HK1165992B - Combination of photodynamic therapy and anti-vegf agents in the treatment of unwanted choroidal neovasculature - Google Patents

Abstract

The use of a combination of photodynamic therapy and an anti-VEGF agent in the treatment of conditions characterized by unwanted choroidal neovasculature is described. These conditions include wet age-related macular degeneration Preferred anti-VEGF agents are antibodies such as bevacizumab or ranibizumab Photosensitizers may be selected from green porphyrins such as BPD-MA (verteporfin) and the photodynamic activation of the photosensitizer may be accomplished using a reduced fluence rate. The use may further comprises an anti-inflammatory agent such a dexamethasone.

Description

Combination of photodynamic therapy and anti-VEGF agents for the treatment of unwanted choroidal neovasculature

Technical Field

The present invention relates generally to methods and compositions for photodynamic therapy for the treatment of ocular diseases. More particularly, the invention relates to the use of photodynamic therapy in combination with one or more other therapeutic agents, more particularly anti-VEGF agents and anti-inflammatory agents, for the treatment of diseases characterized by unwanted or unwanted neovasculature in the eye.

Background

Neovascularization occurs when angiogenesis occurs in a tissue that does not otherwise contain blood vessels or when different types of blood vessels grow in the tissue. Unwanted neovascularization is associated with many disease states, such as those that occur with tumor growth or vision loss. An example of undesirable intraocular neovascularization is Choroidal Neovasculature (CNV), as found in the "wet" form of age-related macular degeneration (AMD).

AMD causes severe, irreversible vision loss and is the leading cause of blindness in individuals over 50 years of age in western countries. Most patients are non-neovascular ("dry") types characterized by drusen and retinal pigment epithelial cell (RPE) abnormalities. However, eighty to ninety percent of the severe vision loss caused by AMD can be attributed to the type characterized by CNVs, also known as "wet" AMD. In the United states, 70,000 to 200,000 individuals over 65 years of age develop neovascular AMD each year (Bressler, N. "cardiovascular surgery: Are random three neurology salt.

In CNV, newly formed blood vessels have a tendency to leak blood and fluid, resulting in blind spots and symptoms of visual deformation (macromolecular photographic assessment group. "organic laser tomography for vascular occlusion. three-layer lipids." Arch opththalmol. 1986; 104: 694-701). New blood vessels are accompanied by fibrous tissue proliferation (macromolecular proliferation Study group. "laser-associated proliferation of sub-vascular neovascularization. updated definitions from within clinical laboratories." Arch opthalmol. 1993; 111: 1200. sup. 1209). The complex of new blood vessels and fibrous tissue is capable of destroying photoreceptors within 3 to 24 months. While existing CNVs destroy retinal tissue where they form, the damage can continue to grow on the macula, resulting in progressive, severe, and irreversible vision loss. If left untreated, the central vision of most affected eyes will deteriorate (< 20/200) (MacularPhotooculation Study group. "Current choroid neobasization after eye lens laser photo-visualization for neobasilar macrocular", ArchOphthalmol. 1986; 104: 503) 512). Furthermore, when One eye of an individual has CNV, the contralateral eye has a probability of developing the same CNV lesions (TAP) Study group, "Photocurable Therapy of sub-visual chorodality and efficiency in related terms-related surgery With visible sensitivity With One-eye failure, of 2 random closed clinical principles-TAP 1," Archhthalmol.1999; 117: 1329-.

Photodynamic therapy (PDT) provides a method to selectively destroy CNV without significantly damaging overlying retinal tissue, possibly by occluding new blood vessels in the CNV lesion. Photodynamic therapy IS a two-step process consisting of intravenous injection of a photosensitizer (a light-activated drug) followed by Application of light (Marcus, S. "Photodynamics therapy of human Cancer: clinical status, potential and needles." In: Gomer C, ed.future guidance and Application of Photodynamics therapy. Berlingham: SPIE Press.1990; IS 6: 5-56; Manyak, M.J.. The most commonly used light sources are non-thermal lasers or Light Emitting Diodes (LEDs). Photosensitizers may preferentially accumulate in neovascular tissues, including choroidal neovascularization of endothelial cells. In combination with the administration of local light, allows selective treatment of pathological tissues (Kreimer-Birmbaum, M. "modifidophoryls, chlorins, phthalocyanines, and neuropurins: second genetic transmitters for photodynamic therapy." minor blood temperature.1989; 26: 157. sup. 173; Moan, J.et. "photosensing efficiencis, tur. and. sup. upper photosensitive reagent for photodynamic therapy." Photobacterium phosphor. 1987; 46: 713. sup. 721-). After exposure to light having a wavelength of 689nm, an energy transfer cascade is initiated, resulting In the formation of singlet oxygen which generates free radicals In the cell (Kreimer-Birmbaum, M., supra; Roberts, W.G.et al, "In vitro phosphorylation I.Celluar uptake and subellurlar localization of mono-l-aspartic chloride 6, chloro-aluminium sulfonated phthalocyanines, and Photofrin II," laser Surg.Med.1989; 9: 90-101). These free radicals are capable of disrupting cellular structures such as cell membranes, mitochondria and lysosomal membranes.

Photodynamic therapy was licensed in the united states in 2000 and approved for treatment of AMD-induced typically major macular subfoveal CNV. Visudorine (Visudyne) therapy targets the vascular fraction of CNV. The approved two-step procedure was through which verteporfin (verteporfin) was administered, one by restPulse (IV) infusion of delivered photoactivated drug (photosensitizer) followed by non-thermal laser application to CNV injury (600 mW/cm at 83 seconds time)²Delivery 50J/cm²)。

It is known in the art to treat CNV using other therapies, including PDT in combination with other therapies.(pegaptanib) is an effective anti-VEGF therapy for all patients with CNV caused by AMD.(ranibizumab) is another effective anti-VEGF therapy in patients with all AMD-induced CNV (Rosenfeld PJ, Brown DM, Heier JS, et al, MARINAStudy group, Ranibizumab used for relative macromolecular evolution. N Engl J Med.2006; 355: 1419. ANG. 1431; Brown DM, Kaiser PK, Michels Metal, ANCHORStudy. group. Ranibizumab used for relative macromolecular evolution. N Engl. Med.2006; 355: 1432. 1444;(Lanitumumab injection) drug prescription information. San francisco, CA: genentech; http:// www.gene.com/gene/products/information/tgr/lucentis/index.jsp.2006, 11/15). Lucentis protocol as defined in the U.S. drug Specification ((Lanitumumab injection) drug prescription information. San Francisco, CA: genentech; http:// www.gene.com/gene/products/information/tgr/Lucentis/index.jsp.2006, visit 11/15/month) states "Lucentis 0.5mg (0.05mL) is recommended to be given by intravitreal injection once a month". Although less effective, treatment can be reduced to one injection every three months after the first four injections if monthly injections are not feasible. Every three months of administration will result in a plateau in the next nine months compared to a continuous monthly administrationEach with a loss of visual acuity of about 5 letters (row 1). Patients should be evaluated periodically. "

(bevacizumab) is an anti-VEGF monoclonal antibody that has been reported in the literature as an intravitreal injection for the treatment of patients with CNV caused by AMD, but is not currently approved for this use. Case analysis of patients with AMD and other retinal diseases treated by Avastin has been published and shows an increase in the mean VA in the treated patients (Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravialbtimings. Ophthallogue 2006; 113(3) 363. 372; Bashshu ZF, Barbachi A, Schaka A, Haddad ZA, El Haibi CP. Nouredpin BN. Intra. 2006: odorsal pulsation in-expression, J. Ameramicin J. Ophthalmia 2006: 78; J. observation of filtration in-expression, J. evaluation [ 1. evaluation ] 19. evaluation of filtration reagent, III, J. evaluation, III. evaluation, D, J. evaluation, III, D, J. evaluation, E. Rosenfeld PJ, Puliaftio CAet al. short-termsafetyand efficacy of intraviral bevacizumab (Avastin) for neoviscular-related molecular evolution, Retina, 2006; 26: 495-511).

Combination therapy with visfatal and intravitreal anti-VEGF therapies including Macugen (Eyetech Study group. anti-vascular intrinsic growth factor therapy for subvarial pulmonary endothelial growth therapy to related macroablation: phase IIstudys results. Ophthalmology 2003; 110 (5): 979. times. 986), Lucentis (Heaer JS, Boyer DS, Ciulla TAet al. Ranibizumab combined with intravitreal photodynamic therapy)thermal in-dependent macromolecular generation: year 1 results of the FOCUSStudy. Arch Ophthalmol.2006; 124: 1532 — 1542; Schmidt-Erfuth U, Gabel P, Hohman T, protectStudGroup.Preliminary results from an open-label, multicenter, phase IIstudyssons of the effects of same-day administration of ranibizumab (Lucentis. TM.) and verteporfin PDT (PROTECT Study.) the papers are listed in: annual Meeting Soft Association for Research in Vision and Ophtalmology (ARVO); may 2, 2006; FortLauderdale, Florida, USA; Schmidt-Erfuth U, Gabel P, Hohman T, protectStudylGroup.Preliminary results from an open-label, multicenter, phaseII Study of the effects of same-day administration of ranibizumab (Lucentis. TM.) and verteporfin PDT (PROTECT Study.) the papers are listed in: annual meeting of the Association for Research in Vision and Ophtalmology (ARVO); may 2, 2006; FortLauderdale, Florida, USA; funk M, Michels S, Wagher J, Kiss C, Sacu S, Schmidt-Erfurth U.S. vascular effects of combinandinavizumaband verteporfinthe therapy in tissues with a genetically modified macromolecular gene is described in: annual Meeting office Association for Research inVision and Ophthalmology (ARVO); april 30, 2006; fort Lauderdale, Florida, USA; wagner J, Simager C, Kiss C, Michels S, Sacu S, Schmidt-Erfunth U.S. Change in functional cellular mapping in cellular mapping near cellular mapping of cellularand ranibizumab(Lucentis^TM) the communication is carried out in: annual Meeting of the Association for Research Vision and Ophthalmology (ARVO); april 30, 2006; fort Lauderdale, Florida, USA; wolf S, Gabel P，Hohman TC，Schmidt-Erfurth U.Fluorescein angiographic and OCTresultsfrom an open-label，multicenter，phase II study assessing the effectsofsame-day ranibizumab(Lucentis^TM)and verteporfin PDTThe papers are published in: annual Meeting of the Association for Research in Vision and Ophtalmology (ARVO); may 3, 2006; fort Lauderdale, Florida, USA) and Avastin (Dhalla MS, Shah GK, Blinder KJ, Ryan EH Jr, Mitta RA, Tewari A. combined photosynamic therapy with a verterborphin and multivitamin acetic ab for choroid iterative information-related macroamplification, Retina, 2006; 26(9): 988-; eter N, Ladevig M, Hamelmann V, Helb HM, Karl S, Holz FG. Combined Intra scientific bevacizumab (Avastin) and Hot dynamic therapy for AMD. communications are carried out in the Annual Meeting of the American Academy of Ophthalmology (AAO), November 12, 2006, Las Vegas, NV. Abstractable: http:// www.aao.org/annular _ meeting/program/onlineprogarm 06.cfm.2006, visit 11/24), which has been evaluated in clinical trials and case analyses of subjects with AMD.

Combination therapy with Viratory and triamcinolone acetonide in the vitreous has been previously reported (Austin AJ, Schmidt-Erfunth U.S. Verteporfin thermally combined with intraventricular triamcinolone in all types of microorganisms, aerobic science, 2006; 113(1) 14-22; sponge RF, Sorenson J, Maran L.Combinationtropic thermal application with vertical fin for intraventricular toxicodendron and agar, aerobic science, aerobic, cicinelli S, Calabria G.Occult with no structural chloro-acquired genetic transformation to a-related macromolecular de-generation treated by a recombinant viral gene and a photodynamic therapy with a very modified fin, Retina 2006; 26(1): 58-64; augustin AJ, Schmidt-Erfuth U.S. Verteporfin and intravertea spinocellular acid combining therapy for an occult chloridal neovascular optimization in related macromolecular degradation, Am J Ophthalmol. 2006; 141: 638-; Ruiz-MorenoJM, Montero JA, Barile S, Zarbin MA. Photodynamic therapy and high-polyseriraphial triamcinolone to linear-detailed cellular generation: 1-year outchome, Retina, 2006; 26: 602-612). Triple therapies using vista, anti-VEGF therapies and steroids have also been reported (collagen-lucez JM, Liggett PE, Tom D, Chaudhury NA, Haffner G, cortex CF. productive and presentation therapeutic evaluation. communication in: environmental measuring of environmental Research in visual and visual science (ARVO); April 30, 2006; Formaldehyde 2006, flow laboratory 2006, USA; analysis A, Schmitt-medical U, analytical J. experimental. expression, evaluation of environmental Research, evaluation of visual evaluation.

There is a need for other methods of photodynamic therapy that can reduce the number of re-treatments required after the first treatment, with acceptable visual acuity results and acceptable safety profiles.

Disclosure of Invention

The present invention provides novel methods and compositions for treating ocular diseases characterized by unwanted or undesired neovasculature in the eye to reduce the number of follow-ups required after the first treatment with acceptable visual acuity results and acceptable safety profiles.

Thus in one aspect of the present invention, there is provided a method of photodynamic therapy (PDT) for treating unwanted Choroidal Neovasculature (CNV) in a human subject, said method comprising administering to a subject having said neovasculature an effective amount of a Photosensitizer (PS) to allow an effective dose to localize to target tissue of the eye and irradiating said target tissue with electromagnetic radiation having a wavelength absorbable by said PS; and administering to the subject an effective amount of an anti-VEGF agent, wherein the administration of the anti-VEGF agent occurs within a short period of time after the step of administering PS, wherein closure of CNVs in the subject can be caused. In one embodiment, the CNV is in a patient having or diagnosed with age-related macular degeneration (AMD). In another embodiment, the AMD is wet. In other embodiments, AMD is typically the predominant, typically the minor, or occult form of the disease.

In one embodiment of the invention, the photosensitizer used in the invention comprises a green porphyrin. In other embodiments, the green porphyrin is selected from BPD-MA, BPD-DB, BPD-DA, EA6, and B3. In a preferred embodiment, the green porphyrin comprises BPD-MA. In another embodiment of the invention, the PS is administered as a pharmaceutical composition. In other embodiments, the PS is administered as a pharmaceutical composition selected from the group consisting of a liposome, an emulsion, or an aqueous solution.

In another embodiment of the invention, the anti-VEGF agent comprises an antibody to vascular endothelial growth factor. In certain embodiments, the anti-VEGF agent comprises bevacizumab or ranibizumab. In a preferred embodiment, the anti-VEGF factor comprises ranibizumab. In other embodiments, the anti-VEGF agent may include peptides that bind to vascular endothelial growth factor to prevent or reduce its binding to its receptor, antibodies that bind to VEGF, and nucleic acids that bind to VEGF, among others.

