CN108478525A - One kind having highly-water-soluble and high stable type Astragaloside IV eye drops and preparation method thereof - Google Patents
One kind having highly-water-soluble and high stable type Astragaloside IV eye drops and preparation method thereof Download PDFInfo
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- CN108478525A CN108478525A CN201810282859.4A CN201810282859A CN108478525A CN 108478525 A CN108478525 A CN 108478525A CN 201810282859 A CN201810282859 A CN 201810282859A CN 108478525 A CN108478525 A CN 108478525A
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- CN
- China
- Prior art keywords
- astragaloside
- eye drops
- rebaudioside
- preparation
- solution
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- 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 146
- 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 146
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Classifications
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- 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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Abstract
The present invention disclose it is a kind of there is highly-water-soluble and high stable type Astragaloside IV eye drops, 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 eye drops prepared by the present invention, administration concentration is up to 10mg/ml, and micella grain size is small and distribution is uniform, medicine stability is good, the absorption for also significantly reducing administration irritation, improving cornea to drug, anti-diabetic, the anti-inflammatory isoreactivity that Rebaudioside A has with glycyrrhizic acid simultaneously, so that there is Astragaloside IV eye drops the drug effect of the eye treatment diabetic keratopathy and cornea neuropathy that cooperate with well, Astragaloside IV eye drops of the invention to have good economy.
Description
Technical field
The present invention relates to a kind of Astragaloside IV eye drops, more particularly to a kind of to have highly-water-soluble and high stable type Radix Astragali first
Glycosides eye drops 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, and Astragaloside IV is in water
In phase at 20 DEG C, solubility is only 0.05mg/ml in water；Half-life short, saturating biomembrane poor performance, the saturating biomembrane such as oral are inhaled
Receipts bioavilability is extremely low, and oral administration biaavailability is only 2.2%.These above-mentioned deficiencies, seriously limit Astragaloside IV and are facing
Application in bed, the application especially in clinical ophthalmology.Because in clinical ophthalmology drug therapy, water-soluble eye drops is to use
Most commonly used preparation, 90% or more clinical ophthalmology medication are water-soluble eye drops.And the above-mentioned deficiency of Astragaloside IV, seriously
Aqueous solution type eye drops is developed into limitation.Therefore, it is necessary to further explore not only safety, not only economic but also effective eye
Treat the Astragaloside IV drug of diabetic keratopathy and cornea neuropathy.
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.But since the water solubility of Astragaloside IV is low, saturating
The reasons such as biomembrane poor performance do not have always Astragaloside IV to be applied to the report of eye disease treatment.Publication No.
In the application for a patent for invention number of CN1543976A, Zhang Weidong, river etc. are a kind of or several using propylene glycol, polyethylene glycol, glycerine etc.
Kind cosolvent and hydrotropy diluent are prepared for Astragaloside IV small-volume injection, powder-injection, glucose infusion liquid and sodium chloride infusion.It is above-mentioned to incite somebody to action
The problem of method that Astragaloside IV is prepared into injection alleviates its poorly water-soluble to a certain extent, but since eye belongs to extremely
Sensitive position, and it is directly exposed to drug, the substances such as cosolvent, surfactant are added in eye-drops preparations to make eyes
At certain harm, safety is poor, will also result in ophthalmic uncomfortable sense, keeps patient dependence poor, therefore, Publication No.
The patent of invention of CN1543976A can not be applied to ophthalmology eye drops.The present inventor is compared by experiment, is found at present
Some document reports and technology cannot meet the requirement of Astragaloside IV eye drip solubility and its aqueous stability.The present inventor
Myricetin (Myricetin, CAS 529-44-2) is had made intensive studies, using Rebaudioside A solubilising myricetin structure
Its stable type eye drops is built, but discovery is compared by experiment, the technology of the structure myricetin eye drops of the present inventor is such as
Simple application finds that the aqueous stability of the Astragaloside IV eye drops of structure is poor, the Radix Astragali of dissolving to Astragaloside IV eye drops
First glycosides is easy to leak out from micella, the requirement of the stability of eye drops is not achieved, concrete reason is still in researching and analysing.
Astragaloside IV does not have good technology and methods to solve its clinical ophthalmology application yet at present.
