CN116157119A - Pharmaceutical composition of ARNi and calcium ion antagonist and application thereof - Google Patents
Pharmaceutical composition of ARNi and calcium ion antagonist and application thereof Download PDFInfo
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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
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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
- A61K31/435—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
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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
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract
A pharmaceutical composition of ARNi and calcium ion antagonist and its application are disclosed, which can be used for treating hypertension and heart failure.
Description
The invention belongs to the technical field of pharmaceutical compositions, and relates to a pharmaceutical composition of ARNi and a calcium ion antagonist and application thereof.
WO2007056546A1 discloses a sodium salt compound (LCZ 696) of Valsartan (Valsartan) -Sha Kuba koji (Sacubitril, AHU 377) and a preparation method thereof, which are commercially available in 2017 in China under the trade name:
(trade name of foreign market)
2015) for heart failure. The molecular structural unit is as follows:
in addition, WO2017125031A1 discloses a series of complexes consisting of an angiotensin receptor antagonist metabolite (EXP 3174) and a NEP inhibitor (sacubrril) with the following molecular structural units:
amlodipine (amodipine) is a calcium ion antagonist which directly acts on peripheral arterial vascular smooth muscle to reduce peripheral vascular resistance and thereby reduce blood pressure. The existing forms of the pharmaceutical composition comprise racemized amlodipine, levoamlodipine, dextrorotatory amlodipine or a mixture of the levoamlodipine and the dextrorotatory amlodipine in any proportion; also, amlodipine may exist in the form of a salt, including amlodipine besylate, amlodipine maleate, and the like.
Prior art Hsiu-ling Hsiao, pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amodinine, or carbodilol, clinical Pharmacology in Drug Development,2015.02.11, doi:10.1002/cpdd.183, disclosed PK data for the combination of LCZ696 and amlodipine, which revealed that there was no increase in exposure of LCZ696+ amlodipine relative to valsartan alone of LCZ 696.
Disclosure of Invention
In view of the problems of the prior art, it is an object of the present invention to provide a pharmaceutical composition, characterized in that the pharmaceutical composition consists of ARNi and a calcium ion antagonist, wherein the structural units of ARNi are as follows:
(EXP3174·AHU377)·1.5Ca·nH 2 o, wherein n=1 to 3;
the structural formula of ARNi is as follows:
as a preferred embodiment of the present invention, n is selected from 1, 1.5, 2, 2.5 and 3.
As a preferred embodiment of the present invention, ARNi can be obtained by the preparation methods of WO2017125031A1 and WO2021143898A1, the relevant preparation methods and the substances obtained are incorporated into the present patent, and specifically ARNi is preferably selected from the group consisting of:
as a preferred embodiment of the present invention, the calcium ion antagonist is selected from amlodipine.
As a preferred embodiment of the present invention, the ARNi (as the anhydrous free acid C 46 H 50 ClN 7 O 7 Meter) with amlodipine (in C 20 H 25 N 2 O 5 Cl meter) is 240:1.25 to 20.
As a preferred embodiment of the present invention, the ARNi (as the anhydrous free acid C 46 H 50 ClN 7 O 7 Meter) with amlodipine (in C 20 H 25 N 2 O 5 Cl meter) is 240:1.25, 240:2.5, 240:5. 240:7.5 and 240:10, preferably 240:5.
as a preferred embodiment of the present invention, ARNi (as anhydrous free acid C in the pharmaceutical composition 46 H 50 ClN 7 O 7 Calculated) is selected from 60 to 480mg.
As a preferred embodiment of the present invention, the ARNi (as the anhydrous free acid C 46 H 50 ClN 7 O 7 Calculated) is selected from 60, 120, 240, 300, 360, 420 and 480mg.
As a preferred embodiment of the present invention, amlodipine (in form of C 20 H 25 N 2 O 5 Cl) is selected from 2.5-10 mg.
As a preferable embodiment of the present invention, the amlodipine (in C 20 H 25 N 2 O 5 Cl meter) is selected from 2.5, 5, 7.5 and 10mg.
As a preferred embodiment of the present invention, the pharmaceutical composition consists of ARNi and a calcium ion antagonist, wherein it comprises:
ARNi (in the form of anhydrous free acid C 46 H 50 ClN 7 O 7 Calculated) 120mg, amlodipine (in C 20 H 25 N 2 O 5 Cl meter) 2.5mg;
or ARNi (as anhydrous free acid C 46 H 50 ClN 7 O 7 Calculated) 240mg, amlodipine (in C 20 H 25 N 2 O 5 Cl meter) 5mg;
or ARNi (as anhydrous free acid C 46 H 50 ClN 7 O 7 Calculated) 360mg, amlodipine (in C 20 H 25 N 2 O 5 Cl meter) 7.5mg;
or ARNi (as anhydrous free acid C 46 H 50 ClN 7 O 7 Calculated) 480mg of amlodipine (in C 20 H 25 N 2 O 5 Cl meter) 10mg.
