Pharmaceutical preparations

Abstract

A pharmaceutical formulation comprising Compound 1, one or more pharmaceutical fillers, one or more pharmaceutical disintegrants, and one or more pharmaceutical lubricants.

Description

[Technical Field]

[0001] (Related Applications) This application claims the benefit of priority from Chinese Patent Application No. 2022 / 116379, filed on August 31, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION This disclosure relates to pharmaceutical formulations comprising 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (Compound 1). This disclosure also relates to uses of the formulations in therapy, particularly in the treatment of heart failure with preserved ejection fraction (HFpEF) and chronic obstructive pulmonary disease (COPD), and methods of treatment that include administering the formulations. [Background technology]

[0003] 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (compound 1 (below)) is disclosed in International Patent Application No. 2016 / 087338.

[0004] [ka]

[0005] Compound 1 is highly adhesive and readily aggregates into large (0.5–1 mm) particles. A suitable formulation must have good manufacturability (the degree to which the product can be manufactured relatively easily with minimal cost and maximum reliability). This is because a robust process is required to deliver the product for late-stage clinical trials and commercial purposes. If the formulation is a tablet, the tablet must achieve adequate tensile strength without the application of high compression forces while maintaining acceptable tablet porosity. These factors minimize the risk of overcompression and variable dissolution rates; a suitable formulation must release its active ingredient in a uniform and acceptable manner. Finally, formulations for human use must use pharmaceutically acceptable excipients that meet regulatory requirements for long-term administration and be stable for a significant period of time, typically >1 year, ideally up to 3 years.

[0006] Described herein are pharmaceutical formulations of Compound 1 that meet these criteria and are suitable for commercial-scale manufacture. DETAILED DESCRIPTION OF THE INVENTION

[0007] Many embodiments are detailed throughout this specification and will be apparent to those skilled in the art, and this specification should not be construed as being limited to any particular embodiment described herein.

[0008] "a" means "at least one." In any embodiment where "a" is used to refer to a given material or element, "a" can mean one.

[0009] "Comprising" means that a given material or element may contain other materials or elements. In any embodiment where "comprising" is mentioned, the given material or element may be formed from at least 10% w / w, at least 20% w / w, at least 30% w / w, or at least 40% w / w of the given material or element. In any embodiment where "comprising" is mentioned, "comprising" can also mean "consisting of" (or "consists of") or "consisting essentially of" (or "consists essentially of") the given material or element.

[0010] "Consisting of" or "consists of" means that a given material or element is formed entirely from that material or element. In any embodiment in which "consisting of" or "consists of" is mentioned, the given material or element may be formed from 100% w / w material or element.

[0011] "Consisting essentially of" or "consists essentially of" means that a given material or element is made up almost entirely of that material or element. In any embodiment in which "consisting essentially of" or "consists essentially of" is referred to, the given material or element may be formed from at least 50% w / w, at least 60% w / w, at least 70% w / w, at least 80% w / w, at least 90% w / w, at least 95% w / w, or at least 99% w / w of the material or element.

[0012] "w / w" means weight / weight.

[0013] In any embodiment where "is" or "may be" is used to define a material or element, "is" or "may be" can mean that the material or element "consists of" or "consists essentially of" the material or element.

[0014] The claims are embodiments.

[0015] compound 1 Compound 1 is 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (disclosed in International Patent Application No. 2016 / 087338).

[0016] [ka]

[0017] In some embodiments, Compound 1 refers to the free base Compound 1.

[0018] In some embodiments, Compound 1 refers to a pharmaceutically acceptable salt of Compound 1.

[0019] In some embodiments, the pharmaceutical formulations described herein contain 1-10% w / w Compound 1.

[0020] In some embodiments, the pharmaceutical formulations described herein contain 10% w / w Compound 1.

[0021] In some embodiments, the pharmaceutical formulations described herein contain 5% w / w Compound 1.

[0022] In some embodiments, the pharmaceutical formulations described herein contain 2.5% w / w Compound 1.

[0023] Filler In some embodiments, the pharmaceutical formulations described herein comprise one or more pharmaceutically acceptable fillers. In further embodiments, the one or more pharmaceutically acceptable fillers are selected from mannitol, microcrystalline cellulose, and anhydrous dicalcium phosphate.

[0024] In certain embodiments, the pharmaceutical formulations described herein comprise about 80-95% w / w of one or more pharmaceutically acceptable fillers, including all values ​​and subranges therebetween, e.g., about 80-85% w / w; about 80-90% w / w; about 80-92%; about 82-87% w / w; about 82-90% w / w; about 82-92% w / w; about 82-95% w / w; about 85-87% w / w; about 85-90% w / w; about 85-92% w / w. about 85-95% w / w; about 87-90% w / w; about 87-92% w / w; about 87-95% w / w; about 89-92% w / w; about 89-95% w / w; about 91-93% w / w; about 91-95%, about 83%, about 84%, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w, about 91% w / w, about 92% w / w, about 93% w / w, about 94% w / w, and about 95% w / w.

