Sustained release bactericidal cannula

• US 5,261,896 A
• Filed: 12/13/1991
• Issued: 11/16/1993
• Est. Priority Date: 01/10/1990
• Status: Expired due to Term

• Current Assignee: Rochester Medical Corporation (Becton, Dickinson & Co)
• Original Assignee: Rochester Medical Corporation (Becton, Dickinson & Co)
• Inventors: Conway, Anthony J., Fryar, Richard D. Jr., Conway, Philip J.
• Primary Examiner(s): Yasko, John D.
• Assistant Examiner(s): CERMAK, ADAM
• Application Number:
  US07/809,281
• Time in Patent Office: 704 Days
• Field of Search: 604/93, 604/264, 604/265, 604/280
• US Class Current: 604/265
• CPC Class Codes: A61L 2300/204 with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
• CPC Class Codes: A61L 2300/222 Steroids, e.g. corticosteroids
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 29/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61M 2025/0056 provided with an antibacterial agent, e.g. by coating, residing in the polymer matrix or releasing an agent out of a reservoir
• CPC Class Codes: A61M 2025/0062 having features to improve the sliding of one part within another by using lubricants or surfaces with low friction
• CPC Class Codes: A61M 2025/1075 having a balloon composed of several layers, e.g. by coating or embedding
• CPC Class Codes: A61M 25/0009 Making of catheters or other medical or surgical tubes
• CPC Class Codes: A61M 25/0017 specially adapted for long-term hygiene care, e.g. urethral or indwelling catheters to prevent infections
• CPC Class Codes: A61M 25/0045 multi-layered, e.g. coated coating materials A61L29/08
• CPC Class Codes: A61M 25/10 Balloon catheters A61M25/0125 takes precedence; embolectomy A61B17/22032; retractors A61B17/02; inflatable balloons for placing stents or stent-grafts A61F2/958 ; stomach balloons for treatment of obesity A61F5/0003; oesophagal tubes A61J15/00
• CPC Class Codes: A61M 25/1011 Multiple balloon catheters
• CPC Class Codes: A61M 25/1029 Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
• CPC Class Codes: C08L 83/04 Polysiloxanes

Abstract

A sustained release bactericidal cannula or catheter for residence within a portion of a human body through which aqueous biological fluids can pass. The bactericidal cannula for catheter including a tube having an inner surface, defining and interior lumen, and an outer surface. The tube has a polymeric matrix and antibacterial agent residing within at least a portion of the polymeric matrix. The polymeric matrix includes cured silicon rubber and the antibacterial agent is a finely divided nitrofuran compound which is soluble in water and effective to prevent proliferation of certain bacteria in an otherwise growth supporting aqueous environment when dissolved in the aqueous environment to the limit of its solubility therein at 37° C. The solubility of the nitrofuran compound is preferably about 0.2% by weight or less at a pH of about 6 and a temperature of about 25° C. The antibacterial agent can diffuse out of the polymeric matrix and into an aqueous biological environment when the polymeric matrix comes into contact with such an aqueous biological environment. Preferably, at least a finite portion of the polymeric matrix proximate the outer surface includes an amount of from about 10 to about 60% by weight of the nitrofuran compound and the amount of the nitrofuran compound and the solubility thereof cooperate to provide a potential for a sustained release diffusion thereof for a period of not less than about three weeks during normal use of the cannula within the human body. Methods of making a sustained release bactericidal cannula and of catheterizing a patient are also disclosed.

Claims

1. A sustained release bactericidal cannula, through which aqueous biological fluids can pass for residence within a portion of a human body said bactericidal cannula comprising:

a tube having an inner surface, defining an internal lumen, and an outer surface, said tube having a polymeric matrix and an antibacterial agent residing within at least a portion of the polymeric matrix;

wherein the polymeric matrix includes cured silicone rubber, said antibacterial agent is a finely divided nitrofuran compound which is soluble in water and effective to prevent proliferation of certain bacteria in an otherwise, growth supporting, aqueous environment when dissolved in the aqueous environment to the limit of its solubility therein at 37°

C., the solubility of the nitrofuran compound is about 0.2% by weight or less in water at a pH of about 6 and a temperature of about 25°

