CN110251465A - Nano liposomes composition, preparation method and eye drops - Google Patents
Nano liposomes composition, preparation method and eye drops Download PDFInfo
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Abstract
The present invention relates to nano liposomes composition, preparation method and eye drops.The nano liposomes composition includes nano liposomes and the active component that is supported on the nano liposomes；The active component is selected from linarin or linarin extract；The drugloading rate of the nano liposomes is 0.05mg/mL~0.1mg/mL.The nano liposomes composition drugloading rate is suitable for improving the solubility and stability of linarin, capable of reaching higher anti-inflammatory concentration, substantially improve the bioavilability of linarin, can be used for eye drops.The preparation method of the nano liposomes composition is easy to operate efficiently, the period is short, and solvent utilization is few and can recycle, while can effectively avoid preparation process to active compound component structural damage.
Description
Technical field
The present invention relates to nano liposomes fields, in particular to nano liposomes composition, preparation method and drop
Eye agent.
Background technique
Liposome has certain targeting as a kind of biological degradability and biocompatibility functional components pharmaceutical carrier
Property and slow release, it is widely paid close attention in recent years because of following several advantages: (1) increase hydrophobic drug dissolubility；(2)
Increase the stability of drug in vivo；(3) release time of extended treatment agent；(4) intake of the normal tissue to drug is reduced,
Reduce the side effect of therapeutic agent to a certain extent；(5) by carrying out functional modification to liposome, to increase disease sites
To drug susceptibility, fixed point release drug and increase cell to the phagocytosis amount of drug.Liposome is generally formed by water
Vesica, diameter is generally between 25-500nm, and wall thickness is in 5nm or so.And parent/hydrophobicity of drug is utilized, or will be close
Aqueous pharmaceutical contains the water phase into liposome interior, or in the bilayer that hydrophobic drug insertion lipid molecular is constituted.And
And by adjusting lipid molecular parent/hydrophobic part ratio, thus it is possible to vary the form of vesica, to increase the lotus to different pharmaceutical
Carrying capacity.
Linarin is the highest flavones ingredient of activity in wild chrysanthemum, and it is anti-that modern pharmacology research shows that linarin has
Scorching analgesic effect, can inhibit the expression of Inflammatory mediators such as tumor necrosis factor, interleukins, and crystalline to rat
The aldose reductase of body has inhibitory activity.Furthermore also there is linarin anti-aging effects, oxygen lack resistant function, anti-pessimal stimulation to make
With, to body dual regulation, antifatigue effect, inhibit blood glucose rise effect.
Presently commercially available wild chrysanthemum eye drops is mostly compound preparation, containing Multiple components, plays curative effect jointly.And cover flower
Characteristic constituents of the glycosides as wild chrysanthemum, extraction purification mainly use reflux extraction, ethanol extract from water precipitation, efficiently preparation
Liquid chromatography, Flavonoids by Macroporous Adsorption Resin etc..But aforesaid operations complex process and be easier to destroy compound structure, cause existing
Each active constituent includes that the drug concentration of linarin is possible lower, and operating procedure is complicated, the period in some wild chrysanthemum eye drops
It is long, it is time-consuming to take solvent, cause the drug availability of wild chrysanthemum lower, cause a large amount of wastage of material, bulk pharmaceutical chemicals occurs and largely throw
Enter, but the phenomenon that yield is little.
In addition, linarin has the characteristic of low solubility, low permeability, equilbrium solubility in water is 0.059 μ g/
ML is practically insoluble in water, and the solubility in alkaline solution increased, fat-soluble difference, it is difficult to be absorbed by organisms, lead to biology
Availability is poor.It is very few about the preparation research of linarin at present, greatly limit its application clinically.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention is to provide a kind of nano liposomes composition, and the nano liposomes composition has
Using linarin or its extract as active constituent, and it is carried on nano liposomes；The nano liposomes composition carries
Dose is suitable for improving the solubility and stability of linarin, capable of reaching higher anti-inflammatory concentration, substantially improve linarin
Bioavilability.
