Oral composition containing an Lp(a) inhibitor compound

Abstract

The present invention provides an oral composition comprising an Lp(a) inhibitor compound having a reduced level of nitrosamine. [Solution] An oral composition comprising muvalaprin and histidine is used, wherein novel polymorphs of muvalaprin, such as muvalaprin hydrate form A, muvalaprin hydrate form B, muvalaprin hemihydrate, and muvalaprin hydrate 1:6.5 molar equivalents, muvalaprin hemihydrate and / or muvalaprin hydrate 1:6.5 molar equivalents are used. Furthermore, the composition provides a method for treating cardiovascular disease, a method for treating atherosclerotic cardiovascular disease, and / or a method for lowering Lp(a) levels in an individual by administering one of the oral compositions.

Description

[Technical Field]

[0001] The present invention relates to an oral composition comprising an Lp(a) inhibitor compound, such as mubaraprin, and histidine. The present invention also relates to an oral composition comprising an Lp(a) inhibitor compound, histidine, and a reduced level of nitrosamine, such as less than 50 ppm of nitrosamine. The present invention also relates to a novel polymorph of mubaraprin, such as mubaraprin hydrate. The present invention also relates to an oral composition comprising an Lp(a) inhibitor compound such as mubaraprin and an excipient having a low nitrite content. [Background technology]

[0002] There have been dramatic advances in the treatment of cardiovascular disease (CVD). Despite these advances, patients continue to experience cardiovascular events such as angina, myocardial infarction, and stroke, which can be fatal if left untreated. Dyslipidemia remains a major risk factor for CVD. Dyslipidemia can be divided into four common risk factors: elevated low-density lipoprotein cholesterol (LDL-c), decreased high-density lipoprotein cholesterol (HDL-c), elevated triglycerides (TG), and elevated lipoprotein(a) (Lp(a)). There are various treatment regimens targeting elevated LDL-c, decreased HDL-c, and elevated triglycerides. There are few approved treatment options for patients with elevated Lp(a) levels. In some cases, apheresis can be used to filter the blood and remove LDL and Lp(a), however, its effect is temporary and typically needs to be repeated every two weeks. Proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors reduce Lp(a) by about 25%, and niacin reduces Lp(a) moderately, but neither is approved for Lp(a) reduction. There are no approved drug treatments to lower Lp(a) levels. The physiological function of Lp(a) is complex, but elevated Lp(a) plasma levels have been reported to be an independent risk factor for CVD.

[0003] Lp(a) can exhibit both prothrombus-forming and antithrombotic properties, as well as both atherosclerotic and atherothrombotic properties. Lp(a) inhibits fibrinolysis and can accumulate in the vascular wall, inducing thrombus formation and atherosclerotic lesions. Plasma levels of Lp(a) vary substantially among individuals. Unlike other risk factors, Lp(a) plasma levels are not significantly altered by diet and exercise. Lp(a) plasma levels are primarily determined by genetic predisposition.

[0004] Lp(a) is similar to LDL-c in that it contains an LDL lipid core with an associated apolipoprotein B (apoB), but unlike LDL-c, Lp(a) also contains an intrinsic apolipoprotein (a) (apo(a)) covalently bonded to apoB via a disulfide bond. apo(a) is synthesized in the liver. Aggregations of apo(a) and Lp(a) from LDL particles can occur in hepatocytes, on the cell wall, or in plasma. Inhibition of LDL particle aggregation with apo(a) can lower Lp(a) levels.

[0005] It has been previously reported, such as in U.S. Patent No. 11,286,249, that Lp(a) levels can be reduced using certain pyrrolidine compounds such as (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]aminomethyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid or mubaraprin.

[0006] However, certain secondary amines, such as nitrogen atoms in unsubstituted pyrrolidine compounds, can react under certain conditions to form nitrosamine functional groups. N-nitrosamines (commonly referred to as nitrosamines) are, according to the International Agency for Research on Cancer, an agency within the World Health Organization, likely to be carcinogens. Therefore, there is a need for oral compositions containing Lp(a) inhibitor compounds with reduced levels of nitrosamines, such as less than 50 ppm, without affecting other pharmaceutically relevant properties of the oral composition, such as the decay time or overall stability of the composition.

[0007] In addition, while Lp(a) inhibitor compounds such as mubalaprine have already been reported in U.S. Patent No. 11,286,249, there is a need for alternative solid-state forms of Lp(a) inhibitor compounds such as mubalaprine that offer improved stability. [Overview of the Initiative]

[0008] Therefore, the present invention relates to an oral composition comprising an Lp(a) inhibitor compound and histidine. Unexpectedly, it has been found that the addition of histidine to the oral composition can result in an oral composition having reduced levels of nitrosamines without significantly affecting the disintegration time or overall stability of the oral composition.

[0009] In addition, the present invention relates to an oral composition comprising an Lp(a) inhibitor compound, histidine, and a bulking agent, such as microcrystalline cellulose, together with a small amount of nitrite. Unexpectedly, it has been found that adding a bulking agent together with a small amount of nitrite to the oral composition can result in an oral composition having reduced levels of nitrosamines.

[0010] In one embodiment, the herein provides an oral composition comprising (a) an Lp(a) inhibitor compound of the following formula

[0011] [Chemical formula] wherein, L is selected from the group consisting of -CH2NHCH2-, -CH2NH-, -NH-, -S-, -S(O)-, -S(O)2-, -O-, -OCH2-, -OCH2CH2O-, -NHSO2NH-,

[0012] [Chemical formula] selected from the group consisting of R 1 R 2 R 3 R 4 R 5 and R 6 are each independently selected from the group consisting of H and CH3, a compound, or a pharmaceutically acceptable salt thereof, an Lp(a) inhibitor compound, and (b) histidine, an oral composition.

[0013] In another aspect, provided herein is an oral composition comprising (a) an Lp(a) inhibitor compound of the following formula

[0014] [Chemical formula] or a pharmaceutically acceptable salt thereof, an Lp(a) inhibitor compound, and (b) histidine, an oral composition.

[0015] In a further aspect, provided herein is an oral composition comprising (a) an Lp(a) inhibitor compound of the following formula

[0016] [Chemical formula] Or an oral composition comprising (b) a pharmaceutically acceptable salt thereof and (b) about 1.0% to about 3.0% by weight of histidine in the oral composition, wherein the oral composition is a tablet and contains less than 50 ppm of nitrosamine.

[0017] In a further embodiment, the foregoing provides any one of the disclosed oral compositions for use in the treatment of cardiovascular disease in an individual.

[0018] In a further embodiment, the Specified Provision is a method for treating an individual having elevated Lp(a) levels, wherein the method comprises orally administering one of the disclosed oral compositions to the individual.

[0019] In a further embodiment, the Specified herein provides a method for treating an atherosclerotic cardiovascular disease in an individual, the method comprising orally administering one of the disclosed oral compositions to the individual.

[0020] The present invention also relates to novel polymorphs of mubaraprin, such as mubaraprin hydrate (morph A) and mubaraprin hydrate (morph B).

[0021] In one embodiment, the compound provided herein is the compound of the following formula.

[0022] [ka] That is the case.

[0023] In a further embodiment, the following compound is provided herein:

[0024] [ka] That is the case.

[0025] In a further embodiment, the herein provides a composition comprising mubaraprin hydrate. [Brief explanation of the drawing]

[0026] [Figure 1] The XPRD pattern for Example 2 is shown. [Figure 2] The SCXRD of Example 2 is shown. [Figure 3] The XPRD pattern for Example 3 is shown. [Figure 4] The SXRD of Example 3 is shown. [Modes for carrying out the invention]

[0027] The following section headings are provided for convenience only. In some cases, a compound may be included in one or more of the section headings listed below. For example, microcrystalline cellulose may be considered a bulking agent and / or binder.

