Solvent system for co-dissolution of thermoplastic polyurethane and active pharmaceutical ingredients

Abstract

A solvent system co-dissolves thermoplastic polyurethane and an active pharmaceutical ingredient (API) to form a dip-coating solution. The solvent system provides increased solubility of the API compared to prior art solvent systems which use tetrahydrofuran (THF) as the main solvent. A particularly useful API is chlorhexidine to provide antimicrobial properties. The solvent system includes methanol and 1,3-dioxolane in a ratio of about 10 vol.% to 40 vol.% of methanol in the 1,3-dioxolane. The dip-coating solution may be used to coat medical devices, such as catheters, with a polyurethane coating configured to release an API, such as chlorhexidine. The solvent system can dissolve greater than 55 mg / mL chlorhexidine.

Description

SOLVENT SYSTEM FOR CO-DISSOLUTION OF THERMOPLASTIC POLYURETHANE AND ACTIVE PHARMACEUTICAL INGREDIENTSBACKGROUND

[0001] The invention relates to a solvent system which co-dissolves a thermoplastic polyurethane and an active pharmaceutical ingredient (API).

[0002] The disclosed solvent system with dissolved thermoplastic polyurethane and active pharmaceutical ingredient may be used as a dip-coating solution for coating medical devices with a polyurethane coating containing the active pharmaceutical ingredient. In some embodiments, the medical device is an extruded catheter body.

[0003] In some embodiments, the active pharmaceutical ingredient (API) has antimicrobial properties. In some embodiments, the active pharmaceutical ingredient is chi orhexi dine.

[0004] 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.

[0005] Catheters are commonly introduced into the vasculature of a patient as part of an intravenous catheter assembly. 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 beveledportion of the needle is exposed beyond a tip of the catheter. The beveled 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.

[0006] Catheter-related bloodstream infections (CRB Sis) are caused by the colonization of microorganisms in patients with intravascular catheters and I.V. access devices. 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.

[0007] Coating catheters with various antimicrobial agents is one approach that has been implemented to prevent these infections. These catheters, however, have given less than satisfactory results.

[0008] Prior art solvent systems used to prepare dip-coating solutions containing polyurethane and an active pharmaceutical ingredient often use tetrahydrofuran (THF) as the main solvent system. These prior art solutions are not able to dissolve a significant amount of API, such as chi orhexi dine. Consequently, less API is coated onto the surface of the medical device, impacting its antimicrobial strength and duration.

[0009] Accordingly, there is a need in the art for an improved solvent system for preparing dip-coating solutions containing polyurethane and an active pharmaceutical ingredient (API),which can dissolve higher amounts of APT compared to conventional solvents, such as THF. Such solvent systems are disclosed herein.

[0010] 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

[0011] 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 solvent systems for co-dissolving thermoplastic polyurethane and an active pharmaceutical ingredient (API). The disclosed solvent system provides increased solubility of the API compared to prior art solvent systems which use tetrahydrofuran (THF) as the main solvent.

[0012] One advantage of the disclosed solvent system is that significantly higher amounts of API, such as chi orhexi dine, can be dissolved, thereby enabling more API to be coated on the device in its final, finished form, providing a stronger antimicrobial effect for a longer duration.

[0013] The disclosed solvent system comprises two solvents, methanol and 1,3 -di oxolane, in a specific ratio of about 10-40% by volume of methanol in 1,3-dioxolane. This specific solvent composition enables co-dissolution of a medical grade thermoplastic polyurethane and an active pharmaceutical ingredient (API), such as chlorhexidine. Dissolving these two ingredients creates a dip-coating solution, which is applied to the surface of medical devices, such as catheters, leaving a coating behind that provides therapeutic value to patients. Non-limiting examples of catheters include Central Venous Catheters (CVCs) and Peripherally Inserted Central-line Catheters(PICCs). In the case of chlorhexidine, the coating provides antimicrobial protection againstCatheter Related Blood Stream Infections (CRB Sis).

[0014] Prior art solutions similar to this solvent system are not able to dissolve a significant amount of API, such as chlorhexidine. Consequently, less API is coated onto the surface of the devices, impacting its antimicrobial strength and duration.

