CN109602949A - A kind of vitreum alternative materials and preparation method thereof suitable for proliferative vitreoretinopathy - Google Patents
A kind of vitreum alternative materials and preparation method thereof suitable for proliferative vitreoretinopathy Download PDFInfo
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- CN109602949A CN109602949A CN201811619474.9A CN201811619474A CN109602949A CN 109602949 A CN109602949 A CN 109602949A CN 201811619474 A CN201811619474 A CN 201811619474A CN 109602949 A CN109602949 A CN 109602949A
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- Prior art keywords
- vitreum
- microballoon
- fluorouracil
- alternative materials
- proliferative vitreoretinopathy
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- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 title claims abstract description 21
- 206010038934 Retinopathy proliferative Diseases 0.000 title claims abstract description 21
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 title claims abstract description 21
- 230000006785 proliferative vitreoretinopathy Effects 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims description 9
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims abstract description 80
- 239000000017 hydrogel Substances 0.000 claims abstract description 41
- 229960002949 fluorouracil Drugs 0.000 claims abstract description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000006210 lotion Substances 0.000 claims abstract description 24
- 239000007864 aqueous solution Substances 0.000 claims abstract description 22
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- AVPCPPOOQICIRJ-UHFFFAOYSA-L sodium glycerol 2-phosphate Chemical compound [Na+].[Na+].OCC(CO)OP([O-])([O-])=O AVPCPPOOQICIRJ-UHFFFAOYSA-L 0.000 claims description 7
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
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- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
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- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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Abstract
The invention discloses a kind of vitreum alternative materials suitable for proliferative vitreoretinopathy, are prepared by following steps: (1) heated PVA aqueous solution, and addition crosslinking agent crosslinks reaction, and pH value is adjusted to neutrality, and PVA hydrogel is made；(2) it takes 5 FU 5 fluorouracil and PLGA to be dissolved in organic solvent, is then slowly added dropwise into the atoleine containing emulsifier, heated at constant temperature stirring and emulsifying obtains lotion；(3) petroleum ether to lotion is added to be completely formed precipitating into lotion described in step (2), centrifugation obtains microballoon；(4) petroleum ether centrifuge washing microballoon is used, obtains 5 FU 5 fluorouracil microballoon after dry；(5) the PVA hydrogel and 5 FU 5 fluorouracil microballoon are mixed and stirred in a heated condition, obtain vitreum alternative materials.The material has the performance being close with natural vitreum, provides ideal therapeutic modality for proliferative vitreoretinopathy patient.
Description
Technical field
The invention belongs to biological fields, and in particular to a kind of vitreum suitable for proliferative vitreoretinopathy replaces
For material and preparation method thereof.
Background technique
Proliferative vitreoretinopathy (proliferative vitreoretinopathy, PVR) is common cause
Blind property eye disease, often betides the patients such as eye traumas, rhegmatogenous detachment of retina and severe diabetes mellitus retinopathy.
Vitrectomy is the main means for treating PVR at present, must select to close after cutting off nature vitreum in art
Suitable artificial vitreous's substitute filling glass body cavity maintains the support of retina, makes on retinal pigment to repair eye injury
Skin and neural epithelium attach, and rebuild visual function, and prevent atrophia bulbi.
Artificial vitreous is that field of ophthalmology is most interesting and most challenging research field, is controlled carrying out vitrectomy
It selects suitable artificial vitreous's substitute filling glass body cavity that can maintain eyeball volume and intraocular pressure after treatment, restores nerve view
The anatomical position of nethike embrane layer and layer of retina,pigment epithelium rebuilds visual function, prevents the atrophy of eyeball.
Ideal artificial vitreous does not require nothing more than the structure that can restore nature vitreum, while also needing that nature glass can be simulated
The function of glass body；It is postoperative usual to combine the anti-inflammatory anti-proliferative drugs of intravitreal further, since the complexity of PVR disease
Treatment to reduce recurrence rate, however do not develop yet so far it is a kind of there is good biocompatibility so that postoperative nothing is seriously simultaneously
Send out disease, and the ideal artificial vitreous that can be filled for a long time.
