Pharmaceutical formulation

Abstract

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

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to PCT patent application No. PCT / CN2022 / 116379 filed on August 31, 2022, the entire text of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to a pharmaceutical preparation 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). The present specification also relates to the use of the preparation in therapy, in particular to the treatment of heart failure with preserved ejection fraction (HFpEF) and chronic obstructive pulmonary disease (COPD), and to a therapeutic method of administering the preparation. Background Art

[0004] 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (Compound 1 (hereinafter)) is disclosed in International Patent Application WO2016 / 087338.

[0005]

[0006] Compound 1 is very sticky and tends to agglomerate into large (0.5mm-1mm) particles. A suitable formulation must have good manufacturability (the degree to which the product can be manufactured relatively easily at minimal cost and maximum reliability) because a robust method is required to deliver products for late-stage clinical trials and commercial purposes. When the formulation is a tablet, the tablet must achieve suitable tensile strength without the need to apply high compressive forces while maintaining acceptable tablet porosity. These factors minimize the risk of over-compression and variable dissolution rates—a suitable formulation must release its active ingredient in a uniform and acceptable manner. Finally, formulations for human use must employ pharmaceutically acceptable excipients that meet regulatory requirements for chronic administration and must be stable over a meaningful period of time, typically more than 1 year and ideally up to 3 years.

[0007] The present specification describes a pharmaceutical formulation of Compound 1 that meets these criteria and is suitable for production on a commercial scale. DETAILED DESCRIPTION

[0008] Many embodiments are described in detail throughout the specification and will be apparent to those skilled in the art. The specification should not be construed as being limited to any of the enumerated embodiments.

[0009] “A” means “at least one.” In any embodiment where “a” is used to refer to a given material or element, “a” may mean one.

[0010] "Comprising" means that a given material or element may contain other materials or elements. In any embodiment referring to "comprising", a given material or element may be formed of at least 10% w / w, at least 20% w / w, at least 30% w / w, or at least 40% w / w of the material or element. In any embodiment referring to "comprising", "comprising" may also mean "consisting of" or "consisting essentially of" a given material or element.

[0011] "Consisting of" means that a given material or element is completely formed of that material or element. In any embodiment referring to "consisting of", the given material or element may be formed of 100% w / w of the material or element.

[0012] "Consisting essentially of means that a given material or element consists almost entirely of that material or element. In any embodiment referring to "consisting essentially of," the given material or element may be formed of 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.

[0013] "w / w" means weight / weight.

[0014] In any embodiments where "is" or "may be" are used to define a material or element, "is" or "may be" may mean that the material or element "consists of" or "consists essentially of" the material or element.

[0015] The claims are embodiments.

[0016] Compound 1

[0017] 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 WO2016 / 087338).

[0018]

[0019] In some embodiments, Compound 1 refers to the free base Compound 1.

[0020] In some embodiments, Compound 1 refers to a pharmaceutically acceptable salt of Compound 1.

[0021] In some embodiments, the pharmaceutical formulations described herein comprise 1% w / w-10% w / w Compound 1.

[0022] In some embodiments, the pharmaceutical formulations described herein comprise 10% w / w Compound 1.

[0023] In some embodiments, the pharmaceutical formulations described herein comprise 5% w / w Compound 1.

[0024] In some embodiments, the pharmaceutical formulations described herein comprise 2.5% w / w Compound 1.

[0025] filler

[0026] 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 calcium hydrogen phosphate.

[0027] In certain embodiments, the pharmaceutical formulations described herein comprise about 80% w / w-95% w / w of one or more pharmaceutically acceptable fillers, including all values ​​and subranges therebetween, such as about 80% w / w-85% w / w; about 80% w / w-90% w / w; about 80%-92%; about 82% w / w-87% w / w; about 82% w / w-90% w / w; about 82% w / w-92% w / w; about 82% w / w-95% w / w; about 85% w / w-87% w / w; about 85% w / w-90% w / w; about 85% w / w-92% w / w; about 85% w / w - 95% w / w; about 87% w / w - 90% w / w; about 87% w / w - 92% w / w; about 87% w / w - 95% w / w; about 89% w / w - 92% w / w; about 89% w / w - 95% w / w; about 91% w / w - 93% w / w; 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.

[0028] Mannitol

[0029] Mannitol has the chemical formula C6H 14 O6 polyols (sugar alcohols). Mannitol can be used as a filler.