[0015] The advantage of the solvent system disclosed in this submission is that significantly higher amounts of API, such as chlorhexidine, can be dissolved, thereby enabling more API to be coated on the device in its final, finished form, providing a stronger antimicrobial effect for a longer duration.

[0016] The disclosed solvent system is useful in manufacturing medical devices, such as catheters, having a coating configured to release chlorhexidine to provide antimicrobial properties. The disclosed manufacturing method may apply chlorhexidine to thermoplastic polyurethane catheter extrusions. The catheter extrusion is dip-coated with chlorhexidine inside of a matrix of polyurethane.

[0017] The resulting catheter elutes chlorhexidine over a period of time. The elution rate is affected by the concentration of chlorhexidine coated on the catheter. It is further affected by properties of the polyurethane in the dip-coating solution. These properties - molecular weight, coating thickness, and copolymer hard / soft segment ratios and chemistries - affect release kinetics of the chlorhexidine and maintain antimicrobial activity over an extended period of time.

[0018] The disclosed catheter is manufactured by coating the catheter extrusion with a polyurethane coating comprising chlorhexidine.

[0019] Non-limiting examples of chlorhexidine include chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof.

[0020] The coating step may be accomplished by dip-coating the catheter extrusion in a dipcoating solution comprising polyurethane and chlorhexidine in a solvent system comprising from 10 to 40 vol.% methanol in 1,3 -di oxolane. The polyurethane in the dip-coating solution may comprise an aliphatic polyurethane. The polyurethane in the dip-coating solution may comprise an aromatic polyurethane.

[0021] The chlorhexidine in the dip-coating solution may comprise chlorhexidine base. The chlorhexidine concentration in the dip-coating solution may range from 0.5 wt.% to 20 wt.%. In some embodiments, the solvent system of the dip-coating solution dissolves greater than 55 mg / mL chlorhexidine.

[0022] The solvent system for the dip-coating polymer solution may comprise a mixture of methanol and 1,3 -di oxolane. In a non-limiting embodiment, the solvent comprises from 10 vol.% to 40 vol.%, methanol, e.g., 10, 15, 20, 25, 30, 35, or 40 vol. % methanol, and from 60 vol.% to 90 vol.% 1,3 -dioxolane, e.g., 60, 65, 70, 75, 80, 85, or 90 vol. % 1,3 -di oxolane, where any of the stated values can form an upper or lower endpoint of a range. The solvent system may comprise any mixture of methanol and 1,3-dioxolant ranging from 10 vol. % methanol and 90 volume percent 1,3-dioxolane to 40 vol.% methanol and 60 vol.% 1,3 -dioxolane. In an embodiment, the solvent system comprises from about 15 vol.% to 25 vol.% methanol and from about 85 vol. % to 75 vol.% 1,3-dioxolane. In an embodiment, the solvent system comprises about 20 vol. % methanol and about 80 vol. % 1,3-dioxolane.

[0023] 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 maybe 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

[0024] Example embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

[0025] Figure 1A is cross-sectional representation of portion of a catheter body fabricated having an exterior coating comprising thermoplastic polyurethane and chlorhexidine to provide antimicrobial functionality.

[0026] Figure IB is cross-sectional representation of portion of a catheter body fabricated having an interior coating comprising thermoplastic polyurethane and chlorhexidine to provide antimicrobial functionality.

[0027] Figure 1C is cross-sectional representation of portion of a catheter body fabricated having an exterior and interior coating comprising thermoplastic polyurethane and chlorhexidine to provide antimicrobial functionality.DESCRIPTION OF EMBODIMENTS

[0028] The disclosure relates to a solvent system for co-dissolving thermoplastic polyurethane and an active pharmaceutical ingredient (API). The disclosed solvent system provides increased solubility of the API compared to prior art solvent systems which use tetrahydrofuran (THF) as the main solvent.

[0029] Because significantly higher amounts of API, such as chlorhexidine, can be dissolved in the solvent system, more API may be coated on a medical device in its final, finished form, to provide a stronger antimicrobial effect for a longer duration.

[0030] The disclosed solvent system comprises two solvents, methanol and 1,3 -di oxolane, in a specific ratio of about 10 vol.% to 40 vol.% of methanol in 1,3-dioxolane. This specific solvent composition enables co-dissolution of medical grade thermoplastic polyurethane and an active pharmaceutical ingredient (API), such as chlorhexidine.

