CN102631711B - Hydrogel corneal contact lenses drug carrier - Google Patents
Hydrogel corneal contact lenses drug carrier Download PDFInfo
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- CN102631711B CN102631711B CN201210153382.2A CN201210153382A CN102631711B CN 102631711 B CN102631711 B CN 102631711B CN 201210153382 A CN201210153382 A CN 201210153382A CN 102631711 B CN102631711 B CN 102631711B
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- hydrogel
- chitosan
- contact lens
- hydroxyethyl methacrylate
- drug carrier
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 135
- 239000003937 drug carrier Substances 0.000 title claims abstract description 21
- 229920001661 Chitosan Polymers 0.000 claims abstract description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000003999 initiator Substances 0.000 claims abstract description 20
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 10
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 claims abstract 10
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims abstract 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 42
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical group [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 21
- 229920000858 Cyclodextrin Polymers 0.000 claims description 19
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 19
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 19
- 239000000126 substance Substances 0.000 claims description 12
- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims 2
- 150000004676 glycans Chemical class 0.000 claims 1
- 239000004310 lactic acid Substances 0.000 claims 1
- 235000014655 lactic acid Nutrition 0.000 claims 1
- 229920001282 polysaccharide Polymers 0.000 claims 1
- 239000005017 polysaccharide Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 80
- 229940079593 drug Drugs 0.000 abstract description 30
- 229920001897 terpolymer Polymers 0.000 abstract description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 20
- 239000001301 oxygen Substances 0.000 abstract description 20
- 229910052760 oxygen Inorganic materials 0.000 abstract description 20
- 239000000499 gel Substances 0.000 abstract description 15
- 108090000623 proteins and genes Proteins 0.000 abstract description 12
- 102000004169 proteins and genes Human genes 0.000 abstract description 12
- 230000008961 swelling Effects 0.000 abstract description 11
- 229920001577 copolymer Polymers 0.000 abstract description 7
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 230000035699 permeability Effects 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000001179 sorption measurement Methods 0.000 abstract description 2
- 238000013267 controlled drug release Methods 0.000 abstract 1
- 230000000379 polymerizing effect Effects 0.000 abstract 1
- VLCAYQIMSMPEBW-UHFFFAOYSA-N methyl 3-hydroxy-2-methylidenebutanoate Chemical compound COC(=O)C(=C)C(C)O VLCAYQIMSMPEBW-UHFFFAOYSA-N 0.000 description 38
- 239000000178 monomer Substances 0.000 description 18
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 13
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 12
- 229940098773 bovine serum albumin Drugs 0.000 description 12
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 10
- 230000001186 cumulative effect Effects 0.000 description 10
- 239000000607 artificial tear Substances 0.000 description 9
- 230000003204 osmotic effect Effects 0.000 description 9
- VAZSKTXWXKYQJF-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)OOS([O-])=O VAZSKTXWXKYQJF-UHFFFAOYSA-N 0.000 description 8
- 239000003125 aqueous solvent Substances 0.000 description 8
- 239000012966 redox initiator Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000007334 copolymerization reaction Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229960001180 norfloxacin Drugs 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 2
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical compound OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 2
- 239000001166 ammonium sulphate Substances 0.000 description 2
- 235000011130 ammonium sulphate Nutrition 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000004083 nasolacrimal duct Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种水凝胶角膜接触镜药物载体，该载体由含双键的壳聚糖衍生物、甲基丙烯酸羟乙酯和N-乙烯基吡咯烷酮在引发剂存在下聚合制备而成。本发明所提供的三元共聚物水凝胶聚合后吸水溶胀透明性良好，无明显形变发生，保水性能佳，透氧值高，药物负载量大，抗蛋白质吸附能力强于二元共聚物水凝胶。上述具有好的透氧性能和药物控释能力新型角膜接触镜药物载体，其性能符合角膜接触镜的基本要求，可控制眼药的释放，具有较大的社会效益和经济效益。The invention discloses a hydrogel contact lens drug carrier, which is prepared by polymerizing chitosan derivatives containing double bonds, hydroxyethyl methacrylate and N-vinyl pyrrolidone in the presence of an initiator. The terpolymer hydrogel provided by the present invention has good water absorption and swelling transparency after polymerization, no obvious deformation, good water retention performance, high oxygen permeability value, large drug load, and stronger protein adsorption resistance than binary copolymer hydrogels. gel. The above-mentioned new type of contact lens drug carrier with good oxygen permeability and controlled drug release ability meets the basic requirements of contact lens, can control the release of eye medicine, and has great social and economic benefits.
