Multilayer antimicrobial coated catheter with top coating layer having lower active pharmaceutical ingredient concentration

Abstract

A multilayer catheter having antimicrobial properties includes a catheter body comprising a lumen, the catheter body forming a catheter substrate, an inner coating layer disposed on the catheter substrate, and a top coating layer disposed on the inner coating layer. The inner coating layer includes an antimicrobial active pharmaceutical ingredient (API) having a first concentration in the inner coating layer. The top coating layer includes the first antimicrobial API having a second concentration in the top coating layer. The first concentration is greater than the second concentration. The catheter body may include a plurality of lumens. The catheter substrate and the inner coating layer may be integral such that the catheter substrate is impregnated with the first antimicrobial API. The multilayer catheter may include a plurality of inner coating layers having different antimicrobial API concentrations.

Description

MULTILAYER ANTIMICROBIAL COATED CATHETER WITH TOP COATING LAYER HAVING LOWER ACTIVE PHARMACEUTICAL INGREDIENT CONCENTRATIONBACKGROUND

[0001] The invention relates to indwelling catheters which release or elute an antimicrobial active pharmaceutical ingredient (API). More specifically, the invention relates to a multilayer catheter wherein the layers comprise an antimicrobial API and the concentration of antimicrobial API in an inner coating layer or substrate is greater than the concentration of antimicrobial API in a top coating layer. Because the top coating layer has a lower antimicrobial API concentration, the initial burst API release / elution rate is lower. Because the inner coating layer or substrate has a higher antimicrobial API concentration, the extended API release / elution rate is higher.

[0002] Catheters are commonly used for a variety of infusion therapies. Infusion therapy is one of the most common health care procedures. Hospitalized, home care, and other patients receive fluids, pharmaceuticals, and blood products via a vascular access device inserted into the vascular system. Infusion therapy may be used to treat an infection, provide anesthesia or analgesia, provide nutritional support, treat cancerous growths, maintain blood pressure and heart rhythm, or many other clinically significant uses. For example, catheters are used for infusing fluids, such as normal saline solution, various medicaments, and total parenteral nutrition into a patient, withdrawing blood from a patient, as well as monitoring various parameters of the patient’s vascular system.

[0003] Catheters are commonly introduced into the vasculature of a patient as part of an intravenous catheter assembly. For short PIVC, the catheter assembly generally includes a catheter hub, which supports the catheter, the catheter hub being coupled to a needle hub which supports an introducer needle. The introducer needle is extended and positioned within the catheter such that a beveled portion of the needle is exposed beyond a tip of the catheter. Thebeveled portion of the needle is used to pierce the skin of the patient to provide an opening whereby to insert the needle in the vasculature of the patient. Following insertion and placement of the catheter, the introducer needle is removed from the catheter thereby providing intravenous access to the patient. For longer catheters such as PICC and CVC, the catheters are inserted into the patient through the use of introducer needle, dilater, and guidewire in a method such as Seidinger or modified Seidinger techniques.

[0004] Catheter-related bloodstream infection (CRBSI) is a major concern with indwelling catheters such as peripherally inserted central catheters (PICCs) and central venous catheters (CVCs). Concern with CRBSI has also been raised with respect to peripheral intravenous catheters (PIVCs) and midline catheters.

[0005] Catheter-related bloodstream infections (CRBSIs) are caused by the colonization of indwelling intravascular catheter surfaces by microorganisms that can migrate into the bloodstream causing systemic infection. These infections are an important cause of illness and excess medical costs, as approximately 250.000 - 400,000 cases of central venous catheter (CVC) associated bloodstream infections occur annually in US hospitals. In addition to the monetary costs, these infections are associated with anywhere from 20,000 to 100,000 deaths each year. Despite guidelines to help reduce healthcare associated infections (HAIs), catheter- related bloodstream infections continue to plague our healthcare system.