Currently, the major glass body substitute for clinically more using Medical silicone oil postoperative as PVR, however silicone oil conduct
Vitreous substitute is there are many disadvantage, such as secondary glaucoma, Cataractogenesis, long sight displacement, oil emulsification, keratopathy, and
And in invalid filler, lower retinal rupture.This all promotes researcher to research and develop replacing more suitable for vitreous chamber
For object.It is clinically higher and higher for the demand of novel glass body substitute with gradually increasing for Silicone oil eye patient populations.
Hydrogel can be simulated well because having good optical property, good biocompatibility, damping property and rheological property
The characteristic of natural vitreum is known as being the optimal material of artificial vitreous.According to the type classification of substance, hydrogel is main
There are polyvinyl alcohol [poly (vinyl alcohol), PVA], polyethylene glycol [poly (ethylene glycol), PEG], poly- third
Olefin(e) acid [poly (acrylic acid), PAA], polyacrylamide [poly (acrylamide), PAM], polyvinylpyrrolidone
[poly (1-vinyl-2-pyrrolidone), PVP], poly- glyceryl acrylate [poly (glyceryl
Methacrylate), PGMA], it is polyvinyl alcohol acrylate [polyvinylalcohol methacrylate, PVA-MA], poly-
Methyl -2- acrylate -2- ethyl acetate [poly (methyl-2-acrylamido-2-methoxyacetate)] etc..Mesh
After preceding such hydrogel is mainly obtained by external crosslinked first, vitreous chamber is then injected by injection needle, is deposited
In following defect: hydrogel structure can be destroyed in injection process and form broken section of polymer, and then lead to hydrogel mechanicalness
The decline of energy；And broken section of polymer of formation can accelerate the degradation of hydrogel and absorb, and reduce the intraocular filling time.
Therefore, a kind of novel hydrogel starts to be studied, have under specific conditional stimulus (such as pH value, temperature,
The change of luminous energy or pressure) or it is formed in situ according to intraocular biotic factor the characteristic of gel.Such hydrogel is referred to as
For " intelligent aqueous gel ".This hydrogel can destroy to avoid because of structure caused by injection process, while expanded application is in more
Function such as construct drug sustained release system.On the other hand, it current study show that only hydrogel can be effectively combined drug, mentions
The therapeutic effect of high PVR operation, and inert gas, silicone oil, weight silicone oil, perfluorocarbon liquid (heavy water) etc. cannot be with drug knots
It closes.But patient is such as preferably treated, such hydrogel fills long-term safety within the eye and validity still needs to further mention
It is high.
It is current the study found that obtain PVA hydrogel similar with nature vitreum performance by external crosslinked, and by its
Be injected in vivo and find up to the Germicidal efficacy of half a year: 3%PVA hydrogel possesses good optical physics performance, retina
Support function and biocompatibility；But it is not avoided that hydrogel structure resulted in injection process destroys, and fill out for a long time
The problem of hydrogel degradation after filling absorbs.
Summary of the invention
The first purpose of this invention is to provide a kind of vitreum suitable for proliferative vitreoretinopathy and replaces
For material, which has the performance being close with natural vitreum, and for proliferative vitreoretinopathy, patient is provided
Ideal therapeutic modality.
Second object of the present invention is to provide the preparation method of the material.
The first purpose of this invention is achieved through the following technical solutions:
A kind of vitreum alternative materials suitable for proliferative vitreoretinopathy are prepared by following steps
At:
(1) PVA aqueous solution is heated, addition crosslinking agent crosslinks reaction, and pH value is adjusted to neutrality, and PVA water is made
Gel；
(2) it takes 5 FU 5 fluorouracil and PLGA to be dissolved in organic solvent, is then slowly added dropwise to the liquid containing emulsifier
In paraffin, heated at constant temperature stirring and emulsifying obtains lotion；
(3) into lotion described in step (2), increasing amount petroleum ether to lotion is completely formed precipitating, is centrifugally separating to obtain micro-
Ball；
(4) petroleum ether centrifuge washing microballoon is used, obtains 5 FU 5 fluorouracil microballoon after dry；
(5) the PVA hydrogel and 5 FU 5 fluorouracil microballoon are mixed and stirred in a heated condition, obtain vitreum
Alternative materials.