[0031] Dissolving the medical grade thermoplastic polyurethane and an API in the mixture of methanol and 1,3-dioxolane creates a dip-coating solution, which is applied to the surface of a medical device, such as a catheter, leaving a coating behind that provides therapeutic value to patients. In the case of chlorhexidine, the coating provides antimicrobial functionality.

[0032] An important aspect of the disclosed invention is a solvent system which dissolves high amounts of an active pharmaceutical ingredient, such as chlorhexidine, compared to prior art solvent systems comprising tetrahydrofuran.

[0033] The chlorhexidine in the dip-coating solution may comprise chlorhexidine base. The chlorhexidine concentration in the dip-coating solution may range from 0.5 wt.% to 20 wt.%. In some embodiments, the solvent system of the dip-coating solution dissolves greater than 55 mg / mL chlorhexidine.

[0034] The solvent system for the dip-coating polymer solution may comprise a mixture of methanol and 1,3-dioxolane. In a non-limiting embodiment, the solvent comprises from 10 vol.% to 40 vol.%, methanol, e.g., 10, 15, 20, 25, 30, 35, or 40 vol. % methanol, and from 60 vol.% to 90 vol.% 1,3-dioxolane, e.g., 60, 65, 70, 75, 80, 85, or 90 vol. % 1,3-dioxolane, where any of the stated values can form an upper or lower endpoint of a range. The solvent system may compriseany mixture of methanol and 1,3-dioxolant ranging from 10 vol. % methanol and 90 volume percent 1,3-dioxolane to 40 vol.% methanol and 60 vol.% 1,3 -dioxolane. In an embodiment, the solvent system comprises about 20 vol. % methanol and about 80 vol. % 1,3-dioxolane.

[0035] The disclosure further relates to methods of manufacturing a catheter having a coating comprising an active pharmaceutical ingredient, such as chlorhexidine. The resulting catheter configured to release chlorhexidine to provide antimicrobial properties is manufactured by coating a thermoplastic polyurethane catheter extrusion with a polyurethane coating comprising chlorhexidine.

[0036] The coating step may be accomplished by dip-coating the catheter extrusion in a dipcoating solution comprising polyurethane and chlorhexidine dissolved in a solvent system comprising from 10 vol.% to 40 vol.% methanol in 1,3-dioxolane.

[0037] The dwell time of the catheter extrusion in the dip-coating solution may range from about 1 minute to about 120 minutes.

[0038] The polyurethane in the dip-coating polymer solution may comprise an aliphatic or aromatic polyurethane. The polyurethane may be a solution grade aliphatic polyurethane, such as commercially available Tecoflex® aliphatic poly ether-based thermoplastic polyurethane manufactured by Lubrizol. The polyurethane may be a thermoplastic silicone-polycarbonate- urethane (TSPCU), such as commercially available CarboSil® TSPCU manufactured by DSM Biomedical.

[0039] The practical polymer concentration in the dip-coating polymer solution is related to its molecular weight. For instance, a low molecular weight thermoplastic polyurethane (TPU) having a molecular weight of about 50 kDa may be present at a higher concentration, up to 5 wt.%and provide a usable viscosity. A high molecular weight TPU having a molecular weight of about 240 kDa may be present at a lower concentration, 0.5 wt.% to 1 wt.%.

[0040] Chlorhexidine is characterized as being a strong base with cationic properties. It is commercially available in both the free base and stable salt forms. Non-limiting examples of chlorhexidine include chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof. In some embodiments, chlorhexidine in the dip-coating solution comprises chlorhexidine base.

[0041] The chlorhexidine concentration in the dip-coating solution may range from 0.5 wt.% to 7.5 wt.%.

[0042] In some embodiments greater than 55 mg / mL chlorhexidine is dissolved in the solvent system which forms the dip-coating solution.

[0043] The coating step may occur at room temperature. The coating step may occur at a temperature in the range from about 25 to 50 °C.

