CN108101788A - Composition and its application containing salvianolic acid salt - Google Patents
Composition and its application containing salvianolic acid salt Download PDFInfo
- Publication number
- CN108101788A CN108101788A CN201711467378.2A CN201711467378A CN108101788A CN 108101788 A CN108101788 A CN 108101788A CN 201711467378 A CN201711467378 A CN 201711467378A CN 108101788 A CN108101788 A CN 108101788A
- Authority
- CN
- China
- Prior art keywords
- acid
- double salt
- preparation
- salt
- tanshin polyphenolic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides the melbine salts and its pharmaceutical composition of salvianolic acid compound, and the invention further relates to effect of this substance in terms of diabetic complication is prevented and treated.
Description
Technical field
The present invention relates to Field of Drug Discovery, and in particular to melbine salt of pressure differential self and preparation method thereof
And purposes.
Background technology
Diabetes are one of most important non-communicable diseases of current threat global human health, according to international diabetes
Alliance (IDF) counts for 2015, and 4.15 hundred million adults are shared in world wide and suffer from diabetes, wherein diabetes mellitus in China number most
It is more, it is 1.1 hundred million, ranks the first in the world, because the number of Diabetes Death accounts for the 14.5% of All-cause death number, wherein 46.6%
For patient age less than 60 years old, diabetes and its complication were the main reason for causing patient's premature death.
Diabetic nephropathy DN (diabetic nephropathy) and diabetic neuropathy (diabetic
Neuropathy it is) most common two chronic complicating diseases in diabetes, the study found that can mitigate or prolong by reducing blood glucose
Slow chronic complicating diseases of diabetes, but cannot fundamentally control the occurrence and development of diabetic complication.
At present, melbine is proposed as the fiest-tire medication of diabetes B control blood glucose, and first choice is used for diet alone control
System or the invalid diabetes B of physical training, are particularly suitable for obese patient, are also used for 1 type and 2 type glycosurias with insulin combination
Disease.Its main pharmacological is to reduce blood glucose by reducing glycogen output and improving peripheral insulin resistance, but clinically
The Metformin used is due to water-soluble strong, gastrointestinal tract absorption difference, can generate some such as diarrhea, vomiting gastrointestinal tract
Adverse reaction.
Danshinolic acid is the phenolic acid compound in Radix Salviae Miltiorrhizae aqueous solution, at present the monomer salvianolic acid A to therefrom isolating and purifying out
More with tanshin polyphenolic acid B research, pharmacological research is shown, the injured nerve and kidney tool of salviandic acid A or tanshin polyphenolic acid B to diabetic animal
There is significant protective effect.Patent CN101347422, which discloses salviandic acid A, can reduce animal blood glucose, promote grape cell sugar
It absorbs and reduces blood fat, reduce weight of mammal, promote wound healing and metabolic function.Illustrate that salviandic acid A can be used for
Prevent diabetic hyperglycemia, diabetic cardiovascular complications, diabetic nephropathy, diabetic peripheral neuropathy；
CN102961372, which discloses tanshin polyphenolic acid B, has effect in the aggregation of inhibition amylin and treatment diabetes；
CN101095720 discloses preparation method and salvianolic acid the answering in terms of diabetic nephropathy is prevented of salvianolic acid
With.
But the chemical stability of salviandic acid A and tanshin polyphenolic acid B is all very poor, and easily water suction is rotten, and pH value, illumination and temperature are also held
Yi Rangqi degrades, therefore limits its clinical practice.
The content of the invention
To overcome drawbacks described above existing in the prior art, the present invention by salviandic acid A or tanshin polyphenolic acid B and melbine into salt,
It is significantly improved into the salviandic acid A after salt or tanshin polyphenolic acid B one side stability, another aspect drug activity has also obtained significantly
Enhancing.
Present invention firstly discloses the double salt with general formula structure：
X·(Y)n
Wherein X is the phenolic acid compound in Radix Salviae Miltiorrhizae, is existed in double salt in the form of anion, specifically, X can
For salviandic acid A, tanshin polyphenolic acid B, salvianolic acid C, alkannic acid or Rosmarinic acid, preferably salviandic acid A or tanshin polyphenolic acid B；Y is melbine,
It exists in double salt in the form of cation, and X and Y are combined with ionic bond, and n represents the number of Y, n=1/2,1 or 2.