In another embodiment of the invention, the PS is irradiated with electromagnetic radiation having a wavelength absorbed by the PS at a reduced flux rate. In certain embodiments of the invention, the flux rate delivers a total light dose in the range of about 12.5 to about 25J/cm². In a preferred embodiment, the flux rate is delivered at about 25J/cm²Total light dose of 15J/cm²Total light dose of (c). In another embodiment of the invention, the fluence rate is less than about 500mW/cm²Or in other embodiments about 300mW/cm²Or, in other embodiments, about 180mW/cm²。

In another aspect of the invention, there is provided a method of photodynamic therapy (PDT) for treating unwanted Choroidal Neovasculature (CNV) in a human subject, said method comprising administering to a subject suffering from said neovasculature an effective amount of a Photosensitizer (PS) to allow an effective dose to localize to target tissue of the eye and irradiating said target tissue with electromagnetic radiation having a wavelength absorbable by said PS; and administering to the subject an effective amount of an anti-angiogenic factor (anti-VEGF) and an anti-inflammatory agent, wherein said administration of said anti-VEGF factor and anti-inflammatory agent occurs within a shortened time period following the administration of the PS step, wherein occlusion of CNV in said subject can be caused. In one embodiment of the invention, the anti-inflammatory agent comprises a steroid. In a preferred embodiment, the steroid comprises dexamethasone. In another embodiment of the invention, dexamethasone is delivered into the vitreous. In other embodiments, dexamethasone is administered at a dose between about 0.4mg and about 0.8mg within about 2 hours after administration of the PS and subsequent administration of the anti-VEGF factor. In one embodiment of the invention, dexamethasone is delivered at a dose of about 0.5 mg.

In another aspect of the invention, the method of the invention is repeated for about at least 6 months or at least about 12 months after the first treatment. In another aspect of the invention, the method is repeated about every three months for a period of about at least 6 months or more after the first treatment. In other aspects of the invention, the method is repeated no less than about every 55 days for a period of at least 6 months after the first treatment. In another aspect of the invention, the method is repeated for a period of time sufficient to increase the visual acuity of the subject.

In another aspect of the invention, the following methods are provided for improving the visual acuity of a subject in need thereof: (i) administering BPD-MA to a subject at 300mW/cm²Irradiated for 83 seconds to deliver 25J/cm²Followed by intravitreal administration of ranibizumab within about two hours; (ii) administration of BPD-MA at 300mW/cm²Irradiated for 83 seconds to deliver 25J/cm²Followed by intravitreal administration of ranibizumab over two hours, followed by intravitreal administration of dexamethasone; and (iii) administration of BPD-MA at 180mW/cm²Irradiated for 83 seconds to deliver 15J/cm²Followed by intravitreal administration of ranibizumab over two hours, followed by intravitreal administration of dexamethasone. In one embodiment, the method is repeated no less than about every 55 days for a period of about 6 months or more, wherein said visual acuity of said subject is improved. In one embodiment of the invention, the visual acuity letter score improvement from baseline after six months is at least about 2.5 letters or more. In another embodiment, the visual acuity letter score improvement from baseline after six months is at least about 4 letters or more, or 7 letters or more. In another embodiment, the visual acuity letter score improvement from baseline after twelve months is at least about 2.5 letters or more, or about 4 letters or more, or about 7 letters or more.

In certain embodiments, the methods comprise triple therapy of a Photosensitizer (PS) followed by an anti-VEGF agent and then an anti-inflammatory agent, wherein the PS is administered at a reduced flux rate. In certain embodiments, the PS is administered at a flux of about one-half of the recommended flux rate utilized in PDT monotherapy, e.g., at a certain rateIn some embodiments, the concentration is 300mW/cm²Lasting 83 seconds to deliver 25J/cm². In other embodiments, the PS is administered at a flux of about one-fourth relative to the recommended flux rate utilized in PDT monotherapy, e.g., 180mW/cm in certain embodiments²Lasting 83 seconds to deliver 15J/cm². In certain embodiments, the PS comprises vesudalar, the anti-VEGF agent comprises Lucentis, the anti-inflammatory agent comprises dexamethasone, and in certain embodiments, the rate of repeat treatment is about 3 times, or about 4 times, for twelve months. In certain embodiments, the time between the administration of vesudael and the Lucentis is about 2 hours or less than 2 hours.

In other embodiments, the method comprises a dual therapy of a Photosensitizer (PS) followed by an anti-VEGF agent, wherein the PS is administered while decreasing the flux rate. In certain embodiments, the PS is administered at a dose of one-half relative to the recommended dose rate utilized in PDT monotherapy, e.g., 300mW/cm in certain embodiments²Lasting 83 seconds to deliver 25J/cm². In certain embodiments, the PS comprises vesudall and the anti-VEGF agent comprises Lucentis. In certain embodiments, the dual therapy is repeated at a rate of about 4 times for twelve months. In certain embodiments, the treatment time between administration of vesudael and Lucentis is about 2 hours or less than 2 hours, e.g., one hour or less, or 45 minutes or less, or 35 minutes or less. In other embodiments of the invention, the rate of repeat treatment is decreased in the combination therapy methods described herein relative to the number of repeat treatment rates for anti-VEGF monotherapy used alone without the combination with PS, wherein the rate of visual acuity increase is similar to the rate of anti-VEGF monotherapy.

In certain embodiments of the invention, the shortened time period between the first administration of PS and the subsequent administration of the anti-VEGF agent is no more than about 48 hours. In other embodiments, the shortened time period is no more than about 24 hours. More preferably, the shortened time period is no more than about 4 hours, or no more than 3 hours or no more than 2 hours, or about 2 hours, or in other embodiments, less than 2 hours. In a preferred embodiment, the reduced time includes a period of time that allows for subsequent treatment with the anti-VEGF agent and, in certain embodiments, the anti-inflammatory agent during the time that the individual treatment is performed by the physician. In other embodiments, the shortened time period is a time period during which the intraocular pressure observed, as monitored by techniques known to those skilled in the art, is within an acceptable range after administration of the PS and does not result in an unacceptable increase in IOP prior to administration of the anti-VEGF agent. Likewise, subsequent administration of the anti-inflammatory agent is administered at a time period subsequent to administration of the anti-VEGF agent, wherein intraocular pressure in the eye is observed not to rise to unacceptable levels.

Drawings

Having thus described the invention in general terms, reference will now be made to the accompanying drawings, which illustrate preferred embodiments and in which:

FIG. 1 shows inclusion criteria for the studies of examples 1-3 described herein;

FIG. 2 shows exclusion criteria for the studies of examples 1-3 described herein;

FIG. 3 shows the study design of examples 1-3 described herein, comparing combination therapy with monotherapy with ranibizumab;

FIG. 4 shows the treatment schedules of the different treatment groups in the study described in examples 1-3;

FIG. 5 shows the repeat treatment criteria used in the study described in examples 1-3;

FIG. 6 shows initial characteristics of patients in the study described in examples 1-3;

FIGS. 7-10 show the change from initial mean visual acuity after six months of the study described in examples 1-3 herein;

FIG. 11 shows mean change in central retinal thickness from initial after six months of the study described in examples 1-3 herein;

figure 12 shows the number of OCT or FA based cumulative revisions six months after the study described in examples 1-3 herein;

FIG. 13 shows the number of cumulative revisions to meet OCT criteria six months after the study described in examples 1-3 herein;

FIG. 14 shows the number of cumulative revisions when FA standards are met six months after the study described in examples 1-3 herein;

FIG. 15 shows a comparison of the number of cumulative follow-ups to reach OCT versus FA criteria six months after the study described in examples 1-3 herein;

figure 16 shows a summary of adverse events six months after the study described in examples 1-3 herein;

figure 17 shows a summary of treatment-related ocular adverse events six months after the study described in examples 1-3 herein;

FIG. 18 shows the initial lesion composition for different treatment groups in the study;

FIGS. 19-21 show the change in visual acuity from baseline twelve months after the study described in examples 1-3 herein;

FIG. 22 shows mean change in central retinal thickness from initial after twelve months of the study described in examples 1-3 herein;

figure 23 shows cumulative repeat treatment values after twelve months of the study as described in examples 1-3 herein;

figures 24-25 show a summary of adverse events twelve months after the study described in examples 1-3 herein.

Detailed Description

Unless defined otherwise, scientific and technical terms and names used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains, and should not be construed as limiting the scope of the invention.

Modes for carrying out the invention

In a general method forming the subject of the present invention, the present invention provides novel methods and compositions for treating ocular diseases characterized by unwanted or undesired neovasculature in the eye, which can reduce the number of repeat treatments after the first treatment, with acceptable visual acuity results and acceptable safety profiles.

Photosensitizers

The present invention utilizes PDT methods which generally involve the administration of a Photosensitizer (PS) and irradiation with a wavelength of electromagnetic radiation capable of activating the PS. The invention also includes the use of PS in the preparation of a medicament for use in any of the methods described herein.

The preferred PS of the present invention is green porphyrin and the preferred irradiation is with visible light. One particularly preferred PS is a lipid preparation of the benzoporphyrin derivative monoacid ring a, also known as verteporfin or BPD-MA. After or simultaneously with the delivery of the PS, irradiation is performed with any radiation source. Examples of visible radiation sources include operating room lights, halogen lights, fluorescent lights, laser sources, and combinations thereof. Examples of other light sources include Light Emitting Diode (LED) panels that may surround a blood vessel or a flexible light diffuser.

As used herein, "electromagnetic radiation," unless otherwise specified, generally refers to the visible range of the electromagnetic spectrum, and generally includes wavelengths between 400nm and 700 nm. The terms "visible light" and "visible radiation" and variations thereof are meant to be included within the scope of the term "electromagnetic radiation". Further, the term may also be used herein to refer to electromagnetic radiation in the ultraviolet (including wavelengths below 400 nm) and infrared (including wavelengths above 700 nm) spectra.

Preferably, radiation is delivered, such as 690nm light used in the case of BPD-MA. In one embodiment, the light is from a laser, such as one capable of stable delivery 689+/-3nm, and delivered to the ocular environment.

Administration of the PS can be delivered using any suitable means, including but not limited to systemic, local, or even direct application to the target tissue. Local delivery of PS provides high local concentrations while reducing the likelihood of transient skin photosensitivity or other undesirable side effects following systemic administration of PS. Other suitable PS's are of a wide variety, including but not limited to porphyrin-related compounds such as hematoporphyrin derivatives,Porfimer sodium, green porphyrins such as BPD, purpurin, chlorin, fluorescein, protopurpurin (etiopurpurin), and the like, as well as phthalocyanines, pheophorbides, deuteroporphyrins, texaphyrin (texaphrin), and the like.

As used herein, the terms "photosensitizer", "photoactive compound", "photoactive drug", "PS" and "photoactive agent" are used interchangeably. Any variation in meaning between these terms is not meant to depart from the spirit and scope of the claimed invention.

Examples of these and other PS useful in the present invention include, but are not limited to, angelicin, some biological macromolecules such as lipofuscin; a photosystem II reaction center; and D1-D2-cyt b-559 photosystem II reaction center, chalcogenopyridine dye (chalcogenoapyridium dye), chlorins, chlorophylls, coumarins, cyanines, keratin DNA and related compounds such as adenosine; a cytosine; 2 '-deoxyguanosine-5' -monophosphate; deoxyribonucleic acid; guanine; 4-thiourea nucleosides; 2 '-thymidine-5' -monophosphate; thymidylate (3 ' -5 ') -2 ' -deoxyadenosine; thymidylate (3 ' -5 ') -2 ' -deoxyguanosine; thymine; and uracil, certain drugs such as doxorubicin; a fluoroquinolone; amodiaquine dihydrochloride; chloroquine diphosphate; chlorpromazine hydrochloride; daunorubicin; rubberubicin; 5-iminodaunorubicin; doxycycline; furosemide; fuscinotin M; fuscinotin V; hydroxychloroquine sulfate; lumiphoric doxycycline (lumidoxycycline); mefloquine hydrochloride; mequitazine; mercury bromored (mercurous chloride); primaquine phosphate; quinazine dihydrochloride; quinine sulfate; and tetracycline hydrochloride, certain flavins and related compounds such as alloxazines; flavin mononucleotide; 3-hydroxyflavone; photochromic elements (limichromes); photopigmenins (limiflavanins); 6-methyl alloxazine; 7-methyl alloxazine; 8-methyl alloxazine; 9-methyl alloxazine; 1-methyl limichromene (1-methyl limichrome); methyl-2-methoxybenzoic acid; 5-nitrosalicylic acid; a prebiotic compound; and riboflavin, fullerenes, metalloporphyrins, metallophthalocyanines, methylene blue derivatives, naphthalimides, naphthalocyanines, certain natural compounds such as bis (4-hydroxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione; 4- (4-hydroxy-3-methoxyphenyl) -3-buten-2-one; n-formyl kynurenine; kynurenic acid; kynurenine; 3-hydroxykynurenine; DL-3-hydroxykynurenine; sanguinarine; berberine; carmane; and 5,7, 9(11), 22-ergosta-tetraen-3 β -ol, nile blue derivatives, NSAIDs (non-steroidal anti-inflammatory drugs), perylenequinones, phenols, pheophorbides, pheophytins, photosensitizer dimers and conjugates, phthalocyanines, porphyrins, psoralens, purpurins, benzoquinones, retinoids, rhodamines, thiophenes, verdins, vitamins and xanthene dyes (Redmond and Gamlin, photochem, photobiol., 70 (4): 391 (1999)).

Typical angelicins include 3-acetyl-angelicin; angelicin; 3, 4' -dimethyl angelicin; 4, 4' -dimethyl angelicin; 4, 5' -dimethyl angelicin; 6, 4' -dimethyl angelicin; 6, 4-dimethyl angelicin; 4, 4 ', 5' -trimethylangelicin; 4, 4 ', 5 ' -trimethyl-1 ' -thioangelicin; 4, 6, 4 '-trimethyl-1' -thioangelicin; 4, 6, 4' -trimethylangelicin; 4, 6, 5 '-trimethyl-1' -thioangelicin; 6, 4, 4' -trimethylangelicin; 6, 4 ', 5' -trimethylangelicin; 4, 6, 4 ', 5 ' -tetramethyl-1 ' -thioangelicin; and 4, 6, 4 ', 5' -tetramethyl angelicin.

