Monolithic maleic anhydride drug delivery systems

• US 5,474,780 A
• Filed: 03/30/1993
• Issued: 12/12/1995
• Est. Priority Date: 04/27/1990
• Status: Expired due to Fees

• Current Assignee: Allergan SPA (Abbvie Incorporated)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Inventors: Chang, James N.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/030,479
• Time in Patent Office: 987 Days
• Field of Search: 424/486, 424/426, 424/428, 424/501, 526/936, 526/318.2, 526/318.25
• US Class Current: 424/428
• CPC Class Codes: A61F 2013/8452 being contained in microcapsules
• CPC Class Codes: A61F 9/0017 implantable in, or in contact with, the eye, e.g. ocular inserts
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• 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: Y10S 526/936 Physiological use, e.g. pharmaceutical, veterinary, dental

Abstract

Erodible bioadhesive drug delivery vehicles for use in delivering pharmaceutical compounds to the eye and similar physiological environments are disclosed. The drug delivery vehicles are formed of a homopolymer or copolymer of maleic anhydride or lower alkyl maleic anhydride incorporating a pharmaceutical compound in either a monolithic matrix or encapsulated form. The bioadhesive erodible drug delivery vehicles are configured to be retained in the eye following administration while providing specific erosion profiles allowing convenient drug delivery schedules ranging from hourly to daily or weekly intervals.

Claims

1. An erodible, self-lubricating, bio-adhesive drug delivery vehicle consisting essentially of:

homogeneous poly(methylvinylether/maleic anhydride) copolymer; and

from approximately 1% to 60% by weight therapeutic or diagnostic pharmaceutical compound incorporated therein, wherein said vehicle erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

2. The drug delivery vehicle of claim 1 wherein said pharmaceutical compound is incorporated within said homogeneous copolymer to form a monolithic matrix.

3. The drug delivery vehicle of claim 2 wherein said monolithic matrix comprises a plurality of microparticulates, said microparticulates being sized from approximately 2 μ

m to approximately 200 μ

m.

4. The drug delivery vehicle of claim 3 wherein said plurality of microparticulates are suspended in a liquid carrier.

5. The drug delivery vehicle of claim 2 wherein said monolithic matrix is formed to produce an insert sized from approximately 500 μ

m to approximately 5000 μ

m.

6. The drug delivery vehicle of claim 2 wherein said pharmaceutical compound is present at a concentration of approximately 1% to 20% by weight.

7. A dropable or injectable self-lubricating, self-adhesive, bio-adhesive, erodible drug delivery vehicle comprising:

a microparticulate suspension of a monolithic matrix of claim 2 and a pharmaceutically effective amount of a therapeutic or diagnostic/pharmaceutical compound, each of said microparticulates being sized from approximately 2 μ

m to approximately 200 μ

m, wherein said vehicle erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

8. An erodible, self-lubricating, self-adhesive, bio-adhesive drug delivery vehicle comprising an insert formed of a monolithic matrix of the vehicle of claim 2 and a pharmaceutically effective amount of a therapeutic or diagnostic pharmaceutical compound, said insert being sized from approximately 500 μ

m to approximately 5000 μ

m, wherein said vehicle erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

9. The drug delivery vehicle of claim 1 wherein said pharmaceutical compound is encapsulated by said homogeneous copolymer to form a plurality of microcapsules.

10. The drug delivery vehicle of claim 9 wherein each of said microcapsules is sized from approximately 2 μ

m to approximately 200 μ

m.

11. The drug delivery vehicle of claim 9 wherein said microcapsules are suspended in a liquid carrier.

12. The drug delivery vehicle of claim 9 wherein said pharmaceutical compound is present at a concentration of approximately 2% to 60% by weight.

13. The drug delivery vehicle of claim 1 wherein said pharmaceutical compound is selected from the group consisting of antibacterials, antiinflammatories, miotics, mydriatics, antiglaucoma compounds, antivirals, carbonic anhydrase inhibitors, anti-fungal agents, anesthetic agents, diagnostic agents and immunosuppressive agents.