PLGA of the present invention is poly lactide-glycolide acid.
The present invention passes through PVA aqueous solution first and is equipped with crosslinking agent appropriate, is crosslinked and filters out and natural vitreum performance
Closest temperature sensitive type PVA hydrogel, the hydrogel keep collosol state under low-temperature condition, are formed when the temperature increases solidifying
Gluey state is very suitable as the matrix of vitreum filler, the chemical structure of PVA are as follows:
On the other hand, PVR is characterized in being formed the scar shape fibr tissue containing myofibroblast, these fleshes are at fiber
Cell origin such as enters the glue of vitreous chamber in retinal pigment epithelium (RPE) cell of transdifferentiation and other kinds of cell
Contraction of the cell membrane on isolated retinal surface in cell plastid, and induction vitreous chamber.Clinical trial proves 5- fluorine
The regeneration of RPE cell can be effectively suppressed in uracil, and the contraction of fibroproliferation film is led after reducing rhegmatogenous detachment of retina reattachment surgery
Drawing effect.But when current 5 FU 5 fluorouracil is applied to PVA patient's treatment, multiple injection is needed to be administered, to the psychology and life of patient
Reason has secondary injury；
The present invention prepares 5 FU 5 fluorouracil PLGA microballoon using PLGA as carrier, and by 5 FU 5 fluorouracil PLGA microballoon and liquid
Injection PVR patient is intraocular after the mixing of state PVA hydrogel, is cross-linked in situ, becomes gel-like state.After injection patient is intraocular,
Original 5 FU 5 fluorouracil drug on 5 FU 5 fluorouracil PLGA microballoon gradually can be sustained out, bring treatment for patient.It is demonstrate,proved through experiment
Bright, support effect, intraocular toxicity, pharmacokinetics, the hydrogel of the vitreum alternative materials are degraded and PVR therapeutic effect is good
It is good, it is the ideal material for treating vitreoretinal diseases.
Preferably, crosslinking agent described in step (1) is the aqueous acetic acid of sodium β-glycerophosphate or chitosan, quality point
Number is 1.5~2.5%, preferably 2%.PVA aqueous solution is set to crosslink the PVA water-setting obtained after reaction by above-mentioned crosslinking agent
Colloidality can be closest with natural vitreum.The chemical structure of chitosan are as follows:
Step (1) PVA aqueous solution and the ratio of crosslinking agent mixing are 1:1~1:1.5, and the mass fraction of PVA aqueous solution is 1
~7%, preferably 3%；Heating temperature is 80~90 DEG C.Preferably, crosslinking catalyst can also be added in step (1), it is described
Crosslinking catalyst be calcium chloride solution.
Preferably, the mixed proportion of 5 FU 5 fluorouracil and PLGA are 1:9~1:10 in step (2).
Organic solvent described in step (2) can be one of acetonitrile, acetone, methylene chloride, chloroform, DMF or a variety of.
Through experiments, it was found that above-mentioned organic solvent is good to the solubility of carrier material PLGA, found after further experiment, described has
Solvent is preferably acetonitrile/DMF double solvents, which is conducive to subsequent emulsion process.The emulsifier is preferred
For sorbester p17.
Preferably, the temperature of step (2) heated at constant temperature is 50~60 DEG C, and mixing speed is 1500~2000rpm.
Preferably, the heating temperature of step (5) is 36~38 DEG C.
Second object of the present invention is achieved through the following technical solutions:
A kind of preparation method of the vitreum alternative materials suitable for proliferative vitreoretinopathy, including following step
It is rapid:
(1) PVA aqueous solution is heated, addition crosslinking agent crosslinks reaction, and pH value is adjusted to neutrality, and PVA water is made
Gel；
(2) it takes 5 FU 5 fluorouracil and PLGA to be dissolved in organic solvent, is then slowly added dropwise to the liquid containing emulsifier
In paraffin, heated at constant temperature stirring and emulsifying obtains lotion；
(3) into lotion described in step (2), increasing amount petroleum ether to lotion is completely formed precipitating, is centrifugally separating to obtain micro-
Ball；
(4) petroleum ether centrifuge washing microballoon is used, obtains 5 FU 5 fluorouracil microballoon after dry；
(5) the PVA hydrogel and 5 FU 5 fluorouracil microballoon are mixed and stirred in a heated condition, obtain vitreum
Alternative materials.