Description
Technical field
The invention belongs to new material technology field, be specifically related to synthetic and loading and the release of medicine in glasses of contact lens.
Background technology
The treatment of ocular disease mainly completes by medicine at present.In this process, too low drug level can not play therapeutical effect; Too high drug level can have side effects, and even can damage normal histoorgan.In addition, therapeutic effect also depends on that can medicine keep time enough at disease sites.In the ophthalmic preparation using at present, more than 90% be eye drop or Eye ointments, in eye time of staying about 2min only, only 1 ~ 7% medicine can be used effectively, most of medicine enters blood system through nasolacrimal duct discharge or via intranasal application, causes and uses the shortcomings such as inconvenient, utilization rate is low, therapeutic effect is not obvious.For improving curative effect of medication, often will increase drug level and drip number of times, but too much medicine can damage normal part tissue of eye and organ.
In order to overcome the shortcoming of above-mentioned common ophthalmic preparation, researcher uses pharmaceutical carriers such as viscosifier, corneal osmosis agent, lamellar insert to come prolong drug in the time of staying of eye, or the organ that increases eye is as cornea, sclera, the permeance property of conjunctiva to medicine.These pharmaceutical carriers have strengthened the curative effect of medicine to a certain extent, but in use still exist, have certain zest, poor adhesion, easily by eyes, as foreign body, discharged, exist the problems such as danger of medicine violent release.
As pharmaceutical carrier, the time of staying that corneal contact lens can prolong drug, control the rate of release of medicine, increase the service efficiency of medicine, reduce side effect, have again and use the features such as simple, convenient simultaneously, in medicament for the eyes transmission field, attract wide attention.Softness after hydrogel water suction and high resilience is difficult for causing tissue injury, can be endowed again certain optical property, can meet well that people correct defects of vision and the requirement of " natural vision ", becomes the leading material of a class of manufacturing corneal contact lens.
The corneal contact lens using on the market is at present divided into two kinds: hard mirror and soft lens.And hydrogel is the primary raw material of preparation soft corneal contact lens.Traditional hydrogel corneal contact lens is by initiator trigger monomer hydroxyethyl methylacrylate, to carry out free radicals copolymerization reaction to form hydrogel network.Although poly hydroxy ethyl acrylate has good flexibility and elasticity, its water content is lower, oxygen permeability is poor, so this class corneal contact lens is not suitable for long periods of wear.In order to improve the oxygen permeability of poly hydroxy ethyl acrylate, researcher is prepared hydrogel by hydrophilic monomer as NVP and hydroxyethyl methylacrylate copolymerization, the water content of gained hydrogel increases, and this has just improved the comfortable wearing degree of corneal contact lens; The increase of water content also increases the oxygen permeating amount of hydrogel accordingly, thereby has extended wearing the time of hydrogel corneal contact lens.Yet, the elastic modelling quantity that too much water content can be shone into again hydrogel declines and the shortcoming such as yielding and cannot meet the requirement that corneal contact lens is corrected defects of vision, hydrophilic monomer also can increase the protein adsorption of corneal contact lens simultaneously, increases the probability of breed bacteria.In addition, traditional hydrogel corneal contact lens also lacks the part with drug interaction.
Summary of the invention
The object of the invention is to overcome the deficiency of above-mentioned conventional contact lenses, a kind of novel hydrogels corneal contact lens carrier discharging for curing eye diseases, control medicament for the eyes is provided.
Another object of the present invention is to provide a kind of preparation method of above-mentioned material.
Object of the present invention can reach by following measures:
A hydrogel corneal contact lens pharmaceutical carrier, this carrier is prepared from by the polymerization under initiator exists of double bond containing chitosan derivatives, hydroxyethyl methylacrylate (HEMA) and NVP (NVP).Relative medicine can load to by the mode of copolymerization or absorption in hydrogel corneal contact lens pharmaceutical carrier.