[0028] Oral composition The present invention relates to an oral composition comprising an Lp(a) inhibitor compound and histidine. In addition, the oral composition may contain other optional components as described below.

[0029] The oral composition provided contains minimal levels of nitrosamine. As is known to those skilled in the art, compounds containing secondary amines, such as those containing pyrrolidine functional groups, can result in the formation of nitrosamine functional groups in the presence of nitrite (HONO). Nitrite can exist under acidic conditions, (1) in aqueous solutions and (2) in the presence of nitrite salts, and its suitability for pharmaceutical compositions can be found in many excipients known in the art. Unexpectedly, it has been found that the addition of histidine to the oral composition can result in minimizing and / or completely preventing the formation of nitrosamine by-products after the preparation of the oral composition.

[0030] In addition, unexpectedly, it was found that the level of nitrosamine by-products could be further reduced by minimizing the amount of nitrates present in the oral composition. For example, the amount of nitrosamine formation can be further reduced if other excipients are selected due to their low nitrite content.

[0031] Suitable oral compositions include those having reduced levels of nitrosamines. Reduced levels of nitrosamines may include less than 50 ppm, less than 25 ppm, less than 15 ppm, less than 12.5 ppm, about 1 ppb to about 50 ppm, about 1 ppb to about 25 ppm, about 1 ppb to about 15 ppm, about 1 ppb to about 12.5 ppm, about 0.5 ppm to about 50 ppm, about 0.5 ppm to about 25 ppm, about 0.5 ppm to about 15 ppm, or about 0.5 ppm to about 12.5 ppm. Other reduced levels of nitrosamines include oral compositions that are substantially nitrosamine-free, essentially nitrosamine-free, or nitrosamine-free.

[0032] As used herein, the term “substantially absent” means that the material shown in the composition is present in an amount of 0.05% or less, preferably 0.01% or less, and more preferably 0.001% or less, relative to the total weight of the composition.

[0033] As used herein, the term “essentially not present” means that the material shown is not intentionally added to the composition, or, preferably, is not present at an analytically detectable level, such as 1 ppb or 0.5 ppm for nitrosamines. It also means that the composition includes compositions in which the material shown is present only as an impurity among other substances that have been intentionally added.

[0034] The oral composition may be a tablet composition or a capsule composition.

[0035] Accordingly, a tablet composition comprising any one of the Lp(a) inhibitor compounds disclosed herein, histidine, and optionally one or more pharmaceutically acceptable excipients (e.g., volume expanders, disintegrants, binders, and / or lubricants) is disclosed herein.

[0036] Tablets can be manufactured by high-shear wet granulation. The high-shear wet granulation manufacturing process can be carried out by blending powders by diffusion, convection, or pneumatic mixing. The powders can be granulated by adding water, water and a nitrosamine inhibitor, water and a binder, or water, a binder, and a nitrosamine inhibitor to form granules. The grinding step can be carried out by impact, cutting, compression, sieving mill, or separator. After granulation, the powders can be dried by direct heating-stationary solid bed, direct heating-moving solid bed, direct heating-fluidized bed, indirect conduction heating-moving solid bed, or indirect conduction heating-stationary solid bed. The tablets can be compressed by gravity, power-assisted, or centrifugal tablet press. Core tablets can be film-coated using non-perforating or perforating coating systems. All processes can be carried out as batch processes or continuous processes.

[0037] Also disclosed herein are capsule compositions comprising any one of the Lp(a) inhibitor compounds and histidine. The capsule composition may include suitable capsules such as gelatin or hypromellose, with or without a gelling agent. The capsules may be of size 000, 00, 0, 1, or 2, depending on the total amount of added material.

[0038] Lp(a) inhibitor compounds The oral composition of the present invention comprises an Lp(a) inhibitor compound. The Lp(a) inhibitor compound can be used in combination with other oral composition compounds as described herein.

[0039] Suitable Lp(a) inhibitor compounds may include compounds of formula I, or pharmaceutically acceptable salts thereof, wherein L is -CH2NHCH2-, -CH2NH-, -NH-, -S-, -S(O)-, -S(O)2-, -O-, -OCH2-, -OCH2CH2O-, -NHSO2NH-,

[0040]

Chemical formula

[0041]

Chemical formula

[0042] In one embodiment, one of R1, R3, or R5, if present, is H. In another embodiment, each of R1, R3, and R5, if present, is H.

[0043] The Lp(a) inhibitor compound may also include a compound of formula II or a pharmaceutically acceptable salt thereof.

[0044]

Chemical formula

[0045] The Lp(a) inhibitor compound may also include a compound of formula III, IV, or V.

[0046]

Chemical formula

[0047] The present invention also discloses novel polymorphs of mubaraprin, such as mubaraprin hydrate (morph A) and mubaraprin hydrate (morph B).

[0048] Mubaraprin hydrate (form A) can be characterized by an XRPD pattern using CuKα radiation, having diffraction peaks (2θ°) as described in Table 1 below. In one embodiment, mubaraprin hydrate (form A) can be characterized by an XRPD pattern using CuKα radiation, having one or more diffraction peaks (2θ) selected from the group consisting of 14.3°±0.2°2θ and 4.7° and 9.5°±0.2°2θ. In another embodiment, mubaraprin hydrate (form A) can be characterized by an XRPD pattern using CuKα radiation, having diffraction peaks (2θ) at 4.7°, 9.5°, and 14.3°±0.2°2θ. In another embodiment, Example 2 can be characterized by an XRPD pattern using CuKα radiation, having diffraction peaks (2θ) at 4.7°, 9.5°, 14.3°, and 19.2°±0.2°2θ. In another embodiment, mubaraprine hydrate (morphology A) can be characterized by an XRPD pattern using CuKα radiation, having diffraction peaks (2θ) at 4.7°, 9.5°, 14.3°, 15.2°, 17.4°, and 19.2°±0.2°2θ.

[0049] Analysis of a single crystal of mubaraprin hydrate (morphology A) indicates that this material is a hemihydrate crystallized in monoclinic space group P21. Mubaraprin hydrate (morphology A) can be characterized by having unit cell parameters of approximately a=11.25 Å, b=18.21 Å, c=18.65 Å, α=90°, β=100.19°, and γ=90° at 100 Kelvin.

[0050] Mubaraprin hydrate (form B) can be characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ) as described in Table 3 below. In one embodiment, mubaraprin hydrate (form B) can also be characterized by an XRPD pattern using CuKα radiation having a diffraction peak (2θ) at 12.3°±0.2°2θ in combination with one or more peaks selected from the group consisting of 8.2° and 20.6°±0.2°2θ. In another embodiment, mubaraprin hydrate (form B) can also be characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ) at 8.2°, 12.3°, and 20.6°±0.2°2θ. In another embodiment, mubaraprin hydrate (morphology B) can also be characterized by an XRPD pattern using CuKα radiation, having diffraction peaks (2θ) at 8.2°, 12.3°, 16.4°, 20.6°, and 21.1°±0.2°2θ°.

[0051] Analysis of the single crystal (morphology B) of muvalaprine hydrate indicates that this material is a 6.5 mol equivalent hydrate crystallizing in monoclinic space group P21. Table 4 outlines the unit cell parameters and properties of the single crystal (morphology B) isolated from muvalaprine hydrate. Figure 4 shows the bonding scheme (hydrogen atoms have been omitted for clarity). The single crystal (morphology B) isolated from muvalaprine hydrate can be characterized by having unit cell parameters of approximately a=11.06 Å, b=18.52 Å, c=21.58 Å, α=90°, β=97.36°, and γ=90° at 100 Kelvin.

