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Publication numberWO2006100155 A1
Publication typeApplication
Application numberPCT/EP2006/050895
Publication date28 Sep 2006
Filing date13 Feb 2006
Priority date24 Mar 2005
Publication numberPCT/2006/50895, PCT/EP/2006/050895, PCT/EP/2006/50895, PCT/EP/6/050895, PCT/EP/6/50895, PCT/EP2006/050895, PCT/EP2006/50895, PCT/EP2006050895, PCT/EP200650895, PCT/EP6/050895, PCT/EP6/50895, PCT/EP6050895, PCT/EP650895, WO 2006/100155 A1, WO 2006100155 A1, WO 2006100155A1, WO-A1-2006100155, WO2006/100155A1, WO2006100155 A1, WO2006100155A1
InventorsTor Peters
ApplicantNolabs Ab
Export CitationBiBTeX, EndNote, RefMan
External Links: Patentscope, Espacenet
Device for wound care, and manufacturing method thereof, involving the use of nitric oxide
WO 2006100155 A1
Abstract
A device, and a manufacturing process of said device, is provided that allows for treatment of wounds. The device comprises a nitric oxide (NO) eluting polymer arranged to contact the wound area to be treated, such that a therapeutic dose of nitric oxide is eluted from said nitric oxide eluting polymer to said wound area, thus promoting healing of a wound at said wound area. The nitric oxide (NO) eluting polymer is integrated with a carrier material, such that said carrier material, in use, regulates and controls the elution of said therapeutic dosage of nitric oxide (NO). Furthermore, a manufacturing method for said device is disclosed.
Claims  (OCR text may contain errors)
1. A wound care device configured to treat at least one wound on a mammal body, wherein said device comprises a nitric oxide (NO) eluting polymer configured to elute a therapeutic dosage of nitrogen oxide (NO) when used for said treatment, and wherein said device is configured to expose a topical wound area of said wound on a body to said nitric oxide when said polymer, in use, elutes nitrogen oxide (NO) , c h a r a c t e r i z e d in that said nitric oxide (NO) eluting polymer is integrated with a carrier material, such that said carrier material, in use, regulates and controls the elution of said therapeutic dosage of nitric oxide (NO) .
2. Device according to claim 1, wherein said nitric oxide (NO) eluting polymer comprises diazeniumdiolate groups, S-nitrosylated groups, and O-nitrosylated groups, or any combination these.
3. Device according to claim 1 or 2, wherein said nitric oxide (NO) eluting polymer is L-PEI (linear polyethyleneimine) , loaded with nitric oxide (NO) through said diazeniumdiolate groups, S-nitrosylated groups, or 0- nitrosylated groups, or any combination these, arranged for release of the nitric oxide (NO) at said treatment site of said at least one wound on a body.
4. Device according to claim 1, wherein said nitric oxide eluting polymer is selected from the group comprising amino cellulose, amino dextrans, chitosan, aminated chitosan, polyethyleneimine, PEI-cellulose, polypropyleneimine, polybutyleneimine, polyurethane, poly (buthanediol spermate) , poly (iminocarbonate) , polypeptide, Carboxy Methyl Cellulose (CMC) , polystyrene, poly (vinyl chloride), and polydimethylsiloxane, or any combinations of these, and these mentioned polymers grafted to an inert backbone, such as a polysaccharide backbone or cellulosic backbone.
5. Device according to claim 1, wherein the device has a form selected from the group consisting of a condom/sheath, a sock, a patch/pad/dressing, ostomy bag, gaskets for ostomy bags, and a tape/coating, adapted to be applied on or at said treatment site of said at least one wound on a body for treatment of wounds .
6. Device according to claim 5, wherein said condom/sheath, sock, patch/pad/dressing, ostomy bag, gaskets for ostomy bags, and tape/coating is manufactured of polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC), protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these, and said condom/sheath, sock, patch/pad/dressing, ostomy bag, gaskets for ostomy bags, or tape/coating, includes said nitric oxide (NO) eluting polymer, is configured to, in use, elute said nitric oxide (NO) to said treatment site of said at least one wound on a body for treatment of said wounds.
7. Device according to any of claims 1 to 6, including a proton donor bag, sealed water sponge, or microencapsulated proton donor, configured to release a proton donor there from, when activated, to said device, and wherein said nitric oxide eluting polymer is activateable to elute nitric oxide (NO) upon contact with said proton donor.
8. Device according to claim 1 or 7, wherein said device is partly disintegrable when subjected to a proton donor.
9. Device according to claim 7 or 8, wherein said proton donor is selected from the group comprising water, blood, lymph, bile, methanol, ethanol, propanols, buthanols, pentanols, hexanols, phenols, naphtols, polyols, phosphates, succinates, carbonates, acetates, formats, propionates, butyrates, fatty acids, and amino acids, or any combinations of these.
10. Device according to claim 1 or 7, wherein said polymer comprises silver, configured to therapeutically treat said site of said at least one wound on the body.
11. Device according to claim 1 or 7, wherein said nitric oxide eluting polymer is comprised in the device in form of fibers, nano-particles or micro-spheres.
12. Device according to claim 11, wherein said fibres, nano-particles, or micro-spheres, are integrated in a gel, cream, foam, or hydrogel, or combinations thereof.
13. Device according to claim 11 or 12, wherein said nano-particles, or micro-spheres, are integrated with, preferably encapsulated in, a material, selected from the group consisting of polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.
14. Device according to claim 1, wherein said carrier material is selected from the group consisting of polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC), protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.
15. Device according to claim 1, wherein said nitric oxide eluting polymer comprises a secondary amine in the backbone or a secondary amine as a pendant.
16. Device according to claim 15, wherein a positive ligand is located on the neighbour atom to the secondary amine .
17. Device according to claim 1, 7, or 14, comprising an absorbent agent.
18. Device according to claim 17, wherein said absorbent agent is selected from the group comprising polyacrylate, polyethylene oxide, Carboxy Methyl Cellulose (CMC) , microcrystalline cellulose, cotton, or starch, or any combinations thereof.
19. Device according to claim 1, 7, 14, 15, 16, 17, or 18, comprising a cation, said cation stabilizing the nitric oxide eluting polymer.
20. Device according to claim 19, wherein said cation is selected from the group comprising Na+, K+, Li+, Be2+, Ca2+, Mg2+, Ba2+, and/or Sr2+, or any combinations thereof.
21. Device according to claim 1, wherein said device comprises a compound comprising a drug and said nitric oxide (NO) eluting polymer, and wherein said device is configured to expose said wound area to said drug and to said nitric oxide when said nitric oxide eluting polymer in use elutes nitrogen oxide (NO) , such that that wound area is more susceptible to said drug.
