CN110237072B - Process for preparing pharmaceutical composition - Google Patents
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- CN110237072B CN110237072B CN201810196583.8A CN201810196583A CN110237072B CN 110237072 B CN110237072 B CN 110237072B CN 201810196583 A CN201810196583 A CN 201810196583A CN 110237072 B CN110237072 B CN 110237072B
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- 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
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- 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
- A61K31/4164—1,3-Diazoles
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- 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
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- 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
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- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- 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
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- 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
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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
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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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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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
- A61P9/06—Antiarrhythmics
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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
- 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
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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
- A61P9/12—Antihypertensives
Abstract
The invention belongs to the field of medicines, and particularly relates to a preparation method of a pharmaceutical composition. The preparation process effectively solves the problems that the conventional process cannot prepare a medicinal composition with better performance and the like, so that the problem that the preparation cannot be disintegrated is solved, and the disintegration of the solid preparation and the release of the medicament can be promoted. The invention also effectively improves the fluidity of the materials and avoids the problems of decomposition of active ingredients and the like caused by high-temperature drying in the conventional process. Moreover, the preparation process of the preparation is simple and convenient, and the industrial mass production is easy to realize.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of a pharmaceutical composition.
Background
Cardiovascular diseases, also known as circulatory diseases, refer to a series of diseases involving the circulatory system. The circulatory system mainly comprises the heart and blood vessels (arteries, veins and capillaries). It is statistical that cardiovascular disease is the first cause of death worldwide, with more people dying from cardiovascular disease than any other cause of death annually. Common cardiovascular diseases include: hypertension, heart failure, coronary heart disease, atherosclerosis, angina pectoris, left ventricular insufficiency, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and sequelae thereof, and the like. Cardiovascular diseases generally have similar etiology, disease process and treatment method, and most cardiovascular diseases can be prevented by solving risk factors such as tobacco use, unhealthy diet, obesity, hypertension, diabetes and blood lipid increase.
The world health organization believes that the risk of cardiovascular disease recurrence or death can be substantially reduced by the use of a combination of drugs, for example, a cholesterol-lowering statin in combination with a blood pressure-lowering drug and aspirin. However, any combination of cardiovascular disease drugs of different mechanisms of action may not necessarily lead to a beneficial effect. Therefore, the development of pharmaceutical compositions that exert a combined therapeutic effect is likely to provide more effective prophylactic and therapeutic effects on cardiovascular diseases.
Neutral Endopeptidase (NEP) is a zinc metallopeptidase on the surface of endothelial cells, and the inhibition of NEP can increase the levels of Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP), C-type natriuretic peptide (CNP), bradykinin and adrenomedullin, so that the NEP inhibitor can play the roles of diuresis, expanding blood vessels, improving endothelial function and inhibiting the proliferation of vascular smooth muscle cells under pathological conditions, thereby improving the vascular hemodynamic state, preventing the formation of atherosclerosis and delaying the progress of heart failure.
Angiotensin II (Ang II) is an important regulatory factor for regulating fluid homeostasis in the body, and is involved in blood pressure, electrolyte balance, and the like, and a large number of documents have confirmed that Ang II plays a major role in the pathogenesis of hypertension, arterial disease, cardiac hypertrophy, heart failure, diabetes, nephropathy, and the like. Since the abnormal continuous increase of the Ang II level is directly related to the occurrence and development of hypertension, cardiac hypertrophy, heart failure and the like, the blocking of the Ang II binding with its specific Receptor can play a role in protecting the cardiovascular and cerebrovascular systems, the Angiotensin II Receptor Antagonists (ARBs) have been proved in a plurality of random clinical trials in terms of the benefit of reducing the mortality and disability rate of cardiovascular diseases, ARB drugs have been widely used abroad in the prevention and treatment of hypertension and other cardiorenal diseases, and the ARBs currently used clinically can be classified into 2 types according to the structure: (1) biphenyltetrazoles including losartan (losartan), valsartan (valsartan), irbesartan (irbesartan), candesartan cilexetil (candesartan cilexetil) and Azilsartan medoxomil; (2) non-biphenyltetrazole species, including eprosartan (eprosartan) and telmisartan (telmisartan).
Chinese patent application 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 pharmaceutical composition comprising a salt of the NEP inhibitor sabotabistril (Sacubitril, AHU377, CAS No.149709-62-6) and a pharmaceutical excipient and an AT1 receptor antagonist such as losartan, eprosartan, valsartan, irbesartan, etc. or a pharmaceutically acceptable salt thereof; chinese patent application CN105837464A discloses a pharmaceutical composition comprising the NEP inhibitor sabotazole sodium and a pharmaceutical excipient as well as other active ingredients such as losartan, eprosartan, valsartan, irbesartan, etc. or pharmaceutically acceptable salts thereof.
Chinese patent application publication No. CN103709154A discloses for the first time a compound having the structure shown in the following formula (I):
the compound is a sartan drug coupled with ligustrazine or NO donors, is a prodrug of an angiotensin II receptor antagonist azilsartan (TAK-536), and releases hydroxyligustrazine or NO in vivo, so that the compound and the azilsartan have effective synergistic effect, the antihypertensive effect is enhanced, a certain heart rate reducing effect is achieved, adverse reactions are reduced, and the heart and the kidney of a patient are also protected ideally. In further research, the applicant finds that the potassium salt of the compound shown in the formula (I), namely the compound shown in the formula (II) has better solubility, higher bioavailability, stronger and longer-acting blood pressure reducing effect, more obvious and longer-lasting heart rate reducing effect and high safety, has ideal protective effect on heart and kidney functions of patients, and can be used for preventing and/or treating hypertension, chronic heart failure, diabetic nephropathy and the like.
However, the applicant found in further research on the formulation process that it is difficult to obtain a pharmaceutical composition product having good dissolution release properties when a neutral endopeptidase and a compound represented by formula (I) are used to prepare a pharmaceutical composition using an existing process such as a fluidized bed process.