[0030] In some embodiments, the pharmaceutical formulations described herein comprise mannitol having an average particle size between about 50 μm and 300 μm.

[0031] In some embodiments, the pharmaceutical formulations described herein comprise mannitol having an average particle size between about 100 μm and 200 μm.

[0032] In some embodiments, the pharmaceutical formulations described herein comprise mannitol having an average particle size of about 100 μm.

[0033] In some embodiments, the pharmaceutical formulations described herein comprise mannitol having an average particle size of about 200 μm.

[0034] In certain embodiments, the pharmaceutical formulations described herein comprise about 20% w / w-75% w / w of mannitol, including all values ​​and subranges therebetween, such as 20% w / w-30% w / w; 20% w / w-40% w / w; 20% w / w-50% w / w; 20% w / w-60% w / w; 20% w / w-70% w / w; 30% w / w-40% w / w; 30% w / w-50% w / w; 30% w / w-60% w / w; 30% w / w-70% w / w; 30% w / w-40% w / w; 30% w / w-5 ... %w / w-50%w / w; 30%w / w-60%w / w; 30%w / w-75%w / w; 40%w / w-50%w / w; 40%w / w-60%w / w; 40 % w / w to 75% w / w; 50% w / w to 60% w / w; 50% w / w to 75% w / w; 60% w / w to 75% w / w; and 65% w / w to 75% w / w.

[0035] In certain embodiments, the pharmaceutical preparations described herein comprise about 55% w / w mannitol. In some embodiments, the pharmaceutical preparations described herein comprise about 55% w / w mannitol with an average particle size between about 50 μm and 300 μm. In some embodiments, the pharmaceutical preparations described herein comprise about 55% w / w mannitol with an average particle size between about 100 μm and 200 μm. In some embodiments, the pharmaceutical preparations described herein comprise about 55% w / w mannitol with an average particle size of about 200 μm. In some embodiments, the pharmaceutical preparations described herein comprise about 55% w / w mannitol with an average particle size of about 100 μm.

[0036] In certain embodiments, the pharmaceutical preparations described herein comprise 55% w / w mannitol. In some embodiments, the pharmaceutical preparations described herein comprise 55% w / w mannitol with an average particle size between about 50 μm and 300 μm. In some embodiments, the pharmaceutical preparations described herein comprise 55% w / w mannitol with an average particle size between about 100 μm and 200 μm. In some embodiments, the pharmaceutical preparations described herein comprise 55% w / w mannitol with an average particle size of about 200 μm. In some embodiments, the pharmaceutical preparations described herein comprise 55% w / w mannitol with an average particle size of about 100 μm.

[0037] Microcrystalline Cellulose

[0038] Microcrystalline cellulose (MCC) can also be used as a filler. Microcrystalline cellulose comes in different grades and particle sizes. It may also be called powdered cellulose, cellulose gum, or carboxymethyl cellulose.

[0039] In some embodiments, microcrystalline cellulose refers to microcrystalline cellulose having a median particle size of about 40 μM-200 μM.

[0040] In some embodiments, microcrystalline cellulose refers to microcrystalline cellulose having a median particle size of about 80 μM-120 μM.

[0041] In some embodiments, microcrystalline cellulose refers to microcrystalline cellulose having a median particle size of about 100 μM.

[0042] In some embodiments, microcrystalline cellulose is PH-102 microcrystalline cellulose.

[0043] In some embodiments, the pharmaceutical formulations described herein comprise 20% w / w-50% w / w microcrystalline cellulose.

[0044] In some embodiments, the pharmaceutical formulations described herein comprise 30% w / w-40% w / w microcrystalline cellulose.

[0045] In some embodiments, the pharmaceutical formulations described herein comprise 30% w / w-36% w / w microcrystalline cellulose.

[0046] In some embodiments, the pharmaceutical formulations described herein comprise 33% w / w-34% w / w microcrystalline cellulose.

[0047] In some embodiments, the pharmaceutical formulations described herein comprise about 33.5% w / w microcrystalline cellulose.

[0048] In some embodiments, the pharmaceutical formulations described herein comprise 33.5% w / w microcrystalline cellulose.

[0049] In some embodiments, the microcrystalline cellulose refers to European Pharmacopoeia standard microcrystalline cellulose.

[0050] In some embodiments, the microcrystalline cellulose refers to microcrystalline cellulose of the Japanese Pharmacopoeia standard.

