EP2736546A1

EP2736546A1 - Medical device comprising a wetted hydrophilic coating

Info

Publication number: EP2736546A1
Application number: EP12740180.0A
Authority: EP
Inventors: Johannes Wilhelmus Belt
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2011-07-29
Filing date: 2012-07-27
Publication date: 2014-06-04
Also published as: WO2013017547A1; US20140190846A1; CN103561789A

Abstract

The invention is directed to the use of a wetting agent having a boiling point higher than 100 °C and a viscosity lower than 500 mPa.s, wherein the wetting agent comprises water in an amount between 0 and 4.9 wt% based on the total weight of the wetting agent, for the lubrication of a hydrophilic polymer coating. The invention further relates to a medical device comprising a hydrophilic polymer coating that is wetted by a wetting agent, a method for the preparation of a medical device and a package comprising a medical device.

Description

MEDICAL DEVICE COMPRISING A WETTED HYDROPHILIC COATING

The invention is directed to the use of a wetting agent having a boiling point higher than 100 °C and a viscosity lower than 500 mPa.s, wherein the wetting agent can comprise water in an amount between 0 and 4.9 wt% based on the total weight of the wetting agent for the lubrication of a hydrophilic polymer coating. The invention further relates to a medical device comprising a hydrophilic polymer coating that is wetted by a wetting agent having boiling point higher than 100 °C and a viscosity lower than 500 mPa.s, wherein the wetting agent can comprise water in an amount between 0 and 4.9 wt% based on the total weight of the wetting agent, a method for the preparation of a medical device and a package comprising a medical device.

Many medical devices, such as guide wires, urinary and

cardiovascular catheters, syringes, and membranes need to have a lubricant applied to the outer and/or inner surface to facilitate insertion into and removal from the body and/or to facilitate drainage of fluids from the body. Lubricious properties are also required so as to minimize soft tissue damage upon insertion or removal. Especially, for lubrication purposes, such medical devices may have a hydrophilic surface coating or layer which becomes lubricious and attains low-friction properties upon wetting, i.e. applying a wetting fluid for a certain time period prior to insertion of the device into the body of a patient. A coating or layer which becomes lubricious after wetting is hereinafter referred to as a hydrophilic coating. A coating obtained after wetting is hereinafter referred to as a lubricious coating. Herein lubricious is defined as having a smooth or slippery surface.

In the prior art the following wetting fluids are described; water, water- containing mixtures further comprising one or more organic solvents and/or one or more dissolved components, such as salts. According to the prior art a wetting fluid can also be a body fluid or a saline solution having (approximately) physiological osmolarity.

In principle, the medical devices can be wetted (and thereby become lubricious) immediately prior to use. However, from a user's point of view it is desirable to be able to use the device directly after opening of the packaging wherein it is stored. In view of this, medical devices with a hydrophilic coating have been introduced that are sterile-packaged in a package that contains enough wetting fluid to keep the coating wetted (and thus lubricious). WO-0405909A1 discloses the use of plasticizers in a cross-linked hydrophilic coating of a hydrophilic polymer on a substrate. The plasticizers form part of the polymer solution that is applied to the substrate. After application the polymer solution is dried and cured. The substrate can be a medical device, such as a catheter, guide wire or endoscope. The medical devices that are coated with the hydrophilic coating are wetted with water before use on a patient. The plasticizers have the effect that a hydrophilic coating is provided showing high abrasion resistance and low friction coefficient when wet.

EP-1809345A1 discloses a medical device having a wetted hydrophilic coating comprising a coating composition containing a hydrophilic polymer and a wetting agent comprising water and one or more lubricant(s). The wetting agent comprises one or more lubricants in a total amount between 0.1 and 95 % by weight. The medical devices have a low friction surface, have an extended dry-out period and do not drip or have a reduced tendency to drip.

The above described hydrophilic coatings have the disadvantage that water is used for the lubrication of the hydrophilic coatings. By using water as the main component in a wetting agent the hydrophilic coating will dry out and will thus not be lubricous for a long time. The hydrophilic coating will usually not be lubricous anymore within a time period of 15 minutes after wetting or after removal of a medical device from the package.

