CN101594904A - Influence the photochemical therapy of systemic machinery and/or chemical property - Google Patents

Influence the photochemical therapy of systemic machinery and/or chemical property Download PDF

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CN101594904A
CN101594904A CNA2007800397014A CN200780039701A CN101594904A CN 101594904 A CN101594904 A CN 101594904A CN A2007800397014 A CNA2007800397014 A CN A2007800397014A CN 200780039701 A CN200780039701 A CN 200780039701A CN 101594904 A CN101594904 A CN 101594904A
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purposes
eyes
cornea
tissue
sclera
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D·M·施沃茨
M·S·梅特森
J·A·科恩菲尔德
R·K·马罗尼
R·H·格鲁布斯
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California Institute of Technology CalTech
University of California
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University of California
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Abstract

The present invention relates to change the machinery and/or the chemical property of bodily tissue, particularly eye tissue.In a particular case, it relates to and changing or the shape of stable cornea, for example suffer from or exists expand or the experimenter of the risk of keratoconus in.In other specific situations, it relates to suffering from or exist among the experimenter of risk of myopia strengthens sclera.But the present invention has utilized the chemical compound to photoactivation, for example, is used for and the irradiate light of organizing crosslinked photoactivity chemical compound.

Description

Influence the photochemical therapy of systemic machinery and/or chemical property
Relevant application
[0001] priority of the U.S. Provisional Patent Application submitted to number on August 07th, 60/853,949 and 2007 of the application's U.S. Provisional Patent Application of requiring to submit on October 24th, 2006 number 60/954,541.
About the research of federal government's patronage or the statement of exploitation
[0002] the present invention uses at least in part from the fund of the appropriation R41EY017484 of National Institutes of Health and develops.U.S. government may have some right in the present invention.
Technical field
[0003] the field of the invention relates to materia medica, anatomy, cytobiology or molecular biology for instance.Especially, the field of the invention relates to opthalmological, comprises the ophthalmology.
Background of invention
[0004] keratoconus
[0005] keratoconus (Rabinowitz, 1998; Krachmer et al, 1994; Bron, 1988) be modal cerneal dystrophy, 2000 philtrums influence 1 people.Keratoconus causes the cornea attenuation, is to name with the cone shape of cornea development.The gradual distortion of cornea shape usually in early days adult age become noticeable, cause more and more serious astigmatism, myopia and higher order aberrations, it is difficult to correct by glasses or contact lens.Proofread and correct no longer possiblely when some when distortion reaches refrangibility, corneal transplantation is unique selection.
[0006] method that needs to strengthen cornea and stop disease progression.Evidence suggests that the corneal collagen that takes place crosslinked provides the protection to keratoconus (Seiler et al., 2000) in diabetes.In addition, some groups have reported the reinforcement by common cross-linking agent corneal.Glyceraldehyde has been used as the cornea cross-linking agent, but it has significant toxicity.The toxic method of a kind of minimum medication itself has been utilized the riboflavin of surperficial administration, and it accepts ultraviolet light (Tae etal., 2000 then; Tessier et al., 2002; Spoerl and Seiler, 1999; Spoerl et al., 1997; Wollensak et al., 2003).3 years or more of a specified duration studying for a long period of time show, can provide enough structures to strengthen development (Wollensak et al., 2003 to slow down or to stop keratoconus with the activatory crosslinked treatment cornea of UV; Wollensak, 2006).
[0007] represented progress possible in the treatment of keratoconus when the riboflavin of ultraviolet activation, it will be that to overcome the limitation of this treatment optimal.Riboflavin/UV need be with the epithelium removal of the misery of ulcer risk for a long time; It utilizes UV light, has the inherent risk to the infringement of eye tissue; It needs 30 minutes irradiation, and this is undesirable clinically and has improved the risk of corneal infection.Thereby, clinically, need a kind of treatment of shortcoming that stop disease progression and remedy the riboflavin treatment of ultraviolet activation.Particularly, need in the opthalmological field below one or more: 1) improved medicine; 2) improved drug administration; With 3) improved illumination scheme.
[0008] myopia
[0009] at US and European, myopia has influenced crowd's 30%, has influenced crowd's 70-90% in some Asian countries.(Lin?LL，Shih?YF，Hsiao?CK，Chen?CJ，Lee?LA，Hung?PT.Epidemiologic?study?of?the?prevalence?and?severity?of?myopiaamong?schoolchildren?in?Taiwan?in?2000.J?Formos?Med?Assoc.2001；100(10)：684-91；Chow，Y.C，Dhillon，B.B.，Chew，P.T.&Chew，S.J.Refractive?errors?in?Singapore?medical?students.Singapore?MedicalJournal?45，470-474(1990)；Wong，T.Y.，Foster，P.J.，Hee，J.J.，Ng，T.P.，Tielsch，J.M.，Chew，S.J.，Johnson，G.J.&Seah，S.K.Prevalence?and?risk?factors?for?refractive?errors?in?adult?Chinese?inSingapore.Investigative?Ophthalmology&Visual?Science?41，2486-2494(2000))。Influenced the 0.2-0.4% of American population greater than 8 dioptric high myopias, in Asian countries up to 1% crowd (Sperduto, R.D., Seigel, D.D., Roberts, J.J.﹠amp; Rowland, M.M.Prevalence of myopia in the United States.405-407 (1983); Tokoro, T.On the definition of pathologic myopia in groupstudies.Acta Opthalmol Suppl 185,107-108 (1998)).In fact, degenerative myopia is the blind main cause that can not treat in China's Mainland, Taiwan Province and Japan, ranked seventh position (Xu L in the U.S., Wang Y, Li Y, Wang Y, Cui T, Li J, Jonas JB.Causes of blindness and visual impairment in urban and rural areas inBeijing:the Beijing Eye Study.Ophthalmology.2006113:1134.el-ll; HsuWM, Cheng CY, Liu JH, Tsai SY, Chou P.Prevalence and causes of visualimpairment in an elderly Chinese population in Taiwan:the Shihpai EyeStudy.Ophthalmology.2004; 111 (1): 62-9; Iwase A, Araie M, TomidokoroA, Yamamoto T, Shimizu H, Kitazawa Y; Tajimi Study Group.Prevalenceand causes of low vision and blindness in a Japanese adult population:theTajimi Study.Ophthalmology.2006; 113 (8): 1354-62; Curtin, B.J.Themyopias:basic science and clinical management (Lippincott Williams﹠amp; Wilkins, 1985).
[0010] in degenerative myopia, exists the gradual axial elongation of eyes.Over-drastic axial elongation has caused the elongation and the attenuation of eyes surface layers (sclera and choroid retinal tissues) in the degenerative myopia.Because this elongation and attenuation preferentially take place and relate to macula lutea at the back utmost point, the eyes of suffering from degenerative myopia have experienced visual deprivation.The reason of sclera attenuation and elongation does not also have understanding fully in degenerative myopia, but the change of the aminopolysaccharide of the enhanced turnover of sclera collagen and sclera has played effect in disease.Because the mechanical performance of sclera is changed in myopia, eyes are because the load effect of intraocular pressure tends to elongation.When sclera in pathologic myopia extended, contiguous retina and choroid had also extended, and elongation is out-of-proportion in macular region, and here sclera and retina attenuation are maximum.This has caused focus evagination (focalout-pouching) or staphylomatous formation.Along with the macula lutea tissue lengthening, the retina cell atrophy causes irreversible visual deprivation.
[0011] visual deprivation from macula lutea atrophy and choroid neovascularization is modal in the degenerative myopia, and the patient who suffers from this disease also tends to detachment of retina and the formation of macula lutea hole.Though worldwide very big crowd is subjected to the influence of this disease, the current ratio that does not have effective method to come delay of progression and reduce visual deprivation.
[0012] ametropia that brings out of progressive myopia is corrected by glasses, contact lens, cornea refractive surgery or intraocular lens easily, and these forms can not stop the visual deprivation of being brought out by the elongation of choroid retinal tissue.In addition, the current approach of treatment degenerative myopia median nexus film neovascularization, for example optical dynamic therapy is effectively (Blinder, K.J., Blumenkranz of minimally, M.S., Bressler, N.M., Bressler, S.B., Donati, G., Lewis, H., Lim, J.I., Menchini, U., Miller, J.W., Mones, J.M., Potter, M.J., Pournaras, C, Reaves, A., Rosenfeld, P., Schachat, A.P., Schmidt-Erfurth, U., Sickenberg, M., Singerman, L.J., Slakter, J., Strong, H.A., Virgili, G.﹠amp; Williams, G.A.Verteporfin therapy ofsubfoveal choroidal neovascularization in pathologic myopia-2-year resultsof a randomized clinical Trial-VIP report NO.3.Ophthalmology 110,667-673 (2003)).For the treatment of choroid neovascularization, anti-vascular endothelial growth factor (VEGF) is for example treated
Figure A20078003970100081
Effect also be not established.Carried out the development that various trials come retarding myopia, comprised consolidating and use film angioplasty, sclera to strengthen, even attempt foam of polymers (Avetisov, E.S., Tarutta, E.P., Iomdina, E.N., Vinetskaya, M.I.﹠amp around eyes; Andreyeva, L.D.Nonsurgical and surgical methods ofsclera reinforcement in progressive myopia.Acta OphthalmologicaScandinavica 75,618-623 (1997); Chua, W.H., Tan, D., Balakrishnan, V.﹠amp; Chan, Y.H.Progression of childhood myopia following cessation ofatropine treatment.Investigative Ophthalmology﹠amp; Visual Science 46 (2005); Tarutta, Y.P., Iomdina, Y.N., Shamkhalova, E.S., Andreyeva, L.D.﹠amp; Maximova, M.V.Sclera Fortification In Children At A High-RiskOf Progressive Myopia.Vestnik Oftalmologii 108,14-17 (1992); Politzer, M.Experiences In Medical-Treatment Of Progressive Myopia.KlinischeMonatsblatter Fur Augenheilkunde 171,616-619 (1977); Belyaev, V.S.﹠amp; Flyina, T.S.Late Results Of Scleroplasty In Surgical Treatment OfProgressive Myopia.Eye Ear Nose And Throat Monthly 54,109-113 (1975); Chauvaud, D., Assouline, M.﹠amp; Perrenoud, F.Scleralreinforcement.Journal Francais D Ophtalmologie 20,374-382 (1997); Jacob, J.T., Lin, J.J.﹠amp; Mikal, S.P.Synthetic scleral reinforcementmaterials.3.Changes in surface and bulk physical properties.Journal OfBiomedical Materials Research 37,525-533 (1997); Korobelnik, J.F., D ' Hermies, F., Chauvaud, D., Legeais, J.M., Hoang-Xuan, T.﹠amp; Renard, G.Expanded polytetrafluoroethylene episcleral implants used as encirclingscleral buckling-An experimental and histopathological study.OphthalmicResearch 32,110-117 (2000); Mortemousque, B., Leger, F., Velou, S., Graffan, R., Colin, J.﹠amp; Korobelnik, J.F.S/e-PTFE episcleral bucklingimplants:An experimental and histopathologic study.Journal OfBiomedical Materials Research 63,686-691 (2002); Jacoblabarre, J.T., Assouline, M., Conway, M.D., Thompson, H.W.﹠amp; McDonald, M.B.Effects Of Scleral Reinforcement On The Elongation Of Growing Cat Eyes.Archives Of Ophthalmology 111,979-986 (1993)).It is unverified that main because these forms are still in the clinical trial of good contrast, and they are not all adopted to control the patient who suffers from degenerative myopia widely.Other treatment, for example eye drop (Chua WH, Balakrishnan V, Chan YH, Tong L, Ling Y, Quah BL, Tan D.Atropinefor the treatment of childhood myopia.Ophthalmology.2006Dec; 113 (12): 2285-91; Siatkowski RM, Cotter S, Miller JM, Scher CA, CrockettRS, Novack GD; US Pirenzepine Study Group.Safety and efficacy of 2%pirenzepine ophthalmic gel in children with myopia:a 1-year, multicenter, double-masked, placebo-controlled parallel study.Arch Ophthalmol.2004; 122 (11): 1667-74), eye motion (Khoo CY, Chong J, Rajan U.A 3-yearstudy on the effect of RGP contact lenses on myopic children.SingaporeMedJ 1999; 40:230-7) with contact lens treatment (Shih YF, Lin LL, Hwang CY, et al.The effects of qi-qong ocular exercise on accommodation.Clin JPhysiol 1995; 38:35-42) has very little or unproved effectiveness.If possible slow down or stop the unusual axial elongation of eyeball in the degenerative myopia, visual deprivation may be prevented from.