The present invention also provides the preparation method of above-mentioned double salt, this method comprises the following steps：
The first step：Metformin hydrochloride and strong alkaline substance are dissolved into alcohol organic solvent respectively, filtered after stirring；
Second step：Free X acid is dissolved into alcohol organic solvent, adds weak acid stirring；
3rd step：First step acquired solution is added in second step acquired solution, it is X (Y) n that solid, which is precipitated,.
Wherein described highly basic is selected from amino-compound, guanidine compound, quaternary ammonium alkaloid compound, sodium alkoxide, potassium alcoholate, hydroxide
Potassium or sodium hydroxide, preferably potassium hydroxide；The preferred acetic acid of weak acid, the alcohol organic solvent can be methanol, ethyl alcohol, isopropyl
Alcohol, n-butanol etc., preferred alcohol；In the above method, the molar ratio of Metformin hydrochloride and free X acid is (1-2): 1.
When free X acid is salviandic acid A, the preparation method of the double salt can also comprise the following steps：
The first step：Metformin hydrochloride and highly basic are dissolved into alcohols solvent respectively, filtered after stirring；
Second step：Salviandic acid A is dissolved into organic solvent；
3rd step：First step acquired solution is added in second step acquired solution, it is X (Y) n that solid, which is precipitated,.
In above-mentioned preparation method, the highly basic be selected from amino-compound, guanidine compound, quaternary ammonium alkaloid compound, sodium alkoxide,
Potassium alcoholate, potassium hydroxide or sodium hydroxide, preferably potassium hydroxide or sodium hydroxide, the organic solvent are selected from ethyl acetate, acetic acid
Propyl ester, butyl acetate, petroleum ether or acetonitrile；The molar ratio of Metformin hydrochloride and salviandic acid A is 1: 1.
The present invention also provides the pharmaceutical composition for including above-mentioned double salt and pharmaceutical acceptable carrier, above-mentioned double salt specifically includes pellet
The melbine salt of phenolic acid A, the melbine salt of tanshin polyphenolic acid B, the melbine salt of salvianolic acid C, the melbine salt of alkannic acid
Or the one or more in the melbine salt of Rosmarinic acid, the melbine salt of pharmaceutical composition salviandic acid A and tanshin polyphenolic acid B
The molar ratio of melbine salt is 1: 1,1: 2 or 2: 1, preferably 2: 1.
Aforementioned pharmaceutical compositions, double salt ingredient is except the melbine salt and 20 of the salviandic acid A containing 50~99 mass %
The melbine salt of the tanshin polyphenolic acid B of~99 mass %, can also the melbine salt containing the salvianolic acid C of 0.1~5 mass %, 1
The melbine salt of the alkannic acid of~5 mass %, 1~5 mass % Rosmarinic acid melbine salt.
Double salt provided by the present invention or pharmaceutical composition can be used for preparing prevention diabetes or diabetes complicated disease drug,
Wherein diabetic complication is selected from nephrosis, neuropathy, retinopathy, cataract, cardiomyopathy and cardiac tissue ischemia, preferably
Diabetic nephropathy or diabete peripheral herve pathology.
The present invention also provides second group of pharmaceutical composition, it includes the phenolic acid compound in (1) Radix Salviae Miltiorrhizae or its can medicine
With salt, (2) melbine or its officinal salt, antioxidant, excipient.The wherein described phenolic acid compound for salviandic acid A,
One or more in tanshin polyphenolic acid B, salvianolic acid C, alkannic acid and Rosmarinic acid, the officinal salt of the phenolic acid compound are
The metal salt or amino-acid salt of phenolic acid compound, preferably magnesium salts, lysine salt, histidine salt or arginine salt, described two
The officinal salt of first biguanides is specially Metformin.Phenolic acid compound described in the pharmaceutical composition includes 50%
~99% salviandic acid A, 40%~90% tanshin polyphenolic acid B, 0.1%~5% salvianolic acid C, 1%~5% alkannic acid, 1%
The molar ratio of~5% Rosmarinic acid, wherein salviandic acid A and tanshin polyphenolic acid B is (1-2): 1.
The molar ratio of phenolic acid compound and melbine is 1 in second group of pharmaceutical composition disclosed in this invention:
5th, 1: 10,1: 15 or 1: 20.
The administration route of presently disclosed pharmaceutical composition can be oral, intravenous injection, intramuscular injection, hypodermic injection,
The modes such as nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum are administered.
