CN1753702A - 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
- CN1753702A CN1753702A CNA2004800053751A CN200480005375A CN1753702A CN 1753702 A CN1753702 A CN 1753702A CN A2004800053751 A CNA2004800053751 A CN A2004800053751A CN 200480005375 A CN200480005375 A CN 200480005375A CN 1753702 A CN1753702 A CN 1753702A
- Authority
- CN
- China
- Prior art keywords
- hydrogen peroxide
- coating
- instruments
- parts
- medical apparatus
- 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.)
- Granted
Links
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 title claims abstract description 437
- 238000000576 coating method Methods 0.000 title claims abstract description 159
- 239000011248 coating agent Substances 0.000 title claims abstract description 158
- 238000002360 preparation method Methods 0.000 title claims abstract description 55
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 59
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 59
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 59
- 239000003381 stabilizer Substances 0.000 claims abstract description 53
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 230000000813 microbial effect Effects 0.000 claims abstract description 8
- 238000011321 prophylaxis Methods 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims description 131
- 238000012856 packing Methods 0.000 claims description 96
- 239000000203 mixture Substances 0.000 claims description 71
- 229920000642 polymer Polymers 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 27
- 230000000845 anti-microbial effect Effects 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000000872 buffer Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 150000002978 peroxides Chemical class 0.000 claims description 10
- -1 for dialysis Substances 0.000 abstract description 30
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- 208000019206 urinary tract infection Diseases 0.000 abstract description 8
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- 229960002163 hydrogen peroxide Drugs 0.000 description 194
- 239000002609 medium Substances 0.000 description 122
- 239000000243 solution Substances 0.000 description 42
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 36
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- 238000006731 degradation reaction Methods 0.000 description 25
- 239000003814 drug Substances 0.000 description 25
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000015556 catabolic process Effects 0.000 description 21
- 230000005855 radiation Effects 0.000 description 21
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- 238000004659 sterilization and disinfection Methods 0.000 description 13
- 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 description 12
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 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 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 5
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- 108010010803 Gelatin Proteins 0.000 description 4
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 4
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- YIROYDNZEPTFOL-UHFFFAOYSA-N 5,5-Dimethylhydantoin Chemical compound CC1(C)NC(=O)NC1=O YIROYDNZEPTFOL-UHFFFAOYSA-N 0.000 description 3
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- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
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Images
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, described 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 described 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, as hydrophilic coating, and hydrogel, support, binding agents etc. can be used for contacting closely with human body.Medical apparatus and instruments can also be used for importing, cover, or fill the human body body cavity.The example of body cavity or opening can be naturally occurring chamber, as urethra, the oral cavity, ear, nose, eyes, rectum perhaps can also be the artificial opening by 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, as colostomy, ileostomy, regeneration of urethra art, or the opening or the chamber that form because of unexpected action.Described medical apparatus and instruments or described polymer composition also can be used for being positioned between the limbs (lower limb, finger, toe, axillary fossa), or are used for by binding agent and human body physical bond.
The polymer composition of medical apparatus and instruments can be transformed into softishly and resilient by engineering method, and reduce friction between the slide unit.For example, applying medical apparatus and instruments with hydrophilic coating, is known as the way of conduit, so that it is imported the human body body cavity, and as blood vessel, digestive organs and urinary system.When described coating was expanded by aqueous solution or water, it is smooth that the surface of described 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, may penetrate normal human body defensive barrier with described type, cause the importing of microorganism, promptly import, antibacterial, fungus such as virus, mycete, phage, or organize the minicell of sample 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, may 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.By reacting, by 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 by the realization that reacts of it and various compositions in the coat system.For example, by 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 by 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 being not suitable for long term storage usually.
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 by using oxidant to suppress the method for restenosis on blood vessel, for example, carry hydrogen peroxide by balloon catheter.Described United States Patent (USP) does not have to solve the stability of peroxide problem that is present 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.
A 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), described coating covers at least a portion of described parts, (ii) be used to occupy at least a liquid in the hole of described polymer composition, (iii) hydrogen peroxide is originated, (iv) packing device, described packing device are fit to described medical apparatus and instruments parts, and described liquid and described hydrogen peroxide source are contained in two independent cavity at least.
A 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.
A third aspect of the present invention relates to medical apparatus and instruments, has the coating of porous polymeric compositions at least on its a part of surface, and wherein, described coating comprises the liquid that contains hydrogen peroxide and preparation that can stable peroxide hydrogen.
A 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 allow described apparatus contact with the mammiferous body part that needs described medical apparatus and instruments.
A fifth aspect of the present invention relates to a kind of treatment, and the method that alleviation or prophylaxis of microbial infect wherein, allows above-mentioned medical apparatus and instruments contact with the mammiferous body part that needs described medical apparatus and instruments.
A sixth 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), described coating covers at least a portion of described parts, and, there is the packing device that contains the liquid of hydrogen peroxide and (ii) be fit to hold described medical apparatus and instruments parts in the described 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 for above-mentioned relevant Stability of Hydrogen Peroxide, 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 be about to use the assembly for preparing medicine equipment before, wherein, the coating of described apparatus comprises the hydrogen peroxide of exact amount.
Therefore, the invention provides the solution to the problems referred to above, comprise and be provided for obtaining to have the coating of porous polymeric compositions on its a part of surface at least, for example, the medical device of hydrophilic coating (being assembly), wherein, described coating comprises liquid, for example, the expansion of liquids medium, this medium comprises hydrogen peroxide.
As confirming by illustrative embodiment of the present invention already that described medicine equipment provided the advantage that suppresses in use the infected by microbes development effectively, for example, urinary tract infection. In addition, alleviated the aforementioned stable problem.
More particularly, the invention provides a kind of assembly, at least one has the medicine equipment parts of the coating of porous polymeric compositions to comprise (i), described coating covers at least a portion of described parts, (ii) be used for occupying at least a liquid in the hole of described polymer composition, (iii) hydrogen peroxide source, (iv) packing device, described packing device is fit to described medicine equipment parts, and described liquid and described hydrogen peroxide source are contained at least two independently in the chamber. In its preferred embodiment, described packing device also is adapted at setting up contact between described medicine equipment parts, described liquid and the described hydrogen peroxide source.
Medicine equipment
Term " medicine equipment " should be understood by the implication with broad sense. The suitable example of medicine equipment (comprising instrument) is conduit (for example, catheter), endoscope, laryngoscope, be used for feeding the conduit of raising, be used for the conduit of drainage, lead, sheath, urisheaths, curtain coating for example, is used for gloves, expander and other are inserted thing, outside tangible vessel catheter, film, for example, be used for dialysis, the film of blood filtration, be used for circulation auxiliary apparatus, the dressing of wound care and neostomy sack. Maximally related is conduit, endoscope, and laryngoscope is used for feeding the conduit of raising, and is used for the conduit of drainage, and lead and expander and other are inserted thing. Within the scope of the present invention especially interested medicine equipment is conduit, such as catheter.
Some medicine equipment can be made of one or more medicine equipment parts, when assembling or reinstalling, has formed ready-made medicine equipment. The part of said " medicine equipment parts " and " parts of vessels " described medicine equipment of expression or conduit itself (that is, a medicine equipment or conduit) or " ready-made " medicine equipment or conduit.
Medicine equipment and medicine equipment parts can be made of polytype basic material, such as plastics, and metal, glass, pottery etc. The exemplary that is used for the plastic material of medicine equipment is polymer, such as polyurethane and copolymer thereof, or polyether block amide, such as PebaxTMOr other polymeric materials, comprise polyvinyl chloride, polyamide, silicone, styrene-ethylene/butylene-styrene block copolymer (SEBS), SIS (SIS), styrene-ethylene/propylene-styrene block copolymer (SEPS), vinyl-vinyl acetate copolymer (EVA), polyethylene (PE), the copolymer of the polyethylene of metallocene-catalysis and ethene and propylene or their mixture. Very relevant material is polyurethane and copolymer thereof at present.
