CN102258524B - The medical usage of enoxolone - Google Patents
The medical usage of enoxolone Download PDFInfo
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- CN102258524B CN102258524B CN201110155118.8A CN201110155118A CN102258524B CN 102258524 B CN102258524 B CN 102258524B CN 201110155118 A CN201110155118 A CN 201110155118A CN 102258524 B CN102258524 B CN 102258524B
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Abstract
The present invention relates to medicine, particularly relate to a kind of medical usage of enoxolone.Enoxolone of the present invention can be used for the hepatic injury of curative physical property.
Description
Technical field
The present invention relates to medicine, particularly relate to a kind of medical usage of enoxolone.
Background technology
Liver is the major organs of drug accumulation, conversion, metabolism, and especially namely oral drugs enter liver by after gastrointestinal absorption, and the concentration in liver is comparatively high in blood and other organs.When the consumption of medicine is excessive or administration time is long, will damage liver.When particularly share two or more medicine irrelevantly, infringement more very, can cause part of hepatocytes downright bad, occur the abnormal liver function situation such as jaundice, serum glutamic pyruvic transminase rising.Because the toxic action of medicine and metabolite or body produce anaphylaxis to medicine, liver is caused damage, causes liver tissues inflammatory, cause hepatic necrosis, be drug induced hepatic injury.The medicine of drug induced hepatic injury can be caused to mainly contain antipyretic-antalgic class antibiotic medicine (as acamol), sedative hypnotic, antitubercular agent, antiparasitic and some antimicrobial drug and hormone medicine etc.
Most fat-soluble medicine is metabolized to water-soluble products by the P450 system of liver through first-phase redox reaction and second-phase association reaction.Medicine causes the mechanism of hepatocyte injury to comprise:
1, drug metabolite formation oxygen-derived free radicals makes lipid peroxidation cause hepatocyte injury;
2, because genetic background difference makes P450 phenotype different, some drugs produces electrophilic product through metabolism, causes cell injury by covalent bond damage liver plasma membrane and hepatic mitochondria, microsomal membrane;
3, the super oxidative ionic of drug metabolism generation impels lipid peroxidation, causes hepatocyte injury etc.
Cold, fever is common disease, paracetamol etc. are containing acetaminophen (Acetaminophen, be abbreviated as APAP, have another name called acamol, paracetamol) medicine be usually used in antipyretic-antalgic, treatment cold, fever, apply very extensive.But, through clinical observation and laboratory proofing, heavy dose or prolonged application APAP, the serious lesions of liver and kidney of animal and human (James LP can be caused, Mayeux PR, HinsonJA.Acetaminophen-induced Hepato-toxicity [J] .Drug metabolism and dispositkm, 2003,31 (12): 1499.), even dead.APAP is in vivo through liver cell pigment P450 metabolism, overwhelming majority product is combined with sulphuric acid, Portugal's glucuronic acid, only seldom a part generates toxicity intermediate product (N-acetyl-p-benzoquinonimine, NAPQI), participates in deactivation by reduced glutathion (GSH).When NAPQI generates too much or GSH declines, NAPQI regulating liver-QI intracellular macromolecules covalent bond forms adduct.NAPQI induced oxidation stress causes peroxide injury, with mitochondrion in conjunction with the energy metabolism (KnightR in interference cell, Fariss MW, Farhood A, et al.Role oflipid peroxidation as a mechanism of liverinjury after acetaminophen overdose in mice [J] .Toxicol Sci, 2003,76 (1): 229.).Oxygen molecule also activates Viability oxygen through P450, and the generation of this kind of free radical and membrane lipid peroxidatio reaction combined effect, cause liver GSH to exhaust, cause hepatic necrosis, cause hepatic injury.
Medical glycyrrhiza is the dry root welding technology of glycyrrhizic legume Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. Glycyrrhizainflate Bat. or Glycyrrhiza glabra L. Glycyrrhiza glabra L..Containing multiple triterpene saponin in Radix Glycyrrhizae, wherein glycyrrhizic acid and enoxolone are its principle active component.Enoxolone (Glycyrrhetinic acid is called for short GA), be white crystalline powder, water insoluble, widely, clinical research confirmation enoxolone has antiinflammatory, antiulcer and the effect of adrenocortical hormone sample etc. in pharmacological action.But have no any report of liver injury protection effect APAP caused about enoxolone.
