CN1753702B - Components for the preparation of medical devices with coatings comprising hydrogen peroxide - Google Patents

Abstract

The present invention provides an assembly for preparing a medical device having a porous coating comprising hydrogen peroxide. Medical devices of particular interest are catheters (e.g. urinary catheters), endoscopes, laryngoscopes, catheters for feeding, catheters for drainage, guide wires, condoms, urisheaths, barrier coatings, such as gloves, dilators and other implants, extra corporeal blood conduits, membranes, such as membranes for dialysis, blood filtration, circulatory aids, dressings for wound care, and ostomy bags. The coating is in particular a hydrophilic coating formed with crosslinked polyvinylpyrrolidone. In one embodiment, the assembly holds the dried catheter component in one chamber of the package and the aqueous hydrogen peroxide solution in another chamber. The solution may also include a stabilizer, e.g., a chelating agent, and an osmolarity enhancing agent. Catheters for insertion into the urinary tract may be used to treat, alleviate or prevent microbial infections, such as Urinary Tract Infections (UTIs).

Description

Components for the preparation of medical devices with coatings comprising hydrogen peroxide

field of invention

The present invention relates to components useful for providing a medical device having a coating of a porous polymer composition, e.g. a hydrophilic coating, on at least a portion of its surface, wherein the coating comprises a liquid, e.g. A liquid expansion medium comprising hydrogen peroxide.

The invention also relates to the medical device itself, in particular the expansion medium containing hydrogen peroxide, and the medical use of said components and medical devices.

Background of the invention

In many medical applications, polymer compositions constitute at least a part of medical devices, such as hydrophilic coatings, hydrogels, stents, adhesives, etc., which can be used in close contact with the human body. Medical devices can also be used to introduce, cover, or fill body cavities. Examples of body cavities or openings may be naturally occurring cavities such as the urethra, mouth, ear, nose, eyes, rectum, or artificial openings such as those formed in arteries, veins, lymph nodes through surgical or planned manipulations A lumen or opening, or an opening formed in the gastrointestinal tract, such as a colostomy, ileostomy, urinary tract regeneration, or as a result of an unintended action. The medical device or the polymer composition can also be used for positioning between limbs (legs, fingers, toes, armpits), or for physical bonding to the human body by adhesives.

The polymer composition of medical devices can be engineered to be soft and resilient, and to reduce friction between sliding parts. For example, it is known to coat medical devices, such as catheters, with a hydrophilic coating for introduction into body cavities such as blood vessels, digestive organs and the urinary system. When the coating is swelled by aqueous solution or water, the surface of the medical device becomes smooth and is ideal for painless introduction into body cavities with minimal damage to tissues.

When devices of the type described, for example catheters with a hydrophilic coating, are introduced into body cavities, normal body defense barriers may be penetrated, resulting in the introduction of microorganisms, i.e. introduction of viruses, bacteria, fungi, molds, bacteriophages, Or tissue-like or small cells of various organized cells. It is well known that people who undergo intermittent daily urinary catheterization often have problems with symptomatic urinary tract infection (UTI). Similarly, a variety of other medical devices that come into close contact with human tissue can lead to microbial infections.

Hydrogen peroxide is known to have antimicrobial effects. Also understand that it breaks down easily. By reacting with reducing transition metal ions such as iron(II) and copper(I), hydrogen peroxide is decomposed by the Fenton reaction to form highly reactive hydroxyl groups. In addition to destroying hydrogen peroxide, and thus shortening the shelf life of products containing hydrogen peroxide, the hydroxyl groups from the Fenton reaction can potentially damage polymer coatings, especially hydrophilic coatings, through which they interact with the coating. The various components in the layer system react to achieve. Contamination of water by transition metal ions occurs, for example, by storing water in steel or glass containers. Even in water that has been purified, for example, by ion exchange, trace amounts of transition metal ions are still present. Thus, polymer coatings comprising liquids containing hydrogen peroxide may generally be considered unsuitable for long-term storage.

US 5,130,124 discloses film-forming antimicrobial compositions of stabilized hydrogen peroxide.

US 5,951,458 discloses a method of inhibiting restenosis by applying oxidative agents to blood vessels, for example, delivery of hydrogen peroxide via a balloon catheter. Said US patent does not address the stability of hydrogen peroxide present in hydrophilic coatings.

Summary of the invention

_The present invention takes advantage of the beneficial properties of hydrogen peroxide ( _H2O2 ), while employing means to avoid potentially harmful effects due to the instability of hydrogen peroxide.

A first aspect of the present invention relates to an assembly comprising (i) at least one medical device component having a coating of a porous polymer composition covering at least a portion of the component, (ii) for occupying the at least one liquid for the pores of the polymer composition, (iii) a source of hydrogen peroxide, and (iv) a packaging device suitable for placing the medical device component, the liquid and the source of hydrogen peroxide Contained in at least two separate chambers.

A second aspect of the invention relates to an antimicrobial liquid swelling medium comprising:

0.1-3.0% (w/w) hydrogen peroxide,

25-1200mg/L of one or more stabilizers,

0-10 mM of one or more buffers,

0-300mM osmolarity-enhancing preparations,

0-2000mg/L of other ingredients, and

Balanced amount of purified water,

And, the range of pH is 2.0-8.5.

A third aspect of the invention relates to a medical device having on at least a part of its surface a coating of a porous polymer composition, wherein the coating comprises a liquid comprising hydrogen peroxide and a formulation capable of stabilizing the hydrogen peroxide.

A fourth aspect of the present invention relates to a method of treating, alleviating or preventing microbial infection, wherein the first step is to prepare a medical device using the above-mentioned components, and the second step is to make the device and the medical device in need of body parts of mammals.

A fifth aspect of the present invention relates to a method of treating, alleviating or preventing microbial infections, wherein the above-mentioned medical device is brought into contact with a body part of a mammal in need of said medical device.

A sixth aspect of the present invention relates to an assembly comprising (i) at least one medical device component having a coating of a porous polymer composition, the coating covering at least a portion of the component, and, in the coating There is a liquid containing hydrogen peroxide, and (ii) a packaging device suitable for containing said medical device components.

Description of drawings

Figures 1 and 2 are examples of packaging devices having two separate chambers.

Detailed Description of the Invention

components

In response to the aforementioned potential problems with the stability of hydrogen peroxide, at least when it is present in polymeric coatings, especially hydrophilic coatings, the present invention provides components useful in the preparation of medical devices immediately prior to use, wherein, The coating of the device includes a defined amount of hydrogen peroxide.

Accordingly, the present invention provides a solution to the above-mentioned problems, including the provision of a medical device (i.e. a component) for obtaining a coating, e.g., a hydrophilic coating, of a porous polymer composition on at least a part of its surface. , wherein the coating comprises a liquid, eg, a liquid swelling medium comprising hydrogen peroxide.

As has been demonstrated by the illustrative examples of the invention, the medical device effectively provides the advantage of inhibiting the development of microbial infections, eg urinary tract infections, when in use. Additionally, the aforementioned stability issues are mitigated.

More specifically, the present invention provides an assembly comprising (i) at least one medical device component having a coating of a porous polymer composition covering at least a portion of the component, (ii) for at least one liquid occupying the pores of the polymer composition, (iii) a source of hydrogen peroxide, and (iv) a packaging device suitable for containing the medical device component, the liquid and the peroxide The source of hydrogen is housed in at least two separate chambers. In its preferred embodiment, said packaging means is further adapted to establish a link between said medical device component, said liquid and said source of hydrogen peroxide.

medical instruments

The term "medical device" should be understood in a broad sense. Suitable examples of medical devices (including instruments) are catheters (e.g. urinary catheters), endoscopes, laryngoscopes, catheters for feeding, catheters for voiding, guide wires, condoms, urisheaths, barrier coatings , for example, for gloves, dilators and other implants, external tangible vascular catheters, membranes, for example, for dialysis, membranes for hemofiltration, devices for circulatory assistance, dressings for wound care, and ostomy bag. Most relevant are catheters, endoscopes, laryngoscopes, catheters for feeding, catheters for voiding, guide wires, and dilators and other implants. Medical devices of particular interest within the scope of the present invention are catheters, such as urinary catheters.

Certain medical devices may be constructed from one or more medical device components which, when assembled or reassembled, form a ready-to-use medical device. References to "medical device component" and "catheter component" mean the medical device or catheter itself (ie, a medical device or catheter) or a portion of an "off-the-shelf" medical device or catheter.

Medical devices and medical device components can be constructed from many types of base materials such as plastics, metals, glass, ceramics, etc. Typical examples of plastic materials used in medical devices are polymers such as polyurethane and its copolymers, or polyether block amides such as Pebax ^TM or other polymeric materials including polyvinyl chloride, polyamide, silicone, styrene -Ethylene/butylene-styrene block copolymer (SBBS), styrene-isoprene-styrene block copolymer (SIS), styrene-ethylene/propylene-styrene block copolymer (SEPS) , ethylene-vinyl acetate copolymer (EVA), polyethylene (PE), metallocene-catalyzed polyethylene, and copolymers of ethylene and propylene or mixtures thereof. Currently very relevant materials are polyurethanes and their copolymers.

In the present invention, the medical device has a coating of the porous polymer composition, eg, a hydrophilic coating, on at least a part of its surface (ie, on a part of the surface of the base material). In certain embodiments, the coating of the porous polymer composition (e.g., the hydrophilic coating) is applied over the entire (outer) surface of the matrix polymer, while in certain other embodiments In the scheme, apply to only a part of the surface. In the most relevant embodiment, said coating is applied to at least a portion of the surface (preferably the entire surface) of said medical device which, when properly used, is capable of interacting with the body of the person who is required to use the medical device. some direct contact.

In the present invention, a polymer composition is "porous" in the sense that (i) the coating of the polymer composition has voids suitable for receiving a liquid medium by capillary forces, for example, a sponge, or (ii) the polymer composition Coatings of composition compositions may be porous due to hydrophilic properties, eg, as is known from swellable hydrophilic polymers, which are capable of retaining large amounts of water within the swollen polymer network. In some instances, the "porosity" of the polymeric composition may be the result of a combination of the two aforementioned "phenomena".

Polymer compositions of particular interest include a substantial amount (i.e., at least 50% (w/w)) of a swellable, hydrophilic polymer that imparts hydrophilicity on at least a portion of the surface of a medical device, e.g., a catheter. coating. For some uses, the polymer composition (eg, a hydrophilic polymer such as polyvinylpyrrolidone) is preferably crosslinked.