[0025] Mannitol Mannitol has the chemical formula: CH 14 Mannitol is a polyol (sugar alcohol) with O6. Mannitol can be used as a bulking agent.

[0026] In some embodiments, the pharmaceutical formulations described herein comprise mannitol having an average particle size of about 50-300 μm.

[0027] In some embodiments, the pharmaceutical formulations described herein comprise mannitol having an average particle size of about 100-200 μm.

[0028] In some embodiments, the pharmaceutical formulations described herein comprise mannitol having an average particle size of about 100 μm.

[0029] In some embodiments, the pharmaceutical formulations described herein comprise mannitol having an average particle size of about 200 μm.

[0030] In certain embodiments, the pharmaceutical formulations described herein comprise about 20-75% w / w mannitol, including all values ​​and subranges therebetween, such as 20-30% w / w; 20-40% w / w; 20-50% w / w; 20-60% w / w; 20-70% w / w; 30-40% w / w; 30-50% w / w; 30-60% w / w; 30-75% w / w; 40-50% w / w; 40-60% w / w; 40-75% w / w; 50-60% w / w; 50-75% w / w; 60-75% w / w; and 65-75% w / w.

[0031] In certain embodiments, the pharmaceutical formulations described herein comprise about 55% w / w mannitol. In some embodiments, the pharmaceutical formulations described herein comprise about 55% w / w mannitol having an average particle size of about 50-300 μm. In some embodiments, the pharmaceutical formulations described herein comprise about 55% w / w mannitol having an average particle size of about 100-200 μm. In some embodiments, the pharmaceutical formulations described herein comprise about 55% w / w mannitol having an average particle size of about 200 μm. In some embodiments, the pharmaceutical formulations described herein comprise about 55% w / w mannitol having an average particle size of about 100 μm.

[0032] In certain embodiments, the pharmaceutical formulations described herein comprise 55% w / w mannitol. In some embodiments, the pharmaceutical formulations described herein comprise 55% w / w mannitol having an average particle size of about 50-300 μm. In some embodiments, the pharmaceutical formulations described herein comprise 55% w / w mannitol having an average particle size of about 100-200 μm. In some embodiments, the pharmaceutical formulations described herein comprise 55% w / w mannitol having an average particle size of about 200 μm. In some embodiments, the pharmaceutical formulations described herein comprise 55% w / w mannitol having an average particle size of about 100 μm.

[0033] Microcrystalline cellulose Microcrystalline cellulose (MCC) can also be used as a filler. Microcrystalline cellulose is available in various grades and particle sizes. It can also be called powdered cellulose, cellulose gum, or carboxymethyl cellulose.

[0034] In some embodiments, microcrystalline cellulose refers to microcrystalline cellulose having a median particle size of about 40-200 μM.

[0035] In some embodiments, microcrystalline cellulose refers to microcrystalline cellulose having a median particle size of about 80-120 μM.

[0036] In some embodiments, microcrystalline cellulose refers to microcrystalline cellulose having a median particle size of about 100 μM.

[0037] In some embodiments, microcrystalline cellulose refers to Avicel® PH-102 microcrystalline cellulose.

[0038] In some embodiments, the pharmaceutical formulations described herein contain 20-50% w / w microcrystalline cellulose.

[0039] In some embodiments, the pharmaceutical formulations described herein contain 30-40% w / w microcrystalline cellulose.

[0040] In some embodiments, the pharmaceutical formulations described herein comprise 30-36% w / w microcrystalline cellulose.

[0041] In some embodiments, the pharmaceutical formulations described herein comprise 33-34% w / w microcrystalline cellulose.

[0042] In some embodiments, the pharmaceutical formulations described herein comprise about 33.5% w / w microcrystalline cellulose.

[0043] In some embodiments, the pharmaceutical formulations described herein comprise 33.5% w / w microcrystalline cellulose.

[0044] In some embodiments, microcrystalline cellulose refers to European Pharmacopoeia standard microcrystalline cellulose.

[0045] In some embodiments, microcrystalline cellulose refers to Japanese Pharmacopoeia standard microcrystalline cellulose.

[0046] In some embodiments, microcrystalline cellulose refers to United States Pharmacopoeia standard microcrystalline cellulose.

