CN108498457A - One kind having high stability Astragaloside IV soluble type compound and preparation method thereof - Google Patents
One kind having high stability Astragaloside IV soluble type compound and preparation method thereof Download PDFInfo
- Publication number
- CN108498457A CN108498457A CN201810282858.XA CN201810282858A CN108498457A CN 108498457 A CN108498457 A CN 108498457A CN 201810282858 A CN201810282858 A CN 201810282858A CN 108498457 A CN108498457 A CN 108498457A
- Authority
- CN
- China
- Prior art keywords
- astragaloside
- rebaudioside
- compound
- glycyrrhizic acid
- preparation
- 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.)
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Links
- QMNWISYXSJWHRY-BCBPIKMJSA-N astragaloside IV Natural products CC(C)(O)[C@@H]1CC[C@@](C)(O1)[C@H]2[C@@H](O)C[C@@]3(C)[C@@H]4C[C@H](O[C@@H]5O[C@H](CO)[C@H](O)[C@@H](O)[C@H]5O)[C@H]6C(C)(C)[C@H](CC[C@@]67C[C@@]47CC[C@]23C)O[C@@H]8OC[C@@H](O)[C@H](O)[C@H]8O QMNWISYXSJWHRY-BCBPIKMJSA-N 0.000 title claims abstract description 150
- PFKIBRPYVNVMRU-UHFFFAOYSA-N cyclosieversioside F Natural products CC(C)(O)C1COC(C)(C1)C2C(O)CC3(C)C4CC(OC5OC(CO)C(O)C(O)C5O)C6C(C)(C)C(CCC67CC47CCC23C)OC8OCC(O)C(O)C8O PFKIBRPYVNVMRU-UHFFFAOYSA-N 0.000 title claims abstract description 150
- QMNWISYXSJWHRY-YLNUDOOFSA-N astragaloside IV Chemical compound O1[C@H](C(C)(O)C)CC[C@]1(C)[C@@H]1[C@@]2(C)CC[C@]34C[C@]4(CC[C@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)CO4)O)C4(C)C)[C@H]4[C@@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)C[C@H]3[C@]2(C)C[C@@H]1O QMNWISYXSJWHRY-YLNUDOOFSA-N 0.000 title claims abstract description 107
- 238000002360 preparation method Methods 0.000 title claims abstract description 52
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- -1 Astragaloside IV compound Chemical class 0.000 claims abstract description 50
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 claims abstract description 48
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- HELXLJCILKEWJH-SEAGSNCFSA-N Rebaudioside A Natural products O=C(O[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@@]1(C)[C@@H]2[C@](C)([C@H]3[C@@]4(CC(=C)[C@@](O[C@H]5[C@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@H](O)[C@@H](CO)O5)(C4)CC3)CC2)CCC1 HELXLJCILKEWJH-SEAGSNCFSA-N 0.000 claims abstract description 43
- HELXLJCILKEWJH-UHFFFAOYSA-N entered according to Sigma 01432 Natural products C1CC2C3(C)CCCC(C)(C(=O)OC4C(C(O)C(O)C(CO)O4)O)C3CCC2(C2)CC(=C)C21OC(C1OC2C(C(O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1O HELXLJCILKEWJH-UHFFFAOYSA-N 0.000 claims abstract description 43
- 235000019203 rebaudioside A Nutrition 0.000 claims abstract description 43
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- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims abstract description 36
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- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 claims abstract description 33
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The present invention disclose it is a kind of there is high stable type Astragaloside IV soluble type compound, including Astragaloside IV is main ingredient, it is characterised in that further includes Rebaudioside A and glycyrrhizic acid is excipient substance, the Astragaloside IV and Rebaudioside A mass ratio are 1:15‑1:Between 30, the glycyrrhizic acid and Rebaudioside A mass ratio are 1:3‑1:Between 6；Astragaloside IV compound prepared by the present invention, Rebaudioside A and glycyrrhizic acid spontaneously form Micellar Solubilization Astragaloside IV in aqueous solution, Astragaloside IV solubility reaches 13.6mg/ml, micella grain size is small and uniform, medicine stability is good, significantly improve oral administration biaavailability, Rebaudioside A and glycyrrhizic acid all have anti-diabetic, anti-inflammatory isoreactivity simultaneously, so that Astragaloside IV compound has collaboration pharmacological activity well, the Astragaloside IV compound preparation process of the present invention is simple, it is suitble to industrialized production, there is good economy.
