CN112569356B - A pharmaceutical composition containing diuretic - Google Patents
A pharmaceutical composition containing diuretic Download PDFInfo
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- CN112569356B CN112569356B CN201910942300.4A CN201910942300A CN112569356B CN 112569356 B CN112569356 B CN 112569356B CN 201910942300 A CN201910942300 A CN 201910942300A CN 112569356 B CN112569356 B CN 112569356B
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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
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim 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
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory 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
- A61P9/12—Antihypertensives
Abstract
The invention provides a pharmaceutical composition for treating pulmonary hypertension, which consists of effective dose of dual endothelin receptor antagonists, folic acid substances, indapamide and a carrier acceptable in pharmaceutics. The pharmaceutical composition provided by the invention can effectively reduce pulmonary hypertension and can reduce the side effect of a single active ingredient; in addition, the medicine composition can also facilitate the taking of the medicine by patients and improve the compliance.
Description
Technical Field
The invention provides a pharmaceutical composition for treating pulmonary hypertension, which consists of a dual endothelin receptor antagonist, folic acid substances, indapamide and a pharmaceutically acceptable carrier. The invention belongs to the field of pharmacy.
Background
Pulmonary Arterial Hypertension (PAH) refers to a disease state in which the mean pulmonary arterial pressure is not less than 25mmHg (1mmhg = 0.133kpa) and the pulmonary capillary wedge pressure is not more than 15mmHg at rest. PAH is usually progressive and seriously harmful to human health. The causes of PAH include idiopathic, hereditary, drug or poison induced, connective tissue disease, human Immunodeficiency Virus (HIV) infection, portal hypertension, and systemic-pulmonary circulatory shunt. The basic pathological changes of pulmonary hypertension are progressive vascular endothelium, smooth muscle proliferation and hypertrophy, fibrosis, vasoconstriction and in situ thrombosis. The pathophysiological mechanism relates to inflammation, dysfunction of vascular endothelium and blood platelets, abnormal proliferation of smooth muscle, fibrous tissue and collagen matrix under the action of various molecular mechanisms and the like. The incidence rate of Idiopathic PAH (IPAH) is about (7-8)/100 ten thousand, the incidence rate of connective tissue disease-related PAH (PAH-CTD) is about (5-6)/100 ten thousand, and the incidence rate in patients suffering from connective tissue diseases is up to 40%. The median survival time for PAH is 2.8 years if no effective treatment is available.
Endothelins play an important role in the development and progression of PAH. Normally, the body controls vasoconstriction, hyperplasia and hypertrophy through the balancing action of endothelin and its receptors. Both endothelin type receptors ETA and ETB are expressed in vascular smooth muscle cells, and ETA receptors are significantly more potent than ETB; vascular endothelium has equal expression of ETB as smooth muscle. Endothelin binds to ETA causing vasoconstriction, hyperplasia, hypertrophy, and fibrosis. Endothelin binds to ETB on endothelial cells and smooth muscle to accelerate endothelin degradation, vasodilation (elevated nitric oxide, prostacyclin I2 concentrations), anti-fibroplasia, and promote arterial hyperplasia (elevated nitric oxide concentrations), but binds to ETB on vascular smooth muscle to cause fibroplasia and vasoconstriction. The application of endothelin receptor antagonist to block the pathophysiological link of PAH is one of the targeted therapeutic methods. Endothelin receptor antagonists fall into two broad categories: one is a selective endothelin receptor antagonist such as ambrisentan (ambrisentan), sitaxentan (sitaxentan, withdrawn from the market), and the other is a dual endothelin receptor antagonist such as bosentan (bosentan, totallin), macitentan (macitentan). Research shows that the effect of double-blocking endothelin receptors is better from the viewpoint of interfering the pathophysiological link of PAH.
