Fixed dose formulations

Abstract

To provide stable and effective pharmaceutical compositions that allow a formulation of Bempedoic acid and ezetimibe hat have improved, desirable PK and bulk physical properties.SOLUTION: A pharmaceutical composition comprises: Bempedoic acid admixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate; ezetimibe; and a pharmaceutically acceptable excipient. The composition provides a pharmaceutical composition with excellent stability and release properties for both drug products. These improved formulations are useful in the treatment and prevention of cardiovascular disease.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 511,889, filed May 26, 2017, and U.S. Application No. 15 / 859,279, filed December 29, 2017, the entireties of which are incorporated by reference herein.

[0002] FIELD OF THEINVENTION The present disclosure relates to formulations, kits, methods of use and methods of making pharmaceutical formulations comprising bempedoic acid and ezetimibe. [Background technology]

[0003] 2. Description of Related Art Certain therapeutic molecules belonging to categories or chemical classes have been identified or rather recognized to have poor flowability and sticky bulk properties. Furthermore, although not a formally stated rule, chemists have generally observed that compounds from Biopharmaceutical Classification System (BCS) Class II are difficult to formulate due to the fact that Class II compounds are poorly soluble in water and therefore poorly soluble in the gastrointestinal tract. Both bempedoic acid (ETC-1002) and ezetimibe are included in the pharmaceutical BCS Class II compounds. Both are poorly soluble in water and highly permeable. In the solid state, bempedoic acid exhibits poor flowability properties and is very sticky. The observed stickiness adversely affects various stages during the development of pharmaceutical formulations, including weighing, blending, granulation and compression. These problems adversely affect drug manufacturing operations, especially tablet compression (low rpm operation, weight changes, frequent machine stoppages, etc.). Standard granulation of bempedoic acid only slightly reduces the sticky behavior, thereby improving processability. Bempedoic acid also has a relatively low melting point, 88-91°C, thus contributing to reduced bulk plasticity.

[0004] Formulation chemists have offered solutions, but such work is specific to the particular drug being studied. A balance must be struck between stability and release characteristics with tailored flowability and other bulk physical properties to meet predefined safety requirements for each API. This makes the art of API formulation highly unpredictable. Thus, formulation chemists do not have a single universal set of rules or excipients that will enhance the pharmacodynamic and / or bulk properties of any given API. Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, there is a need to develop stable and efficacious pharmaceutical compositions that allow for the formulation of bempedoic acid and ezetimibe with improved, desirable PK and bulk physical properties.

[0006] The present disclosure overcomes the problems associated with co-formulating bempedoic acid and ezetimibe, as described in detail below. [Means for solving the problem]

[0007] Summary of the Invention Disclosed herein is the development of a novel combination formulation for a pharmaceutical comprising bempedoic acid (ETC-1002) and ezetimibe. Also disclosed herein is a granular composition of bempedoic acid.

[0008] Two formulation options for the combination: monolayer and bilayer tablet formulations are identified as improved and compatible for both bempedoic acid (ETC-1002) and ezetimibe from the bioavailability studies performed and disclosed herein. Monolayer tablets are prepared by blending the granulation mixtures from both compounds together in a single layer. Bilayer tablets are prepared by compressing the granulation mixtures from each compound into two separate layers.

[0009] The inventors have found that surface treatment of ETC-1002 with colloidal silicon dioxide reduces or eliminates the stickiness problem. This treatment involves first blending ETC-1002 with colloidal silicon dioxide, then mixing the blend with hydroxypropyl cellulose (HPC-L) and microcrystalline cellulose in a high-speed mixer granulator before granulation. Granulation is also performed with a binder solution that includes colloidal silicon dioxide and hydroxypropyl cellulose (HPC-L). The preparation of the premix for processing and granulation of ETC1002 is performed such that 1) excessive hydrophobicity is not imparted to the active substance, 2) the dissolution and release profile of ETC-1002 is not adversely affected, 3) the stability of ETC-1002 is not adversely affected, and 4) no incompatibility from any of the excipients occurs in the fixed dose combination formulation containing ezetimibe, especially in the monolayer formulation. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows Zetia dissolution profile for ezetimibe in 500 mL dissolution media using USP Apparatus-II at 50 rpm. [Diagram 2] FIG. 1 shows the dissolution profile of bempedoic acid tablets in different media with 2.0% w / v sodium lauryl sulfate (SLS). [Diagram 3] FIG. 1 shows dissolution profiles for a combination of reference products at various dissolution conditions. [Figure 4] 1 is a graph of the dissolution profiles of a reference product and a fixed dose combination product in discriminating dissolution media reflecting differences in the granulation process. [Diagram 5] FIG. 1 shows the dissolution profile of bempedoic acid in three different discrimination media. [Figure 6] FIG. 1 is a graph showing the comparative dissolution profiles of bempedoic acid tablets (reference product) versus fixed dose combination monolayer tablets with coarse and fine grades of bempedoic acid. [Figure 7]FIG. 1 shows the surface treatment of granulated particles with bempedoic acid by Aerosil® and HPC-L binder. [Figure 8] 1 is a graph showing the dissolution profiles of tablets with different binder concentrations. [Figure 9] FIG. 1 shows comparative dissolution profiles of the prototype fixed dose combination tablet and test ezetimibe tablet (10 mg) in discriminating dissolution media. [Figure 10] FIG. 1 shows comparative dissolution profiles for different batches of granulated ezetimibe. [Figure 11] FIG. 1 illustrates the fixed dose combination-monolayer tablet manufacturing process. [Figure 12] FIG. 1 illustrates the fixed dose combination-bilayer tablet manufacturing process. [Figure 13] FIG. 1 shows comparative dissolution profiles for ezetimibe from monolayer and bilayer tablets versus a reference product. [Figure 14] FIG. 1 shows comparative dissolution profiles of bempedoic acid from monolayer and bilayer tablets versus a reference product. [Figure 15] FIG. 1 shows comparative dissolution profiles of ezetimibe from fixed dose combination-monolayer tablets versus ezetimibe test product. [Figure 16] FIG. 1 shows comparative dissolution profiles of bempedoic acid from monolayer and bilayer tablets versus ezetimibe test product. [Figure 17] FIG. 1 shows comparative dissolution profiles of bempedoic acid from monolayer and bilayer tablets versus ezetimibe test product. [Figure 18] FIG. 1 shows comparative dissolution profiles of bempedoic acid from fixed dose combination test products in QC media. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Detailed Description of the Invention Briefly, described herein are novel compositions, kits, methods of using and methods of making compositions that contain bempedoic acid or bempedoic acid and ezetimibe, as described in more detail below.The advantages of this approach are numerous, including but not limited to improved pharmacokinetic (PK) properties of one or both of bempedoic acid and ezetimibe, and improved flowability and other bulk physiochemical properties of the composition in solid state.As mentioned above, many BCS class II compounds suffer from reduced PK and bulk properties.Therefore, there is a significant need for formulations that improve the physiochemical properties of pharmaceutical compositions that contain bempedoic acid.

[0012] definition The terms used in the claims and specification are defined as set forth below, unless otherwise specified. Furthermore, if any term or symbol used herein is not defined as set forth below, it is intended to have its ordinary meaning in the art.

[0013] The practice of the present invention involves the use of conventional techniques of organic chemistry, molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art.

[0014] As used herein and in the appended claims, in the context of describing elements (particularly in the context of the claims below), singular articles such as "a," "an," and "the" and similar referents should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitations of ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each value within the range, including the upper and lower limits of the range, unless otherwise indicated herein, and each value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. Any and all examples provided herein, or the use of illustrative language (e.g., "etc."), unless otherwise stated, are intended merely to better illustrate the embodiments and do not pose a limitation on the scope of the claims. No language in this specification should be construed as indicating that any non-claimed element is required.

[0015] As used herein, the term "cardiovascular disease" refers to diseases of the heart and circulatory system. These diseases are often associated with dyslipoproteinemia and / or dyslipidemia. Cardiovascular diseases that the compositions of the present invention are useful for preventing or treating include, but are not limited to, arteriosclerosis, atherosclerosis, stroke, ischemia, endothelial dysfunction, particularly dysfunction affecting vascular elasticity, peripheral vascular disease, coronary heart disease, myocardial infarction, cerebral infarction and restenosis.

[0016] As used herein, the term "dyslipidemia" refers to disorders that lead to or are manifested by abnormal levels of circulating lipids. When blood lipid levels are too high, the compositions of the present invention are administered to patients to restore normal levels. Normal levels of lipids are reported in medical treatises 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 American Heart Association website and the National Cholesterol Education Program website of the National Heart, Lung and Blood Institute (http: / / www.americanheart.org / cholesterol- / about_level.html and http: / / www.nhlbi.nih.gov / health / public / heart / chol / hb-c_what.html, respectively). Currently, the recommended blood level of HDL cholesterol is greater than 35 mg / dL, the recommended blood level of LDL cholesterol is less than 130 mg / dL, the recommended blood LDL:HDL cholesterol ratio is less than 5:1, ideally 3.5:1, and the recommended blood free triglyceride level is less than 200 mg / dL.

[0017] The term "subject" refers to any mammal, including humans, and therefore includes mammals, such as animals of veterinary and research interest, including, but not limited to, monkeys, cows, horses, dogs, cats, and rodents. The term "subject" is interchangeable with the term "patient."

[0018] The term "sufficient amount" means an amount sufficient to produce a desired effect, for example an amount sufficient to modulate protein aggregation in a cell.

[0019] The term "therapeutically effective amount" is an amount effective for ameliorating symptoms of a disease. A therapeutically effective amount can, in some embodiments, be a "prophylactically effective amount" since prevention can be considered a therapy.

[0020] The terms "administering" a drug and / or therapy to a subject or "administration" of a drug and / or therapy to a subject (and grammatical equivalents of this phrase) refer to both direct or indirect administration, which may be administration to a subject by a medical professional, which may be self-administration, and / or indirect administration, and may be the act of prescribing the drug and / or therapy to a subject or inducing a subject to prescribe the drug and / or therapy.

