CN1753702B - An assembly for the preparation of a medical device having a coating comprising hydrogen peroxide - Google Patents
An assembly for the preparation of a medical device having a coating comprising hydrogen peroxide Download PDFInfo
- Publication number
- CN1753702B CN1753702B CN2004800053751A CN200480005375A CN1753702B CN 1753702 B CN1753702 B CN 1753702B CN 2004800053751 A CN2004800053751 A CN 2004800053751A CN 200480005375 A CN200480005375 A CN 200480005375A CN 1753702 B CN1753702 B CN 1753702B
- Authority
- CN
- China
- Prior art keywords
- hydrogen peroxide
- coating
- expansion
- chamber
- conduit
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 title claims abstract description 427
- 238000000576 coating method Methods 0.000 title claims abstract description 151
- 239000011248 coating agent Substances 0.000 title claims abstract description 150
- 238000002360 preparation method Methods 0.000 title claims abstract description 55
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 57
- 239000003381 stabilizer Substances 0.000 claims abstract description 49
- -1 for dialysis Substances 0.000 claims abstract description 33
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
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- 238000012856 packing Methods 0.000 claims description 94
- 239000000203 mixture Substances 0.000 claims description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000872 buffer Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 229960000958 deferoxamine Drugs 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 12
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Images
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- Materials For Medical Uses (AREA)
- Paints Or Removers (AREA)
- Apparatus For Disinfection Or Sterilisation (AREA)
Abstract
The present invention provides an assembly for the preparation of a medical device having a porous coating comprising hydrogen peroxide. Particularly interesting medical devices are catheters (such as urinary catheters), endoscopes, laryngoscopes, tubes for feeding, tubes for drainage, guide wires, condoms, urisheaths, barrier coatings e.g. for gloves, stents and other implants, extra corporeal blood conduits, membranes e.g. for dialysis, blood filters, devices for circulatory assistance, dressings for wound care, and ostomy bags. The coating is in particular a hydrophilic coating formed from cross-linked polyvinylpyrrolidone. In one embodiment, the assembly holds a dry catheter element in one compartment of a package and an aqueous hydrogen peroxide solution in another compartment. The solution may also comprise stabilizers, e.g. chelators, and osmolality increasing agents. The catheter for insertion in the urethra is useful for the treatment, alleviation or prophylaxis of microbial infections such as urinary tract infections (UTI).
Description
Invention field
The present invention relates to can be used for providing the assembly of medical apparatus and instruments, this medical apparatus and instruments has the coating of porous polymeric compositions at least on its a part of surface, for example; Hydrophilic coating, wherein, said coating comprises liquid; For example, the expansion of liquids medium, this medium comprises hydrogen peroxide.
The invention still further relates to medical apparatus and instruments itself, particularly contain the inflating medium of hydrogen peroxide, and the medical usage of said assembly and medical apparatus and instruments.
Background of invention
In a lot of medical applications, polymer composition has constituted at least a portion of medical apparatus and instruments, like hydrophilic coating, and hydrogel, support, binding agents etc. can be used for contacting closely with human body.Can also medical apparatus and instruments be used for importing, cover, or fill the human body body cavity.The example of body cavity or opening can be naturally occurring chamber, like urethra, and oral cavity, ear; Nose, eyes, rectum perhaps can also be the artificial opening through surgical operation or schedules operations; As at tremulous pulse, vein, chamber that forms on the lymph node or opening, or the opening that on gastrointestinal tract, forms; Like colostomy, ileostomy, regeneration of urethra art, or the opening or the chamber that form because of unexpected action.Said medical apparatus and instruments or said polymer composition also can be used for being positioned between the limbs (lower limb, finger, toe, axillary fossa), or are used for through binding agent and human body physical bond.
Can the polymer composition of medical apparatus and instruments be transformed into softishly and resilient through engineering method, and reduce the friction between the slide unit.For example, applying medical apparatus and instruments with hydrophilic coating, is known like the way of conduit, so that it is imported the human body body cavity, and like blood vessel, digestive organs and urinary system.When said coating was expanded by aqueous solution or water, it is smooth that the surface of said medical apparatus and instruments can become, and very be fit to painless importing body cavity, and tissue is had only very little damage.
At apparatus, for example, when the conduit of possess hydrophilic property coating imports the human body body cavity, possibly penetrate normal human body defensive barrier with said type; Cause the importing of microorganism, promptly import, antibacterial, fungus such as virus; Mycete, phage, or the minicell of tissue appearance or multiple systematism cell.Well-knownly be, carry out the people that intermittent urethral catheter inserts every day, have the problem of Symptomatic urinary tract infection (UTI) usually.Similarly, possibly cause infected by microbes with multiple other medical apparatus and instruments that tissue contacts closely.
Known in which hydrogen peroxide has anti-microbial effect.Also understanding it is easy to decompose.Through reacting, through Fenton reaction decomposes hydrogen peroxide, so that form hydroxyl with high activity with reduction transition metal ions such as ferrum (II) and copper (I).Except destroying hydrogen peroxide; And therefore shorten outside the shelf life of the product that contains hydrogen peroxide; Hydroxyl from Fenton reaction also might destroy polymer coating, particularly hydrophilic coating potentially, is through the realization that reacts of it and various compositions in the coat system.For example, through water being stored in steel vessel or the glass container, the pollution of transition metal ions to water can take place.Even in the water that purification is crossed, for example, in the water of crossing through ion-exchange purification, still there is the transition metal ions of trace.Therefore, comprise the polymer coating of the liquid that contains hydrogen peroxide, can be regarded as usually and be not suitable for long term storage.
US 5,130, and 124 have disclosed the film forming antimicrobial compositions of the hydrogen peroxide of stabilisation.
US 5,951, and 458 have disclosed through on blood vessel, using oxidant to suppress the method for restenosis, for example, carry hydrogen peroxide through balloon catheter.Said United States Patent (USP) does not have solution to be present in the stability of peroxide problem in the hydrophilic coating.
Summary of the invention
The present invention has utilized hydrogen peroxide (H
2O
2) advantageous feature, adopted the device of avoiding the potential illeffects that the unstability owing to hydrogen peroxide produces simultaneously.
First aspect of the present invention relates to a kind of assembly; At least one has the medical apparatus and instruments parts of the coating of porous polymeric compositions to comprise (i), and said coating covers at least a portion of said parts, (ii) is used to occupy at least a liquid in the hole of said polymer composition; (iii) hydrogen peroxide is originated; (iv) packing device, said packing device are fit to said medical apparatus and instruments parts, and said liquid and said hydrogen peroxide source are contained in two independent cavity at least.
Second aspect of the present invention relates to the antimicrobial liquid inflating medium, comprising:
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.
The third aspect of the invention relates to medical apparatus and instruments, on its a part of surface, has the coating of porous polymeric compositions at least, and wherein, said coating comprises the liquid that contains hydrogen peroxide and preparation that can stable peroxide hydrogen.
Fourth aspect of the present invention relates to a kind of treatment; The method that alleviation or prophylaxis of microbial infect, wherein, first step is to prepare medical apparatus and instruments with said modules; With, second step is to let said apparatus contact with the mammiferous body part that needs said medical apparatus and instruments.
The 5th aspect of the present invention relates to a kind of treatment, and the method that alleviation or prophylaxis of microbial infect wherein, lets above-mentioned medical apparatus and instruments contact with the mammiferous body part that needs said medical apparatus and instruments.
The 6th aspect of the present invention relates to a kind of assembly; At least one has the medical apparatus and instruments parts of the coating of porous polymeric compositions to comprise (i); Said coating covers at least a portion of said parts; And, have the packing device that contains the liquid of hydrogen peroxide and (ii) be fit to hold said medical apparatus and instruments parts in the said coating.
Description of drawings
Fig. 1 and 2 is the example with packing device of two independent cavity.
Detailed description of the present invention
Assembly
Potential problems to above-mentioned relevant hydrogen peroxide stability; At least work as it and be present in polymer coating, in the time of particularly in the hydrophilic coating, the invention provides to be used in and soon use the assembly for preparing medical apparatus and instruments before; Wherein, the coating of said apparatus comprises the hydrogen peroxide of exact amount.
Therefore, the invention provides solution, comprise the coating that is provided for obtaining on its a part of surface, to have at least the porous polymeric compositions the problems referred to above; For example, the medical device of hydrophilic coating (being assembly), wherein; Said coating comprises liquid; For example, the expansion of liquids medium, this medium comprises hydrogen peroxide.
Through what illustrative example of the present invention confirmed, said medical apparatus and instruments provided the advantage that suppresses the infected by microbes development in use effectively as already, for example, and urinary tract infection.In addition, alleviated aforementioned stable property problem.
More particularly, the invention provides a kind of assembly, at least one has the medical apparatus and instruments parts of the coating of porous polymeric compositions to comprise (i); Said coating covers at least a portion of said parts; (ii) be used to occupy at least a liquid in the hole of said polymer composition, (iii) hydrogen peroxide source and (iv) packing device; Said packing device is fit to said medical apparatus and instruments parts, and said liquid and said hydrogen peroxide source are contained in two independent cavity at least.In its preferred embodiment, said packing device also is adapted at setting up contact between said medical apparatus and instruments parts, said liquid and the said hydrogen peroxide source.
Medical apparatus and instruments
Term " medical apparatus and instruments " should be by with generalized sense.The suitable example of medical apparatus and instruments (comprising instrument) is conduit (for example, catheter), endoscope, and laryngoscope is used for the conduit of feed, is used for excretory conduit; Lead, condom, urisheaths, curtain coating, for example; Be used for glove, dilator is inserted thing with other, outside tangible vessel catheter, and film, for example; Be used for dialysis, the film of blood filtration, the auxiliary apparatus that is used to circulate, the dressing of wound care and neostomy sack.Maximally related is conduit, endoscope, and laryngoscope is used for the conduit of feed, is used for excretory conduit, and lead and dilator are inserted thing with other.Interested especially within the scope of the present invention medical apparatus and instruments is a conduit, like catheter.
Some medical apparatus and instruments can be made up of one or more medical apparatus and instruments parts, when assembling or reinstalling, has formed ready-made medical apparatus and instruments.The part of said " medical apparatus and instruments parts " and " parts of vessels " said medical apparatus and instruments of expression or conduit itself (that is, a medical apparatus and instruments or conduit) or " ready-made " medical apparatus and instruments or conduit.
Medical apparatus and instruments and medical apparatus and instruments parts can be made up of polytype basic material, like plastics, and metal, glass, pottery etc.The exemplary that is used for the plastic material of medical apparatus and instruments is a polymer, like polyurethane and copolymer thereof, or polyether block amide, like Pebax
TMOr other polymeric materials, comprise polrvinyl chloride, polyamide; Silicone, styrene-ethylene/butylene-styrene block copolymer (SBBS), SIS (SIS); Styrene-ethylene/propylene-styrene block copolymer (SEPS), vinyl-vinyl acetate copolymer (EVA), polyethylene (PE); The copolymer of metallocene-catalytic polyethylene and ethylene and propylene or their mixture.Very relevant at present material is polyurethane and copolymer thereof.
