US2019000983A1PendingUtilityA1

An eye drop solution for enhanced hyaluronic acid retention and delivery

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Assignee: UNIV JOHNS HOPKINSPriority: Aug 20, 2015Filed: Aug 17, 2016Published: Jan 3, 2019
Est. expiryAug 20, 2035(~9 yrs left)· nominal 20-yr term from priority
Inventors:Anirudha SinghJennifer H. ElisseeffDavid LeeNicole Minhui Lu
H10P 72/0442H10P 72/0428H10W 72/0711H10W 72/00H10W 72/07178H10W 72/07173A61P 27/04A61K 31/728A61K 47/60A61K 38/08
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Claims

Abstract

The present invention provides biomaterial compositions that can immobilize HA to the ocular surfaces through an HABpep and transmembrane mucins and collagen of ocular tissues can act as anchoring sites. These biomaterial compositions provide prolonged HA binding and retention in both ex vivo and in vivo animal models. HA eye drop solutions with these the inventive biomaterials can prolong the biological and physical benefits to the ocular surface and potentially be more effective in treating eye disorders including dry eye than standard HA-eye drop presently available. Methods of making and use of the compositions are also provided.

Claims

exact text as granted — not AI-modified
1 . A biomaterial comprising at least one biologically compatible polymer having one or more HA binding peptides (HABPep) covalently linked to the biologically compatible polymer, and one or more sialic acid binding peptides (SABPep) covalently linked to the biologically compatible polymer. 
     
     
         2 . (canceled) 
     
     
         3 . A biomaterial comprising at least one biologically compatible polymer having one or more HA binding peptides (HABPep) covalently linked to the biologically compatible polymer, and one or more sialic acid binding peptides (SABPep) and one or more collagen binding peptides (ColBPep) covalently linked to the biologically compatible polymer. 
     
     
         4 . The biomaterial of  claim 1 , wherein HA is mixed into the biologically compatible polymer. 
     
     
         5 . The biomaterial of  claim 1 , further comprising HA bound to the HABPep. 
     
     
         6 . The biomaterial of  claim 5 , wherein the HA has a molecular weight of between 5000 Da and 20,000,000 Da. 
     
     
         7 . The biomaterial of  claim 6 , wherein the HA is crosslinked. 
     
     
         8 . The biomaterial of  claim 1 , wherein the HABPep is a peptide comprising the following amino acid sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                     
                   RRDDGAHWQFNALTVR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 2) 
                 
                     
                   CRRDDGAHWQFNALTVR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 3) 
                 
                     
                   GAAWQFNALTVR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 4) 
                 
                     
                   GAHWQFAALTVR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   GAHWQFNALTVA, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   GAHWQFNALTVR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   STMMSRSHKTRSHHV, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 8) 
                 
                     
                   RYPISRPRKRC, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 9) 
                 
                     
                   TAGHGRRWS, 
                 
                     
                   or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 10) 
                 
                     
                   LKQKIKHVVKLKVVVKLRSQLVKRKQN. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         9 . The biomaterial of  claim 1 , wherein the ColBpep is selected from the group consisting of RRANAALKAGELYKSILYGC (SEQ ID NO: 11), SYIRIADTNIT (SEQ ID NO: 12), YSFYSDESLQ (SEQ ID NO: 13) and WYRGRL (SEQ ID NO: 14). 
     
     
         10 . The biomaterial of  claim 1 , wherein the SABpep is selected from the group consisting of GGSPYGRC (SEQ ID NO: 15), and GGPQEQITQHGSPYGRC (SEQ ID NO: 16). 
     
     
         11 . The biomaterial of  claim 1 , wherein the biocompatible polymer is hydrophilic. 
     
     
         12 . The biomaterial of  claim 11 , wherein the biocompatible polymer is selected from the group consisting of: Poly(ethylene glycol), Poly(propylene glycol), Poly(methyl vinyl ether), Oligoethylene, Poly(isobutylene) Poly(tetrahydrofuran) Poly(oxytrimethylene), Poly(dimethylsiloxsane), Poly(dimethylsilane), Nylon 6, Nylon 11, Poly(acrylonitrile), Squalane, Poly(1,3-dioxolane), Poly(iminooligomethylene), Poly(l-lysine), Polyethyleneimine, Poly(adipate), Poly(l-caprolactone), Poly(L-lactic acid), or derivatives thereof. 
     
     
         13 . The biomaterial of  claim 11 , wherein the one or more biocompatible polymers are mono, disubstituted, or multisubstituted with at least one functional group. 
     
     
         14 . The biomaterial of  claim 1 , comprising SABpep linked to Poly(ethylene glycol) linked to HABpep (SABpep-PEG-HABpep). 
     