Inventor has been applied using it and has obtained patent of invention " a kind of ciclosporin A micelle eye drop and its preparation of mandate
Method " (ZL201210529616.9) technology is prepared for Astragaloside IV nano-micelle eye drops, in therapeutic effect evaluation study
In, the redox that the administration of Astragaloside IV nano-micelle ocular can partly be corrected in cornea is unbalance, but because being based purely on poly- second
The micella and its aqueous solution of alkene caprolactam-polyvinyl acetate-ethylene glycol copolymer (PVCL-PVA-PEG) structure are being store
During depositing, Astragaloside IV gradually the separate out from micella, aqueous solution can only have 1 in 25 DEG C of effective stabilities at room temperature
A week, and under 35 DEG C of environment, there is white precipitate in 10 minutes in aqueous solution, and it is extremely unstable to show apparent aqueous solution
Qualitative, concrete reason is also still in researching and analysing.Patent of invention " a kind of curcumin micella drop that inventor has been applied using it
Ocular fluid and preparation method thereof " (number of patent application：201510391874.9) technology is prepared for Astragaloside IV nano-micelle eye drops,
Aqueous solution unstability does not solve effectively, and in therapeutic effect evaluation study, it has been found that because being used in system
Dequalinium Chloride, ocular irritation is larger during long-time service, and long-time service easily causes ocular toxicity, drug induccd keratitis etc.
Problem.In addition, two above-mentioned patent of invention technologies use Polyvinylcaprolactame-polyvinyl acetate-polyethylene glycol total
Polymers (PVCL-PVA-PEG) is come the micella that builds, but Polyvinylcaprolactame-polyvinyl acetate-ethylene glycol copolymer
(PVCL-PVA-PEG) be can not biodegradable polymer, clinic be used for a long time in there are the high molecular materials in vivo
Accumulation is so as to cause potential risks such as toxic side effects.
Currently used ophthalmically acceptable Nano medication delivery system such as micella, nanoparticle etc. mainly uses Polyvinylcaprolactame-
Polyvinyl acetate-ethylene glycol copolymer (PVCL-PVA-PEG), polyglycolic acid (PGA), polylactic acid (PLA), hydroxyl second
The copolymer (PLGA) of acid and lactic acid, glycolide-lactide-caprolactone ternary atactic copolymer (PGLC) etc., itself is only
A kind of carrier, without therapeutic effect, and these artificial synthesized polymeric carrier materials, because of the problems such as there are degradabilities,
There are some potential safety problemss for long-time service.As can using natural extract matter, the small-molecule substance especially naturally extracted is made
For a kind of novel carriers, this carrier can play the role of building Nano medication delivery system, improve medicine stability, enhance angle
Film drug absorption improves curative effect.The natural small molecule substance reported at present has ginsenoside (patent of invention Shen as carrier
Please 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 can meet dialogue as carrier
The indissolubles chemicals such as veratryl alcohol, curcumin contain, but the present inventor has found existing document report at present by Experimental comparison
Ginsenoside, the Stevioside in road cannot meet the requirement of Astragaloside IV eye drip solubility and its aqueous stability, and this hair
Person of good sense's experimental result finds that ginseng saponin concentrations can table after 20mg/ml lagophthalmos Local eye drops in 15mg/ml, Stevioside concentration
Reveal strong impulse, is not suitable as the carrier of ocular drug delivery.Ginsenoside, sweet tea in above-mentioned existing document report
Chrysanthemum glucoside etc. does not have good stabilization, Astragaloside IV to be leaked out from micella quickly the Astragaloside IV that it is contained, up to not
To the effect steady in a long-term of eye drops.Therefore, as can selecting a kind of natural small molecule substance, Radix Astragali first can effectively be encapsulated
Glycosides maintains its pharmacological activity, while effectively wrapping to improve the solubility and its stability of Astragaloside IV in aqueous solution
This natural small-molecule substance is nonirritant to eye under envelope concentration, is safely and effectively just 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 ( 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 one day eye drip of Rebaudioside A at concentrations up to 500mg/ml 4 times, do not send out by continuous eye drip 4 weeks
Existing eye local irritation illustrates Rebaudioside A ophthalmic applications good security.And from feverfew Stevia Rebaudia
(also known as steviol glycoside, CAS are stepped on another ingredient Stevioside extracted in the leaf of (plant is referred to as STEVIA REBAUDIANA in China)
Mark 57817-89-7, molecular formula C38H60O18, molecular weight 804.87), the present inventor the study found that concentration 20mg/ml stevia rebaudianum
Glucoside eye drip can find significant eye local irritation, illustrate that Stevioside is not suitable for ocular drug delivery then.Ginsenoside is dense
Degree after 15mg/ml lagophthalmos Local eye drops namely can express out strong impulse (some document report ginsenosides have draws
Play haemocylolysis), it is also not suitable for the carrier as ocular drug delivery.
