CN116549427B - Application of hydroxycitric acid lactone in preparation of medicine for treating gall-stone - Google Patents

Application of hydroxycitric acid lactone in preparation of medicine for treating gall-stone Download PDF

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Publication number
CN116549427B
CN116549427B CN202310607581.4A CN202310607581A CN116549427B CN 116549427 B CN116549427 B CN 116549427B CN 202310607581 A CN202310607581 A CN 202310607581A CN 116549427 B CN116549427 B CN 116549427B
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hydroxycitric acid
stone
gall
application
preparation
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CN116549427A (en
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徐吉银
韩亮
钟志勇
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Shizhen Bencao Biotechnology Zhongshan Co ltd
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Shizhen Bencao Biotechnology Zhongshan Co ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/194Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a novel application of hydroxycitric acid in treating gall-stone and cholecystitis induced by the gall-stone. Animal modeling experiments prove that the hydroxycitric acid and the derivatives thereof have statistically effective treatment effects on calculus and cholecystitis induced by the calculus or related diseases, and have good application prospects.

Description

Application of hydroxycitric acid lactone in preparation of medicine for treating gall-stone
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a novel application of hydroxycitric acid in treating gall-stone and cholecystitis induced by the gall-stone.
Background
Cholelithiasis is one of the common and multiple diseases in clinical gastroenterology, and can stimulate the mucosa of the gallbladder after stones are formed in the gallbladder, so that not only can chronic inflammation of the gallbladder be caused, but also secondary infection can be caused after stones are embedded in the neck or duct of the gallbladder, and acute inflammation of the gallbladder is caused.
Cholelithiasis can be classified into cholesterol-based calculus, cholelithiasis-pigment-based calculus explained and mixed calculus; wherein at least 80% of the gall stones are cholesterol-based stones; the cause of gall stones is not single and is the result of the combined actions of environment, heredity and personal life style; however, the direct cause of gall stones is mostly insufficient secretion of bile, and is insufficient to dissolve cholesterol.
The formation of kidney stones and the formation process of kidney stones are caused by the fact that the concentration of stone-forming substances in urine is increased or the solubility is reduced due to certain factors, the urine is supersaturated, crystals are precipitated, and the crystals locally grow and accumulate, so that the stones are finally formed.
Hydroxycitric acid can help dissolve calcium oxalate (main component of kidney stones), and has effects of preventing and treating kidney stones; however, there is no description of the related treatment of hydroxycitric gallstones.
CN1082354C hydroxycitric acid concentrate and method of preparation disclose that hydroxycitric acid has an effect of inhibiting the synthesis of fats and cholesterol. It appears that in principle, inhibition of fat absorption and cholesterol synthesis may improve gallstones; however, according to the studies of "Effect of vegetarianism on development of gall stones in women, F Pixley et. al Br Med J (Clin Res Ed)," 1985 "," Gallstone formation during weight-reduction cutting, R A Liddle, R B Goldstein, J Saxton, arch Intern Med 1989 "," The role of gallbladder emptying in gallstone formation during diet-induced rapid weight loss, R L Gebhard et. al Hepatology 1996 ", it was found that long-term low-fat, low-cholesterol diet did not cause the gall stones to disappear, but rather caused the stones to become more severe.
The study of "Effect of various food ingredients on gall bladder injection, L margini et. al Eur J Clin Nutr 2013" shows that fat is the most effective food ingredient for stimulating gallbladder contraction and promoting gallbladder emptying. That is, dietary intake of cholesterol is not an important factor in causing gallstones.
Disclosure of Invention
The invention aims to provide a novel application of hydroxycitric acid for treating gall stones and cholecystitis induced by the stones.
The invention discloses application of hydroxycitric acid and derivatives thereof in preparing medicines for treating gall-stone and/or cholecystitis.
Specifically, the hydroxycitric acid and the derivative thereof are at least one of the following components:
hydroxycitric acid, hydroxycitric lactone, and hydroxycitric acid salt.
More specifically, the hydroxycitrate includes sodium hydroxycitrate, potassium hydroxycitrate, calcium hydroxycitrate.
The medicine for the application can be a specific preparation form prepared from the hydroxycitric acid and derivatives thereof and pharmaceutically acceptable auxiliary materials by adopting a conventional preparation process, and the preparation form is not limited, and can be a preparation form prepared from the trichosanthin, including but not limited to tablets, capsules and granules.
The preparation method of the medicine for the application is not limited, and can be any preparation process which can be adopted in the pharmaceutical field.
The medicine for the application can mainly adopt an oral administration method according to the self characteristics, and the preparation formulation of the medicine can be tablets, granules, capsules, soft capsules, oral liquid, suspension and the like.
Animal modeling experiments prove that the hydroxycitric acid and the derivatives thereof have statistically effective treatment effects on cholecystitis or related diseases induced by stones, and meanwhile, the safety experiments also prove that the hydroxycitric acid and the derivatives thereof have good safety and definite application prospect.
