CN101028512A - Use of matrix metal protease inhibitor in preparation of medicine for treating nearsightedness - Google Patents
Use of matrix metal protease inhibitor in preparation of medicine for treating nearsightedness Download PDFInfo
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- CN101028512A CN101028512A CNA2007100870620A CN200710087062A CN101028512A CN 101028512 A CN101028512 A CN 101028512A CN A2007100870620 A CNA2007100870620 A CN A2007100870620A CN 200710087062 A CN200710087062 A CN 200710087062A CN 101028512 A CN101028512 A CN 101028512A
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Abstract
An application of the matric metalloprotease depressant GM6001 in preparing the medicines in the form of eyedrops, injection, or slow-release explant for preventing the depravation of myopia is disclosed.
Description
Technical field
The present invention relates to the purposes of matrix metallo-proteinase inhibitor GM6001 aspect pharmacy, specifically, is to prevent purposes aspect the myopia development medicine in preparation.
Background technology
Myopia is the highest ametropia illness of global incidence rate, and wherein near-sighted diopter 〉=6D person is a high myopia.Sickness rate and high myopia the ratio among myopes of myopia in teenager population all has the trend that increases gradually.Myopia often is after generation carries out sexual development, and part high myopia patient myopic degree carries out sexual development all the life.High myopia patient Chang Bingfa retina and choroidal atrophy, detachment of retina etc. finally cause losing one's sight.Operative treatment, comprise that cornea refractive surgery, ophthalmic refractive surgery and back sclera Reinforcement etc. are the common methods of treatment high myopia, these operations are corrective procedure ametropia at that time effectively, but the carrying out property variation that can not prevent the postoperative eyeball myopia takes place once again and constantly increases the near-sighted number of degrees.International medical community does not still have the effective ways that stop myopia progression at present.
The GM6001 that the present invention relates to is at present at matrix metalloproteinase (the Matrix metalloproteinases of the clinical the most frequently used synthetic of medical experiment and medical treatment, MMPs) inhibitor, can suppress matrix metalloproteinase MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 etc., belong to the wide spectrum matrix metallo-proteinase inhibitor.GM6001 also is called as titles such as " Ilomastat ", " Galardon " in different documents, its molecular weight is 388.5, and molecular formula is C
20H
28N
4O
4, normality is a liquid or Powdered.Molecular structural formula such as figure below.
The GM6001 tradition is used for the treatment of corneal alkali burn.There is the scholar that GM6001 is applied to prevent the filtration bubble adhesion that fibroblast is divided a word with a hyphen at the end of a line and causes behind the rabbit anti-glaucoma operation, thereby delays to filter the bubble retention time, and suppress the formation of proliferative vitreoretinopathy; Also there is the scholar to find that GM6001 can reduce the substrate contraction of the human fibroblasts mediation of In vitro culture.Shang Weijian is used for the treatment of GM6001 and any matrix metallo-proteinase inhibitor or prevents bathomorphic report.
Summary of the invention
The object of the present invention is to provide the purposes of matrix metallo-proteinase inhibitor GM6001 aspect pharmacy, particularly prevent purposes aspect the myopia development medicine, thereby open up an approach that prevents the myopia development by biochemical method in preparation.
GM6001 is used to prepare the medicine that prevents the myopia development, generally is to use with the form of pharmaceutical composition.Its method is, the GM6001 and the pharmaceutically acceptable auxiliaries as active component of treatment effective dose is mixed with suitable dosage form, for example makes injection and is used for that operating field sprays, retrobulbar injection; Makes eye drop and do eye external etc., and preferred dosage form is to make the slow releasing agent that contains GM6001 that dosage forms such as collagen cover, microgranule, release membranes for example after implementing myopia during the sclera Reinforcement, are implanted in reinforcement material and between the body sclera.Before the sclera Reinforcement, GM6001 being dissolved in or immerses the sclera reinforcement material that is used for implanting eye after enforcement, also is effective method.
So slow release formulation becomes preferably, be because slow releasing agent as one " interim Drug Storage ", scleral surface discharges GM6001 behind eye in a long time, stops the degraded of collagen in the sclera, thus the progress of control myopia.The slow releasing agent used carrier can be degraded gradually, is absorbed by the body, and need not the taking-up of performing the operation once more.
The medicament of making by the present invention that contains GM6001 is applicable to various myopes, to control the development of myopia, is specially adapted to the high myopia patient of diopter 〉=6D.Simultaneously, the medicament that contains GM6001 also is applicable to the potential crowd that myopia may take place, and promptly makes related preventive and uses.
The present invention contains the medicament of GM6001, in order to stop the development of myopia, realizes by following mechanism.