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
In view of the above-mentioned problems, the object of the present invention is to provide a kind of innovative Astragaloside IV micelle eye drop, improve Radix Astragali
First glycosides is water-soluble, improves the cornea drug absorption rate after eye drop administration, improves the bin stability of eye drops, while improving ophthalmically acceptable
Safety.Meanwhile the carrier for building Astragaloside IV micelle eye drop is the small-molecule substance of two kinds of natural safety, has anti-sugar
The effects that urine sick, anti-inflammatory, immunological regulation so that its Astragaloside IV micelle eye drop built has the eye treatment glycosuria cooperateed with
The drug effect of characteristic of disease keratopathy and cornea neuropathy.It selects glycyrrhizic acid as micelle modified dose simultaneously, makes the Radix Astragali first of encapsulating
Glycosides is not easy to leak out from micella, improves the stability of Astragaloside IV eye drops.
Another object of the present invention is to provide the preparation method of above-mentioned Astragaloside IV micelle eye drop.
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 molecular structure is insoluble in water, bioavilability is low seriously limits Astragaloside IV in eye
Application in section's drug therapy, especially eye drops are mainly aqueous solution.And Astragaloside IV is prepared as stablizing in aqueous solution
, eye topical eye drops the effect of capable of effectively improving topical application, using Nano medication delivery system by Astragaloside IV structure
Nano eye drop is built up, because of advantage specific to of Nano medication delivery system itself, Astragaloside IV eye drops will be made further
Stability is improved, extends the precorneal residence time after being administered, heighten the effect of a treatment.Using biologically active Small-molecule compounds
As the carrier of structure Astragaloside IV nano eye drop, effectively structure Astragaloside IV eye drops is not only acted as, also because carrier has
Pharmacological activity, then the effect of can further enhancing Astragaloside IV eye drops.The present inventor is the study found that Rebaudioside A and sweet
Oxalic acid can spontaneously form the nanostructure with similar micella in aqueous solution, play the effect of solubilized Astragaloside IV, and because auspicious
The antioxidant activity of Bao Di glycosides A itself, glycyrrhizic acid can carry out cooperateing with work with Astragaloside IV well similar to the anti-inflammatory activity of hormone
With the drug effect of enhancing Astragaloside IV micelle eye drop eye treatment diabetic keratopathy and cornea neuropathy.Rui Baodi
The Astragaloside IV solution of the mixed micelle of glycosides A and glycyrrhizic acid solubilising, i.e. Astragaloside IV micellar solution, stability significantly improve, into
The experiment of one step finds that there is significant promotion cornea to absorb, improve Astragaloside IV treatment diabetic keratopathy angle for Astragaloside IV micellar solution
The validity of film lesion acts on.
Technical scheme of the present invention：A kind of Astragaloside IV micellar solution eye drops, including Astragaloside IV are main ingredient, feature
It also resides in including Rebaudioside A and glycyrrhizic acid as excipient substance, the Astragaloside IV main ingredient and Rebaudioside A excipient substance matter
Ratio is measured 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%.The glycyrrhizic acid (Glycyrrhizic acid) is that legume is sweet
Root extract (the CAS registration numbers of grass:1405-86-3, molecular formula:C42H62O16, molecular weight:822.93), glycyrrhizic acid purity >=
97%.
The preparation method of the eye drops of the present invention is as follows：Astragaloside IV and Rebaudioside A, glycyrrhizic acid are dissolved into anhydrous second
In alcohol, is formed a film in container inner homogeneous by 40 DEG C of water-bath rotatory vacuum ethanol evaporations, add distilled water fully to wash film, water
Ultrasonic micellar solution is bathed, it is 0.2~1.0% to measure and adjust Astragaloside IV mass percentage concentration, and anti-according to needing to be added
Be sterile filtered packing after rotten agent, pH adjusting agent, isotonic regulator.Wherein preservative, pH adjusting agent, isotonic regulator can
To be added according to existing routine techniques.
