placebo. The screening took place up to 21 days before ranking. Individuals admitted to the Clinical Research Unit (CRU) on the night of Day -1 until the morning of Day 2. On the morning of Day 1, individuals were randomized to receive a single dose of 50 mg prolonged-release formulation of bempedoic acid ( n = 6), 100 mg (n = 6) or 200 mg (n = 6). The formulation of prolonged release of bempedoic acid was described in Tables 13 and 17. These treatments were administered in parallel (not sequentially). The serial PK test took place on Day 1. On the morning of Day 2, additional blood samples were collected, a meal was provided and, if appropriate, subjects were released from the CRU. Subjects returned to CRU for morning outpatient clinic visits to collect additional blood samples on Days 3, 5, 7, 9 and 11. Preliminary period 1 safety, tolerance and PK data were assessed prior to the start of Period 2.

[00290] Period 2 evaluated repeated dose PK, safety and tolerability during the 14-day treatment phase. Lipogenesis again was assessed on Day 7 and Day 1, and PD biomarkers were assessed on Day 13. Period 2 was randomized, placebo-controlled and double-blind. The screening took place up to 28 days before ranking. The individuals were admitted to CRU on 3 separate occasions. The first occasion was on the afternoon of Day -8, followed by Day -7 with a new and high CRU lipogenesis test. The second occasion on which individuals were admitted to the CRU was on the afternoon of Day -1, followed on Day 1 by the first dose of bempedoic acid SR, a new and high CRU lipogenesis test. Eligible individuals were ranked on Day 1 and received 50 mg (n = 10), 100 mg (n = 10) or 200 mg (n = 10) or placebo (n = 10) prolonged release formulation of bempedoic acid for 14 days. The formulation for prolonged release of bempedoic acid is described in Tables 13 and 17. These treatments were administered in parallel (not sequentially). The third occasion that individuals were admitted to the CRU was on the night of Day 13 until the morning of Day 15 for serial PK sampling. On Days 3 to 13, individuals were reported to CRU in the morning for dosing and, if necessary, collecting PK samples. Individuals returned to the clinic for PK sampling and safety monitoring on the morning of Days 17 and 22. Lipogenesis was again assessed during Period 2 at baseline (Day -7) and with a single dose of study drug (Day 1). The stable isotope tracer (2H2O) was prepared for 2 days before each assessment of lipogenesis again, with 3 small doses of 2H2O taken throughout each day. Starting on the morning of the lipogenesis assessment again for 10 hours, the synthesis of hepatic fatty acids was stimulated with oral fructose feeding every 30 minutes and hourly blood samples were collected to assess the incorporation of the label into triglycerides. circulating very low density lipoprotein (VLDL).

[00291] During periods 1 and 2, individuals received the study drug after fasting for a minimum of 10 hours with up to 236.59 mL (8 ounces) of water. On days when PK blood samples in series were collected (Period 1 = Day 1; Period 2 = Day 14), dosing was followed by 4 hours of additional fasting and a standardized meal 4 and 10 hours after the dose. The concentrations of bempedoic acid and metabolite ESP15228 were measured from serial blood samples to assess PK parameters. Results

[00292] Table 22 shows the PK parameters measured from patients after administration of a single dose of a prolonged-release tablet of bempedoic acid. Table 22 - PK Parameters Measured After a Single Dose of Extended Release Formulation of the SR Study Prolonged Dose Release (mg) Extended Release of Single Dose in Obese and Healthy Individuals AUCinf (h.µg / mL) Cmax (µg / mL) ) 50 37.8 1.8 4.5 to 5 hours 100 126 5.54 200 242 8.68 a The prolonged-release formulation of bempedoic acid is described in Tables 13 and 17.

[00293] Table 23 shows the average PK parameters in steady-state of prolonged-release tablets of well pedoic acid. Table 23 - Average PK Parameters in Steady State of

Bempedoic Acid Tablet Extended Release Formulation (SR Study) Parameter Cmax values (ug / mL) 15.9 AUC, SS (hr * µg / mL) at 283 Peak Fluctuation to Depression (µg / mL) 6, 7th to Median

[00294] Table 24 describes the data of percentage change from baseline in LDL-C levels in patients treated with prolonged release formulation of bempedoic acid during period 2 of this study. Table 24 - Percentage Change from Baseline in LDL-C in Patients Treated with Extended Release Formulation of Bempedoic Acid During Period 2 of the SR Study

Treatment Visit N Average SD Min. Median Max N Average SD Min. Median Max.