[0051] In some embodiments, the microcrystalline cellulose refers to USP standard microcrystalline cellulose.

[0052] Dicalcium Phosphate Anhydrous(DCPA)

[0053] Anhydrous dibasic calcium phosphate (DCPA) has the chemical formula: CaHPO4. DCPA can be used as a water-insoluble filler. DCPA is also known as dibasic calcium phosphate and calcium phosphate salt (1:1).

[0054] In some embodiments, the pharmaceutical formulations described herein comprise about 5% w / w-40% w / w anhydrous dibasic calcium phosphate.

[0055] In some embodiments, the pharmaceutical formulations described herein comprise about 5% w / w-15% w / w anhydrous dibasic calcium phosphate.

[0056] In some embodiments, the pharmaceutical formulations described herein comprise about 10% w / w anhydrous dibasic calcium phosphate.

[0057] In some embodiments, the pharmaceutical formulations described herein comprise about 20% w / w-30% w / w anhydrous dibasic calcium phosphate.

[0058] In some embodiments, the pharmaceutical formulations described herein comprise about 25% w / w anhydrous dibasic calcium phosphate.

[0059] In some embodiments, the pharmaceutical formulations described herein comprise about 30% w / w-40% w / w anhydrous dibasic calcium phosphate.

[0060] In some embodiments, the pharmaceutical formulations described herein comprise about 36.5% w / w anhydrous dibasic calcium phosphate.

[0061] In some embodiments, the pharmaceutical formulations described herein comprise 36.5% w / w anhydrous dibasic calcium phosphate.

[0062] In some embodiments, the anhydrous calcium hydrogen phosphate refers to anhydrous calcium hydrogen phosphate of the European Pharmacopoeia standard.

[0063] In some embodiments, the anhydrous calcium hydrogen phosphate refers to anhydrous calcium hydrogen phosphate of the Japanese Pharmacopoeia standard.

[0064] In some embodiments, the anhydrous dibasic calcium phosphate refers to anhydrous dibasic calcium phosphate of the United States Pharmacopoeia standard.

[0065] Disintegrants

[0066] In some embodiments, the pharmaceutical formulations described herein comprise one or more pharmaceutically acceptable disintegrants.

[0067] In some embodiments, the pharmaceutical formulations described herein comprise one or more pharmaceutically acceptable disintegrants selected from croscarmellose sodium and low-substituted hydroxypropyl cellulose.

[0068] In some embodiments, the pharmaceutical formulations described herein comprise croscarmellose sodium.

[0069] In some embodiments, the pharmaceutical formulations described herein comprise low-substituted hydroxypropyl cellulose.

[0070] Croscarmellose Sodium

[0071] Croscarmellose sodium (or sodium CMC) is a cross-linked polymer of sodium carboxymethylcellulose.

[0072] In some embodiments, the pharmaceutical formulations described herein comprise 1% w / w-10% w / w croscarmellose sodium.

[0073] In some embodiments, the pharmaceutical formulations described herein comprise 3% w / w-5% w / w croscarmellose sodium.

[0074] In some embodiments, the pharmaceutical formulations described herein comprise about 4% w / w croscarmellose sodium.

[0075] In some embodiments, the pharmaceutical formulations described herein comprise 4% w / w croscarmellose sodium.

[0076] Low substituted hydroxypropyl cellulose

[0077] Hydroxypropyl cellulose (HPC) is an ether of cellulose in which some of the hydroxyl groups in the repeating glucose units are hydroxypropylated to form -OCH2CH(OH)CH3 groups. L-HPC is a low-substituted hydroxypropyl ether of cellulose within a small fraction of the hydroxypropyl groups in the glucose units. Typically, L-HPC has a molar substitution of 0.2-0.4. L-HPC is available in various grades, including LH-11, LH-21, LH-22, LH-31, and LH-B1.

[0078] In some embodiments, the pharmaceutical formulations described herein comprise 5% w / w-20% w / w low-substituted hydroxypropylcellulose.

[0079] In some embodiments, the pharmaceutical formulations described herein comprise 7.5% w / w-12.5% ​​w / w low-substituted hydroxypropylcellulose.

[0080] In some embodiments, the pharmaceutical formulations described herein comprise about 10% w / w low-substituted hydroxypropylcellulose.