[0013] the over-drastic axial elongation of the eyeball that takes place in degenerative myopia preferentially takes place in extremely at the back of macula lutea.The reason of sclera attenuation and elongation does not also have understanding fully in degenerative myopia, but the change of the enhanced turnover of the reduction of collagen fiber diameter, sclera collagen and sclera aminopolysaccharide is influence factor (McBrien, N.A.﹠amp; Gentle, A.Role ofthe sclera in thedevelopment and pathological complications of myopia.Progress In RetinalAnd Eye Research 22,307-338 (2003)).Because the mechanical performance of sclera is changed in the myopia, eyes are because the load effect of intraocular pressure tends to elongation.The hot strength or the coefficient that improve sclera fully will stop the eyes elongation and reduce near-sighted development.This treatment will be not only among in the early stage the degenerative myope, and be useful in the patient who suffers from early onset thereof myopia, prevents to develop into the more ametropia of height.
[0014] current, also there are not certified means to prevent the over-drastic eyes elongation that in degenerative myopia, takes place.If possible slow down or prevent eyes elongations, the development of myopia can be lowered, and prevents visual deprivation at least in part.If the gradual elongation of sclera is delayed in the macular region, retina elongation or further retina elongation will can not take place, and vision can be held.Carried out effort, use the donor sclera or the synthetic polymer bar of the outside that places around eyes to bring the support macular region, but this has not been proved to be effective.Hot strength or modulus itself that the artificially increases sclera are the methods that prevents the eyes elongation and reduce the development of myopia.
[0015] Wollensak and Speorl have reported and have utilized collagen crosslinking agent, comprise glutaraldehyde, glyceraldehyde and riboflavin-UVA treatment reinforcement sclera (Wollensak, G.﹠amp of the mankind and pig externally; Spoerl, E.Collagen crosslinking of human and porcinesclera.Journal Of Cataract And Refractive Surgery 30,689-695 (2004)).Compare with untreated contrast, glutaraldehyde, glyceraldehyde and riboflavin-UVA treatment has improved Young's modulus 122%, 34% and 29% respectively.Because they are not that light is activatory, the author reports, may be difficult to spatially control the cross-linking effect of glutaraldehyde and glyceraldehyde.Undesirable collagen cross-linking may have special side effect in blood vessel and neuromechanism.Use the riboflavin of photoactivation to it seems it is desirable at this point; Yet, UVA light is potential Cytotoxic, and the comparable exposure of the cornea of treatment keratoconus needs 30 minutes irradiation (Wollensak G.Crosslinkingtreatment of progressive keratoconus:new hope.Curr Opin Ophthalmol.2006; 17 (4): 356-60).Though after extremely in stroma of sclera composition crosslinked will improve sclera modulus and retarding myopia progression potentially, still need nontoxic cross-linking agent, it can utilize the exposure to the weak point of the light source of low toxicity to activate.
[0016] the disclosed application number 20050271590 of the U.S., its content is incorporated in this by reference, discloses to utilize the cross-linking chemistry material to come covalently bound sclera collagen and/or other sclera albumen to improve the method for sclera hot strength or modulus.This method has been utilized chemical cross-linking agent, some has undesirable toxicity profile, by chemical substance being wrapped in the destroyed in a controlled manner photo-labile structure that discharges the cross-linking agent chemical substance, thus the zone of limit exposure and toxic effect in some cases.
[0017] considers the limitation of current therapies, need not have this circumscribed new therapy for treatment keratoconus and myopia.The present invention has satisfied this demand.
Summary of the invention
[0018] the present invention relates in individuality the therapy of systemic one or more machineries of influence and/or chemical property.In specific embodiment, the present invention relates in individuality, influence one or more photochemical therapies of systemic one or more machineries and/or chemical property.Described therapy can be used for any tissue of health, comprises the heart tissue of ocular tissue, blood vessel wall, alveolar structure (for example, in COPD patient) and damage at least, for example, is used for the alleviation of dilatancy cardiomyopathy.In specific embodiment, described therapy is used for ocular tissue.Exemplary ocular tissue comprises space under cornea, sclera, optic nerve, trabecular reticulum, conjunctiva, choroid and the retina at least.
[0019] in specific embodiment, the present invention has adopted a kind of therapy, and it is the improvement to the specific therapy that is used for some ophthalmic applications.In further specific embodiment, the present invention has improved the crosslinked UV irradiation treatment that is used to organize, described for example cornea or the sclera organized.This treatment will have one or more following exemplary specifications: 1) can activate with the machinery of influence tissue and/or the photoinitiator compound of chemical property with visible light, for example improve the mechanical performance of cornea and resist gradual expansion; 2) photoinitiator compound that can be imported into the risk of minimum pain and/or minimum; 3) for the nontoxic photoinitiator compound of eye structure; 4) activatory photoinitiator compound takes place in the illumination levels with safety; 5) activatory photoinitiator compound takes place in irradiation in 30 minutes for example to be less than or equal to.
[0020] in specific embodiment of the present invention, the invention provides one or more following demands: 1) represented and be used for enhanced tissue (for example cornea or sclera, effective photoinitiator compound for instance) has hypotoxicity and by visible-light activated; 2) the photoinitiator compound or derivatives thereof that improves has been described, it can avoid mobile epithelium (for example keratoconus of cornea treatment) to come administration, comprise, the surface applications of (a) medicine for example, described medicine itself or after modifying, can cross over corneal epithelium to treat effective dose angle of arrival membrane matrix with enough concentration; And/or (b) utilize the pin of fine gauge that medicine is expelled in the substrate; And/or 3) represented and utilized about 30 minutes or the irradiation time of the reduction of shorter the light that applies, influenced described tissue, for example come to stablize the shape of cornea, for instance.
[0021] provide the present invention to be used for the exemplary application of ophthalmology demand.In specific embodiment, the present invention is used to cornea, comprises following: by the development and other keratectasia that stop keratoconus, for example expansion behind the LASIK, clear edge degeneration prevent the needs of corneal transplantation (ceratoplasty); Allow to suffer from the patient safety ground experience refractive surgery of keratoconus or other corneal degenerations; And/or behind refractive surgery, stablize cornea shape, if particularly keratoconus became obvious afterwards.The present invention also provides and has utilized the photoactivated cross-linking that uses visible light to come in the stabilize eye Anywhere tissue, comprises for example method of sclera.
[0022] though in specific embodiment the present invention adopted visible light, in selectable embodiment, the present invention has utilized ultraviolet light or infrared light.In further specific embodiment, the present invention also is applied to utilize two-photon or the activatory light trigger activation of multi-photon.
[0023] of the present invention aspect some, adopted photoinitiator compound influence among the experimenter in crosslinked between the formation molecule of source tissue.
[0024] some embodiment herein is to change the machinery organized among the experimenter and/or the method for chemical property, comprises step:
A) to described experimenter's tissue provide photoinitiator compound and
B) activate described photoinitiator compound by radiation of visible light to described tissue,
Thereby described photoinitiator compound directly changes the machinery and/or the chemical property of described tissue.
[0025] some embodiment herein is the method for paragraph [0024], and wherein said method is further defined as the described tissue of reinforcement, stablizes described shape or its combination of organizing shape, changing described tissue.
[0026] some embodiment herein is the method for paragraph [0024] or [0025], and wherein said tissue is an eye tissue.
[0027] some embodiment herein is the method for paragraph [0024] to [0026], and wherein said eye tissue comprises a part of cornea and/or sclera at least.
[0028] some embodiment herein is the method for paragraph [0024] to [0027], and wherein said eye tissue comprises a part of cribriform plate at least.
[0029] some embodiments herein are paragraph [0024] methods to [0028], wherein said organizing comprises a part of cornea at least, described method and operation on cornea side by side carry out basically, provide described light trigger with the treatment effective dose, it directly reduces the risk of post-operative cornea distortion situation.
[0030] some embodiment herein is the method for paragraph [0024] to [0029], wherein
A) described experimenter suffers from eyes distortion situation or is in the risk that eyes distortion situation takes place, and described eyes distortion situation comprises one or more in rheumatoid situation, degenerative myopia, conventional myopia, scleral staphyloma, eyes high pressure glaucoma or the low tension glaucoma of expansion, cornea of expansion behind keratoconus, the laser-assisted original position keratomileusis (LASIK), the expansion after the anaclasis keratectomy (PRK), metainfective expansion, periphery.
B) provide described light trigger with the treatment effective dose, its directly treat or directly reduce described eyes distortion situation risk and
C) described radiation of visible light took place in 30 minutes or shorter time.
[0031] some embodiment herein is the method for paragraph [0024] to [0030], and wherein said experimenter suffers from keratectasia.
[0032] some embodiment herein is the method for paragraph [0024] to [0031], and wherein said experimenter suffers from keratoconus.
[0033] some embodiment herein is the method for paragraph [0024] to [0032], and wherein said individuality suffers from degenerative myopia.
[0034] some embodiment herein is the method for paragraph [0024] to [0033], and wherein said photoinitiator compound comprises light trigger, PEG light trigger or its combination, and described light trigger has formula I:
Figure A20078003970100131
R wherein 1, R 2, R 3And R 4Be H, halogen or NO independently of one another 2, and salt pharmaceutically.
[0035] some embodiment herein is the method for paragraph [0034], wherein R 1, R 2, R 3, R 4Be H, Br or NO independently of one another 2
[0036] some embodiment herein is the method for paragraph [0024] to [0035], and wherein said photoinitiator compound comprises eosin W or W S, eosin B or fluorescein.
[0037] some embodiment herein is a paragraph [0024] to the method for [0036], wherein saidly provides step to be further defined as outwardly or provides described light trigger by injection.
[0038] some embodiment herein is treatment or the method that reduces the risk of eyes distortion situation among the experimenter, comprises step:
A) provide photoinitiator compound with the treatment effective dose to described experimenter's eye tissue; With
B) activate described photoinitiator compound by radiation of visible light to described tissue,
Thereby the risk of described eyes distortion situation is directly treated or reduced to described photoinitiator compound.
[0039] some embodiment herein is the method for paragraph [0038], wherein provide described light trigger to treat eyes distortion situation, and the described light trigger of treatment effective dose is by strengthening described eye tissue, stablize described eye tissue shape, changing the shape of described eye tissue or it makes up the symptom for the treatment of eyes distortion situation.
[0040] some embodiment herein is the method for paragraph [0038] or [0039], and wherein said eye tissue comprises a part of cribriform plate, cornea and/or sclera at least.
[0041] some embodiment herein is the method for paragraph [0038] to [0040], wherein said experimenter suffers from or is in the risk of suffering from eyes distortion situation, and described eyes distortion situation comprises one or more in rheumatoid situation, degenerative myopia, conventional myopia or scleral staphyloma, eyes high pressure glaucoma or the low tension glaucoma of expansion, cornea of expansion behind keratoconus, the laser-assisted original position keratomileusis (LASIK), the expansion after the anaclasis keratectomy (PRK), metainfective expansion, periphery.
[0042] some embodiment herein is the method for paragraph [0038] to [0041], and wherein said eyes distortion situation is a degenerative myopia.
[0043] some embodiment herein is the method for paragraph [0038] to [0042], and wherein said eyes distortion situation is a keratoconus.
[0044] some embodiment herein is the method for paragraph [0038] to [0043], and wherein said photoinitiator compound comprises the defined chemical compound of formula I:
Figure A20078003970100141
R wherein 1, R 2, R 3And R 4Be H, halogen or NO independently of one another 2, and salt pharmaceutically.
[0045] some embodiment herein is the method for paragraph [0038] to [0044], and wherein said photoinitiator compound comprises the polyethyleneglycol derivative of the chemical compound of formula I representative.
[0046] some embodiment herein is the method for paragraph [0038] to [0045], and wherein said photoinitiator compound can comprise 500 ± 50nm wavelength, 1-100mW/cm in utilization 2Intensity of illumination the described photoinitiator compound of irradiate light 30 minutes or more directly the treatment described eyes the distortion situation.
[0047] some embodiment herein is a paragraph [0038] to the method for [0046], and wherein said light trigger is that the administration by the surface provides.
[0048] some embodiment herein is the method for paragraph [0038] to [0047], and wherein said light trigger provides by injection.
[0049] some embodiments herein are paragraph [0038] methods to [0048], wherein said eye tissue comprises a part of cornea at least, described method and operation on cornea side by side carry out basically, provide described light trigger with the treatment effective dose, it directly reduces the risk of post-operative cornea distortion situation.
[0050] some embodiment herein is the purposes that photoinitiator compound is used to make medicine, and described medicine is used for directly treating or prevention eyes distortion situation by described photoinitiator compound.
[0051] some embodiment herein is a photoinitiator compound, the risk that it is used for directly treatment or reduces eyes distortion situation as medicine.
[0052] some embodiment herein is according to each the purposes of aforementioned paragraphs [0050] to [0051], and wherein said direct treatment, prevention or the risk that reduces eyes distortion situation comprise the modulus that improves eye tissue.