Although the dual endothelin receptor antagonist is the first-line drug for treating PAH at present, certain side effects can be generated in the using process, and risks are brought to patients. For example, a common adverse effect of bosentan is transaminase elevation, i.e., liver function impairment, and sitaxentan can cause severe peripheral edema or fluid retention. The incidence of edema caused by taking 100mg of sitaxsentan is about 9%, and the retention of body fluid can also cause cough, dyspnea, increased risk of heart failure and the like. Therefore, there is a need for product improvements in dual endothelin receptor antagonists that provide a more effective and/or less side-effect treatment for PAH patients, meeting important clinical needs.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition with remarkable curative effect and less toxic and side effects aiming at the defects of a double-endothelin receptor antagonist for treating PAH.
In order to achieve the purpose, the invention adopts the following technical scheme:
a pharmaceutical composition for treating pulmonary hypertension comprises the following components:
(1) A therapeutically effective amount of a dual endothelin receptor antagonist;
(2) A therapeutically effective amount of a folate;
(3) A therapeutically effective amount of indapamide;
(4) A pharmaceutically acceptable carrier.
In the invention, the dual endothelin receptor antagonist is macitentan.
In the pharmaceutical composition provided by the invention, macitentan can exist in the form of salts, esters, active metabolites or medicinal precursors. The macitentan provided by the invention is used as a pharmaceutical ingredient, and the existing forms of salts, esters, active metabolites or medicinal precursors of macitentan are also within the scope of the application. In the present invention, the therapeutically effective amount of macitentan is 2.5 to 10mg, preferably 5 to 10mg. The therapeutically effective amount of salts, esters, active metabolites or pharmaceutically acceptable precursors of macitentan and the like may be converted accordingly.
In the pharmaceutical composition provided by the invention, the folic acid substances comprise folic acid, 5-methyltetrahydrofolic acid, leucovorin calcium, L-methylfolic acid, folate, active metabolites of folic acid or folate and substances capable of releasing/generating folic acid in vivo, namely various folic acid forms including artificial synthesis and plant extract sources. The therapeutically effective amount of folic acid is selected from 0.2 to 1.2mg, preferably 0.4 to 0.8mg.
In the pharmaceutical composition provided by the invention, indapamide can exist in the forms of salts, esters, active metabolites or medicinal precursors and the like. The indapamide provided by the invention is used as a medicinal ingredient, and the existing forms of the salts, esters, active metabolites or medicinal precursors of the indapamide and the like are also included in the scope of the application. In the present invention, the therapeutically effective amount of indapamide is selected from 1.25 to 5mg, preferably 1.25 to 2.5mg. The therapeutically effective amounts of the salts, esters, active metabolites or pharmaceutically acceptable precursors of indapamide and the like can be converted accordingly.
In the present invention, the therapeutically effective amount of the active ingredient of the composition means a dose range in which the active ingredient of the composition exerts its pharmacological effect when combined with other active ingredients in the composition. The preferred dosage is the dosage of the effective component of the composition with a therapeutically effective dose, and the preferred dosage has better efficacy than the therapeutically effective dose. Generally, the pharmaceutically acceptable dose of the active ingredient of the composition will include an optimum dose or range of optimum doses for the composition to produce the maximum effect, which will benefit the patient even more.
Preferably, the pharmaceutical composition provided by the invention comprises 5mg of macitentan, 0.4mg of folic acid and 1.25mg of indapamide.
As another preferred mode, the pharmaceutical composition provided by the invention comprises 5mg of macitentan, 0.8mg of folic acid and 2.5mg of indapamide.
As another preferred mode, the pharmaceutical composition provided by the invention comprises 5mg of macitentan, 0.4mg of folic acid and 2.5mg of indapamide.
As another preferred mode, the pharmaceutical composition provided by the invention comprises 5mg of macitentan, 0.8mg of folic acid and 1.25mg of indapamide.
As another preferred mode, the pharmaceutical composition provided by the invention comprises 10mg of macitentan, 0.4mg of folic acid and 2.5mg of indapamide.
As another preferred mode, the pharmaceutical composition provided by the invention comprises 10mg of macitentan, 0.8mg of folic acid and 2.5mg of indapamide.