[0006] Coating catheters with various antimicrobial agents is one approach that has been implemented to prevent these infections. Catheter manufacturers have been working on technologies to integrate an antimicrobial active pharmaceutical ingredient (API) such as silver, chlorhexidine (CHX), chlorhexidine acetate (CHA), etc. into their products either as a component of the bulk catheter material or as an additive of a surface coating. Many of these technologies function when sufficient amount of API (meeting minimum efficacy concentration) is eluted into the surrounding area killing the microorganisms.

[0007] However, API elution is a function of coating thickness, API concentration, and time, among other factors. The API present on the top surface will release or elute out much quicker than the API further away from the top surface. The elution will also decrease over time as more API elutes out and the API concentration near the surface is diminished.

[0008] FIG. 1 shows an example of the daily elution rate of four different coatings of various thickness but same API concentration within the coating composition. On Day 1, the initial elution rates (burst elution rate) were significantly higher than subsequent indwell days. The elution rate increases with coating thickness. It should be noted that Day 1 elution rate for the thickest coating was close to the unacceptable toxicity limit.

[0009] FIG. 2 shows the daily elution concentration of the same example as in FIG. 1 , but at a different scale and longer duration. The daily elution decreased significantly from Day 1 with increasing indwell days. Some configurations had daily elution below the minimum limit for efficacy on day 2, while other configurations had unacceptable daily elution at later time. However, all configurations had unacceptable elution rate post 10 days to meet the antimicrobial efficacy requirements.

[0010] To increase the antimicrobial efficacy duration, the coating thickness and / or API concentration must be increased. However, this would cause the risk of the initial Day 1 elution rate (burst elution rate) being higher than the unacceptable toxicity limit, as shown in FIG. 1.

[0011] Accordingly, there is a need in the art for indwelling catheters which release or elute an antimicrobial API and which provide a safe initial burst elution rate and an extended elution efficacy rate. Such indwelling catheters are disclosed herein.

[0012] The subject matter claimed herein is not limited to embodiments that solve any disadvantages or that operate only in environments such as those described above. Rather, this background is only provided to illustrate one example technology area where some implementations described herein may be practiced.SUMMARY

[0013] The present invention has been developed in response to problems and needs in the art that have not yet been fully resolved by currently available antimicrobial indwelling catheters.

[0014] This invention discloses a layered antimicrobial coating structure which comprises a top coating layer having an antimicrobial API concentration lower than the antimicrobial API concentration in one or more underlying layers or catheter substrate. Because the top coating layer has lower API concentration, the initial burst API release / elution rate during the first day of catheter indwell is reduced such that the antimicrobial API toxicity limit is not exceeded. In addition, the higher concentration of antimicrobial API in one or more underlying layers or catheter substrate provides sufficient API release / elution during the extended catheter indwell time when antimicrobial activity is required.

[0015] In some embodiments, a multilayer catheter having antimicrobial properties includes a catheter body comprising a lumen, the catheter body forming a catheter substrate, an inner coating layer disposed on the catheter substrate, and a top coating layer disposed on the inner coating layer.

[0016] In some embodiments, the inner coating layer includes a first antimicrobial active pharmaceutical ingredient, and the first antimicrobial active pharmaceutical ingredient has a first concentration in the inner coating layer. In some embodiments, the top coating layer includes the first antimicrobial active pharmaceutical ingredient, the first antimicrobial active pharmaceutical ingredient has a second concentration in the top coating layer, and the first concentration is greater than the second concentration.

[0017] In some embodiments, the catheter body includes a plurality of lumens.

[0018] In some embodiments, the top coating layer includes a material different from the inner coating layer which dissolves on exposure to infusate. In some embodiments, the top coating layer includes a material such as Glycolube® lubricant, silicone oil, stearic acid, oleamide, etc. selected to increase a lubricity of the multilayer catheter. Increased lubricity provides decreased friction when inserting / removing a guidewire or stylet and inserting the catheter into the vein.

[0019] In some embodiments, the top coating layer further includes an active pharmaceutical ingredient different than the first antimicrobial active pharmaceutical ingredient of the inner coating layer.

