CN113134086B - Pharmaceutical composition for reducing blood fat - Google Patents
Pharmaceutical composition for reducing blood fat Download PDFInfo
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- CN113134086B CN113134086B CN202010067725.8A CN202010067725A CN113134086B CN 113134086 B CN113134086 B CN 113134086B CN 202010067725 A CN202010067725 A CN 202010067725A CN 113134086 B CN113134086 B CN 113134086B
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- pharmaceutical composition
- acid
- fenofibrate
- folic acid
- ldl
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
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- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 1
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- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a pharmaceutical composition for reducing blood fat, which consists of Bempedoic acid, fibrate lipid-lowering drugs, folic acid and a proper amount of auxiliary materials. The pharmaceutical composition provided by the invention provides an effective medicament for patients with hyperlipidemia, and the three medicaments are combined to have a synergistic effect. In addition, the pharmaceutical composition can also facilitate the patients to take medicine, improve compliance and reduce medical cost.
Description
Technical Field
The invention relates to a pharmaceutical composition, in particular to a pharmaceutical composition with better lipid-lowering curative effect. Belongs to the field of pharmacy.
Background
Along with the change of dietary structure and life style, human diseases are evolving continuously, and in recent years, the health care consciousness of people is relatively thin, and the incidence rate of hyperlipidemia, coronary heart disease and related diseases is increasing year by year. Dyslipidemia (DYSLIPIDEMIA) is one of the important risk factors of cardiovascular diseases, hyperlipidemia is an independent risk factor of coronary heart disease, and plays a main role in the whole process of atherosclerosis occurrence, development and exacerbation, and is related to the onset of coronary heart disease, the stabilization or progressive exacerbation of lesions, and seriously threatens the life and life quality of patients. The clinical tests for blood lipid are more, and the basic tests for blood lipid are TC, TG, high Density lipoprotein Cholesterol (High DensityLipoprotein-Cholesterol, HDL-C) and Low Density lipoprotein Cholesterol (Low Density LipoproteinCholesterol, LDL-C).
Elevated LDL-C levels are among other factors responsible for the occurrence of atherosclerotic cardiovascular disease (atherosclerotic cardio-vascular disease, ASCVD). According to the guidelines for prevention and treatment of dyslipidemia of adult China (revision 2016), it is reported that the total prevalence of dyslipidemia of adult China is up to 40.4% nowadays, and it is predicted that cardiovascular events in China will increase by about 920 ten thousand cases in 2010-2030. In order to reduce the malignant increase of ASCVD, LDL-C can be used as the most main target for reducing blood fat. Clinical practice has shown that the use of 3-hydroxy-3-methylglutaryl coenzyme a (3-hydroxy-3-methylglutarylcoenzymeA, HMG-CoA) reductase inhibitors, statins, is a very successful approach to reducing the risk of ASCVD. However, the effectiveness of statins in clinical practice is limited by many factors, such as poor therapeutic compliance, drug intolerance, muscle-related adverse events, and the like. Even statins in combination with currently available lipid regulating drugs are unlikely to restore normal LDL-C levels in patients, especially those at high CVD risk. Proprotein convertase subtilisin-9 (PCSK 9) inhibitors such as evolocumab require subcutaneous injection and are expensive. Thus, there remains a great clinical need for new drugs that effectively and safely lower LDL-C levels. ATP-citrate lyase (ACL) is a key metabolic enzyme in the cytoplasm connecting glucose degradation with fatty acid and cholesterol synthesis, and it catalyzes the production of acetyl-CoA, which is an important basic raw material for endogenous fatty acid and cholesterol biosynthesis, from intracellular citrate. Therefore, ACL is a potential target for intervention in cholesterol synthesis. Inhibitors of this enzyme hold promise for the treatment of dyslipidemia and become a new strategy for reducing CVD risk. Bempedoicacid (also known as ETC-1002), which is the first ACL inhibitor developed by Nascok corporation (EsperionTherapeutics), the target of Bempedoicacid is ACL. Bempedoicacid is rapidly absorbed in the small intestine following oral administration and metabolized to the active form (ETC-1002-CoA) by acyl-CoA synthetase-1 (ASCVL) after entering the human liver. The active form can competitively inhibit ACL activity, thereby reducing synthesis of cholesterol and fatty acid, further up-regulating LDL-C receptor level, promoting absorption of LDL-C by liver, and achieving the purpose of reducing LDL-C. Whereas the ASCVL isoform is present only in the liver and kidneys and is absent in skeletal muscle cells and adipose tissue, muscle toxicity due to impaired cholesterol synthesis in skeletal muscle can be avoided. Can effectively regulate blood lipid level, and is suitable for patients with elevated LDL-C, atherosclerosis and cardiovascular disease or familial hypercholesterolemia, which are intolerant to statin treatment.
