Stable suspension formulations of bioerodible polymer matrix microparticles incorporating drug loaded ion exchange resin particles

• US 5,275,820 A
• Filed: 12/27/1990
• Issued: 01/04/1994
• Est. Priority Date: 12/27/1990
• Status: Expired due to Fees

• Current Assignee: Allergan Incorporated (Abbvie Incorporated)
• Original Assignee: Allergan Incorporated (Abbvie Incorporated)
• Inventors: Chang, Nienyuan J.
• Primary Examiner(s): WEBMAN, EDWARD J
• Application Number:
  US07/634,500
• Time in Patent Office: 1,104 Days
• Field of Search: 424/80, 424/79, 424/497, 424/426, 424/428, 424/457, 424/482, 424/78.1, 424/78.24, 514/912-915
• US Class Current: 424/426
• CPC Class Codes: A61K 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

Sustained release pharmaceutical compound delivery compositions and methods for their production are disclosed wherein ion exchange resin particles are loaded with releasably bound pharmaceutical compounds prior to incorporation in an erodible polymeric matrix to form microparticulates. The microparticulates are suspended in a fluid medium where the encapsulating polymeric matrix shields the drug loaded ion exchange resin from solvent interaction. Administration to a target tissue site initiations erosion of the polymer matrix and release of the loaded pharmaceutical compound.

Claims

1. A sustained release pharmaceutical compound delivery composition having improved delivery characteristics and enhance long-term storage stability, said composition comprising:

a non-ionic liquid suspension of microparticulates, said microparticulates formed of an erodible bioadhesive polymeric matrix of poly and polyvinylpyrrolidone wherein the ratio of poly (methylvinylether/maleic anhydride) to polyvinylpyrrolidone ranges from approximately 1;

1 to 4;

1 by weight, incorporating at least one ion exchange resin particle sized from approximately 1 μ

m to 100 μ

m, said ion exchange resin particle having approximately 2 to 50 wt % of a pharmaceutical compound releasably bound thereto.

2. The sustained release pharmaceutical compound delivery composition of claim 1 wherein said liquid is water having a pH less than about 5.

3. The sustained release pharmaceutical compound delivery composition of claim 1 wherein the ratio of poly(methylvinylether/maleic anhydride) to polyvinylpyrrolidone is approximately 3:

1 by weight.

4. The sustained release pharmaceutical compound delivery composition of claim 1 wherein each of said microparticulates is sized from about 10 um to about 500 um.

5. The sustained release pharmaceutical compound delivery composition of claim 1 wherein each of said ion exchange resin particle has a pore size ranging from about 10 angstroms to about 100 angstroms.

6. The sustained release pharmaceutical compound delivery composition of claim 1 wherein said ion exchange resin particle is selected from the group consisting of cation exchange resin particles, anion exchange resin particles, and combinations thereof.

7. The sustained release pharmaceutical compound delivery composition of claim 6 wherein said cation exchange resin particles include at least one exchange functionality selected from the group consisting of sulfonic acid and carboxylic acid.

8. The sustained released pharmaceutical compound delivery composition of claim 1 wherein said releasably bound pharmaceutical compound is selected from a group consisting antibacterials, antiinflammatories, miotics, anticholinergics, antiglaucoma compounds, antivirals, carbonic anhydrase inhibitors, aesthetic agents, diagnostic agents, and immunosuppressive agents.

9. The sustained release pharmaceutical compound delivery composition of claim 1 wherein said releasably bound pharmaceutical compound in selected from the group consisting of mydriatics, antihistaminics, and antiparasitic compounds.

10. The sustained release pharmaceutical compound delivery composition of claim 1 wherein said releasably bound pharmaceutical compound is selected from the group consisting of dipivalyl epinephrine, levobunolol, ofloxacin, 5-bromo-6-(imidazolin-2-ylamino)-quinoxaline, clonidine, pilocarpine, flurbiprofen, timolol, betaxolol, ibuprofen, and acetaminophen.