Typical sulfur-based pyridine dyes (chalcogenoapyrollium dye) include 4, 4' - (1, 3-propenyl) -bis [2, 6-bis (1, 1-dimethylethyl) ] pyridine perchlorate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) selenopyran-4-ylidene ] -3-propenyl-pyridine perchlorate; 2, 6-bis- (1, 1-dimethyl-ethyl) -selenopyran-4-ylidene ] -3-propenyl-pyridinehexafluorophosphate; 2, 6-bis (1, 1-dimethyl-ethyl) -selenopyran-4-ylidene ] -3-propenyl-pyridium hexafluorophosphate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) telluropyran-4-ylidene ] -3-propenyl-pyridine perchlorate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) telluropyran-4-ylidene ] -3-propenyl-pyridine hexafluorophosphate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) thiopyran-4-ylidene ] -3-propenyl ] -pyridine perchlorate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) selenopyran-4-ylidene ] -3-propenyl ] -selenopyridine hexafluorophosphate; 2, 6-bis (1, 1-dimethylethyl) -4- [1- [2, 6-bis (1, 1-dimethylethyl) selenopyran-4-ylidene ] -3-propenyl ] -selenopyridine; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) telluropyran-4-ylidene ] -3-propenyl ] -selenopyridine perchlorate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) telluropyran-4-ylidene ] -3-propenyl ] -selenopyridine hexafluorophosphate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [2- [2, 6-bis (1, 1-dimethyl-ethyl) selenopyran-4-ylidene ] -4- (2-butenyl) ] -selenopyridine hexafluorophosphate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [2- [2, 6-bis (1, 1-dimethyl-ethyl) selenopyran-4-ylidene ] -4- (2-pentenyl) ] -selenopyridine hexafluorophosphate; 2, 6-bis (1, 1-dimethylethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) -telluropyran-4-ylidene ] -3-propenyl ] -telluropyridine tetrafluoroborate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) telluropyran-4-ylidene ] -3-propenyl ] -telluropyridine hexafluorophosphate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) telluropyran-4-ylidene ] ethyl-telluropyridine hexafluorophosphate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) -telluropyran-4-ylidene ] methyl-telluropyridine hexafluorophosphate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) thiopyran-4-ylidene ] -3-propenyl ] -thiopyridine hexafluorophosphate; 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) selenopyran-4-ylidene ] -3-propenyl ] -thiopyridine hexafluorophosphate; and 2, 6-bis (1, 1-dimethyl-ethyl) -4- [1- [2, 6-bis (1, 1-dimethyl-ethyl) telluropyran-4-ylidene ] -3-propenyl ] -thiopyridine hexafluorophosphate.

Typical chlorin dyes include 5-azachlorin dimethyl ester derivatives; 5, 10, 15, 20-tetra- (m-hydroxyphenyl) bacteriochlorin; benzoporphyrin derivative monoacid ring a; benzoporphyrin derivative monoacid ring-a; 7- [ 2-dimethyl-amino) -2-oxoethyl]-8-ethylene-7, 8-dihydro-3, 7, 12, 17-tetramethylporphine-2, 18-dipropanoic acid dimethyl ester; 7- [ 2-dimethyl-amino) -2-oxoethyl]-8-ethylene-8-ethyl-7, 8-dihydro-3, 7, 12, 17-tetramethylporphine-2, 18-dipropanoic acid dimethyl ester Z; 7- [ 2-dimethyl-amino) -2-oxoethyl]-8-ethylene-8-ethyl-7, 8-dihydro-3, 7, 12, 17-tetramethylporphine-2, 18-dipropanoic acid dimethyl ester Z ECHL; 7- [ 2-dimethyl-amino) -2-oxoethyl]-8-ethylene-8-n-heptyl-7, 8-dihydro-3, 7, 12, 17-tetramethylporphine-2, 18-dipropanoic acid dimethyl ester Z; 7- [2- (dimethylamino-2-oxoethyl group)]-8-ethylene-8-n-heptyl-7, 8-dihydro-3, 7, 12, 17-tetramethyltin (II) porphyrin-2, 18-dipropionic acid dimethyl ester Z; chlorins e₆(ii) a Chlorins e₆Dimethyl ester; chlorins e₆k₃(ii) a Chlorins e₆Monomethyl ester; chlorins e₆Na₃(ii) a Dihydroporphin p₆(ii) a Dihydroporphin p₆-trimethyl ester; 7- [2- (dimethylamino) -2-oxoethyl]-8-ethylene-8-n-heptyl-7, 8-dihydro-3, 7, 12, 17-tetramethylchlorin derivative zinc (II) chlorin-2, 18-dipropionate dimethyl ester Z; 13¹-deoxy-20-formyl-vic-dihydroxy-bacteriochlorophyll di-tert-butylaspartic acid; 13¹-deoxy-20-formyl-4-one-bacteriochlorin di-tert-butyl aspartic acid; Di-L-aspartyl chlorin e₆(ii) a Meso-chlorin; 5,10, 1520-tetrakis- (m-hydroxyphenyl) chlorin; meta- (tetrahydroxyphenyl) chlorins; methyl-13¹-deoxy-20-formyl-4-one-bacteriochlorin; mono-L-aspartyl chlorin e₆(ii) a Photo energy protoporphyrin IX dimethyl ester; phycocyanin dimethyl ester; a ortho-chlorophyllin ester a; tin (IV) chlorins e₆(ii) a Stannic chlorins e₆(ii) a Tin L-aspartyl chlorin e₆(ii) a Stannyl-octaethyl-chroman; tin (IV) chlorin; zinc chlorin e₆(ii) a And zinc L-aspartyl chlorin e₆。

Typical chlorophyll dyes include chlorophyll a; chlorophyll b; oil-soluble chlorophyll; a bacteriochlorophyll a; bacteriochlorophyll b; a bacteriochlorophyll c; a bacteriochlorophyll d; a primary chlorophyll; a primary chlorophyll a; amphiphilic chlorophyll derivative 1; and amphiphilic chlorophyll derivative 2.

Typical coumarins include 3-benzoyl-7-methoxycoumarin; 7-diethylamino-3-thenoyl coumarin; 5, 7-dimethoxy-3- (1-naphthoyl) coumarin; 6-methylcoumarin; 2H-selenopheno [3, 2-g ] [1] benzopyran-2-one; 2H-selenopheno [3, 2-g ] [1] benzothiopyran-2-one; 7H-selenopheno [3, 2-g ] [1] benzoselenopyran-7-one; 7H-selenopyrano [3, 2-f ] [1] benzofuran-7-one; 7H-selenopyrano [3, 2-f ] [1] benzo-thiophen-7-one; 2H-thieno [3, 2-g ] [1] chromen-2-one; 7H-thieno [3, 2-g ] [1] benzothiopyran-7-one; 7H-thiopyrano [3, 2-f ] [1] benzofuran-7-one; a coal tar mixture; kaolin; RG 708; RG 277; and ametholin.

Typical cyanine dyes include benzoselenazole dyes; a benzoxazole dye; 1, 1' -diethyloxacarbonylcyanine; 1, 1' -diethyloxadicarbonyl cyanine; 1, 1' -diethylthiacarbocyanine; 3, 3' -dialkylthiacarbocyanine (n ═ 2-18); 3, 3' -diethylthiacarbocyanine iodide; 3, 3' -dihexylselenocyclocyanine; a cryptocyanine; MC540 benzoxazole derivatives; MC540 quinoline derivatives; a partial cyanine 540; and meso-ethyl, 3, 3' -dihexylselenocyclocyanine.

Typical fullerenes include C₆₀；C₇₀；C₇₆(ii) a A dihydrofullerene; 1, 9- (4-hydroxy-cyclohexylo) -buckminster fullerene; [ 1-methyl-succinic acid-4-methyl-cyclohexadiene-2, 3]-a buckminster fullerene; and a tetrahydrofullerene.

Typical metalloporphyrins include cadmium (II) chlorotexaphyrin nitrate; cadmium (II) meso-diphenyltetraphenylporphyrin; cadmium meso-tetrakis- (4-N-methylpyridyl) -porphine; cadmium (II) texaphyrin; cadmium (II) texaphyrin nitrate; cobalt meso-tetrakis- (4-N-methylpyridinyl) -porphine; cobalt (II) meso- (4-sulfonylphenyl) -porphine; copper hematoporphyrin; copper meso-tetrakis- (4-N-methylpyridinyl) -porphine; copper (II) meso (4-sulfonylphenyl) -porphine; europium (III) dimethyltexaphyrin dihydroxide; gallium tetraphenylporphyrin; iron meso-tetrakis (4-N-methylpyridinyl) -porphine; lutetium (III) tetrakis (N-methyl-3-pyridyl) -porphyrin chloride; magnesium (II) meso-diphenyltetraphenylporphyrin; magnesium tetraphenylporphyrin; magnesium tetraphenylporphyrin; magnesium (II) meso (4-sulfonylphenyl) -porphine; magnesium (II) texaphyrin hydroxide metalloporphyrin; magnesium meso-tetrakis- (4-N-methylpyridinyl) -porphine; manganese meso-tetrakis- (4-N-methylpyridinyl) porphine; nickel meso-tetrakis (4-N-methylpyridinyl) -porphine; nickel (II) meso-tetrakis (4-sulfonylphenyl) -porphine; palladium (II) meso-tetrakis- (4-N-methylpyridinyl) -porphine; palladium meso-tetrakis- (4-N-methylpyridyl) -porphine; palladium tetraphenylporphyrin; palladium (II) meso (4-sulfonylphenyl) -porphine; platinum (II) meso (4-sulfonylphenyl) -porphine; samarium (II) dimethyl texaphyrin dihydroxide; silver (II) meso (4-sulfonylphenyl) -porphine; tin (IV) protoporphyrin; stannic meso-tetrakis- (4-N-methylpyridinyl) -porphine; stannic meso-tetrakis (4-sulfonylphenyl) -porphine; tin (IV) tetrakis (4-sulfonylphenyl) porphyrin dichloride; zinc (II) 15-aza-3, 7, 12, 18-tetramethyl-porphyrin-13, 17-diyl-dipropionic acid-dimethyl ester; zinc (II) chloridebrasaporphyrin chloride; zinc coproporphyrin III; zinc (II)2, 11, 20, 30-tetrakis- (1, 1-dimethyl-ethyl) tetranaphtho (2, 3-b: 2 ', 3' -g: 2 '3' -l: 2 '3' -q) tetraazaporphyrin; zinc (II)2- (3-pyridyloxy) benzo [ b ] -10, 19, 28-tris (1, 1-dimethylethyl) trinaphtho [2 ', 3' -g: 2 "3" 1: : 2 ', 3' -q ] porphyrazine; zinc (II)2, 18-bis- (3-pyridyloxy) dibenzo [ b, 1] -10, 26-bis (1, 1-dimethyl-ethyl) dinaphtho [2 ', 3' -g: 2 ', 3' -q ] porphyrazine; zinc (II)2, 9-bis- (3-pyridyloxy) dibenzo [ b, g ] -17, 26-bis (1, 1-dimethyl-ethyl) dinaphtho [2 ", 3" -l: 2 ', 3' -q ] porphyrazine; zinc (II)2, 9, 16-tris- (3-pyridyloxy) tribenzo [ b, g, 1] -24- (1, 1-dimethyl-ethyl) naphtho [2 '", 3'" -q ] tetraazaporphyrin; zinc (II)2, 3-bis- (3-pyridyloxy) benzo [ b ] -10, 19, 28-tris (1.1-dimethyl-ethyl) trinaphtho [2 ', 3' -g: 2 ", 3" l: 2 ', 3' -q ] porphyrazine; zinc (II)2, 3, 18, 19-tetrakis- (3-pyridyloxy) dibenzo [ b, 1] -10, 26-bis (1, 1-dimethyl-ethyl) trinaphtho [2 ', 3' -g: 2 ', 3' -q ] porphyrazine; zinc (II)2, 3, 9, 10-tetrakis- (3-pyridyloxy) dibenzo [ b, g ] -17, 26-bis (1, 1-dimethyl-ethyl) dinaphtho [2 ", 3" -l: 2 ', 3' -q ] porphyrazine; zinc (II)2, 3, 9, 10, 16, 17-hexa- (3-pyridyloxy) tribenzo [ b, g, 1] -24- (1, 1-dimethyl-ethyl) naphtho [2 '", 3'" -q ] porphyrazine; zinc (II)2- (3-N-methyl) pyridyloxy) benzo [ b ] -10, 19, 28-tris (1, 1-dimethyl-ethyl) trinaphtho [2 ', 3' -g: 2 ", 3" l: 2 ', 3' -q ] porphyrazine iodide; zinc (II)2, 18-bis- (3- (N-methyl) pyridyloxy) dibenzo [ b, 1] -10, 26-bis (1, 1-dimethylethyl) dinaphtho [2 ', 3' -g: 2 ', 3' -q ] porphyrazine diiodide; zinc (II)2, 9-bis- (3- (N-methyl) pyridyloxy) dibenzo [ b, g ] -17, 26-bis (1, 1-dimethylethyl) dinaphtho [2 ", 3" -l: 2 ', 3' -q ] porphyrazine diiodide; zinc (II)2, 9, 16-tris- (3- (N-methyl-pyridyloxy) tribenzo [ b, g, 1] -24- (1, 1-dimethylethyl) naphtho [2 ', 3' -q ] porphyrazine triiodide, zinc (II)2, 3-bis- (3- (N-methyl) pyridyloxy) benzo [ b ] -10, 19, 28-tris (1, 1-dimethylethyl) trinaphtho [2 ', 3' -g: 2 ', 3' -l: 2 ', 3' -q ] porphyrazine diiodide, zinc (II)2, 3, 18, 19-tetrakis- (3- (N-methyl) pyridyloxy) dibenzo [ b, 1] -10, 26-bis (1, 1-dimethyl) dinaphtho [2 ', 3' -g: 2 ', 3' -q ] porphyrazine tetraiodide; zinc (II)2, 3, 9, 10-tetrakis- (3- (N-methyl) pyridyloxy) dibenzo [ g, g ] -17, 26-bis (1, 1-dimethylethyl) dinaphtho [2 ", 3" -l: 2 ', 3' -q ] porphyrazine tetraiodide; zinc (II)2, 3, 9, 10, 16, 17-hexa- (3- (N-methyl) pyridyloxy) tribenzo [ b, g, 1] -24- (1, 1-dimethylethyl) naphtho [2 '", 3'" -q ] porphyrazine hexaiodide; zinc (II) meso-diphenyltetraphenylporphyrin; zinc (II) meso-triphenyltetraphenylporphyrin; zinc (II) meso-tetrakis (2, 6-dichloro-3-sulfonylphenyl) porphyrin; zinc (II) meso-tetrakis- (4-N-methylpyridinyl) -porphine; zinc (II)5, 10, 15, 20-meso-tetrakis (4-octyl-phenylpropynyl) -porphine; zinc porphyrin c; zinc protoporphyrin; zinc protoporphyrin IX; zinc (II) meso-triphenyl-tetraphenylporphyrin; zinc tetraphenylporphyrin; zinc (II) tetraphenylporphyrin; zinc tetranaphthoporphyrin; zinc tetraphenylporphyrin; zinc (II)5, 10, 15, 20-tetraphenylporphyrin; zinc (II) meso (4-sulfonylphenyl) -porphine; and zinc (II) texaphyrin chloride.