In the present invention, the mol ratio of hydroxyethyl methylacrylate and NVP is 7～8:2, is preferably 7.4:2; Described double bond containing chitosan derivatives is 0.1%～1% of hydroxyethyl methylacrylate and NVP gross mass, is further 0.2%～0.7%, take 0.3%～0.5% as best.
Chitosan has degradability, good biocompatibility and the good advantages such as antibiotic property, the present invention introduces hydrogel by two key chitosan derivatives, improve mesh size and the connectedness that has increased hydrogel network between hydrogel, thereby increase the oxygen permeating amount of hydrogel corneal contact lens.Double bond containing chitosan derivatives has the chitosan of methacrylic acid anhydride modification, acrylic acid modified chitosan, the chitosan of methacrylic acid modification, the chitosan of the chitosan of hydroxyethyl methacrylate-modified, methacrylic acid and lactic modified.Preferred chitosan derivatives has the chitosan of chitosan, methacrylic acid and the lactic modified of hydroxyethyl methacrylate-modified.In double bond containing chitosan derivatives, the percent grafting of two keys, between 5 ~ 49%, is further 10 ~ 40%, and best percent grafting is 15 ~ 35%.
In order to increase the controlled release ability of hydrogel to hydrophobic drug, in hydrogel corneal contact lens, introduce cyclodextrin, and the mode of introducing by introducing the derivant (it still belongs to double bond containing chitosan derivatives in the present invention) with the chitosan of two keys containing cyclodextrin simultaneously in polymerization process.The double bond containing chitosan derivatives with cyclodextrin grafting like this mainly contains the chitosan of chitosan, cyclodextrin and the methacrylic acid anhydride modification of cyclodextrin and hydroxyethyl methacrylate-modified, and preferred chitosan derivatives like this adopts the chitosan of cyclodextrin and hydroxyethyl methacrylate-modified.Have in the double bond containing chitosan derivatives of cyclodextrin grafting, the percent grafting of cyclodextrin is between 10 ~ 51%, further 15 ~ 40%, best percent grafting 25 ~ 35%.
Above-mentioned double bond containing chitosan derivatives of the present invention generally adds reaction with the form of aqueous acetic acid; In this double bond containing chitosan derivatives aqueous acetic acid, the mass content of double bond containing chitosan derivatives is 0.5～5%, is preferably 0.5～2%, is further 1%; Wherein the mass concentration of acetic acid is 0.5～2%, is further 1%.
Initiator in the present invention can be selected ammonium sulphate (APS) and tetramethylethylenediamine (TEMED), and wherein the mol ratio of ammonium sulphate and tetramethylethylenediamine is 1:0.9～1.1, preferably 1:1.The consumption of initiator is 0.1～1% (M of hydroxyethyl methylacrylate and NVP gross mass
aPS+TMEDA: M
hEMA+NVP), be preferably 0.3～0.7%, take 0.5% as good.
It is solvent that polyreaction of the present invention adopts water, therefore initiator can directly add reaction system, also form that can aqueous solution adds polymerization system to carry out polyreaction, and two key chitosan derivatives can 1% aqueous acetic acid form add polymerization system to carry out polyreaction, aqueous solvent can be according to circumstances without adding or continuing supplementary when mixing or before reaction.In polyreaction, make the quality of water reach 30～40% of reaction system (comprising each reactant, as HEMA, NVP, two key chitosan derivatives and initiator, and water) gross mass, be preferably 32～37%, most preferably be 35%.
Polymeric reaction temperature of the present invention is 35 ℃～90 ℃, is preferably 40 ℃～60 ℃, and the response time is 0.2～5 hour, preferably 1～2 hour.
The hydrogel corneal contact lens pharmaceutical carrier of this method, can, by the mode carrying medicament of copolymerization or absorption, can make again medicine steadily discharge lentamente in use.This loading process refers to following formula:
Here the medicine of indication is generally the medicine for curing eye diseases, concrete as norfloxacin, ciclosporin etc., more particularly, for example the mode that is written into of medicine has following two kinds: the one, this terpolymer hydrogel is immersed in 1.5 ~ 3mg/ml eye drop, allow drug osmotic in hydrogel network, another kind is by by the mode of monomer and medicine copolymerization, and the consumption of medicine is 1～5mg/g.