Form of administration can be liquid preparation such as solution, colloidal solution, emulsion, suspension, injection, eye drops, drop
Nose agent, lotion etc.；Solid dosage forms such as conventional tablet, enteric coatel tablets, lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet, glue
Wafer such as hard shell capsules, soft capsule, capsulae enterosolubilis, granule, powder, pellet, dripping pill, suppository, film, patch, aerosol, spraying
Agent etc.；It can also be semisolid dosage form such as ointment, gelling agent, paste etc..
Pharmaceutical composition of the present invention can be made ordinary preparation, be also made be sustained release preparation, controlled release preparation, targeting preparation and
Various particulate delivery systems.
If drug of the present invention is made tablet, various excipient well known in the art can be widely used, including diluent,
Binder, wetting agent, disintegrant, lubricant, glidant；Diluent can be starch, dextrin, sucrose, glucose, lactose, sweet
Reveal alcohol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, ethyl alcohol, different
Propyl alcohol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, mucialga of arabic gummy, bright
Rubber cement, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer,
Polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, friendship
Join polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium acid carbonate and citric acid, polyoxyethylene mountain
Pears sugar alcohol fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, stearate,
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.
If drug of the present invention is made capsule, active ingredient of the present invention can be mixed with diluent, glidant, it will be mixed
Object is closed to be placed directly in hard shell capsules or soft capsule；Or active ingredient of the present invention is first made with diluent, binder, disintegrant
Particle or pellet, then be placed in hard shell capsules or soft capsule.It is used to prepare each diluent, binder, profit of medicinal tablet of the present invention
Humectant, disintegrant, glidant kind can also be used for preparing the capsule of drug of the present invention.
If drug of the present invention is made injection, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used to make
Solvent simultaneously adds in appropriate solubilizer commonly used in the art, cosolvent, pH adjustments agent, osmotic pressure regulator；Solubilizer or cosolvent
Can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, hydrogen-oxygen
Change sodium etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder
Agent can also add in mannitol, glucose etc. as proppant.
The dosage of pharmaceutical composition of the present invention is according to the property and severity to be prevented or treated disease, patient
Individual instances, administration route and dosage form etc. can have large-scale variation.In general, the daily conjunction of the compounds of this invention
Suitable dosage range is 50-2500mg or 100-2000mg, preferred dose 140mg, 180mg, 220mg, 260mg, 300mg,
340mg、380mg、420mg、460mg、500mg、540mg、580mg、620mg、650mg、680mg、720mg、750mg、
800mg、820mg、850mg、900mg、950mg、1000mg、1200mg、1500mg。
Description of the drawings
Fig. 1：The 1H-NMR collection of illustrative plates of product prepared by 2 method two of embodiment.
Fig. 2：The 1H-NMR collection of illustrative plates of product prepared by 2 method three of embodiment.
Fig. 3：The 1H-NMR collection of illustrative plates of product prepared by 2 method four of embodiment.
Fig. 4：The 1H-NMR collection of illustrative plates of product prepared by 2 method five of embodiment.
Fig. 5：The 1H-NMR collection of illustrative plates of product prepared by 2 method six of embodiment.
Fig. 6：The 1H-NMR collection of illustrative plates of product prepared by 3 method one of embodiment.
Fig. 7：The 1H-NMR collection of illustrative plates of product prepared by 3 method two of embodiment.
Fig. 8：In vivo blood concentration variation after the melbine salt of rat oral gavage tanshin polyphenolic acid B.
Specific embodiment
Embodiment 1：The preparation of root of red-rooted salvia phenolic acid compound
1st, the preparation of salviandic acid A
Take Radix Salviae Miltiorrhizae coarse powder 100g, add 8 times amount water, 80 DEG C temperature leaching 3 times, every time 1 it is small when, filtration, merging filtrate, 4000
Rev/min centrifugation 10 minutes, takes supernatant to cross 1400 large pore resin absorption columns, is first washed with water to sugar detection reaction as after negative,
20% ethanol elution is used instead again to FeCl3It reacts for feminine gender, then it is feminine gender to be changed to 40% ethanol elution to FeCl3 reactions, is collected
Eluent under the conditions of 60 DEG C, is concentrated under reduced pressure into no alcohol taste, adds salt acid for adjusting pH value to 3~5, with the second of 1.5 times of amount volumes of liquid
Acetoacetic ester extracts 4 times, combined ethyl acetate phase, and acetic acid ethyl acetate extract is concentrated under reduced pressure into medicinal extract shape, and 60 DEG C of vacuum drying 6 are small
When, pale yellow powder is obtained, is salviandic acid A.