[0052] [ka]

[0053] [ka]

[0054] The oral composition may contain approximately 10 mg to approximately 240 mg, approximately 30 mg to approximately 240 mg, approximately 60 mg to approximately 240 mg, approximately 30 mg, approximately 60 mg, approximately 120 mg, or approximately 240 mg of the Lp(a) inhibitor compound. The oral composition may contain approximately 30% to approximately 50% by weight, approximately 35% to approximately 45% by weight, or approximately 45% by weight of the Lp(a) inhibitor compound of the oral composition.

[0055] Histidine The oral composition of the present invention contains histidine. The addition of histidine to the oral composition prevents and / or minimizes the formation of nitrosamine by-products after the preparation of the oral composition. In addition, surprisingly, it was found that the addition of histidine did not significantly affect other pharmaceutically relevant properties of the oral composition, such as decay time and / or overall stability.

[0056] The oral composition may contain histidine in amounts of approximately 0.1% to 5.0% by weight, approximately 0.25% to 5.0% by weight, 0.5% to 5.0% by weight, approximately 0.25% to 3.0% by weight, approximately 0.5% to 3% by weight, approximately 1.0% to 3.0% by weight, approximately 1.0% to 2.0% by weight, or approximately 1.5% by weight.

[0057] The oral composition may also contain approximately 1 mg to approximately 10 mg, approximately 1.125 mg to approximately 9 mg, approximately 1.125 mg, approximately 2.25 mg, approximately 4.5 mg, or approximately 9 mg of histidine.

[0058] Other nitrosamine inhibitors, such as ascorbic acid, sodium ascorbate, and / or bases, such as sodium bicarbonate, can also be used instead of or in addition to histidine. These nitrosamine inhibitors can act to prevent and / or minimize the formation of nitrosamine functional groups via a redox scavenging mechanism or by increasing the pH of the tablet. However, each of these possible alternatives is shown herein to affect either the disintegration time and / or the stability of the oral composition.

[0059] Volume expander The oral composition of the present invention may also contain a bulking agent. The bulking agent may be any compound added to the tablet to increase its size and volume. The bulking agent can ensure the tablet has appropriate physical properties, such as stability, hardness, and uniform drug distribution. In the absence of a bulking agent, the tablet may not hold together properly or may not disintegrate and dissolve as intended, which may affect the efficacy of the tablet.

[0060] Suitable bulking agents include lactose (e.g., spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose®, or Fast-FloC®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai®, or Solka-Floc®), other cellulose derivatives, sucrose, sorbitol, mannitol, dextrin, dextran, maltodextrin, dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugars, starch or modified starch (including potato starch, corn starch, and rice starch), calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, and / or sodium alginate.

[0061] The bulking agent may be microcrystalline cellulose. In one embodiment, the microcrystalline cellulose is a low-nitrite microcrystalline cellulose such as Avicel® PH LN. In another embodiment, the bulking agent is microcrystalline cellulose, and the microcrystalline cellulose has a nitrite content of 200 μg / kg or less.

[0062] The oral composition may contain an extender in an amount of approximately 25% to 75% by weight, approximately 40% to 50% by weight, or approximately 46.5% by weight of the oral composition.

[0063] The oral composition may contain a volume extender in amounts of approximately 30 mg to 300 mg, approximately 34.875 mg to 279 mg, approximately 34.875 mg, approximately 69.75 mg, approximately 139.5 mg, or approximately 279 mg.

[0064] Disintegrant The oral composition of the present invention may also contain a disintegrant. The disintegrant may be any compound added to the tablet formulation to break down (disintegrate) the tablet when placed in an aqueous environment such as the stomach of an individual requiring treatment.

[0065] Suitable disintegrants include magnesium aluminum silicate (Veegum HV), alginic acid, alginates, microcrystalline cellulose, hydroxypropyl cellulose, other cellulose derivatives, croscarmellose sodium, crospovidone, polaritrin potassium, sodium starch glycolate, starch, pregelatinized starch, or carboxymethyl starch (e.g., Primogel® and Explotab®).

[0066] In one embodiment, the disintegrant is croscarmellose sodium.

[0067] The oral composition may contain a disintegrant in an amount of about 1% to about 15% by weight, about 3% to about 10% by weight, about 3% by weight, about 5% by weight, or about 8% by weight of the oral composition.

[0068] The oral composition may also contain approximately 3 mg to 50 mg, approximately 6 mg to 48 mg, approximately 6 mg, approximately 11 mg, approximately 24 mg, or approximately 48 mg of disintegrant.

[0069] Binder The oral composition of the present invention may also contain a binder. The binder may be any compound added to the tablet composition to form granules in a dry or liquid form during wet granulation, or in a dry form during dry granulation, or to form directly compressed tablets.

[0070] Suitable binders include lactose (e.g., spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose®, or Fast-FloC®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai®, or Solka-Floc®), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substitution), and hydroxypropyl methylcellulose (HPMC) (e.g., Methocel E, F, and K, Shin-Etsu, Ltd's Metolose SH, e.g., 4,000 cps grade Methocel E and Metolose 60 SH, 4,000 cps grade Methocel F and Metolose 65 SH, 4,000, 15,000, and 100,000 cps grade Methocel). Examples include Metolose 90 SH grades K, and grades 4,000, 15,000, 39,000, and 100,000), methylcellulose polymers (e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, other cellulose derivatives, sucrose, dextrin, maltodextrin, starch or modified starch (including potato starch, corn starch, and rice starch), calcium lactate, calcium carbonate, acacia, sodium alginate, agar, carrageenan, gelatin, guar gum, pectin, polyethylene glycol, and / or povidone.

[0071] In one embodiment, the binder is hydroxypropyl cellulose.

[0072] The oral composition may contain a binder in an amount of about 1% to 5% by weight, about 2% to about 4% by weight, or about 3% by weight of the oral composition.

[0073] The oral composition may contain approximately 1 mg to approximately 20 mg, approximately 2.25 mg to approximately 18 mg, approximately 2.25 mg, approximately 4.5 mg, approximately 9 mg, or approximately 18 mg of a binder.

[0074] lubricant The oral composition of the present invention may also contain a lubricant. The lubricant may be any compound added to the formulation to reduce friction between the surface of the tablet and the cavity in the die wall in which the tablet is formed. The lubricant may be used to reduce wear and tear of the die and punch. The lubricant may be added directly to the tablet composition powder or as part of the manufacturing process.

[0075] Suitable lubricants include stearic acid, magnesium stearate, calcium stearate or other metal stearates, talc, wax, glycerides, light mineral oil, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycol, alkyl sulfates, sodium benzoate, magnesium silicate, talc, and / or colloidal silica.

[0076] In one embodiment, the lubricant is magnesium stearate.

[0077] The oral composition may contain a lubricant in an amount of about 0.5% to about 3% by weight or about 1% by weight of the oral composition.

[0078] The oral composition may also contain approximately 0.5 mg to 10 mg, approximately 0.75 mg to 6 mg, approximately 0.75 mg, approximately 1.5 mg, approximately 3 mg, or approximately 6 mg of a lubricant.

[0079] Method of using the oral composition Oral compositions, as disclosed herein, may also be used to treat conditions, disorders, and diseases.

[0080] In certain embodiments, the conditions, disorders, and diseases are selected from cardiovascular disease, elevated Lp(a) levels, and ASCVD. In further embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered to individuals having elevated Lp(a) levels that put them at risk of cardiovascular events. Individuals at risk of cardiovascular events or who are at risk of cardiovascular events include individuals with coronary artery disease (CAD), individuals with stroke, or individuals with risk equivalents of peripheral artery disease or ASCVD (familial hypercholesterolemia or type 2 diabetes).

