CN1760212A - Derivatives of new chitosan, preparation method, and application in use for making ophthalmic preparation - Google Patents
Derivatives of new chitosan, preparation method, and application in use for making ophthalmic preparation Download PDFInfo
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- CN1760212A CN1760212A CN 200510095133 CN200510095133A CN1760212A CN 1760212 A CN1760212 A CN 1760212A CN 200510095133 CN200510095133 CN 200510095133 CN 200510095133 A CN200510095133 A CN 200510095133A CN 1760212 A CN1760212 A CN 1760212A
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Abstract
A temp-sensitive chitosan derivative, its preparing process and its application as the additive of eyedrops for quickly changing it to gel to stay on cornea for longer time, so durably playing its role are disclosed.
Description
Technical field
The present invention relates to chemical field and field of pharmaceutical preparations, be specifically related to a kind of new responsive to temperature type chitosan derivatives.The invention also discloses this new responsive to temperature type chitosan derivatives the preparation method, be used for the purposes of ophthalmic preparation and contain the ophthalmic composition of this responsive to temperature type chitosan derivatives.
Background technology
Chitosan is biodegradable and has the natural polymer of biocompatibility, wide material sources, low price, safety non-toxic.Because chitosan has good film-forming properties and thickening property, CN02110501.4A discloses that chitosan is used for recessive glasse liquid medicine and as the purposes of profit eye liquid, and CN02122397.1A discloses chitosan is used for the treatment of xeropthalmus as the artificial tears purposes.Because chitosan can not be dissolved in water and the organic solvent, can only be dissolved in weakly acid soln, therefore limited its application greatly.CN02129937.4 discloses chitin modified one-tenth water-soluble chitosan derivative, refabrication eye drop treatment xeropthalmus, but this eye drop does not have intelligent response to envrionment temperature.
Poly-(N-N-isopropylacrylamide) (PNIPAAm) has very strong susceptibility to envrionment temperature, and low temperature is solution state in water, and high temperature is gel state, and sensitive temperature is 32 ℃.The preparation method of bibliographical information has two kinds: method one under the effect of Potassium Persulphate (KPS), by radical polymerization, is grafted to the 2-NH of chitosan or cm-chitosan with the N-N-isopropylacrylamide
2Go up (S.G.Gholap; M.V.Badiger.Synthesis and Characterization of Polyamphoteric HydrogelMembrane Based on Chitosan.Journal of Applied Polymer Science.2004,93, win orchid 1454-1461. open, Shen Xinyuan, the preparation of Yang Qing thermo-sensitivity chitosan-g-N-N-isopropylacrylamide and sign chemistry world, 2000; 182.Zheng Jing, Wang Junqing, Soviet Union causes emerging chitosan and N-N-isopropylacrylamide graft copolymerization applied chemistry, and 12,2003,1204-1207).See III and IV with the structural formula that this method is prepared.Method two, open loop takes place in chitosan under initiator ceric ammonium nitrate (CAN) effect, and the 3-C that the N-N-isopropylacrylamide is grafted to again chitosan goes up (Kim, So Yeon; Cho, Sung Min; Lee, YoungMoo; Kim, Seon Jeong.Thermo-and pH-responsive behaviors of graft copolymer and blend basedon chitosan and N-isopropylacrylamide.Journal of Applied Polymer Science, 2000,78,1381-1391.J.W.Lee; M.C.Jung; H.D.Park; K.D.Park; G.H.Ryu.Synthesis and characterization ofthermosensitive chitosan copolymer as a novel biomaterial.J.Biomater.Sci.Polymer Edn, 2004; 15 (8): 1065-1079), see V with the structural formula of this method preparation.Because these methods all are directly that the N-N-isopropylacrylamide is monomer-grafted to chitosan under the effect of catalyzer, have more homopolymer PNIPAM by product in the product, influence productive rate.
Summary of the invention
The invention discloses a kind of new chitosan derivatives, it contains temperature sensitive group poly-(N-N-isopropylacrylamide), and structure is seen I, and it possesses the temperature sensitive characteristic of III, IV, V, and the preparation method is much simpler than III, IV, V, is fit to industrialized production.