22. A device configured for therapeutic treatment, according to any of the preceding claims, wherein said device comprises a compound comprising a drug and a said nitric oxide (NO) eluting polymer, wherein said nitric oxide (NO) eluting polymer is configured to elute a therapeutic dosage of nitrogen oxide (NO) when used for said therapeutic treatment, wherein said device is configured to expose a treatment site in or on a body to said drug and to said nitric oxide when said nitric oxide eluting polymer in use elutes nitrogen oxide (NO) , such that that treatment site is more susceptible to said drug.
23. Device according to claim 1, wherein said carrier material is a hydrogel .
24. Device according to claim 1, wherein the nitric oxide eluting polymer is activateable by proton donors, wherein a the nitric oxide eluting polymer is, prior to use, stored separate from the proton donor until initiation of elution of nitric oxide therefrom.
25. Device according to claim 24, wherein the device is a syringe-type device having two separate containers, wherein a first container contains a proton donor-based NO release activation agent, such as a gel, and a second container contains a non proton donor-based gel, comprising the nitric oxide eluting polymer, wherein the syringe-type device is configured to provide admixing upon administration to said area of said wound site.
26. Device according to claim 1, wherein the NO eluting polymer and/or said carrier is non-fibrous.
27. A manufacturing process for a device configured to treat at least one wound on a mammal body, according to claim 1, comprising: selecting a nitric oxide (NO) eluting polymer configured to elute a therapeutic dosage of nitric oxide (NO) when used for said treatment, selecting a carrier material, which carrier material is configured to regulate and control the elution of said therapeutic dosage of nitric oxide (NO) , incorporating the NO-eluting polymer with said carrier material into an nitric oxide (NO) eluting material, such that said carrier material, in use of said device, regulates and controls the elution of said therapeutic dosage of nitric oxide (NO) , and deploying said nitric oxide eluting material into a suitable form, or as a coating onto a carrier, to form at least a part of said device, such that said device is configured to expose a topical wound area of said wound on said body to said nitric oxide when said NO-eluting polymer in use elutes nitric oxide (NO) .
28. The manufacturing process according to claim 27, wherein said deploying comprises electro spinning, air spinning, gas spinning, wet spinning, dry spinning, melt spinning, or gel spinning of NO-eluting polymer.
29. The manufacturing process according to claim 27 or 25, wherein said selecting said nitric oxide (NO) eluting polymer comprises selecting a plurality of nitric oxide (NO) eluting polymeric particles, preferably nano fibres, nano particles or micro spheres.
30. The manufacturing process according to claim 27 or 27, wherein said incorporating said NO-eluting polymer with said carrier material comprises integrating said NO- eluting polymer in said carrier material, spinning said NO- eluting polymer together with said carrier material, or spinning said NO-eluting polymer on top of said carrier material, in order to predefine nitric oxide eluting characteristics of said device.
31. The manufacturing process according to claim 27, further comprising integrating silver in said device.
32. The manufacturing process according to claim 27, further comprising microencapsulating a proton donor in micro capsules, and applying the micro capsules to said nitric oxide (NO) eluting material.
33. The manufacturing process according to claim 32, wherein said applying comprises pattern gluing, or spinning the NO eluting material onto said micro capsules .
34. The manufacturing process according to claim 32, comprising forming the micro capsules into a first film, tape, or sheath, forming a second film, tape, or sheath of said NO eluting material, and gluing the first film, tape, or sheath of micro capsules to said second film, tape, or sheath of said NO eluting material .
35. The manufacturing process according to claim 34, wherein said gluing comprises patterned gluing, such that a pattern is obtained including glue free spaces.
36. The manufacturing process according to claim 32, comprising forming the micro capsules into a first film, tape, or sheath, and directly spinning the NO eluting material onto the film, tape, or sheath of micro capsules, containing a proton donor.
37. The manufacturing process according to claim 32, comprising providing an activation indicator configured to indicate when the micro capsules are broken such that the NO eluting material is subjected to said proton donor to elute NO.
38. The manufacturing process according to claim 37, wherein said providing an activation indicator comprises providing a coloring agent inside the micro capsules.
39. The manufacturing process according to claim 37, wherein said providing an activation indicator comprises selecting a material for the micro capsules, or choosing a wall thickness of said micro capsules, that creates a sound when the micro capsules break.
40. The manufacturing process according to claim 37, wherein said providing an activation indicator comprises admixing a scent material into the micro capsules.
41. The manufacturing process according to claim 37, wherein said providing an activation indicator comprises providing a substance that changes color when it comes in contact with the proton donor.
42. Use of a nitric oxide (NO) eluting polymer for the manufacture of a device for the treatment of at least one wound, according to claim 1, wherein nitric oxide is loaded to said device so said device elutes nitric oxide (NO) from said eluting polymer in a therapeutic dose when used at a site of at least one wound on a body.
43. Use according to claim 42, wherein said therapeutic dose is 0.001 to 5000 ppm, such as 0.01 to 3000 ppm, such as 0.1 to 1000 ppm, such as 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, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 ppm.
44. A method of treating at least one wound, comprising applying a device, that comprises a nitric oxide (NO) eluting polymer configured for eluting a therapeutic dosage of nitrogen oxide (NO) when used for said treatment, and a carrier material, configured to regulate or control the elution of nitric oxide from said nitric oxide eluting polymer, thereby exposing said treatment site of said at least one wound on a body to said nitric oxide when said nitric oxide eluting polymer in use elutes nitrogen oxide (NO) by eluting a therapeutic dose of nitric oxide from said nitric oxide eluting polymer to said treatment site.
45. The method according to claim 44, wherein said site of said at least one wound is a head, face, neck, shoulder, back, arm, hand, stomach, genital, thigh, leg, or foot, of a body, and wherein said method comprises applying a condom/sheath, sock, patch/pad, cream, ointment, foam, hydrogel, and tape/coating to said head, face, neck, shoulder, back, arm, hand, stomach, genital, thigh, leg, or foot, of a body, for said exposure.
46. Use of nitric oxide (NO) in a therapeutic dose for therapeutically treating and/or preventing at least one wound on a body.
Description  (OCR text may contain errors)

