medical plaster and its use

专利摘要:
MEDICAL PLASTER AND ITS USE. The present invention relates to a medical patch composed of a modular form of at least two layers, which is capable of dissociating photolabile nitrogen monoxide precursors through the emission of electromagnetic radiation from a light module, inserted in an adjacent absorption module at the same time, so that the photolytically generated nitrogen monoxide can be used to assist medical therapies in animals and humans, as well as to generate NO.
公开号:BR112016009986B1
申请号:R112016009986-9
申请日:2014-11-07
公开日:2020-12-29
发明作者:Christoph V. Suschek
申请人:Bsn Medical Gmbh；
IPC主号:

专利说明:

[001] The present invention relates to a medical patch that releases NO. This plaster is composed in a modular way, in particular, from at least two layers and is capable of dissociating photolabile nitrogen monoxide precursors through the emission of electromagnetic radiation from a light module, inserted in an absorption module adjacent, preferably just such that the photolytically generated nitrogen monoxide can be used to aid medical therapies in animals and humans, as well as to generate NO.
[002] The treatment of circulatory disorders and the resulting chronic injuries is still insufficient in clinical practice. These complaints are not only a serious medical problem, but also an economic one. Thus, it is estimated that in Germany alone, approximately 2.4 million diabetics suffer from a circulatory disorder and / or abnormal healing. The quality of life of patients is limited and they suffer from preventable pain. Treatment costs are estimated at € 3 billion annually. And with the aging of the population, in the future even more people will suffer from such injuries that are difficult to heal. Thus, the predictions of a doubling of the numbers are from 2025.
[003] Current therapy relies mainly on moderately efficient pharmacological support for tissue perfusion, as well as insufficient support for the healing of chronic lesions through patch systems.
[004] An important physiological principle of human skin is the enzymatic production of nitrogen monoxide with the aid of enzymes from the NO synthase family, which can be synthesized by all types of cells [1]. The substrate for NO synthases is the amino acid L-arginine. Today it differs between two constitutively expressed NO synthases and an inducible isoform of NO synthases. Constitutively expressed NO synthases include predominantly neural NO synthase (nNOS) and predominantly endothelial NO synthase (eNOS), which, however, is also expressed in dermal fibroblasts and in the skin's muscular tube , while the inducible isoform, iNOS, is induced only through the effect of proinflammatory stimuli and, unlike constitutive isoforms, it can locally produce high concentrations of NO over a longer period (days).
[005] Next, the terms nitrogen monoxide, nitrogen oxide, nitrogen monoxide radical, NO and NO ^ are used as synonyms for the same molecule.
[006] In addition, NO can also be released non-enzymatically from nitrite or nitrosothiols. Non-enzymatic NO generation takes place under acidic and reducing conditions. In this case, for example, NO is released from nitrite. This reaction is physiologically important in the acidic environment of the stomach as well as the skin. In addition, it is known that nitrite UVA light can release a substance with the physiological properties of NO [2]. In fact, it could be demonstrated that NO can result from nitrite through the decomposition pathway induced by light energy [3; 4].
[007] Within the scope of inflammatory skin processes, in the interaction of different cellular systems, NO controls, among others, the proliferation, differentiation of skin cells and, in this way, for example, healing [5]. In skin healing processes, a series of dominant genes have been identified as regulated by NO [6; 7] and correspondingly, healing in mice with iNOS deficiency presented itself as a significant delay process [8]. Other genes, which are under transcriptional control through NO, are stress protection genes with a protective effect, such as heat shock proteins, chaperones or also hemoxigenase-1. Another part of NO-regulated genes serves either to counter the inflammatory reaction or to repair local damage (these include, in particular, many members of the matrix metalloproteinase (MMP) family). NO can influence the gene expression of MMPs, but also their physiological inhibitors, tissue inhibitors of matrix proteinases (TIMP) and, moreover, modulate their activity through nitrosation and thus react against an increase in degradation collagen through MMPs [9]. In addition, NO also influences the expression and activity of growth factors, such as, for example, VEGF [37; 38]. Thus, for example, angiogenesis, in addition to collagen synthesis, which is a key component of healing, could be stimulated through NO donors [39], and NO can induce the synthesis of angiogenesis factor VEGF in keratinocytes and macrophages [5; 40].