In the present invention, described medicine equipment 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 described porous polymeric compositions (for example, described hydrophilic coating) is painted on whole (outward) surface of described matrix polymer, and in certain other embodiments, only is coated on the part on described surface. In maximally related embodiment, described coating is painted at least a portion surface (preferred whole surface) of described medicine equipment, and it can use the people's of this medicine equipment body part directly to contact with needs when correctly using when this medicine equipment.
In the present invention, polymer composition is that the implication of " porous " is that the coating of (i) described polymer composition has the space that is fit to by the capillary force receiving liquid medium, for example, sponge, or (ii) coating of described polymer composition may 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 polymer network of expansion. Under some occasion, " porous " of described polymeric compositions may be the result of two kinds above-mentioned " phenomenon " combination.
Especially interested polymer composition comprises the expandable hydrophilic polymer of a large amount of (that is, at least 50% (w/w)), at least at medicine equipment, for example, has formed hydrophilic coating on a part of surface of conduit. Concerning some purposes, described polymer composition (for example, hydrophilic polymer is such as polyvinylpyrrolidone) is preferably crosslinked.
The exemplary of described expandable hydrophilic polymer is polyvinylpyrrolidone, polyvinyl alcohol, poly-(methyl) acrylic acid, poly-(methyl) acrylamide, polyethylene glycol, carboxymethyl cellulose, cellulose acetate, cellulose acetate propionate, shitosan, polysaccharide; Or any homopolymers or the copolymer of two or more described monomer; The N-vinylpyrrolidone, vinyl alcohol, (methyl) acrylic acid, (methyl) acrylamide, (methyl) acrylate, such as hydroxyethyl methacrylate, maleic anhydride, maleimide, methyl vinyl ether, alkyl vinyl ether and other unsaturated compounds. In addition, described hydrophilic polymer can be the blend of described homopolymers or copolymer. Other radiation curing hydrophilic polymers that comprise undersaturated vinyl double bond are suitable for described coating equally. Described polymer can pass through acrylic substance, such as dimethylaminoethyl methacrylate and NVP, and methacrylic acid, methacrylate, methyl vinyl ethers etc. are copolymerized into oligomer and prepare. Usually described prepolymer is coated on the described surface, and final radiation curing. The hydrophilic polymer of described coating can also add to by the monomer with acrylic acid character in the polymer of the above-mentioned type and prepares. Polyethylene glycol and polyvinylpyrrolidone are specially adapted to described hydrophilic coating.
Most preferably, the hydrophilic polymer of described coating is selected from following one group: polyvinylpyrrolidone or its copolymer, for example, the PVP-VA copolymer. The polymer of described type can also be by crosslinking with radiation. Be suitable for pure polyvinylpyrrolidone (poly-(NVP); PVP) time, can select various chain lengths, give respectively described coating various features. Usually, the number-average molecular weight of described polyvinyl pyrrolidone polymers is higher than 100,000. For instance, can select molecular weight is 1,200,000 PVP K-90, but, can also use the PVP of the other types with other molecular weight.
In a kind of interested embodiment, described matrix polymer is a polyurethane, and described hydrophilic polymer is a polyvinylpyrrolidone.
When preparation during described hydrophilic coating, can add one or multiple additives, for example,, or improve combining of described polymer and stromal surface so that promote the crosslinked of described hydrophilic polymer.Described 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 Esacures
KIP 150.Hydrophilic coating can also comprise plasticizer, as acetyl triethyl citrate, 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 by soaking polymer solution, and spray or be applied to medical apparatus and instruments or the medical apparatus and instruments parts that need described hydrophilic coating, or on its part.In addition, described coating can be by coextrusion formation.
Polyvinylpyrrolidone coating on the medical apparatus and instruments parts can form by the following solution of coating, this solution contains N-Methyl pyrrolidone, polyvinylpyrrolidone or its copolymer (N-vinylpyrrolidone and poly-(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, as Esacuree
KIP 150 and be dissolved in plasticizer in the ethanol.
Before the described hydrophilic coating of coating, particularly for matrix polymer and hydrophilic coating some the combination, the described polymer composition (for example, described hydrophilic coating) that forms the porous polymeric compositions in coating is the preferred coated prime coat layer before.In certain embodiments, described prime coat layer can prepare with the dilute solution of described polymer solution.
In other embodiments, the coating of described polymer composition is " sponge sample " structure, it has the space that is fit to by the capillary force receiving liquid medium, described coating can be by the basic material of coextrusion medical apparatus and instruments and the material preparation of formation described " sponge sample " structure, or be immersed in a kind of material (or its solution) by basic material with medical apparatus and instruments, this material can expand when solidifying subsequently and form " sponge sample " structure, constitutes described porous coating etc.
Liquid (expansion of liquids medium)
Wish in use to contact with the porous polymeric compositions as follows as the described liquid of a described assembly part, make described liquid and hydrogen peroxide can fill the hole of described porous polymeric compositions.In certain embodiments, part or all of described liquid is contained in the described porous polymeric compositions at first.For hydrophilic polymer (for example, the cross-linked hydrophilic polymer is as crosslinked PVP), described liquid (that is, the expansion of liquids medium) expands described hydrophilic polymer when contact, so that form expansible hydrophilic coating.
Described assembly can comprise one or more liquid (for example, the expansion of liquids medium), and if comprise two or more liquid, described liquid should preferably can be blended.
In the most preferred embodiment, described 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), as at least 95% (w/w), or the water of at least 97% (w/w).
The hydrogen peroxide source
Described 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 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, be combined on the chemical compound hydrogen peroxide (for example, be combined in the solid peroxygen hydrogen compound on the polyvinylpyrrolidone (PVP)) and chemical compound with the potentiality that form hydrogen peroxide, for example, by reacting with water, as perborate (for example, Dexol), percarbonate (for example, SODIUM PERCARBONATE), perphosphate (for example, peroxophosphoric acid sodium), persulfuric acid (for example, potassium peroxydisulfate), peroxy-monosulfate, peroxydisulfate, urea peroxide etc.
Should be understood that hydrogen peroxide mentioned in this article source 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, described hydrogen peroxide at liquid (for example before using, inflating medium) concentration in should remain on low-level on, as 0.01-5.0%, as 0.1-3.0%, as 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 be obtained when contacting when all liq and described 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 may decompose under the condition that is fit to medical usage quite easily, when the coating with porous polymeric compositions (for example, hydrophilic coating) medical apparatus and instruments (for example, catheter) with condition that the expansion of liquids medium that contains hydrogen peroxide contacts under may produce stability problem when preserving.After medical apparatus and instruments is being produced, need to have for example surpass some months or even when reaching the shelf life of growing of 1 year or several years, this problem become outstanding especially (referring to embodiment).
Packing device
For the aforementioned stable problem, assembly of the present invention also comprises (iv) packing device, it is fit to (i) described medical apparatus and instruments parts, (ii) described liquid and (iii) described hydrogen peroxide source are contained in two independent cavity at least, promptly, when described packing device is in the ad hoc structure, more than three (i)-(iii) can directly not contact with each other promptly described three (i)-(iii) be in " at least two independent cavity ".
(i) can be installed two independent cavity in the described packing device like this so that close second chamber of first 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 described 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, described second chamber has sealing device, is adapted at removing described sealing device and afterwards described hydrogen peroxide source is discharged in first chamber.