As a preferable technical scheme of the invention, the amlodipine
Selected from raceme amlodipine, and levo-amlodipine
Right-handed amlodipine or a mixture of left-handed amlodipine and right-handed amlodipine in any proportion; amlodipine is in the form of salt selected from amlodipine besylate
Amlodipine maleate, levamlodipine besylate and levamlodipine maleate
Etc.
As a preferred technical scheme of the invention, the pharmaceutical composition also contains more than one pharmaceutically acceptable carrier, and is prepared into a proper pharmaceutical dosage form by a preparation method, wherein the dosage form comprises solid oral administration and other dosage forms.
The invention further provides a use of a pharmaceutical composition, wherein the pharmaceutical composition is used for preparing a medicament for treating heart failure and/or hypertension, wherein the hypertension comprises primary hypertension, and the heart failure comprises heart failure with reduced ejection fraction and retained ejection fraction.
The application comprises the application of the ARNi single drug in the medicines of patients with poor control of hypertension/heart failure or the application of the calcium ion antagonist single drug in the medicines of patients with poor control of hypertension/heart failure.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) The invention provides a combination of ARNi and a calcium ion antagonist, which realizes synergistic effect through the mass ratio of specific ARNi and the calcium ion antagonist and is beneficial to improving the effect of treating heart failure and/or hypertension.
(2) The ARNi and amlodipine are prepared according to the mass ratio of 240: the exposure of EXP3174 is obviously increased after 1.25-20 proportion administration, and the mass ratio is 240:5 is most preferred.
(3) The exposure of the angiotensin receptor antagonist ARB (EXP 3174 of the ARNi complex of the invention compared to valsartan of LCZ 696) is significantly increased in the combination of amlodipine compared to the combination of amlodipine with LCZ 696.
(4) The application of the pharmaceutical composition further comprises the application of the ARNi single drug in the medicines of patients with the hypertension/heart failure, or the application of the calcium ion antagonist single drug in the medicines of the patients with the hypertension/heart failure, which are not well controlled, and the pharmaceutical composition has better effects.
The present invention will be described in further detail with reference to examples, but embodiments of the invention are not limited thereto.
The starting materials used in the present invention may be obtained by methods of preparation known in the art, including the methods described in WO2017125031A1 and WO2021143898A 1.
The ARNi of the examples of the present invention, unless otherwise specified, is a compound of the formula 46 H 50 ClN 7 O 7 And (3) counting:
the amlodipine is amlodipine besylate, and the dosage is free concentration C 20 H 25 N 2 O 5 Cl meter:
example 1
1.1 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.
1.2SD 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 table 1, and the corresponding medicaments are respectively administrated by stomach infusion, 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.
TABLE 1
1.3 data statistics:
the WinNonlin software was used to calculate the EXP3174 or valsartan pharmacokinetic parameters.
1.4 experimental results are shown in table 2 below:
TABLE 2
1.5 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 (about 11.5% reduction) compared to 240mg/kg ARNi alone after 0.625 formulation combination, but EXP3174 exposure was increased compared to the ARNi alone group with increasing ARNi to amlodipine formulation, wherein ARNi to amlodipine was calculated at 240:5 dosing EXP3174 exposure was the highest (35.8% increase).
However, LCZ696 and amlodipine are as per 240: the exposure rate of valsartan after gastric lavage administration of rats with the proportion of 5 is only 4.6%, and the exposure rate is obviously lower than that of the rats with the proportion of 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.
Example 2
The preparation methods described in WO2017125031A1 and WO2021143898A1 are adopted to respectively obtain ARNi with the following structural formulas, and the ARNi and amlodipine respectively correspond to 240:1.25 to 20, and the experimental results substantially identical to those of example 1 were obtained, showing a synergistic effect on the exposure to EXP 3174.
In summary, EXP3174 and AHU377 achieve synergistic effects of exposure to EXP3174 by combining 1.5Ca complex ARNi with amlodipine (in a free concentration mass ratio of 240:1.25-20, particularly mass ratio 240:5), and the combined use is expected to enhance effects for hypertension and/or heart failure.
Example 3 effect of amlodipine single drug administration on SHR rats with poor control of arni+amlodipine
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, amlodipine and LCZ696 are all supplied by Shenzhen Xinritai pharmaceutical Co., ltd.
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 specific groupings and dosing regimens are shown in table 3.
TABLE 3 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 group 4 was randomly divided into three groups (group 4, group 5 and group 6), and specific groupings and administration schemes are shown in Table 4.
TABLE 4 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: for hypertension with poor single amlodipine control, the compound pharmaceutical composition formed by the ARNi compound and the amlodipine has a synergistic effect on blood pressure control, is better in blood pressure control for 24 hours, and is better than the blood pressure reducing effect of the compound pharmaceutical composition formed by LCZ696 and the amlodipine, so that the compound pharmaceutical composition formed by the ARNi compound and the amlodipine can effectively prevent cardiovascular and cerebrovascular complications.