This seminar finds in the research to the responsive to temperature type chitosan derivatives, with the polymerization of N-N-isopropylacrylamide elder generation, makes the carboxylic acid derivative of poly-(N-N-isopropylacrylamide), then its-2-NH of COOH and chitosan
2Reaction prepares graft copolymer.Prepare the chitosan derivatives that structure is I like this, the structure of gathering (N-N-isopropylacrylamide) for preparing with usefulness method of reporting in the prior art one and method two is different, is a novel texture:
The chitosan derivatives preparation method of this novel texture is simple, by product is few, and can make the temperature sensitive property chitosan derivatives of different degree of substitution according to reaction conditions, makes chitosan have the water-soluble characteristics such as sensitivity that reach temperature simultaneously.
Chitosan derivatives I molecular-weight average of the present invention is 30,000-8,000,000, and the substitution value of poly-(N-N-isopropylacrylamide) is 0.08-0.52.
Structural formula of the present invention is that the chitosan derivatives of I can prepare in order to the below method:
Synthesizing of the carboxylic acid derivative (II) of a, poly-(N-N-isopropylacrylamide)
Methyl alcohol or ethanolic soln, under protection of inert gas, be warming up to 65-75 ℃, slowly add N-N-isopropylacrylamide, azobis isobutyronitrile and 3-thiohydracrylic acid and stir 10-48h down at 65-75 ℃, boil off solvent, mixture is with acetone or ether dissolution, drip sherwood oil or normal hexane, throw out filters, and makes II;
Synthesizing of b, poly-(N-N-isopropylacrylamide) chitosan (I)
Chitosan is dissolved in 1-10% hydrochloric acid or the acetate, the aqueous solution of the II that adding a makes, dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and Tetramethyl Ethylene Diamine solution splash in the above-mentioned reaction solution, stir room temperature reaction 48-96h, filter, filtrate dialysis 2-4d filters the elimination water-insoluble, drying, the chitosan derivatives of structural formula I.The viscosity-average molecular weight relatively more suitable as the chitosan of raw material is 20,000-100, and 000, deacetylation is more than 90%.
More preferred manufacturing procedure is:
A, methanol solution are warming up to 70 ℃ under nitrogen or argon shield, slowly add N-N-isopropylacrylamide, azobis isobutyronitrile and 3-thiohydracrylic acid and stirred 22-26 hour down at 70 ℃, boil off solvent, the mixture acetone solution, drip normal hexane, throw out filters, and makes II;
B, chitosan are dissolved in 1%-10% hydrochloric acid or the acetate, stir down, the aqueous solution of the II that adding a makes, dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and a small amount of Tetramethyl Ethylene Diamine solution splash in the above-mentioned reaction solution room temperature reaction 70-74h, filter, filtrate dialysis 2-4d filters the elimination water-insoluble, lyophilize, promptly.
Responsive to temperature type chitosan derivatives phase transition temperature of the present invention (LCST) is 32 ℃, near human body surface body temperature, and when multipolymer is lower than LCST in temperature, the solution clear.When temperature was higher than LCST, the side chain on the multipolymer underwent phase transition by liquid state and changes gel state into.The contriver is first used as the carrier of dosing eyes, find that it can be used as the ocular in-situ gel material, it has excellent biological compatibility, stimulation is little, it is liquid under the normal temperature, after splashing into eye, can be transformed into gel rapidly, therefore, if it is added in the ophthalmological as new pharmaceutical excipient, when medicine at normal temperatures is an eye drop, after splashing into eye, soup is transformed into gel rapidly, can increase the residence time of medicine like this, prolong drug action time and reach the purpose of slow release long-acting at cornea.For treating ophthalmic diseases clinically, provide a safe and effective medicine carrier.
The invention also discloses a kind of eye drop composition, it is characterized in that containing the eye medicinal and the chitosan derivatives I of the present invention that treat significant quantity.Because it at room temperature is liquid, after splashing into eyes gel, therefore, claim that also this eye drop is the situ-gel eye drop.
The preferred timolol maleate of ophthalmological, acyclovir, erythromycin, Rifampin, gentamicin sulphate, paraxin, Hydrobenzole, iodoxuridine, Ciprofloxacin, Sulf-10, ribavirin, norfloxicin, tobramycin, Ofloxacine USP 23, Pilocarpine nitrate, carteolol hydrochloride, dipivefrine hydrochloride, Tenso-Timelets, cortisone acetate, dexamethasone sodium phosphate or Cortilet described in the above-mentioned situ-gel eye drop.
At situ-gel eye drop composition of the present invention, the preferred content of chitosan derivatives I is 0.01-0.5%, is percent weight in volume.Evidence when the content of chitosan derivatives I in the eye drop is lower than 0.01%, just is not easy to form gel-film when splashing into eyes; And when the content of chitosan derivatives I was higher than 0.5%, then the gel of Xing Chenging can influence the transparency of eyes, therefore, and preferred 0.01-0.5%.
