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WO2001070199A1 - Matrices renfermant des donneurs d'oxyde nitrique ainsi que des agents reducteurs et leur utilisation - Google Patents

Matrices renfermant des donneurs d'oxyde nitrique ainsi que des agents reducteurs et leur utilisation Download PDF

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Publication number
WO2001070199A1
WO2001070199A1 PCT/US2001/008806 US0108806W WO0170199A1 WO 2001070199 A1 WO2001070199 A1 WO 2001070199A1 US 0108806 W US0108806 W US 0108806W WO 0170199 A1 WO0170199 A1 WO 0170199A1
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Prior art keywords
nitric oxide
matrix
donor
composition
reductant
Prior art date
Application number
PCT/US2001/008806
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English (en)
Inventor
Yi-Ju Zhao
James A. Braatz
Gerald M. Rosen
Original Assignee
Novovascular, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Novovascular, Inc. filed Critical Novovascular, Inc.
Priority to JP2001568397A priority Critical patent/JP2003527209A/ja
Priority to EP01920538A priority patent/EP1267837A4/fr
Priority to IL15160401A priority patent/IL151604A0/xx
Priority to AU4757901A priority patent/AU4757901A/xx
Priority to AU2001247579A priority patent/AU2001247579B2/en
Priority to MXPA02009236A priority patent/MXPA02009236A/es
Priority to CA002403818A priority patent/CA2403818A1/fr
Publication of WO2001070199A1 publication Critical patent/WO2001070199A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
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    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
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    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/114—Nitric oxide, i.e. NO
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings

Definitions

  • This invention relates to matrices that release nitric oxide.
  • the invention relates to matrices containing a compound that releases nitric oxide (NO) and, optionally, a reducing agent that promotes NO release from the matrix.
  • NO nitric oxide
  • the invention also relates to uses of such matrices.
  • Invasive therapy such as vascular catheterization can be complicated by local infection and induced sepsis, which usually causes the failure of the therapy and is often life-threatening.
  • About 6% ⁇ 10% catheters used for long-term venous access become infected (Bernard RW, et al., "Subclavian vein catheterization: a prospective study. II. Infectious complications," Ann Surg 173:191 , 1971 ; Uldall PR, Joy C, Merchant N., "Further experience with a double-lumen subclavian cannula for hemodialysis, Trans Am Soc Artif Intern Organs 28:71, 1982).
  • the catheter can allow microorganisms to gain access directly into the patient's vascular system.
  • Biomaterials may alter host humoral and cellular immune response.
  • the relatively hydrophobic property of the biomaterial makes it easy for bacteria to adhere to its surface.
  • Endoscopic catheters and instruments suffer similar problems.
  • Efforts have been made to reduce catheter infection, such as modifying the biomaterial surface to diminish bacterial adhesion, and binding antibiotics to the surface of biomaterials.
  • catheter infection such as modifying the biomaterial surface to diminish bacterial adhesion, and binding antibiotics to the surface of biomaterials.
  • none of these has been successfully used in clinical practice, and administering antibiotics systemically is unsatisfactory.
  • Catheter-induced infection still remains a problem to be solved.
  • Nitric oxide-containing compounds may be characterized into several groups. (1) N-nitroso compounds are stable and do not readily release NO absent hydrolysis. In addition, N-nitroso compounds present risks of carcinogenicity. (2) A variety of S-nitrosothiols are known to generate NO in vivo. (3) C-nitroso compounds tend to be stable and release NO at body temperature, as in Rosen et al., U.S.
  • Nitrosyl-containing organometallic compounds are described in Rosen et al., U.S. 5,797,887. According to the latter patent, decomposition of a nitrosyl-containing organometallic compound, such as nitroprusside, into NO is restricted by a polymer coating with a small porosity that inhibits the diffusion of blood-borne reductants to the NO-releasing compound; yet this small porosity allows NO to diffuse through the polymer into the surrounding fluid. There is a need for matrices demonstrating enhanced release of NO.
  • Green, U.S. 5,944,444 describes release of NO from biodegradable polymer matrices containing nitrites in an acid environment.
  • the picomolar concentrations of NO released are undesirably low, and are not sustained over time.