[0081] The normal range for Lp(a) levels varies depending on the individual's ethnicity, as described in the European Heart Journal (2022) 43, 3925-3946. An elevated Lp(a) level is one that exceeds the normal range for that individual from the perspective of their ethnicity. In certain embodiments, an elevated Lp(a) level refers to an Lp(a) plasma level of 75 nmol / L or higher, 125 nmol / L or higher, or 175 nmol / L or higher. In certain embodiments, an elevated Lp(a) level refers to an Lp(a) plasma level of 30 mg / dL or higher, 50 mg / dL or higher, or 70 mg / dL or higher. Both nmol / L and mg / dL are widely recognized and used as units of measurement for Lp(a) plasma levels.

[0082] In one embodiment, a method is provided for treating or preventing coronary artery disease in an individual, the method comprising orally administering one of the disclosed oral compositions to an individual in need thereof.

[0083] In one embodiment, a method is provided for preventing cardiovascular death, myocardial infarction, emergency coronary revascularization, death from any cause or ischemic stroke in an individual having elevated Lp(a) levels, the method comprising orally administering one of the oral compositions disclosed herein to an individual in need thereof.

[0084] In one embodiment, a method for treating acute coronary syndrome in an individual is provided, the method comprising orally administering one of the oral compositions disclosed herein to an individual in need thereof.

[0085] In one embodiment, a method is provided for reducing cardiovascular events in an individual having ASCVD and elevated Lp(a) levels, the method comprising orally administering one of the oral compositions disclosed herein to an individual in need thereof.

[0086] In one embodiment, a method is provided for treating cardiovascular disease in an individual, the method comprising orally administering one of the oral compositions disclosed herein to an individual in need thereof, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases to at least 150 nmol / L after 12 weeks of treatment.

[0087] In one embodiment, a method is provided for treating an individual having elevated Lp(a) levels, the method comprising orally administering one of the oral compositions disclosed herein to an individual in need thereof, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher prior to treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases to at least 150 nmol / L after 12 weeks of treatment.

[0088] In one embodiment, a method is provided for treating an individual having elevated Lp(a) levels at risk of cardiovascular events, the method comprising orally administering one of the oral compositions disclosed herein to an individual in need thereof, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher prior to treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases to at least 150 nmol / L after 12 weeks of treatment.

[0089] In one embodiment, a method is provided for treating ASCVD in an individual, the method comprising orally administering one of the oral compositions disclosed herein to an individual in need thereof, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases to at least 150 nmol / L after 12 weeks of treatment.

[0090] In one embodiment, a method for treating an individual having elevated Lp(a) levels, wherein this method is i. A step of measuring the individual's Lp(a) plasma level, ii. A method is provided comprising the step of orally administering one of the oral compositions disclosed herein to an individual if the individual has an Lp(a) plasma level of 175 nmol / L or higher.

[0091] In one embodiment, there is one of the oral compositions disclosed herein for use in the treatment or prevention of coronary artery disease in an individual.

[0092] In one embodiment, one of the oral compositions disclosed herein is provided for use in preventing cardiovascular death, myocardial infarction, emergency coronary revascularization, death from any cause, or ischemic stroke in an individual having elevated Lp(a) levels.

[0093] In one embodiment, one of the oral compositions disclosed herein is provided for use in the treatment of acute coronary syndrome in an individual.

[0094] In one embodiment, there is one of the oral compositions disclosed herein for use in reducing cardiovascular events in individuals having ASCVD and elevated Lp(a) levels.

[0095] In one embodiment, an oral composition is provided for use in the treatment of cardiovascular disease in an individual, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases to at least 150 nmol / L after 12 weeks of treatment.

[0096] In one embodiment, an oral composition is provided for use in treating an individual having elevated Lp(a) levels, wherein the compound is administered orally, and the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases to at least 150 nmol / L after 12 weeks of treatment.

[0097] In one embodiment, an oral composition is provided for use in the treatment of an individual having elevated Lp(a) levels at risk of cardiovascular events, wherein the compound is administered orally, and the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases to at least 150 nmol / L after 12 weeks of treatment.

[0098] In one embodiment, an oral composition is provided for use in the treatment of ASCVD in an individual, wherein the compound is administered orally and the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases to at least 150 nmol / L after 12 weeks of treatment.

[0099] In one embodiment, one of the oral compositions disclosed herein for use in treating an individual having elevated Lp(a) levels, wherein this treatment is i. A step of measuring the individual's Lp(a) plasma level, ii. If the individual has an Lp(a) plasma level of 175 nmol / L or higher, an oral composition is provided, comprising the step of orally administering one of the oral compositions disclosed herein to the individual.

[0100] As used herein, “approximately” means within a statistically significant range of one or more values, such as concentration, length, molecular weight, pH, sequence identity, time frame, temperature, or volume. “Approximately” can also mean ±10%, or have the same rounding to a particular value; for example, the expression “approximately 200°C” is interpreted as having the same rounding to “200°C”.

[0101] As used herein, “the individual in need of it” means a mammal, such as a human, having a condition, disease, disorder, or symptom in need of treatment or therapy, including, for example, those listed herein. Specifically, the preferred individual to be treated is a human.

[0102] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that is acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and general methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and SMBerge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. Salt formation can be carried out by adding a pharmaceutically acceptable acid to form an acid addition salt, or by adding a pharmaceutically acceptable base to form a base addition salt. Salts may also be formed simultaneously with the deprotection of nitrogen or oxygen, i.e., the removal of a protecting group. Examples, reactions, and conditions for salt formation are known to those skilled in the art.

[0103] As used herein, “to treat,” “treating,” “in order to treat,” etc., mean to slow, halt, or reduce the progression or severity of an existing condition, disease, disorder, or symptom.

[0104] Plasma levels of Lp(a) can be determined using commercially available immunoturbidimetric assays, such as those available from Randox Laboratories Ltd (RX SERIES LP 3403). Agglutination occurs due to an antigen-antibody reaction between Lp(a) in the sample and anti-Lp(a) antibodies adsorbed to latex particles. This agglutination is detected as a change in absorbance at 700 nm, which is proportional to the concentration of Lp(a) in the sample. [Examples]

[0105] Preparation of Lp(a) inhibitor compounds Example 1 - (2S)-3-[3-[[Bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]aminomethyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid (Mubaraprin)

[0106] [ka] In a round-bottom flask, tert-butyl(3R)-3-[(1S)-1-[[3-[[bis[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidine-3-yl]-3-oxopropyl]phenyl]methyl]amino]methyl]phenyl]methyl]2-tert-butoxy-2-oxoethyl]pyrrolidine-1-carboxylate was prepared according to U.S. Patent No. 11,286,249 (499.3 g, 423.3 mmol), and combined with 1,4-dioxane (1997 mL) and hydrochloric acid solution (12 M in water, 529.1 mL, 15 equivalents). The mixture was stirred at 40°C for 1 hour and concentrated under high pressure to remove 1,4-dioxane and obtain an aqueous slurry. The mixture was filtered through a propylene filter to remove insoluble particles. The pH of the filtrate was adjusted to 9-10 using a NaOH solution (2M in water). The mixture was stirred overnight at room temperature. The resulting solid was slowly filtered using filter paper (slow filtration with low high pressure). The solid was washed with water and dried at 45°C under high pressure to obtain the title compound (281g, 88%) as a white solid. ES / MS (m / z): 711(M+H); 1H-NMR (500MHz, D2O)δ 7.33(t,J=7.6Hz,3H),7.27(d,J=7.8Hz,3H),7.13(d,J=7.8Hz,3H),7.09(s,3H),4.2 0(s,6H),3.54(dd,J=7.9,11.6Hz,3H),3.39-3.34(m,3H),3.23-3.17(m,3H),3.02-2 .98(m,3H),2.84(dd,J=4.6,13.7Hz,3H),2.76(dd,J=10.6,13.3Hz,3H),2.60(td,J= 9.9,4.8Hz,3H),2.48(td,J=17.3,9.6Hz,3H),2.12-2.07(m,3H),1.73-1.65(m,3H).