Description
Technical field
The present invention relates to a kind of Astragaloside IV soluble type compounds, more particularly to a kind of to have high stability Astragaloside IV
Molten type compound and preparation method thereof.
Background technology
Astragaloside IV (Astragaloside IV, CAS 83207-58-3), is a kind of isolated ring from Radix Astragali
Propane triterpenoid saponin is the principle active component of Radix Astragali, has prevention and cure of cardiovascular disease, anticancer, anti-inflammatory, anti-oxidant, disease-resistant
A variety of pharmacological activity such as poison, antihyperglycemic and neuroprotection have good medical value, great exploitation potential.It is newest to grind
Study carefully and shows that Astragaloside IV has hypoglycemic, reducing blood lipid, improvement insulin resistance, inhibition inflammation anti-in treatment diabetes etc.
Should wait extensive pharmacological activity, and in the retinopathy caused by diabetes Astragaloside IV to retinal ganglial cells
With protective effect, this shows that Astragaloside IV has in treatment diabetes and its complication etc. such as diabetic keratopathy
Wide application prospect.But there is following deficiency in Astragaloside IV, seriously affect its development and utilization：Water-soluble is poor, Radix Astragali
First glycosides is in water phase at 20 DEG C, and solubility is only 0.05mg/ml in water；Half-life short, saturating biomembrane poor performance take orally and wait life
Object availability is extremely low, and only 2.2%.These above-mentioned deficiencies, seriously limit Astragaloside IV in clinic and as beverage, diet agent
Etc. the fields such as food industry application.Therefore, it is necessary to further explore a kind of economic and effective novel Astragaloside IV system
Agent or product.
Astragaloside IV is the main active of Radix Astragali, usually as the standard of evaluation Milkvetch Root quality good or not, Radix Astragali
Medication history in China is very long, and has extensive pharmacological activity.The present inventor is compared by experiment, is sent out
Now existing document report and technology cannot meet wanting for Astragaloside IV aqueous solubilities and its aqueous stability at present
It asks.Application for a patent for invention number 200610013088.6 " liposome of astragaloside IV and its pharmaceutical preparation " discloses a kind of using yellow
Liposome prepared by stilbene first glycosides, phosphatide and lipophilicity additive, significantly improves the oral administration biaavailability of Astragaloside IV, but
It is technology disclosed in the patent of invention there is no solving Astragaloside IV solubility in aqueous solution and its aqueous stability,
The aqueous solution preparation demand of the clinical demands such as eye drops can not be solved, can not also solve Astragaloside IV in some health products, beverage
The application demand in the fields such as industry, and in the application for a patent for invention, the liposome of Astragaloside IV is prepared using phosphatide etc., because of phosphatide
Nature is unstable, is easy oxidation, can not be in long-term preservation under aqueous solution state.
Application for a patent for invention 200510095308.X " Astragaloside IV cyclodextrin inclusion compound, preparation and preparation method ", it is public
A kind of cyclodextrin encapsulated Astragaloside IV of use has been opened, the solubility and oral administration biaavailability of Astragaloside IV are improved, but should
Technology disclosed in patent of invention is not significantly increased the solubility of Astragaloside IV in aqueous solution, only dissolves Astragaloside IV
Degree is improved by 22.2 μ g/ml to 188.4~386.8 μ g/ml, and the inclusion compound is finally that solid state preserves, and aqueous solution is steady
The qualitative number not being improved it is disclosed that but according to inclusion compound common-sense infer, and prepared in the application for a patent for invention ring paste
Spermatophore closes Astragaloside IV can not be in long-term preservation under aqueous solution state.And research shows that Astragaloside IV eye drops concentration needs
2mg/ml concentrations above, the invention improve the limited extent of solubility, the effective eye drops concentration requirement of Astragaloside IV are not achieved.
Application for a patent for invention number 200510014971.2 " a kind of astragaloside injection and preparation method thereof ", discloses one
Kind improves the solubility of Astragaloside IV using nonaqueous solvents, cosolvent, is used to prepare injection.But because the invention uses second
The nonaqueous solvents such as alcohol, and the concentration of nonaqueous solvents can not be applied to eye drops, the conventional beverage of field of medicaments up to 20%~60%
Equal fields.