Typical metal phthalocyanines include aluminum mono- (6-carboxy-pentyl-amino-sulfonyl) -trisulfonated phthalocyanine; aluminum bis- (6-carboxy-pentyl-amino-sulfonyl) -trisulfonated phthalocyanine; aluminum (III) octa-n-butoxy phthalocyanine; aluminum phthalocyanine; aluminum (III) phthalocyanine disulfonate; aluminum phthalocyanine disulfonate; aluminum phthalocyanine disulfonate (cis isomer); aluminum phthalocyanine disulfonate (clinical formulation); aluminum phthalocyanine phthalimide methanesulfonate; aluminum phthalocyanine sulfonate; aluminum phthalocyanine trisulfonate; aluminum (III) phthalocyanine trisulfonate; aluminum (III) phthalocyanine tetrasulfonate; aluminum phthalocyanine tetrasulfonate; chloroaluminum phthalocyanines; chloroaluminum phthalocyanine sulfonate; chloroaluminum phthalocyanine disulfonate; chloroaluminum phthalocyanine tetrasulfonate; chloroaluminum-tert-butyl phthalocyanine; cobalt phthalocyanine sulfonate; copper phthalocyanine sulfonate; copper (II) tetra-carboxy-phthalocyanine; copper (II) -phthalocyanine; copper tert-butyl-phthalocyanine; copper phthalocyanine sulfonate; copper (II) tetrakis- [ methylene-thio [ (dimethyl-amino) methine]]Phthalocyanine tetrachloride; dichlorosilicon phthalocyanine; gallium (III) octa-n-butoxy phthalocyanine; gallium (II) phthalocyanine disulfonate;gallium phthalocyanine disulfonate; gallium phthalocyanine tetrasulfonic acid-chloride; gallium (II) phthalocyanine tetrasulfonate; gallium phthalocyanine trisulfonic acid-chloride; gallium (II) phthalocyanine trisulfonate; GaPCS₁tBu₃；GaPcS₂tBu₂；GaPcS₃tBu₁(ii) a Germanium (IV) octa-n-butoxy phthalocyanine; a germanium phthalocyanine derivative; a silicon phthalocyanine derivative; germanium (IV) phthalocyanine octa-alkoxy-derivatives; iron phthalocyanine sulfonate; lead (II)2, 3, 9, 10, 16, 17, 23, 24-octa (3, 6-dioxaheptyloxy) phthalocyanine; magnesium tert-butyl-phthalocyanine; nickel (II)2, 3, 9, 10, 16, 17, 23, 24-octa (3, 6-dioxaheptyloxy) phthalocyanine; palladium (II) octa-n-butoxy phthalocyanine; palladium (II) tetra (tert-butyl) -phthalocyanine; (diol) (tert-butyl)₃-palladium (II) phthalocyanine; ruthenium (II) dipotassium [ bis (triphenylphosphine-monosulfonate) phthalocyanine; silicon phthalocyanine bis (tri-n-hexyl-siloxy) -; silicon phthalocyanine bis (tri-phenyl-siloxy) -; HOSiPcOSi (CH)₃)₂(CH₂)₃N(CH₃)₂；HOSiPcOSi(CH₃)₂(CH₂)₃N(CH₂CH₃)₂；SiPc[OSi(CH₃)₂(CH₂)₃N(CH₃)₂]₂；SiPc[OSi(CH₃)₂(CH₂)₃N(CH₂CH₃)(CH₂)₂N(CH₃)₂]₂(ii) a Tin (IV) octa-n-butoxy phthalocyanine; vanadium phthalocyanine sulfonate; zinc (II) octa-n-butoxy phthalocyanine; zinc (II)2, 3, 9, 10, 16, 17, 23, 24-octa (2-ethoxy) phthalocyanine; zinc (II)2, 3, 9, 10, 16, 17, 23, 24-octa (3, 6-dioxaheptyloxy) phthalocyanine; zinc (II)1, 4, 8, 11, 15, 18, 22, 25-octa-n-butoxy-phthalocyanine; zn (ii) -phthalocyanine-octabutoxy; zn (ii) -phthalocyanine; zinc phthalocyanine; zinc (II) phthalocyanine; zinc phthalocyanine and fully deuterated zinc phthalocyanine; zinc (II) phthalocyanine disulfonate; zinc phthalocyanine disulfonate; zinc phthalocyanine sulfonate; tetrabromo-zinc phthalocyanine; zinc (II) phthalocyanine tetra-tert-butyl-; zinc (II) phthalocyanine tetra- (t-tert-butyl) -; zinc phthalocyanine tetracarboxyl-; zinc phthalocyanine tetrachloro-; zinc phthalocyanine tetrahydroxy; zinc phthalocyanine tetraiodo-; zinc ((I) tetra- (1, 1-dimethyl-2-phthalimide) ethyl phthalocyanine, zinc (II) tetra- (1, 1-dimethyl-2-amino) -ethyl-phthalocyanine; zinc (II) phthalocyanine tetrakis (1, 1-dimethyl-2-trimethylammonium) ethyl tetraiodide; zinc phthalocyanine tetrasulfonate; zinc phthalocyanine tetrasulfonate; zinc (II) phthalocyanine tetrasulfonate; zinc (II) phthalocyanine trisulfonate; zinc phthalocyanine trisulfonate; zinc (II) (tert-butyl)₃-a phthalocyanine diol; zinc tetrabenzobistetrabenzoquinolinyl-octabutoxy-phthalocyanine; zinc (II)2, 9, 16, 23, -tetrakis- (3- (N-methyl) pyridyloxy) phthalocyanine tetraiodide; and zinc (II)2, 3, 9, 10, 16, 17, 23, 24-octa- (3- (N-methyl) pyridyloxy) phthalocyanine complex octaiodide; and zinc (II)2, 3, 9, 10, 16, 17, 23, 24-octa- (3-pyridyloxy) phthalocyanine.

Typical methylene blue derivatives include 1-methyl methylene blue; 1, 9-dimethylmethylene blue; methylene blue; methylene blue (16 μ M); methylene blue (14 μ M); methylene violet; methylene bromide violet; 4-iodomethylene violet; 1, 9-dimethyl-3-dimethyl-amino-7-diethyl-amino-phenothiazine; and 1, 9-dimethyl-3-diethylamino-7-dibutyl-amino-phenothiazine.

Typical naphthalimide blue derivatives include N, N' -bis- (hydroperoxy-2-methoxyethyl) -1, 4, 5, 8-naphthalimide; n- (hydroperoxy-2-methoxyethyl) -1, 8-naphthalimide; 1, 8-naphthalimide; n, N' -bis (2, 2-dimethoxyethyl) -1, 4, 5, 8-naphthalenetetracarboxylic diimide; and N, N' -bis (2, 2-dimethylpropyl) -1, 4, 5, 8-naphthalenetetracarboxylic diimide.

Typical naphthalocyanines include aluminum tert-butyl-chloronaphthalocyanine; silicon bis (dimethyl octadecyloxy) 2, 3-naphthalocyanine; silicon bis (dimethyl octadecyloxy) naphthalocyanine; silicon bis (dimethyl t-hexylsiloxy) 2, 3-naphthalocyanine; silicon bis (dimethyl t-hexylsiloxy) naphthalocyanine; silicon bis (tert-butyldimethylsilyloxy) 2, 3-naphthalocyanine; silicon di (t-butyldimethylsilyloxy) naphthalocyanine; silicon bis (tri-n-hexylsiloxy) 2, 3-naphthalocyanine; silicon bis (tri-n-hexylsiloxy) naphthalocyanine; silicon naphthalocyanine; tert-butyl naphthalocyanine; zinc (II) naphthalocyanine; zinc (II) tetraamidonaphthalocyanine; zinc (II) tetraaminonaphthalocyanine; zinc (II) tetrabenzoylaminonapthalophthalocyanine; zinc (II) tetrahexylamido naphthalocyanine; zinc (II) tetramethoxy-benzoylaminonaphthalocyanine; zinc (II) tetramethoxynaphthalocyanine; zinc naphthalocyanine tetrasulfonate; and zinc (II) a forty-dialkyl amido naphthalocyanine.

Typical nile blue derivatives include benzo [ a ] phenothiazine, 5-amino-9-diethylamino-; benzo [ a ] phenothiazine, 5-amino-9-diethylamino-6-iodo-; benzo [ a ] phenothiazine, 5-benzylamino-9-diethylamino-; benzo [ a ] phenoxazine, 5-amino-6, 8-dibromo-9-ethylamino-; benzo [ a ] phenoxazine, 5-amino-6, 8-diiodo-9-ethylamino-; benzo [ a ] phenoxazine, 5-amino-6-bromo-9-diethylamino-; benzo [ a ] phenoxazine, 5-amino-9-diethylamino- (nile blue a); benzo [ a ] phenoxazine, 5-amino-9-diethylamino-2, 6-diiodo-; benzo [ a ] phenoxazine, 5-amino-9-diethylamino-2-iodo; benzo [ a ] phenoxazine, 5-amino-9-diethylamino-6-iodo-; benzo [ a ] phenoxazine, 5-benzylamino-9-diethylamino- (nile blue 2B); 5-ethylamino-9-diethylamino-benzo [ a ] phenoselenazine chloride; 5-ethylamino-9-diethyl-aminobenzo [ a ] phenothiazine chloride; and 5-ethylamino-9-diethyl-aminobenzo [ a ] phenoxazine chloride.

Typical NSAIDs (nonsteroidal anti-inflammatory drugs) include benoxaprofen; ibuprofen carprofen; dechlorinated-carisoprofen (2- (2-carbazole) propionic acid); carprofen (3-chlorocarbazole); clofenoprofen; 2, 4-dichlorobenoxaprofen; cinoxacin; ciprofloxacin; ketoprofen decarboxylation; decarboxylated suprofen; decarboxylated benoxaprofen; decarboxylated tiaprofenic acid; enoxacin; fleroxacin; fleroxacin-N-oxide; flumequine; indoprofen; ketoprofen; lomefloxacin; 2-methyl-4-oxo-2H-1, 2-benzothiazine-1, 1-dioxide; n-desmethylfleroxacin; nabumetone; nalidixic acid; naproxen; norfloxacin; ofloxacin; pefloxacin; pipemidic acid; piroxicam; suprofen; and tiaprofenic acid.

Typical perylenequinones (perylenequinones) include hypericins such as hypericin; hypericin monosodium salt; diaverine; copper hypericin; gadolinium hypericin; terbium hypericin, hypocrellin such as acetoxy bambooErythromycin A; acetoxyhypocrellin B; acetoxy isohypocrellin a; acetoxy isohypocrellin B; 3, 10-bis [2- (2-aminoethylamino) ethanol]Hypocrellin B; 3, 10-bis [2- (2-aminoethoxy) ethanol]Hypocrellin B; 3, 10-bis [4- (2-aminoethyl) morpholine]Hypocrellin B; n-aminated butyl hypocrellin B; 3, 10-di (butylamine) hypocrellin B; 4, 9-di (butylamine) hypocrellin B; hypocrellin B carboxylate; cystamine hypocrellin B; 5-chlorohypocrellin A or 8-chlorohypocrellin A; 5-chlorohypocrellin B or 8-chlorohypocrellin B; 8-chlorohypocrellin B; 8-chlorohypocrellin A or 5-chlorohypocrellin A; 8-chlorohypocrellin B or 5-chlorohypocrellin B; deacetylaldehyde hypocrellin B; deacetylated hypocrellin B; deacetylated hypocrellin A; deacylated aldehyde hypocrellin B; demethylated hypocrellin B; 5, 8-dibromo hypocrellin A; 5, 8-dibromo hypocrellin B; 5, 8-dibromo-isohypocrellin B; 5, 8-dibromo [1, 12-CBr ═ CMeCBr (COMe)]Hypocrellin B; 5, 8-dibromo [1, 12-CHBrC (═ CH)₂)CBr(COMe)]Hypocrellin B; 5, 8-dibromo [1-CH₂COMe，12-COCOCH₂Br-]Hypocrellin B; 5, 8-dichlorohypocrellin a; 5, 8-dichlorohypocrellin B; 5, 8-dichloro-deacetylated hypocrellin B; 5, 8-diiodohypocrellin a; 5, 8-diiodohypocrellin B; 5, 8-diiodo [1, 12-CH ═ CMeCH (COCH)₂I₂)-]Hypocrellin B; 5, 8-diiodo [1, 12-CH₂C(CH₂I)＝C(COMe)-]Hypocrellin B; 2- (N, N-diethylamino) aminated butylhypocrellin B; 3, 10-bis [2- (N, N-diethylamino) -ethylamine]Hypocrellin B; 4, 9-bis [2- (N, N-diethylamino) -ethylamine]Isohypocrellin B; dihydro-1, 4-thiazinecarboxylic acid hypocrellin B; dihydro-1, 4-thiazine hypocrellin B; 2- (N, N-dimethylamino) propylamine hypocrellin B; dimethyl-1, 3, 5,8, 10, 12-hexamethoxy-4, 9-perylenequinone-6, 7-diacetate; dimethyl-5, 8-dihydroxy-1, 3, 10, 13-tetramethoxy-4, 9-perylenequinone-6, 7-diacetate; 2, 11-diketohypocrellin a; ethanolamine hypocrellin B; ethanolamine isohypocrellin B; ethylenediamine hypocrellin B; 11-hydroxyhypocrellin B or 2-hydroxyhypocrellin B; hypocrellin A; hypocrellin B; 5-iodo [1, 12-CH₂C(CH₂I)＝C(COMe)-]HypocrellinB; 8-iodo [1, 12-CH₂C(CH₂I)＝C(COMe)-]Hypocrellin B; 9-methylamino-isohypocrellin B; 3, 10-bis [2- (N, N-methylamino) propylamine]Hypocrellin B; 4, 9-di (methylamino) isohypocrellin B; 14-methylaminoisohypocrellin B; 4-methylaminoisohypocrellin B; methoxyhypocrellin A; methoxyhypocrellin B; methoxyiso-hypocrellin a; methoxyiso-hypocrellin B; hypocrellin B methylamine; 2-morpholinoaminated ethyl hypocrellin B; pentaacetoxy hypocrellin a; a PQP derivative; tetraacetoxy hypocrellin B; 5,8, 15-tribromohypocrellin B; calphosponin C, cercosporins such as acetoxycercosporin; acetoxyisocauelanin; amino cercosporin; cercosporin; cercosporin + isoccercosporin (1/1 molar ratio); diamino cercosporin; cercosporin dimethyl; 5, 8-diphenylthiophenol cercosporin; isocauniscidin; a methoxycercosporin; a methoxyisocratin; cercosporin methyl; dessicated cercosporin; elsinochrome a; elsinochrome B; a folacin; and lubaining poison A.