[0053] some embodiment herein is the purposes according to paragraph [0052], and wherein said eye tissue comprises a part of sclera and/or cornea at least, randomly comprises the whole of sclera and/or cornea.
[0054] some embodiment herein is according to each the purposes of aforementioned paragraphs [0050] to [0053], and wherein said eyes distortion situation is selected from by rheumatoid situation, degenerative myopia, conventional myopia or scleral staphyloma, eyes high pressure glaucoma or the low tension glaucoma of the expansion of the expansion behind keratoconus, the laser-assisted original position keratomileusis (LASIK), the expansion after the anaclasis keratectomy (PRK), metainfective expansion, periphery, cornea and and the group that constitutes thereof.
[0055] some embodiment herein is that wherein said eyes distortion situation is a degenerative myopia according to each the purposes of aforementioned paragraphs [0050] to [0054].
[0056] some embodiment herein is that wherein said eyes distortion situation is a keratoconus according to each the purposes of aforementioned paragraphs [0050] to [0055].
[0057] some embodiment herein is that wherein said photoinitiator compound comprises the chemical compound with formula I according to each the purposes of aforementioned paragraphs [0050] to [0056]:
Figure A20078003970100161
R wherein 1, R 2, R 3And R 4Be H, halogen or NO independently of one another 2, and salt pharmaceutically.
[0058] some embodiment herein is the purposes according to aforementioned paragraphs [0057], wherein R 1, R 2, R 3, R 4Be H, Br or NO independently of one another 2
[0059] some embodiment herein is that wherein said photoinitiator compound comprises eosin W or W S, eosin B or fluorescein according to each the purposes of aforementioned paragraphs [0050] to [0058].
[0060] some embodiment herein is that wherein said photoinitiator compound comprises its polyethyleneglycol derivative according to each the purposes of aforementioned paragraphs [0050] to [0059].
[0061] some embodiment herein is according to each the purposes of aforementioned paragraphs [0050] to [0060], and wherein said photoinitiator compound can utilize the described photoinitiator compound of visible illumination 30 minutes or directly treat or reduce the risk of described eyes distortion situation more in short-term in eye tissue.
[0062] some embodiment herein is that wherein said medicine is used for the administration on surface according to each the purposes of aforementioned paragraphs [0050] to [0061].
[0063] some embodiment herein is that wherein said medicine is used to pass through drug administration by injection according to each the purposes of aforementioned paragraphs [0050] to [0062].
[0064] some embodiment herein is the purposes that photoinitiator compound is used to make medicine, and described medicine is used for directly changing the machinery and/or the chemical property of tissue.
[0065] some embodiment herein is the purposes according to paragraph [0064], and wherein said tissue is an eye tissue, and the direct change of the machinery of described eye tissue and/or chemical property comprises the modulus of the eye tissue of increase.
[0066] some embodiment herein is the purposes according to paragraph [0065], and wherein said eye tissue comprises a part of sclera, cribriform plate or cornea at least, and randomly comprises the whole of sclera and/or cornea and/or cribriform plate.
[0067] some embodiment herein is according to the purposes of paragraph [0065] to [0066], wherein said eye tissue is in to be suffered from or exists risk to suffer from experimenter's the eyes of situation, and described situation is selected from by rheumatoid situation, degenerative myopia, conventional myopia or scleral staphyloma, eyes high pressure glaucoma or the low tension glaucoma of the expansion of the expansion behind keratoconus, the laser-assisted original position keratomileusis (LASIK), the expansion after the anaclasis keratectomy (PRK), metainfective expansion, periphery, cornea and and the group that constitutes thereof.
[0068] some embodiment herein is the purposes according to paragraph [0067], and wherein said eyes distortion situation is a degenerative myopia.
[0069] some embodiment herein is the purposes according to paragraph [0067], and wherein said eyes distortion situation is a keratoconus.
[0070] some embodiment herein is that wherein said photoinitiator compound comprises the chemical compound with formula I according to the purposes of paragraph [0064] to [0069]:
R wherein 1, R 2, R 3And R 4Be H, halogen or NO independently of one another 2, and salt pharmaceutically.
[0071] some embodiment herein is the purposes according to paragraph [0070], wherein R 1, R 2, R 3, R 4Be H, Br or NO independently of one another 2
[0072] some embodiment herein is that wherein said photoinitiator compound comprises eosin W or W S, eosin B or fluorescein according to the purposes of paragraph [0064] to [0071].
[0073] some embodiment herein is that wherein said photoinitiator compound comprises the polyethyleneglycol derivative of the chemical compound of formula I according to the purposes of paragraph [0064] to [0072].
[0074] some embodiment herein is that wherein said photoinitiator compound can comprise 500 ± 50nm wavelength, 1-100mW/cm in utilization according to the purposes of paragraph [0064] to [0073] 2Intensity of illumination the described photoinitiator compound of irradiate light 30 minutes or directly treat or reduce the risk of described eyes distortion situation more in short-term.
[0075] some embodiment herein is that wherein said medicine is used for the administration on surface according to the purposes of paragraph [0064] to [0074].
[0076] some embodiment herein is that wherein said medicine is used to pass through drug administration by injection according to the purposes of paragraph [0064] to [0075].
[0077] some embodiment herein be according to paragraph [0064] to the purposes of [0076], wherein said direct treatment eyes distortion situation, directly reduce the risk of eyes distortion situation or directly prevent eyes distortion situation to comprise with 500 ± 50nm wavelength, 1-100mW/cm 2Intensity of illumination shine described medicine.
[0078] some embodiment herein is a paragraph [0024] to the method for [0049], wherein said provide and activation step between persistent period be between about 1 to 120 minute; Between about 1 to 60 minute; Between about 60 to 120 minutes; Between about 1 to 30 minute; Between about 30 to 60 minutes; Between about 60 to 90 minutes; Between about 90 to 120 minutes; Between about 5 minutes to about 10 minutes; Or between about 1 minute to 5 minutes.
[0079] some embodiment herein is the method for paragraph [0024] to [0049] or [0078], and wherein said method is repeated one, two, three, four, five time or more times.
[0080] some embodiment herein is the method for paragraph [0024] to [0049] or [0078] to [0079], and wherein said activation step is no more than about 30 minutes; Be no more than about 20 minutes; Be no more than about 10 minutes; Be no more than about 5 minutes; Be no more than about 1 minute; Or be no more than about 30 seconds.
[0081] some embodiment herein be according to paragraph [0050] to the purposes of [0077], wherein said medicine is used for being provided for tissue after photoactivation, described provide and activation step between persistent period be between about 1 to 120 minute; Between about 1 to 60 minute; Between about 60 to 120 minutes; Between about 1 to 30 minute; Between about 30 to 60 minutes; Between about 60 to 90 minutes; Between about 90 to 120 minutes; Between about 5 minutes to about 10 minutes; Or between about 1 minute to 5 minutes.
[0082] some embodiment herein is according to the purposes of paragraph [0050] to [0077] or [0081], wherein activates described medicine with light and is no more than about 30 minutes; Be no more than about 20 minutes; Be no more than about 10 minutes; Be no more than about 5 minutes; Be no more than about 1 minute; Or be no more than about 30 seconds.
[0083] above listed some feature of the present invention and technique effect, purpose is that detailed description of the invention subsequently can be better understood.To describe other features and advantages of the present invention hereinafter, it has formed the theme of claim of the present invention.What it will be understood by those skilled in the art that is that the disclosed design and the specific embodiment can be used as the basis and easily utilize, and are used for revising or designing other structures being used to carry out identical purpose of the present invention.What those skilled in the art also will be familiar with is that this suitable framework does not deviate from the spirit and scope of the present invention of setting forth in subsidiary claim.Be considered to the new design of feature of the present invention, comprise its structure and How It Works,, will be better understood according to following being described in when considering together with accompanying drawing with further purpose and advantage.Yet what will be expressly understood that is that each accompanying drawing provides just to the purpose of illustration and description, and is not intended to the definition as boundary of the present invention.
Brief description of the drawings
[0084] in order to understand the present invention more fully, with the following description of accompanying drawing reference.
[0085] Fig. 1 is the exemplary equipment that monitors that eye shape changes during high pressure applies.
[0086] Fig. 2 illustrates that ground is for example understood because the eyes of the intraocular pressure that improves expand (size is the quantity of pixel of the digital image of eyes).
[0087] Fig. 3 has shown from the expand exemplary data of research of eyes, and the eyes that wherein enucleate remained among the IOP of 22mmHg one hour in the same manner, and the contrast eye is in the IOP of 22mmHg 23 hours subsequently, among the IOP of test eye 85mmHg 23 hours.Eyes in accompanying drawing below all expand to study and follow this scheme, are described in further detail in the embodiment trifle.
[0088] Fig. 4 has shown the exemplary data that expand and study from eyes, and wherein three pairs of treatments and contrast eyes that accompany (I2959 and DPBS respectively) have experienced the IOP that improves.Time t=0 corresponding to 85mmHg IOP after 1 hour measurement.The change of PS and DE shows that UV activatory 12959 stablizes the ability of sclera.
[0089] Fig. 5 has shown the exemplary data that expand and study from eyes, and wherein five pairs of treatments and contrast eyes that accompany (eosin W or W S/TEOA and DPBS respectively) have experienced the IOP that improves.Time, t=0 brought up to 85mmHg corresponding to IOP from normal level.The variation of PS and DE shows that in 24 hour time visible-light activated eosin W or W S stablizes the ability of sclera.
[0090] Fig. 6 has shown the exemplary tissue slice from the tissue pathology checking of the lagophthalmos eyeball of eosin W or W S/TEOA (group 2) and eosin W or W S/TEOA carrier (group 3) processing, a) irradiation area of group 2 rabbits has shown slight inflammation and moderate cicatrix, b) conjunctiva of the rabbit of group 2 does not have the zone of contraction to show normal CSC, c) zone of the irradiation of group 3 (contrast) rabbit has shown slight inflammation and moderate cicatrix, and d) conjunctiva of group 3 rabbits does not have the zone of contraction to show normal CSC.Arrow indication among all figure is on the border of sclera/conjunctiva of noticing inflammation and scar place.
[0091] Fig. 7 A and 7B have shown the expand typical consequence (measuring with the digital image pixel) of research of the eyes that use eosin W or W S on the complete eye of corneal epithelium.
[0092] Fig. 8 A and 8B have shown the typical consequence (measuring with the digital image pixel) of the eyes expansion research of using eosin W or W S on the eye that removed corneal epithelium before adding eosin W or W S.
[0093] Fig. 9 has shown the exemplary chemosynthesis approach that produces the PEG derivant of eosin W or W S.
[0094] Figure 10 has duplicated the confocal microscopy image, has shown the background fluorescence of (Figure 10 A) sclera, and the penetrating of fluorescein-labeled PEG-acrylate after the hatching of (Figure 10 B) 10 minutes.Drawing shown hatched in 10 minutes and subsequently irradiation after, as function, the standardized fluorescence mean intensity of the degree of depth of sclera.
[0095] Figure 11 A has shown and has been used to measure for example exemplary slit lamp equipment of the drug diffusion of cornea of organizing that enters.A) top view of equipment.B) fluorescence seen in the photographing unit.Figure 11 B.The slit lamp pictorial display A) the complete thickness (light filter 2 is external, Figure 11 A) of cornea of eosin W or W S treatment, B) isolating fluorescence (light filter 2 is built-in, as shown in Figure 11 A) in the substrate; C) and utilize
Figure A20078003970100201
The automatic fluorescence intensity analysis of software.
[0096] Figure 12 has shown by immersing in the Treatment Solution (above-mentioned eosin W or W S concentration, each be listed as corresponding to the preparation in the table 2) 1 hour (or * 6 hours) (top row) that handle, that the epithelium reservation is complete or removing the slit lamp image of the substrate of the Oculus sus domestica eyeball that (bottom line) of epithelium enucleate before.
Detailed description of the invention
[0097] be consistent with long-standing Patent Law convention, when using in this manual, word " " is consistent with the word that comprises statement " one or more " with " a kind of ", comprises claim.Word " comprises " and " comprising " shows open claim or claim boundary.Some embodiment of the present invention can by or form by one or more elements of the present invention, method step and/or method basically.What expect is that any method described here or compositions can realize with respect to any other method described here or compositions.
[0098] definition
[0099] term " cornea " is meant the forward covering transparent, the cima shape of eyes as used herein.It works as plane of refraction usually, and the focusing function that surpasses half of eyes is provided.In cornea, do not have blood vessel, thereby it is normally clear and bright and have a smooth surface.It comprises 5 layers: epithelium, Bao Man film, substrate, descemet membrane and endothelium.Cornea also comprises more teleneuron than any other place of health.