  • the requirement of a low pH environment is inconsistent with use at physiological pH as in blood and other tissues.
  • Polymer matrices containing porosigens taught in the prior art, e.g., Eury, et al., U.S. 5,605,696, designed to facilitate the release of the therapeutic drug from the polymer coating into the vasculature, are unsatisfactory for enhancing nitric oxide release from nitric oxide donors.
  • Nitroprusside (as in, for examp e, so um n troprusside or SNP) has drawbacks w en administered systematically as a NO donor, including short biological half time and systemic effects. There is a need for techniques that would prolong SNP biological effects and limit SNP effects to a local area.
  • the invention relates to compositions that release NO and uses thereof.
  • the self contained system of the invention may be used as a drug delivery device or a coating on a medical device that contacts blood or other body fluids to bring about biological effects. Desired biological effects include preventing aggregation of platelets and inhibiting proliferation of tissue within or near the device (which could decrease functioning of the device), and antimicrobial effects. Further, the favorable effects of the NO release include reducing damage caused by the device itself, and providing a broadened therapeutic benefit.
  • the matrix may comprise a polymer.
  • Nitric oxide donors may be nitrosyl-containing organometallic compounds, or S-nitroso compounds.
  • the NO donor is a reducible NO donor such as sodium nitroprusside or S-nitrosoglutathione and may be present in an amount between about 0.1% and about 50% and preferably from about 1% to about 10%.
  • the invention is a composition comprising means for releasing NO in the presence of a reducing agent, and means for incorporating the NO releasing compound with a reducing agent together in a hydrophobic matrix.
  • the invention is a method for improving the performance of a device in a target medium by providing the device with a surface comprising a hydrophobic matrix comprising a compound that releases NO in the presence of a reductant, and associated therewith a reductant, the matrix being capable of releasing NO into the target medium in an amount effective to produce a desired effect.
  • the desired effect may be to: inhibit cell proliferation, retard growth of cancer cells, act as a second messenger in stimulating host immune response toward bacteria, viruses, fungi, parasites and other microbes and cancer cells, promote gastrointestinal motility, stimulate penile erection, relax the uterus during pregnancy, dilate blood vessels, inhibit platelet adhesion, aggregation, and activation, inhibit neutrophil adhesion, and regulate smooth muscle tone. Inhibition of target cell growth is particularly preferred.
  • the invention is a method comprising providing a first compound that releases NO when reduced, providing a second compound that reduces the first compound, the first and second compounds being associated together within a hydrophobic matrix, contacting the hydrophobic matrix with a target medium, allowing the second compound to reduce the first compound so as to produce NO, and selectively allowing the NO to be released from the matrix into the target medium.
  • S-nitrosoglutathione One or more donors may be used depending on the circumstances.
  • a biological medium is a preferred target medium.
  • the biological medium is preferably a biological fluid such as blood or urine or interestitial fluid. It may be a non-fluid tissue such as skin, cells, or a urethral lining.
  • the target cells are preferably one or more selected from the group consisting of bacteria, fungi, virally infected cells, parasitic microorganisms, and cancer cells.
  • the method is preferably effective such that the growth rate inhibition is at least about 25%, preferably about 50%, or greater than about 90%. In most preferred embodiments, the method kills target cells. More particularly, the method may extend the length of time for 50% of saturation to occur (T 50 ) in a growth medium by 25%, 50%, double, or longer. The method may reduce the count of cells that grow on a surface such as an interventional catheter within a given period by 25%, 50%, or 90%. Most preferably, the method completely prevents growth of cells on such surfaces.
  • the nitrosyl-containing organometallic compound is preferably nitroprusside
  • the S-nitrosothiol is preferably S-nitrosoglutathione
  • the hydrophobic polymer matrix preferably comprises silicone
  • the reductant is preferably ascorbic acid or glutathione.
  • the coating inhibits the diffusion into the polymer matrix of blood-borne reductants, but is nonetheless able to release NO without exposure to light or hydrolysis.
  • a further embodiment of the invention envisions providing a tissue contacting surface that releases NO, thereby having improved properties such that it is less susceptible to infection, and has lower likelihood of failure by for example, inhibiting cell proliferation such as myointimal hype ⁇ lasia.