Preferably, crosslinking agent described in step (1) is the aqueous acetic acid of sodium β-glycerophosphate or chitosan, quality point
Number is 1.5~2.5%, preferably 2%.
Preferably, step (1) PVA aqueous solution and the ratio of crosslinking agent mixing are 1:1~1:1.5, the quality of PVA aqueous solution
Score is 1~7%, preferably 3%；Heating temperature is 80~90 DEG C.Preferably, cross-linking catalyst can also be added in step (1)
Agent, the crosslinking catalyst are calcium chloride solution.
Preferably, the mixed proportion of 5 FU 5 fluorouracil and PLGA are 1:9~1:10 in step (2).
Organic solvent described in step (2) can be one of acetonitrile, acetone, methylene chloride, chloroform, DMF or a variety of,
Preferably acetonitrile/DMF double solvents；The emulsifier is preferably sorbester p17.
Preferably, the temperature of step (2) heated at constant temperature is 50~60 DEG C, and mixing speed is 1500~2000rpm.
Preferably, the heating temperature of step (5) is 36~38 DEG C.
Compared with prior art, the invention has the following advantages:
1. PVA hydrogel prepared by the present invention is temperature-sensitive hydrogel, collosol state is kept under low-temperature condition, works as temperature
Gel state is formed when raising, is very suitable as the matrix of vitreum filler；
2. the 5 FU 5 fluorouracil microballoon and the compatibility of PVA hydrogel that the present invention is prepared using PLGA as carrier are fine, in hand
It is intraocular to enter patient for disposable co-injection during art, solves the problems, such as to need to inject drug in therapeutic process repeatedly, mitigate
The pain of patient's treatment；
3. PVA hydrogel and 5 FU 5 fluorouracil microballoon are combined together by the present invention, vitreum alternative materials solution obtained
The problem of hydrogel of having determined forms broken section of polymer in injection process, while bioaffinity is strong, it can be long-term in human body
It is stabilized, is the ideal material for treating PVR patient.
Detailed description of the invention
Below by way of attached drawing, the present invention is further illustrated.
The microcosmic electron microscope of Fig. 1 vitreum alternative materials.
Fig. 2, Fig. 3 rheological property, viscosity measurements result figure.
Fig. 4 croop property testing result figure.
The external drug accumulation release testing result figure of Fig. 5.
Fig. 6 cytotoxicity experiment result figure.
Specific embodiment
Below by way of specific embodiment, the present invention is further illustrated.
Reagent used in following embodiment:
Polyvinyl alcohol (PVA): (Sigma Aldrich, St.Louis, MO) direct use is not further purified；Chitosan
(CS): biochemical reagents, deacetylation: 80.0~95.0%, Sinopharm Chemical Reagent Co., Ltd.；Aqueous acetic acid: concentration
0.1mol/L。
Embodiment 1
(1) 7%PVA aqueous solution is heated to 80 DEG C to make it completely dissolved, takes sodium β-glycerophosphate to be dissolved in acetic acid water-soluble
2.5% sodium β-glycerophosphate solution is made in liquid, filtering and impurity removing after dissolving completely is then water-soluble by PVA according to the ratio of 1:1.5
Calcium chloride solution to the volume of liquid and the mixing of sodium β-glycerophosphate solution, slow cooling to room temperature and dropwise addition 2% becomes original volume
1.5 times, be allowed to crosslink reaction, using disodium hydrogen phosphate saturated solution by pH value adjust 7.21, formed gel after steaming
It dialyses 48 hours in distilled water, to remove the residue of non-crosslinked PVA, PVA hydrogel is made；
(2) 5 FU 5 fluorouracil is mixed in the ratio of 1:10 with PLGA and is dissolved in methylene chloride, is then slowly added dropwise
To in the atoleine containing sorbester p17, the heated at constant temperature at 60 DEG C obtains lotion with 1800rpm speed stirring and emulsifying 1h；
(3) into lotion described in step (2), increasing amount petroleum ether to lotion is completely formed precipitating, is centrifugally separating to obtain micro-
Ball；
(4) petroleum ether centrifuge washing microballoon is used, obtains 5 FU 5 fluorouracil microballoon after dry；
(5) the PVA hydrogel and 5 FU 5 fluorouracil microballoon are mixed and stirred under 36 DEG C of heating condition, are obtained
Vitreum alternative materials.
