Summary of the invention
The objective of the invention is to overcome above-mentioned existing ophthalmic and implant the shortcoming of weak point, intraocular drug concentration instability or drug effect difference of the drug release time release preparation, lasting, a kind of implantation slow release medicine in eyes is provided, implant the delivery system of long-term release for ophthalmic, can not penetrate the paropion barrier to avoid present ophthalmic to implant the release preparation, reach the difficult problem of effective intraocular drug concentration.
Task of the present invention is realized by following technical scheme, has developed a kind of implantation slow release medicine in eyes, and it contains the FK-506 macrolide antibiotics, absorbs promotion/protective agent and biodegradable voluntarily pharmaceutical carrier; Three's weight ratio is 1: 0.05-1.5: 0.25-4.
Described absorption promotion/protective agent, it comprises: the chitosan compounds, its chemical name is for gathering-1, and 4-β-glucamine, its chemical general formula are (C
6H
11O
4N) n, wherein n is: 10-20.
Described chitosan chemical compound, it comprises: trimethyl chitosan glutamate, Glu, its chemical general formula are (C
14H
27O
7N
2) n, wherein n is: 10-20; The hydrochlorate of chitosan, its chemical general formula are (C
6H
10O
3NCl) n, wherein n is: 10-20; Chitosan glutamate, Glu, its chemical general formula are (C
11H
18O
7N
2) n, wherein n is; 10-20.
Described biodegradable voluntarily pharmaceutical carrier, it comprises: lactic acid/ethanol copolymer (PLGA), poly-DL-lactic acid (PDLLA), glycolic/lactic acid/caprolactone terpolymer (PGLC), polycaprolactone/polyether block copolymer (PCE), polycaprolactone/polylactic acid terpolymer (PCEI) and poly-L-lactic acid (PLLA) select one or more as pharmaceutical carrier.Slow degraded by pharmaceutical carrier reaches the purpose that discharges medicine.
The size of above-mentioned pharmaceutical carrier pore structure and density are realized by the method for control solution evaporation speed.That is, by the mixed proportion of control solvent and polymer, by control solution evaporation speed, drain afterwards earlier, make the solvent evaporates leaving space, just can obtain the polymer in different apertures as freezing.Or the method for control pore dosage, or, control the size and the density of carrier hole structure by controlling the method for Density.
The invention has the advantages that: because this slow releasing pharmaceutical contains the FK-506 macrolide antibiotics, absorb promote, protective agent, can biodegradable voluntarily pharmaceutical carrier; Because as absorbing promotion/protectant chitosan salt, molecular level studies confirm that, having the mechanism of action that improves mucosa permeability is to be connected on the cell membrane to carry positive charge on its molecule, make on the film iuntercellular proteic structure of combining closely change, thereby cause the opening of transmembrane channel, have high-hydroscopicity and high liposuction, can liposoluble, again can be water-soluble, and itself and cell affinity are good, promote cell activity; Therefore can assist the FK-506 macrolide antibiotics by or act on cornea substrate, play the absorption that promotes FK-506 and the effect of protection cornea.Experiment confirm, in little acid environment the hydrochlorate of chitosan, chitosan glutamate, Glu, can reduce significantly monomolecular film to stride membrane resistance anti-, thereby increase its permeability, promote drug absorption.This drug delivery system is drug release under the interaction between the three, can penetrate the paropion barrier, reach effective intraocular drug concentration, can keep certain intensity and shape, thereby and can be absorbed and excrete by natural degradation under the physiological condition in vivo by metabolism, neither can become foreign body body is produced stimulation, also can not make body produce foreign body reaction, therefore not need the row second operation that it is taken out.FK-506 delivery system of the present invention is long lasting delivery system, and the release cycle of FK-506 is that three weeks are to half a year; It is few to have dosage, is not subjected to the influence of tear towards Xian, dilution, can slowly discharge the medicine characteristics for a long time within the eye.The vitrification point that this drug delivery system is the same with human temperature, have the medicine of this specific character to implant eye after, to not damage of ocular tissue, histocompatibility is good.For as the unapproachable position of medicines such as eyeball, can meet the requirements of drug level and good medication effect.This drug delivery system can be used for the prevention of ophthalmology disease and the rejection after the treatment corneal transplantation, simultaneously also can be used for treating chronic uveitis, behcets disease, the ophthalmology autoimmune diseases such as vernal conjunctivitis of stevene-Johnson syndrome, stubbornness.