The present invention further discloses the preparation method of this hydrogel corneal contact lens pharmaceutical carrier: by after hydroxyethyl methylacrylate and NVP mixing, add double bond containing chitosan derivatives aqueous acetic acid and initiator, add or maintain the aqueous solvent in reaction system, after each material mix homogeneously, pour into and in mould, carry out polyreaction, after reaction, in water, soak the demoulding, obtain terpolymer hydrogel, i.e. hydrogel corneal contact lens pharmaceutical carrier of the present invention.Wherein each raw material select and usage ratio or concentration and solvent load as above-mentioned institute, wherein polymeric reaction temperature is 35 ℃～90 ℃, is preferably 40 ℃～60 ℃, the response time is 0.2～5 hour, preferably 1～2 hour.
Terpolymer hydrogel provided by the present invention has following performance:
(1) gel time of terpolymer hydrogel is basicly stable in 25 ± 2min left and right, shorter than the gel time 30 ± 3min of HEMA-NVP bipolymer, but both there was no significant differences.
(2) after the polymerization of terpolymer hydrogel, the water absorption and swelling transparency is good, without obviously deformation generation.
(3) equilibrium moisture content of terpolymer hydrogel, between 52%-55%, is slightly larger than bipolymer 50% left and right.
(4) speed that terpolymer hydrogel dries out in air is slightly slower than bipolymer hydrogel, and terpolymer hydrogel water retention property is also slightly better than bipolymer hydrogel thus.
(5) oxygen value of terpolymer hydrogel (Dk/t) is at 86 ~ 94*10
-9mL/m
2* s*mmHg, is greater than oxygen value (Dk/t) 71*10 of bipolymer hydrogel
-9mL/m
2* s*mmHg, and there is significant difference.
(6) amount of terpolymer hydrogel adsorbed proteins (BSA) is 7.0 ± 0.2 ~ 8.0 ± 0.1mg/g hydrogel, is less than bipolymer hydrogel 9.3 ± 0.3mg/g hydrogel, and has significant difference.Illustrate that terpolymer hydrogel anti-protein absorbability is better than bipolymer hydrogel.
(7) the drug loading amount that terpolymer hydrogel obtains by infusion method is 19 ~ 30mg/g, is slightly larger than the drug loading amount 12mg/g left and right of bipolymer hydrogel.
(8) prolong drug along with the time discharges stably gradually from the terpolymer hydrogel of load, can reach slowly mild release in 1 ~ 3h, reaches balance after 2 ~ 6h, and the cumulative release amount of medicine is between 60 ~ 90%.
The above-mentioned oxygen permeability having had provided by the present invention and the novel corneal contact lens pharmaceutical carrier of medicine controlled releasing ability, its performance meets the basic demand of corneal contact lens, can control the release of medicament for the eyes, has larger Social benefit and economic benefit.
The specific embodiment
Experimental technique
The mensuration of gel time:
By the variation of observational method observation water gel periods of monomer flow, the gel time of the timing definition hydrogel losing flowability from solution.
The mensuration of equilibrium moisture content:
Copolymer sample is placed in to enough distilled water, takes out after being swelling to constant mass, with filter paper, carefully blot surperficial moisture, at room temperature weigh its mass M
1(g), then copolymer is dried to constant weight in 60 ℃ of drying baker, weighs its mass M (g).According to following formula, calculate the equilibrium moisture content of hydrogel corneal contact lens: EWC (%)=(M
1-M)/M
1* 100%
Water retention property:
Hydrogel W after water suction is saturated
s(g), be placed under the environment of room temperature, at set intervals, take out and weigh W
t(g), obtain the relation that gel quality affects changed along with the time, percentage of water loss is WL (%)=(W
s-W
t)/W
s* 100%.
The mensuration of oxygen permeability:
OX2/231 type oxygen light transmittance tester: Labthink Instruments Co., Ltd., at epicoele gas (first N
2rear O
2) flow 20.00mL/min, cavity of resorption gas (N
2) flow is that 10.00mL/min, temperature are at 37 ℃, to record hydrogel oxygen permeating amount.
Anti-protein absorption property:
With UV1101M054 ultraviolet spectrophotometer, measure the absorbance of bovine serum albumin (BSA) absorption front and back 280nm, by standard curve, calculate the solubility of BSA, by solubility volume differences, calculate the amount that is adsorbed to the protein in copolymer aquagel.