11. A sustained release aqueous pharmaceutical compound delivery composition having improved delivery characteristics and enhanced long term storage ability, said composition comprising:

a nonionic aqueous suspension of microparticulates, said aqueous suspension having a pH value of less than about 5, and said microparticulates formed of a bioerodible, bioadhesive polymeric matrix of poly(methylvinylether/maleic anhydride) and polyvinylpyrrolidone wherein the ratio of poly (methylvinylether/maleic anhydride) to polyvinylpyrrolidone ranges from approximately 1;

1 to 4;

1 by weight, incorporating at least one ion exchange resin particle sized from approximately 1 μ

m to 100 μ

m, said ion exchange resin particle having from 2 to 50 wt % of a pharmaceutical compound releasably bound thereto.

12. The sustained release pharmaceutical compound delivery composition of claim 11 wherein the ratio of poly(methylvinylether/maleic anhydride) to polyvinylpyrrolidone is approximately 3:

1 by weight.

13. The sustained release pharmaceutical compound delivery composition of claim 11 wherein each of said microparticulates is sized from about 10 um to about 500 um.

14. The sustained release pharmaceutical compound delivery composition of claim 11 wherein each said ion exchange resin particles has a pore size ranging from about 10 angstroms to about 100 angstroms.

15. The sustained release pharmaceutical compound delivery composition of claim 11 wherein said ion exchange resin particle is selected from the group consisting of cation exchange resin particles, anion exchange resin particles, and combinations thereof.

16. The sustained release pharmaceutical compound delivery composition of claim 15 wherein said cation exchange resin particles include at least one exchange functionality selected from the group consisting of sulfonic acid and carboxylic acid.

17. The sustained release pharmaceutical compound delivery composition of claim 11 wherein said releasably bound pharmaceutical compound is selected from the group consisting of antibacterials, antiinflammatories, miotics, anticholinergics, antiglaucoma compounds, antivirals, carbonic anhydrase inhibitors, anitfungal agents, anesthetic agents, diagnostic agents, and immunosuppressive agents.

18. The sustained released pharmaceutical compound delivery composition of claim 11 wherein said releasably bound pharmaceutical compound is selected from the group consisting of mydriatics, antihistaminics, and antiparasitic compounds.

19. The sustained release pharmaceutical compound delivery composition of claim 11 wherein said releasably bound pharmaceutical compound is selected from the group consisting of dipivalyl epinephrine, levobunolol, ofloxacin, 5-bromo-6-(imidazolin-2-ylamino)-quinoxaline, clonidine, pilocarpine, flurbiprofen, timolol, betaxolol, ibuprofen, and acetaminophen.

20. A process for forming a sustained release pharmaceutical compound delivery composition having improved delivery characteristics and enhanced long term storage stability, said process comprising the steps of:

reversibly loading at least one ion exchange resin particles sized form approximately 1 μ

m to 100 μ

m with from approximately 2 to 50 wt % of at least one pharmaceutical compound;

incorporating said loaded ion exchange resin particle into an erodible polymeric matrix formed of poly(methylvinylether/maleic anhydride) and polyvinylpyrrolidone wherein the ratio of poly(methylvinylether/maleic anhydride) to polyvinylpyrrolidone ranges from approximately 1;

1 to 4;

1 by weight; and

suspending said erodible polymeric matrix incorporating said loaded ion exchange resin particle in a nonionic aqueous solution having a pH value of less than about 5.

21. The process of claim 20 wherein said loaded ion exchange resin particles is incorporated into said erodible polymeric matrix through the additional steps of:

suspending said loaded ion exchange resin particle in a solution of poly(methylvinylether/maleic anhydride); and

adding a solution of polyvinylpyrrolidone thereto to form an erodible polymeric matrix precipitate incorporating said loaded ion exchange resin particle.

22. The process of claim 20 wherein said releasably bound pharmaceutical compound is selected from the group consisting of antibacterials, antiinflammatories, miotics, anticholinergics, antiglaucoma compounds, antivirals, carbonic anhydrase inhibitors, antifungal agents, anesthetic agents, diagnostic agents, and immunosuppressive agents.

23. The process of claim 20 wherein said releasably bound pharmaceutical compound is selected from the group consisting mydriatics, antihistaminics, and antiparasitic compounds.

24. The process of claim 20 wherein said releasably bound pharmaceutical compound is selected from the group consisting of dipivalyl epinephrine, levobunolol, ofloxacin, 5-bromo-6-(imidazolin-2-ylamino)-quinoxaline, clonidine, pilocarpine, flurbiprofen, timolol, betaxolol, and acetaminophen.