CN117137913A - New application of compound pharmaceutical composition of ARNi compound and amlodipine - Google Patents
New application of compound pharmaceutical composition of ARNi compound and amlodipine Download PDFInfo
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- CN117137913A CN117137913A CN202310623084.3A CN202310623084A CN117137913A CN 117137913 A CN117137913 A CN 117137913A CN 202310623084 A CN202310623084 A CN 202310623084A CN 117137913 A CN117137913 A CN 117137913A
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- arni
- amlodipine
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- pharmaceutical composition
- exp3174
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- 229960000528 amlodipine Drugs 0.000 title claims abstract description 55
- 150000001875 compounds Chemical class 0.000 title claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 31
- 241000320892 Clerodendrum phlomidis Species 0.000 title claims abstract description 28
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 23
- 206010020772 Hypertension Diseases 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims abstract description 17
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims description 56
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 claims description 29
- 229960003953 sacubitril Drugs 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 13
- 229960004005 amlodipine besylate Drugs 0.000 claims description 5
- TZNOWAJJWCGILX-BTJKTKAUSA-N (z)-but-2-enedioic acid;3-o-ethyl 5-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound OC(=O)\C=C/C(O)=O.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl TZNOWAJJWCGILX-BTJKTKAUSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- 230000036772 blood pressure Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- ZEUXAIYYDDCIRX-UHFFFAOYSA-N losartan carboxylic acid Chemical compound CCCCC1=NC(Cl)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 ZEUXAIYYDDCIRX-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000005541 ACE inhibitor Substances 0.000 description 3
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 3
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- DDLCKLBRBPYKQS-OXXXZDCLSA-L calcium 4-[[(2S,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate Chemical compound [Ca++].CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(cc1)-c1ccccc1)NC(=O)CCC([O-])=O.CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(cc1)-c1ccccc1)NC(=O)CCC([O-])=O DDLCKLBRBPYKQS-OXXXZDCLSA-L 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 3
- 229960004699 valsartan Drugs 0.000 description 3
- 102000008873 Angiotensin II receptor Human genes 0.000 description 2
- 108050000824 Angiotensin II receptor Proteins 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000003729 Neprilysin Human genes 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- 101100288143 Rattus norvegicus Klkb1 gene Proteins 0.000 description 2
- 102100025490 Slit homolog 1 protein Human genes 0.000 description 2
- 101710123186 Slit homolog 1 protein Proteins 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000036454 renin-angiotensin system Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940127282 angiotensin receptor antagonist Drugs 0.000 description 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000011706 wistar kyoto rat Methods 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a new application of a compound pharmaceutical composition of an ARNi compound and amlodipine, which is the application of the pharmaceutical composition containing the ARNi compound in preparing medicines for treating patients with hypertension with poor control of single drug of the ARNi.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel application of a compound pharmaceutical composition of an ARNi compound and amlodipine.
Background
At present, 10 hundred million patients suffering from hypertension are estimated worldwide, and the hypertension can cause damage to organs such as heart, brain, kidney and the like of the patients, has close relation with sugar and lipid metabolism disorder and diabetes, obviously reduces the life quality of the patients, and even endangers life when serious. There are six general classes of therapeutic drugs for hypertension: beta receptor blockers, angiotensin II receptor Antagonists (ARBs), angiotensin Converting Enzyme Inhibitors (ACEi), diuretics, calcium channel antagonists (CCBs), peripheral vasodilators, wherein both angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors are inhibitors of the renin-angiotensin-aldosterone system (RASS). However, the treatment of hypertension is currently suffering from a bottleneck period of unsatisfactory single drug control of 60% of patients, and the simultaneous use of two or more antihypertensive drugs in this case has a need and a value, so research on the combined application of the antihypertensive drugs is getting more and more attention from the medical world at home and abroad.
Currently, ARNi (inhibitors of angiotensin receptor enkephalinase, angiotensin II Receptor Blocker Neprilysin Inhibitor) drugs for the treatment of hypertension are only marketed in the chinese lot in 2017 under the trade name:the molecular structural unit is as follows:
in addition, WO2017125031Al discloses a series of complexes consisting of an angiotensin receptor antagonist metabolite (EXP 3174) and a NEP inhibitor (sacubrril) and exhibiting a certain effect on heart failure and hypertension, the molecular structural units of which are as follows:
hypertension drugs may be resistant or drug-resistant in clinical practice, and there is an unmet clinical need in clinic for new drugs to address such problems.