C., and the antibacterial agent can diffuse out of the polymeric matrix and into an aqueous biological environment when the polymeric matrix comes into contact with the aqueous biological environment; and

wherein at least a finite portion of the polymeric matrix proximate the outer surface includes an amount of from about 10 to about 60% by weight of the nitrofuran compound, and the amount of the nitrofuran compound in the finite portion of the polymeric matrix, and the solubility of the nitrofuran compound, cooperate to provide a potential for a sustained release diffusion of the antibacterial agent into the aqueous biological fluids within the human body, during normal therapeutic use of the cannula within the human body, so long as the aqueous biological fluids are not saturated with the antibacterial agent, such that the antibacterial agent within the finite portion of the polymeric matrix can continue to diffuse into the aqueous biological fluids within the human body in an amount effective to prevent proliferation of certain bacteria immediately adjacent to the cannula in aqueous biological environments for a period of not less than about three weeks.

2. The sustained release bactericidal cannula of claim 1 wherein the antibacterial agent has a solubility in water at a pH of about 6 and a temperature of about 25°

C. of from about 0.001 to about 0.2% by weight.

3. The sustained release bactericidal cannula of claim 2 wherein the antibacterial agent is selected from the group consisting of nitrofurazone, nitrofurantoin, furaltadone, furazolidone, nifuradene, nidroxyzone, nifuroxime and nihydrazone.

4. The sustained release bactericidal cannula of claim 2 wherein the antibacterial agent is selected from the group consisting of nitrofurazone, nitrofurantoin, furaltadone and furazolidone.

5. The sustained release bactericidal cannula of claim 2 wherein the antibacterial agent is nitrofurazone.

6. The sustained release bactericidal cannula of claim 1 wherein the polymeric matrix includes silicone fluid.

7. The sustained release bactericidal cannula of claim 1 wherein the finite portion of the polymeric matrix contains an amount of a water soluble anti-inflammatory agent sufficient to diffuse into the aqueous biological fluids and reduce inflammation within the human body immediately adjacent to the cannula.

8. A sustained release bactericidal urinary catheter for residence within a urinary tract of a human body, said bactericidal urinary catheter comprising:

a tube having an inner surface, defining an internal lumen, and an outer surface, said tube having a polymeric matrix and an antibacterial agent residing within the polymeric matrix, wherein the polymeric matrix includes silicone rubber, the antibacterial agent is a nitrofuran compound which is soluble in water and effective to reduce proliferation of bacteria in an otherwise growth supporting, aqueous environment when dissolved in the aqueous environment to the limit of its solubility therein at 37°

C., and the antibacterial agent can diffuse out of the polymeric matrix and into an aqueous biological environment when the polymeric matrix comes into contact with the aqueous biological environment; and

wherein the antibacterial agent has a solubility in water, at a pH of about 6 and a temperature of about 25°

C., of about 0.2% by weight or less, and at least a finite portion of the polymeric matrix proximate the outer surface contains an amount of from about 10 to about 60% by weight of the nitrofuran compound, and the amount of the nitrofuran compound in the finite portion of the polymeric matrix and the solubility of the nitrofuran compound cooperate to provide a potential for a sustained release diffusion of the antibacterial agent into the aqueous biological fluids within the human body during normal therapeutic use of the catheter within the urinary tract so long as the aqueous biological fluids are not saturated with the antibacterial agent, such that the antibacterial agent within the finite portion of the polymeric matrix can continue to diffuse into the aqueous biological fluids within the urinary tract in an amount effective to prevent proliferation of certain bacteria immediately adjacent to the catheter in aqueous biological environments for a period of not less than about three weeks.

9. The sustained release bactericidal urinary catheter of claim 8 wherein at least a portion of the polymeric matrix includes a cured silicone rubber matrix, and the cured silicone matrix includes silicone fluid.

10. The sustained release bactericidal urinary catheter of claim 8 wherein the nitrofuran compound is a finely divided solid compound residing within the polymeric matrix and the outer surface is a smooth polymeric surface through which the nitrofuran compound can diffuse when the outer surface comes into contact with an aqueous environment.

11. The sustained release bactericidal urinary catheter of claim 10 wherein the antibacterial agent is selected from the group nitrofurazone, nitrofurantoin, furaltadone and furazolidone.

