CN109718230A - Application of the salviandic acid A in preparation inhibiting hyperuricemia and anti-gout drugs - Google Patents
Application of the salviandic acid A in preparation inhibiting hyperuricemia and anti-gout drugs Download PDFInfo
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- CN109718230A CN109718230A CN201811264902.0A CN201811264902A CN109718230A CN 109718230 A CN109718230 A CN 109718230A CN 201811264902 A CN201811264902 A CN 201811264902A CN 109718230 A CN109718230 A CN 109718230A
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Abstract
The invention discloses application of the salviandic acid A in inhibiting hyperuricemia and/or the preparation of anti-gout drugs and/or health care product, hyperuricemia includes that uric acid in blood concentration caused by primary and secondary hyperuricemia and various factors is higher than (male) 420 μm of ol/L, (female) 357 μm of ol/L (measurement of phosphotungstic acid reduction method), or uricase-peroxidase conjugate method measurement is higher than the adult of 420 μm of ol/L, gout includes primary gout and secondary gout.Present invention discover that, oral salviandic acid A can significantly reduce mice serum uric acid level, dramatically increase the expression of URAT1 gene mRNA, reduce the gene mRNA expression of GLUT9, show that salviandic acid A can be used for preparing treatment inhibiting hyperuricemia and/or anti-gout drugs and/or health care product, provides a kind of active material safely, effectively, economic for the drug or health care product of preparation prevention and/or the disease for the treatment of hyperuricemia or/and gout.
Description
Technical field
The present invention relates to the new opplication of salviandic acid A in medicine preparation, relate generally to salviandic acid A and preparing anti-gout drugs
In application, in particular to salviandic acid A preparation inhibiting hyperuricemia drug and/or health care product in application, belong to medical skill
Art field.
Background technique
Gout be monosodium urate mineralization formed crystal caused by arthropathy, with purine metabolic disturbance and (or) uric acid arrange
It is directly related to let out the caused hyperuricemia of reduction.
Newest viewpoint thinks that the clinical disease course of gout includes: (1) hyperuricemia, no uric acid crystal, no gout symptom；
(2) observe that uric acid crystal or calculus exist, no gout symptom；(3) internal deposition uric acid crystal, gout acute attack or has hair
Make history；(4) severe gout has tophus to be formed, and causes gouty arthritis,chronic and gouty nephropathy.
Hyperuricemia refers to that adult blood plasma uric acid concentration measures male's uric acid in blood concentration by phosphotungstic acid reduction method
Higher than 420 μm ol/L, women uric acid in blood concentration is higher than 357 μm of ol/L, or is surveyed by uricase-peroxidase conjugate method
Uric acid concentration is higher than the state of 420 μm of ol/L in fixed adult's blood, is since uric acid generates increase in human body and (or) excretion subtracts
Caused by few.
The treatment of hyperuricemia can be divided into drug therapy and non-drug therapy.Clinical Report shows that non-drug is controlled
Treatment is only capable of reducing about 10~18% plasma uric acid levels, therefore is necessary to the drug therapy of hyperuricemia.
The therapeutic agent of hyperuricemia can be divided into anti-trioxypurine drug and control the anti-inflammatory drug of acute inflammation breaking-out.Drop urine
The uricosureic agent that sour medicine can be divided the xanthine oxidase inhibitor for reducing uric acid and generating by mechanism of action, increase uric acid excretion
With uricolytic uricase three classes.But existing each drug has different degrees of adverse reaction, super quick anti-such as allopurinol
Syndrome is answered, so not ideal enough.
Salviandic acid A (Salvianolic acid A) belongs to phenolic acid compound.Chemical name: (2R) -3- (3,4- dihydroxy benzenes
Base) -2- [(E) -3- [2- [(E) -2- (3,4- dihydroxy phenyl) vinyl] -3,4- dihydroxy phenyl] propyl- 2- alkene acyl] oxygen third
Acid, molecular formula C26H22O10, No. CAS: 96574-01-5.Its chemical structure is as follows:
So far seen in salviandic acid A related patents be concentrated mainly on salviandic acid A preparation method, detection method and crystal form α,
β and its in medicine preparation application and the therapeutic effect to diabetes and its complication, the effect to vascular remodeling, to lung
Therapeutic effect of arterial hypertension etc..But to it in preparation inhibiting hyperuricemia and/or anti-gout drugs and/or health care product
Effect there is not been reported.
Summary of the invention
Present invention solves the technical problem that being to provide salviandic acid A in preparation inhibiting hyperuricemia and/or anti-gout drugs
And/or the application in health care product, thus to reduce uric acid in blood concentration and treating gout to provide a kind of adverse reaction slight
Solution.