[0100] term " crosslinked (crosslink) " or " crosslinked (crosslinking) " are meant the formation of covalent bond between two molecules as used herein.For example, tropocollagen molecule can with the crosslinked network that forms the tropocollagen molecule that the inside that keeps together by covalent bond is connected of other tropocollagen molecules.
[0101] term " expansion " is meant hollow organ's expansion or elongation as used herein.In specific embodiment of the present invention, this term is meant eye tissue, for example the bulge of cornea.In further specific embodiment, described expansion is that operation is inductive, and in selectable embodiment, it is not because operation can be because exemplary medical condition keratoconus.Under specific situation, expansion is the result of laser-assisted original position keratomileusis (LASIK).
[0102] term " keratoconus " is meant a kind of medical condition as used herein, wherein is generally circular cornea and develops into cone sample shape owing to the attenuation and/or the bulge of cornea.Enter eyes at light and go in the light sensitive retina way, the shape of cone causes the irregular refraction of light, and this causes disorderly looks.Keratoconus is a PD, can take place in eyes or eyes.
[0103] term " sclera " is meant the fibrous layer in tough and tensile, opaque (usually white), the outside of eyes as used herein, and the place ahead links to each other with cornea, and the rear links to each other with optic nerve.It comprises collagen and elastic fibers, is commonly called " white of the eye ".Many muscle centers on the motion that eyes are connected on the sclera and control it.In the rear end of eyes, optic nerve is connected on the sclera.Term " sclera " is meant the fibrous layer in the outside of eyes as used herein, and the place ahead links to each other with cornea, and the rear links to each other with optic nerve.
[0104] term " machinery of tissue and/or chemical property " is meant the biophysical properties of tissue as used herein.The example of mechanical performance includes but not limited to hot strength, comprcssive strength, bending strength, modulus, elongation and toughness (stress-strain).The example of chemical property includes but not limited to the character of the chemical bond of component of organization (for example, the crosslinked collagen of collagen contrast), water number amount, the biodegradation of organizing ingredient or the conversion ratio of aquation that tissue can keep.
[0105] term " shape of change tissue " is meant that organizing the device of shape to make up light trigger treatment and change is stabilized in described tissue in the shape of described change.For example, by the mode of the plastics casting mold in the shape that is designed to induce cornea to be in the vision that to improve arbitrary, can temporarily reinvent cornea.By making up the light trigger of this moulding device and treatment effective dose,, after removing, can keep in the alteration of form device the corrigent shape of tissue by irradiation when moulding device is in place.
[0106] term " treatment effective dose " be meant one or more machineries that directly cause tissue or chemical property change to enough degree, with the required quantity of symptom of treatment eyes distortion situation.
[0107] term " eyes distortion situation " is meant that disease or physics in experimenter's the eye change as used herein, and it causes the change of size of one or more structures of research.In some embodiments, this size changes the change that causes vision.The particular instance of eyes distortion situation comprises corneal distortion situation such as keratoconus (comprising the rear portion keratoconus); The post-operative cornea distortion situation of the expansion after expansion behind the laser-assisted original position keratomileusis (LASIK) and the anaclasis keratectomy (PRK); The situation of the rheumatoid of the expansion of expansion, periphery, cornea, degenerative myopia, conventional myopia, scleral staphyloma and glaucoma (comprising eyes high pressure glaucoma and low tension glaucoma) after infecting.
[0108] term " light trigger " is meant generally to be that UV or visible light change into initiation species form, for example chemical compound of free radical or cationic chemical energy with the light energy that absorbs as used herein.According to the mechanism that the free radical that causes forms, light trigger is generally divided into two types: the type i light trigger experiences monomolecular bond cleavage and separates the generation free radical when irradiation; Type II light trigger experience bimolecular reaction, wherein the excited state of light trigger and second molecule (auxiliary initiator) reaction produces free radical.The UV light trigger of type i and Type II is known, and the visible light light trigger generally belongs to the Type II classification.Those skilled in the art recognize that the type of the light source of employing has been determined in the selection of light trigger, and different light triggers has activity and has different effectiveness under different wavelength.Especially, the light trigger spatial resolution that can be excited depends on that light trigger is through single-photon or through a plurality of photon excitations.Light trigger can be water miscible in specific embodiment, and is by oxygen quenching, preferably biocompatible.The size of chemical compound is depended in the diffusion that light trigger enters sclera and/or cornea, and the hydrophilic and/or hydrophobic interaction of light trigger and tissue.The diffusion rate of wishing will be fast, to minimize treatment time.High efficiency light trigger is wished, because irradiation energy, irradiation time and photoinitiator concentration are minimized.Preferably, oxygen serves as the inhibitor of the effectiveness that reduces light trigger.This inhibition will provide the method for any adverse effect of the photoactivation of protecting the blood vessel that carries oxygen to avoid light trigger.In specific embodiment, adopt water miscible, nontoxic and to the light trigger of the amount sensitivity of oxygen concentration.Exemplary light trigger comprise formula I herein chemical compound, 2959 and in Figure 10 B, the 10C of the disclosed application number 20050271590 of the U.S. and 10E those disclosed light trigger.
[0109] term " modulus " is meant constant or coefficient as used herein, its representative, and for example digital upward representative species or body have the degree (for example intensity or elasticity) of mechanical performance.Those skilled in the art recognize, the scope of modulus depends on the particular type of definite measuring method, measured modulus, the material of measurement, for sclera, and the situation of tissue (as age or health status) and be organized in epibulbar position.The example of modulus comprises Young's modulus (being also referred to as Young modulus, modulus of elasticity, elastic modelling quantity or stretch modulus), bulk modulus (K) and modulus of shearing (G, or S or (i) be also referred to as rigidity modulus sometimes.
[0110] term " eye tissue " is meant discontinuous types of organization that exist in the eyes or relevant with eyes as used herein.In some embodiments, described eye tissue is the structure organization of setting up and/or keep shape of eyes.In other embodiments, described eye tissue has contribution to the vision of eyes.The particular instance of eye tissue comprises sclera, cribriform plate and cornea.
[0111] term " directly treatment ", " directly handling ", " directly reducing risk " or the like are meant the therapy based on light trigger, wherein light trigger directly and component of organization interact and cause the change of tissue property.The direct treatment of light trigger is different from indirect light trigger treatment, and wherein light trigger and one or more other chemical reagent interact and change the structure of another kind of chemical reagent, and the change of another kind of chemical reagent causes the change of tissue property.The example of indirect light trigger treatment finds in the disclosed application number 20050271590 of the U.S., and wherein eosin W or W S/TEOA is used as the reinforcement that the crosslinked light trigger of PEGDM is used for scleral tissue.The present invention does not comprise indirect light trigger therapy.Term " directly treatment ", " directly handling " or the like are meant for example improvement of at least a symptom of eyes distortion situation of disease or situation in addition as used herein.For instance, in myopia, symptom comprises the stretching length of sclera, the attenuation of sclera or the weakening of sclera.In addition, those skilled in the art recognize that described treatment does not need to improve vision, for example improve vision to its maximum degree.Aspect specific, this term be meant stop eyes distortion situation for example degenerative myopia or keratoconus development or slow down development.In concrete embodiment, vision stability.
[0112] term " Polyethylene Glycol " and " PEG " are meant a kind of chemical compound as used herein, it comprises surpassing of ethylene glycol poly-(ethylene glycol) trunk monomers part or whole, there is or do not have different end group, and comprise some monomer or do not have other monomers, for example, dimethyl siloxane, methyl methacrylate, lysine, arginine, chondroitin sulfate, keratin sulfate, or the like.In specific embodiment, it is defined as comprising ethylene glycol (oligomer of repetitive OCH2CH2-) or polymer.
[0113] term " myopia (myopia) " as used herein also can be called myopia (near-sightedness), is meant the object of clearly seeing nearby but can not sees the ability of object in a distance clearly.The present invention is suitable for the myopia of form of ownership and degree.In specific embodiment, myopia is pathologic and is diagnosed that this moment, the eyeball elongation was relevant with the attenuation of the eye tissue at eyeball rear portion.High myopia is defined as surpassing 8 diopters.
[0114] as used herein, term " pharmaceutically acceptable salt " is meant those salt, in the scope of acceptable medical judgment, they are suitable for contacting with zootic tissue with the mankind and not having over-drastic toxicity, stimulation, allergy or the like, and match with rational benefit/risk ratio.The pharmaceutically acceptable salt of the chemical compound of amine, carboxylic acids and other types is well known in the art.For example, people such as S.M.Berge are at J.Pharmaceutical Sciences, and 66:119 has described pharmaceutically acceptable salt in (1977), is incorporated in this by list of references.Described salt can preparation in situ during the final separation of chemical compound of the present invention and purification, or by free acid or free alkali functional group and the reagent reacting that is fit to are prepared individually, as general description hereinafter.For example, free alkali functional group can with the acid reaction that is fit to.In addition, when chemical compound of the present invention had acidic moiety, its pharmaceutically acceptable salt that is fit to can comprise slaine, for example alkali metal salt, for example sodium or potassium salt; And alkali salt, for example calcium or magnesium salt.Pharmaceutically acceptable, nontoxic acid is amino and mineral acid for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid and perchloric acid with the example of salt, or with organic acid for example acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using for example salt that forms of ion exchange of additive method used in the art.Other pharmaceutically acceptable salts comprise adipate, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphorate, camsilate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxyl-ethane sulfonate, Lactobionate, lactate, laruate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalates, palmitate, embonate, pectate, persulfate, 3-phenylpropionic acid salt, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, rhodanate, tosilate, the hendecane hydrochlorate, valerate, or the like.Representational alkaline or alkaline-earth salts comprises sodium, lithium, potassium, calcium, magnesium salt or the like.When appropriate, further pharmaceutically acceptable salt comprises nontoxic ammonium, quaternary ammonium and utilizes for example amine cation of halogen ion, hydroxyl, carboxylate radical, sulfate radical, phosphate radical, nitrate anion, lower alkyl sulfonate radical and the formation of aryl sulfonic acid root of equilibrium ion.
[0115] as used herein " side by side carrying out " meaning basically is to be applied in this disclosed method within a certain period of time, and it is in time with prevention or to reduce the operation of potential complication risk enough approaching.The medical professional who carries out described operation will be informed well by herein guidance and example, thereby can determine suitable opportunity.In some embodiments, being applied in after the medical procedure of method disclosed herein, and in specific embodiment, after medical procedure 5,10,15,20,25,30,35,40,45,50,60,75,90 or 120 minutes or more of a specified duration at the most.
[0116] as used herein " operation on cornea " is meant any medical procedure, and it relates to reinvents or change cornea in the surgery mode, for example laser-assisted original position keratomileusis (LASIK) or anaclasis keratectomy (PRK).
[0117] as used herein " visible light " is meant and has the electromagnetic radiation of about 400nm to about 780nm wavelength.In some embodiments, visible light is to have an a) about 750nm of about 400nm-, and b) about 400nm is to about 700nm, or c) about 450nm arrives the electromagnetic radiation of the wavelength of about 700nm.
[0118] embodiments of the present invention
[0119] in embodiments of the present invention, have to relate to and change one or more machineries organized in the individual health and/or the method and composition of chemical property.In some cases, described tissue is an eye tissue, and in specific embodiment, described eye tissue is cornea or sclera.In special exemplary embodiments again, the present invention relates to one or more machineries and/or the chemical property of Change Example as the cornea of the individuality of suffering from keratoconus.
[0120] in specific embodiment, in order to prevent because the vision loss of keratoconus, the inventor designed minimally-invasive, safety and fast method to come to import in for example cornea, cribriform plate or sclera therapeutic crosslinked.The development of keratoconus is a specific embodiment of the present invention though slow down, other parts that the present invention provides that also routine is molecule crosslinked or has been aggregated to eyes for example, the ability of those parts within cornea, sclera and the cribriform plate.The present invention is applicable to various situations, and wherein Zu Zhi shape is unsettled (can not keep its normal shape) and/or shaping again.The example relevant with vision comprises the expansion (for example clear edge corneal degeneration) of expansion behind keratoconus, rear portion keratoconus, the laser-assisted original position keratomileusis (LASIK), the expansion after the anaclasis keratectomy (PRK), metainfective expansion, periphery, rheumatoid situation, degenerative myopia, conventional myopia, scleral staphyloma, glaucoma and the normal tension glaucoma of cornea.