[0081] In some embodiments, the pharmaceutical formulations described herein comprise 10% w / w low-substituted hydroxypropylcellulose.

[0082] In some embodiments, the low-substituted hydroxypropyl cellulose is LH-21 grade low-substituted hydroxypropyl cellulose.

[0083] In some embodiments, the low-substituted hydroxypropyl cellulose is LH-31 grade low-substituted hydroxypropyl cellulose.

[0084] In some embodiments, the low-substituted hydroxypropyl cellulose is LH-B1 grade low-substituted hydroxypropyl cellulose.

[0085] In some embodiments, the low-substituted hydroxypropyl cellulose refers to low-substituted hydroxypropyl cellulose of European Pharmacopoeia standard.

[0086] In some embodiments, the low-substituted hydroxypropyl cellulose refers to low-substituted hydroxypropyl cellulose of national formula standards.

[0087] In some embodiments, the low-substituted hydroxypropyl cellulose refers to low-substituted hydroxypropyl cellulose of the Japanese Pharmacopoeia standard.

[0088] Lubricants

[0089] Magnesium Stearate

[0090] Magnesium stearate has the following formula: Mg(C 18 H 35 O2)2. It is used as a lubricant to reduce friction and is usually a white, water-insoluble powder.

[0091] In some embodiments, the pharmaceutical formulations described herein comprise 1% w / w-3% w / w magnesium stearate.

[0092] In some embodiments, the pharmaceutical formulations described herein comprise about 2% w / w magnesium stearate.

[0093] In some embodiments, the pharmaceutical formulations described herein comprise 2% w / w magnesium stearate.

[0094] In some embodiments, magnesium stearate refers to USP standard magnesium stearate.

[0095] In some embodiments, magnesium stearate refers to British Pharmacopoeia standard magnesium stearate.

[0096] In some embodiments, magnesium stearate refers to European Pharmacopoeia standard magnesium stearate.

[0097] In some embodiments, magnesium stearate refers to magnesium stearate of Japanese Pharmacopoeia standard.

[0098] In some embodiments, magnesium stearate refers to magnesium stearate of Chinese Pharmacopoeia standard.

[0099] Pharmacopoeia

[0100] In this document, when referring to a pharmacopoeial standard, it is to be understood that the standard is as published in the following pharmacopoeial editions:

[0101] Table 1: Pharmacopoeia Versions

[0102] Pharmacopoeia Version United States Pharmacopeia 43 British Pharmacopoeia 2020 Edition European Pharmacopoeia 10th Edition Japanese Pharmacopoeia 17th Edition Chinese Pharmacopoeia 2020 Edition National recipe 38

[0103] tablet

[0104] In some embodiments, the pharmaceutical formulations described herein may be tablets.

[0105] In some embodiments, the pharmaceutical formulations described herein may be tablets for oral administration.

[0106] In some embodiments, the pharmaceutical formulations described herein may be immediate release tablets.

[0107] In some embodiments, the pharmaceutical formulations described herein can be administered daily.

[0108] In some embodiments, the pharmaceutical formulations described herein may be tablets for daily administration.

[0109] In some embodiments, the pharmaceutical formulations described herein can be administered orally.

[0110] In some embodiments, the pharmaceutical formulations described herein may be tablets for oral administration.

[0111] In some embodiments, the pharmaceutical formulations described herein may contain 1 mg to 10 mg of Compound 1.

[0112] In some embodiments, the pharmaceutical formulations described herein may contain 10 mg of Compound 1.

[0113] In some embodiments, the pharmaceutical formulations described herein may contain 5 mg of Compound 1.

[0114] In some embodiments, the pharmaceutical formulations described herein may contain 2.5 mg of Compound 1.

[0115] In some embodiments, the pharmaceutical formulation described herein may be a tablet comprising 2.5 mg of Compound 1.

[0116] In some embodiments, the pharmaceutical formulation described herein may be a tablet comprising 5 mg of Compound 1.

[0117] In some embodiments, the pharmaceutical formulation described herein may be a tablet comprising 10 mg of Compound 1.

[0118] In some embodiments, the pharmaceutical formulations described herein may include:

[0119] About 2.5% w / w Compound 1;

[0120] About 55% w / w mannitol;

[0121] About 36.5% w / w microcrystalline cellulose;

[0122] About 4% w / w croscarmellose sodium;

[0123] About 2% w / w magnesium stearate.