Disclosure of Invention
The invention aims to provide a novel application of a compound pharmaceutical composition of an ARNi compound and amlodipine, which is the application of a pharmaceutical composition containing the ARNi compound shown in a formula (I) in preparing a medicament for treating patients with hypertension with poor single-drug control of the ARNi.
The ARNi single drug-controlled poor hypertension refers to the complex shown in the formula (I) or the formula (II) which is poor in control,
wherein n=0-3;
the patients with hypertension having poor therapeutic effects of the ARNi single drug may also be accompanied by heart failure, angina pectoris, diabetes, hypertension in patients with diabetes, diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renal vascular hypertension, and the like.
The application comprises administering to a patient in need of such treatment a compound pharmaceutical composition comprising an effective amount of an ARNi complex of formula (I) and amlodipine.
Specifically, the invention is realized by the following technical scheme:
a novel use of a compound pharmaceutical composition of an ARNi complex and amlodipine, said novel use being the use of a pharmaceutical composition comprising an ARNi complex represented by formula (I) in the manufacture of a medicament for the treatment of a patient suffering from hypertension who has poor single administration control of ARNi, said ARNi complex being selected from complexes represented by formula (I):
wherein n=0-3,
wherein the ARNi single drug-controlled poor hypertension refers to the complex shown in the formula (I) or the formula (II) which is poor in control,
wherein n=0-3;
as a preferred embodiment of the present invention, in the ARNi complex represented by the formula (I), x=0.5, 1, 1.5 or 2, and n=0, 0.5, 1, 1.5, 2, 2.5 or 3.
As a preferred embodiment of the present invention, the ARNi complex represented by formula (I) is selected from complexes represented by formula (Ia):where n=0, 0.5, 1, 1.5, 2, 2.5 or 3.
As a preferred embodiment of the present invention, n=2 or 2.5 is preferred in the ARNi complex represented by formula (I).
As a preferred technical scheme of the present invention, amlodipine may be a pharmaceutically acceptable salt selected from amlodipine maleate and amlodipine besylate.
As a preferred embodiment of the present invention, the pharmaceutical composition may contain the ARNi complex (calculated as ARNi anhydrous free acid) in an amount of 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg or 600mg; the dosage of the amlodipine is 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg or 10mg.
As a preferred embodiment of the present invention, the administration unit of the pharmaceutical composition may contain the amount of the ARNi complex (calculated as ARNi anhydrous free acid) of 60mg, 120mg, 180mg, 240mg, 300mg, 360mg, 420mg, 480mg, and the amount of amlodipine of 2.5mg, or 5mg, or 10mg.
The method specifically comprises the following steps: arni+amlodipine = 60mg+2.5mg, 60mg+5mg, 60mg+10mg; or 120mg+2.5mg, 120mg+5mg, 120mg+10mg; or 180mg+2.5mg, 180mg+5mg, 180mg+10mg; or 240mg+2.5mg, 240mg+5mg, 240mg+10mg; or 300mg+2.5mg, 3000mg+5mg, 3000mg+10mg; or 360mg+2.5mg, 360mg+5mg, 360mg+10mg; or 420mg+2.5mg, 420mg+5mg, 420mg+10mg; or 480mg+2.5mg, 480mg+5mg, 480mg+10mg.
As a preferable technical scheme of the invention, the mass ratio of the ARNi compound (calculated by ARNi anhydrous free acid) to the amlodipine in the pharmaceutical composition is 1:1-200:1.
As a preferred embodiment of the present invention, the mass ratio of ARNi complex (calculated as ARNi anhydrous free acid) to amlodipine is specifically 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 18:1, 24:1, 30:1, 36:1, 42:1, 48:1, 54:1, 60:1, 66:1, 72:1, 78:1, 84:1, 90:1, 96:1, 102:1, 108:1, 114:1, 120:1, 126:1, 132:1, 138:1, 144:1, 150:1, 156:1, 162:1, 168:1, 174:1, 180:1, 186:1, 192:1.
The ARNi complex may be obtained by methods known in the art, wherein the ARNi complex disclosed in WO2017125031A1 and a method for its preparation are incorporated in the present invention.
As a more preferred embodiment of the present invention, the complex is selected from:
(EXP3174·AHU377)·1.5Ca·1H 2 O；
(EXP3174·AHU377)·1.5Ca·1.5H 2 O；
(EXP3174·AHU377)·1.5Ca·2H 2 O；
(EXP3174·AHU377)·1.5Ca·2.5H 2 O；
(EXP3174·AHU377)·1.5Ca·3H 2 O；
(EXP3174·AHU377)·2Ca·1H 2 O；
(EXP3174·AHU377)·2Ca·1.5H 2 O；
(EXP3174·AHU377)·2Ca·2H 2 O；
(EXP3174·AHU377)·2Ca·2.5H 2 O；
(EXP3174·AHU377)·2Ca·3H 2 O。
as will be appreciated by those skilled in the art, the complex is a supramolecular complex (complex) in which the alisartan ester metabolite (EXP 3174), AHU377, calcium ions (Ca 2+ ) And solvent molecules will be filled therein in the form of several structural units.