12. The sustained release bactericidal urinary catheter of claim 8 wherein the antibacterial agent has a solubility in water at a pH of about 6 and a temperature of about 25°

C. of about 0.001 to about 0.2% by weight.

13. The sustained release bactericidal urinary catheter of claim 11 wherein the antibacterial agent is nitrofurazone.

14. The sustained release bactericidal urinary catheter of claim 8 wherein the finite portion of the polymeric matrix contains an amount of a water soluble anti-inflammatory agent sufficient to diffuse into the aqueous biological fluids and reduce inflammation within the human body immediately adjacent to the catheter.

15. The sustained release bactericidal urinary catheter of claim 14 wherein the water soluble anti-inflammatory agent is a hydrocortisone compound.

16. The sustained release bactericidal urinary catheter of claim 15 wherein the hydrocortisone compound has a solubility in water of less than about 0.1% by weight.

17. The elongated sustained release bactericidal cannula of claim 16 wherein the nitrofuran compound is a solid powder having a mean particle diameter of not more than about 200 microns.

18. The elongated sustained release bactericidal cannula of claim 16 further comprising an expandable balloon having an expandable balloon cavity, a second lumen in communication with the expandable balloon cavity, and an enclosed sleeve cavity wherein the enclosed sleeve cavity is located between the respective interior and exterior surfaces and encircling the first lumen in a position removed from the expandable balloon cavity, wherein a first portion of the silicone rubber coating coats the exterior surface proximate the expandable balloon, said first portion stretching when the expandable balloon expands, wherein the rate of diffusion of the nitrofuran compound can increase when the first portion stretches.

19. A sustained release bactericidal urinary catheter for residence within a urinary tract of a human body, the sustained release bactericidal urinary catheter comprising:

an interior surface defining a first lumen, an expandable balloon having an expandable balloon cavity, a second lumen in communication with the expandable balloon cavity, and an exterior surface, wherein the exterior surface is coated to form a coating having a silicone rubber polymeric matrix containing an antibacterial agent capable of diffusing out of the polymeric matrix in aqueous environments, the antibacterial agent is a finely divided nitrofuran compound which is soluble in water, the solubility of the nitrofuran compound is about 0.2% by weight or less in water at a pH of about 6 and a temperature of about 25°

C., and the amount of the nitrofuran compound in the silicone rubber polymeric matrix is an amount in a range from about 10 to about 60% by weight of the coating, and wherein the amount of the nitrofuran compound in the coating and the solubility of the nitrofuran compound cooperate to provide a potential for a sustained release diffusion of the antibacterial agent into the aqueous biological fluids within the human body during normal therapeutic use of the catheter within the urinary tract, so long as the aqueous biological fluids are not saturated with the antibacterial agent, such that the antibacterial agent within the coating can continue to diffuse into the aqueous biological fluids within the urinary tract in an amount effective to prevent proliferation of certain bacteria immediately adjacent to the catheter in aqueous biological environments for a period of not less than about three weeks.

20. The sustained release bactericidal urinary catheter of claim 19 wherein the silicone rubber polymeric matrix is a cured silicone rubber matrix, the silicone rubber polymeric matrix includes silicone fluid, and the nitrofuran compound is selected from the group consisting of nitrofurazone, nitrofurantoin, furaltadone, furazolidone, nifuradene, nidroxyzone, nifuroxime and nihydrazone.

21. The sustained release bactericidal urinary catheter of claim 19 wherein the coating contains an amount of a water soluble anti-inflammatory agent sufficient to diffuse into the aqueous biological fluids and reduce inflammation within the human body immediately adjacent to the catheter.

22. The sustained release bactericidal urinary catheter of claim 21 wherein the coating contains an amount of the antibacterial agent in a range from about 10 to about 60% by weight thereof and the antibacterial agent is a nitrofuran compound having a solubility of about 0.2% by weight or less in water at a pH of about 6 and a temperature of about 25°

C.

23. An elongated sustained release bactericidal cannula comprising an interior surface, defining a first lumen, an exterior surface and an enclosed sleeve cavity located between the respective interior and exterior surfaces and encircling the first lumen, said elongated bactericidal cannula further comprising a resilient sleeve portion encircling the first lumen and said sleeve cavity, said sleeve cavity containing a lubricating substance, wherein the bactericidal cannula further includes a silicone rubber coating containing an amount of an antibacterial agent effective to diffuse out of the silicone rubber coating when immersed in an aqueous environment, the silicone rubber is a cured silicone rubber matrix containing silicone fluid, the antibacterial agent is a finely divided nitrofuran compound which is soluble in water and has antibacterial activity in aqueous biological environments when dissolved in such an aqueous biological environment to the limit of its solubility in water at 37°

C., the solubility of the nitrofuran compound is about 0.001 to 0.2% by weight in water at a pH of about 6 and a temperature of about 25°

C., and the amount of the nitrofuran compound in the silicone rubber coating is an amount in a range of from about 10 to about 60% by weight of the coating.