[0124] In some embodiments, the pharmaceutical formulations described herein may include:

[0125] About 2.5% w / w Compound 1;

[0126] About 55% w / w mannitol;

[0127] About 36.5% microcrystalline cellulose;

[0128] About 4% w / w croscarmellose sodium;

[0129] Approximately 2% magnesium stearate.

[0130] In some embodiments, the pharmaceutical formulations described herein may include:

[0131] 1%w / w-10%w / w compound 1;

[0132] 45% w / w-60% w / w mannitol;

[0133] 30% w / w-40% w / w microcrystalline cellulose;

[0134] 3% w / w - 5% w / w croscarmellose sodium; and

[0135] 1% w / w - 3% w / w magnesium stearate.

[0136] In some embodiments, the pharmaceutical formulations described herein may include:

[0137] 2.5% w / w Compound 1;

[0138] 55% w / w mannitol;

[0139] 36.5% w / w microcrystalline cellulose;

[0140] 4% w / w croscarmellose sodium; and

[0141] 2% w / w magnesium stearate.

[0142] In some embodiments, the pharmaceutical formulations described herein may include:

[0143] 2.5% w / w Compound 1;

[0144] 55% w / w mannitol with an average particle size of about 100 μm;

[0145] 36.5% w / w microcrystalline cellulose with a median particle size of approximately 100 μM;

[0146] 4% w / w croscarmellose sodium; and

[0147] 2% w / w magnesium stearate.

[0148] In some embodiments, the pharmaceutical formulations described herein may include:

[0149] 2.5 mg compound 1;

[0150] 55 mg mannitol;

[0151] 36.5 mg microcrystalline cellulose;

[0152] 4.0 mg croscarmellose sodium; and

[0153] 2.0mg magnesium stearate.

[0154] In some embodiments, the pharmaceutical formulations described herein may include:

[0155] 5.0 mg compound 1;

[0156] 110.0 mg mannitol;

[0157] 73.0 mg microcrystalline cellulose;

[0158] 8.0 mg croscarmellose sodium; and

[0159] 4.0mg magnesium stearate.

[0160] Coating

[0161] In some embodiments, when the pharmaceutical formulation is in tablet form, it may be advantageous to coat the tablet with a coating. The resulting coated tablet will then comprise a tablet core and a coating. Coated tablets can help patients swallow the tablets. Colored coatings can aid in patient compliance and / or differentiation from other drugs, particularly those administered as part of a combination therapy.

[0162] In some embodiments, the pharmaceutical formulations described herein may be coated tablets. If the tablet is a coated tablet, it is to be understood that any % w / w value cited herein refers to the w / w composition of the tablet core.

[0163] In some embodiments, the pharmaceutical formulations described herein may be color-coated tablets.

[0164] In some embodiments, the pharmaceutical formulations described herein may be film-coated tablets.

[0165] In some embodiments, the pharmaceutical formulations described herein can be tablets coated with a film coating comprising a film-forming polymer. In further embodiments, the film-forming polymer is selected from hydroxypropyl methylcellulose (hydroxypropyl methylcellulose, HPMC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), cross-linked polyvinyl pyrrolidone (PVPP) and mixtures thereof. In further embodiments, the film-forming polymer is selected from HPMC, HPC and mixtures thereof. In further embodiments, the film-forming polymer is HPMC.

[0166] In still further embodiments, the film coating further comprises a pigment, such as titanium dioxide, yellow iron oxide, red iron oxide, ferrosoferric oxide, and mixtures thereof.

[0167] In some embodiments, the pharmaceutical formulations described herein may be colored film-coated tablets.

[0168] In some embodiments, the pharmaceutical formulations described herein may be white film-coated tablets.

[0169] In some embodiments, the pharmaceutical formulations described herein may be orange film-coated tablets.

[0170] In some embodiments, the coating is present at about 1.5% w / w-4.5% w / w, including all values ​​and subranges therebetween, including about 1.5% w / w-3.5% w / w, 1.5% w / w-2.5% w / w, 2% w / w-4% w / w, 2% w / w-3% w / w, 2.5% w / w-4.5% w / w, 2.5% w / w-3.5% w / w, 3% w / w / w-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.

[0171] Treatment

[0172] Prevention of diseases or conditions in which modulation of myeloperoxidase (MPO) activity is desired. In particular, the link between MPO activity and disease has been implicated in a number of diseases, including those with inflammatory, cardiovascular, and / or neurodegenerative components, as well as neutrophil-driven diseases.