Drawings
The invention will be further described with reference to the drawings and examples.
FIG. 1 is a structural formula of 2-hydroxycitric acid.
FIG. 2 is a structural formula of hydroxycitric lactone.
FIG. 3 is a structural formula of potassium hydroxycitrate.
FIG. 4 is a photograph of a model set of cholesterol crystallized pellets of an example.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are not intended to limit the present invention, but are merely illustrative of the present invention. The experimental methods used in the following examples are not specifically described, but the experimental methods in which specific conditions are not specified in the examples are generally carried out under conventional conditions, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.
In specific embodiments, steps, material selections, numerical parameters that are not described in detail are all routine selections in the art, or any prior art that is presently disclosed.
EXAMPLE influence of monohydroxy citric acid on C57BL/6 mouse gall bladder stones
1. Modeling and intervention method
SPF class C57BL/6 mice, 60 males, 7-8 weeks. After quarantine is qualified, the random classification is divided into 5 groups: normal group 12, model group 48. Model mice were fed with high fat, high calories, high cholesterol (15.0% fat, 1.0% cholesterol, 0.5% cholic acid) and normal mice were fed with normal feed. After molding for 1 month, 8 mice were randomly selected from the model group, 2 mice were randomly selected from the normal group, bile was collected in a glass test tube by dissecting and collecting gall bladder, the color was observed, a portion of the bile sample was sampled and put on a glass plate for smear, and observed under a high power microscope, a large amount of cholesterol crystal particles were found under the microscope of the model group, the crystal particles were not found in the normal group, and the molding was confirmed to be successful.
Model mice were randomly assigned to model control, experimental low, medium, and high dose groups, 10 mice/group. After 1 week of adaptive feeding, normal mice were fed normal feed, and the remaining mice were given high fat, high calorie, high cholesterol (15.0% fat, 1.0% cholesterol, 0.5% bile acid) feed for 4 weeks for modeling. The drug intervention is performed during molding, the drug administration method and the drug dosage are performed according to the pre-experimental dosage of the subject group, and the drug administration is performed for 4 weeks, 1 time a day.
Mixed solvent: 10% DMSO (dimethyl sulfoxide) +40% PEG300 (polyethylene glycol; polyethylene glycol 300) +5% Tween-80 (Tween 80) +45% Saline (physiological Saline)
Medicament: and (3) dissolving the hydroxycitric acid by using a mixed solvent.
The administration mode is as follows: gastric lavage, once per day:
the dosage is as follows:
model control group: 15mg/kg mixed solvent
Experimental low dose group: 2.5mg/kg hydroxycitric acid
Dose group in experiment: 5mg/kg hydroxycitric acid
Experimental high dose group: 10mg/kg hydroxycitric acid
Wherein the residual amounts of the low, medium and high dose groups are supplemented to 15mg/kg by using the mixed solvent.
2. Specimen collection
After 8 weeks, blood was collected and the concentrations of Total Bile Acid (TBA), total Cholesterol (TC), triglyceride (TG), total Bilirubin (TBiL), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured as shown in Table 1.
In table 1, N groups are normal groups, M groups are model control groups, low groups are experimental Low dose groups, mid groups are experimental medium dose groups, hig are experimental high dose groups.
In the table 1, the contents of the components, N represents P < 0.05 compared to N groups; M represents P < 0.05 compared to group M;
as shown in Table 1, the experimental groups showed a statistically different decrease in TBA, TG, TC, TBiL, LDL-C, HDL-C compared to the model control group, demonstrating the therapeutic effect of hydroxycitric acid.
Example Effect of dihydroxycitric acid derivatives on C57BL/6 mouse gall bladder stones
In order to investigate the quality effect of hydroxycitric acid derivatives on cholecystolithiasis, the potential medical value of various hydroxycitric acid derivatives was tested in the same manner as in example one, specifically:
hydroxycitric acid lactone [ CAS 546-43-0]
Hydroxy sodium citrate [ CAS 6132-04-3]
Potassium hydroxycitrate [ CAS 866-84-2]
Calcium hydroxycitrate [ CAS 814-80-2]
The grouping is as follows:
A-Low 2.5mg/kg hydroxycitric lactone
A-Mid 5mg/kg hydroxycitric lactone
A-Hig 10mg/kg hydroxycitric lactone
B-Low 2.5mg/kg sodium hydroxy citrate
B-Mid 5mg/kg sodium hydroxy citrate
B-Hig 10mg/kg sodium hydroxy citrate
C-Low 2.5mg/kg Potassium hydroxycitrate
C-Mid 5mg/kg potassium hydroxycitrate
C-Hig 10mg/kg Potassium hydroxycitrate
D-Low 2.5mg/kg calcium hydroxycitrate
D-Mid 5mg/kg calcium hydroxycitrate
D-Hig 10mg/kg calcium hydroxycitrate
The remainder was the same as in example one, and the results are shown in Table 2.
In the table 2 of the description of the present invention, N represents P < 0.05 compared to N groups; M represents P < 0.05 compared to group M;
from table 2, it can be seen that the therapeutic effect ratio: hydroxycitric acid lactone > calcium hydroxycitrate > sodium hydroxycitrate > potassium hydroxycitrate. But any group has a statistically significant therapeutic effect.
The foregoing detailed description is directed to one of the possible embodiments of the present invention, which is not intended to limit the scope of the invention, but is to be accorded the full scope of all such equivalents and modifications so as not to depart from the scope of the invention.