The preparation method of above-mentioned Astragaloside IV micelle eye drop, Astragaloside IV micella particle size range obtained is in 6~15nm
Between.
The preparation method of above-mentioned Astragaloside IV micelle eye drop, the buffer solution used are the common phosphate-buffered of eye drops
Liquid or borate buffer solution, pH value are 6.5~6.8.
Astragaloside IV micelle eye drop prepared by the present invention so that Astragaloside IV has good dissolubility in aqueous solution,
The solubility of Astragaloside IV is up to 10mg/ml, and micella grain size is minimum, and distribution is uniform, and medicine stability is good.The Radix Astragali
First glycosides micelle eye drop not only increases stability of the Astragaloside IV in aqueous solution state, can also significantly reduce administration stimulation
Property, improve cornea to the absorption of drug, reduce administration concentration, extend drug treating time, reduce administration number of times, from
And the biddability of patient can be improved, while the Rebaudioside A anti-diabetic, anti-inflammatory isoreactivity and the glycyrrhizic acid that have have it is anti-
Scorching, immunological regulation isoreactivity makes Astragaloside IV micelle eye drop have the eye treatment diabetic corneal disease cooperateed with well
Become the drug effect with cornea neuropathy.Therefore, Astragaloside IV micelle eye drop of the invention has good economy.
Description of the drawings
Fig. 1 is 0.5% Astragaloside IV micelle eye drop (prepared by embodiment 1, be set as 1 group of solution), using patent of the present invention
1 preparation method of embodiment, but it is not added with glycyrrhizic acid, remaining preparation process is consistent, 0.5% Astragaloside IV micelle eye drop of preparation
(being set as 2 groups of solution) (is set as solution 3 to configure 0.5% Astragaloside IV eye drops containing the phosphate buffer of 15% propylene glycol
Group), with phosphate buffer configure 90mg/ml containing Rebaudioside A and glycyrrhizic acid 30mg/ml solution (being set as 4 groups of solution),
The solution (being set as 5 groups of solution) of the 90mg/ml containing Rebaudioside A, each group mouse cornea epithelial defect are configured with phosphate buffer
Area quantitative analysis chart.
Fig. 2 be administered 7 days after to each group diabetic mice corneal nerve sensitivity analysis figure.
Fig. 3 is in 0.5% Astragaloside IV micelle eye drop (prepared by embodiment 1, be set as 1 group of solution), embodiment 1
300mg Rebaudioside A and 50mg glycyrrhizic acids change 300mg Steviosides into, remaining is constant, the 0.5% Astragaloside IV micella drop of preparation
Ocular fluid (being set as 2 groups of solution) prepares 0.5% Astragaloside IV micelle eye drop using ginsenoside, and preparation method and process are adopted
With 1 preparation method of embodiment, i.e., in embodiment 1 300mg Rebaudioside A and 50mg glycyrrhizic acids change 300mg ginsenosides into,
Remaining is constant, the 0.5% Astragaloside IV micelle eye drop (being set as 3 groups of solution) of preparation, each group cytotoxicity experiment result figure.
Fig. 4 is 0.5% Astragaloside IV micelle eye drop (being set as 1 group of solution) prepared by embodiment 1 and uses the present invention specially
1 preparation method of sharp embodiment, but it is not added with glycyrrhizic acid, remaining preparation process is consistent, 0.5% Astragaloside IV micella eye drip of preparation
Liquid (is set as 2 groups of solution), stability experiment result figure.
Specific implementation mode
Below in conjunction with the accompanying drawings and by specific embodiment come 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 alcohols, obtain the evenly dispersed thin of drug and copolymer
Then distilled water is added in film, fully wash film, and 300w power water bath sonicator 10min obtain micellar solution.Micellar solution is crossed into 0.22 μ
After m miillpore filters, preservative benzalkonium chloride, isotonic regulator sodium chloride is added, pH is adjusted to 6.5, is settled to 10ml, sterile mistake
Filter packing.The average grain diameter that laser particle analyzer measures Astragaloside IV micella is 10.1nm, dispersion index PDI=0.015, is divided
It is good to dissipate homogeneity.The Astragaloside IV micella eye drops is preserved 3 months at ambient temperature, Astragaloside IV is leaked from micella
Amount is less than 10%.