Embodiment 2
(1) 1%PVA aqueous solution is heated to 80 DEG C to make it completely dissolved, takes chitosan to be dissolved in aqueous acetic acid and makes
At 2.5% chitosan solution, filtering and impurity removing after dissolving completely is then molten by PVA aqueous solution and chitosan according to the ratio of 1:1.2
Calcium chloride solution to the volume of liquid mixing, slow cooling to room temperature and dropwise addition 2% becomes 1.5 times of original volume, is allowed to hand over
PH value is adjusted 7.08 using disodium hydrogen phosphate saturated solution, dialysed 48 hours in distilled water after forming gel by connection reaction, with
The residue of non-crosslinked PVA is removed, PVA hydrogel is made；
(2) 5 FU 5 fluorouracil is mixed in the ratio of 1:9 with PLGA and is dissolved in acetone, is then slowly added dropwise to containing
In the atoleine of sorbester p17, the heated at constant temperature at 55 DEG C obtains lotion with 2000rpm speed stirring and emulsifying 1h；
(3) into lotion described in step (2), increasing amount petroleum ether to lotion is completely formed precipitating, is centrifugally separating to obtain micro-
Ball；
(4) petroleum ether centrifuge washing microballoon is used, obtains 5 FU 5 fluorouracil microballoon after dry；
(5) the PVA hydrogel and 5 FU 5 fluorouracil microballoon are mixed and stirred under 38 DEG C of heating condition, are obtained
Vitreum alternative materials.
Embodiment 3
(1) 3%PVA aqueous solution is heated to 80 DEG C to make it completely dissolved, takes chitosan to be dissolved in aqueous acetic acid and makes
At 2% chitosan solution, then filtering and impurity removing after dissolving completely mixes PVA aqueous solution and chitosan solution according to the ratio of 1:1
It closes, calcium chloride solution to the volume of slow cooling to room temperature and dropwise addition 2% becomes 1.5 times of original volume, is allowed to crosslink anti-
It answers, pH value is adjusted 7.14 using disodium hydrogen phosphate saturated solution, is dialysed 48 hours in distilled water after forming gel, to remove
PVA hydrogel is made in the residue of non-crosslinked PVA；
(2) 5 FU 5 fluorouracil is mixed in the ratio of 1:9 with PLGA and is dissolved in acetonitrile/DMF double solvents, then delayed
Slowly it is added dropwise in the atoleine containing sorbester p17, the heated at constant temperature at 50 DEG C, with 1500rpm speed stirring and emulsifying 1h, obtains
Lotion；
(3) into lotion described in step (2), increasing amount petroleum ether to lotion is completely formed precipitating, is centrifugally separating to obtain micro-
Ball；
(4) petroleum ether centrifuge washing microballoon is used, obtains 5 FU 5 fluorouracil microballoon after dry；
(5) the PVA hydrogel and 5 FU 5 fluorouracil microballoon are mixed and stirred under 37 DEG C of heating conditions, obtain glass
Glass body alternative materials.
The measurement result of vitreum alternative materials performance described in embodiment 3:
1. microstructure
It is as shown in Figure 1 the electron microscope of vitreum alternative materials, it can be seen that vitreum alternative materials obtained are one
The particulate polymers of kind three-dimensional structure, the structure have certain support hardness, and inner space allows 5 FU 5 fluorouracil microballoon attached
And discharge 5 FU 5 fluorouracil.
2. rheological property
Using the rotational rheometer (production of TA company, the U.S.) of model DHR-2, according to examination criteria GB/T 33095.1-
2016 pairs of vitreum alternative materials detect, under conditions of 37 ± 0.5 DEG C of temperature, 50 ± 10%RH of humidity, to sample into
Row amplitude scanning, measures gelation, mechanical performance and the kinetics of hydrogel, and according to the frequency pair of oscillatory shear stress
The storage modulus and loss modulus (elasticity modulus) of PVA hydrogel are analyzed.
