Coatings comprising protein resistant components and therapeutic components on medical devices are disclosed. The coatings act to down-regulate complement activation. Medical devices can be coated with these coatings to prevent side effects and improve patency.

Description of the Invention

SUMMARY OF THE INVENTION

One embodiment is a medical device comprising a structure adapted for introduction into a patient, wherein the structure comprises a surface; a layer of surfactant adsorbed on the surface of the medical device, wherein the surfactant on the surface of the medical device is substantially non-activating or deactivating to the complement cascade as compared to the non-coated surface of the medical device.

A related aspect is a method for coating a medical device with a surface coating comprising: providing the medical device with a surface; providing a surfactant;adsorbing the surfactant on the surface of the medical device; wherein the surfactant on the surface of the medical device is substantially non-activating or deactivating to the complement cascade as compared to the non-coated surface of the medical device.

One embodiment is a class of compounds for coating a medical device with the formula -- see Original Patent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

A combined approach is described herein that provides advantages both in terms of manufacturability and expected clinical outcomes for ECC devices, cardiovascular devices and other medical devices. In this approach, a coating is applied to the device comprising a protein-resistant component and a therapeutic component. The coating renders the material inert and prevents activation of the complement and coagulation systems. In preferred embodiments, one or more areas of the materials are coated with a copolymer that is also end group activated to link to a therapeutic entity. The therapeutic entity can be a protein, peptide, oligonucleotide, protein fragment, protein analog, proteoglycan, antibody, carbohydrate, drug or other natural or synthetic molecule that is capable of down-regulating the complement or coagulation systems. Hence, a coating of preferred embodiments provides a component for rendering the material inert and a component for preventing activation of the complement or coagulation systems and is shown below -- see Original Patent.

In certain embodiments, the surface to be coated is hydrophobic. Examples of preferred surfaces include, but are not limited to, polystyrene, polyurethane, polyethersulfone, polytetrafluoroethylene, and silicone. Lesser hydrophobic materials and biodegradable materials are also included in preferred embodiments. These materials include, but are not limited to, polyvinyl acetate (PVAC), cellulose acetate, biodegradable polymers such as (PGA), polylactide (PLA), poly(.epsilon.-caprolactone, poly(dioxanone) (PDO), trimethylene carbonate, (TMC) polyaminoacids, polyesteramides, polyanhydrides, polyorthoesters and copolymers of these materials.

The coating composition can also be used to coat metals, including, but not limited to, stainless steel, nitinol, tantalum and cobalt chromium alloys. It is recognized that some metals may require a pretreatment to achieve stable bonding of the coating composition to the substrate. Such pretreatments are well known to those skilled in the art and may involve such processes as silanization or plasma modification. A coating is applied to the material in the form of a multiblock copolymer that contains one or more hydrophilic domains and at least one hydrophobic domain. The hydrophobic domain can be adsorbed to a hydrophobic surface by hydrophobic bonding while the hydrophilic domains can remain mobile in the presence of a fluid phase.

Preferred copolymer units for forming the copolymer coating of preferred embodiments include, but are not limited to, polyethylene oxide (PEO) and polypropylene oxide (PPO), PEO and polybutadiene, PEO and poly(N-acetylethyleneimine), PEO and phenyl boronic acid, PEO and polyurethane, PEO and polymethylmethacrylate (PMMA), and PEO and polydimethyl sulfoxide. In the preceding pairs of copolymer units, preferably, the hydrophilic domain comprises PEO. Copolymers using copolymer units of this type and their application to coating materials to prevent protein adsorption have been described previously[39, 41-48].

In a certain embodiment, the copolymer comprises pendant or dangling hydrophilic domains, such as poly(ethylene oxide) (PEO) chains. The other domain(s) of the copolymer comprises a hydrophobic domain, such as a poly(propylene oxide) (PPO) chain. Additionally, a linking group (R) is attached to the copolymer on one end adjacent to the hydrophilic domain to form an end-group activated polymer. For example, the end-group activated polymer may be in the form of any arrangement of the PEO and PPO blocks with the general formula: (R--PEO).sub.a(PPO).sub.b (1) where a and b are integers, are the same or different and are at least 1, preferably a is between 1 and 6, and b is between 1 and 3, more preferably a is 1 to 2, and b is 1. The polymeric block copolymer has a PEO (--C.sub.2H.sub.4--O--) content between 10 wt % and 80 wt %, preferably 50 wt % and 80 wt %, more preferably between 70 wt % and 80 wt %.