In the present invention, said medical apparatus and instruments at least on its a part of surface (that is, on a part of surface of basic material) have the coating of porous polymeric compositions, for example, hydrophilic coating.In certain embodiments, the coating of said porous polymeric compositions (for example, said hydrophilic coating) is painted on whole (outward) surface of said matrix polymer, and in some other embodiment, only is coated on the part on said surface.In maximally related embodiment, said coating is painted at least a portion surface (preferred whole surface) of said medical apparatus and instruments, and it can use the people's of this medical apparatus and instruments body part directly to contact with needs when correctly using when this medical apparatus and instruments.
In the present invention; Polymer composition is that the implication of " porous " is that the coating of (i) said polymer composition has the space that is fit to through the capillary force receiving liquid medium, for example, and sponge; Or (ii) the coating of said polymer composition maybe be because hydrophilic characteristics but porous; For example, as what recognize from expandable hydrophilic polymer, it can be retained in a large amount of water in the expansible polymer network.Under some occasion, " porous " of said polymeric compositions possibly be the result of two kinds above-mentioned " phenomenon " combination.
Interested especially polymer composition comprises the expandable hydrophilic polymer of a large amount of (that is, at least 50% (w/w)), at least at medical apparatus and instruments, for example, has formed hydrophilic coating on a part of surface of conduit.Concerning some purposes, said polymer composition (for example, hydrophilic polymer is like polyvinylpyrrolidone) is preferably crosslinked.
The exemplary of said expandable hydrophilic polymer is a polyvinylpyrrolidone, and polyvinyl alcohol gathers (methyl) acrylic acid, gathers (methyl) acrylamide, Polyethylene Glycol, carboxymethyl cellulose, cellulose acetate, cellulose acetate propionate, chitosan, polysaccharide; Or two or more said monomeric any homopolymer or copolymer; The N-vinylpyrrolidone, vinyl alcohol, (methyl) acrylic acid, (methyl) acrylamide, (methyl) acrylic ester, like hydroxyethyl methacrylate, maleic anhydride, maleimide, methyl vinyl ether, alkyl vinyl ether and other unsaturated compounds.In addition, said hydrophilic polymer can be the blend of said homopolymer or copolymer.Other radiation curing hydrophilic polymeies that comprise undersaturated vinyl double bond are suitable for said coating equally.Said polymer can pass through acrylic substance, like dimethylaminoethyl methacrylate and N-vinyl pyrrolidone, and methacrylic acid, methacrylate, methyl vinyl ethers etc. are copolymerized into oligomer and prepare.Usually said prepolymer is coated on the said surface, and final radiation curing.The hydrophilic polymer of said coating can also add to through the monomer with acrylic acid character in the polymer of the above-mentioned type and prepares.Polyethylene Glycol and polyvinylpyrrolidone are specially adapted to said hydrophilic coating.
Most preferably, the hydrophilic polymer of said coating is selected from following one group: polyvinylpyrrolidone or its copolymer, for example, polyvinylpyrrolidone-vinyl acetate copolymer.The polymer of said type can also be through crosslinking with radiation.(gather (N-vinyl-2-Pyrrolidone) at suitable pure polyvinylpyrrolidone; PVP) time, can select various chain lengths, give said coating various characteristics respectively.Usually, the number-average molecular weight of said polyvinyl pyrrolidone polymers is higher than 100,000.For instance, can select molecular weight is 1,200,000 PVPK-90, but, can also use the PVP of the other types with other molecular weight.
In a kind of interested embodiment, said matrix polymer is a polyurethane, and said hydrophilic polymer is a polyvinylpyrrolidone.
When preparation during said hydrophilic coating, can add one or multiple additives, for example,, or improve combining of said polymer and stromal surface so that promote the crosslinked of said hydrophilic polymer.Said additive is well known in the art, and comprises the UV-initiator, for example, and referring to WO 98/58990.The example of suitable UV-polymerization initiator is
KIP 150.
Hydrophilic coating can also comprise plasticizer, like ATEC, and dimethyl sulfone, ethylene carbonate; Diacetine, glyceryl triacetate, hexamethyl phosphoramide, isophorone; Methyl salicylate, N-acetyl group morpholine, propylene carbonate, quinoline; Sulfolane, triethyl citrate, and triethyl phosphate.
Applying of hydrophilic coating can be through soaking polymer solution, and spray or be applied to medical apparatus and instruments or the medical apparatus and instruments parts that need said hydrophilic coating, or on its part.In addition, said coating can be through coextrusion formation.
Polyvinylpyrrolidone coating on the medical apparatus and instruments parts can form through applying following solution, and this solution contains N-Methyl pyrrolidone, polyvinylpyrrolidone or its copolymer (N-vinylpyrrolidone and gather (methyl) acrylic acid; Acrylamide; Vinyl alcohol, Polyethylene Glycol, polyvinyl methyl ether; Polyvinyl methyl ether-maleic anhydride; Carboxymethyl cellulose, or hydroxyethyl-cellulose), optionally use the UV light trigger; Like
KIP 150 be dissolved in the plasticizer in the ethanol.
Before applying said hydrophilic coating, particularly for some combination of matrix polymer and hydrophilic coating, at the said polymer composition (for example, said hydrophilic coating) that applies formation porous polymeric compositions preferred coated prime coat layer before.In certain embodiments, said prime coat layer can be used the dilute solution preparation of said polymer solution.
In other embodiments; The coating of said polymer composition is " sponge " structure; It has the space that is fit to through the capillary force receiving liquid medium, and said coating can be through the basic material of coextrusion medical apparatus and instruments and the material preparation of formation said " sponge " structure, or is immersed in a kind of material (or its solution) through the basic material with medical apparatus and instruments; This material can expand when solidifying subsequently and form " sponge " structure, constitutes said porous coating etc.
Liquid (expansion of liquids medium)
Said liquid as a said assembly part hopes to contact with the porous polymeric compositions as follows in use, makes said liquid and hydrogen peroxide can fill the hole of said porous polymeric compositions.In certain embodiments, said liquid a part or all be contained at first in the said porous polymeric compositions.For hydrophilic polymer (for example, cross-linked hydrophilic property polymer is like crosslinked PVP), said liquid (that is, the expansion of liquids medium) expands said hydrophilic polymer when contact, so that form expansible hydrophilic coating.
Said assembly can comprise one or more liquid (for example, the expansion of liquids medium), and if comprise two or more liquid, said liquid should preferably can be blended.
In most preferred embodiment, said one or more liquid are selected from water (water preparation) and aqueous solution (for example, aqueous hydrogen peroxide solution).Aqueous solution generally includes at least 90% (w/w), like at least 95% (w/w), or the water of at least 97% (w/w).
The hydrogen peroxide source
Said hydrogen peroxide source is selected from liquid hydrogen peroxide source (that is, aqueous hydrogen peroxide solution) and solid peroxygen hydrogen source (that is, solid chemical compound can discharge hydrogen peroxide when heating or contact with water) usually.Originate stabilisation preferably of liquid hydrogen peroxide is so that reduce or eliminate the decomposition (vide infra) of hydrogen peroxide.
The example in solid peroxygen hydrogen source is for example, to be combined in the hydrogen peroxide (for example, being combined in the solid peroxygen hydrogen compound on the polyvinylpyrrolidone (PVP)) on the chemical compound and the chemical compound of the potentiality with formation hydrogen peroxide, for example; Through reacting with water, like perborate (for example, Dexol), percarbonate (for example; SODIUM PERCARBONATE), perphosphate (for example, peroxophosphoric acid sodium), persulfuric acid is (for example; Potassium peroxydisulfate), peroxy-monosulfate, peroxydisulfate, urea peroxide etc.
Should be understood that the hydrogen peroxide source that this paper mentioned can comprise the source of one or more types, and can be the solids source that makes up with the liquid hydrogen peroxide source.
In order to obtain the bio-compatibility between hydrogen peroxide coating composition and the human tissue cell, before using said hydrogen peroxide the concentration in the liquid (for example, inflating medium) should remain on low-level on; Like 0.01-5.0%, like 0.1-3.0%, like 0.2-2.0%; As 1%; It is at middle (w/w) that measures of the liquid (for example, inflating medium) with ready-made medical apparatus and instruments (for example, conduit) preparation.This concentration is equivalent to obtained when contacting when all liq and said liquid or solid hydrogen peroxide source.
Hydrogen peroxide is a kind of well-known material, and it can resolve into water and oxygen rapidly in human body.Therefore, when low concentration was taken, hydrogen peroxide can not damage human body.But; In fact; Hydrogen peroxide possibly decompose under the condition that is fit to medical usage quite easily; When the medical apparatus and instruments (for example, catheter) of the coating with porous polymeric compositions (for example, hydrophilic coating) with condition that the expansion of liquids medium that contains hydrogen peroxide contacts under possibly produce stability problem when preserving.After medical apparatus and instruments is being produced, need have for example surpass some months or even when reaching the shelf life of length of 1 year or several years, this problem become outstanding especially (referring to embodiment).
Packing device
For aforementioned stable property problem; Assembly of the present invention also comprises (iv) packing device, and it is fit to (i) said medical apparatus and instruments parts, and (ii) said liquid and (iii) said hydrogen peroxide source are contained in two independent cavity at least; Promptly; When said packing device is in the ad hoc structure, more than three (i)-(iii) can directly not contact with each other promptly said three (i)-(iii) be in " at least two independent cavity ".
Two independent cavity in the said packing device (i) can be installed like this in case first chamber near second chamber; (ii) so that second chamber is installed in first chamber, vice versa; (iii) so that first chamber and second chamber are the sacks by loose installation in the 3rd chamber of said packing device, ampere bottle, capsule etc. constitute etc.The technical staff can be understood that, also comprises the structure that other are possible.
In a kind of embodiment of packing device, said second chamber has sealing device, is adapted at removing said sealing device and afterwards said hydrogen peroxide source is discharged in first chamber.
Term " packing device " expression is hoped to comprise other objects, the structure of liquid etc., so that make said object, and the external isolation of liquid etc. and said packing device.
Packing device can comprise plastics, like polrvinyl chloride (PVC), and polyethylene (PE), polypropylene (PP); Polyvinylidene fluoride (PVDF), polytetrafluoroethylene (PTFE), rubber, for example; Synthetic raw rubber-second diene monomer (EPDM), FKM fluorubber and with the paper of said polymer and rubber coated.The plastics and the rubber that are fit to the preservation hydrogen peroxide should be corrosion resistant, and should not can cause the degraded of hydrogen peroxide.The inner surface that the chamber of hydrogen peroxide is housed can also use the inert metal such as titanium and platinum to apply.
Polyethylene is at present as the originate preferred material of the liner that contacts of said chamber and said hydrogen peroxide, because it can only react with hydrogen peroxide lentamente.
The formation of said packing device comprise the parts of the chamber of hydrogen peroxide or hydrogenperoxide steam generator; In one embodiment; Process with multilayer material, so that obtain gas impermeability (and possibly be opaque) so that avoid any illeffects to hydrogen peroxide stability.Said multilayer material can be three layers of paillon foil that are made up of PETG (PET)/aluminum/polyethylene (PE), and wherein, polyethylene is the internal layer of said chamber, and it directly contacts with said hydrogen peroxide or the inflating medium that contains hydrogen peroxide.
Term " gas is impermeable " is to be understood as in the present invention that expression is enough closely, stops any material of the evaporation diffusion of said expansion of liquids medium in the time of the shelf life that surpassing this assembly of recommending; Said shelf life maybe be as long as five years, common about 36 months or longer time.
The preferred further improvement of said packing device, so that can set up said medical apparatus and instruments parts, the contact between said liquid and the said hydrogen peroxide source.