The supramolecular complexes (complexes) according to the invention are distinguished from mixtures of two active ingredients obtained by simple physical mixing. The XRD spectra of the obtained supermolecular complex (compound) are obviously different from those of EXP3174 and AHU377 calcium salt, the solubility of the supermolecular complex (compound) in various solvents (such as water, ethanol-water and the like) is obviously different, and other physicochemical properties such as hygroscopicity, melting point, infrared spectra and the like are obviously different.
Compared with the prior art, the invention has the following advantages and beneficial effects:
according to the test results, the pharmaceutical composition containing the ARNi and amlodipine of the present invention is expected to have a good antihypertensive effect when clinically used for treating patients suffering from hypertension, whose ARNi single drug therapy is poorly controlled.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the invention are not limited thereto.
In the following examples:
x-ray powder diffraction was detected using a sharp (Empyrean) X-ray diffractometer apparatus, detection conditions: cu target K alpha rays, voltage 40KV, current 40mA, emission slit 1/32 DEG, anti-scattering slit 1/16 DEG, anti-scattering slit 7.5mm,2 theta range: 3-60 deg., step size of 0.02 deg., dwell time of 40s per step.
Differential scanning calorimeter spectra were measured using a DSC204F1 differential scanning calorimeter apparatus from NETZSCH, germany, under the following conditions: atmosphere: n (N) 2 20mL/min; scanning procedure: from room temperatureThe temperature was raised to 250℃at 10℃per minute and a temperature rise curve was recorded.
The moisture content was measured using a TG209 thermogravimetric analyzer device from NETZSCH, germany, under the following conditions: atmosphere: n (N) 2 20mL/min; scanning procedure: room temperature-700 ℃, temperature rising rate: 10 ℃/min.
EXP3174 used in the examples was prepared by the company with a purity of 98.3%.
The AHU377 calcium salt used in the examples was made by the company and had a purity of 99.4%.
Example 1
Preparation of AHU377 Anhydrous free acid:
2.1g AHU377 calcium salt, 40mL isopropyl acetate were added to a 250mL single-necked flask, and 4.5mL stirring solution of 2mol/L hydrochloric acid was added at room temperature. Separating, collecting an organic layer, and washing the organic layer twice by using 20mL of water; decompression desolventizing at 35 deg.c to obtain AHU377 anhydrous free acid.
Example 2
Preparation of the composite: (prepared according to example 2 of patent WO2017125031A 1)
AHU377 anhydrous free acid 2.36g, EXP3174 g and 40mL acetone obtained in accordance with example 1 were added to a 250mL three-necked flask at room temperature, and the solution was cleared; adding 1.3 equivalent of calcium hydroxide solid and 1mL of water relative to AHU377 at room temperature, stirring at room temperature for 10h, adding 40mL of acetone, reacting for 8h, filtering by a Buchner funnel under the protection of nitrogen, leaching the solid by acetone to obtain white solid, vacuum drying at 35 ℃ for 8h, and drying to obtain 3.5g of solid (EXP 3174. AHU 377) 3- ·1.5Ca 2+ ·2.5H 2 O, 99% purity by HPLC. The test was repeated to obtain a sufficient amount of the drug effect test.
Example 3
Preparation of the composite: (prepared according to example 3 of patent WO2017125031A 1)
AHU377 anhydrous free acid 2.36g, EXP3174 g and 40mL acetone obtained in accordance with example 1 were added to a 250mL three-necked flask at room temperature, and the solution was cleared; 1.6 equivalent of calcium hydroxide solid and 0.6mL of water relative to AHU377 are added at room temperature, stirring is carried out for 6 hours at 35 ℃, 40mL of acetone is added, the mixture is reacted for 8 hours again, suction filtration is carried out on the solid through a Buchner funnel under the protection of nitrogen, the solid is leached by acetone, white solid is obtained, vacuum drying is carried out for 8 hours at 50 ℃, and 3.1g of solid (EXP 3174. AHU 377) is obtained after drying 3- ·1.5Ca 2+ ·2H 2 O. The test was repeated to obtain a sufficient amount of the drug effect test.