[0020] In some embodiments, the top coating layer further includes an active pharmaceutical ingredient selected to provide anticoagulant or antithrombus activity, such as heparin, nitric oxide, or nitric oxide donors, etc.

[0021] In some embodiments, the top coating layer further includes a second antimicrobial active pharmaceutical ingredient different from the first antimicrobial active pharmaceutical ingredient of the inner coating layer.

[0022] In some embodiments, the catheter substrate and the inner coating layer are integral such that the catheter substrate is impregnated with the first antimicrobial active pharmaceutical ingredient. In some embodiments, the antimicrobial active pharmaceutical ingredient is dispersed nonhomogeneously throughout catheter substrate. In some embodiments, the antimicrobial active pharmaceutical ingredient is dispersed homogeneously throughout catheter substrate.

[0023] In some embodiments, the multilayer catheter further includes a second top coating layer disposed on the top coating layer. In some embodiments, the second top coating layer includes the first antimicrobial active pharmaceutical ingredient and the first antimicrobialactive pharmaceutical ingredient has a third concentration in the second top coating layer. In some embodiments, the third concentration differs from the second concentration.

[0024] In some embodiments, the multilayer catheter further includes a second top coating layer disposed on the top coating layer. In some embodiments, the second top coating layer comprises a second antimicrobial active pharmaceutical ingredient.

[0025] In some embodiments, the catheter substrate includes a luminal surface and an exterior surface. In some embodiments, the inner coating layer is disposed on the exterior surface. In some embodiments, the inner coating layer is disposed on the luminal surface.

[0026] In some embodiments, a first inner coating layer is disposed on the luminal surface and a second inner coating layer is disposed on the exterior surface. In some embodiments, a first top coating layer is disposed on the first inner coating layer and a second top coating layer is disposed on the second inner coating layer. In some embodiments, the inner coating layer is one of the first inner coating layer or the second inner coating layer and the top coating layer is one of the first top coating layer or the second top coating layer. In some embodiments, the first top coating layer and the second top coating layer have different compositions.

[0027] In some embodiments, the antimicrobial active pharmaceutical ingredient is selected from hydrogen peroxide, zinc oxide, ionic zinc (Zn2+), chlorhexidine, chlorhexidine acetate, chlorhexidine gluconate, copper, silver (ionic), silver nanoparticles, triclosan, polyhexamethylene biguanide (PHMB), quaternary ammonium compound, guanidine, guanidinium, porphyrin, methylene blue, toluidine blue, and rose Bengal.

[0028] In some embodiments, a multilayer catheter having antimicrobial properties includes a catheter body having a lumen, the catheter body forming a catheter substrate, the catheter substrate containing a first antimicrobial active pharmaceutical ingredient, and the first antimicrobial active pharmaceutical ingredient has a first concentration in the catheter substrate.

[0029] In some embodiments, a top coating layer is disposed on the catheter substrate and the top coating layer includes the first antimicrobial active pharmaceutical ingredient, and the first antimicrobial active pharmaceutical ingredient has a second concentration in the top coating layer. In some embodiments, the first concentration is greater than the second concentration.

[0030] In some embodiments, the catheter body includes a plurality of lumens.

[0031] In some embodiments, the antimicrobial active pharmaceutical ingredient is selected from hydrogen peroxide, zinc oxide, ionic zinc (Zn2+), chlorhexidine, chlorhexidine acetate, chlorhexidine gluconate, copper, silver (ionic), silver nanoparticles, triclosan, polyhexamethylene biguanide (PHMB), quaternary ammonium compound, guanidine, guanidinium, porphyrin, methylene blue, toluidine blue, and rose Bengal.

[0032] In some embodiments, the catheter substrate includes a luminal surface and an exterior surface. In some embodiments, the top coating layer is disposed on the luminal surface and on the exterior surface.