The specific embodiment
Embodiment 1
Embodiment 1.1
Extracting lactic acid/ethanol copolymer (PLGA, molecular weight 6~110,000) 5 parts, with adding 20 parts in FK-506 powder after 40 parts of dissolvings of chloroform, (be FK-506/PLGA weight ratio=20/5=1/0.25) available from the great marine health food company limited in Qingdao (address: 3 parts of trimethyl chitosan glutamate, Glus Chengyang District Dan Shan industry park, Qingdao City), (be that the politef mould is injected in the back that stirs of FK-506/ trimethyl chitosan glutamate, Glu weight ratio=20/3=1/0.15), treat the chloroform volatilization, and behind the bone dry, this medicine film that contains lactic acid/ethanol copolymer of FK-506 is taken off from the politef mould, further desolventizing is 72 hours under the room temperature vacuum, getting thickness is the 1.5--2.0 millimeter, have the flaky of nano grade pore structure, the medicine film that contains lactic acid/ethanol copolymer of FK-506, reuse aperture are that the punch die of 1.5--2.0 millimeter is washed into the thick 1.5--2.0 millimeter that is, diameter is the FK-506 preparation of 1.5--2.0 millimeter.1 week back implantation lagophthalmos anterior chamber was sterilized, placed to this FK-506 preparation in 24 hours with epoxyethane fumigation.
The perusal of postoperative and local histopathological examination result show: the reaction of anterior chamber's NIP; Cornea, crystalline lens transparency and iris are normal; Intraocular pressure is also normal, the perioperatively no change.In addition, there are not obvious inflammatory cell infiltration, inorganization degeneration and downright bad performance from iris, corpus ciliare and the cornea meat skin cell at the indicated position, FK-506 delivery system place of local organization pathological examination result, and the angle, room at position, FK-506 delivery system place do not have obvious difference with normal room corner structure, proves that the ophthalmic biocompatibility of FK-506 delivery system is good.
In addition, in 12 weeks of implanting the FK-506 delivery system, the aqueous humor midium or long term keeps certain FK-506 concentration and is not less than 10ng/ml, generally maintains between 10~25ng/ml, FK-506 aqueous humor concentration releasing curve diagram is steady, can effectively prevent corneal allograft rejection.In blood, detect simultaneously existence, illustrate that this delivery system can avoid FK-506 to the toxicity damage of kidney and cause complication such as hypertension less than FK-506.Corpus ciliare choroideaes etc. are organized the higher about 8~15ng/g of the drug level of FK-506.This FK-506 delivery formulations can take out in 12-48 complete obiteration after week of implanting again.
Embodiment 1.2
Press method and the step of embodiment 1.1, (address: the hydrochlorate of chitosan Chengyang District Dan Shan industry park, Qingdao City) is short absorbent, and 3 parts of the hydrochlorates of chitosan (are FK-506/ trimethyl chitosan hydrochlorate weight ratio=20/3=1/0.15) available from the great marine health food company limited in Qingdao in employing.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, and the FK-506 aqueous humor concentration is between 5~20ng/ml in the week of 12 after the implantation.Detect existence in the blood less than FK-506.Corpus ciliare choroideaes etc. organize the drug level of FK-506 low than embodiment 1.1, between 3~8ng/g.12-48 is the complete obiteration of FK-506 preparation after week, can take out again.
Embodiment 2
Embodiment 2.1
Get poly-DL-lactic acid (PDLLA, molecular weight 3~60,000) 3 parts, 2 parts of 20 parts of dioxane and FK-506 medicines, (being FK-506/PDLLA weight ratio=2/3=1/1.5), (address: 3 parts of trimethyl chitosan glutamate, Glus Chengyang District Dan Shan industry park, Qingdao City) (are FK-506/ trimethyl chitosan glutamate, Glu weight ratio=2/3=1/1.5) available from the great marine health food company limited in Qingdao, inject the politef mould behind dissolving and the mix homogeneously, put into freeze dryer, desolventizing is 72 hours under frozen state and vacuum, getting thickness is the 1.5--2.0 millimeter, the aperture is about 50 microns flake film, and the reuse aperture is that 1.5 ~ 2.0 millimeters punch die is washed into the thick 1.5--2.0 millimeter that is, diameter is the FK-506 preparation of 1.5--2.0 millimeter.This FK-506 preparation was sterilized, places the anterior chamber who implements 1 method implantation lagophthalmos together after 1 week in 24 hours with epoxyethane fumigation.