[0121] inventor developed relevant clinically exemplary surperficial administration or the light trigger of injection and the combination of radiation of visible light, produce enough crosslinked to delay the development of keratoconus.Utilization enters the distribution in the cornea and the understanding of transhipment to molecule, and people can modify or produce and penetrate epithelium and do not have the toxic new molecule of epithelium.The light trigger of infiltration cornea is diffused in the corneal stroma to realize utilizing the clinical effectiveness of photoactivation subsequently fully with enough concentration.The light trigger of infiltration corneal epithelium is to be used to permeate for example fabulous chemical compound of sclera of its hetero-organization.The impermeable corneal epithelium of some interested light trigger can be delivered in the substrate by injection.This allows that people do not remove corneal epithelium and treat.Then, the inventor shown, people can treated tissue and tissue are not exposed to the UV light of latent lesion.Provide by visible-light activated treatment, the retina that is caused by ultraviolet radiation and the risk of corneal injury are avoided.In addition, people can utilize irradiation mode to make crosslinked localization to avoid crosslinked in the non-destination organization.The interaction of photoinitiator concentration and light intensity has determined to produce the time of exposure required to the crosslinking degree of patient's necessity.The result shows that it is possible that irradiation time is lower than 5 minutes.This will shorten to about 5 minutes to 30 minute treatment time utilizing riboflavin and ultraviolet light, and simplify widely by the treatment individuality, for example patient, and nursing supplier, for example surgical operation.The further control of photoactivation (being included in the activation of in-house selected depth, for example under the epithelium and on the endothelium of cornea) can activate and realizes by the present invention being expanded to two-photon or multi-photon.Utilize the toxic risk of infrared light activation further reduction radiation-induced of high concentration.
[0122] photoactivation
[0123] of the present invention aspect some in, one or more light triggers are offered one or more tissues in the health, and utilize light to activate them.Yet in some aspects, described light can be any kind of, and in specific embodiment, it is visible light, ultraviolet light or infrared light.Described activation can be two-photon or multi-photon activation.In further specific embodiment, adopt radiation of visible light.
[0124] persistent period that is exposed to exposure can be an any kind of, as long as target molecule is activated from described light.In aspect specific, be exposed to exposure and continue, and be intermittently in some cases.In aspect other, light is employed about one second or many seconds, and one minute or several minutes, or one hour or a few hours.In a particular case, light is employed about at least one minute, at least about two minutes, at least about three minutes, at least about four minutes, at least about five minutes, at least about six minutes, at least about seven minutes, at least about eight minutes, at least about nine minutes, at least about ten minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, or the like.In other cases, light use and to be no more than about 30 minutes, be no more than about 25 minutes, minute, be no more than about 20 minutes, be no more than about 15 minutes, be no more than about ten minutes, be no more than about nine minutes, be no more than about eight minutes, be no more than about seven minutes, be no more than about six minutes, be no more than about five minutes, be no more than about four minutes, be no more than about three minutes, be no more than about two minutes or be no more than about one minute.
[0125] the exemplary light source that is used for radiation of visible light comprises lamp (for example, the hydrargyrum xenon arc lamp is randomly launched group's optical wavelength by colour filter), laser and light emitting diode (LED).Light is generally with 1-100mW/cm 2Intensity be used, specific light intensity depends on related tissue and photoinitiator compound and other factors.The technical staff can easily be light intensity and the time that specific application adjustment is shone.
[0126] light trigger
[0127] the exemplary light trigger of A.
[0128] In some embodiments of the present invention, one or more light triggers are provided for individual tissue, thereby the machinery of described tissue and/or chemical property are affected.In specific embodiment, one or more light triggers are provided for individual tissue, thereby the shape that described tissue is reinforced and/or organizes is changed.In some aspects, adopt the light trigger of treatment effective dose, it is meant that one or more machineries that directly cause tissue or the change of chemical property reach the symptom required quantity of enough degree with treatment eyes distortion situation.
[0129] can use any suitable light trigger in the present invention, but as long as it is photoactivation, it directly influences at least a machinery and/or the chemical property of the tissue of wishing when photoactivation.In some embodiments, described light trigger is the Type II light trigger.In other embodiments, described light trigger is a visible light Type II light trigger.
[0130] at some in other the embodiment, described light trigger is by the chemical compound of formula I representative and the salt pharmaceutically of formula I:
Figure A20078003970100271
Formula I
R wherein 1, R 2, R 3And R 4Be H, halogen or NO independently of one another 2
[0131] in some embodiments, R 1, R 2, R 3And R 4Be H, Br, F or NO independently of one another 2In some embodiments, R 1, R 2, R 3And R 4Be H, Br or NO independently of one another 2In other again embodiment, R 1, R 2, R 3, R 4Each is hydrogen (this chemical compound is also referred to as fluorescein) naturally.In other embodiments, R 1And R 4Each is NO naturally 2, and R 2And R 3Each is Br (this chemical compound is also referred to as eosin B) naturally.In other again embodiment, R 1, R 2, R 3, R 4Each is bromine (this chemical compound is also referred to as eosin W or W S) naturally.
[0132] exemplary compound eosin W or W S of the present invention will be used to describe in more detail the present invention.
[0133] eosin W or W S is modal water solublity xanthene dye, is the common dyestuff of collagen.Eosin W or W S is the Type II light trigger, and its general and triethanolamine (TEOA) is used in combination.Yet, the same with other types II light trigger, can use any suitable coinitiator.Eosin W or W S has the absorption peak of about 514nm, is activated efficiently by hypotoxic, visible (green) light.
Eosin W or W S TEOA
[0134] notably, as shown in table 1, in a series of application, eosin W or W S itself has the record of the biocompatibility of establishing well.
[0135] table 1. shows the document of the biocompatibility of eosin W or W S photoinitiator system.
The author Use
People such as Nakayama The hemostasis of liver organization
People such as Orban Cardiovascular is used
People such as Cruise, people such as Pathak, people such as Desmangles Islet cell encapsulation/microencapsulation
People such as Elisseeff Wear the polymerization of epidermis
People such as people Carnahan such as Luman Closed linear corneal incision, fixed L asik flap
People such as Alleyne Duralumin sealant (FocalSeal) in the dog craniotomy
People such as West Thrombosis suppresses
[0136] in specific embodiment, described light trigger and the combination of one or more labels, thus in a single day being delivered to the experimenter, the position of light trigger and/or quantity can be monitored.Exemplary label comprises fluorescent marker, and it randomly can be selected to fluoresce under the optical wavelength that does not activate described light trigger basically.
[0137] though exist the almost permeability measured value of 150 kinds of different chemical compounds (Wollensak, 2006), the diffusion of crossing over cornea for chemical substance does not also have reliable predictability equation (Prausnitz and Noonan, 1998).Trend demonstrates, and the lipophile of raising can help to cross over transhipment (Tangliu et al., 1994 of epithelium barrier; Sasaki et al., 1995).Simultaneously, remove electric charge from medicine and can improve permeability.For penetrating of epithelium, the in-vitro measurements value is well relevant with the interior result of body, as long as the epithelium of tissue samples is complete.In some embodiments, improvement formula I chemical compound is by producing the electric charge that its carboxylate derivatives reduces it by a kind of method of the penetrance of epithelium.A kind of such modification is to add short PEG to the carboxylate site.For instance, people can and be grafted to the carboxylic acid site with it by tosylation PEG-OH and prepared grafting the eosin W or W S of PEG (PEG-EY).For example, can use three kinds of length commercially available, but be exemplary PEG-OH: about 200,400 and 800g/mol.
[0138] the thickest layer---the substrate of cornea comprises the complex array of collagen fiber, aminopolysaccharide and proteoglycan.Allow the variant of eosin W or W S or the specificity interaction that new photoinitiator compound realizes improving effectiveness according to the understanding of the stable molecular basis of the described corneal of model system (collagenous network, polylysine, poly arginine, polycysteine, hyaluronic acid, dermatan sulfate, keratan sulfate, chondroitin sulfate sulfate or heparin sulfate).
[0139] the B. light trigger sends
[0140] in some embodiments, light trigger can and utilize any suitable method to be sent by any suitable mode, as long as applied the treatment effective dose.In specific embodiment, light trigger be outwardly, by injection, send by contact (comprise continue discharge contact), sponge or the like by having absorbed light trigger.Can adopt eye drop, described in some cases light trigger is by lyophilizing.Light trigger can also be expelled to by the pin with fine gauge and be delivered to cornea in the substrate, and the light trigger of this substrate injection can be spread in the stromal lamellae.
[0141] can be adjusted at independent patient light trigger send and shine between time, and this time can be depended on multiple factor, the diffusion rate that comprises described light trigger target approach tissue, and the stability of light trigger under administration condition (for example, ambient light intensity).Light trigger can be provided for individuality, then at certain hour with after guaranteeing that light trigger arrives ad-hoc location and/or enough levels, for instance, can shine then.For example, when light trigger reaches a certain degree of depth in the particular organization, can monitor light trigger, activate described light trigger with light then with slit lamp and/or confocal microscope.In specific example, when penetrating cornea, monitor described light trigger to a certain degree of depth, activate described light trigger with light then.
[0142] light trigger send and the photoactivation of light trigger between time can be any suitable persistent period, and in specific embodiment, this time second, minute or hour the order of magnitude on.In specific embodiment, the described time was about one minute, about two minutes, about three minutes, up to about 120 minutes.In other specific embodiments, light trigger send and the photoactivation of light trigger between persistent period be no more than about one minute, about two minutes, about three minutes, about 5 minutes, about 10 minutes, about 20 minutes, up to about 120 minutes.
[0143] C. irradiated tissue
[0144] illumination to the tissue of light trigger treatment can realize by plurality of devices and technology.Slit lamp delivery system, optical fiber photosystem, the illumination by indirect ophthalmoscope delivery system all are the examples that can easily be fit to the irradiation unit of purposes disclosed herein and method.Can use any suitable equipment or technology, it can send the time of the lasting q.s of light of suitable wavelength with suitable intensity, usually based on employed specific light initiator and other parameters disclosed herein.
[0145] treatment of medical condition
[0146] of the present invention specific aspect, described method and composition can be used to have any medical condition of the experimenter of needs.Though described experimenter is human aspect specific, further in, the present invention is for other mammals, for example horse, cattle, Canis familiaris L., cat, goat, sheep or pig are useful.
[0147] as required can be in individuality repetitive therapy.For example, in for the second time or repeatedly treatment can be formerly treatment a couple of days, in treatment several weeks before or carry out in the treatment several months before.
[0148] A. eyes medical condition
The treatment of eyes distortion situation is arranged [0149] in embodiments of the present invention.In specific embodiment, described eyes distortion situation comprises expansion behind keratoconus, rear portion keratoconus, the LASIK, the expansion behind the PRK, metainfective expansion, the expansion (for example clear edge corneal degeneration) of periphery, rheumatoid situation, degenerative myopia, conventional myopia and/or scleral staphyloma, glaucoma, normal tension glaucoma and the eyes high pressure of cornea.In some embodiments, method herein can be used for reducing or prevent to comprise the risk of above-mentioned arbitrary eyes distortion situation by prophylactically being made.In specific embodiment, method herein is when carrying out LASIK, PRK or other operation on cornea or be applied to cornea afterwards soon, reduces the risk of postoperative expansion or other corneal distortion situations, and these are complication of such operation.
[0150] 1. glaucoma
[0151] glaucoma is the main cause of visual deprivation in the world.In glaucoma, exist the gradual loss of the retinal ganglial cells relevant with the depression of optic nerve head.The most common ground, this optic nerve injury takes place under the intraocular pressure greater than the raising of 21mm Hg.Yet not rare, we can see identical optic nerve depression (normal tension glaucoma) under normal intraocular pressure.Burgoyne and colleague have shown that intraocular pressure changes the shape of supporting construction, cribriform plate and the peripapillary sclera of optic nerve.(1.Burgoyne，CF，Downs?JC，Bellezza?AJ?et?al.The?optic?nerve?head(ONH)as?a?biomechanical?structure：a?new?paradigm?for?understanding?the?role?of?IOP-related?stress?and?strainin?the?pathophysiology?of?glaucomatous?optic?nerve?head?damage.ProgRetina?Eye?Res.2005；24：39-732.Bellezz?AJ，Rintalan?CJ，Thompson?HW，et?al.Deformation?of?the?lamina?cribrosa?and?anterior?scleral?canal?wall?inearly?experimental?glaucoma.Invest?Ophthalmol?Vis?Sci.2003；44：623-6373.Yang?J，Downs?JC，Girkin?C，et?al.3-D?histomorphometry?of?the?normaland?early?glaucomatous?monkey?optic?nerve?head：lamina?cribrosa?andperipapillary?scleral?position?and?thickness.Invest?Ophthalmol?Vis?Sci.2007；48：4597-4607)。The inductive rear portion of intraocular pressure distortion and thicken the cribriform plate connective tissue and be considered to have promoted infringement to aixs cylinder, they stretch out outside the eye, and the result causes atrophia nervi optici glaucomatosa." from the angle of through engineering approaches, should be directly related to the ONH connective tissue of damage and permanent deformation sensitivity with its rigidity of structure, it is the geometry (tissue volume and form) of structure and the combination of material character (tissue rigidity) ".(Yang?J，Downs?JC，Girkin?C，et?al.3-D?histomorphometry?of?the?normal?and?early?glaucomatous?monkey?opticnerve?head：lamina?cribrosa?and?peripapillary?scleral?position?and?thickness.Invest?Ophthalmol?Vis?Sci.2007；48：4597-4607)。Thereby, if we change the mechanical performance of (reinforcements) cribriform plate and stop glaucoma or the normal tension glaucoma in the distortion of this tissue, we can reduce even stop these development of losing one's sight and lacking of proper care.In addition, in patient with glaucoma risk, have eyes highly compressed those (intraocular pressure of raising and do not have optic nerve head damage), the similar reinforcement of connective tissue will prevent or reduce glaucomatous risk or glaucomatous development speed in cribriform plate and/or peripapillary sclera.