Typical examples of said expandable hydrophilic polymers are polyvinylpyrrolidone, polyvinyl alcohol, poly(meth)acrylic acid, poly(meth)acrylamide, polyethylene glycol, carboxymethylcellulose, cellulose acetate cellulose acetate propionate, chitosan, polysaccharide; or any homopolymer or copolymer of two or more of the above monomers; N-vinylpyrrolidone, vinyl alcohol, (meth)acrylic acid, (meth)acrylic acid, (meth) base) acrylamide, (meth)acrylates such as hydroxyethyl methacrylate, maleic anhydride, maleimide, methyl vinyl ether, alkyl vinyl ether, and other unsaturated compounds. Additionally, the hydrophilic polymer may be a blend of the homopolymers or copolymers. Other radiation curable hydrophilic polymers comprising unsaturated vinyl double bonds are also suitable for use in the coating. The polymers can be prepared by copolymerizing acrylic substances, such as dimethylaminoethyl methacrylate, with N-vinylpyrrolidone, methacrylic acid, methacrylates, methyl vinyl ether, etc. to form oligomers. Typically the prepolymer is coated on the surface and eventually cured by radiation. The hydrophilic polymer of the coating can also be prepared by adding monomers of acrylic nature to polymers of the above-mentioned type. Polyethylene glycol and polyvinylpyrrolidone are particularly suitable for the hydrophilic coating.

Most preferably, the hydrophilic polymer of the coating is selected from the group consisting of polyvinylpyrrolidone or a copolymer thereof, eg, polyvinylpyrrolidone-vinyl acetate copolymer. Polymers of the type described can also be crosslinked by radiation. When pure polyvinylpyrrolidone (poly(N-vinyl-2-pyrrolidone); PVP) is used, various chain lengths can be selected, each giving the coating various characteristics. Typically, the polyvinylpyrrolidone polymer has a number average molecular weight above 100,000. For example, PVPK-90 with a molecular weight of 1,200,000 may be chosen, however, other types of PVP with other molecular weights may also be used.

In one interesting embodiment, the matrix polymer is polyurethane and the hydrophilic polymer is polyvinylpyrrolidone.

When preparing the hydrophilic coating, one or more additives may be added, for example, to facilitate crosslinking of the hydrophilic polymer, or to improve the binding of the polymer to the substrate surface. Such additives are well known in the art and include UV-initiators, see eg WO 98/58990. Examples of suitable UV-polymerization initiators are KIP 150.

Hydrophilic coatings may also include plasticizers such as acetyl triethyl citrate, dimethyl sulfone, ethylene carbonate, diacetin, triacetin, hexamethylphosphoramide, isophorone , methyl salicylate, N-acetylmorpholine, propylene carbonate, quinoline, sulfolane, triethyl citrate, and triethyl phosphate.

The application of the hydrophilic coating can be by dipping, spraying or painting the polymer solution onto the medical device or medical device component requiring the hydrophilic coating, or a portion thereof. Alternatively, the coating may be formed by co-extrusion.

KIP 150，和溶解在乙醇中的增塑剂。Polyvinylpyrrolidone coatings on medical device components can be formed by applying a solution containing N-methylpyrrolidone, polyvinylpyrrolidone or its copolymers (N-vinylpyrrolidone with poly(meth)acrylic acid, acrylamide, vinyl alcohol, polyethylene glycol, polyvinyl methyl ether, polyvinyl methyl ether-maleic anhydride, carboxymethyl cellulose, or hydroxyethyl cellulose), optionally using a UV photoinitiator such as

KIP 150, and plasticizer dissolved in ethanol.

Prior to applying the hydrophilic coating, particularly for certain combinations of matrix polymers and hydrophilic coatings, the polymer composition forming the porous polymer composition (e.g., The hydrophilic coating) is preferably preceded by a primer coating. In certain embodiments, the primer coating can be prepared with a dilute solution of the polymer solution.

In other embodiments, the coating of the polymer composition is a "sponge-like" structure having voids suitable for containing a liquid medium by capillary forces, and the coating can be formed by co-extruding the base material of a medical device and The material preparation of the "sponge-like" structure, or by soaking the base material of the medical device in a material (or a solution thereof) that will subsequently expand upon curing to form a "sponge-like" structure that constitutes the Porous coating etc.

liquid (liquid expansion medium)

The liquid which is part of the assembly is intended to be in contact with the porous polymer composition in such a way that the liquid and hydrogen peroxide can fill the pores of the porous polymer composition in use. In certain embodiments, some or all of the liquid is initially contained within the porous polymer composition. For hydrophilic polymers (e.g., cross-linked hydrophilic polymers, such as cross-linked PVP), the liquid (i.e., liquid swelling medium) swells the hydrophilic polymer upon contact, In order to form a swollen hydrophilic coating.

The assembly may include one or more liquids (eg, a liquid expansion medium), and, if two or more liquids are included, the liquids should preferably be miscible.

In a most preferred embodiment, the one or more liquids are selected from water (aqueous) and aqueous solutions (eg, aqueous hydrogen peroxide). Aqueous solutions typically comprise at least 90% (w/w), such as at least 95% (w/w), or at least 97% (w/w) water.

source of hydrogen peroxide

The hydrogen peroxide source is typically selected from liquid hydrogen peroxide sources (ie, aqueous hydrogen peroxide solutions) and solid hydrogen peroxide sources (ie, solid compounds that release hydrogen peroxide when heated or in contact with water). The source of liquid hydrogen peroxide is preferably stabilized so as to reduce or eliminate decomposition of hydrogen peroxide (see below).

Examples of sources of solid hydrogen peroxide are, for example, hydrogen peroxide bound to compounds (e.g., solid hydrogen peroxide compounds bound to polyvinylpyrrolidone (PVP)) and compounds with the potential to form hydrogen peroxide, such as , by reacting with water, such as perborate (for example, sodium perborate), percarbonate (for example, sodium percarbonate), perphosphate (for example, sodium superphosphate), persulfuric acid (for example, persulfuric acid Potassium), Peroxomonosulfate, Peroxodisulfate, Carbamide Peroxide, etc.

It should be understood that the sources of hydrogen peroxide referred to herein may include one or more types of sources, and may also be solid sources combined with liquid hydrogen peroxide sources.

In order to obtain biocompatibility between the hydrogen peroxide coating composition and human tissue cells, the concentration of the hydrogen peroxide in the liquid (for example, swelling medium) before use should be kept at a low level, such as 0.01-5.0 %, such as 0.1-3.0%, such as 0.2-2.0%, such as 1%, which is determined (w/w) in the liquid (eg, swelling medium) of as-made and ready-to-use medical devices (eg, catheters). This concentration corresponds to that obtained when all liquid is in contact with the liquid or solid source of hydrogen peroxide.

Hydrogen peroxide is a well-known substance that rapidly decomposes into water and oxygen in the human body. Therefore, hydrogen peroxide will not cause harm to the human body when taken in low concentrations. In practice, however, hydrogen peroxide may decompose quite easily under conditions suitable for medical use, when a medical device (e.g., a urinary catheter) with a coating (e.g., a hydrophilic coating) of a porous polymer composition is exposed to Stability problems may arise when stored in contact with liquid swelling media containing hydrogen peroxide. This problem becomes particularly acute when the medical device is required to have a long shelf life after production, for example more than a few months or even up to 1 or several years (see examples).

Packaging device

With regard to the aforementioned stability issues, the assembly of the present invention also includes (iv) packaging means adapted to contain (i) said medical device component, (ii) said liquid and (iii) said source of hydrogen peroxide in a In at least two independent chambers, that is, when the packaging device is in a specific configuration, none of the above three items (i)-(iii) will directly contact each other, that is, the three items (i)-( iii) in "at least two separate chambers".

The two separate chambers in the packaging unit may be mounted (i) so that the first chamber is adjacent to the second chamber; (ii) so that the second chamber is mounted within the first chamber and vice versa. However; (iii) so that the first chamber and the second chamber are constituted by loosely fitted bags, ampoules, capsules etc. in the third chamber of said packaging device. Those skilled in the art will understand that other possible structures are also included.

In one embodiment of the packaging device, said second chamber has sealing means adapted to release said source of hydrogen peroxide into the first chamber after removal of said sealing means.

The term "packaging device" denotes a structure intended to include other objects, liquids, etc., in order to isolate said objects, liquids, etc. from the exterior of said packaging device.

Packaging devices may include plastics such as polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), polyvinylidene fluoride (PVDF), polytetrafluoroethylene (PTFE), rubber, e.g., synthetic rubber - Ethylene Propylene Diene Monomer (EPDM), FKM Viton, and paper coated with said polymers and rubbers. Plastics and rubbers suitable for holding hydrogen peroxide should be corrosion resistant and should not lead to degradation of hydrogen peroxide. The interior surfaces of the chamber containing the hydrogen peroxide can also be coated with inert metals such as titanium and platinum.

Polyethylene is currently the preferred material for lining the chamber in contact with the source of hydrogen peroxide because it only reacts slowly with hydrogen peroxide.

The parts of the packaging device constituting the chamber containing hydrogen peroxide or hydrogen peroxide solution are, in one embodiment, made of multiple layers of material in order to obtain gas impermeability (and possibly opaque ) in order to avoid any detrimental effect on the stability of hydrogen peroxide. The multilayer material may be a three-layer foil consisting of polyethylene terephthalate (PET)/aluminum/polyethylene (PE), where polyethylene is the inner layer of the chamber and is The hydrogen peroxide or expansion medium containing hydrogen peroxide is in direct contact.

The term "gas-impermeable" should be understood in the present invention to mean any material that is sufficiently tight to resist the diffusion of vaporization of said liquid expansion medium beyond the recommended shelf life of the component, which may be long Up to 5 years, usually about 36 months or more.

The packaging device is preferably further modified so as to be able to establish contact between the medical device component, the liquid and the source of hydrogen peroxide.

In use of the assembly, one or both (or all) of the chambers are opened in such a way that (i) the medical device component, (ii) the liquid and (iii) the source of hydrogen peroxide are Contacting, the purpose of which is to provide a liquid containing hydrogen peroxide for the coating of the medical device component. Opening of the chambers as described above may be achieved by protruding the walls of one or both (or all) chambers, by breaking the seal, by twisting the lid, etc. (see also below).

In a preferred variant, the components are brought into contact with each other in the packaging device, ie while the packaging device still contains the components. In this way, the wetting of the coating of the medical device can be performed under sterile conditions.

A wide variety of designs of said packaging device can be proposed, and examples of suitable packaging devices for this purpose are, for example, see EP 0 923 398 and WO 03/092779, and see FIGS. 1 and 2 .

Figure 1 shows an example of a packaging device (3) with two separate chambers (4 and 5). The first chamber (4) accommodates a catheter consisting of two catheter parts (1 and 2), one of which (1) has a coating of a porous polymer composition. A second chamber (5) in the form of a bladder is fitted inside the first chamber (4) and contains a liquid swelling medium (eg hydrogen peroxide solution). The outlet portion (6) of the bladder (5) is directed toward said catheter parts (1 and 2). The outlet portion (6) is closed by a breakable seal in the form of a weld (7), providing a weak joint which can rupture when pressure is applied to the bladder (5). This purpose can be achieved by squeezing said packaging means (3) without actually opening said packaging means. In this way, wetting (expansion) of the catheter part (1) can be achieved under aseptic conditions.