DEVICE FOR WOUND CARE, AND MANUFACTURING METHOD THEREOF, INVOLVING THE USE OF NITRIC OXIDE

Field of the Invention This invention pertains in general to the field of a device for wound care, involving the use of nitric oxide (NO) . More particularly the invention relates to a device for performing said wound care, and a process for manufacturing of said device, involving the use of nitric oxide (NO) .

Background of the Invention

Wounds, of some sort, are a common occurrence in the daily life. These wounds may vary widely, depending on how they are obtained. Irrespectively, these wounds need to be taken care of in one way or another.

The normal way to take care of such wounds, according to the prior art, is to provide the wound with a wound care, such as plaster, bandage, dressing, wound dressing, pressure bandage etc., depending on the severity and size of the obtained wound.

However, the wound cares according to the prior art do only consider the stoppage of blood flow and prevention of microbial attacks in the inflicted wound. They do not promote healing or present an anti-microbial, antiinflammatory, or anti-viral, effect in a satisfactory way. Nitric oxide (NO) is a highly reactive molecule that is involved in many cell functions. In fact, nitric oxide plays a crucial role in the immune system and is utilized as an effector molecule by macrophages to protect itself against a number of pathogens, such as fungi, viruses, bacteria etc., and general microbial invasion. This improvement of healing is partly caused by NO inhibiting the activation or aggregation of blood platelets, and also by NO causing a reduction of inflammatory processes at the site of an implant. NO is also known to have an anti-pathogenic, especially an anti-viral, effect, and furthermore NO has an anti-cancerous effect, as it is cytotoxic and cytostatic in therapeutic concentrations, i.e. it has among other effects tumoricidal and bacteriocidal effects . NO has for instance cytotoxic effects on human haematological malignant cells from patients with leukaemia or lymphoma, whereby NO may be used as a chemotherapeutic agent for treating such haematological disorders, even when the cells have become resistant to conventional anti-cancer drugs. This anti- pathogenic and anti-tumour effect of NO is taken advantage of by the present invention, without having adverse effects .

However, due to the short half-life of NO, it has hitherto been very hard to treat viral, bacteria, virus, fungi or yeast infections with NO. This is because NO is actually toxic in high concentrations and has negative effects when applied in too large amounts to the body. NO is actually also a vasodilator, and too large amounts of NO introduced into the body will cause a complete collapse of the circulatory system. On the other hand, NO has a very short half-life of fractions of a second up to a few seconds, once it is released. Hence, administration limitations due to short half-life and toxicity of NO have been limiting factors in the use of NO in the field of anti-pathogenic and anti-cancerous treatment so far.

In recent years research has been directed to polymers with the capability of releasing nitrogen oxide when getting in contact with water. Such polymers are for example polyalkyleneimines, such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible with natural products, after the release of nitrogen oxide. Other example for NO eluting polymers are given in US-5, 770, 645, wherein polymers derivatized with at least one -NOx group per 1200 atomic mass unit of the polymer are disclosed, X being one or two. One example is an S- nitrosylated polymer and is prepared by reacting a polythiolated polymer with a nitrosylating agent under conditions suitable for nitrosylating free thiol groups .

Akron University has developed NO-eluting L-PEI molecule that can be nano-spun onto the surface of medical devices to be permanently implanted in the body, such as implanted grafts, showing significant improvement of the healing process and reduced inflammation when implanting such devices. According to US-6, 737, 447, a coating for medical devices provides nitric oxide delivery using nanofibers of linear poly (ethylenimine) -diazeniumdiolate . Linear poly (ethylenimine) diazeniumdiolate releases nitric oxide (NO) in a controlled manner to tissues and organs to aid the healing process and to prevent injury to tissues at risk of injury. Electrospun nano-fibers of linear poly (ethylenimine) diazeniumdiolate deliver therapeutic levels of NO to the tissues surrounding a medical device while minimizing the alteration of the properties of the device. A nanofiber coating, because of the small size and large surface area per unit mass of the nanofibers, provides a much larger surface area per unit mass while minimizing changes in other properties of the device.

However, the meaning of "controlled" in the context of US 6,737,447 is only directed to the fact that nitric oxide is eluted from the coating during a period of time. Therefore, the interpretation of "controlled" in respect of US 6,737,447 is different from the meaning of "regulating" in the present invention. "Regulate", according to the present invention is intended to be interpreted as the possibility to vary the elution of nitric oxide to thereby achieve different elution profiles. US 2004/0131753 discloses a coating for medical devices, which coating provides NO delivery by using nanofibers of L-PEI . The fibers according to US 2004/0131753 may be used for wound healing. Nothing in US 2004/0131753 is mentioned about how NO is released from the coating, and in particularly nothing is mentioned about proton donor dependant release of NO. As a matter of fact, US 2004/0131753 points out, and stresses, that the coating is insoluble in water. This can only be interpreted as the release of NO is initiated by something else than water. Furthermore, the elution of nitric oxide from the coating according to US 2004/0131753 is not regulated in any way.

WO 96/13164 describes water insoluble polymeric NONOate complexes, which are capable of accelerating wound repair through the controlled release of NO. The polymeric NONOate according to WO 96/13164 is PEI-C. Furthermore, the elution of nitric oxide from the polymer according to US 2004/0131753 is not regulated in any way.

US 2004/0259840 discloses nitric oxide releasing lipid molecules. Thus, US 2004/0259840 does not disclose a nitric oxide eluting polymer. The elution of nitric oxide from the lipid according to US 2004/0259840 is not regulated in any way.

US 6,261,594 discloses a chitosan based nitric oxide donor composition, comprising a modified chitosan polymer, for wound dressings. The elution of nitric oxide from the composition according to US 6,261,594 is not regulated in any way.

US 5,405,919 discloses a polymeric composition capable of releasing nitric oxide. In particular, US 5,405,919 discloses compositions comprising nitric oxide/nucleophile adducts which are bound to a polymer and which release nitric oxide in a physiological environment. Nothing is mentioned about integrating polyethyleneimine in other biocompatible polymers. Thus, the elution of nitric oxide from the composition according to US 5,405,919 is not regulated in any way.

Thus, the disclosure is both silent concerning an improvement of present technology in respect of treatment of wounds by the use of NO and a carrier material that regulates and/or controls the elution of nitric oxide. Hence, an improved, or more advantageous, device for the treatment of wounds is needed. It is desired that the device presents an improved wound healing and anti- microbial, anti-inflammatory, and anti-viral effect, would be advantageous, and in particular a device allowing for target treatment of wounds would be advantageous .

Summary of the Invention Accordingly, the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves, among others, at least some of the problems mentioned above, by providing a device for said treatment of wounds, a manufacturing method for the latter and a use of nitric oxide according to the appended patent claims .