24. The elongated sustained release bactericidal cannula of claim 23 wherein the antibacterial agent is selected of the group consisting of nitrofurazone, nitrofurantoin, furaltadone and furazolidone.

25. A method of catheterizing a patient, the patient having a urinary tract through which aqueous fluids can pass, said method comprising the steps of:

(a) providing a sustained release bactericidal urinary catheter including an interior surface defining a first lumen and an exterior surface, wherein the exterior surface is coated with a cured silicone rubber polymeric matrix forming a coating containing an antibacterial agent capable of diffusing out of the cured silicone rubber polymeric matrix in aqueous environments, wherein the antibacterial agent is a nitrofuran compound which soluble having a solubility of about 0.2% by weight or less in water at a pH of about 6 and a temperature of about 25°

C., and the amount of the nitrofuran compound in the cured polymeric matrix is in a range of from about 10-60% by weight of the total weight of the cured silicone rubber polymeric matrix, and wherein the amount of the nitrofuran compound in the coating and the solubility of the nitrofuran compound cooperate to provide a potential for a sustained release diffusion of the antibacterial agent into the aqueous biological fluids within the human body during normal therapeutic use of the catheter within the urinary tract so long as the aqueous biological fluids are not saturated with the antibacterial agent, such that the antibacterial agent within the coating can continue to diffuse into the aqueous biological fluids within the urinary tract in an amount effective to prevent proliferation of certain bacteria immediately adjacent to the catheter in aqueous biological environments for a period of not less than about three weeks;

(b) placing the catheter within the urinary tract for residence therein, wherein the aqueous fluids within the urinary tract interact with the cured silicone polymeric matrix, and a sufficient amount of the antibacterial agent is provided such that the antibacterial agent can diffuse into the aqueous fluids for a period of at least about three weeks such that the aqueous fluids are less capable of sustaining bacterial growth therein during this period as a result of the presence of the antibacterial agent.

26. The method of claim 25 wherein the nitrofuran is selected from the group consisting of nitrofurazone, nitrofurantoin, furaltadone, furazolidone, nifuradene, nidroxyzone, nifuroxime and nihydrazone.

27. The method of claim 25 wherein the step of placing includes retaining the catheter within the urinary tract for a period of at least about 20 days, wherein the antibacterial agent within the polymeric matrix continues to diffuse into the aqueous fluid in the urinary tract as the aqueous fluid passes therethrough.

28. A sustained release bactericidal cannula through which aqueous biological fluids can pass, said bactericidal cannula comprising:

a tube having a surface, the surface being coated at least in part by a polymeric material, the polymeric material providing a polymeric matrix, the polymeric matrix containing an antibacterial agent which is at least partially soluble in water, wherein the antibacterial agent can diffuse out of the polymeric matrix and into an aqueous biological environment when the polymeric matrix comes into contact with such an aqueous biological environment, wherein said antibacterial agent is a nitrofuran compound which is at least partially soluble in water and effective to prevent proliferation of certain bacteria in an otherwise, growth supporting, aqueous environment when dissolved in the aqueous environment to the limit of its solubility therein at 37°

C.

29. The sustained release bactericidal cannula of claim 28 wherein the polymeric matrix includes cured silicone rubber.

30. The sustained release bactericidal cannula of claim 29 wherein the polymeric matrix includes silicone fluid.

31. The sustained release bactericidal cannula of claim 28 wherein the antibacterial agent has a solubility in water at a pH of about 6 and a temperature of about 25°

C. of from about 0.001 to about 0.2% by weight.

32. The sustained release bactericidal cannula of claim 28 wherein the antibacterial agent is a finely divided nitrofuran compound which is soluble in water.

33. The sustained release bactericidal cannula of claim 32 wherein the antibacterial agent is selected from the group consisting of nitrofurazone, nitrofurantoin, furaltadone, furazolidone, nifuradene, nidroxyzone, nifuroxime and nihydrazone.

