WO2001070199A1 - Matrices containing nitric oxide donors and reducing agents and their use - Google Patents
Matrices containing nitric oxide donors and reducing agents and their use Download PDFInfo
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- 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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- nitric oxide
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- 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, pantothenic acid
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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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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- 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
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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.
Abstract
Description
Claims
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CA002403818A CA2403818A1 (en) | 2000-03-20 | 2001-03-20 | Matrices containing nitric oxide donors and reducing agents and their use |
IL15160401A IL151604A0 (en) | 2000-03-20 | 2001-03-20 | Matrices containing nitric oxide donors and reducing agents |
EP01920538A EP1267837A4 (en) | 2000-03-20 | 2001-03-20 | Matrices containing nitric oxide donors and reducing agents and their use |
JP2001568397A JP2003527209A (en) | 2000-03-20 | 2001-03-20 | Matrix containing nitric oxide donor and reducing agent and use thereof |
MXPA02009236A MXPA02009236A (en) | 2000-03-20 | 2001-03-20 | Matrices containing nitric oxide donors and reducing agents and their use. |
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 |
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US19057100P | 2000-03-20 | 2000-03-20 | |
US19054600P | 2000-03-20 | 2000-03-20 | |
US60/190,571 | 2000-03-20 | ||
US60/190,546 | 2000-03-20 |
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JP (1) | JP2003527209A (en) |
AU (2) | AU4757901A (en) |
CA (1) | CA2403818A1 (en) |
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- 2001-03-20 WO PCT/US2001/008806 patent/WO2001070199A1/en active IP Right Grant
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Also Published As
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AU2001247579B2 (en) | 2005-01-06 |
EP1267837A1 (en) | 2003-01-02 |
JP2003527209A (en) | 2003-09-16 |
EP1267837A4 (en) | 2006-05-03 |
IL151604A0 (en) | 2003-04-10 |
AU4757901A (en) | 2001-10-03 |
MXPA02009236A (en) | 2004-04-05 |
CA2403818A1 (en) | 2001-09-27 |
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