The mensuration of medicine useful load:
The norfloxacin (NFX) of take is model drug, the copolymer aquagel corneal contact lens of preparing gained is placed in to the Chibroxin of finite concentration, 1mL, in 37 ℃ of waters bath with thermostatic control, loads 48h to balance.With ultraviolet spectrophotometer, measure the absorbance that NFX loads front and back 274nm, by standard curve, calculate the solubility of medicine, by solubility volume differences, calculate the amount that is loaded onto the medicine in copolymer aquagel.
Or the medicine of specified quantitative is directly sneaked into monomer and hydrogel copolymerization, and the useful load of medicine is exactly the amount of sneaking into monomer medicine.
The mensuration of release amount of medicine:
The copolymer aquagel corneal contact lens having loaded is placed in respectively to artificial tears ATS, and be placed in 37 ℃ of waters bath with thermostatic control, the absorbance that drug level by UV spectrophotometer measuring different release time of section goes out at 274nm, by standard curve, calculate the solubility of medicine, thereby obtain the cumulative release amount of medicine.
The preparation of the chitosan of cyclodextrin and hydroxyethyl methacrylate-modified:
Steps A (grafted by beta cyclodextrin chitosan): add beta-schardinger dextrin-and solvent dimethyl sulfoxide and isopropyl alcohol in reactor, then add epoxychloropropane, and add immediately NaOH solution, react, then add chitosan, continue reaction, reaction finishes, and obtains graft product CC.
Step B(beta-schardinger dextrin-, methacrylic anhydride grafted chitosan): in reactor, add graft product CC and water, then add triethylamine, methacrylic anhydride and tetrabutyl ammonium bromide, at 40～80 ℃, reaction, obtains.Reaction finishes, and carries out post processing and can obtain graft product cyclodextrin and methacrylic anhydride grafted chitosan.
Step C(beta-schardinger dextrin-, hydroxyethyl methylacrylate grafted chitosan, CS-β-CD-HEMA, CCH): in reactor, add hydroxyethyl methylacrylate and isopropyl alcohol, add again epoxychloropropane, and add immediately NaOH solution, after reaction, add graft product CC, continue reaction, obtain beta-schardinger dextrin-and hydroxyethyl methylacrylate grafted chitosan.
Embodiment 1
In container, by the ratio of amount of substance, be that 7.4:2 adds hydroxyethyl methylacrylate (HEMA), NVP (NVP) monomer, then chitosan derivatives (the CH that adds 1wt% hydroxyethyl methacrylate-modified, the percent grafting of two keys is 19%) aqueous acetic acid, wherein the quality of this chitosan derivatives is 0.4% (M of HEMA and NVP gross mass
chitosan derivatives: M
hEMA+NVP); Adding mol ratio is Ammonium persulfate. (APS), tetramethylethylenediamine (TMEDA) redox initiator of 1:1 again, and wherein the quality of initiator is 0.5% (M of HEMA and NVP gross mass
aPS+TMEDA: M
hEMA+NVP); Mass content to the 35% (M of aqueous solvent is added or maintained to whole system
water: M
totally system).After reaction system is stirred, pour in mould, at 60 ℃ of temperature, after reaction 1h, in water, soak the demoulding, obtain terpolymer hydrogel.
The gel time of this hydrogel is 25 ± 2min; The transparency is good, after swelling, without obvious deformation, occurs; Equilibrium moisture content is 52 ± 1%; The oxygen value of terpolymer hydrogel (Dk/t) is 91*10
-9mL/m
2* s*mmHg; The amount of adsorbed proteins (BSA) is 8.0 ± 0.1mg/g hydrogel.Hydrogel is immersed in 2.5mg/ml Chibroxin, allows drug osmotic in hydrogel network, and useful load is 19.9 ± 0.1mg/g hydrogel.The hydrogel of medicine carrying is placed in to artificial tears, along with the prolong drug of time discharges stably gradually from hydrogel, can reaches slowly mild release in 2h, reach balance after 4h, the cumulative release amount of medicine is in 80% left and right.