[008] Furthermore, in trials with exogenous NO donors it has been shown that NO leads to a significant increase in collagen synthesis in fibroblasts [10; 11]. An important physiological inducer of the new collagen synthesis is the transforming growth factor beta (TGF-β), whereas interleukins-1 (IL-1), IL-6, TNF-α, as well as reactive oxygen species (ROS) significantly decrease the new collagen synthesis or may even prevent it [12; 13]. NO can also, due to its ability to react with other radicals and, thus, eliminate them, have a protective effect [14]. Thus, NO is able to protect against DNA damage induced by the hydroxyl radical and against cell death induced by H2O2 and it has a greater capacity to terminate the lipid peroxidation as vitamin E induced by the radical [15; 16].
[009] In addition, numerous other protective properties of NO are also described. Thus, NO must protect against damage induced by hypoxia, it develops protective effects of hepatocytes and neuroprotectors and through an inactivation of effector caspases, it can protect against apoptosis [17]. Furthermore, NO, already in low concentrations, can modulate important components of antioxidant protection, such as, for example, the metabolism of glutathione (GSH), in which it induces an increase in the expression of the two key enzymes of GSH synthesis, Y-glutamyl-cysteine synthase (Y-GCS) and Y-glutamyl transpeptidase [18].
[010] Once formed, NO diffuses easily to both the vascular wall as well as the vascular lumen and, for example, is involved in the regulation of thrombocyte adhesion and thrombocyte aggregation, in vascular scrolling, as well as in the transmigration of granulocytes and neutrophil monocytes, as well as in endothelial permeability [20]. NO also relaxes smooth muscle cells in the vascular wall by activating soluble guanylathocyclase, the key enzyme in regulating blood pressure. The NO formed in the endothelial form is, therefore, of essential importance for the maintenance of both the vascular function, as well as the vascular structure and, in this way, essentially influences the hemodynamic parameters, in particular the blood pressure, but also the ischemic states tissue [21; 22].
[011] In the case of a reduced rate of NO synthesis, vascular regeneration and delayed healing are observed in the animal model, as well as a very disturbed re-epithelialization of skin lesions, due to a decrease in the rate of keratinocyte proliferation. As transmitters of vascular relaxation, NO can increase the rate of blood flow in the area of the lesion and, thus, lead to an increase in oxidation and supply of nutrients, as well as an increasing cellular infiltration of the tissue [5].
[012] Topical treatment of lesions with NO donors during the early stage of skin healing leads to significantly accelerated lesion closure and re-epithelialization in the rat [23], as well as better healing in mice with a bottom diabetic [24]. The daily topical exposure of lesions to air plasma containing NO also significantly improved the healing of septic as well as aseptic lesions in the rat model [25]. Despite numerous references about the positive influence of NO on healing, only one pilot study with a 55-year-old patient has been documented in humans so far, with NO gas therapy for complete healing of a venous ulcer. on the foot (Ulcus cruris) of several years resistant to therapy [26]. NO exogenously administered can slow the lesions conditioned by ischemia and reperfusion through the degradation of reactive oxygen species and essentially improve the microcirculation of the skin tissue. These properties have a particular role in revitalizing peripheral areas of free skin plastic surgery within the scope of soft tissue coverings [26].
[013] Current therapy principles, which refer to NO metabolism, predominantly cause the cGMP-dependent signal cascade induced by the NO to be routed. Principles of therapy to directly influence the availability of NO in the body are limited to the use of organic nitrites and nitrates [27]. NO gas is used in the clinic so far only inhaled in the therapy of various acute pulmonary disorders, and in experimental studies it has also been possible to prove a systemic effect of inhaled NOs [28]. The diffusion coefficient of NO at 37 oC is about 1.4 times greater than that of oxygen or carbon monoxide, so a diffusion course obtainable for the NO molecule in 500 μm tissues has been calculated [29] .
[014] Ghaffari and collaborators were able to prove significant antibacterial effects and, thus, the relevance in the treatment of lesions infected by bacteria and burn injuries, as well as non-healing lesions through exogenous NO gas [31; 32], with NO concentrations used in vitro showing no toxic effects on human fibroblasts, keratinocytes or endothelial cells [33].
[015] In summary, by this means, nitrogen monoxide (NO) proved to be a physiologically important bioactive molecule. Through its wide effect on blood vessels that, in addition, occurs very quickly, NO is of great importance for the blood supply of organs. In addition, NO also plays a role in other physiological processes as an important messenger. Thus, NO as an antioxidant protects against damage induced by hypoxia and modulates important components of antioxidant protection. Significantly, NO controls, for example, the proliferation and differentiation of skin cells in inflammatory skin processes in the interaction of different cellular systems and thus promotes healing.