Use the continuous record storage of rheology advantage instrument control software and loss modulus value, the relative contribution of elasticity and viscosity
It can be quantified by fissipation factor (tan δ), which is the ratio of loss with storage modulus: fissipation factor is higher, generation
Table sample product are more biased towards in viscosity, more like liquid；Fissipation factor is lower, and representative sample is more biased towards in elasticity, more like colloid.
As shown in Fig. 2, the testing result of oscillatory shear is shown, storage modulus and loss modulus (elasticity modulus) with
In the trend risen, storage modulus is higher for the raising of frequency, elastic more good, the environment suitable for vitreous chamber；Such as Fig. 3
Shown, during frequency is increased, fissipation factor is always held at lower numerical value, further illustrates that the vitreum substitutes material
Material has good elasticity.
3. viscosity
Using the rotational rheometer (production of TA company, the U.S.) of model DHR-2, according to examination criteria GB/T 33095.1-
2016 pairs of vitreum alternative materials detect, and under conditions of 37 ± 0.5 DEG C of temperature, 50 ± 10%RH of humidity, survey to sample
Determine viscosity, by lasting shearing frequency, obtains shear stress data.
As shown in Fig. 2, the viscosity of vitreum alternative materials subtracts with the increase of shear rate from the point of view of viscosity results
Small, sample is gradually thinning after shearing, belongs to the pseudoplastic fluid in non-newtonian fluid, this belongs to the vitreum alternative materials
The essence of high polymer (containing high molecular colloidal particle) is consistent.
The silicone oil with low viscosity clinically used can be considered as Newtonian fluid, and viscosity is lower, after implantation glass body cavity easily
Emulsification forms Silicone oil eye.Therefore, for compared to silicone oil, the vitreum alternative materials are more suitable in PVR therapeutic process
Natural vitreous substitute.
4. croop property
Using the dynamic thermomechanical analysis apparatus (production of Mettler Toledo Inc., Switzerland) of model DMA/SDTA861e,
Vitreum alternative materials are detected according to examination criteria GB/T 13464-2008, in temperature -45 ± 0.5 DEG C, 25 ± 0.5
DEG C, 37 ± 0.5 DEG C, under conditions of 50 ± 10%RH of humidity, by analyzer pick up calibration, sample clamping, measure creep curve.
Creep strength refers to material at a certain temperature, by after a certain period of time, when creep compliance is no more than certain limit
Maximum allowable stress.As shown in figure 4, creep strength increases with frequency and is risen.Finally, -45 DEG C, 25 DEG C and 37 DEG C
Under the conditions of, the creep strength of vitreum alternative materials increases with frequency and is risen.
5. the carrying drug ratio of microballoon
Appropriate 5 FU 5 fluorouracil microballoon is weighed in 5ml volumetric flask, the dissolution of 1ml acetonitrile is added completely, flowing is then added
Phase dilution takes appropriate solution to be centrifuged 10min in 10,000rpm, collects supernatant, it is dense to measure drug using HPLC method to concentration to be measured
Degree.
The calculation formula of drugloading rate and encapsulation rate is as follows:
Drug quality/microspheres quality × 100% in drugloading rate=microballoon；
Drug quality/dosage × 100% in encapsulation rate=microballoon.
Test result: the carrying drug ratio of 5 FU 5 fluorouracil microballoon is 10%, 6.8 ± 0.9um of particle size, encapsulation rate 87%.
6. external drug accumulation release
It weighs appropriate 5 FU 5 fluorouracil microballoon and is scattered in 10ml PBS (pH 7.4), at the uniform velocity shaken under the conditions of 37 DEG C
(100rpm) takes out 200 μ l dissolution mediums, and supplements same volume fresh dissolution medium respectively at 1,2,4,6,8,12,24,48h.
Using the drug concentration in HPLC method measurement dissolution medium, drug accumulation release is calculated.As a result as shown in figure 5, with the time
Passage, drug accumulation release constantly increases, and rate of release gradually slows down.