Embodiment 2
In container, by the ratio of amount of substance, be that 7.4:2 adds hydroxyethyl methylacrylate (HEMA), NVP (NVP) monomer, then chitosan derivatives (the CH that adds 1wt% hydroxyethyl methacrylate-modified, the percent grafting of two keys is 25%) aqueous acetic acid, wherein the quality of this chitosan derivatives is 0.3% (M of HEMA and NVP gross mass
chitosan derivatives: M
hEMA+NVP); Adding mol ratio is Ammonium persulfate. (APS), tetramethylethylenediamine (TMEDA) redox initiator of 1:1 again, and wherein the quality of initiator is 0.5% (M of HEMA and NVP gross mass
aPS+TMEDA: M
hEMA+NVP); Mass content to the 35% (M of aqueous solvent is added or maintained to whole system
water: M
totally system).After reaction system is stirred, pour in mould, at 60 ℃ of temperature, after reaction 1h, in water, soak the demoulding, obtain terpolymer hydrogel.
The gel time of this hydrogel is 25 ± 2min; The transparency is good, after swelling, without obvious deformation, occurs; Equilibrium moisture content is 53 ± 2%; The oxygen value of terpolymer hydrogel (Dk/t) is 89*10
-9mL/m
2* s*mmHg; The amount of adsorbed proteins (BSA) is 8.0 ± 0.2mg/g hydrogel.Hydrogel is immersed in 2.5mg/ml Chibroxin, allows drug osmotic in hydrogel network, and useful load is 19.5 ± 0.3mg/g hydrogel.The hydrogel of medicine carrying is placed in to artificial tears, along with the prolong drug of time discharges stably gradually from hydrogel, can reaches slowly mild release in 2h, reach balance after 4h, the cumulative release amount of medicine is in 80% left and right.
Embodiment 3
In container, by the ratio of amount of substance, be that 7.4:2 adds hydroxyethyl methylacrylate (HEMA), NVP (NVP) monomer, then chitosan derivatives (the CH that adds 2wt% hydroxyethyl methacrylate-modified, the percent grafting of two keys is 19%) aqueous acetic acid, wherein the quality of this chitosan derivatives is 0.4% (M of HEMA and NVP gross mass
chitosan derivatives: M
hEMA+NVP); Adding mol ratio is Ammonium persulfate. (APS), tetramethylethylenediamine (TMEDA) redox initiator of 1:1 again, and wherein the quality of initiator is 0.5% (M of HEMA and NVP gross mass
aPS+TMEDA: M
hEMA+NVP); Mass content to the 35% (M of aqueous solvent is added or maintained to whole system
water: M
totally system).
After reaction system is stirred, pour in mould, at 60 ℃ of temperature, after reaction 1h, in water, soak the demoulding, obtain terpolymer hydrogel.The gel time of this hydrogel is 25 ± 2min; The transparency is good, after swelling, without obvious deformation, occurs; Equilibrium moisture content is 55 ± 2%; The oxygen value of terpolymer hydrogel (Dk/t) is 94*10
-9mL/m
2* s*mmHg; The amount of adsorbed proteins (BSA) is 7.8 ± 0.3mg/g hydrogel.Hydrogel is immersed in 2.5mg/ml Chibroxin, allows drug osmotic in hydrogel network, and useful load is 19.8 ± 0.4mg/g hydrogel.The hydrogel of medicine carrying is placed in to artificial tears, along with the prolong drug of time discharges stably gradually from hydrogel, can reaches slowly mild release in 2h, reach balance after 4h, the cumulative release amount of medicine is in 80% left and right.
Embodiment 4
In container, by the ratio of amount of substance, be that 7.4:2 adds hydroxyethyl methylacrylate (HEMA), NVP (NVP) monomer, then chitosan derivatives (the CDH that adds 1wt% cyclodextrin and hydroxyethyl methacrylate-modified, the percent grafting of cyclodextrin is 17%, the percent grafting of two keys is 33%) aqueous acetic acid, wherein the quality of this chitosan derivatives is 0.5% (M of HEMA and NVP gross mass
chitosan derivatives: M
hEMA+NVP); Adding mol ratio is Ammonium persulfate. (APS), tetramethylethylenediamine (TMEDA) redox initiator of 1:1 again, and wherein the quality of initiator is 0.5% (M of HEMA and NVP gross mass
aPS+TMEDA: M
hEMA+NVP); Mass content to the 35% (M of aqueous solvent is added or maintained to whole system
water: M
total system).After reaction system is stirred, pour in mould, at 60 ℃ of temperature, after reaction 1h, in water, soak the demoulding, obtain terpolymer hydrogel.