The second object of the present invention is to provide the preparation method of above-mentioned nano liposomes composition, and this method is easy to operate
Efficiently, the period is short, and solvent utilization is few and can recycle, while effectively preparation process can be avoided to active ingredient compound
Object structural damage.
The third object of the present invention is to provide the eye drops including above-mentioned nano liposomes composition.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
Nano liposomes composition comprising nano liposomes and the active group being supported on the nano liposomes
Point；
The active component is selected from linarin or linarin extract；
The drugloading rate of the nano liposomes is 0.05mg/mL~0.1mg/mL.
As active constituent, linarin is a kind of effective monomer of anti-angiogenic inflammation damnification with applications well prospect.
The NF- kB protein overexpression that linarin (5,10,20 μm of ol/L) can effectively inhibit LPS to induce；Meanwhile linarin (10,20 μ
Mol/L it) can be substantially reduced the phosphorylation of MAPK family protein, inhibit the activation of NF- κ B, to reduce inflammatory factor and stick
The generation of the factor weakens vascular endothelial inflammation injury degree.
Optionally, the drugloading rate lower limit of the nano liposomes can independently selected from 0.05mg/mL, 0.06mg/mL,
0.07mg/mL、0.08mg/mL、0.09mg/mL、0.1mg/mL。
Optionally, the drugloading rate upper limit of the nano liposomes can independently selected from 0.055mg/mL, 0.06mg/mL,
0.065mg/mL、0.07mg/mL、0.075mg/mL、0.08mg/mL、0.085mg/mL、0.09mg/mL、0.095mg/mL、
0.1mg/mL。
Optionally, the partial size of the nano liposomes is 100nm~300nm.
Optionally, the particle diameter limit of the nano liposomes can independently selected from 100nm, 120nm, 150nm, 180nm,
200nm、250nm、280nm、300nm。
Optionally, the partial size upper limit of the nano liposomes can independently selected from 110nm, 130nm, 150nm, 180nm,
200nm、220nm、250nm、280nm、300nm。
Optionally, the partial size of the nano liposomes is 120nm~250nm.
Optionally, the partial size of the nano liposomes is 150nm~200nm.
Optionally, the encapsulation rate of the nano liposomes composition is 50%~100%.
Optionally, by weight, the nano liposomes include 15~30 parts of cholesterol and 70~85 parts of lecithin
Rouge.
Another object according to the present invention provides the preparation method of any of the above-described nano liposomes composition comprising
Step:
A) according to the ratio, the solution of active component, cholesterol and lecithin is obtained；
B) solvent in the solution obtained in step a) is obtained into lipid membrane by evaporation removing；
C) at 40 DEG C~60 DEG C, water, stirring and/or ultrasound are added into the lipid membrane obtained in step b),
Suspension is obtained, filtering obtains nano liposomes composition.
Optionally, the solvent of solution described in step a) is selected from least one of ethyl alcohol, methanol, ethyl acetate.
Optionally, the temperature of removing solvent is 40 DEG C~60 DEG C in step b).
Optionally, the solvent of solution described in step a) is ethyl alcohol.
Optionally, the temperature of removing solvent is 45 DEG C in step b).
Optionally, the method for removing solvent is rotary evaporation in step b).
Optionally, the mixed volume ratio of water described in step c) and the lipid membrane is 2~10:1.
Optionally, the revolving speed of stirring described in step c) is 200~600rpm.
Optionally, stirring described in step c) is magnetic agitation.
Optionally, the power of the ultrasound is 100~300W, and frequency is 10~40Hz, and ultrasonic time is 10~30min.
Optionally, described to be filtered into micro porous filtration, the aperture of the micro porous filtration is 0.2~0.45 μm.
Optionally, the aperture of the micro porous filtration is 0.22 μm or 0.45 μm.
Optionally, the nano liposomes composition being prepared saves at low temperature.
Optionally, the temperature range that the low temperature is 0~5 DEG C.