[0047] Dibasic calcium phosphate anhydrous (DCPA) Dicalcium phosphate anhydrous (DCPA) has the chemical formula: CaHPO4. DCPA can be used as a water-insoluble filler. DCPA is also known as calcium hydrogen phosphate and calcium phosphate salt (1:1).

[0048] In some embodiments, the pharmaceutical formulations described herein contain about 5-40% w / w anhydrous dicalcium phosphate.

[0049] In some embodiments, the pharmaceutical formulations described herein contain about 5-15% w / w anhydrous dicalcium phosphate.

[0050] In some embodiments, the pharmaceutical formulations described herein comprise about 10% w / w anhydrous dicalcium phosphate.

[0051] In some embodiments, the pharmaceutical formulations described herein contain about 20-30% w / w anhydrous dicalcium phosphate.

[0052] In some embodiments, the pharmaceutical formulations described herein comprise about 25% w / w anhydrous dicalcium phosphate.

[0053] In some embodiments, the pharmaceutical formulations described herein contain about 30-40% w / w anhydrous dicalcium phosphate.

[0054] In some embodiments, the pharmaceutical formulations described herein comprise about 36.5% w / w anhydrous dicalcium phosphate.

[0055] In some embodiments, the pharmaceutical formulations described herein comprise 36.5% w / w anhydrous dicalcium phosphate.

[0056] In some embodiments, anhydrous dicalcium phosphate refers to the European Pharmacopoeia standard anhydrous dicalcium phosphate.

[0057] In some embodiments, anhydrous dicalcium phosphate refers to anhydrous dicalcium phosphate according to the Japanese Pharmacopoeia standard.

[0058] In some embodiments, anhydrous dicalcium phosphate refers to USP standard anhydrous dicalcium phosphate.

[0059] Disintegrant In some embodiments, the pharmaceutical formulations described herein comprise one or more pharmaceutically acceptable disintegrants.

[0060] In some embodiments, the pharmaceutical formulations described herein comprise one or more pharmaceutically acceptable disintegrants selected from croscarmellose sodium and low-substituted hydroxypropyl cellulose.

[0061] In some embodiments, the pharmaceutical formulations described herein comprise croscarmellose sodium.

[0062] In some embodiments, the pharmaceutical formulations described herein comprise low-substituted hydroxypropyl cellulose.

[0063] Croscarmellose sodium Croscarmellose sodium, or sodium CMC, is a cross-linked polymer of sodium carboxymethylcellulose.

[0064] In some embodiments, the pharmaceutical formulations described herein contain 1-10% w / w croscarmellose sodium.

[0065] In some embodiments, the pharmaceutical formulations described herein contain 3-5% w / w croscarmellose sodium.

[0066] In some embodiments, the pharmaceutical formulations described herein contain about 4% w / w croscarmellose sodium.

[0067] In some embodiments, the pharmaceutical formulations described herein contain 4% w / w croscarmellose sodium.

[0068] Low-substituted hydroxypropyl cellulose Hydroxypropyl cellulose (HPC) is an ether of cellulose in which some of the hydroxyl groups in the repeating glucose units have been hydroxypropylated to form -OCH2CH(OH)CH3 groups. L-HPC is a low-substituted hydroxypropyl ether of cellulose in which a small proportion of the hydroxypropyl groups in the glucose units are substituted. Typically, L-HPC has a molar substitution of 0.2 to 0.4. L-HPC is available in various grades, including LH-11, LH-21, LH-22, LH-31, and LH-B1.

[0069] In some embodiments, the pharmaceutical formulations described herein contain 5-20% w / w low-substituted hydroxypropyl cellulose.

[0070] In some embodiments, the pharmaceutical formulations described herein contain 7.5-12.5% ​​w / w low-substituted hydroxypropyl cellulose.

[0071] In some embodiments, the pharmaceutical formulations described herein comprise about 10% w / w low-substituted hydroxypropyl cellulose.

[0072] In some embodiments, the pharmaceutical formulations described herein comprise 10% w / w low-substituted hydroxypropyl cellulose.

[0073] In some embodiments, the low-substituted hydroxypropyl cellulose is LH-21 grade low-substituted hydroxypropyl cellulose.

[0074] In some embodiments, the low-substituted hydroxypropyl cellulose is LH-31 grade low-substituted hydroxypropyl cellulose.

[0075] In some embodiments, the low-substituted hydroxypropyl cellulose is LH-B1 grade low-substituted hydroxypropyl cellulose.

[0076] In some embodiments, low-substituted hydroxypropyl cellulose refers to European Pharmacopoeia standard low-substituted hydroxypropyl cellulose.

[0077] In some embodiments, low-substituted hydroxypropyl cellulose refers to National Formulary standard low-substituted hydroxypropyl cellulose.