14. The drug delivery vehicle of claim 1 wherein said pharmaceutical compound is selected from the group consisting of dipivalyl epinephrine hydrochloride (DPE), levo-bunolol hydrochloride, flurbiprofen, 5-bromo-6-(imidazolin-2-ylamino)quinoxaline, pilocarpine, sodium fluorescein, timolol, betaxolol, ofloxacin and ibuprofen.

15. A dropable or injectable self-lubricating, self-adhesive, bio-adhesive, erodible drug delivery vehicle comprising a plurality of microcapsules, each of said microcapsules formed of approximately 5% to 60% by weight therapeutic or diagnostic pharmaceutical compound encapsulated by the vehicle of claim 1, wherein said vehicle erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

16. A method for delivering a pharmaceutical compound to the eye, said method comprising the steps of:

preparing a dropable or injectable suspension of self-lubricating, erodible, self-adhesive, bio-adhesive microcapsules, each of said microcapsules being formed of from approximately 2% to 60% by weight of said pharmaceutical compound encapsulated in the vehicle of claim 1; and

introducing said suspension into the conjunctival sac of the eye, wherein said microcapsules erode by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

17. The drug delivery vehicle of claim 1 wherein said pharmaceutical compound is selected from the group consisting of antihistaminics, anticholinergics and antiparasitic compounds.

18. A method for delivering a pharmaceutical compound to the eye, said method comprising the steps of:

preparing an erodible, self-lubricating, self-adhesive, bio-adhesive monolithic matrix consisting essentially of homogeneous poly(methylvinylether/maleic anhydride) copolymer and a pharmaceutically an effective concentration of at least one pharmaceutical compound; and

introducing said monolithic matrix into the conjunctival sac of the eye, wherein said copolymer erodes by hydrolysis of the maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals of about 3.5.

19. The method of claim 18 further comprising the additional step of:

forming a microparticulate suspension of said monolithic matrix prior to introducing the matrix into said conjunctival sac.

20. The method of claim 18 further comprising the additional step of:

forming an ocular insert from said monolithic matrix prior to introducing the matrix into said conjunctival sac.

21. An erodible, self-lubricating, bio-adhesive drug delivery vehicle consisting essentially of:

a lower alkyl maleic anhydride or maleic anhydride homogeneous copolymer of the formula ##STR4## wherein R¹ is C_1-4 alkyl, alkylether, alkylester, or halogen;

R² and R³ are each selected from the group consisting hydrogen and C_1-4 ; and

from approximately 1% to 60% by weight therapeutic or diagnostic pharmaceutical compound incorporated therein, wherein said vehicle erodes by hydrolysis of the maleic anhydride or lower alkyl maleic anhydride units to provide two carboxylic radicals for each maleic anhydride unit and said copolymer has a ratio of carbon atoms to carboxylic radicals ranging from about 3 to 7.

22. An erodible, self-lubricating, bio-adhesive drug delivery vehicle consisting essentially of:

a maleic anhydride or a lower alkyl maleic anhydride homogeneous homopolymer or copolymer; and

from approximately 1% to 60% by weight therapeutic or diagnostic pharmaceutical compound incorporated therein, wherein said vehicle erodes by hydrolysis of the maleic anhydride or lower alkyl maleic anhydride units to provide two carboxylic radicals for each anhydride unit and said polymer has a ratio of carbon atoms to carboxylic radicals ranging from 2 to 7.

23. The vehicle of claim 22 wherein said ratio of carbon atoms to carboxylic radicals ranges from 3 to 7.

24. The vehicle of claim 22 comprising a maleic anhydride copolymer.

25. The vehicle of claim 23 comprising a hydrocarbon comonomer or a hydrocarbon comonomer substituted with non-hydrophilic substituents selected from the group consisting of --X, --O--R, ##STR5## wherein X is a halogen radical and R is an alkyl radical having from 1 to 12 carbon atoms.

