CN113133997B - Pharmaceutical composition containing berberine and application thereof - Google Patents

Pharmaceutical composition containing berberine and application thereof Download PDF

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Publication number
CN113133997B
CN113133997B CN202010067724.3A CN202010067724A CN113133997B CN 113133997 B CN113133997 B CN 113133997B CN 202010067724 A CN202010067724 A CN 202010067724A CN 113133997 B CN113133997 B CN 113133997B
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berberine
acid
pharmaceutical composition
composition
hyperlipidemia
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CN113133997A (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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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)

Abstract

The invention provides a pharmaceutical composition for treating hyperlipidemia, which consists of berberine and Bempedioic Acid. The invention provides an effective synergistic blood lipid-lowering pharmaceutical composition for patients with hyperlipidemia, which is especially suitable for patients with liver dysfunction, and has 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 Bempechoic Acid and berberine. Belongs to the field of pharmacy.
Background
With the continuous development of the social life level, the life quality of people is continuously improved, the dietary structure is changed, the high-fat and high-calorie diet is gradually changed into a normal diet state, modern people are busy, exercise time is insufficient, the people are in a sub-health state for a long time, the occurrence frequency of cardiovascular events is continuously increased, and the diseases are commonly manifested by hyperlipidemia, diabetes, atherosclerosis, gastrointestinal tract inflammation, immune function decline and the like.
The investigation results of 2013-2014 Chinese chronic disease and risk factor monitoring investigation (CCDRFS) on 163 641 Chinese adults in 31 Chinese provinces 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 with the age of more than or equal to 18 years in China are respectively 4.70, 2.88, 1.14 and 1.35mmol/L, and the TC levels are obviously increased compared with the investigation results of 2002 CHNS (3.81 mmol/L) and 2010 Chinese chronic disease monitoring (4.04 mmol/L).
The most commonly used lipid-lowering drugs in clinic are statin drugs, and clinical application shows that the statin drugs can effectively lower the LDL-c level, but the side effects of the statin drugs are gradually developed along with the increment of dosage and the lengthening of the administration time, such as hepatotoxicity, rhabdomyolysis and the like. How to reduce the side effects in the lipid-lowering therapy or find better drugs is a problem to be solved. Bempedocoid acid is a non-statin drug, and targeted therapy mainly acts on the liver, can inhibit adenosine triphosphate citrate lyase (ACL), reduce cholesterol synthesis, cause LDL-c receptor up-regulation and increase LDL clearance from the blood stream. Bempedocoic acid is converted to its active moiety by acyl-CoA Synthetase-1 (acyl-CoA Synthetase 1: ACSVL 1). Because ACSVL1 is not present in skeletal muscle, bempedocalcid will not be converted to an active moiety in skeletal muscle. A phase two clinical trial of Bempechoic acid showed that 120mg of Bempechoic acid could lower LDL-c by 27.5% and 180mg could lower LDL-c by 30.1%. Meanwhile, compared with a control group (2.1%), the Bempedoic Acid group (32.5%) has obvious anti-inflammatory effect when the Bempedoic Acid reduces hsCRP reactive protein IL-6 antibody Canokinumab.
The berberine which is a natural medicine component can be used for treating bacillary dysentery, has the effect of regulating blood fat, can obviously up-regulate the expression of a hepatocyte Low Density Lipoprotein Receptor (LDLR) in vitro, and plays a role by activating extracellular signal regulation kinase of cells, which is completely different from the mechanism of statin cholesterol-lowering medicines commonly used in clinic at present. Clinical application shows that the berberine has good curative effect for treating 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 less side effect for patients with hyperlipidemia. In order to achieve the above purpose, the present 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 of berberine;
(3) A pharmaceutically acceptable carrier.
In the pharmaceutical composition provided by the invention, the Bemperoic Acid can exist in the forms of salts, esters, active metabolites or medicinal precursors and the like. The Bemperoic Acid provided by the invention is used as a medicinal component, and the existence forms of salts, esters, active metabolites and the like of the Bemperoic Acid are also within the scope of the application. In the present invention, the pharmaceutical dosage of bempedocoid Acid is selected from 50-200mg, preferably 120-200mg. The pharmaceutical dosage of the salts, esters, active metabolites or pharmaceutical precursors of bempedoc Acid and the like can be correspondingly converted.
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 taken as a medicinal component, and the existence forms of salts, esters, active metabolites, medicinal precursors and the like of the berberine are also within the scope of the application. In the present invention, the pharmaceutical dosage of berberine is selected from 10-100mg, preferably 50-100mg. The pharmaceutical dosage of the berberine in the form of salts, esters, active metabolites or pharmaceutical precursors can be converted accordingly.
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 preferable mode, the composition provided by the invention comprises 120mgBempedoic Acid and 50mg berberine.
