WO2006084914A2

WO2006084914A2 - Device for gastric treatment and manufacturing process for the same

Info

Publication number: WO2006084914A2
Application number: PCT/EP2006/050894
Authority: WO
Inventors: Tor Peters
Original assignee: Nolabs Ab
Priority date: 2005-02-11
Filing date: 2006-02-13
Publication date: 2006-08-17
Also published as: WO2006084914A3

Abstract

A device is provided that allows for target treatment of gastric and gastrointestinal complications, including gastric ulcer. 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. 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.

Description

DEVICE FOR GASTRIC TREATMENT , MANUFACTURING PROCESS FOR THE SAME , AND USE OF NITRIC OXIDE

Field of the Invention This invention pertains in general to the field of treatment of gastric and gastrointestinal complications , such as gastric ulcer . More particularly the invention relates to a device for gastric and gastrointestinal treatment, and a process for manufacturing of said device, involving the use of nitric oxide (NO) .

Background of the Invention

About 10 percent of the population experience some kind of gastric and gastrointestinal complications , such as gastric ulcer, during some point of time during their life . Some of these persons experience long lasting problems , and their gastric and gastrointestinal complications may be looked upon as chronic . The hectic way life style of the western world is maj or factor in respect of gastric and gastrointestinal complications , such as gastric ulcer .

For years it is the understanding that stress , smoking, coffee drinking, consumption of alcohol, bad diet etc, are the main causes of gastric ulcers . In fact, gastric and gastrointestinal complications , such as gastric ulcer, are developed as a result of unbalance between stomach acid and pepsin and the defence mechanism of the mucous membrane in the stomach against these corroding substances . The last couple of years it has been established that gastric and gastrointestinal complications , such as gastric ulcer, develop during simultaneous presence of Helicobacter Pylori in the stomach . When Helicobacter Pylori is present in the oesophagus it is not pathogenic . Helicobacter Pylori has only a pathogenic effect in the stomach . The treatment of gastric and gastrointestinal complications , such as gastric ulcers , is a huge market, and a lot different medications relating to this matter have been widely discussed, others have been very- lucrative . These medications concentrate on controlling the production of stomach acid, and the unbalance between stomach acid and pepsin and the defence mechanism of the mucous membrane . In respect of the infection of

Helicobacter Pylori the only treatment is antibiotics . Treatment with antibiotics has certain disadvantages , such as that the bacteria develops tolerance and resistance to the antibiotics over time, and thus become difficult to eradicate .

It is known that nitric oxide (NO) provides an alternative to conventional therapies , such as antibiotics . Nitric oxide 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 as for instance many anti-cancer drugs . 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 . Other example for NO eluting polymers are given in US-5, 770 , 645, wherein polymers derivatized with at least one -NO_x 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 .

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 .

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 .

CA 2 , 106, 105 discloses a polymeric composition capable of releasing nitric oxide through N₂θ2^~-groups bound to a polymer . It is indicated in CA 2 , 106, 105 that oral administration is possible . However, this is only the administration route and not intended to treat disorders in the gastrointestinal tract . Thus , nothing is mentioned in CA 2 , 106, 105 about regulating and/or controlling the elution of nitric oxide, nor is anything mentioned about treating the gastrointestinal tract . US 6, 451 , 337 discloses a chitosan-based polymeric nitric oxide donor composition comprising a modified chitosan polymer and a nitric oxide dimer . This composition can be incorporated into formulations suitable for oral administration, such as via tablets , capsules etc . However, this is only the administration route and not intended to treat disorders in the gastrointestinal tract . Thus , nothing is mentioned in CA 2 , 106, 105 about regulating and/or controlling the elution of nitric oxide, nor is anything mentioned about treating the gastrointestinal tract .