According to one aspect of the invention, a device is provided that allows for target treatment of wounds . The device comprises a nitric oxide (NO) eluting polymer arranged to contact the area to be treated, such that a therapeutic dose of nitric oxide is eluted from said nitric oxide eluting polymer to said area.

According to another aspect of the invention, a manufacturing process for such a device is provided, wherein the process is a process for forming a device that allows for target treatment of wounds. The process comprises selecting a plurality of nitric oxide eluting polymeric particles, such as nano fibres, fibres, nano particles, or microspheres, and deploying said nitric oxide eluting particles in a condom/sheath, tape/coating, fibres, nano-particles, or micro-spheres to be comprised in said device. Alternatively the NO eluting particles are admixed to an ointment, gel, hydrogel, foam, cream, gel, or foam. The present invention has at least the advantage over the prior art that it provides target exposure of a wound to NO, whereby blood perfusion and vasodilatation are increased, simultaneously as an anti-viral, an antiinflammatory, and an anti-microbial, therapy is achievable.

Brief Description of the Drawings

These and other aspects, features and advantages of which the invention is capable of will be apparent and elucidated from the following description of embodiments of the present invention, reference being made to the accompanying drawings, in which

Fig. 1 is a schematic illustration of a patch/pad 10 according to an embodiment of the invention,

Fig. 2 is a schematic illustration of a tape or coating 20 according to an embodiment of the invention,

Fig. 3 is a schematic illustration of a condom/sheath 30 according to an embodiment of the invention,

Fig. 4 is a schematic illustration of a sock 40 according to an embodiment of the invention, and Fig. 5 is an illustration of two different elution profiles for two different mixtures of nitric oxide eluting polymer and carrier material .

Description of Embodiments The following description focuses on embodiments of the present invention applicable to a device, which allows for target treatment of wounds . With regard to nitric oxide (nitrogen monoxide, NO) , its physiological and pharmacological roles have attracted much attention and thus have been studied. NO is synthesized from arginine as the substrate by nitric oxide synthase (NOS) . NOS is classified into a constitutive enzyme, cNOS, which is present even in the normal state of a living body and an inducible enzyme, iNOS, which is produced in a large amount in response to a certain stimulus. It is known that, as compared with the concentration of NO produced by cNOS, the concentration of NO produced by iNOS is 2 to 3 orders higher, and that iNOS produces an extremely large amount of NO.

In the case of the generation of a large amount of NO as in the case of the production by iNOS, it is known that NO reacts with active oxygen to attack exogenous microorganisms and cancer cells, but also to cause inflammation and tissue injury. On the other hand, in the case of the generation of a small amount of NO as in the case of the production by cNOS, it is considered that NO takes charge of various protective actions for a living body through cyclic GMP (cGMP) , such as vasodilator action, improvement of the blood circulation, anti-platelet- aggregating action, anti-bacterial action, anti-viral action, anti-inflammatory action, anticancer action, acceleration of the absorption at the digestive tract, renal function regulation, neurotransmitting action, erection (reproduction), learning, appetite, and the like. Heretofore, inhibitors of the enzymatic activity of NOS have been examined for the purpose of preventing inflammation and tissue injury, which are considered to be attributable to NO generated in a large amount in a living body. However, the promotion of the enzymatic activity (or expressed amount) of NOS (in particular, cNOS) has not been examined for the purpose of exhibiting various protective actions for a living body by promoting the enzymatic activity of NOS and producing NO appropriately.

In recent years research has been directed to polymers with the capability of releasing nitrogen oxide when getting in contact with water. Such polymers are for example polyalkyleneimines, such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible. Another advantage is that NO is released without any secondary products that could lead to undesired side effects .

The polymers according to the present invention may be manufactured by electro spinning, gas spinning, air spinning, wet spinning, dry spinning, melt spinning, and gel spinning. Electro spinning is a process by which a suspended polymer is charged. At a characteristic voltage a fine jet of polymer releases from the surface in response to the tensile forces generated by interaction by an applied electric field with the electrical charge carried by the jet. This process produces a bundle of polymer fibres, such as nano-fibres. This jet of polymer fibres may be directed to a surface to be treated.

Furthermore, US 6,382,526, US 6,520,425, and US 6,695,992 disclose processes and apparatuses for the production of such polymeric fibres. These techniques are generally based on gas stream spinning, also known within the fiber forming industry as air spinning, of liquids and/or solutions capable of forming fibers .

Other example for NO eluting polymers are given in US-5, 770, 645, wherein polymers derivatized with at least one -NOX group per 1200 atomic mass unit of the polymer are disclosed, X being one or two. One example is an S- nitrosylated polymer and is prepared by reacting a polythiolated polymer with a nitrosylating agent under conditions suitable for nitrosylating free thiol groups . Akron University has developed NO-eluting L-PEI molecule that can be nano-spun onto the surface of permanently implanted medical devices, such as implanted grafts, showing significant improvement of the healing process and reduced inflammation when implanting such devices. According to US-6, 737, 447, a coating for medical devices provides nitric oxide delivery using nanofibers of linear poly (ethylenimine) -diazeniumdiolate . Linear poly (ethylenimine) diazeniumdiolate releases nitric oxide (NO) in a controlled manner.

However, the meaning of "controlled" in the context of US 6,737,447 is only directed to the fact that nitric oxide is eluted from the coating during a period of time, i.e that the nitric oxide not is eluted all in once. Therefore, the interpretation of "controlled" in respect of US 6,737,447 is different from the meaning of "regulating" in the present invention. "Regulate or control", according to the present invention is intended to be interpreted as the possibility to vary the elution of nitric oxide to thereby achieve different elution profiles.

A polymer comprising an O-nitrosylated group is also a possible nitric oxide eluting polymer. Thus, in one embodiment of the present invention, the nitric oxide eluting polymer comprises diazeniumdiolate groups, S- nitrosylated and O-nitrosylated groups, or any combinations thereof.

In still another embodiment of the present invention said nitric oxide eluting polymer is a poly (alkyleneimine) diazeniumdiolate, such as L-PEI-NO (linear poly (ethyleneimine) diazeniumdiolate) , where said nitric oxide eluting polymer is loaded with nitric oxide through the diazeniumdiolate groups and arranged to release nitric oxide at a treatment site.

