WO2019170136A1 - 药物制剂及其应用 - Google Patents

药物制剂及其应用 Download PDF

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Publication number
WO2019170136A1
WO2019170136A1 PCT/CN2019/077449 CN2019077449W WO2019170136A1 WO 2019170136 A1 WO2019170136 A1 WO 2019170136A1 CN 2019077449 W CN2019077449 W CN 2019077449W WO 2019170136 A1 WO2019170136 A1 WO 2019170136A1
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Prior art keywords
amino
group
pharmaceutically acceptable
acid
less
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PCT/CN2019/077449
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English (en)
French (fr)
Inventor
胡晓婧
钱丽娜
张志超
王远苹
陈永凯
冯伟
祁雯雯
王朝东
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Wuhan Zy Pharmaceuticals Co Ltd
Wuhan LL Science and Technology Development Co Ltd
Wuhan QR Pharmaceuticals Co Ltd
Original Assignee
Wuhan Zy Pharmaceuticals Co Ltd
Wuhan LL Science and Technology Development Co Ltd
Wuhan QR Pharmaceuticals Co Ltd
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Application filed by Wuhan Zy Pharmaceuticals Co Ltd, Wuhan LL Science and Technology Development Co Ltd, Wuhan QR Pharmaceuticals Co Ltd filed Critical Wuhan Zy Pharmaceuticals Co Ltd
Priority to US16/979,305 priority Critical patent/US11337972B2/en
Priority to JP2020544834A priority patent/JP7316289B2/ja
Priority to EP19764431.3A priority patent/EP3763373B1/en
Publication of WO2019170136A1 publication Critical patent/WO2019170136A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a pharmaceutical preparation and application thereof.
  • Cardiovascular disease also known as circulatory disease, refers to a series of diseases involving the circulatory system.
  • the circulatory system mainly includes the heart and blood vessels (arteries, veins, and microvessels).
  • cardiovascular disease is the number one cause of death worldwide, with more deaths from cardiovascular disease each year than any other cause of death.
  • Common cardiovascular diseases include: hypertension, heart failure, coronary heart disease, heart disease, atherosclerosis, angina pectoris, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmia, housing Tremor, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae.
  • Cardiovascular diseases generally have similar causes, processes, and treatments. Most cardiovascular diseases can be prevented by addressing risk factors such as tobacco use, unhealthy diet, obesity, high blood pressure, diabetes, and elevated blood lipids.
  • the World Health Organization believes that a combination of drugs, such as cholesterol-lowering statins and blood pressure lowering drugs, as well as aspirin, can significantly reduce the risk of cardiovascular recurrence or death.
  • any combination of cardiovascular disease drugs with different mechanisms of action does not necessarily have a beneficial effect. Therefore, the development of a pharmaceutical composition that can exert a combined therapeutic effect may provide a more effective control effect on cardiovascular diseases.
  • Neutral endopeptidase is a zinc metalloproteinase on the surface of endothelial cells. Inhibition of NEP can increase atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). ), the levels of C-type natriuretic peptide (CNP), bradykinin and adrenomedullin, so NEP inhibitors can play a role in diuresis, vasodilation, improvement of endothelial function, and inhibition of vascular smooth muscle cell proliferation under pathological conditions, thereby Improve vascular hemodynamics, prevent atherosclerosis, and delay the progression of heart failure.
  • NEP atrial natriuretic peptide
  • BNP brain natriuretic peptide
  • CNP C-type natriuretic peptide
  • bradykinin bradykinin
  • adrenomedullin adrenomedullin
  • Angiotensin II (Ang II) is an important regulator of the regulation of humoral homeostasis in the body, involving blood pressure, electrolyte balance, etc.
  • a large number of literatures have confirmed that Ang II is in hypertension, arterial disease, cardiac hypertrophy, heart failure and diabetes.
  • the pathogenesis of kidney disease plays a major role. Because the abnormal increase of Ang II level is directly related to the occurrence and development of hypertension, cardiac hypertrophy, heart failure, etc., blocking the binding of Ang II to its specific receptor can protect the heart and blood vessels, and the blood vessels are tight.
  • Angiotensin Receptor Blockers ARB have been proven in many randomized clinical trials to reduce the risk of cardiovascular mortality and morbidity. ARB drugs have been widely used in hypertension abroad.
  • biphenyl tetrazolium including losartan (losartan), valsartan (valsartan), irbesartan (irbesartan), candesartan cilexetil and azsarartan medoxomil
  • non-biphenyltetrazolium including eprosartan and telmisartan
  • Chinese Patent Application No. CN1615134A discloses a pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof and a NEP inhibitor or a pharmaceutically acceptable salt thereof;
  • Chinese Patent Application CN105693543A discloses a NCP inhibitor Sacubitril (AHU 377). , CAS No. 149709-62-6) salt and medicinal adjuvants and combinations of AT1 receptor antagonists such as losartan, eprosartan, valsartan, irbesartan, etc.
  • Chinese patent application CN105837464A discloses a NEP inhibitor containing sacuron and sodium medicinal excipients and other active ingredients such as losartan, eprosartan, valsartan, irbesartan, etc. or a pharmaceutically acceptable salt thereof Pharmaceutical composition.
  • the above compound is a sultan drug coupled with ligustrazine or a NO donor, and is a prodrug of angiotensin II receptor antagonist azilsartan (TAK-536), which releases hydroxyprosin in vivo or NO, thus effective synergy with azilsartan, enhance antihypertensive effect, has a certain heart rate reduction effect, reduce adverse reactions, and has an ideal protective effect on patients' heart and kidney.
  • TAK-536 angiotensin II receptor antagonist azilsartan
  • the pressure effect has a more obvious and lasting effect of lowering heart rate, and has high safety, and has an ideal protective effect on the heart and kidney function of the patient, and can be used for preventing and/or treating hypertension, chronic heart failure, diabetic nephropathy and the like.
  • the applicant conducted further prescription studies and found that the compound of the formula (I) has strong hygroscopicity and becomes sticky after moisture absorption, and cannot be effectively disintegrated, resulting in dissolution of the active ingredient. The release performance is poor. Further studies, Applicants have found that a pharmaceutical composition of a neutral endopeptidase inhibitor and a compound of the formula (I) has a property of being highly hygroscopic to water and becoming sticky after moisture absorption, and is incapable of effectively disintegrating, resulting in The dissolution release properties of the active ingredient are poor.
  • the present invention provides a pharmaceutical preparation comprising a first active ingredient, a second active ingredient and a pharmaceutically acceptable excipient;
  • the first active component is at least one selected from the group consisting of a neutral endopeptidase inhibitor and a precursor thereof, an active metabolite, a stereoisomer, a pharmaceutically acceptable salt, a prodrug, and a solvate;
  • the second active component is at least one selected from the group consisting of a compound represented by the following formula (I) or a precursor thereof, an active metabolite, a stereoisomer, a pharmaceutically acceptable salt, a prodrug and a solvate:
  • Each a is the same or different and is independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 1 represents a substituted or unsubstituted group: C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) n O(CH 2 ) m , Aryl or heteroaryl, wherein Wherein C b and C c represent an alkyl group each containing b or c carbon atoms; b and c are the same or different and are independently selected from each other, 0, 1, 2 , 3, 4, 5 or 6, wherein (CH 2 n , m in n O (CH 2 ) m is the same or different, independently selected from each other, 1, 2, 3, 4, 5 or 6;
  • R 2 represents hydrogen, halogen, nitro, cyano, or a substituted or unsubstituted group: C 1 -C 8 alkoxy, C 1 -C 8 alkyl, C 1 -C 8 alkylsulfonylamino , arylsulfonylamino, heteroarylsulfonylamino, aminosulfonyl, amino;
  • R 3 represents a group which is absent or substituted or unsubstituted: C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkoxy, C 2 -C 8 alkyne Base, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, Aryl, heteroaryl, wherein Wherein b and c represent the number of carbon atoms of the alkyl chain, independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 4 represents a cyano group, or a substituted or unsubstituted group of an aryl group, an arylsulfonyl group, a heteroaryl group, a C 1 -C 8 alkoxy group, a C 1 -C 8 nitrate ester (-C 1 -C) 8- alkyl-ONO 2 ), C 1 -C 8 alkyl;
  • R 5 represents a cyano group, or a substituted or unsubstituted group: aryl, heteroaryl, C 1 -C 8 alkoxy, C 1 -C 8 nitrate, C 1 -C 8 alkyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, (CH 2 ) n O(CH 2 ) m CH 3 , wherein R 3 , R 4 , a, m, n independently of each other have the definitions as described above;
  • R 6 and R 7 independently represent hydrogen, unsubstituted or substituted C 1 -C 8 alkoxy or C 1 -C 8 alkyl;
  • R 8 and R 9 independently represent hydrogen, unsubstituted or substituted C 1 -C 8 alkoxy, C 1 -C 8 nitrate or C 1 -C 8 alkyl.
  • the pharmaceutically acceptable excipient comprises one or more disintegrants and / or one or more fillers.
  • at least one disintegrant has a particle diameter of 100 ⁇ m or less
  • at least one filler has a particle diameter of 100 ⁇ m or less.
  • the at least one disintegrant and/or at least one filler has a particle diameter of 95 ⁇ m or less, such as 90 ⁇ m or less, such as 85 ⁇ m or less, such as 80 ⁇ m or less, such as 75 ⁇ m or less; more preferably, at least one of the foregoing
  • the particle size of the disintegrant and/or at least one filler is 10 ⁇ m or more, such as 15 ⁇ m or more, such as 20 ⁇ m or more, such as 25 ⁇ m or more, such as 30 ⁇ m or more.
  • the at least one disintegrant and / or at least one filler is microcrystalline cellulose.
  • the particle size of the adjuvant of the present invention may be selected from 30 ⁇ m, 32 ⁇ m, 40 ⁇ m, 50 ⁇ m, 60 ⁇ m, 70 ⁇ m or 75 ⁇ m.