26. The vehicle of claim 25 wherein said comonomer is selected from the group consisting of C₁ to C₄ lower alkyl vinylethers wherein the alkyl chain comprises from 1 to 4 carbon atoms, butadiene, styrene, isoprene, ethylene, propylene, vinylchloride and alkylesters, said alkylesters selected from the group consisting of acrylic acid having from 1 to 8 carbon atoms in the alkyl chain and methacrylic acid having from 1 to 8 carbon atoms in the alkyl chain.

32. A method for delivery a pharmaceutical compound to the eye, said method comprising the steps of:

preparing a dropable or injectable suspension of self-lubricating, erodible, self-adhesive, bio-adhesive microcapsules, each of said microcapsules being formed of from approximately 2% to 60% by weight of said pharmaceutical compound encapsulated in the vehicle of claim 22 and

introducing said suspension into the conjunctival sac of the eye, wherein said microcapsules erode by hydrolysis of the maleic anhydride or lower alkyl maleic anhydride units of the vehicle to provide two carboxylic radicals for each maleic anhydride unit and said polymer has a ratio of carbon atoms to carboxylic radicals from 2 to 7.

33. The method of claim 32 wherein said ratio of carbon atoms to carboxylic radicals ranges from 3 to 7.

34. The method of claim 32 comprising a maleic anhydride copolymer.

35. The method of claim 33 comprising a hydrocarbon comonomer or a hydrocarbon comonomer substituted with non-hydrophilic substituents selected from the group consisting of --X, --O--R, ##STR7## wherein X is a halogen radical and R is an alkyl radical having from 1 to 12 carbon atoms.

36. The method of claim 35 wherein said comonomer is selected from the group consisting of C₁ to C₄ lower alkyl vinylethers wherein the alkyl chain comprises from 1 to 4 carbon atoms, butadiene, styrene, isoprene, ethylene, propylene, vinylchloride and alkylesters, said alkylesters selected from the group consisting of acrylic acid having from 1 to 8 carbon atoms in the alkyl chain and methacrylic acid having from 1 to 8 carbon atoms in the alkyl chain.

27. A method for delivering a pharmaceutical compound to the eye, said method comprising the steps of:

preparing an erodible, self-lubricating, self-adhesive, bio-adhesive monolithic matrix consisting essentially of a maleic anhydride or a lower alkyl maleic anhydride homogeneous homopolyer or copolymer and a pharmaceutically effective concentration of at least one pharmaceutical compound; and

introducing said monolithic matrix into the conjunctival sac of the eye, wherein said matrix erodes by hydrolysis of the maleic anhydride or lower alkyl maleic anhydride units to provide two carboxylic radicals for each anhydride unit and said polymer has a ratio of carbon atoms to carboxylic radicals from 2 to 7.

28. The vehicle of claim 27 wherein said ratio of carbon atoms to carboxylic radicals ranges from 3 to 7.

29. The vehicle of claim 27 comprising a homogeneous maleic anhydride copolymer.

30. The vehicle of claim 28 comprising a hydrocarbon comonomer or a hydrocarbon comonomer substituted with non-hydrophilic substituents selected from the group consisting of --X, --O--R, ##STR6## wherein X is a halogen radical and R is an alkyl radical having from 1 to 12 carbon atoms.

31. The vehicle of claim 30 wherein said comonomer is selected from the group consisting of C₁ to C₄ lower alkyl vinylethers wherein the alkyl chain comprises from 1 to 4 carbon atoms, butadiene, styrene, isoprene, ethylene, propylene, vinylchloride and alkylesters, said alkylesters selected from the group consisting of acrylic acid having from 1 to 8 carbon atoms in the alkyl chain and methacrylic acid having from 1 to 8 carbon atoms in the alkyl chain.