[0033] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The singular forms also include the plural unless the context clearly dictates otherwise. Thus, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0034] Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in some embodiments,” “in the embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to thesame embodiment. Additionally, while the following description refers to several embodiments and examples of the various components and processes of the described invention, all of the described embodiments and examples are to be considered, in all respects, as illustrative only and not as being limiting in any manner.

[0035] As used herein, the expression [A], [B], [C], “and / or” [D] means that one or more of the cases connected by the expression “and / or” may occur individually or in combination. Thus, the expression means [A] or [B] or [C] or [D] may occur individually, or combinations of any two or more cases may occur, such as [A] and [B], [A] and [C], [B] and [C], [A], [C], and [D], etc.

[0036] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention, as claimed. It should be understood that the various embodiments are not limited to the arrangements and instrumentality shown in the drawings. It should also be understood that the embodiments may be combined, or that other embodiments may be utilized and that structural changes, unless so claimed, may be made without departing from the scope of the various embodiments of the present invention. The following detailed description is, therefore, not to be taken in a limiting sense.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0037] Example embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

[0038] FIG. 1 is a graph of the daily elution rate of four different coatings of various thickness but same API concentration within the coating composition.

[0039] FIG. 2 is a graph of the daily elution rate of four different coatings of various thickness as in FIG. 1 , but at a different scale and longer duration.

[0040] FIG. 3 is a cross-sectional representation of a multilayer catheter within the scope of the disclosure.

[0041] FIG. 4 is a cross-sectional representation of a multilayer catheter having a plurality of lumens within the scope of the disclosure.DESCRIPTION OF EMBODIMENTS

[0042] The disclosure relates to a multilayer catheter having antimicrobial properties. The multilayer catheter includes a catheter body comprising a lumen, the catheter body forming a catheter substrate. The catheter substrate may be impregnated and / or coated with one or more antimicrobial active pharmaceutical ingredients (APIs) to provide surface antimicrobial functionality. The catheter substrate coating may be an inner coating layer. The antimicrobial API has a first concentration in the impregnated and / or coated catheter substrate.

[0043] A top coating layer is disposed on the impregnated and / or coated catheter substrate. The top coating layer comprises the antimicrobial API. The antimicrobial API has a second concentration in the top coating layer, and wherein the first concentration is greater than the second concentration.

[0044] The lower concentration of antimicrobial API in the top coating layer allows for a lower initial burst antimicrobial API release / elution rate is lower.

[0045] The lower concentration of antimicrobial API in the top coating layer allows for the underlying impregnated and / or coated catheter substrate to have much higher API concentration which will provide effective API elution over longer catheter indwell time.

[0046] The inclusion of multiple layers additionally allows for altering surface properties to improve the user experience, such as decreased friction leading to easier guidewire passage and device insertion through subcutaneous space into the vein.

[0047] A multilayer system allows for enhanced options for providing multiple antimicrobial APIs and providing multiple APIs at different concentrations specific to needs of catheter placement and continued dwell.

[0048] With the incorporation of a top coating layer with lower API concentration, the Day 1 elution rate can be reduced significantly because of the lower concentration of API on thetop coating layer. The long indwell elution can be increased since the base layer has a higher API concentration.

[0049] Alternatively, the top coating layer can be made of material that would slowly dissolve when exposed to infusate, such as degradable polyurethane co-polymers, PGS (polyglycerol sebacate) co-polymers, PDC (poly diol citrate) co-copolymers, etc., further maintaining the elution rate during long indwell.

[0050] FIG. 3 discloses a cross-sectional representation of a multilayer catheter 10 having antimicrobial properties. The catheter 10 includes a catheter body 15 comprising a lumen 20, the catheter body 15 forming a catheter substrate 25. The catheter substrate includes a luminal surface 30 and an exterior surface 35.

[0051] In some embodiments, a first inner coating layer 40 is disposed on the luminal surface 30. In some embodiments, a second inner coating layer 45 is disposed on the exterior surface 35. In some embodiments, an inner coating layer 40, 45 is disposed on both the luminal surface and exterior surface.