[0152] in order optionally to treat sieve plate and/or the contiguous nipple week sclera looked improves resistance to the distortion of pressure inducement, light trigger can be before irradiation be injected in the ophthalmic mode and/or in mode near the eyes.Can shine by the pupil of eyes then, and be positioned at cribriform plate and/or look on nipple week sclera.As selection, can utilize fiber optics probe under the capsula bulbi under the capsula bulbi method use irradiation.Multi-photon irradiation may be useful especially, is used for optionally controlling light trigger at destination organization cribriform plate and/or look nipple intrascleral activation of week.If the supporting tissue of optic nerve thereby be stabilized, the glaucomatous atrophy of optic nerve can be prevented from or slow down.
[0153] the non-eyes medical condition of B.
[0154] in embodiments of the present invention, the tissue of treatment comprises a part of blood vessel.For instance, can strengthen the risk that the blood vessel wall with aneurysm risk reduces the aneurysm development according to method disclosed herein, or strengthen existing aneurysm and reduce the disruptive risk of blood vessel wall.
[0155] in other embodiments, described tissue comprises hernia or is in tissue in the risk that hernia forms.By according to the method herein enhanced tissue, the risk that the risk that hernia forms or the hernia of raising form can be lowered.
[0156] in other embodiments, the tissue of treatment comprises the alveolar structure with degeneration risk, for example in COPD patient.Method herein is strengthened generation and the speed that alveolar structure reduces the alveolar degeneration.
[0157] in other embodiments, the tissue of treatment can be the heart tissue of damage, for example, and after myocardial infarction.Can strengthen the heart tissue of damage to improve the loss speed of cardiac function and/or reduction cardiac function by method herein.For instance, the heart tissue of strengthening under the myocarditic situation of expanding can stop or reducing the loss speed of heart pumpability.
[0158] to the machinery of tissue and/or the analysis of the change of chemical property
[0159] aspect some, the machinery of tissue and/or the change of chemical property have been tested of the present invention.Various testing of materials technology are that the technical staff is obtainable.For instance, the Young's modulus of tissue can utilize TA instrument AR1000 hemotachometer (utilizing the parallel-plate geometry of bolt system) to measure.
[0160] of the present invention aspect some, the change that comes test organization by the alteration of form of appraisement organization visually.For example, the expansion of structure of visually measuring eyes under the intraocular pressure that improves is tested in eyes expansion as described below.
[0161] also can and adopt other instruments known in the art and the technology of the mechanical performance of characterizing tissues before treatment afterwards.These known technology can be at for example Ahearne M, YangY, Then KY, Liu KK.An indentation technique to characterize themechanical and viscoelastic properties of human and porcine corneas.AnnBiomed Eng.2007Sep; 35 (9): 1608-16; And Gatinel D, Chaabouni S, Adam PA, Munck J, Puech M, Hoang-Xuan T.Corneal hysteresis, resistance factor, topography, and pachymetry after corneal lamellar flap.JRefract Surg.2007Jan; 23 (1): find among the 76-84 and in other lists of references that this quotes.
[0162] exemplary eye therapy
[0163] exemplary treatment operation can be as follows.The topical of the eye drop that comprises eosin W or W S that will prepare in 1-120 minute before irradiation is given individual.This provides diffusion of reagents to enter the time of sclera.After about 1-120 minute, with the about 1-5 of radiation of visible light eyes minute (1-100mW/cm 2, wavelength is suitable for specific light trigger, for example, is 500 ± 50nm) for eosin W or W S.The balanced salt aqueous solution eye drop of ophthalmology can be used to clean eyes after the administration light trigger He before the photoactivation.The mode that is fit to of the clinical implementation of irradiation comprises makes the patient be in supine position, emits light by operating microscope, or the patient is sat down and utilizes the slit lamp system to emit light.People also can use by conjunctiva down or under the capsula bulbi method point to the fibre-optic light source of sclera.The light source that is fit to that is used to shine comprises lamp, laser or light emitting diode, for instance.Control comprises the optical fiber that irradiation wave beam rasterisation, usage space photomodulator, the digital illuminator equipment of use or use are linked to each other with laser to the method that is fit to of the irradiation mode incident of tissue, for instance.The current shape of sclera is stablized in described treatment, and stops or slowing down the gradual change relevant with for example degenerative myopia.When treatment related to cornea, the refraction that utilizes cornea topology for example to assess to monitor the experimenter changed.If alteration of form recovers, can be repetitive therapy when essential (for example, with 3 to 36 months interval).
[0164] the exposure amount that also can change exposure is adjusted at the crosslinked degree that takes place in the tissue.This can come quantitatively by the reduction of the fluorescence intensity of light trigger during the measurement irradiation process.Crosslinked in the localized area can utilize light pattern or even activate by the multi-photon light source and to carry out.
Embodiment
[0165] following examples are included with the preferred implementation of the present invention of demonstrating.Those technology that it will be understood by those of skill in the art that on behalf of the inventor, disclosed technology find among the following embodiment can be worked in practice of the present invention well, therefore can think to have constituted the preferred mode that is used for its practice.Yet those skilled in the art should be appreciated that and can carry out many variations in disclosed concrete scheme according to current disclosed content, still obtains similar or similar result under the situation that does not deviate from the spirit and scope of the present invention.
Embodiment 1
Utilize poly-(ethylene glycol) dimethylacrylate (PEGDM) of the photic initiation of eosin W or W S/TEOA Polymerization
[0166] according to the instruction of the disclosed application number 20050271590 of the U.S., the inventor uses eosin W or W S/TEOA to be used for the reinforcement of scleral tissue as the crosslinked optionally light trigger of PEGDM.What find surprisingly is that (for example, under situation PEGDM), eosin W or W S/TEOA is effective comparably for the intensity that strengthens scleral tissue there not being the target cross-linking agent.Especially unexpectedly, utilize about 30 minutes or shorter irradiation time, the Type II light trigger can be strengthened sclera and reach upward useful degree of treatment.Do not wish to be subjected to the restriction of any theory, what believe is that eosin W or W S can promote the direct crosslinked intensity that directly strengthens scleral tissue of collagen and other sclera compositions fully.Though this does not get rid of for example combined effect of PEGDM of cross-linking agent, the result of eosin W or W S has hinted that simpler preparation is possible, the reagent that it utilizes U.S. food and drug administration to ratify.
Embodiment 2
The dose response and the mechanical performance of the tissue of treatment
[0167] many different technology have been used to the reinforcement of entry evaluation scleral tissue, comprise that extension test, oscillatory shear are measured and the following eyes expansion of more completely discussing is analyzed.
[0168] utilize tissue slice the rheological analysis entry evaluation have or do not have the initiator of cross-linking compounds to strengthen the ability of sclera.Sclera section (8mm diameter) is downcut the change of modulus before TA instrument AR1000 rheometer (parallel-plate geometry of utilizing bolt to be) upward tests quantitative Treatment and after handling from the Oculus sus domestica eyeball.Select the light trigger of two examples to be used for entry evaluation.
Figure A20078003970100341
2959 (2-hydroxyl-1-[4-(2-hydroxyl-oxethyl) phenyl]-2-methyl isophthalic acid-acetone and have the eosin W or W S (eosin W or W S/TEOA) of triethanolamine.
Figure A20078003970100342
2959 (12959) is the light trigger that has shown hypotoxic UV photoactivation in cell encapsulation research.Select eosin W or W S/TEOA as from the example light initiator group of formula I definition, that visible light is reacted.The modulus of shearing of scleral tissue adds the PEGDM treatment along with 12959 and improves, and the quantity that modulus changes improves (oxygen quenching polymerization) along with the reduction of oxygen.Utilize eosin W or W S/TEOA to add PEGDM and realized similar result.As discussed above, find surprisingly, with 12959 or the modulus of eosin W or W S/TEOA generation when treating separately aspect comparable raising.
Embodiment 3
Eye shape in the inflationary model of myopia and keratoconus
[0169] utilize the paired eyes that enucleate from immature (1-2 week) New Zealand white rabbit to assess the stabilisation of eye shape in external mode, an eye is processed, and its companion's eye in contrast.For simulate with acceleration bodies in the load geometry that exists, mechanically test complete eyeball by the intraocular pressure of forcing raising: syringe stores up the pond with the high position that ophthalmic liquid is connected to Dulbecco ' s (DPBS), and among the DPBS of the outside of eyes immersion ambient pressure (Fig. 1).The eyes that enucleate from immature rabbit provide the model of distensible cornea and scleral tissue: when in the external intraocular pressure that stands to improve, cornea is outside bulge little by little, scleral walls expansion (Fig. 2 and 3).
[0170] from size and the shape of two rectangular viewpoints along with the track record eyeball of time.For the eyes of preparing to be used to test, randomly wipe away from cornea and remove epithelium with cotton, remove external fat from eyeball.(note, check individually that hereinafter light trigger enters penetrating of tissue).Then eyes were immersed in contrast (Dulbecco ' s PBS) or the Treatment Solution (for example, 0.029mM eosin W or W S, 90mM TEOA are among the DPBS) 5 minutes.After soaking, pat dry eyes and remove extra solution from the surface, then for example for eosin W or W S/TEOA 34mW/cm 2500 ± 50nm quadrature in the past penetrated 5 minutes and shone 5 minutes from the rear.Then eyes are loaded in the cell of DPBS, intraocular pressure (IOP) maintains 85mmHg (～4 times of normal values).Analyzing the photo of taking 24 hours in per 10 minutes comes the elongation of quantitative cornea and sclera long.Measured the stabilisation of the eye tissue of handling by the above-mentioned complete eyes expanding method of inventor design, for the change of record modulus, additive method is not enough sensitivity.
Embodiment 4
Elongation of mechanical performance and eyes and eye shape in the inflationary model of myopia The dependency of stripped stability
[0171] tests the ability that has shown the direct stabilizing tissue of this method with the activatory light trigger 12959 of UV.Eyes were immersed in 0.3%12959 5 minutes, the front portion of eyes is exposed to light (10mW/cm 2, 365nm) 10 minutes, rear portion 10 minutes.Then eyes are connected to the saline storage pool, pressure is directly brought up to 85mmHg.Along with the past of time, the eyes of processing keep stable shape, and untreated eyes are expanded (Fig. 4) constantly.
[0172] proved the probability of strengthening eye tissue and stoping expansion with 12959 tests; Yet visible-light activated preparation generally will be more suitable in clinical practice.Eyes were immersed in 0.0289mM eosin W or W S/90mM TEOA solution 5 minutes, then by the eyes front portion is exposed to visible light (34mW/cm 2, 450-550nm) 5 minutes, eyes rear portion activated in 5 minutes.This processing also can stop eyes expansions (Fig. 5).
[0173] sensitivity of research because eye shape expands, the preparation of the enough low concentrations of our energy carries out.The illustrated visible-light activated system of eosin W or W S/TEOA has shown that low-intensity, visible light expose and hang down the quick treatment time under the photoinitiator concentration, and described concentration is similar to the concentration of using in the medicine of the FDA approval that comprises eosin W or W S/TEOA.
Embodiment 5
Toxicity research
[0174] carries out toxicity research and determine whether aforesaid preparation and exposure are suitable for using in the animal model of myopia and in clinical trial.Existing document has widely been put down in writing the compatibility of eosin W or W S and TEOA.Because the promising history of this low toxicity, for the biocompatibility in eyes, this preparation has shown big potentiality.In order to test body internal reaction, utilized the following experiment of adopting various delivery techniques to eosin W or W S/TEOA and visible light exposure.
The isoflurane that sucks with the 1-5% by the mask administration gives six adult New Zealand white rabbit general anesthesias, to surperficial administration 0.5% keracaine of right eye (0D).With 5% povidone iodine the right eye of each animal is sterilized.In whole process, wash eyes with balanced salt aqueous solution (BBS) with aseptic eye.In conjunctiva, make the otch of a 15mm, draw back conjunctiva and expose sclera.In the following manner 200 microlitre solution are applied to the rabbit sclera.