[0021] The term "treating" a disorder or disease or "treatment" of a disorder or disease refers to taking steps to alleviate symptoms of the disorder or disease or otherwise obtain some beneficial or desired result in a subject, including clinical results. Any beneficial or desired clinical result may include, but is not limited to, alleviation or amelioration of one or more symptoms of cancer or conditional survival and reduction in tumor burden or tumor volume; reduction in the extent of disease; delay or slowing of tumor or disease progression; improvement, mitigation or stabilization of the tumor and / or disease state; or other beneficial result.

[0022] The compounds of the present technology can exist as solvates, particularly hydrates. Hydrates can form during the preparation of the compounds or compositions containing the compounds, or hydrates can form slowly over time due to the hygroscopic nature of the compounds. The compounds of the present technology can also exist as organic solvates, including DMF, ether and alcohol solvates, among others. The identification and preparation of any particular solvate is within the skill of a person skilled in the art of synthetic organic chemistry or medicinal chemistry.

[0023] For purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, ratios, shapes, formulations, parameters, percentages, parameters, quantities, features and other numerical values ​​used in the specification and claims are to be understood in all instances as being modified by the term "about," even if the term "about" does not explicitly appear in conjunction with a value, amount or range. Thus, unless indicated to the contrary, the numerical parameters set forth in the following specification and the appended claims are not, and need not be, precise, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement errors and the like, as well as other factors known to those of ordinary skill in the art depending upon the desired properties sought to be obtained by the subject matter of the present disclosure. For example, the term "about" when referring to a value can be intended to encompass variations of in some embodiments ±100%, in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the particular amount, as variations are appropriate for practicing the disclosed methods or utilizing the disclosed compositions.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0025] Throughout this application, the text refers to various embodiments of the compounds, compositions and methods. The various embodiments described are intended to provide various examples and should not be interpreted as descriptions of alternative species. Rather, it should be noted that the descriptions of the various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not intended to limit the scope of the technology.

[0026] Formulations and pharmaceutical compositions Disclosed herein is a combination of bempedoic acid and ezetimibe formulated into a pharmaceutical composition.

[0027] In one aspect, the present disclosure provides a pharmaceutical composition comprising bempedoic acid, ezetimibe and pharma- ceutically acceptable excipients mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate.

[0028] In some aspects, the present disclosure provides a pharmaceutical composition comprising at least 40% and no more than 95% bempedoic acid by weight of the total composition and at least 0.5% and no more than 20% ezetimibe by weight of the total composition.

[0029] In some aspects, the present disclosure provides pharmaceutical compositions further comprising one or more of magnesium stearate, hydroxypropyl cellulose (HPC-L), a pyrrolidone compound, a sugar, an anionic surfactant, microcrystalline cellulose, and starch.

[0030] In some aspects, the present disclosure provides pharmaceutical compositions further comprising one each of magnesium stearate, hydroxypropyl cellulose (HPC-L), a pyrrolidone compound, a sugar, an anionic surfactant, microcrystalline cellulose, and starch.

[0031] In some aspects, the disclosure provides pharmaceutical compositions, wherein the microcrystalline cellulose, if present, comprises an average particle size of at least 100 μm and a moisture content of at least 3% and no more than 5% by weight of the microcrystalline cellulose.

[0032] In some aspects, the disclosure provides pharmaceutical compositions, where the anionic surfactant, if present, is sodium lauryl sulfate.

[0033] In some aspects, the present disclosure provides a pharmaceutical composition, wherein the pyrrolidone compound, when present, is povidone.

[0034] In some aspects, the disclosure provides pharmaceutical compositions, where the sugar, if present, is lactose monohydrate.

[0035] In some aspects, the present disclosure provides a pharmaceutical composition, wherein, if present, 1.03% by weight of the total magnesium stearate has a particle size of at least 45 μm and no greater than 150 μm.

[0036] In some aspects, the disclosure provides a pharmaceutical composition, wherein the composition is in the form of a tablet and further comprises a polyvinyl alcohol (PVA)-based coating, the coating comprising polyvinyl alcohol (PVA), glycerol monocaprylocaprate type 1, sodium lauryl sulfate, titanium dioxide, and talc.

[0037] In some aspects, the disclosure provides pharmaceutical compositions, wherein the amount of magnesium stearate is between 1 mg and 10 mg, the amount of hydroxypropyl cellulose (HPC-L) is between 5 mg and 25 mg, the amount of pyrrolidone compound is between 0.5 mg and 5 mg, the amount of sugar is between 50 mg and 100 mg, the amount of anionic surfactant is between 0.5 mg and 5 mg, the amount of microcrystalline cellulose is between 25 mg and 100 mg, and the amount of sodium starch glycolate is between 5 mg and 50 mg.

[0038] In some embodiments, the present disclosure provides pharmaceutical compositions in which the amount of bempedoic acid is between 80mg and 250mg and the amount of ezetimibe is between 5mg and 25mg. In some embodiments, the amount of bempedoic acid is between 100mg and 200mg and the amount of ezetimibe is between 7mg and 15mg. In some embodiments, the amount of bempedoic acid is between 150mg and 200mg and the amount of ezetimibe is between 9mg and 12mg.

[0039] In some aspects, the disclosure provides a pharmaceutical composition, wherein the amount of bempedoic acid is 180 mg and the amount of ezetimibe is 10 mg.

[0040] In some aspects, the disclosure provides pharmaceutical compositions, wherein the amount of bempedoic acid is a fixed dose and the amount of ezetimibe is a fixed dose.

[0041] In some aspects, the present disclosure provides pharmaceutical compositions comprising ezetimibe and bempedoic acid as described herein, having the improved flow properties as described herein.

[0042] In some aspects, the present disclosure provides pharmaceutical compositions comprising ezetimibe and bempedoic acid as described herein, having the improved non-stick properties as described herein.

[0043] In some aspects, the present disclosure provides pharmaceutical compositions comprising ezetimibe and bempedoic acid as described herein, having the improved PK properties as described herein.

[0044] In some aspects, the present disclosure provides pharmaceutical compositions comprising ezetimibe and bempedoic acid as described herein, having the improved solubility properties as described herein.

[0045] In some aspects, the present disclosure provides pharmaceutical compositions comprising ezetimibe and bempedoic acid as described herein having the improved extended release properties as described herein.

[0046] In some aspects, the present disclosure provides pharmaceutical compositions comprising ezetimibe and bempedoic acid as described herein having improved chemical and physical properties, such as particle size, surface area, pore volume, and other properties as described herein.

[0047] In some aspects, the ezetimibe in the pharmaceutical composition is amorphous. In some aspects, the ezetimibe in the pharmaceutical composition is polymorphic.

[0048] In some embodiments, the bempedoic acid in the pharmaceutical composition is amorphous. In some embodiments, the bempedoic acid in the pharmaceutical composition is polymorphic.

[0049] In some embodiments, one of bempedoic acid or ezetimibe is amorphous. In some embodiments, one of bempedoic acid or ezetimibe is a polymorph.

[0050] The formulations disclosed herein include active compounds, pharma- ceutically acceptable excipients, carriers, buffers, stabilizers, or other materials known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material may depend on the route of administration, e.g., oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.

[0051] The combined compounds of the present disclosure and their solvates can be formulated in pharmaceutical compositions. These compositions may contain pharma- ceutically acceptable excipients, carriers, buffers, stabilizers, or other substances known to those skilled in the art. The exact nature of the carrier or other substances may depend on the route of administration, for example, oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal.

[0052] Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. Tablets may contain a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally contain a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Saline, dextrose or other sugar liquids or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may also be included.

[0053] For intravenous, cutaneous or subcutaneous injection, or injection into the painful area, the active ingredient is in the form of a pyrogen-free parenterally acceptable aqueous solution with suitable pH, isotonicity and stability.Those skilled in the art can fully prepare suitable solutions using isotonic vehicles such as sodium chloride injection, Ringer's solution, lactated Ringer's solution, etc.Preservatives, stabilizers, buffers, antioxidants and / or other additives may be included as necessary.

[0054] The compositions may be administered alone or in combination with other treatments, either simultaneously or sequentially, depending on the condition being treated.

[0055] Generally, the compound of the present technology is administered in a therapeutically effective amount by any of the administration modes that are accepted for drugs that provide similar utility.The actual amount of the compound of the present technology, i.e., active ingredient, depends on many factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors well known to those skilled in the art.The drug can be administered at least once a day, preferably once or twice a day.

[0056] The effective amount of such drugs, as well as the most effective and convenient route of administration and the most suitable formulation, can be easily determined by routine experimentation. A variety of formulations and drug delivery systems are available in the art. See, for example, Gennaro, AR, ed. (1995) Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co.

[0057] The therapeutically effective dose can be initially estimated using various techniques well known in the art. The initial dose used in animal studies can be based on the effective concentration established in cell culture assays. The dosage range suitable for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays.

[0058] An effective amount or therapeutically effective amount or dose of an agent, e.g., a compound of the present technology, refers to that amount of the agent or compound that results in amelioration of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 (lethal dose for 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 / ED50 Agents that exhibit large therapeutic indices are preferred.

[0059] An effective amount or therapeutically effective amount is that amount of a compound or pharmaceutical composition that elicits the biological or medical response in a tissue, system, animal or human that is desired by a researcher, veterinarian, physician or other clinician. The dosage is particularly suitable for administering EDs with little or no toxicity. 50 The circulating concentration range includes: 0.1 to 0.5% by weight of the compound of formula (I) and / or 0.1 to 0.5% by weight of the compound of formula (I). Dosage may vary within this range depending on the dosage form employed and / or the route of administration utilized. The precise formulation, route of administration, dosage, and interval should be selected according to methods known in the art, taking into account the specifics of a subject's condition.

[0060] Dosage and interval can be adjusted individually to provide plasma levels of the active moiety sufficient to achieve the desired effect, i.e., the minimum effective concentration (MEC). The MEC varies for each compound, but can be estimated, for example, from in vitro data and animal experiments. The dosage required to achieve the MEC depends on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0061] The amount of drug or composition administered can depend on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0062] The present technology is not limited to any particular composition or pharmaceutical carrier, and therefore may vary.Generally, the compound of the present technology is administered as a pharmaceutical composition by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.The preferred mode of administration is oral, using a convenient daily dosing regimen that can be adjusted according to the degree of pain.The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained release formulation, solution, suspension, elixir, aerosol or any other suitable composition.Another preferred mode of administration of the compound of the present technology is inhalation.