[0107] Example 2-(2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]aminomethyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid hydrate (mubaraprin hydrate, form A) Example 2 was prepared by placing Example 1 in a round-bottom flask with 2.75V water and 1.75V MeOH. A 1V KOH solution (0.24 g / g KOH / water) was added to the mixture at 40°C. The reaction mixture was heated to 75°C for 4 hours, or until completely dissolved. The solution was filtered through a liquid material filter and placed in a new round-bottom flask. The mixture was stirred at 60-90 RPM and heated to approximately 60°C.

[0108] A 0.25V 20% AcOH solution was added dropwise to the reaction mixture and stirred for 2 hours. A 0.72V 5% AcOH solution was added dropwise to the reaction mixture and stirred for a further 2 hours. A 0.28V 5% AcOH solution was added dropwise to the reaction mixture and stirred for a further 2 hours. A 1.4V 5% AcOH solution was added dropwise to the reaction mixture and stirred for a further 2 hours. A 0.92V 5% AcOH solution was added to the reaction mixture and stirred for a further 2 hours. If necessary, the pH of the mixture was adjusted by adding further aliquots of 5% AcOH until the pH was 7.5-7.8. The solution was cooled to 20°C at a rate of 15°C / hour. Crystalline solid crystallized from the solution. The crystalline material was isolated and dried. Yield: 87%.

[0109] Example 2 could be characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ°) as described in Table 1 below. In one embodiment, Example 2 can be characterized by an XRPD pattern using CuKα radiation having one or more diffraction peaks (2θ) selected from the group consisting of 14.3°±0.2°2θ and 4.7° and 9.5°±0.2°2θ. In another embodiment, Example 2 can be characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ) at 4.7°, 9.5°, and 14.3°±0.2°2θ. In yet another embodiment, Example 2 can be characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ) at 4.7°, 9.5°, 14.3°, and 19.2°±0.2°2θ. In another embodiment, Example 2 can be characterized by an XRPD pattern using CuKα radiation, having diffraction peaks (2θ) at 4.7°, 9.5°, 14.3°, 15.2°, 17.4°, and 19.2°±0.2°2θ.

[0110] Analysis of the single crystal of Example 2 indicates that this material is a hemihydrate crystallizing in monoclinic space group P21. Table 2 outlines the unit cell parameters and properties of Example 2. Figure 2 shows the bonding scheme (hydrogen atoms have been omitted for clarity). Example 2 can be characterized by having unit cell parameters of approximately a=11.25 Å, b=18.21 Å, c=18.65 Å, α=90°, β=100.19°, and γ=90° at 100 Kelvin.

[0111] [Table 1]

[0112] [Table 2]

[0113] Example 3-(2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]aminomethyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid hydrate (mubaraprin hydrate, form B) Example 3 was prepared by slurring Example 2 (mubaraprin hydrate, form A) in a 4:1 acetone:water mixture. Form B was stable enough to obtain an XRPD pattern only when the resulting polymorph was stored at 85% RH.

[0114] Example 3 can be characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ) as described in Table 3 below. In one embodiment, Example 3 can also be characterized by an XRPD pattern using CuKα radiation having a diffraction peak (2θ) at 12.3°±0.2°2θ in combination with one or more peaks selected from the group consisting of 8.2° and 20.6°±0.2°2θ. In another embodiment, Example 3 can also be characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ) at 8.2°, 12.3°, and 20.6°±0.2°2θ. In yet another embodiment, Example 3 can also be characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ) at 8.2°, 12.3°, 16.4°, 20.6°, and 21.1°±0.2°2θ°.

[0115] Analysis of the single crystal of Example 3 indicates that this material is a 6.5 mol equivalent hydrate crystallizing in monoclinic space group P21. Table 4 outlines the unit cell parameters and properties of Example 3. Figure 4 shows the bonding scheme (hydrogen atoms have been omitted for clarity). Example 3 can be characterized by having unit cell parameters of approximately a=11.06 Å, b=18.52 Å, c=21.58 Å, α=90°, β=97.36°, and γ=90° at 100 Kelvin.

[0116] [Table 3]

[0117] [Table 4]

[0118] Method for manufacturing oral compositions The tablet compositions in Tables 5 and 6 were manufactured by a typical high-shear wet granulation process, which includes powder safety screening, blending, granulation, wet grinding, drying, dry grinding, blending, tablet compression, and coating, all of which are well known to those skilled in the art. Components tested for inhibition of nitrosamine formation, such as histidine, ascorbic acid / ascorbate, and / or sodium bicarbonate, were incorporated into the tablets by using three different methods. The three methods are described as “addition drying,” “pretreatment MCC,” and “aqueous solution.”

[0119] The "addition and drying" method was completed by adding histidine, ascorbic acid / ascorbate, and / or sodium bicarbonate, along with all other excipients, to the granulator during the initial powder blending. This was followed by the other tablet manufacturing steps listed above.

[0120] The "pre-treated MCC" method was completed by dissolving histidine, ascorbic acid / ascorbate, and / or sodium bicarbonate in water and spraying the aqueous solution of the compound to be tested onto microcrystalline cellulose. It was then dried. The dried pre-treated MCC, along with all other excipients, was added to the granulator during the initial powder blending. This was followed by the other tablet manufacturing steps listed above.

[0121] The "aqueous solution" method was completed by dissolving and adding histidine, ascorbic acid / ascorbate, and / or sodium bicarbonate in water. Other excipients were added to the granulator and blended. The inhibitor and aqueous solution were then sprayed onto the powder as part of the granulation process. This was followed by the other tablet manufacturing steps listed above.

[0122] [Table 5] 1 Avicel(R) PH LN

[0123] [Table 6] a 30mg anhydride equivalent, b 60mg anhydride equivalent, c 120 mg anhydrous equivalent, and d 240mg anhydride equivalent

[0124] [Table 7] * The LOQ is 0.5 ppm.

[0125] [Table 8]

[0126] [Table 9]

[0127] Tables 5 and 6 show the oral compositions of this disclosure. Table 7 shows how well the oral compositions of Table 5 prevented nitrosamine formation after storage under accelerated conditions at 40°C and 75% RH. Formulation 1 did not contain the nitrosamine inhibitor tested, and its initial nitrosamine content was 0.191 ppm, and after 3 months of storage under accelerated conditions it was 3.51 ppm. Formulation 2 contained 1 wt% ascorbic acid added to the dried product, and its initial nitrosamine content was 0.222 ppm, and after 3 months of storage under accelerated conditions it was 0.253 ppm. Formulation 3 contained 1 wt% histidine added to the dried product, and its initial nitrosamine content was 0.390 ppm, and after 3 months of storage under accelerated conditions it was 1.06 ppm. Formulation 6 contained 1% by weight sodium ascorbate added and dried. The initial nitrosamine content was 0.245 ppm, and after storage for 3 months under accelerated conditions, it was 0.370 ppm. Formulation 7 contained 2% by weight sodium bicarbonate added and dried. The initial nitrosamine content was 0.312 ppm, and after storage for 3 months under accelerated conditions, it was 0.173 ppm. In addition, Formulation 9 contained histidine as an aqueous solution, and the initial nitrosamine content and the nitrosamine content after storage for 1 month under accelerated conditions were below the detection limit. Therefore, all four test compounds (histidine, ascorbic acid, sodium ascorbate, and sodium bicarbonate) resulted in nitrosamine inhibition compared to the tested control sample (Form 1).