The PEO chains or blocks are of the general formula: --(--C.sub.2H.sub.4--O--).sub.u (2) where u is the same or different for different PEO blocks in the molecule. Typically, u is greater than 50, preferably between 50 and 150, more preferably between 80 and 130. The PPO blocks are of the general formula; --(--C.sub.3H.sub.6--O--).sub.v (3) where v may be the same or different for different PPO blocks in the molecule. Typically, v is greater than 25, preferably between 25 and 75, more preferably between 30 and 60.

The copolymers may be branched structures and include other structures (e.g. bridging structures, or branching structures) and substituents that do not materially affect the ability of the copolymer to adsorb upon and cover a hydrophobic surface. Examples include the following copolymers described in the following paragraphs.

In another embodiment, the end-group activated polymer of preferred embodiments is a derivative of a polymeric tri-block copolymer with pendant R groups, as in Formula (4), below. For example, these tri-block copolymers have a hydrophobic center block of polypropylene oxide and hydrophilic end blocks of polyethylene oxide with terminal R groups, and can be represented by the formula: R--(--C.sub.2H.sub.4--O--).sub.x--(--C.sub.3H.sub.6--O--).sub.y--(--C.sub- .2H.sub.4--O--).sub.z--H (4) where y is between 25 and 75, preferably between 30 and 60, and x and z are preferably the same, but may be different, and are between 50 and 150, preferably 80 and 130. Certain types of these polymeric surfactants are commercially referred to as "PLURONIC.TM." or "POLOXAMERS.TM.", and are available, for example, from BASF. As used herein, "PLURONIC" refers to an end-group activated polymer.

Another suitable class of polymeric block copolymers is the di-block copolymers where a=1 and b=1, and can be represented by the formula; R--PEO--PPO--H (5) where PEO and PPO are defined above.

Another suitable class of polymeric block copolymers is represented by the commercially available TETRONIC.TM. surfactants (from BSAF), which are represented by the formula: (R--(O--C.sub.2H.sub.4).sub.u--(O--C.sub.3H.sub.6).sub.v).sub.2N--CH.sub.- 2--CH.sub.2--N((--C.sub.3H.sub.6--O--).sub.v--(--C.sub.2H.sub.4--O--).sub.- u--H).sub.2 (6)

As used herein, the terms "PLURONIC" or "PLURONICS" refer to the block copolymers defined in Equation (1), which include the PLURONICS.TM. tri-block copolymer surfactants, the di-block surfactants, the TETRONIC.TM. surfactants, as well as other block copolymer surfactants as defined.

As disclosed previously, a specific functional group is attached to the free end of a hydrophilic domain to form an end-group activated polymer. The specific functional group (R) may contain a member of the reactive group, such as, hydrazine group, maleimide group, thiopyridyl group, tyrosyl residue, vinylsulfone group, iodoacetimide group, disulfide group or any other reactive group that is stable in an aqueous environment and that does not significantly impair the adsorption of the copolymer on the surface. R may also comprise functional groups capable of forming ionic interactions with proteins, for example a nitrilotriacetic acid (NTA) group, which, when bound to a metal ion forms a strong bond with histidine tagged proteins. NTA modified PLURONICS are described in U.S. Pat. No. 6,987,452 to Steward et al., hereby incorporated by reference. R may also comprise oligonucleotides that can bind to oligonucleotide tagged proteins. Oligonucleotide modified PLURONICS are described in PCT application No PCT/US02/03341 to Neff et al., hereby incorporated by reference.

In a preferred embodiment, the R group comprises an R'--S--S group where R' is to be displaced for the immobilization of a therapeutic entity. In one embodiment, the substituent R' can be selected from the group consisting of (1) 2-benzothiazolyl, (2) 5-nitro-2-pyridyl, (3) 2-pyridyl, (4) 4-pyridyl, (5) 5-carboxy-2-pyridyl, and (6) the N-oxides of (2) to (5). A preferred end group includes 2-pyridyl disulfide (PDS). The reactivity of these groups with proteins and polypeptides is discussed in U.S. Pat. No. 4,149,003 to Carlsson et al. and U.S. Pat. No. 4,711,951 to Axen et al, all of which are hereby incorporated by reference. As mentioned above, end group activated polymers (EGAP)s are generally a class of composition comprising a block copolymer backbone and an activation or reactive group.