The invention also discloses the situ-gel eye drop composition of timolol maleate, it mainly contains the timolol maleate of 0.25%-0.5% weight percent and the chitosan derivatives I of the present invention of 0.01%-0.04% weight percent.Consisting of of more preferred eye drop composition:
Timolol maleate: 0.25-0.5%
Chitosan derivatives I:0.01-0.1%
Sodium-chlor: 0-0.9%
Fungistat: 0.001%-0.05%
Surplus is that water is percent weight in volume.
Wherein fungistat be Morpan BB, to the hydroxyphenyl methyl ester or to the hydroxyphenyl ethyl ester.When selecting Morpan BB for use, most preferred percent weight in volume is 0.01%.Other two preferred weightmeasurement ratios of fungistat are 0.02%-0.05%.
In the above-mentioned prescription, sodium-chlor plays etc. and to ooze effect, when solution under finite concentration has reached etc. and to have oozed when medicine and auxiliary material, then need not add isotonic agent, does not ooze if reach etc., then is added into etc. to ooze.
Find after chitosan derivatives of the present invention is used for dosing eyes as auxiliary material, eyes not to be had any irritant reaction through the local irritation test.Effect experiment is the result prove: the situ-gel medicine that has added chitosan derivatives I of the present invention is compared with ordinary eye drops, and under same dosage, situ-gel pharmaceutical composition of the present invention is not only more rapid-action than ordinary eye drops, and it is long to keep time of drug effect.
Be part animal experiment and data below:
One. the test of thermosensitive in situ gel local irritation
1. single medication eye irritant test
1.1 lagophthalmos irritation test purpose:
Observe the irritant reaction that produces behind the animal eyes single contact thermosensitive in situ gel solution.
1.2 experimental animal:
Get 6 of healthy rabbits, body weight 2.0-2.5kg, male and female half and half, the animal subject eyes guarantee no any Inflammatory response and ocular injury.
1.3 tried thing:
Chitosan thermosensitive in situ gel solution (0.04% (W/V)) directly splashes into the experimental animal intraocular, each one during test.
1.4 test method:
Adopt the method for consubstantiality own control, select 6 rabbit, observe and write down situations such as each rabbit cornea, iris and conjunctiva before the medication, existing pathology or inflammation person, rejecting need not.In the test, left eye splashes into 1 of chitosan thermosensitive in situ gel solution, and 1 in right eye 0.9% physiological saline compares, and makes the passive closed 10s of eyes after splashing into, observation 2,4,6,8,24,48,96h eyes local reaction situation.
1.5 judging criterion and test-results:
(1993:208-209) middle eye irritation judgement criteria is marked for new drug (Western medicine) preclinical study governing principle compilation (pharmacy, pharmacology, toxicity), bureau of drug administration of Ministry of Health of the People's Republic of China volume to press reference.
1.6 test-results:
Behind the temperature sensitive chitosan gel rubber solution single-dose 2,4,6,8,24,48,96h, eye stimulates an integration not have significant difference compared with the control, each observes eye droppings irritant reaction integration is 0 minute.
1.7 conclusion (of pressure testing):
After single was given temperature sensitive chitosan gel rubber solution, eye irritant reaction integration was compared equal no significant difference with the contrast eye, and each rabbit, each time eye droppings irritant reaction integration are 0 fen.The temperature sensitive chitosan as the medication of ophthalmic gel base single to the eye nonirritant.
2. multiple dosing eye irritant test
2.1 lagophthalmos irritation test purpose:
Observe animal eyes and repeatedly contact the irritant reaction situation that produces behind the thermosensitive in situ gel solution.
2.2 experimental animal:
Get 2 of healthy rabbits, body weight 2.0-2.5kg, male and female half and half, the animal subject eyes guarantee no any Inflammatory response and ocular injury.
2.3 tried thing:
Chitosan thermosensitive in situ gel solution (0.04% (W/V)) directly splashes in the experimental animal eye during test.
2.4 test method:
Adopt the method for consubstantiality own control, select 2 rabbit, observe and write down situations such as each rabbit cornea, iris and conjunctiva before the medication, existing pathology or inflammation person, rejecting need not.In the test, left eye splashes into 1 of chitosan thermosensitive in situ gel solution, and 1 in right eye 0.9% physiological saline compares, make the passive closed 10s of eyes after splashing into, give every day and tried thing twice, continuously 7d, observe the local reaction situation every day twice during the medication, and twice score value is average, as this day score value.