[0063] The choice of formulation depends on various factors such as the mode of drug administration and the bioavailability of the drug substance. For delivery by inhalation, the compound can be formulated as a liquid solution, suspension, aerosol propellant or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices, such as nebulizer inhalers, metered dose inhalers (MDIs) and dry powder inhalers (DPIs). Nebulizer devices generate a high velocity air stream that causes the therapeutic agent (formulated in a liquid form) to spray as a mist that is carried to the subject's airways. MDIs are typically compressed gas filled formulations. Upon actuation, the device releases a measured amount of the therapeutic agent by the compressed gas, thus providing a reliable method of administering a set amount of the drug. DPIs dispense the therapeutic agent by the device in the form of a free-flowing powder that can be dispersed into the subject's inspiratory air stream during breathing. To obtain a free-flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a capsule form and dispensed with each actuation.

[0064] Pharmaceutical dosage forms of the compounds of the present technology can be prepared by any of the methods well known in the art, such as, for example, conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extrusion, spray-drying, wet-grinding, emulsifying, (nano / micro)encapsulating, encapsulating or lyophilizing processes. As mentioned above, the compositions of the present technology can include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecules into preparations for pharmaceutical use.

[0065] tablet In some aspects, the present disclosure provides a monolayer or bilayer tablet as described herein, comprising a composition of bempedoic acid and ezetimibe, and optionally one or more pharma- ceutically acceptable excipients as described herein.

[0066] In some aspects, the present disclosure provides a bilayer tablet comprising bempedoic acid and ezetimibe, wherein a first layer comprises ezetimibe granulated with a pharmaceutically acceptable excipient and a second layer comprises bempedoic acid granulated with a lubricant and a pharmaceutically acceptable excipient, wherein the lubricant is selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate.

[0067] In some aspects, the disclosure provides a bilayer tablet, wherein bempedoic acid is at least 20% and not more than 64% by weight of the whole tablet, and ezetimibe is at least 1% and not more than 7% by weight of the whole tablet.

[0068] In some embodiments, the disclosure provides bilayer tablets, wherein the first layer is at least 0.1% and not more than 23% by weight of the entire tablet, and the second layer is at least 0.1% and not more than 74% by weight of the entire tablet.

[0069] In some embodiments, the present disclosure provides bilayer tablets, the tablet friability being at least 0.01% and no more than 0.1%. Friability is a routine test for tablet compositions, and those skilled in the art can determine friability by a number of methods. For example, those skilled in the art can refer to the monograph USP Tablet Friability, which describes the recommended equipment and testing procedures. <1216> The friability of the compositions of the present disclosure can be determined by the method described in USP Tablet Friability. <1216> is incorporated by reference in its entirety.

[0070] In some aspects, the present disclosure provides monolayer or bilayer tablets comprising ezetimibe and bempedoic acid as described herein having improved physical characteristics, such as friability and other properties as described herein.

[0071] granular composition In some aspects, the present disclosure provides a granular composition comprising bempedoic acid mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate.

[0072] In some aspects, the present disclosure provides a granular composition further comprising a pharma- ceutically acceptable excipient.

[0073] In some aspects, the present disclosure provides a granular composition, wherein the lubricant is colloidal silicon dioxide.

[0074] In some aspects, the present disclosure provides a granular composition having a bulk density of at least 0.25 gm / ml and no greater than 0.55 gm / ml.

[0075] In some embodiments, the present disclosure provides a granular composition having a Carr index of at least 10 and no more than 30. The Carr index is related to the compressibility of a material and therefore the flowability of the material. The Carr index is a common measure for those skilled in the art, and a number of methods are available. For example, those skilled in the art can use the methods, apparatus and procedures described in monograph USP29-NF24 (page 2638) to determine the Carr index of the composition of the present disclosure. The entirety of monograph USP29 is incorporated herein by reference.

[0076] In some embodiments, the present disclosure provides a granular composition, wherein the granules of the composition have an angle of repose of at least 20° and no more than 45°. The form of both a given material and its composition affects the angle of repose. The angle of repose is related to the density, surface area, particle shape and coefficient of friction of the material. Those skilled in the art can use many methods to determine the angle of repose, one example is to use the methods and procedures described in USP29.

[0077] In some aspects, the present disclosure provides granular compositions, wherein bempedoic acid is present in an amount of at least 50% and no more than 95% by weight of the total formulation.

[0078] In some embodiments, the present disclosure provides a granular composition further comprising hydroxypropyl cellulose (HPC-L). In some embodiments, the present disclosure provides a granular composition further comprising microcrystalline cellulose. In some embodiments, the amount of HPC-L is at least 3% and not more than 10% by weight of the total formulation, the amount of bempedoic acid is at least 50% and not more than 95% by weight of the total formulation, and the amount of microcrystalline cellulose is at least 1% and not more than 20% by weight of the total formulation.

[0079] In some embodiments, the bempedoic acid in the granular composition is amorphous. In some embodiments, the bempedoic acid in the granular composition is polymorphic.

[0080] kit The disclosure also provides kits that include one or more compositions that themselves include bempedoic acid or a combination of bempedoic acid and ezetimibe, and instructions for use. The disclosure further provides kits that include one or more compositions.

[0081] The present disclosure further provides kits comprising one or more compositions comprising bempedoic acid or bempedoic acid and ezetimibe, optionally the compositions and / or kits comprising at least one pharma- ceutically acceptable carrier or excipient.

[0082] In some aspects, the disclosure provides a kit comprising a combination composition comprising bempedoic acid mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate, and ezetimibe, and optionally at least one pharma- ceutically acceptable carrier or excipient.

[0083] In one aspect, the disclosure provides a kit and instructions for use, the instructions describing a method or instructions for mixing one or more of the granular compositions or one or more pharmaceutical compositions or one or more tablets with one or more compositions.

[0084] The individual components of the kit may be packaged in separate containers and associated with such containers may be a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, which notice reflects approval by the agency of the manufacture, use, or sale. The kit may optionally contain instructions or instructions outlining the method of use or administration regimen for the antigen-binding construct.

[0085] Where one or more components of the kit are provided as a liquid solution, such as an aqueous solution or a sterile aqueous solution, the container means may itself be an inhaler, syringe, pipette, eye dropper or other such similar device from which the solution may be administered to a subject or applied to and mixed with other components of the kit.

[0086] The components of the kit may also be provided in dried or lyophilized form, and the kit may further contain a suitable solvent for reconstituting the lyophilized components. Regardless of the number or type of containers, the kits described herein may also include an instrument to aid in the administration of the composition to a patient. Such an instrument may be an inhaler, a nasal spray device, a syringe, a pipette, forceps, a measuring spoon, an eye dropper, or a similar medically approved delivery vehicle.

[0087] Synthesis of Bempedoic Acid (ETC-1002) and Ezetimibe The structure of ETC-1002 is

[0088] [ka] It is.

[0089] ETC-1002 and methods of synthesizing ETC-1002 are disclosed in issued U.S. Patent No. 7,335,799. Details of the methods can be found in published U.S. Patent Publication No. US2005 / 0043278A1 (paragraphs

[0247] to

[0343] of this specification), which is incorporated herein by reference.

[0090] The structure of ezetimibe is

[0091] [ka] It is.

[0092] Ezetimibe and methods of synthesizing ezetimibe are disclosed in issued U.S. Patent No. 5,631,365, details of which can be found therein beginning at page 4, right column, line 43 through page 11, right column, line 65, each of which is incorporated herein by reference.

[0093] Moreover, both compounds are small molecules with molecular weights of less than 500 Da, and one skilled in the art can use synthesis reference texts to synthesize the desired final compound from readily available or commercially available chemicals. Such references include, but are not limited to, Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, volumes 1-5 and supplements (Elsevier Science Publishers, 1989), Organic Reactions, volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 5th Edition, 2001) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, 1999.

[0094] Granulation In some aspects, the present disclosure provides a method of granulating bempedoic acid, comprising dry blending bempedoic acid, a lubricant and a pharma- ceutically acceptable excipient, wherein the lubricant is selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate, separately blending an aqueous preparation of HPC-L, blending the dry blend and the aqueous preparation, and granulating the blend.

[0095] In some aspects, the present disclosure provides a method of granulating bempedoic acid, further comprising the step of granulating the blend using a high speed mixer.

[0096] In some aspects, the present disclosure provides a method of granulating bempedoic acid, further comprising drying the blend.

[0097] In some aspects, the present disclosure provides a method of granulating bempedoic acid further comprising the steps of milling and co-sifting the blend.

[0098] In some embodiments, the present disclosure provides a method of granulating bempedoic acid, wherein the dry blending is carried out for at least 45 minutes.

[0099] In some embodiments, the present disclosure provides a method of granulating bempedoic acid, wherein the dry blending is carried out for a period of time of 24 hours or less.

[0100] manufacturing In some aspects, the disclosure provides a method for producing a monolayer tablet comprising ezetimibe and bempedoic acid, the method comprising the steps of granulating a composition comprising ezetimibe and granulating a composition comprising bempedoic acid, each composition being granulated separately, blending the granules of ezetimibe and bempedoic acid together, compressing the blend into a single layer, and coating the single layer.

[0101] In some aspects, the present disclosure provides a method of making a monolayer tablet, further comprising drying the tablet.

[0102] In some aspects, the present disclosure provides a method of making a monolayer tablet, wherein the coating comprises one or more of PVA, glycerol monocaprylocaprate type 1, sodium lauryl sulfate, titanium dioxide, and talc.

[0103] In some aspects, the present disclosure provides a method of making a monolayer tablet, wherein the coating comprises one each of PVA, glycerol monocaprylocaprate type 1, sodium lauryl sulfate, titanium dioxide, and talc.

[0104] In some aspects, the disclosure provides a method for producing a bilayer tablet comprising ezetimibe and bempedoic acid, the method comprising the steps of granulating a composition comprising ezetimibe and granulating a composition comprising bempedoic acid, each composition being granulated separately, blending the granules of ezetimibe with a pharma- ceutically acceptable excipient, blending the granules of bempedoic acid with a pharma- ceutically acceptable excipient, compressing the blend of ezetimibe and bempedoic acid into a single composition containing two separate layers, and coating the compositions.

