CN108619134A - The reduce blood ammonia of swertiamarin acts on and its medical usage - Google Patents
The reduce blood ammonia of swertiamarin acts on and its medical usage Download PDFInfo
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- CN108619134A CN108619134A CN201810859966.9A CN201810859966A CN108619134A CN 108619134 A CN108619134 A CN 108619134A CN 201810859966 A CN201810859966 A CN 201810859966A CN 108619134 A CN108619134 A CN 108619134A
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
The present invention relates to pharmaceutical fields, more particularly to the medical usage of the swertiamarin compound of formula (1)：Swertiamarin or its pharmaceutically acceptable salt, the hydrate or prodrug of the present invention, can significantly decrease blood ammonia, can be used for preparing the drug of drop hyperammonemia, such as treat the drug of hepatic encephalopathy.The swertiamarin chemical constitution of the present invention is as follows：
Description
Technical field
The invention belongs to pharmaceutical fields, more particularly to the medical usage of swertiamarin (swertiamarin).River deer bud
Dish hardship glycosides can significantly decrease blood ammonia, can prepare the drug of drop hyperammonemia, such as treat the drug of hepatic encephalopathy.
Background technology
Hepatic encephalopathy (hepatic encephalopathy) be caused by severe liver disease, based on metabolic disorder,
The syndrome of central nervous system function imbalance, main clinical manifestation sickens for consciousness, behavioral disorder and stupor (1) [Ge Jun
Wave, Xu Yongjian clinical practice [M] the 8th edition.Beijing：People's Health Publisher, 2013：434-438].Ammonia poisoning theory is important
Hepatic encephalopathy pathogenesis.The generation and removing of Healthy People ammonia maintain dynamic equilibrium, when the generation of ammonia increases and remove deficiency
When, excess of ammonia, which by blood-brain barrier enters intracerebral, is used as neurotoxin and induces hepatic encephalopathy (2) [Jinhui engraves, and king builds pathology
Physiology [M] the 7th edition.Beijing：People's Health Publisher, 2008：237-245].Lactulose is clinically commonly used as hepatic encephalopathy
Medicine, completely can reach colon after taking and be broken down into lactic acid and acetic acid, reduce enteron aisle pH value.The thorn of lactulose
Sharp effect can lead to laxative, and [Yang Lili, Zou Bing, Wang Junping wait lactuloses and benefit for the final formation for reducing ammonia and absorption (1,3)
Clinical observation on the therapeutic effect [J] Chinese Medicine Leader of probiotics preparation prevention hepatic encephalopathy, 2011,8：75-76].Duration liver property brain
The treatment of disease is a long process, reduces source, generation and the absorption of enteron aisle ammonia and the removing of ammonia, ammonia is made to be changed into nothing
Toxicant is main countermeasure (4) [Liang Kuohuan, Li Shaobai, hepatology [M] second edition of hepatic encephalopathy treatment.Beijing：The people
Hygienic publishing house, 2006：1015-1016].
Swertiamarin is a kind of natural driffractive ring cyclenes fan's terpene compound, is primarily present in Gentianaceae river deer bean sprout platymiscium
In, such as swertia mileensis.It is civil to be usually used in clear liver and gallbladder damp-heat, stomach fire is removed, is the common herbal medicine with long history.The platymiscium is rich
The fan's terpenoid of cyclenes containing driffractive ring, such as swertiamarin (swertiamarin), chiratin (sweroside).
Invention content
The present inventor is found that the swertiamarin compound of formula (I) for the first time, can significantly decrease blood ammonia, can prepare
The drug of hyperammonemia is dropped, the drug of hepatic encephalopathy is such as treated.
The swertiamarin chemical constitution of formula (I) is：
The invention also includes corresponding all pharmaceutically acceptable salts, hydrate or prodrugs of above-mentioned formula (I) compound.
" prodrug of formula (I) ", is often referred to a kind of substance, after being applied with method appropriate, can be carried out in subject's body generation
Thank or chemically react and change the compound or its salt of an accepted way of doing sth (I).
More preferably, above compound of the invention or pharmaceutically acceptable salt, hydrate or prodrug, are as only
One bulk pharmaceutical chemicals are applied to prepare the drug of drop hyperammonemia, in the drug as treated hepatic encephalopathy.
Formula (I) compound of the present invention can be carried, column chromatography etc. by the conventional method such as alcohol extracting, water of this field, from river deer bud
It extracts and obtains in the plants such as Lepidium, Gentiana, also can buy or utilize marketable material by commercial sources, pass through the prior art
Middle traditional compound separation method obtains.
Those skilled in the art can synthesize the compound of the present invention according to existing known technology.The change of synthesis
Closing object can be further purified by the methods of column chromatography, high pressure lipuid chromatography (HPLC) or crystallization.