Figure 2 shows another example of a packaging device (3) with two separate chambers (4 and 5). The first chamber (4) accommodates a catheter consisting of two catheter parts (1 and 2), one of which (1) has a coating of a porous polymer composition. A second chamber (5) in the form of a rigid container is mounted adjacent to the first chamber (4) and contains a liquid expansion medium (eg hydrogen peroxide solution). The end wall (8) of the rigid container (5) faces the end wall (9) of the first chamber (4). As shown in the figure (Fig. 2 (b)), the second chamber (5) is installed to be rotatable relative to the end wall (9) of the first chamber (4), so that the ) and the liquid outlet and liquid inlet on the end wall (9) form a liquid flow alignment. Thus, the liquid expansion medium of the second chamber (5) can be transferred into the first chamber (4), so that the liquid expansion medium can enter the pores of the coating of the catheter part (1).

在所述产品中，具有所述液体膨胀介质的所述安培瓶是与干燥的、涂层的导管分离的。在使用之前，破坏安培瓶，并且将所述液体膨胀介质吸收到所述亲水性涂层中。An example of a commercial product that can employ the present invention is a hydrophilic coated urinary catheter assembly having an ampoule (second chamber) containing a liquid swelling medium integral to said product, e.g., Supplied by Astra Tech AB and provided by Coloplast A/S

In said product, said ampoule with said liquid expansion medium is separated from the dry, coated catheter. Prior to use, the ampoule was broken and the liquid swelling medium absorbed into the hydrophilic coating.

Various implementations of components

In an interesting embodiment of the above assembly, the polymer composition comprises a hydrophilic polymer forming a hydrophilic coating on at least a portion of the surface of the medical device component, and the liquid is Liquid expansion medium.

In other interesting embodiments, the medical device component comprises a catheter component. More specifically, the medical device is a catheter, such as a urinary catheter. In a preferred variant, at least a portion of the catheter member has a hydrophilic coating adapted to reduce friction and introduce the hydrogen peroxide into an opening in the body, eg, the urethra.

In the most presently preferred embodiment, the assembly is a catheter assembly comprising (i) at least one catheter component covered at least a portion of said catheter component by a hydrophilic coating, (ii) for expanding said hydrophilic at least one swelling medium for an aqueous coating, (iii) a source of hydrogen peroxide, and (iv) a packaging device suitable for containing said catheter component, said swelling medium and said source of hydrogen peroxide in in at least two separate chambers.

In one embodiment thereof, said packaging device is adapted to establish contact between said catheter component, said inflation medium and said source of hydrogen peroxide, eg, as described above.

The invention is primarily described in connection with the "catheter" embodiment and the "hydrophilic coating" embodiment below, however, it should be understood that these descriptions apply equally to other embodiments of the invention.

In one main embodiment of the catheter assembly, a first chamber of the packaging device is adapted to contain a catheter component and a second chamber of the packaging device is adapted to contain a source of hydrogen peroxide. The source of hydrogen peroxide may be a solid provided in one or more pellets or powder form, or a liquid hydrogen peroxide solution may be provided as at least part of the liquid swelling medium, which is added to the catheter component prior to use middle.

A preferred embodiment of the above embodiment is such, wherein the first chamber of the packaging device is adapted to contain the catheter component, and wherein the second chamber of the packaging device is adapted to contain the liquid at least a portion of the expansion medium and the source of hydrogen peroxide. When present in the same chamber, i.e., in a second chamber, the liquid expansion medium and the source of hydrogen peroxide typically form an aqueous hydrogen peroxide solution, i.e., the second chamber will peroxide A hydrogen solution is contained in at least a portion of the liquid expansion medium. Thus, in this embodiment, the source of hydrogen peroxide is hydrogen peroxide present in an aqueous solution.

In a variation of the above embodiment, the first chamber of the packaging device contains at least a portion of the liquid expansion medium, i.e. the catheter member is at least partially inflated by the liquid expansion medium, and Another portion of the liquid expansion medium is combined with the hydrogen peroxide. This has the advantage that the catheter component can be provided in a pre-inflated condition. In this variant, however, it is important to ensure that a suitable portion of the swelling medium containing hydrogen peroxide enters the hydrophilic coating.

In another variation of the above embodiment, the second chamber of said packaging means contains all of said liquid expansion medium, i.e. said catheter component is present in substantially "dry" form in the first chamber. in the chamber.

Thus, in a variant of particular interest, a first chamber of said packaging means is adapted to contain said catheter part, while a second chamber of said packaging means is adapted to contain all of said liquid expansion medium and hydrogen peroxide, ie, the second chamber contains aqueous hydrogen peroxide.

Regardless of the choice of embodiment above, the contents of said liquid (e.g., liquid expansion medium) and said hydrogen peroxide source in said assembly are preferably selected so that said peroxidation in the liquid (e.g., liquid expansion medium) The concentration of hydrogen is in the range of 0.01-5.0% (w/w), such as 0.1-3.0% (w/w), such as 0.2-2.0% (w/w), at this time, the liquid (expansion medium) and the Hydrogen peroxide is present in the pores of the polymer composition (eg, a hydrophilic coating that has been swollen). In the embodiment in which the second chamber of the packaging device contains a solution of hydrogen peroxide present throughout the liquid expansion medium, the aforementioned concentrations will of course correspond to the concentrations in such an aqueous solution.

In the above embodiments, where the second chamber of the packaging device contains hydrogen peroxide solution in at least a portion of the liquid expansion medium, it is of considerable importance to the manufacturer of the assembly to ensure that the peroxide solution The concentration of hydrogen remains at a stable level even after storage for many months or even years under variable conditions regarding temperature and light. Accordingly, the hydrogen peroxide solution in at least a portion of the liquid expansion medium preferably includes a stabilizer.

More specifically, the inventors have identified preferred options for embodiments wherein said hydrogen peroxide solution in said liquid swelling medium further comprises one or more selected from the group consisting of stabilizers, buffers and The osmolarity enhancing formulation, particularly at least the stabilizer, is an aqueous hydrogen peroxide solution.

Examples of stabilizers (most commonly selected from chelating agents, added to bind metal ions that would otherwise facilitate the breakdown of hydrogen peroxide) are deferoxamine, polysaccharides, gelatin, acetate, citrate , EDTA and corresponding salts, diethylenetriaminepentaacetic acid (DETAPAC) and corresponding salts, ethylenediaminetetrakis (methylenephosphonic acid) (EDATMP) or corresponding salts, diethylenetriaminepenta( Methylenephosphonic acid) (DETAPMP) or corresponding salt, 1-hydroxyethane-1,1-diphosphonic acid (HEDP) or corresponding salt, gluconate, orthophosphonate, pyrophosphate, tris Phosphate, hexametaphosphate, phytate, sorbitol, tartrate, silicate (as colloidal silicate), colloidal stannate, sodium pyrophosphate, and organic phosphonate. Preferred examples are EDTA, gelatin, deferoxamine, polysaccharides, and diethylenetriaminepentaacetic acid (DETAPAC). In other preferred embodiments of the present invention, the chelating agent is DETAPMP or deferoxamine-polyhydroxime, which is also known as deferoxamide.

The content of the stabilizer in the aqueous hydrogen peroxide solution is usually in the range of 0-2000 mg/L, more preferably 25-1200 mg/L.

Examples of buffers are citrate, acetate, glycolate, phosphate, benzoate, amino acid, formate, oxalate, malonate, succinate, glutarate, hexanoate Di-Acids, Malates, Lactates, Sulfonamides, Borates, Bicarbonates, Sulfates, and Similar Substances.

The content of the buffer in the aqueous hydrogen peroxide solution is usually in the range of 0-200 mM, more preferably 0-50 mM, for example, up to 50 mM, such as 2-50 mM.

Examples of osmolarity-enhancing agents are alkali metal (e.g., lithium, sodium, potassium, etc.) and alkaline earth metal (magnesium, calcium, etc.) nitrates, alkali metal and alkaline earth metal sulfates, alkali metal and alkaline earth metal hydrochlorides, Glycine, Glycerin and Urea. An osmolarity-enhancing formulation is not strictly necessary, however, it is often important in order to improve comfort during use of the medical device.

The content of the osmolarity-increasing agent in the aqueous hydrogen peroxide solution is usually in the range of 0-1000 mM, more preferably 0-300 mM, for example, up to 300 mM, such as 5-300 mM.

It should be noted that the aqueous hydrogen peroxide solution may include trace amounts of other components not explicitly mentioned above. The content of the "other ingredients" is usually 0-2000 mg/L, such as 0-500 mg/L.

Typically, the pH of the aqueous solution is in the range of 2.0-8.5, preferably in the range of 3.0-5.0.

In one embodiment, the aqueous hydrogen peroxide solution comprises:

0.01-5.0% (w/w) hydrogen peroxide,

0-2000mg/L of one or more stabilizers,

0-200mM of one or more buffers,

0-1000mM osmolarity-enhancing formulations,

And, the range of pH is 2.0-8.5.

In another embodiment, the aqueous hydrogen peroxide solution comprises:

0.01-5.0% (w/w) hydrogen peroxide,

25-1200mg/L of one or more stabilizers,

0-25mM of one or more buffers,

0-300mM osmolarity-enhancing preparations,

And, the range of pH is 2.0-8.5.

In another embodiment, the aqueous hydrogen peroxide solution comprises:

0.1-3.0% (w/w) hydrogen peroxide,

25-1200mg/L of one or more stabilizers,

0-10 mM of one or more buffers,

0-300mM osmolarity-enhancing preparations,

0-2000mg/L of other ingredients, and

Balanced amount of purified water,

And, the range of pH is 2.0-8.5.

In the most preferred embodiment at present, described hydrogen peroxide aqueous solution comprises:

0.3-2% (w/w) hydrogen peroxide,

25-1200mg/L stabilizer, preferably selected from the following group: DETAPMP and deferoxamine,

0-300 mM sodium sulfate or sodium nitrate as an osmolality increasing formulation,

0-2000mg/L of other ingredients, and

Balanced amount of purified water,

And, the range of pH is 2.0-8.5.

The pH is usually adjusted with sodium hydroxide and sulfuric or nitric acid as needed.

The aqueous solution described above is particularly preferred for embodiments where the second chamber contains all of the liquid expansion medium.

As for the above-mentioned swelling medium, the present invention also provides a liquid swelling medium corresponding to an embodiment of the "aqueous hydrogen peroxide solution described above", which can be used to swell a hydrophilic coating. Specifically, the present invention provides antimicrobial liquid swelling media comprising:

0.01-5.0% (w/w) hydrogen peroxide,

25-1200mg/L of one or more stabilizers,

0-25mM of one or more buffers,

0-300mM osmolarity-enhancing preparations,

And, the range of pH is 2.0-8.5.

In another embodiment, the packaging device for the catheter assembly includes at least one source of hydrogen peroxide in solid form. In this embodiment, the first chamber of the packaging device preferably contains at least one source of hydrogen peroxide and at least one catheter component. More specifically, the first chamber of the packaging device is adapted to contain the catheter component and the source of solid hydrogen peroxide. Preferably, the second chamber of said packaging device is adapted to contain said liquid expansion medium.