Disclosure of Invention
In order to improve the technical problems, the invention provides a preparation method of a pharmaceutical composition, which comprises the following steps:
(1) taking a first active component, a second active component, a first auxiliary material and a second auxiliary material;
(2) mixing the first active component, the second active component and the first auxiliary material, and dispersing the first active component and the second active component in the internally added first auxiliary material so as to obtain a first mixture;
(3) preparing the first mixture into first granules by adopting dry granulation;
(4) adding a second auxiliary material into the first granules through an external adding method, and mixing to obtain a second mixture;
and optionally, adding or not adding a third auxiliary material in the step (2) and/or (4);
wherein the content of the first and second substances,
the first active component is at least one selected from the group consisting of neutral endopeptidase inhibitors and precursors, active metabolites, stereoisomers, pharmaceutically acceptable salts, prodrugs and solvates thereof;
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, an active metabolite, a stereoisomer, a pharmaceutically acceptable salt, a prodrug and a solvate thereof:
wherein R represents
Or
Each a is the same or different and is independently selected from 0, 1,2, 3, 4, 5 or 6;
R1represents the following substituted or unsubstituted groups: c1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, alkynyl,
(CH2)nO(CH2)m、
Aryl or heteroaryl, wherein
C in (1)b、CcRepresents an alkyl group containing b or c carbon atoms, respectively; b. c are identical or different and are independently selected from 0, 1,2, 3, 4, 5 or 6Wherein (CH)2)nO(CH2)mN and m in (A) are the same or different and are independently selected from 1,2, 3, 4, 5 or 6;
R2represents hydrogen, halogen, nitro, cyano, or the following substituted or unsubstituted groups: c1-C8Alkoxy radical, C1-C8Alkyl radical, C1-C8Alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aminosulfonyl, amino;
R3represents the following groups, absent, or substituted or unsubstituted: c1-C8Alkyl radical, C1-C8Alkoxy radical, C2-C8Alkylene oxy, C2-C8Alkenoxy radical, C1-C6alkoxy-C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,
Aryl, heteroaryl, wherein
Wherein b and c represent the number of carbon atoms in an alkyl chain and are independently selected from 0, 1,2, 3, 4, 5 or 6;
R4represents cyano, or the following substituted or unsubstituted groups: aryl, arylsulfonyl, heteroaryl, C1-C8Alkoxy radical, C1-C8Nitrate ester (-C)1-C8alkyl-ONO2)、C1-C8An alkyl group;
R5represents cyano, or the following substituted or unsubstituted groups: aryl, heteroaryl, C1-C8Alkoxy radical, C1-C8Nitric ester, C1-C8Alkyl radical, C1-C8Alkenyl radical, C1-C8Alkynyl, alkynyl,
(CH2)nO(CH2)mCH3Wherein R is3、R4A, m, n independently of one another have the definitions as described above;
R6and R7Independently represent hydrogen, unsubstituted or substituted C1-C8Alkoxy or C1-C8An alkyl group;
R8and R9Independently represent hydrogen, unsubstituted or substituted C1-C8Alkoxy radical, C1-C8Nitrate esters or C1-C8An alkyl group;
the first auxiliary material is at least one selected from a filling agent, a disintegrating agent and a lubricating agent;
the second auxiliary material is at least one selected from a disintegrating agent and a lubricating agent;
the third auxiliary material is selected from at least one of auxiliary lipid, glidant, sweetener, flavoring agent, preservative, antioxidant, colorant and foaming agent.
According to an exemplary embodiment of the invention, the neutral endopeptidase inhibitor or the pharmaceutically acceptable salt of the compound of formula (I), which are identical or different, are independently selected from Na, K or ammonium salts (e.g. with NH)3Addition salts of (a); the neutral endopeptidase inhibitor or the pharmaceutically acceptable prodrug of the compound of formula (I), which may be the same or different, is independently selected from the group including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl;
according to an embodiment of the invention, the first active ingredient is selected from at least one of the following compounds, pharmaceutically acceptable salts, prodrugs or solvates thereof:
(S) - (2-biphenyl-4-yl) -1- (1H-tetrazol-5-yl) ethylamino) methylphosphonic acid,
(S) -5- (N- (2- (phosphonomethyl-amino) -3- (4-biphenyl) -propionyl) -2-aminoethyl) tetrazole,
(+/-) N- (1-oxo-2-mercaptomethyl-3-phenylpropionyl) glycine,
N- ((2S) -2- (4-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl) glycine,
N- (alpha-rhamnopyranosylphosphonamide) -L-leucine-L-tryptophan,
N- [ N- [ (L) -1-carboxy-2-phenylethyl ] -L-phenylalanyl ] - (R) -alanine,
N- [ N- [ ((1S) -carboxy-2-phenyl) ethyl ] - (S) -phenylalanyl ] -beta-alanine,
N- (S) - [ 3-mercapto-2- (2-methylphenyl) propionyl ] - (S) -2-methoxy- (R) -alanine,
3- [1,1' -biphenyl ] -4-yl-N- [ diphenoxyphosphinyl) -methyl ] -L-alanyl-beta-alanine,
N- (1- (N-hydroxycarbamoyl-methyl) -1-cyclopentanecarbonyl) -L-phenylalanine,
N- [ 2-mercaptomethyl-3-phenyl-propionyl ] -3-aminobenzoic acid,
4- [ [2- (mercaptomethyl) -1-oxo-3-phenylpropyl ] amino ] benzoic acid,
N- [ 2-acetylthiomethyl-3-phenyl-propionyl ] -3-aminobenzoic acid,
N- [ 2-mercaptomethyl-3- (2-methylphenyl) -propionyl ] -methionine,
N- (3-phenyl-2- (mercaptomethyl) -propionyl) - (S) -4- (methylmercapto) -methionine,
N- [1- (2-carboxy-4-phenylbutyl) -cyclopentanecarbonyl ] - (S) -isoserine,
N- [2(S) -mercaptomethyl-3- (2-methylphenyl) propanoyl ] - (S) -isoserine,
N- (1- (3- (N-tert-butoxycarbonyl- (S) -prolinamido) -2(S) -tert-butoxy-carbonylpropyl) cyclopentanecarbonyl) -O-benzyl- (S) -serine,
3(S) - [2- (acetylthiomethyl) -3-phenyl-propionyl ] amino-epsilon-caprolactam,
N- [1- (acetylthiomethyl) -cyclopentylcarbonyl ] - (S) -methionine,
N- [ 2-acetylthiomethyl-3- (2-methyl-phenyl) propionyl ] -methionine,
N- [2(S) -mercaptomethyl-3- (2-methylphenyl) -propionyl ] methionine,
N- [2- (mercaptomethyl) -1-oxo-3-phenylpropyl ] -beta-alanine,
7- [ [2- (mercaptomethyl) -1-oxo-3-phenylpropyl ] amino ] -heptanoic acid,