[016] Correspondingly, it is verified in the animal model, that a reduced NO synthesis rate occurs together with vascular regeneration and delayed healing.
[017] Based on the findings of NO, there are already principles for using gaseous NO for therapy of circulatory disorders or chronic injuries. Until now, a gas containing NO used for therapeutic purposes is available in gas cylinders (industrial gas), which are expensive to store and handle in a clinic or other therapy equipment due to the necessary safety measures. This applies, in particular, to a mobile device. In addition, the quality of the gas stored for medical applications must satisfy high requirements, which further increase the expense for production and storage. A small impurity of the gas leads to the formation of undesirable and possibly poisonous by-products. As a result, the European health and medicine authorities have placed great demands on the purity of the nitrogen monoxide to be used. In addition to the use of “technical” NO gases for medical application, there are processes for the chemical production of plasma from nitrogen monoxide. These processes require purification processes that are partially very expensive, connected in series and it is difficult to adjust an optimal concentration of NO for the respective therapeutic purposes.
[018] Therefore, there is still a need for new processes for the treatment of circulatory disorders and chronic injuries.
[019] The aim of the invention is, therefore, to make a new therapeutic principle available for the treatment of circulatory disorders and chronic injuries, which is improved in relation to at least one of the disadvantages mentioned above.
[020] Summary of the Invention
[021] This objective is solved according to the invention by the fact that a medicinal plaster is available, which comprises the following: a. a radiation emitting module (SEM) with a radiation source for the emission of electromagnetic radiation and b. a NO module (NOM), which contains photolabile nitrogen monoxide (NOD) precursors, and the electromagnetic radiation emitted from the SEM can dissociate these NOD, so that in the NOM NO is generated, which can be released from the NOM;
[022] and in the plaster a system is used, which degrades or neutralizes nitric oxides several times oxidized, anions of oxygen radicals, hydroxyl radicals or quantized electrons.
[023] According to the invention, the medicinal plaster comprises, in this way: a. a radiation emitting module (SEM) with a radiation source for the emission of electromagnetic radiation and b. a NO module (NOM), which contains photolabile nitrogen monoxide (NOD) precursors, and the electromagnetic radiation emitted from the SEM can dissociate these NOD, so that in the NOM NO is generated, which can be released from the NOM; ç. a system, which degrades or neutralizes oxidized nitric oxides, anions of oxygen radicals, hydroxyl radicals or quantized electrons.
[024] The medical plaster according to the invention has several decisive advantages in comparison with the therapeutic principles known from the current state of the art.
[025] It has been surprisingly found that even in the context of such a medicinal patch, NO can be produced reliably by a system, which degrades or neutralizes several times oxidized nitric oxides, anions of oxygen radicals, hydroxyl radicals or quantized electrons (in the context of the invention it is also referred to as an "antioxidant system"), which is free of impurities and correspondingly suitable for a medicinal application.
[026] The medicinal plaster allows a transdermal application of NO, which is accompanied by several advantages, thus, in particular, a gastrointestinal intolerance and a hepatic first-pass effect are treated.
[027] In addition, through NO-induced vasodilation of the skin's microcirculation, the percutaneous absorption of pharmacologically active substances can be significantly increased. In this regard, NO acts as a facilitator of penetration or transportation mediator.
[028] Due to the limited NO solubility behavior, in NOM, in fact, physiologically relevant concentrations of NO can be generated as an absorption module, which, however, are well below those, which could cause damage to human health.
[029] In addition, through direct contact of the surface of the human body with the nitrogen-monoxide releasing module of the photolytically produced device, an essentially more precise treatment with NO can be obtained than, for example, with gas mixtures containing NO or with NO donors that decompose spontaneously.
[030] Generally, the short half-life of NO makes therapeutic use difficult. With the device according to the invention, despite the short half-life, it is possible to maintain a constant NO level through continuous post-synthesis of NO from the NODs.
[031] This ability to regulate and control is of decisive advantage precisely within the therapeutic range, since it allows an adapted treatment for each patient.
[032] The modular structure of the medical plaster also allows the use of a module containing NOD as a replaceable consumable item, which can guarantee a safe and reproducible production of NO.