34. The sustained release bactericidal cannula of claim 32 wherein the antibacterial agent is selected from the group consisting of nitrofurazone, nitrofurantoin, furaltadone and furazolidone.

35. The sustained release bactericidal cannula of claim 32 wherein the antibacterial agent is nitrofurazone.

36. The sustained release bactericidal cannula of claim 32 wherein the nitrofuran compound is a solid powder having a mean particle diameter of not more than about 200 microns.

37. The sustained release bactericidal cannula of claim 28 wherein a finite portion of the polymeric matrix contains an amount of a water soluble anti-inflammatory agent sufficient to diffuse into the aqueous biological fluids and reduce inflammation within a portion of the human body immediately adjacent to the cannula.

38. The sustained release bactericidal cannula of claim 37 wherein the water soluble anti-inflammatory agent is a hydrocortisone compound.

39. The sustained release bactericidal cannula of claim 38 wherein the hydrocortisone compound has a solubility in water of less than about 0.1% by weight.

40. The sustained release bactericidal cannula of claim 28, said tube having an outer surface and inner surface, the inner surface defining an internal lumen, the outer surface being coated at least in part by the polymeric material, wherein the polymeric matrix provided by the polymeric material on the outer surface contains an amount of the antibacterial agent sufficient to diffuse out of the polymeric matrix wherein the polymeric matrix comes into contact with the aqueous biological environment.

41. The sustained release bactericidal cannula of claim 40 wherein the internal lumen is a first lumen, said cannula further including an expandable balloon having an expandable balloon cavity, a second lumen in communication with the expandable balloon cavity.

42. The sustained release bactericidal cannula of claim 40 wherein the cannula further includes a sleeve cavity encircling the internal lumen within the cannula, said sleeve cavity being located between the outer surface and the inner surface.

43. The sustained release bactericidal cannula of claim 42 further including an expandable balloon, an expandable balloon cavity, and a second lumen in communication with the expandable balloon cavity.

44. A sustained release bactericidal cannula through which aqueous biological fluids can pass, said bactericidal cannula being made from a tube having an uncured silicone rubber outer surface, said bactericidal cannula being made by a process comprising the steps of:

(a) providing an antibacterial agent containing mixture including uncured silicone rubber and finely divided particles of a solid antibacterial agent, wherein the antibacterial agent is a nitrofuran compound having a solubility in water of 0.2% by weight or less;

(b) coating at least a portion of the outer surface of the tube with the antibacterial agent containing mixture to form an uncured nitrofuran containing silicone rubber outer layer; and

(c) curing the silicone rubber of both the uncured silicone rubber outer surface and the uncured nitrofuran containing silicone rubber outer layer to form a cured antibacterial agent containing silicone rubber outer layer bonded to the silicone rubber outer surface;

wherein the step of providing includes providing an antibacterial agent containing mixture containing a sufficient amount of the nitrofuran compound that the cured antibacterial agent containing silicone rubber outer layer contains about 10 to about 60 percent by weight of the nitrofuran compound;

wherein the outer surface of the resulting bactericidal cannula is coated at least in part by a polymeric material including silicone rubber, the polymeric material providing a polymeric matrix, the polymeric matrix containing the antibacterial agent, wherein the antibacterial agent can diffuse out of the polymeric matrix and into an aqueous biological environment when the polymeric matrix comes into contact with such an aqueous biological environment, wherein said antibacterial agent is a nitrofuran compound which is at least partially soluble in water and effective to prevent proliferation of certain bacteria in an otherwise, growth supporting, aqueous environment when dissolved in the aqueous environment to the limit of its solubility therein at 37°

C.

45. The sustained release bactericidal cannula of claim 44 wherein the antibacterial agent is selected from the group consisting of nitrofurazone, nitrofurantoin, furaltadone, furazolidone, nifuradene, nidroxyzone, nifuroxime and nihydrazone.

46. The sustained release bactericidal cannula of claim 45 wherein the finite portion of the polymeric matrix contains an amount of a water soluble anti-inflammatory agent sufficient to diffuse into the aqueous biological fluids and reduce inflammation within a portion of the human body immediately adjacent to the cannula.

47. The sustained release bactericidal cannula of claim 46 wherein the water soluble anti-inflammatory agent is a hydrocortisone compound.