Insoluble drug solubility can be improved using Nano medication delivery technique, pharmaceutical aqueous solution stability is improved, carry
High oral administration biaavailability.Currently used ophthalmically acceptable Nano medication delivery system such as micella, nanoparticle etc. mainly uses polyethylene
Caprolactam-polyvinyl acetate-ethylene glycol copolymer (PVCL-PVA-PEG), polyglycolic acid (PGA), polylactic acid
(PLA), the copolymer (PLGA) of hydroxyacetic acid and lactic acid, glycolide-lactide-caprolactone ternary atactic copolymer (PGLC)
Deng, itself it is only a kind of carrier, without therapeutic effect, and these artificial synthesized polymeric carrier materials, because existing
The problems such as degradability, there are some potential safety problemss for long-time service.As can using natural extract matter, especially naturally extract
As a kind of novel carriers, this carrier can play the role of building Nano medication delivery system small-molecule substance, improve drug
Stability, enhancing cornea drug absorption improve curative effect.The natural small molecule substance reported at present has ginseng soap as carrier
Glycosides (application for a patent for invention number 201310155639.2), Stevioside (modern food science and technology, 2014,30 (1):115-119；J
Agric Food Chem, 2013,61(18):4433-4440) etc..The natural small molecule substance of above-mentioned existing research and report
It can meet as carrier and the indissolubles chemicals such as resveratrol, curcumin are contained, but the present inventor passes through Experimental comparison, hair
Now at present existing document report ginsenoside, Stevioside cannot meet Astragaloside IV eye drip solubility and its aqueous solution is steady
Qualitatively require.The Astragaloside IV that ginsenoside, Stevioside etc. in above-mentioned existing document report contain it is not good
Stabilization, Astragaloside IV are leaked out from micella quickly, and the effect steady in a long-term of eye drops is not achieved.Therefore, as can choosing
A kind of natural small molecule substance is selected, Astragaloside IV can be effectively encapsulated, to improve the dissolving of Astragaloside IV in aqueous solution
Degree and its stability, maintain its pharmacological activity, at the same under effectively encapsulating concentration this natural small-molecule substance to eye
It is nonirritant, safely and effectively just it is particularly important.
Rebaudioside A (Rebaudioside A, CAS registration number 58543-16-1, molecular formula C44H70O23, molecular weight
967.03) it is to be extracted from the leaf of feverfew Stevia Rebaudia (plant is referred to as STEVIA REBAUDIANA in China)
A kind of glucosides is widely used in as a kind of new type natural sweetener in the production of food, beverage, seasoning.In South America
There is centuries history using STEVIA REBAUDIANA as medicinal herbs and for sugar.In recent years studies have shown that Rebaudioside A have strong anti-oxidation
Activity (Saravanan R, Ramachandran V.Modulating efficacy of Rebaudioside A, a
diterpenoid on antioxidant and circulatory lipids in experimental diabetic
rats.Environ Toxicol Pharmacol.2013,36(2):472-83), meanwhile, Rebaudioside A has strong anti-glycosuria
The effects that sick, anti-inflammatory, immunological regulation (V,S,N,et al.Insight into anti-
diabetic effect of low dose of stevioside.Biomed Pharmacother. 2017,90:216-
221).The present inventor the study found that Rebaudioside A can significantly solubilized Astragaloside IV, improve Astragaloside IV stability, and significantly carry
High Astragaloside IV oral administration biaavailability.And from feverfew Stevia Rebaudia (plant is referred to as STEVIA REBAUDIANA in China)
Leaf in another ingredient Stevioside (also known as steviol glycoside, CAS registration number 57817-89-7, the molecular formula that extract
C38H60O18, molecular weight 804.87), then fail to have the function that while improving Astragaloside IV water solubility and its stability.
Glycyrrhizic acid (Glycyrrhizic Acid, CAS registration numbers:1405-86-3, molecular formula:C42H62O16, molecular weight:
822.93) be Radix Glycyrrhizae main ingredient, have anti-inflammatory, antioxygen, antibacterial, treatment wound, effectively remove superoxide ion and hydroxyl from
By base, significantly inhibit the effect of liposome peroxidation object.
Invention content
The object of the present invention is to provide one kind having high stable type Astragaloside IV soluble type compound, improves Astragaloside IV water
Dissolubility improves solubility, improves and improves the bioavilability after being administered orally, and improves the bin stability of Astragaloside IV,
Meanwhile the carrier for building Astragaloside IV compound is the small-molecule substances of two kinds of natural safety, have anti-diabetic, it is anti-inflammatory,
The effects that immunological regulation so that its Astragaloside IV compound built has the function of synergy, for example, enhancing Astragaloside IV
Treat the drug effect of diabetic complication such as diabetic keratopathy and cornea neuropathy.Meanwhile Astragaloside IV improvement is water-soluble
Xie Du after improving its stability in aqueous solution, can expand Astragaloside IV in food industry and the application in field, for example,
For health care drink etc..