Term " packing device " expression is wished to comprise other objects, the structure of liquid etc., so that make described object, and the external isolation of liquid etc. and described packing device.
Packing device can comprise plastics, as polrvinyl chloride (PVC), 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 described 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 described chamber and described hydrogen peroxide, because it can only react lentamente with hydrogen peroxide.
The formation of described packing device comprise the parts of the chamber of hydrogen peroxide or hydrogenperoxide steam generator, in one embodiment, make with multilayer material, so that obtain gas impermeability (and may be opaque) so that avoid any illeffects to hydrogen peroxide stability.Described multilayer material can be three layers of paillon foil that are made of polyethylene terephthalate (PET)/aluminum/polyethylene (PE), and wherein, polyethylene is the internal layer of described chamber, and it directly contacts with described 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 described expansion of liquids medium in the time of the shelf life that surpassing this assembly of recommending, described shelf life may be as long as five years, common about 36 months or longer time.
The preferred further improvement of described packing device, so that can set up described medical apparatus and instruments parts, the contact between described liquid and the described hydrogen peroxide source.
When using described assembly, one or two (or all) chamber is opened by this way, feasible (i) described medical apparatus and instruments parts, (ii) described liquid and (iii) described hydrogen peroxide source are touched, and its objective is that the coating for described medical apparatus and instruments parts provides the liquid that contains hydrogen peroxide.The unlatching of described chamber as indicated above can be by the wall of outstanding one or two (or all) chamber, by breakseal, by realizations (also can vide infra) such as screw capping.
In a kind of preferred variation, allow described composition in described packing device, contact with each other, that is, this moment, packing device still held described composition.Like this, the moistening of coating of described medical apparatus and instruments can carry out under aseptic condition.
Can propose a variety of designs of described 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 represents 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 (as hydrogenperoxide steam generator).The exit portion (6) of blister cavities (5) is towards described parts of vessels (1 and 2).Exit portion (6) be by 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 by the described packing device of extruding (3), and in fact can not open described packing device.Like this, can under aseptic condition, realize moistening (expansion) of described parts of vessels (1).
Fig. 2 represents 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 (as 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 second chamber (5) can rotate relative to the end wall (9) of first chamber (4), 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 described second chamber (5) can be transferred in first chamber (4), so that described expansion of liquids medium can enter the hole of the coating of described 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, and it has ampere bottle (second chamber), is equipped with and the incorporate expansion of liquids medium of described product, for example, is provided " LoFric H by Astra Tech AB
2O " and provide by Coloplast A/S " EasiCath Set ".In described product, the described ampere bottle with described expansion of liquids medium is isolating with conduit exsiccant, coating.Before using, destroy the ampere bottle, and described expansion of liquids medium is absorbed in the described hydrophilic coating.
The various embodiments of assembly
In a kind of interested embodiment of said modules, described polymer composition is included in the hydrophilic polymer that forms hydrophilic coating at least a portion surface of described medical apparatus and instruments parts, and described liquid is the expansion of liquids medium.
In other interested embodiments, described medical apparatus and instruments parts comprise parts of vessels.More particularly, described medical apparatus and instruments is a conduit, as catheter.In preferred version, at least a portion possess hydrophilic property coating of described parts of vessels is fit to reduce friction, and described hydrogen peroxide is imported the opening of health, for example, and in the urethra.
In present the most preferred embodiment, described assembly is a conduit tube component, it comprises (i) at least one parts of vessels, cover at least a portion of described parts of vessels by hydrophilic coating, (ii) be used to the to expand at least a inflating medium of described hydrophilic coating, (iii) hydrogen peroxide source and (iv) packing device, described packing device is fit to described parts of vessels, and described inflating medium and described hydrogen peroxide source are contained in two independent cavity at least.
In its a kind of embodiment, described packing device is adapted at described parts of vessels, sets up contact between described inflating medium and the described hydrogen peroxide source, and is for example, as indicated above.
The present invention mainly describes in conjunction with following " conduit " embodiment and " hydrophilic coating " embodiment, but, should be understood that these explanations are equally applicable to other embodiments of the present invention.
In a kind of main embodiment of described conduit tube component, first chamber of described packing device is fit to the holding conduit parts, and second chamber of described packing device is fit to hold the hydrogen peroxide source.Described 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 described expansion of liquids medium maybe can be provided, and it added in the described parts of vessels before using.
A kind of preferred embodiment of above-mentioned embodiment is such, wherein, first chamber of described packing device is fit to hold described parts of vessels, and second chamber of wherein said packing device is fit to hold at least a portion and the described hydrogen peroxide source of described expansion of liquids medium.In the time of in being present in identical chamber, that is, be present in second chamber, described expansion of liquids medium and described 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 described expansion of liquids medium.Therefore, in this embodiment, described 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 described expansion of liquids medium of first chamber housing of described packing device, promptly, described parts of vessels is at least by the demi-inflation of described expansion of liquids medium, and another part of described expansion of liquids medium makes up with described hydrogen peroxide.The advantage of doing like this is that described parts of vessels can provide under the expansible condition in advance.But, in this version, importantly guarantee to allow the inflating medium that contains hydrogen peroxide of suitable part enter described hydrophilic coating.
In the another kind of version of above-mentioned embodiment, the described expansion of liquids medium that second chamber housing of described packing device is all, that is, described parts of vessels is present in first chamber with " drying " form substantially.
Therefore, in a kind of interested especially version, first chamber of described packing device is fit to hold described parts of vessels, and second chamber of described packing device is fit to hold all described expansion of liquids medium and hydrogen peroxide, that is second chamber housing aqueous hydrogen peroxide solution.
Irrelevant with the selection of above-mentioned embodiment, liquid (for example described in the described assembly, the expansion of liquids medium) and the content in described hydrogen peroxide source preferably selected, so that the concentration of the described hydrogen peroxide in liquid (inflating medium) is in 0.01-5.0% (w/w) scope, as 0.1-3.0% (w/w), as 0.2-2.0% (w/w), at this moment, described liquid (inflating medium) and hydrogen peroxide are present in the hole of described polymer composition (for example, expansible already hydrophilic coating).Second chamber housing at described 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 the above-described embodiment, second chamber of described packing device is contained in hydrogenperoxide steam generator at least a portion of described expansion of liquids medium, considerable for the manufacturer of described assembly is to guarantee the concentration of described hydrogen peroxide is remained on the maintenance level, even preserved under the contingent condition of relevant temperature and illumination a lot of months or even after time several years.Therefore, the described hydrogenperoxide steam generator at least a portion of described expansion of liquids medium preferably includes stabilizing agent.
More particularly, the inventor had determined the preferential selection to embodiment already, wherein, described hydrogenperoxide steam generator in described expansion of liquids medium is to comprise that also one or more are selected from stabilizing agent, 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) is (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 (as 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, described chelating agen is DETAPMP or deferoxamine-poly-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 described 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 described aqueous hydrogen peroxide solution, more preferably 0-50mM, for example, up to 50mM, as 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 described medical apparatus and instruments, it is normally important.
Morie osmolarity improves the content of preparation in described aqueous hydrogen peroxide solution usually in the 0-1000mM scope, more preferably 0-300mM, for example, up to 300mM, as 5-300mM.
Should be pointed out that other compositions of the trace that described aqueous hydrogen peroxide solution can comprise that the front was not clearly mentioned.The content of described " other compositions " is generally 0-2000mg/L, as 0-500mg/L.
Usually, the pH of described aqueous solution is in the 2.0-8.5 scope, preferably in the 3.0-5.0 scope.