2.5 judging criterion and test-results:
(1) judging criterion: with 1.5.
(2) test-results: temperature sensitive chitosan gel rubber solution multiple dosing stimulates each time point of integration to be 0 fen.
2.6 conclusion:
The responsive chitosan gel rubber solution of the continuous dropping temperature of lagophthalmos 7d, and observe the eye situation that begins to drip in the 7d of back continuously, eye irritant reaction integration is compared with the contrast eye does not have noticeable change, and each time point eye irritant reaction integration of lagophthalmos is 0 fen.Thermosensitive in situ gel solution does not have the eye pungency after repeatedly giving lagophthalmos.
Two. the test of lagophthalmos residence time
1 test objective:
Select for use fluorescein as colour development material, observe temperature sensitive chitosan gel for eye use and the difference condition of aqueous solution residence time in animal eye.
2 experimental animals
6 of adult healthy rabbit, body weight 2.0-2.5kg, male and female half and half, the animal subject eyes do not have any Inflammatory response and ocular injury.
3 materials
Uranine temperature sensitive chitosan gel rubber solution; The uranine aqueous solution.
Take by weighing temperature sensitive chitosan 0.02g and be dissolved in the water for injection of 50ml, behind the homodisperse, slowly add Fluress 2ml, preparation becomes uranine temperature sensitive chitosan gel rubber solution, and is stand-by;
Measure 50ml water for injection, drip uranine 2ml solution for later use, be prepared into the uranine aqueous solution, stand-by.
4 instruments
The multi-functional ultraviolet analysis instrument for three purposed of UV-I type (Shanghai standing grain vapour Chemical Industry Science Co., Ltd); BS110S electronic analytical balance (Beijing Sai Duolisi balance company limited)
5 test methods:
Select 6 of healthy rabbits for use, with each rabbit fixing head, mention lower eyelid during test, conjunctival sac is pulled into ring-type, right eye splashes into uranine gel 2d, and left eye splashes into Fluress 2d in contrast, and the passive 30s that closes places the back observation and develops the color and disappear the time of taking off.
6 judging criterions and test-results:
Uranine has tangible yellow fluorescence under the 365nm uviolizing, observe the fluorescence residence time in rabbit cornea, conjunctiva and the conjunctival sac after the administration.The maximum duration that can observe fluorescence with three position naked eyes in lagophthalmos during interpretation of result is a standard.
Find in the observation that Fluress is difficult to stop on rabbit cornea, the i.e. all disappearances of fluorescence behind the 10min after the general administration.
The uranine thermosensitive in situ gel can form persistent gel-film in cornea, conjunctiva, conjunctival sac, see obviously that under ultraviolet lamp there is yellow fluorescence on the lagophthalmos surface, prolong in time, though fluorescence intensity weakens, naked eyes still can observe fluorescence for a long time.
Result such as Fig. 1 show that the uranine aqueous solution is 6min (n=6) at the average retention time of lagophthalmos, and the uranine thermosensitive in situ gel is at the average retention time 114min of lagophthalmos (n=6).The average retention time of thermosensitive in situ gel in lagophthalmos compared with the average retention time in the aqueous solution, and both have significant difference (p＜0.01).
7 experiment conclusion:
Lagophthalmos residence time test-results explanation situ-gel is transformed into gel rapidly after splashing into eye, viscosity increases, and has prolonged the residence time at cornea.
Three. to the influence of the high Intraocular Pressure Model of prototype version rabbit
1. test objective:
Timolol maleate situ-gel eye drop pharmacodynamic study.This test is animal pattern with the rabbit, by the glaucoma rabbit model that Chymetin brings out, investigates the preliminary drug effect of timolol maleate situ-gel eye drop.
2. experimental animal and instrument:
Tonometer press-fall tonometer (Suzhou Medical Instruments Factory), the timolol maleate situ-gel eye drop that embodiment 3 makes, commercially available common Timolol maleate eye drops (25mg: 5ml), Chymetin (Beijing chemical reagents corporation)
4 of New Zealand white rabbit, body weight 2-3kg, health, no eye illness, the male and female dual-purpose, continuously measured 3d intraocular pressure is normal and stable.