  • the pharmaceutically acceptable excipient comprises a pharmaceutically acceptable first excipient and a second excipient optionally present or absent;
  • the pharmaceutically acceptable first excipient may be selected from at least one of a filler and a disintegrant; preferably, the particle size of at least one of the filler and/or disintegrant 100 ⁇ m or less, such as 95 ⁇ m or less, such as 90 ⁇ m or less, such as 85 ⁇ m or less, such as 80 ⁇ m or less, such as 75 ⁇ m or less; more preferably, at least one of the filler and/or disintegrant has a particle diameter of 10 ⁇ m or more, For example, 15 ⁇ m or more, such as 20 ⁇ m or more, such as 25 ⁇ m or more, such as 30 ⁇ m or more; preferably, at least one of the filler and/or disintegrant has a particle diameter of 20-85 ⁇ m, for example, 30-75 ⁇ m;
  • the pharmaceutically acceptable second adjuvant may be selected from the group consisting of, but not limited to, lubricants, wetting agents, auxiliary lipids, glidants, sweeteners, flavoring agents, solvents, dissolution aids, suspensions At least one of a dose, an isotonic agent, a buffer, a preservative, an antioxidant, a colorant, and a foaming agent.
  • the filler is selected from the group consisting of starch, lactose, lactose monohydrate, cellulose lactose, pregelatinized starch, sucrose, mannitol, sorbitol, calcium phosphate, dextrin, microcrystalline fiber. At least one of a pigment, a calcium hydrogen phosphate, and a mannitol-starch composite; for example, the filler is selected from at least one of microcrystalline cellulose and mannitol;
  • the disintegrant is selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, and low-substituted hydroxypropyl fibers. At least one of a crosin, a crospovidone and a chitosan; for example, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone;
  • the lubricant is selected from the group consisting of magnesium stearate, colloidal silica, talc, sodium lauryl sulfate, calcium stearate, polyethylene glycol 4000, polyethyl b. At least one of diol 6000, sodium stearyl fumarate, glyceryl monostearate, and hydrogenated vegetable oil; for example, the lubricant is selected from at least one of magnesium stearate and colloidal silica.
  • the lubricant is selected from at least one of magnesium ste
  • the pharmaceutically acceptable adjuvant comprises microcrystalline cellulose and other adjuvants, wherein the microcrystalline cellulose may have a particle diameter of 95 ⁇ m or less, such as 90 ⁇ m or less, such as 85 ⁇ m or less, such as 80 ⁇ m or less, such as 75 ⁇ m or less; more preferably, the microcrystalline cellulose has a particle diameter of 10 ⁇ m or more, such as 15 ⁇ m or more, such as 20 ⁇ m or more, such as 25 ⁇ m or more, such as 30 ⁇ m or more; as an example, the particle diameter of the microcrystalline cellulose may be selected from 30 ⁇ m and 32 ⁇ m. 40 ⁇ m, 50 ⁇ m, 60 ⁇ m, 70 ⁇ m or 75 ⁇ m.
  • the particle diameter of the other solid excipients in the pharmaceutical preparation of the present invention is not particularly limited unless the particle diameter of the specific excipient is defined.
  • the excipients suitable for use in the pharmaceutical formulations of the invention may also be in liquid or colloidal form.
  • suitable excipients can include various commercially available specifications such as granules or micronized excipients. Suitable examples include colloidal silica having a surface area of about 200 m 2 /g.
  • the neutral endopeptidase inhibitor or the pharmaceutically acceptable salt of the compound of the formula (I) is the same or different and is independently selected from Na, K or an ammonium salt (eg, The addition salt of NH 3 );
  • the neutral endopeptidase inhibitor or the pharmaceutically acceptable prodrug of the compound of formula (I) is the same or different and is independently selected from the group consisting of, but not limited to, methyl ester and ethyl ester. , propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester;
  • the compound of the formula (I) has a structure represented by the following formula:
  • the first active component is selected from at least one of the following compounds, pharmaceutically acceptable salts, prodrugs or solvates thereof:
  • the first active component is selected from at least one of the following compounds:
  • the first active component is selected from the group consisting of AHU 377, AHU 377 ethyl ester, AHU 377Na, AHU 377K, N-(3-carboxy-1-oxopropyl)-(4S)-pair -Phenylphenylmethyl)-4-amino-2R-methylbutyric acid, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4 -Amino-2R-methylbutyrate, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyric acid Potassium or 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2- At least one of amino)amino)-4-ox
  • the second active component is a K salt selected from the compound of the formula (I), for example, a compound represented by the following formula (II):
  • the K salt of the compound of formula (I) is selected from the structures shown in the formula:
  • the pharmaceutical preparation of the present invention can be prepared into various dosage forms suitable for oral, inhalation, rectal, topical, parenteral and the like, including but not limited to: powders suitable for oral administration, tablets (including various coated tablets). , slow release or controlled release tablets), tablets, capsules (including soft and hard capsules), granules, pills, dispersible powders, aqueous or oily solutions, emulsions, tinctures, syrups, etc.
  • the dosage form may be a tablet (including various coated tablets, sustained release or controlled release tablets), capsules (including soft and hard capsules), pills; according to an exemplary embodiment of the invention, the dosage form may be a tablet (including various coated tablets, sustained release or controlled release tablets).
  • the present invention may also be administered as separate pharmaceutical compositions in different dosage forms or in different dosage intervals by combining separate drugs in the form of a pharmaceutical pack.
  • the pharmaceutical preparation according to the present invention wherein the mass ratio of the first active component to the second active component is (0.5-5):1, for example, (0.5-3): 1, such as mass ratio It is 0.5:1, 1:1, 1.5:1, 1.8:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1.
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • the pharmaceutical formulation comprises:
  • the potassium salt of Compound 1 is selected from the group consisting of the following compounds:
  • the present invention also provides a method of preparing the pharmaceutical preparation comprising: mixing a first active component, a second active component, and a pharmaceutically acceptable adjuvant.
  • the preparation may be carried out by dry granulation of the above components and auxiliary materials, followed by tableting or encapsulation.
  • the present invention also provides the use of the above pharmaceutical preparation for the preparation of a medicament for preventing and/or treating cardiovascular diseases.
  • the cardiovascular disease is selected from the group consisting of: hypertension, heart failure, chronic heart failure, coronary heart disease, rheumatic heart disease, congenital heart disease, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophy Cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmia, atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina pectoris, primary And secondary pulmonary hypertension, renal vascular hypertension.
  • hypertension hypertension
  • heart failure chronic heart failure
  • coronary heart disease rheumatic heart disease
  • congenital heart disease left ventricular dysfunction
  • endothelial dysfunction diastolic dysfunction
  • hypertrophy Cardiomyopathy diabetic cardiomyopathy, supraventricular and ventricular arrhythmia
  • atrial fibrillation cardiac fibrosis
  • atrial flutter harmful vascular remodeling
  • the present invention also provides a method of preventing and/or treating a cardiovascular disease comprising administering the above pharmaceutical preparation to an individual in need thereof.
  • one or more includes one or more than one, including, but not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • halogen means fluoro, chloro, bromo and iodo.
  • the substituent may be unsubstituted or optionally further substituted by one or more substituents which may be the same or different selected from the above.
  • Alkyl as used singly or as a suffix or prefix in the present invention is intended to include both branched and straight-chain saturated fats having from 1 to 20 carbon atoms (or the specific number if a specific number of carbon atoms are provided) A hydrocarbon group.
  • C 1 -C 8 alkyl means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • an alkyl group When an alkyl group is substituted by a substituent, it includes an alkyl group substituted with one or more halogens, for example, an alkyl group substituted with 1, 2, 3, 4, 5, 6 halogens, such as a trifluoromethyl group.
  • alkenyl as used herein, alone or as a suffix or prefix, is intended to include a chain comprising alkenyl or olefins having from 2 to 20 carbon atoms, if specified, the specific number of carbon atoms. And a linear aliphatic hydrocarbon group.
  • C 2-6 alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3 Methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • alkynyl used alone or as a suffix or prefix in the present invention is intended to include alkynyl or alkyne containing from 2 to 20 carbon atoms (or the specific number if a specific number of carbon atoms is provided) Branched and linear aliphatic hydrocarbon groups.
  • alkynyl eg, 1-propynyl, 2-propynyl
  • 3-butynyl pentynyl, hexynyl, and 1-methylpent-2-ynyl.
  • aryl as used herein means an aromatic ring structure composed of 5 to 20 carbon atoms.
  • an aromatic ring structure containing 5, 6, 7 and 8 carbon atoms may be a monocyclic aromatic group such as a phenyl group; a ring structure comprising 8, 9, 10, 11, 12, 13 or 14 carbon atoms It may be polycyclic such as naphthyl.
  • the aromatic ring may be substituted with one or more of the above substituents at one or more ring positions.
  • aryl also includes polycyclic ring systems having two or more rings wherein two or more carbons are shared by two adjacent rings (the ring is a "fused ring"), wherein at least One ring is aromatic and the other ring may be, for example, a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and/or heterocyclic group.
  • polycyclic rings include, but are not limited to, 2,3-dihydro-1,4-benzodioxadiene and 2,3-dihydro-1-benzofuran.
  • cycloalkyl as used herein is intended to include saturated cyclic groups having the indicated number of carbon atoms. These terms may include fused or bridged polycyclic systems.
  • the cycloalkyl group has 3 to 40 carbon atoms in its ring structure. In one embodiment, the cycloalkyl has 3, 4, 5 or 6 carbon atoms in its ring structure.
  • C 3-6 cycloalkyl means a group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • heteroaryl refers to a heteroaromatic heterocycle having at least one ring heteroatom such as sulfur, oxygen or nitrogen.
  • Heteroaryl groups include monocyclic systems and polycyclic systems (eg, having 2, 3 or 4 fused rings).
  • heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, fluorene , pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, 1,2,4 -thiadiazolyl, isothiazolyl, benzothienyl, fluorenyl, oxazolyl, benzimidazolyl, benzoxazolyl, azabenzoxazolyl, imidazothiazolyl, benzo[1] 4] dioxolyl, benzo[1,3]dioxolyl and the
  • a heteroaryl has from 3 to 40 carbon atoms and in other embodiments from 3 to 20 carbon atoms. In some embodiments, a heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, a heteroaryl has 1 to 4, 1 to 3 or 1 to 2 heteroatoms. In some embodiments, a heteroaryl has 1 heteroatom.
  • heterocyclyl refers to a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring containing from 3 to 20 atoms, wherein 1, 2, 3, 4 or 5 Ring atoms are selected from nitrogen, sulfur or oxygen, and unless otherwise indicated, may be attached via carbon or nitrogen, wherein the -CH 2 - group is optionally replaced by -C(O)-; and unless otherwise stated to the contrary
  • the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or a ring nitrogen atom, optionally quaternized; wherein -NH in the ring is optionally acetyl, formyl, methyl Or a methylsulfonyl group; and the ring is optionally substituted with one or more halogens.
  • heterocyclic group when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these hetero atoms are not adjacent to each other.
  • the heterocyclic group is bicyclic or tricyclic, at least one ring may be optionally a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is a monocyclic ring, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl.
  • the compounds of the invention may also contain one or more asymmetric centers.
  • Asymmetric carbon atoms may exist in the (R) or (S) configuration, with only one asymmetric center, resulting in a racemic mixture containing multiple asymmetric centers, resulting in a mixture of diastereomers.
  • the substituent may exist in a cis or trans isomer form.
  • the compounds of formula (I) also include all possible stereoisomers thereof, which are single stereoisomers or stereoisomers (for example R-isomers or S-isomers, or E-isomers) The form of any mixture of any ratio of the bulk or Z-isomer).
  • Single stereoisomers (e.g., single enantiomers or single diastereomers) of a compound of the invention can be achieved by any suitable prior art method (e.g., chromatography, particularly, for example, chiral chromatography). Separation.
  • the compounds may also exist in tautomeric forms.
  • the compounds of the invention include all possible tautomers of the compounds of formula (I) which are in the form of a single tautomer or any mixture of said tautomers in any ratio.
  • neutral endopeptidase inhibitors of the invention and the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center ( For example, an amino group, it can also form an internal salt.
  • acid addition salts include, but are not limited to, hydrochloride, hydrofluoride, hydrobromide, hydroiodide, sulfate, pyrosulfate, phosphate, nitrate, methanesulfonate , ethanesulfonate, 2-hydroxyethanesulfonate, besylate, tosylate, sulfamate, 2-naphthalenesulfonate, formate, acetoacetate, pyruvic acid, silicate , cinnamate, benzoate, acetate, glycolate, trifluoroacetate, trimethylacetate, propionate, butyrate, hexanoate, heptanoate, ten Monoacid salt, stearate, ascorbate, camphorate, camphor sulfonate, citrate, fumarate, malate, maleate, hydroxymaleate, oxalate, water Salicylate, succinate, glu
  • the pharmaceutical preparation of the invention can effectively improve the viscosity of the active ingredient in contact with water, thereby causing the problem that the preparation cannot be disintegrated, promoting the disintegration of the pharmaceutical preparation, and releasing the medicine.
  • the pharmaceutical preparation of the invention adopts the conventional pharmaceutical auxiliary material, does not need to add special auxiliary materials or make it into a special preparation, realizes rapid disintegration through prescription adjustment, dissolves the active ingredient, and improves the bioavailability.
  • the present invention surprisingly finds that by controlling the particle size of the key excipients, it is possible to achieve a good fluidity of the preparation material, and uniform granulation property, and to ensure the effective absorption of the active substance (active ingredient) which becomes sticky after moisture absorption. Disintegration, so that the active ingredient is dissolved, and the bioavailability is improved.
  • the pharmaceutical preparation of the present invention can be used for preventing and/or treating cardiovascular diseases such as hypertension and chronic heart failure.
  • the pharmaceutical preparation of the present invention is administered by, for example, oral administration, and is convenient to use.
  • the pharmaceutical preparation of the present invention can improve the drug-forming properties of the active ingredient and patient compliance.
  • First active component prepared by the method of Example 1.
  • the second active component a compound of formula (I) can be prepared by methods known in the art, for example, as disclosed in CN 103709154 A, which is incorporated herein by reference in its entirety.