Whereas fibrates significantly lower elevated Triglycerides (TG), HDL-C, TC and LDL-C, elevated lipoprotein a [ Lp (a) ] and fibrinogen. Is effective for most primary and secondary hyperlipidemia, and is especially beneficial for people with high TG and/or HDL-C deficiency.
Fibrates stimulate expression of lipoprotein lipase (lipoproteinlipase, LPL), apolipoprotein ai (apolipoproteinA i, apoai), apolipoprotein ai (apoai), apolipoprotein AV (apoAV) genes by activating peroxisome proliferator-activated receptor alpha agonists (peroxisomeproliferatorsactivatedreceptor α, pparα), enhance LPL activity, remove TG-rich lipoproteins in plasma, thereby lowering TG and increasing HDL-C levels, promoting reverse transport of cholesterol, and shift LDL subtypes from small dense granules to large dense granules. The fibrate can reduce the plasma TG level by 30% -50%, reduce the LDL-C level by 15% -20%, and obviously increase the HDL-C level by 5% -15%.
The fibrate has the function of regulating blood fat at least partially through the coding of transcription genes, so as to control lipoprotein metabolism. Fibrates activate PPAR-alpha, further activate LPL, apoAV and reduce the production of the LPL inhibitor apolipoprotein CIII (apoCIII), thereby increasing fat dissolution and scavenging atherosclerosis-causing TG in the plasma. The fibrate treatment can also promote the beta-oxidation of fatty acid and reduce the synthesis of TG from free fatty acid. In addition, fibrates inhibit the de novo synthesis of fatty acids by decreasing the activity of acetyl-coa carboxylase and fatty acid synthase, thereby reducing the synthesis of fatty acids to TG. Activation of PPAR-alpha also increases apoai, a major protein in high density lipoproteins, synthesis of apoAII. Fenofibrate, also known as phenoxy acid, is an artificially synthesized PPARα, which is an ideal and widely used lipid-regulating drug in recent years, and has the effects of reducing high TG, LDL-C and slightly increasing high density lipoprotein (HDL-C).
Disclosure of Invention
The invention aims to provide a pharmaceutical composition with obvious blood lipid reducing effect on people with hyperlipidemia.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
A pharmaceutical composition for reducing blood lipid consists of the following components:
(1)Bempedoic acid；
(2) Fibrates lipid lowering agents;
(3) Folic acid;
(4) A pharmaceutically acceptable carrier.
In the pharmaceutical composition provided by the application, bempedoic acid can exist in the forms of salts, esters, active metabolites and the like. The Bempedoic acid provided by the application is used as a medicine component, and the existence forms of salts, esters, active metabolites and the like of Bempedoic acid are also included in the application. In the present application, the pharmaceutical dosage of Bempedoic acid is 60-240mg, preferably 120-180mg. The pharmaceutical dosages of Bempedoic acid salts, esters, active metabolites, etc. can be converted accordingly.
In the present application, fenofibrate may exist in the form of salts, esters, active metabolites, or pharmaceutically acceptable precursors. The present application also provides the fenofibrate as a pharmaceutical ingredient in the form of salts, esters, active metabolites or pharmaceutically acceptable precursors of fenofibrate and the like. In the present application, the pharmaceutical dosage of fenofibrate is selected from 100-300mg, preferably 100mg, 200mg or 300mg. The pharmaceutical dosage of salts, esters, active metabolites or pharmaceutically acceptable precursors of fenofibrate, etc. can be converted accordingly.
In the pharmaceutical composition provided by the application, folic acid comprises synthetic folic acid, 5-methyltetrahydrofolate, leucovorin, calcium levofolinate and the like, namely various forms of folic acid comprising artificial synthesis and plant extract sources. Folic acid can exist in the form of salts, esters, active metabolites or pharmaceutically acceptable precursors. The present forms of folic acid provided by the present application as a pharmaceutical ingredient, such as salts, esters, active metabolites, or pharmaceutically acceptable precursors of folic acid, are also within the scope of the present application. In the present application, the pharmaceutical dosage of folic acid is selected from 0.02 to 1mg, preferably 0.4 to 0.8mg. The pharmaceutical dosage of salts, esters, active metabolites or pharmaceutically acceptable precursors of folic acid, etc. can be correspondingly converted.
In the present invention, the pharmaceutically acceptable dosage of the active ingredient of the composition means a dosage range in which the pharmaceutically active ingredient of the drug is combined with other pharmaceutically active ingredients in the composition to exert the drug effect of the composition. The preferred dosage is a preferred pharmaceutical dosage of the active ingredient of the composition, the preferred dosage having a better potency than the pharmaceutical dosage. Typically, the pharmaceutical dosage of the active ingredient of the composition includes an optimal dosage or optimal dosage range that maximizes the efficacy of the composition, which would benefit the patient even more.