Optionally, the low temperature is 4 DEG C.
The present invention prepares nano liposomes composition using film dispersion-magnetic agitation method, being capable of biggish increase illiteracy flower
Solubility in the water of glycosides improves bioavilability.
As an implementation, nano liposomes composition preparation method comprising steps of
A) weigh 0.01~1.00mg of linarin extract, 8.00~15.00mg of cholesterol, lecithin 25.00~
35.00mg is added the dissolution of 10mL dehydrated alcohol, obtains solution in 50mL eggplant-shape bottle；
B) under 45 DEG C of water-baths, above-mentioned solution is placed on Rotary Evaporators and is rotated, after dehydrated alcohol recycles completely, eggplant shape
One layer of uniform film of milky is formed on bottle inner wall；
C) ultrapure water 10mL, heating stirring or heating water bath under 40 DEG C~60 DEG C water-baths are added into above-mentioned uniform film
Ultrasound obtains milky homogenous suspension after evenly mixing, crosses 0.45m miillpore filter, obtains nano liposomes composition；
D) it saves at 4 DEG C, is spare.
Another object according to the present invention provides the eye drops including any of the above-described nano liposomes composition.
Compared with prior art, the invention has the benefit that
(1) nano liposomes composition provided by the invention improves the solubility and stability of linarin, can reach
Higher anti-inflammatory concentration, substantially improves the bioavilability of linarin.
(2) nano liposomes composition provided by the invention, drug carrying ability is good, and encapsulation rate is high, may be used as eye medicinal,
Such as eye drops.
(3) preparation method of nano liposomes composition provided by the invention, it is easy to operate efficiently, the period it is short, solvent benefit
Dosage is few and can recycle, while can effectively avoid preparation process to active compound component structural damage.
Detailed description of the invention
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art
Embodiment or attached drawing needed to be used in the description of the prior art be briefly described, it should be apparent that, it is described below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, is also possible to obtain other drawings based on these drawings.
Fig. 1 is the diameter characterization result of nano liposomes composition in one embodiment of the present invention；
Fig. 2 is the potential diagram of nano liposomes composition in one embodiment of the present invention；
Fig. 3 is the transmission electron microscope photo of nano liposomes composition in one embodiment of the present invention；
Fig. 4 is linarin and pure linarin in the nano liposomes composition being prepared in one embodiment of the present invention
Release in vitro performance comparison result.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
The preparation of 1 nano liposomes composition of embodiment
1#Nano liposomes composition
A) linarin extract 1.00mg, cholesterol 8.00mg, lecithin 35.00mg are weighed in 50mL eggplant-shape bottle, is added
Enter the dissolution of 10mL dehydrated alcohol, obtains solution；
B) under 45 DEG C of water-baths, above-mentioned solution is placed on Rotary Evaporators and is rotated, after dehydrated alcohol recycles completely, eggplant shape
One layer of equally distributed milky lipid membrane is formed on bottle inner wall；
C) ultrapure water 10mL, the heating stirring under 40 DEG C of water-baths, stirring rate are added into above-mentioned uniform lipid membrane
Milky homogenous suspension is obtained after evenly mixing for 500rpm, 0.45 μm of miillpore filter is crossed, obtains nano liposomes composition；
D) it saves at 4 DEG C, is spare.
2#Nano liposomes composition
2#The preparation process of nano liposomes composition and 1#Nano liposomes composition is roughly the same, the difference is that:
The additive amount of each substance is respectively as follows: linarin extract 0.01mg, cholesterol 15.00mg, lecithin in step a)
25.00mg is added the dissolution of 10mL dehydrated alcohol, obtains solution in 50mL eggplant-shape bottle；
In step c), " heating stirring under 40 DEG C of water-baths " is replaced with " ultrasound is heated under 60 DEG C of water-baths ", and ultrasound
Power is 300W, frequency 40Hz, ultrasonic time 10min.