N- [ N- [1(S) -carboxy-3-phenylpropyl ] - (S) -phenylalanyl ] - (S) -isoserine,
N- [1- [ [1(S) -carbonyl-3-phenylpropyl ] amino ] -cyclopentylcarbonyl ] - (S) -isoserine,
N- [1- [ [1(S) -benzyloxycarbonyl-3-phenylpropyl ] amino ] -cyclopentylcarbonyl ] - (S) -isoserine,
N- [ N- [ (L) - [1- [ (2, 2-dimethyl-1, 3-dioxolan-4-yl) -methoxy ] carbonyl ] -2-phenylethyl ] -L-phenylalanyl ] - (R) -alanine,
N- (2-carboxyl-4-thienyl) -3-mercapto-2-benzyl propionamide,
2- (2-mercaptomethyl-3-phenylpropionylamino) thiazol-4-yl carboxylic acid,
(L) - (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) -methoxy) carbonyl) -2-phenylethyl) -L-phenylalanyl) -beta-alanine,
Cis-4- [ [ [1- [ 2-carboxy-3- (2-methoxyethoxy) propyl ] -cyclopentyl ] carbonyl ] amino ] -cyclohexanecarboxylic acid,
3- (1- [ 6-endo-hydroxymethylbicyclo [2,2,1] heptane-2-exo-carbamoyl ] cyclopentyl) -2- (2-methoxyethyl) propionic acid,
3- [1- (cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1-carbamoyl) cyclopentyl ] -2S- (2-methoxyethoxy-methyl) propionic acid,
(S) -cis-4- [1- [2- (5-indanyloxy-carbonyl) -3- (2-methoxyethoxy) propyl ] -1-cyclopentaneamido ] -1-cyclohexanecarboxylic acid,
1,1' - [ dithiobis- [2(S) - (2-methylbenzyl) -1-oxo-3, 1-propylidene ] ] -bis- (S) -isoserine,
1,1' - [ dithiobis- [2(S) - (2-methylbenzyl) -1-oxo-3, 1-propylidene ] ] -bis- (S) -methionine,
4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoic acid,
N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino-2R-methylbutyric acid.
According to an embodiment of the invention, said first active ingredient is selected from at least one of the following compounds:
n- [1- (acetylthiomethyl) -cyclopentylcarbonyl ] - (S) -methionine ethyl ester,
N- [ 2-acetylthiomethyl-3- (2-methyl-phenyl) propionyl ] -methionine ethyl ester,
N- (1- (3- (N-tert-butoxycarbonyl- (S) -prolinamido) -2(S) -tert-butoxy-carbonylpropyl) cyclopentanecarbonyl) -O-benzyl- (S) -serine methyl ester,
3(S) - [2- (acetylthiomethyl) -3-phenyl-propionyl ] amino-epsilon-caprolactam,
4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoic acid (AHU 377 or sabotamust),
N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino-2R-methylbutyric acid,
Sodium N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino-2R-methylbutyrate,
Potassium N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino-2R-methylbutyrate,
Ethyl 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoate (AHU 377 ethyl ester or sabotaryl ethyl ester),
Sodium 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoate (AHU 377Na or sabotatory sodium),
Potassium 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoate (AHU 377K or potassium shakubikok),
Ammonium 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoate (AHU 377 ammonium salt or sabotabicinchi ammonium salt).
For example, the first active ingredient is selected from the group consisting of AHU377, AHU377 ethyl ester, AHU377 Na, AHU377 ammonium salt, AHU 377K, N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino-2R-methylbutyric acid, sodium N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino-2R-methylbutyrate, potassium N- (3-carboxy-1-oxopropyl) - (4S) -p-phenylphenylmethyl) -4-amino-2R-methylbutyrate or 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoic acid ammonium salt.
According to an embodiment of the invention, the second active ingredient is a K salt selected from compounds of formula (I), such as compounds of formula (II) below:
wherein R has the definition as described above;
by way of example, the K salt of the compound of formula (I) is selected from the structures shown below:
according to an embodiment of the present invention, the filler in the first auxiliary material is at least one selected from the group consisting of starch, lactose monohydrate, cellulose lactose, pregelatinized starch, sucrose, mannitol, sorbitol, calcium phosphate, dextrin, microcrystalline cellulose, calcium hydrogen phosphate, and mannitol-starch complex; for example, the filler is selected from at least one of microcrystalline cellulose and mannitol.
According to an embodiment of the present invention, the disintegrant in the first auxiliary material is at least one selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropylcellulose, crospovidone, and chitosan; for example, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone.
According to an embodiment of the present invention, the lubricant in the first auxiliary material is at least one selected from magnesium stearate, colloidal silicon dioxide, talc, sodium lauryl sulfate, calcium stearate, polyethylene glycol 4000, polyethylene glycol 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 silicon dioxide.
According to an embodiment of the present invention, the disintegrant in the second auxiliary material is at least one selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropylcellulose, crospovidone, and chitosan; for example, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone.
According to an embodiment of the present invention, the lubricant in the second auxiliary material is at least one selected from magnesium stearate, colloidal silicon dioxide, talc, sodium lauryl sulfate, calcium stearate, polyethylene glycol 4000, polyethylene glycol 6000, sodium stearyl fumarate, glyceryl monostearate, hydrogenated vegetable oil; for example, the lubricant is selected from at least one of magnesium stearate and colloidal silicon dioxide.
Unless otherwise indicated, the above-mentioned suitable excipients of known specifications may be used in the pharmaceutical compositions of the invention. For example, suitable excipients may include commercially available excipients of various sizes, such as granules or micropowder. Suitable examples include, for example, microcrystalline cellulose having a particle size of from 10 to 200 μm, and/or a surface area of about 200m2Colloidal silica in terms of/g, as long as it can be applied to the production method of the present invention.
It will be appreciated that, in addition to solid excipients, excipients suitable for use in the pharmaceutical formulations of the invention may also be liquid or colloidal.