The intravital matrix metalloproteinase of people is that the main endogenous protein hydrolytic enzyme that participates in extracellular matrix and basement membrane degradation is.Matrix metalloproteinase divides four classes, wherein gelatinase (MMP-2, MMP-9) I, II, the III Collagen Type VI of IV Collagen Type VI and degeneration of mainly degrading.The main component of people's eye sclera is the IV Collagen Type VI, is matrix metalloproteinase 2 (matrix etalloproteinase-2, specific effect substrate MMP-2).Matrix metalloproteinase is suppressed by its natural inhibitor, and the two keeps dynamic equilibrium in the normal human.Utmost point portion sclera fibroblast matrix metalloproteinase 2 overexpressions after certain reason makes eye, when activity increases, promptly degrade as the collagen and the Dan Baijutang of sclera main matrix, make sclera become weak, creep (creep refers to the variation that organ length takes place under long-time external force effect) increases the passive growth of sclera and moulding again, cause the axis oculi elongation, form myopia and carrying out property and increase the weight of.Behind the existing simple eye form deprivation of experiment confirm tree mouse, sclera MMP-2mRNA level increases, and axis oculi increases, and the near-sighted number of degrees increase.
The inventor confirms through experimentation and document verification, matrix metallo-proteinase inhibitor GM6001 is as the potent matrix metallo-proteinase inhibitor of a kind of wide spectrum of synthetic, can combine with the substrate recognition site in the matrix metalloproteinase molecule, and with the Zn of enzyme active center
2+Complexation and inhibitory enzyme activity.GM6001 is made the topical application of eye, do the ball rear portion especially and use, can suppress the sclera fibroblast MMP-2 of utmost point portion up-regulated after the myopia, stop the degraded of collagen in the sclera, the creep that stops or slow down sclera reduces the plasticity of sclera, thereby controls the development of myopia.The medicament that clinical practice contains GM6001 is the approach that a kind of applied biochemistry method fundamentally prevents myopia progression.
The specific embodiment
The invention will be further described by the following examples.
Embodiment 1 preparation GM6001 aqueous solution
Commercially available liquid GM6001 is diluted to the solution of 50uM～900uM concentration with water for injection, is used for eye dripping after handling by the medicine for external use mode; Be used for retrobulbar injection after handling by the injection mode.
Embodiment 2 preparations contain one of slow releasing agent of GM6001---collagen cover
Before high myopic eye is implemented back sclera Reinforcement, with standby reinforcement material---people, pig or cattle sclera collagen are immersed in the GM6001 solution of 500-1000uM 24～48 hours, take out airing, make a hood-shaped thing that is in the nature collagen, claim the collagen cover, wherein contain GM6001, be used for behind the high myopic eye sclera and implant.
Embodiment 3 preparation contain GM6001 slow releasing agent two---microgranule (comprising microcapsule, microsphere)
Slow-released carrier can be selected natural polymer for use, for example collagen, chitosan (chitin) etc.; Also can select the polymer of synthetic preparation for use, for example the copolymer of polyglycolic acid, polylactic acid, polyethylene Methane Carboxylic Acid ester and copolymer hydroxyacetic acid and lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester-lactide-caprolactone ternary atactic copolymer etc.GM6001 powder or liquid envelope in above-mentioned slow-released carrier, are made the microgranule of diameter 1-250um, can be small capsule or small ball, when high myopic eye was implemented back sclera Reinforcement, the many places point-like was planted between back sclera stiffener and sclera.
Embodiment 4 preparation contain GM6001 slow releasing agent three---release membranes
The GM6001 drug particles is encapsulated in the membranaceous slow-released carrier.The artificial synthetic polymeric film of the optional usefulness of slow-released carrier, be the copolymer that several crosslinked polymers form: as the copolymer and the Acetic acid, hydroxy-, bimol. cyclic ester-lactide-caprolactone ternary atactic copolymer of hydroxyacetic acid and lactic acid, various constituents are carried out copolymerization by different proportion can regulate the slow-released carrier degradation time, thereby regulate release rate of drugs and time.Not only drug loading is big for Acetic acid, hydroxy-, bimol. cyclic ester-lactide-caprolactone ternary atactic copolymer, and the medicament slow release time is long, and balance release medicine reached more than 3 months within the eye, and release is more steady.When high myopic eye was implemented back sclera Reinforcement, the release membranes that will contain GM6001 was planted between back sclera stiffener and sclera, and release membranes is identical with back sclera stiffener size.