[0078] In some embodiments, low-substituted hydroxypropyl cellulose refers to low-substituted hydroxypropyl cellulose according to the Japanese Pharmacopoeia standard.

[0079] lubricant Magnesium stearate Magnesium stearate has the formula Mg(C 18 H 35 O2)2. It is used as a lubricant to reduce friction and is typically a white, water-insoluble powder.

[0080] In some embodiments, the pharmaceutical formulations described herein contain 1-3% w / w magnesium stearate.

[0081] In some embodiments, the pharmaceutical formulations described herein contain about 2% w / w magnesium stearate.

[0082] In some embodiments, the pharmaceutical formulations described herein contain 2% w / w magnesium stearate.

[0083] In some embodiments, magnesium stearate refers to United States Pharmacopoeia standard magnesium stearate.

[0084] In some embodiments, magnesium stearate refers to British Pharmacopoeia standard magnesium stearate.

[0085] In some embodiments, magnesium stearate refers to European Pharmacopoeia standard magnesium stearate.

[0086] In some embodiments, magnesium stearate refers to Japanese Pharmacopoeia standard magnesium stearate.

[0087] In some embodiments, magnesium stearate refers to Chinese Pharmacopoeia standard magnesium stearate.

[0088] Pharmacopoeia When pharmacopoeial standards are referred to herein, it should be understood that the standards are as published in the following editions of the pharmacopoeias:

[0089] [Table 1]

[0090] tablet In some embodiments, the pharmaceutical formulations described herein may be tablets.

[0091] In some embodiments, the pharmaceutical formulations described herein may be tablets for oral administration.

[0092] In some embodiments, the pharmaceutical formulations described herein may be immediate release tablets.

[0093] In some embodiments, the pharmaceutical formulations described herein may be administered daily.

[0094] In some embodiments, the pharmaceutical formulations described herein may be tablets that are administered daily.

[0095] In some embodiments, the pharmaceutical formulations described herein may be administered orally.

[0096] In some embodiments, the pharmaceutical formulations described herein may be orally administered tablets.

[0097] In some embodiments, the pharmaceutical formulations described herein may contain 1-10 mg of Compound 1.

[0098] In some embodiments, the pharmaceutical formulations described herein may contain 10 mg of Compound 1.

[0099] In some embodiments, the pharmaceutical formulations described herein may contain 5 mg of Compound 1.

[0100] In some embodiments, the pharmaceutical formulations described herein may contain 2.5 mg of Compound 1.

[0101] In some embodiments, the pharmaceutical formulation described herein can be a tablet containing 2.5 mg of Compound 1.

[0102] In some embodiments, the pharmaceutical formulation described herein can be a tablet containing 5 mg of Compound 1.

[0103] In some embodiments, the pharmaceutical formulation described herein can be a tablet containing 10 mg of Compound 1.

[0104] In some embodiments, the pharmaceutical formulations described herein comprise: Approximately 2.5% w / w of Compound 1 Approximately 55% w / w mannitol Approximately 36.5% w / w microcrystalline cellulose Approximately 4% w / w croscarmellose sodium It may contain about 2% w / w magnesium stearate.

[0105] In some embodiments, the pharmaceutical formulations described herein comprise: Approximately 2.5% w / w of Compound 1 Approximately 55% w / w mannitol Approximately 36.5% microcrystalline cellulose Approximately 4% w / w croscarmellose sodium It may contain about 2% magnesium stearate.

[0106] In some embodiments, the pharmaceutical formulations described herein comprise: 1-10% w / w of Compound 1; 45-60% w / w mannitol; 30-40% w / w microcrystalline cellulose; 3-5% w / w croscarmellose sodium; and It may contain 1-3% w / w magnesium stearate.

[0107] In some embodiments, the pharmaceutical formulations described herein comprise: 2.5% w / w Compound 1; 55% w / w mannitol; 36.5% w / w microcrystalline cellulose; 4% w / w croscarmellose sodium; and It may contain 2% w / w magnesium stearate.

[0108] In some embodiments, the pharmaceutical formulations described herein comprise: 2.5% w / w Compound 1; 55% w / w mannitol with an average particle size of about 100 μm; 36.5% w / w microcrystalline cellulose with a median particle size of approximately 100 μM; 4% w / w croscarmellose sodium; and It may contain 2% w / w magnesium stearate.

[0109] In some embodiments, the pharmaceutical formulations described herein comprise: 2.5 mg of Compound 1; 55 mg of mannitol; 36.5 mg microcrystalline cellulose; 4.0 mg croscarmellose sodium; and May contain 2.0 mg magnesium stearate.

