Methods and compositions for enhancing the bioadhesive properties of polymers

• US 5,985,312 A
• Filed: 01/26/1996
• Issued: 11/16/1999
• Est. Priority Date: 01/26/1996
• Status: Expired due to Term

• Current Assignee: Perosphere Inc.
• Original Assignee: Brown University
• Inventors: Mathiowitz, Edith, Jacob, Jules S.
• Primary Examiner(s): Kulkosky, Peter F.
• Application Number:
  US08/592,565
• Time in Patent Office: 1,390 Days
• Field of Search: 424/9.1, 424/9.3, 424/111, 424/434
• US Class Current: 424/434
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• 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 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)

Abstract

Methods and compositions are provided for enhancing the bioadhesive properties of polymers used in drug delivery devices. The bioadhesive properties of a polymer are enhanced by incorporating a metal compound into the polymer to enhance the ability of the polymer to adhere to a tissue surface such as a mucosal membrane. Metal compounds which enhance the bioadhesive properties of a polymer include water-insoluble metal compounds such as water-insoluble metal oxides, including oxides of calcium, iron, copper and zinc. The metal compounds can be incorporated within a wide range of polymers including proteins, polysaccharides and synthetic biocompatible polymers. In one embodiment, metal oxides can be incorporated within polymers used to form or coat drug delivery devices, such as microspheres, which contain a drug or diagnostic agent. The metal oxides can be provided in the form of a fine dispersion of particles on the surface of a polymer that coats or forms the devices, which enhances the ability of the devices to bind to mucosal membranes. The polymers, for example in the form of microspheres, have improved ability to adhere to mucosal membranes, and thus can be used to deliver a drug or diagnostic agent via any of a range of mucosal membrane surfaces including those of the gastrointestinal, respiratory, excretory and reproductive tracts.

Claims

1. A method for improving the bioadhesiveness of a polymer, the method comprising incorporating a water-insoluble metal compound in the polymer to allow for exposure of the metal compound at a surface of the polymer, thereby to enhance the ability of the polymer to adhere to a mucosal membrane,

wherein the metal compound is derived from a metal selected from the group consisting of aluminum, tin, calcium, iron, copper, zinc, zirconium, nickel, and titanium, and

wherein the polymer is selected from the group consisting of proteins, polysaccharides, polyamides, pplycarbonates, polyalkylenes, polyaryalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl polymers, polyphosphazenes, polyacrylamides, polysiloxanes, polyurethanes, polymers of acrylic and methacryic acid, celluloses, polyanhydrides, polyesters, poly(hydroxy acids), and blends and copolymers of these polymers.

2. The method of claim 1 wherein the metal compound is associated with the polymer by ionic interactions.

3. The method of claim 1 wherein the polymer is in the form of a microsphere, and wherein the method comprises improving the bioadhesiveness of the microsphere by incorporating a water-insoluble metal compound in the polymer during formation of the microsphere, thereby to enhance the ability of the microsphere to adhere to a mucosal membrane.

4. The method of claim 3 wherein the metal compound is in the form of a fine dispersion of metal oxide particles on at least the surface of the microsphere.

5. The method of claim 4 wherein the metal oxide is selected from the group consisting of ferric oxide, zinc oxide, titanium oxide, copper oxide, stannic oxide, aluminum oxide, nickel oxide, and zirconium oxide.

6. The method of claim 3 wherein the polymer incorporating the metal compound is coated onto the surface of a microsphere formed of a different material.

7. The method of claim 3 wherein the microsphere further comprises a therapeutic or diagnostic agent.

8. The method of claim 7 wherein the diagnostic agent is selected from the group consisting of gases, gas evolving agents and radio-opaque compounds.

9. The method of claim 1 wherein the polymer defines or coats a drug delivery device containing a therapeutic agent.

10. The method of claim 1 wherein the polymer defines or coats a surgical implant device.

11. The method of claim 1 wherein the microsphere has a diameter greater than or equal to about 10 microns.

12. The method of claim 1 wherein the microsphere has a diameter between about 2 and 5 microns.

13. The method of claim 1 wherein the microsphere has a diameter of less than about 2 microns.

14. The method of claim 1 wherein the microsphere has a diameter less than about 1 micron.

15. The method of claim 1 wherein the metal compound is selected from the group consisting of a water-insoluble metal oxide and a water-insoluble metal hydroxide.