The pharmaceutical composition also contains pharmaceutically acceptable carriers, can be prepared into common oral preparations, including common tablets, common capsules, granules and the like, and the pharmaceutically acceptable carriers comprise excipients and auxiliary medicaments which are helpful for preparing active compounds into the pharmaceutical preparations when the pharmaceutical compositions are prepared into the tablets, such as microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite and one or more compositions of substances, belonging to the common knowledge in the field.
The pharmaceutical compositions of the present invention may also be used interchangeably as "combination kits". The above-mentioned "combined medicine box" is a box-shaped container, in which the medicine combination with several dosage forms is placed, and its administration instruction. The combined medicine box is more suitable for individual medicine.
The invention has the beneficial effects that: the medicinal effective components of the medicinal composition provided by the invention comprise a double endothelin receptor antagonist, a folic acid substance and indapamide, wherein the double endothelin receptor antagonist has side effects of edema, liver function damage, heart failure risk increase and the like when being used singly, and can achieve the synergistic effects of increasing the curative effect and lightening the side effects by combining with the indapamide and the folic acid substance, and in addition, the medicinal effective components can ensure that patients can take the medicinal composition conveniently and improve the treatment compliance.
The present invention is further described with reference to the following detailed description, which is not intended to be limiting, but rather is intended to cover all equivalent art-recognized alternatives falling within the scope of the invention.
Detailed Description
EXAMPLES 1-6 preparation of macitentan, folic acid and Indapamide (1000 tablets)
The preparation process comprises the following steps:
mixing macitentan, folic acid and indapamide, adding carboxymethyl starch sodium and sodium lauryl sulfate, mixing, adding microcrystalline cellulose and pregelatinized starch, mixing, adding appropriate amount of 10% polyvidone ethanol solution to obtain soft material, granulating, drying, grading, mixing the granule with water content of about 3% and appropriate amount of magnesium stearate, and tabletting to obtain 1000 tablets.
EXAMPLES 7-10 preparation of macitentan, folic acid and Indapamide (1000 tablets)
The preparation process comprises the following steps:
mixing macitentan, folic acid and indapamide, adding carboxymethyl starch sodium and sodium lauryl sulfate, mixing, adding microcrystalline cellulose and pregelatinized starch, mixing, adding appropriate amount of 10% polyvidone ethanol solution to obtain soft material, granulating, drying, grading, mixing the granule with water content of about 3% and appropriate amount of magnesium stearate, and tabletting to obtain 1000 tablets.
Example 11: efficacy and safety evaluation of macitentan/folic acid/indapamide for treating pulmonary hypertension rats
(one) method
And (3) experimental modeling: after 70 male SD rats were acclimatized for one week, 10 rats were used as a normal control group without any treatment. The remaining rats were intraperitoneally injected with 0.5ml Monocrotaline (MCT) 60mg/kg once, and two weeks later, pulmonary hypertension rats were formed and then randomly grouped.
Experimental groups and dosing regimens: normal control group (n = 10), the rats after model creation were randomly divided into model group and administration group, the specific grouping and administration dose are shown in table 1, each group was fasted overnight after 4 weeks of gavage administration, and each group was subjected to hemodynamic determination including right atrial pressure and pulmonary artery mean pressure after 48 hours of drug withdrawal.
Statistical analysis:
1. data and results of the test data are all as follows
And (4) showing. Comparison between groups by t test, P<0.05 statistically significant difference, P<0.01 had a very significant statistical difference, P>0.05 had no statistical difference.
