Photokinetic Ocular Drug Delivery Methods and Apparatus

Abstract

The present invention relates generally to transscleral, transcorneal, and transocular delivery of biologically active substances through the tissues, blood vessels and cellular membranes of the eyes of patients without causing damage to the cellular surface, tissue or membrane. The invention provides compositions and methods for enhanced transscleral, transcorneal and transocular delivery of biologically active substances using pulsed incoherent light, and particularly the transcleral, transcorneal or transocular delivery of high molecular weight biologically active substances to a patient using pulsed incoherent light. The invention further provides a device for the application of the pulsed incoherent light to cellular surfaces and membranes of the eye of a subject using those compositions and methods.

1 . A method for the photokinetic transscleral ocular delivery of a biologically active substance to a subject, the method comprising: preparing a solution comprising the biologically active substance and a solvent; applying the solution to an exterior ocular surface of an eye of the subject; and illuminating the solution on the exterior ocular surface with a pulsed incoherent light directed through the solution and towards an interior of the eye of the subject at a wavelength selected to induce photokinetic transocular translocation of the biologically active substance. 
     
     
         2 . The method of  claim 1 , wherein the solution further comprises a gelling agent. 
     
     
         3 . The method of  claim 1 , wherein the biologically active substance has a molecular weight greater than 500 Daltons. 
     
     
         4 . The method of  claim 1 , wherein the biologically active substance is selected from one or more anesthetics, anti-infectives, antibiotics, antifungals, antivirals, antineoplastics, anti-VEGFs, antineovasculars, steroids, anti-inflammatories, immunomodulators, gases, antioxidants, nanoparticles, genes, cytokines, peptides, antithrombotics, nucleotides, RNAs, anti-compliment medications, compliment modulating medications, peptides, immunoglobulins, antibodies, antigens, anti-glaucoma medications, hormones, vitamins, amino acids, silicone liquids, heavy liquid tamponades, cellular nutrients, anti-apoptotic agents, anticoagulants, tissue adhesives, cofactors, coenzymes, enzymes and combinations thereof. 
     
     
         5 . The method of  claim 4 , wherein the hormone is selected from the group consisting of methionine enkephalin acetate, leucine enkephalin, angiotensin II acetate, β-estradiol, methyl testosterone, methyl prednisolone, corticosteroids, budenoside, progesterone, insulin, and combinations thereof. 
     
     
         6 . The method of  claim 4 , wherein the biologically active substance is insulin. 
     
     
         7 . The method of  claim 4 , wherein the biologically active substance is triamcinolone acetonide. 
     
     
         8 . The method of  claim 4 , wherein the antibody is a monoclonal antibody selected from the group consisting of adalimumab, bevacizumab, daclizumab, etanercept, infliximab, ranibizumab, rituximab, and combinations thereof. 
     
     
         9 . The method of  claim 4 , wherein the antibiotic is selected from the group consisting of amoxycillin, ampicillin, penicillin, clavulanic acid, aztreonam, imipenem, streptomycin, gentamicin, vancomycin, clindamycin, ephalothin, erythromycin, polymyxin, bacitracin, amphotericin, nystatin, rifampicin, tetracycline, coxycycline, chloramphenicol, zithromycin, and combinations thereof, as well as pharmaceutically acceptable derivatives thereof. 
     
     
         10 . The method of  claim 1 , wherein the biologically active substance is insulin-like growth factor-1 (IGF-1). 
     
     
         11 . The method of  claim 4 , wherein the antiviral agent is selected from the group consisting of guanosine derivatives, nucleoside phosphonates, phosphonic acid derivatives, oligonucleotides, and combinations thereof, as well as pharmaceutically acceptable salts, solvates, hydrates, and derivatives thereof. 
     
     
         12 . The method of  claim 4 , wherein antiviral drug is selected from the group consisting of foscarnet, fomivirsen sodium, trifluridine, vidarabine, and combinations thereof, as well as pharmaceutically acceptable derivatives thereof. 
     