Formula (I) compound or its pharmaceutically acceptable salt, hydrate or prodrug of the present invention, can significantly decrease
Blood ammonia, thus can be used for preparing the drug of drop hyperammonemia, such as treat the drug of hepatic encephalopathy.
Compound or its pharmaceutically acceptable salt, the hydrate or prodrug of the formula (I) of the present invention, can prepare patent medicine
Compositions, which is characterized in that these compositions include the compound of the structure formula (I) of the present invention or its is pharmaceutically acceptable
Salt, hydrate or prodrug, and pharmaceutically acceptable carrier, these compositions can be used for prepare the medicine of drop hyperammonemia
Object such as treats the drug of hepatic encephalopathy.
Compound or its pharmaceutically acceptable salt, the hydrate or prodrug of the formula (I) of the present invention, can prepare patent medicine
Object preparation, these pharmaceutical preparations include formula (I) compound or its pharmaceutically acceptable salt, hydrate or prodrug of the present invention,
These pharmaceutical preparations can be used for dropping the purposes of hyperammonemia, such as treat hepatic encephalopathy.
Compound or its pharmaceutically acceptable salt, the hydrate or prodrug of the formula (I), in pharmaceutical composition or medicine
Content such as 0.001-50% in object preparation；Preferable 0.01-30%；More preferably 0.05-20%.
Therapeutically effective amount is (i.e.：Function or active and can be received by people and/or animal can be generated to people and/or animal
Amount) the present invention formula (I) compound, with pharmaceutically acceptable carrier (be used for therapeutic administratp carrier, themselves
It is not necessary active constituent, and does not have excessive toxicity after applying) pharmaceutical preparation can be formed, these pharmaceutical preparations can be with
It is prepared into oral preparation, injection, tablet, powder preparation, capsule, dispersible tablet, sustained release preparation etc..
The dosage of the pharmaceutical composition of the present invention of therapeutically effective amount, it is any between 1-5000mg/kg body weight/days
Dosage within above range is all the effective quantity of the present invention.Preferably, composition dosage of the invention is between 20-
Between 2000mg/kg body weight/days, it is furthermore preferred that the composition dosage of the present invention is between 50-1000mg/kg body weight/days.
One of skill in the art is it is understood that the dosage when being actually administered can be higher or lower than above-mentioned dosage range.For a certain
" therapeutically effective amount " of object and specific therapeutic scheme can be influenced by factors, include the medicine of compound used therefor or its prodrug
Imitate activity, the age of administration object, weight, ordinary circumstance, gender, diet, administration time, disease susceptibility, disease process with
And accept the judgement etc. of doctor for medical treatment." treatment " refers to giving formula (I) compound of the body present invention, with treatment, mitigation,
Slow down, change, curing, influencing, improving the symptom of hepatic encephalopathy or the omen of hepatic encephalopathy.
Formula (I) compound of the present invention or its pharmaceutically acceptable salt, hydrate or prodrug or combinations thereof object or its medicine
Object preparation, can be by the way that approach are administered in oral, intravenous, intramuscular, subcutaneous, nasal cavity, in rectum etc..Solid carrier is such as：It forms sediment
Powder, lactose, phosphoric acid glycol, microcrystalline cellulose, brown sugar and white bole, and liquid-carrier is such as：Sterile water, polyethylene glycol, nonionic
Type surfactant and edible oil (such as corn oil, peanut oil and sesame oil), as long as being suitble to the characteristic of active constituent and required
Specific administration mode.Prepare adjuvant usually used in pharmaceutical composition also can effectively by including, e.g., flavoring agent, color
Element, preservative and antioxidant such as vitamin E, vitamin C, BHT and BHA.
The invention has the beneficial effects that：
(1) present invention firstly discovers that the novel medical use of formula (I) swertiamarin compound.That is, swertiamarin energy
Blood ammonia is enough significantly decreased, the drug of drop hyperammonemia can be prepared, such as treat the drug of hepatic encephalopathy, clinical value is huge.
(2) present invention firstly discovers that, swertiamarin is reacted with the ammonia in intestinal tube, and internal ammonia is eliminated and (is generated nitrogenous
Product), to reduce blood ammonia.
(3) present invention firstly discovers that, swertiamarin can reduce rat plasma millet straw and turn ammonia while reducing blood ammonia
Enzyme (AST) and glutamic-pyruvic transaminase (ALT) have protective effect to hepatic injury caused by TAA.
(4) formula (I) swertiamarin compound of the invention, extraction process is simple and practical, is suitble to industrialized production.
(5) formula (I) swertiamarin compound of the invention, is widely present in gentianaceae plant, medicine resource is very
It is abundant, it disclosure satisfy that the demand of medical market.
The details of various aspects of the present invention will be able to detailed description in subsequent chapters and sections.By hereafter and right is wanted
The description asked, the features of the present invention, purpose and advantage will become apparent from.
