Compositions and Methods for Effecting Controlled Posterior Vitreous Detachment
A composition comprises plasmin or an enzymatically equivalent derivative thereof and an inhibitor of at least an enzyme that is activatable, directly or indirectly, by plasmin or one of its enzymatically equivalent derivatives. The composition can be used to effect or induce a controlled posterior vitreous detachment (“PVD”) to prevent, treat, or ameliorate a potential complication of a pathological ocular condition. Such a composition can be administered intravitreally.
1 . A composition comprising: (a) plasmin or an enzymatically equivalent derivative thereof; and (b) at least an inhibitor of another enzyme, a pro-enzyme form of which is activatable, directly or indirectly, by said plasmin or said enzymatically equivalent derivative thereof.
2 . The composition of claim 1 , wherein said another enzyme comprises a matrix metalloproteinase (“MMP”).
3 . The composition of claim 2 , wherein said another enzyme is selected from the group consisting of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, MMP-14, MMP-15, combinations thereof, and mixtures thereof.
4 . The composition of claim 2 , wherein said inhibitor of said another enzyme is selected from the group consisting of tissue inhibitors of MMPs (“TIMPs”), synthetic molecules capable of binding to the zinc-binding domain of an MMP, hydroxamate derivatives, carboxylate derivatives, tetracycline derivatives, chelators of zinc, antibodies against an MMP, combinations thereof, and mixtures thereof.
5 . The composition of claim 2 , wherein the enzymatically equivalent derivative of plasmin is selected from the group consisting of microplasmin, miniplasmin, truncated forms of plasmin, variants of plasmin, combinations thereof, and mixtures thereof.
6 . The composition of claim 2 , wherein the composition further comprises a stabilizing agent for said plasmin or said enzymatically equivalent derivative thereof.
7 . The composition of claim 6 , wherein the stabilizing agent is selected from the group consisting of tranexamic acid, ε-aminocaproic acid, L-lysine, analogs of L-lysine, L-arginine, L-ornithine, γ-aminobutyric acid, glycylglycine, gelatin, human serum albumin (“HSA”), glycerin, combinations thereof, and mixtures thereof.
8 . The composition of claim 7 , wherein the L-lysine analogs are selected from the group consisting of L-2-amino-3-guanidinopropionic acid, L-citruline, D-citruline, 2,6-diaminoheptanoic acid, ε,ε-dimethyl-L-lysine, α-methyl-DL-ornithine, δ-benzyloxycarbonyl-L-ornithine, (N-d-4-methyltrityl)-L-ornithine, N-δ-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-D-ornithine, p-aminomethylbenzoic acid, and 2-aminoethylcysteine.
9 . The composition of claim 2 , wherein said inhibitor of said another enzyme is selected from the group consisting of hydroxamate derivatives, carboxylate derivatives, combinations thereof, and mixtures thereof.
10 . The composition of claim 2 , wherein said inhibitor of said another enzyme is selected from the group consisting of Barimastat, Marimastat, Solimstat, Prinomastat, Rebimastat, MMI-270, CGS27023, Ro32-3555, RS130,830, Tanomastat (BAY 12-9566), S-3304, Metastat, tetracycline derivatives, minocycline, doxycycline, combinations thereof, and mixtures thereof.
11 . The composition of claim 2 , wherein said inhibitor of said another enzyme is selected from the group consisting of ethylenediaminetetraacetic acid (“EDTA”), ditehylenetriaminepentaacetic acid (“DTPA”), combinations thereof, and mixtures thereof.
12 . A composition comprising: (a) plasmin or an enzymatically equivalent derivative thereof; and (b) at least an inhibitor of an MMP, a pro-enzyme form of said MMP being activatable, directly or indirectly, by said plasmin or said enzymatically equivalent derivative thereof, wherein said at least an inhibitor of an MMP is selected from the group consisting of TIMPs, synthetic molecules capable of binding to the zinc-binding domain of an MMP, chelators of zinc, antibodies against an MMP, hydroxamate derivatives, carboxylate derivatives, tetracycline derivatives, combinations thereof, and mixtures thereof.
13 . The composition of claim 12 , wherein a concentration of each of said plasmin, said enzymatically equivalent derivative of plasmin, and said inhibitor is in a range from about 10 −4 to about 5 weight percent.
14 . The composition of claim 13 , further comprising a stabilizing agent for plasmin or an enzymatically equivalent derivative thereof.
15 . A method for producing a composition for use in inducing a controlled posterior vitreous detachment (“PVD”), the method comprising:
(a) providing plasmin or an enzymatically equivalent derivative thereof; and
(b) adding said plasmin or enzymatically equivalent derivative thereof to an inhibitor of at least another enzyme, a latent form of which is activatable, directly or indirectly, by said plasmin or enzymatically equivalent derivative thereof.
16 . The method of claim 15 , wherein said plasmin or an enzymatically equivalent derivative thereof has been preserved at a pH less than about 5.
