Ocular Compositions and Methods Thereof

Abstract

Methods and pharmaceutical compositions (or delivering a therapeutic agent, treating a neovascularization disorder, and treating an ocular infection include make use of a compound that includes an clastin-likc polypeptide (ELP) coupled to a therapeutic agent, wherein the ELP comprises at least one repeat of the amino acid sequence VPGXG (SEQ ID NO: 1), and where the composition is suitable for ocular administration.

1 . A method of delivering a therapeutic agent to an eye, comprising: administering to the eye of a subject an effective amount of a compound that comprises an elastin-like polypeptide (ELP) coupled to a therapeutic agent, wherein the ELP comprises at least one repeat of the amino acid sequence VPGXG (SEQ ID NO: 1). 
     
     
         2 . The method of  claim 1 , wherein administration comprises one or more of topical administration, subconjunctival administration, and intraocular injection. 
     
     
         3 . The method of  claim 1 , wherein a size of the ELP is configured to permit ocular penetration of the compound. 
     
     
         4 . The method of  claim 3 , wherein the ELP comprises about 5 to about 300 VPGXG sequences. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the X amino acid is hydrophilic to permit stability of the compound in the ocular environment. 
     
     
         9 . The method of  claim 8 , wherein X is selected from a mixture of Val, Ala, and Gly in a 1:8:7 ratio (SEQ ID NO:2), a mixture of Val, Ala, and Gly in a 1:4:3 ratio (SEQ ID NO:3), Gly (SEQ ID NO: 4), Ser (SEQ ID NO: 5), or His (SEQ ID NO:6). 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein X is hydrophobic to permit corneal penetration of the compound. 
     
     
         15 . The method of  claim 14 , wherein X is selected from Val (SEQ ID NO:7), Leu (SEQ ID NO: 8), or Ile (SEQ ID NO:9). 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the compound further comprises a cell-penetrating peptide (CPP) coupled to the ELP. 
     
     
         19 . The method of  claim 18 , wherein the cell-penetrating peptide is selected from penetratin, Tat, SynB1, Bac, polyArg, MTS, Transportan, and pVEC. 
     
     
         20 . The method of  claim 1 , wherein the compound further comprises an attachment site configured to couple to a therapeutic agent. 
     
     
         21 . The method of  claim 20 , wherein the attachment site comprises one or more Cys or Lys residues at a N-terminus, a C-terminus, or an interior of the compound. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein the compound forms a hydrogel after topical application or intraocular injection. 
     
     
         24 . The method of  claim 23 , wherein the compound has a phase transition below the ocular temperature, and wherein ocular injection or application induces phase transfer and hydrogel formation. 
     
     
         25 . The method of  claim 23 , wherein the hydrogel formation increases ocular residence time and bioavailability of the therapeutic. 
     
     
         26 . The method of  claim 1 , wherein the therapeutic agent is linked to the ELP carrier with a cleavable linker to allow release of the therapeutic agent intraocularly. 
     
     
         27 . The method of  claim 1 , wherein the administering of the compound further comprises treating a disorder in the subject. 
     
     
         28 . The method of  claim 27 , wherein the therapeutic agent is a VEGF antagonist. 
     
     
         29 . The method of  claim 27 , wherein the therapeutic agent is a member of the sFlt-1 family, a portion of the sFlt-1 protein (SEQ ID NO:10), or a combination thereof. 
     
     
         30 . The method of  claim 27 , herein the therapeutic agent is sFlt-1 Ig-like domains 1, 2, and 3 (SEQ ID NO:11). 
     
     
         31 . The method of  claim 27 , wherein the therapeutic agent is sFlt-1 Ig-like domains 2 and 3 (SEQ ID NO:12). 
     
     
         32 . The method of  claim 27 , wherein the therapeutic agent is PEDF (SEQ ID NO:13). 
     
     
         33 . The method of  claim 28 , wherein the therapeutic agent is an anti-inflammatory drug, an anti-inflammatory peptide, or a combination thereof. 
     