[0110] In some embodiments, the pharmaceutical formulations described herein comprise: 5.0 mg of Compound 1; 110.0 mg mannitol; 73.0 mg microcrystalline cellulose; 8.0 mg croscarmellose sodium; and May contain 4.0 mg magnesium stearate.

[0111] coating In some embodiments, when the pharmaceutical formulation is in the form of a tablet, it may be advantageous to coat the tablet with a coating. The resulting coated tablet then comprises a tablet core and a coating. The coated tablet can aid the patient in swallowing the tablet. The color coating can aid in patient compliance and / or differentiation from other drugs, especially drugs administered as part of a combination therapy.

[0112] In some embodiments, the pharmaceutical formulations described herein may be coated tablets. When the tablet is a coated tablet, it should be understood that any % w / w value cited herein refers to the w / w composition of the tablet core.

[0113] In some embodiments, the pharmaceutical formulations described herein may be color-coated tablets.

[0114] In some embodiments, the pharmaceutical formulations described herein may be film-coated tablets.

[0115] In some embodiments, the pharmaceutical formulations described herein may be tablets coated with a film coating comprising a film-forming polymer. In further embodiments, the film-forming polymer is selected from hydroxypropylmethylcellulose (hypromellose, HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyvinylpolypyrrolidone (PVPP), and mixtures thereof. In further embodiments, the film-forming polymer is selected from HPMC, HPC, and mixtures thereof. In yet further embodiments, the film-forming polymer is HPMC.

[0116] In still further embodiments, the film coating further comprises a pigment such as titanium dioxide, yellow iron oxide, red iron oxide, triiron tetroxide, and mixtures thereof.

[0117] In some embodiments, the pharmaceutical formulations described herein may be colored film-coated tablets.

[0118] In some embodiments, the pharmaceutical formulations described herein may be white film-coated tablets.

[0119] In some embodiments, the pharmaceutical formulations described herein may be orange film-coated tablets.

[0120] In some embodiments, the coating is present at about 1.5-4.5% w / w, including all values ​​and subranges therebetween, including about 1.5-3.5% w / w, 1.5-2.5% w / w, 2-4% w / w, 2-3% w / w, 2.5-4.5% w / w, 2.5-3.5% w / w, 3-4% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7%, 2.8% w / w, 2.9% w / w, 3% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w, 3.7% w / w, 3.9% w / w, 3.9% w / w, and 4% w / w.

[0121] Treatment methods Prevention of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable. In particular, the association of MPO activity with disease has been implicated in numerous diseases, including those with inflammatory, cardiovascular, and / or neurological components, as well as neutrophil-driven diseases.

[0122] In some embodiments, there is provided a pharmaceutical formulation disclosed herein for use in a method of treatment of the human or animal body by therapy.

[0123] In some embodiments, methods are provided for treating diseases or conditions in a warm-blooded animal, such as a human, in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable, comprising administering to said animal an effective amount of a pharmaceutical formulation described herein.

[0124] In some embodiments, methods are provided for treating a disease or condition in a warm-blooded animal, such as a human, in which inhibition of the activity of the enzyme myeloperoxidase (MPO) is desirable, comprising administering to said animal an effective amount of a pharmaceutical formulation described herein.

[0125] In some embodiments, provided are methods for treating a disease or condition in a warm-blooded animal, such as a human, that involves an inflammatory, cardiovascular, and / or neurological component and / or a neutrophil-driven disorder, comprising administering to said animal an effective amount of a pharmaceutical formulation described herein.

[0126] In some embodiments, the present invention is directed to the treatment of autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), Methods for treating rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modifications, and / or type 2 diabetes are provided, which comprise administering to said animal an effective amount of a pharmaceutical formulation described herein.

[0127] In some embodiments, a method of treating coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and / or chemotherapy-induced cardiotoxicity in a warm-blooded animal such as a human is provided, comprising administering to said animal an effective amount of a pharmaceutical formulation described herein.

[0128] In some embodiments, methods are provided for treating Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and / or epilepsy in a warm-blooded animal, such as a human, comprising administering to said animal an effective amount of a pharmaceutical formulation described herein.

[0129] In some embodiments, provided are methods for treating heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, non-alcoholic steatohepatitis (NASH), or chronic obstructive pulmonary disease (COPD) in a warm-blooded animal such as a human, comprising administering to said animal an effective amount of a pharmaceutical formulation described herein.

[0130] In some embodiments, provided is a pharmaceutical formulation described herein comprising Compound 1 for use as a medicament.

[0131] In some embodiments, there is provided a pharmaceutical formulation described herein for use in therapy.

[0132] In some embodiments, there is provided a use of the pharmaceutical formulation described herein in the manufacture of a medicament for treating a disease or condition in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable.

