Method for the production of polymerized nanoparticles and microparticles by ternary agent concentration and temperature alteration induced immiscibility

• US 20060057222A1
• Filed: 09/15/2004
• Published: 03/16/2006
• Est. Priority Date: 09/15/2004
• Status: Active Grant

• Current Assignee: Bausch & Lomb Incorporated (Bausch Health Cos., Inc.)
• Original Assignee: Bausch & Lomb Incorporated (Bausch Health Cos., Inc.)
• Inventors: Salamone, Joseph C., Raiche, Adrian T., Linhardt, Jeffrey
• Granted Patent: US 7,495,052 B2
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 9/1682 Processes
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: C08F 2/22 Emulsion polymerisation

Abstract

Polymerized drug delivery devices are described. Additionally, methods are described for producing and for using polymerized particles for use as drug delivery devices.

Claims

1. A method for the production of polymerized particles comprising:

combining one or more non-solvents, one or more ternary agents, one or more surfactants, one or more monomers, macromonomers or a combination thereof, and one or more initiators to produce a non-solvent solution;

combining one or more solvents miscible with said one or more non-solvents, and one or more polymers or one or more matrices or a combination thereof to produce a solvent solution; and

combining said non-solvent solution and said solvent solution to produce polymerized particles.

13. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein said one or more monomers, macromonomers or a combination thereof are selected from the group consisting of poly(ethylene glycol) diamethacrylate, methylene bisacrylamide, 2-hydroxyethyl methacrylate, methyl methacrylate, acrylic acid, methacrylic acid2-ethylhexyl methacrylate, 3-methacryloyloxypropyldiphenylmethylsilane, 3-methacryloyloxypropyltris (trimethylsiloxy)silane, 2-phenyoxyethyl methacrylate, poly(proprionic acid) and copolymers containing poly(proprionic acid), polycaprolactone dimethacrylate and other methacrylate, glycidyl and cyanoacrylate end-capped macromonomers.

14. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein said one or more initiators are selected from the group consisting of azobis-isobutyronitrile, acetyl peroxide, lauroyl peroxide, decanoyl peroxide, stearoyl peroxide, benzoyl peroxide, tert-butyl peroxypivalate, peroxydicarbonate, benzoin methyl ether, benzoin ethyl ether.

15. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein said one or more initiators are selected from the group consisting of free radical thermal polymerization initiators, ultraviolet light initiators, and blue light initiators.

16. The method of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9 wherein size of said polymerized particle is controlled through temperature variation.

17. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein said polymerized particles are about 1 mm to about 0.10 nm in size.

18. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein said polymerized particles are about 400 nm to about 0.10 nm in size.

19. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein said polymerized particles are about 350 nm to about 0.50 nm in size.

20. The method of claim 1, 4, 7 or 10 wherein said one or more solvents are selected from the group consisting of acetone, acetonitrile, ethanol, isopropyl alcohol, dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran and dioxane.

22. The method of claim 1, 4, 7 or 10 wherein one of said one or more solvents is acetone, acetonitrile or a combination thereof.

24. The method of claim 1, 4, 7 or 10 wherein said one or more non-solvents are selected from the group consisting of water, alcohols, ethers, amine-containing solvents, carboxyl-containing solvents and organic solvents.

25. The method of claim 1, 4, 7 or 10 wherein one of said one or more non-solvents is water, methanol, ethanol or a combination thereof.

26. The method of claim 1, 4, 7 or 10 wherein said one or more ternary agents are selected from the group consisting of ammonium azide, ammonium bisulfite, barium acetate hydrate, barium hypophosphate, cadmium chloride, calcium acetate dihydrate, calcium chromate, calcium ethyl methyl acetate, cobalt perchlorate, iron perchlorate hexahydrate, lead chlorate hydrate, lithium hydroxide monohydrate, lithium sulfate, lithium sulfite monohydrate, potassium carbonate, potassium chloride, sodium selenate, sodium stannate (hydroxo), strontium acetate and yttrium chloride.

27. The method of claim 1, 4, 7 or 10 wherein one of said one or more ternary agents is sodium chloride, sodium bromide or a combination thereof.

28. The method of claim 1, 4, 7 or 10 wherein said one or more polymers are selected from the group consisting of polyesters, polyanhydrides, polyorthoesters, polyurethanes, polyethylene and its derivatives, all acrylate-based polymers including poly(acrylic acid), poly(methyl methacrylate) and poly(2-hydroxyethyl methacrylate), poly(N-vinylpyrrolidone) and polyethylenimine.