[0128] Table 8 shows the disintegration times of the oral compositions in Table 5. Formulation 1 yielded an initial disintegration time of 2.84 minutes and a disintegration time of 4.97 minutes after 1 month of storage under accelerated storage conditions. Formulation 2 (1 wt% ascorbic acid) yielded an initial disintegration time of 5.51 minutes and a disintegration time of 15.27 minutes after 1 month of storage under accelerated storage conditions. Formulation 3 (1 wt% histidine) yielded an initial disintegration time of 5.82 minutes and a disintegration time of 4.49 minutes after 1 month of storage under accelerated storage conditions. Formulation 7 (2 wt% sodium bicarbonate) yielded an initial disintegration time of 6.78 minutes and a disintegration time of 34.44 minutes after 1 month of storage under accelerated storage conditions. Formulations containing ascorbic acid or sodium bicarbonate yielded significantly longer disintegration times after 1 month of storage under accelerated storage conditions compared to the control (Formulation 1). Formulation 2 (1% by weight histidine) had a disintegration time comparable to the control formulation, indicating that histidine did not affect the tablet's disintegration time.

[0129] Table 9 shows the total related substances (A%) for the oral compositions in Table 5. Higher A% values ​​compared to the control indicated that the excipients and / or APIs were reacting with the tested nitrosamine inhibitors. Formulation 1 had an initial total related substances (A%) of 0.70 and a total related substances of 0.76 after 3 months under accelerated storage conditions. Formulation 2 (1 wt% ascorbic acid) had an initial total related substances (A%) of 1.33 and a total related substances of 1.55 after 3 months under accelerated storage conditions. Formulation 6 (1 wt% sodium ascorbate) had an initial total related substances (A%) of 0.79 and a total related substances of 0.92 after 1 month under accelerated storage conditions. Formulation 7 (2 wt% sodium bicarbonate) had an initial total related substances (A%) of 0.76 and a total related substances of 1.64 after 3 months under accelerated storage conditions. Formulations containing ascorbic acid, sodium ascorbate, and sodium bicarbonate showed significant degradation of the oral composition compared to the control.

[0130] Unexpectedly, the oral compositions containing histidine did not affect the physical properties of the tablets overall, while also preventing nitrosamine formation. The oral compositions containing histidine showed similar degradation of the oral compositions compared to the control formulation 1. For example, formulation 3 (1% by weight histidine) had an initial total related substance (A%) of 0.71 and a total related substance of 0.75 after 3 months under accelerated storage conditions. In addition, formulation 4 (1% by weight histidine added to microcrystalline cellulose as a pretreatment) had an initial total related substance (A%) of 0.71 and a total related substance of 0.61 after 2 months under accelerated storage conditions.

[0131] Surprisingly, overall, the addition of histidine resulted in the inhibition of nitrosamine formation without significantly affecting other pharmaceutically appropriate properties, such as overall tablet stability and / or the disintegration of the oral composition.

[0132] Method for determining the amount of nitrosamines in an oral composition The amount of nitrosamine in oral compositions containing Lp(a) inhibitor compounds was determined using each of the following methods. While we do not wish to be bound by theory, it is believed that each of the following methods can be used interchangeably to determine the amount of nitrosamine in the disclosed oral compositions within the range of normal analytical variability.

[0133] Nitrosamine method 1 - Acid method Lumos: LC-MS / MS assay development: Assay development was performed using an Agilent 1290 UPLC system and a Fusion Lumos tribrid mass spectrometer. A Zorbax SB-Phenyl (2.1 mm × 150 mm, 1.8 μm particle size) analytical column was used for analysis. A 3 μL injection volume was used, and the autosampler needle was washed before and after all sample injections. The column temperature was maintained at 40°C, and the autosampler temperature was maintained at 5°C. The mobile phase consisted of water (A) and methanol (B) containing 0.1% formic acid. The gradient was performed at a flow rate of 0.3 mL / min as follows: For the 13-minute method, a linear increase from 5% to 50% B was performed from 0 to 8 minutes, a linear increase from 50% to 95% B was performed from 8 to 9 minutes, a hold at 95% B was performed from 9 to 10 minutes, and then the process was terminated with a 3-minute re-equilibrium period at 5% B. After LC separation, the sample was analyzed using a fusion lumos tribrid mass spectrometer with the following parameters: 45 sheath gases (arbitrary units), 6 auxiliary gases (arbitrary units), 230°C vaporizer temperature, and 275°C ion transfer tube temperature. The experiment was performed using tMS with an orbit trap resolution of 60k, an isolation window of m / z 1.6, an RF lens (%) of 50, a microscan of 1, and negative ion mode (3.3kV). 2 This is an OT CID scan. Collision-induced dissociation was used for fragmentation at 28% collision energy.

[0134] Nitrosamine method 2 - Acid method 240: LC-MS / MS assay development: Assay development was performed using a Vanquish Horizon LC system and Exploris 240 mass spectrometer from Thermo Fisher Scientific (San Jose, CA). A Zorbax SB-Phenyl (2.1 mm × 150 mm, 1.8 μm particle size) analytical column was used for analysis. A 3 μL injection volume was used, and the autosampler needle was washed before and after all sample injections. The column temperature was maintained at 40°C, and the autosampler temperature was maintained at 5°C. The mobile phase consisted of water (A) and methanol (B) containing 0.1% formic acid. The gradient was performed at a flow rate of 0.3 mL / min as follows: For the 13-minute method, a linear increase from 5% to 50% B was performed from 0 to 8 minutes, a linear increase from 50% to 95% B was performed from 8 to 9 minutes, a hold at 95% B was performed from 9 to 10 minutes, followed by a 3-minute re-equilibrium period at 5% B to end the process. After LC separation, the sample was analyzed using an Exploris 240 orbitrap mass spectrometer with the following parameters: 40 sheath gases (arbitrary units), 6 auxiliary gases (arbitrary units), 230°C vaporizer temperature, and 275°C ion transfer tube temperature. The experiment was performed using tMS with a 120k orbitrap resolution, m / z² isolation window, 95% RF lens, 1 microscan, and negative ion mode (3.7kV). 2 This is a scan. Higher energy collisional dissociation was used for fragmentation at 40% of the collision energy.

[0135] Nitrosamine method 3 - Basic method 240: DOE sample LC-MS / MS assay development: Assay development was performed using a Vanquish Horizon LC system and an Exploris 240 mass spectrometer from Thermo Fisher Scientific (San Jose, CA). An Acquity Premier Protein BEH C4 (2.1 mm × 50 mm, 1.7 μm particle size) analytical column was used for analysis. A 3 μL injection volume was used, and the autosampler needle was washed before and after all sample injections. The column temperature was maintained at 35°C, and the autosampler temperature was maintained at 5°C. The mobile phase consisted of 0.01% TEA (A) and methanol (B). The gradient was performed at a flow rate of 0.3 mL / min as follows: For the 13-minute method, a linear increase from 5% to 40% B was performed from 0 to 5 minutes, a linear increase from 40% to 95% B was performed from 5 to 7 minutes, retention at 95% B was performed from 7 to 10 minutes, followed by a 3-minute re-equilibrium period at 5% B to end the process. After LC separation, the samples were analyzed using an Exploris 240 orbitrap mass spectrometer with the following parameters: 30 sheath gases (arbitrary units), 5 auxiliary gases (arbitrary units), 1 sweep gas (arbitrary units), 150°C vaporizer temperature, and 300°C ion transfer tube temperature. The experiment was performed using tMS with a 120k orbitrap resolution, m / z 1 isolation window, 90 RF lens (%), 5 microscan, and negative ion mode (3.2kV). 2 This is a scan. Higher energy collisional dissociation was used for fragmentation at 30% of the collision energy.