Another object of the present invention is to provide the preparation method of above-mentioned Astragaloside IV compound.
The technology of the present invention is conceived：Astragaloside IV has the specific pharmacology such as anti-oxidant, anti-inflammatory, anti-diabetic and neuroprotection
The problems such as active, but Astragaloside IV is insoluble in water, oral administration biaavailability is low seriously limits Astragaloside IV in clinical medicine
Application in the fields such as object treatment, food industry.And the stability of Astragaloside IV is improved, especially improve it in aqueous solution
Stability can significantly expand its clinical application (for example, can be prepared into the aqueous solution preparations such as oral solution, eye drops) and its in health care
The application (for example, beverage etc. can be prepared into) in the fields such as food.Astragaloside IV is built into using Nano medication delivery system and is received
Metric system agent will be such that Astragaloside IV stability significantly improves because of advantage specific to of Nano medication delivery system itself, improve mouth
Bioavilability is taken, is heightened the effect of a treatment.And use biologically active Small-molecule compounds as structure Astragaloside IV nanometer
The carrier of preparation, not only acting as effectively structure Astragaloside IV nanometer formulation then can be further also because carrier has pharmacological activity
Enhance the pharmacological effect of Astragaloside IV.The present inventor is the study found that Rebaudioside A and glycyrrhizic acid in aqueous solution can spontaneous shapes
At the nanostructure with similar micella, the effect of solubilized Astragaloside IV is played, and because of the anti-oxidant work of Rebaudioside A itself
Property, glycyrrhizic acid can act synergistically with Astragaloside IV well similar to the anti-inflammatory activity of hormone, and enhancing Astragaloside IV micella is molten
The pharmacological activity of liquid.The Astragaloside IV solution of the mixed micelle of Rebaudioside A and glycyrrhizic acid solubilising, i.e. Astragaloside IV micella are molten
Liquid, stability significantly improve, further experiment find Astragaloside IV micellar solution tool increase significantly oral administration biaavailability,
Improve the validity effect of Astragaloside IV treatment diabetic keratopathy.
Technical scheme of the present invention：A kind of Astragaloside IV soluble type compound, including Astragaloside IV are main ingredient, and feature is also
It is to include Rebaudioside A and glycyrrhizic acid as excipient substance, the Astragaloside IV main ingredient and Rebaudioside A excipient substance quality
Than 1:15-1:Between 30, two kinds of excipient substance mass ratioes of the glycyrrhizic acid and Rebaudioside A are 1:3-1:Between 6.
The Rebaudioside A (Rebaudioside A) is that (plant is in China by feverfew Stevia Rebaudia
Referred to as STEVIA REBAUDIANA) leaf in a kind of glucosides (CAS registration numbers for extracting:58543-16-1, molecular formula:C44H70O23, point
Son amount:967.03), Rebaudioside A purity >=98%.Glycyrrhizic acid (Glycyrrhizic Acid, the CAS registration numbers:
1405-86-3, molecular formula: C42H62O16, molecular weight:822.93) be Radix Glycyrrhizae main ingredient, glycyrrhizic acid purity >=97%.
The preparation method of the Astragaloside IV soluble type compound of the present invention is as follows：By Astragaloside IV and Rebaudioside A, Radix Glycyrrhizae
Acid is dissolved into absolute ethyl alcohol, by 40 DEG C of water-bath rotatory vacuum ethanol evaporations (recyclable ethyl alcohol), is formed inside container solid
Body powder is up to Astragaloside IV compound of the invention.Preparation process is simple, environmentally protective, and it is extensive raw to be suitable for industrialization
Production.
The preparation method of above-mentioned Astragaloside IV micelle complex, Astragaloside IV compound obtained are highly soluble in water, dissolving
For degree up to 13.6mg/ml, Astragaloside IV compound, which is dissolved in after water, spontaneously forms micella, micella particle size range 6~15nm it
Between.
Above-mentioned Astragaloside IV micelle complex is also applied for suitable for being further prepared into the aqueous solution preparations such as oral solution
Filling capsule, or it is directly packed at powder.
The preparation method of above-mentioned Astragaloside IV micelle complex, preparation process and simple for process is easy to operate, without spraying
The large-scale instrument and equipments such as dry, are suitable for industrialized production, are also very applicable for the purifying of pharmacy corporation or food enterprise etc.
