CN113133997A - Pharmaceutical composition containing berberine and application thereof - Google Patents

Pharmaceutical composition containing berberine and application thereof Download PDF

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CN113133997A
CN113133997A CN202010067724.3A CN202010067724A CN113133997A CN 113133997 A CN113133997 A CN 113133997A CN 202010067724 A CN202010067724 A CN 202010067724A CN 113133997 A CN113133997 A CN 113133997A
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berberine
pharmaceutical composition
bempedoic acid
composition
hyperlipidemia
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CN113133997B (en
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李锦良
白洁
邢厚恂
张朝当
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Shenzhen Changqing Medical Science Research Institute
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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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Abstract

The invention provides a pharmaceutical composition for treating hyperlipidemia, which consists of berberine and Bempedoic Acid. The invention provides an effective pharmaceutical composition for synergistically reducing blood fat for patients with hyperlipidemia, is particularly suitable for patients with liver dysfunction, and also has an anti-inflammatory effect.

Description

Pharmaceutical composition containing berberine and application thereof
Technical Field
The invention provides a pharmaceutical composition for treating hyperlipidemia, which consists of Bempedoic Acid and berberine. Belongs to the field of pharmacy.
Background
With the continuous development of the social living standard, the quality of life of people is continuously improved, the change of the dietary structure, the diet with high fat and high calorie gradually becomes the normal diet, and the people are in a sub-health state for a long time due to the busy modern labor work and insufficient exercise time, so the occurrence frequency of cardiovascular events is continuously increased, and the cardiovascular events are generally expressed as hyperlipidemia, diabetes, atherosclerosis, gastrointestinal inflammation, immunologic function reduction and the like.
The investigation results of Chinese chronic disease and risk factor monitoring investigation (CCDRFS) in 2013-2014 on 163641 Chinese adults in 31 provinces in China show that the serum Total Cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), Triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels of people aged more than or equal to 18 years in China are 4.70, 2.88, 1.14 and 1.35mmol/L respectively, and the TC level is obviously higher than that of CHNS (3.81mmol/L) in 2002 and that of Chinese chronic disease monitoring (4.04mmol/L) in 2010.
The most commonly used lipid-lowering drugs in clinic are statins, and clinical application shows that the statins can effectively lower LDL-c level, but the side effects of the statins are gradually shown along with the increment of dosage and the lengthening of taking time, such as hepatotoxicity, rhabdomyolysis and the like. How to reduce the side effects in lipid-lowering therapy or find better drugs is a problem to be solved. Bempedoic acid is a non-statin drug that targets therapy, acts primarily on the liver, inhibits adenosine triphosphate citrate lyase (ACL), reduces cholesterol synthesis, leads to upregulation of LDL-c receptors, and increases LDL clearance from the bloodstream. Bempedioic acid is converted to its active portion by acyl-CoA Synthetase-1 (acyl-CoA Synthetase 1: ACSVL 1). Since ACSVL1 is not present in skeletal muscle, Bempedoicacid is not converted to the active fraction in skeletal muscle. Bempedoic acid phase II clinical trial showed that Bempedoic acid120mg was able to lower LDL-c by 27.5%, and 180mg was able to lower LDL-c by 30.1%. Meanwhile, the Bempedoic Acid reduces the HsCRP-reactive protein IL-6 antibody Canakinamiab, and compared with a control group (2.1%), the Bempedoic Acid group (32.5%) shows obvious anti-inflammatory effect.
The berberine which is a natural medicine component can be used for treating bacillary dysentery and is found to have the function of regulating blood fat, the berberine can obviously regulate the expression of low-density lipoprotein receptor (LDLR) of liver cells in vitro and plays a role by activating extracellular signal regulation kinase of the cells, and the mechanism is completely different from that of the currently and clinically commonly used statin cholesterol-reducing medicines. Clinical application shows that the berberine has good curative effect on patients with hyperlipidemia, is also suitable for patients with liver dysfunction, has good safety, and has no adverse reaction of statin drugs.
Disclosure of Invention
The invention aims to provide a lipid-lowering pharmaceutical composition with remarkable curative effect and little side effect for patients with hyperlipidemia. In order to achieve the purpose, the invention adopts the following technical scheme: a pharmaceutical composition for treating hyperlipidemia comprises the following components:
(1)50-200mg of Bempedoic Acid;
(2)10-100mg berberine;
(3) a pharmaceutically acceptable carrier.
In the pharmaceutical composition provided by the invention, the Bempedoic Acid can exist in the forms of salts, esters, active metabolites or medicinal precursors and the like. The Bempedoic Acid provided by the invention is used as a medicine component, and the existing forms of salts, esters, active metabolites and the like of the Bempedoic Acid are also within the protection scope of the application. In the present invention, the pharmaceutical dosage of the Bempedoic Acid is selected from 50-200mg, preferably 120-200 mg. The pharmaceutical dosage of the salts, esters, active metabolites or precursors of the Bempedoic Acid can be converted accordingly.
In the pharmaceutical composition provided by the invention, berberine can exist in the forms of salts, esters, active metabolites or medicinal precursors and the like. The berberine provided by the invention is used as a medicinal component, and the existence forms of the berberine salts, esters, active metabolites or medicinal precursors and the like are also within the protection scope of the application. In the present invention, the pharmaceutical dosage of berberine is selected from 10-100mg, preferably 50-100 mg. The medicinal dosage of the salt, ester, active metabolite or precursor of berberine can be converted accordingly.