The gel time of this hydrogel is 25 ± 2min; The transparency is good, after swelling, without obvious deformation, occurs; Equilibrium moisture content is 53 ± 1%; The oxygen value of terpolymer hydrogel (Dk/t) is 86*10
-9mL/m
2* s*mmHg; The amount of adsorbed proteins (BSA) is 7.0 ± 0.2mg/g hydrogel.Hydrogel is immersed in 2.5mg/ml Chibroxin, allows drug osmotic in hydrogel network, and useful load is 19.9 ± 0.1mg/g hydrogel.The hydrogel of medicine carrying is placed in to artificial tears, along with the prolong drug of time discharges stably gradually from hydrogel, can reaches slowly mild release in 2h, reach balance after 4h, the cumulative release amount of medicine is in 80% left and right.
Embodiment 5
In container, by the ratio of amount of substance, be that 7.4:2 adds hydroxyethyl methylacrylate (HEMA), NVP (NVP) monomer, then chitosan derivatives (the CDH that adds 1wt% cyclodextrin and hydroxyethyl methacrylate-modified, the percent grafting of cyclodextrin is 17%, the percent grafting of two keys is 33%) aqueous acetic acid, wherein the quality of this chitosan derivatives is 0.4% (M of HEMA and NVP gross mass
chitosan derivatives: M
hEMA+NVP); Adding mol ratio is Ammonium persulfate. (APS), tetramethylethylenediamine (TMEDA) redox initiator of 1:1 again, and wherein the quality of initiator is 0.5% (M of HEMA and NVP gross mass
aPS+TMEDA: M
hEMA+NVP); Mass content to the 35% (M of aqueous solvent is added or maintained to whole system
water: M
total system).After reaction system is stirred, pour in mould, at 40 ℃ of temperature, after reaction 2h, in water, soak the demoulding, obtain terpolymer hydrogel.
The gel time of this hydrogel is 25 ± 2min; The transparency is good, after swelling, without obvious deformation, occurs; Equilibrium moisture content is 52 ± 2%; The oxygen value of terpolymer hydrogel (Dk/t) is 86*10
-9mL/m
2* s*mmHg; The amount of adsorbed proteins (BSA) is 7.1 ± 0.3mg/g hydrogel.Hydrogel is immersed in 2.5mg/ml Chibroxin, allows drug osmotic in hydrogel network, and useful load is 20.0 ± 0.2mg/g hydrogel.The hydrogel of medicine carrying is placed in to artificial tears, along with the prolong drug of time discharges stably gradually from hydrogel, can reaches slowly mild release in 2h, reach balance after 4h, the cumulative release amount of medicine is in 80% left and right.
Comparative example 1
In container, by the ratio of amount of substance, be that 7.4:2 adds hydroxyethyl methylacrylate (HEMA), NVP (NVP) monomer, and then add 35% (M
water: M
always) water, by the ratio of amount of substance, be that 1:1 adds Ammonium persulfate. (APS) and tetramethylethylenediamine (TMEDA) redox initiator, initiator amount is 0.5% (M of monomer gross mass
aPS+TMEDA: M
hEMA+NVP), after stirring, pour in mould, at 60 ℃ of temperature, after reaction 1h, in water, soak the demoulding, obtain bipolymer hydrogel.
The gel time of this hydrogel is 30 ± 3min; The transparency is good, after swelling, without obvious deformation, occurs; Equilibrium moisture content is 50 ± 2%; The oxygen value of terpolymer hydrogel (Dk/t) is 71*10
-9mL/m
2* s*mmHg; The amount of adsorbed proteins (BSA) is 9.3 ± 0.3mg/g hydrogel.Hydrogel is immersed in 2.5mg/ml Chibroxin, allows drug osmotic in hydrogel network, and useful load is 12.0 ± 0.4mg/g hydrogel.The hydrogel of medicine carrying is placed in to artificial tears, along with the prolong drug of time discharges stably gradually from hydrogel, can reaches slowly mild release in 1.5h, reach balance after 4h, the cumulative release amount of medicine is in 75% left and right.