     
         15 . The biomaterial of  claim 1 , comprising ColBpep linked to Poly(ethylene glycol) linked to HABpep (ColBpep-PEG-HABpep). 
     
     
         16 . A biomaterial comprising at least one biologically compatible polymer having HA conjugated to a linker molecule covalently linked to the biologically compatible polymer, and one or more sialic acid binding peptides (SABPep) covalently linked to the biologically compatible polymer. 
     
     
         17 . The biomaterial of  claim 16 , wherein HA is mixed into the biologically compatible polymer. 
     
     
         18 . The biomaterial of  claim 16 , wherein HA is conjugated to a linker molecule and conjugated to a detectable moiety which is one or more sialic acid binding peptides (SABPep) covalently linked to the biologically compatible polymer. 
     
     
         19 . The biomaterial of  claim 18 , wherein the detectable moiety is selected from the group consisting of: radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, electron-dense reagents, enzymes, biotin, digoxigenin, or haptens. 
     
     
         20 . The biomaterial of  claim 19 , wherein the detectable moiety is fluorescein. 
     
     
         21 . A pharmaceutical composition comprising the biomaterial of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the pharmaceutically acceptable carrier is suitable for ophthalmic use. 
     
     
         23 . The pharmaceutical composition of either of  claim 22 , further comprising an additional therapeutic agent. 
     
     
         24 . A method for treatment of a disease or condition of the eye of a subject in need of treatment, comprising administering to the subject an effective amount of the biomaterial composition of  claim 1 , or the pharmaceutical composition of  claim 21 . 
     
     
         25 . The method of  claim 24 , wherein the disease or condition is Dry Eye. 
     
     
         26 . A method for treating eye diseases by means of an eye surgery treatment in a subject in need of treatment comprising administering to the subject an effective amount of the biomaterial composition of  claim 1  or the pharmaceutical composition of  claim 21 . 
     
     
         27 . The method of  claim 26 , wherein the surgery treatment is selected from the group consisting of corneal transplantation, cataract surgery, glaucoma surgery, and surgery to repair retinal detachment. 
     
     
         28 . The biomaterial of  claim 3  wherein HA is mixed into the biologically compatible polymer. 
     
     
         29 . The biomaterial of  claim 3 , further comprising HA bound to the HABPep. 
     
     
         30 . The biomaterial of  claim 29 , wherein the HA has a molecular weight of between 5000 Da and 20,000,000 Da. 
     
     
         31 . The biomaterial of  claim 30 , wherein the HA is crosslinked. 
     
     
         32 . The biomaterial of  claim 3 , wherein the HABPep is a peptide comprising the following amino acid sequence: RRDDGAHWQFNALTVR (SEQ ID NO: 1), CRRDDGAHWQFNALTVR (SEQ ID NO: 2), GAAWQFNALTVR (SEQ ID NO: 3), GAHWQFAALTVR (SEQ ID NO: 4), GAHWQFNALTVA (SEQ ID NO: 5), GAHWQFNALTVR (SEQ ID NO: 6), STMMSRSHKTRSHHV (SEQ ID NO: 7), RYPISRPRKRC (SEQ ID NO: 8), TAGHGRRWS (SEQ ID NO: 9), or LKQKIKHVVKLKVVVKLRSQLVKRKQN (SEQ ID NO: 10). 
     
     
         33 . The biomaterial of  claim 3 , wherein the ColBpep is selected from the group consisting of RRANAALKAGELYKSILYGC (SEQ ID NO: 11), SYIRIADTNIT (SEQ ID NO: 12), YSFYSDESLQ (SEQ ID NO: 13) and WYRGRL (SEQ ID NO: 14). 
     
     
         34 . The biomaterial of  claim 3 , wherein the SABpep is selected from the group consisting of GGSPYGRC (SEQ ID NO: 15), and GGPQEQITQHGSPYGRC (SEQ ID NO: 16). 
     
     
         35 . The biomaterial of  claim 3 , wherein the biocompatible polymer is hydrophilic. 
     
     
         36 . The biomaterial of  claim 35 , wherein the biocompatible polymer is selected from the group consisting of: Poly(ethylene glycol), Poly(propylene glycol), Poly(methyl vinyl ether), Oligoethylene, Poly(isobutylene) Poly(tetrahydrofuran) Poly(oxytrimethylene), Poly(dimethylsiloxsane), Poly(dimethylsilane), Nylon 6, Nylon 11, Poly(acrylonitrile), Squalane, Poly(1,3-dioxolane), Poly(iminooligomethylene), Poly(l-lysine), Polyethyleneimine, Poly(adipate), Poly(l-caprolactone), Poly(L-lactic acid), or derivatives thereof. 
     
     
         37 . The biomaterial of  claim 35 , wherein the one or more biocompatible polymers are mono, disubstituted, or multisubstituted with at least one functional group.

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