Description of the drawings
Nothing
Specific implementation mode
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate this hair
It is bright, rather than limit the scope of the invention.It is the experimental method of noted provisos, usually according to conventional strip in the following example
Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise all percentage, ratio, ratio or number is pressed
Weight meter.
Unless otherwise defined, all pre- scientific words of profession used herein and meaning known to one skilled in the art
It is identical.In addition, any or equalization method similar to contents and material all can be applied in the present invention.It is described herein preferable
Implementation is for illustrative purposes only with material.
The feature that the features described above or embodiment that the present invention mentions are mentioned can be in any combination.
Embodiment 1
The preparation of Swertiamarin：
Swertia mileensis (swertia mileensis) medicinal material crushes, and the extraction of 95% ethyl alcohol soaking at room temperature is secondary, and 24 is small every time
When, merge extracting solution, is evaporated in 50 degree or less reduced pressures, obtains Herba Swertiae Mileensis extract.
Herba Swertiae Mileensis extract is refined with macroporous resin column chromatography method, is first eluted with water, then with 20% ethanol elution.It collects
20% ethanol eluate is evaporated in 50 degree or less reduced pressures, is recrystallized repeatedly with absolute ethyl alcohol, obtain Swertiamarin, purity
More than 98%.
The Structural Identification of product：
TOF-MS：m/z 375[M+1]+, 195 [M-Glc]+；UVmax(MeOH)nm：236；1H-NMR(CD30D)：4.65
(- the H of 1H, d, J=7.1Hz, 1 '), 5.32-5.52 (3H, m, 8-H, 10-H), 5.76 (1H, d, J=1.9Hz, 1-H), 7.66
(1H, s, 3-H).13C-NMR(CD30D)：167.9 (s, C-11), 154.8 (d, C-3), 133.8 (d, C-8), 121.1 (t, C-
10), 108.9 (s, C-4), 100.2 (d, C-1), 99.1 (d, C-1 '), 78.5 (d, C-3 '), 77.8 (d, C-5 '), 74.4 (d,
C-2 '), 71.4 (d, C-4 '), 65.9 (s, C-5), 64.3 (t, C-7), 62.6 (t, C-6 '), 51.9 (d, C-9), 33.7 (t, C-
6)。
Above-mentioned number is it was demonstrated that products therefrom is Swertiamarin [Chen Dechang, traditional Chinese chemical contrast operation manuals, China
Medical Science Press, 166-167,2000 the 1st edition].
Embodiment 2
The reduce blood ammonia of Swertiamarin acts on and the protective effect to hepatic injury
Materials and methods
Experimental animal
Wistar male rats (dimension tonneau China), 32,260 ± 20g of weight, cleaning grade.Reagent and drug
Thioacetamide (TAA analyses are pure, and work is given birth in Shanghai), using normal saline 30mg/ml solution, by rat abdominal cavity
It injects TAA 300mg/kg and modeling is administered.
Lactulose oral solution (Duphalac, Beijing Hanmei Medicine Co., Ltd), rat oral gavage dosage are 6g/kg.
Swertiamarin, using normal saline 15mg/ml solution, rat oral gavage dosage 150mg/kg.
Chloraldurate, NaCl and KCl analyze pure, glucose, 4% formaldehyde fixer, physiological saline.
Key instrument
Quick determination of blood ammonia instrument, full-automatic biochemical detector, centrifuge, pH meter, assay balance, small-sized eddy blending machine
Deng.
Rat grouping, administration and modeling method
Rat is randomly divided into 4 groups, i.e.,：Normal group (physiological saline), model group, positive drug group (lactulose 6g/kg), river deer tooth
Dish hardship glycosides group (150mg/kg), every group 8.Each group presses weight gavage different pharmaceutical, successive administration 7 days respectively.5th day administration knot
Start modeling after beam, rats by intraperitoneal injection TAA 300mg/kg, continuous two days, the free diet of rat, drinking-water during modeling.For the first time
Blood is taken after intraperitoneal injection TAA 48h, the content of ammonia in whole blood is detected using quick determination of blood ammonia instrument, is detected using full-automatic biochemical
Instrument detects glutamic-oxalacetic transaminease (AST), glutamic-pyruvic transaminase (ALT) value.
Experimental result
The reduce blood ammonia of Swertiamarin acts on and the protective effect to hepatic injury
Compared with blank group, * * P ＜ 0.01；Compared with model group, #P ＜ 0.05, ##P ＜ 0.01
The above results show that Swertiamarin can significantly decrease ammonia concentration, have to hepatic encephalopathy symptom notable
Improvement result；Rat plasma glutamic-oxalacetic transaminease (AST) and glutamic-pyruvic transaminase (ALT) are significantly reduced simultaneously, liver caused by TAA is damaged
Wound has protective effect.
