A formulation for the treatment of ophthalmic diseases containing a chelating agent, a penetration enhancer, and hydroxyethylcellulose.

Abstract

To provide an ophthalmic formulation that reduces discomfort associated with chelating agents / transport promoters and enhances their effects. [Solution] An ophthalmic formulation is provided comprising a chelating agent (e.g., EDTA and its salts), a transport promoter (e.g., methylsulfonylmethane; MSM), and an effective amount of a viscoelastic polymer (e.g., hydroxymethylcellulose; HEC). The chelating agent and the transport promoter are present in an effective proportion to result in a significant reduction of polymer aggregation in the eye to which they are applied, with the percentage of the chelating agent being about 0.1% to 15% by weight and the percentage of the transport promoter being about 0.1% to 40% by weight in the composition.

Claims

1. An ophthalmic preparation for the treatment of adverse eye conditions, (a) Chelating agents or their salts; (b) Transport promoters that are charge masking agents; (c) A concentration of a viscoelastic material thickener sufficient to reduce side effects and improve efficacy; and (d) Pharmacologically acceptable inactive vehicle It is a formulation containing, The chelating agents and transport promoters are present in effective proportions to result in a significant reduction in polymer aggregation in the eye to which they are applied. The percentage of the chelating agent in the composition is approximately 0.1% to 15% by weight, and the percentage of the transport is approximately 0.1% to 40% by weight. formulation.

2. The formulation according to claim 1, wherein the transport promoter is MSM.

3. The formulation according to claim 1, wherein the amount of MSM is less than 5%.

4. The formulation according to claim 2, wherein the ratio of chelating agent to MSM is in the range of approximately 10:1 to 1:

20.

5. The formulation according to claim 1, wherein the viscoelastic polymer is selected from hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethylcellulose (HEC), and polyvinyl alcohol.

6. The formulation according to claim 1, wherein the viscoelastic polymer is hydroxyethylcellulose (HEC).

7. The formulation according to claim 6, wherein the concentration of HEC is 0.5% to 5.0%.

8. The formulation according to claim 6, wherein the concentration of HEC is 0.5% to 1.0%.

9. The formulation according to claim 6, wherein the concentration of HEC is 0.8% to 0.85%.

10. The formulation according to claim 1, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ArPA), citric acid, acetic acid and acceptable salts thereof, and combinations thereof.

11. The formulation according to claim 10, wherein the EDTA salt is selected from EDTA diammonium, EDTA disodium, EDTA dipotassium, EDTA triammonium, EDTA trisodium, EDTA tripotassium, EDTA tetrasodium, EDTA tetrapotassium, EDTA disodium calcium, and combinations thereof.

12. The formulation according to claim 1, wherein the chelating agent is selected from phosphates, pyrophosphates, tripolyphosphates, and hexametaphosphates.

13. The formulation according to claim 1, wherein the chelating agent is a chelating antibiotic, chloroquine, or tetracycline.

14. The formulation according to claim 1, wherein the chelating agent is a nitrogen-containing chelating agent containing two or more chelated nitrogen atoms in the imino group or aromatic ring, diimine, or 2,2'-bipyridine.

15. The chelating agent is cyclo(1,4,7,11-tetraazacyclotetradecane), N-(C 1 ~C 30 Alkyl)-substituted cyclamates (e.g., hexadecyclam, tetramethylhexadecylcyclam), diethylenetriamine (DETA), spermine, diethylnorspermine (DENSPM), diethylhomospermine (DEHOP), deferoxamine (N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide, or N'-[5-(acetyl-hydroxy-amino)pentyl] The formulation according to claim 1, wherein the polyamine is selected from [(5-aminopentyl-hydroxycarbamoyl)propanoylamino]pentyl]-N-hydroxybutanediamide), desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB, desferal, deferipron, pyridoxal isonicotinoylhydrazone (PIH), salicylaldehyde isonicotinoylhydrazone (SIH), and ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol).

16. The chelating agents are ([2-(bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([4-(bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-( The formulation according to claim 1, which is an EDTA-4-aminoquinoline conjugate selected from bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloroquinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([2-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloroquinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, ([3-(bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloroquinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate, and ([4-(bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloroquinoline-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-ethyl acetate.

17. The formulation according to claim 1, wherein the chelating agent is a natural chelating agent selected from citric acid, phytic acid, lactic acid, acetic acid and their salts, and curcumin.

18. The formulation according to claim 1, wherein the vehicle is aqueous.

19. The formulation according to claim 1, wherein administration of the formulation reduces polymer aggregates in the eye.

20. The formulation according to claim 19, wherein the polymer aggregate is a peptidyl compound.

21. The formulation according to claim 19, wherein the polymer aggregate is a protein.

22. The formulation according to claim 19, wherein the polymer aggregate is a lipoprotein.

23. The formulation according to claim 1, wherein the formulation includes an ocular implant.

24. The formulation according to claim 1, wherein the formulation is for timed release.

25. polymer aggregates The formulation according to claim 19.

26. The formulation according to claim 1, wherein the formulation comprises 2.7% w / w MSM; 1.3% w / w EDTA disodium; and 0.85% w / w HEC.

27. A method for reducing the signs of adverse ocular syndrome by administering the formulation according to claim 1 to the eye of a subject requiring reduction of the signs of adverse ocular syndrome.

28. The method according to claim 27, wherein the harmful eye condition is the accumulation of polymer aggregates in the eye.

29. The method according to claim 27, wherein the formulation comprises a chelating agent and a penetration enhancer in an amount such that it is effective in the presence of a viscoelastic polymer to the extent that it is effective in the presence of a viscoelastic polymer compared to its effectiveness in the absence of the viscoelastic polymer.

30. The method according to claim 27, wherein the formulation comprises MSM, MSM and HEC as a viscoelastic polymer as a penetration enhancer.

31. The method according to claim 30, wherein the formulation used comprises MSM 2.7% w / w; EDTA disodium 1.3% w / w; and HEC 0.85% w / w.

32. The method according to claim 27, wherein the formulation comprises a chelating agent, a penetration enhancer, and a viscoelastic polymer in an amount that significantly reduces the stinging sensation in the eye of a target body in the presence of a viscoelastic polymer compared to the stinging sensation in the absence of the viscoelastic polymer.

33. The method according to claim 27, wherein the formulation comprises MSM, MSM and HEC as a viscoelastic polymer as a penetration enhancer.

34. The method according to claim 30, wherein the formulation used comprises MSM 2.7% w / w; EDTA disodium 1.3% w / w; and HEC 0.85% w / w.

35. A formulation for treating harmful eye conditions while reducing the sensation of stinging pain in the target body, (a) Chelating agents or their salts; (b) A charge masking agent which is methylsulfonylmethane (MSM); (c) A thickening agent which is hydroxyethylcellulose (HEC) in a concentration of 0.5% to 5.0%; and (d) Pharmacologically acceptable inactive vehicle A formulation containing, The HEC concentration is sufficient to reduce the release of the chelating agent / MSM combination in the eye and maintain a concentration level below the level at which stinging sensation occurs. The HEC concentration is sufficient to retain the chelating agent / MSM in the eye for a period effective in resulting in a significant reduction in adverse eye conditions. The percentage of the chelating agent in the composition is approximately 0.1% to 3.0% by weight, and the percentage of the transport is approximately 0.1% to 6.0% by weight. formulation.

36. The formulation according to claim 35, wherein the adverse eye condition is caused by polymer aggregation.

37. The formulation according to claim 35, wherein the adverse eye condition is caused by dry eye syndrome.

38. The formulation according to claim 37, wherein dry eye syndrome is caused by inflammation.

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