[0105] In some aspects, the present disclosure provides a method of making a bilayer tablet, further comprising drying the tablet.

[0106] In some aspects, the disclosure provides a method of making a bilayer tablet, wherein the bempedoic acid composition comprises colloidal silicon dioxide, sodium stearyl fumarate, or magnesium stearate.

[0107] In some aspects, the present disclosure provides a method of making a bilayer tablet, wherein the ezetimibe composition comprises an anionic surfactant.

[0108] How to use In one aspect, the disclosure provides a method of treating or preventing cardiovascular disease comprising administering a pharmaceutical composition comprising ezetimibe and bempedoic acid mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate.

[0109] In one aspect, the disclosure provides a method of treating or preventing cardiovascular disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising bempedoic acid, ezetimibe and pharma- ceutical acceptable excipients mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate.

[0110] In one aspect, the disclosure provides a method of treating or preventing cardiovascular disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising a fixed dose of bempedoic acid, a fixed dose of ezetimibe, and pharmaceutically acceptable excipients mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate.

[0111] In some aspects, the present disclosure provides a method of treating or preventing cardiovascular disease comprising administering a fixed-dose pharmaceutical composition disclosed herein.

[0112] In some aspects, the disclosure provides a method of treating or preventing dyslipidemia comprising administering a pharmaceutical composition comprising bempedoic acid mixed with ezetimibe and a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate.

[0113] In some aspects, the disclosure provides a method of treating or preventing dyslipidemia, comprising administering to a subject in need thereof a pharmaceutical composition comprising bempedoic acid, ezetimibe and pharma- ceutical acceptable excipients mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate.

[0114] The dyslipidemia that the compositions of the present invention are useful for preventing or treating includes, but is not limited to, hyperlipidemia and low blood levels of high density lipoprotein (HDL) cholesterol.In certain embodiments, the hyperlipidemia that the compounds of the present invention are used for preventing or treating is familial hypercholesterolemia; familial combined hyperlipidemia; reduced or deficient lipoprotein lipase level or activity, including reduced or deficient lipoprotein lipase caused by lipoprotein lipase mutation; hypertriglyceridemia; hypercholesterolemia; high blood levels of urea bodies (e.g., β-OH butyric acid); high blood levels of Lp(a) cholesterol; high blood levels of low density lipoprotein (LDL) cholesterol; high blood levels of very low density lipoprotein (VLDL) cholesterol and high blood levels of non-esterified fatty acids.

[0115] The present disclosure relates to methods of altering lipid metabolism in a patient, e.g., methods of reducing LDL in the blood of a patient, methods of reducing free triglycerides in the blood of a patient, methods of increasing the level of high density lipoprotein (HDL) in the blood of a patient, methods of reducing the level of very low density lipoprotein (VLDL) in the blood of a patient, methods of reducing the number of very low density lipoprotein (VLDL) particles in the blood of a patient, methods of reducing the size of VLDL particles in the blood of a patient, methods of increasing the level of apolipoprotein A-1 (ApoA1) in the blood of a patient, methods of increasing the level of LDL in the blood of a patient, methods of increasing the level of free triglycerides in the blood of a patient, methods of increasing the level of high density lipoprotein (HDL) in the blood of a patient, methods of decreasing the level of very low density lipoprotein (VLDL) in the blood of a patient, methods of decreasing the number of very low density lipoprotein (VLDL) particles in the blood of a patient, methods of decreasing the size of VLDL particles in the blood of a patient, methods of increasing the level of apolipoprotein A-1 (ApoA1) in the blood of a patient, methods of decreasing the level of free triglycerides in the blood of a patient, methods of increasing the level of free triglycerides in the blood of a patient, methods of increasing the level of free triglycerides in the blood of a patient, methods of decreasing ... Provided are methods for decreasing the ratio of apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoA1) in the blood, for increasing the ratio of HDL to LDL in the blood of a patient, and for inhibiting saponified and / or non-saponified fatty acid synthesis, comprising administering to a patient a pharmaceutical composition comprising bempedoic acid, ezetimibe, and a pharma- ceutically acceptable excipient mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate, in an amount effective to alter lipid metabolism.

[0116] [Example] Formulation development was initiated with characterization of both APIs along with evaluation of the respective reference products. Dissolution profiles and drug-drug and drug-excipient compatibility were characterized. Additionally, process operations were defined and process control strategies were explored. Manufacturing process development identified wet granulation, blending, compression and coating as the primary process options. Risks were assessed throughout development to identify high-risk formulation and process variables and determine paths for developing control strategies. Risk assessments were updated post-development to capture risk reduction due to improved product and process understanding.

[0117] Dissolution parameters (e.g., dissolution media, volumes, equipment, and agitation speeds) were selected based on analytical methods listed in the pending USP monograph for ezetimibe and IND # 106,654 for bempedoic acid. Particle size of ezetimibe is important for dissolution, therefore micronized forms of each API were used. Limits for single known and unidentified impurities were set according to ICH Q3B(R2) to control impurities in the final drug product.

[0118] The Quality Target Product Profile (QTPP) is defined based on the properties of the drug substance, the characterization of the reference product and other information available for the two compounds. Critical Quality Attributes (CQAs) were identified as those drug product characteristics that may impact the risk (safety and efficacy) to the patient. This disclosure focuses on those CQAs that are affected to affect realistic changes to the drug formulation or manufacturing process, i.e., assay, content uniformity, dissolution and degradation products.

[0119] First, it was found that bempedoic acid exhibits sticky behavior as a granular material. This behavior poses a great challenge to making tablets by compression. To address this challenge, the granulation process was modified by treating the active substance with a mixture of colloidal silicon and a cellulose-based binder.

[0120] The granulation of bempedoic acid is altered by a mixture of colloidal silicon dioxide and hydroxypropyl cellulose (HPC-L). This blend was further granulated using a solution of HPC-L. The solubility of ezetimibe was improved by homogenization with sodium lauryl sulfate (SLS) and povidone. This dispersion was then used to granulate the excipient blend using a top spray attachment of a fluid bed processor. Opadry AMBII White 88A180040 was selected as the coating agent to avoid the incompatibility of ezetimibe with polyethylene glycol and / or polyvinyl alcohol.

[0121] For the purposes of this development, bempedoic acid film-coated tablets (180 mg) manufactured by Esperion Therapeutics, Inc. and a drug product containing Zetia® (ezetimibe, 10 mg) manufactured by MSD International GmbH (NDA No: 21445) were utilized as reference products.

[0122] The objectives were categorized into the following activities: Study of the compatibility of both drug substances together and with the selected excipients; Development of a product with a satisfactory process and stability profile; QC and matching of the release profile of the FDC product in the discriminatory dissolution media with the respective reference products. Study of the pharmacokinetics of the developed FDC product together with the reference products (ETC-1002 (180 mg) tablets and Zetia (10 mg) co-administration).

[0123] Zetia® (ezetimibe): Zetia is available as a tablet containing 10 mg of ezetimibe for oral administration. It was approved in the United States in 2002 (NDA No: 21445).

[0124] Bempedoic Acid (ETC-1002) Tablets: Bempedoic Acid (ETC-1002) is an innovative, first-in-class small molecule designed to lower elevated levels of LDL-C and avoid the side effects associated with existing LDL-C lowering therapies. It is intended to be taken once daily.

[0125] [Example 1] Drug release Both ezetimibe and bempedoic acid are BCS class-II compounds (poorly soluble and highly permeable) and therefore drug release is the rate-limiting process for absorption. A thorough evaluation of the drug release profile of the reference products was performed.

[0126] Zetia Dissolution in Multiple Media: Dissolution characterization was performed according to the pending USP monograph (500 mL of 0.45% SLS (dissolution media) in 0.05 M acetate buffer, pH 4.5, Apparatus-II, 50 rpm). The temperature of the dissolution media was maintained at 37±0.5° C. and HPLC was used to determine the released drug concentration. Drug release was also studied in two additional media at different pH (0.1 N HCl with 0.45% w / v SLS and phosphate buffer pH 6.8 with 0.45% w / v SLS). The dissolution profiles in multiple media are shown in Table 1 and Figure 1.

[0127] [Table 1]

[0128] Zetia demonstrated rapid dissolution with greater than 80% drug release within 15 minutes in all three studied media. Although the aqueous solubility of ezetimibe is very low, the use of 0.45% SLS allows for precipitation conditions.

[0129] Dissolution of Bempedoic Acid Tablets in Multiple Media. Dissolution characterization was performed according to the dissolution method detailed in IND # 106,654. Dissolution conditions were 900 mL of phosphate buffer (pH 6.8) using Apparatus-II at 50 rpm. Data are shown in Table 2 and Figure 2.

[0130] [Table 2]

[0131] Bempedoic acid has two carboxylic acid functional groups (-COOH), which makes the solubility pH dependent, as observed in this multi-media dissolution study: low dissolution values ​​were observed in 0.1 N HCl and acetate buffers (pH 4.5), whereas in QC medium (phosphate buffer (pH 6.8)) more than 85% of the drug was released in 20 min.

[0132] The physicochemical characterization of the reference products is summarized in Table 3.

[0133] [Table 3]

[0134] Based on reference product labeling and related literature, Table 4 lists the expected composition of Zetia (10 mg). The composition of bempedoic acid 180 mg tablets provided by Esperion is detailed in Table 5.

[0135] [Table 4]

[0136] [Table 5]

[0137] Fixed Dose Combination (FDC) Products The Quality Target Product Profile (QTPP) is an expected outline of the characteristics of a drug product that are ideally achieved to ensure the desired quality, taking into account the drug product's safety and efficacy. QTPPs are an essential element of the Quality by Design (QbD) approach and form the basis for the design of drug products. The QTPP set for the FDC product is listed in Table 6.

[0138] [Table 6]

[0139] Table 7 summarizes the quality attributes of the FDCs of ezetimibe (10 mg) and bempedoic acid (180 mg) and indicates which attributes were classified as critical quality attributes (CQAs). CQAs that are likely to be affected by formulation and / or process variables were investigated during the development studies. CQAs that are unlikely to be affected by formulation and / or process variables were not studied. However, these CQAs remain target elements of the QTPP and will be assured by good pharmaceutical quality systems and control strategies.