3#Nano liposomes composition
3#The preparation process of nano liposomes composition and 1#Nano liposomes composition is roughly the same, the difference is that:
The additive amount of each substance is respectively as follows: linarin extract 0.8mg, cholesterol 10.00mg, lecithin in step a)
30.00mg is added the dissolution of 10mL dehydrated alcohol, obtains solution in 50mL eggplant-shape bottle.
The characterization of 1 nano liposomes composition of experimental example
Drugloading rate and encapsulation rate
Be prepared in embodiment 11#~3#Nano liposomes composition is typical case, using 1100LC high-efficient liquid phase technique
(HPLC) its drugloading rate and encapsulation rate, measuring method are measured specifically:
The drafting of linarin standard curve: taking 1mg bulk pharmaceutical chemicals in beaker, and proper amount of methanol dissolution is added, solution is moved to
In 10mL volumetric flask, methanol constant volume to graduation mark is prepared into the linarin methanol mother liquor of 0.1mg/mL.A certain amount of mother is drawn respectively
Liquid is in 10mL volumetric flask, and with methanol constant volume, being configured to concentration is respectively 0.01mg/mL, 0.02mg/mL, 0.04mg/mL,
The standard solution of 0.06mg/mL, 0.08mg/mL, are measured with HPLC, and measurement wavelength is 326nm, using concentration as abscissa, peak face
Product is that ordinate prepares standard curve.
The measuring method of drugloading rate and encapsulation rate: it is appropriate to accurately weigh linarin liposome packet solution, and a small amount of methanol is added
Dissolve ultrasound 30min, after be transferred in 10mL volumetric flask, be added be diluted to scale.Using methanol as blank, in 326nm wave
Strong point measures the peak area of inclusion compound, obtains the content of linarin in inclusion compound according to regression equation, is calculated according to formula and carries medicine
Amount:
The quality of linarin/linarin input amount in encapsulation rate=plastid
Quality/inclusion compound quality of linarin in drugloading rate=inclusion compound
After measured and calculate, 1#The drugloading rate of nano liposomes composition is 0.054mg/mL, encapsulation rate 54.491%；
2#The drugloading rate of nano liposomes composition is 0.05mg/mL, encapsulation rate 51.626%；3#The load of nano liposomes composition
Dose is 0.051mg/mL, encapsulation rate 51.232%.
Particle size determination
Be prepared in embodiment 13#Nano liposomes composition is typical case, takes 3 part 3#Nano liposomes combination
Object is diluted to suitable multiple with ultrapure water, measures its particle diameter distribution feelings using Nano-ZS90 type laser nano Particle Size Analyzer
Condition, particle size results and potential diagram difference are as depicted in figs. 1 and 2.As shown in Figure 1,3#The particle size range of nano liposomes composition
In 100nm~300nm, average grain diameter 151nm, particle diameter distribution (PDI) is 0.401.
Morphology characterization
Be prepared in embodiment 13#Nano liposomes composition is typical case, and visually observing linarin liposome is in
Milky has white opalescence；Using its pattern of HT7700 150kV type transmission electron microscope observing is used, shone by the transmission electron microscope of Fig. 3
Piece is it can be found that the shape of nano liposomes composition is regular, rounded particle, distribution uniform, dispersion, solely each other between particle
It is vertical.
The stability of 2 nano liposomes composition of experimental example
3 will be prepared in embodiment 1#Nano liposomes composition is placed in 25 ± 2 DEG C of environment, is being placed respectively
The the 0th, 1,3,5,7,9 day in the case where observe its appearance, measure partial size, current potential, investigate the stability of preparation, as a result such as table 1
Shown in, from the data in the table, after placing 9 days, macroscopic change does not occur in appearance for nano liposomes composition
Change, still maintains as milky uniform solution, microcosmic partial size and drugloading rate also maintain good stability.