[0052] In some embodiments, the inner coating layers 40, 45 have the same composition. In some embodiments, the inner coating layers 40, 45 have different compositions.

[0053] In some embodiments, at least one of the inner coating layers 40, 45 includes a first antimicrobial active pharmaceutical ingredient. The first antimicrobial active pharmaceutical ingredient has a first concentration in at least one of the inner coating layers 40, 45.

[0054] In some embodiments, a first top coating layer 50 is disposed on the first inner coating layer 40. In some embodiments, a second top coating layer 55 is disposed on the second inner coating layer 45. In some embodiments, top coating layer 50, 55 are disposed on both the inner coating layers 40, 45.

[0055] In some embodiments, the top coating layers 50, 55 have the same composition. In some embodiments, the top coating layers 50, 55 have different compositions.

[0056] In some embodiments, at least one of the top coating layers 50, 55 includes the first antimicrobial active pharmaceutical ingredient. The first antimicrobial active pharmaceutical ingredient has a second concentration in at least one of the top coating layers 50, 55. The first concentration of the antimicrobial active pharmaceutical ingredient is greater than the second concentration of the antimicrobial active pharmaceutical ingredient. In some embodiments, the second concentration is zero.

[0057] In some embodiments, the catheter substrate 25 comprises a first antimicrobial active pharmaceutical ingredient. The first antimicrobial active pharmaceutical ingredient has a first concentration in the catheter substrate. In some embodiments, the catheter substrate 25 and the inner coating layers 40, 45 are integral such that the catheter substrate is impregnated with the first antimicrobial active pharmaceutical ingredient. A nonlimiting embodiment of the catheter substrate impregnated with the first antimicrobial active pharmaceutical ingredient is shown in Fig. 4.

[0058] In some embodiments, the first antimicrobial active pharmaceutical ingredient has a first concentration in the catheter substrate at the luminal surface 30. In some embodiments, the first antimicrobial active pharmaceutical ingredient has a first concentration in the catheter substrate at the exterior surface 35. In some embodiments, the first antimicrobial active pharmaceutical ingredient has a first concentration in the catheter substrate at the luminal surface 30 and the exterior surface 35.

[0059] In some embodiments the antimicrobial active pharmaceutical ingredient includes, but is not limited to, an antimicrobial active pharmaceutical ingredient selected from hydrogen peroxide, zinc oxide, ionic zinc (Zn2+), chlorhexidine, chlorhexidine acetate, chlorhexidine gluconate, copper, silver (ionic), silver nanoparticles, triclosan, polyhexamethylene biguanide (PHMB), quaternary ammonium compound, guanidine, guanidinium, porphyrin, methylene blue, toluidine blue, and rose bengal.

[0060] In some embodiments the catheter substrate 25 comprises a plurality of antimicrobial active pharmaceutical ingredients. A plurality of antimicrobial active pharmaceutical ingredients may provide a broader spectrum of antimicrobial activity.

[0061] In some embodiments the catheter substrate 25 is impregnated with an antimicrobial active pharmaceutical ingredient.

[0062] FIG. 4 discloses a cross-sectional representation of a multilayer catheter 100 having antimicrobial properties and having a plurality of lumens. The catheter 100 includes a catheter body 115 comprising a plurality of lumens 120, the catheter body 115 forming a catheter substrate 125. The catheter substrate includes a luminal surface 130 and an exterior surface 135.

[0063] In some embodiments, the antimicrobial active pharmaceutical ingredient is an additive to a polymeric material from which the catheter substrate 125 is manufactured.

[0064] In some embodiments the antimicrobial active pharmaceutical ingredient is dispersed homogeneously throughout the polymeric material from which the catheter substrate is manufactured. In some embodiments, the antimicrobial active pharmaceutical ingredient has a first concentration in the catheter substrate.