According to an embodiment of the present invention, in step (1), the prescribed amount of the first active component is 5 to 70 parts by weight, preferably 5 to 40 parts by weight.
According to an embodiment of the invention, the prescribed amount of the second active component is 5 to 70 parts, for example 5 to 40 parts.
According to an embodiment of the invention, the prescribed amount of said filler in the first auxiliary material is 5-90 parts, for example 30-70 parts.
According to an embodiment of the invention, the amount of said disintegrant in the first excipient is prescribed to be 1-29 parts, for example 1.5-26 parts, such as 6-15 parts.
According to an embodiment of the invention, the lubricant in the first auxiliary material is formulated in an amount of 0.025 to 7.5 parts, for example 0.05 to 5 parts, such as 0.25 to 2.5 parts.
According to an embodiment of the invention, the amount of said disintegrant in the second excipient is prescribed to be 0.3-17.5 parts, for example 0.5-8 parts, such as 2-5 parts.
According to an embodiment of the invention, the lubricant in the second auxiliary material is formulated in an amount of 0.025 to 7.5 parts, for example 0.05 to 5 parts, such as 0.25 to 2.5 parts.
According to an embodiment of the present invention, in the step (2), the first active ingredient, the second active ingredient, the filler of the first auxiliary material, the disintegrant, and the lubricant may be mixed, and then the lubricant of the first auxiliary material may be added and mixed;
according to an embodiment of the invention, the mixing time of step (2) is 2 to 15 minutes, for example 5 to 10 minutes.
According to an embodiment of the present invention, the conditions for the dry granulation in step (3) are: the width of the roller is 25mm, the diameter of the roller is 200mm, and the gap of the roller is 2 mm; the feeding speed is 7-70rpm, preferably 7rpm, 34rpm, 50rpm and 70rpm, the pinch roller speed is 3-12rpm, preferably 3rpm, 8rpm and 12rpm, and the whole grain speed is 200rpm and 700rpm, preferably 200rpm, 550rpm, 600rpm and 700 rpm.
According to an embodiment of the present invention, the mixing time of said step (4) is 1 to 12 minutes, preferably 3 to 5 minutes.
Preferably, the second mixture obtained in step (4) comprises first granules and second auxiliary materials attached to the surfaces of the first granules.
According to an embodiment of the invention, the attachment may be achieved by adsorption or adhesion, such as physisorption.
According to an embodiment of the invention, the method further comprises step (5): preparing the second mixture into a formulation, for example, tableting or filling the second mixture into a capsule;
according to an embodiment of the present invention, the tabletting in step (5) may be followed by a drying step, which may be drying under reduced pressure; preferably, the drying temperature is 5-60 deg.C, such as 10-50 deg.C, e.g., 10 deg.C, 20 deg.C, 25 deg.C, 40 deg.C, 50 deg.C; preferably, the drying time is from 0.5 to 18 hours, for example from 1 to 16 hours.
The invention also provides a pharmaceutical composition prepared by the preparation method.
The invention also provides a pharmaceutical agent precursor comprising a mixture of the first particles and a second excipient attached to the surface of the first particles.
The invention also provides a pharmaceutical preparation, which comprises the pharmaceutical preparation precursor formed by preparation molding. Preferably, the formulation shaping may be e.g. a tableting or capsule filling step. Preferably, the tabletting may be followed by a drying step.
The invention also provides application of the pharmaceutical composition in preparing a medicament for preventing and/or treating cardiovascular diseases.
According to the invention, the cardiovascular disease is selected from: hypertension, heart failure, chronic heart failure, coronary heart disease, rheumatic heart disease, congenital heart disease, left ventricular insufficiency, endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina pectoris, primary and secondary pulmonary hypertension, and renovascular hypertension.
The present invention also provides a method for the prevention and/or treatment of cardiovascular diseases comprising administering said pharmaceutical composition or pharmaceutical formulation precursor to an individual in need thereof.
Term interpretation and description
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and definitions of groups and structures of compounds after combination are intended to fall within the scope of the present disclosure.
Where a range of numerical values is recited in the specification and claims herein, and where the range of numerical values is defined as an "integer," it is understood that the two endpoints of the range are recited and each integer within the range is recited. For example, "an integer of 0 to 10" should be understood to describe each integer of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10. When a range of values is defined as "a number," it is understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "a number of 0 to 10" should be understood to not only recite each integer of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10, but also to recite at least the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
As used herein, "one or more" includes one or more than one, for example, including but not limited to 1,2, 3, 4, 5, 6, 7, 8, 9, or 10.
"halogen" as used herein refers to fluorine, chlorine, bromine and iodine.
"substituted" means substituted with optionally one or more optional substituents. Suitable substituents include, but are not limited to, halogen, amino, cyano, nitro, carbonyl (oxo), mercapto (thio), hydroxyl, ether, carboxyl, alkyl, alkoxy, alkenyl, alkynyl, alkenyloxy, alkynyloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted acyl, substituted sulfonyl, substituted ester, -CH ═ CHCO2H、-CH＝CHCO2An alkyl group. The substituents may be unsubstituted or optionally further substituted by one or more of the same or different substituents selected from the list above.
"alkyl" used herein alone or as a suffix or prefix is intended to include both branched and straight chain saturated aliphatic hydrocarbons having from 1 to 20 carbon atoms (or the specific number of carbon atoms if provided)And (4) a base. For example, "C1-C8Alkyl "denotes straight-chain and branched alkyl groups having 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. When the alkyl group is substituted with a substituent, it includes alkyl groups substituted with one or more halogens, for example alkyl groups substituted with 1,2, 3, 4, 5, 6 halogens, for example trifluoromethyl.
"alkenyl" as used herein alone or as a suffix or prefix, is intended to include both branched and straight chain aliphatic hydrocarbon groups containing alkenyl or alkene groups having from 2 to 20 carbon atoms (the particular number of carbon atoms, if provided). For example, "C2-6Alkenyl "denotes alkenyl having 2,3, 4, 5 or 6 carbon atoms. Examples of 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 herein alone or as a suffix or prefix is intended to include both branched and straight chain aliphatic hydrocarbon groups containing alkynyl groups or alkynes having 2 to 20 carbon atoms (or a particular number of carbon atoms if provided). For example ethynyl, propynyl (e.g., l-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl.