  • a coating is able to release NO without hydrolysis.
  • Nitric oxide may be generated by reduction, thermolysis, nucleophilic decomposition, electrophilic decomposition, catalysis and combinations thereof. Reduction is a preferred pathway for generating nitric oxide; thus, preferred nitric oxide releasing compositions include a reductant.
  • the claimed invention relies on a specific kind of NO donor: a therapeutic agent precursor that produces NO in therapeutic amounts, such as SNP or S-nitrosoglutathione (GSNO).
  • a therapeutic agent precursor that produces NO in therapeutic amounts, such as SNP or S-nitrosoglutathione (GSNO).
  • Preferred compositions include a reductant such as ascorbate, retained together with the NO donor in the matrix. Decomposition of SNP or GSNO by ascorbic acid within the matrix produces a by-product, NO. It is NO, not SNP or GSNO, which diffuses from within the polymer into the blood stream or other bodily fluids.
  • Advantages of this invention include:
  • Toxic byproducts of NO donor decomposition such as cyanide in the case of nitroprusside, may be trapped in the coating, preventing or reducing toxic response to these byproducts.
  • Release of effective amounts o NO accord ng to the invention occurs within a controlled solid matrix, and does not involve releasing the NO donor into the biological medium to generate NO there, under poorly controllable conditions.
  • compositions according to the invention that contain a reducing agent in the matrix include: 3) NO release does not depend on exterior reducing agents, light or hydrolysis. It can provide a controlled release of NO by varying the concentration of the reductant in the polymer that is applied onto the surface of implanted devices and catheters.
  • the invention differs from the prior art in the use of nitrosyl-containing organometallic compounds, S-nitroso compounds, and C-nitroso compounds as nitric oxide-releasing antimicrobial agents, in a device coating with a biostable matrix that includes and retains such compounds, where the device exhibits cytotoxic or cytostatic effects.
  • compositions of the invention satisfy a long felt need for a composition that releases NO in a controlled pattern.
  • This invention is contrary to the teachings of the prior art in that it associates nitroso-containing compounds with reductants in the polymer to release NO, whereas the prior art taught inhibiting the ability of reductants to diffuse into the polymer. Further objectives and advantages will become apparent from a consideration of the description, drawings, and examples.
  • Figure 1 shows NO release from SNP/Si coating containing 1% L-ascorbic acid (LAA) in the dark.
  • LAA L-ascorbic acid
  • Figure 2 shows NO release from SNP/Si coating containing 10% L-ascorbic acid (LAA) in the dark.
  • LAA L-ascorbic acid
  • Figure 3 shows NO release from GSNO/Si coating containing 3% L-ascorbic acid (LAA) in the dark.
  • LAA L-ascorbic acid
  • Figure 4 shows the inhibitory effects of SNP/Si coating on S. aureus growth.
  • Figure 5 shows the inhibitory effects of SNP/Si coating on S aureus growth starting from a lower bacterial concentration.
  • Figure 6 shows the inhibitory effects of SNP/Si coating on E. coli growth.
  • Figure 7 shows the inhibitory effects of SNP/Si coating on E. coli growth starting from a lower bacterial concentration.
  • Figure 8 shows that SNP and GSNO with a reducing agent inhibits growth of bacteria.
  • a device according to the invention may be a medical, veterinary, or laboratory device having a surface that contacts a biological medium in use.
  • These include blood vessel and urinary tract implants such as catheters, stents, intraco ⁇ oreal or extraco ⁇ oreal blood circuits, endoscopy equipment, insertable laparascopic devices, implants of bone, polymer, metal, or composites, artificial joints, membranes, tubing, grafts, and other devices inserted into biological media.
  • the materials from which these devices may he made include plastic, sta nless stee , n t no , acron, po ytetra uoroet y ene, and countless ot er mate als known to practitioners.
  • NO donor refers to a compound that releases NO on decomposition.
  • reducible NO donor refers to a nitrosyl-containing compound that releases NO in the presence of a reducing agent under the mild conditions encountered within a biostable hydrophobic polymer matrix.