[0065] In some embodiments where the catheter substrate 125 is impregnated with one or more antimicrobial active pharmaceutical ingredients. In some embodiments the catheter substrate is imbibed with the antimicrobial active pharmaceutical ingredient.

[0066] The catheter substrate 125 may be imbibed with the antimicrobial active pharmaceutical ingredient by exposing the catheter substrate to a solvent containing the antimicrobial active pharmaceutical ingredient. Typical solvents include, but are not limited to methanol, ethanol, isopropyl alcohol (IPA), dioxolane, methyl ethyl ketone (MEK), tetrahydrofuran (THF), and acetone. The imbibe coating process may be performed at a temperature in the range from room temperature to about 100°C. Examples of antimicrobialactive pharmaceutical ingredients which may be used to imbibe the catheter substrate include, but are not limited to, chlorhexidine, chlorhexidine acetate, chlorhexidine gluconate, copper, silver (ionic), triclosan, polyhexamethylene biguanide (PHMB), quaternary ammonium compounds, guanidine, and guanidinium compounds.

[0067] In some embodiments the antimicrobial active pharmaceutical ingredient is dispersed nonhomogeneously throughout the polymeric material from which the catheter substrate is manufactured. In some embodiments the antimicrobial active pharmaceutical ingredient is a first antimicrobial active pharmaceutical ingredient having a first concentration at the luminal surface 130 and / or at the exterior surface 135. In some embodiments, a relatively greater amount of the antimicrobial active pharmaceutical ingredient is present at the luminal surface 130 of the catheter substrate compared to an interior of the catheter substrate. In some embodiments, a relatively greater amount of the antimicrobial active pharmaceutical ingredient is present at the exterior surface 135 of the catheter substrate 125 compared to an interior of the catheter substrate.

[0068] In some embodiments, a first top coating layer 150 is disposed on the catheter substrate 125 at the luminal surface 130. In some embodiments, a second top coating layer 155 is disposed on the catheter substrate 125 at the exterior surface 135. In some embodiments, top coating layers 150, 155 are disposed on the catheter substrate 125 at the luminal surface 130 and exterior surface 135.

[0069] In some embodiments, the top coating layers 150, 155 have the same composition. In some embodiments, the top coating layers 150, 155 have different compositions.

[0070] In some embodiments, at least one of the top coating layers 150, 155 includes the first antimicrobial active pharmaceutical ingredient. The first antimicrobial active pharmaceutical ingredient has a second concentration in at least one of the top coating layers150, 155. The first concentration of the antimicrobial active pharmaceutical ingredient isgreater than the second concentration of the antimicrobial active pharmaceutical ingredient. In some embodiments, the second concentration is zero.

[0071] In some embodiments the polymeric material from which the catheter substrate is manufactured is selected from polypropylene, polyethylene, polyvinylchloride, polyurethane, polysulfone, polyphenyl sulfone, acrylonitrile butadiene styrene, polyethylene terephthalate, polyamide, polyarcrylates, polyvinyl acetates, polyimide, polyamideimide, polymethylmethacrylate, polyetherimide, polyetheretherketone, polyethersulfone, polycarbonate, and polyester.

[0072] In some embodiments the antimicrobial active pharmaceutical ingredient is present in an antimicrobial coating disposed on the catheter substrate. The antimicrobial coating may be an inner coating layer. The inner coating layer may be disposed on an exterior surface of the catheter substrate. The inner coating may be disposed on a luminal surface of the catheter substrate.

[0073] In some embodiments the inner coating layer is deposited on the catheter substrate by a process selected from a dip coating, a spray coating, and a hydrogel coating.

[0074] Known coating technologies which incorporate the antimicrobial active pharmaceutical ingredient may be used. Examples of such coating technologies include, but are not limited to, a dip coating, a spray coating, and a hydrogel coating. In some embodiments a primer chemistry may be used to improve coating adhesion.