Summary of the invention
Object of the present invention aims to provide a kind of new medical usage of enoxolone or its officinal salt, prodrug.
A first aspect of the present invention there is provided enoxolone or its officinal salt, prodrug for the preparation of the medicine of prevention or the hepatic injury of curative physical property.
In another preference, described hepatic injury is caused by antipyretic-antalgic class antibiotic medicine.
In another preference, described antipyretic-antalgic class antibiotic medicine is acamol.
A second aspect of the present invention there is provided a kind of pharmaceutical composition, comprises described enoxolone or its officinal salt, prodrug and pharmaceutically suitable carrier for the treatment of effective dose.
The details of various aspects of the present invention is able to detailed description by chapters and sections subsequently.By hereafter and the description of claim, other features of the present invention, object and advantage will be more obvious.
Detailed description of the invention
Appearance part of the present invention unexpected to find based on such one: enoxolone or its officinal salt, prodrug have good prevention and therapy effect to drug induced hepatic injury in animal body.Therefore, enoxolone or its officinal salt, prodrug can be used for the medicine preparing prevention or the hepatic injury of curative physical property.
And then, the invention provides a kind of enoxolone or its officinal salt, prodrug for the preparation of the purposes of the medicine of prevention or treatment hepatic injury.Wherein, the molecular formula of enoxolone of the present invention is: C
30h
46o
4, molecular weight: 470.68, structural formula is as follows:
Enoxolone of the present invention or its officinal salt, prodrug obtain or use the synthesis material of this area routine and method preparation or purify by commercial sources.
The officinal salt of enoxolone of the present invention comprises various inorganic or acylate example hydrochloric acid salt, hydrobromate, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalates; Various inorganic or organic alkali salt is as sodium hydroxide, Tris (TRIS, tromethane) and N-methyl-glucamine.
The carboxylate that the prodrug of enoxolone of the present invention comprises containing enoxolone (can by the conventional method C of this area
1-4pure and strong contraction obtain), hydroxy ester containing enoxolone (can by the conventional method C of this area
1 -4carboxylic acid, C
3-6dicarboxylic acids or its sour liver, as maleic anhydride, fumaric acid anhydride etc. are concentrated obtained), enamine containing enoxolone (can by the conventional method C of this area
1-4aldehydes or ketones concentrated obtained) or acetal containing enoxolone or ketal (can by the conventional method chloromethyl methyl ether of this area or chloromethyl ether concentrated obtained) etc. (Albert S.Kearney Advanced Drug Reviews.19 (1996): 229-234).
Present invention also offers a kind of pharmaceutical composition, comprise described enoxolone or its officinal salt, prodrug and pharmaceutically suitable carrier for the treatment of effective dose." treatment effective dose " refers to the amount of the extract that can reach therapeutic effect.One of skill in the art can understand, and " treatment effective dose " along with the use of the mode of administration, carrier and may can to share etc. with other treatment agent and different.
Research confirms, most fat-soluble medicine is metabolized to water-soluble products by the liver cell pigment P450 system of liver through first-phase redox reaction and second-phase association reaction.Medicine causes the mechanism of hepatocyte injury to comprise:
1, drug metabolite formation oxygen-derived free radicals makes lipid peroxidation cause hepatocyte injury;
2, because genetic background difference makes P450 phenotype different, some drugs produces electrophilic product through metabolism, causes cell injury by covalent bond damage liver plasma membrane and hepatic mitochondria, microsomal membrane;
3, the super oxidative ionic of drug metabolism generation impels lipid peroxidation, causes hepatocyte injury etc.
Be appreciated that, enoxolone of the present invention or its officinal salt, prodrug can be used for the medicine preparing prevention or the hepatic injury of curative physical property, the drug induced hepatic injury preferably caused by antipyretic-antalgic class antibiotic medicine is particularly preferably the drug induced hepatic injury caused by acamol.One of skill in the art can understand, described drug induced hepatic injury perhaps can be proved to be from now on have other, pathogeny that may not be relevant to liver cell pigment P450 systemic metabolism, but this does not affect enoxolone of the present invention or its officinal salt, prodrug for the preparation of the medicine of prevention or the hepatic injury of curative physical property.
