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Novel heparin entities and methods of use

a technology of heparin and heparin-like cells, applied in the field of new heparin-like cells, can solve the problems of adverse body response, loss of medical device function, and negative impact on the biological activity of these “biologics”

Inactive Publication Date: 2011-03-17
WL GORE & ASSOC INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to medical substrates that have heparin entities immobilized onto them. These substrates retain significant biological activity after immobilization, sterilization, mechanical compaction, and storage. The heparin entities can be bound onto the substrate via at least one heparin molecule, and the substrate can be selected from a variety of materials such as polyethylene, polyurethane, silicone, polyamide-containing polymers, polypropylene, polytetrafluoroethylene, and biocompatible metals. The heparin entities can also be bound onto the substrate via at least one heparin molecule and a core molecule such as a protein, hydrocarbon, aminoglycoside, polysaccharide, or polymer. The invention also includes a method for determining the structure of the heparin entity bonded to the substrate using depolymerization and column chromatography. The substrate can be a component of a medical device such as a graft, stent, or catheter.

Problems solved by technology

However, the use of biomaterials in medical devices can stimulate adverse body responses, including rapid thrombogenic action.
These actions lead to vascular constriction that hinder blood flow, and the inflammatory reaction that follows can lead to the loss of function of the medical device.
When biologically active compounds, compositions, or entities are immobilized, the biological activity of these “biologics” can be negatively impacted by the process of immobilization.
Despite an optimized covering and immobilization scheme, additional processing, such as sterilization, can degrade the biological activity of the immobilized biologic.
Sterilization of such devices often requires exposure of the devices to elevated temperature, pressure, and humidity, often for several cycles.
In addition to sterilization, mechanical compaction and expansion, or long-term storage of an immobilized biologic can degrade the activity of the biologic.

Method used

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  • Novel heparin entities and methods of use
  • Novel heparin entities and methods of use
  • Novel heparin entities and methods of use

Examples

Experimental program
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example 1

[0065]This example describes the construction of heparin entities comprising heparin and colistin sulfate as the core. This heparin entity contains free terminal aldehydes that can be used for attachment to a surface of a substrate.

[0066]Colistin sulfate (0.10 g, Alpharma, Inc.) was dissolved in 300 ml of deionized (DI) water containing MES buffer (pH 4.7, BupH™ Thermo Scientific). To this was added 10 g USP heparin, 4 g N-hydroxysulfosuccinimide (sulfo-NHS, Thermo Scientific), and 4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC hydrochloride, Sigma-Aldrich, St. Louis, Mo.). The reaction was allowed to proceed at room temperature for 4 hours, followed by dialysis overnight with a 50,000 MWCO membrane (Spectra / Por®). The retentate (about 350 ml out of 500 ml) was transferred to a beaker, and cooled to 0° C. Sodium nitrite (10 mg) and acetic acid (2 ml) were added and the reaction was allowed to proceed for 1 hour at 0° C. Dialysis was performed overnight with a 50,000 MWCO ...

example 2

[0067]This example describes the construction of heparin entities comprising heparin and neomycin sulfate as the core. This heparin entity contains free terminal aldehydes that can be used for attachment to a surface of a substrate.

[0068]Neomycin sulfate (0.0646 g, Spectrum Chemical) was dissolved in 300 ml of DI water containing MES buffer (pH 4.7, BupH™ Thermo Scientific). To this was added 10 g USP heparin, 4 g N-hydroxysulfosuccinimide (sulfo-NHS), and 4 g of EDC hydrochloride. The reaction was allowed to proceed at room temperature for 4 hours, followed by dialysis overnight with a 50,000 MWCO membrane (Spectra / Por®). The retentate (about 400 ml out of 505 ml) was transferred to a beaker and cooled to 0° C. Sodium nitrite (10 mg) and acetic acid (2 ml) were added and the reaction was allowed to proceed for 1 hour at 0° C. Dialysis was performed overnight with a 50,000 MWCO membrane with the addition of 1 g NaCl to the dialysis liquid. The dialyzed retentate was filtered twice u...

example 3

[0069]This example describes the construction of heparin entities comprising heparin and capreomycin sulfate as the core. This heparin entity contains free terminal aldehydes that can be used for attachment to a surface of a substrate.

[0070]Capreomycin sulfate (0.0501 g, Sigma-Aldrich, St. Louis, Mo.) was dissolved in 300 ml of DI water containing MES buffer (pH 4.7, BupH™ Thermo Scientific). To this was added 10 g USP heparin, 4 g N-hydroxysulfosuccinimide (sulfo-NHS), and 4 g of EDC hydrochloride. The reaction was allowed to proceed at room temperature for 4 hours. The reaction mixture was filtered once using a 20 micrometer, 0.00079 inches U.S.A. standard testing sieve, A.S.T.M.E.-11 specification No. 635 to remove small particles and the filtrate was dialyzed overnight with a 50,000 MWCO membrane (Spectra / Pore). The retentate (about 400 ml out of 515 ml) was transferred to a beaker and cooled to 0° C. Sodium nitrite (10 mg) and acetic acid (2 ml) were added and the reaction was ...

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Abstract

The present invention relates to immobilized biologically active entities that retain a significant biological activity following manipulation. The invention also comprises a medical substrate comprising a heparin entity bound onto a substrate via at least one heparin molecule, wherein said bound heparin entity is heparinase-1 sensitive.

Description

RELATED APPLICATION[0001]The present application is a continuation of U.S. application Ser. No. 12 / 561,927, filed Sep. 17, 2009, the content of which is incorporated by reference in its entirety for all purposes.FIELD OF THE INVENTION[0002]The present invention relates to medical substrates having immobilized biologically active entities that maintain their biological activity after sterilization. Specifically the present invention relates to new heparin entities and their method of use.BACKGROUND OF THE INVENTION[0003]Medical devices which serve as substitute blood vessels, synthetic and intraocular lenses, electrodes, catheters and the like in and on the body or as extracorporeal devices intended to be connected to the body to assist in surgery or dialysis are well known. However, the use of biomaterials in medical devices can stimulate adverse body responses, including rapid thrombogenic action. Various plasma proteins play a role in initiating platelet and fibrin deposition on b...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/527
CPCA61L27/54A61L29/16A61L31/022A61L31/048A61L31/10A61L31/16A61L33/128A61L2300/236A61L2300/42A61L33/0011A61L33/08C08L27/12A61P25/00A61P9/00
Inventor BIRAN, ROYCLAUDE, CHARLES D.CLEEK, ROBERT L.DRUMHELLER, PAUL D.
Owner WL GORE & ASSOC INC
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