  • NO donors include reducible NO donors and others.
  • a target cell is any cell or cell population that is targeted for growth inhibition or killing. Examples include bacteria, fungi, viruses, parasitic microorganisms, cancer cells, and cells that are foreign or undesirable in a patient animal such as a human or animal.
  • Growth inhibition means that the method results in a growth rate slower than that which would be present in the absence of the inventive method. The extent of inhibition may be small or complete, and the method may involve killing cells (reversing the growth of the population).
  • the target medium is one that does not prevent the NO donor from reacting within the matrix to produce NO and release it into the medium.
  • Nitric oxide is generally considered hydrophobic.
  • the target medium is a biological medium, such as an aqueous liquid like blood, urine, interstitial fluid, or cell growth medium in vitro.
  • the liquid is preferably at physiologic pH or is pH neutral, i.e. having a pH greater than about 5, and most preferably has a pH of about 7 or slightly above, such as blood.
  • the medium may also be tissue such as skin, internal tracts, or interstitial tissue.
  • Nitrosyl-containing organometallic compounds such as sodium nitroprusside, are readily susceptible to reduction, and are preferred.
  • S-nitroso compounds such as S- nitrosoglutathione
  • the release of NO from the NO donor is not pH dependent. The practitioner will be able to use such nitrosyl-containing organometallic or S-nitroso compounds, selecting those that generate NO in the presence of a reducing agent and a hydrophobic matrix, without toxic byproducts.
  • Re uc ng agents accor ng to t e nvent on nc u e ascor c ac an ot ers t at are effective to reduce the reducible NO donor in the polymer matrix.
  • the reductant must be selected to be compatible with the reducible NO donor.
  • examples of other reducing agents include cysteine, penicillamine, N-acetylcysteine, glutathione, mercaptosuccinic acid, thiosalicyhc acid, methylthiosalicylic acid, dithiothreitol, dithioerythritol, 2-mercaptoethanol, and FeCl 2 .
  • a biostable matrix according to the invention is preferably hydrophobic, that is, one that absorbs a limited amount of water, preferably less than 10-20%, although other, less hydrophobic polymers absorbing 50% or 100% of their weight in water, or higher, may also be suitable according to the invention.
  • Any biostable matrix is useable as long as it retains the nitric oxide donor, reductant, if present, and other reactants and by-products, while releasing nitric oxide, and prevents unwanted or uncontrolled reactions resulting from water penetration.
  • the matrix may be hydrated before contacting the biological medium.
  • Polymer matrices are preferred for their simplicity, although ceramic or other types of alloys could accomplish the same function. Silicone is a preferred polymer.
  • hydrophobic polymer examples include but are not limited to: PVC, polystyrene, polymethylmethacrylate (PMMA), polyolefms, polyfluorocarbons, etc.
  • PMMA polymethylmethacrylate
  • the hydrophobic matrix must entrap and retain the reducible NO donor and reductant together in a reactive relationship so they are not released in a significant amount, but must permit the NO to be released.
  • a polyurethane matrix releases ascorbic acid and is therefore incompatible with the inventive compositions absent modification according to the invention.
  • Sustained release in this context means that the concentration does not drop below a threshold of effectiveness and/or remains within a certain proportion of the initial concentration for a suitable period. For example, in some applications it is desirable that the concentration not drop by more than one order of magnitude, e.g., 1 nmole, over a two week period. In other applications the period of sustained release may need to be shorter (e.g. minutes) or longer (e.g. months). In yet other applications, the effective range may be broader.
  • the inventive method relates to inhibition of non-platelet target cell growth.
  • inhibition of platelet aggregation and anti-restenosis effects are referred to specifically but not as inhibition of target cell growth.
  • the invention is better understood upon consideration of the following non-limiting examples illustrating preferred embodiments of the invention. Periods skilled in the art may identify other embodiments which are within the scope of the invention upon consideration of the examples.
  • RT2 dissolve 0.5 g N-(l-Naphtyl) ethylenediamine in 500 ml distilled water. Mix RT1 and RT2 in the ratio 1 :1 before use.