US 2002/0012816 discloses hydrogels , comprising macromers , with the ability to release nitric oxide nitric . Examples of these macromers are PVA and PEG . Nowhere in D3 is oral administration, or any synonymous term, mentioned. It may be questioned if theses polymers are suitable for swallowing, why it is not strange that no oral administration or gastrointestinal treatment is mentioned in US 2002/0012816. Thus , nothing is mentioned in US 2002/0012816 about regulating and/or controlling the elution of nitric oxide, nor is anything mentioned about treating the gastrointestinal tract .

WO 03/092763 discloses nanotubules , i . e . not polymers , with the ability to bind nitric oxide or gas with nitric oxide like properties . D4 also describes that pharmaceuticals may be administered or infused orally . However, this is only the administration route and not intended to treat disorders in the gastrointestinal tract . Thus , nothing is mentioned in WO 03/092763 about regulating and/or controlling the elution of nitric oxide, nor is anything mentioned about treating the gastrointestinal tract .

WO 95/24908 discloses methods comprising administration of nitric oxide for the amelioration, treatment, and prevention of restenosis and related disorders . However, this is only the administration route and not intended to treat disorders in the gastrointestinal tract . Thus , nothing is mentioned in WO 95/24908 about regulating and/or controlling the elution of nitric oxide, nor is anything mentioned about treating the gastrointestinal tract . Pulfer, S . K . , et al . , in "Incorporation of nitric oxide-releasing crosslinked polyethyleneimine microspheres into vascular grafts", vol 37 , no . 2 , November 1997 , discloses site-specific delivery of nitric oxide by entrapping nitric oxide releasing polyethyleneimine microspheres in the pores of a vascular graft . Nowhere in this article is even oral administration described. Thus , nothing is mentioned in this article about regulating and/or controlling the elution of nitric oxide, nor is anything mentioned about treating the gastrointestinal tract .

WO 01/26702 discloses a coating for medical devices , which coating provides nitric oxide delivery using fibers of L-PEI . Thus , nothing is mentioned in WO 01/26702 about regulating and/or controlling the elution of nitric oxide, nor is anything mentioned about treating the gastrointestinal tract .

WO 98/05689 discloses S-nitrosylated polymers , which can be used to cover medical devices to deliver nitric oxide in vivo to treatment sites . ent gastric and gastrointestinal ulcers . Nothing is mentioned in WO 98/05689 about regulating and/or controlling the elution of nitric oxide, nor is anything mentioned about treating the gastrointestinal tract . However, the disclosure is both silent concerning an improvement of present technology in respect of treatment of gastric and gastrointestinal complications , such as gastric ulcer, and the anti pathogenic potential of nitric oxide . Hence, an improved, or more advantageous , device for the treatment and/or prevention of gastric and gastrointestinal complications , such as gastric ulcers is needed in the art . It is desired that said device presents the possibility to treat and/or prevent both ulcers and the occurrence of Helicobacter Pylori in the same time, does not develop resistance against the active pharmaceutical substance, is easy to apply, provides improved circulation in form of a vasodilating effect, provides a painless treatment, has fast inset of treatment effect, would be advantageous , and in particular a device allowing for target prevention and treatment of gastric and gastrointestinal complications , such as gastric ulcer, 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 the some of the problems mentioned above, by providing a device according to the appended patent claims . According to one aspect of the invention, a device is provided that allows for target treatment of gastric and gastrointestinal complications , such as gastric ulcer . 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 gastric and gastrointestinal complications , such as gastric ulcer . The process comprises selecting a plurality of nitric oxide eluting polymeric particles , such as nano fibres , fibres , nano particles , or microspeheres , and deploying said nitric oxide eluting particles into forms such as nano-particles , micro-spheres , or powder to be comprised in said device .

According to still another aspect of the present invention, a use of nitric oxide in a medicament to treat or prevent gastric ulcers or ulcers in the gastrointestinal tract is provided.