17 . The method of claim 15 , further comprising adding a stabilizing agent selected from the group consisting of tranexamic acid, ε-aminocaproic acid, L-lysine, analogs of L-lysine, L-arginine, L-ornithine, γ-aminobutyric acid, glycylglycine, gelatin, HSA, glycerin, combinations thereof, and mixtures thereof.
18 . The method of claim 15 , wherein said at least another enzyme is selected from the group of MMPs.
19 . The method of claim 15 , wherein said inhibitor of at least another enzyme is selected from the group consisting of TIMPs, synthetic molecules capable of binding to the zinc-binding domain of an MMP, hydroxamate derivatives, carboxylate derivatives, tetracycline derivatives, chelators of zinc, antibodies against an MMP, combinations thereof, and mixtures thereof.
20 . Use of plasmin or an enzymatically equivalent derivative thereof and an inhibitor of at least another enzyme, a latent form of which is activatable, directly or indirectly, by said plasmin or enzymatically equivalent derivative thereof, to produce a composition for inducing a controlled PVD in a subject in need therefor.
21 . The use of claim 20 , wherein said inhibitor of at least another enzyme is selected from the group consisting of TIMPs, synthetic molecules capable of binding to the zinc-binding domain of an MMP, hydroxamate derivatives, carboxylate derivatives, tetracycline derivatives, chelators of zinc, antibodies against an MMP, combinations thereof, and mixtures thereof.
22 . A method for inducing a controlled PVD in an eye of a patient, the method comprising:
(a) providing a composition that comprises plasmin or an enzymatically equivalent derivative thereof and an inhibitor of at least another enzyme, a latent form of which is activatable, directly or indirectly, by plasmin or by said enzymatically equivalent derivative thereof, said at least another enzyme being present in a normal vitreous; and
(b) administering said composition into the vitreous humor of the eye, thereby inducing said controlled PVD in said eye.
23 . The method of claim 22 , wherein said another enzyme comprises an MMP.
24 . The method of claim 22 , wherein said another enzyme is selected from the group consisting of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, MMP-14, MMP-15, combinations thereof, and mixtures thereof.
25 . The method of claim 22 , wherein said inhibitor of said another enzyme is selected from the group consisting of TIMPs, synthetic molecules capable of binding to the zinc-binding domain of an MMP, hydroxamate derivatives, carboxylate derivatives, tetracycline derivatives, chelators of zinc, antibodies against an MMP, combinations thereof, and mixtures thereof.
26 . The method of claim 22 , wherein said inhibitor of said another enzyme is selected from the group consisting of TIMPs, hydroxamate derivatives, carboxylate derivatives, tetracycline derivatives, antibodies against an MMP, combinations thereof, and mixtures thereof.
27 . The method of claim 22 , wherein said enzymatically equivalent derivative of plasmin is selected from the group consisting of microplasmin, miniplasmin, truncated forms of plasmin, combinations thereof, and mixtures thereof.
28 . The method of claim 22 , wherein the composition further comprises a stabilizing agent for said plasmin or said enzymatically equivalent derivative thereof.
29 . The method of claim 22 , wherein said plasmin or enzymatically equivalent derivative thereof has been preserved at a pH less than about 5.
30 . The method of claim 22 , wherein said controlled PVD is induced to prevent, treat, or ameliorate at least a potential complication of an ocular condition selected from the group consisting of vitreoretinal traction, diabetic retinopathy, retinal detachment, macular edema, macular hole, epiretinal membrane, macular pucker and retinal tears.
31 . The method of claim 22 , wherein said composition is administered in an amount sufficient to induce said controlled PVD.
32 . A kit for producing a composition useful for inducing a controlled PVD, the kit comprising:
(a) plasmin or an enzymatically equivalent derivative thereof disposed in a first container; and
(b) an inhibitor of at least another enzyme that is activatable, directly or indirectly, by plasmin or an enzymatically equivalent derivative thereof, disposed in a second container, wherein contents of said first and second containers are combined to produce said composition.
33 . The kit of claim 32 , wherein said another enzyme comprises a matrix metalloproteinase (“MMP”).
34 . The kit of claim 33 , wherein said another enzyme is selected from the group consisting of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, MMP-14, MMP-15, combinations thereof, and mixtures thereof.
35 . The kit of claim 33 , wherein said inhibitor of said another enzyme is selected from the group consisting of TIMPs, synthetic molecules capable of binding to the zinc-binding domain of an MMP, hydroxamate derivatives, carboxylate derivatives, tetracycline derivatives, chelators of zinc, antibodies against an MMP, combinations thereof, and mixtures thereof.
36 . The kit of claim 33 , wherein the enzymatically equivalent derivative of plasmin is selected from the group consisting of microplasmin, miniplasmin, truncated forms of plasmin, variants of plasmin, combinations thereof, and mixtures thereof.
37 . The kit of claim 33 , wherein said second container further contains a stabilizing agent for said plasmin or said enzymatically equivalent derivative thereof.