In one embodiment, described 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 embodiment, described 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 embodiment, described 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 the most preferred embodiment, described 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 uses sodium hydroxide and sulphuric acid or nitric acid to regulate.
For the embodiment with all expansion of liquids media of second chamber housing, above-mentioned aqueous solution is particularly preferred.
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 embodiment, the packing device of described conduit tube component comprises the hydrogen peroxide source of at least one solid form.In this embodiment, first chamber of described packing device preferably holds at least one hydrogen peroxide source and at least one parts of vessels.More particularly, first chamber of described packing device is fit to hold described parts of vessels and described solid peroxygen hydrogen source.Preferably, second of described packing device chamber is fit to hold described expansion of liquids medium.
Described 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 described first chamber or thin film, or described hydrogen peroxide source is combined on the described parts of vessels, for example, as the grumeleuse that is embedded in the described hydrophilic coating, one deck in the coating or as the one deck on the coating surface.In use, add described expansion of liquids medium, and described hydrogen peroxide source is dissolved in the described expansion of liquids medium, perhaps reacts so that discharge hydrogen peroxide, and described hydrogen peroxide is expand in the described hydrophilic coating with described expansion of liquids medium.
In a kind of version of this embodiment, the coating that described parts of vessels is mixed in solid peroxygen hydrogen source, as the molecule in the hole that is trapped in described hydrophilic coating, perhaps as the part of at least a chemical compound that is used to prepare described hydrophilic coating.In its a kind of version, described solid peroxygen hydrogen source comprises the hydrogen peroxide that cooperates with polyvinylpyrrolidone (PVP).Specifically, at least a portion of described hydrophilic coating prepares with polyvinylpyrrolidone (PVP)-peroxide compound.
In this embodiment, described polymer molecule chemical crosslinking or to be assembled into polymer composition be to carry out existing under the condition of described hydrogen peroxide has caused the delay to described hydrogen peroxide.Described hydrogen peroxide can exist with free form, perhaps cooperates as a part that participates in one of described 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, as PVP or relevant polymer.
The initial hydrogen peroxide that cooperates with described polymer can be linked on the substrate subsequently, so that for example form hydrophilic coating.
In the another embodiment of conduit tube component, described packing device comprises first chamber that is fit to hold described parts of vessels, is fit to hold second chamber of described expansion of liquids medium and is fit to hold the 3rd chamber in described hydrogen peroxide source.
In a kind of preferred variation of this embodiment, described conduit tube component comprises packing device, when this device is adapted at unpacking device described hydrogen peroxide source is discharged in the described expansion of liquids medium automatically.This purpose can be by holding hydrogen peroxide in described chamber, and have and chamber that the expansion of liquids medium is housed is separated by foil membrane realize that described film breaks when unpacking.
Preferred embodiment
In present the most preferred embodiment, the invention provides conduit tube component, comprise (i) at least one parts of vessels, hydrophilic coating with at least a portion that covers described parts of vessels, described hydrophilic coating comprises crosslinked polyvinylpyrrolidone, at least a expansion of liquids medium of described hydrophilic coating (ii) is used to expand, (iv) packing device, described packing device has first chamber that holds described parts of vessels, with second chamber that is used to hold described expansion of liquids medium, described 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 defined as favourable anti-microbial agents with hydrogen peroxide, be understandable that, one or more other anti-microbial agents can be used for described liquid (inflating medium), make up, perhaps substituting as hydrogen peroxide with hydrogen peroxide.The example of described 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-colored 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 described anti-microbial agents and hydrogen peroxide is relevant with embodiment in the above-mentioned aspect of described assembly (for example, conduit tube component).
In addition, the above-mentioned aspect of described assembly (for example, conduit tube component) and embodiment are also relevant with the described 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) by being used for preparation, is used for the simple combination preparation of conventional method of the packing device of the liquid of goals of medicine and medical apparatus and instruments.
Therefore, in described embodiment, wherein, first chamber of described packing device is fit to hold described parts of vessels, and, second chamber of wherein said packing device is fit to hold described expansion of liquids medium and described hydrogen peroxide source, and described assembly can prepare by the method that may further comprise the steps: by mixing the described expansion of liquids medium of relevant composition (referring to other parts of this paper) preparation; Use routine techniques to prepare described parts of vessels; Described parts of vessels is installed in first chamber (may comprise the described chamber wall of welding) of described packing device; The expansion of liquids device is installed in second chamber of described packing device (may comprise and being welded on the described chamber wall); And may carry out disinfection to described 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 described expansion of liquids medium, preferably by in described expansion of liquids medium, mixing the hydrophilic polymer of 0.3-10%, for example, low-molecular-weight hydrophilic polymer (Mw1500-50,000) described expansion of liquids medium is carried out modification, as the applicant in (also can referring to example 1 of the present invention) disclosed in the EP 0935478.The example of useful hydrophilic polymer has PVP C-15 (ISP) and PVP K-12 (BASF).
The preparation of described packing device and the actual selection of material are conventionally known to one of skill in the art.
The purposes of described assembly and medical apparatus and instruments
Said modules is fit to the ready-made medical apparatus and instruments of preparation, as conduit.With the first, the second and may other the contents of chamber put together, so that make described liquid and/or hydrogen peroxide enter the hole of described polymer composition.In one embodiment, allow 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 at the detailed description of described accompanying drawing according to the method described above.
After the described ready-made medical apparatus and instruments of preparation, can use described medical apparatus and instruments in a usual manner, that is, the conventional method that should not take any special measure under user or the practitioner's normal condition or use described medical apparatus and instruments relatively is without any running counter to part.
For catheter, described 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, as virus, antibacterial, the inhibitory action of fungus or mycete.The part of described anti-microbial effect can contact acquisition with the direct of urethra by medical apparatus and instruments, and after taking out described apparatus, because may there be certain effect in a part of coating and/or liquid deposition in urethra.During inserting conduit and partial action afterwards can also produce owing to effusive described hydrogen peroxide from described coating.
Therefore by described 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 described 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 the danger of the relevant infection that causes by the described conduit of operation before inserting with polluting (from finger, environment).
New type medical equipment
As can be seen from the above description, 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, has the coating of porous polymeric compositions at least on its a part of surface, and wherein, described 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 described coating is in 0.01-5.0% (w/w) scope, as 0.1-3.0% (w/w), as 0.2-2.0% (w/w).
The example of preparation that can stable peroxide hydrogen is the preparation that above is defined as " stabilizing agent ".Described 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 described porous polymeric compositions is the hydrophilic coating of at least a hydrophilic polymer, and described liquid is the expansion of liquids medium of described hydrophilic polymer.Described hydrophilic coating/polymer is preferably selected as stated above.Preferably, at least a hydrophilic polymer is a polyvinylpyrrolidone.More preferably, described 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, described 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, described medical apparatus and instruments is a conduit, as 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, allow it contact with the body part of the mammal (as the people) that needs described medical apparatus and instruments.
In addition, the invention provides treatment, alleviate or method that prophylaxis of microbial infects, wherein, allow the medical apparatus and instruments that this paper limited contact with the body part of the mammal (as the people) of the described medical apparatus and instruments of needs.
Xiang Guan infected by microbes is the infected by microbes that causes urinary tract infection (UTI) especially.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 reduced urine, the number of bacteria in urethra and/or the urethral orifice when replacing conventional catheter with assembly of the present invention and catheter.