[0133] In some embodiments, there is provided a use of the pharmaceutical formulation described herein in the manufacture of a medicament for treating a disease or condition in which inhibition of the activity of the enzyme myeloperoxidase (MPO) is desirable.

[0134] In some embodiments, there is provided a use of a pharmaceutical formulation described herein in the manufacture of a medicament for use in treating a disease or condition with an inflammatory, cardiovascular, and / or neurological component and / or a neutrophil-driven disorder.

[0135] In some embodiments, there is provided a use of a pharmaceutical formulation described herein in the manufacture of a medicament for use in the treatment of autoimmune disease, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, or type 2 diabetes.

[0136] In some embodiments, there is provided a use of a pharmaceutical formulation described herein in the manufacture of a medicament for use in the treatment of coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and / or chemotherapy-induced cardiotoxicity.

[0137] In some embodiments, there is provided a use of a pharmaceutical formulation described herein in the manufacture of a medicament for use in the treatment of Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and / or epilepsy.

[0138] In some embodiments, there is provided a use of a pharmaceutical formulation described herein in the manufacture of a medicament for use in the treatment of heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, non-alcoholic steatohepatitis (NASH), or chronic obstructive pulmonary disease (COPD) in a warm-blooded animal such as a human.

[0139] In some embodiments, there is provided a use of the pharmaceutical formulations described herein for use in the treatment of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable.

[0140] In some embodiments, there is provided a use of the pharmaceutical formulations described herein for use in the treatment of a disease or condition in which inhibition of the activity of the enzyme myeloperoxidase (MPO) is desirable.

[0141] In some embodiments, there is provided a use of the pharmaceutical formulations described herein for use in treating a disease or condition with an inflammatory, cardiovascular, and / or neurological component and / or a neutrophil-driven disorder.

[0142] In some embodiments, there is provided a use of the pharmaceutical formulations described herein for use in the treatment of autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), renal glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, or type 2 diabetes.

[0143] In some embodiments, there is provided a use of the pharmaceutical formulation described herein for use in the treatment of coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmia, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, atherosclerotic plaque rupture, abdominal aortic aneurysm, and / or chemotherapy-induced cardiotoxicity.

[0144] In some embodiments, there is provided a use of the pharmaceutical formulations described herein for use in the treatment of Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and / or epilepsy.

[0145] In some embodiments, there is provided a use of the pharmaceutical formulations described herein for use in treating heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, non-alcoholic steatohepatitis (NASH), or chronic obstructive pulmonary disease (COPD).

[0146] As used herein, the terms "treatment" and "treating," as used herein, refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay recurrence. [Brief explanation of the drawings]

[0147] [Figure 1] 1 illustrates the direct compression process described herein. [Figure 2A] Comparison of compression pressure (CP) versus tensile strength for variations 1, 2, 3, and 14. [Figure 2B] Compare the solid fraction versus compaction pressure (CP) of variants 1, 2, 3, and 14. [Figure 2C] The solid fraction versus tensile strength (TS) of variants 1, 2, 3, and 14 is compared. [Figure 3A] Comparing the compression pressure (CP) versus tensile strength of variants 5 and 10. [Figure 3B] Compare the solid fraction versus compaction pressure (CP) of variants 5 and 10. [Figure 3C] The solid fraction versus tensile strength (TS) of variants 5 and 10 is compared. [Figure 4A] Comparing the compression pressure (CP) versus tensile strength of variations 3, 7 and 11. [Figure 4B] Compare the solid fraction versus compaction pressure (CP) of variants 3, 7 and 11. [Figure 4C] The solid fraction versus tensile strength (TS) of variants 3, 7 and 11 is compared. [Figure 5A] The compression pressure (CP) versus tensile strength of variations 9 and 12 is compared. [Figure 5B] Compare the solid fraction versus compaction pressure (CP) of variants 9 and 12. [Figure 5C] The solid fraction versus tensile strength (TS) of variants 9 and 12 is compared. [Figure 6] The dissolution profiles of variants 1, 2, and 3 are compared. [Figure 7] The dissolution profiles of variants 5 and 10 are compared. [Figure 8] The dissolution profiles of variants 3, 11, and 15 are compared. [Figure 9] The dissolution profiles of variants 9, 12, and 15 are compared. [Figure 10A] 1 shows the dissolution profile of Variation 15 before and after coating. [Figure 10B] 1 shows the dissolution profile of Variation 15 before and after coating. [Figure 11]1 illustrates the coating process described herein. [Figure 12] The dissolution profiles of various film-coated tablets coated at 2% w / w are compared. [Figure 13] The dissolution profiles of various film-coated tablets coated at 4.5% w / w are compared. [Figure 14] The dissolution profiles of coated and uncoated tablets containing 2.5 mg of Compound 1 or 5 mg of Compound 1 are compared. [Example]

[0148] Compound 1 was prepared by the synthetic route disclosed in WO 2016 / 087338. The excipients used in the Examples and Results section are listed in Table 2.