The perusal of postoperative and local histopathological examination result show that the FK-506 delivery system has good ophthalmic biocompatibility, it is steady regularly to detect FK-506 aqueous humor concentration releasing curve diagram in after the implantation 14 week, concentration is not less than 15ng/ml, generally maintain between 20~30ng/ml, and in blood, detect less than there being FK-506 to exist, corpus ciliare choroideaes etc. are organized the about 10~20ng/g of the drug level of FK-506.The back FK-506 preparation complete obiteration of 14 weeks can be taken out again.
Embodiment 2.2
Press method and the step of embodiment 2.1, (address: the hydrochlorate of chitosan Chengyang District Dan Shan industry park, Qingdao City) is short absorbent, 3 parts of the hydrochlorates of chitosan available from the great marine health food company limited in Qingdao in employing.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, regularly detect FK-506 in the week of 14 after the implantation and can keep certain concentration at aqueous humor, generally between 8~20ng/ml.Detect existence in the blood less than FK-506.Corpus ciliare choroideaes etc. organize the drug level of FK-506 low than embodiment 2.1, about 5~10ng/g.The back FK-506 preparation complete obiteration of 14 weeks can be taken out again.
Embodiment 3
Embodiment 3.1
Press method and the step of embodiment 1.1, but adopt (glycolic/lactic acid/caprolactone terpolymer (PGLC of pressing the preparation of Chinese invention patent ZL 99105984.0 methods, molecular weight 80,000) 3 part, 9 parts of 18 parts of dichloromethane and FK-506 medicines, (being FK-506/PGLC weight ratio=9/3=1/0.33), (address: 3 parts of trimethyl chitosan glutamate, Glus Chengyang District Dan Shan industry park, Qingdao City) (are FK-506/ trimethyl chitosan glutamate, Glu weight ratio=9/3=1/0.33) available from the great marine health food company limited in Qingdao, make the block that is nano-pore structure, the reuse aperture is that to be washed into diameter be 2 millimeters medicine rod to 2.0 millimeters punch die.This medicine rod cut into further in the room temperature vacuum drying oven, keep 48 hours after the Formulation that requires thickness again, then carry out epoxyethane fumigation sterilization in 24 hours to eliminate solvent fully.Place the 1 Zhou Houzai anterior chamber of method implantation lagophthalmos similarly to Example 1.
The perusal of postoperative and local histopathological examination result show that the FK-506 delivery system has good ophthalmic biocompatibility, without any inflammatory reaction, FK-506 can keep finite concentration in after the implantation 10~20 week in aqueous humor, the aqueous humor concentration releasing curve diagram is steady, generally maintains between 40~50ng/ml.And in blood, detect less than there being FK-506 to exist, corpus ciliare choroideaes etc. are organized the about 25~40ng/g of the drug level of FK-506.10~20 week back FK-506 and the complete obiterations of pharmaceutical carrier preparation can be taken out again.
Embodiment 3.2
Press method and the step of embodiment 3.1, (address: the hydrochlorate of chitosan Chengyang District Dan Shan industry park, Qingdao City) is short absorbent, and 3 parts of the hydrochlorates of chitosan (are FK-506/ trimethyl chitosan hydrochlorate weight ratio=9/3=1/0.33) available from the great marine health food company limited in Qingdao in employing.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, and FK-506 can keep finite concentration in the week of 10~20 after the implantation in aqueous humor, generally maintains between 20~35ng/ml.Detect existence in the blood less than FK-506.Corpus ciliare choroideaes etc. are organized the about 15~25ng/g of the drug level of FK-506.The back FK-506 preparation complete obiteration of 10~20 weeks can be taken out again.