For this purpose, the present invention provides the following technical scheme that
Invention provides salviandic acid A answering in preparation inhibiting hyperuricemia and/or anti-gout drugs or/and health care product
With.
Further, the hyperuricemia includes but is not limited to blood caused by primary and secondary and various factors
Uric acid concentration is higher than (male) 420 μm of ol/L, (female) 357 μm of ol/L (measurement of phosphotungstic acid reduction method) or uricase-peroxidating in liquid
The measurement of object enzyme coupling method is higher than the adult of 420 μm of ol/L.
Further, the gout includes but is not limited to primary gout and secondary gout.
Further, the salviandic acid A can routinely various dosage forms be made in formulation method with pharmaceutically acceptable auxiliary material
Inhibiting hyperuricemia and/or anti-gout drugs.
Further, the salviandic acid A can include with health care product health food and the acceptable auxiliary material of functional food routinely
The health care product of various inhibiting hyperuricemias and/or antigout is made in formulation method.
Therefore the present invention further relates to the pharmaceutical composition using the compounds of this invention as active constituent.The pharmaceutical composition can
It is prepared according to method well known in the art.It can be by inventing the salviandic acid A and one or more pharmaceutically acceptable solids
Or liquid excipient and/or auxiliary material combination, any dosage form used with human or animal is made.The compounds of this invention is in its medicine group
The content closed in object is usually 0.1-99%.
Further, the invention further relates to the Halth-care compositions using the compounds of this invention as active constituent.The composition
It can be prepared according to method well known in the art.It can be by the way that invent can on the salviandic acid A and one or more health care products and food
Any dosage form used with human or animal is made in the solid or liquid excipient and/or auxiliary material combination of receiving.The compounds of this invention
Content in its pharmaceutical composition is usually 0.1-99%.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be stomach
Enteron aisle or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin
Skin, vagina, rectum etc..
The drug combination dosage form includes oral preparation, injecting medicine-feeding form, skin and mucosa approach form of administration.
Application according to claim 7, it is characterised in that: affiliated oral preparation include tablet, sustained release agent, capsule,
Controlled release agent, pill, liquid preparation, the injecting medicine-feeding form include intramuscular injection, intravenous injection, intravenous drip.
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including
True solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder-injection
And infusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge,
Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), granule, dissipate
Agent, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel
Agent, paste etc..
It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made,
Particulate delivery system.
In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute
Release agent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, cream
Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second
Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum
Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, carboxylic propyl methocel, ethyl cellulose, acrylic resin, card
Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber
Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second
Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin
Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double
Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, glidant can be mixed
It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding
Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet
Release agent, binder, wetting agent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used
Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure regulator is added.Solubilizer or hydrotropy
Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphate, cruel hydrochlorate, hydrochloric acid, hydrogen
Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder
Mannitol, glucose etc. can be also added as proppant in injection.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition can use any well known medication
Administration.The dosage of the compounds of this invention pharmaceutical composition according to the property and severity to be prevented or be treated disease,
The individual instances of patient or animal, administration route and dosage form etc. can have large-scale variation.In general, the compounds of this invention
Daily Suitable dosage ranges be 0.001-400mg/kg weight.Above-mentioned dosage with a dosage unit or can be divided into several doses
Unit administration is measured, this depends on the clinical experience of doctor and includes the dosage regimen with other treatment means.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs.
When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
The beneficial effects of the present invention are: the present invention uses antihyperuricemic disease mouse model, to the anti-antihyperuricemic of salviandic acid A
Disease and/or anti-gout drugs, the especially effect of reduction serum uric acid level are investigated, the results show that being administered orally pellet
Phenolic acid A can significantly reduce mice serum uric acid level, the mRNA expression that can be dramatically increased UART1, reduce GLUT9, so
A kind of solution safely, effectively, economic is provided for the Prevention of hyperuricemia and/or gout and treatment.
Detailed description of the invention
Fig. 1 salviandic acid A is horizontal on hyperuricemia model mice serum uric acid (UA) to be influenced.N=10.
Fig. 2 salviandic acid A expresses water to the mRNA of hyperuricemia model mouse lithate anion transport body 1 (URAT1)
It is flat to influence.N=3.
Fig. 3 salviandic acid A influences the mRNA expression of hyperuricemia model mouse glucose transport body 9 (GLUT9).N=3.
Specific embodiment
To keep the purpose of the present invention, technical solution, advantage clearer, the present invention is made below in conjunction with attached drawing further
Detailed description.
It is horizontal that 1. salviandic acid A of experimental example reduces hyperuricemia model mice serum uric acid (UA).