Industrial production.
Astragaloside IV compound prepared by the present invention, because in aqueous solution, composite materials Rebaudioside A can with glycyrrhizic acid
It is self-assembly of micella, rapid solubilisation Astragaloside IV so that Astragaloside IV has good dissolubility, Astragaloside IV in aqueous solution
Solubility up to 13.6mg/ml, and micella grain size is minimum, and distribution is uniform, and medicine stability is good.The Astragaloside IV is multiple
It closes object and not only increases stability of the Astragaloside IV in aqueous solution state, can also significantly increase oral administration biaavailability, this hair
It is bright the experimental results showed that, the oral bio profit of the Astragaloside IV compound of the patent of the present invention of same dose after rat oral gavage
Expenditure is 9.7 times of the Astragaloside IV ordinary powder before preparing, while the anti-diabetic, anti-inflammatory etc. living that Rebaudioside A has
Property and glycyrrhizic acid anti-inflammatory, the immunological regulation isoreactivity that have make Astragaloside IV compound that there is good synergistic treatment glycosuria
The drug effect of characteristic of disease complication such as diabetic keratopathy and cornea neuropathy.Therefore, Astragaloside IV compound of the invention
With good economy.
Specific implementation mode
Below by specific embodiment, present invention be described in more detail.
Embodiment 1：
50mg Astragaloside IVs, 900mg Rebaudioside A, 300mg glycyrrhizic acids are placed in 100mL round-bottomed flasks, 50mL is added
Absolute ethyl alcohol, fully after dissolving, 40 DEG C of water-bath rotatory vacuums evaporate absolute ethyl alcohol and recycle ethyl alcohol, obtain Astragaloside IV and Rui Bao
The evenly dispersed Astragaloside IV compound of enlightening glycosides A, glycyrrhizic acid.
Embodiment 2：
20mg Astragaloside IVs, 300mg Rebaudioside A, 50mg glycyrrhizic acids are placed in 100mL round-bottomed flasks, 50mL is added
Absolute ethyl alcohol, fully after dissolving, 40 DEG C of water-bath rotatory vacuums evaporate absolute ethyl alcohol and recycle ethyl alcohol, obtain Astragaloside IV and Rui Bao
The evenly dispersed Astragaloside IV compound of enlightening glycosides A, glycyrrhizic acid.
Embodiment 3：
100mg Astragaloside IVs, 3000mg Rebaudioside A, 750mg glycyrrhizic acids are placed in 100mL round-bottomed flasks, are added
50mL absolute ethyl alcohols, fully after dissolving, 40 DEG C of water-bath rotatory vacuums evaporation absolute ethyl alcohols simultaneously recycle ethyl alcohol, obtain Astragaloside IV and
The evenly dispersed Astragaloside IV compound of Rebaudioside A, glycyrrhizic acid.
Embodiment 4：
100mg Astragaloside IVs, 3000mg Rebaudioside A, 1000mg glycyrrhizic acids are placed in 100mL round-bottomed flasks, are added
50mL absolute ethyl alcohols, fully after dissolving, 40 DEG C of water-bath rotatory vacuums evaporation absolute ethyl alcohols simultaneously recycle ethyl alcohol, obtain Astragaloside IV and
The evenly dispersed Astragaloside IV compound of Rebaudioside A, glycyrrhizic acid.
Experiment effect example 1：The Astragaloside IV compound solubility property and its aqueous stability of the present invention measures.
Experimental drug：Astragaloside IV compound (prepared by embodiment 1, be set as experimental group).
Control drug：Using 1 preparation method of patent Example of the present invention, but it is not added with glycyrrhizic acid, remaining preparation process one
It causes, the Astragaloside IV compound (being set as control drug 1) of preparation；Using 1 preparation method of patent Example of the present invention, but it is not added with
Rebaudioside A, remaining preparation process is consistent, the Astragaloside IV compound (being set as control drug 2) of preparation；Using application number
200610013088.6 " liposome of astragaloside IV and its pharmaceutical preparations ", using Astragaloside IV, phosphatide and lipophilicity additive
The liposome (control drug 3) of preparation；Astragaloside IV ordinary powder (control drug 4).