Embodiment 4
Embodiment 4.1
With embodiment 2.1 same procedure and step, but adopt polycaprolactone/polyether block copolymer (PCE by the preparation of patent of invention ZL 92113100.3 methods, molecular weight 4~80,000) preparation, the pore structure size is 10 microns a FK-506 preparation, (address: 0.1 part of trimethyl chitosan glutamate, Glu Chengyang District Dan Shan industry park, Qingdao City) (is a FK-506/ trimethyl chitosan glutamate, Glu weight ratio=2/0.1=1/0.05), with epoxyethane fumigation sterilization in 24 hours available from the great marine health food company limited in Qingdao, place the anterior chamber of 1 week back implantation lagophthalmos again.
The perusal of postoperative and local histopathological examination FK-506 delivery system as a result have good ophthalmic biocompatibility, FK-506 can keep finite concentration in 1 year after the implantation in aqueous humor, the aqueous humor concentration releasing curve diagram is steady, generally maintains between 20~30ng/ml.Corpus ciliare choroideaes etc. are organized the about 10~20ng/g of the drug level of FK-506.And in blood, detect less than there being FK-506 to exist, FK-506 preparation complete obiteration after a year can be taken out again.
Embodiment 4.2
Press method and the step of embodiment 4.1, (address: the hydrochlorate of chitosan Chengyang District Dan Shan industry park, Qingdao City) is short absorbent, and 0.1 part of the hydrochlorate of chitosan (is a FK-506/ trimethyl chitosan hydrochlorate weight ratio=2/0.1=1/0.05) available from the great marine health food company limited in Qingdao in employing.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, regularly detect FK-506 in 1 year after the implantation and can keep finite concentration in aqueous humor, generally maintain between 15~25ng/ml.Corpus ciliare choroideaes etc. are organized the about 8~15ng/g of the drug level of FK-506.Detect existence in the blood less than FK-506.The complete obiteration of FK-506 preparation can be taken out again after 1 year.
Embodiment 5
Embodiment 5.1
With embodiment 2.1 same procedure and step, but adopt the polycaprolactone/polylactic acid terpolymer (PCEI that presses the preparation of Chinese invention patent application number 98102212X method, molecular weight 5~90,000) add that (address: 0.2 part of trimethyl chitosan glutamate, Glu Chengyang District Dan Shan industry park, Qingdao City) (is a FK-506/ trimethyl chitosan glutamate, Glu weight ratio=2/0.2=1/0.1) available from the great marine health food company limited in Qingdao, prepare the pore structure size and be 10 microns FK-506 preparation, steaming 24 hours sterilizations with oxirane, place the anterior chamber of 1 week back implantation lagophthalmos again.
The perusal of postoperative and local histopathological examination result show that the FK-506 delivery system has good ophthalmic biocompatibility, FK-506 can keep finite concentration in after the implantation 30 week in aqueous humor, the aqueous humor concentration releasing curve diagram is steady, generally maintains between 20~30ng/ml.Corpus ciliare choroideaes etc. are organized the about 10~20ng/g of the drug level of FK-506.And in blood, detect less than there being FK-506 to exist, 40 all FK-506 preparations are intact to disappear, and can take out again.
Embodiment 5.2
Press method and the step of embodiment 5.1, (address: the hydrochlorate of chitosan Chengyang District Dan Shan industry park, Qingdao City) is short absorbent, and 0.2 part of the hydrochlorate of chitosan (is a FK-506/ trimethyl chitosan hydrochlorate weight ratio=2/0.2=1/0.1) available from the great marine health food company limited in Qingdao in employing.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, regularly detect FK-506 in the week of 30 after the implantation and can keep finite concentration in aqueous humor, generally maintain between 15~25ng/ml.Corpus ciliare choroideaes etc. are organized the about 8~15ng/g of the drug level of FK-506.Detect existence in the blood less than FK-506.The back FK-506 preparation complete obiteration of 40 weeks can be taken out again.
Embodiment 6
Embodiment 6.1
With embodiment 2.1 same procedure steps, but adopt 95% (weight) poly-L-lactic acid (PLLA, molecular weight 60,000) (address: trimethyl chitosan glutamate, Glu Chengyang District Dan Shan industry park, Qingdao City) (is FK-506/ trimethyl chitosan glutamate, Glu weight ratio=2/3=1/1.5 for 3 parts available from the great marine health food company limited in Qingdao with 5% (weight),), make mixture as carrier, obtain the pore structure size and be 10 microns FK-506 preparation, the sterilization in 24 hours of reuse epoxyethane fumigation, the anterior chamber who places 1 week back implantation lagophthalmos again.