Bempedoic Acid 50 mg / day (N = 10) Baseline 10 108.1 24.7 69 109.0 151 Day 14 10 96.8 26.52 64 93.0 141 10 -10.6 12.27 -26 -7.9 11 Bempedoic acid Baseline 10 112.7 24.83 63 117.5 151 100 mg / day (N = 10) Day 14 10 82.1 21.57 50 84.5 123 10 -27.0 10.43 -44 -27.5 -12 Day 15 1 124.0 124 124.0 124 1 -17.9 -18 -17.9 -18 End of Study 1 137.0 137 137.0 137 1 -9 , 3 -9 -9.3 -9 Bempedoic acid Baseline 10 113.0 36.33 65 105.5 190 88/94 200 mg / day (N = 10) Day 14 9 81.2 30.38 36 71 , 0 132 9 -27.1 16.25 -45 -30.5 10 Total (N = 30) Baseline 30 111.3 28.20 63 113.0 190 Day 14 29 86.9 26.32 36 86 , 0 141 29 -21.3 14.91 -45 -24.1 11 Day 15 1 124.7 124 124.0 124 1 -17.9 -18 -17.9 -18 End of Study 1 137.0 137 137.0 137 1 -9.3 -9 -9.3 -9 Placebo (N = 10) Baseline 10 105.1 27.67 114.5 114.5 132 Day 14 10 112.1 28.56 118 , 0 118.0 151 10 8.8 16.48 -10 4.3 41

[00295] Table 25 shows the Mean Least Squares (LS) percentage change from baseline in LDL-C of patients after administration of prolonged-release formulation tablets of bempedoic acid on day 14 during period 2. Table 25 - Mean Percentage Change of Baseline LS in LDL-C After a Single Dose of Extended Release Formulation of Bempedoic Acid in the SR Study SR Study Comparison Treatment Time Point Average LS Treatment Group (SE) PBO difference p-value Day 14 Placebo 3.8 50 mg -8.1 -11.9 0.41 100 mg -24.7 -28.5 0.09 200 mg -26.3 -26.3 0.11 a Statistics are estimated based on a Covariance Analysis model (ANCOVA) with fixed terms for treatment and baseline LDL-C level. ANCOVA analysis (mean LS and p-value) was performed post hoc without repeated measures. The baseline is defined as the last value collected before the first dose of the study drug.

[00296] In addition to the results in Table 31, Figure 5 also demonstrates the change in LDL-C among patients who received placebo versus patients who received 100 mg of prolonged-release formulation of bempedoic acid tablet, in which a change -24.7% in the LDL-C level was estimated from the baseline in patients who received the prolonged-release tablet of bempedoic acid. Example 12: Comparison of PK parameters and PD endpoints from IR studies 1, 2 and 3 with those from the SR study

[00297] This example compares several PK parameters and PD endpoints of the IR Study 1 (Example 8), IR Study 2 (Example 9) and IR Study 3 (Example 10) with those of the SR Study (Example

11).

[00298] Table 26 shows the comparison between the dose-corrected PK parameters of the IR Study 1 and those obtained from the SR study at the dosages of 50 mg, 100 mg and 200 mg, respectively. Table 26 - Comparison of PK between the Study of IR 1 and the Study of SR Immediate dosage release Study of IR 1 in Healthy Individuals (mg) AUCinf rate (h.µg / mL) to Cmax (µg / mL) at 50 46 2.95 3-3.5 hours 100 128 7.38 200 334 16.3 Prolonged doseb release SR study in Obese and Healthy Individuals (mg) tmmax AUCinf (h.g / mL) Cmax (g / mL ) 50 4.5 to 5 hours 37.8 1.8 100 126 5.54 200 242 8.68 a The parameters were corrected per dose for a dose of 50, 100 or 200 mg, respectively. b The formulation of prolonged release of bempedoic acid is described in Tables 13 and 17.

[00299] Table 27 shows the comparison of the mean steady-state PK parameters of the IR 3 study and those obtained from the SR study. Table 27 - Comparison of Pharmacokinetic Parameters in Steady-State Average of IR Study 3 and RS Study Parameter Extended Release Immediate Release Percent Difference Cmax (g / mL) 15.9 21.6 -26 AUC, SS (hr * g / mL) at 283 307 -8 Peak Fluctuation at De- 6.7 13.1 -49 pressure (ug / mL) a Median b Prolonged release formulation of bempedoic acid is described in Tables 13 and 17. c Predicted from 180 mg dose data assuming linear kinetics

[00300] As evident from Table 26 and Table 27, the SR formulation provided delayed release of bempedoic acid compared to the IR formulation, since less amount of bempedoic acid was detected in patients who received the formulation of SR at similar times and dosages compared to those who received the IR formulation.