Preferred embodiments include the use of EGAP coatings for inhibiting biological signaling pathways. In that respect, the second component of the coating of preferred embodiments can be a therapeutic entity that is attached to the material through the activated end groups of the EGAP. The therapeutic entity can be a protein, protein fragment, peptide, oligonucleotide, carbohydrate, proteoglycan or other natural or synthetic molecule that is capable of down-regulating the complement or coagulation systems. As mentioned above, many therapeutic factors that influence the complement and/or coagulation cascades have been described recently and many of these can be considered practical options for down-regulating complement or coagulation from the solid phase as described herein. Regulators of complement activation, including, but not limited to, factor H, factor H like protein 1 (FHL-1), factor H related proteins (FHR-3, FHR-4), C4 binding protein (C4bp), complement receptor 1 (CR1), decay-accelerating factor (DAF), and membrane cofactor protein (MCP), VCP SPICE, and compstatin can be used for this purpose. RCA proteins can be acquired from either natural sources or produced recombinantly. Furthermore, the active domains of these proteins have been identified and recombinantly produced fragments that include these domains or variants of these domains may be used. In a certain embodiment, more than one therapeutic entity can be immobilized onto one surface with the use of EGAP material. The use of EGAP for protein immobilization has been described previously by Caldwell and others. However, Caldwell and others used EGAP to prepare biologically active surfaces for the purpose of evaluating or promoting specific protein-protein interactions and cell adhesion to surfaces [49-53].

Alternatively, the second component of the coating of preferred embodiments can be a therapeutic entity that is capable of removing specific components from a fluid. For example, to remove specific components from blood, the second component can be an antibody.

In a certain embodiment, a material is coated with a block copolymer that displays an immobilized factor H with a disulfide group as a linker to the block copolymer. Factor H is a plasma protein that acts as a multifaceted complement regulator [54]. It facilitates the degradation of C3b by acting as a cofactor to factor I; it has decay accelerating activity for the alternate pathway C3 convertase, (C3bBb); and it competes with Factor B for binding to C3b. It has also been reported to interfere with the C1 complex and may, thereby, inhibit the classical pathway [55]. Because it can potentially down-regulate both the classical and the alternative pathways of complement, factor H is a preferred candidate for developing materials for ECC devices and other medical devices. It is also advantageous to use factor H from the standpoint that it is natural component of blood and is therefore not likely to cause side effects given the amounts that would be incorporated on a material surface. Furthermore, Andersson et al have previously investigated the potential to use Factor H as a complement regulator from the solid phase and found that indeed, the protein can function to down regulate complement when attached to a material surface [39]. However, limitations were encountered in Andersson et al. that indicated that an improved technique for bonding the protein to surfaces was needed. The approach described herein addresses these limitations and provides a valuable method for improving biocompatibility and, simultaneously, incorporating a therapeutic component into materials used for medical devices.

The modified polymeric surfactant adsorbs with the hydrophobic domain of the copolymer upon the hydrophobic surface and the pendant hydrophilic domain of the copolymer and attached therapeutic entity dangling away from the surface into the aqueous surroundings. Using a triblock copolymer as an example, the adsorbed surface can be illustrated by the formula below -- see Original Patent.

As used herein, the term "surfactant" refers to a surface-active substance. A surfactant can adhere to a surface and provide an effect. In a preferred embodiment, a surfactant can render a surface inert and prevent activation of the complement and coagulation systems.

Preferred embodiments provide for a method for coating a medical device with a surface coating comprising: providing the medical device with a surface; providing a surfactant; adsorbing the surfactant on the surface of the medical device; wherein the surfactant on the surface of the medical device is substantially non-activating or deactivating to the complement cascade as compared to the non-coated surface of the medical device. In a certain embodiment, a medical device comprises a surfactant comprising a block copolymer. In another embodiment, a medical device comprises a surfactant comprising a block copolymer comprising hydrophobic regions and hydrophilic regions. In another embodiment, a medical device comprises a surfactant comprising a PLURONICS block copolymer. In another embodiment, a medical device comprises a surfactant comprising a therapeutic entity attached thereto. In another embodiment, a medical device comprises a surfactant comprising a compound with the formula -- see Original Patent.

Preferred embodiments can be formed by dipcoating a substrate in a aqueous solution containing EGAP. The EGAP material is applied to the substrate in a solution of water, buffer, or a combination of water and an organic solvent, such as alcohol. Due to their ampiphilic nature, these copolymers will self assemble on hydrophobic materials from aqueous solutions. The hydrophobic block forms a hydrophobic bond with the material while the hydrophilic blocks remain mobile in the fluid phase. In this way, the hydrophilic chains form a brush like layer at the surface that prevents adsorption of proteins and cells.

When the EGAP material is bonded to the substrate, the material displays an aryl disulfide. A therapeutic entity comprising at least one cysteine is incubated with the substrate containing the EGAP material. Through a nucleophilic reaction, the therapeutic entity is bonded to the EGAP material by a disulfide bond.