2. In order to confirm the scientificity of the pharmaceutical composition provided by the invention, the three components of the pharmaceutical composition are reasonably compatible and can exert a synergistic interaction effect in combination with each other, rather than the simple superposition of pharmacological effects, and the results of the group experiments are analyzed by a golden mean Q value method. The Jinzheng average Q value, also known as a probability addition method, is calculated according to the pharmacological action of the combination of the three medicaments and the pharmacological action of the single use of the three medicaments in a dose-effect curve region by using the following calculation formula: q = E A+B+C /(E A +E B +E C -E A *E B -E A *E C -E B *E C -E A *E B *E C ) In the formula, the numerator represents the 'actually measured combined effect', the denominator represents the 'expected combined effect' (in order to satisfy the analysis of the relationship of the pharmacological actions of the components and the composition, the pharmacological actions are converted into the effect which can visually represent the strength of the pharmacological actions, and the calculation formula is as follows: ei =1-Pi/P model group, pi is a pharmacological index of each component, P model group is a pharmacological index of the model group), Q is a ratio of: when Q is less than 0.85, the combination of the two medicines is considered as antagonism; an additive effect is considered when less than 1.15 is greater than 0.85; a value greater than 1.15 is considered synergistic.
(II) results:
TABLE 1 Effect of the compositions of the invention on the hemodynamic index of rats: (
n＝10-12)
Compared with the normal control group, the preparation method has the advantages that, # P<0.05， ## P<0.01; comparison with model group<0.05，**P<0.01; in comparison with the macitentan group, □ P<0.05， □□ P<0.01。
TABLE 2 analysis of the Effect of the compositions of the invention on the hemodynamic index of patients with pulmonary hypertension in rats
The results in table 1 show that the mean pulmonary artery pressure and right atrial pressure levels are significantly increased in the model group compared with the normal control group, indicating that the modeling is successful. Compared with the model group, the pulmonary artery average pressure and the right atrial pressure of the macitentan group, the macitentan + folic acid + indapamide group are obviously reduced, the statistical difference is realized (P is less than 0.01), and the folic acid or the indapamide has no obvious effect on the pulmonary artery average pressure and the right atrial pressure when being singly used. Compared with a macitentan single-drug group, the macitentan + folic acid + indapamide group has further remarkable reduction of the mean pulmonary artery pressure and the right atrial pressure (P < 0.05). The Q values of the lung artery average pressure and the right atrial pressure of the composition analyzed by the Jinzhengyun Q value are respectively 1.34 and 1.30, and are both more than 1.15, so that the macitentan, folic acid and indapamide combined drug shows an unexpected synergistic effect.
Example 12: clinical trial of macitentan/folic acid/indapamide for treating pulmonary hypertension
(one) method
The source of the patient is: 43 patients with pulmonary hypertension who were admitted to a certain hospital in the cardiovascular department in 2015, 1 month to 2017, 1 month were taken as research objects, and all the patients who underwent pulmonary artery pressure detection through the right-heart duct all met the pulmonary hypertension diagnosis standards issued by the foundation of the national institute of heart disease (ACCF) and the american association of heart diseases (AHA) in 2009.
Patient exclusion criteria: excluding those that meet any of the following:
(1) patients with various types of congenital heart malformations; (2) patients with PAH who are closely related to other factors than congenital heart disease, such as genetics or HIV; (3) those who are confirmed to have pulmonary artery embolic diseases or pulmonary parenchymal diseases; (4) patients with tumor, kidney disease, endocrine system disease and metabolic systemic disease; (5) patients with bleeding history or having occurred in the digestive tract bleeding and intracranial bleeding within about 6 months; (6) blood pressure < 90/50mmHg or > 170/110mmHg, liver enzyme > 3 times the upper limit of normal value, creatinine > 450 value upper limit, creatinine, any one or more of the above three items; (7) patients who have received calcium ion antagonist-related drugs within about 3 months; (8) women in gestational period.
The treatment scheme comprises the following steps:
group a (22 people): macitentan tablets, indapamide tablets and folic acid tablets (5/2.5 mg/0.8 mg) are taken orally once a day for 20 weeks;
group B (21 people): macitentan tablets (10 mg), once daily, orally administered for 20 weeks
(II) detection and statistical method:
after each group had taken off drug, hemodynamic measurements were performed, including right atrial pressure and mean pulmonary artery pressure.
Statistical analysis: as above.