The perusal of postoperative and partial histopathological examination result show that the FK-506 delivery system has good ophthalmic biocompatibility, FK-506 can keep finite concentration in after the implantation 50 week in aqueous humor, the aqueous humor concentration releasing curve diagram is steady, generally maintains between 15~30ng/ml.Corpus ciliare choroideaes etc. are organized the about 10~15ng/g of the drug level of FK-506.And in blood, detect less than there being FK-506 to exist, FK-506 preparation complete obiteration after a year can be taken out again.
Embodiment 6.2
Press method and the step of embodiment 6.1, (address: the hydrochlorate of chitosan Chengyang District Dan Shan industry park, Qingdao City) is short absorbent, 3 parts of the hydrochlorates of chitosan available from the great marine health food company limited in Qingdao in employing.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, regularly detect FK-506 in 1 year after the implantation and can keep finite concentration in aqueous humor, generally maintain between 10~25ng/ml.Corpus ciliare choroideaes etc. are organized the about 6~10ng/g of the drug level of FK-506.Detect existence in the blood less than FK-506.The complete obiteration of FK-506 preparation can be taken out again after 1 year.
Embodiment 7
Embodiment 7.1
Method and step with embodiment 6.1, but adopt the poly-DL-lactic acid (PDLLA of 95% (weight), molecular weight 60,000) makes mixture as carrier with the collagen of 5% (weight), obtain the pore structure size and be 10 microns FK-506 preparation, 24 hours sterilizations of reuse epoxyethane fumigation, the anterior chamber who places 1 week back implantation lagophthalmos again.
The ophthalmic biocompatibility, FK-506 can keep finite concentration in the week of 20 after the implantation in aqueous humor, and the aqueous humor concentration releasing curve diagram is steady, generally maintains between 10~20ng/ml.Corpus ciliare choroideaes etc. are organized the about 5~10ng/g of the drug level of FK-506.And in blood, detect less than there being FK-506 to exist, the back FK-506 preparation complete obiteration of 20 weeks can be taken out again.
Embodiment 7.2
Press method and the step of embodiment 7.1, (address: the hydrochlorate of chitosan Chengyang District Dan Shan industry park, Qingdao City) is short absorbent, and 3 parts of the hydrochlorates of chitosan (are FK-506/ trimethyl chitosan hydrochlorate weight ratio=2/3=1/1.5) available from the great marine health food company limited in Qingdao in employing.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, regularly detect FK-506 in the week of 20 after the implantation and can keep finite concentration in aqueous humor, generally maintain between 6~15ng/ml.Corpus ciliare choroideaes etc. are organized the about 5~10ng/g of the drug level of FK-506.Detect existence in the blood less than FK-506.The back FK-506 preparation complete obiteration of 20 weeks can be taken out again.
Embodiment 8
Embodiment 8.1
With the method for embodiment 3.1 and step (be FK-506/ trimethyl chitosan glutamate, Glu weight ratio=9/3=1/0.33), with the FK-506 tablet be cut into thick be 2 millimeters, wide be that 5 millimeters, length are 30 millimeters FK-506 preparation.This FK-506 preparation was sterilized, placed in the anterior chamber of 1 week back implantation rabbit with epoxyethane fumigation in 24 hours.
The perusal of postoperative and local histopathological examination result show: NIP reaction, edema, new vessels, atrophy or downright bad phenomenon, and blood pressure is normal, the perioperatively no change.Biocompatibility is good in the body of proof FK-506 delivery system.Blood testing is the result show, no FK-506 exists in blood, but this can be avoided FK-506 to the toxicity damage of kidney and cause complication such as hypertension.This FK-506 delivery formulations can take out in the 10 weeks back complete obiteration of implanting again.
Embodiment 9,
10 of high-risk corneal transplantation rats, the anterior chamber is implanted into by embodiment 3.1 preparations, contains 1 of 0.5mg FK-506 slow release rod in the art, and immunological rejection did not take place in individual month in postoperative 1-2.It is transparent that corneal graft keeps, the reaction of cornea skin crystalline lens NIP.