The present invention has at least the advantage over the prior art that it presents the possibility to treat and/or prevent both ulcers and the occurrence of

Helicobacter Pylori in the same time, does not develop resistance against the active pharmaceutical substance, is easy to apply, provides improved circulation in form of a vasodilating effect, provides a painless treatment, and has fast inset of treatment effect, by the exposure of an infected and/or wounded area to NO, whereby a very- effective anti-gastric and anti-gastrointestinal ulcer 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 nano- particles , or micro-spheres , according to embodiments of the present invention,

Fig . 2 is a schematic illustration of a drink according to an embodiment of the invention,

Fig . 3 is a schematic illustration of a capsule/pill according to an embodiment of the invention, and Fig . 4 is an illustration of two elution profiles (NO concentration vs . time) for two different polymer mixtures .

Description of Embodiments

The following description focuses on embodiments of the present invention applicable to a device, in form of nano-particles , or micro-spheres , which allows for target treatment of gastric and gastrointestinal complications , such as gastric ulcer or intestinal cancer, such as colon cancer . 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, antiplatelet- aggregating action, antibacterial 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 . The polymers according to the present invention may be manufactured by electro spinning, gas spinning, air spinning, wet spinning, dry spinning, melt spinning, or gel spinning . Electro spinning is a process by which a suspended polymer is charged. At a characteristic voltage a fine j et 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 j et . This process produces a bundle of polymer fibres , such as nano-fibres . This j et 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 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 permanently implanted 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 . Another advantage of L-PEI is that NO is released without any secondary products that could lead to undesired side effects .

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 an embodiment of the invention, according to Fig . 1 , the device is embodied in form of nano-particles , or micro spheres . These nano-particles , or micro-spheres , may be formed from the NO-eluting polymers according to the present invention . These nano-particles , or micro-spheres , may be swallowed for accessing the gastro-intestinal tract of a body . When the nano-particles , or micro-spheres , get in contact with the moisture in the stomach, the NO-eluting polymer starts to elute NO on the area to be treated, such as the stomach . At this point an effective healing process of the ulcer is initiated at the same time as an antimicrobial effect against the Helicobacter Pylori sets in .

In another embodiment the nano-particles , or micro- spheres , according to the present invention may be formed from the NO-eluting polymers according to the present invention, encapsulated, or integrated, 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, biogradable polymers , cotton, and latex, or any combinations of these . The integration of, or encapsulation in, these materials is performed to regulate and/or control the elution of NO in the stomach, and to provide continuous exposure of the gastrointestinal tract to NO . The encapsulation may be such that the material breaks by the movement of the stomach, or dissolves in the aqueous acidic environment in the stomach .

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 , other materials with the capability to fixate the NO eluting polymer, or enclosing the nitric oxide eluting polymer in any suitable material .

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 the 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 . 4 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 example 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, 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 .

In yet another embodiment of the present invention, the device is in form of a powder, said powder being obtained by grounding or pulverizing the NO-eluting polymer according to the invention . When the nano-particles , or micro-spheres , or powder, according to this embodiment, gets in contact with the moisture in the stomach, they/it start/starts to elute NO on the area to be treated. At this point an effective healing process of the ulcer is initiated at the same time as an antimicrobial effect against the Helicobacter Pylori sets in .

In still another embodiment the nano-particles , or micro-spheres , are encapsulated in a suitable, acid dissolving, but not aqueous dissolving, material and integrated in a suitable liquid, said liquid being drinkable, according to Fig . 2. When the liquid reaches the stomach the encapsulation material is dissolved and the nano-particles , or micro-spheres starts to elute NO . At this point an effective healing process of the ulcer is initiated at the same time as an antimicrobial effect against the Helicobacter Pylori sets in .

