Hydrogel formulation for dermal and ocular delivery

Abstract

Formulations of cross-linkable polymers, capable of forming non-toxic and biocompatible hydrogels in situ, containing at least one of doxycycline or minocycline. Methods of using the hydrogels for treating the skin or ocular tissues of mammals exposed to vesicant compounds such as sulfur mustard (SM), nitrogen mustard (NM) or half mustard (2-chloroethyl ethyl sulfide (CEES)) are also disclosed.

1 . A formulation comprising a cross-linkable polymer capable of forming a non-toxic and biocompatible hydrogel in situ and at least one of doxycycline or minocycline. 
     
     
         2 . The formulation of  claim 1  adapted for ocular or topical administration to a mammal. 
     
     
         3 . The formulation of  claim 1 , wherein, upon administration to a mammal, said cross-linkable polymer forms a hydrogel having said at least one of doxycycline or minocycline entrapped in the hydrogel. 
     
     
         4 . The formulation of  claim 1 , wherein said cross-linkable polymer is a linear or branched PEG. 
     
     
         5 . The formulation of  claim 1 , wherein said polymer is derivatized with —SH, —NH 2 , —COOH, or any combination thereof. 
     
     
         6 . The formulation of  claim 1 , further comprising a cross-linker, wherein the ratio of polymer to the cross-linker is from about 0.05:10 to about 10:0.05. 
     
     
         7 . The formulation of  claim 6 , wherein said ratio is between 1:1 and 1:2. 
     
     
         8 . The formulation of  claim 4 , wherein said PEG is a linear or multi-arm having from 2 to 8 arms, has a molecular weight of 1000-100,000 Da, and is derivatized with multiple thiol groups. 
     
     
         9 . The formulation of  claim 8 , wherein the cross-linker is selected from the group consisting of TP, NHS, vinylsulfone, maleimide, BM[PEO] 3  (1,8-bis-maleimido-triethylene-glycol), BM[PEO] 4  (1,11-bis-maleimidotriethyleneglycol), BMH (bis-maleimido-hexane) or BMOE (bis-maleimidoethane) and combinations thereof. 
     
     
         10 . The formulation of  claim 1 , further comprising an oxidizing agent, and wherein said polymer is self-cross-linkable. 
     
     
         11 . The formulation of  claim 10 , wherein said oxidizing agent is hydrogen peroxide. 
     
     
         12 . The formulation of  claim 1 , wherein the concentration of said at least one of doxycycline or minocycline is 0.1-12% (w/v). 
     
     
         13 . The formulation of  claim 1 , wherein the at least one of doxycycline or minocycline is unmodified. 
     
     
         14 . The formulation of  claim 1 , wherein the at least one of doxycycline or minocycline is coupled to the polymer through degradable bonds. 
     
     
         15 . The formulation of  claim 14 , wherein said degradable bonds are enzyme-sensitive peptide linker bonds, self-immolative linker bonds, acid and base-sensitive linker bonds, pH sensitive linker bonds, multifunctional organic linking agent bonds, multifunctional inorganic crosslinking agent bonds or peptidic backbone bonds. 
     
     
         16 . The formulation of  claim 15 , wherein said peptide backbone bonds contain a sequence CH 3 CO—(X—Z—Z) x —(Y—Z—Z) y —CONH 2 , where X=Lys, Glu, Asp or diaminobutyric acid; Y=Cys, homocysteine or 1-amino-2-methyl-2-propanethiol; Z=β-Ala, Gly, Ala, or GABA (gamma-amino butyric acid); x and y are interchangeable; x is between 1 to 4; y is between 1 to 4; minimum number of Z-spacer on the peptide backbone=2; maximum number of Z-spacer on the peptide backbone=4. 
     
     
         17 . The formulation of  claim 15 , wherein said peptide linker bonds comprise at least one of Leu-Gly, Glu(Leu-Gly) 2 , Arg-Gly-Asp, Arg-Gly-Asp-Cys, Gly-Arg-Gly-Asp-Ser, Gly-Arg-Gly-Asp-Ser-Pro, or cyclic Arg-Gly-Asp-Tyr-Lys. 
     
     
         18 . The formulation of  claim 1 , wherein the at least one of doxycycline or minocycline is bound to a targeting moiety. 
     
     
         19 . The formulation of  claim 18 , wherein the targeting moiety is a peptide. 
     
     
         20 . The formulation of  claim 19 , wherein said peptide is selected from the group consisting of an RGD peptide, EGF peptide, DV3 (LGASWHRPDKC) peptide, a LYP peptide (CGNKRTRGC), membrane-binding domain of IGFBP3 (QCRPSKGRKRGFCW), fMLF, mannose, transferrin ligand, and monoclonal antibodies. 
     
     
         21 . A method of treating the skin or eyes of a mammal exposed to a vesicant compound comprising administering to said exposed skin or eyes of said mammal a formulation according to  claim 1 . 
     
     
         22 . The method of  claim 21 , wherein said vesicant compound is selected from the group consisting of sulfur mustard (SM), nitrogen mustard (NM) and half mustard (2-chloroethyl ethyl sulfide (CEES)). 
     
     
         23 . The method of  claim 21 , wherein said formulation administered in a form of an ocular formulation to an eye of said mammal. 
     
     
         24 . The method of  claim 23 , wherein said ocular formulation is fabricated as a contact lens. 
     
     
         25 . The method of  claim 21 , wherein said formulation is administered in a form of a topical formulation to a portion of said mammal skin exposed to said vesicant compound. 
     
     
         26 . A contact lens fabricated from a hydrogel formulation according to  claim 1 . 
     
     
         27 . A hydrogel contact lens comprising at least one of doxycycline or minocycline in an amount effective for the controlled and sustained delivery of said doxycycline or minocycline to the surface of the eye from said hydrogel. 
     
     
         28 . (canceled)