[0140] [Table 7] TIFF2024178341000010.tif117161

[0141] Dissolution method Dissolution Method Development for FDC Products of Bempedoic Acid and Ezetimibe. Table 8 shows the dissolution methods used to measure drug release from the FDC products. Drug release profiles for both actives were estimated using common chromatographic conditions with different injection volumes.

[0142] [Table 8]

[0143] Method development of differential dissolution method for ezetimibe Ezetimibe exhibits low aqueous solubility (insoluble in aqueous media at all pH) and therefore requires the incorporation of SLS into the dissolution medium.

[0144] The QC dissolution medium, 0.45% SLS in 0.05 M acetate buffer (pH 4.5), results in greater than 85% drug release within 15 minutes. Lower concentrations of SLS and different volumes of dissolution medium were evaluated to identify appropriate discrimination for the dissolution of the reference product.

[0145] Table 9 and Figure 3 show the dissolution data for the reference product combinations at various dissolution conditions.

[0146] [Table 9]

[0147] Based on the obtained dissolution profiles, medium 2 (900 mL acetate buffer (pH 4.5) containing 0.1% SLS) was proposed to be the discriminating medium. Media 1 and 3 were not selected because medium 3 (0.2% SLS) showed dose dumping (as also observed in the QC release medium) and medium 1 (low volume medium) showed inappropriate precipitation conditions for complete drug release.

[0148] The FDC prototype formulation (Batch No.: 4759-S1-096) demonstrated comparable release to the combination reference product (Zetia (10 mg) + bempedoic acid tablet (180 mg)) in the discriminatory dissolution media, and the discriminatory power of the method is demonstrated in the examples shown in Table 10 and Figure 4.

[0149] To understand the discriminatory ability of the dissolution media, the dissolution profiles of two batches were monitored: Batch number: 4759-S1-096 - Ezetimibe homogenized by top spray granulation · Batch number: 4490-S1-047 - Ezetimibe mixed with excipients (diluent and superdisintegrant) followed by wet granulation.

[0150] The batch with homogenized API, batch number: 4759-S1-096, was expected to have a faster release profile compared to the other batches where ezetimibe was not homogenized. Table 10 shows the results of the dissolution comparison with ezetimibe tablets (10 mg). The dissolution conditions were as follows: 0.1% SLS in 0.05 M acetate buffer (pH 4.5), USP Apparatus-II, 50 rpm, 900 mL.

[0151] [Table 10]

[0152] The discriminatory dissolution media reflected the differences in processing for ezetimibe granulation and correlated with the expected dissolution behavior. The discriminatory ability of the selected media was confirmed. The dissolution profile of Zetia (10 mg) + bempedoic acid (180 mg) (reference product) was found to be comparable to the test FDC product (batch number: 4759-S1-096).

[0153] Method development of a differential dissolution method for bempedoic acid The QC release medium (phosphate buffer, pH 6.8) showed dose dumping (approximately 90% in 15 min). Optimization of surfactant concentrations (0.1%-0.45%) was performed with 1000 mL of different dissolution media using a USP Apparatus II at 50 rpm.

[0154] Dissolution was performed on Zetia (10 mg) + bempedoic acid (180 mg) reference product and the dissolution data are shown in Table 11 and FIG.

[0155] [Table 11]

[0156] Medium 1 (0.1% SLS in acetate buffer, pH 4.5) showed a slower release profile and complete recovery was not observed within 2 hours. Medium 3 (0.2 M phosphate buffer, pH 6.8) showed dumping behavior. Medium 2 (0.45% SLS in acetate buffer, pH 4.5) showed a significant gradual dissolution profile for bempedoic acid. Therefore, 0.45% SLS in acetate buffer, pH 4.5, 1000 mL, 50 rpm, USP App-II was established as the discriminatory dissolution condition.

[0157] The discriminatory power of this method is demonstrated by the slight variation in particle size of bempedoic acid in the formulations and is shown in Table 12 and FIG.

[0158] [Table 12]

[0159] As expected, the batch with the coarser grade of bempedoic acid (#60 Retained / Passed=32 / 68) showed slower release compared to the batch with the finer grade of bempedoic acid (#60 Retained / Passed=11.5 / 88.5). The difference in the dissolution profiles (due to the change in particle size of the active substance) reflects the discriminatory power of the selected dissolution conditions.

[0160] 5. Active Pharmaceutical Ingredients Bempedoic acid was obtained from Esperion Therapeutics, Inc. and ezetimibe was obtained from Teva API India Ltd.

[0161] 5.1 Physical properties Table 13 shows the physical properties for both APIs.

[0162] [Table 13]

[0163] The compressibility index was 32.6% and 29.60% and the Hausner's ratio was 1.48 and 1.42 for bempedoic acid and ezetimibe, respectively, suggesting very poor flowability of the APIs.

[0164] 5.2 Chemical properties: The chemical properties are detailed in Table 14.

[0165] [Table 14]

[0166] 5.2.1 Polymorphism Ezetimibe drug substance has different polymorphic / hydrate forms. Anhydrous (designated as Form A) Hydrate form (designated as Form B)

[0167] Both polymorphs exhibit the same physicochemical properties. For FDC drug development, the anhydrous form of ezetimibe (Form A) was used.

[0168] Bempedoic acid is a crystalline powder with no evidence of polymorphism.

[0169] 5.2.2 Chemical stability Forced degradation of bempedoic acid was performed to study the impurity profile, degradation pathways, and to facilitate the development of a stability indicating method. Knowledge gained from the forced degradation study was used during formulation and process design and development to further prevent impurities from forming. Specific stress conditions were designed to achieve 5-20% degradation. Stressed samples were compared to non-stressed samples (control).

[0170] The forced degradation conditions and results for bempedoic acid are listed in Table 15.

[0171] [Table 15] (1) Appropriate control samples were prepared for each stressor but are not shown in the table above. (2) Results for bempedoic acid (w / w%) in NaOH differ from the expected value of approximately 100% due to non-quantitative neutralization prior to injection.

[0172] No significant changes were observed in the purity profile of bempedoic acid during the stress test study, indicating that the API is stable under all studied conditions.

[0173] A summary of the forced degradation data for ezetimibe is presented in Table 16.

[0174] [Table 16]

[0175] Ezetimibe has been observed to be relatively unstable, especially when exposed to alkali (NaOH) and peroxide (H2O2). The main degradation product identified is the EZT cyclic ether. However, in solid form, it is stable to heat and light irradiation. Therefore, ezetimibe is classified as sensitive to alkali and peroxide.

[0176] 5.3 Biological properties The biological properties are shown in Table 17.

[0177] [Table 17]

[0178] 5.4 Risk Assessment of Drug Substance Attributes A risk assessment of drug substance attributes was performed to evaluate the impact of each attribute on drug product CQAs. The relative risk ranking system used throughout drug development is summarized in Table 18. The results of the assessment and associated rationale are shown in Tables 19, 20, 21, and 22. The relative risk of each drug substance attribute was ranked as high, medium, or low. Those attributes that could have a large impact on drug product CQAs required further investigation, whereas those attributes with a small impact on drug product CQAs did not require further investigation.

[0179] [Table 18]

[0180] [Table 19]

[0181] [Table 20] TIFF2024178341000024.tif246133

[0182] [Table 21]

[0183] [Table 22] TIFF2024178341000027.tif189162

[0184] 5.5 Drug-drug interactions Since the fixed dose combination product under development is a novel combination of two drug substances, it was considered important to determine the compatibility of the active substances with each other. The compatibility of the active substances was evaluated by HPLC analysis of a binary mixture of the drug substances in a 1:18 ratio (ezetimibe:bempedoic acid) in the solid state. Samples were stored at 60° C. and 40° C. / 75% RH for 2 and 4 weeks, respectively, in both open and closed containers. Degradation products were evaluated for accelerated condition (40° C. / 75% RH) and open (stressed) samples at 60° C. Assays on the samples were also performed. The results are summarized in Table 23.

[0185] [Table 23]

[0186] There was no significant increase in any of the impurities for each of the active substances in the presence of each other under accelerated conditions and the assays were found to be within acceptable limits. Therefore, bempedoic acid and ezetimibe can be considered chemically compatible.

[0187] 5.6 Excipients The excipients used in the combination drug products were selected based on excipients used in the individual reference products, excipient compatibility studies, and prior use in approved drug products. Drug-excipient compatibility was studied in which both APIs were combined with the selected excipients.

[0188] 5.6.1 Drug-excipient compatibility studies Excipient-drug substance compatibility was evaluated using HPLC analysis of ternary mixtures of excipients and both APIs together in the required ratio in solid state. Samples were stored at 60°C and 40°C / 75%RH for 2 and 4 weeks in both open and closed containers, respectively. Common excipients acting as fillers, disintegrants, binders and lubricants were evaluated. Degradant levels (related substances) for each API were evaluated using HPLC analysis to quantify degradants in case of any incompatibility. Degradation products were evaluated for open (stressed) samples at accelerated conditions (40°C / 75%RH) and 60°C. Samples kept closed at accelerated conditions (40°C / 75%RH) were evaluated in case there was a significant increase in degradation observed in the open (stressed) conditions. Assays on samples were also performed. Results are summarized in Table 24.

[0189] Table 25 lists the compatibility studies of both active substances along with the excipients used in the formulation.

[0190] [Table 24]

[0191] [Table 25] TIFF2024178341000031.tif50159

[0192] No significant change in appearance was observed for bempedoic acid, but an increase in cyclic ether impurities was observed for open ezetimibe at 40°C / 75%RH. It is possible that a combination of high temperature and humidity could have caused this degradation. However, in the presence of bempedoic acid and excipients, ezetimibe was diluted, which could reduce the effects of heat and humidity.

[0193] An increase in ezetimibe cyclic ether was observed when combined with HPC-L in an open container maintained at 40° C. / 75% RH for 4 W. However, this drug-excipient combination was found to be compatible at 40° C. / 75% RH for 4 W in a closed container. HPC-L was used in the granulation of bempedoic acid and does not come into direct contact with ezetimibe, so this excipient was selected in the final formulation.