3. animal model:
Rabbit is fixed on the rabbit platform after anaesthetizing with vetanarcol, insert human eye's anterior chamber with needle tubing along the cornea upper limb again, injection 0.5ml etc. oozes Chymetin solution (containing the 15ul Chymetin), measures the varieties of intraocular pressure situation in 2-7 day, reached 50mmHg when continuous 3 days when above, i.e. modeling success.
4. intraocular pressure determination after the administration:
Select for use modeling successfully to suffer from 4 of glaucomatous rabbit, after head fixed, mention lower eyelid, conjunctival sac pulls into ring-type, and right eye splashes into 2 of common Timolol maleate eye drops, and 2 of the timolol maleate situ-gel eye drops that left eye splashes into embodiment 3 preparation in contrast, the passive 30s that closes of eyes, behind the eye drip, respectively 0,0.5,1,2,4,5,6,8,10,12,24h measures intraocular pressure, each intraocular pressure drop-out value is constantly represented with △ IOP: △ IOP=(IOP) t-(IOP) t
0, (△ IOP) is the intraocular pressure drop-out value in the t time in the formula, (IOP) t is the intraocular pressure measured value of t time, (IOP) t
0It is 0 time point intraocular pressure measured value.
5. test-results:
Timolol maleate situ-gel eye drop and Timolol maleate eye drops show 4 groups of experimental results such as Fig. 3 of the reducing iop of chronic eye high pressure model, ordinary eye drops reaches maximum reducing value 2.4kpa about 4h, and thermosensitive in situ gel solution reaches maximum reducing value 3.4kpa at 2h, data are carried out t-text and 3p87 statistical study, the area under curve AUC of timolol maleate situ-gel eye drop and Timolol maleate eye drops and average retention time t
MRTHave significance to change, p＜0.05 has significant difference.
6 conclusions:
Effect experiment presentation of results timolol maleate situ-gel eye drop is strong than the ordinary eye drops reducing iop, and onset time early.
Description of drawings:
Fig. 1 compares the uranine eye residence time
Fig. 2 is the mensuration curve of chitosan derivatives phase transition temperature LCST of the present invention
Fig. 3 is timolol maleate situ-gel eye drop of the present invention and the Timolol maleate eye drops intraocular pressure lowering curve to new zealand rabbit chronic eye high pressure model
Embodiment
Embodiment 1
Responsive to temperature type chitosan derivatives I's is synthetic:
The deacetylation of chitosan is more than 90%, and viscosity-average molecular weight is 60,000.Agents useful for same is analytical pure and chemical pure.The dialysis tubing molecular weight cut-off is 10000 (MWCO=10 000).
1.1 the carboxylic acid derivative (PNIPAAm-COOH) of poly-(N-N-isopropylacrylamide) is synthetic
Add the 10ml methanol solution in the three-necked bottle, under nitrogen protection, be warming up to 70 ℃, slowly add N-N-isopropylacrylamide (IPN; 1g, 8.9mmol), azobis isobutyronitrile (AIBN, 20mg; 0.12mmol) and the 3-thiohydracrylic acid (3-MPA, 0.2ml, 0.11mmol); continue logical nitrogen, and stir 24h down, boil off solvent at 70 ℃; mixture 20ml acetone solution drips the 1ml normal hexane, and throw out filters; 40 ℃ of following vacuum-dryings, make PNIPAAm-COOH 980mg.
By the titration measuring product-COOH content, can extrapolate the molecular-weight average of product.With the NaOH solution titration polymer ends carboxyl of 0.01mol/L, the PNIPAAm-COOH molecular weight that obtains is about 2500 in this experiment.
1.2 poly-(N-N-isopropylacrylamide) chitosan (PNIPAAm-CS) is synthetic
(250mg 1.55mmol) is dissolved in 10ml 2% hydrochloric acid chitosan, stirs down, the 10ml aqueous solution of the 980mgPNIPAAm-COOH that 1.1 steps of adding make, dicyclohexylcarbodiimide (DCC, 200mg, 1.24mmol) and 0.5ml Tetramethyl Ethylene Diamine (TEMED) solution splash in the above-mentioned reaction solution, stir room temperature reaction 72h, filter, filtrate places dialysis tubing (MWCO=10 000) to use distill water dialysis 4d, filters the elimination water-insoluble once more, freeze-drying gets light brown powder 141mg.
The ultimate analysis data of PNIPAAm-CS: N 6.52%, and C 36.29%, and H 7.16%, C/N=6.52 (mol ratio), and the substitution value that can calculate PNIPAAm according to the ultimate analysis data is 52%.