Typical phenols include 2-benzylphenol; 2, 2' -dihydroxybiphenyl; 2, 5-dihydroxybiphenyl; 2-hydroxybiphenyl; 2-methoxybiphenyl; and 4-hydroxybiphenyl.

Typical pheophorbides include pheophorbide a; methyl-13¹-deoxy-20-formyl-7, 8-vic-dihydro-bacteri-meso-pheophorbide a; methyl-2- (1-dodecyloxyethyl) -2-devinyl-pyropheophorbide a; methyl-2- (1-heptyl-oxyethyl) -2-devinyl-pyropheophorbide a; methyl-2- (1-hexyl-oxyethyl) -2-devinyl-pyropheophorbide a; methyl-2- (1-methoxy-ethyl) -2-devinyl-pyropheophorbide a; methyl-2- (1-pentyl-oxyethyl) -2-devinyl-pyropheophorbide a; pheophorbide d, a magnesium methylobacterium; methyl-bacterial pheophorbide d; and pheophorbide.

Typical pheophytins include bacteriopheophytin a; bacterial pheophytin b; bacterial pheophytin c; bacterial pheophytin d; 10-hydroxypheophytin a; pheophytin removal; pheophytin a; and protoporphyringate.

Typical photosensitizer dimers and conjugates include aluminum mono- (6-carboxy-pentyl-amino-sulfonyl) -trisulfonated phthalocyanine bovine serum albumin conjugate; bishematoporphyrin ethers (esters); bishematoporphyrin ethers; bis hematoporphyrin ether (ester) -chlorin; hematoporphyrin-chlorin ester; hematoporphyrin-low density lipoprotein conjugates; hematoporphyrin-high density lipoprotein conjugates; porphine-2, 7, 18-tripropionic acid, 13, 13' - (1, 3-propanediyl) bis [3, 8, 12, 17-tetramethyl ] -; porphine-2, 7, 18-tripropionic acid, 13, 13' - (1, 11-dodecadiyl) bis [3, 8, 12, 17-tetramethyl ] -; porphine-2, 7, 18-tripropionic acid, 13, 13' - (1, 6-hexanediyl) bis [3, 8, 12, 17-tetramethyl ] -; SnCe6-MAb conjugate 1.7: 1; SnCe6-MAb conjugate 1.7: 1; SnCe6-MAb conjugate 6.8: 1; SnCe6-MAb conjugate 11.2: 1; SnCe6-MAb conjugate 18.9: 1; SnCe 6-dextran conjugate 0.9: 1; SnCe 6-dextran conjugate 3.5: 1; SnCe 6-dextran conjugate 5.5: 1; SnCe 6-dextran conjugate 9.9: 1; alpha-terthiophene-bovine serum albumin conjugate (12: 1); alpha-terthiophene-bovine serum albumin conjugate (4: 1); and tetraphenylporphin attached to 7-chloroquinoline.

Typical phthalocyanines include (diols) (tert-butyl)₃-a phthalocyanine; (tert-butyl)₄-a phthalocyanine; cis-octabutoxy-dibenzo-dinaphtho-porphyrazine; trans-octabutoxy-dibenzo-dinaphtho-porphyrazine; 2, 3, 9, 10, 16, 17, 23, 24-octa 2-ethoxyethoxy) phthalocyanine; 2, 3, 9, 10, 16, 17, 23, 24-octa (3, 6-dioxaheptyloxy) phthalocyanine; octa-n-butoxy phthalocyanine; phthalocyanines; phthalocyanine sulfonate; phthalocyanine tetrasulfonate; phthalocyanine tetrasulfonate; tert-butyl-phthalocyanine; tetra-tert-butyl phthalocyanine; and tetrabenzobistetrabenyl-octabutoxy-phthalocyanine.

Typical porphyrinones (porphycene) include 2, 3- (2)³-carboxy-2⁴-methoxycarbonylphenyl) -7, 12, 17-tris (2-methoxyethyl) porphyrinoene; 2- (2-hydroxyethyl) -7, 12, 17-tris (2-methoxyethyl) porphyrinoene; 2- (2-hydroxyethyl) -7, 12, 17-tri-n-propyl-porphyrinoene; 2-(2-methoxyethyl) -7, 12, 17-tri-N-propyl-porphyrinene, 2, 7, 12, 17-tetra (2-methoxyethyl) -9-hydroxy-porphyrinene, 2, 7, 12, 17-tetra (2-methoxyethyl) -9-methoxy-porphyrinene, 2, 7, 12, 17-tetra (2-methoxyethyl) -9-N-hexyloxy-porphyrinene, 2, 7, 12, 17-tetra (2-methoxyethyl) -9-acetoxy-porphyrinene, 2, 7, 12, 17-tetra (2-methoxyethyl) -9-hexanoyloxy-porphyrinene, 2, 7, 12, 17-tetra (2-methoxyethyl) -9-nonanoyloxy-porphyrinene, 2, 7, 12, 17-tetra (2-methoxyethyl) -9-octadecanoyloxy-porphyrinene, 2, 7, 12, 17-tetra (2-methoxyethyl) -9-porphyrinoxy-porphyrinolene, 2, 7, 12, 17-tetra (2-methoxyethyl) -9-N-ethoxyethyl) -9-porphyrinolene, 7, 17-N-ethoxyethyl) -9-porphyrinolene, 2, 7, 17-N- (2-N-ethoxyethyl) -9-N-propyl-porphyrinoethyl) -9-N, 7, 12, 17-N-ethoxyethyl) -9-porphyrinoethyl) -9-N-porphyrinoethyl-N, 7-N-ethoxyethyl-N-2, 7, 17-N-ethoxyethyl-N-2, 7-ethyl-N-2, 7-N-2, 7-N-2, 7-ethoxyethyl-2, 12, 17-N-ethoxyethyl-N-2, 7-N-2, 17-N-2, 7, 17-N-ethoxyethyl-N-ethoxyethyl-N-2, 17-N-ethoxyethyl-N-2Aminomethyl) porphyrinones; 2, 7, 12, 17-tetra-n-propyl-9, 10-benzoporphyrinoene; 2, 7, 12, 17-tetra-n-propyl-9-p-benzoylcarboxy-porphyrinoene; 2, 7, 12, 17-tetra-n-propyl-porphyrinoene; 2, 7, 12, 17-tetra-tert-butyl-3, 6; 13, 16-dibenzoporphyrinoene; 2, 7-bis (2-hydroxyethyl) -12, 17-di-n-propyl-porphyrinoene; 2, 7-bis (2-methoxyethyl) -12, 17-di-n-propyl-porphyrinoene; and porphyrinones.

Typical porphyrins include dimethyl 5-azaprotoporphyrin; di-porphyrins; coproporphyrin III; coproporphyrin III tetramethyl ester; a deuteroporphyrin; deuteroporphyrin IX dimethyl ester; diformyl deuteroporphyrin IX dimethyl ester; a dodecaphenyl porphyrin; hematoporphyrin; hematoporphyrin (8 μ M); hematoporphyrin (400 μ M); hematoporphyrin (3 μ M); hematoporphyrin (18 μ M); hematoporphyrin (30 μ M); hematoporphyrin (67 μ M); hematoporphyrin (150 μ M); a hematoporphyrin IX; a hematoporphyrin monomer; a hematoporphyrin dimer; a hematoporphyrin derivative; hematoporphyrin derivative (6 μ M); hematoporphyrin derivative (200 μ M); hematoporphyrin derivative a (20 μ M); hematoporphyrin derivative IX dihydrochloride; hematoporphyrin dihydrochloride; hematoporphyrin IX dimethyl ester; hematoporphyrin IX dimethyl ester; dimethyl m-porphyrin; m-porphyrin IX dimethyl ester; mono-formyl-monovinyl-deuteroporphyrin IX dimethyl ester; monohydroxyethyl vinyl deuteroporphyrin; 5, 10, 15, 20-tetrakis (o-hydroxyphenyl) porphyrin; 5, 10, 15, 20-tetrakis (m-hydroxyphenyl) porphyrin; 5, 10, 15, 20-tetrakis- (m-hydroxyphenyl) porphyrin; 5, 10, 15, 20-tetrakis (p-hydroxyphenyl) porphyrin; 5, 10, 15, 20-tetrakis (3-methoxyphenyl) porphyrin; 5, 10, 15, 20-tetrakis (3, 4-dimethoxyphenyl) porphyrin; 5, 10, 15, 20-tetrakis (3, 5-dimethoxyphenyl) porphyrin; 5, 10, 15, 20-tetrakis (3, 4, 5-trimethoxyphenyl) porphyrin; 2, 3,7, 8, 12, 13, 17, 18-octaethyl-5, 10, 15, 20-tetraphenylporphyrin;II, performing phase-change reaction; porphyrin c; protoporphyrin; protoporphyrin IX; protoporphyrin dimethyl ester; protoporphyrin IX dimethyl ester; protoporphyrin propyl amino ethyl formamide iodineA compound; protoporphyrin N, N-dimethylaminopropyl formamide; protoporphyrin propyl aminopropyl formamide iodide; protoporphyrin butyl carboxamide; protoporphyrin N, N-dimethylamino-formamide; protoporphyrin carboxamide; thialine 13, 12, 13, 22-tetraethyl-2, 7, 18, 23 tetramethylthialine-8, 17-dipropanol; thialine 23, 12, 13, 22-tetraethyl-2, 7, 18, 23 tetramethylthialine-8-monoglycoside; thialine 3; meso-tetrakis- (4-N-carboxyphenyl) -porphine; tetrakis- (3-methoxyphenyl) -porphine; tetrakis- (3-methoxy-2, 4-difluorophenyl) -porphine; 5, 10, 15, 20-tetrakis (4-N-methylpyridinyl) porphine; meso-tetrakis- (4-N-methylpyridinyl) -porphine tetrachloride; meso-tetrakis (4-N-methylpyridinyl) -porphine; meso-tetrakis- (3-N-methylpyridinyl) -porphine; meso-tetrakis- (2-N-methylpyridinyl) -porphine; tetrakis (4-N, N-trimethylphenylammonium) porphine; meso-tetrakis- (4-N, N "-trimethylaminophenyl) porphine tetrachloride; tetralin porphyrin; 5, 10, 15, 20-tetraphenylporphyrin; tetraphenylporphyrin; meso-tetrakis- (4-N-sulfonated phenyl) -porphine; tetraphenylporphin tetrasulfonate; meso-tetrakis (4-sulfonated phenyl) porphine; tetrakis (4-sulfonated phenyl) porphine; tetraphenylporphyrin sulfonate; meso-tetrakis (4-sulfonated phenyl) porphine; tetrakis (4-sulfonated phenyl) porphine; meso-tetrakis (4-sulfonated phenyl) porphine; meso (4-sulfonated phenyl) porphine; meso-tetrakis (4-sulfonated phenyl) porphine; tetrakis (4-sulfonated phenyl) porphine; meso-tetrakis (4-N-trimethylanilinium) -porphine; uroporphyrin; uroporphyrin I (17 μ M); uroporphyrin IX; and uroporphyrin I (18 μ M).

Typical psoralens include psoralen; 5-methoxypsoralen; 8-methoxypsoralen; 5, 8-dimethoxy psoralen; 3-ethoxycarbonylpsoralen; 3-ethoxycarbonyl-pseudoosteoproliferation; 8-hydroxy psoralen; pseudoplenin; 4, 5', 8-trimethylpsoralen; psoralen; 3-acetyl-psoralen; 4, 7-dimethyl-allopsoralen; 4, 7, 4' -trimethyl-allopsoralen; 4, 7, 5' -trimethyl-allopsoralen; isopseudoosteoproliferation; 3-acetyl isopseudoosteoproliferation; 4, 5' -dimethyl-isopseudoosteoproliferation; 5', 7-dimethyl-isopseudoosteoprolidin; pseudoplenin; 3-acetylpseudoisopsoralen; 3/4 ', 5' -trimethyl-aza-psoralen; 4, 4 ', 8-trimethyl-5' -amino-methylpsoralen; 4, 4', 8-trimethyl-phthalyl pentyl-psoralen; 4, 5 ', 8-trimethyl-4' -aminomethylpsoralen; 4, 5', 8-trimethyl-bromopsoralen; 5-nitro-8-methoxy-psoralen; 5' -acetyl-4, 8-dimethyl-psoralen; 5' -acetyl-8-methyl-psoralen; and 5' -acetyl-4, 8-dimethyl-psoralen.

Typical purpurins include octaethyl purpurin; octaethyl purpurin zinc; oxidized octapurpurin; reduced octapurpurin; reduced octaethyl purpurin tin; purpurin 18; purpurin-18; purpurin-18-methyl ester; purpurin; tin ethyl primary purpurin I; zn (II) ethyl mono-purpurin; and zinc-protopurpurin.

Typical quinones include 1-amino-4, 5-dimethoxyanthraquinone; 1, 5-diamino-4, 8-dimethoxyanthraquinone; 1, 8-diamino-4, 5-dimethoxyanthraquinone; 2, 5-diamino-1, 8-dihydroxyanthraquinone; 2, 7-diamino-1, 8-dihydroxyanthraquinone; 4, 5-diamino-1, 8-dihydroxyanthraquinone; mono-methylated 4, 5-or 2, 7-diamino-1, 8-dihydroxyanthraquinone; anthralin (ketone form); an anthralin; an anthralin anion; 1, 8-dihydroxyanthraquinone; 1, 8-dihydroxyanthraquinone (chrysazine); 1, 2-dihydroxyanthraquinone; 1, 2-dihydroxyanthraquinone (alizarin); 1, 4-dihydroxyanthraquinone (quinizarine); 2, 6-dihydroxyanthraquinone; 2, 6-dihydroxyanthraquinone (anthraflavin); 1-hydroxyanthraquinone (erythroxy-anthraquinone); 2-hydroxy-anthraquinone; 1, 2, 5, 8-tetra-hydroxyanthraquinone (quinizarin); 3-methyl-1, 6, 8-trihydroxyanthraquinone (emodin); anthraquinone; anthraquinone-2-sulfonic acid; benzoquinone; tetramethyl benzoquinone; hydroquinone; chlorohydroquinone; resorcinol; and 4-chlororesorcinol.

Typical retinoids (retinoids) include all-trans retinal; c₁₇An aldehyde; c₂₂An aldehyde; 11-cis retinal; 13-cis retinal; retinal; and retinyl palmitate.