Some other examples of a suitable nitric oxide eluting polymer are selected from the group comprising amino cellulose, amino dextrans, chitosan, aminated chitosan, polyethyleneimine, PEI-cellulose, polypropyleneimine, polybutyleneimine, polyurethane, poly (buthanediol spermate) , poly (iminocarbonate) , polypeptide, Carboxy Methyl Cellulose (CMC) , polystyrene, poly (vinyl chloride), and polydimethylsiloxane, or any combinations of these, and these mentioned polymers grafted to an inert backbone, such as a polysaccharide backbone or cellulosic backbone. In still another embodiment of the present invention the nitric oxide eluting polymer may be a O-derivatized NONOate . This kind of polymer often needs an enzymatic reaction to release nitric oxide.

Other ways of describing polymers, which may be suitable as nitric oxide eluting polymer, is polymers comprising secondary amine groups (=N-H) , such as L-PEI, or have a secondary amine (=N-H) as a pendant, such as aminocellulose .

In one embodiment of the device, said device is in form of a patch/pad, according to Fig. 1, which patch/pad is suitable to be applied on the face, arm, hand, thigh, back, stomach, neck, on which body part the wound to be treated is located.

In another embodiment of the present invention this patch/pad is attached by any suitable adhering means, such as materials that adhere to the skin.

In another embodiment of the device, said device may be manufactured in the form of a polyurethanes, or polyethylene, tape or coating, according to Fig. 2. This polyurethane tape or coating may easily be wrapped around, or applied on, the wounded area to be treated. At least the side facing the body may be covered with NO-eluting nano- particles, or micro-spheres, or nano-filament of NO-eluting L-PEI . When these particles or filaments get in contact with the moisture, in form of sweat, on the inside of the tape or coating, the elution of NO starts .

In other embodiments of the invention, the patch/pad or tape/coating may be manufactured by any other suitable material, such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of thesebiodegrad. The NO-eluting polymer may be integrated in, spun together with, or spun on top of, any of these materials in all of the embodiments of the present invention .

The device according to the present invention is applied on the area to be treated, such as any part of the body in need of treatment of at least one wound, such as the face, neck, shoulders, hands, arms, back, chest, stomach, bottom, thigh, genitals, lower leg, and/or foot.

When the patch/pad according to the present invention has been applied, an elution of NO is initiated by adding water in any possible way. This may for example be accomplished by applying a water soaked patch on said patch/pad, or spraying or bathing said patch/pad with water. Often, the moisture/water obtained from the sweat secreted underneath the device according to the present invention, is enough to obtain a satisfactory elution of NO from said NO eluting polymer.

The healing effect of the wound is obtained, as the NO eluting polymer elutes NO on the area to be treated, by an increased blood perfusion and vasodilatation, whereby an increased healing effect of the tissue of interest is achieved. The increased blood perfusion and vasodilatation may, in another embodiment of the present invention, result in an improved effect when combined with other wound care products, comprising active components. Thus, the synergistic effect from NO and other wound healing, or anti-microbial, anti-inflammatory, or anti-viral, components is within the scope of the present invention.

In other embodiments of the present invention the device is in form of fibres, nano-particles, or micro- spheres of a NO eluting polymer, which fibres, nano- particles, or micro-spheres are integrated in a gel, cream, or foam, that may either be in a smearing or compressed structure. In one of these embodiments the nitric oxide eluting polymer, such as powder, nano-particles or micro- spheres, can be incorporated in foam. The foam may have an open cell structure, which facilitates the transport of the proton donor to the nitric oxide eluting polymer. The foam can be of any suitable polymer such as polyurethane, polystyrene, polyester, polyvinylchloride, polyolefins, or latex. In another of these embodiments the device is in form of a cream, a gel or a combination of the two. Since the nitric oxide eluting polymer is activated by proton donors the nitric oxide eluting polymer has to be separate from the proton donor until one wants to initiate the elution of nitric oxide, i.e. use the device. One way to accomplish this is to have a syringe with two separate containers . In one container you have a proton donor-based gel and in the other a non proton donor-based gel, comprising the nitric oxide eluting polymer. Upon using the device the two gels are squeezed from the syringe and mixed together, the proton donor in the first gel comes in contact with the nitric oxide eluting polymer in the second gel and the elution of nitric oxide starts .

These fibres, nano-particles, or micro-spheres, may be formed from the NO-eluting polymers comprised in the present invention, for example polyalkyleneimines, such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible, after the release of nitrogen oxide. They may also be encapsulated in any suitable material, such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC), protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.

In the context of the present invention the term "encapsulating" is intended to be interpreted as fixating the nitric oxide eluting polymer in a three dimensional matrix such as a foam, a film, a nonwoven mat of nano- fibers or fibers, or other materials with the capability to fixate the NO eluting polymer, or enclosing the nitric oxide eluting polymer in any suitable material.

The fibres, nano-particles, or micro-spheres may also be integrated in a hydrogel, which is mixed directly before use .

This embodiment has the advantage of being able to penetrate pockets and corners in the skin, and/or wound, for closer elution of NO on the area to be treated.

In another embodiment of the invention, according to Fig. 3, the device is in form of a latex or rubber condom/sheath, said condom/sheath being covered with nano- filament of any of the NO-eluting polymers according to above, such as polyalkyleneimines, such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible, after the release of nitrogen oxide. In another embodiment of the present invention the condom/sheath is covered on the inside with nano-filament of L-PEI.

This condom/sheath may be in any suitable size, such as a suitable size for rolling said condom/sheath over the thigh, arm, neck, head, foot etc., to be treated. These sizes may for example vary from small, medium, and large sized condoms/sheaths in accordance with the different sizes, in respect of the different body parts, of persons in the population. The condom/sheath according to the invention may even have a size suitable for covering a foot, such as a sock, according to Fig. 4, or a foot- condom/sheath, or other specific part of the body, to be able to obtain treatment of a wound. According to an embodiment, the condoms/sheaths are coated with NO eluting nano fibres . According to another embodiment the condoms/sheaths are made of, or comprise nanofilaments, e.g. made by electro or gas jet spinning. According to a further embodiment the condoms/sheaths comprises microspheres eluting NO in use. Preferably the three aforementioned embodiments employ L-PEI material loaded with NO. Activation on NO release may be done by e.g. foot sweat, proton donor, such as water, sprayed onto the condoms/sheaths immediately prior to use, or a proton donor bag configured for releasing proton donor upon activation, e.g. by pushing onto the bag thus bursting (see below) .