When using said assembly; One or two (or all) chamber is opened by this way; Make (i) said medical apparatus and instruments parts, (ii) said liquid is originated with (iii) said hydrogen peroxide and is contacted, and its objective is that the coating for said medical apparatus and instruments parts provides the liquid that contains hydrogen peroxide.The unlatching of said chamber as indicated above can be through the wall of outstanding one or two (or all) chamber, through breakseal, through realizations (also can vide infra) such as screw capping.
In a kind of preferred variation, let said composition in said packing device, contact with each other, that is, this moment, packing device still held said composition.Like this, the moistening of coating of said medical apparatus and instruments can carry out under aseptic condition.
Can propose a variety of designs of said packing device, and the example of the packing device of suitable this purpose has, for example, referring to EP 0 923 398 and WO 03/092779, and referring to Fig. 1 and 2.
Fig. 1 representes to have the example of the packing device (3) of two independent cavity (4 and 5).First chamber (4) holds the conduit of being made up of two parts of vessels (1 and 2), and one of them (1) has the coating of porous polymeric compositions.Second chamber (5) of blister cavities form is installed in first chamber (4), and receiving fluids inflating medium (like hydrogenperoxide steam generator).The exit portion (6) of blister cavities (5) is towards said parts of vessels (1 and 2).Exit portion (6) be through the welding (7) form rupturable hermetically enclosed, more weak joint is provided, this is bonded on and can breaks when exerting pressure to blister cavities (5).This purpose can realize through the said packing device of extruding (3), and in fact can not open said packing device.Like this, can under aseptic condition, realize moistening (expansion) of said parts of vessels (1).
Fig. 2 representes to have another example of the packing device (3) of two independent cavity (4 and 5).First chamber (4) holds the conduit of being made up of two parts of vessels (1 and 2), and one of conduit wherein (1) has the coating of porous polymeric compositions.Second chamber (5) of rigid container form installed near first chamber (4), and receiving fluids inflating medium (like hydrogenperoxide steam generator).The end wall (8) of rigid container (5) is towards the end wall (9) of first chamber (4).(Fig. 2 (b)) as shown in the figure is mounted to end wall (9) rotation of first chamber (4) relatively with second chamber (5), so that make the liquid outlet and the liquid inlet that are separately positioned on end wall (8) and the end wall (9) form the liquid communication alignment.Therefore, the expansion of liquids medium of said second chamber (5) can be transferred in first chamber (4), so that said expansion of liquids medium can get into the hole of the coating of said parts of vessels (1).
The example that can adopt commercially produced product of the present invention is the catheter assembly of possess hydrophilic property coating; It has ampere bottle (second chamber); Be equipped with and the incorporate expansion of liquids medium of said product; For example;
that is provided by Astra Tech AB and
that provided by Coloplast A/S are in said product, and the said ampere bottle with said expansion of liquids medium is isolating with conduit exsiccant, coating.Before using, destroy the ampere bottle, and said expansion of liquids medium is absorbed in the said hydrophilic coating.
The various embodiments of assembly
In a kind of interested embodiment of said modules, said polymer composition is included in the hydrophilic polymer that forms hydrophilic coating at least a portion surface of said medical apparatus and instruments parts, and said liquid is the expansion of liquids medium.
In other interested embodiments, said medical apparatus and instruments parts comprise parts of vessels.More particularly, said medical apparatus and instruments is a conduit, like catheter.In preferred version, at least a portion possess hydrophilic property coating of said parts of vessels is fit to reduce friction, and said hydrogen peroxide is imported the opening of health, for example, and in the urethra.
In present most preferred embodiment, said assembly is a conduit tube component, and it comprises (i) at least one parts of vessels; Cover at least a portion of said parts of vessels by hydrophilic coating; (ii) be used to the to expand at least a inflating medium of said hydrophilic coating, (iii) hydrogen peroxide source and (iv) packing device; Said packing device is fit to said parts of vessels, and said inflating medium and said hydrogen peroxide source are contained in two independent cavity at least.
In its a kind of embodiment, said packing device is adapted at said parts of vessels, sets up contact between said inflating medium and the said hydrogen peroxide source, and is for example, as indicated above.
The present invention combines following " conduit " embodiment and " hydrophilic coating " embodiment to describe, and but, should be understood that these explanations are equally applicable to other embodiments of the present invention.
In a kind of main embodiment of said conduit tube component, first chamber of said packing device is fit to the holding conduit parts, and second chamber of said packing device is fit to hold the hydrogen peroxide source.Said hydrogen peroxide source can be the solid that provides with one or more pills or powder type, and liquid hydrogen peroxide solution at least a portion as said expansion of liquids medium maybe can be provided, and it added in the said parts of vessels before using.
A kind of preferred embodiment of above-mentioned embodiment is such; Wherein, First chamber of said packing device is fit to hold said parts of vessels, and second chamber of wherein said packing device is fit to hold at least a portion and the said hydrogen peroxide source of said expansion of liquids medium.In the time of in being present in identical chamber; That is, be present in second chamber, said expansion of liquids medium and said hydrogen peroxide source have formed aqueous hydrogen peroxide solution usually; That is, second chamber is contained in hydrogenperoxide steam generator at least a portion of said expansion of liquids medium.Therefore, in this embodiment, said hydrogen peroxide source is the hydrogen peroxide that is present in the aqueous solution.
In a kind of version of above-mentioned embodiment; At least a portion of the said expansion of liquids medium of first chamber housing of said packing device; Promptly; Said parts of vessels is at least by the demi-inflation of said expansion of liquids medium, and another part of said expansion of liquids medium makes up with said hydrogen peroxide.The advantage of doing like this is that said parts of vessels can provide under the expansible condition in advance.But, in this version, importantly guarantee to let the inflating medium that contains hydrogen peroxide of suitable part get into said hydrophilic coating.
In the another kind of version of above-mentioned embodiment, the said expansion of liquids medium that second chamber housing of said packing device is all, that is, said parts of vessels is present in first chamber with " drying " form substantially.
Therefore; In a kind of interested especially version, first chamber of said packing device is fit to hold said parts of vessels, and second chamber of said packing device is fit to hold all said expansion of liquids medium and hydrogen peroxide; That is second chamber housing aqueous hydrogen peroxide solution.
Irrelevant with the selection of above-mentioned embodiment, the content in liquid described in the said assembly (for example, expansion of liquids medium) and said hydrogen peroxide source was preferably selected; So that the concentration of the said hydrogen peroxide in liquid (inflating medium) is in 0.01-5.0% (w/w) scope; Like 0.1-3.0% (w/w), like 0.2-2.0% (w/w), at this moment; Said liquid (inflating medium) and hydrogen peroxide are present in the hole of said polymer composition (for example, expansible already hydrophilic coating).Second chamber housing at said packing device is present in the embodiment of the hydrogenperoxide steam generator in the whole liquid inflating medium, and above-mentioned concentration is equivalent to the concentration in this aqueous solution in the nature of things.
In above-mentioned embodiment; Second chamber of said packing device is contained in hydrogenperoxide steam generator at least a portion of said expansion of liquids medium; Considerable for the manufacturer of said assembly is to guarantee the concentration of said hydrogen peroxide is remained on the maintenance level, even under the contingent condition of relevant temperature and illumination, preserved a lot of months or even after time several years.Therefore, the said hydrogenperoxide steam generator at least a portion of said expansion of liquids medium preferably includes stabilizing agent.
More particularly; The inventor had confirmed the preferential selection to embodiment already; Wherein, Said hydrogenperoxide steam generator in said expansion of liquids medium is to comprise that also one or more are selected from stabilizing agent, and buffer agent and Morie osmolarity improve preparation, particularly the aqueous hydrogen peroxide solution of stabilizing agent at least.
The example of stabilizing agent (modal is to be selected from chelating agen, and adding it is for bind metal ion, otherwise these metal ions can promote the decomposition of hydrogen peroxide) is a deferoxamine, polysaccharide, gelatin; Acetate, citrate, EDTA and corresponding salt, diethylene-triamine pentaacetic acid (DETAPAC) and corresponding salt; Ethylenediamine tetraacetic (methylene phosphonic acid) (EDATMP) or corresponding salt, diethylenetriamines five (methylene phosphonic acid) (DETAPMP) or corresponding salt, 1-hydroxyl ethane-1,1-di 2 ethylhexyl phosphonic acid (HEDP) or corresponding salt; Gluconate, phosphorane hydrochlorate, pyrophosphate, triphosphate; Hexametaphosphate, phytate, Sorbitol, tartrate; Silicate (like colloidal silicate), colloidal stannate, tetrasodium pyrophosphate, and organic phosphonate.Preferred example is EDTA, gelatin, deferoxamine, polysaccharide, and diethylene-triamine pentaacetic acid (DETAPAC).In other preferred embodiments of the present invention, said chelating agen is DETAPMP or deferoxamine-gather different hydroxyl oxime, and it is known as desferrioxamine again.
The content of stabilizing agent is usually in the 0-2000mg/L scope in the said aqueous hydrogen peroxide solution, more preferably 25-1200mg/L.
The example of buffer agent has citrate, acetate, glycollate, phosphate, benzoate, aminoacid, formates; Oxalates, malonate, succinate, glutarate, adipate, malate; Lactate, sulfanilate, borate, heavy carbonate, sulfate, and similar substance.
The content of buffer agent is usually in the 0-200mM scope in the said aqueous hydrogen peroxide solution, more preferably 0-50mM, for example, up to 50mM, like 2-50mM.
The example that Morie osmolarity improves preparation has alkali metal (for example, lithium, sodium, potassium etc.) and alkaline-earth metal (magnesium, calcium etc.) nitrate, alkali metal and alkali earth metal sulfate, alkali metal and alkaline-earth metal hydrochlorate, glycine, glycerol and carbamide.It is not strict essential that Morie osmolarity improves preparation, and but, in order to improve the comfortableness during using said medical apparatus and instruments, it is normally important.
Morie osmolarity improves the content of preparation in said aqueous hydrogen peroxide solution usually in the 0-1000mM scope, more preferably 0-300mM, for example, up to 300mM, like 5-300mM.
Should be pointed out that other compositions of the trace that said aqueous hydrogen peroxide solution can comprise that the front was not clearly mentioned.The content of said " other compositions " is generally 0-2000mg/L, like 0-500mg/L.
Usually, the pH of said aqueous solution is in the 2.0-8.5 scope, preferably in the 3.0-5.0 scope.
In one embodiment, said aqueous hydrogen peroxide solution comprises:
The hydrogen peroxide of 0.01-5.0% (w/w),
One or more stabilizing agents of 0-2000mg/L,
One or more buffer agents of 0-200mM,
The 0-1000mM Morie osmolarity improves preparation,
And the scope of pH is 2.0-8.5.
In another kind of embodiment, said 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.
In another kind of embodiment, said aqueous hydrogen peroxide solution comprises:
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.
In present most preferred embodiment, said aqueous hydrogen peroxide solution comprises:
The hydrogen peroxide of 0.3-2% (w/w),
The stabilizing agent of 25-1200mg/L is preferably selected from following one group: DETAPMP and deferoxamine,
Sodium sulfate or Chile saltpeter that 0-300mM improves preparation as Morie osmolarity,
Other compositions of 0-2000mg/L and
The pure water of aequum,
And the scope of pH is 2.0-8.5.