The term "aryl" as used herein refers to an aromatic ring structure made up of 5 to 20 carbon atoms. For example: the aromatic ring structure containing 5, 6, 7 and 8 carbon atoms may be a monocyclic aromatic group such as phenyl; the ring structure containing 8, 9, 10, 11, 12, 13 or 14 carbon atoms may be polycyclic, for example naphthyl. The aromatic ring may be substituted with the above substituents at one or more ring positions. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings"), wherein at least one of the rings is aromatic and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and/or heterocyclyl. Examples of polycyclic rings include, but are not limited to, 2, 3-dihydro-1, 4-benzodioxine and 2, 3-dihydro-1-benzofuran.
The term "cycloalkyl" as used herein is intended to include saturated cyclic groups having the specified number of carbon atoms. These terms may include fused or bridged polycyclic ring systems. Cycloalkyl groups have 3 to 40 carbon atoms in their ring structure. In one embodiment, the cycloalkyl group has 3, 4, 5, or 6 carbon atoms in its ring structure. For example, "C3-6Cycloalkyl "denotes a group such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
As used herein, "heteroaryl" refers to a heteroaromatic heterocycle having at least one ring heteroatom (e.g., sulfur, oxygen, or nitrogen). Heteroaryl groups include monocyclic ring systems and polycyclic ring systems (e.g., having 2,3, or 4 fused rings). Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, benzoxazolyl, azabenzoxazolyl, imidazothiazolyl, benzo [1,4] dioxanyl, benzo [1,3] dioxolyl, and the like. In some embodiments, heteroaryl groups have from 3 to 40 carbon atoms and in other embodiments from 3 to 20 carbon atoms. In some embodiments, heteroaryl groups contain 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, heteroaryl has 1 to 4, 1 to 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.
The term "heterocyclyl", as used herein, unless otherwise specified, 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, which, unless otherwise specified, may be attached through carbon or nitrogen, wherein-CH is2-the group is optionally replaced by-c (o) -; and wherein, unless otherwise stated to the contrary, a ring nitrogen atom or a ring sulfur atomOptionally oxidized to form an N-oxide or S-oxide or optionally quaternized; wherein-NH in the ring is optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens. It is understood that when the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is monocyclic, it is not necessarily aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1, 1-dioxide, 1H-pyridin-2-one, and 2, 5-dioxoimidazolidinyl.
Depending on the position and nature of the various substituents, the compounds of the present invention may also contain one or more asymmetric centers. Asymmetric carbon atoms may exist in either the (R) or (S) configuration, with only one asymmetric center yielding a racemic mixture and multiple asymmetric centers yielding a diastereomeric mixture. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, for example, the central bond connects two substituted aromatic rings of a particular compound. Also, the substituents may exist in cis or trans isomeric forms.
The compounds of formula (I) also include all possible stereoisomers of each, either in the form of a single stereoisomer or any mixture of said stereoisomers (e.g. R-or S-isomers, or E-or Z-isomers) in any proportion. Separation of individual stereoisomers (e.g. individual enantiomers or individual diastereomers) of the compounds of the invention may be achieved by any suitable prior art method (e.g. chromatography, particularly, for example, chiral chromatography).
In addition, 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.
All such isomers and mixtures thereof are included in the present invention.
It will be appreciated by those skilled in the art that the NEP 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; these compounds may also form inner salts if they contain both an acidic centre (e.g. carboxyl) and a basic centre (e.g. amino).
In the present invention, acid addition salts include, but are not limited to: hydrochloride, hydrofluoride, hydrobromide, hydroiodide, sulfate, pyrosulfate, phosphate, nitrate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate, sulfamate, 2-naphthalenesulfonate, formate, acetoacetic acid, pyruvic acid, lauric acid ester, cinnamate, benzoate, acetate, glyoxylate, trifluoroacetate, pivalate, propionate, butyrate, hexanoate, heptanoate, undecanoate, stearate, ascorbate, camphorate, camphorsulfonate, citrate, fumarate, malate, maleate, hydroxymaleate, oxalate, salicylate, succinate, gluconate, quinic acid, pamoate, glycolate, tartrate, lactate, 2- (4-hydroxybenzoyl) benzoate, Cyclopentanepropionate, digluconate, 3-hydroxy-2-naphthoate, nicotinate, embonate, pectinate, 3-phenylpropionate, picrate, pivalate, itaconate, triflate, dodecylsulfate, p-toluenesulfonate, napadisylate, malonate, adipate, alginate, mandelate, glucoheptonate, glycerophosphate, sulfosalicylate, hemisulfate or thiocyanate, aspartate, and the like(ii) a Base addition salts such as alkali metal salts, alkaline earth metal salts, ammonium salts and the like, specifically include but are not limited to: sodium salt, lithium salt, potassium salt, aluminum salt, magnesium salt, calcium salt, barium salt, ferric salt, ferrous salt, manganese salt, manganous salt, zinc salt and ammonium salt (including NH)3Salts with organic amines (NH)4Salts), methylammonium salts, trimethylammonium salts, diethylammonium salts, triethylammonium salts, propylammonium salts, tripropylammonium salts, isopropylammonium salts, tertiarybutylammonium salts, N' -dibenzylethylenediamine salts, dicyclohexylammonium salts, 1, 6-hexadimethrine salts, benzylammonium salts, ethanolamine salts, N-dimethylethanolamine salts, N-diethylethanolamine salts, triethanolamine salts, tromethamine salts, lysine salts, arginine salts, histidine salts, glucammonium salts, N-methylglucammonium salts, dimethylglucammonium salts, ethylglucammonium salts, meglumine salts, betaine salts, caffeine salts, chloroprocaine salts, procaine salts, lidocaine salts, pyridine salts, picoline salts, piperidine salts, morpholine salts, piperazine salts, purine salts, cacao salt, choline salts), and the like.
The invention has the beneficial effects that:
1. the preparation process, the preparation and the precursor thereof are particularly suitable for preparing the pharmaceutical composition with good dissolution or release performance, which comprises the compound shown in the formula (I) or the precursor, the active metabolite, the stereoisomer, the pharmaceutically acceptable salt, the prodrug and the solvate thereof, surprisingly improve the problems that the conventional process is difficult to prepare the pharmaceutical composition with satisfactory performance and the like, remarkably improve the disintegration performance of the preparation, and can effectively promote the release of the medicine.