When the NO-eluting condom/sheath according to certain embodiments of the present invention is treated with or gets in contact with the moisture, in form of secreted sweat, the NO-eluting condom/sheath starts to elute NO to the area to be treated. Alternatively the device is moistured or wettened immediately prior to application or use for controlling or activating the elution of NO. In another embodiment of the present invention the condom/sheath, sock, patch/pad, or tape/coating, is covered on the inside with NO-eluting nano-particles, or microspheres, according to above. When the nano-particles, or micro-spheres, according to this embodiment, gets in contact with the secreted moisture, in form of sweat, on the inside of the condom/sheath, they start to elute NO on the area to be treated. In yet another embodiment of the present invention the condom/sheath, sock, patch/pad, or tape/coating, contains a small proton donor bag or sealed proton donor sponge. This proton donor bag or sealed proton donor sponge is used to activate the elution of NO from the NO-eluting nano-particles, or micro-spheres. Persons that not easily sweat may be helped by the use of this embodiment.

In another embodiment of the present invention a nitric oxide eluting polymer is provided, and/or combined, with microencapsulated proton donor. This may for example be done by first manufacture micro capsules, containing a proton donor, such as water or water containing liquid, in a state of the art manner. These micro capsules are then applied on the NO eluting polymer. The application of the micro capsules on the NO eluting polymer may for example be done by gluing, such as pattern gluing, or instead spinning the NO eluting polymer onto said micro capsules. In this way a device or a system, comprising NO eluting polymer and micro encapsulated proton donor is manufactured. When the device or system is applied on the target area the device or system is compressed or squeezed. Said compression or squeezing results in breakage of the micro capsules. The NO eluting polymer is thus exposed to proton donor, and the elution of NO from the NO eluting polymer is initiated on the target area. In other embodiments of the present invention the proton donor inside the micro capsules is released by heating or shearing the micro capsules until the micro capsules are ruptured.

In still another embodiment the micro capsules are formed into a film, tape, or sheath. Thereafter, a film, tape, or sheath of an NO eluting polymer is glued onto the film, tape, or sheath of micro capsules. Preferably the film, tape, or sheath of the NO eluting polymer is glued onto the film, tape, or sheath of the micro capsules in patterned way. The obtained pattern includes spaces where there is no glue, in which spaces the proton donor will be transported to the NO eluting polymer once the micro capsules are broken from compression or squeezing. When the proton donor gets in contact with the NO eluting polymer the elution of NO starts. Thus, the combination of film, tape, or sheath of micro capsules and NO eluting polymer may be applied on a target area. Thereafter the combination is compressed or squeezed, which results in that the target area is exposed to NO. I yet another embodiment the NO eluting polymer is spun directly onto the film, tape, or sheath of micro capsules, containing proton donor. The combination of film, tape, or sheath of micro capsules and spun NO eluting polymer may be applied on a target area. Thereafter the combination is compressed or squeezed, which results in that the target area is exposed to NO.

In still another embodiment of the present invention the device or system is provided with an activation indicator. This activation indicator indicates when the micro capsules are satisfyingly broken, hence when the NO eluting polymer is subjected to enough proton donor to elute an efficient amount of NO. This activation indicator may for example be obtained by colouring the proton donor that is trapped inside the micro capsules. When the micro capsules are broken the coloured proton donor escapes the microcapsules and the colour gets visualised while efficiently wetting the NO eluting polymer. Another way of obtaining an activation indicator is to choose to manufacture the micro capsules in a material, or choose a wall thickness of said micro particles, that creates a sound when the micro capsules break. It is also possible to admix a scent in the proton donor, contained in the micro capsules. This results in that the user of the device or system may smell the scent when the proton donor escapes from the micro capsules after breakage thereof.

In another embodiment a substance that changes color when it comes in contact with water can be incorporated in the device. Thus when the water capsules or water bag breaks the material changes color, thereby indicating that the material is activated.

In another embodiment of the present invention the device or system only allows NO-elution in one direction. In this kind of embodiment one side of the device according to the invention has low permeability, or substantially no permeability, to nitric oxide. This may be accomplished by applying a material on one side of the device according to the invention that is not permeable to NO. Such materials may be chosen from the group comprising common plastics, such as fluoropolymers, polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these. This embodiment is also easy to manufacture as the NO eluting polymer, e.g. L-PEI (or nitric oxide eluting polymer and carrier material, which will be explained in more detail below) may be electro or gas-jet spun onto the surface of the device according to the invention of e.g. the mentioned plastics, latex, or cotton.

In still another embodiment the device is provided with one membrane, which is permeable to nitric oxide, on a first side of the device, and another membrane, which has low permeability or substantially no permeability to nitric oxide, on a second side of said device. This embodiment provides the possibility to direct the elution to said first of the device, while the elution of nitric oxide is substantially prevented from said second side. Thereby, a greater amount of nitric oxide will reach the intended area to be treated.

The activation of the nitric oxide eluting polymer may be accomplished by contacting said polymer with a suitable proton donor. In one embodiment the proton donor may be selected from the group comprising water, body fluids (blood, lymph, bile, etc.), alcohols (methanol, ethanol, propanols, buthanols, pentanols, hexanols, phenols, naphtols, polyols, etc.), aqueous acidic buffers (phosphates, succinates, carbonates, acetates, formats, propionates, butyrates, fatty acids, amino acids, etc.), or any combinations of these.

By adding a surfactant in the proton donor one can facilitate the wettening of the device. The surfactant lowers the surface tension and the activating fluid is easily transported throughout the device.

In another embodiment the fibres, nano-particles, or micro-spheres, may be integrated in a soluble film that disintegrates on the inside of the condom/sheath, sock, patch/pad, or tape/coating, according to the present invention, in order to elute NO at the area of interest when the soluble film gets in contact with the moisture, in form of sweat or from the water bag or sealed water sponge, on the area to be treated. When placed on an area to be treated the device provides prevention and treatment of wounds .

In another embodiment of the present invention the device only allows NO-elution in one direction. In this kind of embodiment one side of the device, such as condom/sheath, sock, patch/pad, or tape/coating, is non- permeable to NO. This may be accomplished by applying a material on one side of the device that is not permeable to NO. Such materials may be chosen from the group comprising common plasties, such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these. This embodiment is also easy to manufacture as the NO eluting polymer, e.g. L-PEI nano fibres may be electro or gas-jet spun onto the surface of the device of e.g. the mentioned plastics, latex, or cotton. In the case of a condom it may be rolled up, or a sheath may be turned outside in after manufacturing to protect the NO eluting polymer during packaging, transport and prior to use from external influences, being e.g. mechanical (abrasion of the polymer) , chemical (moisture deactivating the device prior to use) etc.