Figure A20078003970100361
After [0175] 5 minute, by being exposed to zone (about 450-550nm, the approximately 34mW/cm that light came the photoactivation treatment in 5 minutes 2).By sewing up the otch in the closed conjunctiva.Allow the subconjunctival injection of all animals received betamethasones (75-150 microlitre) and cefazolin sodium (75-150 microlitre).The injection and the 2-3 that give all animal carprofens (5mg/kg) and buprenorphine (0.05mg/kg) drip neomycin, aerosporin, Gramicidin OD.Check pain or any symptom of inflammation, for example ptosis of blood-shot eye illness, ejection, eyelid, blepharospasm or the photophobia of eyes.Check that eyes once continued for 1 week every day, weekly then lasting other 3 weeks.After 4 weeks, allow all animal euthanasias, remove the eyes of treatment, fixing in 10% formalin, processing is used for light microscopic examination (eosin/hematoxylin dyeing).Write down the existence of any inflammatory cell.
[0176] eyes in operation all operations in back 2 days exist some swelling and inflammation.This is corresponding to the result that expectation obtains from operation technique itself.Representational result is shown in Figure 6.Back 3 days of operation with in each inspection after this, in any eyes, there is not the symptom of pain or inflammation.When histological examination, in the animal of group 1 and 2, under irradiation area, exist slight inflammation and moderate scar along conjunctiva sclera border.In the contrast eyes of group 3, some inflammation and scar are arranged also.In all experimental grouies, iris, retina and ciliary body all are normal in appearance.
[0177] the treatment with the contrast eyes scleras in do not have significant difference, show slight inflammation and scar be the operation but not the treatment the result.Similarly, the viability of in-house cell and normal eye is suitable near in the eyes of treatment.
Embodiment 6
Long and the eye shape of mechanical performance and eyes stretching in the inflationary model of keratoconus The dependency of stripped stability
[0178] the eye shape inflationary model is well suited for the cornea reinforcement (Fig. 7 and 8) as the therapy of keratoconus.As shown in Figure 7, utilize brief as mentioned above eosin W or W S/TEOA treatment step can not allow that enough light triggers penetrate cornea and are used for strengthening by the crosslinked cornea subsequently of direct sunshine initiator.What compare with this is, under the parameter of in this model system, testing, sclera fully the absorbing light initiator to allow sufficient build up.The corneal light initiator absorbs and can realize (Fig. 8) to allow light trigger to the direct administration of destination organization by removing the epithelium that covers cornea fully.This result is the expansion (Fig. 8) that prevents cornea elongation in eyes inflationary model system fully.
[0179] the medicine ability that penetrates epithelium can be designed to change the chemistry of epithelium or the molecule of physical property strengthens (Sasaki H by co-administered, Yamamura K, Mukai T, Nishida K, Nakamura J, Nakashima M, Ichikawa M.Enhancement ofOcular Drug Penetration.Critical Reviews in Therapeutic Drug CarrierSystems.1999; 16 (1): 85-146).Use the suitable medicine that destroys the epithelium barrier, it will be unnecessary that epithelium is removed.For example, what report was arranged is, after the keracaine that has used the surface to apply, the medicine of Xiang Shuizhong is sent and has been improved 4 times of (Ehlers W, Crouch E, WilliamsP, Riggs P.Factors Affecting Therapeutic Concentration of TopicaiAminocaproic Acid in Traumatic Hyphema.10VS.1990; 31 (11): 2389-2394).Especially, topical anesthetic cream for example keracaine and tetracaine changes the function of sodium-ion channel, and thereby changes the electrophysiology of epithelium.The for example diffusion of those molecules of formula I representative of charged molecule is convenient in the change of crossing over the potential difference of epithelium.In addition, these anesthetis change combining of cell and cell in epitheliums, reduce its effectiveness as barrier.In this selectable method, the drop (for example 0.5% drop) of keracaine drop of ophthalmology (for example, 0.5% drop) or tetracaine is used to the complete cornea of epithelium.After about 15 minutes, handle cornea according to method herein.
Embodiment 7
Be used for the modification of the eosin W or W S that epithelium penetrates
[0180] though above-described epithelium removal operation is the acceptable medical procedure that is used for the treatment of eyes, and the inventor has represented eosin W or W S can be in compliance with chemical modification, it improves the penetrance that it enters the sclera and the cornea of complete epithelium.In an example, Polyethylene Glycol (PEG) is covalently bound to the carboxyl (Fig. 9) of eosin W or W S, although reduced the electric charge on the molecule, it allows that the PEG-eosin W or W S is soluble in water.This chemical modification has strengthened eosin W or W S and has entered the penetrance of tissue, and has reduced the quantity of the chemical substance that realizes that enough build ups are required.Also change photochemical activity with the PEG covalent modification, can influence the effectiveness and the time course of light trigger therapy.Generally should keep balance to optimize treatment from the penetrance result of the improvement of modifying at the time course of the irradiation of hope.For example, the mixture of eosin W or W S and PEG-eosin W or W S can be used for realizing the time course that the light trigger of optimizing penetrates and shines.
[0181] utilize opposite ends at chain have acrylate grafting the PEG of fluorescein carry out exemplary research (fluorescein, another kind of chemical compound in the defined classification of formula I has and other candidate light triggers similar size and the hydrophobicity of eosin W or W S with formula I definition).Continue the specified time in the solution with PEG-fluorescein among the complete Oculus sus domestica ball immersion DPBS and 12959.Then, the Oculus sus domestica eyeball is come the plain covalent bond (12959 photocrosslinking is used for fixing the PEG-medicine, thereby its distribution can be by imaging) with tissue of induced fluorescence with the 365nm irradiate light.Imaging in the tissue slice that downcuts on the thickness of degree of depth figure at sclera of the fluorescein that in the sclera of handling, produces.Model PEG-light trigger conjugate has penetrated the hundreds of micron and has entered (Figure 10) in the tissue in several minutes.After the solution with the PEG-drug conjugates contacts 5 minutes, in the fluorescence micrograph of tissue slice, be penetrated into 100 microns or mostly be tangible.After the solution with the PEG-drug conjugate contacts 30 minutes, observe and infiltrate into 500 microns.These results show that the medicine that the surperficial administration in 5 to 30 minutes time is suitable for suitably modifying reaches the required degree of depth of build up.
[0182] for the eosin W or W S that uses the Oculus sus domestica eyeball and the research of PEG-eosin W or W S, utilized the analytical method that relies on the slit lamp of revising, it can be transformed into clinical instrumentation (Figure 11 A) easily.Improved and allowed replacement or remove light filter 1 and 2, digital camera has been placed, fixed angle in the same way with described slit, and during checking the Oculus sus domestica eyeball that enucleates is remained on correct position.
[0183] by the suitable light filter of light source (light filter 1 by 500 ± 20nm) and from the light scattering of cornea (light filter 2 is by 560 ± 25nm), and the fluorescence of eosin W or W S allows us to inspect its penetration profile figure in substrate.The use of these light filters allows that we distinguish the scattered light of autofluorescence.Untreated cornea does not show fluorescence (visual field showed dark-coloured when two light filters were in place).In fresh that enucleate, the Oculus sus domestica eyeball handled, we can measure the fluorescence profile (Figure 11 B) on the whole corneal thickness.Utilize
Figure A20078003970100391
Program is analyzed the digital image from equipment, and this software determined anterior corneal surface, with the intensity equalization of cornea different depth hypograph, and has drawn the graph of a relation of the reference intensity and the degree of depth.After this manner, we can check quantity and its distribution in substrate of the medicine that passes epithelium.
[0184] eyes that enucleate from 3-4 monthly age pig are to obtain from the Sierra of Medical Science.Fresh eyes are placed in the saline, load and transport on ice.When arriving, come directly cleaning eyes (less than after death 42 hours) by removing the tissue that still is attached on the eyes.Then, take a picture, the baseline comparison of background fluorescence and the original dimension of cornea are provided with scattering method and fluorescence mode corneal.Remove epithelium or be kept perfectly with dissecting knife, afterwards eyes are placed the Treatment Solution (table 2) of 2ml.Eyes were remained in the solution 1 hour, shift out then, clean, take a picture with scattering and fluorescence mode with the DulbeccoShi PBS of about 4ml.Then, remove and to have the eyes of complete epithelium and in this photograph.Removing epithelium in this step has separated owing to penetrated the fluorescence of the medicine of substrate.
Treatment Solution Eosin W or W S (mM) Triethanolamine (mM)
1 0.0289 90
2 1 90
3 10 225
[0185] table 2. blended Treatment Solution in the phosphate buffered saline (PBS) of Dulbecco
[0186] eosin W or W S penetrating in substrate (Figure 12) when having and do not have epithelium to exist shows that epithelium suppresses eosin W or W S and penetrates into cornea.The significant infiltration that eosin W or W S is crossed over epithelium is significantly in the cornea of handling with highly concentrated solution (2 and 3), shows that the removal of epithelium can be by using the light trigger of enough concentration, and particularly the light trigger of formula I representative is avoided.Except the image of independent substrate (Figure 12), also exist the image that adopts the epithelium collection to show that epithelium absorbs eosin W or W S.These results show, can modify the eosin W or W S molecule and improve the infiltration that enters substrate by improving the epithelium permeability, shown that the medicine that epithelium absorbs may be released to along with the time in the substrate, allows in the variation aspect delivery method and processing time.
Embodiment 8 (indication)
External test is stablized the optimum condition of sclera and cornea shape
[0187] stabilisation of eye shape---the chemical compound that will use the complete eyes of New Zealand white rabbit to study photoactivation is strengthened the ability of sclera.After the operation of above exploitation, complete lagophthalmos eyeball is removed all fat, immerse in the Treatment Solution, activate described processing with irradiate light, place DPBS to bathe then, be connected to the saline storage pool of rise by hypodermic needle.The height of regulating storage pool obtains the IOP of 85mmHg, gathers picture and monitors alteration of form in 24 hours.To test the process variables of studying the degree that can change stabilisation with this.Some variablees of testing comprise:
[0188] ratio of photoinitiator concentration and constituent: minimize the quantity of stablizing required light trigger and will reduce toxic risk, and the quantity of raising light trigger can reduce treatment time.Improve the quantity that photoinitiator concentration will increase the free radical that produces, but under some concentration, the absorption of dyestuff may limit light and see through, and only allows the activation on the sclera anterior corneal surface.In addition, the binary system of eosin W or W S and TEOA may not show best activation under current component ratio.With the eosin W or W S concentration of test from 0.0289mM to 1mM and 3mM TEOA concentration range to 90mM.
[0189] the light trigger time of contact during carrying out surperficial administration to scleral surface: surperficial administration depends on the diffusion that eosin W or W S and TEOA enter sclera.Improve and to improve in-house photoinitiator concentration time of contact, improve the depth of penetration, but also can improve the risk of patient's complication.To be used to check the influence of the diffusion time of raising up to 20 minutes soak time from 1 minute.
[0190] time delay between light trigger applies and shines:, the diffusion of light trigger takes place still from sclera cleaning light trigger with the time between the irradiate light.Initial concentration gradient from surperficial administration will become more even along with the time.In-house crosslinked concentration with the light trigger that exists is relevant.By producing gradient and more uniform crosslinked stabilization effect with expanding to this time delay to reach 20 minutes and study.
[0191] illumination scheme: the operation of current realization stabilisation adopt 5 minutes, from the process of 500 watts of hydrargyrum xenon arc lamps of Thermo Oriel filtering broadband exposure (450-550nm is with 34mW/cm 2).Though this dosage belongs to the maximum PEL according to ansi standard, the reduction of time and intensity will further improve the safety of this operation.Eosin W or W S has peak absorbance at the 514nm place, illumination wavelength is matched to improve render a service.Export according to the absorption spectrum of eosin W or W S and the spectrum of mercury xenon lamp, dope the half (15mW/cm that realizes present level in the suitable illumination scheme that is calculated as of the arrowband of 514nm (28nm) light source for the center 2) intensity.Exposed time and intensity will be lowered to determine the minimum irradiation time that treatment is required.Our preliminary result shows that surprisingly the LED at the 525nm place launches and only about 7mW/cm during five minutes 2Power be enough to be stabilized in shape of eyes in our the eyes inflationary model.
Embodiment 9 (indication)
Strengthen sclera and/or cornea in vivo
[0192] handle in the body, particularly Therapeutic Method generally will be referred to light trigger and light to experimenter's sclera or sending of cornea.
[0193] will anaesthetize New Zealand white rabbit by the isoflurane and the 0.5% surperficial keracaine that suck via mask administration 1-5%.With the 5% povidone iodine eyes of sterilizing.In whole operation, eyes are in eye washing in the balanced salt aqueous solution (BBS).Produce otch in conjunctiva, retractor will be used to expose the gap in socket of the eye week.Change in the final operating procedure will be used to send the independent studies with activatory effect.