2. The invention effectively improves the material fluidity problem in the process, for example, the material fluidity is improved, thereby ensuring that the tablet weight difference of the product in the tabletting process is smaller, and the invention has the advantages that the tablet weight difference of the final product can be controlled within +/-5 percent, and the like.
3. By adopting the process, the preparation and the precursor thereof, the preparation process can be carried out at normal temperature, and the decomposition of active ingredients caused by a high-temperature drying step is avoided.
4. The preparation process of the preparation is simple and convenient, and is easy for industrial mass production.
Detailed Description
The present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
EXAMPLE 1 preparation of the first active component
Adding the Saccharum sinensis Roxb koji into an acetone solvent, stirring at room temperature, cooling to 0-10 ℃, dropwise adding slightly excessive concentrated ammonia water, continuously stirring for 4 hours after dropwise adding, filtering, washing with acetone, and drying in vacuum to obtain AHU377 ammonium salt with the purity of more than 99.5%, MS: m/z 412.3(M + H)+。
AHU 377K was prepared similarly to this procedure, replacing concentrated ammonia with potassium hydroxide.
Example 2 preparation of a second active ingredient: preparation of Compound 1K
Dissolving the compound 1(1.0g) in dichloromethane (5ml), stirring at room temperature to form a solution, adding potassium phthalimide (0.27g) into the solution, keeping the temperature for reaction for 4 hours, cooling to-50 ℃, filtering, and spin-drying the solvent to obtain a solid which is the compound 1K (amorphous).
Melting point: 135 ℃ and 145 ℃.
MS/HRMS m/z：717[M+H]+；677[M-K]-。
1H-NMR(400MHz,DMSO-d6)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)。
The research finds that: compositions consisting of the products of examples 1 and 2 alone (100 mg: 50mg) without formulation adjuvants, hygroscopic and gained 28.31% weight for 5 days at a relative humidity of 92.5% and a temperature of 25 ℃.
Example 3
Weighing compound 1K, AHU377 ammonium salt, mannitol in first adjuvant, microcrystalline cellulose, colloidal silicon dioxide, and crospovidone according to prescription amount, mixing, sieving with 40 mesh sieve, adding into mixer, mixing for 6 min, adding into the first adjuvant magnesium stearate, and mixing for 3 min.
The granules are prepared by adopting a dry granulating machine, and the specific granulating conditions are as follows: the width of the roller is 25mm, the diameter of the roller is 200mm, and the gap of the roller is 2 mm; the feeding speed is 34rpm, the pressing wheel speed is 3rpm, and the whole grain speed is 550 rpm.
Weighing colloidal silicon dioxide in the second auxiliary material according to the prescription amount, sieving the colloidal silicon dioxide by a 40-mesh sieve, mixing the colloidal silicon dioxide with crospovidone, magnesium stearate (an additional part) and the granules in the second auxiliary material, and putting the mixture into a mixer to mix for 3 minutes to obtain the total mixed granules physically adsorbed with each other. Tabletting the total mixed granules, wherein the hardness is 80-120N, and the tablet weight difference is within +/-5%. Drying at 25 deg.C under reduced pressure for 5 hr to obtain the final product.
Example 4
Weighing the compound 1K, AHU377 ammonium salt, microcrystalline cellulose, colloidal silicon dioxide and crospovidone in the first auxiliary material according to the prescription amount, mixing, sieving with a 40-mesh sieve, putting into a mixer, mixing for 6 minutes, adding the first auxiliary material magnesium stearate added internally, and mixing for 2 minutes.
The granules are prepared by adopting a dry granulating machine, and the specific granulating conditions are as follows: the width of the roller is 25mm, the diameter of the roller is 200mm, and the gap of the roller is 2 mm; the feeding rotating speed is 70rpm, the pressing wheel rotating speed is 3rpm, the whole grain rotating speed is 700rpm, and the mesh opening of the screen mesh is 18 meshes.
Weighing colloidal silicon dioxide in the second auxiliary material according to the prescription amount, sieving the colloidal silicon dioxide by a 40-mesh sieve, mixing the colloidal silicon dioxide with crospovidone, magnesium stearate (an additional part) and the granules in the second auxiliary material, and putting the mixture into a mixer to mix for 3 minutes to obtain the total mixed granules physically adsorbed with each other. Tabletting the total mixed granules, wherein the hardness is 80-120N, and the tablet weight difference is within +/-5%. Drying under reduced pressure at 20 deg.C for 8 hr to obtain the final product.
Example 5
Weighing compound 1K, AHU377 potassium salt of formula amount, mannitol in first adjuvant, microcrystalline cellulose, colloidal silicon dioxide, and crospovidone, mixing, sieving with 40 mesh sieve, adding into mixer, mixing for 5 min, adding magnesium stearate of first adjuvant, and mixing for 2 min.
The granules are prepared by adopting a dry granulating machine, and the specific granulating conditions are as follows: the width of the roller is 25mm, the diameter of the roller is 200mm, and the gap of the roller is 2 mm; the feeding speed is 7rpm, the pressing wheel speed is 12rpm, and the whole grain speed is 200 rpm.
Weighing colloidal silicon dioxide in the second auxiliary material according to the prescription amount, sieving the colloidal silicon dioxide by a 40-mesh sieve, mixing the colloidal silicon dioxide with crospovidone, magnesium stearate (an additional part) and the granules in the second auxiliary material, and putting the mixture into a mixer to mix for 5 minutes to obtain the total mixed granules physically adsorbed with each other. Tabletting the total mixed granules, wherein the hardness is 80-120N, and the tablet weight difference is within +/-5%. Drying at 40 deg.C under reduced pressure for 3 hr to obtain the final product.
Example 6
Weighing the compound 1K, AHU377 ammonium salt, microcrystalline cellulose, colloidal silicon dioxide and crospovidone in the first auxiliary material according to the prescription amount, mixing, sieving with a 40-mesh sieve, putting into a mixer, mixing for 6 minutes, adding the first auxiliary material magnesium stearate added internally, and mixing for 3 minutes.