The source of solid hydrogen peroxide may be in powder form, one or more pellets, one or more tablets, capsules, beads, or a coating or film on the inside of the first chamber, or the The source of hydrogen peroxide is bound to the catheter component, for example, as a clot embedded in the hydrophilic coating, as a layer in the coating or as a layer on the surface of the coating. In use, the liquid swelling medium is added, and the hydrogen peroxide source is dissolved in the liquid swelling medium, or reacted with the liquid swelling medium to release hydrogen peroxide, and the hydrogen peroxide Swells into the hydrophilic coating.

In a variation of this embodiment, a solid source of hydrogen peroxide is incorporated into the coating of the catheter component, either as a molecule trapped in the pores of the hydrophilic coating, or as a Part of at least one compound of the hydrophilic coating. In one of its variations, the source of solid hydrogen peroxide comprises hydrogen peroxide complexed with polyvinylpyrrolidone (PVP). In particular, at least a portion of the hydrophilic coating is prepared with a polyvinylpyrrolidone (PVP)-hydroperoxide compound.

In this embodiment, the chemical crosslinking or assembly of the polymer molecules into the polymer composition occurs in the presence of the hydrogen peroxide, resulting in retention of the hydrogen peroxide. The hydrogen peroxide can be present in free form, or as part of or complexed with one of the components involved in the chemical crosslinking process or required for this process. For example, the polymer composition may include a polymer capable of forming a complex with hydrogen peroxide, such as PVP or a related polymer.

The hydrogen peroxide initially complexed with the polymer can then be cross-linked to the substrate to form, for example, a hydrophilic coating.

In another embodiment of the catheter assembly, said packaging device includes a first chamber adapted to contain said catheter component, a second chamber adapted to contain said liquid expansion medium, and a second chamber adapted to contain said peroxide The third chamber for the hydrogen source.

In a preferred variation of this embodiment, said catheter assembly includes packaging means adapted to automatically release said source of hydrogen peroxide into said liquid expansion medium upon opening of the packaging means. This object can be achieved by containing hydrogen peroxide in said chamber and having the chamber containing the liquid expansion medium separated by a foil membrane which ruptures when the package is opened.

preferred embodiment

In a presently most preferred embodiment, the present invention provides a catheter assembly comprising (i) at least one catheter component having a hydrophilic coating covering at least a portion of said catheter component, said hydrophilic coating comprising linked polyvinylpyrrolidone, (ii) at least one liquid swelling medium for swelling the hydrophilic coating, and (iv) a packaging device having a first chamber containing the catheter component , and a second chamber for containing said liquid expansion medium, said liquid expansion medium having the following composition:

0.1-3.0% (w/w) hydrogen peroxide,

25-1200mg/L of one or more stabilizers,

0-10 mM of one or more buffers,

0-300mM osmolarity-enhancing preparations,

0-2000mg/L of other ingredients, and

Balanced amount of purified water,

And, the range of pH is 2.0-8.5.

Components that include other or alternative antimicrobial agents

Notwithstanding the fact that the above components identify hydrogen peroxide as an advantageous antimicrobial agent, it will be appreciated that one or more other antimicrobial agents may be used in said liquid (expansion medium), in combination with hydrogen peroxide, Or as an alternative to hydrogen peroxide. Examples of such additional or alternative antimicrobial agents are silver sulfadiazine, silver hydantoin, silver 5,5-dimethylhydantoin, silver polymeric imidazole, silver chloride, monosilver trisodium thiosulfate ( SST), silver thiosalicylate, silver tris complex, polyvinylpyrrolidone-iodine (polyvinylpyrrolidone-iodine, PVP-I ₂ ), algicide, bronopol (2-bromo-2-nitro- 1,3-propanediol), Kathon (80:20 mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one), Phenyl Salicylate, Zinc Chloride, Copper Chloride, Hexamethylenetetramine, Diazolidinyl Urea, Mandelic Acid, Hippuric Acid, Chloramine T, Chloramine B, Chlorhexidine Digluconate, Chlorhexidine Taidi hydrochloride, and nitrofurazone. The antimicrobial agents of greatest current interest are algicides, silver sulfadiazine, silver hydantoin, silver 5,5-dimethylhydantoin and silver polymeric imidazoles, especially algicides.

Accordingly, the above aspects and embodiments of the assemblies (eg, catheter assemblies) also relate to combinations of one or more of the antimicrobial agents with hydrogen peroxide.

Additionally, the above aspects and embodiments of the assembly (eg, catheter assembly) also relate to the alternative antimicrobial agents used alone or in combination with each other, ie, in the absence of hydrogen peroxide, mutatis mutandis.

Preparation of components

The components of the invention are generally prepared by a simple combination of conventional methods for preparing medical devices with porous coatings, especially hydrophilic coatings, liquids for medical purposes, and packaging devices for medical devices.

Thus, in the embodiment wherein the first chamber of the packaging device is adapted to contain the catheter component, and wherein the second chamber of the packaging device is suitable for containing the liquid expansion medium and the said source of hydrogen peroxide, said assembly may be prepared by a method comprising: preparing said liquid expansion medium by mixing relevant ingredients (see elsewhere herein); preparing said catheter components using conventional techniques; Installing components in a first chamber of the packaging (possibly including welding the chamber walls); installing the liquid expansion device in a second chamber of the packaging (possibly including welding wall); and possibly sterilize said components, for example by radiation.

When radiation sterilization is performed on components in which components have a hydrophilic coating comprising at least a portion of said liquid swelling medium, preferably by incorporating 0.3-10% of a hydrophilic polymeric The liquid swelling medium is modified by, for example, a low molecular weight hydrophilic polymer (Mw 1500-50,000), as disclosed by the applicant in EP 0935 478 (see also Example 1 of the present invention). Examples of useful hydrophilic polymers are PVP C-15 (ISP) and PVP K-12 (BASF).

The preparation of such packaging means and the actual selection of materials are well known to those skilled in the art.

Use of said components and medical devices

The above-mentioned components are suitable for preparing ready-made medical devices, such as catheters. The contents of the first, second and possibly other chambers are brought together to allow the liquid and/or hydrogen peroxide to enter the pores of the polymer composition. In one embodiment, an aqueous solution of hydrogen peroxide (eg, a swelling medium containing hydrogen peroxide) is allowed to swell the coating of the hydrophilic polymer.

For the exemplified packaging device shown in FIGS. 1 and 2 , this purpose can be carried out in the manner described above with respect to the detailed description of said figures.

After preparation of the ready-to-use medical device, the medical device can be used in a conventional manner, i.e. the user or practitioner should normally not take any special measures or deviate from the usual methods of using the medical device. place.

For urinary catheters, the catheter (or catheter part) is inserted into the urethra, or artificial urethral opening, so that hydrogen peroxide is introduced into the urethral opening, i.e., at a concentration that provides protection against at least some microorganisms, such as viruses. , Inhibition of bacteria, fungi or molds. Part of the antimicrobial effect may be obtained by direct contact of the medical device with the urethra, and there may be some effect due to a portion of the coating and/or fluid deposited in the urethra after removal of the device. Part of the effect during and after catheterization may also be due to the hydrogen peroxide escaping from the coating.

By incorporating the hydrogen peroxide throughout the coating it is ensured in each case that bacteria including all parts of the urinary tract are exposed to effective doses/concentrations of the hydrogen peroxide and are thus killed or inhibit. Due to the antimicrobial activity of the entire catheter component surface, the risk of infection related to contamination (from fingers, environment) by handling said catheter before insertion can also be reduced before or during use of the catheter.

new medical device

From the above description it can be seen that the present invention provides an assembly that can be used to provide a ready-to-use medical device. Certain medical devices derived from components of the present invention are also believed to be novel.

Accordingly, the present invention also provides a medical device having, on at least a part of its surface, a coating of a porous polymer composition, wherein said coating comprises a liquid comprising hydrogen peroxide and a formulation capable of stabilizing the hydrogen peroxide.

Most commonly, the concentration of said hydrogen peroxide in the liquid in said coating is in the range of 0.01-5.0% (w/w), such as 0.1-3.0% (w/w), such as 0.2-2.0% (w/w).

Examples of formulations capable of stabilizing hydrogen peroxide are those defined above as "stabilizers". The liquid may also comprise a buffering agent, an osmolarity increasing formulation, and have an adjusted pH, in particular a pH as described above.

In a preferred embodiment, the coating of the porous polymer composition is a hydrophilic coating of at least one hydrophilic polymer and the liquid is a liquid swelling of the hydrophilic polymer. medium. The hydrophilic coating/polymer is preferably selected as described above. Preferably, at least one hydrophilic polymer is polyvinylpyrrolidone. More preferably, said at least one hydrophilic polymer is crosslinked.

Examples of liquid swelling media suitable for use in hydrophilic coatings, especially cross-linked polyvinylpyrrolidone coatings, are the media mentioned above as the embodiment of "aqueous hydrogen peroxide solution", e.g., the liquid swelling media is such a medium, including:

0.01-5.0% (w/w) hydrogen peroxide,

25-1200mg/L of one or more stabilizers,

0-25mM of one or more buffers,

0-300mM osmolarity-enhancing preparations,

And, the range of pH is 2.0-8.5.

In certain embodiments of particular interest, the medical device is a catheter, such as a urinary catheter.

other aspects

The present invention also provides a method for treating, alleviating or preventing microbial infection, wherein, in the first step, a medical device is prepared using the components defined herein, and in the second step, it is combined with the medical device in need of contact with body parts of mammals such as humans.

In addition, the present invention provides a method of treating, alleviating or preventing microbial infections, wherein a medical device as defined herein is brought into contact with a body part of a mammal, such as a human, in need thereof.

Particularly relevant microbial infections are those leading to urinary tract infections (UTIs). A particularly relevant medical device for use in the above respects is therefore a catheter, in particular a urinary catheter, wherein the incidence of urinary tract infections is reduced. It is believed that this result is achieved due to the reduction in the number of bacteria in the urine, urethra and/or urethral meatus when conventional urinary catheters are replaced with the assemblies and catheters of the present invention.

other aspects

Medical devices with coatings comprising liquids containing hydrogen peroxide

Although the inventors presently prefer to select an embodiment wherein said medical device component (e.g. said catheter component), said inflation medium and said source of hydrogen peroxide are housed in at least two separate chambers, The advantageous properties of hydrogen peroxide can also be used in a component comprising (i) a medical device (e.g., a catheter) having a coating (e.g., a hydrophilic coating) in which a liquid exists, and wherein the The liquid comprises hydrogen peroxide, and (ii) a packaging device adapted to contain said medical device in its chamber. The medical device can be used due to the fact that it is readily available, although the components may have only a moderate shelf life, which is nevertheless satisfactory for some purposes.

Accordingly, the present inventors also provide assemblies comprising (i) at least one medical device component having a coating of a porous polymer composition covering at least a portion of the component, and wherein the coating contains a liquid hydrogen peroxide, and (ii) a packaging device suitable for containing said medical device components. Preferably, said medical device components are accommodated in a chamber of said packaging device.

Most commonly, the concentration of said hydrogen peroxide in said liquid in said coating is in the range of 0.01-5.0% (w/w), such as 0.1-3.0% (w/w), such as 0.2 -2.0% (w/w).