As another preferred aspect, the composition provided by the invention comprises 120mg Bempedoic Acid mg of berberine and 100mg of berberine.
As another preferred aspect, the composition provided by the invention comprises 150mg Bempedoic Acid mg and 50mg berberine.
As another preferred aspect, the composition provided by the invention comprises 150mg Bempedoic Acid mg of berberine and 100mg of berberine.
As another preferred aspect, the composition provided by the invention comprises 180mg Bempedoic Acid mg of berberine and 100mg of berberine.
The pharmaceutical composition also contains a pharmaceutically acceptable carrier, and can be prepared into common oral preparations, including common tablets, common capsules, granules and the like. The pharmaceutically acceptable carrier comprises excipients or adjuvants which facilitate the formulation of the active compound into pharmaceutical preparations, such as microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite, etc., in the form of tablets, and are well known in the art.
The pharmaceutical compositions of the present invention may also be used interchangeably in the form of a "combination kit". The "combination kit" is a box-like container into which a plurality of dosage forms of the pharmaceutical combination, together with instructions for administration thereof, are placed. The combined medicine box is more suitable for individual medicine application.
The composition of berberine and bempedocoid Acid provided by the invention can exert lipid-lowering curative effect, reduce single drug dosage, has higher safety and effectiveness than single drug, has synergistic effect between the berberine and the bempedocoid Acid, has anti-inflammatory effect and low liver toxicity, can be used for treating patients with hyperlipidemia accompanied by liver function injury, and has remarkable curative effect.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Examples 1-2: preparation of Berberine, bempedoic 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
Carboxymethyl starch sodium 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 dodecyl sodium sulfate, mixing, adding microcrystalline cellulose and pregelatinized starch, mixing, making into soft material with appropriate amount of 10% povidone K30 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.
Examples 3-4: preparation of berberine+Bempedoic Acid composite capsule (1000 capsules)
Formulation composition Example 3 Example 4
Berberine 50g 100g
Bempedoic Acid 150g 150g
Lactose and 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 dodecyl sulfate, adding microcrystalline cellulose and lactose, granulating with 5% hypromellose solution, drying at 50-60deg.C for 2 hr, mixing the obtained material with magnesium stearate, and encapsulating with No. 1 capsule. Making into 1000 granule.
Examples 5 to 6: preparation of berberine+Bempedoic Acid granule (1000 bags)
Formulation composition Example 5 Example 6
Berberine 50g 100g
Bempedoic Acid 120g 180g
Lactose and lactose 80g 80g
Pregelatinized starch 100g 100g
Carboxymethyl starch sodium 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 Bemperoic Acid with prescription amount, sieving with 100 mesh sieve, and mixing well; (2) sieving other auxiliary materials with 100 mesh sieve respectively for standby; (3) Weighing lactose, pregelatinized starch, carboxymethyl starch sodium and aspartame with a prescription amount, uniformly mixing the lactose, pregelatinized starch, carboxymethyl starch sodium and aspartame with the mixed raw materials, and uniformly mixing the lactose, pregelatinized starch, carboxymethyl starch sodium and aspartame with the mixed raw materials; (4) Adding a proper amount of adhesive to prepare a soft material, granulating by 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 proper amount of magnesium stearate into the dry granules, mixing uniformly, measuring the content of the magnesium stearate, and bagging.
Example 7: observation of lipid-lowering efficacy of berberine+Bemperoic Acid on hyperlipidemic animals
Molding a high-fat animal:
purchasing male golden mice (SPF grade, beijing vitamin Torilhua), feeding with common daily ration, quarantining for 7 days, and randomly selecting 12 normal feeds to continue feeding until the experiment is finished, wherein the normal feeds are used as a control group; the remaining rats were fed with high fat feed (10% hydrogenated coconut oil, 1.25% cholesterol, 88% basal feed) (formulation below),
and (5) drinking water freely. 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%.
Grouping and administration:
after 4 weeks of high fat diet, the diet was fasted overnight. Blood is collected from the eye sockets of golden-yellow mice, the supernatant is collected for standby after standing and centrifugation, and four blood fat items are detected. LDL (low density polyethylene) for model animal C Animals with a level of 20% above the mean of the normal control group were alternatively enrolled in the group according to LDL-in-situ in the animals C The levels were randomly grouped, giving consideration to both TC levels and animal body weight, and the high-fat model animals were randomly divided into 4 groups, namely, model group, berberine+Bempenocoid Acid group (5+12 mg), berberine group (5 mg), bempenocoid Acid group (12 mg). The administration is performed by stomach irrigation once a day, and the administration volume is 10ml/kg. The administration was continued for 8 weeks.
After the experiment, blood collection was sacrificed, and four blood lipid and liver function indexes (AST, ALT) were measured, and inflammatory factors (hs-CRP, IL-6).