[033] By simply adjusting the NOMs in relation to size, shape and material, the medical patch can be specifically adapted to the treatment needs.
[034] Thus, through the use of layers impermeable to NO, here, in particular, a posterior layer or marginal adhesive layers, NO can be supplied specifically to the area of the skin to be exposed and, in this way, it does not pass to the environment.
[035] Since the NO generator module represents a component of the medical patch according to the invention, an external supply of NO can be dispensed with, as is most often the case via gas plugs.
[036] This allows the use as a mobile system, which makes it possible, precisely in the therapeutic area, to be applied outside offices or clinics and, with this, in particular, in the case of chronic diseases, it occurs together with a more expensive treatment and with a greater patient compliance.
[037] In the case of the plaster according to the invention, it is a medical plaster of simple structure with commercially available components, so that it is not only economical in production, but also with a low margin of errors is simple application.
[038] In summary, the patch according to the invention represents a form of NO-based therapy, in which NO is released from a medical patch in a cheap, reliable, safe and individual manner for the patient.
[039] The invention in detail
[040] In a second aspect, the invention makes a medical plaster available, which comprises a NO module (NOM), which contains photolabile nitrogen monoxide (NOD) precursors, and electromagnetic radiation can dissociate these NODs from so that in the NOM NO is generated, which can be released from the NOM. In this case, the NOM contains a system, which degrades or neutralizes nitric oxides several times oxidized, anions of oxygen radicals or hydroxyl radicals (antioxidant system).
[041] In a third aspect, the invention makes a medical patch available, which comprises a NO module (NOM), which contains photolabile nitrogen monoxide (NOD) precursors, with the NOM additionally containing transition metal cations , which can release NO through reduction from NOD (so-called NO-active transition metal cations).
[042] In the context of the present invention, transition metals are understood to mean chemical elements with the order numbers 21 to 30, 39 to 48, 57 to 80 and 89 to 112.
[043] It was found that in the medical plaster during the generation of NO induced by radiation through the cations of NO-active transition metals present, NO can be generated in much higher yields and the formation of oxygen species is not carried out reactive, as well as nitric oxide species with greater oxidation, so that the NO obtained is of high purity. In that aspect of the invention, in this way, the antioxidant system in the medical patch can be dispensed with.
[044] In addition, it has been found that these transition metal cations can also release NO without electromagnetic radiation through a single reduction of the precursor of NO. With this, on the one hand, it is possible to dispense with the radiation source during application, on the other hand, however, this conditions, that the two reaction components, therefore, the NO-active transition metal cations and the NOD can coincide during application only. To this end, several forms of implementation are possible:
[045] The NO-active transition metal cation is produced in situ from an inactive valence step of the corresponding cation through reduction or oxidation. In this case, it must be ensured that the redox reaction only occurs during application. This can be guaranteed by separating the redox agent from the inactive cation, and the reaction is initiated on application by mixing the components. Alternatively, the NO-active transition metal cation and the NODs can also be present in the NOM separately from each other.
[046] In a preferred embodiment, the NO-active transition metal cation is produced through a light-induced redox reaction in the NOM.
[047] In one embodiment, in the case of the NO-active transition metal cation, it is a low-valence cation, that is, for the corresponding cation there is also a cation with a higher valence.
[048] These two valences of the transition metal cation form, in this case, a redox pair, and the low valence cation, in the reduction of the NO precursor, is transformed into the cation with the highest valence. These two cations thus form the redox pair of a NO generating reaction, which can be formulated as follows: Men + + NO2- + 2H + - ^ Me (n + 1) + NO * + H2O
[049] Preferably, in this case, Fe2 +, Co +, Ru2 + or Cu + are used as cations. These can be present in the NOM in the form of inorganic or organic salts.
[050] As NOD for the reaction with the transition metal cations, nitrites or S-nitrosothiols are preferably used. A corresponding reaction of Cu + with nitrite is carried out as follows: Cu + + NO2- + 2H + - ^ Cu2 + + NO- + H2O
[051] Since in this redox reaction the low valence cation is spent according to the NO generation that occurs with the reaction, it is convenient to either keep this cation in excess or to generate it again through reduction.
[052] In a preferred embodiment, the NOM additionally contains a reducing agent in addition to the transition metal cation to generate that metal cation.