2nd, the preparation of tanshin polyphenolic acid B
Red rooted salvia is taken, ethyl alcohol extraction is filtered, and filtrate merges, and concentrates, centrifugation, and supernatant is taken to cross the suction of HPD-400A macropores
Attached resin column, washing discard, 20% ethanol elution, collect eluent, are concentrated into ethyl alcohol to the greatest extent, centrifugation takes supernatant to cross polyamides
Amine adsorption resin column, washing discard, 40% ethanol elution, discard eluent, and 65% ethanol elution collects eluent and is concentrated into second
For alcohol to the greatest extent, concentrate adjusts pH value 3, is extracted, is dried in vacuo to get tanshin polyphenolic acid B with organic solvent ethyl acetate.
Embodiment 2：The preparation of the melbine salt of tanshin polyphenolic acid B
Method one：Metformin hydrochloride (17mg, 0.1mmol), which is dissolved in 0.2 milliliter of water, is added dropwise to tanshin polyphenolic acid B
0.3 milliliter of the aqueous solution of (72mg, 0.1mmol) has substantial amounts of solid to generate, add sodium acid carbonate (8.4mmol,
0.1mmol) there is substantial amounts of bubble to generate, continue stirring 5 minutes, then add 1 milliliter of ethyl alcohol, reaction solution becomes limpid, adds third
Ketone has a small amount of solid to be precipitated, and amount is seldom.
Method two：Metformin hydrochloride (17mg, 0.1mmol) and sodium acid carbonate (8.4mg, 0.1mmol) are dissolved in 0.2 milli
It is added dropwise in the water risen in 0.3 milliliter of aqueous solution of tanshin polyphenolic acid B (72mg, 0.1mmol), there is solid and bubble to generate,
Continue stirring 5 minutes, pour out liquid phase, remaining brown oil drawing is dry to obtain brown solid, send1H-NMR is detected, and collection of illustrative plates shows pure
It spends not high (see attached drawing 1).
The solid forms for the melbine salt that method one and method two prepare obtained tanshin polyphenolic acid B are bad, it is above-mentioned into
In salt method, product amount is less, and nuclear-magnetism detection purity is also general, and the sodium chloride of sodium acid carbonate and hydrochloric acid reaction generation is also not easy
It removes.
Method three：Metformin hydrochloride (256mg, 1.5mmol) and potassium hydroxide (83mg, 1.5mmol) are added to 10 millis
Rise ethyl alcohol in, 50 DEG C stirring 2 it is small when, then be stirred at room temperature 1 it is small when, filtering, filtrate added drop-wise to tanshin polyphenolic acid B (1.08g,
In 25 milliliters of ethanol solution 1.5mmol), there is solid precipitation to be directly spin-dried for, obtain bright yellow solid 1.3g, send 1H-NMR, scheme
Spectrum shows that purity is not high, and containing substantial amounts of ethyl alcohol, part tanshin polyphenolic acid B cannot be into salt (see attached drawing 2).
Method four：Metformin hydrochloride (68mg, 0.4mmol) and potassium hydroxide (22.4mg, 0.4mmol) are added to 5 millis
In the ethyl alcohol risen, be stirred at room temperature 3 it is small when, filtering, 3 milliliters of ethyl alcohol of filtrate added drop-wise to tanshin polyphenolic acid B (142mg, 0.2mmol) is molten
In liquid, there is solid precipitation, continue stirring 10 minutes, there is substantial amounts of solid to be precipitated, pour out supernatant liquor, solid, which is drawn, to be done, and obtains shallow palm fibre
Color solid send 1H-NMR, and collection of illustrative plates shows that the purity of solid is poor, and product contains ethyl alcohol (see attached drawing 3).
Method five：Tanshin polyphenolic acid B (141mg, 0.2mmol) is dissolved in 2 milliliters of ethyl alcohol, by melbine (51.6mg,
It 0.4mmol) is added in said mixture, there is substantial amounts of solid to be precipitated, stir 5 minutes, add ethyl acetate has solid again
It is precipitated, stands, pour out liquid phase, solid, which is drained, send 1H-NMR, and collection of illustrative plates shows that the purity of solid is poor (see attached drawing 4).