[0136] [Table 10] 1 Avicel(R) PH LN

[0137] [Table 11] * RL is 1.25 ppm

[0138] [Table 12] * RL is 1.25 ppm

[0139] Table 10 shows additional oral compositions of the present disclosure. Table 11 shows how much the oral formulations of Table 10 inhibited nitrosamine formation after storage under accelerated conditions of 35°C and 65% RH. Table 12 shows how much the oral formulations of Table 10 inhibited nitrosamine formation after storage under accelerated conditions of 40°C and 75% RH. Under both conditions, histidine reduced nitrosamine formation.

[0140] Additional analysis methods Powder X-ray diffraction (XRPD) XRPD patterns of crystalline solids are obtained using a Bruker D8 Endeavor X-ray powder diffractometer operating at 40 kV and 40 mA, equipped with a CuKα (1.5418 Å) source and a Linxeye detector. The sample is scanned at 4–42 2θ° with a step size of 0.009 2θ° and a scanning speed of 0.5 sec / step, using a 0.3° primary slit aperture and a 3.9° PSD aperture. Dry powder is packed into a quartz or silicon sample holder, and a smooth surface is obtained using a glass slide. Crystalline morphological diffraction patterns are collected at ambient temperature and relative humidity. Crystalline peak positions are determined by MDI-Jade after overall pattern shift based on an internal NIST 675 standard with peaks at 8.853 and 26.774 2θ°. In the field of crystallography, it is well known that for any crystalline form, the relative intensity of diffraction peaks may vary due to preferred orientations resulting from factors such as crystalline form and crystal habit. While peak intensity changes when a preferred orientation effect is present, the characteristic peak positions of the polymorph remain constant. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, in the field of crystallography, it is also well known that for any crystalline form, the angular peak positions may vary slightly. For example, peak positions may shift due to variations in the temperature at which the sample is analyzed, displacement of the sample, or the presence or absence of an internal standard. In this case, a peak position variation of ±0.2 2θ° is estimated to account for these potential variations without hindering the clear identification of the indicated crystalline form. Confirmation of the crystalline form can be performed based on any unique combination of characteristic peaks.

[0141] Single-crystal X-ray diffraction (SCXRD) SCXRD was performed using a Bruker D8 VENTURE dual-source diffractometer (serial K209362) equipped with a 3-circle goniometer and a Bruker PHOTON II CPAD detector, providing an average area resolution of 7.41 pixels / mm. CuKα radiation (λ=1.54178 Å) was used exclusively for all experiments. X-rays were generated by an Incoatec IμS 3.0 microfocus sealed X-ray tube with mirror optics, operating at 50 kV and 1 mA. Data acquisition was performed using φ and ω scans, with the sample mounted on a MiTeGen Nylon Loop or MicroMount using Grade A immersion oil, achieving a resolution of up to 0.78 Å. The resolution cutoff was highly dependent on the quality of the crystal being measured. Low-temperature experiments were performed using an open-flow N2 cold stream generated by an Oxford Cryostream 800, and all low-temperature measurements were fixed at 100 K.

[0142] Data acquisition was managed using APEX5 v2023.9-2, and cell refinement and data processing were performed using SAINT V8.40B (Bruker AXS LLC, 2019). Experimental multi-scan absorption correction was applied to twin data using either SADABS (2016 / 2) or TWINAB-2012 / 1. Structural analysis was performed using SHELXT 2018 / 2 or XM 2013 / 2 (Sheldrick, 2018), and then refined using SHELXL-2019 / 2 (Sheldrick, 2019) with ShelXle (CBHuebschle, 2011). The final published material was prepared using Mercury (CCDC, 2024).

[0143] Collapse The disintegration test was performed using purified water on uncoated or plain-coated tablets using the USP-NF standard. <701> The test was conducted according to the disintegration test procedure. The reported results are the average of three tablets.

[0144] Related substances A reversed-phase HPLC method was designed to determine the relevant substances in Examples 1-3. This was performed using a 4.6 mm × 150 mm Zorbax column (3.5 μm) set to 30°C. A multi-step gradient was used with 0.05% TFA in water as mobile phase A and 0.05% TFA in acetonitrile as mobile phase B, with a flow rate of 1.2 ml / min and a UV detector set to 215 nm.

Claims

1. Oral composition, (a) An Lp(a) inhibitor compound of the following formula, 【Chemistry 1】 During the ceremony, Lが、-CH ２ NHCH ２ -、-CH ２ NH-、-NH-、-S-、-S(O)-、 -S(O) ２ -、-O-、-OCH ２ -、-OCH ２ CH ２ O-、-NHSO ２ NH-、 【Chemistry 2】 Selected from the group consisting of, R １ 、R ２ 、R ３ 、R ４ 、R ５ 、and R ６ are each independently a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of H and CH ３ and an Lp(a) inhibitor compound (b) An oral composition comprising histidine.

2. R １ , R ３ , or R ５ The oral composition according to claim 1, wherein one of the is H if present.

3. R １ , R ３ , and R ５ The oral composition according to claim 1 or 2, wherein H is present.

4. The Lp(a) compound is the compound shown in the following formula, 【Transformation 3】 The oral composition according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. The Lp(a) compound is the compound shown below. 【Chemistry 4】 The oral composition according to claim 4.

6. The Lp(a) compound is the compound shown below. 【Transformation 5】 The oral composition according to claim 4.

7. The oral composition according to any one of claims 1 to 6, wherein the oral composition contains histidine in an amount of about 0.25 to about 5.0% by weight of the oral composition.

8. The oral composition according to any one of claims 1 to 7, wherein the oral composition contains histidine in an amount of about 0.5 to about 5.0% by weight of the oral composition.

9. The oral composition according to any one of claims 1 to 8, wherein the oral composition contains histidine in an amount of about 1.0% to about 3.0% by weight of the oral composition.

10. The oral composition according to any one of claims 1 to 9, wherein the oral composition contains histidine in an amount of about 1.0% to about 2.0% by weight of the oral composition.

11. The oral composition according to any one of claims 1 to 10, wherein the oral composition comprises about 1.5% by weight of histidine.

12. The oral composition according to any one of claims 1 to 11, wherein the oral composition contains less than 50 ppm of nitrosamine.

13. The oral composition according to any one of claims 1 to 12, wherein the oral composition contains less than 25 ppm of nitrosamine.

14. The oral composition according to any one of claims 1 to 13, wherein the oral composition contains less than 12.5 ppm of nitrosamine.

15. The oral composition according to any one of claims 1 to 14, wherein the oral composition does not contain a nitrosamine, is essentially free of a nitrosamine, or is substantially free of a nitrosamine.

16. The oral composition according to any one of claims 1 to 15, wherein the oral composition comprises a volume extender.

17. The oral composition according to claim 16, wherein the bulking agent comprises lactose, microcrystalline cellulose, other cellulose derivatives, sucrose, sorbitol, mannitol, dextrin, dextran, maltodextrin, dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starch or modified starch, calcium phosphate, calcium sulfate, calcium carbonate, or sodium alginate.

18. The oral composition according to claim 16 or 17, wherein the bulking agent comprises microcrystalline cellulose.

19. The oral composition according to any one of claims 16 to 18, wherein the oral composition comprises the filler in an amount of about 40% to about 50% by weight of the oral composition.

20. The oral composition according to claim 16, wherein the bulking agent contains less than 200 μg of nitrite per 1 kg of the bulking agent.

21. The oral composition according to any one of claims 1 to 20, wherein the oral composition comprises a disintegrant.

22. The oral composition according to claim 21, wherein the disintegrant comprises magnesium aluminum silicate, alginic acid, alginate, microcrystalline cellulose, hydroxypropyl cellulose, other cellulose derivatives, croscarmellose sodium, crospovidone, polaritrin potassium, sodium starch glycolate, starch, pregelatinized starch, or carboxymethyl starch.

23. The oral composition according to claim 21 or 22, wherein the oral composition comprises about 1% to about 15% by weight of the disintegrant.

24. The oral composition according to any one of claims 21 to 23, wherein the oral composition comprises about 3% to about 10% by weight of the disintegrant.