Enoxolone of the present invention or its officinal salt, prodrug can be used alone or use with the form of pharmaceutical composition.Pharmaceutical composition comprises enoxolone of the present invention as active component or its officinal salt, prodrug and pharmaceutically suitable carrier.Preferably, pharmaceutical composition of the present invention contains the enoxolone of the present invention as active component or its officinal salt, the prodrug of 0.1-99.9% percentage by weight." pharmaceutically suitable carrier " can not destroy the pharmaceutical active of enoxolone of the present invention or its officinal salt, prodrug, simultaneously its effective dose, and consumption when can play pharmaceutical carrier effect is to human non-toxic.
Described pharmaceutically suitable carrier includes but not limited to: soft phospholipid, aluminium stearate, aluminium oxide, ion exchange material, self-emulsifying drug delivery system, tween or other surfactants, serum albumin, buffer substance are if phosphate, glycine, sorbic acid, water, salt, electrolyte are as sulfate protamine, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, magnesium silicate, satisfied fatty acid partial glyceride mixtures etc.
Other conventional excipient substances are as binding agent (as microcrystalline Cellulose), filler (as starch, glucose, Lactis Anhydrous and lactose beadlet), disintegrating agent (as cross-linked pvp, crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose), lubricant (as magnesium stearate) and absorption enhancer, absorption carrier, flavouring agent, sweeting agent, excipient, diluent, wetting agent etc.
Enoxolone of the present invention or its officinal salt, prodrug and pharmaceutical composition can by the preparations of this area conventional method and can by intestinal or non-bowel or topical routes.Oral formulations comprises tablet, granule, suspension, capsule, solution etc., and non-intestinal drug delivery agent comprises injection.Local administration preparation comprises cream, patch, ointment, spray etc.
The route of administration of enoxolone of the present invention or its officinal salt, prodrug and pharmaceutical composition can be oral, Sublingual, percutaneous, through muscle or subcutaneous, mucocutaneous, vein, urethra, vagina etc.
The consumption of enoxolone of the present invention or its officinal salt, prodrug and pharmaceutical composition can be different from the difference of the age of route of administration, patient and body weight, disorder severity, its daily dose can be 0.001 ~ 100mg/kg, can be in single or divided doses.
Below in conjunction with specific embodiment, the invention will be further described, but and do not mean that the present invention is only limitted to this.
Embodiment 1 enoxolone is to the therapeutic effect of the mouse liver injury caused by acamol
Enoxolone is provided by Xi'an Caulis et Folium Polygalae Tenuifoliae plant Science and Technology Ltd., and agents useful for same is as follows:
1.0.9% injection normal saline, manufacturer: Zhejiang Sapuaisi Pharmacy Co., Ltd., lot number: 101102-2.
2. paracetamol injection determined (APAP injection), manufacturer: animal drug factory of Harbin HTC, authentication code (2006) 080022531, lot number: 20100118.
3. enoxolone, manufacturer: Xi'an Caulis et Folium Polygalae Tenuifoliae plant Science and Technology Ltd., lot number: XC101202.
4. ammonium glycyrrhizinate, manufacturer: Xi'an Caulis et Folium Polygalae Tenuifoliae plant Science and Technology Ltd., lot number: XC110312.
5. mice ALT biochemical instruments detects, and is acted on behalf of detect by generation promise clinical diagnosis goods (Shanghai) trade Co., Ltd.
Laboratory animal:
ICR mice, purchased from Si Laike, the quality certification number: 0046303, body weight 22g ± 2g, is divided into 4 groups at random according to body weight by 32, often organizes 8.
Experimental technique:
1.32 mice adaptabilities are divided into 4 groups according to body weight after feeding, and often organize 8,4 groups are respectively normal group, model group, positive controls, enoxolone group.Test first and second sky, 1st, 2 groups of normal saline 0.2ml gavages 1 times/day, 3rd, positive control drug ammonium glycyrrhizinate and enoxolone gavage 1 times/day is used respectively for 4 groups, dosage is all 250mg/kg, after within second day, each treated animal gavage terminates, during 1h, the 1st group of intraperitoneal injection of saline, 2nd, 3,4 groups of lumbar injection APAP injection, dosage is 600mg/kg.