The granules are prepared by adopting a dry granulating machine, and the specific granulating conditions are as follows: the width of the roller is 25mm, the diameter of the roller is 200mm, and the gap of the roller is 2 mm; the feeding speed is 50rpm, the pressing wheel speed is 8rpm, and the whole grain speed is 600 rpm.
Weighing colloidal silicon dioxide in the second auxiliary material according to the prescription amount, sieving the colloidal silicon dioxide by a 40-mesh sieve, mixing the colloidal silicon dioxide with crospovidone, magnesium stearate (an additional part) and the granules in the second auxiliary material, and putting the mixture into a mixer to mix for 3 minutes to obtain the total mixed granules physically adsorbed with each other. Tabletting the total mixed granules, wherein the hardness is 80-120N, and the tablet weight difference is within +/-5%. Drying under reduced pressure at 10 deg.C for 16 hr to obtain the final product.
Example 7
Weighing compound 1K, AHU377 ammonium salt, mannitol in first adjuvant, microcrystalline cellulose, colloidal silicon dioxide, and crospovidone, mixing, sieving with 40 mesh sieve, adding into mixer, mixing for 5 min, adding magnesium stearate, and mixing for 3 min.
The granules are prepared by adopting a dry granulating machine, and the specific granulating conditions are as follows: the width of the roller is 25mm, the diameter of the roller is 200mm, and the gap of the roller is 2 mm; the feeding speed is 34rpm, the pressing wheel speed is 12rpm, and the whole grain speed is 200 rpm.
Weighing colloidal silicon dioxide in the second auxiliary material according to the prescription amount, sieving the colloidal silicon dioxide by a 40-mesh sieve, mixing the colloidal silicon dioxide with crospovidone, magnesium stearate (an additional part) and the granules in the second auxiliary material, and putting the mixture into a mixer to mix for 5 minutes to obtain the total mixed granules physically adsorbed with each other. Tabletting the total mixed granules, wherein the hardness is 80-120N, and the tablet weight difference is within +/-5%. Drying at 50 deg.C under reduced pressure for 1 hr to obtain the final product.
Comparative example 1
Preparing 8% HPC (hydroxypropyl cellulose) solution for later use, weighing compound 1K, AHU377 ammonium salt, microcrystalline cellulose in the first auxiliary material and crospovidone according to the prescription amount, putting into a fluidized bed, spraying the prepared adhesive for granulation, and drying in the fluidized bed until the water content is less than or equal to 1.0%. Weighing colloidal silicon dioxide in the second auxiliary material according to the prescription amount, sieving the colloidal silicon dioxide with a 40-mesh sieve, mixing the colloidal silicon dioxide with the crospovidone, the magnesium stearate and the first granules in the second auxiliary material, and putting the mixture into a mixer to mix for 3 minutes. Tabletting the total mixed granules, wherein the hardness is 80-120N, and the tablet weight difference is within +/-5%. Drying to obtain the finished product.
Comparative example 2
Weighing the compound 1K, AHU377 ammonium salt and microcrystalline cellulose, mannitol, crospovidone and colloidal silicon dioxide in the first auxiliary material according to the prescription amount, putting the mixture into a mixer to mix for 7 minutes, adding magnesium stearate as the second auxiliary material to mix for 3 minutes, and tabletting by using a rotary tablet press. Due to the fact that the particle sizes of the AHU377 ammonium salt and the compound 1K are small and about 10 mu m, the flowability is poor, the problem of flowability of a sample in a tabletting process in a vertical compression process cannot be solved due to the addition of a large amount of flow aids and fillers, the sample weight difference fluctuation in the tabletting process is large (the tablet weight difference is larger than 5%), and a qualified finished product cannot be obtained.
Comparative example 3
Preparing 8% of HPC ethanol solution for later use, weighing compound 1K, AHU377 ammonium salt with the prescription amount, mannitol, microcrystalline cellulose and crospovidone in the first auxiliary material, putting the mixture into a wet granulator, premixing for 8 minutes, spraying the prepared adhesive solution for granulation, finishing granules by using a swing granulator with a 20-mesh sieve after the preparation is finished, and drying until the water content is less than or equal to 1%. Weighing colloidal silicon dioxide in the second auxiliary material according to the prescription amount, mixing the colloidal silicon dioxide with the colloidal silicon dioxide, sieving the colloidal silicon dioxide with a 40-mesh sieve, mixing the colloidal silicon dioxide with crospovidone, magnesium stearate (an additional part) and the first granules in the second auxiliary material, and putting the mixture into a mixer to mix for 3 minutes. The total mixed particles are tabletted, the hardness is 100- & lt 140 & gtN, and the tablet weight difference is within +/-5%. Drying to obtain the finished product.
Example 8
The dissolution rates of the drugs of examples 3 to 7, comparative examples 1 and 3 were measured.
The instrument comprises the following steps: RC-12AD intelligent dissolution tester (Tianjin Datiansujian science and technology Co., Ltd.).
The method comprises the following steps: and (3) sampling 5ml by a paddle method, discarding 2ml of primary filtrate, taking subsequent filtrate in a liquid phase small bottle, and using a filter membrane made of polyether sulfone with the pore diameter of 0.45 mu m.
Medium: 900ml of 0.1M HCl medium containing 0.5% Tween 80.
Rotating speed: 50 rpm.
Temperature: 37 ℃ is carried out.