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, described medical apparatus and instruments parts (for example, described parts of vessels), described inflating medium and described hydrogen peroxide source are contained in two independent cavity at least, the advantageous feature of hydrogen peroxide can also be used for a kind of assembly, comprise (i) have wherein have liquid coating (for example, hydrophilic coating) medical apparatus and instruments (for example, conduit), and, wherein, described liquid comprises hydrogen peroxide and (ii) packing device, and it is fit to described medical apparatus and instruments is contained in its chamber.Can use described medical apparatus and instruments, because in fact it is ready-made, although described assembly may 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), described coating covers at least a portion of described parts, and there is the packing device that contains the liquid of hydrogen peroxide and (ii) be fit to hold described medical apparatus and instruments parts in the described coating.Preferably, described medical apparatus and instruments parts are contained in the chamber of described packing device.
Modal is that the concentration of the described hydrogen peroxide in the described liquid in described coating is in 0.01-5.0% (w/w) scope, as 0.1-3.0% (w/w), as 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 described liquid.The useful example of preparation that can stable peroxide hydrogen is above defined " stabilizing agent ".Described liquid can also comprise buffer agent, and Morie osmolarity improves preparation, and has the pH of adjusting, particularly has above disclosed probability and scope.
Described polymer composition preferably includes at least a hydrophilic polymer.For example, hydrophilic polymer can be used for hydrophilic coating, so that medical apparatus and instruments is provided, as the low-friction surface of catheter.
When needs carry out disinfection to described assembly by radiation, preferably by adding the hydrophilic polymer of 0.3-10%, for example, low-molecular-weight hydrophilic polymer (Mw 1500-50,000) described expansion of liquids medium is carried out modification, as the applicant in (also can referring to example 1 of the present invention) 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 described porous polymeric compositions is the hydrophilic coating of at least a hydrophilic polymer, and described liquid is the expansion of liquids medium that is used for described hydrophilic polymer.Described 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 described hydrophilic polymer is crosslinked.
More particularly, the present invention relates to catheter, at least the hydrophilic coating of possess hydrophilic property polymer (particularly crosslinked polyvinylpyrrolidone) on its a part of surface, wherein, described coating comprises the expansion of liquids medium, this medium comprises hydrogen peroxide, and optionally comprises the preparation of energy stable peroxide hydrogen, and described conduit is accommodated in the chamber of packing device.
In this embodiment, described aqueous hydrogen peroxide solution normally imports described polymer composition after described hydrophilic polymer is carried out chemical crosslinking at once.More commonly, the described medical apparatus and instruments that carries the coating of described polymer composition may be dipped in the aqueous hydrogen peroxide solution.Described hydrogenperoxide steam generator can be diffused into by passive method in the described polymer composition then, perhaps can force to enter described coating by 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 when carrying out disinfection (particularly need by radiation) by the hydrophilic polymer that adds 0.3-10% as stated above.For example, described 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.
Described medical apparatus and instruments can be according to above-mentioned explanation, and in conjunction with described medical apparatus and instruments, described 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, described medical apparatus and instruments is a conduit, as catheter.The example of the catheter that scribbles hydrophilic polymer that can obtain by the commercial channel provides " SpeediCath " by Coloplast A/S, and wherein, the conduit of described coating contacts with described 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 (as the people) that needs described medical apparatus and instruments.
Embodiment
The embodiment 1-preparation 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 A1 that comprises light trigger.The content of the PVP of described solution is in 1-8% (w/w) scope.Described first and second kinds of solution may be identical.
B) the original conduit of polyurethane is immersed in first kind of solution, and allows 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 described conduit of higher temperature (for example, under 70-80 ℃).
E) by allowing the conduit of described coating contact the ultraviolet 1/2-15 in the 200nm-300nm scope minute crosslinked described PVP of wave-length coverage.
F) conduit with crosslinked coating is placed in the packing device, and fills described the packing with inflating medium, and wherein, described inflating medium is the aqueous solution that low-molecular-weight PVP (Plasdone C15) and Morie osmolarity improve preparation (NaCl).
G) by 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 described solution is in 1-8% (w/w) scope.Described first and second kinds of solution may be identical.
B) the original conduit of polyurethane is immersed in first kind of solution, and allows 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 described conduit of higher temperature (for example, under 70-80 ℃).
E) by allowing the conduit of described coating contact the ultraviolet 1/2-15 in the 200nm-300nm scope minute crosslinked described PVP of wave-length coverage.
F1) conduit with crosslinked coating is placed in the packing device, and fills described the packing with inflating medium, and wherein, described 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 by the described 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 described inflating medium is put into second chamber, wherein, described 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 by the described packing device (chamber 1) and the described 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 the following method:
Dry catheter (1) with polyvinylpyrrolidone (PVP) coating prepares by embodiment 1 described method.Described conduit is put into first chamber (4) of described packing device (3), and this chamber is by 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 described 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) and go into the alignment of interruption-forming liquid communication, wherein, the inclusions of the described expansion of liquids medium in the container (5) can be transferred in first chamber of the conduit that holds described coating.
In a kind of version, the catheter of described coating is that a part of expansion of liquids medium (preferred low-molecular-weight PVP and Na are being provided in first chamber (4) before the described chamber by welded seal
2SO
4Aqueous solution) carry out expansible in advance.In use, by allowing 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 by what passed through before using) so that described coating can absorb the described inflating medium that comprises hydrogen peroxide, preferably absorbed in 20 seconds.Described conduit can directly use subsequently.
Embodiment 4-uses the PEG 2000 that is present in the inflating medium to preserve the hydrogen peroxide conduit of a chamber
Experimentize, so that determine 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.Described conduit is according to the described methods preparation of embodiment 2, and use pure water, hydrogen peroxide (referring to table 1.1), and expansion of liquids medium as described in PEG 2000 (as described in table 1.1) prepares, and comprise the 50mM citrate buffer of pH 5.5.As described in embodiment 2, described 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 described 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, may be because following generation HO
-Fenton
Reaction:
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 described conduit is well below the frictional force of not using PEG 2000 (0.53N) after preserving, but, meanwhile, pH is reduced to 5.13, described 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, described coating has been subjected to heavy damage.With after 60 ℃ are preserved down, compare, do not have the sample of PEG2000 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, may destroy the long-time stability of the packing of the inflating medium that hydrophilic catheters is housed and contains hydrogen peroxide in identical chamber.
Embodiment 5-uses the PVP C-15 that is present in the inflating medium to preserve the hydrogen peroxide conduit of a chamber
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 considered as 100%, and calculates degradation speed (%/sky), present 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 adding PVP C-15 in described inflating medium 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, described conduit has the hydrophilic coating that is present in the inflating medium, inflating medium comprises 1%-point hydrogen peroxide at first, 1g/L chelating agen (EDTA, 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.
| The 10mg/L metal ion | The 1000mg/L chelating agen | ||||
| EDTA | DETAPAC | Gelatin | Deferoxamine | Do not have | |
| Cu(2+) | 0.37 | 0.44 | 0.30 | 0.31 | 0.15 |
| Fe(2+) | 0.29 | 0.46 | 0.25 | 0.66 | 0.28 |
| Do not have | 0.59 | 0.61 | 0.60 | 0.68 | 0.59 |
At 10mg/L Cu
2+When not adding chelating agen, the concentration of described 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, has therefore kept 0.30-0.44%-point hydrogen peroxide after preserving.
By 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 can improve the basicly stable property of hydrogen peroxide when not adding metal ion: keep 0.68%-point H after preserving with deferoxamine
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 research described conduit and the PVP effect to hydrogen peroxide stability.