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 alcohols, obtain the evenly dispersed thin of drug and copolymer
Then distilled water is added in film, fully wash film, and 300w power water bath sonicator 10min obtain micellar solution.Micellar solution is crossed into 0.22 μ
After m miillpore filters, preservative benzalkonium chloride, isotonic regulator sodium chloride is added, pH is adjusted to 6.6, is settled to 10ml, sterile mistake
Filter packing.It is 10.7nm, dispersion index PDI=0.021, dispersion that laser particle analyzer, which measures Astragaloside IV micella average grain diameter,
Homogeneity is good.The Astragaloside IV micella eye drops is preserved 2 months at ambient temperature, Astragaloside IV leakage from micella
Less than 10%.
Embodiment 3：
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 evaporate absolute ethyl alcohol, obtain uniform point of drug and copolymer
Film is dissipated, distilled water is then added, fully washes film, 300w power water bath sonicator 10min obtain micellar solution.By micellar solution mistake
After 0.22 μm of miillpore filter, preservative benzalkonium chloride, isotonic regulator sodium chloride is added, pH is adjusted to 6.8, is settled to 10ml,
Be sterile filtered packing.It is 10.5nm, dispersion index PDI=that laser particle analyzer, which measures Astragaloside IV micella average grain diameter,
0.019, dispersion homogeneity is good.The Astragaloside IV micella eye drops is preserved 2.5 months at ambient temperature, Astragaloside IV from
Leakage is less than 10% in micella.
Embodiment 4：
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 alcohols, obtain the evenly dispersed thin of drug and copolymer
Then distilled water is added in film, fully wash film, and 300w power water bath sonicator 10min obtain micellar solution.Micellar solution is crossed into 0.22 μ
After m miillpore filters, preservative benzalkonium chloride, isotonic regulator sodium chloride is added, pH is adjusted to 6.8, is settled to 10ml, sterile mistake
Filter packing.It is 10.5nm, dispersion index PDI=0.019, dispersion that laser particle analyzer, which measures Astragaloside IV micella average grain diameter,
Homogeneity is good.The Astragaloside IV micella eye drops is preserved 2.5 months at ambient temperature, Astragaloside IV is leaked from micella
Amount is less than 10%.
Embodiment 5：
20mg Astragaloside IVs, 600mg Rebaudioside A, 200mg 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 alcohols, obtain the evenly dispersed thin of drug and copolymer
Then distilled water is added in film, fully wash film, and 300w power water bath sonicator 10min obtain micellar solution.Micellar solution is crossed into 0.22 μ
After m miillpore filters, preservative benzalkonium chloride, isotonic regulator sodium chloride is added, pH is adjusted to 6.8, is settled to 10ml, sterile mistake
Filter packing.It is 11.2nm, dispersion index PDI=0.020, dispersion that laser particle analyzer, which measures Astragaloside IV micella average grain diameter,
Homogeneity is good.The Astragaloside IV micella eye drops is preserved 2.5 months at ambient temperature, Astragaloside IV is leaked from micella
Amount is less than 10%.
Embodiment 6：
50mg Astragaloside IVs, 900mg Rebaudioside A, 150mg 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 alcohols, obtain the evenly dispersed thin of drug and copolymer
Then distilled water is added in film, fully wash film, and 300w power water bath sonicator 10min obtain micellar solution.Micellar solution is crossed into 0.22 μ
After m miillpore filters, preservative benzalkonium chloride, isotonic regulator sodium chloride is added, pH is adjusted to 6.6, is settled to 10ml, sterile mistake
Filter packing.It is 10.7nm, dispersion index PDI=0.017, dispersion that laser particle analyzer, which measures Astragaloside IV micella average grain diameter,
Homogeneity is good.The Astragaloside IV micella eye drops is preserved 2.5 months at ambient temperature, Astragaloside IV is leaked from micella
Amount is less than 10%.
Experiment effect example 1：The 0.5% Astragaloside IV micelle eye drop validity experiment of the present invention.
Experimental drug：0.5% Astragaloside IV micelle eye drop (prepared by embodiment 1, be set as 1 group of solution).