  • Nitric oxide release from SNP/Si coating The coated flask was filled with PBS, or TSB 15 ml. The flasks were placed in a shaking incubator, shaking speed 200 RPM @ 37°C. Samples were collected for nitrite assay. A curve of accumulation of nitrite was generated. Bacterial growth curve: 15 ml TSB was placed in each flask. Equal amount of bacteria was added to each flask. The flasks were placed in a shaking incubator, shaking 200 RPM @ 37°C. Samples were collected for O.D. measurement. An accumulation curve were generated.
  • SNP/silicone coatings inhibit bacteria growth. Flasks were coated with silicone containing 1%, 5%, and 10% SNP (w/v). A flask coated with only silicone was used as control (see method 1). Light absorbency was measured (@ 600 nm) to evaluate bacteria growth. Figures 4 and 5 present the results of experiments with S. aureus. Figures 6 and 7 show the results of experiments with E. coli. A very high titer of bacteria, about 400,000 cells, was transferred to each flask ( Figures 4, 6). Compared with control, SNP/Si coating inhibits the growth of S. aureus and E. coli in a dose-dependent manner.
  • These results support the existence of a dose-dependent relationship between release of NO from a nitrosyl-containing organometallic compound and cell growth inhibition. The results also support the use of matrices that are less hydrophobic than silicone.
  • Segments of polyurethane catheter for extraco ⁇ oreal blood dialysis were coated by dipping in a solution of silicone in tetrahydrofuran and with or without the other components, and allowed to dry. The dipping process was repeated three times.
  • the coatings tested were: 1) silicone, as control; 2) silicone plus 1% (w/v) L-ascorbic acid (AA) as control; 3) silicone plus 5% (w/v) SNP and 1% AA; and 4) silicone plus 1% S- nitrosoglutathione (GSNO) (Sigma) and 1 % AA.
  • the coated catheter segments were placed in 15 ml plastic test tubes containing 10 ml Tryptic Soy Broth. An equal amount of E. coli was added to each tube. The tubes were put in a shaking incubator. The speed was set at 200 RPM, and temperature 37°C. Samples were collected for O.D. measurement every hour. Cumulative growth curves were plotted.

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Abstract

Cette composition, qui comprend une matrice hydrophobe, un donneur d'oxyde nitrique (NO) susceptible d'être réduit ainsi qu'un agent réducteur intrinsèque associé au donneur de NO dans la matrice, libère de la matrice une quantité efficace de NO après humectation à un pH physiologique, indépendamment de la présence ou de l'absence d'agents réducteurs extrinsèques. Cette composition inhibe la croissance de cellules cibles dans un milieu cible.
PCT/US2001/008806 2000-03-20 2001-03-20 Matrices renfermant des donneurs d'oxyde nitrique ainsi que des agents reducteurs et leur utilisation WO2001070199A1 (fr)

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JP2001568397A JP2003527209A (ja) 2000-03-20 2001-03-20 一酸化窒素供与体及び還元剤を含有するマトリックス並びにその使用
EP01920538A EP1267837A4 (fr) 2000-03-20 2001-03-20 Matrices renfermant des donneurs d'oxyde nitrique ainsi que des agents reducteurs et leur utilisation
IL15160401A IL151604A0 (en) 2000-03-20 2001-03-20 Matrices containing nitric oxide donors and reducing agents
AU4757901A AU4757901A (en) 2000-03-20 2001-03-20 Matrices containing nitric oxide donors and reducing agents and their use
AU2001247579A AU2001247579B2 (en) 2000-03-20 2001-03-20 Matrices containing nitric oxide donors and reducing agents and their use
MXPA02009236A MXPA02009236A (es) 2000-03-20 2001-03-20 Matrices que contienen donadores de oxido nitrico y agentes reductores, y su uso.