[0149] [Table 2]

[0150] Example 1: Tablet production Tablets of Compound 1 described herein were manufactured using a dry process involving direct compression.

[0151] The formulations described in Tables 3-A and 3-B were prepared at 1 kg scale according to (or similar to) the procedure described below and summarized in Figure 1. Values ​​shown in the tables are % w / w.

[0152] 1. Compound 1 was blended with mannitol, and DCPA, if present, in an ERWEKA DKM (Double Cone Mixer), 11 L blender at approximately 200 revolutions, 20 rpm.

[0153] 2. The powder blend obtained from step 1 was sieved through a 600 μm screen in a Frewitt mill CW-150 at a milling speed of approximately 500 rpm.

[0154] 3. The milled powder blend was then blended with MCC, L-HPC, and / or croscarmellose sodium in an ERWEKA DKM (Double Cone Mixer), 11 L blender at approximately 200 revolutions at 20 rpm.

[0155] 4. The blend obtained from step 3 was then blended with magnesium stearate in an ERWEKA DKM (Double Cone Mixer), 11 L blender at approximately 200 revolutions and a speed of 20 rpm.

[0156] 5. Tablet compression was performed on a Korsch XL-100 equipped with appropriately sized oval or round tooling to prepare 400 mg (10 mg Compound 1), 200 mg (5 mg Compound 1), and 100 mg (2.5 mg Compound 1) tablets.

[0157] [Table 3]

[0158] [Table 4]

[0159] Example 2: Tablet testing Compression Profile All batches were compressed separately using a suitable rotary tablet press (e.g., Korsch XL100) with the same punch design (round 6 mm for 2.5 mg strength, round 8 mm for 5 mg strength, and oval 14 mm x 7 mm for 10 mg strength) under different compression forces. The breaking force and thickness of the produced tablets were characterized using a suitable hardness and thickness measuring device. The tensile strength was calculated in terms of the breaking force and dimensions of the produced tablets. The results are shown in Figures 2-5.

[0160] Compression profiles show tablet tensile strength as a function of applied compression force for every batch. The profiles are normalized to punch tip face area and tablet geometry, allowing a true comparison of formulation robustness independent of tablet size.

[0161] Dissolution Profile Dissolution profiles of tablets were performed according to the United States Pharmacopoeia and the European Pharmacopoeia using Apparatus II (paddle apparatus) in a pH 6.1 sodium phosphate (0.075 M) / citric acid (0.025 M) buffer at a stirring speed of 75 rpm. The concentration of Compound 1 was quantified by comparing the UV response at 290 nm with background correction at 400 nm of the dissolution sample to that of an external reference standard solution.

[0162] The dissolution profiles of the tablets were measured in USP medium at pH 6.1 using Method 2. Figures 6-9 compare the dissolution profiles of the various formulations.

[0163] Example 3: Coating Tablets with Variant 15 formulations containing 2.5 mg of Compound 1 and 5 mg of Compound 1 were film coated with an HPMC / HPC coating (Aquarius Prime White, BKN318005, Ashland) to a weight gain of 3.5% w / w of the uncoated tablet for the 5 mg tablets and 3.5% w / w of the uncoated tablet for the 2.5 mg tablets using standard pan coating techniques as shown in Figure 11. The dissolution profiles of the 5 mg coated tablets were measured in USP media at pH 6.1 using Method 2 described in Example 2. Figures 10A and 10B show the dissolution profiles of the uncoated and coated tablets, respectively.

[0164] Tablets containing 2.5 mg of compound 1 (total weight 100 mg, hereinafter referred to as "2.5 mg core tablet") and 5 mg of compound 1 (total weight 200 mg, hereinafter referred to as "5 mg core tablet") having the compositions shown in Table 4 were prepared according to Example 1.

[0165] [Table 5]

[0166] 5 mg core tablets were film coated with aqueous suspensions of the proprietary coatings listed in Table 5 for a weight gain of 2% or 4.5% w / w using standard pan coating techniques as shown in Figure 11.

[0167] [Table 6]

[0168] The dissolution profiles of the tablets were measured in USP medium at pH 6.1 using Method 2 described in Example 2. Figures 12 and 13 compare the dissolution profiles of the 2% w / w coating and the 4.5% coating, respectively.