Hydrogen peroxide 33%Panreac Ph.Eur, BP, REF. (14.1077.14.10)
The citric acid monohydrate compound, Riedel-de Ha ê n
Pasdone C-15，ISP
0.02M KMnO
4，Riedel de Ha ên
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 in from these two kinds of solution each 10.0mL etc. duplicate samples, 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 after 60 ℃ keep 2 weeks and 4 weeks, described sample is 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).
| Radiation dose | After the radiation | 60 ℃ of 1 week | 60 ℃ of 2 week |
| 0kGy 25kGy 50kGy 75kGy | 1.00 0.85 0.73 0.57 | 0.97 0.79 0.58 0.37 | 0.87 0.70 0.46 0.26 |
Table 7.2. expansible conduit (serial II) in distilled water.H
2O
2Concentration (%-point).Meansigma methods (n=3).
| Radiation dose | After the radiation | 60 ℃ of 1 week | 60 ℃ of 2 week |
| 0kGy 25kGy 50kGy 75kGy | 1.00 0.93 0.87 0.81 | 0.98 0.91 0.81 0.74 | 0.92 0.85 0.75 0.66 |
Table 7.3. is present in the H in the distilled water
2O
2-solution (serial III).H
2O
2Concentration (%-point).Meansigma methods (n=3).
| Radiation dose | After the radiation | 60 ℃ of 1 week | 60 ℃ of 2 week |
| 0kGy 25kGy 50kGy 75kGy | 1.00 0.95 0.92 0.89 | 0.87 0.91 0.84 0.79 | 0.76 0.88 0.85 0.77 |
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, as can be seen, 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 determined to cause the most stable H
2O
2The concentration of the stabilizing agent DETAPMP of solution.Another purpose is to determine that degraded contains the stabilizing agent DETAPMP of pH4 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)
0.02M KMnO
4，Riedel de Ha ên
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 1M HCl the pH-value of this solution is adjusted to pH4.
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 described each inflating medium, get 20mL etc. duplicate samples, and add in each bar-shaped packing.Described bar-shaped packing be after filling by welded seal and deliver to Ris φ National Laboratory and carry out radiation.Radiation dose is 2*26 kGy.
Described 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).Described bar-shaped packing is made by the punching press area of 13 * 35mm, and this area welds by 1 * 3 unit on welder along the longitudinal direction.It is to weld 2 * 2.2 units by described 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
| Storage temperature | Rate constant (k) (%/sky) | Log k (%/sky) |
| 40℃ 50℃ 60℃ | 0.0932 0.1722 0.3691 | -1.031 -0.764 -0.433 |
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 (%).
| Natural law | 50 | 100 | 150 | 200 | 250 | 350 | 500 |
| 0 14 25 | 0.92 0.89 0.89 | 0.91 0.89 0.88 | 0.91 0.90 0.89 | 0.91 0.89 0.89 | 0.90 0.89 0.89 | 0.91 0.89 0.89 | 0.91 0.89 0.89 |
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 described 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
4M NaOH，Merck
1M HCl, BHD AnalR volumetric soiutions
NaCl(Extra pure，Ph.Eur，BP，USP)
0.02M KMnO
4，Riedel de Ha ên
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 described 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 it can be improved preparation as Morie osmolarity.Citric acid is added in described each inflating medium, so that reach the concentration of 25mM, so that keep initial pH-value at whole test period.By in final solution, adding 4M NaOH and 1M HCl the final pH-value of this solution is adjusted to 4.0,5.5 and 7.0.
From described each inflating medium take out 20mL etc. duplicate samples, 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 described 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).Described bar-shaped packing is made from the punching press area of 13 * 35mm, welds 1 * 3 unit along the longitudinal direction on welder.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 by described bar-shaped packing.
Preserve described bar-shaped being packaged in and carry out described 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 described 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 reach the Study on degradation in 18 weeks under 23 ℃.
| pH | DETAPMP | DETAPMP+NaCl | The sodium salt of | EDATMP | |
| 4 5.5 7 | 5.3％ 17.6％ 15.3％ | 13.5％ 13.5％ 12.9％ | 27.5％ 18.0％ 29.2％ | 22.2％ 30.9％ 173.3％ | |
| pH | HEDP | The sodium salt of EDATMP | Acetanilide | | |
| 4 5.5 7 | 65.4％ 150.0％ 351.1％ | 18.3％ 14.5％ 25.8％ | 21.2％ 21.4％ 20.2％ | 15.7％ 31.7％ 54.7％ |
By above result as can be seen, the most stable H
2O
2Solution is to obtain in the solution of the stabilizing agent DETAPMP that contains pH4.Generally, compare, under pH7, have higher propensity for degradation with pH4.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 pH7.
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 the pH4 condition 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 Ana1R volumetric soiutions
NaCl(Extra pure，Ph.Eur，BP，USP)
0.02M KMnO
4，Riedel de Ha ên
Constant-current titration Titrino 702, Metrohm
Described inflating medium contains about 1% (w/w) hydrogen peroxide; 0,10 and 25mM citrate and 0.7% (w/w) NaCl and stabilizing agent.Regulate the pH-value of this solution with 4M NaOH and 1M HCl.The concentration of described stabilizing agent is DETAPMP (500mg/L), and the sodium salt of EDATMP (500mg/L, 1000mg/L) and the sodium salt (1000mg/L) of DETAPMP.
Take out each inflating medium 10mL etc. duplicate samples, and add each bar-shaped packing to and (" crust " arranged; Referring to embodiment 7).After filling by the described 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 (%).
| | pH 5.5 | pH 7 | |
| DETAPMP | 8.4 | 28.0 | 18.2 |
| The sodium salt of DETAPMP | 16.8 | 22.4 | 26.6 |
| Sodium salt-500mg/L of EDATMP | 15.4 | 18.2 | 35.0 |
| The sodium salt 1000mg/L of EDATMP | 15.4 | 21.0 | 25.2 |
| No stabilizing agent | 15.4 | 22.4 | 60.2 |
Table 10.2.10mM citrate.At 23 ℃ of H that calculate after preserving 2 years down
2O
2(%) degradation amount
| pH |
| 4 | pH 5.5 | pH 7 | |
| DETAPMP | 23.8 | 29.4 | 19.6 |
| The sodium salt of DETAPMP | 22.4 | 26.6 | - |
| Sodium salt-500mg/L of EDATMP | 19.6 | 53.2 | 86.8 |
| The sodium salt 1000mg/L of EDATMP | 37.8 | 30.8 | 43.4 |
| No stabilizing agent | 47.6 | 63.0 | 277.1 |
Table 10.3.25mM citrate. after 23 ℃ are preserved 2 years down, the H of calculating
2O
2(%) degradation amount.
| | pH 5.5 | pH 7 | |
| DETAPMP | 25.2 | 42.0 | 32.2 |
| The sodium salt of DETAPMP | 33.6 | 30.8 | 29.4 |
| Sodium salt-500mg/L of EDATMP | 50.4 | 103.6 | 137.1 |
| The sodium salt 1000mg/L of EDATMP | 50.4 | 39.2 | 158.1 |
| No stabilizing agent | 39.2 | 74.2 | 201.5 |
Table 10.4.pH4.After 23 ℃ are preserved 2 years down, the H of calculating
2O
2(%) degradation amount.
| The 0mM citrate | The 10mM citrate | The 25mM citrate | |
| DETAPMP | 8.4 | 23.8 | 25.2 |
| The sodium salt of DETAPMP | 16.8 | 22.4 | 33.6 |
| Sodium salt-500mg/L of EDATMP | 15.4 | 19.6 | 50.4 |
| The sodium salt 1000mg/L of EDATMP | 15.4 | 37.8 | 50.4 |
| No stabilizing agent | 15.4 | 47.6 | 39.2 |
Table 10.5.pH5.5.After 23 ℃ are preserved 2 years down, the H of calculating
2O
2(%) degradation amount.