For certain uses, where a longer shelf life is desired, it may be preferable to also include a formulation that stabilizes the hydrogen peroxide in the liquid. Useful examples of agents capable of stabilizing hydrogen peroxide are "stabilizers" as defined above. The liquid may also comprise a buffer, an osmolarity increasing formulation, and have an adjusted pH, in particular with the possibilities and ranges disclosed above.

The polymer composition preferably comprises at least one hydrophilic polymer. For example, hydrophilic polymers can be used in hydrophilic coatings to provide low friction surfaces for medical devices such as urinary catheters.

Where it is desired to sterilize the component by irradiation, the liquid expansion medium is preferably modified by adding 0.3-10% of a hydrophilic polymer, e.g. a low molecular weight hydrophilic polymer (Mw 1500-50,000) , as disclosed by the applicant in EP 0 935 478 (see also Example 1 of the present invention). Examples of useful hydrophilic polymers are PVP C-15 (ISP) and PVP K-12 (BASF).

In a preferred embodiment, the coating of the porous polymer composition is a hydrophilic coating of at least one hydrophilic polymer and the liquid is a liquid for the hydrophilic polymer expansion medium. The hydrophilic coating/polymer is preferably selected as described above. Preferably, at least one hydrophilic polymer is polyvinylpyrrolidone. More preferably, at least one of said hydrophilic polymers is crosslinked.

More particularly, the present invention relates to urinary catheters having, on at least a portion of their surface, a hydrophilic coating of a hydrophilic polymer, in particular cross-linked polyvinylpyrrolidone, wherein said coating comprises a liquid An expansion medium comprising hydrogen peroxide, and optionally a formulation capable of stabilizing hydrogen peroxide, the conduit is contained within the chamber of the packaging device.

In this embodiment, the aqueous hydrogen peroxide solution is generally introduced into the polymer composition immediately after chemically crosslinking the hydrophilic polymer. More generally, the medical device carrying the coating of the polymer composition may be immersed in an aqueous hydrogen peroxide solution. The hydrogen peroxide solution can then diffuse into the polymer composition by passive means, or can be forced into the coating by applying pressure.

Examples of liquid swelling media suitable for use in hydrophilic coatings, especially cross-linked polyvinylpyrrolidone coatings, are those described above as embodiments of "aqueous hydrogen peroxide", however, preferably by adding 0.3- 10% hydrophilic polymer modification (especially when disinfection by irradiation is required). For example, the liquid expansion medium is a medium comprising:

0.01-5.0% (w/w) hydrogen peroxide,

Optionally, but preferably 0.3-10% of a hydrophilic polymer,

0-2000mg/L of one or more stabilizers,

0-200mM of one or more buffers,

0-1000mM osmolarity-enhancing formulations,

And, the range of pH is 2.0-8.5.

or such media, including:

0.01-5.0% (w/w) hydrogen peroxide,

Optionally, but preferably 0.3-10% of low molecular weight hydrophilic polymers,

25-1200mg/L of one or more stabilizers,

0-25mM of one or more buffers,

0-300mM osmolarity-enhancing preparations,

And, the range of pH is 2.0-8.5.

The medical device may be prepared as described above, combining the medical device, the porous polymer composition and the liquid/liquid expansion medium comprising hydrogen peroxide, and then packaged into a suitable packaging device.

其中，所述涂层的导管与所述膨胀介质接触。In certain embodiments of particular interest, the medical device is a catheter, such as a urinary catheter. An example of a commercially available urinary catheter coated with a hydrophilic polymer is provided by Coloplast A/S

Wherein said coated conduit is in contact with said swelling medium.

Another aspect of the above is a method of treating, alleviating or preventing microbial infections, wherein a medical device of the above assembly is in contact with a body part of a mammal, such as a human, in need thereof.

Example

Example 1 - Preparation of Catheter Coated with Polyvinylpyrrolidone

A urinary catheter with a hydrophilic coating of polyvinylpyrrolidone can be prepared as follows:

a) Prepare first and second solutions of high molecular weight polyvinylpyrrolidone (PVP) (for example, Plasdone K-90) dissolved in N-methylpyrrolidone (NMP), ethanol and Citrofol Al including photoinitiator in solvent/plasticizer mixtures. The PVP content of the solution is in the range of 1-8% (w/w). The first and second solutions may be the same.

b) Soak the polyurethane raw catheter in the first solution and let it dry at room temperature for 10-120 seconds.

c) Soak the resulting catheter in a second solution of PVP.

d) Further drying the catheter at higher temperature (eg, at 70-80°C).

e) crosslinking the PVP by exposing the coated conduit to UV light in the wavelength range of 200nm-300nm for 1/2-15 minutes.

f) Place the cross-linked coated catheter in the packaging device and fill the packaging with an expansion medium, wherein the expansion medium is a combination of low molecular weight PVP (Plasdone C15) and an osmolarity increasing agent (NaCl) aqueous solution.

g) Sterilization of the packaging including the moistened catheter by ionizing radiation (beta- or gamma-irradiation).

Example 2 - Preparation of Catheters Comprising Hydrogen Peroxide

The preparation of a sterile catheter with a hydrophilic coating comprises the following steps:

a) Prepare first and second solutions of high molecular weight polyvinylpyrrolidone (PVP) (e.g., Plasdone K-90) dissolved in N-methylpyrrolidone (NMP), ethanol and Citrofol A1 including photoinitiator in solvent/plasticizer mixtures. The PVP content of the solution is in the range of 1-8% (w/w). The first and second solutions may be the same.

b) Soak the polyurethane raw catheter in the first solution and let it dry at room temperature for 10-120 seconds.

c) Soak the resulting catheter in a second solution of PVP.

d) Further drying the catheter at higher temperature (eg, at 70-80°C).

e) crosslinking the PVP by exposing the coated conduit to UV light in the wavelength range of 200nm-300nm for 1/2-15 minutes.

f1) Place the cross-linked coated catheter in a packaging device and fill the package with an expansion medium, wherein the expansion medium is hydrogen peroxide, low molecular weight PVP (Plasdone C15) and an osmolarity-enhancing formulation ( Na ₂ SO ₄ or NaNO ₃ ) and a stabilizer (DETAPMP) in water; and

G1) Sterilize said packaging of the moistened catheter by ionizing radiation (β- or γ-irradiation);

or

f2) placing the cross-linked coated catheter in one chamber of the packaging device and placing the swelling medium in a second chamber, wherein the swelling medium is hydrogen peroxide, osmolarity Raising the aqueous solution of formulation ₍ eg, _Na2SO4 or _NaNO3 ) and stabilizer (DETAPMP); and

g2) Sterilization of said packaging device (chamber 1 ) and said hydrogen peroxide solution (chamber 2 ) including the coated catheter in dry state by ionizing radiation (beta- or gamma-radiation).

Example 3 - Preparation of Catheter Assembly

The catheter assembly shown in Figure 2 can be prepared as follows:

A dry urinary catheter (1) coated with polyvinylpyrrolidone (PVP) was prepared as described in Example 1. The catheter is placed in the first chamber (4) of the packaging device (3), which chamber is sealed by welding. A liquid expansion medium (eg, as shown in Example 2) containing aqueous hydrogen peroxide, DETAPMP, and an _osmolarity -enhancing agent (eg, _Na2SO4 or _NaNO3 ) is prepared and loaded into an external rigid container (5) In the second chamber formed, the container is installed as an integral part of said packaging device (3). As shown in Figure 2 (b), the container (5) is installed to be able to rotate about 90 degrees relative to the end wall (8), so that the end wall (8) of the container (5) is provided towards the chamber (4) The liquid outlet and inlet of the rigid end wall (9) of the rigid end wall (9) form a liquid flow alignment, wherein the contents of the liquid expansion medium in the container (5) can be transferred to the first chamber of the catheter containing the coating middle.

In a variant, the coated catheter is provided with a portion of a liquid swelling medium (preferably low molecular weight PVP and _Na2SO4 ) into the first chamber (4) before sealing said chamber by _welding . aqueous solution) for pre-expansion. In use, the two expansion media are mixed by letting the contents of the container (5) flow into the first chamber. Therefore, the two swelling media are mixed immediately (for example, by inverting the package from one end to the other 2-10 times before use) so that the coating can absorb the swelling media comprising hydrogen peroxide, preferably Absorbs within 20 seconds. The catheter can then be used directly.

Example 4 - Preservation of a lumen hydrogen peroxide catheter with PEG 2000 present in the expansion medium

Experiments were performed in order to determine the effects of storage temperature, initial hydrogen peroxide concentration and PEG 2000 on pH, hydrogen peroxide degradation and friction of catheters with hydrophilic coatings. The catheter was prepared according to the method described in Example 2, and the liquid swelling medium was prepared with purified water, hydrogen peroxide (see Table 1.1), PEG 2000 (as described in Table 1.1), and also included pH 5.5 50 mM citrate buffer. The catheters were packaged together with inflation medium in a chamber as described in Example 2 and maintained at 60 or 80°C for a period of 1 week. 1-3 non-sterile samples were used for each assay. The results are shown in Table 1.1.

Table 1.1

Starting %-point H ₂ O ₂ Storage temperature Whether to add 6% PEG2000 Friction (N) pH after storage Catheter appearance (0-5; 0 = good, 5 = unacceptable) Expansion medium appearance (0-5) After saving - _{point H2O2} H ₂ O ₂ reduction (%/day) 0.2 60 - 0.06 5.64 0 0 0.20 0.3 0.4 60 - 0.10 5.63 0 0 0.37 1.0 0.8 60 - 0.27 5.63 0 0 0.75 0.9 1.6 60 - 0.53 5.71 0 0 1.41 1.7 1.6 60 yes 0.12 5.13 1 0 1.25 3.2 0.2 80 - 1.06 5.63 0 0 0.15 3.5 0.4 80 - 1.15 5.79 0 0 0.29 3.8 0.8 80 - 1.26 5.86 0 0 0.58 4.0 1.6 80 - 1.02 6.28 0 0 1.13 4.2 1.6 80 yes 1.68 3.46 3 0 0.02 14.1

At 60°C, without the addition of PEG 2000, the catheter friction and the relative decomposition of hydrogen peroxide increased with increasing initial hydrogen peroxide concentration. The pH increased only slightly from the starting value of 5.5, probably due to the following Fenton reaction to HO ^- :

Fe ²⁺ +H ₂ O ₂ →Fe ³⁺ +HO ^- +HO ^-

The above results indicated that hydrogen peroxide was able to attack the catheter during storage, however, the outer end of the catheter and the expansion medium were intact (scored 0 on the appearance score).

With the addition of PEG 2000, the friction of the catheter after storage (0.12N) was much lower than that without PEG 2000 (0.53N), however, at the same time the pH decreased to 5.13 and the catheter became It was milky and opaque (score 1), and the reduction in hydrogen peroxide was 3.2%/day, or almost twice as much as the starting concentration of hydrogen peroxide (1.6%-point) but without PEG 2000 (reduction of 1.7%/day). sky). PEG 2000 appears to be oxidized by hydrogen peroxide to a carboxylic acid, which lowers the pH and cooperates with PVP to produce an opaque coating.