25. The oral composition according to any one of claims 1 to 24, wherein the oral composition comprises a binder.

26. The oral composition according to claim 25, wherein the binder comprises lactose, microcrystalline cellulose, hydroxypropyl cellulose, L-hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose polymer, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethylcellulose, other cellulose derivatives, sucrose, dextrin, maltodextrin, starch or modified starch, calcium lactate, calcium carbonate, acacia, sodium alginate, agar, carrageenan, gelatin, guar gum, pectin, polyethylene glycol, or povidone.

27. The oral composition according to claim 25 or 26, wherein the oral composition comprises about 1% to about 5% by weight of the binder.

28. The oral composition according to any one of claims 1 to 27, wherein the oral composition comprises a lubricant.

29. The oral composition according to claim 28, wherein the lubricant comprises stearic acid, magnesium stearate, calcium stearate or other metal stearate, talc, wax, glyceride, light mineral oil, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycol, alkyl sulfate, sodium benzoate, magnesium silicate, talc, or colloidal silica.

30. The oral composition according to claim 28 or 29, wherein the oral composition comprises about 0.5% to about 3% by weight of the lubricant.

31. The oral composition according to any one of claims 1 to 30, wherein the oral composition is a tablet or a capsule.

32. The oral composition according to any one of claims 1 to 31, wherein the oral composition is a tablet.

33. The oral composition according to claim 32, wherein the tablets are manufactured by dry granulation, wet granulation, or high-shear wet granulation.

34. The oral composition is (a) Lp(a) inhibitor compound, wherein the Lp(a) inhibitor compound is a compound of the following formula, 【Transformation 6】 An Lp(a) inhibitor compound, or a pharmaceutically acceptable salt thereof, (b) comprising about 1.0% to about 3.0% by weight of histidine in the oral composition, The oral composition according to claim 1, wherein the oral composition is a tablet and contains less than 50 ppm of nitrosamine.

35. The oral composition according to claim 34, wherein the oral composition comprises about 40% to about 50% by weight of microcrystalline cellulose.

36. The oral composition according to claim 34 or 35, wherein the oral composition comprises about 3% to about 10% by weight of croscarmellose sodium.

37. The oral composition according to any one of claims 34 to 36, wherein the oral composition comprises about 1% to about 5% by weight of hydroxypropyl cellulose.

38. The oral composition according to any one of claims 34 to 37, wherein the oral composition comprises about 0.5 to about 3% by weight of magnesium stearate.

39. The oral composition according to any one of claims 34 to 38, wherein the oral composition comprises 30 mg to 240 mg of the anhydrous equivalent of the Lp(a) inhibitor compound.

40. The oral composition according to any one of claims 34 to 39, wherein the oral composition comprises 30 mg, 60 mg, 120 mg, or 240 mg of the anhydrous equivalent of the Lp(a) inhibitor compound.

41. The following crystalline hydrated Lp(a) inhibitor compounds 【Transformation 7】 And, A crystalline hydrated Lp(a) inhibitor compound, wherein m is the molar equivalent of water molecules per Lp(a) inhibitor molecule, and m is a number between approximately 0.33 and approximately 10.

42. The crystalline hydrated Lp(a) inhibitor compound according to claim 41, wherein the compound is mubaraprin hydrate (form A), and the powder X-ray diffraction pattern using Cu Kα radiation is characterized in that the compound includes one or more peaks selected from the group consisting of a peak at 14.3°±0.2°2θ and peaks at 4.7° and 9.5°±0.2°2θ.

43. The crystalline hydrated compound according to claim 42, characterized by a powder X-ray diffraction pattern using Cu Kα radiation in which the compound has peaks at 4.7°, 9.5°, and 14.3°±0.2°2θ.

44. The crystalline hydrated compound according to claim 42 or 43, characterized by a powder X-ray diffraction pattern using Cu Kα radiation in which the compound has peaks at 4.7°, 9.5°, 14.3°, and 19.2°±0.2°2θ.

45. The crystalline hydrated compound according to any one of claims 42 to 44, characterized in that the compound has a powder X-ray diffraction pattern using Cu Kα radiation, with peaks at 4.7°, 9.5°, 14.3°, 15.2°, 17.4°, and 19.2°±0.2°2θ.

46. The crystalline hydrated compound according to any one of claims 42 to 45, characterized in that the compound has unit cell parameters of approximately a = 11.25 Å, b = 18.21 Å, c = 18.65 Å, α = 90°, β = 100.19°, and γ = 90° at 100 Kelvin.

47. The crystalline hydrated Lp(a) inhibitor compound according to claim 41, wherein the compound is mubaraprin hydrate (form B), and the powder X-ray diffraction pattern using Cu Kα radiation is characterized by the compound being combined with one or more peaks selected from the group consisting of 8.2° and 20.6°±0.2°2θ to include a peak at 12.3°±0.2°2θ.

48. The crystalline compound according to claim 47, characterized by a powder X-ray diffraction pattern using Cu Kα radiation in which the compound has peaks at 8.2°, 12.3°, and 20.6°±0.2°2θ.

49. The crystalline compound according to claim 47 or 48, characterized by a powder X-ray diffraction pattern using Cu Kα radiation in which the compound has peaks at 8.2°, 12.3°, 16.4°, 20.6°, and 21.1°±0.2°2θ°.

50. The crystalline compound according to any one of claims 47 to 49, characterized in that the compound has unit cell parameters of approximately a = 11.06 Å, b = 18.52 Å, c = 21.58 Å, α = 90°, β = 97.36°, and γ = 90° at 100 Kelvin.

51. An oral composition comprising a crystalline hydrate according to any one of claims 41 to 50.

52. An oral composition comprising the compound described in any one of claims 42 to 46.

53. An oral composition comprising the compound described in any one of claims 47 to 50.

54. Oral composition, (a) A compound according to any one of claims 42 to 46, (b) An oral composition comprising the compound according to any one of claims 47 to 50.

55. The oral composition according to any one of claims 51 to 54, wherein the oral composition comprises histidine.

56. An oral composition according to any one of claims 1 to 41 or 51 to 55, for use in the treatment of cardiovascular disease in an individual.

57. The oral composition according to claim 56, wherein the individual has an elevated Lp(a) plasma level.

58. The oral composition according to claim 56, wherein the cardiovascular disease is an atherosclerotic cardiovascular disease.

59. A method for treating an individual having an elevated Lp(a) level, the method comprising orally administering to the individual a composition according to any one of claims 1 to 41 or 51 to 55.

60. A method for treating atherosclerotic cardiovascular disease in an individual, the method comprising orally administering to the individual a composition according to any one of claims 1 to 41 or 51 to 55.

61. The method according to claim 60, wherein the individual has an Lp(a) plasma level of 75 nmol / L or higher before treatment.

62. The method according to claim 61, wherein the individual has an Lp(a) plasma level of 125 nmol / L or higher before treatment.

63. The method according to claim 62, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment.

64. The method according to any one of claims 60 to 63, wherein the individual is at risk of cardiovascular events.

65. Oral composition, (a) An Lp(a) inhibitor compound of the following formula, 【Transformation 8】 During the ceremony, Lが、-CH ２ NHCH ２ -、-CH ２ NH-、-NH-、-S-、-S(O)-、 -S(O) ２ -、-O-、-OCH ２ -、-OCH ２ CH ２ O-、-NHSO ２ NH-、 【Chemistry 9】 Selected from the group consisting of, R １ , R ２ , R ３ , R ４ , R ５ , and R ６ However, H and CH are independent of each other. ３ An Lp(a) inhibitor compound, which is a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following: (b) An oral composition comprising low nitrite microcrystalline cellulose.

66. The composition according to claim 65, further comprising histidine.

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