[00301] Table 28 shows the comparison of the mean percentage change of least squares in LDL-C levels in patients in the IR Study 1, IR Study 2 and the SR Study. Table 28 - Comparison of Average Percentage Change in LDL-C Levels in Patients in the IR 2 Study, IR 3 Study and the SR Study. Study of RI 2 Treatment Comparison Timepoint Treatment Group Mean LS (SE) Difference in PBO p-value Day 15 Placebo 10.6 (4.5) 20 mg 3.5 (5.0) -7.1 0 , 2974 60 mg -11.2 (5.1) -21.8 0.0035 100 mg -16.5 (5.1) -27.1 0.0003 200 mg -15.0 (5.0) - 25.6 0.0004 RI Study 3 Treatment Comparison Time Point Treatment Group Mean LS (SE) Difference in PBO p-value Day 15 Placebo 4.4 (5.4) 140 mg -21.3 (5, 4) -25.7 0.0012 180 mg -27.1 (5.4) -31.5 0.0001 220 mg -36.1 (5.4) -40.5 <0.0001 a SR Study Treatment Comparison Time Point Treatment Group Mean LS (SE) Difference in PBO p-value Day 14 Placebo 3.8 50 mg -8.1 -11.9 0.41

100 mg -24.7 -28.5 0.09 200 mg -26.3 -26.3 0.11 a Statistics are estimated based on a Covariance Analysis model (ANCOVA) with fixed terms for the treatment and baseline LDL-C level. ANCOVA analysis (mean LS and p-value) was performed post hoc without repeated measures. The baseline is defined as the last value collected before the first dose of the study drug.

[00302] As Table 28 demonstrates, treatment with the SR formulation of bempedoic acid in obese / overweight patients, however, otherwise healthy, provided a dose-related and consistent line reduction of LDL-C of up to 27%. In addition, treatment with the SR formulation of bempedoic acid provided a reduction in LDL-C through dosages that were consistent with the treatments of the IR formulation of similar studies, that is, IR Studies 1, 2 and 3. Example 13: Preparation of Extended Release Formulation of Bempedoic Acid

[00303] The following describes the process for preparing a prolonged release formulation of bempedoic acid. The process comprises four general steps: granulation, extrusion, spheronization and drying. During the granulation stage, the raw materials bempedoic acid, microcrystalline cellulose, sodium carboxymethyl cellulose and sodium lauryl are distributed. Separately, HPMC 606 or hydroxypropyl methylcellulose is added to the treated water and mixed until the solution is uniform. Then, a GMX High Shear Granulator is configured with a four-liter container equipped with an impeller and chipper. The remaining raw materials are added to the bowl and the resulting composition is mixed only with the impeller at 560 RPM. After two minutes, the composition inside the GMX bowl is mixed with the addition of the chopper, at a speed of 1800 rpm, while keeping the impeller at 560 RPM. At the same time, the HMPC 606 solution is added to the GMX bowl using a pump at a rate of 30 g / min and the resulting composition is mixed for an additional minute after the complete addition of the HPMC 606 solution. then stopped momentarily to ensure that the entire composition inside the GMX bowl is scraped to the center of the bowl. An additional minute of mixing follows. The granulation process is then interrupted and the granulated composition is collected.

[00304] Then, an DG-L1 Extruder is configured with a 0.8 mm plate and 5 shims for the extrusion step. The granulated composition comprising ETC-1002 is then extruded at a speed of 60 RPM with a record of the exact speed, time and amperage during this process. Then, a QJ-230 Spheronizer with a 2 mm plate is configured for the spheronization step. The ETC-1002 Extrudate from the extrusion step is then spheronized at 1350 RPM. The resulting spheres are collected from the Spheronizer in a drying tray, which is then placed in an oven preheated to 40 ° C.

[00305] The wet spheres comprising ETC-1002 are then dried to their moisture content, as measured in terms of loss on drying (LOD), is <2%. The trays containing the ETC-1002 balls are removed from the oven, and the individual ETC-1002 balls are placed in a plastic bag.

[00306] Although the invention has been particularly shown and described with reference to a preferred modality and several alternative modalities, it will be understood by people versed in the relevant technique that various changes in form and details can be made without departing from the spirit and scope of invention.

[00307] All references, issued patents and requests for

quoted in the body of the present specification are hereby incorporated by reference in their entirety, for all purposes.