Claims (2)

1. Application of hydroxycitric acid lactone in preparing medicine for treating cholelithiasis is provided.
2. The use according to claim 1, wherein the medicament further comprises pharmaceutically acceptable excipients.
CN202310607581.4A 2023-05-26 2023-05-26 Application of hydroxycitric acid lactone in preparation of medicine for treating gall-stone Active CN116549427B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010099460A (en) * 2001-09-29 2001-11-09 서석춘 Cholesterol stones in bile ducts using herbal ingredients
CN103284145A (en) * 2013-04-28 2013-09-11 臧鸿飞 Combination beverage for discharging internal light hepatic calculus
CN105055579A (en) * 2015-09-11 2015-11-18 吉林大学 Compound traditional Chinese medicine composition for treating urolithiasis and preparation method thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10285961B2 (en) * 2014-02-06 2019-05-14 University Of Houston System Organic acids as agents to dissolve calcium minerals in pathological calcification and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010099460A (en) * 2001-09-29 2001-11-09 서석춘 Cholesterol stones in bile ducts using herbal ingredients
CN103284145A (en) * 2013-04-28 2013-09-11 臧鸿飞 Combination beverage for discharging internal light hepatic calculus
CN105055579A (en) * 2015-09-11 2015-11-18 吉林大学 Compound traditional Chinese medicine composition for treating urolithiasis and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
涂宏等.《常见病联合用药手册》.中国医药科技出版社,2021,第242-243页. *
郑建仙.《植物活性成分开发》.中国轻工业出版社,2005,第54-55页. *

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