Pharmaceutical formulation comprising dinucleoside polyphosphates and salts thereof
View Patent ↗The present invention provides a method of treating edematous retinal disorders. The method comprises administration of a pharmaceutical formulation comprising a hydrolysis-resistant P2Y receptor agonist to stimulate the removal of pathological extraneous fluid from the subretinal and retinal spaces and thereby reduce the accumulation of said fluid associated with retinal detachment and retinal edema. The P2Y receptor agonist can be administered with therapeutic and adjuvant agents commonly used to treat edematous retinal disorders. The pharmaceutical formulation useful in this invention comprises a P2Y receptor agonist with enhanced resistance to extracellular hydrolysis, such as dinucleoside polyphosphate compounds, or hydrolysis-resistant mononucleoside triphosphate salts. The present invention also provides P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-)tetraphosphate, tetra-(alkali metal) salts such as tetrasodium, tetralithium, tetrapotassium, and mixed (tetra-alkali metal) salts. The present further provides a pharmaceutical formulation comprising a P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-)tetraphosphate, tetra-(alkali metal) salt, in a pharmaceutically acceptable carrier.
1. P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-)tetraphosphate, tetra-(alkali metal) salt, wherein the tetra-(alkali metal) cations of said salt are selected from the group consisting of: tetrasodium, tetralithium, tetrapotassium, monosodium/tripotassium, disodium/dipotassium, trisodium/monopotassium, monopotassium/trilithium, dipotassium/dilithium, tripotassium/monolithium, monosodium/trilithium, disodium/dilithium, trisodium/monolithium, monosodium/monolithium/dipotassium, monosodium/dilithium/monopotassium and disodium/monolithium/monopotassium.
2. A pharmaceutical formulation comprising P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-) tetraphosphate, tetra-(alkali metal) salt, in a pharmaceutically acceptable carrier, wherein the tetra-(alkali metal) cations of said salt are selected from the group consisting of: tetrasodium, tetralithium, tetrapotassium, monosodium/tripotassium, disodiuni/dipotassium, trisodium/monopotassium, monopotassium/trilithium, dipotassium/dilithium, tripotassium/monolithium, monosodium/trilithium, disodium/dilithium, trisodium/monolithium, monosodium/monolithium/dipotassium, monosodium/dilithium/monopotassium and disodium/monolithium/monopotassium; and mixtures thereof.
3. The pharmaceutical formulation according to claim 2 , in the form of an aqueous, a gel, a gel-like, a two-phase suspension, or a solid formulation.
4. The pharmaceutical formulation according to claim 3 , wherein the pharmaceutical formulation is in the form of an aqueous solution and comprises physiologically safe excipients formulated to osmolarity between 250 –350 mOsm and pH 5–9.
5. The pharmaceutical formulation according to claim 2 , wherein the pharmaceutical formulation is sterile.
6. The pharmaceutical formulation according to claim 2 , wherein the pharmaceutical formulation comprises P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-) tetraphosphate, tetra-(alkali metal) salt, in the amount of 0.1–10% by weight.
7. The pharmaceutical formulation according to claim 6 , wherein the pharmaceutical formulation comprises P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-) tetraphosphate, tetra-(alkali metal) salt, in the amount of 0.2–8% by weight.
8. The pharmaceutical formulation according to claim 7 , wherein the pharmaceutical formulation comprises P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-) tetraphosphate, tetra-(alkali metal) salt, in the amount of 0.5–5% by weight.
9. The pharmaceutical formulation according to claim 2 , wherein said pharmaceutical formulation further comprises an intraocular irrigation solution approved for surgical use.
10. The pharmaceutical formulation according to claim 3 , wherein said gel or gel-like formulation comprises hyaluronic acid or hyaluronic acid-containing formulations approved for intraocular surgical use.
11. The pharmaceutical formulation according to claim 3 , wherein said solid formulation is selected from the group consisting of: lyophilized powder, liposome and biodegradable polymer.
12. The pharmaceutical formulation according to claim 2 , wherein said pharmaceutically acceptable carrier is a physiologically compatible vehicle selected from the group consisting of: aqueous electrolyte solutions, polyethers, polyvinyls, polymers of acrylic acid, lanolin, and glucosaminoglycans.