Claims (47)

1. Pharmaceutical formulation, characterized by the fact that it comprises the components: (i) 50-70% bempedoic acid, (ii) a filler, (iii) a diluent or solubilizer and (iv) a binder, in which the formulation is formulated for the prolonged release of wellic acid. 2. Pharmaceutical formulation according to claim 1, characterized in that the filler is selected from a group consisting of microcrystalline cellulose, sodium carboxymethyl cellulose and a combination of microcrystalline cellulose and sodium carboxymethyl cellulose. 3. Pharmaceutical formulation according to claim 1, characterized by the fact that the diluent or solubilizer is selected from a group consisting of sodium lauryl sulfate and sodium starch glycolate. 4. Pharmaceutical formulation, according to claim 1, characterized by the fact that the binder is hydroxylpropylmethylcellulose (HMPC). Pharmaceutical formulation according to any one of claims 1 to 4, characterized in that the formulation is formulated as a solid. Pharmaceutical formulation according to any one of claims 1 to 5, characterized in that the formulation is formulated for oral administration. 7. Pharmaceutical formulation according to any one of claims 1 to 6, characterized by the fact that the formulation comprises: bempedoic acid dispersed within a polymeric matrix, and in which the formulation exhibits a drug release profile. co corresponding to the following pattern: after 2 hours, no more than 30% of the total mass of bempedoic acid is released; after 4 hours, no more than 75% of the total mass of bempedoic acid is released; and after 8 hours, no more than 90% of the total mass of bempedoic acid is released. Pharmaceutical formulation according to any one of claims 1 to 7, characterized in that the dissolution of the formulation is determined using the United States Pharmacopoeia Apparatus 2 (50 rpm paddles) in 50 mM phosphate buffer at 20 ° Ç. Pharmaceutical formulation according to any one of claims 1 to 8, characterized by the fact that the formulation provides a therapeutically effective concentration of good acid over a period of 24 hours when administered to a human subject. Pharmaceutical formulation according to any one of claims 1 to 9, characterized in that the formulation is a gelatin capsule. 11. Pharmaceutical formulation according to claim 10, characterized in that the gelatin capsule further comprises a powdered excipient. Pharmaceutical formulation according to any one of claims 1 to 11, characterized in that the formulation is a tablet. 13. Pharmaceutical formulation according to any one of claims 1 to 12, characterized by the fact that the filler is microcrystalline cellulose and is 5-50% w / w. 14. Pharmaceutical formulation according to any one of claims 1 to 13, characterized in that the filler is sodium carboxymethyl cellulose and is 5-50% w / w. Pharmaceutical formulation according to any one of claims 1 to 1 to 14, characterized in that the diluent or solubilizing component is sodium lauryl sulfate and is about 1 to 5% w / w. 16. Pharmaceutical formulation according to any one of claims 1 to 15, characterized by the fact that the binding component is HPMC and has about 0.1 to 1.5% w / w. 17. Pharmaceutical formulation according to any one of claims 1 to 16, characterized in that said formulation comprises: 50-70% w / w bempedoic acid, 30% - 45% w / w wt component filler, 1 to 5% w / w of diluent or solubilizing component and 0.1 to 1.5% w / w of agglutinating component. 18. Pharmaceutical formulation according to any one of claims 1 to 17, characterized in that said formulation comprises: 55-65% w / w bempedoic acid, 30-45% w / w filler component , 1 to 5% w / w of diluent or solubilizing component and 0.1 to 1.5% w / w of agglutinating component. 19. Pharmaceutical formulation according to any one of claims 1 to 1 to 18, characterized in that said formulation comprises 60% w / w bempedoic acid, 30-45% w / w filler component, 1 to 5% w / w of diluent or solubilizing component and 0.1 to 1.5% w / w of agglutinating component. Pharmaceutical formulation according to any one of claims 1 to 19, characterized in that said formulation comprises 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160 , 170, 180, 190, 200, 210 or 220 mg of wellpedoic acid co. 21. Pharmaceutical formulation according to any one of claims 1 to 20, characterized in that the dissolution of the formulation has a release rate of zero order for at least 12 hours. 22. Pharmaceutical formulation according to claim 21, characterized in that it comprises bempedoic acid and a polymeric matrix, in which the formulation has a hardness of 2-30 kg and the formulation is in the form of a sphere or else it has an effective thickness to diameter ratio to allow erosion and sufficient penetration control for controlled surface erosion when dissolution is tested. 23. Pharmaceutical formulation according to any one of claims 1 to 22, characterized in that the formulation provides a therapeutically effective concentration of good acid over a period of 24 hours when administered to a human subject. 24. Pharmaceutical formulation according to any one of claims 1 to 23, characterized in that the formulation provides a maximum plasma concentration (Cmax) of well-acidic acid of no more than 60 pg / mL when administered to a human subject . 