It has now surprisingly been discovered that a wetting agent having a boiling point higher than 100 °C and a viscosity lower than 500 mPa.s, wherein the wetting agent can comprise water in an amount between 0 and 4.9 wt% based on the total weight of the wetting agent can be used for the lubrication of a hydrophilic polymer coating on a substrate, where after the lubricious hydrophilic coating will stay lubricous for a time period that is much longer than 15 minutes.

A further advantage is that the lubricious hydrophilic coatings do not drip.

The wetting agent has a boiling point higher than 100 °C, preferably higher than 200 °C. The boiling point is determined at ambient pressure.

A high boiling point of the wetting agent corresponds to a low amount of evaporation of the wetting agent from the lubricous hydrophilic coating. This means that the hydrophilic coating will remain lubricous for a longer time.

The wetting agent can be one liquid or a mixture of liquids. The wetting agent can comprise water, but only in a minor amount. The amount of water in the wetting agent is at most 4.9 weight% based on the total weight of wetting agent. The amount of water preferably is lower than 4 weight%, more preferably lower than 1 weight%.

The wetting agent has a viscosity lower than 500 mPa.s. This is determined by at a temperature of 25 °C on a viscometer according to ASTM D445. The viscosity of water is 1 mPa.s. The viscosity of the wetting agent is preferably below 100 mPa.s. The viscosity of the wetting agent is preferably higher than 1 mPa.s; more preferably higher than 5 mPa.s. A low viscosity of the wetting agent corresponds to a low amount of friction between the lubricious hydrophilic coating and another surface.

The wetting agent preferably comprises at least one hydroxyl group. More preferably, the wetting agent can be chosen from the group consisting of glycerol esters, glycerol ethers, glycols, glycolesters and glycolethers. Examples of wetting agents are glycerol, monoacetin, diacetin and diacetone alcohol.

The wetting agents are used for the lubrication of a hydrophilic polymer coating. The hydrophilic coating may be any coating which comprises a hydrophilic medium that absorbs and/or adsorbs the wetting agent. This can be any coating comprising hydrophilic polymers, an antimicrobial coating, a non-fouling coating or a drug eluting coating.

A hydrophilic polymer coating comprises a hydrophilic polymer capable of providing hydrophilicity to the coating, which polymer may be synthetic or bio-derived and can be blends or copolymers of both. Suitable hydrophilic polymers include but are not limited to poly(lactams), for example polyvinylpyrollidone (PVP), polyurethanes, homo- and copolymers of acrylic and methacrylic acid, polyvinyl alcohol, polyvinylethers, maleic anhydride based copolymers, polyesters, vinylamines, polyethyleneimines, polyethyleneoxides, poly(carboxylic acids), polyamides, polyanhydrides, polyphosphazenes, cellulosics, for example methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, and hydroxypropylcellulose, heparin, dextran, polysacharrides, for example chitosan, hyaluronic acid, alginates, gelatin, and chitin, polyesters, for example polylactides, polyglycolides, and polycaprolactones, polypeptides, for example collagen, fibrins, elastin, albumin, oligo peptides,

polypeptides, short chain peptides, proteins, and oligonucleotides.

Preferably the hydrophilic polymer coating comprises poly(lactams), for example polyvinylpyrollidone (PVP), polyurethanes, homo- and copolymers of acrylic and methacrylic acid, polyvinyl alcohol, polyvinylethers, maleic anhydride based copolymers, polyesters, vinylamines, polyethyleneimines or polyethyleneoxides. More preferably the hydrophilic polymer coating comprises polyvinylpyrrolidone (PVP).

