Injectable Combination Therapy for Eye Disorders

Abstract

The present invention provides composition, methods, and articles of manufacture for treating an eye disorder, e.g., a disorder characterized by macular degeneration, choroidal neovascularization, or retinal neovascularization. One method of the invention comprises the step of: administering first and second therapeutic agents to the subject's eye in a single procedure, wherein the first therapeutic agent provides rapid improvement in the condition of the subject's eye and the second therapeutic agent is administered as a sustained release formulation of the second therapeutic agent. For example, the first and second therapeutic agents are administered by intravitreal injection. The first therapeutic agent may be dissolved in a liquid medium located in the syringe and the sustained formulation of the second therapeutic agent may comprise an ocular implant or plurality of particles located in the needle. The therapeutic agents may be selected from the group consisting of angiogenesis inhibitors and complement inhibitors.

1 . A method of treating an eye disorder characterized by macular degeneration, CNV, or RNV comprising the step of: administering effective amounts of first and second therapeutic agents to the subject's eye in a single procedure, wherein the first therapeutic agent provides rapid improvement in the condition of the subject's eye and the second therapeutic agent is administered as a sustained release formulation of the second therapeutic agent. 
   
   
       2 . The method of  claim 1 , wherein the rapid improvement includes improvement in the visual acuity of the eye that occurs within 2 weeks following administration of the agents. 
   
   
       3 . The method of  claim 1 , wherein the procedure is an injection procedure. 
   
   
       4 . The method of  claim 1 , wherein the procedure is an injection procedure in which the first and second therapeutic agents are injected into the vitreous of the subject's eye. 
   
   
       5 . The method of  claim 1 , wherein the procedure is an injection procedure in which, prior to administration, the first therapeutic agent is contained in a syringe and the sustained release formulation comprising the second therapeutic agent is contained in a needle attached to the syringe. 
   
   
       6 . The method of  claim 5 , wherein the first therapeutic agent is dissolved in a liquid medium located in the syringe and the sustained formulation of the second therapeutic agent comprises an ocular implant located in the needle. 
   
   
       7 . The method of  claim 1 , wherein the first therapeutic agent is an angiogenesis inhibitor. 
   
   
       8 . The method of  claim 1 , wherein the first therapeutic agent is an anti-VEGF agent. 
   
   
       9 . The method of  claim 1 , wherein the first therapeutic agent is an anti-VEGF agent selected from the group consisting of: antibodies that bind to VEGF and nucleic acids that bind to VEGF. 
   
   
       10 . The method of  claim 1 , wherein the first therapeutic agent is selected from the group consisting of bevacizumb, ranibizumab, and pegaptanib. 
   
   
       11 . The method of  claim 1 , wherein the second therapeutic agent is a complement inhibitor. 
   
   
       12 . The method of  claim 1 , wherein the second therapeutic agent is a complement inhibitor selected from the group consisting of: viral complement control proteins and peptides or small molecules that bind to a complement component. 
   
   
       13 . The method of  claim 1 , wherein the second therapeutic agent is compstatin or a derivative thereof. 
   
   
       14 . The method of  claim 1 , wherein the second therapeutic agent is a GPCRA. 
   
   
       15 . The method of  claim 1 , wherein the first therapeutic agent is an angiogenesis inhibitor and the second therapeutic agent is a complement inhibitor. 
   
   
       16 . The method of  claim 1 , wherein compstatin or an analog thereof and a C5a inhibitor are adminstered. 
   
   
       17 . The method of  claim 16 , wherein the C5a inhibitor is a C5a receptor antagonist. 
   
   
       18 . The method of  claim 1 , wherein the first therapeutic agent is dissolved or suspended in a liquid medium prior to administration. 
   
   
       19 . The method of  claim 1 , wherein the sustained release formulation comprises an ocular implant comprising the second therapeutic agent. 
   
   
       20 . The method of  claim 1 , wherein the sustained release formulation comprises a polymeric material. 
   