29. The method of claim 1, 4, 7 or 10 wherein said one or more matrices are selected from the group consisting of trehalose, dextrose, triethanolamine, and calcium carbonate.

30. The method of claim 1, 4, 7 or 10 wherein said one or more surfactants are selected from the group consisting of poly(N-vinylpyrrolidone), poly(ethylene oxide)/poly(propylene oxide) triblock copolymers, Tweens, Sorbitans and triacyl glycerols.

32. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein said polymerized particles are useful as drug delivery agents.

33. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein said polymerized particles are useful as ophthalmic drug delivery agents.

39. A method of using polymerized particles produced through the method of claim 1, 4, 7, 10 or 36 comprising:

topically applying said polymerized particles on a patient in the form of a lotion, gel or suspension.

40. A method of using polymerized particles produced through the method of claim 1, 4, 7, 10 or 36 comprising:

enterically administrating said polymerized particles to a patient through direct ingestion or through indirect ingestion.

41. A method of using polymerized particles produced through the method of claim 1, 4, 7, 10 or 36 comprising:

parenterally administrating said polymerized particles to a patient.

42. A method of using polymerized particles produced through the method of claim 1, 4, 7, 10 or 36 comprising:

administering said polymerized particles to a patient through patient inhalation of said polymerized particles.

2. A method for the production of polymerized particles comprising:

combining water, sodium chloride, sodium bromide, poly(ethylene oxide)/poly(propylene oxide) triblock copolymers, one or more monomers, macromonomers or a combination thereof, and one or more initiators to produce a non-solvent solution;

combining acetone, acetonitrile and one or more polysaccharide and polyurethane polymers, or trehalose, dextrose and triethanolamine matrices, or a combination thereof to produce a solvent solution; and

combining said non-solvent solution with said solvent solution to produce polymerized particles ranging in size from about 0.10 nm to about 1 mm.

3. A method for the production of polymerized particles comprising:

combining water, sodium bromide or sodium chloride ternary agent, poly(ethylene oxide)/poly(propylene oxide) triblock copolymers, one or more monomers, macromonomers or a combination thereof, and one or more initiators to produce a non-solvent solution;

combining acetone or acetonitrile solvent, one or more polysaccharide or polyurethane polymers, and one or more trehalose, dextrose or triethanolamine matrices to produce a solvent solution; and

combining said non-solvent solution with said solvent solution to produce polymerized particles ranging in size from about 0.10 nm to about 1 mm.

4. A method for the production of a drug delivery system comprising:

combining one or more non-solvents, one or more ternary agents, one or more surfactants, one or more monomers, macromonomers or a combination thereof, and one or more initiators to produce a non-solvent solution;

combining one or more solvents and one or more polymers or one or more matrices or a combination thereof to produce a solvent solution;

combining one or more agent solvents and one or more therapeutically active agents to produce an agent solution; and

combining said non-solvent solution, said solvent solution and said agent solution to produce polymerized particles containing a therapeutically effective amount of said one or more therapeutically active agents.

21. The method of claim 4 wherein said one or more agent solvents are selected from the group consisting of chloroform, carbon tetrachloride, 1,2-dichloroethane, dichloromethane, ethyl acetate and toluene.

23. The method of claim 4 wherein one or said one or more agent solvents is ethyl acetate.

5. A method for the production of a drug delivery system comprising:

combining water, sodium chloride or sodium bromide ternary agent, one or more poly(ethylene oxide)/poly(propylene oxide) triblock copolymers, one or more monomers, macromonomers or a combination thereof, and one or more initiators to produce a non-solvent solution;

combining acetone or acetonitrile solvent, one or more polyurethane or polysaccharide polymers, one or more trehalose, dextrose or triethanolamine matrices or a combination thereof to produce a solvent solution;

combining ethyl acetate and one or more therapeutically active agents to produce an agent solution; and

combining said non-solvent solution, said solvent solution and said agent solution to produce polymerized particles containing a therapeutically effective amount of said one or more therapeutically active agents.

6. A method for the production of a drug delivery system comprising:

combining water, sodium chloride, sodium bromide, one or more poly(ethylene oxide)/poly(propylene oxide) triblock copolymers, one or more monomers, macromonomers or a combination thereof, and one or more initiators to produce a non-solvent solution;

combining acetone and acetonitrile solvents, one or more polyurethane and polysaccharide polymers, trehalose, dextrose and triethanol amine matrices or a combination thereof to produce a solvent solution;

combining ethyl acetate and one or more therapeutically active agents to produce an agent solution; and

combining said non-solvent solution, said solvent solution and said agent solution to produce polymerized particles containing a therapeutically effective amount of said one or more therapeutically active agents.