Generally the hydrophilic polymer has a molecular weight in the range of about 8,000 to about 5,000,000 g/mol, preferably in the range of about 20,000 to about 3,000,000 g/mol and more preferably in the range of about 200,000 to about 2,000,000 g/mol. The hydrophilic polymer may be used in the coating in more than 1 wt%, for example more than 5 wt%, or more than 50 wt%, based on the total weight of the dry coating. The hydrophilic polymer can be present up to 99 wt%, or up to 95 %, based on the total weight of the dry coating.

The hydrophilic polymer may for instance be a prepolymer, i.e. a polymer comprising one or more polymerisable groups, in particular one or more radically polymerisable groups such as one or more vinyl groups.

For providing a cross-linked network, a prepolymer having an average number of polymerisable groups per molecule of more than 1 is in particular suitable. Preferably, the average number of reactive groups is at least 1 .2, more preferably at least 1 .5, in particular at least 2.0. Preferably the average number of groups is up to 64, more preferably in the range of up to 15, in particular in the range of up to 8, more in particular up to 7.

However, also a hydrophilic polymer which is free of such

polymerisable groups may be cured in the presence of a photo-initiator, in particular by the formation of grafts when the formulation is exposed to light.

The hydrophilic coating composition may be in the form of a solution or a dispersion comprising a liquid medium. Herein any liquid medium that allows application of the hydrophilic coating formulation on a surface would suffice. Examples of liquid media are alcohols, like methanol, ethanol, propanol, butanol or respective isomers and aqueous mixtures thereof or acetone, methylethyl ketone, tetrahydrofuran, dichloromethane, toluene, and aqueous mixtures or emulsions thereof.

The hydrophilic coating composition according to the invention may additionally include various additives includes conventional ingredients like pigments, dyes, dispersing and stabilising agents (usually surfactants or emulsifiers), rheology control agents, flow-promoting agents, extenders, defoaming agents, plasticisers, thickeners, heat stabilisers, levelling agents, anti-cratering agents, fillers, sedimentation inhibitors, UV absorbers, antioxidants, organic co-solvents, wetting agents, fungicides, bacteriocides, anti-freeze agents, coalescents, waxes and the like introduced at any stage of the production process or subsequently. The hydrophilic coating can be coated on a substrate which may be selected from a range of geometries and materials. The substrate may have a texture, such as porous, non-porous, smooth, rough, even or uneven. The substrate supports the hydrophilic coating on its surface. The hydrophilic coating can be on all areas of the substrate or on selected areas. The hydrophilic coating can be applied to a variety of physical forms, including films, sheets, rods, tubes, molded parts (regular or irregular shape), fibers, fabrics, and particulates. Suitable surfaces are surfaces that provide the desired properties such as porosity, hydrophobicity, hydrophilicity, colorisability, strength, flexibility, permeability, elongation, abrasion resistance and tear resistance. Examples of suitable surfaces are for instance surfaces that consist of or comprise metals, plastics, ceramics, glass and/or composites. The hydrophilic coating may be applied directly to the said surfaces or may be applied to a pretreated or coated surface. The pretreatment or coating can be designed to aid adhesion of the

hydrophilic coating to the substrate.

Preferably, the hydrophilic polymer coating is coated on a medical device. The medical device can be an implantable device or an extracorporeal device. The devices can be of short-term temporary use or of long-term permanent

implantation. In certain embodiments, suitable devices are those that are typically used to provide for medical therapy and/or diagnostics in heart rhythm disorders, heart failure, valve disease, vascular disease, diabetes, neurological diseases and disorders, orthopedics, neurosurgery, oncology, ophthalmology, and ENT surgery.

Suitable examples of medical devices include, but are not limited to, a stent, stent graft, anastomotic connector, synthetic patch, lead, electrode, needle, guide wire, catheter, sensor, surgical instrument, angioplasty balloon, wound drain, shunt, tubing, infusion sleeve, urethral insert, pellet, implant, blood oxygenator, pump, vascular graft, vascular access port, heart valve, annuloplasty ring, suture, surgical clip, surgical staple, pacemaker, implantable defibrillator, neurostimulator, orthopedic device, cerebrospinal fluid shunt, implantable drug pump, spinal cage, artificial disc, replacement device for nucleus pulposus, ear tube, intraocular lens and any tubing used in minimally invasive surgery.