[0075] Polyurethane is a coating matrix which may be used with dip coating and spray coating technologies. Non-limiting examples of solvents which may be used with polyurethane-based coatings include methanol, ethanol, isopropyl alcohol (IP A), dioxolane, methyl ethyl ketone (MEK), tetrahydrofuran (THF), and acetone. The coating solutions typically dissolve at temperatures in the range of 50 to 80°C. The dip coating and spray coating process is typically performed at room temperature. Nonlimiting examples of antimicrobialactive pharmaceutical ingredients which may be used in the dip coating and spray coating technologies include ionic zinc (Zn2+), chlorhexidine, chlorhexidine acetate, chlorhexidine gluconate, copper, silver (ionic), triclosan, polyhexamethylene biguanide (PHMB), quaternary ammonium compounds, guanidine, and guanidinium compounds.

[0076] A hydrogel is a known coating matrix used with dip coating and spray coating technologies. Non-limiting examples of hydrogels include polyvinyl alcohol, polyethylene glycol (PEG), and polyacrylate-based hydrogels. Nonlimiting examples of solvents which may be used with hydrogel-based coatings include water, methanol, ethanol, and isopropyl alcohol (IP A). A pH / acid modifier may be included. The hydrogel coating solutions typically dissolve at temperatures in the range of 60 to 95°C. The dip coating and spray coating process is typically performed at room temperature. The hydrogel coating may be cured in formaldehyde. Nonlimiting examples of antimicrobial active pharmaceutical ingredients which may be used in the hydrogel dip coating and spray coating technologies include ionic zinc (Zn2+), chlorhexidine, copper, silver (ionic), triclosan, polyhexamethylene biguanide (PHMB), quaternary ammonium compounds, guanidine, and guanidinium compounds.

[0077] In some embodiments, a combination of one or more antimicrobial active pharmaceutical ingredients incorporated into the material from which the catheter substrate is fabricated, and one or more antimicrobial active pharmaceutical ingredients incorporated into one or more coatings on the surface of the catheter substrate are utilized to provide antimicrobial properties.

[0078] In some embodiments, the thickness of the inner coating layers may be varied. In some embodiments, the thickness of the top coating layers may be varied.

[0079] In some embodiments, the top coating layer may contain alternate active pharmaceutical ingredients than the base or inner coating layer. Such alternative activepharmaceutical ingredients may include, but are not limited to, an anticoagulant for thrombus prevention and different antimicrobial active pharmaceutical ingredients.

[0080] All examples and conditional language recited herein are intended for pedagogical objects to aid the reader in understanding the invention and the concepts contributed by the inventor to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Although embodiments of the present inventions have been described in detail, the various changes, substitutions, and alterations could be made hereto without departing from the spirit and scope of the invention. It should be understood that the embodiments may be combined.

Claims

CLAIMS1. A multilayer catheter having antimicrobial properties comprising: a catheter body comprising a lumen, the catheter body forming a catheter substrate; an inner coating layer disposed on the catheter substrate, wherein the inner coating layer comprises a first antimicrobial active pharmaceutical ingredient, wherein the first antimicrobial active pharmaceutical ingredient has a first concentration in the inner coating layer; and a top coating layer disposed on the inner coating layer, wherein the top coating layer comprises the first antimicrobial active pharmaceutical ingredient, wherein the first antimicrobial active pharmaceutical ingredient has a second concentration in the top coating layer, and wherein the first concentration is greater than the second concentration.

2. The multilayer catheter of claim 1, wherein the catheter body comprises a plurality of lumens.

3. The multilayer catheter of claim 1, wherein the top coating layer comprises a material different from the inner coating layer which dissolves on exposure to infusate.

4. The multilayer catheter of claim 1, wherein the top coating layer comprises a material selected to increase a lubricity of the multilayer catheter.

5. The multilayer catheter of claim 1, wherein the top coating layer further comprises an active pharmaceutical ingredient different than the first antimicrobial active pharmaceutical ingredient of the inner coating layer.

6. The multilayer catheter of claim 1, wherein the top coating layer further comprises an active pharmaceutical ingredient selected to provide anticoagulant or anti thrombus activity.