CA002403818A CA2403818A1 (fr) 2000-03-20 2001-03-20 Matrices renfermant des donneurs d'oxyde nitrique ainsi que des agents reducteurs et leur utilisation

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US6946484B2 (en) 2000-04-26 2005-09-20 Cellegy Pharmaceuticals, Inc. Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype
US7678391B2 (en) 2000-04-26 2010-03-16 Queen's University At Kingston Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype
US7700819B2 (en) 2001-02-16 2010-04-20 Kci Licensing, Inc. Biocompatible wound dressing
US7763769B2 (en) 2001-02-16 2010-07-27 Kci Licensing, Inc. Biocompatible wound dressing
US20110250152A1 (en) * 2003-06-30 2011-10-13 Rosen Gerald M Anti-Microbial Dental Formulations for the Prevention and Treatment of Oral Mucosal Disease
EP2416731A1 (fr) * 2009-03-11 2012-02-15 Teleflex Medical Incorporated Dispositifs médicaux contenant du nitroprussiate et des agents antimicrobiens
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
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CN107823644A (zh) * 2017-11-07 2018-03-23 福州大学 一种no供体化合物在制备抑制富含巯基分子的肿瘤细胞的侵袭和转移能力药物中的应用
US10898617B2 (en) 2017-01-21 2021-01-26 Biocrede Inc. Medical products and methods configured for controlled release of nitric oxide
US11160932B2 (en) 2008-06-19 2021-11-02 Excelsior Medical Corporation Antiseptic cap that releases a gas such as nitric oxide
US11219706B2 (en) 2009-03-11 2022-01-11 Arrow International Llc Enhanced formulations for coating medical devices
US11229746B2 (en) 2006-06-22 2022-01-25 Excelsior Medical Corporation Antiseptic cap
US11351353B2 (en) 2008-10-27 2022-06-07 Icu Medical, Inc. Packaging container for antimicrobial caps
US11389634B2 (en) 2011-07-12 2022-07-19 Icu Medical, Inc. Device for delivery of antimicrobial agent into trans-dermal catheter
US11400195B2 (en) 2018-11-07 2022-08-02 Icu Medical, Inc. Peritoneal dialysis transfer set with antimicrobial properties
CN114868846A (zh) * 2022-04-25 2022-08-09 闽江学院 外源性一氧化氮供体gsno作为饲料添加剂的应用
US11433215B2 (en) 2018-11-21 2022-09-06 Icu Medical, Inc. Antimicrobial device comprising a cap with ring and insert
US11497904B2 (en) 2016-10-14 2022-11-15 Icu Medical, Inc. Sanitizing caps for medical connectors
US11517732B2 (en) 2018-11-07 2022-12-06 Icu Medical, Inc. Syringe with antimicrobial properties
US11517733B2 (en) 2017-05-01 2022-12-06 Icu Medical, Inc. Medical fluid connectors and methods for providing additives in medical fluid lines
US11534595B2 (en) 2018-11-07 2022-12-27 Icu Medical, Inc. Device for delivering an antimicrobial composition into an infusion device
US11541221B2 (en) 2018-11-07 2023-01-03 Icu Medical, Inc. Tubing set with antimicrobial properties
US11541220B2 (en) 2018-11-07 2023-01-03 Icu Medical, Inc. Needleless connector with antimicrobial properties
US11559467B2 (en) 2015-05-08 2023-01-24 Icu Medical, Inc. Medical connectors configured to receive emitters of therapeutic agents
US11944776B2 (en) 2020-12-07 2024-04-02 Icu Medical, Inc. Peritoneal dialysis caps, systems and methods
US11998715B2 (en) 2014-05-02 2024-06-04 Excelsior Medical Corporation Strip package for antiseptic cap
US12076521B2 (en) 2011-05-23 2024-09-03 Excelsior Medical Corporation Antiseptic cap

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WO2007064895A2 (fr) * 2005-12-02 2007-06-07 The Regents Of The University Of Michigan Compositions polymeres, revetements et dispositifs, et procedes de fabrication et d'utilisation de ceux-ci
HU0800031D0 (en) * 2008-01-16 2008-03-28 Biotech Hungary Kutato Es Fejl Method for stabilization of s-nitrosoglutathione and composition prepared by the same