Experimental method：Excessive experimental drug, control drug 1, control drug 2, control drug 3, control drug 4 are taken, it is close
It is encapsulated in Brown Glass Brown glass bottles and jars only, 5ml water is added, vortex oscillation is after one hour, absorption liquid, will after 0.22 μm of filtering with microporous membrane
The solution of filtering gained is divided into two parts, and portion is dissolved using 100 times of methanol and dilution, high effective liquid chromatography for measuring concentration, separately
Portion is positioned over room temperature (not being protected from light), 24 as a child afterwards by 0.22 μm of miillpore filter mistake of liquid loaded in transparent glass bottle
After filter, high effective liquid chromatography for measuring concentration, and calculate medicament contg and degradation percentage.
The experimental results showed that the amount that experimental drug (i.e. Astragaloside IV compound) vortex oscillation dissolves after one hour is
13.6mg/ml.Using 1 preparation method of patent Example of the present invention, but it is not added with glycyrrhizic acid, remaining preparation process is consistent, prepares
The amount that is dissolved after one hour of Astragaloside IV compound (being set as control drug 1) vortex oscillation be 11.1mg/ml.Using the present invention
1 preparation method of patent Example, but it is not added with Rebaudioside A, remaining preparation process is consistent, the Astragaloside IV compound of preparation
The amount that (being set as control drug 2) vortex oscillation dissolves after one hour is 8.5mg/ml.It is " yellow using application number 200610013088.6
Stilbene first glycosides liposome and its pharmaceutical preparation ", the liposome prepared using Astragaloside IV, phosphatide and lipophilicity additive (control
Drug 3) amount that is dissolved after one hour of vortex oscillation is 0.24mg/ml, Astragaloside IV ordinary powder (control drug 4) whirlpool shakes
The amount dissolved after swinging one hour is 0.038mg/ml.Illustrate that Astragaloside IV compound prepared by the technology of the present invention significantly improves and changes
Kind Astragaloside IV solubility property, and use merely Rebaudioside A or glycyrrhizic acid also can solubilized Astragaloside IV well, but it is solubilized
The mixed micelle that effect does not have Rebaudioside A and glycyrrhizic acid to share is good.Experimental drug (i.e. Astragaloside IV compound) aqueous solution is normal
Avoid light place is not after 24 hours for temperature, and Astragaloside content is the 93% of initial soln in solution.Using patent Example 1 of the present invention
Preparation method, but it is not added with glycyrrhizic acid, remaining preparation process is consistent, the Astragaloside IV compound (being set as control drug 1) of preparation,
Avoid light place is not after 24 hours for aqueous solution room temperature, and Astragaloside content only has the 41% of initial soln concentration in solution.Using
1 preparation method of patent Example of the present invention, but it is not added with Rebaudioside A, remaining preparation process is consistent, and the Astragaloside IV of preparation is multiple
Object (being set as control drug 2) is closed, avoid light place is not after 24 hours for aqueous solution room temperature, and Astragaloside content is only initial in solution
The 27% of solution concentration, and the liposome (control drug 3) and Huang for using Astragaloside IV, phosphatide and lipophilicity additive to prepare
Stilbene first glycosides ordinary powder (control drug 4) aqueous solution room temperature not avoid light place after 24 hours, Astragaloside content is only in solution
There is the 1.3% of initial soln concentration, illustrates that Astragaloside IV compound prepared by the technology of the present invention significantly improves and improves Radix Astragali first
The stability of glycosides aqueous solution, although and use merely Rebaudioside A or glycyrrhizic acid also can solubilized Astragaloside IV well, water
Stability of solution is poor.
Experiment effect example 2：The Astragaloside IV compound of the present invention is concurrent for STZ induction type diabetic mice eyes
The validity of disease.
Experimental drug：Astragaloside IV compound (prepared by embodiment 1, be set as experimental group).
Control drug：Using 1 preparation method of patent Example of the present invention, but it is not added with glycyrrhizic acid, remaining preparation process one
It causes, the Astragaloside IV compound (being set as control drug 1) of preparation；Using 1 preparation method of patent Example of the present invention, but it is not added with
Rebaudioside A, remaining preparation process is consistent, the Astragaloside IV compound (being set as control drug 2) of preparation；Using application number
200610013088.6 " liposome of astragaloside IV and its pharmaceutical preparations ", using Astragaloside IV, phosphatide and lipophilicity additive
The liposome (control drug 3) of preparation；Astragaloside IV ordinary powder (control drug 4).