Comparative example 2
In container, by the ratio of amount of substance, be that 7.4:2 adds hydroxyethyl methylacrylate (HEMA), NVP (NVP) monomer, and then add 35% (M
water: M
always) water, by the ratio of amount of substance, be that 1:1 adds Ammonium persulfate. (APS), tetramethylethylenediamine (TMEDA) redox initiator, initiator amount is 0.5% (M of monomer gross mass
aPS+TMEDA: M
hEMA+NVP), after stirring, pour in mould, at 40 ℃ of temperature, after reaction 2h, in water, soak the demoulding, obtain bipolymer hydrogel.
The gel time of this hydrogel is 30 ± 3min; The transparency is good, after swelling, without obvious deformation, occurs; Equilibrium moisture content is 50 ± 2%; The oxygen value of terpolymer hydrogel (Dk/t) is 72*10
-9mL/m
2* s*mmHg; The amount of adsorbed proteins (BSA) is 9.3 ± 0.4mg/g hydrogel.Hydrogel is immersed in 2.5mg/ml Chibroxin, allows drug osmotic in hydrogel network, and useful load is 12.5 ± 0.6mg/g hydrogel.The hydrogel of medicine carrying is placed in to artificial tears, along with the prolong drug of time discharges stably gradually from hydrogel, can reaches slowly mild release in 1.5h, reach balance after 4h, the cumulative release amount of medicine is in 75% left and right.
Comparative example 3
In container, by the ratio of amount of substance, be that 7.4:2 adds hydroxyethyl methylacrylate (HEMA), NVP (NVP) monomer, and then add the chitosan aqueous acetic acid of 1wt%, by the ratio of amount of substance, be that 1:1 adds Ammonium persulfate. (APS), tetramethylethylenediamine (TMEDA) redox initiator, initiator amount is 0.5% (M of monomer gross mass
aPS+TMEDA: M
hEMA+NVP); Mass content to the 35% (M of aqueous solvent is added or maintained to whole system
water: M
total system).After stirring, pour in mould, at 60 ℃ of temperature, after reaction 1h, in water, soak the demoulding, obtain terpolymer hydrogel.
The gel time of this hydrogel is 25 ± 2min; The transparency is poor, occurs a large amount of white dots on hydrogel, cannot meet vision requirement, after swelling, without obvious deformation, occurs; Equilibrium moisture content is 55 ± 2%; The oxygen value of terpolymer hydrogel (Dk/t) is 90*10
-9mL/m
2* s*mmHg; The amount of adsorbed proteins (BSA) is 8.2 ± 0.3mg/g hydrogel.Hydrogel is immersed in 2.5mg/ml Chibroxin, allows drug osmotic in hydrogel network, and useful load is 23.0 ± 0.2mg/g hydrogel.The hydrogel of medicine carrying is placed in to artificial tears, along with the prolong drug of time discharges stably gradually from hydrogel, can reaches slowly mild release in 2h, reach balance after 4h, the cumulative release amount of medicine is in 80% left and right.
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| CN103800949B (en) * | 2014-01-26 | 2015-06-03 | 金陵科技学院 | Corneal contact lens drug carrier with bionic property and preparation method thereof |
| CN103755992B (en) * | 2014-01-26 | 2016-04-13 | 金陵科技学院 | Surface modification of contact lenses for drug delivery |
| CN105111471B (en) * | 2015-09-10 | 2017-08-08 | 暨南大学 | A kind of medicament slow release type contact lens hydrogel material and preparation method and application |
| TWI698454B (en) * | 2019-02-26 | 2020-07-11 | 國立交通大學 | Amphiphilic polymer and manufacturing method thereof, amphiphilic polymer used as contact lens material, contact lens material including the amphiphilic polymer |
| CN113248656A (en) * | 2021-04-28 | 2021-08-13 | 暨南大学 | Multifunctional pHEMA-based corneal contact lens hydrogel material, and preparation method and application thereof |
| CN115028872B (en) * | 2022-06-15 | 2023-05-09 | 金陵科技学院 | A kind of anti-protein adsorption hydrogel material and its preparation method and application |
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| CN101502458A (en) * | 2009-03-03 | 2009-08-12 | 温州医学院眼视光研究院 | Therapeutic corneal contact lens |
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