TABLE 5 24h blood pressure data after combination of amlodipine single drug and ARNi complex with poor control
Note that: * P<0.05, *** P<0.001 (vs SHR vehicle group); # P<0.05(vsARNi)； $$$ P<0.001 (vs amlodipine).
@ The ARNi Complex of this example 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 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 specific groupings and dosing regimens are shown in table 6.
TABLE 6 grouping of animals
After each dose group is continuously dosed for 7 days, rats with poor blood pressure control (SBP is more than or equal to 140 mmHg) are selected according to 24h blood pressure control conditions for continuous experiment, the group 3 is randomly divided into two groups (group 3 and group 5), and specific grouping and dosing schemes are shown in the table. .
TABLE 7 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 8 blood pressure data 24h after administration of 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 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 (12)
- A pharmaceutical composition comprising ARNi and a calcium antagonist, wherein the structural units of ARNi are as follows:(EXP3174·AHU377)·1.5Ca·nH 2 o, wherein n=1 to 3;the structural formula of ARNi is as follows:
- the pharmaceutical composition of claim 1, wherein ARNi is selected from the group consisting of:
- the pharmaceutical composition according to claim 1, wherein the calcium antagonist is selected from amlodipine.
- A pharmaceutical composition according to claim 3, wherein the ARNi (as anhydrous free acid C 46 H 50 ClN 7 O 7 Meter) with amlodipine (in C 20 H 25 N 2 O 5 Cl meter) is 240:1.25 to 20.
- The pharmaceutical composition of claim 4, wherein the ARNi (as anhydrous free acid C 46 H 50 ClN 7 O 7 Meter) with amlodipine (in C 20 H 25 N 2 O 5 Cl meter) is 240:1.25, 240:2.5, 240:5. 240:7.5 and 240:10.
- the pharmaceutical composition according to any one of claims 1 to 5, wherein ARNi (as anhydrous free acid C 46 H 50 ClN 7 O 7 Calculated) is selected from 60 to 480mg.
- The pharmaceutical composition of claim 6, wherein the ARNi (as anhydrous free acid C 46 H 50 ClN 7 O 7 Calculated) is selected from 60, 120, 240, 300, 360, 420 and 480mg.
- According to any one of claims 3 to 5The pharmaceutical composition is characterized in that amlodipine (in C 20 H 25 N 2 O 5 Cl) is selected from 2.5-10 mg.
- The pharmaceutical composition according to claim 8, wherein the amlodipine (in C 20 H 25 N 2 O 5 Cl meter) is selected from 2.5, 5, 7.5 and 10mg.
- The pharmaceutical composition according to any one of claims 3 to 5, wherein the amlodipine is selected from the group consisting of racemic amlodipine, levamlodipine, dexamlodipine, or a mixture of levamlodipine and dexamlodipine in any ratio; amlodipine is in the form of a salt selected from amlodipine besylate, amlodipine maleate, levamlodipine besylate and levamlodipine maleate.
- Use of a pharmaceutical composition according to any one of claims 1 to 10 for the preparation of a medicament for the treatment of heart failure and/or hypertension.
- The use of a pharmaceutical composition according to claim 11, wherein the use comprises the use of an ARNi single drug in the medicine of a patient with poorly controlled hypertension/heart failure or the use of a calcium antagonist single drug in the medicine of a patient with poorly controlled hypertension/heart failure.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021109858304 | 2021-08-26 | ||
| CN202110985830 | 2021-08-26 | ||
| PCT/CN2022/114659 WO2023025220A1 (en) | 2021-08-26 | 2022-08-25 | Pharmaceutical composition of arni and calcium ion antagonist, and application |
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| Country | Link |
|---|---|
| CN (1) | CN116157119A (en) |
| AR (1) | AR126886A1 (en) |
| TW (1) | TW202327582A (en) |
| WO (1) | WO2023025220A1 (en) |
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| CN118176190A (en) * | 2022-08-04 | 2024-06-11 | 深圳信立泰药业股份有限公司 | ARNi novel crystal form of compound and preparation method and application thereof |
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| AR057882A1 (en) * | 2005-11-09 | 2007-12-26 | Novartis Ag | DOUBLE ACTION COMPOUNDS OF ANGIOTENSIN RECEPTOR BLOCKERS AND NEUTRAL ENDOPEPTIDASE INHIBITORS |
| AU2017209250B2 (en) * | 2016-01-20 | 2021-07-29 | Shenzhen Salubris Pharmaceuticals Co. Ltd | Angiotensin II receptor antagonist metabolite and NEP inhibitor composite, and preparation method thereof |
| CN113230411B (en) * | 2017-12-04 | 2023-04-11 | 深圳信立泰药业股份有限公司 | Compound pharmaceutical composition of allisartan isoproxil or salt thereof and calcium channel antagonist |
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- 2022-08-25 TW TW111131990A patent/TW202327582A/en unknown
- 2022-08-25 WO PCT/CN2022/114659 patent/WO2023025220A1/en active Application Filing
- 2022-08-25 CN CN202280006430.7A patent/CN116157119A/en active Pending
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| WO2023025220A1 (en) | 2023-03-02 |
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