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US6946484B2 (en) 2000-04-26 2005-09-20 Cellegy Pharmaceuticals, Inc. Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype
US8168232B2 (en) 2000-04-26 2012-05-01 Queen's University At Kingston Formulations and methods of using nitric oxide mimetics in cancer treatment
US7678391B2 (en) 2000-04-26 2010-03-16 Queen's University At Kingston Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype
US8084664B2 (en) 2001-02-16 2011-12-27 Kci Licensing, Inc. Biocompatible wound dressing
US7700819B2 (en) 2001-02-16 2010-04-20 Kci Licensing, Inc. Biocompatible wound dressing
US7763769B2 (en) 2001-02-16 2010-07-27 Kci Licensing, Inc. Biocompatible wound dressing
US8735644B2 (en) 2001-02-16 2014-05-27 Kci Licensing, Inc. Biocompatible wound dressing
US8163974B2 (en) 2001-02-16 2012-04-24 Kci Licensing, Inc. Biocompatible wound dressing
US7947299B2 (en) 2001-08-23 2011-05-24 Boston Scientific Scimed, Inc. Compositions and techniques for localized therapy
WO2003017989A1 (fr) * 2001-08-23 2003-03-06 Scimed Life Systems, Inc. Compositions et techniques pour une therapie localisee de la restenose
US7135189B2 (en) 2001-08-23 2006-11-14 Boston Scientific Scimed, Inc. Compositions and techniques for localized therapy
US20110250152A1 (en) * 2003-06-30 2011-10-13 Rosen Gerald M Anti-Microbial Dental Formulations for the Prevention and Treatment of Oral Mucosal Disease
US8877231B2 (en) * 2003-06-30 2014-11-04 Gerald Rosen Anti-microbial dental formulations for the prevention and treatment of oral mucosal disease
US8962029B2 (en) 2005-05-27 2015-02-24 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8956658B2 (en) 2005-05-27 2015-02-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US11691995B2 (en) 2005-05-27 2023-07-04 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403852B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403851B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US11229746B2 (en) 2006-06-22 2022-01-25 Excelsior Medical Corporation Antiseptic cap
US12042640B2 (en) 2006-06-22 2024-07-23 Excelsior Medical Corporation Antiseptic cap that releases a gas such as nitric oxide
US11684720B2 (en) 2006-06-22 2023-06-27 Excelsior Medical Corporation Antiseptic cap that releases a gas such as nitric oxide
US11160932B2 (en) 2008-06-19 2021-11-02 Excelsior Medical Corporation Antiseptic cap that releases a gas such as nitric oxide
US11351353B2 (en) 2008-10-27 2022-06-07 Icu Medical, Inc. Packaging container for antimicrobial caps
EP2416731A1 (fr) * 2009-03-11 2012-02-15 Teleflex Medical Incorporated Dispositifs médicaux contenant du nitroprussiate et des agents antimicrobiens
US11219706B2 (en) 2009-03-11 2022-01-11 Arrow International Llc Enhanced formulations for coating medical devices
EP2754413A1 (fr) * 2009-03-11 2014-07-16 Teleflex Medical Incorporated Dispositifs médicaux contenant du nitroprussiate et des agents antimicrobiens
EP2416731A4 (fr) * 2009-03-11 2012-11-21 Teleflex Medical Inc Dispositifs médicaux contenant du nitroprussiate et des agents antimicrobiens
US10376538B2 (en) 2009-08-21 2019-08-13 Novan, Inc. Topical gels and methods of using the same
US9737561B2 (en) 2009-08-21 2017-08-22 Novan, Inc. Topical gels and methods of using the same
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US11583608B2 (en) 2009-08-21 2023-02-21 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US9713652B2 (en) 2011-02-28 2017-07-25 The University Of North Carolina At Chapel Hill Nitric oxide-releasing S-nitrosothiol-modified silica particles and methods of making the same
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US12076521B2 (en) 2011-05-23 2024-09-03 Excelsior Medical Corporation Antiseptic cap
US11826539B2 (en) 2011-07-12 2023-11-28 Icu Medical, Inc. Device for delivery of antimicrobial agent into a medical device