In the present invention, the pharmaceutically acceptable dose 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 preferred dosage of the active ingredients of the composition, and the preferred dosage has better efficacy than the pharmaceutical dosage. 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 composition provided by the invention comprises 120mg of Bempedioic Acid and 50mg of berberine.
As another preferred, the composition provided by the present invention is composed of 120mg of Bempedoic Acid and 100mg of berberine.
As another preferred embodiment, the composition provided by the present invention is 150mg of Bempedoic Acid and 50mg of berberine.
As another preferred embodiment, the composition provided by the present invention is 150mg of Bempedoic Acid and 100mg of berberine.
As another preferred embodiment, the composition of the composition provided by the present invention is 180mg of Bempedoic Acid and 100mg of berberine.
The pharmaceutical composition also contains pharmaceutically acceptable carriers, and can be made into common oral preparations, such as common tablets, common capsules, granules, etc. The pharmaceutically acceptable carrier when formulated into tablets includes excipients or adjuvants which facilitate the formulation of the active compound into a pharmaceutical formulation, such as combinations of one or more of microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite, and the like, and is within the ordinary skill in the art.
The pharmaceutical compositions of the present invention may also be used interchangeably in the form of "combination kits". The "combination kit" is a box-shaped container, which contains a plurality of dosage forms of the drug combination, and instructions for administration. The combined medicine box is more suitable for individual medicine.
The composition of berberine and Bempedoic Acid provided by the invention can play a role in reducing blood fat, reduces the dosage of single medicine, has safety and effectiveness obviously higher than those of single medicine, has a synergistic effect between the single medicine and the berberine, has an anti-inflammatory effect and low hepatotoxicity, can be used for treating hyperlipidemia patients with liver function damage, and has an obvious curative effect.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Examples 1 to 2: preparation of Berberine and Bempedioic Acid composite tablet (1000 tablets)
Formulation composition Example 1 Example 2
Berberine 50g 100g
Bempedoic Acid 120g 180g
Pregelatinized starch 46g 50g
Microcrystalline cellulose 68g 72g
Sodium starch glycolate 3g 5g
Sodium dodecyl sulfate 2.6g 3.6g
10% Povidone K30 Proper amount of Proper amount of
Magnesium stearate 1.2g 1.2g
The preparation process comprises the following steps: mixing berberine and Bempedoic Acid, adding carboxymethyl starch sodium and sodium lauryl sulfate, mixing, adding microcrystalline cellulose and pregelatinized starch, mixing, adding appropriate amount of 10% polyvidone K30 ethanol solution to obtain soft mass, 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 3 to 4: preparation of Berberine + Bempedoic Acid composite Capsule (1000 granules)
Formulation composition Example 3 Example 4
Berberine 50g 100g
Bempedoic Acid 150g 150g
Lactose 60g 66g
Microcrystalline cellulose 85g 90g
Sodium dodecyl sulfate 8g 8g
Croscarmellose sodium 4.5g ,5.0g
5% hypromellose solution Proper amount of Proper amount of
Magnesium stearate 2g 2g
The preparation process comprises the following steps: sieving carboxymethyl starch sodium with 100 mesh sieve, and sieving lactose and microcrystalline cellulose with 80 mesh sieve; mixing the raw materials with croscarmellose sodium and sodium lauryl sulfate, adding microcrystalline cellulose and lactose, mixing, granulating with 5% hypromellose solution, drying at 50-60 deg.C for 2 hr, mixing the obtained material with magnesium stearate, and encapsulating with No. 1 capsule. Making into 1000 granules.
Examples 5 to 6: preparation of Berberine + Bempedoic Acid granules (1000 bags)
Formulation composition Example 5 Example 6
Berberine 50g 100g
Bempedoic Acid 120g 180g
Lactose 80g 80g
Pregelatinized starch 100g 100g
Sodium starch glycolate 15g， 15g
Aspartame 5g 5g
5% Povidone K-30 Proper amount of Proper amount of
Magnesium stearate 0.5％ 0.5％
The preparation process comprises the following steps: (1) weighing berberine and Bempedioic Acid according to the prescription amount, sieving with a 100-mesh sieve, and mixing uniformly for later use; (2) sieving other adjuvants with 100 mesh sieve respectively; (3) weighing lactose, pregelatinized starch, carboxymethyl starch sodium and aspartame according to the prescription amount, uniformly mixing, and then uniformly mixing with the mixed raw material medicines; (4) adding a proper amount of adhesive to prepare a soft material, granulating by using a 24-mesh sieve, and drying at 40-45 ℃; (5) sieving with 20 mesh sieve, and sieving with 80 mesh sieve to remove fine powder; (6) adding magnesium stearate into the dry granules, mixing, measuring content, and packaging.
Example 7: observation of lipid-lowering efficacy of berberine + Bempedoic Acid on hyperlipidemia animals
Modeling the high-fat animal:
purchasing male golden hamster (SPF grade, Beijing vitamin Tonglihua), feeding on common daily ration, and randomly selecting 12 mice fed with common feed until the experiment is finished after 7 days of quarantine, and using the mice as a control group; the rest of the rats were fed with high-fat feed (10% hydrogenated coconut oil, 1.25% cholesterol, 88% basal feed) according to the following formula,
Figure BDA0002376454710000051
the water is freely drunk. The illumination was alternated every 12/12 hours. The temperature is controlled between 18 and 25 ℃, and the humidity is controlled between 40 and 70 percent.
Grouping and administration:
after feeding with high-fat diet for 4 weeks, fasting was performed overnight. And (4) taking blood from the eye sockets of the golden hamster, standing, centrifuging, taking the supernatant for later use, and detecting four items of blood fat. LDL-plus material for molding animalCAnimals with a level above 20% of the normal control group are selected into the group based on their LDL-CLevels were randomized into groups, giving consideration to TC levels and animal weights, and high-fat model animals were randomized into 4 groups, model group, berberine + Bempedoic Acid group (5+12mg), berberine group (5mg), Bempedoic Acid group (12mg), respectively. The administration is performed by intragastric administration once a day, and the administration volume is 10 ml/kg. The administration was continued for 8 weeks.
After the experiment, blood is sacrificed and blood fat, liver function index (AST, ALT) and inflammatory factor (hs-CRP, IL-6) are measured.
In order to confirm the scientificity of the pharmaceutical composition provided by the invention, a t test is adopted among groups to verify the statistical difference. In order to show that the two components of the pharmaceutical composition are reasonable in compatibility and can exert a synergistic effect by combining with each other, rather than simple pharmacological action superposition, the experimental result is analyzed by a golden positive average Q value method. The "Jinzheng-average Q value" is also called probability phaseAnd (3) adding, according to the pharmacological action of the two drugs in combination and the pharmacological action of the two drugs in single use in the dose-effect curve region, calculating by using the following calculation formula: q ═ EA+B/(EA+EB-EA*EB) 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/PModel setPi is the pharmacological index of each component, PModel setPharmacological index of model group), Q is the ratio of the two: when Q is less than 0.85, the combination of the two medicines is considered as antagonistic action; an additive effect is considered when less than 1.15 is greater than 0.85; a value greater than 1.15 is considered synergistic.
Table 1: four-item blood fat and weight measurement after 4 weeks of golden hamster molding
Figure BDA0002376454710000061
Figure BDA0002376454710000062
Note: as compared with the normal group, the group,##P<0.01。
table 2: effect of the composition of the present invention on the blood lipid level of golden hamster 8 weeks after administration
Figure BDA0002376454710000063
Figure BDA0002376454710000064
Figure BDA0002376454710000071
Note: as compared with the normal group, the group,#P<0.05，##P<0.01, comparison with model group<0.05，**P<0.01。
Table 3: analysis of Effect of the composition on the blood lipid index of golden hamster
Figure BDA0002376454710000072
After high-fat modeling, the blood lipid level of golden-yellow hamster is obviously increased, after berberine, Bempedoic Acid or the composition thereof is used for treatment, the blood lipid level (TC, LDL-C, TG) is obviously reduced (P is less than 0.01), and the berberine and Bempedoic Acid group has a larger reduction amplitude than that of the berberine or the Bempedoic Acid group. The Q values of the gold positive average Q value analysis compositions TC and LDL-C, TG are respectively 1.32, 1.53 and 1.85, and are respectively more than 1.15, which indicates that the berberine and Bempedoic Acid combined medicament shows unexpected synergistic effect in the treatment of lipid lowering. And meanwhile, the medicine composition also shows an additive effect (Q value is 0.94) in raising HDL-C, and the dosages of the berberine and the Bempedoic Acid for the squirrel are respectively 50mg of the berberine and 120mg of the Bempedoic Acid corresponding to the dosages of a human body, so that the medicine composition provided by the invention can synergistically lower blood fat and has a remarkable effect.
Table 4: effect of the inventive composition on inflammatory factors of golden hamster 8 weeks after administration
Figure BDA0002376454710000073
Figure BDA0002376454710000074
Figure BDA0002376454710000081
Note: as compared with the normal group, the group,#P<0.05，##P<0.01, comparison with model group<0.05，**P<0.01
Table 5: effect analysis of the composition of the invention on the inflammation index of golden hamster
Figure BDA0002376454710000082
After high-fat modeling, inflammatory factors hs-CRP and IL-6 of golden-yellow hamster are obviously increased (P <0.01) compared with a normal group, but after treatment, the hs-CRP and IL-6 of three treatment groups are obviously reduced, and the reduction amplitude of the berberine + Bempedoic Acid group is obviously increased (P <0.01) compared with that of the berberine or the Bempedoic Acid which is singly used, which shows that the composition achieves the anti-inflammatory effect by reducing the level of the hs-CRP and IL-6, and has more effective curative effect than that of the berberine or the Bempedoic Acid which is singly used, and the composition has synergistic effect calculated from the Q value (hs-CRP: Q is 2.36, and IL-6: Q is 2.33).
Table 6: effect of the inventive composition on liver function of golden hamster 8 weeks after administration
Figure BDA0002376454710000083
Figure BDA0002376454710000084
Note: as compared with the normal group, the group,#P<0.05，##P<0.01, comparison with model group<0.05，**P<0.01
Table 7: effect analysis of the composition of the present invention on liver function index of golden hamster
Figure BDA0002376454710000091
The liver function indexes (ALT and AST) of golden yellow hamster after high-fat modeling are obviously increased (P is less than 0.01) compared with the normal group, but after treatment, ALT and AST of three treatment groups are obviously reduced, the reduction amplitude of berberine and Bempedoic Acid groups is obviously increased (P is less than 0.01) compared with that of berberine or Bempedoic Acid which is singly used, which shows that the composition has more effective curative effect on liver function protection by reducing the levels of ALT and AST compared with that of berberine or Bempedoic Acid which is singly used, and the composition has synergistic effect on improving liver function by calculating the Q value (ALT: Q is 1.91 and AST: Q is 1.81).