At 80° C., the friction force for all catheters was higher than 1 N, so the coating was severely damaged. The samples without PEC2000 had a slightly higher pH after storage at 80°C compared to after storage at 60°C. During 1 week storage of samples without PEG 2000 at 80°C, 25-30% of the hydrogen peroxide disappeared, regardless of the initial hydrogen peroxide concentration.

Upon addition of 6% PEG 2000, almost all hydrogen peroxide disappeared after 1 week of storage, and the pH dropped abruptly to 3.46 despite the presence of 50 mM citrate buffer. Friction was as high as the sample without PEG 2000, and the catheter became very cloudy (score 3).

The above results confirmed the ability of hydrogen peroxide to erode catheters with and without PEG 2000. Thus, the long-term stability of packages containing a hydrophilic catheter and an expansion medium containing hydrogen peroxide in the same chamber may be compromised.

Example 5 - Preservation of a chambered hydrogen peroxide catheter with PVP C-15 present in the expansion medium

A simplified factorial experiment was performed in order to find out the storage stability of 1%-dot hydrogen peroxide in a liquid swelling medium without pH 7 buffer with or without PVP C-15 substituted for PEG2000. Samples were beta-sterilized at a dose of 50 kGy and stored at 23°C for 8 months.

Taking the concentration of hydrogen peroxide on day 0 after disinfection as 100%, and calculating the degradation rate (%/day), a linear degradation curve was presented. For example, if the hydrogen peroxide concentration is reduced to 75% after 8 months (approximately 250 days), the degradation rate is 25/250%/day=0.1%/day.

Results are calculated (mean ± standard error of the mean) from 86 independent samples (Table 5.1).

Table 5.1

Initial %H ₂ O ₂ %PVP C-15 β-disinfection dose (kGy) Storage temperature Daily reduction of H ₂ O ₂ (%) 1 0 50 twenty three 0.088±0.029 1 6 50 twenty three 0.167±0.048

The degradation rate was higher when PVP C-15 was added to the swelling medium than without PVP C-15. Similar trends were observed at other storage temperatures (5°C, 40°C, 60°C).

The influence of embodiment 6-chelating agent on the stability of hydrogen peroxide

Chelating agents and/or metal ions are added to the aqueous hydrogen peroxide solution prior to storage. Table 6.1 below shows the %-point hydrogen peroxide remaining after 24 days of storage at 40°C for β-sterilized (50 kGy) polyurethane catheters with a hydrophilic coating present in the swelling medium which initially Contains 1%-dot hydrogen peroxide, 1 g/L chelating agent (EDTA, DETAPAC, deferoxamine, gelatin) or no chelating agent, 10 mg/L metal ion (Fe ²⁺ , Cu ²⁺ ) or no metal ion, 6 % PVP K-12, and 10 mM citrate (pH 7).

Table 6.1 %-point hydrogen peroxide remaining after storage at 40°C for 24 days.

At a concentration of 10 mg/L Cu ²⁺ without the addition of a chelating agent, the concentration of hydrogen peroxide decreased from the 1%-point to the 0.15% point after storage. Each of the four chelating agents significantly increased the stability of hydrogen peroxide so that 0.30-0.44%-point hydrogen peroxide remained after storage.

The stability of hydrogen peroxide was improved by adding 10 mg/L Fe ²⁺ , DETAPAC and deferoxamine. Specifically, the effect of deferoxamine was so great that the stability of hydrogen peroxide with addition of Fe ²⁺ (0.66%-point H ₂ O ₂ remained after storage) was comparable to that without addition of Fe ²⁺ The properties are just as good (0.68% _{-point H2O2} retained). That said, deferoxamine completely disables Fe2 ⁺ . Additionally, deferoxamine was the only chelating agent able to improve the basic stability of hydrogen peroxide in the absence of added metal ions: 0.68%-point _H2O2 was retained after _storage with deferoxamine, whereas after addition of the other three 0.59-0.61%-point H ₂ O ₂ was retained when the chelating agent or no chelating agent was added.

Thus, deferoxamine and other chelating agents have a favorable effect on the storage stability of hydrogen peroxide.

The impact of embodiment 7-β-sterilization on the degradation of hydrogen peroxide

The purpose of this series of experiments was to investigate the effect of increasing beta-irradiation doses on the degradation of hydrogen peroxide. In addition, it was aimed to study the effect of the catheter and PVP on the stability of hydrogen peroxide.

Hydrogen Peroxide 33% Panreac Ph. Eur, BP, REF. (14.1077.14.10)

Citric acid monohydrate, Riedel-de Haên

Plasdone C-15, ISP

0.02 M KMnO ₄ , Riedel de Haên

Brown 50mL PE-container

The H ₂ O ₂ -concentration was determined using KMnO ₄ potentiometric titration.

Titrino 702 titrator (Metrohm).

Two 1.0 L expansion media were produced; one solution contained distilled water and 1% hydrogen peroxide, while the other contained 6% PVP, 10 mM citric acid and 1% hydrogen peroxide. The pH-value of the latter solution was adjusted to 5.5 with 1M NaOH. Aliquots of 10.0 mL were taken from each of these two solutions and placed into 50 mL brown PE-containers.

The samples were beta-irradiated at RisφNational Laboratory. The samples were assayed before irradiation, immediately after irradiation and after 2 weeks and 4 weeks at 60° C. (3 assays were performed). The results are shown in Table 7.1-7.3.

Table 7.1. Catheters expanded in PVP solution (Series I). Concentration _{of H2O2} (%-point). Mean (n=3).

Table 7.2. Catheters Swelled in Distilled Water (Series II). Concentration _{of H2O2} (%-point). Mean (n=3).

Table 7.3. H ₂ O ₂ -solutions in distilled water (series III). Concentration of H2O2 (%-point). Mean (n=3).

Increasing radiation doses resulted in increased series I degradation. The correlation between increasing radiation dose and increased hydrogen peroxide degradation was less pronounced than in series II and III, however, there was a tendency that higher radiation doses resulted in faster degradation rates.

In addition, it can be seen that series I has a higher degradation rate than series II and III, which means that PVP dissolved in distilled water accelerates the degradation of hydrogen peroxide. It cannot be concluded from this study that the catheter itself can affect the stability of hydrogen peroxide.

Example 8 - Degradation of Hydrogen Peroxide and Stabilizer Concentration

The aim of this study was to determine the concentration of the stabilizer DETAPMP that resulted in the most stable H ₂ O ₂ solution. Another objective was to determine the activation energy for _the degradation of _H2O2 containing the stabilizer DETAPMP at pH 4 and 10 mM citrate.

Material

Citric acid monohydrate. Reag.ACS, Reag.ISO

NaOH 4M, Merck

HCl 1M, BHD AnaIR titration solution

NaCl (Extra pure, Ph. Eur, BP, USP)

0.02 M KMnO ₄ , Riedel de Haên

Potentiometric Titrino 702, Metrohm

method

Degradation rate of _H2O2 in solutions containing DETAPMP at 40 °C, 50 °C _and 60 °C.

1 L of expansion medium was produced containing 10 mM citrate, 500 g/mL stabilizer DETAPMP and 0.7% NaCl. The pH-value of the solution was adjusted to pH 4 with 4M NaOH and 1 M HCl.

Dose-response curve of stabilizer DETAPMP

Seven swelling media were produced, each containing 10 mM citrate, 0.7% NaCl and the stabilizer DETAPMP (50, 100, 150, 200, 250, 350, 500 mg/L).

A 20 mL aliquot was taken from each of the swelling media and added to each stick pack. The stick packs were sealed by welding after filling and sent to RisφNational Laboratory for irradiation. The radiation dose is 2*26kGy.

The stick pack with "skin" is a laminate comprising PETP (12 μm), aluminum (9 μm) and polyethylene skin (polyethylene + 10% polybutylene) (70 μm). The stick pack is made from a stamped area of 13 x 35 mm welded in longitudinal direction by 1 x 3 units on a welding device. It is soldered 2 x 2.2 units through the stick pack at one end and through 4.0 bar, 130°C and 3.5 seconds at the other end (breakable seal).

Results and discussion

The results of this study are shown in Tables 8.1 and 8.2

Table 8.1. Degradation rate of 1% _H2O2 containing DETAPMP at _different temperatures

The Arhenius curves of the stabilizer DETAPMP at 40°C, 50°C and 60°C (DETAPMP at pH 4 and 10 mM citrate) showed a practically linear relationship between 1/T and log k, and it was found that the degradation The activation energy of H ₂ O ₂ is 59.6 kJ/mol. The activation energy of 59.6 kJ/mol leads to Q ₁₀ ≈2, which means that every 10°C can increase the degradation rate by 2.

Table 8.2. H ₂ O ₂ concentration (%) of 7 different concentrations of DETAPMP (mg/L) after storage at 40°C.

Table 8.2 shows the correlation between the stabilizer concentration and the degradation rate of _H2O2 , _it can be speculated that for DETAPMP concentrations _up to 150-200 mg/L, the degradation reaction rate of _H2O2 decreases. Thereafter, the curve becomes horizontal. However, the lowest degradation of H ₂ O ₂ occurred at 250 mg/L DETAPMP concentration.

Embodiment 9- various stabilizers

The aim of this study was to identify the stabilizer that would provide the greatest stabilization of the hydrogen peroxide solution. It is known from the literature that the pH-value influences the stability of hydrogen peroxide. Therefore, in this study, the study of the effect of pH-value on stability was included in our system. Packaging materials were also studied in order to see whether the two different types of materials affect hydrogen peroxide degradation in different ways.

Citric acid monohydrate. Reag.ACS, Reag.ISO

4 M NaOH, Merck

1 M HCl, BHD AnalR titration solution

NaCl (Extra pure, Ph. Eur, BP, USP)

0.02 M KMnO ₄ , Riedel de Haên

pH-meter, Jenway 4330 Conductivity and pH-meter

Potentiometric Titrino 702, Metrohm

Chemical name and CAS No. of stabilizer:

DETAPMP-sodium salt (sodium salt of diethylenetriaminepenta(methylenephosphonic) acid; 22042-96-2),

EDATMP (ethylenediaminetetra(methylenephosphonic) acid; 1429-50-1),

HEDP (1-hydroxyethane-1,1 diphosphonic acid; 2809-21-4),

EDATMP-sodium salt (sodium salt of ethylenediaminetetra(methylenephosphonic) acid; 15142-96-8),

DETAPMP (diethylenetriaminepenta(methylenephosphonic) acid; 15827-60-8),

Acetanilide (103-84-4).

24 different types of swelling media were prepared, which contained different stabilizers (one without stabilizer) and 3 different pH-values (pH 4, 5.5 and 7). The volume of each expansion medium was 1 L, and the initial concentration of hydrogen peroxide was about 1% (w/w). In addition, expansion media containing the stabilizer DETAPMP and NaCl were produced at three different pH-values in order to understand the effect of NaCl addition. The concentration of sodium chloride in each of the three swelling media was 0.7% (w/w). Sodium chloride was determined for its use as an osmolarity increasing agent. Citric acid was added to each of the swelling media so as to achieve a concentration of 25 mM in order to maintain the initial pH-value throughout the test period. The final pH-values of this solution were adjusted to 4.0, 5.5 and 7.0 by adding 4 M NaOH and 1 M HCl to the final solution.