[0194] Assays for both ezetimibe and bempedoic acid were comparable to the initial sample, except for Opadry white, where a decrease in the assay of ezetimibe was observed with increasing impurity levels. With increasing impurities in all conditions, the excipient Opadry white (85F18422) was found to be incompatible. It is important to note that the reference product for bempedoic acid monohydrate is a coated tablet, whereas the reference product Zetia is an uncoated tablet. The goal for the fixed dose combination is a coated tablet. Therefore, further compatibility studies with another Opadry system that does not contain polyethylene glycol and polyvinyl alcohol (the main components of Opadry studied) were proposed.

[0195] 5.6.2 Selection of excipient grades Based on the results of the drug-excipient compatibility study, excipients identical to the reference product formulation were selected for the development of the fixed dose combination product. The levels of excipients used in the formulation were investigated in subsequent formulation development studies.

[0196] Lactose monohydrate (Pharmatose® 200M): Lactose monohydrate is commonly used as a filler. Fine grades of lactose are usually used in the preparation of tablets using wet granulation techniques. Pharmatose® 200M, a lactose monohydrate from DFE Pharma, was selected. Particle size distribution data for Pharmatose 200M shows that more than 90% of the particles are less than 100 μm in size and has a bulk density of 0.56 g / cm3.

[0197] Microcrystalline Cellulose (Avicel® PH-102): Microcrystalline cellulose is widely used as a filler in direct compression and roller compaction. Because it is fibrous and ductile, it undergoes plastic deformation during compression. Microcrystalline cellulose (Avicel® PH-102) is used in the current bempedoic acid tablet formulation as a diluent with a larger particle size (100 μm) that helps provide better blend flowability. The moisture content is 3.0-5.0% and the bulk density is 0.28-0.33 g / cc.

[0198] Hydroxypropyl cellulose (HPC-L): Hydroxypropyl cellulose is a partially substituted poly(hydroxypropyl) ether of cellulose. Hydroxypropyl cellulose is commercially available in several different grades with various solution viscosities. The grade used in formulations is a standard grade fine powder with a viscosity range of 6.0-10.0 mPa.s, which is primarily used as a binder in tablet dosage forms.

[0199] Povidone K30 (Kollidon® 30): Povidone (Kollidon® 30) is a medium molecular weight grade of povidone with a K value of 27.0-32.1. It is versatile and widely used as a binder in tablets and granulations. In the current formulation, an aqueous solution of povidone is used as a binder in the top spray granulation process for ezetimibe.

[0200] Sodium Lauryl Sulfate (Kolliphor® SLS Fine): Sodium lauryl sulfate is an anionic surfactant utilized in a wide range of oral pharmaceutical formulations to improve the dissolution of insoluble drug molecules.

[0201] Sodium lauryl sulfate is used as a solubilizer at concentrations above the critical micelle concentration, i.e., greater than 0.0025%. It is used as a wetting agent and is effective in both alkaline and acidic conditions. In the current formulation, it is used as a dissolution enhancer for ezetimibe.

[0202] Sodium Starch Glycolate (Primojel®): Sodium starch glycolate is a white or almost white, free-flowing, highly hygroscopic powder. It is widely used in oral medicines as a disintegrant in tablet production. Disintegration occurs due to the rapid uptake of water, followed by rapid and enormous swelling of the tablet containing sodium starch glycolate.

[0203] The effectiveness of many disintegrants is affected by the presence of hydrophobic excipients such as lubricants. Increasing tablet compression pressure does not appear to affect disintegration time.

[0204] Colloidal silicon dioxide (Aerosil® 200P): Colloidal silicon dioxide (Aerosil® 200 Pharma), a commercial grade of colloidal silicon dioxide manufactured by Evonik, was used as a glidant in the current bempedoic acid tablet formulation.

[0205] Magnesium stearate: Magnesium stearate manufactured by Avantor using vegetable origin was used as the lubricant in the current formulation, with a particle size specification of 99-100% w / w passing through a #325 sieve (ASTM, 45 μm) and an LOD < 5.0% w / w.

[0206] Opadry AMB II 88A180040 White: Opadry AMB II 88A180040 is a polyvinyl acetate (PVA) based non-functional film coating system with glycerol monocaprylocaprate type 1, sodium lauryl sulfate, titanium dioxide and talc used for tablet aesthetic appearance.

[0207] Tables 26 and 27 summarize the grades of excipients selected for the proposed formulations and their IID limits.

[0208] [Table 26] TIFF2024178341000033.tif126162

[0209] [Table 27]

[0210] 6. Pharmaceuticals 6.1 General information

[0211] [Table 28]

[0212] 6.2 Formulation Development Compatibility studies have revealed that both bempedoic acid and ezetimibe are chemically compatible with each other and therefore it is possible to develop a monolayer tablet. However, the individual APIs are granulated separately for the following reasons:

[0213] Ezetimibe exhibits low aqueous solubility over physiological pH, and therefore the surfactant sodium lauryl sulfate (SLS) was utilized in the Zetia formulation. The same is preferred in combination products to achieve bioequivalence. However, bempedoic acid, despite having pH-dependent solubility, does not require a surfactant as established in the single product already developed by Esperion. Its increased solubility at high pH ensures in-vivo dissolution and absorption.

[0214] Bempedoic acid is sticky and has poor flowability. This embodiment requires certain process steps and / or excipients that may not be suitable for ezetimibe.

[0215] Formulation options: Although the compatibility studies ruled out any potential chemical interactions between the two APIs, it is still possible that some physical interactions may lead to impaired dissolution. Furthermore, the presence of SLS in the monolayer formulation may alter the dissolution of bempedoic acid and its absorption. Therefore, it was decided to develop the following two formulations: FDC monolayer with both active substances (in the form of separate granules) compressed into a monolayer tablet, and FDC bilayer with both granules compressed into a bilayer tablet with the active substance present in a separate layer.

[0216] 6.2.1 Initial Risk Assessment of Formulation Variables An overall risk assessment was performed for the impact of the drug formulation on the drug CQAs. Each formulation component with a high risk of impacting the drug CQAs was further evaluated for risk reduction. The initial risk assessment of the formulation variables is shown in Table 29 and the rationale for the risk assignment is shown in Table 30.

[0217] [Table 29]

[0218] [Table 30] TIFF2024178341000038.tif250163

[0219] 6.2.2 Formulation Development Research Formulation development focused on evaluation of high and medium risk formulation variables identified in the initial risk assessment shown in Table 28. Development was conducted in four phases. The first study optimized the bempedoic acid granulation process. The second study evaluated the impact of povidone levels in ezetimibe granulations on drug product CQAs by OFAT (one factor at a time). The third study perfected the process for incorporating sodium lauryl sulfate into the ezetimibe component of the drug product. The fourth study selected an appropriate coating system for compressed tablets containing bempedoic acid and ezetimibe.

[0220] [Table 31]

[0221] Process Selection The development of a fixed dose combination of bempedoic acid and ezetimibe was attempted by manufacturing an immediate release tablet according to a reference product. Both APIs were granulated separately using wet granulation. This approach ensured that ezetimibe was treated with SLS to improve solubility and bempedoic acid was treated with colloidal silicon dioxide to avoid sticky behavior. Initial development work was carried out using a single layer approach.

[0222] [Example 2] Formulation Development Study #1: Bempedoic Acid Granule Composition and Process Selection The goal of Formulation Development Study #1 was to select a bempedoic acid granule composition and manufacturing process based on studies to reduce API stickiness.

[0223] Bempedoic acid showed low flow and adhesion during granulation and compression. The sticking of API was prevented by creating a physical barrier between API and the contact surface. This was achieved by coating API with a material with high surface area. Colloidal silicon dioxide was selected, which has a small particle size and a large specific surface area. In preliminary tests, this approach was found to be promising, therefore further trials were carried out to optimize the concentration of colloidal silicon dioxide and the process for this surface treatment.

[0224] Optimization trials were initiated using the formulation and process received from Esperion. Table 32 shows the formula used for bempedoic acid granulation and Table 33 describes the trial batches to eliminate the sticking behavior.

[0225] [Table 32]

[0226] [Table 33]

[0227] The sticking behavior could be significantly reduced by treating with increasing concentrations of colloidal silicon dioxide prior to granulation. Furthermore, maintaining the level of colloidal silicon dioxide and increasing the duration of surface treatment from 30 to 45 minutes provided satisfactory processing parameters without sticking during the granulation or compression process. The final composition of the bempedoic acid granulation is listed in Table 34.

[0228] [Table 34]

[0229] Table 35 provides selected process parameters for further development work. A depiction of the treatment process is shown in Figure 7.

[0230] [Table 35]

[0231] [Example 3] Formulation Development Study #2: Optimization of Ezetimibe Granules: The goal of formulation development study #2 was to optimize the concentration of binder used for ezetimibe granulation. Wet granulation was used for preparation of ezetimibe granules. Binder solution, povidone with SLS, and ezetimibe were used for granulation of dry mixed powder blend. One trial with higher concentration of povidone (3 mg / tablet) and another trial with lower concentration (1 mg / tablet) were conducted to observe the effect of binder concentration on dissolution. Ezetimibe granules were mixed with bempedoic acid granules separately and compressed into monolayer tablets for both trials. The formulation summary is provided in Table 36. The dissolution profile was studied in QC media (containing 0.45% SLS) and is shown in Table 37 and Figure 8.

[0232] [Table 36]

[0233] [Table 37]

[0234] Tablets with higher binder concentrations initially showed slower release than tablets with lower binder concentrations. Higher binder concentrations may slow the release from the granules initially after tablet disintegration. Therefore, a 1 mg / tablet binder concentration was selected for ezetimibe granulation.

[0235] [Example 4] Formulation Development Study #3: Ezetimibe Granules - SLS Incorporation Process Optimization: The sodium lauryl sulfate concentration was estimated using titration from the reference product, Zetia, which was determined to contain 1.8 mg (approximately 2.0 mg) of SLS per tablet. The same concentration of surfactant was considered for the ezetimibe granulation process to achieve a consistent dissolution profile.

[0236] Initially, ezetimibe granules were prepared by wet granulation. The granulation process involved dry blending ezetimibe with diluents MCC and lactose and super disintegrant SSG, followed by granulation with a binder solution containing Povidone K30 and sodium lauryl sulfate as surfactants in purified water. However, the resulting dissolution profile was slower than the Zetia dissolution profile. Therefore, a series of process modification trials were performed.