In yet another embodiment of the present invention the NO-eluting device is acting as a booster for drug eluting patches, e.g. pharmaceuticals, vitamins, nicotin, nitroglycerin, Non-Steroidal Anti-Inflammatory Drugs (NSAID) , such as diclofenac, ibuprofen, aspirin, naproxen, COX-2 inhibitors, choline magnesium trisalicylate, diflunisal, salsalate, fenoprofen, flurbiprofen, ketoprofen, oxaprozin, indomethacin, sulindac, tolmetin, meloxicam, piroxicam, meclofenamate, mefenamic acid, nabumetone, etodalac, ketorolac, celecoxib, valdecoxib, and rofecoxib; steroids, such as cortisone, prednisone, methylprednisolone, prednisolone, vitamin D, estrogen, cholestrol, beclomethasone, flunisolide, fluticasone, triamcinolone, desonide, clobetasol, alclometasole, desoximetasone, betamethasone, halcinonide and dexamethasone; pain reliefs, such as motrin, feldene, naprosyn, lidocaine, and prilocaine; and other substances, such as indinavirsulfate, finasteride, aprepitant, montelukast sodium, alendronate sodium, rofecoxib, rizatriptan benzoate, simvastatin, finasteride, ezetimibe, caspofungin acetate, ertapenem sodium, dorzolamide hydrochloride, timolol maleate, losartan potassium, and hydrochlorotiazide; etc. This embodiment presents a device with the advantage of combining two treatments, of significant value, in one treatment.

Hence, such devices may achieve a synergetic effect, when NO is eluted from the devices. NO has a vasodilatory effect on the region where the device having the combination compound actuates. Vasodilated tissue is more susceptible to certain medications and thus more easily treated by the medical preparations and still NO has in addition to that the anti-inflammatory, anti-bacterial etc. effect. Hence, an unexpected surprisingly effective treatment is provided.

In another embodiment according to the present invention NO eluting poymer is applied on devices for ostomy care, such as a ostomy bag, gaskets for said ostomy bag etc. This embodiment provides the advantage of providing anti-inflammatory, anti-bacterial, and anti-viral effect, which advantage is especially important in the early stages of ostomy.

In another embodiment according to the present invention NO eluting poymer is applied on a intravenous dressing. When the device is in form of a intravenous dressing, the area surrounding an intravenous catheter is provided with anti-microbial, anti-inflammatory, antithrombotic and anti-viral effect. This embodiment has the advantage of protecting an area which otherwise is exposed to a high possibility of getting in contact with infectious material .

The device elutes nitric oxide (NO) from said eluting polymer in a therapeutic dose, such as between 0.001 to 5000 ppm, such as 0.01 to 3000 ppm, such as 0.1 to 1000 ppm, such as 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, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 ppm. The concentration may vary widely depending on where the concentration is measured. If the concentration is measured close to the actual NO eluting polymer the concentration may be as high as thousands of ppm, while the concentration inside the tissue in this case often is considerably lower, such as between 1 to 1000 ppm.

In the embodiments of the present invention it may be suitable to control or regulate the time span of NO release from the device. This may be accomplished by integrating other polymers or materials in said device. These polymers or materials may be chosen from any suitable material or polymer, such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.

Three important factors in controlling and regulating the elution of nitric oxide from a nitric oxide eluting polymer are how quickly a proton donor comes in contact with the nitric oxide releasing polymer, such as a diazoliumdiolate group, the acidity of the environment surrounding the nitric oxide eluting polymer, and the temperature of the environment surrounding the nitric oxide releasing polymer (higher temperature promotes elution of nitric oxide) .

In one embodiment of the present invention a nitric oxide eluting polymer, such as L-PEI-NO, is mixed with a carrier polymer to slow down or prolong the elution of nitric oxide. Also, in another embodiment, the nitric oxide eluting polymer may be mixed with more than one carrier polymer, whereby be elution or release may be tailor made to fit specific needs. Such a need may for example be a low elution during a first period of time, when the environment of the nitric oxide eluting polymer is hydrophobic, and a faster elution during a second period of time, when the environment of the nitric oxide eluting polymer has been altered to be more hydrophilic. This may for example be accomplished by using biodegradable polymers, whereby a low elution during a first period of time is obtained, after which, when the hydrophobic polymer has been dissolved, the hydrophilic polymer provides a higher elution of nitric oxide. Thus, a more hydrophobic carrier polymer will give a slower elution of nitric oxide, since the activating proton donor, such as water or body fluid, will penetrate the carrier polymer slower. On the other hand, a hydrophilic polymer acts the opposite way. One example of an hydrophilic polymer is polyethylene oxide, and one example of an hydrophobic polymer is polystyrene. These carrier polymers may be mixed with the nitric oxide eluting polymer and then electrospun to suitable fibers. The skilled person in the art knows which other polymers may be used for similar purposes. Fig. 5 illustrates two elution profiles (NO concentration vs. time) for two different polymer mixtures; a nitric oxide eluting polymer mixed with a hydrophilic carrier polymer in an acidic environment (A) , and a nitric oxide eluting polymer mixed with a hydrophobic carrier polymer in a neutral environment (B) .

In one embodiment this carrier polymer is substituted by another material with hydrophobic or hydrophilic properties. Therefore, the term "carrier material" in the present context should be interpreted to include carrier polymers and other materials with hydrophilic or hydrophobic properties . In another embodiment of the present invention the elution of nitric oxide from a nitric oxide eluting polymer, such as L-PEI-NO, is influenced by the presence of protons. This means that a more acidic environment provides a quicker elution of nitric oxide. By activating the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material, with an acidic fluid, such as an ascorbic acid solution, the elution of nitric oxide may be accelerated.

The carrier polymers and carrier materials mentioned above may affect other characteristics than the regulation of nitric oxide elution. An examples of such characteristic is mechanical strength.