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 0.5% Astragaloside IV micelle eye drop (being set as 2 groups of solution) of preparation；Matched with the phosphate buffer containing 15% propylene glycol
Set to 0 .5% Astragaloside IVs eye drops (being set as 3 groups of solution)；With phosphate buffer configuration 90mg/ml containing Rebaudioside A, Radix Glycyrrhizae
The solution (being set as 4 groups of solution) of sour 30mg/ml；The solution that the 90mg/ml containing Rebaudioside A is configured with phosphate buffer (is set as
5 groups of solution)
Experimental animal and experimental method：Because the diabetic mice of STZ inductions is similar to people's diabetes disease as relatively generally acknowledged
Varying model, this part content are studied using this model.Select C57BL/6 mouse, male, 6-8 week old, 18~25 grams of weight
(buying from Beijing Vital River Experimental Animals Technology Co., Ltd.).Animal is randomly divided into two groups, and one group using fresh configuration
Citrate buffer (pH 4.5) is injected intraperitoneally mouse after preparing STZ solution, continuous injection 5 days, in last time
The 8th day (after a week) after (the 5th injection) measures blood glucose to every mouse, and continuous to measure 3 days, STZ injection group blood glucose values are big
Think the success of Type I diabetes model in 300mg/dL (16.7mmol/L).When testing materials at 12 weeks, mouse is carried out same
Weight and blood sugar monitoring meet each parameter index and take the mouse of the condition of organization material for testing.Another group of injection is free of
The citrate buffer solution of STZ is as normal control.The experimental results showed that STZ intraperitoneal injection modeling mouse gradually show it is more
Diabetes classical symptom, the glucostasis such as drink, more food, diuresis, weight loss maintain higher level, and weight is compared with normal mouse
Relatively low (table 1) shows modeling success.
Table 1 is normal and diabetic mice weight and blood sugar test in sample point
Mouse establishes diabetes cornea/nerve injury model at row curettage of corneal epithelium after mould 12 weeks, gives respectively
0.5% Astragaloside IV micelle eye drop (embodiment 1 prepare, be set as 1 group of solution), using 1 side of preparation of patent Example of the present invention
Method, but it is not added with glycyrrhizic acid, remaining preparation process is consistent, the 0.5% Astragaloside IV micelle eye drop (being set as 2 groups of solution) of preparation
To configure 0.5% Astragaloside IV eye drops (being set as 3 groups of solution) containing the phosphate buffer of 15% propylene glycol；Use phosphate-buffered
Liquid configures the solution (being set as 4 groups of solution) of 90mg/ml containing Rebaudioside A, glycyrrhizic acid 30mg/ml；It is configured with phosphate buffer
The solution (being set as 5 groups of solution) of the 90mg/ml containing Rebaudioside A, one day eye drip of above-mentioned each group 6 times are glimmering in different time points cornea
Slit lamp observation is taken pictures after light uniformly dyeing color, and carries out quantitative analysis corneal epithelial defect area, at the 7th day, cornea is selected to touch
Feel that measuring instrument detects each group diabetic mice corneal nerve susceptibility.
As a result, it has been found that (specific corneal epithelium repairs interpretation of result such as Fig. 1)：Compared to PBS control group, to contain 15% the third two
The phosphate buffer of alcohol configures 0.5% Astragaloside IV eye drops (being set as 3 groups of solution) and does not remarkably promote diabetic mice angle
Healing after membrane damage, each time point, there was no significant difference compared with PBS control group (P >=0.05), and 0.5% Radix Astragali first
Glycosides micelle eye drop (prepared by embodiment 1, be set as 1 group of solution) ocular eye drop administration effectively facilitates model mice corneal epithelium and repaiies
Multiple, curative effect is better than using 1 preparation method of patent Example of the present invention, but is not added with glycyrrhizic acid, remaining preparation process is consistent, prepares
0.5% Astragaloside IV micelle eye drop (being set as 2 groups of solution), and Rebaudioside A and Radix Glycyrrhizae acid solution without Astragaloside IV
Group then has certain promotion corneal epithelium repair (being set as 4 groups of solution), and the Rebaudioside A without Astragaloside IV is also seen
Certain promotion corneal epithelium repair (being set as 5 groups of solution) is observed, each time point has conspicuousness compared with PBS control group
Difference (P<0.05).
