Heat cured gel and method of making

• US 8,858,978 B2
• Filed: 09/28/2005
• Issued: 10/14/2014
• Est. Priority Date: 09/28/2004
• Status: Expired due to Fees

• Current Assignee: Atrium Medical Corporation (Getinge AB)
• Original Assignee: Atrium Medical Corporation (Getinge AB)
• Inventors: Labrecque, Roger, McNamara, Philip, Ferraro, Joseph, Rogers, Lisa, Martakos, Paul, Karwoski, Theodore, Herweck, Steve A., Faucher, Keith M., Swanick, Thomas M.
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): EBRAHIM, NABILA G
• Application Number:
  US11/237,263
• Publication Number:
  US 20060110457A1
• Time in Patent Office: 3,303 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61F 13/02 Adhesive bandages or dressings
• CPC Class Codes: A61F 13/023 wound covering film layers without a fluid retention layer
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61K 31/225 Polycarboxylic acids
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 35/60 Fish, e.g. seahorses; Fish eggs
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• 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 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61L 2/07 Steam
• CPC Class Codes: A61L 2/081 Gamma radiation
• CPC Class Codes: A61L 2/087 Particle radiation, e.g. electron-beam, alpha or beta radiation
• CPC Class Codes: A61L 2/206 Ethylene oxide
• CPC Class Codes: A61L 2/208 Hydrogen peroxide
• CPC Class Codes: A61L 2202/24 Medical instruments, e.g. endoscopes, catheters, sharps
• CPC Class Codes: A61L 2300/22 Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• 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 2300/414 : Growth factors
• CPC Class Codes: A61L 2300/42 : Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/602 : Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 27/36 : containing ingredients of undetermined constitution or reaction products thereof , e.g. transplant tissue, natural bone, extracellular matrix isolated natural compounds, e.g. collagen A61L27/24
• CPC Class Codes: A61L 27/3604 : characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
• 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 31/005 : Ingredients of undetermined constitution or reaction products thereof
• CPC Class Codes: A61L 31/10 : Macromolecular materials
• CPC Class Codes: A61L 31/145 : Hydrogels or hydrocolloids
• CPC Class Codes: B05D 3/067 : Curing or cross-linking the coating

Abstract

A method of curing and corresponding resulting non-polymeric cross-linked gel are provided. The cross-linked gel can be combined with a medical device structure. The cross-linked gel can provide anti-adhesion characteristics, in addition to improved healing and anti-inflammatory response. The cross-linked gel is generally formed of a naturally occurring oil, or an oil composition formed in part of a naturally occurring oil, that is at least partially cured forming a cross-linked gel derived from at least one fatty acid compound. In addition, the oil composition can include a therapeutic agent component, such as a drug or other bioactive agent. The curing method can vary the application of heat in both temperature and duration to achieve a desired amount of cross-linking forming the gel.

Claims

1. A method of forming a non-polymeric gel, comprising:

providing an oil or oil composition to be cured;

determining an amount of non-polymeric cross-linking desired within the oil or oil composition as a result of curing;

applying heat at a selected temperature for a selected time period based on the determination of amount of non-polymeric cross-linking desired to achieve the desired amount of non-polymeric cross-linking within the oil or oil composition to form the non-polymeric gel;

wherein the oil or oil composition comprises one or more of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or alpha-linolenic acid (ALA);

wherein the gel further comprises at least one therapeutic agent; and

wherein release of the therapeutic agent from the gel occurs at a predetermined rate.

2. The method of claim 1, wherein the oil or oil composition comprises at least one component selected from a group of components consisting of fatty acids, monoglycerides, diglycerides, triglycerides, free fatty acids, and esters of fatty acids.

3. The method of claim 1, wherein the at least one therapeutic agent comprises an agent selected from a group of agents comprised of antioxidants, anti-inflammatory agents, anti-coagulant agents, drugs to alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissue growth stimulants, functional protein/factor delivery agents, anti-infective agents, imaging agents, anesthetic agents, chemotherapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, analgesics, prodrugs, and antiseptics.

4. The method of claim 1, wherein the oil or oil composition to be cured comprises at least partially cured oil or oil composition to reduce the amount of time required to achieve the desired amount of cross-linking.

5. The method of claim 1, wherein the step of determining comprises selecting the amount of cross-linking based on a desired rate of degradation of the gel following implantation.

6. The method of claim 5, wherein the application of heat occurs at a relatively higher temperature if more cross-linking is desired and at a relatively lower temperature if a lesser amount of cross-linking is desired.

7. The method of claim 5, wherein the application of heat occurs for a relatively greater duration of time if more cross-linking is desired and at a relatively lesser duration of time if a lesser amount of cross-linking is desired.

8. The method of claim 5, wherein curing at a relatively greater temperature for a relatively lesser amount of time results in a greater amount of cross-linking within the substance than curing at a relatively lesser temperature for a relatively greater amount of time.

9. The method of claim 5, wherein a relatively faster rate of degradation provides for a relatively faster release of therapeutic agent contained within the gel, while a relatively slower rate of degradation provides for a relatively slower and more controlled release of therapeutic agent contained within the gel.