Typical rhodamines include 4, 5-dibromo-rhodamine methyl ester; 4, 5-dibromo-rhodamine n-butyl ester; rhodamine 101 methyl ester; rhodamine 123; rhodamine 6G; rhodamine 6G hexyl ester; tetrabromo-rhodamine 123; and tetramethyl-rhodamine ethyl ester.

Typical thiophenes include trithiophenes such as 2, 2': 5', 2 "-trithiophene; 2,2': 5', 2 "-trithiophene-5-carboxamide; 2,2': 5', 2 "-trithiophene-5-carboxylic acid; 2,2': 5', 2 "-trithiophene-5-L-serine ethyl ester; 2,2': 5', 2 "-trithiophene-5-N-propynyl-carboxamide; 5-acetoxymethyl-2, 2': 5', 2 "-trithiophene; 5-benzyl-2, 2': 5', 2 "-trithiophene-sulfide; 5-benzyl-2, 2': 5', 2 "-trithiophene-sulfoxide; 5-benzyl-2, 2': 5', 2 "-trithiophene-sulfone; 5-bromo-2, 2': 5', 2 "-trithiophene; 5- (butynyl-3 '-hydroxy) -2, 2': 5', 2 "-trithiophene; 5-carboxy-5 "-trimethylsilyl-2, 2': 5', 2 "-trithiophene; 5-cyano-2, 2': 5', 2 "-trithiophene; 5, 5 "-dibromo-2, 2': 5' 2 "-trithiophene; 5- (1 ' ", 1 '" -dibromovinyl) -2, 2 ': 5', 2 "-trithiophene; 5, 5 "-dicyano-2, 2': 5', 2 "-trithiophene; 5, 5 "-diformyl-2, 2': 5', 2 "-trithiophene; 5-difluoromethyl-2, 2': 5' 2 "-trithiophene; 5, 5 "-diiodo-2, 2': 5', 2 "-trithiophene; 3, 3 "-dimethyl-2, 2': 5' 2 "-trithiophene; 5, 5 "-dimethyl-2, 2': 5' 2 "-trithiophene; 5- (3 ', 3 ' -dimethylacryloxymethyl) -2, 2 ': 5' 2 "-trithiophene; 5, 5 "-di- (tert-butyl) -2, 2': 5' 2 "-trithiophene; 5, 5 "-dithiomethyl-2, 2': 5' 2 "-trithiophene; 3 '-ethoxy-2, 2': 5' 2 "-trithiophene; ethyl 2, 2': 5' 2 "-trithiophene-5-carboxylic acid; 5-formyl-2, 2': 5', 2 "-trithiophene; 5-hydroxyethyl-2, 2': 5', 2 "-trithiophene; 5-hydroxymethyl-2, 2': 5' 2 "-trithiophene; 5-iodo-2, 2': 5' 2 "-trithiophene; 5-methoxy-2, 2': 5' 2 "-trithiophene; 3 '-methoxy-2, 2': 5', 2 "-trithiophene; 5-methyl-2, 2': 5' 2 "-trithiophene; 5- (3 ' -methyl-2 ' -butenyl) -2, 2 ': 5' 2 "-trithiophene; methyl 2, 2': 5 ', 2 "-trithiophene-5- [ 3'" -acrylate ]; methyl 2, 2': 5 '2 "-trithiophene-5- (3'" -propionate); n-allyl-2, 2': 5', 2 "-trithiophene-5-sulfonamide; n-benzyl-2, 2': 5', 2 "-trithiophene-5-sulfonamide; n-butyl-2, 2': 5', 2 "-trithiophene-5-sulfonamide; n, N-diethyl-2, 2': 5', 2 "-trithiophene-5-sulfonamide; 3, 3 ', 4 ', 3 "-tetramethyl-2, 2 ': 5' 2 "-trithiophene; 5-tert-butyl-5 "-trimethylsilyl-2, 2': 5', 2 "-trithiophene; 3 '-thiomethyl-2, 2': 5', 2 "-trithiophene; 5-thiomethyl-2, 2': 5', 2 "-trithiophene; 5-trimethylsilyl-2, 2': 5 '2 "-trithiophenes, dithiophenes such as 2, 2' -dithiophene; 5-cyano-2, 2' -bithiophene; 5-formyl-2, 2' -dithiophene; 5-phenyl-2, 2' -bithiophene; 5- (propynyl) -2, 2' -bithiophene; 5- (hexynyl) -2, 2' -bithiophene; 5- (octynyl) -2, 2' -bithiophene; 5- (butynyl-4 "-hydroxy) -2, 2' -bithiophene; 5- (pentynyl-5 "-hydroxy) -2, 2' -bithiophene; 5- (3 ' 4 ' -dihydroxybutylkynyl) -2, 2 ' -bithiophene derivatives; 5- (ethoxybutynyl) -2, 2' -dithiophene derivatives, and hetero (misscaleous) thiophenes such as 2, 5-diphenylthiophene; 2, 5-bis (2-thienyl) furan; pyridine, 2, 6-bis (2-thienyl) -; pyridine, 2, 6-bis (thienyl) -; thiophene, 2- (1-naphthylvinyl) -; thiophene, 2- (2-naphthylvinyl) -; thiophene, 2, 2' - (1, 2-phenylene) bis-; thiophene, 2, 2' - (1, 3-phenylene) bis-; thiophene, 2, 2' - (1, 4-phenylene) bis-; 2,2': 5 '2': 5 "2'" -tetrathiophene; alpha-tetrathienyl; alpha-tetrathiophene; alpha-pentathiophene; alpha-hexathiophene; and alpha-heptathiophene.

Typical verbs include coproporphyrin (II) verten trimethyl ester (copro (II) vertentrimester); deuteroverdin methyl ester (deuteroverdin methyl ester); mesoverdin methyl ester (mesoverdin methyl ester); and zinc methyl pyrophylldin (zinc methyl pyrophylldin).

Typical vitamins include ergosterol (provitamin D2); hexamethyl-cobaia-7-des (carboxymethyl) -7, 8-didehydro-cobicister (Pyrocobester); a pyrocobester; and vitamin D3.

Typical xanthene dyes include eosin B (4 ', 5' -dibromo, 2 ', 7' -dinitro-fluorescein, dianion); eosin Y; eosin Y (2 ', 4', 5 ', 7' -tetrabromo-fluorescein, dianion); eosin (2 ', 4', 5 ', 7' -tetrabromo-fluorescein, dianion); eosin (2 ', 4', 5 ', 7' -tetrabromo-fluorescein, dianion) methyl ester; eosin (2 ', 4', 5 ', 7' -tetrabromo-fluorescein, monoanion) p-isopropyl phenyl ester; eosin derivatives (2 ', 7' -dibromo-fluorescein, dianion); eosin derivatives (4 ', 5' -dibromo-fluorescein, dianion); eosin derivatives (2 ', 7' -dichloro-fluorescein, dianion); eosin derivatives (4 ', 5' -dichloro-fluorescein, dianion); eosin derivatives (2 ', 7' -diiodo-fluorescein, dianion); eosin derivatives (4 ', 5' -diiodo-fluorescein, dianion); eosin derivatives (tribromo-fluorescein, dianion); eosin derivatives (2 ', 4', 5 ', 7' -tetrachloro-fluorescein, dianion); eosin; eosin triacontyl pyridinium chloride ion pair; erythrosin B (2 ', 4', 5 ', 7' -tetraiodo-fluorescein, dianion); erythrosine; erythrosine dianion; erythrosine B; fluorescein; a fluorescein dianion; phloxine B (2 ', 4', 5 ', 7' -tetrabromo-3, 4, 5, 6-tetrachloro-fluorescein, dianion); phloxine B (tetrachloro-tetrabromo-fluorescein); a phloxine B; rose bengal (3, 4, 5, 6-tetrachloro-2 ', 4', 5 ', 7' -tetraiodofluorescein, dianion); rose bengal; rose bengal dianion; rose bengal O-methyl ester; rose bengal 6' -O-acetyl ethyl ester; rose bengal benzyl ester diphenyl-diiodonium salt; rose bengal benzyl ester triethylammonium salt; rose bengal benzyl ester, 2, 4, 6, -triphenylpyridinium salt; rose bengal benzyl ester, benzyltriphenyl-phosphonium salt; rose bengal benzyl ester, benzyltriphenylphosphonium salt; rose bengal benzyl ester, diphenyl iodonium salt; rose bengal benzyl ester, diphenyl-methylsulfonium salt; rose bengal benzyl ester, diphenyl-methyl-sulfonium salt; rose bengal benzyl ester, triethyl-ammonium salt; rose bengal benzyl ester, triphenylpyridinium salt; rose bengal bis (triethyl-ammonium) salt) (3, 4, 5, 6-tetrachloro-2 ', 4', 5 ', 7' -tetraiodofluorescein, bis (triethyl-ammonium salt); rose bengal bis (triethyl-ammonium) salt; rose bengal bis (benzyl-triphenyl-phosphine) salt (3, 4, 5, 6-tetrachloro-2 ', 4', 5 ', 7' -tetraiodofluorescein, bis (benzyl-triphenyl-phosphine) salt); rose bengal bis (diphenyl-iodonium) salt (3, 4, 5, 6-tetrachloro-2 ', 4', 5 ', 7' -tetraiodofluorescein, bis (diphenyl-iodonium) salt); rose bengal dihexadecyl-pyridinium chloride ion pair; rose bengal ethyl ester triethylammonium salt; rose bengal ethyl ester triethylammonium salt; rose bengal ethyl ester; rose bengal methyl ester; rose bengal octyl ester tri-n-butyl-ammonium salt RB; rose bengal, 6' -O-acetyl-, and ethyl ester.

Particularly preferred PS are green porphyrins, such as BPD-DA, -DB, -MA and-MB, especially BPD-MA, EA6 and B3. These compounds are porphyrin derivatives obtained by reacting a porphyrin core with an alkyne in a Diels-Alder type reaction to obtain a monohydrobenzoporphyrin and are described in detail in issued U.S. Pat. No. 5,171,749, the entire contents of which are incorporated herein by reference. Other photosensitizers that may be used in the present invention include those described in U.S. Pat. nos. 5,308,608, 6,093,739, 5,703,230, 5,831,088, 5,726,304, and 5,405,957. Of course, combinations of photosensitizers may also be used. Preferably, the absorption spectrum of the photosensitizer is in the visible range, typically between 350nm and 1200nm, more preferably between 400-900nm, and most preferably between 600-900 nm.

BPD-MA is described, for example, in U.S. Pat. No. 5,171,749; EA6 and B3 are described in U.S. serial nos. 09/088,524 and 08/918,840, respectively, which are incorporated herein by reference in their entirety. Preferred green porphyrins have the basic structure:

wherein R is⁴Is vinyl or 1-hydroxyRadical ethyl, R¹、R²And R³Is H or alkyl or substituted alkyl.

BPD-MA has a structure as shown in formula 1, wherein R¹And R²Is methyl, R⁴Is vinyl, R³One is H and the other is methyl. EA6 is formula 2, wherein R¹And R²Is methyl, two R³Are all 2-hydroxyethyl (i.e., ethylene glycol esters). B3 is formula 2, wherein R¹Is methyl, R²Is H, two R³Are all methyl. In EA6 and B3, R⁴Are also all vinyl groups.

BPD-MA (BPD-MA) consisting of verteporfin_CAnd BPD-MA_DAnd the A and B rings that make up EA6 and B3 are as follows:

related compounds of formulas 3 and 4 are also useful; in general, R⁴Is vinyl or 1-hydroxyethyl, R¹、R²And R³Is H or alkyl or substituted alkyl.

Light therapy

The irradiation levels are within the range commonly employed in PDT treatment of CNVs as is well known in the art. Typical levels of practice of the invention are about 12.5, 25, 50, 75 and 100J/cm²The range of (1). The radiation may be provided by any suitable light source using a wavelength that the PS used is capable of absorbing. Embodiments of the light source for use in the present method include any component capable of producing visible light.

PS spectra and wavelengths of PS activation have been described in the art. The radiation given to the PS is preferably within the wavelength of selective absorption by the PS. For any particular PS, it is a trivial matter to determine the spectrum. However, for green porphyrins, the desired wavelength range is typically between 550 and 695 nm. Preferred wavelengths for the practice of the invention are about 685-695nm, particularly about 686, about 687, about 688, about 689, about 690, about 691, and about 692 nm.

Throughout this disclosure, the abbreviated term "reduced flux rate" is used to refer to "achieving a rate of reduction of the light dose used by the reduced flux rate". Preferably, the reduced flux rate of the present invention results in better selectivity for CNVs, while reducing occlusion of normal choroidal capillaries and other deleterious or undesirable damage to normal tissues at or near the CNV being treated. Since standard, higher light flux rates may lead to hypoxia, angiogenic stimulation, further CNV growth and possible reduction in duration of therapeutic effect, the reduced flux rates used in the present invention may avoid these possibilities by reducing the potential for molecular oxygen consumption levels at the PDT site. Without being bound by any theory, it is believed that a reduced light flux rate will result in more selective therapeutic efficacy compared to a control group using a higher flux rate.

In a preferred embodiment of the invention, the subject treated is a human, and the site of CNV is within the eye. In a particularly preferred embodiment, the human subject suffers from the "wet" form of age-related macular degeneration (AMD). In other preferred embodiments of the present invention, the step of irradiating uses light having a wavelength in the visible region.

As used herein, "photodynamic productivity" or "photodynamic product" refers to a reaction product resulting from the interaction of PS and electromagnetic radiation and molecular oxygen.

In the present invention, PDT with reduced flux rate can be used to treat subjects suffering from or diagnosed with CNV. PDT is essentially performed by conventional means, wherein a suitable PS compound is administered to the subject in a dose sufficient to provide an effective concentration of PS at the site of CNV. After a suitable period of time to allow an effective concentration of PS to accumulate, the area to be treated is irradiated (or irradiated or activated) with electromagnetic radiation containing one or more wavelengths that activate the PS. In a preferred embodiment of the invention, the dual therapy with PS and anti-VEGF agent is performed at reduced flux, preferably at a flux of about one-half relative to the standard flux. In certain embodiments, the reduced flux comprises 25J/cm². In other embodiments, triple therapy with PS and an anti-VEGF agent and an anti-inflammatory agent is performed at reduced flux, preferably at about one-half or one-fourth flux relative to standard flux. In certain embodiments, the reduced flux of the triple therapy comprises 25J/cm²Or 15J/cm²。

The light dose (flux) associated with standard verteporfin PDT was 50J/cm²At 600mW/cm²Given an intensity of (flux rate) of 83 seconds. Reducing the flux (light dose) can be achieved by reducing the flux rate (light intensity) or reducing the time of light administration. As disclosed herein, reduced flux rates are preferred for the practice of the present invention using dual and triple therapies with PS. The reduced flux rate should not be confused with the total PDT dose, which is usually described as a combination of photosensitizing drug concentrations, the intensity of the radiation used and the time of exposure to light determining the total amount of energy ultimately delivered to the target tissue. The fluence rate is but only a fraction of the total PDT dose and thus, depending on the time of light exposure, may or may not have an effect on the total PDT dose when it is varied. For example, if the flux rate is reduced and the time is kept constant, a reduced total PDT dose is provided. Alternatively, if the fluence rate is decreased and the exposure time is increased, the same total PDT dose can be provided. The reduced flux rate has the additional advantage that the likelihood of overheating conditions and other deleterious effects may be reduced. Methods of performing reduced-flux PDT are taught in U.S. patent No. 6,800,086, the entire contents of which are incorporated herein by reference.