[0173] In some embodiments, provided are pharmaceutical formulations as disclosed herein for use in a method of treating the human or animal body by therapy.

[0174] In some embodiments, provided are methods of treating a disease or condition in a warm-blooded animal, such as a human, in which modulation of myeloperoxidase (MPO) activity is desired, the method comprising administering to the animal an effective amount of a pharmaceutical formulation described herein.

[0175] In some embodiments, provided are methods of treating a disease or condition in a warm-blooded animal, such as a human, in which inhibition of myeloperoxidase (MPO) activity is desired, the method comprising administering to the animal an effective amount of a pharmaceutical formulation described herein.

[0176] In some embodiments, a method of treating a disease or disorder and / or a neutrophil-driven disease in a warm-blooded animal (such as a human) having an inflammatory component, a cardiovascular component, and / or a neural component is provided, the method comprising administering to the animal an effective amount of a pharmaceutical formulation described herein.

[0177] In some embodiments, a method of treating an autoimmune disease, chronic kidney disease (CKD), acute kidney injury (AKI), 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, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modifications and / or type 2 diabetes in a warm-blooded animal (such as a human) is provided, the method comprising administering to the animal an effective amount of a pharmaceutical formulation described herein.

[0178] 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), arrhythmias, 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, the method comprising administering to the animal an effective amount of a pharmaceutical formulation described herein.

[0179] In some embodiments, a method of 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) is provided, the method comprising administering to the animal an effective amount of a pharmaceutical formulation described herein.

[0180] In some embodiments, a method of 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) is provided, the method comprising administering to the animal an effective amount of a pharmaceutical formulation described herein.

[0181] In some embodiments, provided are pharmaceutical formulations comprising Compound 1 as described herein for use as a medicament.

[0182] In some embodiments, provided are pharmaceutical formulations as described herein for use in therapy.

[0183] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein in the preparation of a medicament for treating a disease or condition in which modulation of the activity of myeloperoxidase (MPO) is desired.

[0184] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein in the preparation of a medicament for treating a disease or condition wherein inhibition of myeloperoxidase (MPO) activity is desired.

[0185] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein in the preparation of a medicament for treating a disease or disorder having an inflammatory, cardiovascular, and / or neural component and / or a neutrophil driven disease.

[0186] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein in the preparation of a medicament for treating an autoimmune disease, chronic kidney disease (CKD), acute kidney injury (AKI), 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, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modification, or type 2 diabetes.

[0187] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein in the preparation of a medicament for treating coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, 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.

[0188] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein in the preparation of a medicament for treating Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS) and / or epilepsy.

[0189] In some embodiments, there is provided use of a pharmaceutical formulation as described herein in the preparation of a medicament 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).

[0190] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein for treating a disease or condition wherein modulation of the activity of myeloperoxidase (MPO) is desired.

[0191] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein for treating a disease or condition wherein inhibition of myeloperoxidase (MPO) activity is desired.

[0192] In some embodiments, there is provided use of a pharmaceutical formulation as described herein for treating a disease or disorder having an inflammatory component, a cardiovascular component, and / or a neural component and / or a neutrophil driven disease.

[0193] In some embodiments, use of a pharmaceutical formulation as described herein is provided for treating an autoimmune disease, chronic kidney disease (CKD), acute kidney injury (AKI), 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 colon syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, liver steatosis, liver fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein modifications, or type 2 diabetes.

[0194] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein for treating coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, 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.

[0195] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein for treating Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), and / or epilepsy.

[0196] In some embodiments, there is provided a use of a pharmaceutical formulation as described herein 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).

[0197] As used herein, the term "treatment" refers to reversing, alleviating, delaying the onset of a disease or disorder as described herein or one or more of its symptoms, or inhibiting its progression. In some embodiments, treatment can be performed after one or more symptoms have developed. In other embodiments, treatment can be performed in the absence of symptoms. For example, susceptible individuals can be treated before the onset of symptoms (e.g., according to symptom history and / or according to genetic or other predisposing factors). Treatment can also continue after symptoms have subsided, for example to present or delay their recurrence. BRIEF DESCRIPTION OF THE DRAWINGS

[0198] Figure 1 The direct compression method described herein is depicted.