Embodiment 2
The mensuration of the phase transition temperature LCST of situ-gel solution
The copolymer solution of preparation 5mg/ml, stirring at room 24h puts into the polystyrene cuvette, measures transmittance on ultraviolet spectrophotometer.Sample pool is placed on heating in water bath after the mensuration temperature, puts into sample cell, measure transmittance at the 500nm place.Temperature is from 26-40 ℃, every 1 ℃ of mensuration once.
As Fig. 2, when temperature takes place rapidly to change mutually at 32-33 ℃ of this synthetic chitosan derivatives, and this changes mutually and has reversibility, and therefore being applied to eye can be transformed into gel very soon.The phase transformation that takes place when storage temperature raises also can recover original proterties as long as give suitable cooling.
Embodiment 3
Timolol maleate situ-gel eye drop and preparation method thereof
Temperature sensitive timolol maleate situ-gel eye drop 1000ml, it consists of the 5.0g timolol maleate, responsive to temperature type chitosan derivatives I 0.4g, sodium-chlor 9g, Morpan BB 0.12g, yellow soda ash is regulated pH, and all the other are sterilized water for injection.
Get temperature sensitive chitosan derivatives and add an amount of sterilized water for injection, stir, make its abundant swelling, make blank gelating soln; To write out a prescription in addition main ingredient timolol maleate, sodium-chlor, Morpan BB, be dissolved in the sterilized water for injection, stir and make its dissolving, filter, filtrate is added in the blank gelating soln, mixing, pH is 7 with the yellow soda ash adjusting.Add sterilized water for injection to capacity, stirring to make becomes homogeneous solution, that is, more than operation is all carried out under aseptic condition below 30 ℃.
Embodiment 4
Acyclovir situ-gel eye drop and preparation method thereof
Temperature-sensitive situ-gel eye drop 1000ml, it consists of the 1g acyclovir, responsive to temperature type chitosan derivatives 0.2g, boric acid 9.3g, borax 4.8g, Morpan BB 0.12g, tween-80 2ml, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 5
Ribavirin situ-gel eye drop
Temperature sensitive ribavirin (ribavirin) situ-gel eye drop 1000ml, it consists of the 11g ribavirin, responsive to temperature type chitosan derivatives 0.8g, sodium-chlor 9g, ethyl p-hydroxybenzoate 0.3g, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 6
Rifampin situ-gel eye drop and preparation method thereof
Temperature sensitive Rifampin situ-gel eye drop 1000ml, it consists of the 1g Rifampin, responsive to temperature type chitosan derivatives 0.5g, tween-80 10ml, the hydrochloric acid 94ml of 1mol/L, 1mol/L potassium hydroxide 94ml, boric acid 11.7g, all the other are sterilized water for injection.
Get the boric acid and the tween-80 of recipe quantity, add an amount of sterilized water for injection, stir and make it dissolving, filter, add the injection water, stir evenly to 500ml; Other gets Rifampin, and the hydrochloric acid 94ml that adds 1mol/L places the 300ml volumetric flask, and the dissolving back adds in the above-mentioned solution, slowly adds 1mol/L potassium hydroxide 94ml again, stirs.Temperature sensitive chitosan derivatives adds an amount of sterilized water for injection, stir, make its abundant swelling, make blank gelating soln, join the solution of above-mentioned preparation, mix, add sterilized water for injection to 1000ml, stir evenly, filter, promptly get (above operation is all carried out) under aseptic condition below 30 ℃.