[0044] The resulting catheter manufactured as described above is configured to release chlorhexidine to provide antimicrobial properties. Figure 1A is cross-sectional representation of portion of a catheter 100 fabricated to contain chlorhexidine to provide dual anti-platelet and antimicrobial functionality. The catheter 100 includes an extruded thermoplastic polyurethane catheter body 110. The catheter 100 further includes an exterior polyurethane coating 120 on the polyurethane catheter body 110 comprising chlorhexidine.

[0045] Figure IB is cross-sectional representation of portion of a catheter 100 fabricated to contain chlorhexidine to provide dual anti-platelet and antimicrobial functionality, similar toFigure 1A. The catheter 100 includes an extruded thermoplastic polyurethane catheter body 110.The catheter 100 further includes an interior polyurethane coating 130 on the polyurethane catheter body 110 comprising chlorhexidine.

[0046] Figure 1C is cross-sectional representation of portion of a catheter 100 fabricated to contain chlorhexidine to provide dual anti-platelet and antimicrobial functionality. The catheter 100 includes an extruded thermoplastic polyurethane catheter body 110. The catheter 100 includes an exterior polyurethane coating 120 on the polyurethane catheter body 110 comprising chlorhexidine. The catheter 100 further includes an interior polyurethane coating 130 on the polyurethane catheter body 110 comprising chlorhexidine.

[0047] It was observed that pure tetrahydrofuran (THF) or 1,3 -dioxolane dissolved less than 10 mg / mL chlorhexidine, and typically dissolved closer to 1 mg / mL chlorhexidine. In contrast, the solvent system comprising 20 vol.% methanol in 1,3-dioxolane dissolved greater than 55 mg / mL chlorhexidine. The significantly greater solubility of chlorhexidine in the dip-coating solution enabled polyurethane coatings to be prepared having much higher concentrations of chlorhexidine compared coatings prepared using THF-based solvent systems.

[0048] 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, it should be understood that 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 dip-coating solution comprising: a solvent system comprising from 10 vol.% to 40 vol.% methanol and from 90 vol.% to60 vol.% 1,3 -di oxolane; medical grade thermoplastic polyurethane; and an active pharmaceutical ingredient.

2. The dip-coating solution of claim 1, wherein the active pharmaceutical ingredient comprises chlorhexidine.

3. The dip-coating solution of claim 2, wherein the chlorhexidine is selected from chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof.

4. The dip-coating solution of claim 1, wherein the solvent system comprises from 15 vol.% to 25 vol.% methanol and from 85 vol.% to 75 vol.% 1,3 -di oxolane.

5. The dip-coating solution of claim 1, wherein the medical grade thermoplastic polyurethane comprises an aliphatic polyurethane.

6. The dip-coating solution of claim 1, wherein the medical grade thermoplastic polyurethane comprises an aromatic polyurethane.

7. The dip-coating solution of claim 1, wherein the chlorhexidine concentration in the dip-coating solution is greater than 55 mg / mL.

8. A method of manufacturing a catheter configured to release chlorhexidine to provide antimicrobial properties, comprising: dip-coating a thermoplastic polyurethane catheter extrusion with a dip-coating solution, wherein the dip-coating solution comprises: a solvent system comprising from 10 vol.% to 40 vol.% methanol and from 90 vol.% to 60 vol.% 1,3-dioxolane; medical grade thermoplastic polyurethane; and an active pharmaceutical ingredient; and evaporating the solvent system from the dip-coating solution to form a polyurethane coating on the thermoplastic polyurethane catheter extrusion.

9. The method of manufacturing a catheter of claim 8, wherein the active pharmaceutical ingredient comprises chlorhexidine.

10. The method of manufacturing a catheter of claim 9, wherein the chlorhexidine is selected from chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof.

11. The method of manufacturing a catheter of claim 8, wherein the solvent system comprises from 15 vol.% to 25 vol.% methanol and from 85 vol.% to 75 vol.% 1,3-dioxolane.

12. The method of manufacturing a catheter of claim 8, wherein the medical grade thermoplastic polyurethane comprises an aliphatic polyurethane.

13. The method of manufacturing a catheter of claim 8, wherein the medical grade thermoplastic polyurethane comprises an aromatic polyurethane.

14. The method of manufacturing a catheter of claim 8, wherein the chlorhexidine concentration in the dip-coating solution is greater than 55 mg / mL.

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