As a preferred embodiment, the pharmaceutical composition provided by the invention comprises Bempedoic acid mg of fenofibrate, 100mg of fenofibrate and 0.4mg of folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 120mgBempedoic acid, 200mg fenofibrate and 0.4mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 120mgBempedoic acid, 300mg fenofibrate and 0.4mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 180mgBempedoic acid, 100mg fenofibrate and 0.4mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 180mgBempedoic acid, 200mg fenofibrate and 0.4mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 180mgBempedoic acid, 300mg fenofibrate and 0.4mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 120mgBempedoic acid, 100mg fenofibrate and 0.8mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 120mgBempedoic acid, 200mg fenofibrate and 0.8mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 120mgBempedoic acid, 300mg fenofibrate and 0.8mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 180mgBempedoic acid, 100mg fenofibrate and 0.8mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 180mgBempedoic acid, 200mg fenofibrate and 0.8mg folic acid.
As another preferred aspect, the pharmaceutical composition provided by the present invention is composed of 180mgBempedoic acid, 300mg fenofibrate and 0.8mg folic acid.
The pharmaceutical composition also contains pharmaceutically acceptable carriers which 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 agents which are helpful for preparing active compounds into pharmaceutical preparations when preparing tablets, such as microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite and the like, and the composition of one or more substances belongs to the common general knowledge in the field.
The invention provides a pharmaceutical composition with better curative effect for patients with hyperlipidemia. The medicinal active ingredients of the pharmaceutical composition provided by the invention are Bempedoic acid, fibrate lipid-lowering drugs and folic acid. Bempedoicacid is effective in lowering LDL-C, while fenofibrate has the main effects of lowering high TG and slightly raising HDL-C, folic acid can lower HCY level. Bempedoic acid, the fibrate lipid-lowering drug and folic acid can be combined to effectively regulate blood lipid (TG, TC, LDL-C, HDL-C), exert a synergistic effect obviously stronger than that of single drugs, and reduce the side effect of the fibrate drug in increasing blood homocysteine.
The invention is further described in connection with the following detailed description, which is not intended to be limiting, but is set forth in the following claims, along with any such equivalents in the art, which are intended to be encompassed by the invention
Detailed Description
Example 1-example 6 preparation of Bempedoic acid and fenofibrate folic acid tablets (1000 tablets)
| Formulation composition | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| Bempedoic acid | 120g | 120g | 120g | 180g | 180g | 180g |
| Fenofibrate | 100g | 200g | 300g | 100g | 200g | 300g |
| Folic acid | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 | 0.4 |
| Pregelatinized starch | 46g | 66g | 78g | 73g | 81g | 79g |
| Microcrystalline cellulose | 68g | 99g | 116g | 109g | 122g | 118g |
| Carboxymethyl starch sodium | 3g | 8g | 5g | 5g | 6g | 6.4g |
| Sodium dodecyl sulfate | 0.45g | 3.6g | 0.9g | 0.9g | 1.8g | 1.8g |
| 10% Povidone K-30 | Proper amount of | Proper amount of | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Magnesium stearate | 0.75g | 2.5g | 1.5g | 1.5g | 1.5g | 1.5g |
The preparation process comprises the following steps:
Mixing Bempedoic acid, fenofibrate and folic acid, adding carboxymethyl starch sodium and dodecyl sodium sulfate, mixing, adding microcrystalline cellulose and pregelatinized starch, mixing, making into soft material with appropriate amount of 10% povidone ethanol solution, granulating, drying, grading, mixing granule with water content of about 3% and appropriate amount of magnesium stearate, and tabletting to obtain 1000 tablets.
Example 7-example 12 preparation of Bempedoic acid and fenofibrate folic acid tablets (1000 tablets)
The preparation process comprises the following steps:
Mixing Bempedoic acid, fenofibrate and folic acid, adding carboxymethyl starch sodium and dodecyl sodium sulfate, mixing, adding microcrystalline cellulose and pregelatinized starch, mixing, making into soft material with appropriate amount of 10% povidone ethanol solution, granulating, drying, grading, mixing granule with water content of about 3% and appropriate amount of magnesium stearate, and tabletting to obtain 1000 tablets.
Example 13: the following experiments are designed, and the efficacy of the composition is inspected mainly through the detection of TC, TG, LDL-blood fat and endothelial function indexes of experimental animals, and the experiments prove that the composition has the efficacy of synergetic lipid reduction and endothelial protection against atherosclerosis.
The experimental method comprises the following steps:
And (3) molding: after 60 male SD rats (200-250 g) were adaptively bred for one week, 10 rats were not subjected to any treatment and served as a normal control group. The remaining rats were fed with high fat diet. Hyperlipidemia rats were formed after 4 weeks and then randomly grouped.