Devices that are particularly suited to be used in the present invention include medical devices or components such as catheters, for example intermittent catheters, guidewires, stents, syringes, metal and plastic implants, contact lenses and medical tubing. The hydrophilic polymer coating can be applied to the substrate by for example dip-coating. Other methods of application include spray, wash, vapor deposition, brush, roller and other methods known in the art.

The hydrophilic polymer coating may have one or more layers. One layer may be a primer layer useful for attaching the coating layer to the medical device.

The invention is further related to a method for the preparation of a medical device comprising the steps of:

- providing a medical device that is at least partially coated with a hydrophilic

polymer coating,

- providing a wetting agent with a boiling point higher than 100 °C and a viscosity lower than 500 mPa.s, wherein the wetting agent can comprise water in an amount between 0 and 4.9 wt% based on the total weight of the wetting agent,

- contacting the part of the medical device that is coated with the hydrophilic

polymer coating with the wetting agent in such a way that the hydrophilic coating is lubricated by the wetting agent,

- optionally, sterilizing the medical device.

The hydrophilic polymer coating on the medical device must be wetted by the wetting agent. The term "wetted" is generally known in the art and - in a broad sense - means "containing a wetting agent". In particular the term is used herein to describe a coating that contains sufficient wetting agent to be lubricious. A lubricious coating has a Coefficient of Friction (COF), as defined below, lower than 0.15. In terms of the concentration of the wetting agent, usually a wetted coating contains at least 10 wt. % of wetting agent, based on the dry weight of the coating, preferably at least 50 wt. %, based on the dry weight of the coating, more preferably at least 100 wt. % based on the dry weight of the coating. For instance, in a particular embodiment of the invention an uptake of wetting agent of about 300-500 wt. % is feasible.

Preferably, a lubricious coating is obtained with a dry-out time longer than 15 minutes as determined on the Harland Friction tester. Within the context of the invention, the dry-out time is the duration of the coating remaining lubricious after the device has been taken out of the wetting agent wherein it has been stored and wetted or after the device has been taken out of the package wherein it has been stored in a wetted condition. Dry-out time can be determined by measuring the coefficient of friction as a function of time the catheter had been exposed to air on the Harland Friction tester. The dry-out time is the point in time wherein the coefficient of friction reaches a value of 0.2 or higher, or in a stricter test 0.15 or higher. The protocol is as indicated in the Examples.

Preferably, a lubricious hydrophilic coating is obtained with a coefficient of friction lower than 0.20 as determined on the Harland Friction tester. A coating is considered lubricious if it has a friction as measured on a Harland FTS Friction Tester of 0.20 or less at a clamp-force of 100 g and a pull speed of 1 cm/s, preferably of 0.15 or less. The protocol is as indicated in the Examples.

Optionally, the medical device is sterilized. Sterilization can be achieved by applying the proper combinations of heat, chemicals and/or irradiation.

Heat sterilization can be performed in an autoclave, wherein steam is heated to 120-135 °C. During chemical sterilization the medical device is for instance contacted with ethylene oxide (EtO), ozone or hydrogen peroxide. Sterilization by irradiation can, for instance, be performed by electron beam, x-ray or gamma ray irradiation.

The hydrophilic coating and or the wetting agent may comprise additives that protect the coating against a detrimental effect of radicals formed during sterilization. These additives are for example aliphatic compounds, alicyclic compounds and/or antioxidants.

In principle any aliphatic stabilising compound and/or alicyclic stabilising compound may be used, in particular any such compound that is physiologically allowable and preferably non-toxic in the used concentration.