2. start the clock after use APAP, the centrifugal rear Virus monitory ALT of blood sampling after 24 hours.
Experimental result:
Each group of ALT testing result is as following table:
*compared with model group, P < 0.01
From the ALT result of each group, model group and normal group ALT value have significant difference (P < 0.01), and model success is described; In positive drug and enoxolone group, ALT and model group have significant difference, and normal group is compared with positive drug group, enoxolone group, does not have significant difference.
Result shows: enoxolone has good prophylactic treatment effect to the hepatic injury that APAP causes.
The preparation of embodiment 2 tablet
Tablet forms:
By enoxolone, HPMCLVIOO, lactose, starch mixing, add and make soft material with starch slurry, granulate, 60 DEG C of aeration-drying 40 minutes, cross 75% ethanol soft material, 24 mesh sieves are granulated, 50 DEG C of dryings 3 hours, 18 mesh sieve granulate, add magnesium stearate mixing tabletting, make 1000, every sheet 0.1g.For patient, oral, 3 times on the one, each 2.
The preparation of embodiment 3 capsule
Capsule forms:
By enoxolone, starch mixing, add starch slurry and make soft material, granulate, 60 DEG C of aeration-dryings, cross 24 mesh sieve granulate, add magnesium stearate mixing, encapsulated, totally 1000, every 0.1g.For patient, oral.
The preparation of embodiment 4 injection
Injection forms:
Enoxolone 0.5g is dissolved in ethanol, mixes, inject water to 100mL, make emulsion with polyoxyethylene (40) Oleum Ricini, adds 0.1% biological activated carbon and filters, subpackage, embedding, 100 DEG C of flowing steam sterilizations, 30min and get final product.
Many aspects involved in the present invention have been done and have as above been set forth.It is to be understood, however, that put before not departing from spirit of the present invention, those skilled in the art can carry out equivalent change and modification to it, and described change and modification fall into the coverage of the application's claims equally.
Claims (1)
1. enoxolone or its officinal salt purposes in the medicine of the hepatic injury that preparation prevents or treatment acamol causes.
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| CN201110155118.8A CN102258524B (en) | 2011-06-10 | 2011-06-10 | The medical usage of enoxolone |
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| CN102258524B true CN102258524B (en) | 2015-08-19 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106806376A (en) * | 2015-11-27 | 2017-06-09 | 苏州科信医药科技有限公司 | The pharmaceutical composition of paracetamol and glycyrrhizic acid or its salt or derivatives thereof |
| CN114272254B (en) * | 2020-09-28 | 2024-01-26 | 中国科学院上海药物研究所 | Application of combination of glycyrrhetinic acid and paeoniflorin in treating liver injury and liver fibrosis |
| CN114480256B (en) * | 2022-03-14 | 2023-05-26 | 军事科学院军事医学研究院环境医学与作业医学研究所 | Glycyrrhetinic acid induced hepatocyte oxidative stress and inflammatory response and application thereof |
| CN115645413A (en) * | 2022-09-23 | 2023-01-31 | 中南大学湘雅二医院 | New application of glycyrrhetinic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101926815A (en) * | 2010-05-07 | 2010-12-29 | 宁波立华制药有限公司 | Paeoniflorin and glycyrrhetinic acid composition and preparation method and application thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101926815A (en) * | 2010-05-07 | 2010-12-29 | 宁波立华制药有限公司 | Paeoniflorin and glycyrrhetinic acid composition and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 张宝旭 等.中药六号先导物的药效研究.《中国国际中医药博览会论文集(A)》.2003,54-57. * |
| 甘草对小鼠扑热息痛肝毒性的保护作用;陈重阳 等;《中国药理学通报》;19881231;第4卷(第2期);124 * |
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Address after: 313000 Hongfeng Road, Huzhou, Zhejiang 1366 Patentee after: Huzhou Zhongke nutrition and health innovation center Address before: 313000 South Taihu science and technology innovation center, 1366 Hongfeng Road, Huzhou City, Zhejiang Province Patentee before: HUZHOU R & D CENTER FOR NUTRITION AND HEALTH, SHANGHAI INSTITUTES FOR BIOLOGICAL SCIENCES, CHINESE ACADEMY OF SCIENCE |
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