Corneal sensitivity testing result shows (such as Fig. 2), compared to PBS control group, with the phosphate containing 15% propylene glycol
It is extensive that buffer solution 0.5% Astragaloside IV eye drops of configuration (being set as 3 groups of solution) does not remarkably promote diabetic mice corneal sensitivity
Multiple effect, each time point, there was no significant difference compared with PBS control group (P >=0.05), and 0.5% Astragaloside IV micelle eye drop
(prepared by embodiment 1, be set as 1 group of solution) ocular eye drop administration effectively facilitates the recovery of model mice susceptibility, and curative effect is better than use
1 preparation method of patent Example of the present invention, but it is not added with glycyrrhizic acid, remaining preparation process is consistent, 0.5% Astragaloside IV of preparation
Micelle eye drop (is set as 2 groups of solution), and Rebaudioside A and Radix Glycyrrhizae acid solution group without Astragaloside IV then have certain rush
Into susceptibility restitution (being set as 4 groups of solution), and the Rebaudioside A without Astragaloside IV also observes certain promotion cornea
Susceptibility restitution (is set as 5 groups of solution), and each time point has significant difference (P compared with PBS control group<0.05).
Experiment effect example 2：The cytotoxicity experiment of 0.5% Astragaloside IV micelle eye drop.
Experimental drug：0.5% Astragaloside IV micelle eye drop (prepared by embodiment 1, be set as 1 group of solution).
Control drug：0.5% Astragaloside IV micelle eye drop, preparation method and process are prepared using real using Stevioside
Apply 1 preparation method of example, i.e., in embodiment 1 300mg Rebaudioside A and 50mg glycyrrhizic acids change 300mg Steviosides into, remaining is not
Become, the 0.5% Astragaloside IV micelle eye drop (being set as 2 groups of solution) of preparation；0.5% Astragaloside IV is prepared using ginsenoside
Micelle eye drop, preparation method and process use 1 preparation method of embodiment, i.e., in embodiment 1 300mg Rebaudioside A and
50mg glycyrrhizic acids change 300mg ginsenosides into, remaining is constant, and 0.5% Astragaloside IV micelle eye drop of preparation (is set as solution 3
Group)
Experimental method：Using Human glioma, system is tested.2 × 10 are inoculated in 24 well culture plates per hole4It is a thin
Born of the same parents use the DMEM/F12 (1 containing 10% fetal calf serum:1) it after culture solution culture 48 hours, is changed to serum-free medium and is used for
It tests in downstream.HCECs is made into individual cells suspension with the culture solution containing 10% fetal calf serum, with 1000~3000 cells/
The density in hole is inoculated into 96 orifice plates, and blank eye drops is added in culture after 24 hours, 0.5% Astragaloside IV micelle eye drop (is implemented
Prepared by example 1, be set as 1 group of solution), 0.5% Astragaloside IV micelle eye drop prepared using Stevioside, preparation method and process are adopted
With 1 preparation method of embodiment, i.e., in embodiment 1 300mg Rebaudioside A and 50mg glycyrrhizic acids change 300mg Steviosides into,
Remaining constant, the 0.5% Astragaloside IV micelle eye drop (being set as 2 groups of solution) of preparation prepares 0.5% Radix Astragali using ginsenoside
First glycosides micelle eye drop, preparation method and process use 1 preparation method of embodiment, i.e., the 300mg rebaudiosides in embodiment 1
A and 50mg glycyrrhizic acids change 300mg ginsenosides into, remaining is constant, and 0.5% Astragaloside IV micelle eye drop of preparation (is set as molten
3 groups of liquid) it is handled.After being incubated 4 hours and 24 hours respectively after the above-mentioned solution of cell addition, original fluid is discarded, is changed to and contains
The serum free medium of 0.5mg/ml MTT continues to be incubated 4 hours, discards supernatant, 150ul DMSO are added per hole, vibrates 10 minutes
Fully to dissolve the bluish violet crystal in cell, enzyme-linked immunosorbent assay instrument measures the absorbance value at 490nm.
Obviously, from Fig. 3 it can be found that the present invention 0.5% Astragaloside IV micelle eye drop (embodiment 1 prepare, be set as
1 group of solution) cell incubation after 4 hours without finding cytotoxicity, and control experiment group to prepare 0.5% using Stevioside yellow
Stilbene first glycosides micelle eye drop, preparation method and process use 1 preparation method of embodiment, i.e., the 300mg Rui Baodi in embodiment 1
Glycosides A and 50mg glycyrrhizic acid changes 300mg Steviosides into, remaining is constant, and 0.5% Astragaloside IV micelle eye drop of preparation (is set as molten
2 groups of liquid), using ginsenoside come prepare 0.5% Astragaloside IV micelle eye drop, preparation method and process using embodiment 1 make
Preparation Method, i.e., in embodiment 1 300mg Rebaudioside A and 50mg glycyrrhizic acids change 300mg ginsenosides into, remaining is constant, system
Standby 0.5% Astragaloside IV micelle eye drop (being set as 3 groups of solution) then shows significant cytotoxicity.