A 20 mL aliquot was taken from each expansion medium and added to each stick pack. Two different types of material were used for the stick pack, one with a "skin" and one without. The stick packs were sealed after filling and sent to RisφNational Laboratory for irradiation. The radiation dose is 2*26kGy.

Stick packs with "skins" had laminated materials including PETP (12 μm), aluminum (9 μm) and polyethylene skins (polyethylene + 10% polybutylene) (70 μm). Stick packs without a "skin" are laminated materials including PETP (12 μm), aluminum (9 μm) and polyethylene (PE) (50 μm). The stick packs are made from a stamped area of 13 x 35 mm, welded 1 x 3 units in longitudinal direction on a welding device. 2 x 2.2 units were welded through one end of the stick pack and through 4.0 bar, 130°C and 3.5 seconds at the other end (breakable seal).

The stick packs were stored at 23°C and 40°C for the test. Samples were taken after irradiation, and after 2 and 4 weeks of storage at 40°C and after 8 and 16 weeks of storage at 23°C. Determination of the pH-value and the concentration of the hydrogen peroxide (repeat determination), see Table 9.1.

_Table 9.1. Calculated amount of degraded _H2O2 after 2 years storage at 23°C. Calculations are based on degradation studies at 23°C for up to 18 weeks.

From the above results, it can be seen that the most stable _H2O2 solution was obtained in _the solution containing the stabilizer DETAPMP at pH 4. In general, there is a higher propensity for degradation at pH 7 compared to pH 4. It can also be seen that _the stabilizers _EDTMP and HEDP actually enhanced the degradation of _H2O2 , especially at pH 7, compared to the _H2O2 solution without the stabilizer.

Additional experiments (data not shown) confirmed that the two different types of packaging, "skinned" and "no-skinned", did not _differ in their impact on _H2O2 degradation.

Finally, the degradation at pH 4 was faster for DETAPMP + NaCl compared to DETAPMP alone. This may indicate that NaCl accelerates the degradation of hydrogen peroxide.

Example 10 - Effect of Buffer in Expansion Media

The purpose of this study was to clarify the influence of different pH-value buffers (citrate) on the degradation rate of hydrogen peroxide and to demonstrate that the use of the stabilizer DETAPMP resulted in the most stable hydrogen peroxide solution.

Citric acid monohydrate. Reag.ACS, Reag.ISO

NaOH 4M, Merck

HCl 1M, BHD AnalR titration solution

NaCl (Extra pure, Ph. Eur, BP, USP)

0.02 M KMnO ₄ , Riedel de Haên

Potentiometric Titrino 702, Metrohm

The swelling medium contained approximately 1% (w/w) hydrogen peroxide; 0, 10 and 25 mM citrate, and 0.7% (w/w) NaCl and stabilizers. The pH-value of the solution was adjusted with 4M NaOH and 1M HCl. The concentration of the stabilizer is DETAPMP (500mg/L), sodium salt of EDATMP (500mg/L, 1000mg/L) and sodium salt of DETAPMP (1000mg/L).

A 10 mL aliquot of each expansion medium was removed and added to each stick pack (with "skin"; see Example 7). After filling the stick packs were sealed by welding and sent to RisφNational Laboratory for irradiation. The radiation dose is 2*26kGy. The results are shown in Table 10.1-10.6.

Table 10. 1.0 mM Citrate. Calculated amount of _H2O2 degradation (%) after _storage at 23°C for 2 years.

Table 10.2.10 mM citrate. Calculated H ₂ O ₂ (%) degradation after storage at 23°C for 2 years

Table 10. 3.25 mM citrate. Calculated H ₂ O ₂ (%) degradation after 2 years storage at 23°C.

Table 10.4. pH 4. Calculated H ₂ O ₂ (%) degradation after storage at 23°C for 2 years.

Table 10.5. pH 5.5. Calculated H ₂ O ₂ (%) degradation after storage at 23°C for 2 years.

Table 10.6. pH 7. Calculated H ₂ O ₂ (%) degradation after storage at 23°C for 2 years.

It can be seen that increasing the pH-value from 4 to 5.5 and 7 increases the degradation rate for almost all solutions. There is a correlation between increasing amounts of citrate in the solution and accelerated degradation rates _{of H2O2} . The most stable solution of H ₂ O ₂ contained the stabilizer DETAPMP, no citrate was added, and the initial pH-value of this solution was 4. Increasing the amount of the stabilizer EDATMP sodium salt did not result in a more stable solution. _Clearly , there was no correlation between the increase in _H2O2 stability and the increase in the concentration of the sodium salt of EDATMP.

Example 11 - Antimicrobial Efficacy of Hydrogen Peroxide

The Effect of Different Concentrations of Hydrogen Peroxide on the Growth Rate of Bacteria

Data are shown for 7 different bacterial strains with and without hydrogen peroxide (0-1%). reproductive capacity under conditions. Briefly, the bacteria were inoculated into growth medium with or without hydrogen peroxide, and growth in mid-log phase was determined by absorbance at 600 nm. Data obtained from each specific bacterial strain were collected. These data are the average of three independent experiments, with each determination replicated in duplicate; see Table 11.1.

Table 11.1.

%hydrogen peroxide Average (% of control) SD 0 (control) 100.0 - 0.00000256 110.0 8.1 0.0000128 99.8 2.8 0.000064 97.9 6.0 0.000320 96.2 6.7 0.0016 87.3 11.2 0.008 63.0 28.2 0.04 35.6 18.6 0.2 16.0 10.6 1.0 11.7 8.2

The Effect of Different Concentrations of Hydrogen Peroxide on the Survival Rate of Bacteria

Data are shown for 7 different bacterial strains with and without hydrogen peroxide (0-1%). survivability under conditions. The bacteria were exposed to hydrogen peroxide for 60 minutes, see Table 11.2.

Table 11.2.

%hydrogen peroxide average SD 0 (control) 100.0 - 0.016 49.8 4.1 0.031 38.1 12.4 0.063 27.8 16.1 0.125 14.5 8.4 0.250 9.1 6.1 0.500 0.2 0.2 1.000 0.0 0.5

Time course of the effect of 1% hydrogen peroxide on bacterial survival

The above data demonstrate the viability of 7 different bacterial strains in the presence of 1% hydrogen peroxide. The number of surviving bacteria (% of control) was determined after 0, 5, 10, and 15 minutes, see Table 11.3.

Table 11.3.

Contact time (min) Average (% of control) SD 0 (control) 100 - 5 37 31 10 17 18 15 6 7

Example 12 - Alternative Antimicrobial Formulations

A series of antimicrobial formulations (see 12.1) are swelled into the hydrophilic coating on the urinary catheter. The catheters were stored at 25°C, 40°C and 60°C for approximately 0, 3, 6 and 12 weeks. Agar plates were inoculated with bacterial strains clinically isolated from infected human urine, and coated catheters were placed on top of the agar surface. The agar plates were incubated at 37°C for 18 hours and inspected visually for the presence or absence of zones of inhibition.

The portion of the catheter with a hydrophilic coating is swollen with a solution of an antimicrobial agent and placed on an agar plate inoculated with bacteria (clinical isolates, - and + denote Gram-positive and Gram-negative, respectively): singular deformation Bacillus (-), Pseudomonas aeruginosa (-), Escherichia coli (-), Providencia stutzeri (-), Staphylococcus aureus (+), Enterococcus faecalis (+) and Klebsiella belongs to (-).

A highly hierarchical factorial design (2 ^15-10 IV ^-design ) was constructed by Design Expert software (version 6.0.6) and used to screen 32 2 ¹⁵ = 32768 possible combinations, where each compound was The relevant concentrations are absent or present. Each mixture also contained 50 mM citrate buffer pH 5.5, 160 mM NaCl and 6% PEG 2000. All samples were beta-sterilized at a dose of 50 kGy. The composition and concentration of the 32 solutions are as shown in Table 12.1:

Table 12.1.

S Six Di-azo- Flat Horse Chlorine PVP Chlorine Bro- Kathon Salicyl Per Chlorine Chlorine Chlorine

Lidi- Lidi- Peach Urine-I2 Taidi algae no-pol Oxidation of benzoic acid benzene

Formazan nylurea acid acid T glucosamine amine base ester chemical zinc copper silver

Hydrogen

Four 20%

Amine

t A B C C D E E F G H J J K K L L M N O P

d g/L g/L g/L g/L g/L g/L g/L g/L g/L g/L g/L g/L g/L g/L mg

1 0 0 0 0 0.6 0 0 0.65 1 1 0 0 0 1 0 1 20

2 0 1 1 1 0.6 0 0 0 0 0 1 0.094 0.02 1 0 0 0

3 0 1 1 0 0 0 1 10 0.65 0 1 0 0.02 1 0 0 20

4 0 1 1 1 0.6 1 0 0 0 0 1 0 0 0 0 1 1 20

5 1 1 1 1 0 0 10 0 0 0 0 0 0 0 1 0 1 20

6 0 0 0 0 0.6 1 0 0.65 1 1 0.094 0.02 0 1 0 0

7 0 0 0 1 0.6 0 10 0.65 0 0 0 0 0.02 1 1 1 1 0

8 1 1 1 0 0 0.6 1 0 0.65 0 0 0.094 0 1 0 1 0

9 1 1 1 1 0 0 1 1 10 0 0 0 0 0.094 0.02 0 1 0 0

10 0 1 0 0 0.6 1 10 0 1 0 0 0 0.02 0 0 1 0

11 1 1 1 0 0 0 0 0 0 0 1 1 1 0 0.02 1 1 1 0

12 0 0 0 0 0 1 0 0 0 0 0 0.094 0.02 1 1 1 20

13 1 1 1 1 0.6 1 10 0.65 1 1 0.094 0.02 1 1 1 20

14 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

15 0 1 1 1 0 0 0 0 0.65 1 0 0.094 0.02 0 0 1 20

16 1 1 1 1 0.6 0 10 0.65 1 1 0 0 0 0 0 0 0

17 1 0 1 0 0 1 0 0.65 0 1 0 0.02 0 0 1 0

18 0 1 0 0 0.6 0 10 0 1 0 0.094 0 1 1 0 20

19 1 1 1 0 0 0.6 0 0 0.65 0 0 0 0 0.02 0 1 0 20

20 0 1 0 0 0 0 10 0.65 0 1 0.094 0 0 1 1 0

21 1 1 1 0 0 0 1 0 0 0 1 1 0.094 0 0 0 0 0 20

22 1 0 1 0.6 0 0 0 0 1 0 0.094 0 0 1 1 0

23 1 0 0 0 0.6 0 10 0 0 1 0.094 0.02 0 0 1 20

24 0 0 0 1 0.6 1 10 0.65 0 0 0.094 0 0 0 0 0 20

25 1 0 1 0.6 1 0 0 0 1 0 0 0 0.02 1 0 0 20

26 0 1 1 1 0 1 1 0 0.65 1 0 0 0 0 1 1 0 0

27 1 0 1 0 0 0 0 0.65 0 1 0.094 0 1 1 0 20

28 1 0 0 0 0 0 0 10 0.65 1 0 0.094 0.02 1 0 0 0

29 0 0 0 1 0 0 0 10 0 1 1 1 0 0 0.02 0 1 0 20

30 0 0 0 1 0 0 1 1 10 0 1 1 1 0.094 0 1 0 1 0

31 1 0 0 0 0 0 1 10 0.65 1 0 0 0 0 0 1 1 20

32 1 0 0 0 0.6 1 10 0 0 1 0 0 1 1 0 0

Many of the 32 mixtures had potent effects (0=no effect; 3=excellent effect) against several of the 7 bacteria species, see Table 12.2 (categorized by diminishing antimicrobial effect).