As required, pH normally regulates with sodium hydroxide and sulphuric acid or nitric acid.
For the embodiment with all expansion of liquids media of second chamber housing, above-mentioned aqueous solution is preferred especially.
For above-mentioned inflating medium, the present invention also provides the expansion of liquids medium of the embodiment that is equivalent to " above-mentioned aqueous hydrogen peroxide solution ", and it can be used for the hydrophilic coating that expands.Specifically, the invention provides the antimicrobial liquid inflating medium, comprising:
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.
In another kind of embodiment, the packing device of said conduit tube component comprises the hydrogen peroxide source of at least one solid form.In this embodiment, first chamber of said packing device preferably holds at least one hydrogen peroxide source and at least one parts of vessels.More particularly, first chamber of said packing device is fit to hold said parts of vessels and said solid peroxygen hydrogen source.Preferably, second of said packing device chamber is fit to hold said expansion of liquids medium.
Said solid peroxygen hydrogen source can be a powder type, one or more pills, one or more tablets; Capsule, beadlet, or coating on the inboard of said first chamber or thin film; Or said hydrogen peroxide source is combined on the said parts of vessels; For example, as the grumeleuse that is embedded in the said hydrophilic coating, one deck in the coating or as the one deck on the coating surface.In use; Add said expansion of liquids medium; And said hydrogen peroxide source is dissolved in the said expansion of liquids medium, perhaps reacts so that discharge hydrogen peroxide, and said hydrogen peroxide is expand in the said hydrophilic coating with said expansion of liquids medium.
In a kind of version of this embodiment; The coating that said parts of vessels is mixed in solid peroxygen hydrogen source; As the molecule in the hole that is trapped in said hydrophilic coating, perhaps as the part of at least a chemical compound that is used to prepare said hydrophilic coating.In its a kind of version, said solid peroxygen hydrogen source comprises the hydrogen peroxide that cooperates with polyvinylpyrrolidone (PVP).Specifically, at least a portion of said hydrophilic coating is with polyvinylpyrrolidone (PVP)-peroxide compound preparation.
In this embodiment, said polymer molecule chemical crosslinking or to be assembled into polymer composition be to carry out existing under the condition of said hydrogen peroxide has caused the delay to said hydrogen peroxide.Said hydrogen peroxide can exist with free form, perhaps cooperates as a part of participating in one of said chemical crosslinking process or this process desirable ingredients or with it.For example, polymer composition can comprise the polymer that can form coordination compound with hydrogen peroxide, like PVP or relevant polymer.
The initial hydrogen peroxide that cooperates with said polymer can be linked on the substrate subsequently, so that for example form hydrophilic coating.
In the another kind of embodiment of conduit tube component, said packing device comprises first chamber that is fit to hold said parts of vessels, is fit to hold second chamber of said expansion of liquids medium and is fit to hold the 3rd chamber in said hydrogen peroxide source.
In a kind of preferred variation of this embodiment, said conduit tube component comprises packing device, when this device is adapted at unpacking device said hydrogen peroxide source is discharged in the said expansion of liquids medium automatically.This purpose can be through holding hydrogen peroxide in said chamber, and have and chamber that the expansion of liquids medium is housed is separated through foil membrane realize that said film breaks when unpacking.
Preferred embodiment
In present most preferred embodiment; The invention provides conduit tube component, comprise (i) at least one parts of vessels, have the hydrophilic coating of at least a portion that covers said parts of vessels; Said hydrophilic coating comprises crosslinked polyvinylpyrrolidone; (ii) be used to the expand at least a expansion of liquids medium of said hydrophilic coating and (iv) packing device, said packing device has first chamber that holds said parts of vessels; With second chamber that is used to hold said expansion of liquids medium, 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.
The assembly that comprises other or alternative anti-microbial agents
Although in fact said modules is confirmed as favourable anti-microbial agents with hydrogen peroxide; It is understandable that; Can one or more other anti-microbial agents be used for said liquid (inflating medium), make up, perhaps substituting as hydrogen peroxide with hydrogen peroxide.The example of said other or alternative anti-microbial agents has silver sulfadiazine, hydantoin silver, 5,5-dimethyl hydantoin silver; Polymerization imidazoles silver, silver chloride, silver sodium thiosulfate (SST), thiosalicylic acid silver; Silver tris coordination compound, polyvinylpyrrolidone-iodine (povidone iodine, PVP-I
2), alkyldimethylbenzylammonium chloride, bronopol (2-bromo-2-nitro-1, ammediol), Kathon (80: 20 the 5-chloro-2-methyl-4-isothiazoline-3-ketone and the mixture of 2-methyl-4-isothiazoline-3-ketone); Phenyl salicytate, zinc chloride, copper chloride, hexamethylenetetramine; The diazole ureine, mandelic acid, hippuric acid, toluene-sodium-sulfonchloramide; Chloramine B, chlohexidine digluconate, chlohexidine dihydrochloride, and nitrofural.Most interested at present anti-microbial agents is an alkyldimethylbenzylammonium chloride, silver sulfadiazine, hydantoin silver, 5,5-dimethyl hydantoin silver and polymerization imidazoles silver, particularly alkyldimethylbenzylammonium chloride.
Therefore, also the combination with one or more said anti-microbial agents and hydrogen peroxide is relevant with embodiment in the above-mentioned aspect of said assembly (for example, conduit tube component).
In addition, the above-mentioned aspect of said assembly (for example, conduit tube component) and embodiment are also relevant with the said alternative anti-microbial agents that independent use or combination with one another are used, and, do not have hydrogen peroxide that is, in addition the change of necessity.
The preparation of assembly
Assembly of the present invention normally has the medical apparatus and instruments of porous coating (particularly hydrophilic coating) through being used for preparation, is used for the simple combination preparation of conventional method of packing device of liquid and the medical apparatus and instruments of goals of medicine.
Therefore; In said embodiment; Wherein, first chamber of said packing device is fit to hold said parts of vessels, and; Second chamber of wherein said packing device is fit to hold said expansion of liquids medium and said hydrogen peroxide source, and said assembly can prepare through the method that may further comprise the steps: through mixing the said expansion of liquids medium of relevant composition (referring to other parts of this paper) preparation; Use routine techniques to prepare said parts of vessels; Said parts of vessels is installed in first chamber (possibly comprise the said chamber wall of welding) of said packing device; The expansion of liquids device is installed in second chamber of said packing device (possibly comprise and being welded on the said chamber wall); And possibly carry out disinfection to said assembly, for example pass through radiosterilization.
When radiosterilization is wherein parts to be had when carrying out on the assembly of hydrophilic coating of at least a portion that comprises said expansion of liquids medium; Preferably through in said expansion of liquids medium, mixing the hydrophilic polymer of 0.3-10%; For example; Low-molecular-weight hydrophilic polymer (Mw1500-50,000) carries out modification to said expansion of liquids medium, as the applicant in (also can referring to of the present invention routine 1) disclosed in the EP 0,935 478.The example of useful hydrophilic polymer has PVP C-15 (ISP) and PVP K-12 (BASF).
The preparation of said packing device and the actual selection of material are conventionally known to one of skill in the art.
The purposes of said assembly and medical apparatus and instruments
Said modules is fit to the ready-made medical apparatus and instruments of preparation, like conduit.With the first, the second and possibly other the contents of chamber put together, so that make said liquid and/or hydrogen peroxide get into the hole of said polymer composition.In one embodiment, let the coating of aqueous hydrogen peroxide solution (inflating medium that for example, contains hydrogen peroxide) expansion hydrophilic polymer.
For illustrative packing device illustrated in fig. 1 and 2, this purpose can be carried out to the detailed description of said accompanying drawing according to the method described above.
After the said ready-made medical apparatus and instruments of preparation; Can use said medical apparatus and instruments in a usual manner; That is, should not take any special measure or use the conventional method of said medical apparatus and instruments to have no the part of running counter to relatively under user or the practitioner's normal condition.
For catheter, said conduit (or parts of vessels) is inserted urethra, or the artificial urethra opening; So that hydrogen peroxide is imported the urethra opening, that is, the concentration of hydrogen peroxide can provide certain micro-organisms at least; Like virus, antibacterial, the inhibitory action of fungus or mycete.The part of said anti-microbial effect can contact acquisition with the direct of urethra through medical apparatus and instruments, and after taking out said apparatus, because possibly there are certain function in a part of coating and/or liquid deposition in urethra.During inserting conduit and partial action afterwards can also produce owing to effusive said hydrogen peroxide from said coating.
Therefore through said hydrogen peroxide is mixed in the whole coating, can both guarantee under each occasion to comprise that the antibacterial that is positioned at the urethra all sites can both touch the said hydrogen peroxide of effective dose/concentration, and be killed or suppress.Because whole parts of vessels surface has antimicrobial acivity, can also be before using conduit or during weaken through before inserting, operating the danger of the relevant infection that said conduit causes with polluting (from finger, environment).
New type medical equipment
Can find out through above explanation, the invention provides the assembly of the medical apparatus and instruments that can be used for providing ready-made.It is believed that some medical apparatus and instruments from assembly of the present invention is novel equally.
Therefore, the present invention also provides medical apparatus and instruments, on its a part of surface, has the coating of porous polymeric compositions at least, and wherein, said coating comprises the liquid that contains hydrogen peroxide and preparation that can stable peroxide hydrogen.
Modal is that the concentration of hydrogen peroxide described in the liquid in said coating is in 0.01-5.0% (w/w) scope, like 0.1-3.0% (w/w), like 0.2-2.0% (w/w).
The example of preparation that can stable peroxide hydrogen is that preceding text are defined as the preparation of " stabilizing agent ".Said liquid can also comprise buffer agent, and Morie osmolarity improves preparation, and has adjusted pH, pH particularly as indicated above.
In a kind of preferred embodiment, the coating of said porous polymeric compositions is the hydrophilic coating of at least a hydrophilic polymer, and said liquid is the expansion of liquids medium of said hydrophilic polymer.Said hydrophilic coating/polymer is preferably selected as stated above.Preferably, at least a hydrophilic polymer is a polyvinylpyrrolidone.More preferably, said at least a hydrophilic polymer is crosslinked.
Be suitable for hydrophilic coating; The example of the expansion of liquids medium of particularly crosslinked polyvinylpyrrolidone coating is the medium of mentioning as the embodiment of top " aqueous hydrogen peroxide solution "; For example, said expansion of liquids medium is a kind of like this medium, comprising:
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.
In some interested especially embodiment, said medical apparatus and instruments is a conduit, like catheter.
Other aspects
The present invention also provides treatment; The method that alleviation or prophylaxis of microbial infect wherein, prepares a kind of medical apparatus and instruments with the assembly that this paper limited in first step; And in second step, let it contact with the body part of the mammal (like the people) that needs said medical apparatus and instruments.
In addition, the invention provides treatment, alleviate or method that prophylaxis of microbial infects, wherein, let the medical apparatus and instruments that this paper limited contact with the body part of the mammal (like the people) of the said medical apparatus and instruments of needs.
Relevant especially infected by microbes is the infected by microbes that causes urinary tract infection (UTI).Therefore, the relevant especially medical apparatus and instruments that is used for above-mentioned aspect is a conduit, and particularly catheter wherein, has reduced the morbidity number of times of urinary tract infection.It is believed that obtaining this result is because when replacing conventional catheter with assembly of the present invention and catheter, reduced urine, the number of bacteria in urethra and/or the urethral orifice.