   
       21 . The method of  claim 20 , wherein the polymeric material is biodegradable. 
   
   
       22 . The method of  claim 20 , wherein the polymeric material is selected from the group consisting of: poly-lactic acid (PLA), poly-glycolic acid (PGA), poly-lactide-co-glycolide (PLGA), poly(phosphazine), poly (phosphate ester), polycaprolactones, polyanhydrides, ethylene vinyl acetate, polyorthoesters, polyethers, poly (beta amino esters), copolymers containing monomeric subunits found in any of the foregoing polymers, collagen, albumin, chitosan, alginate, hyaluronic acid, and mixtures of any of the foregoing polymers. 
   
   
       23 . The method of  claim 1 , wherein the sustained release formulation comprises nanoparticles, microparticles, dendrimers, or liposomes comprising the second therapeutic agent. 
   
   
       24 . The method of  claim 1 , wherein the sustained release formulation comprises a solid or semi-solid material that entraps or encapsulates the second therapeutic agent. 
   
   
       25 . The method of  claim 1 , wherein the sustained release formulation comprises an inactive material to which the second therapeutic agent is covalently attached. 
   
   
       26 . The method of  claim 1 , wherein the first therapeutic agent is administered in soluble or particulate form in a liquid medium and the second therapeutic agent is administered in or attached to a solid or semi-solid matrix. 
   
   
       27 . The method of  claim 1 , wherein the second therapeutic agent, when administered as a component of the sustained release formulation, has an activity period greater than that of the first therapeutic agent. 
   
   
       28 . The method of  claim 1 , wherein administering the second therapeutic agent prolongs the time interval during which the subject experiences improvement in the condition of the subject's eye relative to the time interval during which the subject would have experienced improvement if the first therapeutic agent had been administered as sole therapy. 
   
   
       29 . The method of  claim 1 , wherein the eye disorder is exudative ARMD. 
   
   
       30 . The method of  claim 1 , wherein the subject has experienced a perceptible deterioration in the condition of the subject's eye within the two weeks preceding administration of the first and second therapeutic agents. 
   
   
       31 . The method of  claim 1 , further comprising performing the method one or more additional times at time intervals greater than the activity period of the first therapeutic agent. 
   
   
       32 . A method of treating an eye disorder characterized by macular degeneration, CNV, or RNV comprising the step of: administering first and second compositions to the subject's eye in a single procedure, wherein the first composition comprises an angiogenesis inhibitor or complement inhibitor that provides rapid improvement in the condition of the subject's eye and the second composition comprises a sustained release formulation comprising an angiogenesis inhibitor or a complement inhibitor. 
   
   
       33 . The method of  claim 32 , wherein the single procedure is an intravitreal injection. 
   
   
       34 . The method of  claim 32 , wherein the angiogenesis inhibitor is an anti-VEGF agent. 
   
   
       35 . The method of  claim 32 , wherein the angiogenesis inhibitor is an anti-VEGF agent selected from the group consisting of: antibodies or antibody fragments that bind to VEGF and nucleic acids that bind to VEGF. 
   
   
       36 . The method of  claim 32 , wherein the angiogenesis inhibitor is selected from the group consisting of bevacizumb, ranibizumab, and pegaptanib. 
   
   
       37 . The method of  claim 32 , wherein the complement inhibitor is selected from the group consisting of: viral complement control proteins and peptides that bind to a complement component. 
   
   
       38 . The method of  claim 32 , wherein the complement inhibitor is compstatin or a derivative thereof. 
   
   
       39 . The method of  claim 32 , wherein the angiogenesis inhibitor is selected from the group consisting of bevacizumb, ranibizumab, and pegaptanib and the complement inhibitor is compstatin or a derivative thereof. 
   
   
       40 . The method of  claim 32 , wherein the first therapeutic agent is provided at least in part dissolved or suspended in a liquid medium. 
   
   
       41 . The method of  claim 32 , wherein the second therapeutic agent is released from the ocular implant so as to maintain a therapeutic level in the subject's eye over a period of at least 3 months. 
   