| The 0mM citrate | The 10mM citrate | The 25mM citrate | |
| DETAPMP | 28.0 | 29.4 | 42.0 |
| The sodium salt of DETAPMP | 22.4 | 26.6 | 30.8 |
| Sodium salt-500mg/L of EDATMP | 18.2 | 53.2 | 103.6 |
| The sodium salt 1000mg/L of EDATMP | 21.0 | 30.8 | 39.2 |
| No stabilizing agent | 22.4 | 63.0 | 74.2 |
Table 10.6.pH7.After 23 ℃ are preserved 2 years down, the H of calculating
2O
2(%) degradation amount.
| The 0mM citrate | The 10mM citrate | The 25mM citrate | |
| DETAPMP | 18.2 | 19.6 | 32.2 |
| The sodium salt of DETAPMP | 26.6 | - | 29.4 |
| Sodium salt-500mg/L of EDATMP | 35.0 | 86.8 | 137.1 |
| The sodium salt 1000mg/L of EDATMP | 25.2 | 43.4 | 158.1 |
| No stabilizing agent | 60.2 | 277.1 | 201.5 |
As can be seen, the pH-value is brought up to 5.5 and 7 from 4, improved the degradation speed of nearly all solution.Citrate of in described 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 influence of bacterial growth speed
Tables of data understands that 7 kinds of different bacterial isolateses are being with or without hydrogen peroxide (0-1%).Condition under fertility.Say simply, with described microbionation in the growth medium that is with or without hydrogen peroxide, and the absorption value by under the 600nm wavelength measure in the middle of the growth of logarithmic (log) phase.The data that obtain from each specific bacteria bacterial strain have been collected.These data are meansigma methodss of three independent experiments, measure each time and repeat twice; 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
Tables of data understands that 7 kinds of different bacterial isolateses are being with or without hydrogen peroxide (0-1%).Condition under survival ability.Allow the contacted hydrogen oxide of described 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
Above tables of data is understood the survival ability of 7 kinds of different bacterial isolateses 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.Described conduit was preserved for about 0,3,6 and 12 weeks down for 40 ℃ and 60 ℃ at 25 ℃.With clinical isolated bacterial inoculation agar plate from infected human urine, and the conduit of coating is placed on the top of agar surface.Cultivated described 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 (clinical isolates on the agar plate of having inoculated antibacterial,-and+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 by 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 described 32 kinds of solution and concentration are shown in table 12.1:
Table 12.1.
| S t d | Hexa A g/L | Di-azo- lidi- nylurea B g/L | Mandelic acid C g/L | Hippuric acid D g/L | Toluene-sodium-sulfonchloramide E g/L | PVP -I2 F g/L | CHLORHEXIDINE D-DIGLUCONATE 20% G g/L | Alkyldimethylbenzylammonium chloride H g/L | Bro- no-pol J g/L | Kathon K g/L | Salicylic acid phenylester L g/L | Hydrogen peroxide M g/L | Zinc chloride N g/L | Copper chloride 0 g/L | Silver chlorate P mg |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 | 0 0 0 0 1 0 0 1 1 0 1 0 1 0 0 1 1 0 1 0 1 1 1 0 1 0 1 1 0 0 1 1 | 0 1 1 1 1 0 0 1 1 1 1 0 1 0 1 1 0 1 1 1 1 0 0 0 0 1 0 0 0 0 0 0 | 0 1 0 1 1 0 1 0 1 0 0 0 1 0 1 1 1 0 0 0 0 1 0 1 1 1 1 0 1 1 0 0 | 0.6 0.6 0 0.6 0 0.6 0.6 0.6 0 0.6 0 0 0.6 0 0 0.6 0 0.6 0.6 0 0 0.6 0.6 0.6 0.6 0 0 0 0 0 0 0.6 | 0 0 1 1 0 1 0 1 1 1 0 1 1 0 0 0 1 0 0 0 1 0 0 1 1 1 0 0 0 1 1 1 | 0 0 10 0 10 0 10 0 10 10 0 0 10 0 0 10 0 10 0 10 0 0 10 10 0 0 0 10 10 10 10 10 | 0.65 0 0.65 0 0 0.65 0.65 0.65 0 0 0 0 0.65 0 0.65 0.65 0.65 0 0.65 0.65 0 0 0 0.65 0 0.65 0.65 0.65 0 0 0.65 0 | 1 0 0 0 0 1 0 0 0 1 1 0 1 0 1 1 0 1 0 0 1 1 0 0 1 1 0 1 1 1 1 0 | 1 1 1 1 0 1 0 0 0 0 1 0 1 0 0 1 1 0 0 1 1 0 1 0 0 0 1 0 1 1 0 1 | 0 0.094 0 0 0 0.094 0 0.094 0.094 0 0 0.094 0.094 0 0.094 0 0 0.094 0 0.094 0.094 0.094 0.094 0.094 0 0 0.094 0.094 0 0.094 0 0 | 0 0.02 0.02 0 0 0.02 0.02 0 0.02 0.02 0.02 0.02 0.02 0 0.02 0 0.02 0 0.02 0 0 0 0.02 0 0.02 0 0 0.02 0.02 0 0 0 | 1 1 1 0 1 0 1 1 0 0 1 1 1 0 0 0 0 1 0 0 0 0 0 0 1 1 1 1 0 1 0 1 | 0 0 0 1 0 1 1 0 1 0 1 1 1 0 0 0 0 1 1 1 0 1 0 0 0 1 1 0 1 0 1 1 | 1 0 0 1 1 0 1 1 0 1 1 1 1 0 1 0 1 0 0 1 0 1 1 0 0 0 0 0 0 1 1 0 | 20 0 20 20 20 0 0 0 0 0 0 20 20 0 20 0 0 20 20 0 20 0 20 20 20 0 20 0 20 0 20 0 |
A lot of in 32 kinds of mixture have effective function at some kinds in described 7 kinds of antibacterials, and (0=does not have effect; The effect that 3=is outstanding), referring to table 12.2 (by the anti-microbial effect classification that weakens gradually).
Table 12.2.
| Std | Proteus mirabilis | Pseudomonas aeruginosa | Escherichia coli | Providencia stuartii | Staphylococcus aureus | Enterococcus faecalis | Klebsiella |
| 3 32 29 19 21 20 10 11 5 13 16 24 6 14 30 25 18 28 17 23 22 31 7 2 15 12 9 4 8 1 26 27 | 3 3 3 3 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 | 3 3 3 3 3 2 2 2 1 3 3 0 3 1 0 3 3 2 0 3 3 0 3 3 0 2 2 1 1 0 0 0 | 3 3 3 3 3 3 2 2 1 1 2 2 1 1 0 2 2 1 1 1 0 0 2 1 1 1 1 1 0 0 0 0 | 3 3 3 2 3 2 3 3 1 1 2 0 2 1 0 2 1 1 1 0 1 0 2 2 1 0 1 1 1 1 0 0 | 3 3 3 2 3 3 3 2 2 3 2 2 2 2 2 1 1 1 1 1 0 0 2 2 2 2 1 0 0 0 0 0 | 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 3 3 0 3 3 3 1 3 3 0 0 0 0 | 3 3 2 2 3 3 3 2 2 1 1 3 3 1 3 2 2 1 1 3 3 0 3 3 1 1 1 1 1 0 1 0 |
| Add up to | 35 | 58 | 44 | 44 | 51 | 77 | 59 |
Described result is being analyzed, and further testing, finding that described effect may be that the third level interacts or more senior so that confirm describedly as a result the time.In other words, described 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 feature 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 described 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 pH7 (50mM phosphate buffer) and pH 8.5 (50mM TAPS buffer), 0.3g/L silver sulfadiazine, 0.25g/L hydantoin silver, 1.175g/L 5,5-dimethyl-hydantoin silver and 0.25g/L polymerization imidazoles silver have medium to good anti-microbial effect.Described 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.Described silver compound only just can work when allowing to exist excessive undissolved salt in packing, in other words, does not have anti-microbial effect at them when their precipitate is poured out.In some experiments, 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.