13. A pharmaceutical formulation comprising P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-) tetraphosphate, tetra-ammonium salt or tetra(quaternary ammonium) salt, in a pharmaceutically acceptable carrier.
14. The pharmaceutical formulation according to claim 13 , wherein said quaternary ammonium salt is tetraalkylammonium salt, trialkylphenylammonium salt, dialkyldiarylammonium salt, or trialkylbenzylammonium salt.
15. The pharmaceutical formulation according to claim 13 , in the form of an aqueous, a gel, a gel-like, a two-phase suspension, or a solid formulation.
16. The pharmaceutical formulation according to claim 15 , wherein the pharmaceutical formulation is in the form of an aqueous solution and comprises physiologically safe excipients formulated to osmolarity between 250 –350 mOsm and pH 5–9.
17. The pharmaceutical formulation according to claim 13 , wherein the pharmaceutical formulation is sterile.
18. The pharmaceutical formulation according to claim 13 , wherein the pharmaceutical formulation comprises P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-) tetraphosphate, tetra-ammonium salt or tetra(quaternary ammonium) salt, in the amount of 0.1–10% by weight.
19. The pharmaceutical formulation according to claim 15 , wherein said solid formulation is selected from the group consisting of: lyophilized powder, liposome and biodegradable polymer.
20. The pharmaceutical formulation according to claim 13 , wherein said pharmaceutically acceptable carrier is a physiologically compatible vehicle selected from the group consisting of: aqueous electrolyte solutions, polyethers, polyvinyls, polymers of acrylic acid, lanolin, and glucosaminoglycans.
21. The P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-) tetraphosphate, tetra-(alkali metal) salt according to claim 1 , wherein the tetra-(alkali metal) cations are tetrasodium.
22. The P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-) tetraphosphate, tetra-(alkali metal) salt according to claim 1 , wherein the tetra-(alkali metal) cations are tetralithium or tetrapotassium.
23. The P 1 -(2′-deoxycytidine 5′-)P 4 -(uridine 5′-) tetraphosphate, tetra-(alkali metal) salt according to claim 1 , wherein the tetra-(alkali metal) cations are selected from the group consisting of: monosodium/tripotassium, disodium/dipotassium, trisodium/monopotassium, monopotassium/trilithium, dipotassium/dilithium, tripotassium/monolithium, monosodium/trilithium, disodium/dilithium, trisodium/monolithium, monosodium/monolithium/dipotassium, monosodium/dilithium/monopotassium and disodium/monolithium/monopotassium.
24. The pharmaceutical formulation according to claim 2 , wherein the tetra-(alkali metal) cations of said salt are tetrasodium.
25. The pharmaceutical formulation according to claim 2 , wherein the tetra-(alkali metal) cations of said salt are tetralithium or tetrapotassium.
26. The pharmaceutical formulation according to claim 2 , wherein the tetra-(alkali metal) cations of said salt are selected from the group consisting of: monosodium/tripotassium, disodium/dipotassium, trisodium/monopotassium, monopotassium/trilithium, dipotassium/dilithium, tripotassium/monolithium, monosodium/trilithium, disodium/dilithium, trisodium/monolithium, monosodium/monolithium/dipotassium, monosodium/dilithium/monopotassium and disodium/monolithium/monopotassium; and mixtures thereof.
27. The pharmaceutical formulation according to claim 24 , in the form of an aqueous, a gel, a gel-like, a two-phase suspension, or a solid formulation.
28. The pharmaceutical formulation according to claim 27 , wherein the pharmaceutical formulation is in the form of an aqueous solution and comprises physiologically safe excipients formulated to osmolarity between 250 –350 mOsm and pH 5–9.
29. The pharmaceutical formulation according to claim 25 , in the form of an aqueous, a gel, a gel-like, a two-phase suspension, or a solid formulation.
30. The pharmaceutical formulation according to claim 29 , wherein the pharmaceutical formulation is in the form of an aqueous solution and comprises physiologically safe excipients formulated to osmolarity between 250 –350 mOsm and pH 5–9.
31. The pharmaceutical formulation according to claim 26 , in the form of an aqueous, a gel, a gel-like, a two-phase suspension, or a solid formulation.
32. The pharmaceutical formulation according to claim 31 , wherein the pharmaceutical formulation is in the form of an aqueous solution and comprises physiologically safe excipients formulated to osmolarity between 250 –350 mOsm and pH 5–9.