Other aspects
Medical apparatus and instruments with the coating that comprises the liquid that contains hydrogen peroxide
Although the such embodiment of the preferred at present selection of the inventor, wherein, said medical apparatus and instruments parts (for example; Said parts of vessels), said inflating medium and said hydrogen peroxide source are contained in two independent cavity at least, can also the advantageous feature of hydrogen peroxide be used for a kind of assembly; Comprise that (i) has the medical apparatus and instruments (for example, conduit) of the coating (for example, hydrophilic coating) that wherein has liquid; And wherein, said liquid comprises hydrogen peroxide; (ii) packing device, it is fit to said medical apparatus and instruments is contained in its chamber.Can use said medical apparatus and instruments, because in fact it is ready-made, although said assembly possibly only have medium shelf life,, for some purposes, remain gratifying.
Therefore; The inventor also provides assembly; At least one has the medical apparatus and instruments parts of the coating of porous polymeric compositions to comprise (i); Said coating covers at least a portion of said parts, and has the packing device that contains the liquid of hydrogen peroxide and (ii) be fit to hold said medical apparatus and instruments parts in the said coating.Preferably, said medical apparatus and instruments parts are contained in the chamber of said packing device.
Modal is that the concentration of the said hydrogen peroxide in the said liquid in said coating is in 0.01-5.0% (w/w) scope, like 0.1-3.0% (w/w), like 0.2-2.0% (w/w).
Concerning some purposes, wherein need long shelf life, preferably also comprise the preparation that can stablize the hydrogen peroxide in the said liquid.The useful example of preparation that can stable peroxide hydrogen is preceding text defined " stabilizing agents ".Said liquid can also comprise buffer agent, and Morie osmolarity improves preparation, and has the pH of adjusting, the probability and the scope that particularly have preceding text and disclosed.
Said polymer composition preferably includes at least a hydrophilic polymer.For example, can hydrophilic polymer be used for hydrophilic coating, so that medical apparatus and instruments is provided, like the low-friction surface of catheter.
When needs carry out disinfection to said assembly through radiation; Preferably through adding the hydrophilic polymer of 0.3-10%; For example; Low-molecular-weight hydrophilic polymer (Mw 1500-50,000) carries out modification to said expansion of liquids medium, as the applicant in (also can referring to of the present invention routine 1) disclosed in the EP 0 935 478.The example of useful hydrophilic polymer is PVP C-15 (ISP) and PVP K-12 (BASF).
In a kind of preferred embodiment, the coating of said porous polymeric compositions is the hydrophilic coating of at least a hydrophilic polymer, and said liquid is the expansion of liquids medium that is used for said hydrophilic polymer.Said hydrophilic coating/polymer is preferably selected according to the method described above.Preferably, at least a hydrophilic polymer is a polyvinylpyrrolidone.More preferably, at least a of said hydrophilic polymer is crosslinked.
More particularly; The present invention relates to catheter, the hydrophilic coating of possess hydrophilic property polymer (particularly crosslinked polyvinylpyrrolidone) on its a part of surface at least, wherein; Said coating comprises the expansion of liquids medium; This medium comprises hydrogen peroxide, and optionally comprises the preparation of ability stable peroxide hydrogen, and said conduit is accommodated in the chamber of packing device.
In this embodiment, said aqueous hydrogen peroxide solution normally imports said polymer composition after said hydrophilic polymer is carried out chemical crosslinking at once.More commonly, the said medical apparatus and instruments that carries the coating of said polymer composition may be dipped in the aqueous hydrogen peroxide solution.Said hydrogenperoxide steam generator can be diffused into through passive method in the said polymer composition then, perhaps can force to get into said coating through exerting pressure.
Be suitable for hydrophilic coating; The example of the expansion of liquids medium of particularly crosslinked polyvinylpyrrolidone coating is the medium of the embodiment of above-mentioned conduct " aqueous hydrogen peroxide solution "; But, preferably modify (in the time of particularly need carrying out disinfection) through radiation through the hydrophilic polymer that adds 0.3-10% as stated above.For example, said expansion of liquids medium is such medium, comprising:
The hydrogen peroxide of 0.01-5.0% (w/w),
Optionally, but the hydrophilic polymer of preferred 0.3-10%,
One or more stabilizing agents of 0-2000mg/L,
One or more buffer agents of 0-200mM,
The 0-1000mM Morie osmolarity improves preparation,
And the scope of pH is 2.0-8.5.
Or such medium, comprising:
The hydrogen peroxide of 0.01-5.0% (w/w),
Optionally, but the low-molecular-weight hydrophilic polymer of preferred 0.3-10%,
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.
Said medical apparatus and instruments can be according to above-mentioned explanation, and in conjunction with said medical apparatus and instruments, said porous polymeric compositions prepares with the liquid/liquid inflating medium that comprises hydrogen peroxide, and is packaged into then in the suitable packing device.
In some interested especially embodiment, said medical apparatus and instruments is a conduit, like catheter.The example of the catheter that scribbles hydrophilic polymer that can obtain through the commercial channel provides
wherein by Coloplast A/S, and the conduit of said coating contacts with said inflating medium.
Above-mentioned is treatment on the other hand, the method that alleviation or prophylaxis of microbial infect, and wherein, the medical apparatus and instruments of said modules contacts with the body part of the mammal (like the people) that needs said medical apparatus and instruments.
Embodiment
Embodiment 1-preparation is with the conduit of polyvinylpyrrolidone coating
The catheter that can prepare hydrophilic coating according to the following steps with polyvinylpyrrolidone:
A) first and second kinds of solution of preparation ultra high molecular weight polyethylene ketopyrrolidine (PVP) (for example, Plasdone K-90), it is dissolved in N-Methyl pyrrolidone (NMP), in solvent/plasticiser mixture of ethanol and the Citrofol Al that comprises light trigger.The content of the PVP of said solution is in 1-8% (w/w) scope.Said first and second kinds of solution possibly be identical.
B) the original conduit of polyurethane is immersed in first kind of solution, and lets its at room temperature dry 10-120 second.
C) resulting conduit is immersed in second kind of solution of PVP.
D) at the further dry said conduit of higher temperature (for example, under 70-80 ℃).
E) through letting the conduit of said coating contact the ultraviolet 1/2-15 in the 200nm-300nm scope minute crosslinked said PVP of wave-length coverage.
F) conduit with crosslinked coating is placed in the packing device, and fills said the packing with inflating medium, and wherein, said inflating medium is the aqueous solution that low-molecular-weight PVP (Plasdone C15) and Morie osmolarity improve preparation (NaCl).
G) through ionizing radiation (β-or γ-radiation) packing device that comprises moistening conduit is carried out disinfection.
Embodiment 2-preparation comprises the conduit of hydrogen peroxide
The preparation of the disinfectant conduit of possess hydrophilic property coating may further comprise the steps:
A) first and second kinds of solution of preparation ultra high molecular weight polyethylene ketopyrrolidine (PVP) (for example, Plasdone K-90), it is dissolved in N-Methyl pyrrolidone (NMP), in solvent/plasticiser mixture of ethanol and the Citrofol A1 that comprises light trigger.The content of the PVP of said solution is in 1-8% (w/w) scope.Said first and second kinds of solution possibly be identical.
B) the original conduit of polyurethane is immersed in first kind of solution, and lets its at room temperature dry 10-120 second.
C) resulting conduit is immersed in second kind of solution of PVP.
D) at the further dry said conduit of higher temperature (for example, under 70-80 ℃).
E) through letting the conduit of said coating contact the ultraviolet 1/2-15 in the 200nm-300nm scope minute crosslinked said PVP of wave-length coverage.
F1) conduit with crosslinked coating is placed in the packing device, and fills said the packing with inflating medium, and wherein, said inflating medium is a hydrogen peroxide, and low-molecular-weight PVP (PlasdoneC15) and Morie osmolarity improve preparation (Na
2SO
4Or NaNO
3) and the aqueous solution of stabilizing agent (DETAPMP); With
G1) carry out disinfection through the said packing device of ionizing radiation (β-or γ-radiation) to moistening conduit;
Or
F2) conduit of crosslinked coating is put into a chamber of packing device, and said inflating medium is put into second chamber, wherein, said inflating medium is a hydrogen peroxide, and Morie osmolarity improves preparation (for example, Na
2SO
4Or NaNO
3) and the aqueous solution of stabilizing agent (DETAPMP); With
G2) carry out disinfection through the said packing device (chamber 1) and the said hydrogenperoxide steam generator (chamber 2) of ionizing radiation (β-or γ-radiation) to the conduit of the coating that comprises drying regime.
The preparation of embodiment 3-conduit tube component
Conduit tube component shown in Figure 2 can prepare by following method:
Dry catheter (1) with polyvinylpyrrolidone (PVP) coating prepares by embodiment 1 said method.Said conduit is put into first chamber (4) of said packing device (3), and this chamber is through welded seal.Preparation contains aqueous hydrogen peroxide solution, and DETAPMP and Morie osmolarity improve preparation (for example, Na
2SO
4Or NaNO
3) expansion of liquids medium (for example, shown in embodiment 2) and be loaded in second chamber that forms by external rigidity container (5), this container is to install as the integral part of said packing device (3).Shown in Fig. 2 (b); Container (5) is mounted to and can opposite end walls (8) rotation about 90 spends; So that make on the end wall (8) of container (5), provide towards the liquid outlet of the rigidity end wall (9) of chamber (4) with go into the alignment of interruption-forming liquid communication; Wherein, the inclusions of the said expansion of liquids medium in the container (5) can be transferred in first chamber of the conduit that holds said coating.
In a kind of version, the catheter of said coating is that a part of expansion of liquids medium (preferred low-molecular-weight PVP and Na were provided in first chamber (4) before the said chamber through welded seal
2SO
4Aqueous solution) carry out expansible in advance.In use, through letting contents in the container (5) flow into first chamber two kinds of inflating mediums are mixed.Therefore, these two kinds of inflating mediums are that blended at once (for example, putting upside down this packing 2-10 time through what before using, pass through) so that said coating can absorb the said inflating medium that comprises hydrogen peroxide, preferably absorbed in 20 seconds.Said conduit can directly use subsequently.
Embodiment 4-is with the hydrogen peroxide conduit that is present in the chamber of PEG 2000 preservations in the inflating medium
Experimentize, so that confirm storage temperature, 2000 couples of pH of initial concentration of hydrogen peroxide and PEG, the influence of the frictional force of the conduit of the degraded of hydrogen peroxide and possess hydrophilic property coating.Said conduit prepares according to embodiment 2 said methods, and uses pure water, hydrogen peroxide (referring to table 1.1), and PEG 2000 (of table 1.1) prepares said expansion of liquids medium, and comprises the 50mM citrate buffer of pH 5.5.Of embodiment 2, said conduit and inflating medium are packaged together in the chamber, and keep 1 time-of-week down at 60 or 80 ℃.The individual not disinfectant sample of 1-3 is used for measuring each time.The result is shown in table 1.1.