[053] In one embodiment, the reducing agent is the antioxidant system. Thus, substances such as ascorbate, vitamin or glutathione can reduce the higher valence transition metal cation to a low valence cation.
[054] In a preferred embodiment, the NODs themselves are used as a reducing agent, with the NODs reducing the higher valence transition metal cation to a low valence cation under the effect of electromagnetic radiation.
[055] Thus, the Cu2 + cation can form a nitrite triplet complex with nitrite or S-nitrosothiols, and with the irradiation of light from 400 to 470 nm, preferably 400 to 450 nm, the nitrite anion is oxidized to NO2 and Cu2 + is reduced to Cu +: Cu2 + + NO2- [Cu2 + + 3NO2-] [Cu2 + + 3NO2 H Cu + + NO2
[056] The Cu (I) cation thus obtained can then release NO through the reduction of a nitrite anion, and here also NO is of high purity, that is, it has a purity, as prescribed for therapeutic application.
[057] Correspondingly, the invention, in a particular embodiment, makes a medical patch available, which comprises a NO module (NOM), which contains photolabile nitrogen monoxide (NOD) precursors and Cu2 + cations, being that through the irradiation of light with a wavelength between 400 and 470 nm and preferably between 400 and 450 nm, by reducing the NOD in the NOM NO is generated, which can be released from the NOM.
[058] Since in this special form of light-induced NO release, the formation of harmful by-products is not carried out, the antioxidant system can also be dispensed with.
[059] In a particular embodiment, the transition metal cation is a Cu2 + ion. This can be reduced to Cu1 + through light in the range of 400 to 470 nm (blue light) with complex formation with a reducing agent, the reducing agent being oxidized. Cu1 + can then release NO through a redox reaction of NODs, in particular nitrite. Correspondingly, it is preferred to use Cu (NO2) 2 here.
[060] In one embodiment the antioxidant system can be used as a reducing agent.
[061] In a particular embodiment, the NOM is configured as a multilayer plaster. This multilayer plaster of the present invention comprises (i) a layer containing NOD (also "intermediate layer"), in which at least one photolabile NO precursor (NOD) is present in dissolved or suspended form and (ii) a layer permeable inner layer for NO (“inner layer”), as well as (iii) optionally a protective film and / or a back layer.
[062] In an advantageous embodiment, the multilayered NOM additionally comprises an outer layer ("outer layer"). The outer layer, in this context, is one that joins directly or indirectly with the intermediate layer containing NOD on the side away from the skin.
[063] The outer layer can preferably be arranged between the middle layer and the back layer. According to one embodiment, the outer layer is essentially impermeable to NO. This can be self-adhesive or non-adhesive. If it is not self-adhesive, adhesives may be provided to join the outer layer with the back layer.
[064] In the context of the invention, any device with a flat shape, which can be placed on the body parts, should be understood by a plaster. The placement comprises, in this case, a simple placement without close contact or adhesive, but also at least partially adhesive bonding of the plaster with the skin. Such an adhesive bond or adhesion bond is conveniently configured as a reversible bond bond.
[065] The middle layer of the NOM is characterized by the fact that it contains one or more photolabile NO precursors (NOD). Preferably, it also contains an antioxidant system.
[066] The substances used in the antioxidant system capture not only the radical by-products resulting from the generation of NO, but also ensure that the corresponding layer is low in oxygen or even free of oxygen and, thus, also prevents an initial reaction of the resulting NO with oxygen.
[067] Conveniently, the photolabile NOD and the antioxidant system are present in the same layer. As a result, the radicals resulting from photolysis as by-products can be captured directly, without reacting with other substances to form optionally toxic substances. Preferably, the NOD and the antioxidant system are contained in the intermediate layer.
[068] In an alternative embodiment, for example, in the case of a chemical incompatibility of NOD and antioxidant system, these two components are present in different layers. In this case, it is convenient that the NOD is contained in the middle layer and the antioxidant system in the inner layer, so that the NO generated through photolysis with its by-products is purified before appearing on the skin when passing through the inner layer.
[069] In the case of the "antioxidant system" of the embodiments mentioned above, it is preferably an antioxidant and, particularly preferably, an ascorbate or ascorbic acid.
[070] The concentration of the antioxidant system, based on the total weight of the layer (s) containing it, can make up, in this case, up to 20% by weight, preferably between 0.25 and 10% by weight, of particularly preferred between 3 and 7.5% by weight.