Method six：Metformin hydrochloride (512mg, 3.0mmol) and potassium hydroxide (168mg, 3.0mmol) are separately added into
Into 25 milliliters of ethyl alcohol, when 50 DEG C of stirrings 2 are small, room temperature is cooled back to, is filtered, filtrate is spare.By tanshin polyphenolic acid B (1.08g,
1.5mmol) be dissolved into 20 milliliters of ethyl alcohol, add glacial acetic acid (360mg, 6mmol) be stirred at room temperature it is lower by above-mentioned spare filter
Drop is added in said mixture, has substantial amounts of solid to be precipitated, and is stood, is poured out supernatant liquor, solid is drained, and is obtained light brown and is consolidated
Body 1.0g, obtained product purity is purer, and nuclear magnetic spectrum is shown in attached drawing 5,1H NMR (400MHz, DMSO-d6) δ：10.56~8.00
(m, 9H), 7.16~7.10 (m, 5H), 6.99 (s, 5H), 6.79~6.69 (m, 4H), 6.59~6.37 (m, 5H), 6.19~
6.14 (m, 2H), 5.82 (d, J=5.2Hz, 1H), 4.86~4.82 (m, 2H), 4.18 (d, J=5.2Hz, 1H), 3.04~
2.84 (m, 13H), 2.79~2.73 (m, 1H), 2.60~2.52 (m, 1H)
Embodiment 3：The preparation of the melbine salt of salviandic acid A
Method one：Metformin hydrochloride (165.6mg, 1mmol) and potassium hydroxide (56mg, 1mmol) are added to 5 milliliters
In ethyl alcohol, when 40 DEG C of stirrings 4 are small, filtering, salviandic acid A (494mg, 1mmol) is dissolved in 5 milliliters of ethyl alcohol, adds acetic acid
Filtrate is added in said mixture by (120mg, 2mmol), finishes, and adding ethyl acetate (100 milliliters) has largely admittedly
Body is precipitated, and stirs 10 minutes, stands, pours out liquid phase, solid is drained, and obtains bright yellow solid, and 1H-NMR is sent to detect, and collection of illustrative plates is shown
Above-mentioned salt obtains purity preferably (see attached drawing 6).
Method two：Metformin hydrochloride (87mg, 0.5mmol) and potassium hydroxide (28mg, 0.5mmol) are added to 2.5 millis
In the ethyl alcohol risen, when 50 DEG C of stirrings 2 are small, filter, filtrate is spare；Salviandic acid A (247mg, 0.5mmol) is dissolved in ethyl acetate
In (25 milliliters), filtrate is added in said mixture, has substantial amounts of solid to be precipitated, is stirred 10 minutes, stands, pours out liquid
Phase, solid are drained, and obtain bright yellow solid, send 1H-NMR, and nuclear magnetic spectrum shows (see attached drawing 7) that gained purity salt is fine, in salt
Contain ethyl acetate.1H NMR (400MHz, DMSO-d6)δ：7.82 (d, J=15.6Hz, 1H), 7.23~6.90 (m, 8H),
6.78~6.68 (m, 3H), 6.65~6.52 (m, 3H), 6.44 (d, J=8.8Hz, 1H), 6.21 (d, J=16Hz, 1H), 4.87
~4.83 (m, 1H), 3.02~2.97 (m, 1H), 2.91 (s, 6H), 2.73~2.66 (m, 1H)
Embodiment 4：The stability study of danshinolic acid melbine salt
The tanshin polyphenolic acid B melbine salt prepared by embodiment 2 and tanshin polyphenolic acid B room temperature are protected from light holding respectively, from brand-new, put
It puts 3 days, places 7 days, place 14 days, separately sampled to send LC-MS, the variation of comparative analysis sample purity, LC-MS testing results are shown
Show, as time went on, content of danshinolic acid B changes unobvious in tanshin polyphenolic acid B double salt sample, and in free tanshin polyphenolic acid B sample
Content of danshinolic acid B reduce it is more, more than research show that danshinolic acid is prepared into melbine salt after, stability is improved.
Embodiment 5：Influence of the compounds of this invention to STZ induced diabetic rats blood glucose, renal function and neuropathy
5.1 the compounds of this invention are to the influence of blood glucose in diabetic rats level
After 46 SD rats adaptability are fed 1 week, therefrom randomly select 6 and be only used as Normal group, remaining is as glycosuria
Sick group.Normal group feeding standard rat feed, diabetes group feed high glucose and high fat feed.Diabetes group is big after feeding 3 weeks
Pneumoretroperitoneum injection strepto- assistant rhzomorph 40mg/kg (uses one buffered sodium citrate of 0.1mol/L citric acids of pH4.4 when mouse empty stomach 24 is small
Liquid is made into 0.75% concentration), Normal group only injects one sodium citrate buffer solution of citric acid.Co-injection 3 times, per minor tick
1 week.