Embodiment 5GM6001 suppresses the experimentation of myopia progression
This experiment tree mouse is as myopia model.The teenager tree mouse be present medical circle generally acknowledge be suitable for the mammal of making myopia model.Adopt the method for wearing translucent eyeglass at the moment to make simple eye form deprivation, bring out myopia and take place, observe protein active, vitreous chamber length and the dioptric variation of different covering time MMP-2, observe simultaneously and use GM6001 to stop the effect of myopia progression.Western blot method is used to measure the protein active of MMP-2.
Materials and methods
Animal: 25 of tree mouses, divide 5 groups, 5 every group.4 groups of experimental grouies give left eye simple eye form deprivation, wherein 3 groups of respectively simple eye 1 week of form deprivation, 2 weeks, 6 weeks (2 week+4 week), another organize simple eye 2 weeks of form deprivation+next day retrobulbar injection GM6001 4 weeks of preparation.1 group is matched group, and eyes are all opened naturally.
The equal normal growth of all animals arrived juvenile era in 20 days.5 treated animals all in giving birth to the back the 20th day, are anaesthetized the back in enforcement and are stitched a special eye pad in left eye, are equipped with to make insertion eyeglass making form deprivation eye.Operation back animal has three days off, and gets rid of the interference of seam eye pad operation to the animal overall health of patients.All animals are in giving birth to back conduct experiment in the 24th day beginning.4 groups of experimental grouies insert translucent eyeglass in each left eye eye pad, the matched group left eye is not inserted eyeglass, opens naturally.Wherein 1 group of simple eye form deprivation begins retrobulbar injection GM6001 after 2 weeks.
Preparation GM6001 injection: the GM6001 that buys (Merck, Germany) solution is diluted to desired concn 100uM with water for injection with GM6001, makes retrobulbar injection usefulness, and the next day injects once, each 0.2ml, totally 4 weeks.
Use auto-refractomer (Nidek, Japan) to check refractive status when all zooperies finish, A-mode ultrasonic apparatus is checked vitreous chamber length behind the anesthetized animal.Speed is got eyeball afterwards, removes the sclera surrounding tissue, sclera is put-80 ℃ of preservations, is used for protein extraction.
Extract the sclera total protein, carry out conventional Western blot and detect.The protein concentration of all samples carries out standardization, respectively gets the 40ug total protein and is placed on sds gel and separates, and electrophoresis (70V) was transferred to the capable immunoblotting assay of nitrocellulose membrane after 2 hours.(0.02%NaN3) 30 minutes, monoclonal mouse-anti people MMP-2 antibody (1: 800) spent the night for 4 ° membrane closure under the room temperature for 5% degrease milk, 0.01% defoamer, monoclonal sheep anti-mouse antibody (1: 1000) associating horseradish peroxidase room temperature 1.5 hours.The alkali phosphatase colour developing is taken a picture.
Statistics: use SPSS13.0 software, relatively use paired t-test between two groups, relatively use variance analysis (AN0VA) between many groups.
The result
The active MMP-2 protein level of sclera: protein electrophorese figure shows that simple eye form deprivation has increased the protein level of the active MMP-2 of sclera.Clear band appears in all sample standard deviations at the 57KD place, a little less than the matched group processing signals, with depriving time lengthening, the MMP-2 level raises gradually, is dose dependent.In 2 weeks of form deprivation+retrobulbar injection 4 all GM6001, form deprivation eye MMP-2 level and form deprivation 2 all eyes compare, and band is basic identical.
Diopter: form deprivation has produced tangible myopia and vitreous chamber length increases.The form deprivation eye compares with contrast eye (p＜0.01), and diopter reduces gradually with depriving time lengthening, and the promptly near-sighted number of degrees increase gradually.Normal control eye average eye diopter is+4 ± 0.25D.Form deprivation is after 1 week, and depriving an average eye diopter is-1.25 ± 0.21D, and the contrast eye reduces by 5.32 ± 0.27D (p＜0.01).After 2 weeks, depriving an average eye diopter is-2.14 ± 0.17D, and the contrast eye reduces by 6.25 ± 0.50D (p＜0.01).After 6 weeks, depriving an average eye diopter is-5.14 ± 0.17D, and the contrast eye reduces by 9.13 ± 0.26D (p＜0.01).In 2 weeks of form deprivation+retrobulbar injection 4 all GM6001, form deprivation refraction of eye degree remains unchanged substantially, is-2.25 ± 0.13D, compares difference not statistically significant (p＞0.05) with form deprivation 2 all eyes.