  • the compound represented by the formula (II) can be produced by contacting a compound represented by the formula (I) with a potassium salt reagent.
  • a compound of formula (I) is contacted with a potassium salt reagent in a solvent to prepare a compound of formula (II) (see, in particular, the preparation process of Example 2).
  • the preparation process of the specific embodiment is adjusted according to the prescription excipients and the amount of use.
  • AHU 377K The preparation of AHU 377K is similar to this process, replacing concentrated ammonia with potassium hydroxide.
  • composition consisting of only the API products of Examples 1 and 2 (100 mg: 50 mg) (without preparation excipients), at a relative humidity of 92.5% and a temperature of 25 ° C, a hygroscopic weight gain of 28.31% for 5 days. .
  • the material flowability is good, so that the final product is granulated uniformly, and the difference in tablet weight of the products obtained by the detection of Examples 3-11 is within ⁇ 5%, and the hardness is between 80-120N. .
  • the embodiments of the present invention are not limited to the examples 3-11 listed, but also include replacement with other excipients listed in the specification, for example, cellulose lactose, pregelatinized starch, Replacement of lactose or mannitol with sucrose, sorbitol, calcium phosphate, etc.; replacement of cross-linked carboxymethyl with calcium carboxymethylcellulose, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropylcellulose, chitosan, etc.
  • replacement with other excipients listed in the specification for example, cellulose lactose, pregelatinized starch, Replacement of lactose or mannitol with sucrose, sorbitol, calcium phosphate, etc.; replacement of cross-linked carboxymethyl with calcium carboxymethylcellulose, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropylcellulose, chitosan, etc.
  • the preparations of the pharmaceutical preparations were carried out according to the general methods in Examples 3 to 11, and Comparative Examples 1-2, and the drug dissolution was measured.

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Abstract

本发明公开了一种药物制剂及其应用，所述制剂包括第一活性组分，第二活性组分和药学上可接受的辅料，其中，第一活性组分为选自中性内肽酶抑制剂及其前体、活性代谢产物、立体异构体、药学上可接受的盐、前药和溶剂合物中的至少一种；第二活性组分为选自如下式(I)所示化合物或其前体、活性代谢产物、立体异构体、药学上可接受的盐、前药和溶剂合物中的至少一种；所述药学上可接受的辅料包括一种或多种崩解剂和/或一种或多种填充剂。该制剂能够改善常规辅料无法有效使活性成分溶出的问题。

Description

药物制剂及其应用
本申请要求2018年3月9日向中国国家知识产权局提交的专利申请号为201810195617.1，发明名称为“药物制剂及其应用”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及医药制剂领域，具体涉及一种药物制剂及其应用。
背景技术
心血管疾病，又称为循环系统疾病，是指一系列涉及循环系统的疾病。循环系统主要包括心脏、血管(动脉、静脉、微血管)。据统计，心血管疾病是全球的头号死因，每年死于心血管疾病的人数多于任何其它死因。常见的心血管疾病包括：高血压、心衰、冠心病、心脏病、动脉粥样硬化、心绞痛、左心室功能不全、肥厚性心肌病、糖尿病性心肌病、室上性和室性心律失常、房颤、心脏纤维化、心房扑动、有害的血管重塑、心肌梗塞及其后遗症等。心血管疾病一般有着相似的病因、病发过程及治疗方法，大多数心血管疾病都可以通过解决诸如烟草使用、不健康饮食、肥胖、高血压、糖尿病和血脂升高等危险因素而得到预防。
世界卫生组织认为通过药物组合，例如，降低胆固醇的他汀类药物和降血压药物以及阿斯匹林联合运用，能够大幅度减少心血管疾病复发或死亡的危险。然而，将不同作用机制的心血管疾病药物任意组合不一定会得到有利效果。因此，开发能发挥联合治疗作用的药物组合物可能对心血管疾病提供更加有效的防治效果。
中性肽内切酶(neutral endopeptidase，NEP，也称中性内肽酶)是一种内皮细胞表面的锌金属肽酶，抑制NEP可增高心房利钠肽(ANP)、脑利钠肽(BNP)、C型利钠肽(CNP)、缓激肽和肾上腺髓质素的水平，因此NEP抑制剂在病理状态下可发挥利尿、扩血管、改善内皮功能、抑制血管平滑肌细胞增生的作用，从而改善血管血流动力学状态、防止动脉粥样硬化形成，延缓心衰的病程进展。
血管紧张素II(Ang II)是机体内调节体液动态平衡的重要调控因子，涉及到血压、电解质平衡等，大量文献证实，Ang II在高血压病、动脉疾病、心脏肥大、心力衰竭及糖尿病、肾病等的发病机制上都起着主要的作用。由于Ang II水平的异常持续增高与高血压、心脏肥厚、心力衰竭等的发生发展直接有关，因此，阻断Ang II与其特异性的受体结合，能起到心脑血管的保护作用，血管紧张素II受体拮抗剂(Angiotensin Receptor Blockers，ARB)在降低心血管病死亡率和病残率的效益方面已经在诸多随机临床试验中得到了证实，ARB药物在国外已较广泛用于高血压病及其他心肾疾病的防治，目前临床使用的ARB依据结构可分为2类：(1)联苯四氮唑类，包括氯沙坦(losartan)、缬沙坦(valsartan)、厄贝沙坦(irbesartan)、坎地沙坦酯(candesartan cilexetil)及阿齐沙坦酯(Azilsartan medoxomil)；(2)非联苯四氮唑类，包括依普罗沙坦(eprosartan)及替米沙坦(telmisartan)。
中国专利申请CN1615134A公开了包含缬沙坦或其可药用盐和NEP抑制剂或其可药用盐的药物组合物；中国专利申请CN105693543A公开了包含NEP抑制剂沙库比曲(Sacubitril， AHU 377，CAS No.149709-62-6)的盐和药用辅料以及AT1受体拮抗剂例如氯沙坦、依普沙坦、缬沙坦、厄贝沙坦等或其可药用盐的药物组合物；中国专利申请CN105837464A公开了包含NEP抑制剂沙库比曲钠和药用辅料以及其他活性成分例如氯沙坦、依普沙坦、缬沙坦、厄贝沙坦等或其可药用盐的药物组合物。
公开号为CN103709154A的中国专利申请首次公开了结构如下式(I)所示的化合物：
Figure PCTCN2019077449-appb-000001
上述化合物是偶联了川芎嗪或NO供体的沙坦类药物，是血管紧张素II受体拮抗剂阿齐沙坦(TAK-536)的前药，该化合物在体内释放出羟基川芎嗪或NO，从而与阿齐沙坦发生有效的协同作用，增强抗高血压疗效，具有一定的降心率作用，减少不良反应，对患者心肾也具有较理想的保护作用。申请人在进一步的研究中发现式(I)化合物的钾盐，即结构如下式(II)所示的化合物，溶解性能更好，生物利用度更高，具有更强效和更长效的降压效果，同时具有更明显且持久的降心率效果，且安全性高，对患者心肾功能具有较理想的保护作用，能够用于预防和/或治疗高血压、慢性心衰、糖尿病肾病等。
Figure PCTCN2019077449-appb-000002
为了改善化合物的稳定性和成药性，申请人进行进一步处方研究，结果发现式(I)所示化合物吸湿性强，且在吸湿后会变粘，无法有效使之崩解，导致活性成分的溶出释放性能较差。进一步研究，申请人发现中性内肽酶抑制剂与式(I)所示化合物的药物组合物具有遇水吸湿性强，且在吸湿后会变粘的特性，无法有效使之崩解，导致活性成分的溶出释放性能较差。
发明内容
为改善上述技术问题，本发明提供一种药物制剂，包括第一活性组分，第二活性组分和药学上可接受的辅料；其中，
第一活性组分为选自中性内肽酶抑制剂及其前体、活性代谢产物、立体异构体、药学上可接受的盐、前药和溶剂合物中的至少一种；
第二活性组分为选自如下式(I)所示化合物或其前体、活性代谢产物、立体异构体、药学上可接受的盐、前药和溶剂合物中的至少一种：
Figure PCTCN2019077449-appb-000003
其中，R代表
Figure PCTCN2019077449-appb-000004
Figure PCTCN2019077449-appb-000005
或者
Figure PCTCN2019077449-appb-000006
每一个a相同或不同，独立地选自0、1、2、3、4、5或6；
R 1代表取代或未取代的下列基团：C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、
Figure PCTCN2019077449-appb-000007
(CH 2) nO(CH 2) m、
Figure PCTCN2019077449-appb-000008
芳基或杂芳基，其中
Figure PCTCN2019077449-appb-000009
中的C b、C c分别代表包含b或c个碳原子的烷基；b、c相同或不同，彼此独立地选自0、1、2、3、4、5或6，其中(CH 2) nO(CH 2) m中的n、m相同或不同，彼此独立地选自1、2、3、4、5或6；