[071] In a preferred embodiment of the invention, NOM photolabile nitrogen monoxide (NOD) precursors are selected from the group containing organic nitrates, inorganic nitrates, nitrites, sulfur nitrous compounds, nitrogen or oxygen, NO metal compounds and NO chelating substances.
[072] Photolabile nitrogen monoxide precursors are known in the current state of the art and common to the specialist.
[073] Examples of photolabile NOD comprise diazene diolates (for example, US patents Nos 7,105,502; 7,122; 529, 6,673,338), trans [RuCl ([15] aneN4) NO] +2, nitrosyl linkers, 6 -nitrobenzo [a] pyrol, S-nitroso-glutathione, S-nitroso-thiol, nitroaniline derivatives (see US2013 / 0224083), 2-methyl-2-nitrosopropane, imidazoil, hydroxylnitrosamine, hydroxylamine and hydroxyurea derivatives.
[074] In another embodiment, the NOM and preferably its layer or layers containing NOM has a content of NO precursors of between 0.1 and 50% by weight, preferably between 0.25 and 20% by weight, of particularly preferably between 0.5 and 10% by weight and particularly between 2.5 and 7.5% by weight, based on the total weight of the layer (s) containing the same.
[075] Preferably, in the case of NODs, these are pharmacologically acceptable substances. As such, for example, alkali and alkaline earth metal nitrites are applied. Here are mentioned, for example: LiNO2, NaNO2, KNO2, RbNO2, CsNO2, FrNO2, Be (NO2) 2, Mg (NO2) 2, Ca (NO2) 2, Sr (NO2) 2, Ba (NO2) 2 or Ra (NO2) 2.
[076] In this case, NaNO2 is particularly preferred as NOD which, preferably, in addition, together with ascorbate or ascorbic acid is contained as an antioxidant system in the medical patch.
[077] The concentration of nitrite salts, based on the total weight of the layer (s) containing them, can make up, in this case, up to 20% by weight, preferably between 0.25 and 10% by weight , particularly preferably, between 3 and 7.5% by weight.
[078] In another embodiment of the invention, NODs can be coupled to a polymer. Corresponding methods for coupling NOS to polymers are published, for example, by US patent No. 5,405,919. In one embodiment, in the case of the polymer coupled to the NOD, it is a polymer, which is provided with groups of diazonium diolate. An example for this purpose is linear polyethyleneimine (PEI) derivatized with diazonium diolate groups, published in WO 2006/058318.
[079] The concentration of NO produced in the NOM is between 10 μM and 5 mM, preferably between 100 μM and 3 mM and particularly preferably between 150 μM and 2 mM.
[080] The amount of NO released is between 50 and 600 ppm and preferably between 160 and 400 ppm. Such amounts are therapeutically effective, without leading to serious side effects.
[081] The specialist knows numerous systems, which are capable of degrading or neutralizing nitric oxides that have been oxidized several times, anions of oxygen radicals, hydroxyl radicals or quantized electrons. These will be selected according to the respective layer composition of the NOM.
[082] The antioxidant system, in one embodiment, is contained in the layer containing NOD, so that it can directly degrade or neutralize oxidized nitric oxides, anions of oxygen radicals, hydroxyl radicals resulting from the formation of NO or electrons quantized.
[083] Alternatively, the antioxidant system can also be contained in the inner layer, so that when NO passes through the layer placed on the skin, it can degrade or neutralize oxidized nitric oxides, anions of oxygen radicals, radicals hydroxyl resulting from the formation of NO or quantized electrons.
[084] In addition, there is a possibility that both the middle layer and the inner layer contain the antioxidant system.
[085] For a lipophilic NOM layer, that is, a layer with hydrophobic polymers, such as this can be prepared using a hydrophobic polymer, antioxidants such as tocopherols, tocotrienols, tocomonoenols, Irganox®, are suitable, for example Irgafos®, butylhydroxyanisol (BHA) and butylhydroxytoluene (BHT).
[086] For a hydrophilic NOM layer, that is, a layer with hydrophilic polymers, in particular, organic compounds containing sulfur, such as glutathione, cysteine or thiolatic acid or also organic acids, such as ascorbic acid, alpha acid -liponic, hydroxycinnamic acids, such as p-cumáric acid, ferulic acid, synapic acid or caffeic acid or hydroxybenzoic acids, such as gallic acid, protocatechic acid, siringic acid or vanylic acid.