Table 1.1
| An initial %-H 2O 2 | Storage temperature | Whether add 6%PEG 2000 | Frictional force (N) | PH after preserving | Conduit outward appearance (0-5; 0=is intact, and 5=is unacceptable) | Inflating medium outward appearance (0-5) | After the preservation-H 2O 2 | H 2O 2Reduce (%/sky) |
| 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 | Be | 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 | Be | 1.68 | 3.46 | 3 | 0 | 0.02 | 14.1 |
Under 60 ℃, under the condition of not adding PEG 2000, the relative decomposition of the frictional force of said conduit and hydrogen peroxide improves along with the increase of initial concentration of hydrogen peroxide.PH is relative, and initial value 5.5 has only faint raising, possibly be because following generation HO
-Fenton reaction:
Fe
2++H
2O
2→Fe
3++HO
-+HO
-
Above result shows that hydrogen peroxide during preservation can corrode conduit, and but, the outer end of conduit and inflating medium is intact (on the outward appearance score must be divided into 0).
When adding PEG 2000; The frictional force (0.12N) of said conduit is well below the frictional force of not using PEG 2000 (0.53N) after preserving, but, and meanwhile; PH is reduced to 5.13; Said conduit becomes milky and opaque (score 1), and hydrogen peroxide be reduced to 3.2%/day, or be almost identical hydrogen peroxide initial concentration (1.6%-point) but do not have 2 times of PEG 2000 (reduce 1.7%/day).As if PEG 2000 becomes carboxylic acid by hydrogen peroxide oxidation, and it can reduce pH, and cooperates with PVP, so that produce opaque coating.
Under 80 ℃, the frictional force of all conduits all is higher than 1N, and therefore, said coating has received heavy damage.With after 60 ℃ are preserved down, compare, do not have the sample of PEC2000 to have slightly higher pH after the preservation down at 80 ℃.Do not contain 80 ℃ of following preservations during 1 week of sample of PEG 2000, the hydrogen peroxide of 25-30% has disappeared, and no matter how many initial concentration of hydrogen peroxide is.
When adding 6%PEG 2000, nearly all hydrogen peroxide has all disappeared after preserving for 1 week, although and have the 50mM citrate buffer, pH is reduced to 3.46 suddenly.Frictional force is the same with the sample that does not have PEG 2000 high, and conduit become very fuzzy (score 3).
Above result has confirmed that hydrogen peroxide can corrode conduit under the condition of PEG 2000 having and do not have.Therefore, possibly destroy the long-time stability that the hydrophilic catheters and the packing of the inflating medium that contains hydrogen peroxide are housed in identical chamber.
Embodiment 5-is with the hydrogen peroxide conduit that is present in the chamber of PVP C-15 preservation in the inflating medium
Carried out the factorial experiment of simplifying,, do not had the buffer agent of pH 7 in this medium, be with or without the PVP C-15 that replaces PEG2000 so that find the storage stability of 1%-point hydrogen peroxide in the expansion of liquids medium.Dosage with 50kGy carries out β-sterilization to sample, and preserves 8 months down at 23 ℃.
The concentration of the 0th day afterwards hydrogen peroxide of sterilization is regarded as 100%, and calculates degradation speed (%/sky), demonstrate linear degradation curve.For example, if (about 250 days) concentration of hydrogen peroxide is reduced to 75% after 8 months, degradation speed is exactly 25/250%/sky=0.1%/sky.
The result is according to 86 independently sample calculating (standard error of meansigma methods ± meansigma methods) (table 5.1).
Table 5.1
| Initial %H 2O 2 | ％PVP C-15 | β-sterilization dose (kGy) | Storage temperature | The H that reduce every day 2O 2(％) |
| 1 | 0 | 50 | 23 | 0.088±0.029 |
| 1 | 6 | 50 | 23 | 0.167±0.048 |
Compare with not adding PVP C-15, the degradation speed when in said inflating medium, adding PVP C-15 is higher.Under other storage temperatures (5 ℃, 40 ℃, 60 ℃), observed similar trend.
Embodiment 6-chelating agen is to the influence of hydrogen peroxide stability
Add chelating agen and/or metal ion to aqueous hydrogen peroxide solution, preserve then.Below table 6.1 be illustrated in 40 ℃ and preserve down remaining %-point hydrogen peroxide after β-disinfectant (50kGy) polyurethane catheters 24 days; Said conduit has the hydrophilic coating that is present in the inflating medium, and inflating medium comprises 1%-point hydrogen peroxide, 1g/L chelating agen (EDTA at first; DETAPAC; Deferoxamine, gelatin) or do not have chelating agen, 10mg/L metal ion (Fe
2+, Cu
2+) or non-metallic ion, 6%PVP K-12 and 10mM citrate (pH 7).
Table 6.1 is the remaining hydrogen peroxide of %-point after 40 ℃ are preserved 24 days down.
At 10mg/L Cu
2+When not adding chelating agen, the concentration of said hydrogen peroxide is preserved the back and is reduced to 0.15% point from the 1%-point under the concentration.In four kinds of chelating agen each has all significantly improved stability of peroxide, therefore after preserving, has kept 0.30-0.44%-point hydrogen peroxide.
Through adding 10mg/L Fe
2+, DETAPAC and deferoxamine have improved stability of peroxide.Specifically, the effect of deferoxamine is so big, to such an extent as to add Fe
2+Stability of peroxide (after preserving, kept 0.66%-point H
2O
2) and do not add Fe
2+Stability (kept 0.68%-point H equally well
2O
2).In other words, deferoxamine makes Fe
2+Ineffective fully.In addition, deferoxamine is unique chelating agen that when not adding metal ion, can improve the basicly stable property of hydrogen peroxide: after preserving with deferoxamine, keep 0.68%-point H
2O
2, and when adding other chelating agen of three kinds or not adding chelating agen, kept 0.59-0.61%-point H
2O
2
Therefore, deferoxamine and other chelating agen have advantageous effect to the storage stability of hydrogen peroxide.
Embodiment 7-β-sterilization is to the influence of hydrogen peroxide degradation
The purpose of this serial experiment is that research increases the influence of β-radiation dose to hydrogen peroxide degradation.In addition, its purpose is that research said conduit and PVP are to the stable effect of hydrogen peroxide.
Hydrogen peroxide 33%Panreac Ph.Eur, BP, REF. (14.1077.14.10)
The citric acid monohydrate compound, Riedel-de Ha ê n
Plasdone C-15，ISP
0.02 M KMnO
4，Riedel de Haên
Brown 50mL PE-container
Use KMnO
4H is measured in electrometric titration
2O
2-concentration.
Titrino 702 titrators (Metrohm).
Two kinds of 1.0L inflating mediums have been produced; A kind of solution contains distilled water and 1% hydrogen peroxide, and another kind of solution contains 6%PVP, 10mM citric acid and 1% hydrogen peroxide.With 1MNaOH the pH-value of a kind of solution in back is adjusted to 5.5.Take out the equal portions sample of 10.0mL in from these two kinds of solution each, and put into the brown PE-container of 50mL.
At Ris φ National Laboratory sample is carried out β-radiation.Before radiation, after radiation and then and at 60 ℃, keep after 2 weeks and 4 weeks said sample being measured (carrying out mensuration 3 times).The result is shown in table 7.1-7.3.
Table 7.1. expansible conduit (serial I) in PVP solution.H
2O
2Concentration (%-point).Meansigma methods (n=3).
Table 7.2. expansible conduit (serial II) in distilled water.H
2O
2Concentration (%-point).Meansigma methods (n=3).
Table 7.3. is present in the H in the distilled water
2O
2-solution (serial III).The concentration of H2O2 (%-point).Meansigma methods (n=3).
Improve radiation dose, caused the increase of serial I degraded.Dependency between raising radiation dose and hydrogen peroxide degradation increase is not as obvious in serial II and III, and but, have such tendency: higher radiation dose can cause degradation speed faster.
In addition, can find out that serial I has higher degradation speed than serial II and III, this means that the PVP that is dissolved in the distilled water has accelerated the degraded of hydrogen peroxide.Can not draw the conclusion that conduit itself can influence hydrogen peroxide stability according to this research.
The degraded and the stabilizer concentration of embodiment 8-hydrogen peroxide
The purpose of this research is to have confirmed to cause the most stable H
2O
2The concentration of the stabilizing agent DETAPMP of solution.Another purpose is to confirm that degraded contains the stabilizing agent DETAPMP of pH 4 and the H of 10mM citrate
2O
2Activation energy.
Material
The citric acid monohydrate compound.Reag.ACS，Reag.ISO
NaOH 4M，Merck
HCl 1M, BHD AnaIR volumetric solution
NaCl(Extra pure，Ph.Eur，BP，USP)
0.02 M KMnO
4，Riedel de Haên
Constant-current titration Titrino 702, Metrohm
Method
H
2O
2In containing the solution of DETAPMP at 40 ℃, the degradation speed under 50 ℃ and 60 ℃.
Produce the 1L inflating medium, it contains the 10mM citrate, 500g/mL stabilizing agent DETAPMP and 0.7%NaCl.With 4M NaOH and 1 M HCl the pH-value of this solution is adjusted to pH 4.
The dose response curve of stabilizing agent DETAPMP
Produced seven kinds of inflating mediums, each inflating medium contains the 10mM citrate, and 0.7%NaCl and stabilizing agent DETAPMP (50,100,150,200,250,350,500mg/L).
From said each inflating medium, get the equal portions sample of 20mL, and add in each bar-shaped packing.Said bar-shaped packing be after filling through welded seal and deliver to Ris φ National Laboratory and carry out radiation.Radiation dose is 2*26kGy.
Said bar-shaped packing with " crust " is a laminated material, and it comprises PETP (12 μ m), aluminum (9 μ m) and polyethylene sheath (polyethylene+10% polybutene) (70 μ m).Said bar-shaped packing is processed by the punching press area of 13 * 35mm, and this area welds through 1 * 3 unit on welder along the longitudinal direction.It is to weld 2 * 2.2 units through said bar-shaped packing one end, and passes through 4.0bar at the other end, 130 ℃ and welding (destructible sealing) in 3.5 seconds.
Result and discussion
The result of this research has been shown in table 8.1 and 8.2
Table 8.1. contains the 1%H of DETAPMP under different temperatures
2O
2Degradation speed
Stabilizing agent DETAPMP is at 40 ℃, and the A Heniusi curve (DETAPMP of pH 4 and 10mM citrate) under 50 ℃ and 60 ℃ shows between 1/T and log k and is actually linear relationship, and finds degraded H
2O
2Activation energy be 59.6kJ/mol.59.6kJ/mol activation energy caused Q
10≈ 2, this means that per 10 ℃ can increase by 2 with degradation speed.
The H of the DETAPMP (mg/L) of table 8.2.7 kind variable concentrations after 40 ℃ are preserved down
2O
2Concentration (%).
Table 8.2 expression stabilizer concentration and H
2O
2Degradation speed between dependency, can infer, for the DETAPMP concentration up to 150-200mg/L, H
2O
2Degradation reaction speed reduced.After this, the said curve level that becomes.But, H
2O
2Minimum degraded appear under the 250mg/L DETAPMP concentration.
The various stabilizing agents of embodiment 9-
The purpose of this research is to identify the stabilizing agent that the maximum stable hydrogenperoxide steam generator can be provided.Scrutable according to document is that the pH-value influences stability of peroxide.Therefore, in this research, in our system, comprised of the research of pH-value to the influence of stability.Packaging material have also been studied, so that understand the degraded whether two kinds of dissimilar materials influence hydrogen peroxide in a different manner.