By diabetes rat, 5 groups are randomly divided into, every group 8, be respectively diabetic model group, melbine group (100mg/
Kg), tanshin polyphenolic acid B group (120mg/kg), tanshin polyphenolic acid B melbine double salt group (120mg/kg, 2 final product of embodiment), salviandic acid A
Melbine double salt group (120mg/kg, 3 final product of embodiment), each group drug, which is dissolved in the distilled water containing 1% CMC-Na, to be filled
Stomach, once a day, successive administration carry out rat docking and take blood, 4000rpm centrifugation 10min separate serum, according to blood after 4 weeks
Illustrate to measure rat blood sugar level in sugar determination kit.
Experimental result can be seen that the hypoglycemic of the melbine salt of salviandic acid A and the melbine salt of tanshin polyphenolic acid B is imitated by table one
Fruit is apparent, as a result with significant difference, compared with model group, * p ＜ 0.05, * * p ＜ 0.01.
Table one：Influence of the compound to the blood sugar reducing function of diabetes rat
Influence of 5.2 the compounds of this invention to experimental diabetic peripheral neuropathy in rats
(1) variation that diabetes rat pedionalgia domain is felt after detection administration
Diabetes rat modeling, grouping and medication are referring to 5.1；It is administered the 55th day, by one fixed part of In The Rat Sole portion
Position is at photoelectricity pain area detector detection hole, constant stimulus intensity, gives thermostimulation, the time that observation rat foot is removed.
Experimental result such as table two, the melbine salt of salviandic acid A and the melbine salt of tanshin polyphenolic acid B can improve diabetes
The pain sensation sensitivity of rat has improvement result to the pain nerve function of diabetes rat.
Table two：The influence that compound feels diabetes rat pedionalgia domain
Compared with model group, * p ＜ 0.05
(2) variation of diabetic sciatic nerve-muscle conduction speed after detection is administered
Diabetes rat modeling, grouping and medication are referring to 5.1, when diabetes rat is administered the 70th day, each group animal
Urethane intraperitoneal anesthesia, prostrate are fixed, and stimulating electrode is crosspointer electrode, and with after 75% alcohol disinfecting, insertion rat sits electric shock baton
At bone nerve nest near sciatic nerve-trunk, for recording electrode equally with rat gastrocnemius muscles belly of muscle is inserted into after 75% alcohol disinfecting, two is electric
Pole is at a distance of about 30 millimeters.
Equipment uses BL-420E type biological functional systems, and stimulus signal selects 1 millivolt, and 0.015 millisecond, scanning is fast
It spends for 0.01 second, 10kHz filtering, inducement signal amplifies 50 times, and calculating neuromuscular action potential according to experiment parameters obtained dives
Fu Qi, conduction of velocity calculation formula are：MNCV=stimulating electrodes are to distance (m)/incubation period (ms) of recording electrode.
Experimental configuration is shown in Table three, and the melbine salt of salviandic acid A and the melbine salt of tanshin polyphenolic acid B can improve diabetes
The sciatic nerve of rat-muscle conduction speed has improvement result to the Nerve conduction of diabetes rat.
Table three：Influence of the compound to diabetic rat conduction function
Compared with model group, * p ＜ 0.05
Influence of 5.3 the compounds of this invention to diabetes rat renal function
(1) NAG/ creatinine changes in diabetes rat urine after detection is administered
Diabetes rat modeling, grouping and medication when diabetes rat is administered the 80th day, collect each group referring to 5.1
Diabetes rat urine, with NAG, the creatinine test kit detection diabetes rat that biotechnology research institute is built up purchased from Nanjing
NAG/ creatinine levels in urine.
Four are the results are shown in Table, compared with model group, the melbine salt of salviandic acid A and the melbine salt of tanshin polyphenolic acid B are equal
The NAG that can be reduced in diabetes rat urine is horizontal, has statistical significance.
(2) variation of diabetes rat creatinine in serum, urea nitrogen content after detection is administered
Diabetes rat modeling, grouping and medication when diabetes rat is administered the 80th day, is plucked eyeball and are taken referring to 5.1
Blood, after blood sample collection, 2000r/min centrifugation 10min collect supernatant, biotechnology research institute are built up with purchased from Nanjing
Creatinine, urea nitrogen kit measure the creatinine in diabetes rat serum, urea nitrogen.
Four are the results are shown in Table, it is big that the melbine salt of salviandic acid A and the melbine salt of tanshin polyphenolic acid B can reduce diabetes
Mouse serum creatinine or blood urea nitrogen are horizontal, prompt salviandic acid A melbine salt and tanshin polyphenolic acid B melbine salt to diabetes
Nephrosis has improvement result.