R 2代表氢、卤素、硝基、氰基，或取代或未取代的下列基团：C 1-C 8烷氧基、C 1-C 8烷基、C 1-C 8烷基磺酰基氨基、芳基磺酰基氨基、杂芳基磺酰基氨基、氨基磺酰基、氨基；
R 3代表不存在，或取代或未取代的下列基团：C 1-C 8烷基、C 1-C 8烷氧基、C 2-C 8烯烃氧基、C 2-C 8炔烃氧基、C 1-C 6烷氧基-C 1-C 6烷基、
Figure PCTCN2019077449-appb-000010
芳基、杂芳基，其中
Figure PCTCN2019077449-appb-000011
中的b、c代表烷基链的碳原子个数，独立地选自0、1、2、3、4、5或6；
R 4代表氰基，或取代或未取代的下列基团：芳基、芳基磺酰基、杂芳基、C 1-C 8烷氧基、C 1-C 8硝酸酯(-C 1-C 8烷基-ONO 2)、C 1-C 8烷基；
R 5代表氰基，或取代或未取代的下列基团：芳基、杂芳基、C 1-C 8烷氧基、C 1-C 8硝酸酯、C 1-C 8烷基、C 1-C 8烯基、C 1-C 8炔基、
Figure PCTCN2019077449-appb-000012
(CH 2) nO(CH 2) mCH 3，其中R 3、R 4、a、m、n彼此独立地具有如上所述的定义；
R 6和R 7独立地代表氢，无取代或取代的C 1-C 8烷氧基或C 1-C 8烷基；
R 8和R 9独立地代表氢，无取代或取代的C 1-C 8烷氧基、C 1-C 8硝酸酯或C 1-C 8烷基。
根据本发明优选的实施方案，所述药学上可接受的辅料包括一种或多种崩解剂和/或一种或多种填充剂。优选地，所述药学上可接受的辅料中，至少一种崩解剂的粒径为100μm以下，和/或至少一种填充剂的粒径为100μm以下。更优选地，前述至少一种崩解剂和/或至少一种填充剂的粒径为95μm以下，如90μm以下，如85μm以下，如80μm以下，如75μm以下；更优选地，前述至少一种崩解剂和/或至少一种填充剂的粒径为10μm以上，如15μm以上，如20μm以上，如25μm以上，如30μm以上。优选地，所述至少一种崩解剂和/或 至少一种填充剂为微晶纤维素。
作为实例，本发明所述辅料的粒径可以选自30μm、32μm、40μm、50μm、60μm、70μm或75μm。
根据本发明的实施方案，所述药学上可接受的辅料包括药学上可接受的第一辅料和任选存在或不存在的第二辅料；
根据本发明，所述药学上可接受的第一辅料可以选自填充剂和崩解剂中的至少一种；优选地，所述填充剂和/或崩解剂中的至少一种的粒径为100μm以下，如95μm以下，如90μm以下，如85μm以下，如80μm以下，如75μm以下；更优选地，所述填充剂和/或崩解剂中的至少一种的粒径为10μm以上，如15μm以上，如20μm以上，如25μm以上，如30μm以上；优选地，所述填充剂和/或崩解剂中的至少一种的粒径为20-85μm，例如30-75μm；
根据本发明，所述药学上可接受的第二辅料可以选自包括但不限于润滑剂、湿润剂、辅助脂质、助流剂、甜味剂、矫味剂、溶剂、溶解助剂、悬浮剂、等渗剂、缓冲液、防腐剂、抗氧剂、着色剂和起泡剂中的至少一种。
根据本发明示例性的实施方案，所述填充剂为选自淀粉、乳糖、一水乳糖、纤维素乳糖、预胶化淀粉、蔗糖、甘露醇、山梨醇、磷酸钙、糊精、微晶纤维素、磷酸氢钙和甘露醇-淀粉复合物中的至少一种；例如，所述填充剂选自微晶纤维素和甘露醇中的至少一种；
根据本发明示例性的实施方案，所述崩解剂为选自交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、甲基纤维素、低取代羟丙基纤维素、交联聚维酮和壳聚糖中的至少一种；例如，所述崩解剂选自交联羧甲基纤维素钠和交联聚维酮中的至少一种；
根据本发明示例性的实施方案，所述润滑剂为选自硬脂酸镁、胶态二氧化硅、滑石粉、十二烷基硫酸钠、硬脂酸钙、聚乙二醇4000、聚乙二醇6000、十八烷基富马酸钠、单硬脂酸甘油酯和氢化植物油中的至少一种；例如，所述润滑剂选自硬脂酸镁和胶态二氧化硅中的至少一种。
根据本发明的实施方案，所述药学上可接受的辅料包括微晶纤维素和其他辅料，其中微晶纤维素的粒径可以为95μm以下，如90μm以下，如85μm以下，如80μm以下，如75μm以下；更优选地，微晶纤维素的粒径为10μm以上，如15μm以上，如20μm以上，如25μm以上，如30μm以上；作为实例，微晶纤维素的粒径可以选自30μm、32μm、40μm、50μm、60μm、70μm或75μm。
根据本发明的实施方案，应当理解，除非对特定辅料的粒径进行限定，否则本发明对所述药物制剂中其他固体辅料的粒径没有特别限定。应当理解，除固体辅料外，适用于本发明药物制剂的辅料也可以是液态或胶态的。例如，适宜的辅料可包括市售的各种规格，如颗粒或微粉辅料。适宜的实例包括表面积约为200m 2/g的胶态二氧化硅。
根据本发明示例性的实施方案，所述中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的盐相同或不同，彼此独立地选自Na、K或铵盐(如与NH 3的加成盐)；中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的前药相同或不同，彼此独立地选自包括但不限于甲酯、乙酯、丙酯、异丙酯、丁酯、异丁酯、叔丁酯；
根据本发明示例性的实施方案，式(I)所示化合物具有如下式所示结构：
Figure PCTCN2019077449-appb-000013
Figure PCTCN2019077449-appb-000014
根据本发明示例性的实施方案，所述第一活性组分选自下列化合物、其药学上可接受的盐、前药或溶剂合物中的至少一种：
(S)-(2-联苯-4-基)-1-(1H-四唑-5-基)乙基氨基)甲基膦酸、
(S)-5-(N-(2-(膦酰基甲基-氨基)-3-(4-联苯基)-丙酰基)-2-氨基乙基)四唑、
(±)N-(1-氧-2-巯甲基-3-苯丙酰基)甘氨酸、
N-((2S)-2-(4-联苯基甲基)-4-羧基-5-苯氧基戊酰基)甘氨酸、
N-(α-鼠李吡喃糖基膦酰胺)-L-亮氨酸-L-色氨酸、
N-[N-[(L)-1-羧基-2-苯基乙基]-L-苯丙氨酰基]-(R)-丙氨酸、
N-[N-[((1S)-羧基-2-苯基)乙基]-(S)-苯丙氨酰基]-β-丙氨酸、
N-(S)-[3-巯基-2-(2-甲基苯基)丙酰基]-(S)-2-甲氧基-(R)-丙氨酸、
3-[1,1'-联苯]-4-基-N-[二苯氧基氧膦基)-甲基]-L-丙氨酰基-β-丙氨酸、
N-(1-(N-羟基氨基甲酰基-甲基)-1-环戊烷羰基)-L-苯丙氨酸、
N-[2-巯基甲基-3-苯基-丙酰基]-3-氨基苯甲酸、
4-[[2-(巯基甲基)-1-氧代-3-苯基丙基]氨基]苯甲酸、
N-[2-乙酰硫基甲基-3-苯基-丙酰基]-3-氨基苯甲酸、
N-[2-巯基甲基-3-(2-甲基苯基)-丙酰基]-甲硫氨酸、
N-(3-苯基-2-(巯基甲基)-丙酰基)-(S)-4-(甲基巯基)-甲硫氨酸、
N-[1-(2-羧基-4-苯基丁基)-环戊烷羰基]-(S)-异丝氨酸、
N-[2(S)-巯基甲基-3-(2-甲基苯基)丙酰基]-(S)-异丝氨酸、
N-(1-(3-(N-叔丁氧羰基-(S)-脯氨酰氨基)-2(S)-叔丁氧基-羰基丙基)环戊烷羰基)-O-苄基-(S)-丝氨酸、
3(S)-[2-(乙酰硫基甲基)-3-苯基-丙酰基]氨基-ε-己内酰胺、
N-[1-(乙酰硫基甲基)-环戊羰基]-(S)-甲硫氨酸、
N-[2-乙酰硫基甲基-3-(2-甲基-苯基)丙酰基]-甲硫氨酸、
N-[2(S)-巯基甲基-3-(2-甲基苯基)-丙酰基]蛋氨酸、
N-[2-(巯基甲基)-1-氧代-3-苯基丙基]-β-丙氨酸、
7-[[2-(巯基甲基)-1-氧代-3-苯基丙基]氨基]-庚酸、
N-[N-[1(S)-羧基-3-苯基丙基]-(S)-苯丙氨酰基]-(S)-异丝氨酸、
N-[1-[[1(S)-羰基-3-苯基丙基]氨基]-环戊基羰基]-(S)-异丝氨酸、
N-[1-[[1(S)-苄氧基羰基-3-苯基丙基]氨基]-环戊基羰基]-(S)-异丝氨酸、
N-[N-[(L)-[1-[(2,2-二甲基-1,3-二氧戊环-4-基)-甲氧基]羰基]-2-苯基乙基]-L-苯丙氨酰基]-(R)-丙氨酸、
N-(2-羧基-4-噻吩基)-3-巯基-2-苄基丙酰胺、
2-(2-巯基甲基-3-苯基丙酰氨基)噻唑-4-基甲酸、
(L)-(1-((2,2-二甲基-1,3-二氧戊环-4-基)-甲氧基)羰基)-2-苯基乙基)-L-苯丙氨酰基)-β-丙氨酸、
顺-4-[[[1-[2-羧基-3-(2-甲氧基乙氧基)丙基]-环戊基]羰基]氨基]-环己烷甲酸、
3-(1-[6-内-羟基甲基二环[2,2,1]庚烷-2-外-氨基甲酰基]环戊基)-2-(2-甲氧基乙基)丙酸、
3-[1-(顺-4-羧基羰基-顺-3-丁基环己基-r-1-氨基甲酰基)环戊基]-2S-(2-甲氧基乙氧基-甲基)丙酸、
(S)-顺-4-[1-[2-(5-茚满基氧基-羰基)-3-(2-甲氧基乙氧基)丙基]-1-环戊烷酰氨基]-1-环己烷甲酸、
1,1'-[二硫代双-[2(S)-(2-甲基苄基)-1-氧代-3,1-亚丙基]]-双-(S)-异丝氨酸、
1,1'-[二硫代双-[2(S)-(2-甲基苄基)-1-氧代-3,1-亚丙基]]-双-(S)-甲硫氨酸、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸、
N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸。
在优选的实施方案中，所述第一活性组分选自至少一种下列化合物：
N-[1-(乙酰硫基甲基)-环戊羰基]-(S)-甲硫氨酸乙酯、
N-[2-乙酰硫基甲基-3-(2-甲基-苯基)丙酰基]-甲硫氨酸乙酯、
N-(1-(3-(N-叔丁氧羰基-(S)-脯氨酰氨基)-2(S)-叔丁氧基-羰基丙基)环戊烷羰基)-O-苄基-(S)-丝氨酸甲酯、
3(S)-[2-(乙酰硫基甲基)-3-苯基-丙酰基]氨基-ε-己内酰胺、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(AHU 377或沙库必曲)、
N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸、
N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钠、
N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钾、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸乙酯(AHU 377乙酯或沙库必曲乙酯)、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸钠(AHU 377Na或沙库必曲钠)、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸钾(AHU 377K或沙库必曲钾)、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸铵(AHU 377铵盐或沙库必曲铵盐)。
在优选的实施方案中，所述第一活性组分选自AHU 377、AHU 377乙酯、AHU 377Na、AHU 377K、N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸、N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钠、N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钾或4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸铵中的至少一种。
根据本发明示例性的实施方案，所述第二活性组分为选自式(I)所示化合物的K盐，例如下式(II)所示的化合物：
Figure PCTCN2019077449-appb-000015
