Implantable or insertable medical devices for controlled drug delivery

• US 8,133,501 B2
• Filed: 02/28/2003
• Issued: 03/13/2012
• Est. Priority Date: 02/08/2002
• Status: Active Grant

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Inventors: Li, Jianmin, Conley, Danielle, Couto, Weenna Bucay, Dao, Cang Duy, Davoudi, Hamid, Lareau, Raymond, Miller, Kathleen M.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US10/377,131
• Publication Number:
  US 20030224033A1
• Time in Patent Office: 3,301 Days
• Field of Search: None
• US Class Current: 424/425
• CPC Class Codes: A61F 2002/072 Encapsulated stents, e.g. wire or whole stent embedded in lining
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61L 2/232 layered or coated
• CPC Class Codes: A61L 2300/40 characterised by a specific therapeutic activity or mode of action
• CPC Class Codes: A61L 2300/402 Anaestetics, analgesics, e.g. lidocaine
• 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 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61L 31/18 Materials at least partially X-ray or laser opaque
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Implantable or insertable medical devices are provided, which comprises: (a) a biocompatible polymer; and (b) at least one therapeutic agent selected from an anti-inflammatory agent, an analgesic agent, an anesthetic agent, and an antispasmodic agent. The medical devices are adapted for implantation or insertion at a site associated with pain or discomfort upon implantation or insertion. In many embodiments, the therapeutic will be selected from at least one of (i) ketorolac and pharmaceutically acceptable salts thereof (e.g., ketorolac tromethamine) and (ii) 4-diethylamino-2-butynylphenylcyclohexyl glycolate and pharmaceutically acceptable salts thereof (e.g., oxybutynin chloride). Also provided are uses for the implantable or insertable medical devices, which uses comprise reducing pain or discomfort accompanying the implantation or insertion of such devices. Further uses may comprise reducing microbial buildup along the device. Methods for manufacturing implantable or insertable medical devices are also provided.

Claims

1. An implantable or insertable medical device comprising:

a single-layer matrix polymer structure formed from a mixture comprising an extruded polymeric matrix region comprising (a) a biocompatible polymer, (b) a radio-opacifying agent, and (c) at least one therapeutic agent, wherein said medical device is adapted for implantation or insertion at a site that is associated with pain or discomfort upon implantation or insertion,

wherein said radio-opacifying agent is bismuth subcarbonate,

wherein said therapeutic agent is ketorolac and pharmaceutically acceptable salts thereof, and

wherein said biocompatible polymer is an ethylene-vinyl acetate (EVA) copolymer.

2. The implantable or insertable medical device of claim 1, wherein said medical device comprises (a) a first extruded polymeric matrix region comprising a first biocompatible polymer and said therapeutic agent, and (b) a second extruded polymer matrix region comprising a second biocompatible polymer and said radio-opacifying agent, wherein said first and second biocompatible polymers may be the same or different.

3. The implantable or insertable medical device of claim 1, wherein said extruded polymeric matrix region comprises 5-20% therapeutic agent.

4. The implantable or insertable medical device of claim 1, wherein said therapeutic agent is ketorolac tromethamine.

5. The implantable or insertable medical device of claim 1, wherein said extruded polymeric matrix region comprises 15-30% radio-opacifying agent.

6. The implantable or insertable medical device of claim 1, further comprising a barrier layer.

7. The implantable or insertable medical device of claim 1, further comprising an antimicrobial agent.

8. The implantable or insertable medical device of claim 1, further comprising a hydrogel.

9. The implantable or insertable medical device of claim 1, wherein the extruded polymeric matrix region comprises ethylene-vinyl acetate (EVA) copolymer, ketorolac tromethamine and bismuth subcarbonate.

10. The implantable or insertable medical device of claim 9, wherein the degradation level of the ketorolac tromethamine is less than 2%.

19. The implantable or insertable medical device of claim 1, wherein the implantable or insertable medical device is a ureteral stent.

21. The implantable or insertable medical device of claim 9, wherein the implantable or insertable medical device is a ureteral stent.

22. The implantable or insertable medical device of claim 1, wherein said medical device is a ureteral stent and wherein the cumulative release of therapeutic agent is in an amount selected from 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, and 99%, relative to the total therapeutic agent in the device, after implantation or insertion at said site for a period selected from 1 day, 2 days, 4 days, 1 week, 2 weeks, 1 month, 2 months, 4 months, 1 year and 2 years.

23. The device of claim 1, further comprising a lubricious layer comprising one or more hydrogels comprising a hydrophilic polymeric material.

11. A method of manufacturing an implantable or insertable medical device that comprises a polymeric matrix region comprising:

(a) a biocompatible polymer, (b) at least one therapeutic agent selected from ketorolac and pharmaceutically acceptable salts thereof and (c) a radio-opacifying agent, wherein said medical device is adapted for implantation or insertion at a site that is associated with pain or discomfort upon implantation or insertion, said method comprising;

providing a combination comprising said biocompatible polymer, said therapeutic agent and said radio-opacifying agent;

extruding said combination; and

forming said polymeric matrix from said combination into a single-layer matrix polymer structure, wherein said radio-opacifying agent is bismuth subcarbonate, and wherein said biocompatible polymer is an ethylene-vinyl acetate (EVA) copolymer.

12. The method of claim 11, wherein forming said polymeric matrix comprises (a) forming an initial blend comprising said biocompatible polymer and said radio-opacifying agent;

(b) combining said initial blend and said therapeutic agent; and

(c) forming said polymeric matrix.

13. The method of claim 12, wherein said initial blend is formed using a thermoplastic process.

14. The method of claim 12, wherein said initial blend is formed using an extrusion process.

15. The method of claim 13, wherein said polymeric matrix is formed using a further thermoplastic process.

16. The method of claim 15, wherein said further thermoplastic process is conducted under conditions such that substantial degradation of said therapeutic agent is avoided.

17. The method of claim 15, wherein said further thermoplastic process is conducted under conditions such that degradation of said therapeutic agent is less than 2%.

18. The method of claim 12, wherein said initial blend is formed using a solution process.

20. The method of claim 11, wherein the implantable or insertable medical device is a ureteral stent.