Example 4 effect of administration of arni+amlodipine to SHR rats with poorly controlled ARNi single drug
Experimental animals: WKY rats and SHR rats were purchased from Beijing vitamin Toril Biotechnology Co., ltd, and the animal room time was 13 weeks old, and experiments were conducted after a pot life of about 2 weeks.
Test article: ARNi and amlodipine are both supplied by Shenzhen Xinritai pharmaceutical Co.
Preparing the medicine: formulated with 0.5% cmc-Na, the drug concentrations formulated were all calculated as anhydrous free form.
Experimental grouping: animals were randomly divided into 4 groups based on their basal blood pressure and body weight the day prior to dosing, and the specific groupings and dosing regimens are shown in table 1.
TABLE 1 grouping of animals
After each dose group was continuously administered for 7 days, rats with poor blood pressure control (SBP. Gtoreq.140 mmHg) were selected for further experiments in groups 3 and 4 according to 24h blood pressure control, and the groups 3 were randomly divided into two groups (groups 3 and 5), and the specific grouping and administration schemes are shown in Table 2.
TABLE 2 grouping and administration of animals
The experimental method comprises the following steps: weigh Day 0 and Day 7, 14, respectively. The basic blood pressure is measured by Day 0 before administration, the blood pressure of animals is measured for 1,3,7 and 24 hours every week after administration, when the blood pressure is measured, the animals are placed in a rat bag matched with a BP-2010A noninvasive blood pressure meter, placed in a heat-preserving barrel at 37.5 ℃ for 2-3 minutes, and after the animal state is stable, the blood pressure measurement is started, and each animal is measured for 1-3 times.
Experimental results: as shown by test results, for hypertension with poor control of ARNi single drug, the compound pharmaceutical composition formed by the ARNi compound and amlodipine has a synergistic effect on blood pressure control, and better performance on 24h blood pressure control. The compound of ARNi and amlodipine can be suggested to more effectively prevent the occurrence of cardiovascular and cerebrovascular complications.
TABLE 3 24h blood pressure data after amlodipine alone with poor control of ARNi
Note that: * P＜0.05, *** p < 0.001 (vs SHR vehicle group); ## p < 0.01 (vs amlodipine).
The ARNi Complex of this example is the complex obtained in example 3, which is used in an amount of anhydrous free acid C 46 H 50 ClN 7 O 7 And (5) counting. The amlodipine is amlodipine besylate, and the dosage is free concentration C 20 H 25 N 2 O 5 Cl meter.
Example 5
5.1 dosing solution formulation:
ARNi, LCZ696 and amlodipine besylate are precisely weighed, 0.5 percent CMC-Na is respectively added for vortex dispersion, so that the concentration of ARNi or LCZ696 is 48mg/mL, and the concentration of amlodipine (free concentration) is 0.125, 0.25, 0.5, 1.0, 2.0 and 4.0mg/mL. Equal volumes of ARNi were mixed with 0.125, 0.25, 0.5, 1.0, 2.0 and 4.0mg/mL of amlodipine suspension, respectively, to give ARNi+amlodipine suspensions with drug concentrations of 24+0.0625, 24+0.125, 24+0.25, 24+0.5, 24+1.0 and 24+2.0mg/mL, equal volumes of LCZ696 were mixed with 1.0mg/mL of amlodipine suspension, to give LCZ 696+amlodipine suspensions with drug concentrations of 24+0.5, and either 48mg/mL of ARNi or LCZ696 suspension was diluted 2-fold with 0.5% CMC-Na, respectively, to give concentrations of ARNi and LCZ696 suspensions of 24mg/mL.
5.2 SD rats were dosed and blood was collected:
25 male SD rats of 200-300 g are randomly grouped, 3 rats are respectively used in ARNi and amlodipine combination groups, 2 rats are respectively used in LCZ696 and amlodipine combination groups, the administration doses of each group are shown in the following table, and the corresponding medicaments are respectively administrated by stomach irrigation of each group, and the administration volume is 10mL/kg. And (3) respectively collecting 100 mu L of whole blood from tail vein after 0.25, 0.5, 1, 2, 5, 7 and 24 hours after administration in EDTA-K2 anticoagulant tube, centrifuging at 10000rpm for 2min, separating plasma, and detecting EXP3174 or valsartan blood concentration by LC/MS/MS.
5.3 data statistics:
the WinNonlin software was used to calculate the EXP3174 or valsartan pharmacokinetic parameters.