[0194] light trigger is sent: light trigger will be injected into retro-ocular space and be used for sclera and handle, or is added on the cornea (have or do not remove epithelium) as drop.In order to improve time of contact, will utilize the ophthalmology viscoelastic agent (for example, Rayflo, Rayner Intraocular Lenses, mixture Ltd.) improves the viscosity of photoinitiator solution.Determine the best persistent period that preparation will keep in touch according to external eye shape inflationary model.Use the excessive light trigger of BSS flush away then.After cleaning immediately, with animal euthanasia.With utilize confocal microscopy to the sclera of the eyes that enucleate and/or cornea and surrounding tissue in the existence of light trigger assess, determine the concentration of eosin W or W S, as mentioned at PEG-fluorescein shown (figure X).To analyze the fluorized marking of the eosin W or W S that exists in the microphotograph, determine the horizontal proliferation and the depth of penetration.
[0195] light is sent: will utilize the optical fiber that links to each other with argon laser (514nm) or LED (525nm) to attempt being used for handling the crosslinked location of the specific region of sclera.According to the light trigger delivering method of measuring in the aforesaid external work, will when activating, light come together to give (figure X) by the fluorescently-labeled tracer molecule and the light activating agent preparation of conjunctive tissue.Gap and/or the excessive preparation of anterior corneal surface flush away from socket of the eye week.To enough light be delivered to sclera and/or cornea starts crosslinked (intensity and persistent period are determined as mentioned) by optical fiber source.To wash eyes with BSS, rabbit will be carried out euthanasia, enucleate eyes.Utilize the crosslinked degree of depth and the degree of accuracy of fluorescence microscopy assessment.
[0196] toxicity: the group of 6 rabbits will be accepted the complete treatment of the optimal conditions determined according to above embodiment.Matched group will accept not have the test light initiator preparation of photoactivation, or accept to use the phototherapy of carrier formulation.After light trigger and light are sent, removed volume preparation with BSS flushing eyes.Operative incision is with sewing up the closure procedure otch.Animal will give the subconjunctival injection of cefazolin sodium (antibiotic) and betamethasone (steroid).Check the pain of eyes or any symptom of inflammation clinically, for example the pus in rubescent, the eyes of eyes and the ptosis of eyelid continue a week once a day, continue one month once in a week then.After 1 month, with animal euthanasia.Take out the eyes of handling, in stuck-at-0% formalin, processing is used for light microscopy.Write down the existence of any inflammatory cell.Clinical will come classification by 1 to 4 grade with histopathologic inflammatory reaction, 1 inflammation that is equal to nothing, and 2 equal slight inflammation, and 3 equal moderate inflammation, and 4 equal serious inflammation.
Embodiment 10 (indication)
Strengthen sclera and/or cornea in vivo
[0197] handle external stabilisation in the body: after in aforesaid body, using, will be in the stability of testing in vitro eyes.An eye is processed, second eye served as control.The various times are carried out euthanasia (table 3) to rabbit after processing.The stability that the eyes dilatometric analysis that utilizes pressure inducement mentioned above is tested the eyes that enucleate.
Figure A20078003970100431
[0198] when in the eyes dilatometric analysis that carries out as mentioned above, standing 85mmHg IOP, will keep their shape from one or more groups eyes.
Embodiment 11 (indication)
In the myopia model system, strengthen sclera and/or cornea in the body
[0199] model (Howlett MH, McFadden SA., Form-deprivation myopia in the guinea pig (Caviaporcellus), the Vision Res.2006Jan of form deprivation myopia in Cavia porcellus, have been set up; 46 (1-2): 267-83, Epub 2005Aug 31).5 day age, white plastic hemisphere is placed on the eye of Cavia porcellus.In only after 11 days of form deprivation, compare with companion's eye of not shutoff, there is the axial elongation of more myopia of average-6.6D and 146 μ m.This model will be used to further verify light trigger preparation and operation parameter according to above-mentioned experiment.
[0200] experiment will be tested the normally myopia (group C) of normal contrast therapy of the myopia of eye contrast myopia (organizing A), a normal contrast therapy (group B), treatment, and the myopia of myopia contrast therapy (organizing D).
Figure A20078003970100441
4 day age, the right eye eye socket that will be prolapsed out, exposed rear sclera.This zone will utilize the Week Cell applicator that soaks in photoinitiator solution to handle with light trigger (for example eosin W or W S) preparation above.Waiting for as above definite suitable time (a few minutes) afterwards, the area illumination of handling to induce free radical to form by light trigger.Then eyes are placed eye socket, come closed conjunctiva with absorbable suture.A series of control animals will experience identical operations, but not apply light trigger or irradiation.5 day age, in processed group and matched group the above and below of the right eye of Cavia porcellus gluing on nylon fastener belt, the white plastic diffuser is fixed on the nylon fastener belt.
[0201] at 16 days of life, remove diffuser, carry out following measurement: the infrared ray measurement of corneal astigmatism determines that the cornea sphere becomes curvature; Utilize high frequency ultrasound (20MHz) to measure axial length, and utilize the graticule cproscopy after the cycloplegia to measure error of refraction.After these are measured, sacrifice of animal is used for the Histological research of complete eyeball.
[0202] when in the eyes dilatometric analysis that carries out as mentioned above, standing 85mmHg IOP, will keep their shape from the eyes of the myopia group of handling, perhaps compare the shape of keeping them in vivo with the contrast eye.
Embodiment 11 (indication)
[0203] intraocular pressure that improves and the optic nerve depression of raising appear in the patient who suffers from open-angle glaucoma in eyes.For mechanically stableization that cribriform plate is provided and the progress that reduces optic atrophy, utilize orbiculus ciliaris (pars plana) method ophthalmic ground injection eosin W or W S/TEOA.After 5 to 60 minutes, directly on the sieve page or leaf, shine cribriform plate with the two-photon light source.The crosslinked modulus and the opposing distortion subsequently that has improved it of connective tissue in the sieve page or leaf that is produced.The tomography equipment that uses 2 photon irradiation bombs can connect by means of motion sensitive optics well known in the art and that for example in Application No. 2005/0048044, describe to the targeting of sieve page or leaf.
Embodiment 12 (indication)
[0204] patient who suffers from myopia selects to carry out LASIK.In order to prevent to expand behind the LASIK, after excimer melts, eosin W or W S/TEOA imposed on the substrate bed.Flap then resets.Reduced the risk of expanding behind the LASIK from cornea hardness based on the raising of the treatment of light trigger.
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[0277] Application No. 2005/0271590
[0278] U.S. Patent number 6,161, and 544
[0279] U.S. Patent number 6,478, and 792
[0280] Application No. 2005/0048044
[0281] all lists of references that quote as proof at this or that propose intactly are incorporated in this with them by reference, merge by quoting expressly above as they each.Especially, the specific material of quoting as proof about list of references or rely on, all lists of references are incorporated in this by reference.
[0282] though described the advantage of the present invention and it in detail, it being understood that at this and can carry out various variations, replacement and change and do not deviate from by the subsidiary defined the spirit and scope of the present invention of claim.In addition, the application's scope is not intended to be subject to the specific implementations of process, mechanism, product, combinations of substances, means, method and the step described in the description.To easily understand according to disclosure those of ordinary skill in the art of the present invention, carry out substantially the same function with corresponding embodiment described here or realize substantially the same result, current process, mechanism, product, combinations of substances, means, method or step existing or later exploitation can use according to the present invention.Thereby subsidiary claim intention is in the such process of their encompasses, mechanism, product, combinations of substances, means, method or step.

Claims (28)

1. photoinitiator compound is used to make the purposes of medicine, and described medicine is used for directly treating or prevention eyes distortion situation by described photoinitiator compound.
2. photoinitiator compound is used the medicine that acts on direct treatment or reduce the risk of eyes distortion situation.
3. according to each the purposes in the aforementioned claim, wherein said direct treatment, prevention or the risk that reduces eyes distortion situation comprise the modulus that increases eye tissue.
4. according to the purposes of claim 3, wherein said eye tissue comprises a part of sclera, cribriform plate or cornea at least, and randomly comprises the whole of sclera and/or cornea and/or cribriform plate.
5. according to each the purposes in the aforementioned claim, wherein said eyes distortion situation is selected from by rheumatoid situation, degenerative myopia, conventional myopia or scleral staphyloma, eyes high pressure glaucoma or the low tension glaucoma of the expansion of the expansion behind keratoconus, the laser-assisted original position keratomileusis (LASIK), the expansion after the anaclasis keratectomy (PRK), metainfective expansion, periphery, cornea and and the group that constitutes thereof.
6. according to each the purposes in the aforementioned claim, wherein said eyes distortion situation is a degenerative myopia.
7. according to each the purposes in the aforementioned claim, wherein said eyes distortion situation is a keratoconus.
8. according to each the purposes in the aforementioned claim, wherein said photoinitiator compound comprises the chemical compound with formula I:
R wherein 1, R 2, R 3And R 4Be H, halogen or NO independently of one another 2, and salt pharmaceutically.
9. purposes according to Claim 8, wherein R 1, R 2, R 3, R 4Be H, Br or NO independently of one another 2
10. purposes according to Claim 8, wherein said photoinitiator compound comprises eosin W or W S, eosin B or fluorescein.
11. according to each the purposes in the aforementioned claim, wherein said photoinitiator compound comprises the polyethyleneglycol derivative of the chemical compound of formula I representative.
12. purposes according to Claim 8-10, wherein said photoinitiator compound can utilize the described photoinitiator compound of radiation of visible light 30 minutes or directly treat or reducing the risk of described eyes distortion situation more in short-term.
13. according to each the purposes in the aforementioned claim, wherein said medicine is used for the administration on surface.
14. according to each the purposes in the aforementioned claim, wherein said medicine is used to pass through drug administration by injection.
15. photoinitiator compound is used to make the purposes of medicine, described medicine is used for directly changing the machinery and/or the chemical property of tissue.
16. according to the purposes of claim 15, wherein said tissue is an eye tissue, the direct change of the machinery of described eye tissue and/or chemical property comprises the modulus of the eye tissue of increase.
17. according to the purposes of claim 16, wherein said eye tissue comprises a part of sclera, cribriform plate or cornea at least, and randomly comprises the whole of sclera and/or cornea and/or cribriform plate.
18. according to each the purposes among the aforementioned claim 16-17, wherein said eye tissue is in to be suffered from situation or existence and suffers from experimenter's the eyes of risk of situation, and described situation is selected from by the expansion of the expansion behind keratoconus, the laser-assisted original position keratomileusis (LASIK), the expansion after the anaclasis keratectomy (PRK), metainfective expansion, periphery, rheumatoid situation, degenerative myopia, conventional myopia or scleral staphyloma, eyes high pressure glaucoma or the low tension glaucoma of cornea and the group that constitutes thereof.
19. according to the purposes of claim 18, wherein said eyes distortion situation is a degenerative myopia.
20. according to the purposes of claim 18, wherein said eyes distortion situation is a keratoconus.
21. according to each the purposes among the aforementioned claim 15-20, wherein said photoinitiator compound comprises the chemical compound with formula I:
Figure A2007800397010004C1
R wherein 1, R 2, R 3And R 4Be H, halogen or NO independently of one another 2, and salt pharmaceutically.
22. according to the purposes of claim 21, wherein R 1, R 2, R 3, R 4Be H, Br or NO independently of one another 2
23. according to the purposes of claim 21, wherein said photoinitiator compound comprises eosin W or W S, eosin B or fluorescein.
24. according to the purposes of claim 21-23, wherein said photoinitiator compound comprises the polyethyleneglycol derivative of the chemical compound of formula I representative.
25. according to the purposes of claim 21-24, wherein said photoinitiator compound can comprise the light of 500 ± 50nm wavelength in utilization, with 1-100mW/cm 2Intensity of illumination irradiation 30 minutes or more in short-term, directly treat or reduce the risk of described eyes distortion situation.
26. according to each the purposes among the aforementioned claim 15-25, wherein said medicine is used for the administration on surface.
27. according to each the purposes among the aforementioned claim 15-25, wherein said medicine is used to pass through drug administration by injection.
28., wherein said direct treatment eyes distortion situation, directly reduce the risk of eyes distortion situation or directly prevent eyes distortion situation to comprise with 500 ± 50nm wavelength, 1-100mW/cm according to each the purposes in the aforementioned claim 2Intensity of illumination shine described medicine in the described tissue.
CNA2007800397014A 2006-10-24 2007-10-24 Influence the photochemical therapy of systemic machinery and/or chemical property Pending CN101594904A (en)

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