[087] Other preferred antioxidants comprise polyphenolic compounds, such as anthocyanins, flavonoids and phytoestrogens.
[088] Preferably, the NOM contains, and in this case, preferably, the intermediate layer, in addition, one or more of the following substances: catalysts, detergents, buffer substances, chromophores, substances, which stabilize the NOD, such as, for example, example, dimethylsulfoxide or ethanol, substances that increase the NO half-value time, as published, for example, in US 2003/0039697, NOD stabilizers, antioxidants, dyes, pH indicators, treatment substances, flavorings, substances pharmacologically active.
[089] In another preferred embodiment, the multilayered NOM, and in this case preferably the inner layer, further contains a crystallization inhibitor.
[090] Various surfactants or amphiphilic substances can be used as crystallization inhibitors. These should be pharmaceutically acceptable and tested for use in medicines. A particularly preferred example for such a crystallization inhibitor is soluble polyvinylpyrrolidone, which is commercially available, for example, from the brand Kollidon® (Bayer AG). Other suitable crystallization inhibitors contain copolymers of polyvinylpyrrolidone or vinyl acetate, polyethylene glycol, polypropylene glycol, glycerol and glycerol fatty acid esters or ethylene and vinyl acetate copolymers.
[091] Optionally, the NOM contains a penetration enhancer. Such penetration enhancers (also "permeation enhancers") improve the permeation properties for the penetration of pharmacologically active substances into the skin. Examples of penetration enhancers are, among others, fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerin or glycerin-fatty acid esters, N-methylpyrrolidone, terpenes, such as limonene, α-pinene, α-terpineol, carvones, carveol, limonene oxide, pinene oxide or 1,8-eucalyptol.
[092] With respect to the respective purposes of use and based on his general knowledge, the specialist will select suitable substances or mixtures of substances. In this case, he will mainly consider that, when used as a medical patch, substances and mixtures of physiologically tolerable substances and / or substances and mixtures of dermatologically acceptable substances are applied.
[093] In one embodiment of the invention, the medical patch, and in this case, in particular, the inner and / or intermediate layer, contains one or more pharmacologically active substances. These can aid the pharmacological effect of NO or, independently of NO, they can act in a therapeutically relevant way for a corresponding disease.
[094] In one embodiment of the invention, the medical patch contains one or more of the following pharmacologically active substances: inflammation inhibitors, such as, for example, non-steroidal anti-rheumatics (NSAIDs) or corticosteroids, immunosuppressants, antibiotics, anticoagulants, antithrombotics , antiviral agents, antimycotics, local anesthetics and analgesics.
[095] In a preferred embodiment, the pharmacologically active substance is present in the form of waxy particles with a low melting point, which melt in contact with the skin and release the substance.
[096] The pH value of the intermediate and / or inner layer is conveniently between 3.0 and 10, preferably between 5.5 and 7.4 and particularly preferably between 6.0 and 7 , 0.
[097] In another embodiment, the NOM and preferably, in this case, the layer containing NOD, is low in oxygen or free of oxygen. Correspondingly, the oxygen content of the NOM or the NOD-containing layer is less than 20 ppm, preferably less than 10 ppm, particularly preferably less than 5 ppm.
[098] This oxygen poverty or oxygen exemption according to the invention can be caused by treating the individual components of the NOM or by gasifying intermediate states or the ready NOM with an inert gas (such as argon or nitrogen). Conveniently, such a NOM must be packaged sealed with gas, so that the oxygen poverty or oxygen exemption remains until the moment of application.
[099] In another embodiment, the NOM and preferably, in this case, the layer (s) containing NOD, to achieve oxygen poverty or oxygen exemption, has an oxygen absorber. Suitable oxygen absorbers include: Irganox®, Irgafos®, butylhydroxyanisol, butylhydroxytoluene, ascorbic acid or pyrogallol.
[100] The layer containing NOD suitably has a weight of a maximum of 70 g / m2, preferably of a maximum of 40 g / m2 and particularly preferably of a maximum of 30 g / m2.
[101] A low grammage of the layer containing NOD is advantageous, since the NOM, in this way, can be shaped according to the microscopic folding movements of the skin.
[102] The inner layer preferably has a weight of 15 to 55 g / m2, preferably 15 to 40 g / m2, particularly preferably 15 to 30 g / m2 and, in particular, 15 to 25 g / m2 .