A stabilising compound with a relatively low molecular weight is particularly suitable, such as a compound with a molecular weight of less than

1000 g/mol, more in particular of 800 g/mol or less, preferably of 600 gram/mol or less. The use of a low molecular weight compound may have one or more of the following advantages, compared to a compound having a higher molecular weight:

Particularly preferred aliphatic and/or alicyclic stabilising compounds include alcohols, ethers, aldehydes, ketones, amides, esters, thiols, thioesters, organic acids and combinations thereof. Highly preferred are (saturated) aliphatic compounds selected from the group consisting of (saturated) aliphatic alcohols, ethers, aldehydes, ketones amides, esters, thiols, thioesters, organic acids and combinations thereof.

Preferred alcohols include alkylene glycols, such as diethyleneglycol, triethyleneglycol, tetraethyleneglycol, propyleneglycol, dipropyleneglycol,

triprolyeneglycol, (low molecular) ethoxylated or propoxylated alcohols and/or amines like ethanolamine, diethanolamine, triethanolamine, polyethylene glycol (PEG), in particular polyalkylene glycols having a Mw up to about 600 g/mol lower aliphatic alcohols - in particular C1 -C8 alcohols, more in particular C2-C4 alcohol, such as isopropanol, ethanol, 1 -propanol and 1 -butanol - and combinations thereof. Good results have further been achieved with a carbohydrate, in particular a

monosaccharide, more in particular glucose.

Preferred ethers include polyalkylene glycols, such as PEG.

Suitable aldehydes include C1 -C8 aldehydes. Preferred aldehydes include formaldehyde, acetaldehyde and butanal.

Suitable ketones include C3-C8 ketones. Preferred ketones include acetone and methylethylketone.

Suitable organic acids include C1 -C8 organic acids. Preferred organic acids include formic acid.

The invention is further directed to a package containing a medical device or a part of a medical device comprising a lubricated hydrophilic coating, which package is impermeable to vapor. The package can, for instance, be made of plastic or aluminum foil. The package can contain additional wetting agent.

Preferably, the package comprises a medical device that is sterilized.

The invention will now be illustrated by the following, non-limiting examples.

Examples 1 -5 and Comparative Experiment A-H

Primer coating formulation

The primer formulation was prepared by dissolving the components below in ethanol.

PTGL1000(T-H)₂ oligomer 4.25 % (w/w)

PVP K85 (supplied by BASF) 0.75 % (w/w)

Irgacure 2959 (supplied by Sigma Aldrich) 0.20 % (w/w)

Ethanol 96% (supplied by Merck) : 94.8 % (w/w)

The synthesis of PTGL1000(T-H)₂ oligomer is described in

WO2007/065722. Hydrophilic coating formulation

The hydrophilic coating formulation was prepared by dissolving the components below in a water/ethanol mixture 1 :1 based on weight. Weight%

PVP K85 5.20

Polyacrylamide-co-acrylic acid sodium salt (PAcA) 0.35

(supplied by Sigma Aldrich)

Irgacure 2959 (supplied by Sigma Aldrich) 1

Benzophenone 1

Ethanol (96%) 47.45

Water 45

Coating application

PVC tubes with a diameter of 14 Fr and a length of 30 cm were coated on a Harland PCX coater 175/24.

The PVC tubes were first dip- coated with the primer coating formulation and cured according the dip protocol for the primer in table 1 . Subsequently the hydrophilic coating formulation was applied and cured according the dip protocol for the hydrophilic coating. Temperature and humidity during application were respectively 21 °C +1-2 °C and 40% +/- 15%.

The Harland PCX coater/175/24 was equipped with a Harland Medical systems UVM 400 lamp. Intensity of the lamps of the Harland PCX

coater/175/24 was on average 60 mW/cm² and was measured using a Solatell Sola Sensor 1 equipped with an International Light detector SED005#989, Input Optic:

W#1 1521 , filter: wbs320#27794. The IL1400A instruction manual of International Light was applied, which is available on the internet: www.intl-liqht.com. For the applied parameters in the PCX coater see Table 1 .

The tubes were dipped in the wetting agent, immersed for 2 minutes and thereafter extracted from the wetting agent with a speed of 1 cm/s. The wetted coatings were evaluated directly after removal from the wetting agent.