   
       42 . A method of administering first and second therapeutic agents to the eye of a subject comprising: injecting (i) a solution or suspension containing the first therapeutic agent and (ii) a solid ocular implant, plurality of particles, or gel-forming composition containing the second therapeutic agent into the subject's eye in a single injection procedure. 
   
   
       43 . The method of  claim 42 , wherein the first and second therapeutic agents are injected into the vitreous of the subject's eye. 
   
   
       44 . The method of  claim 42 , wherein (i) the solution or suspension; and (ii) the solid ocular implant, plurality of particles, or gel-forming composition, are injected using a single needle and syringe assembly. 
   
   
       45 . The method of  claim 42 , wherein the first therapeutic agent provides a rapid improvement in the condition of the subject's eye. 
   
   
       46 . The method of  claim 42 , wherein the activity period of the second composition is greater than the activity period of the first composition. 
   
   
       47 . The method of  claim 42 , wherein the second therapeutic agent does not provide rapid improvement in the condition of the subject's eye. 
   
   
       48 . The method of  claim 42 , wherein the second therapeutic agent has an activity period greater than that of the first therapeutic agent. 
   
   
       49 . The method of  claim 42 , further comprising the step of: repeating the administering step once or more at time intervals greater than the activity period of the first therapeutic agent. 
   
   
       50 . An article of manufacture comprising (i) a first therapeutic agent effective for treating an eye disorder; and (ii) a needle containing a second therapeutic agent. 
   
   
       51 . The article of manufacture of  claim 50 , further comprising a syringe. 
   
   
       52 . The article of manufacture of  claim 50 , further comprising a syringe, wherein the syringe contains the first therapeutic agent. 
   
   
       53 . The article of manufacture of  claim 50 , wherein the article of manufacture contains a unit dosage form of the first therapeutic agent. 
   
   
       54 . The article of manufacture of  claim 50 , wherein the article of manufacture contains a unit dosage form of the first therapeutic agent and a unit dosage form of the second therapeutic agent. 
   
   
       55 . The article of manufacture of  claim 50 , further comprising a syringe, wherein the article of manufacture contains at least one compartment and the syringe and needle are housed in a single compartment of the article of manufacture. 
   
   
       56 . The article of manufacture of  claim 50 , further comprising a syringe, wherein the syringe and needle are attached to one another. 
   
   
       57 . The article of manufacture of  claim 50 , further comprising a syringe, wherein the article of manufacture contains at least two compartments, and wherein the syringe and needle are housed in individual compartments. 
   
   
       58 . An article of manufacture comprising (i) a first therapeutic agent effective for treating an eye disorder; (ii) a second therapeutic agent effective for treating an eye disorder, wherein each therapeutic agent is contained in an individual syringe. 
   
   
       59 . The article of manufacture of  claim 58 , further comprising a needle. 
   
   
       60 . A method of supplying a combination therapy for an ocular disorder comprising providing the article of manufacture of any of  claims 50 - 59 . 
   
   
       61 . The method of  claim 60 , wherein the step of providing comprises: shipping the article of manufacture to a pharmacy or to a site of health care delivery. 
   
   
       62 . A needle and syringe assembly, wherein the needle contains a sustained release formulation comprising a first therapeutic agent for an eye disorder and the syringe contains a second therapeutic agent for the eye disorder, wherein the second therapeutic agent is dissolved or suspended in a liquid medium. 
   
   
       63 . The needle and syringe assembly of  claim 62 , wherein the sustained release formulation comprises an ocular implant, plurality of particles, or gel-forming material. 
   
   
       64 . The needle and syringe assembly of  claim 62 , wherein the first therapeutic agent is a complement inhibitor or an angiogenesis inhibitor and the second therapeutic agent is a complement inhibitor or an angiogenesis inhibitor. 
   
   
       65 . The needle and syringe assembly of  claim 62 , wherein the first therapeutic agent is a complement inhibitor and the second therapeutic agent is an angiogenesis inhibitor.