7. The multilayer catheter of claim 1, wherein the top coating layer further comprises a second antimicrobial active pharmaceutical ingredient different from the first antimicrobial active pharmaceutical ingredient of the inner coating layer.

8. The multilayer catheter of claim 1, wherein the catheter substrate and the inner coating layer are integral such that the catheter substrate is impregnated with the first antimicrobial active pharmaceutical ingredient.

9. The multilayer catheter of claim 8, wherein the antimicrobial active pharmaceutical ingredient is dispersed nonhomogeneously throughout catheter substrate.

10. The multilayer catheter of claim 8, wherein the antimicrobial active pharmaceutical ingredient is dispersed homogeneously throughout catheter substrate.

11. The multilayer catheter of claim 1 , further comprising a second top coating layer disposed on the top coating layer, wherein the second top coating layer comprises the first antimicrobial active pharmaceutical ingredient, wherein the first antimicrobial active pharmaceutical ingredient has a third concentration in the second top coating layer, and wherein the third concentration differs from the second concentration.

12. The multilayer catheter of claim 1, further comprising a second top coating layer disposed on the top coating layer, wherein the second top coating layer comprises a second antimicrobial active pharmaceutical ingredient.

13. The multilayer catheter of claim 1, wherein the catheter substrate comprises a luminal surface and an exterior surface, wherein the inner coating layer is disposed on the exterior surface.

14. The multilayer catheter of claim 1, wherein the catheter substrate comprises a luminal surface and an exterior surface, wherein the inner coating layer is disposed on the luminal surface.

15. The multilayer catheter of claim 1, wherein the catheter substrate comprises a luminal surface and an exterior surface, wherein a first inner coating layer is disposed on the luminal surface and a second inner coating layer is disposed on the exterior surface, wherein a first top coating layer is disposed on the first inner coating layer and a second top coating layer is disposed on the second inner coating layer, wherein the inner coating layer is one of the first inner coating layer or the second inner coating layer and wherein the top coating layer is one of the first top coating layer or the second top coating layer, and wherein the first top coating layer and the second top coating layer having different compositions.

16. The multilayer catheter of claim 1, wherein the antimicrobial active pharmaceutical ingredient is selected from hydrogen peroxide, zinc oxide, ionic zinc (Zn2+), chlorhexidine, chlorhexidine acetate, chlorhexidine gluconate, copper, silver (ionic), silver nanoparticles, triclosan, polyhexamethylene biguanide (PHMB), quaternary ammoniumcompound, guanidine, guanidinium, porphyrin, methylene blue, toluidine blue, and roseBengal.

17. A multilayer catheter having antimicrobial properties comprising: a catheter body comprising a lumen, the catheter body forming a catheter substrate, wherein the catheter substrate comprises a first antimicrobial active pharmaceutical ingredient, wherein the first antimicrobial active pharmaceutical ingredient has a first concentration in the catheter substrate; and a top coating layer disposed on the catheter substrate, wherein the top coating layer comprises the first antimicrobial active pharmaceutical ingredient, wherein the first antimicrobial active pharmaceutical ingredient has a second concentration in the top coating layer, and wherein the first concentration is greater than the second concentration.

18. The multilayer catheter of claim 17, wherein the catheter body comprises a plurality of lumens.

19. The multilayer catheter of claim 17, wherein the antimicrobial active pharmaceutical ingredient is selected from hydrogen peroxide, zinc oxide, ionic zinc (Zn2+), chlorhexidine, chlorhexidine acetate, chlorhexidine gluconate, copper, silver (ionic), silver nanoparticles, triclosan, polyhexamethylene biguanide (PHMB), quaternary ammonium compound, guanidine, guanidinium, porphyrin, methylene blue, toluidine blue, and rose Bengal.

20. The multilayer catheter of claim 17, wherein the catheter substrate comprises a luminal surface and an exterior surface, wherein the top coating layer is disposed on the luminal surface and on the exterior surface.

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