It is known that the choice of a particular flux rate will vary depending on the nature of the neovasculature and the tissue being treated and the nature of the PS being used. However, the conditions of PDT (including PS concentration, flux rate and irradiation time) cannot be varied beyond any range. There are practical limitations known to the skilled practitioner of the art to the use of any PS in PDT. Preferred rates for using green porphyrin or BPD are about 180 to 250, about 250 to 300, about 300 to 350, about 350 to 400, about 400 to 450, about 450 to 500 and about 500 to 550mW/cm². Particularly preferred flux rates are 180 or 300mW/cm²。

As mentioned above, the total PDT dose depends on the balance of at least the concentration of PS used, the light intensity (flux rate) and the irradiation time, which determines the total energy. The following values listed herein for these parameters illustrate the range of possible variations thereof; however, the following equivalents are known to practitioners in the art and also fall within the scope of the invention.

Treatment according to the invention can be repeated. Without limiting the invention, for example, if CNV leakage is found to continue or be deemed necessary by a skilled practitioner, treatment may be repeated at intervals of about every fifty-five days (about every 2 months) or about every three months (+/-2 weeks). In one embodiment, the invention provides a reassessment of a patient who has relapsed neovascular leakage at least twice within six months of the first treatment, and if neovascular leakage has occurred, the patient is treated repeatedly using the methods described herein. In a preferred embodiment of the invention, the process is repeated at least once or at least twice or at least three times within about six months from the first treatment. The present invention provides improved treatment by providing less treatment in the first six months after initial treatment.

The efficacy of treatment can be assessed by several different protocols, including but not limited to Fluorescein Angiography (FA) and Optical Coherence Tomography (OCT) to determine the area of CNV leakage. Closure of choroidal neovascularization can also be confirmed histologically by observation of damage to endothelial cells. Observations to detect vacuolated cytoplasm and abnormal nuclei associated with neovascular tissue destruction can also be evaluated.

Of particular importance to the present invention is the evaluation of visual acuity. This is done using methods standard in the art and a conventional "eye chart" in which visual acuity is assessed by the ability to discriminate between letters of a particular size, typically five letters on a row of a given size. Measurements of visual acuity are known in the art and, according to the present invention, visual acuity is assessed using standard methods.

PS concentration

The concentration of PS in the formulation administered will depend on the nature of the tissue being treated, the manner in which the formulation is administered, and the nature of the PS. However, typical concentrations are in the range of about 1ng/ml to about 10. mu.g/ml, preferably about 2ng/ml to about 1. mu.g/ml, typically in the range of about 10ng/ml to about 100 ng/ml. However, these values are merely proposals and may not be applicable to all PS. For topical application of BPD-MA and other green porphyrins or porphyrin derivatives (especially those listed above), ranges from about 0.01 to about 0.2 or about 0.5mg/ml are contemplated. Preferably, about 0.075mg/ml is used. For systemic application of PS, the range may be from about 2 to 8 (or more preferably 6) mg/m²(BPD-MA/body surface area). 6mg/m²About 0.15 mg/kg. In a preferred embodiment, the PS comprises a commercially available PS(verteporfin for injection).

Systemic administration can also be described in terms of the dose of PS versus the body weight of the subject being treated. The dosages determined under this condition of the invention are less than about 10. mu.g/kg to 100mg/kg body weight in humans, preferably less than about 10mg/kg, more preferably about 0.15 mg/kg. Preferably, the PS is infused into the subject within a short period of time, such as, but not limited to, about 5 to about 120 minutes, about 10 to about 90 minutes, about 20 to about 60 minutes, or about 30 to 45 minutes. Infusion for 10 minutes is particularly preferred.

In an embodiment of the invention, verteporfin PDT was administered at reduced flux in all the triple therapy groups of the study listed in the examples below. The reduced light dose is obtained by reducing the flux rate. In both groups (dual and one triple), one-half of the flux (25J/cm) was administered²)(300mW/m²83 seconds) and very low flux (15J/cm) was administered in the remaining triple therapy group²)(180mW/m²Given for 83 seconds).

Photosensitizer formulations

In the use of the invention for the treatment of ocular neovasculature, the photosensitizer is preferably formulated so as to deliver an effective concentration to the target tissue of the eye. Photosensitizers may be conjugated to specific binding ligands, may bind to specific surface components of ocular target tissues, or, if desired, may be delivered to target tissues at higher concentrations by formulation with carriers. The formulation may be a liposomal formulation, an emulsion, or simply an aqueous solution. Buffers and other excipients may also be added. Gelling agents and other excipients may also be used.

The nature of the formulation will depend in part on the mode of administration and the nature of the photosensitizer selected. To prepare a pharmaceutical formulation or composition comprising a PS according to the invention, any pharmaceutically acceptable excipient or combination thereof suitable for the particular photoactive compound may be used. Thus, the photoactive compound may be administered in the form of an aqueous, transmucosal or transdermal composition, or in an oral formulation. Liposome compositions are particularly preferred, especially when the photosensitizer is a green porphyrin. It is believed that the liposome formulation selectively delivers the green porphyrin to the low density lipoprotein fraction in the plasma, which in turn acts as a carrier to deliver the active ingredient more efficiently to the desired site. Increased numbers of LDL receptors have been shown to be associated with neovascularization and appear to be more efficiently delivered to neovasculature by increasing the distribution of green porphyrins in the blood into the lipoprotein phase.

Depending on the mode of administration, the form of administration, and the particular ocular tissue targeted, the optimal time until light treatment after PS administration may also vary widely. Typical times after administration of the photosensitizer range from about 1 minute to about 2 hours, preferably from about 5 to 30 minutes, more preferably from about 10 to 25 minutes. Irradiation is particularly preferably carried out 15 minutes after the start of the PS infusion. The pre-irradiation incubation may occur in the dark or may provide low levels of light during administration of the PS.

anti-VEGF agents

The invention utilizes anti-VEGF agents in combination therapy. Preferred anti-VEGF factors include antibodies, peptides and nucleic acids capable of binding to vascular endothelial growth factor to prevent or reduce its binding to its receptor. A preferred anti-VEGF agent for use in the present invention is an antibody to vascular endothelial growth factor receptor (VEGF-2R). As used herein, antibodies for use in the present invention include monoclonal antibodies, polyclonal antibodies, and antigen binding fragments thereof. The anti-VEGF agent can be administered in a dosage range, for example, from about 0.01 to about 500mg/kg, more preferably from 0.01 to about 250 mg/kg. Antibodies that bind to VEGF can be administered intravenously at a dose ranging from about 5 μ g to about 5mg per eye, more preferably as a bolus injection. Preferred anti-VEGF agents include ranibizumab and bevacizumab.

In embodiments of the invention, the time period between the first administration of PS and the subsequent administration of the anti-VEGF agent may vary. A typical time period is no more than about 48 hours. In other embodiments, a typical time period, including the shortened time, is no more than about 24 hours. More preferably, the time reduction is no more than about 4 hours or no more than about 3 hours or no more than about 2 hours, or in other embodiments, less than 2 hours, such as less than 60 minutes, or less than 45 minutes or between about 15 and 60 minutes, or between about 15 and 45 minutes, or between about 15 and 35 minutes. In a preferred embodiment, the shortened time period comprises a period of time that allows for subsequent treatment with the anti-VEGF agent and, in certain embodiments, the anti-inflammatory agent during a single treatment session by the attending physician. In other embodiments, the shortened time period is a period of time during which intraocular pressure observed with monitoring techniques known to those skilled in the art is observed to be within an acceptable range after administration of PS and does not result in an unacceptable increase in IOP prior to administration of the anti-VEGF agent.

Anti-inflammatory agents

The methods of the invention may be further enhanced by the use of PDT and anti-VEGF agents in combination with anti-inflammatory agents. The anti-inflammatory agent may be any drug that counteracts or inhibits the inflammatory process. Anti-inflammatory agents useful in the present invention include steroidal and non-steroidal drugs. Preferably, the anti-inflammatory agent is administered after administration of the PS. Preferably, the anti-inflammatory agent comprises a steroid, such as dexamethasone. The steroid may be administered intravitreally, although other routes of administration may be utilized, including those shown in the dosages and described in the respective package insert and described herein when using commercially available anti-inflammatory drugs. In other embodiments, dexamethasone is administered at a dose between about 0.4mg and 0.8mg within about two hours after administration of PS followed by administration of the anti-VEGF factor. In one embodiment of the invention, dexamethasone is delivered at a dose of about 0.5 mg. In certain embodiments, the administration of the anti-inflammatory agent is administered at a time period after the administration of the anti-VEGF agent, wherein an intraocular pressure in the eye is observed that is not elevated to an unacceptable level.

Without being limited to any particular theory, the rationale for combination therapy of Choroidal Neovascularization (CNV) caused by AMD has been described (Austin AJ, department I. combination therapy for Choroidal neovascular therapy. drugs Aging 2007; 24 (12): 979-. In combination therapy, each therapeutic component has a different mechanism of action, and thus the combined therapeutic components attack the diseased area in different ways. The development of CNV as a result of AMD is complex and lacks understanding, but is thought to involve inflammation, angiogenesis and neovascularization. In the combination therapy of the present invention, PDT with PS, such as vesudalar, is believed to block existing neovascularization, anti-vascular endothelial growth factor (anti-VEGF) therapy, such as ranibizumab, is believed to prevent angiogenesis and reduce leakage, and anti-inflammatory agents, such as dexamethasone, are employed to combat inflammation. It is believed that this multi-component, multi-target approach to treatment may lead to acceptable visual acuity outcomes that persist longer than those associated with ranibizumab monotherapy, and that monthly ranibizumab monotherapy regimens are currently approved to maintain optimal visual effects (RosenfeldPJ, Brown DM, Heier JSet al, marinastutdy group.N Engl J Med.2006；355：1419-1431；Brown DM，KaiserPK，Michels Met al，ANCHORStudyGroup.Ranibizumab versus verteporfin forneovascular age-related maculardegeneraion.N Engl J Med.2006；355：1432-1444；(ranibizumab) drug prescription information San Francisco, CA: genentech; http:// www.gene.com/gene/products/information/tgr/lucentis/index.jsp. access on day 11/15 2006).

A more permanent result can result in less repeat treatments, which will relieve the patient from the burden of frequent visits, allow the retinal specialist time to treat more patients, and reduce the treatment costs for the patient and institution to pay for healthcare.

The following examples are intended to illustrate, but not limit, the present invention.

Example 1

Design of research

The study was a 24-month randomized control trial designed to evaluate 3 combination treatment regimens: (1) very low flux vPDT (15J/cm)²) In combination with ranibizumab (0.5mg) and dessamson pine (0.5 mg); (2) one-half flux vPDT (25J/cm)²) In combination with ranibizumab (0.5mg) and dexamethasone (0.5 mg); and (3) one-half the flux of vPDT in combination with ranibizumab. These regimens were compared to ranibizumab monotherapy in patients with macular subfoveal Choroidal Neovascularization (CNV) caused by AMD. Inclusion criteria included greater than or equal to 50 years old; untreated for AMD; the Best Corrected Visual Acuity (BCVA) table score is 73-24; depressed central macular CNV caused by AMD; and lesion size < 9 DA. Patients (N ═ 160) were randomized to 1 of 4 treatment groups at the beginning, received 1 initial treatment, and based on new criteria, treatment assessments were repeated monthly using OCT and FA. Patients in the ranibizumab monotherapy group were on the second order based on the same repeat treatment criteriaMandatory doses were received for 1 month and 2 months and thereafter as needed. Patients in the combination therapy group received the indicated treatment as needed (not more frequently than every 2 months) based on repeat treatment criteria; if treatment is required at monthly intervals, ranibizumab injections are given. The results of the study included efficacy, safety and number of double visits.

Patients in the combination treatment group returned to the clinic monthly for repeat treatment evaluations during their initial randomized study treatment. The repeat treatment criteria are based on Optical Coherence Tomography (OCT) and Fluorescein Angiography (FA). If OCT Central Retinal Thickness (CRT) is > 250 μm or more or > 50 μm increase compared to the previous lowest CRT, the patient is treated repeatedly. When both OCT criteria are not applicable, patients can still be treated repeatedly if FA shows signs of increased damage or CNV leakage.

The combination repeat therapy must not be administered more frequently than every 2 months. If repeated treatment is found to be necessary at intervals of months, the patient receives only ranibizumab injections. After their initial randomized study treatment, patients in the ranibizumab monotherapy group received mandatory repeat treatments at months 1 and 2, and thereafter received repeat treatments as needed based on the criteria described above. In all treatment groups, monthly assessments and potential repeat treatments span 12 months of the study. Between 12 and 24 months, patients underwent at least one or more frequent double visits every 3 months, at the discretion of the investigator.

At screening, the day of initial treatment (pre-treatment), monthly visits out of 6 months and visits at 12, 18 and 24 months, the best corrected visual acuity was assessed using the ETDRS method. Evaluation of FA was performed at screening, visit 3 and 12 months, and as needed for repeat treatment criteria. OCT was evaluated to determine the repeat treatment criteria at each visit. Safety, including intraocular pressure, was also assessed at each visit.

The results of the study included visual acuity, CRT, lesion size, number of double visits and safety. The primary efficacy variable was the average number of repeat treatments and the average change from the initial in the visual acuity score.

Example 2

Materials and methods

For this study, 1mL dexamethasone sodium phosphate injection (Baxter Healthcare Corporation), Deerfield, IL, USA or Sandoz Canada Inc., containing USP 10mg/mL was used. Dexamethasone sodium phosphate, corresponding to 10mg dexamethasone phosphate or 8.33mg dexamethasone per ml, was included. The inactive ingredients in this formulation are anhydrous sodium sulfite, anhydrous sodium citrate and benzyl alcohol (preservative) in water for injection.

Randomization occurred on the day of the first treatment in the following group:

lucentis monotherapy.

One-half flux visfatal-Lucentis (V-L) dual therapy.

One-half flux (25J/cm)²) vydal-Lucentis-dexamethasone (V-L-D) triple therapy.