1 nano liposomes composition stability of table
The release in vitro performance of 3 linarin of experimental example
Precision weighs linarin 5mg, nano liposomes composition 10mg, is respectively placed in the dialysis containing 10mL artificial tears
In bag, bag filter both ends are tightened, bag filter is placed in 100mL artificial tears, the constant temperature oscillation in 37 DEG C of water-baths, in regulation
Between precision pipette the outer phase medium of 5mL, and supplement 5mL fresh medium simultaneously, the measurement sample absorbance 326nm at, with linarin
Cumulative release amount to the time wrirte music line chart, investigate the release in vitro performance of linarin, as a result as shown in Figure 4.As shown in Figure 4,
Preparation of the linarin being carried in nano liposomes composition in 8 hours is maintained at more stable level, and pure
The preparation of linarin then constantly increases, and illustrates that nano liposomes composition provided by the invention can significantly delay to live
The release of property component linarin, extends the action time of linarin.
The cytotoxicity experiment of 4 linarin of experimental example
Cytotoxicity experiment (CCK-8 method), experimental method are done to the active constituent linarin of nano liposomes composition
Specifically include step:
A) it by macrophage culture to suitable state, is counted with cell counting board, determines cell suspension extension rate；
B) prepare cell suspension, be laid in 96- orifice plate cultivate it is adherent to cell for 24 hours；
C) the linarin solution of 5-50 μM/L is prepared, every hole is added 100 μ L, is put into incubator culture for 24 hours；
D) the CCK-8 liquid of 10 μ L is added in every hole, continues to cultivate 4h in incubator, the suction at microplate reader detection 450nm
Luminosity.Absorbance result is as shown in table 2:
The absorbance of the different linarin concentration of table 2
| Linarin concentration (μM/L) | 5 | 10 | 20 | 30 | 40 | 50 | Blank | Zeroing |
| Absorbance values | 3.115 | 3.288 | 3.440 | 3.246 | 2.390 | 2.054 | 3.284 | 0.160 |
As shown in Table 2, when the concentration of linarin is greater than 30 μM/L, certain toxic side effect, institute are generated to cell
20 μM/L should be no more than with its preparation and Drug level.
The anti-inflammatory activity of 5 nano liposomes composition of experimental example
Be prepared in embodiment 13#Nano liposomes composition is typical case, research nano liposomes composition
Anti-inflammatory activity, experimental method specifically include step:
A) RAW264.7 mouse macrophage is stimulated using 1 μ g/mL lipopolysaccharides (LPS), it is scorching filters out suitable building
The LPS concentration of disease cell model；
B) RAW264.7 cell is pressed into cell number 1.5 × 104/ hole is inoculated in 96- orifice plate, after culture for 24 hours, discards culture
Liquid；
C) with containing LPS various concentration linarin medical fluid and nano liposomes composition Co stituation for 24 hours after, collect cell
Supernatant carries out ELISA experiment, measurement tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1 (IL-1) water
It is flat.
IL-1, IL-6 one of serious cell factor compared with TNF-α is internal inflammatory damage, by the experiment knot in table 3
Fruit is analyzed it is found that lipopolysaccharides (LPS) can preferably stimulate cell and make the secretion level of cytokine TNF-α, IL-1 and IL-6
Increase.Nano liposomes composition can significantly inhibit at 5~20 μM TNF-α, IL-1, IL-6 compared with LPS control group
Secretion.
Linarin absorbance in the experiment of 3 anti-inflammatory activity of table
| Factor | LPS group | Blank group | 5μM | 10μM | 20μM |
| Absorbance | 3.528 | 0.471 | 2.526 | 1.845 | 1.015 |
6 nano liposomes composition of experimental example is used as eye drops
Lagophthalmos irritant experiment
Be prepared in embodiment 13#Nano liposomes composition is used as eye drops, carries out the Ocular irritation of lagophthalmos
Property experiment, it is specific as follows:
Rabbit 5, weight 2-3kg are taken, eyes are healthy, and the color and vascular distribution of cornea are normal.By linarin nanometer rouge
The side eye conjunctiva that the drop of suspension 2 of liposomal composition instills rabbit is intracapsular, and the other side makes eye quilt as blank control after administration
Dynamic closure 1min~2min, 1h, 2h, 4h, 6h, 8h, eye local reaction situation for 24 hours after record administration are checked with fluorescein sodium
Whether rabbit cornea damage with slit lamp examination cornea, iris, sclera, conjunctiva and has secretion production.