Embodiment 7
Gentamicin sulphate situ-gel eye drop
Temperature sensitive gentamicin sulphate situ-gel eye drop 1000ml, it consists of the 3g gentamicin sulphate, responsive to temperature type chitosan derivatives 0.6g, sodium-chlor 9g, ethylparoben 0.3g, yellow soda ash is regulated pH, and all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 8
Paraxin situ-gel eye drop
Temperature sensitive paraxin situ-gel eye drop 1000ml, it consists of 1g paraxin, responsive to temperature type chitosan derivatives 0.4g, boric acid 12g, borax 0.57g, sodium-chlor 2.2g, ethylparoben 0.3g, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 9
Hydrochloric acid Hydrobenzole situ-gel eye drop
Temperature sensitive hydrochloric acid Hydrobenzole situ-gel eye drop 1000ml, it consists of 1g hydrochloric acid Hydrobenzole, responsive to temperature type chitosan derivatives 0.8g, sodium-chlor 9g, Morpan BB 0.12g, Sodium phosphate dibasic is regulated pH, and all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 10
Iodoxuridine situ-gel eye drop
Temperature sensitive iodoxuridine situ-gel eye drop 1000ml, it consists of the 5.0g iodoxuridine, responsive to temperature type chitosan derivatives 0.3g, sodium-chlor 9g, Morpan BB 0.12g, yellow soda ash is regulated pH, and all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 11
Ciprofloxacin HCl situ-gel eye drop
Temperature sensitive ciprofloxacin HCl situ-gel eye drop 1000ml, it consists of the 3g ciprofloxacin HCl, responsive to temperature type chitosan derivatives 0.5g, sodium-chlor 6.6g, ethylparoben 0.3g, disodium ethylene diamine tetraacetate 0.1g, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 12
Sulf-10 situ-gel eye drop
Temperature sensitive Sulf-10 situ-gel eye drop 1000ml, it consists of the 150g Sulf-10,0.8g responsive to temperature type chitosan derivatives, the 0.1g edetic acid, 10g Sulfothiorine, the 0.3g ethylparoben, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 13
Erythromycin situ-gel eye drop and preparation method thereof
Temperature-sensitive situ-gel eye drop 1000ml, it consists of 5g erythromycin, responsive to temperature type chitosan derivatives 0.1g, sodium-chlor 9g, Morpan BB 0.12g, Sodium phosphate dibasic is regulated pH, and all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 14
The preparation method of norfloxicin (Norxin) situ-gel eye drop
Temperature-sensitive situ-gel eye drop 1000ml, it consists of the 3g norfloxicin, responsive to temperature type chitosan derivatives 0.9g, sodium-chlor 9g, Morpan BB 0.12g, hydrochloric acid (0.1mol/l) 75ml, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 15
The preparation method of tobramycin situ-gel eye drop
Temperature sensitive tobramycin situ-gel eye drop 1000ml, it consists of the 3g tobramycin, responsive to temperature type chitosan derivatives 0.4g, boric acid 16g, Thiomersalate 0.02g, Sodium Citrate 2g, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 16
The preparation method of Ofloxacine USP 23 (Zanocin) situ-gel eye drop
Temperature sensitive Ofloxacine USP 23 (Zanocin) situ-gel eye drop 1000ml, it consists of the 3g Ofloxacine USP 23, responsive to temperature type chitosan derivatives 0.2g, sodium-chlor 9g, ethylparoben 0.3g, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 17
The preparation method of Pilocarpine nitrate (pilocarpine) situ-gel eye drop
Temperature sensitive Pilocarpine nitrate situ-gel eye drop 1000ml, it consists of the 10g Pilocarpine nitrate, responsive to temperature type chitosan derivatives 0.7g, Zonon D 0.5g, ethylparoben 0.3g, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 18
The preparation method of carteolol hydrochloride situ-gel eye drop
Temperature sensitive carteolol hydrochloride situ-gel eye drop 1000ml, it consists of the 10g carteolol hydrochloride, responsive to temperature type chitosan derivatives 0.1g, sodium-chlor 9g, Morpan BB 0.12g, yellow soda ash is regulated pH, and all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 19
The preparation method of dipivefrine hydrochloride situ-gel eye drop
Temperature sensitive dipivefrine hydrochloride situ-gel eye drop 1000ml, it consists of the 1g dipivefrine hydrochloride, responsive to temperature type chitosan derivatives 0.3g, sodium-chlor 9g, Morpan BB 0.12g, yellow soda ash is regulated pH, and all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 20
The preparation method of Tenso-Timelets situ-gel eye drop
Temperature sensitive Tenso-Timelets situ-gel eye drop 1000ml, it consists of the 1g clonidine, responsive to temperature type chitosan derivatives 1.0g, sodium-chlor 9g, Morpan BB 0.12g, yellow soda ash is regulated pH, and all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 21
The preparation method of hydrocortisone acetate situ-gel eye drop
Temperature sensitive hydrocortisone acetate situ-gel eye drop 1000ml, it consists of the 5g hydrocortisone acetate, responsive to temperature type chitosan derivatives 1g, boric acid 20g, tween-80 0.8g, oil of mirbane mercury 0.02g, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 22
The preparation method of dexamethasone sodium phosphate situ-gel eye drop
Temperature sensitive dexamethasone sodium phosphate situ-gel eye drop 1000ml, it consists of the 0.25g dexamethasone sodium phosphate, responsive to temperature type chitosan derivatives 0.6g, sodium-chlor 9g, bromogeramine 0.5g, sodium hydroxide (1mol/l) is regulated pH7, and all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Embodiment 23
The preparation method of Cortilet (fluorometholone) situ-gel suspendible eye drop
Temperature sensitive Cortilet situ-gel eye drop 1000ml, it consists of the 1g Cortilet, responsive to temperature type chitosan derivatives 0.25g, boric acid 16g, borax 2.10g, Morpan BB 0.12g, EDTA-2Na 0.1g, all the other are sterilized water for injection.