Table four：Influence of the compound to the renal function of diabetes rat
Compared with model group, * p ＜ 0.05, * * p ＜ 0.01
Embodiment 6：The pharmacokinetics of the melbine salt of tanshin polyphenolic acid B
12 rats is taken to be divided into two groups, are divided into tanshin polyphenolic acid B (10mg/kg) group, the melbine salt (100mg/ of tanshin polyphenolic acid B
Kg) group administration, each group Oral Administration in Rats gastric infusion, eye socket takes blood when 0,0.5,1,2,4,8,12,24,30 is small after administration
About 0.5 milliliter, after taking blood, sample centrifuges 10 minutes through 2000r/min, takes -20 DEG C of preservations of supernatant, measures blood concentration, and paint
Make corresponding drug-time curve.
It can be found that the melbine salt of tanshin polyphenolic acid B is compared with being used alone tanshin polyphenolic acid B from drug-time curve (Fig. 8),
Absorption and elimination half-life period in blood plasma are obviously prolonged, and improve bioavilability.
Claims (12)
1. the double salt with general formula structure：
X·(Y)n
Wherein X is salviandic acid A or tanshin polyphenolic acid B, is existed in double salt in the form of anion；Y is melbine, in double salt
In exist in the form of cation, X and Y combine with ionic bond, and n represents the number of Y, n=1 or 2.
2. double salt according to claim 1, which is characterized in that X is tanshin polyphenolic acid B；N=2.
3. double salt according to claim 1, which is characterized in that X is salviandic acid A；N=1.
4. a kind of preparation method of double salt described in claim 1, which is characterized in that this method comprises the following steps：
The first step：Metformin hydrochloride and strong alkaline substance are dissolved into alcohol organic solvent respectively, filtered after stirring；
Second step：Free X acid is dissolved into alcohol organic solvent, adds acidulous material stirring；
3rd step：First step acquired solution is added in second step acquired solution, it is X (Y) that solid, which is precipitated,n。
5. preparation method according to claim 4, which is characterized in that the strong alkaline substance is selected from potassium hydroxide or hydrogen-oxygen
Change sodium, the acidulous material is selected from acetic acid, and the molar ratio of Metformin hydrochloride and free X acid is (1-2): 1.
6. preparation method according to claim 4, which is characterized in that the alcohol organic solvent is ethyl alcohol.
7. according to the preparation method described in claim 4-6, which is characterized in that the molar ratio of Metformin hydrochloride and tanshin polyphenolic acid B
For 2: 1, the molar ratio of Metformin hydrochloride and salviandic acid A is 1: 1.
8. the preparation method of double salt described in a kind of claim 3, which is characterized in that this method comprises the following steps：
The first step：Metformin hydrochloride and strong alkaline substance are dissolved into alcohols solvent respectively, filtered after stirring；
Second step：Salviandic acid A is dissolved into organic solvent；
3rd step：First step acquired solution is added in second step acquired solution, it is X (Y) that solid, which is precipitated,n。
9. preparation method according to claim 8, which is characterized in that the strong alkaline substance is selected from potassium hydroxide or hydrogen-oxygen
Change sodium, the organic solvent is ethyl acetate, propyl acetate, butyl acetate, petroleum ether or acetonitrile.
10. according to the preparation method described in claim 8-9, which is characterized in that the molar ratio of Metformin hydrochloride and salviandic acid A
For 1: 1.
11. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition includes pharmaceutically acceptable carrier and/or dilution
The one or more of claim 1-3 any one of them double salt of agent and therapeutically effective amount.