In another embodiment of the present invention the nano-particles , or micro-spheres , or ground/pulverized NO- eluting polymer, may be encapsulated in a suitable material, such as gelatine, starch, cellulose etc, to be swallowed. When the thus obtained capsule reaches the stomach, the gelatine dissolves and the nano-particles , or micro-spheres , starts to elute NO . In still another embodiment of the present invention the nano-particles , or micro-spheres , or ground/pulverized NO-eluting polymer may be encapsulated in a material that is insoluble in the acidic environment of the stomach . In this embodiment the capsule is instead dissolved in the basic environment of the duodenum, to treat gastric and gastrointestinal complications in this region .

In another embodiment of the present invention the nano-particles , or micro-spheres , or ground/pulverized NO- eluting polymer are/is compressed into a pill, tablet or pellet, which pill, tablet or pellet, according to Fig . 3, then is swallowed. When the pill, tablet, or pellet, reaches the stomach, an effective healing process of the ulcer is initiated at the same time as an antimicrobial effect against the Helicobacter Pylori sets in . In yet another embodiment of the present invention the NO-eluting device may be combined with, or acting as a booster for, pharmaceuticals , vitamins , nicotin, nitroglycerin etc . This embodiment presents a device with the advantage of combining two therapeutic treatments , of significant value, in one treatment . A specific example of this embodiment is a combination of the device and active substances in respect of gastric ulcer . Hence, a synergetic effect may be achieved by such devices when NO that is eluted from the device . NO has for instance 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-inflamatory, anti-bacterial etc . effect . Hence, an unexpected surprisingly effective treatment is provided.

In another embodiment of the device the nano- particles , or micro-spheres , are integrated in a gel . It may also be integrated in a hydrogel, which is mixed directly before use . This gel is then swallowed, and the device elutes NO when the gel, or hydrogel, reaches the stomach . This embodiment has the advantage of being able to penetrate pockets and corners in the gastrointestinal tract for closer elution of NO on the area to be treated.

In another embodiment of the present invention the nano-particles , or micro-spheres , of the polymers in the present invention, may be encapsulated in a material that breaks upon the stress from chewing . Then said nano- particles , or micro-spheres , may be integrated in chewing gum. This kind of chewing gum may then be used to prevent or treat gastric and gastrointestinal complications , such as gastric ulcer . The materials used to encapsulate these nano-particles , or micro-spheres , may be chosen from the group comprising 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, biogradable polymers , cotton, and latex, or any combinations of these . When the chewing gum is chewed the nano-particles , or micro-spheres , of NO-eluting polymer are swallowed, and starts to elute NO in the stomach or gastrointestinal tract . The encapsulation materials provide the possibility to regulate and control the elution of NO . This embodiment has the advantages that it provides another option of a way to obtain a continuous dosage of NO is easy to apply, the treatment effect covers the whole oral cavity, and it is easy to manufacture .

In another embodiment the nano-particles , or microspheres , of the polymers in the present invention, may be integrated in a film. When the film is put in the mouth the nano-particles , or micro-spheres , of NO-eluting polymer elutes NO that is swallowed, and said NO treats complications in the stomach or gastrointestinal tract . The encapsulation materials , according to above, provides the possibility to regulate and control the elution of NO . The film may also be swallowed before dissolving, thus effecting directly the stomach/intestinal tract .

In yet another embodiment of the present invention the device is in form of a gel, hydrogel, foam or cream. When the NO-eluting device gets in contact with the moisture in the stomach, the NO-eluting device starts to release NO to the area to be treated. This device does not develop resistance against nitric oxide (NO) , is easy to apply, provides a painless treatment, has fast inset of treatment effect, and combines an ulcer treatment effect with an antimicrobial effect, such as an anti-Helicobacter Pylori effect .

In another embodiment the device is manufactured of a basic carrier material, which basic material is integrated, or covered, with the nano-fibres , nano-particles , powder and/or micro-spheres of NO-eluting polymer according to the invention . When the basic material, for example in form of small granules , reaches the stomach, the nano-fibres , nano- particles , powder and/or micro-spheres of NO-eluting polymer start to elute NO on the area to be treated. At this point an effective healing process of the ulcer is initiated at the same time as an antimicrobial effect against the Helicobacter Pylori sets in . The granules , according to this embodiment of the invention, then passes through the gastrointestinal tract, and exit the body in the faeces .