The preparation method is with embodiment 3.
Claims (10)
1, the chitosan derivatives of following formula structure I:
Molecular-weight average is 30,000-8,000,000, and the substitution value of poly-(N-N-isopropylacrylamide) is 0.08-0.52.
2, the preparation method of the chitosan derivatives of claim 1 comprises: with the polymerization of N-N-isopropylacrylamide elder generation, make poly-(N-N-isopropylacrylamide)) carboxylic acid derivative, the 2-NH of its carboxyl-COOH and chitosan then
2Reaction, promptly.
3, the preparation method of claim 2 comprises:
Synthesizing of the carboxylic acid derivative (II) of a, poly-(N-N-isopropylacrylamide):
Methyl alcohol or ethanolic soln, under protection of inert gas, be warming up to 65-75 ℃, slowly add N-N-isopropylacrylamide, azobis isobutyronitrile and 3-thiohydracrylic acid and stir 10-48h down at 65-75 ℃, boil off solvent, mixture is with acetone or ether dissolution, drip sherwood oil or normal hexane, throw out filters, and makes II;
Synthesizing of b, poly-(N-N-isopropylacrylamide) chitosan (I):
Chitosan is dissolved in 1%-10% hydrochloric acid or the acetate, the aqueous solution of the II that adding a step makes, dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and Tetramethyl Ethylene Diamine solution splash in the above-mentioned reaction solution, stir room temperature reaction 48-96h, filter, the elimination water-insoluble is filtered in filtrate dialysis 2-4 days, drying, the chitosan derivatives of structural formula I.
4, the preparation method of claim 3 comprises:
Methanol solution is warming up to 70 ℃ under nitrogen or argon shield, slowly add N-N-isopropylacrylamide, azobis isobutyronitrile and 3-thiohydracrylic acid and stirred 22-26 hour down at 70 ℃, boils off solvent, the mixture acetone solution, drip normal hexane, throw out filters, and makes II;
Chitosan is dissolved in 2% hydrochloric acid, stir down, the aqueous solution of the II that adding a step makes, dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and Tetramethyl Ethylene Diamine solution splash in the above-mentioned reaction solution room temperature reaction 70-74h, filter, the elimination water-insoluble is filtered in filtrate dialysis 2-4 days, lyophilize, promptly.
5, the chitosan derivatives of claim 1 is used for the purposes of dosing eyes carrier.
6, a kind of eye drop composition wherein contains the ophthalmological for the treatment of significant quantity and the chitosan derivatives of claim 1.
7, the eye drop composition of claim 6, ophthalmological wherein are timolol maleate, acyclovir, erythromycin, Rifampin, gentamicin sulphate, paraxin, hydrochloric acid Hydrobenzole, iodoxuridine, ciprofloxacin HCl, Sulf-10, ribavirin, norfloxicin, tobramycin, Ofloxacine USP 23, Pilocarpine nitrate, carteolol hydrochloride, dipivefrine hydrochloride, Tenso-Timelets, cortisone acetate, dexamethasone sodium phosphate, Cortilet.
8, the eye drop composition of claim 6 wherein contains the chitosan derivatives of the claim 1 of 0.01%-0.5% percent weight in volume.
9, the eye drop composition of claim 6 wherein contains the timolol maleate of 0.25%-0.5% percent weight in volume, the chitosan derivatives of the claim 1 of 0.01-0.1% percent weight in volume, and surplus is a water.
10, the eye drop composition of claim 8, wherein contain:
Timolol maleate: 0.25-0.5%
Chitosan derivatives: 0.01-0.1%
Sodium-chlor: 0-0.9%
Fungistat: 0.001%-0.05%
Surplus is that water is percent weight in volume
Wherein fungistat be Morpan BB, to the hydroxyphenyl methyl ester or to the hydroxyphenyl ethyl ester.
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