The citric acid monohydrate compound.Reag.ACS，Reag.ISO
4 M NaOH，Merck
1 M HCl, BHD AnalR volumetric soiutions
NaCl(Extra pure，Ph.Eur，BP，USP)
0.02 M KMnO
4，Riedel de Haên
The pH-meter, Jenway 4330 Conductivity and pH-meter
Constant-current titration Titrino 702, Metrohm
The chemical name of stabilizing agent and CAS No.:
DETAPMP-sodium salt (the sodium salt of diethylenetriamines five (methylene phosphine) acid; 22042-96-2),
EDATMP (ethylenediamine tetraacetic (methylene phosphine) acid; 1429-50-1),
HEDP (1-hydroxyl ethane-1,1 di 2 ethylhexyl phosphonic acid; 2809-21-4),
EDATMP-sodium salt (the sodium salt of ethylenediamine tetraacetic (methylene phosphine) acid; 15142-96-8),
DETAPMP (diethylenetriamines five (methylene phosphine) acid; 15827-60-8),
Acetanilide (103-84-4).
Prepared 24 kinds of dissimilar inflating mediums, they contain different stabilizing agent (a kind of stabilizing agent that do not contain) the pH-value (pH 4,5.5 and 7) different with 3 kinds.The volume of said each inflating medium is 1L, and the initial concentration of hydrogen peroxide is about 1% (w/w).In addition, produced the inflating medium that contains stabilizing agent DETAPMP and sodium chloride of three kinds of different pH-values, so that understand the effect of adding sodium chloride.The concentration of sodium chloride is 0.7% (w/w) in these three kinds of inflating mediums each.Measuring sodium chloride is because can it be improved preparation as Morie osmolarity.Citric acid is added in said each inflating medium, so that reach the concentration of 25mM, so that keep initial pH-value at whole test period.Through in final solution, adding 4 M NaOH and 1 M HCl the final pH-value of this solution is adjusted to 4.0,5.5 and 7.0.
Take out the equal portions sample of 20mL from said each inflating medium, and add in each bar-shaped packing.Two kinds of dissimilar materials are used for bar-shaped packing, and a kind of have " crust " and a kind ofly do not have " crust ".After filling, seal said bar-shaped packing and deliver to Ris φ National Laboratory and carry out radiation.Radiation dose is 2*26kGy.
Bar-shaped packing with " crust " has laminated material, comprises PETP (12 μ m), aluminum (9 μ m) and polyethylene sheath (polyethylene+10% polybutene) (70 μ m).Not having the bar-shaped packing of " crust " is laminated material, comprises PETP (12 μ m), aluminum (9 μ m) and polyethylene (PE) (50 μ m).Said bar-shaped packing is processed from the punching press area of 13 * 35mm, on welder, welds 1 * 3 unit along the longitudinal direction.In 2 * 2.2 units of end welding, and pass through 4.0 at the other end and cling to, 130 ℃ and welding (destructible sealing) in 3.5 seconds through said bar-shaped packing.
Preserve said bar-shaped being packaged in and carry out said test under 23 ℃ and 40 ℃.Collected specimens after radiation and after 40 ℃ are preserved 2 weeks and 4 weeks down and after preserving 8 weeks and 16 weeks under 23 ℃.Measure the concentration (replication) of pH-value and said hydrogen peroxide, referring to table 9.1.
The H of table 9.1. degraded after 23 ℃ are preserved 2 years down
2O
2Amount of calculation.Calculating is to carry out according to the Study on degradation that under 23 ℃, reached for 18 weeks.
Can find out the most stable H through above result
2O
2Solution is in the solution of the stabilizing agent DETAPMP that contains pH 4, to obtain.Generally, compare, have higher propensity for degradation 7 times at pH with pH 4.It can also be seen that, with the H that does not have stabilizing agent
2O
2Solution is compared, and in fact stabilizing agent EDTMP and HEDP have strengthened H
2O
2Degraded, particularly under the condition of pH 7.
Other experiments (data not shown goes out) have confirmed two kinds of dissimilar packings, promptly " crust is arranged " with " nothing-crust " to H
2O
2The aspect that influences of degraded does not have difference.
At last, compare separately with DETAPMP, the degraded for DETAPMP+NaCl under pH 4 conditions is faster.This can show that NaCl has accelerated the degraded of hydrogen peroxide.
The effect of embodiment 10-buffer agent in inflating medium
The purpose of this research is the influence of the buffer agent (citrate) of the different pH-values of clarification to the degradation speed of hydrogen peroxide, and confirms that the use of stabilizing agent DETAPMP has caused the most stable hydrogenperoxide steam generator.
The citric acid monohydrate compound.Reag.ACS，Reag.ISO
NaOH 4M，Merck
HCl 1M, BHD AnalR volumetric soiutions
NaCl(Extra pure，Ph.Eur，BP，USP)
0.02 M KMnO
4，Riedel de Haên
Constant-current titration Titrino 702, Metrohm
Said inflating medium contains about 1% (w/w) hydrogen peroxide; 0,10 with 25mM citrate and 0.7% (w/w) NaCl and stabilizing agent.PH-value with 4M NaOH and this solution of 1M HCl adjusting.The concentration of said stabilizing agent is DETAPMP (500mg/L), and (500mg/L is 1000mg/L) with the sodium salt (1000mg/L) of DETAPMP for the sodium salt of EDATMP.
Take out the equal portions sample of the 10mL of each inflating medium, and add each bar-shaped packing to and (" crust " arranged; Referring to embodiment 7).After filling through the said bar-shaped packing of welded seal and deliver to Ris φ National Laboratory and carry out radiation.Radiation dose is 2*26kGy.The result is shown in table 10.1-10.6.
Table 10.1.0mM citrate.At 23 ℃ of H that calculate after preserving 2 years down
2O
2Degradation amount (%).
Table 10.2.10mM citrate. at 23 ℃ of H that calculate after preserving 2 years down
2O
2(%) degradation amount
Table 10.3.25mM citrate. after 23 ℃ are preserved 2 years down, the H of calculating
2O
2(%) degradation amount.
Table 10.4.pH 4.After 23 ℃ are preserved 2 years down, the H of calculating
2O
2(%) degradation amount.
Table 10.5.pH 5.5.After 23 ℃ are preserved 2 years down, the H of calculating
2O
2(%) degradation amount.
Table 10.6.pH 7.After 23 ℃ are preserved 2 years down, the H of calculating
2O
2(%) degradation amount.
Can find out, the pH-value is brought up to 5.5 and 7 from 4, improve the degradation speed of nearly all solution.Citrate of in said solution, accelerating and H
2O
2The degradation speed of quickening between have dependency.H
2O
2The most stable solution contain stabilizing agent DETAPMP, do not add citrate, and the initial pH-value of this solution is 4.The consumption that increases stabilizing agent EDATMP sodium salt can not obtain more stable solution.Obviously, at H
2O
2The concentration raising aspect of the raising of stability and the sodium salt of EDATMP does not have dependency.
The antimicrobial efficacy of embodiment 11-hydrogen peroxide
The hydrogen peroxide of variable concentrations is to the bacterial growth velocity effect
The clear 7 kinds of different bacterial isolateses of tables of data are being with or without hydrogen peroxide (0-1%).Condition under fertility.Say that simply in the growth medium that is with or without hydrogen peroxide, and the absorption value through under the 600nm wavelength is measured the growth of centre logarithmic (log) phase with said microbionation.The data that obtain from each specific bacteria bacterial strain have been collected.These data are meansigma methodss of three independent experiments, measure twice of repetition each time; Referring to table 11.1.
Table 11.1.
| The % hydrogen peroxide | On average (% of contrast) | SD |
| 0 (contrast) | 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 hydrogen peroxide of variable concentrations is to the influence of antibacterial bacteria live rate
The clear 7 kinds of different bacterial isolateses of tables of data are being with or without hydrogen peroxide (0-1%).Condition under survival ability.Let the contacted hydrogen oxide of said antibacterial 60 minutes, referring to table 11.2.
Table 11.2.
| The % hydrogen peroxide | On average | SD |
| 0 (contrast) | 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 |
1% hydrogen peroxide is to the time course of bacteria live rate influence
The survival ability of the clear 7 kinds of different bacterial isolateses of above tables of data under the 1% hydrogen peroxide condition of existence.0,5, measured survival number of bacteria (accounting for the percentage ratio of contrast) afterwards in 10 and 15 minutes, referring to table 11.3.
Table 11.3.
| Time of contact (min) | On average (% of contrast) | SD |
| 0 (contrast) | 100 | - |
| 5 | 37 | 31 |
| 10 | 17 | 18 |
| 15 | 6 | 7 |
Embodiment 12-substitutes anti-microbial agents
A series of anti-microbial agents (referring to 12.1) are expand in the hydrophilic coating on the catheter.Said conduit was preserved for about 0,3,6 and 12 weeks down for 40 ℃ and 60 ℃ at 25 ℃.Use clinical bacterial isolated inoculation agar plate from infected human urine, and the conduit of coating is placed on the top of agar surface.Cultivated said agar plate 18 hours down at 37 ℃, and the existence of macroscopy inhibition zone or shortage.
Duct portion with the solution expansion possess hydrophilic property coating of anti-microbial agents; And be placed on the agar plate of having inoculated antibacterial (clinical isolates ,-with+represent Gram-positive and Gram-negative respectively): proteus mirabilis (-), green dense pseudomonas (-); Escherichia coli (-); Providencia stuartii (-), staphylococcus aureus (+), enterococcus faecalis (+) and Klebsiella (-).
Made up the factorial design (2 of stepped height through design specialist's software (version 6.0.6)
15-10IV
-design), and be used to screen 32 kind 2
15=32768 kinds of possible combinations, wherein each chemical compound is with relevant concentration shortage or exists.Each mixture also contains the 50mM citrate buffer of pH5.5,160mM NaCl and 6%PEG 2000.All samples carries out β-sterilization with the dosage of 50kGy.The composition of said 32 kinds of solution and concentration are shown in table 12.1:
Table 12.1.