Vitreous chamber length: deprive the camera vitrea bulbi length variations and change similar to active MMP-2 protein level.The form deprivation eye compares with contrast eye (p＜0.05), and vitreous chamber length conformal feels that depriving time lengthening increases gradually.Normal control vitreum cavity length is 2.43 ± 0.11mm.Form deprivation is after 1 week, and depriving the vitreum cavity length is 3.43 ± 0.11mm, and the contrast eye increases by 1.05 ± 0.21mm (p＜0.05).Form deprivation is after 2 weeks, and depriving the vitreum cavity length is 4.03 ± 0.08mm, and the contrast eye increases by 1.65 ± 0.21mm (p＜0.05).Form deprivation is after 6 weeks, and depriving the vitreum cavity length is 5.63 ± 0.23mm, and the contrast eye increases by 3.22 ± 0.13mm (p＜0.05).2 weeks of form deprivation+retrobulbar injection 4 all GM6001, the form deprivation vitreum cavity length 5.66 ± 0.22mm that remains unchanged, with 2 week of form deprivation eye relatively, difference not statistically significant (p＞0.05).
Conclusion
GM6001 stops the variation of diopter and vitreous chamber length by suppressing the activity of MMP-2, thereby stops the progress of myopia.Use the GM6001 preparation and provide a new way for the development that prevents myopia.
Claims (7)
1. matrix metallo-proteinase inhibitor GM6001 prevents application in the medicine of myopia development in preparation.
2. the application of GM6001 according to claim 1 is characterized in that, GM6001 is diluted to the solution of 50uM～900uM concentration with water for injection, is used for eye dripping after handling by the medicine for external use mode; Be used for retrobulbar injection after handling by the injection mode.
3. the application of GM6001 according to claim 1, it is characterized in that,, take out airing with the GM6001 solution soaking people of 500-1000uM concentration, pig or cattle sclera collagen 24～48 hours, make the collagen cover, the implant when reinforcing operation as sclera behind the high myopic eye.
4. the application of GM6001 according to claim 1, it is characterized in that, GM6001 powder or liquid envelope in slow-released carrier, are made the microgranule of diameter 1um～250um, as when high myopic eye is implemented back sclera Reinforcement, the many places point-like is planted between back sclera stiffener and sclera.
5. the application of GM6001 according to claim 6 is characterized in that, the slow-released carrier that is used for sealing GM6001 is that collagen, chitosan (chitin), polyglycolic acid, polylactic acid, polyethylene Methane Carboxylic Acid ester are any.
6. the application of GM6001 according to claim 1 is characterized in that, the GM6001 drug particles is encapsulated in the membranaceous slow-released carrier, as when high myopic eye is implemented back sclera Reinforcement, plants between back sclera stiffener and sclera.
7. according to the application of claim 6 or 8 described GM6001, it is characterized in that the slow-released carrier that is used for sealing GM6001 is that the copolymer or the Acetic acid, hydroxy-, bimol. cyclic ester-lactide-caprolactone ternary atactic copolymer of artificial synthetic hydroxyacetic acid and lactic acid is any.
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| CN200710087062A CN100579576C (en) | 2007-03-16 | 2007-03-16 | Entoptic embedding material for preventing aggravation of nearsightedness |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104394856A (en) * | 2012-05-21 | 2015-03-04 | Dcb美国公司 | Methods for drug screen using zebrafish model and the compounds screened thereform |
| CN113304108A (en) * | 2021-05-24 | 2021-08-27 | 中国人民解放军军事科学院军事医学研究院 | Ilomastat suspension injection and preparation method thereof |
| CN113633760A (en) * | 2020-04-27 | 2021-11-12 | 北京大学第一医院 | Application of transglutaminase in medicine for inhibiting or delaying myopia |
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2007
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104394856A (en) * | 2012-05-21 | 2015-03-04 | Dcb美国公司 | Methods for drug screen using zebrafish model and the compounds screened thereform |
| JP2015517575A (en) * | 2012-05-21 | 2015-06-22 | ディーシービー−ユーエスエー エルエルシーＤｃｂ−Ｕｓａ Ｌｌｃ | Method for screening drugs by using zebrafish model, and compounds screened by this method |
| EP2852383A4 (en) * | 2012-05-21 | 2016-03-16 | Dcb Usa Llc | Methods for drug screen using zebrafish model and the compounds screened thereform |
| CN113633760A (en) * | 2020-04-27 | 2021-11-12 | 北京大学第一医院 | Application of transglutaminase in medicine for inhibiting or delaying myopia |
| CN113304108A (en) * | 2021-05-24 | 2021-08-27 | 中国人民解放军军事科学院军事医学研究院 | Ilomastat suspension injection and preparation method thereof |
| CN113304108B (en) * | 2021-05-24 | 2022-03-15 | 中国人民解放军军事科学院军事医学研究院 | Ilomastat suspension injection and preparation method thereof |
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| CN100579576C (en) | 2010-01-13 |
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