Table 12.2.

Std Proteus mirabilis Pseudomonas aeruginosa Escherichia coli Staphylococcus aureus Enterococcus faecalis Klebsiella

Wittenella Staphylococcus

3 3 3 3 3 3 3 3 3 3

32 3 3 3 3 3 3 3 3

29 3 3 3 3 3 3 3 2

19 3 3 3 2 2 2 3 2

21 2 3 3 3 3 3 3 3

20 2 2 3 3 2 3 3 3 3

10 2 2 2 2 3 3 3 3 3

11 2 2 2 2 3 3 2 2 3 2

5 2 1 1 1 1 2 2 3 2

13 1 3 1 1 1 3 3 1

16 1 3 2 2 2 2 3 1

24 1 0 0 2 0 0 2 3 3

6 1 3 1 1 2 2 2 3 3

14 1 1 1 1 1 2 2 3 1

30 1 0 0 0 0 2 3 3

25 1 3 2 2 2 1 1 3 2

18 1 3 2 2 1 1 1 3 2

28 1 2 1 1 1 1 3 1

17 1 0 1 1 1 1 1 1 1

23 1 3 3 1 0 0 1 1 3 3

22 1 3 0 0 1 1 0 3 3

31 1 0 0 0 0 0 0 0 0

7 0 3 2 2 2 2 3 3

2 0 3 1 1 2 2 2 3 3

15 0 0 0 1 1 1 2 2 3 1

12 0 2 1 0 0 2 1 1 1

9 0 2 1 1 1 1 1 3 1

4 0 1 1 1 1 0 0 3 1

8 0 1 0 0 1 0 0 1

1 0 0 0 0 1 1 0 0 0 0

26 0 0 0 0 0 0 0 1

27 0 0 0 0 0 0 0 0 0

Total 35 58 44 44 51 77 59

When the results were analyzed and further tests were performed to confirm the results, it was found that the effect could be a tertiary interaction or higher. That is, the effect is from a mixture of 3, 5, 7 or any other odd number compound, but clearly not from the main effect or interaction of the two factors. Thus, there appears to be a large synergy between compounds. Chlorhexidine and silver chloride are practically insoluble in media containing 160 mM chloride; they function better in chloride-free media.

Additional experiments confirmed that the action of hydrogen peroxide (on its own) is rapid compared to a variety of other antimicrobial agents. This feature is advantageous in applications such as intermittent catheterization, which only takes a few minutes. In other experiments, hydrogen peroxide was shown to elute well from the coating, so that treatment could be extended to tissue at some distance from the coating. Another advantage of using hydrogen peroxide is that there is a small chance of certain microorganisms developing resistance to hydrogen peroxide.

Example 13 - Silver compound

0.3g/L silver sulfadiazine, 0.25g/L hydantoin at pH 5.5 (50mM citrate buffer), pH 7 (50mM phosphate buffer) and pH 8.5 (50mM TAPS buffer) Silver, 1.175 g/L silver 5,5-dimethyl-hydantoin, and 0.25 g/L silver polymeric imidazole had moderate to good antimicrobial effects. The solutions also contained 160 mM NaCl and 6% PEG 2000, and all solutions were sterilized using 50 kGy of beta- or gamma-irradiation. Beta-irradiation generally provides better antimicrobial action and produces a lesser degree of product coloration than gamma-irradiation, so beta-irradiation is the preferred method of disinfection. The silver compounds are only effective if excess undissolved salts are allowed in the packaging, that is, they are not antimicrobial when poured from their sediment. In some experiments, 0.01% _H2O2 was added in order to prevent the reduction _of silver ions to elemental silver, as this process resulted in loss of antimicrobial activity, and strong coloration from colloidal silver.

The antimicrobial effect of each of the 7 bacteria in each compound was scored on a scale from 0 (no effect) to 3 (good effect). The antimicrobial index was defined as 5/12 multiplied by the sum of the square roots of the scores for each of the 7 bacteria. Therefore, the antimicrobial index is a rational number from 0 to 5.05.

Appearance index is a weighted average of subjective acceptability after sterilization of catheters packaged in a single chamber with hydrophilic catheter (weight 60%) and the expansion medium (weight 40%) Catheter and distension medium (scale from 0 to 5: 0 = totally unacceptable, eg, by strong color or major precipitation; 5 = perfect, eg, no coloration, no precipitation). Thus, the Appearance Index is a numerical value between 0-5.

Table 13.1 shows the antimicrobial index and appearance index of silver compounds.

The antimicrobial index and appearance index of silver compounds can be seen in the table, sorted by antimicrobial index (5,5-DMH=5,5-dimethylhydantoin):

Table 13.1.

silver compound pH Whether to add 0.01% H ₂ O ₂ Antimicrobial index appearance index imidazolate, pH 5.5 5.5 no 0.8 3.4 5,5-DMH/pH 5.5/H ₂ O ₂ 5.5 yes 1.4 5 5,5-DMH, pH 8.5 8.5 no 1.7 2.2 5,5-DMH, pH 5.5 5.5 no 1.8 2.8 Hydantoin/5.5/H ₂ O ₂ 5.5 yes 2.3 3.6 Imidazolate/pH 5.5/H ₂ O ₂ 5.5 yes 2.7 3 Hydantoin, pH 5.5 5.5 no 2.7 4 imidazolate, pH 8.5 8.5 no 2.8 3.2 Sulfadiazine, pH 8.5 8.5 no 2.9 2.8 Sulfadiazine, pH 7.0 7 no 3.1 2.8 Sulfadiazine, pH 5.5 5.5 no 3.1 3.6 Hydantoin, pH 8.5 8.5 no 3.2 2.8 Sulfadiazine/pH 5.5/H ₂ O ₂ 5.5 yes 3.2 3 Imidazolate, pH 7.0 7 no 3.2 4.2 Hydantoin, pH 7.0 7 no 3.3 3.4 5,5-DMH, pH 7.0 7 no 3.4 3.4

Thus, silver compounds with precipitation have good antimicrobial effects even in media containing 160 mM NaCl, which significantly reduces the solubility of said compounds. Even better results should be obtained in hydrochloride-free media.

Example 14-Algicide

1-5g/L Algicide in 50mM citrate (pH 5.5), 160mM NaCl and 6% PEG 2000 against Enterococcus faecalis, Klebsiella, Staphylococcus aureus, Escherichia coli, Steinprovir Denstella and Pseudomonas aeruginosa are moderately to highly antimicrobial, however, Proteus mirabilis has no effect. Therefore, algicide can also be used in antimicrobial catheters.

Claims (12)

1. a conduit tube component comprises (i) at least one parts of vessels (1,2); Cover at least a portion of said parts of vessels by hydrophilic coating, at least a expansion of liquids medium of the said hydrophilic coating that (ii) is used to expand is (iii) as the aqueous hydrogen peroxide solution of the part of expansion of liquids medium; (iv) packing device (3); Second chamber (5) that first chamber (4) of wherein said packing device (3) is fit to holding conduit parts (1,2) and said packing device (3) is fit to hold aqueous hydrogen peroxide solution; And said aqueous solution also comprises stabilizing agent, and said stabilizing agent is a chelating agen.

2. conduit tube component as claimed in claim 1, wherein, chelating agen is selected from diethylene-triamine pentaacetic acid (DETAPAC), deferoxamine and diethylenetriamines five (methylene phosphonic acid) (DETAPMP).

3. the conduit tube component any like claim 1-2, wherein, second chamber (5) of said packing device (3) is fit to hold at least a portion and the said aqueous hydrogen peroxide solution of said expansion of liquids medium.

4. conduit tube component as claimed in claim 3, wherein, first chamber (4) of said packing device (3) holds at least a portion of said expansion of liquids medium and another part of said expansion of liquids medium is an aqueous hydrogen peroxide solution.

5. conduit tube component as claimed in claim 3, wherein, second chamber (5) of said packing device (3) is fit to hold all expansion of liquids media, and said expansion of liquids medium is an aqueous hydrogen peroxide solution.

6. the conduit tube component any like claim 1-2; Wherein, Said expansion of liquids medium and said aqueous hydrogen peroxide solution have formed and also comprised the aqueous solution that is selected from one or more following compositions: stabilizing agent, buffer agent and Morie osmolarity improve preparation.

7. conduit tube component as claimed in claim 6, wherein, aqueous hydrogen peroxide solution comprises:

The hydrogen peroxide of 0.01-5.0% (w/w),

One or more stabilizing agents of 25-1200mg/L,

One or more buffer agents of 0-25mM,

The 0-300mM Morie osmolarity improves preparation,

And the scope of pH is 2.0-8.5.

8. the conduit tube component any like claim 1-2; Wherein, Said hydrophilic coating comprise crosslinked polyvinylpyrrolidone and wherein first chamber (4) hold said parts of vessels (1,2); Hold said expansion of liquids medium with second chamber (5), said expansion of liquids medium has following composition:

The hydrogen peroxide of 0.1-3.0% (w/w),

One or more stabilizing agents of 25-1200mg/L,

One or more buffer agents of 0-10mM,

The 0-300mM Morie osmolarity improves preparation,

Other compositions of 0-2000mg/L and

The pure water of aequum,

And the scope of pH is 2.0-8.5.

9. a conduit tube component comprises (i) at least one parts of vessels (1,2); Cover at least a portion of said parts with hydrophilic coating; And have in the said coating existence wherein aqueous hydrogen peroxide solution and (ii) be fit to hold the packing device (3) of said parts of vessels (1,2); Said aqueous solution also contains stabilizing agent, and described stabilizing agent is a chelating agen.

10. assembly as claimed in claim 9, wherein, chelating agen is selected from diethylene-triamine pentaacetic acid (DETAPAC), deferoxamine and diethylenetriamines five (methylene phosphonic acid) (DETAPMP).

11. a conduit, possess hydrophilic property coating on its a part of surface at least, wherein, said coating comprises aqueous hydrogen peroxide solution and preparation that can stable peroxide hydrogen, and said preparation is a chelating agen.

12. like the conduit of claim 11, wherein, chelating agen is selected from diethylene-triamine pentaacetic acid (DETAPAC), deferoxamine and diethylenetriamines five (methylene phosphonic acid) (DETAPMP).

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