10. The method of claim 5, wherein a relatively lesser amount of cross-links provides a relatively faster rate of degradation which provides for a relatively faster release of therapeutic agent contained within the gel, while a relatively greater amount of cross-links provides a relatively slower rate of degradation which provides for a relatively slower and more controlled release of therapeutic agent contained within the gel.

11. The method of claim 1, wherein the oil or oil composition is further comprised of at least one component selected from a group of components comprising oils and free fatty acids, that reduce the amount of time required to achieve the desired amount of cross-linking.

12. The method of claim 1, wherein the cross-linked gel is configured to provide controlled release of the therapeutic agent.

13. The method of claim 1, wherein the cross-linked gel is bio-absorbable.

14. The method of claim 1, wherein the cross-linked gel maintains at least one property selected from a group of properties comprised of anti-inflammatory properties, non-inflammatory properties, and wound healing properties.

15. The method of claim 1, further comprising sterilizing the cross-linked gel with a method of sterilization selected from a group of methods of sterilization comprising ethylene oxide, gamma radiation, e-beam, steam, gas plasma, and vaporized hydrogen peroxide (VHP).

16. The method of claim 1, further comprising pre-treating the oil or oil composition to increase viscosity prior to curing.

17. The method of claim 1, further comprising providing vitamin E, or an equivalent thereof, in the oil or oil composition to decrease a degradation rate of the cured gel.

18. A heat cured non-polymeric gel, comprising:

a plurality of non-polymeric cross-links resulting from application of heat at a selected temperature for a selected duration to an oil or oil composition to achieve a desired amount of cross-linking to form the non-polymeric gel, wherein the gel further comprises at least one therapeutic agent and the amount of non-polymeric cross-links is controlled by the application of the heat so that the release of the therapeutic agent in the gel occurs at a predetermined desired rate, and wherein the oil or oil composition comprises one or more of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or alpha-linolenic acid (ALA).

19. The gel of claim 18, wherein the oil or oil composition comprises at least one component selected from a group consisting of fatty acids, monoglycerides, diglycerides, triglycerides, free fatty acids, and esters of fatty acids.

20. The gel of claim 18, wherein the at least one therapeutic agent comprises an agent selected from a group of agents comprised of antioxidants, anti-inflammatory agents, anti-coagulant agents, drugs to alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissue growth stimulants, functional protein/factor delivery agents, anti-infective agents, imaging agents, anesthetic agents, chemotherapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, analgesics, prodrugs, and antiseptics.

21. The gel of claim 18, wherein the oil or oil composition to be cured comprises at least partially cured oil or oil composition to reduce the amount of time required to achieve the desired amount of cross-linking.

22. The gel of claim 18, wherein the gel is configured to maintain a desired rate of degradation of the gel after the gel is implanted.

23. The gel of claim 22, wherein the gel is formed with application of heat at a first temperature if more cross-linking is desired and at a second temperature if a lesser amount of cross-linking is desired, where in the first temperature is higher than the second temperature.

24. The gel of claim 22, wherein the gel is formed with application of heat for a first duration of time if more cross-linking is desired and at a second duration of time if a lesser amount of cross-linking is desired, where in the first duration is greater than the second duration.

25. The gel of claim 22, wherein a relatively lesser amount of cross-links provides a relatively faster rate of degradation which provides for a relatively faster release of therapeutic agent contained within the gel, while a relatively greater amount of cross-links provides a relatively slower rate of degradation which provides for a relatively slower and more controlled release of therapeutic agent contained within the gel.

26. The gel of claim 18, wherein the gel is further comprised of at least one component selected from a group of components comprising oils and free fatty acids, that reduce the amount of time required to achieve the desired amount of cross-linking.

27. The gel of claim 18, wherein the cross-linked gel is configured to provide controlled release of the therapeutic agent.

28. The gel of claim 18, wherein the cross-linked gel is bio-absorbable.

29. The gel of claim 18, wherein the cross-linked gel maintains at least one property selected from a group of properties comprised of anti-inflammatory properties, non-inflammatory properties, and wound healing properties.

30. The gel of claim 18, wherein the gel has been sterilized with a method of sterilization selected from a group of methods of sterilization comprising ethylene oxide, gamma radiation, e-beam, steam, gas plasma, and vaporized hydrogen peroxide (VHP).

31. The gel of claim 18, wherein the gel is configured as a coating on a medical device or as a stand-alone film.

32. The gel of claim 18, wherein the non-polymeric substance is pre-treated to increase viscosity prior to curing.

33. The gel of claim 18, further comprising vitamin E, or an equivalent thereof, in the oil or oil composition to be cured to decrease a degradation rate of the cured gel.

34. The gel of claim 18, wherein the selected duration is within a range between 24 hours and 3 days.

35. The gel of claim 18, wherein the selected temperature is 150°

F. or 200°

F.

36. A heat cured non-polymeric gel, comprising:

a plurality of non-polymeric cross-links, wherein the non-polymeric cross-links result from application of heat at a selected temperature for a selected duration to an oil or oil composition to achieve a desired amount of cross-linking to form the non-polymeric gel, wherein the desired amount of cross-linking is selected based on a desired rate of degradation of the gel after the gel is implanted, and wherein the oil or oil composition comprises one or more of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or alpha-linolenic acid (ALA).