[0199] Figure 2A The compaction pressure (CP) and tensile strength of variants 1, 2, 3 and 14 were compared.

[0200] Figure 2B The solid fraction and compaction pressure (CP) of variants 1, 2, 3 and 14 were compared.

[0201] Figure 2C The solid fraction and tensile strength (TS) of variants 1, 2, 3 and 14 were compared.

[0202] Figure 3A The compaction pressure (CP) and tensile strength of variants 5 and 10 were compared.

[0203] Figure 3B The solid fraction and compaction pressure (CP) of variants 5 and 10 were compared.

[0204] Figure 3C The solid fraction and tensile strength (TS) of variants 5 and 10 were compared.

[0205] Figure 4A The compaction pressure (CP) and tensile strength of variants 3, 7 and 11 were compared.

[0206] Figure 4B The solid fraction and compaction pressure (CP) of variants 3, 7 and 11 were compared.

[0207] Figure 4C The solid fraction and tensile strength (TS) of variants 3, 7 and 11 were compared.

[0208] Figure 5A The compaction pressure (CP) of variants 9 and 12 was compared with respect to tensile strength.

[0209] Figure 5B The solid fraction and compaction pressure (CP) of variants 9 and 12 were compared.

[0210] Figure 5CThe solid fraction and tensile strength (TS) of variants 9 and 12 were compared.

[0211] Figure 6 The dissolution profiles of variants 1, 2 and 3 were compared.

[0212] Figure 7 The dissolution profiles of variants 5 and 10 were compared.

[0213] Figure 8 The dissolution profiles of variants 3, 11 and 15 were compared.

[0214] Fig. 9 The dissolution profiles of variants 9, 12 and 15 were compared.

[0215] Fig. 10A and Fig. 10B The dissolution profiles of variant 15 before and after coating are depicted.

[0216] Fig.11 The coating methods described herein are depicted.

[0217] Fig.12 The dissolution profiles of various film-coated tablets coated at 2% w / w were compared.

[0218] Fig.13 The dissolution profiles of various film-coated tablets coated at 4.5% w / w were compared.

[0219] Fig.14 The dissolution profiles of coated tablets and uncoated tablets containing 2.5 mg of Compound 1 or 5 mg of Compound 1 were compared.

[0220] Example

[0221] Compound 1 was prepared by the synthetic route disclosed in WO2016 / 087338. The excipients used in the Examples and Results section are shown in Table 2.

[0222] Table 2: Excipients, abbreviations and grades

[0223]

[0224] Example 1: Preparation of tablets

[0225] The tablets of Compound 1 described herein were prepared using a direct compression dry process.

[0226] The formulations described in Table 3-A and Table 3-B were prepared on a 1 kg scale according to (or similar to) the process described below and summarized in Figure 1 The values ​​quoted in the table are % w / w.

[0227] 1. Compound 1 was blended with mannitol and DCPA (if present) in an ERWEKA DKM (double cone blender) 11 L blender at about 200 revolutions and a speed of 20 rpm.

[0228] 2. The powder blend obtained in step 1 was sieved through a 600 μm screen on a Frewitt mill CW-150 at a grinding speed of about 500 rpm.

[0229] 3. The milled powder blend was then blended with MCC, L-HPC and / or croscarmellose sodium in an ERWEKADKM (double cone blender) 11 L blender at about 200 revolutions and a speed of 20 rpm.

[0230] 4. The blend obtained in step 3 was then blended with magnesium stearate in an ERWEKA DKM (double cone blender) 11 L blender at about 200 revolutions and a speed of 20 rpm.

[0231] 5. Tablet compression was performed on a Korsch XL-100 using appropriately sized oval or round tools to prepare 400 mg (10 mg Compound 1) tablets, 200 mg (5 mg Compound 1) tablets, and 100 mg (2.5 mg Compound 1) tablets.

[0232] Table 3-A

[0233]

[0234]

[0235] *Not implemented

[0236] Table 3-B

[0237]

[0238]

[0239] Example 2: Testing of tablets

[0240] Compression curve

[0241] All batches were compressed separately at different compression forces 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×7 mm for 10 mg strength). The breaking force and thickness of the produced tablets were characterized using suitable hardness and thickness measuring equipment. The tensile strength was calculated based on the breaking force and size of the produced tablets. The results are presented in Figures 2 to 5.