The basic material of this device, according to the invention, may be 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, biogradable polymers , cotton, and latex, or any combinations of these . The NO-eluting polymer, such as L-PEI , may be integrated in, spun together with, or spun on top of, any of these materials .

When placed on an area to be treated the device provides prevention and treatment of gastric and gastrointestinal complications , such as gastric ulcer or in certain cases for instance intestinal cancer .

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.

The NO-eluting polymers in the devices according to the present invention may be combined with silver, such as hydroactivated silver . The integration of silver in the devices according to the present invention 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 . In the embodiments of the present invention it may be suitable to control or regulate the time span of NO release from the device according to the invention, as described above . 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, biogradable polymers , cotton, and latex, or any combinations of these .

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 device may be manufactured by, for example electro 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 j et of L-PEI releases as a bundle of L-PEI polymer fibres . This j et of polymer fibres may be directed to a surface to be treated. The surface to be treated may for example be any- suitable material . 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 . Such fibres are also easily further processed to other forms , such as the above mentioned powder, which simply is obtainable by applying a shredder or blender type apparatus to the fibres until a powder of desired granulation size is received. It is of course possible to electro spin the other NO-eluting polymers , according to above, on the device according to the invention while still being inside the scope of the present invention .

In one embodiment the NO-eluting polymers according to the present invention are electro spun in such way that pure NO-eluting polymer fibres may be obtained.

Gas stream spinning, air spinning, wet spinning, dry spinning, melt spinning, and gel spinning, of said NO- eluting polymers onto the device is also within the scope of an embodiment of the manufacturing method according to the present invention .

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

Hereinafter, some potential uses of the present invention are described:

A method of therapeutical treatment of gastric and gastrointestinal complications , including gastric ulcer by means of a device comprises a nitric oxide (NO) eluting polymer configured for eluting a therapeutic dosage of nitrogen oxide (NO) when used for said treatment, comprising exposing said treatment site of said complication in or 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 the above, wherein said site of said complication is the stomach, or the gastrointestinal tract, and wherein said method comprises applying nano-particles or micro-spheres , a pill, a tablet, a pellet, a drink, a gel, a hydrogel, a foam, a cream, granules , and/or a capsule to said site for said exposure . Use of nitric oxide (NO) in a therapeutic dose for therapeutically treating gastric ulcer and/or intestinal cancer .

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 .

Claims

1. A device configured to therapeutically target treat and/or prevent gastric and gastrointestinal complications , including gastric ulcer, 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/or prevention, and wherein said device is configured to expose a target site in the stomach or gastrointestinal tract 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 , 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 stomach or gastrointestinal tract .

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 , in a form selected from the group consisting of powder, nano-particles or micro-spheres , pill, tablet, pellet, drink, gel, hydrogel, foam, cream, granules , chewing gum, film, and capsule, or combinations thereof .

6. Device according to claim 1 , wherein said device is partly disintegrable when subj ected to moisture or water .

7. Device according to claim 1 , wherein said polymer comprises silver, configured for said therapeutic target treatment and/or prevention of gastric and gastrointestinal complications of the stomach or gastrointestinal tract .

8. Device according to claim 1 , wherein said polymer is acting as a booster for pharmaceuticals , vitamins , and drugs , or combinations thereof, combined with silver .

9. Device according to claim 1 , wherein said nitric oxide eluting polymer is in form of nano-particles or micro-spheres .

10. Device according to claim 9, wherein said nano- particles , or micro-spheres , are encapsulated, or integrated, 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, biogradable polymers , cotton, and latex, or any combinations of these, for regulating and/or controlling elution of NO .

