Drug delivery via therapeutic hydrogels

• US 6,132,765 A
• Filed: 04/15/1997
• Issued: 10/17/2000
• Est. Priority Date: 04/12/1996
• Status: Expired due to Fees

• Current Assignee: Covalon Technologies Incorporated, Frank Dicosmo, Valerio Ditizio
• Original Assignee: Uroteq, Inc. (Covalon Technologies, Ltd.)
• Inventors: DiTizio, Valerio, DiCosmo, Frank
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US08/843,342
• Time in Patent Office: 1,281 Days
• Field of Search: 424/450, 424/422-426, 424/484-488, 623/1, 606/191, 606/194, 604/27, 604/53
• US Class Current: 424/450
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/436 of receptors
• CPC Class Codes: A61L 2300/626 Liposomes, micelles, vesicles
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Abstract

The present invention is directed to a vehicle for effecting drug delivery from a solid substrate. Hydrogels loaded with liposomal therapeutic agents such as antibiotics are covalently bonded to the surface of substrates such as in-dwelling medical devices, such as implants, catheters, and the like. The present invention is particularly useful in the treatment and prevention of biofilm mediated infection often associated with the use of in-dwelling medical devices.

Claims

1. A medical device comprising:

a. a polymeric liquid conduit having an external surface;

b. a gelatin hydrogel matrix material; and

c. a therapeutic agent encapsulated in a liposome and confined within said matrix material,

wherein said matrix material is affixed to the external surface of said polymeric liquid conduit by a plurality of covalent bonds.

2. The medical device of claim 1, wherein the gelatin hydrogel matrix material is cross-linked with polyethylene glycol.

3. The medical device of claim 1, wherein the polymeric liquid conduit comprises silicone rubber.

4. The medical device of claim 3, wherein the silicone rubber comprises polydimethylsiloxane.

5. The medical device of claim 3, comprising a bifunctional linker molecule covalently linked to an amine functionality of said gelatin and covalently linked to a methylene functionality of said silicone rubber.

6. The medical device of claim 5, wherein said linker molecule is a 4-azido-2,3,5,6-tetrafluorobenzoyl radical.

7. The medical device of claim 1, wherein the liposomal therapeutic agent is selected from the group consisting of:

antibiotics, antihistamines, anti-inflammatories, hormones, steroids, growth factors, colony stimulating factors, interleukins, and combinations thereof.

8. The medical device of claim 1, wherein the liposomal therapeutic agent is an antibiotic.

9. The medical device of claim 1, wherein the liposomal therapeutic agent is a fluoroquinolone antibiotic.

10. The medical device of claim 9, wherein the fluoroquinolone antibiotic is selected from the group consisting of:

ciprofloxacin, norfloxacin, ofloxacin, pefloxacin, enoxacin, rosoxacin, amifloxacin, fleroxacin, temafloxacin, and lomefloxacin.

11. The medical device of claim 9 wherein the fluoroquinolone is ciprofloxacin.

12. The medical device of claim 1, wherein the liposomes are formed of a material selected from the group consisting of dipalmitoylphosphatidylcholine and polyethyleneglycol-distearoylphosphatidylethanolamine.

13. A medical device comprising:

a. a silicone rubber liquid conduit having an external surface;

b. a bifunctional linker molecule comprising a fluorinated aroyl azido group convalently bound to said external surface of said liquid conduit;

c. a layer of polyethylene glycol-gelatin matrix material affixed to the external surface of said liquid conduit by a covalent bond between an amine functionality of said gelatin and said bifunctional linker molecule; and

d. ciprofloxacin encapsulated in a liposome and dispersed throughout said matrix material.

14. A medical device comprising:

a. a polymeric liquid conduit having an external surface;

b. a layer of a gelatin hydrogel matrix material having a plurality of covalent bonds between a surface of the layer of hydrogel matrix material and the external surface of the liquid conduit; and

c. a therapeutic agent encapsulated in a liposome and confined within said layer of said matrix material.

15. The medical device of claim 14 wherein the liquid conduit is a catheter.

16. The medical device of claim 14 wherein the gelatin hydrogel matrix material comprises gelatin cross-linked with polyethylene glycol.

17. The medical device of claim 16 wherein the plurality of covalent bonds between the external surface of the catheter and a surface of the layer of gelatin hydrogel matrix material further comprises a linker molecule covalently bound between said external surface of said catheter and said layer of said gelatin hydrogel matrix material.

18. The medical device of claim 17 wherein the external surface of said polymeric catheter comprises silicone rubber and the linker molecule is a bifunctional aromatic compound comprising carbonyl and azide functionalities;

and wherein the carbonyl fuctionality of said linker molecule is covalently bound to a free amine fuctionality of said gelatin, and the azide fuctionality of said linker molecule is covalently bound to a methylene fuctionality of said silicone rubber.