25. Pharmaceutical formulation according to any one of claims 1 to 24, characterized by the fact that the formulation provides a maximum plasma concentration (Cmax) of well-acid in a range of 45 µg / mL to 57 µg / mL per 24 hours after administration to a human individual. 26. Method of administration of bempedoic acid, characterized by the fact that it comprises: administering an effective amount of a pharmaceutical formulation for a human subject in need thereof, in which the formulation comprises bempedoic acid and a polymeric matrix, and in which said administration results in a maximum plasma concentration (Cmax) of bempedoic acid of no more than about 60 µg / mL, and in which the said blood plasma concentration is in a range of about 45-57 µg / mL for 24 hours after administration. 27. Method of treating cardiovascular disease or reducing the risk of cardiovascular disease in an individual, characterized by the fact that it comprises: administering an effective amount of a pharmaceutical formulation to a human individual in need of it, where the The formulation comprises the components of bempedoic acid and a polymer, and in which the dissolution of the formulation exhibits a drug release profile corresponding to the following pattern: after 2 hours, no more than 30% of the bempedoic acid is released; after 4 hours, no more than 75% of bempedoic acid is released; after 8 hours, no more than 90% of bempedoic acid is released; and wherein the formulation provides a therapeutically effective concentration of bempedoic acid over a 24-hour period to treat cardiovascular disease or reduce the risk of cardiovascular disease when administered to the individual. 28. Method, according to claim 26 or 27, characterized by the fact that the formulation does not release more than 95% of bempedoic acid after 8 hours. 29. Method according to any one of claims 26 to 28, characterized in that the polymer is hydroxypropyl. Methyl cellulose (HPMC). 30. Method according to any of claims 26-29, characterized in that the wellpedoic acid is about 30-80% by weight and the polymer is hydroxypropylmethylcellulose (HPMC) and is 15-35% by weight . 31. Method according to any of claims 26 to 30, characterized by the fact that the method reduces total cholesterol (TC) and low-density lipoprotein (LDL-C) cholesterol when administered to an individual human with hypercholesterolemia, mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver disease or kidney disease. 32. Method according to any of claims 26 to 31, characterized by the fact that the method decreases the level of very low density lipoprotein (VLDL) in the individual below that of a control individual receiving a placebo. 33. Method according to any of claims 26 to 32, characterized by the fact that the method decreases the size of the VLDL particles in the individual below that of a control individual receiving a placebo. 34. Method according to any of claims 26 to 33, characterized by the fact that the method decreases the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in the individual below that of an individual control receiving placebo. 35. Method according to any of claims 26 to 34, characterized by the fact that the individual has hypercholesterolemia. 36. Method according to any one of claims 26 to 35, characterized by the fact that the method decreases the level of low-density lipoprotein (LDL-C) cholesterol in the individual. 37. Method according to any one of the claims 26 to 36, characterized by the fact that the method decreases LDL-C levels by at least 5%, 10%, 15% or 20% in relation to an untreated or placebo-treated individual. 38. Method according to any of claims 26 to 36, characterized by the fact that the method decreases LDL-C levels by at least 5%, 10%, 15% or 30% in relation to an untreated or placebo-treated individual. 39. Method according to any one of claims 26 to 36, characterized by the fact that the method lowers LDL-C levels by 5-40% compared to an untreated or placebo-treated individual. 40. Method according to any one of claims 26 to 39, characterized in that the method lowers LDL-C levels in an individual at least as effectively as an equal dose of a formulation of bempedoic acid immediate release. 41. Method according to claim 40, characterized by the fact that the method lowers LDL-C levels in an individual at least as effectively as a higher dose of an immediate-release formulation of bempedoic acid , in which the highest dose is 180 mg / day. 42. Method of inhibiting the enzyme ATP-citrate lyase (ACL) in an individual, characterized by the fact that it comprises the administration to the individual of the pharmaceutical dosage form according to any one of claims 1 to 25. 43. Method of treating metabolic syndrome in an individual, the method characterized by the fact that it comprises the administration of an effective amount of a pharmaceutical dosage form, according to any one of claims 1 to 25. 44. Method according to claim 43, characterized due to the fact that the individual is obese, has hypercholesterolemia, has mixed dyslipidemia, has type 2 diabetes or any combination thereof. 45. Method, according to claim 43, characterized by the fact that the individual has hypercholesterolemia. 46. Method according to any of claims 43 to 45, characterized by the fact that the metabolic syndrome is non-alcoholic steatosis liver disease (NAFLD). 47. Method according to any of claims 43 to 45, characterized by the fact that the metabolic syndrome is non-alcoholic steatohepatitis (NASH).