     
         34 . The method of  claim 27 , further comprising a cell-penetrating peptide. 
     
     
         35 . The method of  claim 34 , wherein the cell penetrating peptide is selected from penetratin, Tat, SynB1, Bac, polyArg, MTS, Transportan, POD, and pVEC. 
     
     
         36 . The method of  claim 27 , wherein the disorder is selected from the group consisting of an ocular infection and a neovascularization disorder. 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . A composition, comprising:
 a compound that comprises an elastin-like polypeptide (ELP) coupled to a therapeutic agent, wherein the ELP comprises at least one repeat of the amino acid sequence VPGXG (SEQ ID NO: 1).   
     
     
         44 . The composition of  claim 43 , wherein the composition is eye drops, an ointment, or a combination thereof. 
     
     
         45 . The composition of  claim 43 , further comprising at least one thickening agent selected from a group consisting of polyvinyl alcohol, polyethylene glycol, methyl cellulose, and carboxymethyl cellulose. 
     
     
         46 . The composition of  claim 43 , further comprising an agent modulating tonicity, wherein the agent is boric acid or sodium phosphate buffer. 
     
     
         47 . The composition of  claim 43 , further comprising at least one surfactant to increase corneal penetration, wherein the at least one surfactant is selected from a group consisting of benzalkonium chloride, polysorbate 20, polysorbate 80, and dioctyl sodium sulpho succinate. 
     
     
         48 . The composition of  claim 43 , further comprising a buffering agent to adjust the pH of the solution. 
     
     
         49 . The composition of  claim 43 , wherein the ELP comprises about 5 to about 300 VPGXG sequences. 
     
     
         50 . The composition of  claim 43 , wherein the X amino acid is hydrophilic, hydrophobic, or a combination thereof. 
     
     
         51 . The composition of  claim 43 , wherein X is at least one selecting from Val, Ala, or Gly in a 1:8:7 ratio (SEQ ID NO:2), Val, Ala, or Gly in a 1:4:3 ratio (SEQ ID NO:3), Gly (SEQ ID NO:4), Ser (SEQ ID NO:5), His (SEQ ID NO:6), Val (SEQ ID NO:7), Leu (SEQ ID NO:8), Ile (SEQ ID NO:9), and a combination thereof. 
     
     
         52 . The composition of  claim 43 , wherein the compound further comprises a cell-penetrating peptide (CPP) coupled to the ELP. 
     
     
         53 . The composition of  claim 52 , herein the cell-penetrating peptide is selected from penetratin, Tat, SynB1, Bac, polyArg, MTS, Transportan, POD, and pVEC. 
     
     
         54 . The composition of  claim 43 , wherein the compound further comprises an attachment site configured to couple to a therapeutic agent. 
     
     
         55 . The composition of  claim 54 , wherein the attachment site comprises one or more Cys residues, one or more Lys residues, or a combination thereof. 
     
     
         56 . The composition of  claim 43 , wherein the therapeutic agent is at least one selected from a group consisting of a VEGF antagonist, a member of the sFlt-1 family, a portion of the sFlt-1 protein (SEQ ID NO:10), sFlt-1 Ig-like domains 1, 2, 3 (SEQ ID NO:11), PEDF (SEQ ID NO:13), an anti-inflammatory drug and/or peptide, a BLP-1 peptide (SEQ ID NO:14), a parasin-1 peptide (SEQ ID NO:15), a magainin-2 peptide (SEQ ID NO:16), and a ranalexin peptide (SEQ ID NO:17). 
     
     
         57 . The composition of  claim 43 , wherein the ELP comprises at least about 5 repeats of the amino acid sequence VPGXG (SEQ ID NO: 1). 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . (canceled) 
     
     
         63 . (canceled) 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . The composition of  claim 43 , further comprising a pharmaceutically acceptable carrier for topical delivery to an eye.