[0242] The compression curve depicts the tablet tensile strength as a function of the compaction force applied for all batches. The curve is normalized for punch tip frontal area and tablet geometry, allowing a true comparison of formulation robustness independent of tablet size.

[0243] Dissolution curve

[0244] The dissolution profile of the tablets was performed in sodium phosphate (0.075 M) / citric acid (0.025 M) buffer at pH 6.1 using an Apparatus II (paddle apparatus) with a stirring speed of 75 rpm according to the USP and the European Pharmacopoeia. The concentration of Compound 1 was quantified by comparing the UV response of the dissolved sample at 290 nm and the background correction at 400 nm with that of an external reference standard solution.

[0245] The dissolution profile of the tablets in pH 6.1 USP medium was measured using Method 2. Figures 6 to 9 The dissolution profiles of various formulations were compared.

[0246] Example 3: Coating

[0247] Use as Fig.11 Tablets having a formulation of Variant 15 containing 2.5 mg of Compound 1 and 5 mg of Compound 1 were film coated using HPMC / HPC coating (Aquarius Prime White, BKN318005, Ashland) using a standard pan coating technique as shown, with an uncoated tablet weight gain of 3.5% w / w for the 5 mg tablet and an uncoated tablet weight gain of 3.5% w / w for the 2.5 mg tablet. The dissolution profile of the 5 mg coated tablets was measured in pH 6.1 USP medium using Method 2 described in Example 2. Fig. 10A and Fig. 10B The dissolution profiles of uncoated tablets and coated tablets are depicted separately.

[0248] 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 components described in Table 4 were prepared according to Example 1.

[0249] Table 4

[0250] Components w / w% Compound 1 2.5 Mannitol, Pearlitol 100SD 55 Microcrystalline cellulose, Avicel PH102 36.5 Croscarmellose Sodium 4 Magnesium Stearate 2

[0251] For 2% w / w or 4.5% w / w weight gain, aqueous suspensions of the proprietary coatings listed in Table 5 were used using e.g. Fig.11 5 mg core tablets were film coated using standard pan coating techniques as shown.

[0252] Table 5

[0253]

[0254] The dissolution profile of the tablets in pH 6.1 USP medium was measured using Method 2 described in Example 2. Fig.12 and Fig.13 The dissolution profiles of 2% w / w coating and 4.5% coating were compared respectively.

[0255] The 2.5 mg core tablets were coated with Opadry 03K630008-CN Orange to obtain a 3.3% weight gain, and the 5 mg core tablets were coated with Opadry 03K630008-CN Orange to obtain a 2.8% weight gain. The dissolution profiles of the tablets were measured in pH 6.1 USP medium using Method 2 as described in Example 2, and the results are shown in Fig.14 middle.

[0256] All references cited herein, including patents, patent applications, articles, textbooks, etc., and references cited therein, as well as those not cited therein, are hereby incorporated by reference in their entirety for all purposes.

Claims

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

3. The pharmaceutical formulation according to any one of claims 1 and 2, wherein the one or more pharmaceutical disintegrants are selected from hydroxypropyl cellulose and croscarmellose sodium.

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

5. The pharmaceutical formulation according to claim 4, comprising 3% w / w to 5% w / w croscarmellose sodium.

6. The pharmaceutical formulation according to 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. The pharmaceutical formulation according to claim 7, comprising 1% w / w to 3% w / w magnesium stearate.

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

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

11. The pharmaceutical formulation according to claim 10, comprising 45% w / w to 60% w / w mannitol.

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

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

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

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

16. A pharmaceutical preparation comprising Compound 1, mannitol, microcrystalline cellulose, cross-linked carboxymethyl cellulose 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 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. 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. 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. The pharmaceutical formulation according to any one of claims 1 to 19, comprising 1 mg to 10 mg of Compound 1.

21. The pharmaceutical preparation according to claim 20, comprising 2.5 mg of Compound 1.

22. The pharmaceutical preparation according to claim 20, comprising 5 mg of Compound 1.

23. The pharmaceutical preparation according to 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. The pharmaceutical formulation of claim 24, wherein the tablet further comprises a film coating.

26. The pharmaceutical formulation of claim 25, wherein the film coating comprises a polymer selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), cross-linked polyvinyl pyrrolidone (PVPP), and mixtures thereof.

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

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

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

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, non-alcoholic steatohepatitis (NASH), or chronic obstructive pulmonary disease (COPD).

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