(III) results:
after 20 weeks of treatment, in terms of improving pulmonary artery mean pressure and right atrial pressure of patients with pulmonary hypertension, the combination of low dose (5 mg) of macitentan, 2.5mg of indapamide and 0.8mg of folic acid has the same therapeutic effect as 1mg of macitentan, and the pulmonary artery mean pressure and the right atrial pressure of the two groups are remarkably reduced compared with those before use, as shown in table 3.
TABLE 3 Effect of the compositions of the present invention on the hemodynamic index of patients with pulmonary hypertension: (
n＝21-22)
After 20 weeks of treatment, blood routine and biochemical indexes of two groups of patients are checked, and the result shows that 1 patient has anemia in a single-medicine macitentan 10 mg/day group, 2 transaminases are increased to 2-3 times before treatment, 2 cases have edema, and the adverse reactions do not occur in a triple-medicine group, possibly because the dose of macitentan in the triple-medicine combination is low, the corresponding side effects are small, and on the other hand, certain synergistic attenuation effects exist in the aspects of edema diuresis and liver protection due to compatible indapamide and folic acid.
From the research, the lower dosage of macitentan has the synergistic and attenuated effects on the indapamide and folic acid formula, and is beneficial to improving the medication compliance.
Claims (12)
1. A pharmaceutical composition for treating pulmonary hypertension comprises the following components:
(1) 2.5 to 10mg of dual endothelin receptor antagonists;
(2) 0.2 to 1.2mg of folic acid substances;
(3) 1.25 to 5mg of indapamide;
(4) A pharmaceutically acceptable carrier;
the dual endothelin receptor antagonist is macitentan or macitentan salts, and the folic acid substances comprise folic acid, 5-methyltetrahydrofolic acid, folinic acid and calcium levofolinate.
2. The pharmaceutical composition of claim 1, wherein: the macitentan is 5-10mg.
3. The pharmaceutical composition of claim 1, wherein: the folic acid substance is 0.4 to 0.8mg.
4. The pharmaceutical composition of claim 1, wherein: the content of the indapamide is 1.25-2.5 mg.
5. The pharmaceutical composition of claim 1, wherein: the composition of the medicine composition is 5mg of macitentan, 0.4mg of folic acid and 1.25mg of indapamide.
6. The pharmaceutical composition of claim 1, wherein: the composition of the medicine composition is 5mg of macitentan, 0.8mg of folic acid and 2.5mg of indapamide.
7. The pharmaceutical composition of claim 1, wherein: the pharmaceutical composition consists of 5mg of macitentan, 0.4mg of folic acid and 2.5mg of indapamide.
8. The pharmaceutical composition of claim 1, wherein: the composition of the medicine composition is 5mg of macitentan, 0.8mg of folic acid and 1.25mg of indapamide.
9. The pharmaceutical composition of claim 1, wherein: the composition of the medicine composition is 10mg of macitentan, 0.4mg of folic acid and 2.5mg of indapamide.
10. The pharmaceutical composition of claim 1, wherein: the composition of the medicine composition is 10mg of macitentan, 0.8mg of folic acid and 2.5mg of indapamide.
11. The pharmaceutical composition according to any one of claims 1 to 10, wherein: the medicine composition can be prepared into oral preparations such as common tablets, soft capsules and hard capsules.
12. Use of the pharmaceutical composition of any one of claims 1 to 10 in the preparation of a medicament for treating pulmonary hypertension.
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| CN201910942300.4A CN112569356B (en) | 2019-09-30 | 2019-09-30 | A pharmaceutical composition containing diuretic |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104224788A (en) * | 2014-09-29 | 2014-12-24 | 深圳奥萨医药有限公司 | Medicinal composition of indapamide and folic acid and application of medicinal composition |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104224788A (en) * | 2014-09-29 | 2014-12-24 | 深圳奥萨医药有限公司 | Medicinal composition of indapamide and folic acid and application of medicinal composition |
Non-Patent Citations (1)
| Title |
|---|
| 欧盟批准Opsumit用于治疗肺动脉高压;无;《世界临床药物》;20140110;第35卷(第1期);左栏第5段 * |
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