The flat horse chlorine of S six Di-azo-PVP washes and must kill Bro-Kathon bigcatkin willow and cross chlorine chlorine chlorine
Inferior lidi-peach urine amine-I2 is two algae no-pol acid benzene oxidationization too
The sour T glucose of first nylurea amido esterification zinc copper silver
Base hydrochlorate hydrogen
4 20%
Amine
t A B C D E F G H J K 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 0.6 0 0 0.65 1 1 0 0 1 0 1 20
2 0 1 1 0.6 0 0 0 0 1 0.094 0.02 1 0 0 0
3 0 1 0 0 1 10 0.65 0 1 0 0.02 1 0 0 20
4 0 1 1 0.6 1 0 0 0 1 0 0 0 1 1 20
5 1 1 1 0 0 10 0 0 0 0 0 1 0 1 20
6 0 0 0 0.6 1 0 0.65 1 1 0.094 0.02 0 1 0 0
7 0 0 1 0.6 0 10 0.65 0 0 0 0.02 1 1 1 0
8 1 1 0 0.6 1 0 0.65 0 0 0.094 0 1 0 1 0
9 1 1 1 0 1 10 0 0 0 0.094 0.02 0 1 0 0
10 0 1 0 0.6 1 10 0 1 0 0 0.02 0 0 1 0
11 1 1 0 0 0 0 0 1 1 0 0.02 1 1 1 0
12 0 0 0 0 1 0 0 0 0 0.094 0.02 1 1 1 20
13 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
15 0 1 1 0 0 0 0.65 1 0 0.094 0.02 0 0 1 20
16 1 1 1 0.6 0 10 0.65 1 1 0 0 0 0 0 0
17 1 0 1 0 1 0 0.65 0 1 0 0.02 0 0 1 0
18 0 1 0 0.6 0 10 0 1 0 0.094 0 1 1 0 20
19 1 1 0 0.6 0 0 0.65 0 0 0 0.02 0 1 0 20
20 0 1 0 0 0 10 0.65 0 1 0.094 0 0 1 1 0
21 1 1 0 0 1 0 0 1 1 0.094 0 0 0 0 20
22 1 0 1 0.6 0 0 0 1 0 0.094 0 0 1 1 0
23 1 0 0 0.6 0 10 0 0 1 0.094 0.02 0 0 1 20
24 0 0 1 0.6 1 10 0.65 0 0 0.094 0 0 0 0 20
25 1 0 1 0.6 1 0 0 1 0 0 0.02 1 0 0 20
26 0 1 1 0 1 0 0.65 1 0 0 0 1 1 0 0
27 1 0 1 0 0 0 0.65 0 1 0.094 0 1 1 0 20
28 1 0 0 0 0 10 0.65 1 0 0.094 0.02 1 0 0 0
29 0 0 1 0 0 10 0 1 1 0 0.02 0 1 0 20
30 0 0 1 0 1 10 0 1 1 0.094 0 1 0 1 0
31 1 0 0 0 1 10 0.65 1 0 0 0 0 1 1 20
32 1 0 0 0.6 1 10 0 0 1 0 0 1 1 0 0
A lot of in 32 kinds of mixture have effective function to some kinds in said 7 kinds of antibacterials, and (0=does not have effect; The effect that 3=is outstanding), referring to table 12.2 (through the anti-microbial effect classification that weakens gradually).
Table 12.2.
The golden yellow Portugal of general sieve of Std proteus mirabilis Pseudomonas aeruginosa escherichia coli Si Shi enterococcus faecalis Klebsiella
Wei Dengsi bacterium grape coccus
3 3 3 3 3 3 3 3
32 3 3 3 3 3 3 3
29 3 3 3 3 3 3 2
19 3 3 3 2 2 3 2
21 2 3 3 3 3 3 3
20 2 2 3 2 3 3 3
10 2 2 2 3 3 3 3
11 2 2 2 3 2 3 2
5 2 1 1 1 2 3 2
13 1 3 1 1 3 3 1
16 1 3 2 2 2 3 1
24 1 0 2 0 2 3 3
6 1 3 1 2 2 3 3
14 1 1 1 1 2 3 1
30 1 0 0 0 2 3 3
25 1 3 2 2 1 3 2
18 1 3 2 1 1 3 2
28 1 2 1 1 1 3 1
17 1 0 1 1 1 1 1
23 1 3 1 0 1 3 3
22 1 3 0 1 0 3 3
31 1 0 0 0 0 0 0
7 0 3 2 2 2 3 3
2 0 3 1 2 2 3 3
15 0 0 1 1 2 3 1
12 0 2 1 0 2 1 1
9 0 2 1 1 1 3 1
4 0 1 1 1 0 3 1
8 0 1 0 1 0 0 1
1 0 0 0 1 0 0 0
26 0 0 0 0 0 0 1
27 0 0 0 0 0 0 0
Add up to 35 58 44 44 51 77 59
Said result is being analyzed, and further testing, finding that said effect possibly be that the third level interacts or more senior so that confirm saidly as a result the time.In other words, said effect is from 3,5, and 7 mixture or any other odd number chemical compound obviously are not from main effect or two kinds of factor interactions still.Therefore, as if there is bigger potentiation between the chemical compound.Chlohexidine and silver chloride are dissolved in hardly and contain in the muriatic medium of 160mM; They can act in no muriatic medium preferably.
Other experiment confirms the effect of hydrogen peroxide (working separately) to compare with multiple other anti-microbial agents be fast.This characteristic is favourable in the purposes of inserting conduit such as intermittence, and it only needs cost time a few minutes.In other experiments, hydrogen peroxide shows from coating and flows out well, and therefore, treatment can expand in the distance tissue of said some distance of coating.Use another advantage of hydrogen peroxide to be, certain micro-organisms produces the probability of the resistance of hydrogen peroxide very little.
Embodiment 13-silver compound
At pH 5.5 (50mM citrate buffer); Under the condition of pH 7 (50mM phosphate buffer) and pH 8.5 (50mM TAPS buffer); 0.3g/L silver sulfadiazine, 0.25g/L hydantoin silver, 1.175g/L5; 5-dimethyl-hydantoin silver and 0.25g/L polymerization imidazoles silver have medium to good anti-microbial effect.Said solution also contains 160mM NaCl and 6%PEG 2000, and all solution are to use the β of 50kGy-or γ-radiosterilization.β-radiation can provide better anti-microbial effect usually, and with γ-radiation mutually specific energy to produce the product of littler degree painted, therefore, β-radiation is preferred sterilization method.Said silver compound only just can work when allowing in packing, to exist excessive undissolved salt, in other words, when their precipitate is poured out, does not have anti-microbial effect at them.In some experiment, add 0.01%H
2O
2So that stop silver ion to be reduced into elemental silver, because this process has caused the forfeiture of antimicrobial acivity and strong painted from collargol.
Use rating that each the anti-microbial effect in 7 kinds of antibacterials each chemical compound is marked from 0 (no effect) to 3 (good effects).The antimicrobial index be defined as 5/12 multiply by the score of each in said 7 kinds of antibacterials the square root sum.Therefore, the said antimicrobial index rational number that is 0-5.05.
The outward appearance index is to being packaged in the subjective acceptable weighted average of a conduit in single chamber after carrying out disinfection; (grade is unacceptable fully from 0 to 5:0=for the conduit of said chamber possess hydrophilic property conduit (weight 60%) and said inflating medium (weight 40%) and inflating medium; For example, by strong color or main deposition; 5=is perfect, and for example, non-coloring does not have deposition).Therefore, the outward appearance index is the numerical value between the 0-5.
Table 13.1 shows the antimicrobial exponential sum outward appearance index of silver compound.
In table, can see the antimicrobial exponential sum outward appearance index of silver compound, through antimicrobial index ordering (5,5-DMH=5,5-dimethyl hydantoin):
Table 13.1.
| Silver compound | pH | Whether add 0.01%H 2O 2 | The antimicrobial index | The outward appearance index |
| The imidazoles thing, pH 5.5 | 5.5 | Not | 0.8 | 3.4 |
| 5，5-DMH/pH 5.5/H 2O 2 | 5.5 | Be | 1.4 | 5 |
| 5，5-DMH，pH 8.5 | 8.5 | Not | 1.7 | 2.2 |
| 5，5-DMH，pH 5.5 | 5.5 | Not | 1.8 | 2.8 |
| Hydantoin/5.5/H 2O 2 | 5.5 | Be | 2.3 | 3.6 |
| Imidazoles thing/pH 5.5/H 2O 2 | 5.5 | Be | 2.7 | 3 |
| Hydantoin, pH 5.5 | 5.5 | Not | 2.7 | 4 |
| The imidazoles thing, pH 8.5 | 8.5 | Not | 2.8 | 3.2 |
| Sulfadiazine, pH 8.5 | 8.5 | Not | 2.9 | 2.8 |
| Sulfadiazine, pH 7.0 | 7 | Not | 3.1 | 2.8 |
| Sulfadiazine, pH 5.5 | 5.5 | Not | 3.1 | 3.6 |
| Hydantoin, pH 8.5 | 8.5 | Not | 3.2 | 2.8 |
| Sulfadiazine/pH 5.5/H 2O 2 | 5.5 | Be | 3.2 | 3 |
| The imidazoles thing, PH 7.0 | 7 | Not | 3.2 | 4.2 |
| Hydantoin, PH 7.0 | 7 | Not | 3.3 | 3.4 |
| 5，5-DMH，pH 7.0 | 7 | Not | 3.4 | 3.4 |
Therefore, even in the medium that contains 160mM NaCl, have sedimentary silver compound and also have good anti-microbial effect, it can significantly reduce the dissolubility of said chemical compound.In the medium of no hydrochlorate, should obtain even better result.
Embodiment 14-alkyldimethylbenzylammonium chloride
Be present in 50mM citrate (pH 5.5); 1-5g/L alkyldimethylbenzylammonium chloride among 160mM NaCl and the 6%PEG 2000 is to enterococcus faecalis, Klebsiella, staphylococcus aureus; Escherichia coli; Providencia stuartii and green dense pseudomonas have medium to the height anti-microbial effect, still, and to not effect of proteus mirabilis.Therefore, alkyldimethylbenzylammonium chloride also can be used for the antimicrobial conduit.
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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| PCT/DK2004/000129 WO2004075944A2 (en) | 2003-02-26 | 2004-02-26 | A medical device having a coating comprising hydrogen peroxide and package therefore |
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| DK177651B1 (en) * | 2012-10-26 | 2014-02-03 | Mbh Internat A S | Method of preparing a ready-to-use urinary catheter and a catheter assembly for use in said method |
| US9353269B2 (en) * | 2013-03-15 | 2016-05-31 | American Sterilizer Company | Reactive surface coating having chemical decontamination and biocidal properties |
| US11154688B2 (en) | 2016-04-12 | 2021-10-26 | Coloplast A/S | Catheter assembly with a protective sleeve inside of a package |
| WO2020100574A1 (en) * | 2018-11-12 | 2020-05-22 | デンカ株式会社 | Package for accommodating fluorescent substance, and container box |
| CN111731681B (en) * | 2020-07-23 | 2020-11-17 | 苏州微比特自动化有限公司 | Packaging bag (WU JI KE LI) |
| CN113288587B (en) * | 2021-07-28 | 2021-09-21 | 南通跃香拉链有限公司 | Outdoor first aid is with stanching bandage |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4515593A (en) * | 1981-12-31 | 1985-05-07 | C. R. Bard, Inc. | Medical tubing having exterior hydrophilic coating for microbiocide absorption therein and method for using same |
| CN1031650A (en) * | 1987-08-31 | 1989-03-15 | 伊莱利利公司 | Improved antimicrobial coated implants |
| CN1216435A (en) * | 1996-02-23 | 1999-05-12 | 普罗格特-甘布尔公司 | Disinfecting compositions and processes for disinfecting surfaces |
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- 2004-02-26 CN CN2004800053751A patent/CN1753702B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4515593A (en) * | 1981-12-31 | 1985-05-07 | C. R. Bard, Inc. | Medical tubing having exterior hydrophilic coating for microbiocide absorption therein and method for using same |
| CN1031650A (en) * | 1987-08-31 | 1989-03-15 | 伊莱利利公司 | Improved antimicrobial coated implants |
| CN1216435A (en) * | 1996-02-23 | 1999-05-12 | 普罗格特-甘布尔公司 | Disinfecting compositions and processes for disinfecting surfaces |
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| Title |
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| 胡长诚.国外过氧化氢稳定剂研究概况综述.化学推进剂与高分子材料 88.2002,(88),1-3. |
| 胡长诚.国外过氧化氢稳定剂研究概况综述.化学推进剂与高分子材料 88.2002,(88),1-3. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1753702A (en) | 2006-03-29 |
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