12. it is being made according to claim 1-3 any one of them double salt or pharmaceutical composition according to claim 11
Application in standby prevention diabetic nephropathy or diabetic neuropathy drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711467378.2A CN108101788A (en) | 2017-12-27 | 2017-12-27 | Composition and its application containing salvianolic acid salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711467378.2A CN108101788A (en) | 2017-12-27 | 2017-12-27 | Composition and its application containing salvianolic acid salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108101788A true CN108101788A (en) | 2018-06-01 |
Family
ID=62214440
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711467378.2A Pending CN108101788A (en) | 2017-12-27 | 2017-12-27 | Composition and its application containing salvianolic acid salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108101788A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111035636A (en) * | 2020-01-14 | 2020-04-21 | 南京中医药大学 | Composition for preventing and treating diabetic nephropathy and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1651433A (en) * | 2004-12-10 | 2005-08-10 | 山东大学 | Salviolic acid berberine double salt, its preparation method and application |
| CN101367799A (en) * | 2008-10-06 | 2009-02-18 | 李国玉 | Matrine salviol acid B complex salt and kuh-seng native salviol acid B complex salt, preparation method and application thereof |
| CN105434436A (en) * | 2015-12-25 | 2016-03-30 | 于非 | Medical application of salvianolic acid B sophocarpidine salt in protecting from inflammations caused by TNF-alpha or IL6 |
-
2017
- 2017-12-27 CN CN201711467378.2A patent/CN108101788A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1651433A (en) * | 2004-12-10 | 2005-08-10 | 山东大学 | Salviolic acid berberine double salt, its preparation method and application |
| CN101367799A (en) * | 2008-10-06 | 2009-02-18 | 李国玉 | Matrine salviol acid B complex salt and kuh-seng native salviol acid B complex salt, preparation method and application thereof |
| CN105434436A (en) * | 2015-12-25 | 2016-03-30 | 于非 | Medical application of salvianolic acid B sophocarpidine salt in protecting from inflammations caused by TNF-alpha or IL6 |
Non-Patent Citations (2)
| Title |
|---|
| 张娅娇: ""丹酚酸B-黄连素复盐对糖尿病大鼠肾脏的保护作用及其机制的研究"", 《中国优秀博硕士学位论文全文数据库 (硕士) 医药卫生科技辑》 * |
| 殷峻等: ""小檗碱的体外降糖作用"", 《上海第二医科大学学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111035636A (en) * | 2020-01-14 | 2020-04-21 | 南京中医药大学 | Composition for preventing and treating diabetic nephropathy and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10624938B2 (en) | Total flavone extract of flower of abelmoschus manihot L. medic and preparation method thereof | |
| CN101674823A (en) | Method for the treatment of conditions associated with increased 5-lipoxygenase and/or leukotriene activity | |
| CN107488162A (en) | A kind of bicyclic alcohol derivatives and its preparation and application | |
| CN101157692A (en) | Berberinc derivatives, preparation method and medicinal composition and usage thereof | |
| CN103788043B (en) | The brilliant IV type of nicousamide, its method for making and its pharmaceutical composition and purposes | |
| CN1923241B (en) | Medicine composition containing epimedium extract, uncaria extract, and gastrodine, and its preparation and use | |
| CN101273994A (en) | Pharmaceutical composition for curing diabetic retina pathological changes and method of preparing the same | |
| CN101759672B (en) | Salvianolic acid B in radix salviae miltiorrhizae | |
| CN108101788A (en) | Composition and its application containing salvianolic acid salt | |
| CN101143157A (en) | Tyrosol and tyrosol bypass salidroside plant extraction and preparation and use thereof | |
| CN102716135B (en) | Lupenone prevents in preparation or treats the application in the product of diabetes | |
| CN101756955B (en) | Chinonin complex, preparation method and application thereof | |
| US20100034903A1 (en) | Shinyleaf yellowhorn extract, methods for extraction and uses thereof | |
| CN100404534C (en) | Derivative of berberine, and prepartion method, composition of medication, and application | |
| CN103860565B (en) | Medicinal composition for treating diabetes hepatic fibrosis | |
| CN104211640A (en) | Alkaloid compound calamusine A, preparation method, pharmaceutical composition, and applications thereof | |
| CN102389434B (en) | Medicinal composition for treating ischemic cerebrovascular disease, and preparation method thereof | |
| US9943560B2 (en) | Medical compositions containing liquorice extracts with synergistic effect | |
| CN105582546B (en) | A kind of Entecavir phosphatide complexes and the compound enteric-coated tablet of diammonium glycyrrhizinate | |
| CN115192573A (en) | Application of demethyleneberberine hydrochloride in preparation of medicine for treating pulmonary fibrosis | |
| CN112457291B (en) | Salt of benzothiopyrone compound and preparation method and application thereof | |
| CN103906525A (en) | Application of albizzia chinensis extract in preparation of medicine for treatment of gastric ulcer | |
| US20210015881A1 (en) | Agent exhibiting antiarrhythmic effect | |
| CN108403980B (en) | Hypoglycemic plant extract effective part and preparation method and application thereof | |
| CN106554349A (en) | Wild anistree new isopentene group replaces C6‑C3Class compound and preparation method thereof, application and its pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180601 |