其中，R具有上文所述的定义；
作为实例，式(I)所示化合物的K盐选自如下式所示结构：
Figure PCTCN2019077449-appb-000016
Figure PCTCN2019077449-appb-000017
本发明的药物制剂可以制成适于口服、吸入、直肠、局部、胃肠外等给药途径的各种剂型，包括但不限于：适于口服的散剂、片剂(包括各种包衣片剂、缓释或控释片剂)、锭剂、胶囊剂(包括软胶囊和硬胶囊)、颗粒剂、丸剂、可分散粉末、水性或油性溶液剂、乳剂、酏剂、糖浆剂等，适于吸入的粉末或液体气雾剂等，适于直肠的栓剂等，适于局部的霜剂、软膏剂、凝胶、水性或油性溶液剂等，适于经胃肠外给药的静脉内、皮下或肌内注射用无菌水性或油性的注射剂或冻干粉针剂等；优选地，所述剂型可以为片剂(包括各种包衣片剂、缓释或控释片剂)、胶囊剂(包括软胶囊和硬胶囊)、丸剂；根据本发明示例性的实施方案，所述剂型可以为片剂(包括各种包衣片剂、缓释或控释片剂)。本发明还可以通过将独立的药物组合于药物包形式，以不同的剂量形式将独立的组分进行给药或以不同的给药间隔进行给药。
根据本发明所述的药物制剂，其中第一活性组分与所述第二活性组分的质量配比为(0.5-5):1，例如为(0.5-3):1，如质量配比为0.5:1，1:1，1.5:1，1.8:1，2:1，2.5:1，3:1，3.5:1，4:1，4.5:1，5:1。
在本发明的实施方案中，所述药物制剂包括：
5-70重量份的第一活性组分，
5-70重量份的第二活性组分，
5-90重量份的填充剂，
2-35重量份的崩解剂，
0.1-10重量份的润滑剂；
在本发明的实施方案中，所述药物制剂包括：
5-40重量份的第一活性组分，
5-40重量份的第二活性组分，
30-70重量份的填充剂，
8-20重量份的崩解剂，
0.5-5重量份的润滑剂。
作为实例，所述药物制剂包括：
Figure PCTCN2019077449-appb-000018
Figure PCTCN2019077449-appb-000019
作为实例，所述药物制剂包括：
Figure PCTCN2019077449-appb-000020
作为实例，所述药物制剂包括：
Figure PCTCN2019077449-appb-000021
所述化合物1钾盐选自如下化合物：
Figure PCTCN2019077449-appb-000022
本发明还提供一种所述药物制剂的制备方法，包括：将第一活性组分、第二活性组分和药学上可接受的辅料进行混合。
根据本发明，所述制备可以为将上述组分及辅料经干法制粒后压片或装胶囊。
本发明还提供上述的药物制剂在制备用于预防和/或治疗心血管疾病的药物中的用途。
根据本发明，所述心血管疾病选自：高血压、心衰、慢性心衰、冠心病、风湿性心脏病、先天性心脏病、左心室功能不全、内皮功能障碍、舒张期功能障碍、肥厚性心肌病、糖尿病性心肌病、室上性和室性心律失常、房颤、心脏纤维化、心房扑动、有害的血管重塑、心肌梗塞及其后遗症、动脉粥样硬化、心绞痛、原发性和继发性肺性高血压、肾血管性高血压。
本发明还提供一种预防和/或治疗心血管疾病的方法，包括将上述药物制剂施用于有此需要的个体。
术语解释和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请记载和保护的范围。
本申请说明书和权利要求书记载的数值范围，当该数值范围被定义为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～10的整数”应当理解为 记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。当该数值范围被定义为“数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
本申请说明书使用的“一个或多个”包括一个或多于一个，例如包括但不限于1、2、3、4、5、6、7、8、9或10个。
本发明使用的“卤素”指氟、氯、溴和碘。
“取代”意指被任选一个或多个任意取代基取代。适宜的取代基包括但不限于卤素、氨基、氰基、硝基、羰基(氧代)、巯基(硫代)、羟基、醚基、羧基、烷基、烷氧基、烯基、炔基、烯氧基、炔氧基、芳基、杂芳基、环烷基、杂环基、取代的酰基、取代的磺酰基、取代的酯基、-CH＝CHCO 2H、-CH＝CHCO 2烷基。所述取代基可以无取代或任选被一个或多个相同或不同的选自上列的取代基进一步取代。
本发明单独使用或用作后缀或前缀的“烷基”意在包括具有1至20个碳原子(或若提供了碳原子的具体数目，则指该具体数目)的支链和直链饱和脂族烃基。例如，“C 1-C 8烷基”表示具有1、2、3、4、5、6、7或8个碳原子的直链和支链烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基和己基。当烷基被取代基取代时，其包括被一个或多个卤素取代的烷基，例如被1、2、3、4、5、6个卤素取代的烷基，例如三氟甲基。
本发明单独使用或用作后缀或前缀的“烯基”意在包括具有2至20个碳原子(若提供了碳原子的具体数目，则指该具体数目)的包含烯基或烯烃的支链和直链脂族烃基。例如，“C 2-6烯基”表示具有2、3、4、5或6个碳原子的烯基。烯基的实例包括但不限于乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基和4-己烯基。
本发明单独使用或用作后缀或前缀的“炔基”意在包括具有2至20个碳原子(或若提供了碳原子的具体数目，则指该具体数目)的包含炔基或炔烃的支链和直链脂族烃基。例如乙炔基、丙炔基(例如l-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基和1-甲基戊-2-炔基。
本发明使用的术语“芳基”指由5至20个碳原子构成的芳族环结构。例如：包含5、6、7和8个碳原子的芳族环结构可以是单环芳族基团例如苯基；包含8、9、10、11、12、13或14个碳原子的环结构可以是多环的例如萘基。芳环可在一个或多个环位置取代有上述那些取代基。术语“芳基”还包括具有两个或更多个环的多环环系，其中两个或更多个碳为两个相邻环所共有(所述环为“稠环”)，其中至少一个环是芳族的且其它环例如可以是环烷基、环烯基、环炔基、芳基和/或杂环基。多环的实例包括但不限于2,3-二氢-1,4-苯并二氧杂环己二烯和2,3-二氢-1-苯并呋喃。
本发明使用的术语“环烷基”意在包括具有指定数目碳原子的饱和环基。这些术语可包括稠合或桥接的多环系统。环烷基在其环结构中具有3至40个碳原子。在一个实施方案中，环烷基在其环结构中具有3、4、5或6个碳原子。例如，“C 3-6环烷基”表示例如环丙基、环丁基、环戊基或环己基的基团。
本发明使用的“杂芳基”指具有至少一个环杂原子(例如硫、氧或氮)的杂芳族杂环。杂芳基包括单环系统和多环系统(例如具有2、3或4个稠环)。杂芳基的实例包括但不限于吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、喹啉基、异喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、异噁唑基、吡唑 基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、苯并噻吩基、嘌呤基、咔唑基、苯并咪唑基、苯并噁唑基、氮杂苯并噁唑基、咪唑并噻唑基、苯并[1,4]二氧杂环己烯基、苯并[1,3]二氧杂环戊烯基等。在一些实施方案中，杂芳基具有3至40个碳原子且在其它实施方案中具有3至20个碳原子。在一些实施方案中，杂芳基包含3至14个、4至14个、3至7个或5至6个成环原子。在一些实施方案中，杂芳基具有1至4个、1至3个或1至2个杂原子。在一些实施方案中，杂芳基具有1个杂原子。
除非另有说明，本发明使用的术语“杂环基”指包含3至20个原子的饱和、不饱和或部分饱和的单环、二环或三环，其中1、2、3、4或5个环原子选自氮、硫或氧，除非另有说明，其可通过碳或氮连接，其中-CH 2-基团任选被-C(O)-代替；及其中除非另有相反说明，环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化；其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代；及环任选被一个或多个卤素取代。应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。若所述杂环基为二环或三环，则至少一个环可任选为杂芳族环或芳族环，条件是至少一个环是非杂芳族的。若所述杂环基为单环，则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基、四氢噻喃-1-氧化物、四氢噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。
根据不同取代基的位置和性质，本发明的化合物还可以包含一个或多个不对称中心。不对称碳原子可以(R)或(S)构型存在，仅有一个不对称中心时，产生外消旋混合物，含有多个不对称中心时，得到非对映异构体混合物。在某些情况下，由于围绕特定键的旋转受阻还可能存在不对称性，例如该中心键连接特定化合物的两个被取代的芳族环。并且，取代基还可以顺式或反式异构的形式存在。
式(I)化合物还包括其各自所有可能的立体异构体，其是单一立体异构体或所述立体异构体(例如R-异构体或S-异构体，或者E-异构体或Z-异构体)的任意比例的任意混合物的形式。可通过任意适合的现有技术方法(例如色谱法，特别是例如手性色谱法)实现本发明的化合物的单一立体异构体(例如单一对映异构体或单一非对映异构体)的分离。
另外，所述化合物还可以互变异构体的形式存在。本发明化合物包括式(I)化合物所有可能的互变异构体，其是单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。
所有这些异构体及它们的混合物都包括在本发明中。
本领域技术人员可以理解，本发明的中性内肽酶抑制剂和式(I)所示化合物可以以各种药学上可接受的盐的形式存在。如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基)，则其还可以形成内盐。
在本发明中，酸加成盐包括但不限于：盐酸盐、氢氟酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、焦硫酸盐、磷酸盐、硝酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、甲苯磺酸盐、氨基磺酸盐、2-萘磺酸盐、甲酸盐、乙酰乙酸、丙酮酸、月硅酸酯、肉桂酸酯、苯甲酸盐、醋酸盐、二羟乙酸盐、三氟乙酸盐、三甲基乙酸盐、丙酸盐、丁酸盐、己酸盐、庚酸盐、十一酸盐、硬脂酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、富马酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、草酸盐、水杨酸盐、琥珀酸盐、葡萄糖酸盐、奎尼酸盐、双羟萘酸盐、甘醇酸盐、酒石酸盐、乳酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、环戊烷丙酸 盐、二葡糖酸盐、3-羟基-2-萘甲酸盐、烟酸盐、扑酸盐、果胶酯酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、衣康酸盐、三氟甲磺酸盐、十二烷基硫酸盐、对甲苯磺酸盐、萘二磺酸盐、丙二酸盐、己二酸盐、藻酸盐、扁桃酸盐、葡庚酸盐、甘油磷酸盐、磺基水杨酸盐、半硫酸或硫氰酸盐、天冬氨酸盐等；碱加成盐例如碱金属盐、碱土金属盐和铵盐等，具体包括但不限于：钠盐、锂盐、钾盐、铵盐、铝盐、镁盐、钙盐、钡盐、铁盐、亚铁盐、锰盐、亚锰盐、锌盐、铵盐(包括与NH 3和有机胺形成的盐(NH 4盐)、甲铵盐、三甲铵盐、二乙铵盐、三乙铵盐、丙铵盐、三丙铵盐、异丙铵盐、叔丁铵盐、N,N'-二苄基乙二铵盐、二环己铵盐、1,6-己二铵盐、苄铵盐、乙醇铵盐、N,N-二甲基乙醇铵盐、N,N-二乙基乙醇铵盐、三乙醇铵盐、氨丁三醇盐、赖氨酸盐、精氨酸盐、组氨酸盐、葡糖铵盐、N-甲基葡糖铵盐、二甲基葡糖铵盐、乙基葡糖铵盐、葡甲铵盐、甜菜碱盐、咖啡因盐、氯普鲁卡因盐、普鲁卡因盐、利多卡因盐、吡啶盐、甲基吡啶盐、哌啶盐、吗啉盐、哌嗪盐、嘌呤盐、可可碱盐、胆碱盐)等。