5.4 experimental results:
5.5 rat PK experimental conclusion:
the exposure of EXP3174 after the rats are combined and lavaged with the ARNi and the amlodipine according to different proportions is different from that of the rats after being singly dosed with the same dose of ARNi, and the ARNi and the amlodipine are mixed according to 240: EXP3174 exposure was reduced (by about 11.5%) compared to 240mg/kg ARNi alone after 0.625 ratio combination administration, but EXP3174 exposure was increased compared to the ARNi alone group as the ARNi to amlodipine ratio was increased, with the highest increase in EXP3174 exposure (35.8%) for the 240:5 ratio of ARNi to amlodipine.
However, the exposure of valsartan after administration of LCZ696 and amlodipine in a ratio of 240:5 by intragastric administration of rats was increased by only 4.6%, which is significantly lower than that of the equivalent ratio ARNi+amlodipine.
In conclusion, the rat PK experiment shows that the combination of ARNi and amlodipine is better than ARNi single medicine and is also better than the combination of LCZ696 and amlodipine.
Note that: this example ARNi Complex is the complex obtained in example 3, which is used in an amount of anhydrous free acid C 46 H 50 ClN 7 O 7 And (5) counting. The amlodipine is amlodipine besylate, and the dosage is free concentration C 20 H 25 N 2 O 5 Cl meter.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (11)
1. A novel use of a compound pharmaceutical composition of an ARNi complex and amlodipine, said novel use being the use of a pharmaceutical composition comprising an ARNi complex represented by formula (I) in the manufacture of a medicament for the treatment of a patient suffering from hypertension who has poor single administration control of ARNi, said ARNi complex being selected from complexes represented by formula (I):
wherein n=0-3,
wherein the ARNi single drug-controlled poor hypertension refers to the complex shown in the formula (I) or the formula (II) which is poor in control,
wherein n=0-3;
2. the novel use of a compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, wherein x = 0.5, 1, 1.5 or 2, n = 0, 0.5, 1, 1.5, 2, 2.5 or 3.
3. The novel use of a compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, wherein said ARNi complex is selected from the group consisting of the complexes represented by formula (Ia):
where n=0, 0.5, 1, 1.5, 2, 2.5 or 3.
4. The novel use of a compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, wherein n = 2 or 2.5.
5. The new use of a compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, wherein amlodipine may be a pharmaceutically acceptable salt selected from amlodipine maleate and amlodipine besylate.
6. The novel use of a compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, wherein the pharmaceutical composition is administered in an amount of 0.5mg 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg or 10mg of amlodipine.
7. The novel use of a compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, wherein the pharmaceutical composition is administered in an amount of 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 590mg or 600mg.
8. The novel use of a compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, wherein the dosage of amlodipine is 2.5mg, or 5mg, or 10mg when the dosage unit of ARNi complex (calculated as ARNi anhydrous free acid) is 60mg, 120mg, 180mg, 240mg, 300mg, 360mg, 420mg, 480 mg.
9. The novel use of a compound pharmaceutical composition of an ARNi complex and amlodipine according to claim 1, wherein the mass ratio of ARNi complex (calculated by ARNi anhydrous free acid) to amlodipine in the pharmaceutical composition is 1:1-200:1.
10. The novel use of a compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, wherein the mass ratio of ARNi complex to amlodipine in the pharmaceutical composition (calculated as ARNi anhydrous free acid) is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 18:1, 24:1, 30:1, 36:1, 42:1, 48:1, 54:1, 60:1, 66:1, 72:1, 78:1, 84:1, 90:1, 96:1, 102:1, 108:1, 114:1, 120:1, 126:1, 132:1, 138:1, 144:1, 150:1, 156:1, 162:1, 168:1, 174:1, 180:1, 186:1, 192:1).
11. The novel use of a compound pharmaceutical composition of ARNi complex and amlodipine according to claim 1, wherein said complex is selected from the group consisting of:
(EXP3174·AHU377)·1.5Ca·1H 2 O；
(EXP3174·AHU377)·1.5Ca·1.5H 2 O；
(EXP3174·AHU377)·1.5Ca·2H 2 O；
(EXP3174·AHU377)·1.5Ca·2.5H 2 O；
(EXP3174·AHU377)·1.5Ca·3H 2 O；
(EXP3174·AHU377)·2Ca·1H 2 O；
(EXP3174·AHU377)·2Ca·1.5H 2 O；
(EXP3174·AHU377)·2Ca·2H 2 O；
(EXP3174·AHU377)·2Ca·2.5H 2 O；
(EXP3174·AHU377)·2Ca·3H 2 O。
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