To confirm the scientificity of the pharmaceutical composition provided by the invention, t-test was used between groups to verify statistical differences. In order to show that the two components of the pharmaceutical composition are reasonably compatible, can exert a synergistic effect by combining with each other, and are not simply overlapped by pharmacological action, and the experimental result is 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 two medicaments and the pharmacological actions of the single use of the two medicaments in a dose-response curve area, the golden average Q value method is calculated by the following calculation formula: q=e A+B /(E A +E B -E A *E B ) In the formula, the numerator represents the actual measurement combination effect, and the denominator represents the expected combination effect (in order to meet the analysis of the pharmacological action relation of the components and the composition, the pharmacological actions of the components and the composition are converted into the effect capable of intuitively representing the pharmacological action intensity, and the calculation formula is as follows: ei=1-Pi/P Model group Pi is the pharmacological index of each component, P Model group Pharmacological index of model group), 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.
Table 1: blood fat four items and body weight measurement after molding golden yellow mice for 4 weeks
Note that: compared with the normal group ratio, ## P<0.01。
table 2: effects of the compositions of the invention on blood lipid levels in golden mice 8 weeks after administration
Note that: compared with the normal group ratio, # P<0.05， ## P<0.01, compared to model group P<0.05，**P<0.01。
Table 3: analysis of the Effect of the composition of the present invention on the blood lipid index of golden yellow mice
The blood lipid level of golden yellow mice after high-fat modeling is obviously increased, the blood lipid level (TC, LDL-C, TG) is obviously reduced (P < 0.01) after berberine, bemperoic Acid or a combination thereof is treated, and the reduction amplitude of the berberine+Bemperoic Acid group is larger than that of berberine or Bemperoic Acid alone. The Q values of the golden average Q value analysis composition TC and the LDL-C, TG are respectively 1.32, 1.53 and 1.85, which are all more than 1.15, which shows that the berberine and the Bempedocoid Acid combined drug has unexpected synergistic effect in lipid-lowering treatment. Meanwhile, the additive effect (Q value=0.94) is also shown in the process of increasing HDL-C, and the dosages of berberine and Bempedocoid Acid for the mice are respectively 50mg berberine and 120mg Bempedoic Acid corresponding to the dosages of human beings, so that the pharmaceutical composition provided by the invention can synergistically reduce blood fat and has obvious effect.
Table 4: effect of the inventive composition on inflammatory factors of golden mice after 8 weeks of administration
Note that: compared with the normal group ratio, # P<0.05， ## P<0.01, compared to model group P<0.05，**P<0.01
Table 5: analysis of the Effect of the inventive composition on the inflammation index of golden yellow mice
The inflammatory factors hs-CRP and IL-6 of golden-yellow mice after high-fat modeling are obviously increased (P < 0.01) compared with the normal groups, but after treatment, the three treatment groups hs-CRP and IL-6 are obviously reduced, and the reduction amplitude of berberine and Bemperoic Acid is obviously increased (P < 0.01) compared with that of berberine or Bemperoic Acid used alone, which indicates that the composition has a synergistic effect when the composition achieves the anti-inflammatory effect by reducing the level of hs-CRP and IL-6, compared with that of berberine or Bemperoic Acid used alone, and the composition has the synergistic effect calculated from the Q value (hs-CRP: Q=2.36 and IL-6:Q =2.36).
Table 6: effect of the inventive composition on liver function of golden mice after 8 weeks of administration
Note that: compared with the normal group ratio, # P<0.05， ## P<0.01, compared to model group P<0.05，**P<0.01
Table 7: analysis of the Effect of the inventive composition on liver function index of golden yellow mice
The liver function index (ALT, AST) of golden yellow mice after high-fat modeling is obviously improved (P < 0.01) compared with that of normal groups, but after treatment, the ALT, AST of three treatment groups are obviously reduced, and the reduction amplitude of berberine+Bempechoic Acid group is obviously improved (P < 0.01) compared with that of berberine or Bempechoic Acid used alone, which shows that the composition has a synergistic effect in improving liver function by reducing the level of ALT, AST and achieving the effect of liver function protection compared with that of berberine or Bempechoic Acid used alone, and the Q value (ALT: Q=1.91, AST: Q=1.81) is calculated.

Claims (4)

1. A pharmaceutical composition for treating hyperlipidemia comprises the following components:
(1) 120mg of Bempedoic Acid;
(2) 50mg of berberine;
(3) A pharmaceutically acceptable carrier.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated into oral formulations, including tablets, capsules, granules.
3. Use of the pharmaceutical composition of claim 1 for the preparation of a medicament for the treatment of hyperlipidemia.
4. Use according to claim 3, characterized in that the hyperlipidemia is hyperlipidemia with 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 (2)

* Cited by examiner, † Cited by third party
Title
Bempedoic Acid (ETC-1002) A Current Review;Anum Saeed et al;Cardiology Clinics;第36卷(第2期);257-264 *
王晓良主编.《应用分子药理学》.中国协和医科大学出版社,2015,(第第2版版),第271页. *

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