With rating 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 is defined as the 5/12 square root sum that multiply by the score of each in described 7 kinds of antibacterials.Therefore, the described 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 from 0 to 5: 0=is unacceptable fully for the conduit of described chamber possess hydrophilic property conduit (weight 60%) and described inflating medium (weight 40%) and inflating medium, for example, by strong color or main precipitation; 5=is perfect, and for example, non-coloring does not have precipitation).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, by 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 described 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 (11)
1. assembly, at least one has the medical apparatus and instruments parts of porous polymer composition coating to comprise (i), described coating covers the part of described parts at least, (ii) be used to occupy at least a liquid in the hole of described polymer composition, (iii) hydrogen peroxide is originated, (iv) packing device, described packing device are fit to described medical apparatus and instruments parts, and described liquid and described hydrogen peroxide source are contained in two independent cavity at least.
2. assembly as claimed in claim 1, it is a conduit tube component, comprise (i) at least one parts of vessels, has a hydrophilic coating that covers at least a portion of described parts of vessels, (ii) be used to the to expand at least a inflating medium of described hydrophilic coating, (iii) hydrogen peroxide source and (iv) packing device, described packing device is fit to described parts of vessels, and described inflating medium and described hydrogen peroxide source are contained in two independent cavity at least.
3. conduit tube component as claimed in claim 2, wherein, first chamber of described packing device is fit to hold described parts of vessels, and second chamber of described packing device is fit to hold all expansion of liquids medium and hydrogen peroxide.
4. conduit tube component as claimed in claim 3, wherein, described expansion of liquids medium and described hydrogen peroxide have formed and have also comprised the aqueous solution that is selected from one or more following compositions: stabilizing agent, buffer agent, Morie osmolarity improves preparation.
5. conduit tube component as claimed in claim 4, 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.
6. as any one conduit tube component in the above-mentioned claim, it comprises (i) at least one parts of vessels, has a hydrophilic coating that covers at least a portion of described parts of vessels, described hydrophilic coating comprises crosslinked polyvinylpyrrolidone, at least a expansion of liquids medium of described hydrophilic coating (ii) is used to expand, (iv) packing device, described packing device has first chamber that is used to hold described parts of vessels, with second chamber that is used to hold described expansion of liquids medium, described 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.
7. antimicrobial liquid inflating medium 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.
8. a medical apparatus and instruments has the coating of porous polymeric compositions at least on its a part of surface, and wherein, described coating comprises the liquid that contains hydrogen peroxide and preparation that can stable peroxide hydrogen.
9. treatment, the method that alleviation or prophylaxis of microbial infect, wherein, first step is with as medical apparatus and instruments of any defined assembly preparation among the claim 1-6, is that this apparatus is contacted with the mammiferous body part that needs described medical apparatus and instruments with second step.
10. treatment, the method that alleviation or prophylaxis of microbial infect wherein makes medical apparatus and instruments as claimed in claim 8 contact with the mammiferous body part that needs described medical apparatus and instruments.
11. assembly, at least one has the medical apparatus and instruments parts of porous polymer composition coating to comprise (i), described coating covers at least a portion of described parts, and have in the described coating existence wherein the liquid that contains hydrogen peroxide and (ii) be fit to hold the packing device of described medical apparatus and instruments parts.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200300298 | 2003-02-26 | ||
| DKPA200300296 | 2003-02-26 | ||
| DKPA200300298 | 2003-02-26 | ||
| DKPA200300296 | 2003-02-26 | ||
| PCT/DK2004/000129 WO2004075944A2 (en) | 2003-02-26 | 2004-02-26 | A medical device having a coating comprising hydrogen peroxide and package therefore |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1753702A true CN1753702A (en) | 2006-03-29 |
| CN1753702B CN1753702B (en) | 2012-04-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2004800053751A Expired - Fee Related CN1753702B (en) | 2003-02-26 | 2004-02-26 | An assembly for the preparation of a medical device having a coating comprising hydrogen peroxide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1753702B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105101794A (en) * | 2013-03-15 | 2015-11-25 | 美国消毒器公司 | Reactive surface coating having chemical decontamination and biocidal properties |
| CN108434579A (en) * | 2012-10-26 | 2018-08-24 | 医研比赫国际股份公司 | Prepare method, conduit tube component and the packaging of instant conduit |
| CN109069793A (en) * | 2016-04-12 | 2018-12-21 | 科洛普拉斯特公司 | Conduit tube component with the protective case selectively eliminated |
| CN112969647A (en) * | 2018-11-12 | 2021-06-15 | 电化株式会社 | Packaging bag and packaging box for containing phosphor |
| CN113288587A (en) * | 2021-07-28 | 2021-08-24 | 南通跃香拉链有限公司 | Outdoor first aid is with stanching bandage |
| WO2022016636A1 (en) * | 2020-07-23 | 2022-01-27 | 苏州微比特自动化有限公司 | Packaging bag |
Family Cites Families (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 |
| US4846844A (en) * | 1987-08-31 | 1989-07-11 | Eli Lilly And Company | Antimicrobial coated implants |
| EP0791362A3 (en) * | 1996-02-23 | 1998-03-04 | The Procter & Gamble Company | Disinfecting compositions and processes for disinfecting surfaces |
-
2004
- 2004-02-26 CN CN2004800053751A patent/CN1753702B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108434579A (en) * | 2012-10-26 | 2018-08-24 | 医研比赫国际股份公司 | Prepare method, conduit tube component and the packaging of instant conduit |
| US10780245B2 (en) | 2012-10-26 | 2020-09-22 | Teleflex Life Sciences Pte. Ltd. | Method of preparing a ready-to-use urinary catheter and a catheter assembly for use in said method |
| CN108434579B (en) * | 2012-10-26 | 2021-03-16 | 泰利福生命科学无限公司 | Method for preparing a ready-to-use catheter, catheter assembly and package |
| CN105101794A (en) * | 2013-03-15 | 2015-11-25 | 美国消毒器公司 | Reactive surface coating having chemical decontamination and biocidal properties |
| CN108467617A (en) * | 2013-03-15 | 2018-08-31 | 美国消毒器公司 | Reactive surfaces coating with chemical decontamination and biocidal performance |
| CN108467617B (en) * | 2013-03-15 | 2020-08-21 | 美国消毒器公司 | Reactive surface coatings with chemical decontamination and biocidal properties |
| CN109069793A (en) * | 2016-04-12 | 2018-12-21 | 科洛普拉斯特公司 | Conduit tube component with the protective case selectively eliminated |
| CN109069793B (en) * | 2016-04-12 | 2021-07-09 | 科洛普拉斯特公司 | Catheter assembly with selectively eliminated protective sheath |
| US11154688B2 (en) | 2016-04-12 | 2021-10-26 | Coloplast A/S | Catheter assembly with a protective sleeve inside of a package |
| CN112969647A (en) * | 2018-11-12 | 2021-06-15 | 电化株式会社 | Packaging bag and packaging box for containing phosphor |
| WO2022016636A1 (en) * | 2020-07-23 | 2022-01-27 | 苏州微比特自动化有限公司 | Packaging bag |
| CN113288587A (en) * | 2021-07-28 | 2021-08-24 | 南通跃香拉链有限公司 | Outdoor first aid is with stanching bandage |
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| Publication number | Publication date |
|---|---|
| CN1753702B (en) | 2012-04-18 |
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