Experimental animal and experimental method：Because the diabetic mice of STZ inductions is similar to people's non-proliferative phase as compared with what is generally acknowledged
Diabetic retinopathy model, this part content are studied using this model.C57BL/6 mouse are selected, it is male, 6-8 weeks
Age, 18~25 grams of weight (are bought from Beijing Vital River Experimental Animals Technology Co., Ltd.).Animal is grouped at random, one group of use
The citrate buffer (pH 4.5) of fresh configuration is injected intraperitoneally mouse after preparing STZ solution, continuous injection 5 days,
The 8th day (after a week) after last time (the 5th injection) measures blood glucose to every mouse, continuous to measure 3 days, STZ injections
Group blood glucose value thinks the success of Type I diabetes model more than 300mg/dL (16.7mmol/L).After model success, mouse is divided at random
At 6 groups (i.e. experimental group, control 1 group, control 2 groups, control 3 groups, control 4 groups, blank control groups), every group 12, given low
For 25mg/kg weight (determination of gastric infusion dosage combination document report), before gavage, respectively by experimental group, compare the Huang of each group
Stilbene first glycosides is dissolved or dispersed in water, is configured to a concentration of 2.5mg/mL of Astragaloside IV, and gavage volume is 0.1mL/10g weight
(i.e. 25mg Astragaloside IVs per kilogram mouse weight dosage gavage), blank control group gavage gives the physiological saline of respective volume,
Daily gavage is primary, continuous gavage 8 weeks, to the weight, fasting blood-glucose, corneal sensitivity of diabetic mice after 8 weeks gavages
It is measured.
0033 the experimental results showed that, the mouse of STZ intraperitoneal injection modelings, gavage gives the blank control group of physiological saline,
It gradually shows diabetes classical symptom, the glucostasis such as more drinks, more food, diuresis, weight loss and maintains higher level, body
Weight is relatively low compared with normal mouse, shows modeling success.And the weight and blood glucose target of experimental group (Astragaloside IV compound) mouse are then
It is substantially better than each control drug group (table 1).The corneal sensitivity of mouse is detected, the results show that STZ models diabetic mice gavage
The corneal sensitivity for giving the blank control group of physiological saline is remarkably decreased (compared to normal mouse, P<0.05), this is used
The Astragaloside IV compound oral medication group (i.e. experimental group) of patent of invention, mouse cornea susceptibility then have different degrees of improvement
(compared to normal mouse, P>0.05), 1 group of STZ modeling diabetic mices control, 2 groups of control, 3 groups of control, 4 groups of control, it is small
Mouse corneal sensitivity have a degree of improvement, but effect be worse than experimental group (Astragaloside IV compound) mouse (compared to
Experimental mice, P<0.05).
Table 1 is normal and diabetic mice in sample point weight and blood sugar test (N=12)
Experiment effect example 3：The Astragaloside IV compound Oral Administration in Rats bioavilability test experience of the present invention.
Experimental drug：Astragaloside IV compound (prepared by embodiment 1, be set as experimental group).
Control drug：Using 1 preparation method of patent Example of the present invention, but it is not added with glycyrrhizic acid, remaining preparation process one
It causes, the Astragaloside IV compound (being set as control drug 1) of preparation；Using 1 preparation method of patent Example of the present invention, but it is not added with
Rebaudioside A, remaining preparation process is consistent, the Astragaloside IV compound (being set as control drug 2) of preparation；Using application number
200610013088.6 " liposome of astragaloside IV and its pharmaceutical preparations ", using Astragaloside IV, phosphatide and lipophilicity additive
The liposome (control drug 3) of preparation；Astragaloside IV ordinary powder (control drug 4).
Experimental animal and experimental method：SD rats are selected, male, (purchase is magnificent from Beijing dimension tonneau for 290~310 grams of weight
Experimental animal Technology Co., Ltd.).Animal is randomly divided into 5 groups, every group 8, overnight fasting before testing, by experimental drug before gavage
Object, each group control drug are dissolved or dispersed in 1mg/ml concentration in water respectively, and gavage (i.e. 10mg is carried out with 1ml/100g weight
Astragaloside IV per kilogram rat body weight dosage gavage), upon administration 0.25,0.5,1,2,4,6,8,12 and 24 hour, tail was quiet
Arteries and veins takes blood 0.25ml, anticoagulant heparin, centrifugal separation plasma, and High Performance Liquid Chromatography/Mass Spectrometry instrument detects Astragaloside IV concentration in blood sample,
The processing of DAS2.0 softwares and analysis pharmacokinetic parameter.