本发明的有益效果包括：
1、本发明的药物制剂能有效改善了活性成分遇水产生的粘性，从而导致制剂无法崩解的问题，促进药物制剂崩散，释放药物。
2、本发明的药物制剂选用常规药用辅料，不需要添加特殊辅料或将其制成特殊制剂，通过处方调整实现快速崩解，使活性成分溶出，提高了生物利用度。
3、本发明出人意料地发现，通过控制关键辅料粒径，可以实现制剂物料流动性好，且均匀制粒性好，保证吸湿性强且在吸湿后会变粘的活性物质(活性成分)的有效崩解，从而使得活性成分溶出，提高了生物利用度。
4、本发明的药物制剂可用于预防和/或治疗高血压、慢性心衰等心血管疾病。
5、本发明的药物制剂通过例如口服等途径给药，使用方便。
6、本发明的药物制剂能够改善活性成分的成药性和患者的顺应性。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
第一活性组分：参照实施例1方法制备。
第二活性组分：式(I)所示的化合物可以通过本领域已知的方法，例如CN103709154A中公开的方法制备得到，在此将CN103709154A全文引入本文作为参考。式(II)所示的化合物可以通过将如式(I)所示的化合物与钾盐试剂接触反应制备得到。优选，将如式(I)所示的化合物与钾盐试剂在溶剂中接触反应制备得到式(II)化合物(具体见实施例2制备过程)。
通用制剂制备方法：
称取处方量的第一活性组分和第二活性组分，加入微晶纤维素、甘露醇、胶态二氧化硅后过40目筛后，再加入处方量的交联聚维酮混合5-10min，混合均匀，称取处方量的硬脂酸镁，混匀后干法制粒。
具体实施例的制备过程，根据处方辅料及用量进行调整。
实施例1：AHU 377铵盐的制备
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸铵(AHU 377铵盐或沙库必曲铵盐)的制备
Figure PCTCN2019077449-appb-000023
将沙库比曲加入丙酮溶剂中，室温搅拌，冷却至0-10℃，滴加稍过量的浓氨水，滴加完毕，继续搅拌4h，过滤，丙酮洗涤，真空干燥，得目标化合物，纯度大于99.5％，MS：m/z＝412.3(M+H) +。
AHU 377K的制备与此过程类似，将浓氨水替换为氢氧化钾。
实施例2：化合物1钾盐的制备
Figure PCTCN2019077449-appb-000024
将化合物1(1.0g)溶于二氯甲烷(5ml)中，室温搅拌形成溶液，往溶液中加入邻苯二甲酰亚胺钾(0.27g)，保温反应4h，冷却至-50℃，过滤，溶剂旋干所得固体为化合物1钾盐(无定型)。
熔点：135-145℃。
MS/HRMS m/z：717[M+H] +；677[M-K] -。
1H-NMR(400MHz,DMSO-d 6)δ：1.44(t，3H)，1.46(t，3H)，2.38(s，3H)，2.41(s，3H)，2.44(s，3H)，4.64(q，2H)，5.29(d，1H)，5.32(d，1H)，5.52(d，1H)，5.56(d，1H)，6.86(q，1H)，6.90(d，2H)，7.18(m，2H)，7.22(d，2H)，7.33(m，1H)，7.36(m，1H)，7.46(d，1H)，7.52(dd，1H)，7.75(d，1H)。
研究发现：仅由实施例1和2的API产品以(100mg：50mg)组成的组合物(不含制剂辅料)，在92.5％的相对湿度及25℃的温度下，5天吸湿增重28.31％。
实施例3
Figure PCTCN2019077449-appb-000025
Figure PCTCN2019077449-appb-000026
实施例4
Figure PCTCN2019077449-appb-000027
实施例5
Figure PCTCN2019077449-appb-000028
实施例6
Figure PCTCN2019077449-appb-000029
实施例7
Figure PCTCN2019077449-appb-000030
实施例8
Figure PCTCN2019077449-appb-000031
Figure PCTCN2019077449-appb-000032
实施例9
Figure PCTCN2019077449-appb-000033
实施例10
Figure PCTCN2019077449-appb-000034
实施例11
Figure PCTCN2019077449-appb-000035
在实施例3-11的制剂过程中，物料流动性好，使得终产品制粒均匀，经检测实施例3-11所得产品的片重差异均在±5％以内，硬度在80-120N之间。
本领域技术人员可以理解，本发明实施例并不限于所列举的实施例3-11，还包括以说明书中所列举的其他辅料进行替换的情况，例如，以纤维素乳糖、预胶化淀粉、蔗糖、山梨醇、磷酸钙等替换乳糖或甘露醇；以羧甲基纤维素钙、羧甲基淀粉钠、甲基纤维素、低取代羟丙基纤维素、壳聚糖等替换交联羧甲基纤维素钠或交联聚维酮；以滑石粉、十二烷基硫酸钠、硬脂酸钙、聚乙二醇4000、聚乙二醇6000、单硬脂酸甘油酯、氢化植物油等替换硬脂酸镁、十八烷基富马酸钠或胶态二氧化硅。经检测发现，替换后所得制剂的溶出度与实施例3-11接近。
对比实施例1
Figure PCTCN2019077449-appb-000036
Figure PCTCN2019077449-appb-000037
对比实施例2
Figure PCTCN2019077449-appb-000038
实施例12
将实施例3-11，对比实施例1-2按通用方法进行药物制剂的制备，测定药物溶出度。
仪器：RC-12AD智能溶出试验仪(天津天大天发科技有限公司)
方法：桨法，取样5ml，弃去初滤液2ml，取续滤液于液相小瓶中，滤膜为0.45μm孔径的聚醚砜材质。
介质：900ml含0.5％吐温80的0.1M HCl介质
转速：50rpm
温度：37℃
所得产品溶出度数据如下表所示：
Figure PCTCN2019077449-appb-000039
Figure PCTCN2019077449-appb-000040
Figure PCTCN2019077449-appb-000041
研究发现，本申请所得制剂处方具有良好的溶出效果。而当选用粒径不合适的微晶纤维素后，对产品溶出影响较大。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种药物制剂，其包括第一活性组分，第二活性组分和药学上可接受的辅料；其中，
    所述第一活性组分为选自中性内肽酶抑制剂及其前体、活性代谢产物、立体异构体、药学上可接受的盐、前药和溶剂合物中的至少一种；
    所述第二活性组分为选自如下式(I)所示化合物或其前体、活性代谢产物、立体异构体、药学上可接受的盐、前药和溶剂合物中的至少一种：
    Figure PCTCN2019077449-appb-100001
    其中，R代表
    Figure PCTCN2019077449-appb-100002
    Figure PCTCN2019077449-appb-100003
    或者
    Figure PCTCN2019077449-appb-100004
    每一个a相同或不同，独立地选自0、1、2、3、4、5或6；
    R 1代表取代或未取代的下列基团：C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、
    Figure PCTCN2019077449-appb-100005
    (CH 2) nO(CH 2) m、
    Figure PCTCN2019077449-appb-100006
    芳基或杂芳基，其中
    Figure PCTCN2019077449-appb-100007
    中的C b、C c分别代表包含b或c个碳原子的烷基；b、c相同或不同，彼此独立地选自0、1、2、3、4、5或6，其中(CH 2) nO(CH 2) m中的n、m相同或不同，彼此独立地选自1、2、3、4、5或6；
    R 2代表氢、卤素、硝基、氰基，或取代或未取代的下列基团：C 1-C 8烷氧基、C 1-C 8烷基、C 1-C 8烷基磺酰基氨基、芳基磺酰基氨基、杂芳基磺酰基氨基、氨基磺酰基、氨基；
    R 3代表不存在，或取代或未取代的下列基团：C 1-C 8烷基、C 1-C 8烷氧基、C 2-C 8烯烃氧基、C 2-C 8炔烃氧基、C 1-C 6烷氧基-C 1-C 6烷基、
    Figure PCTCN2019077449-appb-100008
    芳基、杂芳基，其中
    Figure PCTCN2019077449-appb-100009
    中的b、c代表烷基链的碳原子个数，独立地选自0、1、2、3、4、5或6；
    R 4代表氰基，或取代或未取代的下列基团：芳基、芳基磺酰基、杂芳基、C 1-C 8烷氧基、C 1-C 8硝酸酯(-C 1-C 8烷基-ONO 2)、C 1-C 8烷基；
    R 5代表氰基，或取代或未取代的下列基团：芳基、杂芳基、C 1-C 8烷氧基、C 1-C 8硝酸酯、C 1-C 8烷基、C 1-C 8烯基、C 1-C 8炔基、
    Figure PCTCN2019077449-appb-100010
    (CH 2) nO(CH 2) mCH 3，其中R 3、R 4、a、m、n彼此独立地具有如上所述的定义；
    R 6和R 7独立地代表氢，无取代或取代的C 1-C 8烷氧基或C 1-C 8烷基；
    R 8和R 9独立地代表氢，无取代或取代的C 1-C 8烷氧基、C 1-C 8硝酸酯或C 1-C 8烷基。
  2. 根据权利要求1所述的药物制剂，其特征在于，所述药学上可接受的辅料包括一种或多种崩解剂和/或一种或多种填充剂；优选地，所述药学上可接受的辅料中，至少一种崩解剂的粒径为100μm以下，和/或至少一种填充剂的粒径为100μm以下；更优选地，前述至少一种崩解剂和/或至少一种填充剂的粒径为95μm以下，如90μm以下，如85μm以下，如80μm以下，如75μm以下；更优选地，前述至少一种崩解剂和/或至少一种填充剂的粒径为10μm以上，如15μm以上，如20μm以上，如25μm以上，如30μm以上；优选地，所述至少一种崩解剂和/或至少一种填充剂为微晶纤维素；
    所述药学上可接受的第一辅料可以选自填充剂和崩解剂中的至少一种；优选地，所述填充剂和/或崩解剂中的至少一种的粒径为100μm以下，如95μm以下，如90μm以下，如85μm以下，如80μm以下，如75μm以下；更优选地，所述填充剂和/或崩解剂中的至少一种的粒径为10μm以上，如15μm以上，如20μm以上，如25μm以上，如30μm以上；优选地，所述填充剂和/或崩解剂中的至少一种的粒径为20-85μm，例如30-75μm；
    所述药学上可接受的辅料包括药学上可接受的第一辅料和任选存在或不存在的第二辅料；
    所述药学上可接受的第二辅料可以选自包括但不限于润滑剂、湿润剂、辅助脂质、助流剂、甜味剂、矫味剂、溶剂、溶解助剂、悬浮剂、等渗剂、缓冲液、防腐剂、抗氧剂、着色剂和起泡剂中的至少一种；
    优选地，所述填充剂为选自淀粉、乳糖、一水乳糖、纤维素乳糖、预胶化淀粉、蔗糖、甘露醇、山梨醇、磷酸钙、糊精、微晶纤维素、磷酸氢钙和甘露醇-淀粉复合物中的至少一种；例如，所述填充剂选自微晶纤维素和甘露醇中的至少一种；
    优选地，所述崩解剂为选自交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、甲基纤维素、低取代羟丙基纤维素、交联聚维酮和壳聚糖中的至少一种；例如，所述崩解剂选自交联羧甲基纤维素钠和交联聚维酮中的至少一种；