US11389634B2 (en) 2011-07-12 2022-07-19 Icu Medical, Inc. Device for delivery of antimicrobial agent into trans-dermal catheter
US12186520B2 (en) 2011-07-12 2025-01-07 Icu Medical, Inc. Device for delivery of antimicrobial agent into a medical device
EP3102240A4 (fr) * 2013-02-07 2017-11-01 The Regents of The University of Michigan Polymeres bactericides/thromboresistants a liberation d'oxyde nitrique dopes par s-nitroso-n-acetylpenicillamine (snap)
US11103622B2 (en) 2013-02-07 2021-08-31 The Regents Of The University Of Michigan Thromboresistant/bactericidal s-nitroso-n-acetylpenicillamine (SNAP)-doped nitric oxide release polymers with enhanced stability
WO2014124125A2 (fr) 2013-02-07 2014-08-14 The Regents Of The University Of Michigan Polymères de libération d'oxyde nitrique dopés par de la s-nitroso-n-acétylpénicillamine (snap) thromborésistante/bactéricide ayant une stabilité améliorée
US20150366831A1 (en) * 2013-02-07 2015-12-24 The Regents Of The University Of Michigan Thromboresistant/bactericidal s-nitroso-n-acetylpenicillamine (snap)-doped nitric oxide release polymers with enhanced stability
EP2953660A4 (fr) * 2013-02-07 2016-09-21 Univ Michigan Polymères de libération d'oxyde nitrique dopés par de la s-nitroso-n-acétylpénicillamine (snap) thromborésistante/bactéricide ayant une stabilité améliorée
EP3673928A1 (fr) * 2013-02-07 2020-07-01 The Regents Of The University Of Michigan Polymères de libération d'oxyde nitrique dopés par de la s-nitroso-n-acétylpénicillamine (snap) thromborésistante/bactéricide ayant une stabilité améliorée
US11998715B2 (en) 2014-05-02 2024-06-04 Excelsior Medical Corporation Strip package for antiseptic cap
US11559467B2 (en) 2015-05-08 2023-01-24 Icu Medical, Inc. Medical connectors configured to receive emitters of therapeutic agents
US11497904B2 (en) 2016-10-14 2022-11-15 Icu Medical, Inc. Sanitizing caps for medical connectors
US10898617B2 (en) 2017-01-21 2021-01-26 Biocrede Inc. Medical products and methods configured for controlled release of nitric oxide
US11517733B2 (en) 2017-05-01 2022-12-06 Icu Medical, Inc. Medical fluid connectors and methods for providing additives in medical fluid lines
CN107823644A (zh) * 2017-11-07 2018-03-23 福州大学 一种no供体化合物在制备抑制富含巯基分子的肿瘤细胞的侵袭和转移能力药物中的应用
US11517732B2 (en) 2018-11-07 2022-12-06 Icu Medical, Inc. Syringe with antimicrobial properties
US11534595B2 (en) 2018-11-07 2022-12-27 Icu Medical, Inc. Device for delivering an antimicrobial composition into an infusion device
US11541220B2 (en) 2018-11-07 2023-01-03 Icu Medical, Inc. Needleless connector with antimicrobial properties
US11400195B2 (en) 2018-11-07 2022-08-02 Icu Medical, Inc. Peritoneal dialysis transfer set with antimicrobial properties
US11541221B2 (en) 2018-11-07 2023-01-03 Icu Medical, Inc. Tubing set with antimicrobial properties
US12201760B2 (en) 2018-11-07 2025-01-21 Icu Medical, Inc Medical device with antimicrobial properties
US11433215B2 (en) 2018-11-21 2022-09-06 Icu Medical, Inc. Antimicrobial device comprising a cap with ring and insert
US12109365B2 (en) 2018-11-21 2024-10-08 Icu Medical, Inc Antimicrobial device comprising a cap with ring and insert
US11944776B2 (en) 2020-12-07 2024-04-02 Icu Medical, Inc. Peritoneal dialysis caps, systems and methods
CN114868846A (zh) * 2022-04-25 2022-08-09 闽江学院 外源性一氧化氮供体gsno作为饲料添加剂的应用

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CA2403818A1 (fr) 2001-09-27
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EP1267837A4 (fr) 2006-05-03
JP2003527209A (ja) 2003-09-16
EP1267837A1 (fr) 2003-01-02
AU2001247579B2 (en) 2005-01-06
AU4757901A (en) 2001-10-03

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