7. cytotoxicity experiment (CCK8)
Taking Human RPE Cells in Vitro ARPE-19 is experimental material cell, and recovery culture, adjustment cell concentration is 1
× 105/ml, 96 orifice plates, every 100 μ l of hole are assigned to, i.e., every hole cell is 1 × 104.The vitreum of various concentration is extracted respectively
Culture medium in each 10ul to hole of alternative materials, attached cell, which is added, to be regathered each time point cell after cell is adherent and carry out
Detection.CCK-8 solution (Dojindo CK04) is added in the cell (0h, for 24 hours, 48h, 72h) for collecting various time points, ratio 1/
10, i.e. 100ul culture solution is added 10ul and detects liquid.After being incubated for 4 hours, OD450 number is read in microplate reader read plate, CCK-8 detection
According to (microplate reader manufacturer: Thermo Fisher Scientific model: multiscan MK3).
As shown in fig. 6, processing carries out CCK8 detection for 24 hours, 3 measurements of OD450 data are averaged, and find experimental group with right
Not occurring significant difference (P < 0.05) according to group, the cell in observation experiment group and control group maintains complete morphosis,
Do not occur aging, cracking, canceration etc..It is believed that the vitreum alternative materials do not inhibit the proliferation and normal metabolism of cell
Activity.
8. index of refraction, light transmittance, swellbility, pH value
Index of refraction: the abbe's refractometer (production of Shanghai Yi electricity object light company) of model WYA (2WAJ) is used, according to detection
Standard GB 6488-1986 carries out vitreum alternative materials under conditions of 37 ± 0.5 DEG C of temperature, 50 ± 10%RH of humidity
Detection；
Light transmittance: the abbe's refractometer (production of Shanghai Yi electricity object light company) of model WYA (2WAJ) is used, according to detection
Standard GB 6488-1986 carries out vitreum alternative materials under conditions of 37 ± 0.5 DEG C of temperature, 50 ± 10%RH of humidity
Detection；
Swellbility: hydrogel sample (50 milligrams) is immersed in PBS, the constant temperature bath at 37 DEG C, until reaching balance.Flat
Under weighing apparatus swelling, the water content of vitreum alternative materials is determined by following formula: SW=(W1-W0)/(gel is swollen W0 in a solvent
Quality W1 after balance, it is dry in vacuum drying oven after quality W0)；
PH value: PHEAST by using digital pH pop one's head in (Trimo Fisher HealthInc., Waltham, MA) measure
After pH meter is calibrated, pH meter probe is inserted directly into sample, probe is completely covered by sample, is read；Successively measurement is surplus
Remaining two parallel samples；The continuous data for reading and recording third sample three times, are asked and calculate average value as a result.
Index of refraction, light transmittance, swellbility, every numerical value comparison of pH value and natural vitreum are as shown in the table, from table
As it can be seen that every numerical value of the vitreum alternative materials is very close with natural vitreum.
| Sample | Water content | Index of refraction | Light transmittance | Acid-base property | Density |
| Natural vitreum | 98~99% | 1.3345–1.3348 | > 90% | 7.0~7.4 | 1.0053~1.0089 |
| Vitreum alternative materials | 97~2% | 1.45 | 91% | 7.22 | 1.0257 |
It should be pointed out that above-described embodiment be only to further explanation of the invention, rather than limit, art technology
Any adjustment or change of the personnel in the comparable meaning and scope with technical solution of the present invention are all considered as being included in this
In the protection scope of invention.
Claims (10)
1. a kind of vitreum alternative materials suitable for proliferative vitreoretinopathy, which is characterized in that pass through following step
Suddenly it is prepared:
(1) PVA aqueous solution is heated, addition crosslinking agent crosslinks reaction, and pH value is adjusted to neutrality, and PVA hydrogel is made；
(2) it takes 5 FU 5 fluorouracil and PLGA to be dissolved in organic solvent, is then slowly added dropwise to the atoleine containing emulsifier
In, heated at constant temperature stirring and emulsifying obtains lotion；
(3) into lotion described in step (2), increasing amount petroleum ether to lotion is completely formed precipitating, is centrifugally separating to obtain microballoon；
(4) petroleum ether centrifuge washing microballoon is used, obtains 5 FU 5 fluorouracil microballoon after dry；
(5) the PVA hydrogel and 5 FU 5 fluorouracil microballoon are mixed and stirred in a heated condition, obtain vitreum substitution
Material.