    优选地，所述润滑剂为选自硬脂酸镁、胶态二氧化硅、滑石粉、十二烷基硫酸钠、硬脂酸钙、聚乙二醇4000、聚乙二醇6000、十八烷基富马酸钠、单硬脂酸甘油酯和氢化植物油中的至少一种；例如，所述润滑剂选自硬脂酸镁和胶态二氧化硅中的至少一种；
    优选地，所述药学上可接受的辅料包括微晶纤维素和其他辅料，其中微晶纤维素的粒径可以为95μm以下，如90μm以下，如85μm以下，如80μm以下，如75μm以下；更优选地，微晶纤维素的粒径为10μm以上，如15μm以上，如20μm以上，如25μm以上，如30μm以上。
  3. 根据权利要求1或2所述的药物制剂，其特征在于，所述中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的盐相同或不同，彼此独立地选自Na、K或铵盐(如与NH 3的加成盐)；中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的前药相同或不同，彼此独立地选自包括但不限于甲酯、乙酯、丙酯、异丙酯、丁酯、异丁酯、叔丁酯；
    优选地，式(I)所示化合物具有如下式所示结构：
    Figure PCTCN2019077449-appb-100011
  4. 根据权利要求1～3任一项所述的药物制剂，其特征在于，所述第一活性组分选自下列化合物、其药学上可接受的盐、前药或溶剂合物中的至少一种：
    (S)-(2-联苯-4-基)-1-(1H-四唑-5-基)乙基氨基)甲基膦酸、
    (S)-5-(N-(2-(膦酰基甲基-氨基)-3-(4-联苯基)-丙酰基)-2-氨基乙基)四唑、
    (±)N-(1-氧-2-巯甲基-3-苯丙酰基)甘氨酸、
    N-((2S)-2-(4-联苯基甲基)-4-羧基-5-苯氧基戊酰基)甘氨酸、
    N-(α-鼠李吡喃糖基膦酰胺)-L-亮氨酸-L-色氨酸、
    N-[N-[(L)-1-羧基-2-苯基乙基]-L-苯丙氨酰基]-(R)-丙氨酸、
    N-[N-[((1S)-羧基-2-苯基)乙基]-(S)-苯丙氨酰基]-β-丙氨酸、
    N-(S)-[3-巯基-2-(2-甲基苯基)丙酰基]-(S)-2-甲氧基-(R)-丙氨酸、
    3-[1,1'-联苯]-4-基-N-[二苯氧基氧膦基)-甲基]-L-丙氨酰基-β-丙氨酸、
    N-(1-(N-羟基氨基甲酰基-甲基)-1-环戊烷羰基)-L-苯丙氨酸、
    N-[2-巯基甲基-3-苯基-丙酰基]-3-氨基苯甲酸、
    4-[[2-(巯基甲基)-1-氧代-3-苯基丙基]氨基]苯甲酸、
    N-[2-乙酰硫基甲基-3-苯基-丙酰基]-3-氨基苯甲酸、
    N-[2-巯基甲基-3-(2-甲基苯基)-丙酰基]-甲硫氨酸、
    N-(3-苯基-2-(巯基甲基)-丙酰基)-(S)-4-(甲基巯基)-甲硫氨酸、
    N-[1-(2-羧基-4-苯基丁基)-环戊烷羰基]-(S)-异丝氨酸、
    N-[2(S)-巯基甲基-3-(2-甲基苯基)丙酰基]-(S)-异丝氨酸、
    N-(1-(3-(N-叔丁氧羰基-(S)-脯氨酰氨基)-2(S)-叔丁氧基-羰基丙基)环戊烷羰基)-O-苄基-(S)-丝氨酸、
    3(S)-[2-(乙酰硫基甲基)-3-苯基-丙酰基]氨基-ε-己内酰胺、
    N-[1-(乙酰硫基甲基)-环戊羰基]-(S)-甲硫氨酸、
    N-[2-乙酰硫基甲基-3-(2-甲基-苯基)丙酰基]-甲硫氨酸、
    N-[2(S)-巯基甲基-3-(2-甲基苯基)-丙酰基]蛋氨酸、
    N-[2-(巯基甲基)-1-氧代-3-苯基丙基]-β-丙氨酸、
    7-[[2-(巯基甲基)-1-氧代-3-苯基丙基]氨基]-庚酸、
    N-[N-[1(S)-羧基-3-苯基丙基]-(S)-苯丙氨酰基]-(S)-异丝氨酸、
    N-[1-[[1(S)-羰基-3-苯基丙基]氨基]-环戊基羰基]-(S)-异丝氨酸、
    N-[1-[[1(S)-苄氧基羰基-3-苯基丙基]氨基]-环戊基羰基]-(S)-异丝氨酸、
    N-[N-[(L)-[1-[(2,2-二甲基-1,3-二氧戊环-4-基)-甲氧基]羰基]-2-苯基乙基]-L-苯丙氨酰基]-(R)-丙氨酸、
    N-(2-羧基-4-噻吩基)-3-巯基-2-苄基丙酰胺、
    2-(2-巯基甲基-3-苯基丙酰氨基)噻唑-4-基甲酸、
    (L)-(1-((2,2-二甲基-1,3-二氧戊环-4-基)-甲氧基)羰基)-2-苯基乙基)-L-苯丙氨酰基)-β-丙氨酸、
    顺-4-[[[1-[2-羧基-3-(2-甲氧基乙氧基)丙基]-环戊基]羰基]氨基]-环己烷甲酸、
    3-(1-[6-内-羟基甲基二环[2,2,1]庚烷-2-外-氨基甲酰基]环戊基)-2-(2-甲氧基乙基)丙酸、
    3-[1-(顺-4-羧基羰基-顺-3-丁基环己基-r-1-氨基甲酰基)环戊基]-2S-(2-甲氧基乙氧基-甲基)丙酸、
    (S)-顺-4-[1-[2-(5-茚满基氧基-羰基)-3-(2-甲氧基乙氧基)丙基]-1-环戊烷酰氨基]-1-环己烷甲酸、
    1,1'-[二硫代双-[2(S)-(2-甲基苄基)-1-氧代-3,1-亚丙基]]-双-(S)-异丝氨酸、
    1,1'-[二硫代双-[2(S)-(2-甲基苄基)-1-氧代-3,1-亚丙基]]-双-(S)-甲硫氨酸、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸、
    N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸。
    在优选的实施方案中，所述第一活性组分选自至少一种下列化合物：
    N-[1-(乙酰硫基甲基)-环戊羰基]-(S)-甲硫氨酸乙酯、
    N-[2-乙酰硫基甲基-3-(2-甲基-苯基)丙酰基]-甲硫氨酸乙酯、
    N-(1-(3-(N-叔丁氧羰基-(S)-脯氨酰氨基)-2(S)-叔丁氧基-羰基丙基)环戊烷羰基)-O-苄基-(S)-丝氨酸甲酯、
    3(S)-[2-(乙酰硫基甲基)-3-苯基-丙酰基]氨基-ε-己内酰胺、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(AHU 377或沙库必曲)、
    N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸、
    N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钠、
    N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钾、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸乙酯(AHU 377乙酯或沙库必曲乙酯)、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸钠(AHU 377Na或沙库必曲钠)、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸钾(AHU 377K或沙库必曲钾)、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸铵(AHU 377铵盐或沙库必曲铵盐)；
    优选地，所述第一活性组分选自AHU 377、AHU 377乙酯、AHU 377Na、AHU 377K、N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸、N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钠、N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钾或4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸铵中的至少一种。
  5. 根据权利要求1～4任一项所述的药物制剂，其特征在于，所述第二活性组分为选自式(I)所示化合物的K盐，例如下式(II)所示的化合物：
    Figure PCTCN2019077449-appb-100012
    其中，R具有权利要求1～4任一项所述的定义；
    优选地，式(I)所示化合物的K盐选自如下式所示结构：
    Figure PCTCN2019077449-appb-100013
    Figure PCTCN2019077449-appb-100014
  6. 根据权利要求1～5任一项所述的药物制剂，其特征在于，所述第一活性组分与所述第二活性组分的质量配比为(0.5-5):1，例如为(0.5-3):1，如质量配比为0.5:1，1:1，1.5:1，1.8:1，2:1，2.5:1，3:1，3.5:1，4:1，4.5:1，5:1。
  7. 根据权利要求1～6任一项所述的药物制剂，其特征在于，
    以重量份计，所述药物制剂包括：
    5-70重量份的第一活性组分，
    5-70重量份的第二活性组分，
    5-90重量份的填充剂，
    2-35重量份的崩解剂，
    0.1-10重量份的润滑剂；
    优选地，以重量份计，所述药物制剂包括：
    5-40重量份的第一活性组分，
    5-40重量份的第二活性组分，
    30-70重量份的填充剂，
    8-20重量份的崩解剂，
    0.5-5重量份的润滑剂。
  8. 根据权利要求1～7任一项所述的药物制剂，其特征在于，所述药物制剂可以制成适于口服、吸入、直肠、局部、胃肠外等给药途径的各种剂型，包括但不限于：适于口服的散剂、片剂(包括各种包衣片剂、缓释或控释片剂)、锭剂、胶囊剂(包括软胶囊和硬胶囊)、颗粒剂、丸剂、可分散粉末、水性或油性溶液剂、乳剂、酏剂、糖浆剂等，适于吸入的粉末或液体气雾剂等，适于直肠的栓剂等，适于局部的霜剂、软膏剂、凝胶、水性或油性溶液剂等，适于经胃肠外给药的静脉内、皮下或肌内注射用无菌水性或油性的注射剂或冻干粉针剂等；以及制成独立的药物组合于药物包形式。
  9. 权利要求1～8任一项所述药物制剂的制备方法，该方法包括：将第一活性组分、第二活性组分和药学上可接受的辅料进行混合；
    优选地，所述制备为将上述组分及辅料经干法制粒后压片或装胶囊。
  10. 权利要求1～8任一项所述药物制剂在制备用于预防和/或治疗心血管疾病的药物中的用途，其中，所述心血管疾病选自：高血压、心衰、慢性心衰、冠心病、风湿性心脏病、先天性心脏病、左心室功能不全、内皮功能障碍、舒张期功能障碍、肥厚性心肌病、糖尿病性心肌病、室上性和室性心律失常、房颤、心脏纤维化、心房扑动、有害的血管重塑、心肌梗塞及其后遗症、动脉粥样硬化、心绞痛、原发性和继发性肺性高血压、肾血管性高血压。
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CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 149709-62-6
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EP3763373B1 (en) 2025-12-17
CN110237071A (zh) 2019-09-17
EP3763373A1 (en) 2021-01-13
US20210052579A1 (en) 2021-02-25
JP7316289B2 (ja) 2023-07-27
EP3763373A4 (en) 2021-05-12
JP2021514977A (ja) 2021-06-17
US11337972B2 (en) 2022-05-24
CN110237071B (zh) 2022-03-22

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