The dissolution data of the obtained product are shown in the following table:
the results show that the preparation process of the invention can prepare products with unexpected dissolution effect, and is suitable for industrial production.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method of preparing a pharmaceutical composition, comprising:
(1) taking a first active component, a second active component, a first auxiliary material and a second auxiliary material;
(2) mixing the first active component, the second active component and the first auxiliary material, and dispersing the first active component and the second active component in the internally added first auxiliary material so as to obtain a first mixture;
(3) preparing the first mixture into first granules by adopting dry granulation;
(4) adding a second auxiliary material into the first granules through an external adding method, and mixing to obtain a second mixture;
and optionally, adding or not adding a third auxiliary material in the step (2) and/or (4);
wherein the content of the first and second substances,
the first active component is:
potassium 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoate or
Ammonium 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoate;
the second active component has the structure
The first auxiliary materials are a filler, a disintegrating agent and a lubricant, wherein the filler is microcrystalline cellulose or microcrystalline cellulose and mannitol; the disintegrant is crospovidone; the lubricant is magnesium stearate and colloidal silicon dioxide;
the second auxiliary material comprises a disintegrant and a lubricant, wherein the disintegrant is crospovidone; the lubricant is magnesium stearate and colloidal silicon dioxide;
in step (1), the prescribed amount of the first active ingredient is 100mg, and the prescribed amount of the second active ingredient is 50 mg;
the prescription amount of the filler in the first auxiliary material is 300 mg of microcrystalline cellulose or 200 mg of microcrystalline cellulose and 100mg of mannitol, the prescription amount of the disintegrant is 48 mg of crospovidone, and the prescription amount of the lubricant is 3mg of magnesium stearate and 3mg of colloidal silicon dioxide;
the prescription amount of the disintegrant in the second auxiliary material is 16 mg of crospovidone, and the prescription amount of the lubricant is 3mg of magnesium stearate and 3mg of colloidal silicon dioxide;
or in step (1), the prescribed amount of the first active ingredient is 100mg and the prescribed amount of the second active ingredient is 50 mg;
in the first auxiliary material, the prescription amount of the filler is 200 mg of microcrystalline cellulose, the prescription amount of the disintegrant is 37.5 mg of crospovidone, and the prescription amount of the lubricant is 3mg of magnesium stearate and 6mg of colloidal silicon dioxide;
the prescription amount of the disintegrant in the second auxiliary material is 12.5 mg of crospovidone, and the prescription amount of the lubricant is 3mg of magnesium stearate and 2mg of colloidal silicon dioxide;
or in step (1), the prescribed amount of the first active ingredient is 90 mg and the prescribed amount of the second active ingredient is 30 mg;
in the first auxiliary material, the prescription amount of the filler is 200 mg of microcrystalline cellulose and 100mg of mannitol, the prescription amount of the disintegrant is 37.5 mg of crospovidone, and the prescription amount of the lubricant is 3mg of magnesium stearate and 6mg of colloidal silicon dioxide;
the prescription amount of the disintegrant in the second auxiliary material is 12.5 mg of crospovidone, and the prescription amount of the lubricant is 3mg of magnesium stearate and 2mg of colloidal silicon dioxide;
the third auxiliary material is at least one of auxiliary lipid, glidant, flavoring agent, preservative, antioxidant, coloring agent and foaming agent.
2. The preparation method according to claim 1, wherein in the step (2), the first active ingredient, the second active ingredient, the filler of the first excipient, the disintegrant and the colloidal silicon dioxide are mixed, and magnesium stearate is added and mixed;
the second mixture obtained in the step (4) comprises the first particles and the second auxiliary materials attached to the surfaces of the first particles.
3. The method for preparing according to claim 1, wherein the method further comprises a step (5): the second mixture is prepared as a formulation.
4. The process according to claim 3, wherein the second mixture is tableted in the step (5), and a drying step is further performed after the tabletting, wherein the drying is drying under reduced pressure; the drying temperature is 5-60 ℃; the drying time is 0.5-18 hours.
5. The method according to claim 4, wherein the drying temperature is 10 to 50 ℃; the drying time is 1-16 hours.
6. A pharmaceutical composition prepared by the process of any one of claims 1 to 5.
7. A prodrug of a pharmaceutical agent comprising a first particle and a second excipient attached to the surface of the first particle;
wherein the first granules and the second excipient have the definitions of any one of claims 1 to 5.
8. A pharmaceutical preparation which is prepared by forming the pharmaceutical preparation precursor of claim 7 into a preparation.
9. Use of the pharmaceutical composition of claim 6 for the preparation of a medicament for the prevention and/or treatment of cardiovascular diseases;
the cardiovascular disease is selected from: hypertension, heart failure, coronary heart disease, rheumatic heart disease, congenital heart disease, left ventricular insufficiency, endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina pectoris.
10. The use according to claim 9, wherein the heart failure is selected from chronic heart failure; the hypertension is selected from primary and secondary pulmonary hypertension, renal vascular hypertension.
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| CN201810196583.8A CN110237072B (en) | 2018-03-09 | 2018-03-09 | Process for preparing pharmaceutical composition |
| PCT/CN2019/077448 WO2019170135A1 (en) | 2018-03-09 | 2019-03-08 | Medicine composition preparation method |
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| CN105693543A (en) * | 2014-12-15 | 2016-06-22 | 四川海思科制药有限公司 | Sacubitril derivatives and medicine compositions, preparation methods and application thereof |
| CN106146333A (en) * | 2015-03-25 | 2016-11-23 | 四川海思科制药有限公司 | Sha Ku is than the novel crystal forms and its production and use of bent potassium salt |
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| CN107595788A (en) * | 2016-07-11 | 2018-01-19 | 武汉朗来科技发展有限公司 | A kind of oral solid formulation for the compound disintegrant system of oral solid formulation and containing the compound disintegrant system |
| WO2018064945A1 (en) * | 2016-10-08 | 2018-04-12 | 武汉朗来科技发展有限公司 | Pharmaceutical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010075347A2 (en) * | 2008-12-23 | 2010-07-01 | Takeda Pharmaceutical Company Limited | Methods of treating hypertension with at least one angiotensin ii receptor blocker and chlorthalidone |
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2018
- 2018-03-09 CN CN201810196583.8A patent/CN110237072B/en active Active
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- 2019-03-08 WO PCT/CN2019/077448 patent/WO2019170135A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1946717A (en) * | 2004-02-25 | 2007-04-11 | 武田药品工业株式会社 | Benzimidazole derivative and its use |
| CN103709154A (en) * | 2012-09-28 | 2014-04-09 | 武汉启瑞药业有限公司 | Benzimidazole derivatives, preparation method and medicinal use thereof |
| CN105693543A (en) * | 2014-12-15 | 2016-06-22 | 四川海思科制药有限公司 | Sacubitril derivatives and medicine compositions, preparation methods and application thereof |
| CN106146333A (en) * | 2015-03-25 | 2016-11-23 | 四川海思科制药有限公司 | Sha Ku is than the novel crystal forms and its production and use of bent potassium salt |
| CN106854164A (en) * | 2015-12-09 | 2017-06-16 | 四川海思科制药有限公司 | A kind of novel crystal forms and its production and use of the Sha Ku than bent amino butanetriol salt |
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| WO2019170135A1 (en) | 2019-09-12 |
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