Alternatively, preferred embodiments can be formed by dipcoating a substrate with an EGAP material and subsequently linking a therapeutic entity with a heterobifunctional crosslinker. As like the above procedure, the EGAP material is applied to the material in a solution of water, buffer, or a combination of water and an organic solvent, such as alcohol. When the EGAP material is bonded to the substrate, the material displays an activated end group. A therapeutic entity is incubated with a heterobifunctional crosslinker; hence, the therapeutic entity would display a crosslinkable functional group. The therapeutic entity linked to the crosslinker is then incubated with the EGAP material to react with the activated end group. Therefore, the preferable active functional groups on the heterobifunctional crosslinker are sulfhydryl group or sulfhydryl reactive group, to react with a terminal disulfide on the EGAP material or sulfhydryl group on the reduced EGAP material, respectively, and any functional group that is reactive toward an available functional group on the therapeutic entity. Ideally, the crosslinker would not alter the activity of the protein and could react with the protein under mild conditions. Such crosslinkers are commercially available from a number of manufacturers. Examples of preferred crosslinkers include N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), m-Maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), and N-Succinimidyl S-Acetylthioacetate (SATA).

Advantages of preferred embodiments include the use of a non hazardous coating method, no harsh environmental conditions, no toxic chemicals and no toxic waste products. Preferred embodiments incorporate a simple coating method that is readily incorporated in production process and does not require highly skilled personnel.

Alternatively, preferred embodiments include a therapeutic entity that is attached to the material of a medical device. The therapeutic entity can be a protein, protein fragment, peptide, oligonucleotide, carbohydrate, proteoglycan or other natural or synthetic molecule that is capable of down-regulating the complement or coagulation systems. As mentioned above, many therapeutic factors that influence the complement and/or coagulation cascades have been described recently and many of these can be considered practical options for down-regulating complement or coagulation from the solid phase as described herein. Regulators of complement activation, including, but not limited to, Factor H, factor H like protein 1 (FHL-1), factor H related proteins (FHR-3, FHR-4), C4 binding protein (C4bp), complement receptor 1 (CR1), decay-accelerating factor (DAF), membrane cofactor protein (MCP), VCP and SPICE can also be used for this purpose. Factor H can immobilize to certain materials, such as stainless steel and nitinol, without the use of EGAP. Factor H can effectively be immobilized on both metal substrates by direct adsorption.

The composition of preferred embodiments can be used for any medical device that is in contact with blood. The term "medical device" appearing herein is a device having surfaces that contact human or animal bodily tissue and/or fluids in the course of their operation. The definition includes endoprostheses implanted in blood contact in a human or animal body such as balloon catheters, A/V shunts, vascular grafts, stents, pacemaker leads, pacemakers, heart valves, and the like that are implanted in blood vessels or in the heart. The definition also includes within its scope devices for temporary intravascular use such as catheters, guide wires, and the like which are placed into the blood vessels or the heart for purposes of monitoring or repair. The medical device can be intended for permanent or temporary implantation. Such devices may be delivered by or incorporated into intravascular and other medical catheters.

The compositions of preferred embodiments can be used for any device used for ECC. As stated above, ECC is used in many medical procedures including, but not limited to, cardiopulmonary bypass, plasmapheresis, plateletpheresis, leukopheresis, LDL removal, hemodialysis, hemofiltration filters, ultrafiltration, and hemoperfusion. Extracorporeal devices for use in surgery include blood oxygenators, blood pumps, blood sensors, tubing used to carry blood and the like which contact blood which is then returned to the patient.

In a preferred embodiment, a medical device comprises a structure adapted for introduction into a patient, wherein the structure comprises a surface; a layer of surfactant adsorbed on the surface of the medical device, wherein the surfactant on the surface of the medical device is substantially non-activating or deactivating to the complement cascade as compared to the non-coated surface of the medical device. In a certain embodiment, a medical device comprises a surfactant comprising a block copolymer. In another embodiment, a medical device comprises a surfactant comprising a block copolymer comprising hydrophobic regions and hydrophilic regions. In another embodiment, a medical device comprises a surfactant comprising a PLURONICS block copolymer. In another embodiment, a medical device comprises a surfactant comprising a therapeutic entity attached thereto. In another embodiment, a medical device comprises a surfactant comprising a compound with the formula -- see Original Patent.

Claim 1 of 12 Claims

1. A medical device comprising: a structure adapted for introduction into a patient, wherein the structure comprises a surface; a layer of coating adsorbed on the surface of the medical device; wherein the coating comprises a block copolymer further comprising at least one regulator of complement activation bound through an end group of the block copolymer; and wherein the regulator of complement activation is selected from the group consisting of factor H, factor H like protein 1 (FHL-1), factor H related proteins, C4 binding protein (C4bp), complement receptor 1 (CR1), compstatin, decay-accelerating factor (DAF), membrane cofactor protein (MCP), vaccinia virus complement control protein (VCP), small pox inhibitor of complement enzymes (SPICE), and fragments thereof such that the surface of the medical device is deactivating to the complement cascade as compared to a non-coated surface of the medical device.
 

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