Reference examples 1:
With polyurethane is that carrier, dimethyl formamide are solvent, and other method by example 1.1 prepares the FK-506 delivery system.Postoperative perusal and local histopathological examination show that the FK-506 delivery system has good ophthalmic biocompatibility, and 15 after the implantation can be kept FK-506 finite concentration in aqueous humor in week, and detect in blood less than there being FK-506 to exist; Detect in the aqueous humor during by six months less than there being FK-506 to exist.But postoperative still had later on implantation preparation size homologue and is present among the anterior chamber in 1 year, therefore must operation take out.
Reference examples 2:
10 of high-risk corneal transplantation rats, postoperative are adopted 0.5%FK-506 eye drop eye drip, every day 4 times. and all rejection takes place about 2 weeks in the rat postoperative.
Reference examples 3:
Press method and the step of embodiment 1.1, do not add trimethyl chitosan glutamate, Glu.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, and in 12 weeks after the implantation, concentration in the aqueous humor generally maintains between 5~15ng/ml.Detect existence in the blood less than FK-506.Corpus ciliare choroideaes etc. organize the drug level of FK-506 low than embodiment 1.2, between 2~5ng/g.12-48 is the complete obiteration of FK-506 preparation after week, can take out again.
Reference examples 4:
Press method and the step of embodiment 2.1, do not add trimethyl chitosan glutamate, Glu.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, and FK-506 can keep finite concentration at aqueous humor in the week of 14 after the implantation, generally between 6~15ng/ml.Detect existence in the blood less than FK-506.Corpus ciliare choroideaes etc. organize the drug level of FK-506 low than embodiment 2.2, about 4~8ng/g.The back FK-506 preparation complete obiteration of 14 weeks can be taken out again.
Reference examples 5:
Press method and the step of embodiment 3.1, do not add trimethyl chitosan glutamate, Glu.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, and FK-506 can keep finite concentration in the week of 10~20 after the implantation in aqueous humor, generally maintains between 15~30ng/ml.Detect existence in the blood less than FK-506.Corpus ciliare choroideaes etc. are organized the about 10~20ng/g of the drug level of FK-506.The back FK-506 preparation complete obiteration of 10~20 weeks can be taken out again.
Reference examples 6:
Press method and the step of embodiment 4.1, do not add trimethyl chitosan glutamate, Glu.Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, regularly detect FK-506 in 1 year after the implantation and can keep finite concentration in aqueous humor, generally maintain between 10~20ng/ml.Corpus ciliare choroideaes etc. are organized the about 5~10ng/g of the drug level of FK-506.。Detect existence in the blood less than FK-506.Corpus ciliare choroideaes etc. organize the drug level of FK-506 low than embodiment 4.2.The complete obiteration of FK-506 preparation can be taken out again after 1 year.
Reference examples 7:
Press method and the step of embodiment 5.1, do not add trimethyl chitosan glutamate, Glu.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, regularly detect FK-506 in the week of 30 after the implantation and can keep finite concentration in aqueous humor, generally maintain between 10~20ng/ml.Corpus ciliare choroideaes etc. are organized the about 5~8ng/g of the drug level of FK-506.Detect existence in the blood less than FK-506.The back FK-506 preparation complete obiteration of 40 weeks can be taken out again.
Reference examples 8:
Press method and the step of embodiment 6.1, do not add trimethyl chitosan glutamate, Glu.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, regularly detect FK-506 in 1 year after the implantation and can keep finite concentration in aqueous humor, generally maintain between 8~16ng/ml.Corpus ciliare choroideaes etc. are organized the about 4~8ng/g of the drug level of FK-506.Detect existence in the blood less than FK-506.The complete obiteration of FK-506 preparation can be taken out again after 1 year.
Reference examples 9:
Press method and the step of embodiment 7.1, do not add trimethyl chitosan glutamate, Glu.
Postoperative perusal and local histopathological examination the ophthalmic biocompatibility of FK-506 delivery system as a result are good, regularly detect FK-506 in the week of 20 after the implantation and can keep finite concentration in aqueous humor, generally maintain between 6~15ng/ml.Corpus ciliare choroideaes etc. are organized the about 3~5ng/g of the drug level of FK-506.Detect existence in the blood less than FK-506.The back FK-506 preparation complete obiteration of 20 weeks can be taken out again.
Those of ordinary skill in the art can understand, and in protection scope of the present invention, makes amendment for the foregoing description, and it all is possible adding and replacing, and it does not all exceed protection scope of the present invention.