Carboxylvinyl polymer-containing nanoparticle suspensions

• US 9,662,398 B2
• Filed: 11/12/2014
• Issued: 05/30/2017
• Est. Priority Date: 12/03/2009
• Status: Active Grant

• Current Assignee: Harrow IP, LLC (Harrow, Inc.)
• Original Assignee: Alcon Research Limited (Nestle SA)
• Inventors: Asgharian, Bahram, Chowhan, Masood A., Ghosh, Malay, Han, Wesley Weshin
• Primary Examiner(s): FAY, ZOHREH A
• Application Number:
  US14/539,996
• Publication Number:
  US 20150072011A1
• Time in Patent Office: 930 Days
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention generally relates to suspension compositions having a carboxyvinyl polymer such as a carbomer, a galactomannan such as guar, and a borate compound. A sparingly soluble particulate compound such as nepafenac is also included in the compositions. The sparingly soluble particulate compound has a small particle size to enhance bioavailability of the compound.

Claims

1. A topically administrable aqueous ophthalmic suspension composition comprising:

a carboxyvinyl polymer at a concentration of 0.1 to 0.5 w/v %, and wherein said carboxyvinyl polymer is a carbomer;

a galactomannan at a concentration of 0.1 to 0.4 w/v %, said galactomannan selected from the group consisting of guar, native guar, and hydroxypropyl guar;

borate at a concentration of 0.4 to 2.0 w/v %; and

a sparingly soluble particulate compound, said compound having a solubility in water at 25°

C. of 0.001 to 0.1 w/v % and wherein said sparingly soluble particulate compound is nepafenac at a concentration of 0.1 to 1.0 w/v %.

2. A composition according to claim 1, further comprising a pH-adjusting agent in an amount sufficient to cause the composition to have a pH of 5.0 to 7.2.

3. A composition according to claim 1, further comprising a tonicity-adjusting agent in an amount sufficient to cause the composition to have an osmolality of 250 to 350 mOsm/kg.

4. A composition according to claim 1 wherein said carboxyvinyl polymer is carbomer at a concentration of 0.4 w/v %.

5. A composition according to claim 1 further comprising a milling agent at a concentration of 0.005 to 0.1 w/v %.

6. A composition according to claim 5 wherein said milling agent is a surfactant or polymer.

7. A composition according to claim 6 wherein said milling agent is sodium carboxylmethylcellulose.

8. A composition according to claim 1 further comprising a metal chloride salt tonicity-adjusting agent.

9. A composition according to claim 8 wherein said metal chloride salt is sodium chloride at a concentration of 0.4 w/v %.

10. A composition according to claim 1 further comprising a non-ionic hydroxyl compound as a tonicity-adjusting agent.

11. A composition according to claim 1 further comprising both a preservative and a chelating agent.

12. A composition according to claim 11 wherein the preservative is benzalkonium chloride at a concentration of 0.005 w/v % and the chelating agent is edetate disodium at a concentration of 0.01 w/v %.

13. A composition according to claim 1 wherein said carboxyvinyl polymer is carbomer, said galactomannan is native guar, said borate is boric acid, and said sparingly soluble particulate compound is nepafenac at a concentration of 0.1 to 1.0 w/v %.

14. A composition according to claim 13 comprising 0.4 w/v % carbomer, 0.2 w/v % native guar, 0.5 w/v % boric acid, and 0.3 w/v % nepafenac.

15. A composition according to claim 14 wherein said nepafenac has an average particle size of 400 nm.

16. The composition according to claim 2, further comprising a pH adjusting agent in an amount sufficient to cause the composition to have a pH of 7.0.

17. The composition according to claim 7 wherein said milling agent is 0.06 w/v % sodium carboxymethylcellulose.

18. The composition according to claim 10, wherein said non-ionic hydroxyl compound is propylene glycol at a concentration of 0.5 w/v %.

19. The composition according to claim 1 wherein said carboxylvinyl polymer is Carbopol®

974p.

20. The composition according to claim 19 wherein said carboxylvinyl polymer is present at a concentration of 0.4 w/v %.

21. The composition according to claim 1 wherein said galactomannan is guar or native guar.

22. The composition according to claim 21 wherein said galactomannan is present at a concentration of 0.2 w/v %.

23. The composition according to claim 1 wherein said borate is boric acid.

24. The composition according to claim 23 wherein said borate is present at a concentration of 0.4 to 0.6 w/v %.

25. The composition according to claim 24 wherein said borate is present at a concentration of 0.5 w/v %.

26. The composition according to claim 1 wherein said sparingly soluble particulate compound is present at a concentration of 0.25 to 0.35 w/v %.

27. The composition according to claim 1 wherein said sparingly soluble particulate compound is present at a concentration of 0.3 w/v %.

28. The composition according to claim 1 further comprising a chelating agent.

29. The composition according to claim 28 wherein said chelating agent is edetate disodium.

30. The composition according to claim 29 wherein said chelating agent is present at a concentration of 0.001 to 0.1 w/v %.

31. The composition according to claim 30 wherein said chelating agent is present at a concentration of 0.01 w/v %.

32. A topically administrable ophthalmic suspension composition consisting essentially of

a) 0.3 w/v % nepafenac;

b) 0.4 w/v % carbomer;

c) 0.2 w/v % native guar;

d) 0.5 w/v % boric acid;

e) 0.06 w/v % sodium carboxymethylcellulose;

f) 0.4 w/v % sodium chloride;

g) 0.5 w/v % propylene glycol;

i) 0.005% (w/v) benzalkonium chloride;

j) 0.01% edetate disodium; and

k) purified water.