[0169] The 2.5 mg core tablets were coated with Opadry 03K630008-CN Orange for a weight gain of 3.3%, and the 5 mg core tablets were coated with Opadry 03K630008-CN Orange for a weight gain of 2.8%. The dissolution profiles of the tablets were measured in USP media at pH 6.1 using Method 2 in Example 2, and the results are shown in Figure 14.

[0170] All references cited herein, including patents, patent applications, articles, textbooks, etc., and the references cited therein, to the extent they are not already cited, are incorporated herein by reference in their entirety for all purposes.

Claims

1. A pharmaceutical formulation comprising Compound 1, one or more pharmaceutical fillers, one or more pharmaceutical disintegrants, and one or more pharmaceutical lubricants, wherein Compound 1 is 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one. 【Chemical 1】 A pharmaceutical preparation.

2. 10. The pharmaceutical formulation of claim 1, wherein the one or more pharmaceutical fillers are selected from mannitol, anhydrous dicalcium phosphate, and microcrystalline cellulose.

3. 3. The pharmaceutical formulation of claim 1, wherein the one or more pharmaceutical disintegrants are selected from hydroxypropyl cellulose and croscarmellose sodium.

4. The pharmaceutical formulation according to any one of claims 1 to 3, wherein one of the pharmaceutical disintegrants is croscarmellose sodium.

5. 5. The pharmaceutical formulation of claim 4, comprising 3-5% w / w croscarmellose sodium.

6. 6. The pharmaceutical formulation of claim 5, comprising 4% w / w croscarmellose sodium.

7. The pharmaceutical formulation according to any one of claims 1 to 6, wherein one of the pharmaceutical lubricants is magnesium stearate.

8. 8. A pharmaceutical formulation according to claim 7, comprising 1-3% w / w magnesium stearate.

9. 9. A pharmaceutical formulation according to claim 8, comprising 2% w / w magnesium stearate.

10. 10. The pharmaceutical formulation according to any one of claims 1 to 9, wherein one of the pharmaceutical fillers is mannitol.

11. 11. The pharmaceutical formulation of claim 10, comprising 45-60% w / w mannitol.

12. 12. The pharmaceutical formulation of claim 11, comprising 55% w / w mannitol.

13. A pharmaceutical formulation according to any one of claims 1 to 12, wherein one of the pharmaceutical fillers is microcrystalline cellulose.

14. 14. A pharmaceutical formulation according to claim 13, comprising 30-40% w / w microcrystalline cellulose.

15. 15. A pharmaceutical formulation according to claim 14, comprising 36.5% w / w microcrystalline cellulose.

16. A pharmaceutical formulation comprising Compound 1, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, wherein Compound 1 is 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one. 【Chemistry 2】 A pharmaceutical preparation.

17. 17. The pharmaceutical formulation of claim 16, wherein Compound 1 is present at about 2.5% w / w, the mannitol is present at about 55% w / w, the microcrystalline cellulose is present at about 36.5% w / w, the croscarmellose sodium is present at about 4% w / w, and the magnesium stearate is present at about 2% w / w.

18. 18. The pharmaceutical formulation according to any one of claims 10 to 17, wherein the mannitol has an average particle size of about 100 μm.

19. 19. The pharmaceutical formulation of any one of claims 14 to 18, wherein the microcrystalline cellulose has a median particle size of about 100 μM.

20. 20. The pharmaceutical formulation of any one of claims 1 to 19, comprising 1 to 10 mg of compound 1.

21. 21. The pharmaceutical formulation of claim 20, comprising 2.5 mg of Compound 1.

22. 21. The pharmaceutical formulation of claim 20, comprising 5 mg of Compound 1.

23. 21. The pharmaceutical formulation of claim 20, comprising 10 mg of Compound 1.

24. The pharmaceutical formulation according to any one of claims 1 to 23, wherein the pharmaceutical formulation is a tablet.

25. 25. The pharmaceutical formulation of claim 24, wherein the tablet further comprises a film coating.

26. 26. The pharmaceutical formulation of claim 25, wherein the film coating comprises a polymer selected from hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyvinylpolypyrrolidone (PVPP), and mixtures thereof.

27. 27. The pharmaceutical formulation of claim 26, wherein the film coating comprises HPMC.

28. 28. The pharmaceutical formulation of any one of claims 25 to 27, wherein the film coating is present at about 2.5 to 3.5% w / w.

29. 30. A method of treating or reducing the risk of a disease or condition in which inhibition of the enzyme MPO is beneficial, said method comprising administering to a human suffering from or at risk of said disease or condition a pharmaceutical formulation according to any one of claims 20 to 28.

30. 30. The method of claim 29, wherein the disease or condition is heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, nonalcoholic steatohepatitis (NASH), or chronic obstructive pulmonary disease (COPD).

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