Experimental result is as shown in table 1, the C of experimental groupmaxIt is significantly higher than 4 groups of (P of control drug<And 2 groups of control drug 0.05)
(P<0.05), the AUC of experimental group0-24hAlso 4 groups of (P of control drug are significantly better than<0.05), 1 group of control drug, 2 groups of control drug
With 3 groups of control drug compared to 4 groups of control drug, CmaxAnd AUC0-24hHave and improves in various degree (compared to 4 groups of control drug, P<
0.05), but 3 groups of 1 group of control drug, 2 groups of control drug and control drug are compared to experimental group, CmaxAnd AUC0-24h is equalThen significantly
It is relatively low (compared to experimental group, P<0.05), illustrate that the Astragaloside IV compound of the present invention has faster oral absorption, preferably
Oral organism-absorbing availability, and glycyrrhizic acid or the Astragaloside IV compound oral result of Rebaudioside A preparation is relatively used alone
More preferably.
2 oral drugs kinetic parameter of table
| Pharmacokinetic parameter | Experimental group | Control drug 1 | Control drug 2 | Control drug 3 | Control drug 4 |
| Cmax(μg/mL) | 0.46±0.38 | 0.141±0.011 | 0.097±0.003 | 0.041±0.003 | 0.026±0.019 |
| Tmax(h) | 1 | 2 | 2 | 2 | 2 |
| AUC0-24h(μg/mL) | 88.95±3.79 | 49.54±5.16 | 32.79±3.73 | 16.52±2.35 | 9.17±0.36 |
The above embodiments merely illustrate the technical concept and features of the present invention, and the protection model of the present invention can not be limited with this
It encloses.It is all any equivalent transformation or modification made according to the spirit of the present invention, should all cover within the scope of the present invention.
Claims (4)
1. a kind of tool high stable type Astragaloside IV soluble type compound, including Astragaloside IV are main ingredient, it is characterised in that further include
Rebaudioside A and glycyrrhizic acid are excipient substance, and the Astragaloside IV main ingredient and Rebaudioside A excipient substance mass ratio are 1:15-
1:Between 30, the glycyrrhizic acid and Rebaudioside A mass ratio are 1:3-1:Between 6.
2. Astragaloside IV compound as described in claim 1, it is characterised in that Rebaudioside A (the CAS registration numbers 58543-
16-1, molecular formula C44H70O23, molecular weight 967.03) and purity >=98%, glycyrrhizic acid (the CAS registration numbers:1405-86-3, point
Minor:C42H62O16, molecular weight:822.93) purity >=97%.
3. a kind of preparation method of Astragaloside IV compound as described in claim 1, it is characterised in that include the following steps：It will
Astragaloside IV main ingredient and Rebaudioside A are dissolved in glycyrrhizic acid medicine auxiliary material in absolute ethyl alcohol, pass through rotatory vacuum evaporative removal
Ethyl alcohol to obtain the final product.
4. the preparation method of Astragaloside IV compound as claimed in claim 3, it is characterised in that Astragaloside IV obtained is compound
Object is self-assembly of micella after can be quickly dissolved into water, and micella particle size range is between 6-15nm.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115469041A (en) * | 2022-08-10 | 2022-12-13 | 广西白云山盈康药业有限公司 | Method for determining contents of nine-ingredient blood-enriching oral liquid traditional Chinese medicine preparation by one-test and multi-evaluation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923211A (en) * | 2005-09-02 | 2007-03-07 | 天津药物研究院 | Astragaloside injection and preparation thereof |
-
2018
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923211A (en) * | 2005-09-02 | 2007-03-07 | 天津药物研究院 | Astragaloside injection and preparation thereof |
Non-Patent Citations (4)
| Title |
|---|
| SAMRIDDH MUDGAL等: "Controlling the taste receptor accessible structure of rebaudioside A via binding to bovine serum albumin", 《FOOD CHEMISTRY》 * |
| 万会达等: "甜菊糖苷类物质的功能性研究进展", 《食品科学》 * |
| 张明发等: "甘草及其有效成分的抗糖尿病药理作用的研究进展", 《抗感染药学》 * |
| 杜薇: "甘草的溶解性研究", 《HUNAN GUIDING JOURNAL OF TCMP》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115469041A (en) * | 2022-08-10 | 2022-12-13 | 广西白云山盈康药业有限公司 | Method for determining contents of nine-ingredient blood-enriching oral liquid traditional Chinese medicine preparation by one-test and multi-evaluation |
| CN115469041B (en) * | 2022-08-10 | 2023-09-29 | 广西白云山盈康药业有限公司 | One-measurement-multiple-evaluation content determination method for nine-ingredient blood-replenishing oral liquid traditional Chinese medicine preparation |
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