7. A method for the production of a drug delivery system comprising:

combining one or more non-solvents, one or more ternary agents, one or more surfactants, one or more monomers, macromonomers or a combination thereof, and one or more initiators to produce a non-solvent solution;

combining one or more solvents, one or more therapeutically active agents and one or more polymers or one or more matrices or a combination thereof to produce a solvent solution; and

combining said non-solvent solution and said solvent solution to produce polymerized particles containing a therapeutically effective amount of said one or more therapeutically active agents.

8. A method for the production of a drug delivery system comprising:

combining water, sodium chloride or sodium bromide ternary agents, one or more poly(ethylene oxide)/poly(propylene oxide) triblock copolymers, one or more monomers, macromonomers or a combination thereof, and one or more initiators to produce a non-solvent solution;

combining acetone or acetonitrile solvent, one or more therapeutically active agents and one or more polymers or one or more matrices or a combination thereof to produce a solvent solution; and

combining said non-solvent solution and said solvent solution to produce polymerized particles containing a therapeutically effective amount of said one or more therapeutically active agents.

9. A method for the production of a drug delivery system comprising:

combining water, sodium chloride, sodium bromide, one or more poly(ethylene oxide)/poly(propylene oxide) triblock copolymers, one or more monomers, macromonomers or a combination thereof, and one or more initiators to produce a non-solvent solution;

combining acetone and acetonitrile solvent, one or more therapeutically active agents and one or more polymers or one or more matrices or a combination thereof to produce a solvent solution; and

combining said non-solvent solution and said solvent solution to produce polymerized particles containing a therapeutically effective amount of said one or more therapeutically active agents.

10. A method for the production of particles comprising:

combining one or more solvents and one or more non-solvents that are miscible;

introducing one or more ternary agents, one or more monomers, macromonomers or a combination thereof, and one or more initiators into said one or more non-solvents to make said one or more solvents and said one or more non-solvents immiscible, with said one or more ternary agents making one or more polymers or one or more matrices and optionally one or more therapeutically active agents in said one or more solvents insoluble; and

varying temperature to control polymerized particle formation to a desired size.

31. The method of claim 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein said one or more therapeutically active agents are selected from the group consisting of beta-blockers, anti-glaucoma agents, anti-cataract agents, anti-diabetic retinopathy agents, anti-cancer agents, anti-clotting agents, anti-tissue damage agents, proteins, nucleic acids, steroids, non-steroidal anti-inflammatory agents, antibiotics, anti-pathogens, anti-viral agents, cycloplegic agents, mydriatic agents, anticholinergics, anticoagulants, antifibrinolytics, antihistamines, antimalarials, antitoxins, chelating agents, hormones, immunosuppressives, thrombolytics, vitamins, salts, desensitizers, prostaglandins, amino acids, metabolites and antiallergenics.

11. A method for the production of particles comprising:

combining acetone or acetonitrile solvent with water;

introducing sodium chloride or sodium bromide ternary agent, one or more monomers, macromonomers or a combination thereof, and one or more initiators to make said acetone or acetonitrile solvent and said water immiscible, with said ternary agent making one or more polymers or one or more matrices and optionally one or more therapeutically active agents in said acetone or acetonitrile solvent insoluble; and

varying temperature to control polymerized particle formation to a desired size.

12. A method for the production of particles comprising:

combining acetone and acetonitrile solvents with water;

introducing sodium chloride and sodium bromide ternary agents, one or more monomers, macromonomers or a combination thereof, and one or more initiators to make said acetone and acetonitrile solvents and said water immiscible, with said ternary agents making one or more polymers or one or more matrices and optionally one or more therapeutically active agents in said acetone and acetonitrile solvents insoluble; and

varying temperature to control polymerized particle formation to a desired size.

34. An improved method for producing spherical polymerized particles by combining a non-solvent solution and a solvent solution wherein the improvement comprises producing said polymerized particles through ternary agent concentration and temperature alteration induced immiscibility.

35. The method of claim 34 wherein said polymerized particles further include one or more therapeutically effective agent.

36. The method of claim 34 or 35 wherein said polymerized particles are about 1 mm to about 0.10 nm in size.

37. The method of claim 34 or 35 wherein said polymerized particles are about 400 nm to about 0.10 nm in size.

38. The method of claim 34 or 35 wherein said polymerized particles are about 350 nm to about 0.50 nm in size.