This is because：Stevioside and ginsenoside, which all have apparent Action of Surfactant, (there is significant haemolysis to make
With), cause corneal epithelial cell to dissolve, to show significant cytotoxicity.
Experiment effect example 3：The bin stability of 0.5% Astragaloside IV micelle eye drop.
Experimental drug：0.5% Astragaloside IV micelle eye drop (prepared by embodiment 1, be set as 1 group of solution).
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 0.5% Astragaloside IV micelle eye drop (being set as 2 groups of solution) of preparation.
Experimental method：Prepare 0.5% Astragaloside IV micelle eye drop (prepared by embodiment 1, be set as 1 group of solution) and using this
1 preparation method of patent of invention embodiment, but it is not added with glycyrrhizic acid, remaining preparation process is consistent, 0.5% Astragaloside IV glue of preparation
Beam eye drops (is set as 2 groups of solution), is packaged in respectively in 2ml ampullas and is protected from light 25 DEG C of preservations, eye drops is periodically taken, using 0.22 μm
It is steady to calculate its storage for filtering with microporous membrane, the Astragaloside IV drug concentration before and after high effective liquid chromatography for measuring filtering in solution
It is qualitative.
Experimental result such as Fig. 4, (prepared by embodiment 1, be set as solution 1 for 0.5% Astragaloside IV micelle eye drop of the invention
Group) bin stability is good, the Astragaloside content after storage 20 weeks 90% or more, using high performance liquid chromatography detection with point
From the altered chemical structures such as oxidation do not occur for tentative confirmation Astragaloside IV.And the use patent Example 1 of the present invention of control experiment
Preparation method, but it is not added with glycyrrhizic acid, remaining preparation process is consistent, and 0.5% Astragaloside IV micelle eye drop of preparation (is set as molten
2 groups of liquid) bin stability is poor, and the Astragaloside content after storage 4 weeks is below 90%.Illustrate to be added in preparation process certain
The stability that the glycyrrhizic acid of amount is conducive to Astragaloside IV micelle eye drop improves.
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 (6)
1. one kind having highly-water-soluble and high stable type Astragaloside IV eye drops, including Astragaloside IV is main ingredient, it is characterised in that
Further include Rebaudioside A and glycyrrhizic acid is excipient substance, the Astragaloside IV main ingredient and Rebaudioside A excipient substance mass ratio exist
1:15-1:Between 30, the glycyrrhizic acid and Rebaudioside A mass ratio are 1:3-1:Between 6.
2. Astragaloside IV eye drops as described in claim 1, it is characterised in that the Astragaloside IV main ingredient a concentration of 0.2%~
1.0%.
3. Astragaloside IV eye drops 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%.
4. a kind of preparation method of Astragaloside IV eye drops 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 40 DEG C of water-bath rotatory vacuums
It evaporates organic solvent to form a film in container inner homogeneous, adds distilled water fully to wash film, water bath sonicator obtains micellar solution, Radix Astragali
First glycosides final mass percentage concentration is 0.2%~1.0%, is eventually adding preservative, pH adjusting agent, sterile after isotonic regulator
Filtering packing.
5. the preparation method of Astragaloside IV eye drops as claimed in claim 4, it is characterised in that the grain of Astragaloside IV obtained
Diameter range is between 6-15nm.
6. the preparation method of Astragaloside IV eye drops as claimed in claim 4, it is characterised in that the buffer solution is common phosphorus
Phthalate buffer or borate buffer solution, pH value are 6.5~6.8.
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| EP4104817A1 (en) * | 2021-06-17 | 2022-12-21 | Skeye Pharma GbR | Ophthalmic composition comprising astragaloside iv |
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| WO2009126950A2 (en) * | 2008-04-11 | 2009-10-15 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Diterpene glycosides as natural solubilizers |
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| CN1543976A (en) * | 2003-11-27 | 2004-11-10 | 上海博泰医药科技有限公司 | Astragaloside injection preparation and its preparing process |
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| EP4104817A1 (en) * | 2021-06-17 | 2022-12-21 | Skeye Pharma GbR | Ophthalmic composition comprising astragaloside iv |
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