It is tested using Draize Ocular irritation and carries out irritation scoring.Irritation judgment criteria: nonirritant, average integral
0-3；Slight stimulation 4-7 points；Moderate irritation 8-12 points；13-16 points are severe irritation.Experimental result is listed in Table 4 below.
In 4 lagophthalmos irritant experiment of table, the Ocular irritation score value of nano liposomes composition is instilled
| Time (h) | Ocular irritation score value summation |
| 1 | 1 |
| 2 | 2 |
| 4 | 1 |
| 6 | 3 |
| 8 | 1 |
| 24 | 3 |
By result in table 4 it is found that linarin nano liposomes composition provided by the invention is used as eye drops, nothing after use
It is apparent congested, shed tears, the irritative symptoms such as photophobia occur, also the general reaction without local absorption occurs, and stimulates degree category nothing
Irritation.
Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；To the greatest extent
Present invention has been described in detail with reference to the aforementioned embodiments for pipe, but those skilled in the art should understand that: its
It is still possible to modify the technical solutions described in the foregoing embodiments, or to some or all of the technical features
It is equivalently replaced；And these are modified or replaceed, various embodiments of the present invention skill that it does not separate the essence of the corresponding technical solution
The range of art scheme.
Claims (10)
1. nano liposomes composition, which is characterized in that including nano liposomes and be supported on the nano liposomes
Active component；
The active component is selected from linarin or linarin extract；
The drugloading rate of the nano liposomes is 0.05mg/mL~0.1mg/mL.
2. nano liposomes composition according to claim 1, which is characterized in that the partial size of the nano liposomes is
100nm~300nm.
3. nano liposomes composition according to claim 1, which is characterized in that the packet of the nano liposomes composition
Envelope rate is 50%~100%.
4. nano liposomes composition according to claim 1, which is characterized in that by weight, the nano-lipid
Body includes 15~30 parts of cholesterol and 70~85 parts of lecithin.
5. the method for preparing the described in any item nano liposomes compositions of Claims 1-4, which is characterized in that comprising steps of
A) according to the ratio, the solution of active component, cholesterol and lecithin is obtained；
B) solvent in the solution obtained in step a) is obtained into lipid membrane by evaporation removing；
C) at 40 DEG C~60 DEG C, water, stirring and/or ultrasound is added into the lipid membrane obtained in step b), obtains
Suspension, filtering obtain nano liposomes composition.
6. according to the method described in claim 5, it is characterized in that, the solvent of solution described in step a) be selected from ethyl alcohol, methanol,
At least one of ethyl acetate；
The temperature of removing solvent is 40 DEG C~60 DEG C in step b).
7. method according to claim 5 or 6, which is characterized in that the solvent of solution described in step a) is ethyl alcohol；
The temperature of removing solvent is 45 DEG C in step b)；
The method of removing solvent is rotary evaporation in step b).
8. according to the method described in claim 5, it is characterized in that, the mixture of water described in step c) and the lipid membrane
Product is than being 2~10:1.
9. according to the method described in claim 5, it is characterized in that, the revolving speed of stirring described in step c) is 200~600rpm；
Preferably, the stirring is magnetic agitation；
The power of the ultrasound is 100~300W, and frequency is 10~40Hz, and ultrasonic time is 10~30min；
Described to be filtered into micro porous filtration, the aperture of the micro porous filtration is 0.2~0.45 μm；
Preferably, the aperture of the micro porous filtration is 0.22 μm or 0.45 μm.
10. eye drops, which is characterized in that including the described in any item nano liposomes compositions of Claims 1-4.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114886849A (en) * | 2022-05-23 | 2022-08-12 | 郑州大学 | Mongolian glycoside liposome nano micelle, preparation method thereof and eye drops |
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