2. the vitreum alternative materials according to claim 1 suitable for proliferative vitreoretinopathy, feature
It is, crosslinking agent described in step (1) is the aqueous acetic acid of sodium β-glycerophosphate or chitosan, mass fraction is 1.5~
2.5%；PVA aqueous solution and the ratio of crosslinking agent mixing are 1:1~1:1.5, and the mass fraction of PVA aqueous solution is 1~7%；Heating
Temperature is 80~90 DEG C.
3. the vitreum alternative materials according to claim 2 suitable for proliferative vitreoretinopathy, feature
It is, the mass fraction of crosslinking agent described in step (1) is 2%；The mass fraction of the PVA aqueous solution is 3%.
4. the vitreum alternative materials according to claim 1 suitable for proliferative vitreoretinopathy, feature
It is, the mixed proportion of 5 FU 5 fluorouracil and PLGA are 1:9~1:10 in step (2)；The organic solvent is acetonitrile, third
One of ketone, methylene chloride, chloroform, DMF or a variety of；The emulsifier is sorbester p17.
5. the vitreum alternative materials according to claim 4 suitable for proliferative vitreoretinopathy, feature
It is, organic solvent described in step (2) is acetonitrile/DMF double solvents；The temperature of step (2) heated at constant temperature is 50~60 DEG C,
Mixing speed is 1500~2000rpm；The heating temperature of step (5) is 36~38 DEG C.
6. a kind of preparation method of the vitreum alternative materials suitable for proliferative vitreoretinopathy, which is characterized in that
The following steps are included:
(1) PVA aqueous solution is heated, addition crosslinking agent crosslinks reaction, and pH value is adjusted to neutrality, and PVA hydrogel is made；
(2) it takes 5 FU 5 fluorouracil and PLGA to be dissolved in organic solvent, is then slowly added dropwise to the atoleine containing emulsifier
In, heated at constant temperature stirring and emulsifying obtains lotion；
(3) into lotion described in step (2), increasing amount petroleum ether to lotion is completely formed precipitating, is centrifugally separating to obtain microballoon；
(4) petroleum ether centrifuge washing microballoon is used, obtains 5 FU 5 fluorouracil microballoon after dry；
(5) the PVA hydrogel and 5 FU 5 fluorouracil microballoon are mixed and stirred in a heated condition, obtain vitreum substitution
Material.
7. the preparation side of the vitreum alternative materials according to claim 6 suitable for proliferative vitreoretinopathy
Method, which is characterized in that crosslinking agent described in step (1) is the aqueous acetic acid of sodium β-glycerophosphate or chitosan, quality point
Number is 1.5~2.5%；PVA aqueous solution and the ratio of crosslinking agent mixing are 1:1~1:1.5, and the mass fraction of PVA aqueous solution is 1
~7%；Heating temperature is 80~90 DEG C.
8. the preparation side of the vitreum alternative materials according to claim 7 suitable for proliferative vitreoretinopathy
Method, which is characterized in that the mass fraction of crosslinking agent described in step (1) is 2%；The mass fraction of the PVA aqueous solution is 3%.
9. the preparation side of the vitreum alternative materials according to claim 6 suitable for proliferative vitreoretinopathy
Method, which is characterized in that the mixed proportion of 5 FU 5 fluorouracil and PLGA are 1:9~1:10 in step (2)；The organic solvent is
One of acetonitrile, acetone, methylene chloride, chloroform, DMF or a variety of；The emulsifier is sorbester p17.
10. the vitreum alternative materials according to claim 9 suitable for proliferative vitreoretinopathy, feature
It is, organic solvent described in step (2) is acetonitrile/DMF double solvents；The temperature of step (2) heated at constant temperature is 50~60 DEG C,
Mixing speed is 1500~2000rpm；The heating temperature of step (5) is 36~38 DEG C.
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