Claims (8)

1. A pharmaceutical composition for treating hyperlipidemia comprises the following components:
(1)50-200mg of Bempedoic Acid;
(2)10-100mg berberine;
(3) a pharmaceutically acceptable carrier.
2. The pharmaceutical composition according to claim 1, wherein the Bempedoic Acid content is 120-200 mg.
3. The pharmaceutical composition according to claim 1, wherein the berberine is present in an amount of 50-100 mg.
4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 120mg of bempedoic Acid and 50mg of berberine.
5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 180mg of Bempedoic Acid and 100mg of berberine.
6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as an oral dosage form selected from the group consisting of tablets, capsules, and granules.
7. Use of the pharmaceutical composition of claim 1 for the preparation of a medicament for the treatment of hyperlipidemia.
8. Use according to claim 7, characterized in that the hyperlipidemia is hyperlipidemia accompanied by liver dysfunction.
CN202010067724.3A 2020-01-20 2020-01-20 Pharmaceutical composition containing berberine and application thereof Active CN113133997B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110536684A (en) * 2017-02-08 2019-12-03 艾斯柏伦治疗公司 Three combination preparations and treatment cardiovascular disease or the method for reducing risk of cardiovascular diseases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110536684A (en) * 2017-02-08 2019-12-03 艾斯柏伦治疗公司 Three combination preparations and treatment cardiovascular disease or the method for reducing risk of cardiovascular diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANUM SAEED ET AL: "Bempedoic Acid (ETC-1002) A Current Review", CARDIOLOGY CLINICS, vol. 36, no. 2, pages 257 - 264 *

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