[0237] Co-sieving of Ezetimibe with hydrophilic excipients (Batch No: 4759-S1-064) Ezetimibe was sieved through a #50 mesh along with hydrophilic excipients, lactose monohydrate (Pharmatose® 200M), polyvinylpyrrolidone (Kollidon® 30) to reduce hydrophobicity. The blend was then granulated with a binder solution containing SLS. The ezetimibe granules were then blended with additional granular excipients and compressed into tablets. This attempt did not result in the desired improvement in dissolution. Homogenization of binder solution with ezetimibe followed by RMG granulation (4759-S1-065) When granulated with SLS, the surfactant was distributed throughout the material, including the excipients. As a result, the desired improvement in dissolution was not achieved. To provide adequate contact between ezetimibe and SLS, ezetimibe was added to the binder solution and then homogenized for 30 minutes to achieve a uniform dispersion. This dispersion was then granulated with an excipient blend. The granules were then blended with additional granular excipients and compressed into tablets. The dissolution profile improved, but was not comparable to that of Zetia.

[0238] Homogenization of binder solution with ezetimibe followed by top spray granulation (Batch No: 4759-S1-094) To further improve the dissolution profile, the homogenized binder solution was incorporated into the top spray granulation using a fluid bed processor (FBP) instead of a high speed mixer granulator. The granules were then blended with additional granular excipients and compressed into tablets. The resulting dissolution in the discriminated dissolution media is shown in Table 38 and Figure 9.

[0239] [Table 38]

[0240] Process parameters for Ezetimibe granulation (Top Spray Method): The process parameters listed in Table 39 were utilized for Ezetimibe granulation:

[0241] [Table 39]

[0242] 2000 tablets Two reproducibility batches (Batch Nos. 4759-S1-104 and 4759-S1-106) were manufactured using the same set of parameters. The dissolution profiles obtained from the reproducibility runs are shown in Table 40, and the comparative dissolution profiles are shown in FIG.

[0243] [Table 40] TIFF2024178341000049.tif31155

[0244] The replicated batches showed similar release profiles to the previous batches and to the reference product. The process can be considered reproducible at laboratory scale.

[0245] Formulation Development Study #4: Coating System Selection During drug-excipient compatibility studies, Opadry white 85F18422 was found to be incompatible with ezetimibe. This observation was confirmed during stability studies of tablets coated with Opadry white. The assay and impurity profile are shown in Table 41.

[0246] [Table 41]

[0247] Opadry White (85F18422) is a polyvinyl alcohol (PVA) based coating system with polyethylene glycol (PEG) utilized as a plasticizer. The increase in cyclic ether impurities was due to one of these substances. Therefore, the following Opadry coating systems were studied for compatibility with ezetimibe. To validate the results, compressed tablets were coated with these Opadry systems and subjected to stress studies.

[0248] Opadry system containing PVA and PEG (Opadry White 88A180040)

[0249] PVA-based PEG-free Opadry White (Opadry White AMB II 88A180040)

[0250] Opadry White is a PVA and PEG free HPMC based formulation (Opadry White 03K58821).

[0251] The impurity profile after one week exposure at 600C in an open container was used as the response for comparative evaluation, and the results are shown in Table 42.

[0252] [Table 42]

[0253] Accelerated Stability Data: Stress stability data for compressed tablets coated with different Opadry systems at 60° C. for 1 week is shown in Table 43.

[0254] [Table 43] TIFF2024178341000053.tif27162

[0255] This study confirmed previous observations of drug instability with Opadry white 88A180040. Alternative Opadry systems, Opadry white AMB II 88A180040 and Opadry white 03K58821, were found to be compatible with the API as reflected by the levels of the ezetimibe cyclic ether impurity. These results were confirmed during stress stability studies on the coated tablet formulation. Of the two Opadry systems, Opadry white selected AMB II 88A180040 because it does not contain polyethylene glycol and has shown relatively superior processability.

[0256] 6.2.3 Updated risk assessment of drug substance attributes 6.2.3 Tables 44 and 45 summarize the updated risk assessment of the drug substance attributes of bempedoic acid and ezetimibe.

[0257] [Table 44]

[0258] [Table 45]

[0259] 6.2.4 Updated risk assessment of formulation components: Acceptable ranges for high-risk formulation variables have been established and are included in the control strategy. Based on the results of formulation development studies, the risk assessment of formulation variables has been updated in Table 46.

[0260] [Table 46] TIFF2024178341000057.tif46162

[0261] 6.3 Manufacturing Process Development Two approaches were used for the preparation of FDC tablets: monolayer and bilayer. Batches were prepared to perform stability studies.

[0262] The monolayer process involved preparing ezetimibe and bempedoic acid granules separately, blending them together, and compressing them into a monolayer tablet. The tablets were then coated.

[0263] The bilayer approach involved blending bempedoic acid granules with additional granular excipients and ezetimibe granules with additional granular excipients. The two lubricated blends were compressed into bilayer FDC tablets, one layer containing bempedoic acid and the other layer containing ezetimibe. The bilayer FDC tablets were then coated.

[0264] 6.3.1 FDC monolayer tablets: Table 47 provides the composition of the monolayer tablets.

[0265] [Table 47] TIFF2024178341000059.tif111163

[0266] The FDC monolayer tablet manufacturing process is shown in FIG.

[0267] 6.3.2 FDC bilayer tablets The composition of the final formulation of the bilayer tablet is shown in Table 48.

[0268] [Table 48] TIFF2024178341000061.tif118162

[0269] The FDC bilayer tablet manufacturing process is shown in FIG.

[0270] Physical parameters of compressed tablets. Table 49 contains the compression parameters for both tablet variants:

[0271] [Table 49]

[0272] Observations: The physical parameters of the lubricated blend and compressed tablets were found to be satisfactory for both variants. The coating parameters were found to be satisfactory.

[0273] Dissolution of FDC formulations in discriminating dissolution media: Dissolution profiles for ezetimibe in discriminating dissolution media: Comparative dissolution profiles of ezetimibe from both variants of the FDC product vs. Zetia (10 mg) + bempedoic acid (180 mg) are shown in Table 50 and Figure 13. Table 50: Ezetimibe release from mono- and bi-phase FDC in discriminating media.

[0274] [Table 50]

[0275] Conclusions: The dissolution of both the monolayer and bilayer FDC tablets was found to be comparable to that of dissolved Zetia (10 mg) (ezetimibe) + bempedoic acid (180 mg) (reference product).

[0276] Dissolution profiles for bempedoic acid in discriminating dissolution media:

[0277] The QC release medium, phosphate buffer (pH 6.8), showed dose dumping (almost >90% in 15 min). Based on optimization of surfactant concentration (0.1%-0.45%) and dissolution volume (500mL-1000mL), 0.45% SLS in acetate buffer (pH 4.5), 1000mL, 50 rpm, paddle type (USP App-II) showed a gradual release profile compared to the QC medium.

[0278] Table 51 and Figure 14 show the comparative dissolution profiles of bempedoic acid from both variants of the FDC product versus Zetia (10 mg) + bempedoic acid (180 mg) (reference product).

[0279] [Table 51]

[0280] The % drug release of bempedoic acid from both variants of FDC shows a comparable release profile to the reference product.

[0281] Dissolution profile of FDC prototype product (ezetimibe component) in QC dissolution media:

[0282] The dissolution profiles of the FDC test products (ezetimibe component) in QC media are shown in Table 52, Table 53, Figure 15 and Figure 16.

[0283] [Table 52]

[0284] [Table 53]

[0285] Dissolution of both variants (monophase and biphase) showed similar dissolution to the reference product Zetia (10 mg) in QC media. Dissolution profile of FDC test product (bempedoic acid component) in QC media: The dissolution profile of FDC test product (bempedoic acid component) is shown in Table 54, Table 55, Figure 17 and Figure 18.

[0286] [Table 54]

[0287] [Table 55]

[0288] Dissolution of bempedoic acid from both variants showed similar dissolution profiles to the reference product in QC media.

[0289] 6.4 Stability studies For stability loading, 30 tablets were loaded into a 30 cc HDPE bottle with a 1 g polyester coil and a 1 g sorbitol canister. The bottle was sealed with a 28 mm CRC cap.

[0290] 6.4.1 Stability data for FDC monolayer variants: The stability data for the monolayer tablets is shown in Table 56.

[0291] [Table 56]

[0292] (FDC bilayer variant) Stability data for the bilayer tablets is shown in Table 57. Conclusions: All physicochemical parameters were found to be satisfactory and comparable to initial at 2 months under accelerated conditions. Dissolution in QC media was found to be comparable (>90% release in 30 min). Unidentified impurities less than 0.1% of bempedoic acid were formed at 2 months under accelerated conditions. Impurity profiling was found to be within specification at 2 months under accelerated conditions according to ICH Q3B(R2) based on maximum daily dose.

[0293] [Table 57]

[0294] List of abbreviations: ACL ATP citrate lyase MCC microcrystalline cellulose BCS Biopharmaceutical Classification System mg milligram BLOQ Below Quantitative Level Min Minutes cfu colony forming units mL milliliters CQA Critical Quality Attribute MLT Microbial Limit Test CR Child-Resistant mm Millimeters CU content uniformity mM millimolar DMF Drug Master File mPa.s Millipascal seconds DMSO Dimethylsulfoxide N Newton EZT Ezetimibe ND Not detected FBP Fluid Bed Processor NDA New Drug Application FDC Fixed Dose Combination NF National Formulary g / mol grams / mole NMT or less GMP Good Manufacturing Practice PDR Pharmaceutical Development Report HDPE High Density Polyethylene PEG Polyethylene Glycol HPC-L Hydroxypropyl Cellulose Low Substituted PI Purity Index HPLC High Performance Liquid Chromatography PK Pharmacokinetics HPMC Hydroxypropyl methylcellulose PSD Particle size distribution hrs hours PVA Polyvinyl alcohol ICH International Conference on Harmonisation QbD Quality by Design IH In-house QL Limit of Quantitation IID: Inactive Ingredients Database QTPP Target Product Quality Profile IR Instant Release RH Relative Humidity LDL-C Low-density lipoprotein cholesterol RLD Reference List Drugs RMG High Speed ​​Mixer Granulator TAMC Total Aerobic Microbial Count RPM Revolutions per minute TYMC Total yeast and mold count SLS Sodium Lauryl Sulfate USP United States Pharmacopeia SSG Sodium starch glycolate XRD X-ray diffraction

[0295] [Example 5] ETC 1002 Research, Laboratory Trials to Solve Adhesion Challenges

[0296] [Table 58]

[0297] Manufacturing process for Formulation I (4490-S1-024): All ingredients in the dry mix were sieved simultaneously and granulated with binder solution, and the resulting granules were dried in a fluid bed dryer. The dried granules were blended with ezetimibe granules along with microcrystalline cellulose, sodium starch glycolate, and lubricated. The granules were then compressed into tablets.

