Acid-base addition salts containing berberine, processes for their preparation and their use as medicines

An addition salt and berberine technology, applied in the field of medicine, can solve the problem of reducing the dosage of berberine, unrevealed, unrevealed beneficial effects of acid-base addition salt of fenofibric acid and berberine, etc. question

Active Publication Date: 2022-03-18
GUANGDONG PHARMA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the dissolution rate of berberine hydrochloride is poor and the bioavailability is extremely low, which leads to the need to use high doses of berberine hydrochloride in clinical practice to achieve the expected curative effect
[0009] Chinese patent applications 201580041177.9 and 201680032575.9 respectively disclose acid-base addition salts of berberine and ursodeoxycholic acid and conjugated compounds of ursodeoxycholic acid and berberine or L-carnitine, which reduce the dosage, but does not suggest the use of acid-base addition salts of berberine and fenofibric acid, butyric acid, Gemcabene, Elafibranor, or their derivatives or structural analogues
Chinese patent application 201510986009.9 discloses a pharmaceutical composition of berberine and fenofibrate and its application in the prevention or treatment of diabetes. It also uses berberine hydrochloride with poor dissolution rate and poor bioavailability as an ingredient. There are great defects, and the use of fenofibrate at the same time is essentially different from the fenofibrate acid involved in the invention of this patent, and the acid-base addition salt composed of fenofibrate acid and berberine involved in the invention The special form is completely different from the simple physical mixing method disclosed in the patent application 201510986009.9 on the dissolution rate and bioavailability of the drug, so the prior art does not reveal anything about the acid-base addition of fenofibric acid and berberine The Beneficial Effects of Salt

Method used

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  • Acid-base addition salts containing berberine, processes for their preparation and their use as medicines
  • Acid-base addition salts containing berberine, processes for their preparation and their use as medicines
  • Acid-base addition salts containing berberine, processes for their preparation and their use as medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 General synthetic method of acid-base addition salt of berberine

[0027] Berberine hydrochloride (1.0 equivalent) was dissolved in hot pure water and cooled to room temperature. At the same time, dissolve the organic acid (0.6-1.2 equivalents) in absolute ethanol, and add an aqueous solution of sodium carbonate (0.6-1.2 equivalents) dropwise thereto. After the addition is completed, stir the reaction system for 30-60 minutes to obtain sodium organic acid saline solution. At a temperature of 60-80°C, add the berberine hydrochloride solution dropwise to the prepared organic acid sodium salt solution, stir for 2 hours, cool, filter and collect the solid precipitate in the reaction system, wash with a small amount of cold water, dry, and Ethanol and ethyl acetate mixed solvent carry out recrystallization to obtain the acid-base addition salt pure product of berberine, can identify the composition ratio of organic acid and berberine in the acid-base addition salt...

Embodiment 2

[0029] Example 2 Screening of lipid-lowering activity of berberine acid-base addition salt

[0030] Eight-week-old male ICR mice were adaptively fed for 5 days and randomly divided into 6 groups. The mice in the blank group and the model group were intragastrically administered with 0.5% CMC-Na solution once a day; the mice in the treatment group were intragastrically administered with the test drug once a day, both at a dose of 30 μM / kg, for 7 consecutive days. Sixteen hours before the last administration, the mice in the blank group were intraperitoneally injected with normal saline, and the mice in the other groups were injected intraperitoneally with 400 mg / kg Triton-WR1339 to establish a model. One hour after the last administration, blood was collected from the orbit, left to stand for one hour, and the serum was separated by centrifugation. The levels of TC and TG in the serum were measured. The experimental results are shown in Table 1.

[0031] Table 1: Effects of ac...

Embodiment 3

[0035] Example 3 Study on improvement of metabolic syndrome in vivo by acid-base addition salt of berberine

[0036] Eight-week-old ob / ob mice, male, were randomly divided into groups, 6 mice in each group, blank control group (blank vehicle: 0.5% sodium carboxymethylcellulose solution), and the test drug group was administered by intragastric administration once a day, respectively. Compound (30mg / kg), after continuous administration for 30 days, blood was collected from the mice on an empty stomach, and the levels of glycosylated hemoglobin, blood lipids, and liver function in the mice were measured with an automatic biochemical analyzer. The results are shown in Table 2. The mouse liver tissue was taken for sectioning, and the pathological changes of the liver tissue were observed by HE staining. The results are shown in the attached figure 1 .

[0037] Table 2: Effects of berberine acid-base addition salts on the levels of glycosylated hemoglobin, blood lipids, and liver ...

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PUM

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Abstract

The present invention relates to a novel acid-base addition salt composed of a class of berberine and a pharmacologically active organic acid, its preparation method and as a preparation method for preventing or / and treating various diseases or dysfunctions, such as diabetes, diabetic complications, Dyslipidemia, dyslipidemia in statin non-tolerant patients, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, diabetes combined with dyslipidemia, obesity, metabolic syndrome, prediabetes, inflammation, cancer, and various liver diseases Or dysfunction, such as fatty liver, non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestatic liver disease, liver transplantation versus host disease, chronic liver disease caused by viruses, and alcoholic liver disease, etc., have broad application prospects.

Description

technical field [0001] The invention relates to a novel therapeutic compound, a pharmaceutical composition, a preparation method thereof and an application in treatment, belonging to the technical field of medicine. The novel acid-base addition salt composed of berberine and pharmacologically active organic acid involved in the present invention has uniqueness and novelty in this field. Background technique [0002] Metabolic syndrome is a common disease characterized by abnormal glucose and lipid metabolism, accompanied by elevated low-density lipoprotein and low high-density lipoprotein cholesterol. The common symptoms are obesity, diabetes, hyperlipidemia, atherosclerosis Cirrhosis and fatty liver, etc. Among them, diabetic patients often have hyperlipidemia, cardiovascular disease, diabetic nephropathy, diabetic neuropathy and other diseases. [0003] According to the World Health Organization, more than 220 million people worldwide suffer from diabetes. Among them, Chi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D455/03C07C59/90C07C59/305C07C53/124C07C323/22A61P1/16A61P31/12A61P3/10A61P3/06A61P3/04A61P3/00A61P9/10A61P29/00A61P35/00A61K31/4375A61K31/216A61K31/205
CPCC07D455/03C07C59/90C07C59/305C07C53/124C07C323/22A61P1/16A61P31/12A61P3/10A61P3/06A61P3/04A61P3/00A61P9/10A61P29/00A61P35/00
Inventor 李政张陆勇蔡宗余
Owner GUANGDONG PHARMA UNIV
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