     
         13 . The method of  claim 1 , wherein the biologically active substance is methotrexate. 
     
     
         14 . The method of  claim 2 , wherein the gelling agent selected from the group consisting of hydroxyethyl cellulose, pectines, agar, alginic acid and its salts, guar gum, pectin, polyvinyl alcohol, polyethylene oxide, cellulose, propylene carbonate, polyethylene glycol, hexylene glycol sodium carboxymethylcellulose, polyacrylates, polyoxyethylene-polyoxypropylene block copolymers, pluronics, wood wax alcohols, tyloxapol, and combinations thereof, as well as pharmaceutically acceptable derivatives thereof. 
     
     
         15 . The method according to  claim 1 , wherein the solvent is an aqueous solvent or an organic solvent. 
     
     
         16 . The method according to  claim 15 , wherein the aqueous solvent is an aqueous solution of ethyl lactate or propylene glycol. 
     
     
         17 . The method according to  claim 1 , wherein the pulsed incoherent light is selected from the group consisting of fluorescent, ultraviolet, visible, near infrared, LED (light emitting diode), and halogen light. 
     
     
         18 . The method according to  claim 1 , wherein the wavelength is in a range from about 260 nm to about 760 nm. 
     
     
         19 . The method according to  claim 1 , wherein the wavelength is in a range from about 340 nm to about 900 mm. 
     
     
         20 . The method according to  claim 1 , wherein the wavelength is selected from the group consisting of 350 nm, 370 nm, 390 nm, 405 nm, 450 nm and combinations thereof. 
     
     
         21 . The method according to  claim 1 , wherein the pulsed incoherent light is applied at a pulse rate between about 1.7 cycles per second (cps) and about 120 cps. 
     
     
         22 . The method according to  claim 21 , wherein the pulse rate is between about 1.7 cps and about 80 cps. 
     
     
         23 . The method according to  claim 1 , wherein the pulsed incoherent light is applied at a duty cycle is between about 50% and about 75%. 
     
     
         24 . A method for the transcleral delivery of one or more high molecular weight biologically active substances to the eye of a subject, the method comprising: preparing a solution comprising a biologically active substance having a molecular weight greater than 1000 Daltons and a solvent; applying the solution to an exterior ocular surface of a subject; illuminating the solution on the exterior ocular surface with a pulsed incoherent light directed through the solution and towards an interior of the eye of the subject at a wavelength selected to induce photokinetic transocular translocation of the biologically active substance. 
     
     
         25 . The method of  claim 24 , wherein the biologically active substance has a molecular weight of greater than 50,000 Daltons. 
     
     
         26 . The method of  claim 24 , wherein the biologically active substance is insulin, bevacizumab, human growth factor, and combinations and/or pharmaceutically acceptable salts, solvates, or derivatives thereof. 
     
     
         27 . The method of  claim 24 , wherein the biologically active substance is selected from the group consisting of anti-infectives, antibiotics, antifungals, antivirals, antineoplastics, anti-VEGFs, antineovasculars, steroids, anti-inflammatories (including NSAIDS), immunomodulators, antioxidants, nanoparticles, genes, cytokines, peptides, antithrombotics, polynucleotides, RNAs, anti-compliment medications, compliment modulating medications, immunoglobulins, antibodies, antigens, anti-glaucoma medications, hormones, vitamins, silicone liquids, heavy liquid tamponades, cellular nutrients, anti-apoptotic agents, anticoagulants, tissue adhesives, cofactors, coenzymes, enzymes and combinations thereof. 
     
     
         28 . A method for the treatment of a subject having a VEGF-related angiogenic disease affecting the eyes of the subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a biologically active substance using the method of  claim 1 , wherein the VEGF-related angiogenic disease is selected from the group consisting of cancer, age-related macular degeneration (AMD), diabetic retinopathy, and combinations thereof.