[0298] Manufacturing process for Formulation II (4759-S1-058): ETC 1002 and colloidal silicon dioxide were simultaneously sieved and blended. Then this blend was further mixed with microcrystalline cellulose and granulated binder solution. Granules were dried and sieved. The dried granules were blended with ezetimibe granules along with microcrystalline cellulose, sodium starch glycolate and lubricated. Granules were then compressed into tablets.

[0299] [Table 59]

[0300] Conclusions: Surface treatment of ETC 1002 with colloidal silicon dioxide reduced the sticking observed during compression with untreated API. (Additional Note) (Appendix 1) A granular composition comprising bempedoic acid mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate. (Appendix 2) 2. The granular composition of claim 1, further comprising a pharma- ceutically acceptable excipient. (Appendix 3) 3. The granular composition of claim 1 or 2, wherein the lubricant is colloidal silicon dioxide. (Appendix 4) 4. A granular composition according to any one of claims 1 to 3, having a bulk density of at least 0.25 gm / ml and not more than 0.55 gm / ml. (Appendix 5) 5. A granular composition according to any one of claims 1 to 4, having a Carr index of at least 10 and no more than 30. (Appendix 6) 6. A granular composition according to any one of claims 1 to 5, wherein the granules of the composition have an angle of repose of at least 20° and no greater than 45°. (Appendix 7) 7. A granular composition according to any one of claims 1 to 6, wherein bempedoic acid is present in an amount of at least 50% by weight and not more than 95% by weight of the total formulation. (Appendix 8) 8. The granular composition of any one of claims 1 to 7, further comprising hydroxypropyl cellulose (HPC-L). (Appendix 9) 9. The granular composition of any one of claims 1 to 8, further comprising microcrystalline cellulose. (Appendix 10) A granular composition as described in Appendix 9, wherein the amount of HPC-L is at least 3% by weight and not more than 10% by weight of the total formulation, the amount of bempedoic acid is at least 50% by weight and not more than 95% by weight of the total formulation, and the amount of microcrystalline cellulose is at least 1% by weight and not more than 20% by weight of the total formulation. (Appendix 11) bempedoic acid mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate; Ezetimibe, and Pharmaceutically acceptable excipients 23. A pharmaceutical composition comprising: (Appendix 12) 12. The pharmaceutical composition of claim 11, comprising at least 40% by weight and no more than 95% by weight of bempedoic acid and at least 0.5% by weight and no more than 20% by weight of ezetimibe. (Appendix 13) 13. The pharmaceutical composition according to any one of claims 11 to 12, further comprising one or more of magnesium stearate, hydroxypropyl cellulose (HPC-L), a pyrrolidone compound, a sugar, an anionic surfactant, microcrystalline cellulose and starch. (Appendix 14) 13. The pharmaceutical composition of any one of claims 11 to 12, further comprising one each of magnesium stearate, hydroxypropyl cellulose (HPC-L), a pyrrolidone compound, a sugar, an anionic surfactant, microcrystalline cellulose and starch. (Appendix 15) 15. The pharmaceutical composition of any one of claims 13 to 14, wherein the microcrystalline cellulose, if present, has an average particle size of at least 100 μm and a moisture content of at least 3% and not more than 5% by weight of the microcrystalline cellulose. (Appendix 16) 16. The pharmaceutical composition according to any one of appendix 13 to 15, wherein the anionic surfactant, if present, is sodium lauryl sulfate. (Appendix 17) 17. The pharmaceutical composition according to any one of claims 13 to 16, wherein the pyrrolidone compound, if present, is povidone. (Appendix 18) 18. The pharmaceutical composition according to any one of claims 13 to 17, wherein the sugar, if present, is lactose monohydrate. (Appendix 19) 19. A pharmaceutical composition according to any one of claims 13 to 18, wherein, if present, 1.03% by weight of the total magnesium stearate has a particle size of at least 45 μm and not more than 150 μm. (Appendix 20) 20. The pharmaceutical composition according to any one of claims 11 to 19, in the form of a tablet and further comprising a polyvinyl alcohol (PVA) based coating, the coating comprising polyvinyl alcohol (PVA), glycerol monocaprylocaprate type 1, sodium lauryl sulfate, titanium dioxide and talc. (Appendix 21) 21. The pharmaceutical composition according to any one of claims 11 to 20, wherein the amount of magnesium stearate is between 1 mg and 10 mg, the amount of hydroxypropylcellulose (HPC-L) is between 5 mg and 25 mg, the amount of pyrrolidone compound is between 0.5 mg and 5 mg, the amount of sugar is between 50 mg and 100 mg, the amount of anionic surfactant is between 0.5 mg and 5 mg, the amount of microcrystalline cellulose is between 25 mg and 100 mg, and the amount of sodium starch glycolate is between 5 mg and 50 mg. (Appendix 22) 22. The pharmaceutical composition according to any one of claims 11 to 21, wherein the amount of bempedoic acid is between 80 mg and 250 mg and the amount of ezetimibe is between 5 mg and 25 mg. (Appendix 23) 22. The pharmaceutical composition according to any one of claims 11 to 21, wherein the amount of bempedoic acid is 180 mg and the amount of ezetimibe is 10 mg. (Appendix 24) dry blending bempedoic acid, a lubricant and a pharma- ceutically acceptable excipient, wherein the lubricant is selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate; mixing separately an aqueous preparation of HPC-L; blending the dry mix and the aqueous preparation; and Granulating the blend A method for granulating bempedoic acid comprising the steps of: (Appendix 25) 25. The method of claim 24, further comprising granulating the blend using a high speed mixer. (Appendix 26) 26. The method of any one of claims 24 to 25, further comprising drying the blend. (Appendix 27) 27. The method of any one of claims 24 to 26, further comprising simultaneously milling and sieving the blend. (Appendix 28) The method according to any one of claims 24 to 27, wherein the dry mixing is carried out for at least 45 minutes. 29. The method of claim 28, wherein the dry blending is performed for a period of time of 24 hours or less. (Appendix 30) 1. A bilayer tablet comprising bempedoic acid and ezetimibe, a first layer comprising ezetimibe granulated with pharma- ceutically acceptable excipients; A bilayer tablet, wherein the second layer comprises bempedoic acid granulated with a lubricant and a pharma- ceutically acceptable excipient, the lubricant being selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate. (Appendix 31) 31. The bilayer tablet of claim 30, wherein bempedoic acid is at least 20% by weight and not more than 64% by weight of the whole tablet, and ezetimibe is at least 1% by weight and not more than 7% by weight of the whole tablet. (Appendix 32) 32. The bilayer tablet according to any one of claims 30 to 31, wherein the first layer is at least 0.1% and not more than 23% by weight of the entire tablet, and the second layer is at least 0.1% and not more than 74% by weight of the entire tablet. (Appendix 33) 33. The bilayer tablet of any one of claims 30 to 32, wherein the tablet has a friability of at least 0.01% and not more than 0.1%. (Appendix 34) 1. A process for preparing a monolayer tablet comprising ezetimibe and bempedoic acid, comprising the steps of: granulating a composition comprising ezetimibe and granulating a composition comprising bempedoic acid, each composition being granulated separately; blending together granules of ezetimibe and bempedoic acid; compressing the blend into a single layer; and Coating a single layer A method comprising: (Appendix 35) 35. The method of claim 34, further comprising drying the tablet. (Appendix 36) 36. The method of any one of claims 34 to 35, wherein the coating comprises one or more of PVA, glycerol monocaprylocaprate type 1, sodium lauryl sulfate, titanium dioxide, and talc. (Appendix 37) 37. The method of any one of claims 34 to 36, wherein the coating comprises one each of PVA, glycerol monocaprylocaprate type 1, sodium lauryl sulfate, titanium dioxide, and talc. (Appendix 38) 1. A process for preparing a bilayer tablet comprising ezetimibe and bempedoic acid, comprising the steps of: granulating a composition comprising ezetimibe and granulating a composition comprising bempedoic acid, each composition being granulated separately; blending the granulation of ezetimibe with pharma- ceutically acceptable excipients; blending the granules of bempedoic acid with a pharma- ceutically acceptable excipient; compressing the blend of ezetimibe and bempedoic acid into a single composition containing two distinct layers; and Coating the composition A method comprising: (Appendix 39) 40. The method of claim 38, further comprising drying the tablet. (Appendix 40) 40. The method of any one of claims 38 to 39, wherein the bempedoic acid composition comprises colloidal silicon dioxide, sodium stearyl fumarate, or magnesium stearate. (Appendix 41) The method of any one of claims 38 to 40, wherein the ezetimibe composition comprises an anionic surfactant. (Appendix 42) A kit comprising one or more granular compositions or pharmaceutical compositions or one or more tablets of the granular compositions or pharmaceutical compositions described in any one of the above appendices and instructions for use. (Appendix 43) The kit of claim 42, wherein the instructions for use describe a method or instructions for mixing one or more of the granular compositions or pharmaceutical compositions or one or more tablets with one or more compositions. (Appendix 44) 1. A method of treating or reducing the risk of cardiovascular disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising bempedoic acid, ezetimibe and pharmaceutically acceptable excipients mixed with a lubricant selected from the group consisting of colloidal silicon dioxide, sodium stearyl fumarate and magnesium stearate. (Appendix 45) 45. The method of claim 44, wherein the pharmaceutical composition comprises a fixed dose of bempedoic acid and a fixed dose of ezetimibe.

Claims

[Claim 1] The invention described in the specification.

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