All measurements were performed at a relative humidity of 40-50%. Table 1. Applied parameters in the PCX Coater

Test methods

Viscosity test

The viscosity of a wetting agent was determined on a viscometer according to ASTM D445 at a temperature of 25 °C. Lubricity test

Lubricity tests were performed on a Harland FTS5000 Friction Tester (HFT). The protocol was selected: see Table 2 for HFT settings. Friction tester pads were used from Harland Medical Systems, P/N 102692, FTS5000 Friction Tester Pads, 0,125^*0,5^**0,125, 60 durometer.

Subsequently the desired test description was inserted when "run test" was activated. A sample was fastened in the sample holder.. The transport of the tester was moved to the desired position and the protocol was activated by pushing "start". The data were saved after finishing. The sample holder was removed from the tester and subsequently the catheter was removed from the holder.

Table 2. HFT settings

The measured coefficient of friction (COF) is used to rate the performance of the coating. The COF is defined as the measured friction\clamp force. The COF was determined on a sample after 10, 15 and 30 minutes of drying. The drying time started directly after removal of the sample from the wetting agent.

A C0FO.15 is judged as good. A COF between 0.15 and 0.20 is judged as too high; a COF>0.20 is judged as bad.

Table 3, Results of the lubricity test

The results obtained with triacetin show a high COF. It was observed that this compound was absorbed insufficiently by the coating.

The results obtained with mono- and diacetin show a low friction value that remained unchanged over the whole test period of 30 minutes. Even after remeasuring the samples after 16 hours in air almost no change in friction was observed (COF was 0.12). Comparative experiments C-F show that the addition of water to the wetting agent shortens the time that a coating remains lubricious after the removal of the wetted coating from the wetting agent.

Claims

CLAIMS:

Use of a wetting agent having a boiling point higher than 100 °C and a viscosity lower than 500 mPa.s for the lubrication of a hydrophilic polymer coating on a substrate, wherein the wetting agent can comprise water in an amount between 0 and 4.9 wt% based on the total weight of the wetting agent. Use according to claim 1 , wherein the wetting agent comprises at least one hydroxyl group.

Use according to claim 1 or 2, wherein the wetting agent is chosen from the group comprising glycerol esters, glycerol ethers, glycols, glycolesters and glycolethers.

Medical device comprising a hydrophilic polymer coating that is wetted by a wetting agent having a boiling point higher than 100 °C and a viscosity lower than 500 mPa.s, wherein the wetting agent comprises water in an amount between 0 and 4.9 wt% based on the total weight of the wetting agent.

Medical device according to claim 4, wherein the wetting agent comprises at least one hydroxyl group.

Medical device according to claim 4 or 5, wherein the wetting agent is chosen from the group consisting of glycerol esters, glycerol ethers, glycols, glycolesters and glycolethers.

Medical device according to anyone of claims 4-6, wherein the hydrophilic polymer coating is crosslinked.

Medical device according to anyone of claims 4-7, wherein the hydrophilic polymer coating comprises polyvinylpyrrollidone (PVP).

Medical device according to anyone of claims 4-8, with a dry-out time longer than 15 minutes as determined on a Harland Friction tester.

Medical device according to anyone of claims 4-9, with a coefficient of friction lower than 0.2 as determined on a Harland Friction tester.

Method for the preparation of a medical device according to anyone of claims

4-10 comprising the steps of:

a. providing a medical device that is at least partially coated with a

hydrophilic polymer coating,

b. providing a wetting agent with a boiling point higher than 100 °C and a viscosity lower than 500 mPa.s, wherein the wetting agent comprises water in an amount between 0 and 4.9 wt% based on the total weight of the wetting agent,

c. contacting the part of the medical device that is coated with the

hydrophilic polymer coating with the wetting agent in such a way that the hydrophilic coating is lubricated by the wetting agent,

d. optionally, sterilizing the medical device.

Package comprising a medical device according to anyone of claims 4-10, wherein the package is impermeable to vapor.

Package according to claim 12, wherein the medical device is sterilized.