Experimental material: kunming mice is purchased from Fukang biotech inc, China, Beijing.Oteracil Potassium, danshinolic acid
A, allopurinol, Benzbromarone are purchased from Sigma-Aldrich (Sigma-Aldrich, Germany).Sodium carboxymethylcellulose purchase
From Sinopharm Chemical Reagent Co., Ltd..Uric acid reagent box is purchased from Zhongsheng Beikong Biological Science & Technology Co., Ltd..
Solution is prepared: 1% sodium carboxymethylcellulose being dissolved, is boiled, solvent is used as after cooling, by salviandic acid A, Oxonic Acid
Potassium, allopurinol, Benzbromarone dissolve respectively is configured to suspension.
Experimental group: 18-20g mouse is randomly divided into Normal group, model group, Benzbromarone group (25mgkg-1, sun
Property control), salviandic acid A low, middle and high dose groups (3,10,30mgkg-1), every group 10.
Oteracil Potassium 300mgkg is injected intraperitoneally daily in addition to control group-1, Normal group injects 1% carboxylic of equivalent daily
Methylcellulose sodium solution, continuous modeling 8 days, then by grouping administration, administration put to death mouse after 14 days, and eye rear vein beard takes
Blood, stands 2h, 5000rpm, 4 DEG C of centrifugation 10min and takes serum, measures serum uric acid level with uric acid reagent box.
As a result: after animal pattern takes orally salviandic acid A (3,10,3mg/kg), serum uric acid level can a degree of drop
It is low, as shown in table 1 and Fig. 1, prompt oral salviandic acid A that can play inhibiting hyperuricemia and/or antigout effect.
1. salviandic acid A of table on hyperuricemia model mice serum uric acid level influence (N=10).
Compared with the control group, a:P < 0.01, compared with model group, b:P < 0.05, c:P < 0.01.
MRNA table of 2. salviandic acid A of embodiment to hyperuricemia model mouse lithate anion transport body 1 (URAT1)
It is influenced up to level.N=3.
Experimental group: 18-20g mouse is randomly divided into Normal group, model group, Allopurinol group (25mgkg-1, positive
Control), Benzbromarone group (25mgkg-1, positive control), salviandic acid A low, middle and high dose groups (3,10,30mgkg-1),
Every group 10.Related solution prepares and experimental program is the same as embodiment 1.Reverse Transcriptase kit, SYBR green dyestuff are purchased from precious day
It cures Bioisystech Co., Ltd (TAKARA, Japan).Primer is purchased from Sheng Gong bioengineering limited liability company, and way of purification is
HAP。
Table 2.URAT1 primer and internal control primer sequence.
Mouse put to death after, take mouse kidney, using Trizol method extract kidney in total serum IgE, with ultraviolet specrophotometer into
Row RNA is quantitative, and A260/280 is preferred close to 2.0, then carries out reverse transcription with Reverse Transcriptase kit and obtain corresponding cDNA, utilizes SYBR
Green dyestuff carries out real-time fluorescence quantitative PCR, and observation mRNA expresses situation of change.
As a result: animal pattern, which takes orally salviandic acid A (10,30mg/kg), can dramatically increase the expression of URAT1, such as table 3 and figure
Shown in 2, salviandic acid A may be played by the expression of increase ion transport body and be increased uric acid transporter excretion and reduce Plasma Uric Acid
The effect of concentration.
3. salviandic acid A of table influences the mRNA expression of hyperuricemia model mouse URAT1.N=3.
Compared with the control group, a:P < 0.05, compared with model group, b:P < 0.05, c:P < 0.01.
MRNA expression shadow of 3. salviandic acid A of embodiment to hyperuricemia model mouse glucose transport body 9 (GLUT9)
It rings.(N=3).
Experimental group: 18-20g mouse is randomly divided into Normal group, model group, Benzbromarone group (25mgkg-1, sun
Property control), salviandic acid A low, middle and high dose groups (3,10,30mgkg-1), every group 10.Related solution is prepared and experimental program
With embodiment 2.Reverse Transcriptase kit, SYBR green dyestuff purchased from Bao Yi Bioisystech Co., Ltd (TAKARA,
Japan).Primer is purchased from Sheng Gong bioengineering limited liability company, way of purification HAP.
Table 4.GLUT9 primer and internal control primer sequence.
Mouse put to death after, take mouse kidney, using Trizol method extract kidney in total serum IgE, with ultraviolet specrophotometer into
Row RNA is quantitative, and A260/280 is preferred close to 2.0, then carries out reverse transcription with Reverse Transcriptase kit and obtain corresponding cDNA, utilizes SYBR
Green dyestuff carries out real-time fluorescence quantitative PCR, and observation mRNA expresses situation of change.
As a result: animal pattern, which takes orally salviandic acid A (3mg/kg), can significantly reduce the expression of GLUT9, as shown in table 5 and Fig. 3,
Salviandic acid A may play and reduce the effect of Plasma Uric Acid concentration by the expression of reduction GLUT9.