The present inventor is creatively in rat colon, it was found that the nitrogenous drug metabolite (rough gentian of swertiamarin
Alkali, Gentianine), and have successfully been isolated, identify its chemical constitution, make the reduce blood ammonia of swertiamarin act on having obtained into
The understanding of one step.
The Structural Identification of the nitrogenous drug metabolite of swertiamarin：
MS m/z(rel.int)：175 (100, M+), 147 (52, M+-CO), 117 (94), 90 (65) .UVmax nm：
218,246 (sh), 284.1H-NMR (CDCl3)：3.05 (2H, t, J=6.1Hz, 6-H), 4.52 (2H, t, J=6.1Hz, 7-
H), 5.52 (1H, dd, J=1.9Hz, 17.5Hz, 10-Ha), 5.76 (1H, dd, J=1.9Hz, 17.5Hz, 10-Hb), 6.74
(1H, ddd, J=1.5Hz, 11.1Hz, 17.6Hz, 8-H), 8.77 (1H, d, J=2.4Hz, 1-H), 9.07 (1H, d, J=
3.5Hz 3-H) .13C-NMR (CDCl3)：23.8 (t, C-6), 66.1 (t, C-7), 120.1 (t, C-10), 120.7 (s, c-4),
129.2 (d, C-8), 130.6 (s, C-9), 144.8 (s, C-5), 149.6 (d, C-1), 150.5 (d, C-3), 163.4. (s, C-
11).Bibliography：[Francols Bailleul, Phytochemistry, 1977, Vol.16.pp.723-726].
Swertiamarin in vivo, is reacted with the ammonia in intestinal tube, generates nitrogen-containing products, internal ammonia is made to be eliminated, to
Significantly decrease blood ammonia.
Embodiment 3：
Swertiamarin oral solution：
It is dissolved in 50000mg swertiamarins in 2000ml water, the aqueous solution of 2.5% concentration is made, adjusts pH to 5.5
~6.5, it dissolves, is uniformly mixed, is fitted into 10ml medicine bottles, sealing, disinfection.
Instructions of taking：It takes orally, daily 250mg-1000mg.
Embodiment 4
Swertiamarin injection：
Swertiamarin 5000mg is taken, is dissolved in 500ml water, aqueous solution is made, adjusts pH to 5.5~6.5, is dissolved, is mixed
Close the injection for being uniformly distributed into 100mg/10ml/ branch, steam circulation sterilizing 30 minutes.
Usage and dosage：Intramuscular injection or intravenous injection, each 100mg-1000mg.
Embodiment 5：
Swertiamarin tablet：
Swertiamarin 2000g is taken, by known method for preparing tablet thereof, starch, dextrin, magnesium stearate etc., mixing system is added
At wet grain, machine punching press is in blocks, every 250mg containing swertiamarin.
Usage and dosage：It is oral, 2-3 times daily, each 250mg-1500mg.
The present invention pharmaceutical dosage form also completely it is without being limited thereto, more dosage forms can also be prepared into, as dripping pill, capsule,
Soft capsule, sustained-release preparation, powder-injection etc..
Several aspects according to the present invention as above illustrate.It is to be understood, however, that without departing from spirit of that invention
Under the premise of, those skilled in the art can carry out it equivalent change and modification, and the change and modification equally fall into this patent
The coverage area of the claim of application.
Claims (3)
1. a kind of swertiamarin compound or its pharmaceutically acceptable salt, the hydrate or prodrug of formula (I) are dropped preparing
Application in hyperammonemia drug, such as application in treating hepatic encephalopathy drug.
2. application according to claim 1, which is characterized in that the swertiamarin compound or its pharmacy of the formula (I)
Upper acceptable salt, hydrate or prodrug are applied in the preparation of hepatic encephalopathy drug as unique bulk pharmaceutical chemicals.
3. treating the composition of hepatic encephalopathy drug, which is characterized in that the composition includes the swertiamarin chemical combination of formula (I)
Object and pharmaceutically acceptable carrier.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115463056A (en) * | 2021-06-11 | 2022-12-13 | 云南英格生物技术有限公司 | Swertia mileensis extract and preparation method and application thereof |
-
2018
- 2018-08-01 CN CN201810859966.9A patent/CN108619134A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115463056A (en) * | 2021-06-11 | 2022-12-13 | 云南英格生物技术有限公司 | Swertia mileensis extract and preparation method and application thereof |
| WO2022257932A1 (en) * | 2021-06-11 | 2022-12-15 | 云南英格生物技术有限公司 | Swertiae mileensis herba extract, and preparation method therefor and use thereof |
| CN115463056B (en) * | 2021-06-11 | 2023-09-29 | 云南英格生物技术有限公司 | Herba Swertiae Mileensis extract and preparation method and application thereof |
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Application publication date: 20181009 |