Experimental grouping and dosing regimen: group 1: normal control group (n=10); group 2: model group (n=10), 3-6 groups: the administration groups, 10 groups, specific groups and administration dosage schemes are shown in Table 1, and blood collection test serum TC, TG, LDL-C, HDL-C, ET-1, NO and HCY are taken 24 hours after 16 weeks of administration.
1. Statistical analysis: statistical treatment is carried out on the test data by adopting graphpad prism5 statistical analysis software; the data results are allAnd (3) representing. The comparison between groups was tested using ANOVA, with a test level set at α=0.05, with statistical differences in P <0.05, and no statistical differences in P > 0.05.
2. In order to prove the scientificity of the pharmaceutical composition provided by the invention, the three components of the pharmaceutical composition are reasonably compatible, can exert a synergistic effect by mutual combination, are not simple pharmacological effect superposition, and are analyzed by adopting a golden average Q value method. The golden average Q value method is also called a probability addition method, and according to the pharmacological actions of the combination of the three medicines and the pharmacological actions of the single use of the three medicines in a dose-response curve area, the golden average Q value method is calculated by the following calculation formula: q=ea+b+c/(ea+eb+ec-EA EB-EA EC-EB EC-EA EC-EC), where the numerator represents the "actually measured combined effect", the denominator represents the "expected combined effect" (to satisfy analysis of the pharmacological action relationship of the components and the composition, the pharmacological actions thereof are converted into effects that intuitively represent the pharmacological action intensity), the calculation formula is ei=1-Pi/P model group, pi is the pharmacological index of each component, P model group is the pharmacological index of the model group), and Q is the ratio of the two: when Q is less than 0.85, the combination of the two drugs is considered to be antagonistic; when less than 1.15 is greater than 0.85, it is considered to be additive; above 1.15, a synergistic effect is considered.
Experimental results: see table 2.
TABLE 1 grouping and dosing schemes
TABLE 2 influence of the composition of the invention on rat serum TC, TG, LDL-C and HDL-Cn＝10)
#P<0.05,## P <0.01 compared to the control group; p <0.05, P <0.01 compared to model group
TABLE 3 influence of the compositions of the invention on rat serum ET-1, NO and HCYn＝10)
#P<0.05,## P <0.01 compared to the control group; p <0.05, P <0.01 compared to model group
TABLE 4 analysis of Effect of the compositions of the invention on rat TC, TG, LDL-C and HDL-C indices
TABLE 5 analysis of Effect of the compositions of the invention on rat ET-1, NO and HCY targets
Table 2 shows that the serum TC, TG and LDL-C of the model group are all significantly increased compared with the normal group (P < 0.05), which indicates that the model of the hyperlipoidemia rat is successfully modeled, and the serum TC, TG, LDL-C of the three drug combination group is significantly decreased after 16 weeks of administration, has no significant difference from the normal group, and HDL-C is increased compared with the normal group. The lipid index of the lipid-lowering drug single drug group is reduced, but the effect is inferior to that of the composition group. Table 4 shows that the Q values of the golden average Q value analysis composition TC, TG, LDL-C and HDL-C are respectively 1.203, 1.153, 1.179 and 1.165 which are respectively more than 1.15, and the Bempedoic acid +fenofibrate+folic acid combined administration shows unexpected synergistic effect in reducing blood fat.
Table 3 shows that the serum ET-1 and HCY of the model group are both significantly increased and NO is significantly decreased (P < 0.05) compared with the normal group, and the serum ET-1, NO and HCY of the three drug combination group are significantly improved and have NO significant difference from the normal group after 16 weeks of administration. The HCY of the fenofibrate group is obviously increased, and the HCY has no obvious difference with the control group after being combined with folic acid, so that the three medicines can be combined for effectively regulating blood fat and also has the efficacy of protecting endothelium from atherosclerosis. Table 5 shows that the compositions ET-1, NO and HCY have Q values 1.247, 1.594 and 2.72, respectively, which are greater than 1.15, indicating that Bempedoic acid +fenofibrate+folic acid combination also exhibits unexpected synergy in endothelial protection against atherosclerosis.
Claims (3)
1. A pharmaceutical composition for reducing blood lipid comprises the following components:
（1）180mg Bempedoic acid；
(2) 200mg of fenofibrate;
(3) 0.8mg folic acid;
(4) A pharmaceutically acceptable carrier.
2. The pharmaceutical composition according to claim 1, wherein: the pharmaceutical composition can be prepared into common tablets, soft capsules and hard capsules.
3. Use of a pharmaceutical composition according to claim 1 for the preparation of a hypolipidemic medicament.
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