Very low flux (15J/cm)²) vydal-Lucentis-dexamethasone (V-L-D) triple therapy.

Treatment occurred within 7 days of the initial FA. Repeat treatment was based on repeat treatment criteria in the Lucentis monotherapy group starting at month 3 and the combination treatment group starting at month 1. All repeat treatment procedures were completed on the same day if possible (i.e., OCT and FA evaluations, if necessary, and repeat treatments). If this is not possible, it is recommended that repeated treatments be completed within 3 days of OCT, if necessary.

Lucentis (ranibizumab) was administered as described in the approved drug prescription information.

The compounded visidall is an opaque dark green solution. Is drawn out of the bottleDesired 6mg/m²Volume of the desired dose of reconstituted visidal of Body Surface Area (BSA) and diluted with 5% dextrose in water (D5W) to a total infusion volume of 30 mL. Full infusion volume was given intravenously at a rate of 3 mL/min over 10 minutes using a suitable syringe pump and in-line filtration (1.2 microns).

Light application to the eye under study was performed 15 minutes after the start of infusion of visadal. The light is administered as follows, depending on the treatment to which the subject is assigned.

vesudall-Lucentis combination therapy and one-half-flux V-L-D combination therapy group: to be provided with300mW/cm ² Delivered within 83 seconds25J/cm ² The light dose of (a).

Very low-throughput V-L-D triple therapy group: to be provided with180mW/cm ² Delivered within 83 seconds15J/cm ² The light dose of (a). For this protocol, the minimum treatment spot size is 3.8mm (the light dose needs to be achieved with available laser systems).

Red light (689 ± 3nm) generated by a laser diode is delivered as a single circular spot through an optical fiber and slit lamp to the CNV lesion using a suitable contact lens.

The size of the CNV lesion is estimated from fluorescein angiograms depicting the CNV and any features that occlude any CNV boundaries.

For dispensing 15J/cm²The V-L-D treatment group of (1), the minimum treatment spot size was 3.8mm, and therefore the lesion boundary with GLD less than 2.8mm was proportionally larger than the 500 micron boundary described above.

Dexamethasone injections were administered under sterile conditions as described for Lucentis. Each drug was administered using a 29 or 30 gauge needle.

Example 3

Results of the study

In the studies described in examples 1 and 2 above, patients diagnosed as eligible for experimental treatment of age-related macular degeneration were divided into four groups, as shown in figures 1-3, 18, and received treatment in one of four regimens as listed in figure 4 below:

lucentis0.5mg monotherapy:

day 0, month 1 and month 2

Monthly assessments from 3-12 months on demand (based on repeat treatment criteria)

Assessment as needed (based on repeat treatment criteria) to month 21, at month 12 to month 24, at least every 3 months

All Lucentis injections must be spaced at intervals of 28 days or more

visfatal-Lucentis dual therapy: giving a half flux (25J/cm)²:300mW/cm²Lasting 83 seconds), followed by intravitreal administration of lucentis0.5 mg:

day 0

Monthly assessments until month 12. The dual therapy was given as needed (based on repeat treatment criteria) but at intervals of no less than 2 months (55 days). If treatment is required at monthly intervals based on repeat treatment criteria, the subject will receive a Lucentis injection (as long as 28 days since the last Lucentis injection).

-evaluation after month 12 to month 24, at least every 3 months. Treatment was as described above until month 21 when needed.

V-L-D triple therapy: administration ofOne-half flux (25J/cm) ² :300mW/cm ² Lasting 83 seconds), followed by intravitreal Lucentis0.5mg (first injection) and dexamethasone 0.5mg (second injection) over 2 hours:

day 0

Monthly assessments until month 12. One-half of the dose of triple therapy was given as needed (based on repeat treatment criteria), but at intervals of no less than 2 months (55 days). If treatment is required at monthly intervals based on repeat treatment criteria, the subject will receive a Lucentis injection (as long as 28 days since the last Lucentis injection).

-evaluation after month 12 to month 24, at least every 3 months. As described above, treatment was carried out up to 21 months when needed.

V-L-D triple therapy: administration hasVery low flux (15J/cm) ² :180mW/cm ² Lasting 83 seconds), followed by intravitreal Lucentis0.5mg (first injection) and dexamethasone 0.5mg (second injection) over 2 hours:

day 0

Monthly assessments until month 12. Very low-throughput triple therapy was given as needed (based on repeat treatment criteria), but at intervals of no less than 2 months (55 days). If treatment is required at monthly intervals based on repeat treatment criteria, the subject will receive a Lucentis injection (as long as 28 days since the last Lucentis injection).

-evaluation after month 12 to month 24, at least every 3 months. As described above, treatment was carried out up to 21 months when needed.

Figure 5 shows the repeat treatment criteria used in this study.

First year of study (initial to 12 months)

On day 0, all subjects received randomized treatment. Subjects randomized to the Lucentis monotherapy group were treated repeatedly at month 1 and month 2 (treatment interval ≧ 28 days). By month 12 thereafter, Lucentis monotherapy was given as needed (PRN as needed) based on repeated treatment criteria assessed monthly (. + -. 1 week, allowed treatment intervals ≧ 28 days) (FIG. 5). Subjects randomized to the combination treatment group were evaluated monthly until month 12; repeat therapy for the indicated combination therapy is given if more than or equal to 55 days from the previous combination therapy and treatment is required based on repeat therapy criteria. If treatment is required and < 55 days from the previous combination treatment, the subjects assigned to the combination treatment group receive a Lucentis injection. The interval of Lucentis injection is more than or equal to 28 days. FA was not required for subjects assigned to the combination treatment group who met OCT repeat criteria but received a Lucentis injection first due to their < 55 days from the last combination treatment. FA is only used when combination therapy is to be performed after OCT repeat therapy is met, as FA is needed to determine lesion size and PDT site (see figure 2).

All subjects underwent OCT at every visit; best-corrected VA (visual acuity) tests were performed initially and at 1-6, 9 and 12 months; and FA was performed initially and at months 3 and 12.

The mean number of repeat treatments (except day 0 treatment) and mean change from baseline were evaluated by best-corrected VA (visual acuity) scores.

The second year (12 th month to 24 th month)

Subjects were enrolled in follow-up visits at least every 3 months, primarily for safety assessment, with treatment on the initially prescribed therapy when needed. (for the first year, if treatment is required more than 55 days from the previous combination treatment and is required based on the criteria of repeated treatment, then repeat treatment of the indicated combination treatment is given. if treatment is required and less than 55 days from the previous combination treatment, then subjects assigned to the combination treatment group receive Lucentis injections.Lucentis injection intervals must be more than or equal to 28 days.

The combination treatment groups were evaluated monthly until month 12. Based on the criteria for repeat treatment, repeat treatments of the combination therapy can be given at intervals of greater than or equal to 55 days. If treatment is required at < 55 days interval, the subject receives a Lucentis injection. It is not expected that combination therapy will necessitate repeated treatments within such short time intervals, but it will be necessary to make an assessment to determine that repeated treatments are not required.

Randomization included grading by day 0 VA (i.e., 25-50 letters and 51-73 letters) for the eye under study, as the initial VA correlated with the rate of visual deterioration in subjects with AMD.

Mid-term results after six months

Initial characteristics of the patients prior to starting treatment are listed in figure 6.

After six months, a mean Visual Acuity (VA) increase from baseline was observed in each group, and this increase was observed in the mid six months, similar between the four treatment groups (fig. 6-10).

In the first six mid-month period, the combination group received a lower mean cumulative treatment than the Lucentis monotherapy group in the study. The data reflect mandatory repeat treatments at months 1 and 2 in the Lucentis monotherapy group. Initially, the mean best corrected acuity chart score was between 53 and 58 across all treatment groups. At six months, each group scored similar increases from the initial average visual acuity chart (group 1: 4.0 letters; group 2: 7.3 letters; group 3: 2.5 letters; group 4: 4.4 letters), and similar decreases in retinal thickness based on OCT were observed (figures 11-15). The cumulative repeat treatment rate was lower in all combination groups compared to the Lucentis monotherapy group. In the Lucentis monotherapy group, this was affected by mandatory repeat treatments at months 1 and 2.

Based on analysis in the mid-six months, the combination treatment regimen in this study showed safety (fig. 16-17).

Main analytical results after twelve months

The primary analysis results throughout the twelve months showed that the following combination therapies required fewer repeat treatments and had statistically significant differences compared to the Lucentis monotherapy.

Mean Visual Acuity (VA) was similarly improved in all treatment groups (fig. 19-21). Over the entire twelve month period, OCT-based retinal thickness reduction was measured (fig. 22). There were no unexpected safety findings and the 12-month adverse event incidence was similar in all treatment groups (fig. 24-25).

Of the four treatment groups, the triple therapy one-half flux group showed the best results, with the lowest repeat treatment rate and an average VA increase of 12 months most similar to Lucentis monotherapy (fig. 23). Patients in the triple therapy one-half flux group had an average of 3.0 repeat treatments (P <.001) compared to an average of 5.4 repeat treatments in patients receiving Lucentis monotherapy. In the month 12 examination, the average VA in the triple therapy one-half flux group increased 6.8 letters from baseline compared to 6.5 letters in the Lucentis monotherapy group (P ═ 94). The average repeat treatment rate and VA improvement for each treatment group are listed in the table below. All results listed are based on ITT analysis; each experimental analysis yielded similar results. At monthly visits over 12 months of study follow-up, patients were assessed for VA and safety, and whether repeat treatment was required. Overall, 10 patients terminated the study by 12 months for reasons unrelated to Lucentis or visodall.

Preliminary results of 12 month breakthrough study

P values were from comparison to the Lucentis monotherapy group.

The percentage of patients with a visual improvement of 3 or more lines in the one-half-flux triple combination group was observed to be 31% compared to 24% in the Lucentis monotherapy group. Approximately one-third of the patients in the combination treatment group were reported to have ocular adverse events considered to be treatment-related compared to approximately one-fourth of the patients in the Lucentis monotherapy group. The higher incidence of these events in the combination treatment group is believed to be mainly due to visual disturbance events (visual abnormalities and vision loss), which are transient and known to be associated with visfatal treatment.

The citation of the above documents is not an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

All references cited herein are hereby incorporated by reference in their entirety, whether or not explicitly incorporated before. As used herein, the terms "a", "an" and "any" each include both the singular and the plural.

Having now fully described this invention, it will be appreciated by those skilled in the art that the same may be performed within a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation.

While the invention has been described in conjunction with specific embodiments thereof, it will be understood that it is capable of further modifications. This application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth.

Claims (24)

1. Use of a combination of a photosensitizer, an anti-VEGF agent and an anti-inflammatory agent in the manufacture of a medicament for the treatment of unwanted choroidal neovasculature CNV in a human subject using photodynamic therapy PDT, said medicament comprising:

(a) an effective amount of the photosensitizer PS to allow an effective amount to localize to a target tissue of the eye and irradiating the target tissue with electromagnetic radiation comprising a wavelength absorbable by the PS, wherein the PS is irradiated with electromagnetic radiation comprising a wavelength absorbed by the PS at a reduced flux rate, wherein the flux rate delivers a total light dose in the range of 12.5J/cm²To 25J/cm²，

(b) An effective amount of the anti-VEGF agent, and

(c) an effective amount of the anti-inflammatory agent,

wherein the anti-VEGF agent is administered within 2 hours after completion of step (a), wherein CNVs in the subject are occluded, wherein the administration is selected from the group consisting of: (i) administration of BPD-MA at 300mW/cm²Irradiated for 83 seconds to deliver 25J/cm²Followed by intravitreal administration of ranibizumab over a two hour period; (ii) administration of BPD-MA at 300mW/cm²Irradiated for 83 seconds to deliver 25J/cm²Followed by intravitreal administration of ranibizumab over two hours, followed by intravitreal administration of dexamethasone; and (iii) administration of BPD-MA at 180mW/cm²Irradiated for 83 seconds to deliver 15J/cm²Followed by intravitreal administration of ranibizumab over two hours, followed by intravitreal administration of dexamethasone.

2. The use of claim 1, wherein the CNV is in a subject suffering from or diagnosed with age-related macular degeneration AMD.

3. The use of claim 2, wherein the AMD is wet.

4. Use according to claim 3, wherein the AMD is typically primary, typically minority or occult.

5. Use according to claim 1, wherein the fluence rate is less than 500mW/cm²。

6. The use of claim 1, wherein the flux rate delivers 25J/cm²Total light dose of (c).

7. Use according to claim 1, wherein the reduced fluxThe rate is 300mW/cm²。

8. The use of claim 1, wherein the fluence rate delivers a total light dose of 15J/cm²。

9. Use according to claim 8, wherein the reduced fluence rate is 180mW/cm²。

10. The use of claim 1, wherein said dexamethasone is administered at a dose between 0.4 and 0.8mg within 2 hours of administration of said photosensitizer and after administration of said anti-VEGF.

11. The use of claim 10, wherein the dexamethasone is delivered at a dose of 0.5 mg.

12. Use according to any preceding claim, wherein the administration is repeated for a period of at least 6 months or more after the first treatment.

13. The use of claim 12, wherein the administration is repeated every three months for a period of at least 6 months or more after the first treatment.

14. The use of claim 13, wherein the administration is repeated no less than every 55 days for a period of at least 6 months after the first treatment.

15. The use of any one of claims 1-11, wherein the visual acuity of the subject is increased.

16. The use of claim 1, wherein said administration is repeated no less than every 55 days for a period of six months or more.

17. The use of claim 1, wherein the administering comprises administering BPD-MA at 300mW/cm²Irradiated for 83 seconds to deliver 25J/cm²Subsequently intravitreally administering ranibizumab over a period of two hours followed by intravitreally administering dexamethasone, and wherein the administration is repeated 3 times over a twelve month period.

18. The use of claim 1, wherein the administering comprises administering BPD-MA at 180mW/cm²Irradiated for 83 seconds to deliver 15J/cm²Subsequently intravitreally administering ranibizumab over a period of two hours followed by intravitreally administering dexamethasone, and wherein the administration is repeated four times over a twelve month period.

19. The use of claim 15, wherein the visual acuity letter score improvement from baseline after six months is at least 2.5 letters or more.

20. The use of claim 19, wherein the visual acuity letter score improvement from baseline after six months is at least 4 letters or more.

21. The use of claim 20, wherein the visual acuity letter score improvement from baseline after six months is at least 7 letters or more.

22. The use of claim 15, wherein the visual acuity letter score improvement from baseline after twelve months is at least 3.6 letters or more.

23. The use of claim 22, wherein the visual acuity letter score improvement from baseline after twelve months is at least 5 letters or more.

24. The use of claim 23, wherein the visual acuity letter score improvement from baseline after six months is at least 6.8 letters or more.