5. salviandic acid A of table influences the mRNA expression of hyperuricemia model mouse GLUT9.(N=3).
Compared with the control group, a:P < 0.05, compared with model group, b:P < 0.05, c:P < 0.01.
In conclusion the present invention is using antihyperuricemic disease mouse model to salviandic acid A inhibiting hyperuricemia and/or antigout
Drug and/or health care product, especially the effect of reduction serum uric acid level is investigated, the results show that passing through gastric infusion pellet phenol
Sour A can significantly reduce mice serum uric acid level, the mRNA expression that can be dramatically increased URAT1, reduce GLUT9.Therefore, red
Phenolic acid A has inhibiting hyperuricemia and/or antigout effect.Using salviandic acid A as active material, be used alone or/have with other
Compound and/or extract the composition compound of pharmacological activity use, and are made according to the conventional preparation method of pharmaceutical field various
The inhibiting hyperuricemia and/or anti-gout drugs and/or health care product of dosage form, or it is fast with other medicine for improving uric acid excretion and/or Huang
Compound preparation is made in purine oxidase inhibitor etc., for reducing the adverse reaction in drug effect in the case where keeping curative effect,
A kind of solution safely, effectively, economic can be provided for the Prevention of hyperuricemia and/or gout and treatment.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention rather than limits, although passing through ginseng
According to the preferred embodiment of this non-invention, invention has been described, but it should be understood by one skilled in the art that can be with
Various changes are made to it on carrying out upper and details, without departing from this hair defined by appended claims specification
Bright spirit and scope.
Claims (8)
1. [(E) -3- [2- [(the E) -2- (3,4- dihydroxy phenyl) of (2R) -3- (3,4- dihydroxy phenyl) -2- as shown in formula I
Vinyl] -3,4- dihydroxy phenyl] propyl- 2- alkene acyl] oxygen propionic acid and its pharmaceutically acceptable salt in preparation prevention and/or control
Treat the application in the product of hyperuricemia or/and gout
2. application according to claim 1, the hyperuricemia is taken from primary and causes with secondary and various factors
Male's uric acid in blood concentration measured by phosphotungstic acid reduction method be higher than 420 μm of ol/L, women uric acid in blood concentration is higher than
357 μm of ol/L, or uric acid concentration in adult blood is measured by uricase-peroxidase conjugate method and is higher than 420 μm of ol/L's
State.
3. application according to claim 1, the gout is since uric acid in blood concentration increases and then leads to uric acid in joint
Secondary gout caused by the primary gout and various factors that are induced as crystal.
4. a kind of application of pharmaceutical composition in preparation prevention and/or treatment hyperuricemia or/and gout product,
It is characterized in that, contains effective dose (2R) -3- (3,4- dihydroxy phenyl) -2- [(E) -3- [2- [(E)-described in claim 1
2- (3,4- dihydroxy phenyl) vinyl] -3,4- dihydroxy phenyl] propyl- 2- alkene acyl] oxygen propionic acid and its crystal shape that may be present
Formula, pharmaceutically acceptable salt and pharmaceutically acceptable carrier and other active components.
5. application according to claim 1, which is characterized in that the product is selected from drug or health care product.
6. application according to claim 4, which is characterized in that the pharmaceutical composition is selected from oral preparation, is administered to medicament
Type, skin and mucosa approach form of administration.
7. application according to claim 6, which is characterized in that oral preparation includes tablet, sustained release agent, capsule, controlled release agent, drop
Pill, liquid preparation, the injecting medicine-feeding form include intramuscular injection, intravenous injection, intravenous drip.
8. uric acid metabolism can be influenced or influence bitterly by being had the active constituent for asking 4 described pharmaceutical compositions to be related to be taken from according to right
The chemical substance of wind pathologic process or pathological manifestations.
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| CN2017110304666 | 2017-10-27 | ||
| CN201711030466 | 2017-10-27 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111533783A (en) * | 2020-05-21 | 2020-08-14 | 昆明医科大学 | Anti-gout active polypeptide RDP2, and preparation method and application thereof |
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| CN102423310A (en) * | 2012-01-04 | 2012-04-25 | 中国药科大学 | Application of salvianolic acid C in preparation of drugs for prevention and treatment of hyperuricemia |
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| CN111533783A (en) * | 2020-05-21 | 2020-08-14 | 昆明医科大学 | Anti-gout active polypeptide RDP2, and preparation method and application thereof |
| CN111533783B (en) * | 2020-05-21 | 2022-03-18 | 昆明医科大学 | Anti-gout active polypeptide RDP2, and preparation method and application thereof |
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