In respect of the carrier polymers or carrier materials, the NO-eluting polymer may be integrated in, spun together with, or spun on top of, any of these materials in all of the embodiments of the present invention. This spinning includes electro spinning, air spinning, dry spinning, wet spinning, melt spinning, and gel spinning. In this way, one may manufacture fibers of a polymer mixture, comprising a nitric oxide eluting polymer and a carrier polymer, or a carrier material, with predefined nitric oxide eluting characteristics. These characteristics may be tailor made for different elution profiles in different applications. The nitric oxide eluting polymer may comprise a secondary amine, either in the backbone or as a pendant, as described previously. This will make a good nitric oxide eluting polymer. The secondary amine should have a strong negative charge to be easy to load with nitric oxide. If there is a ligand close to the secondary amine, such as on a neighbour atom, such as a carbon atom, to the nitrogen atom, with higher electronegativity than nitrogen (N) , it is very difficult to load the polymer with nitric oxide. On the other hand, if there is a electropositive ligand close to the secondary amine, such as on a neighbour atom, such as a carbon atom, to the nitrogen atom, the electronegativity of the amine will increase and thereby increase the possibility to load the nitric oxide elution polymer with nitric oxide. In an embodiment of the present invention the nitric oxide polymer may be stabilized with a salt. Since the nitric oxide eluting group, such as a diazeniumdiolate group, usually is negative, a positive counter ion, such as a cation, may be used to stabilize the nitric oxide eluting group. This cation may for example be selected from the group comprising any cation from group 1 or group 2 in the periodic table, such as Na+, K+, Li+, Be2+, Ca2+, Mg2+, Ba2+, and/or Sr2+. Different salts of the same nitric oxide eluting polymer have different properties. In this way a suitable salt (or cation) may be selected for different purposes. Examples of cationic stabilized polymers are L- PEI-NO-Na, i.e. L-PEI diazeniumdiolate stabilized with sodium, and L-PEI-NO-Ca, i.e. L-PEI diazeniumdiolate stabilized with calcium. Another embodiment of the present invention comprises mixing the nitric oxide eluting polymer, or a mixture of the nitric oxide eluting polymer and a carrier material, with an absorbent agent. This embodiment provides the advantage of an accelerated elution of nitric oxide since the polymer, or polymer mixture, via the absorbent agent, may take up the activating fluid, such as water or body fluid, much faster. In one example 80 % (w/w) absorbent agent is mixed with the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material, and in another embodiment 10 to 50 % (w/w) absorbent agent is mixed with the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material . Since the elution of nitric oxide is activated by a proton donor, such as water, it may be an advantage to keep the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material, in contact with said proton donor. If an indication requires an elution of nitric oxide during a prolonged period of time, a system is advantageous, which presents the possibility to keep the proton donor in contact with the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material. Therefore, in still another embodiment of the present invention, the elution of nitric oxide may be regulated by adding an absorbent agent. The absorbent agent absorbs the proton donor, such as water, and keeps the proton donor in close contact with the nitric oxide eluting polymer during prolonged periods of time. Said absorbent agent may be selected from the group comprising polyacrylates, polyethylene oxide, carboxymethylcellulose, and microcrystalline cellulose, cotton, and starch. This absorbent agent may also be used as a filling agent. In this case said filling agent may give the nitric oxide eluting polymer, or mixture of said nitric oxide eluting polymer and a carrier material, a desired texture.

The NO-eluting polymers in the devices may be combined with silver, such as hydroactivated silver. The integration of silver in the devices gives the healing process an extra boost. Preferably the silver is releasable from the devices in the form of silver ions. The integration of silver in the device may present several advantages. One example of such an advantage is that the silver may keep the device in itself free from bacteria or viruses, while the nitric oxide eluting polymer elutes the therapeutic dosage of nitric oxide to the target site.

The device may be manufactured by, for example electro spinning, gas spinning, air spinning, wet spinning, dry spinning, melt spinning, and gel spinning, of L-PEI or other polymers comprising L-PEI or being arranged in combination with L-PEI. L-PEI is the charged at a characteristic voltage, and a fine jet of L-PEI releases as a bundle of L-PEI polymer fibres. This jet of polymer fibres may be directed to a surface to be treated. The surface to be treated may for example be any suitable material in respect of a device according to the present invention. The electro spun fibres of L-PEI then attach on said material and form a coating/layer of L-PEI on the device according to the invention.

It is of course possible to electro spin the other NO-eluting polymers, according to above, on the device while still being inside the scope of the present invention. In one embodiment the NO-eluting polymers are electro spun in such way that pure NO-eluting polymer fibres may be obtained.

It is also within the scope of the present invention to electro spin a NO-eluting polymer together with other suitable polymer/polymers . Gas stream spinning, air spinning, wet spinning, dry- spinning, melt spinning, and gel spinning, of said NO- eluting polymers, together with a carrier material, onto the device is also within the scope of the present invention.

The manufacturing process of devices according to embodiments of the present invention presents the advantages of large contact surface of the NO-eluting polymer fibres with the area to be treated, effective use of NO-eluting polymer, and a cost effective way of producing the device.

According to certain embodiments, the device according to the invention comprises the NO eluting polymer and/or said carrier in non-fibrous form. These embodiments have the advantage of not creating fibrotic complications during wound healing, which for instance leads to painful or cosmetically unacceptable scars.

Hereinafter, some potential uses of the present invention are described: A method of treating at least one wound, comprising applying a device, that comprises a nitric oxide (NO) eluting polymer configured for eluting a therapeutic dosage of nitrogen oxide (NO) when used for said treatment, and thereby exposing said treatment site of said at least one wound on a body to said nitric oxide when said polymer in use elutes nitrogen oxide (NO) by eluting a therapeutic dose of nitric oxide from said nitric oxide eluting polymer to said treatment site.

The method according to above, wherein said site of said at least one wound is a head, face, neck, shoulder, back, arm, hand, stomach, genital, thigh, leg, or foot, of a body, and wherein said method comprises applying a condom/sheath, sock, patch/pad, cream, ointment, foam, hydrogel, and tape/coating to said head, face, neck, shoulder, back, arm, hand, stomach, genital, thigh, leg, or foot, of a body, for said exposure.

Use of nitric oxide (NO) in a therapeutic dose for therapeutically treating and/or preventing at least one wound on a body.

The invention may be implemented in any suitable form. The elements and components of the embodiments according to the invention may be physically, functionally, and logically implemented in any suitable way. Indeed, the functionality may be implemented in a single unit, in a plurality of units, or as part of other functional units.

Although the present invention has been described above with reference to specific embodiments, it is not intended to be limited to the specific form set forth herein. Rather, the invention is limited only by the accompanying claims and, other embodiments than the specific above are equally possible within the scope of these appended claims .

In the claims, the term "comprises/comprising" does not exclude the presence of other elements or steps.

Furthermore, although individually listed, a plurality of means, elements or method steps may be implemented. Additionally, although individual features may be included in different claims, these may possibly advantageously be combined, and the inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. In addition, singular references do not exclude a plurality. The terms "a", "an", "first", "second" etc do not preclude a plurality. Reference signs in the claims are provided merely as a clarifying example and shall not be construed as limiting the scope of the claims in any way.

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US973756116 Nov 201622 Aug 2017Novan, Inc.Topical gels and methods of using the same
Classifications
International ClassificationA61L27/54, A61L15/44, A61L27/34
Cooperative ClassificationA61L15/44, A61L15/46
European ClassificationA61L15/46, A61L15/44
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