11. 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 , poly (acrylic acid) , Carboxy Methyl Cellulose (CMC) , protein based polymers , gelatine, biogradable polymers , cotton, polyolefins , and latex, or any combinations of these .

12. Device according to claim 10 , wherein said nano- particles , or micro-spheres , are integrated in a drink, gel, hydrogel, chewing gum, film, or foam, and combinations thereof .

13. Device according to claim 5, wherein said granules are of 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, biogradable polymers , cotton, and latex, or any combinations of these, integrated, or covered, with said NO-eluting polymer .

14. 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 .

15. Device according to claim 14 , wherein a positive ligand is located on the neighbour carbon atom to the secondary amine .

16. Device according to claim 1 or 11 , comprising an absorbent agent .

17. Device according to claim 16, 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 .

18. Device according to claim 1 , 11 , or 16, comprising a cation, said cation stabilizing the nitric oxide eluting polymer .

19. Device according to claim 18 , wherein said cation is selected from the group comprising Na⁺, K⁺, Li⁺, Be²⁺, Ca²⁺, Mg²⁺, Ba²⁺, and/or Sr²⁺, or any combinations thereof .

20. A manufacturing process for a device configured to therapeutically target treat and/or prevent gastric and gastrointestinal complications , including gastric ulcer, at a target site in the stomach or gastrointestinal tract, 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 therapeutic treatment and/or prevention of gastric and gastrointestinal complications , 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 therapeutic target site to said nitric oxide when said NO-eluting polymer in use elutes nitric oxide (NO) .

21. The manufacturing process according to claim 20 , wherein said deploying comprises electro spinning, air spinning, gas spinning, wet spinning, dry spinning, melt spinning, or gel spinning of NO-eluting polymer .

22. The manufacturing process according to claim 20 or 21 , 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 .

23. The manufacturing process according to claim 20 or 22 , 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 .

24. The manufacturing process according to claim 20 , further comprising integrating silver in said device .

25. The manufacturing process according to claim 20 , comprising selecting a pharmaceutical .

26. The manufacturing process according to claim 20 , wherein said NO eluting material has the form of nano- particles , or micro-spheres , or comprises ground/pulverized NO-eluting polymer and carrier, said process further comprising compressing said NO eluting material into a pill, tablet or pellet .

27. The manufacturing process according to claim 20 , wherein said NO eluting material has the form of nano- particles , or micro-spheres , or comprises ground/pulverized NO-eluting polymer, wherein said carrier is a gel or hydrogel, said process further comprising mixing said gel or hydrogel directly before oral administration .

28. The manufacturing process according to claim 20 , wherein said NO eluting material has the form of nano- particles , or micro-spheres , or comprises ground/pulverized NO-eluting polymer, wherein said process further comprising encapsulating said NO eluting material in a material that is configured to break upon stress from chewing .

29. The manufacturing process according to claim 28 , further comprising integrating said encapsulated NO eluting material in chewing gum.

30. The manufacturing process according to claim 20 , wherein said NO eluting material has the form of nano- particles , or micro-spheres , or comprises ground/pulverized NO-eluting polymer, wherein said process further comprising integrating said NO eluting material in a film configured to be administered orally .

31. Use of a nitric oxide (NO) eluting polymer for the manufacture of a device for the treatment of gastric and gastrointestinal complications , including gastric ulcer wherein nitric oxide is loaded to said device so that said device elutes nitric oxide (NO) from said eluting polymer in a therapeutic dose when used.

32. Use according to claim 31 , 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.

33. Use of nitric oxide (NO) in a therapeutic dose for therapeutically treating and/or preventing gastric ulcers .

34. Use of nitric oxide (NO) in a medicament for therapeutically treating and/or preventing gastric ulcers .

35. Use of nitric oxide (NO) in a therapeutic dose for therapeutically treating and/or preventing complications in the gastrointestinal tract .

36. Use of nitric oxide (NO) in a medicament for therapeutically treating and/or preventing the gastrointestinal tract .