[103] The outer layer preferably has a weight of 5 to 40 g / m2, preferably from 5 to 30 g / m2, more preferably from 5 to 25 g / m2 and particularly preferably from 5 to 15 g / m2.
[104] A low grammage of the inner and / or intermediate layer is advantageous, since with the decrease of the thickness of the layer, the tendency for cold flow also decreases. In this case, however, it must be considered that the thickness of the inner layer must also provide sufficient adhesion on the skin. Therefore, the inner layer preferably has a weight of at least 15 g / m2, particularly preferably, even of at least 20 g / m2.
[105] In one embodiment, all layers have an identical thickness of 20 to 40 g / m2, preferably 30 g / m2. In a preferred embodiment, the weight of the layer containing NOD is 30 g / m2.
[106] In a particularly preferred embodiment, the weight of the outer layer is 10 g / m2, that of the intermediate layer containing NOD 30 g / m2 and that of the inner layer 20 g / m2. The weight, therefore, makes a total of 60 m / m2.
[107] In one embodiment, the multilayered NOM without backing and protective film has a total weight of a maximum of 120 g / m2, preferably a maximum of 90 g / m2, preferably a maximum of 75 g / m2 and particularly preferably, a maximum of 60 g / m2.
[108] Preferably, the layers of the NOM are configured as flexible layers, so that they can form a full contact with the skin. The specialist knows numerous methods and processes for producing flexible layers, thus, for example, from the US patent documents 6,639,007, 6,673,871 or 7,105,607.
[109] Conveniently, the SEM-facing layer has an area, which is permeable to UV rays. This represents, therefore, an activation window.
[110] In another embodiment, the NOM, due to its shape, is adapted to the part of the body to be treated. So, for example, it can be configured as a socket, stocking, bandage, wrist, glove or finger.
[111] Preferably, therefore, the NOM should be formed from a material, which does not influence the energy properties of an electromagnetic radiation source required for optimal nitrogen monoxide release or, based on its properties, only creates or optimizes the light properties needed for a light-induced release of nitrogen monoxide.
[112] Conveniently, the NOM, and in this case, in particular, the outer and / or intermediate layer, is permeable to UV radiation. Based on his knowledge of UV permeability, the specialist will select the appropriate materials for the container containing the carrier medium. Thus, the use of UV-permeable synthetic materials is conveniently offered. Examples for this purpose are polymethylpentene (PMP), modified polymethyl methacrylate (PMMA) or modified polyvinyl butyral (Trosivol UV + ®).
[113] In a preferred embodiment, the inner layer, facing the skin is not permeable to UV radiation, to protect the skin against a dose of potentially harmful UV radiation.
[114] In one embodiment, the intermediate layer containing NOD contains at least one hygroscopic polymer or copolymer (hereinafter “hygroscopic (co) polymer”). In the case of at least hygroscopic (co) polymer, it is preferably polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), poly (vinylpyrrolidone-co-vinyl acetate) or a carbohydrate polymer or a mixture or a copolymer thereof. In this case, as the carbohydrate polymer, cellulose or cellulose derivatives, starch or derivatives thereof, alginates and pullulan are preferred. The cellulose and starch derivatives are preferably water-soluble.
[115] Particularly preferred are PVP, PVA, as well as mixtures or copolymers thereof. PVP is very particularly preferred.
[116] Preferably, PVP is used with a weighted average molecular weight Mw of 20,000 to 3,000,000 g / mol, preferably from 100,000 to 2,500,000 g / mol, more preferably from 500,000 to 2,000,000 g / mol and of particularly preferred, from 1,000,000 to 1,500,000 g / mol.
[117] Preferably, PVA is used with a weighted average molecular weight Mw of 5,000 to 100,000 g / mol, preferably from 10,000 to 50,000 g / mol, more preferably from 20,000 to 40,000 g / mol and particularly preferably, from about 31,000 g / mol.
[118] The average degree of polymerization Pw of the PVA used is, in this case, preferably between 100 to 2050, preferably between 200 to 1025, more preferably between 400 to 825 and particularly preferably, about 630.
[119] The degree of hydrolysis (saponification) of PVA is preferably 75 to 100 mol%, preferably 80 to 95 mol% and more preferably 85 to 90 mol%.
[120] For example, PVP can be used from the collidone series from the manufacturer BASF, in particular Kollidon 90 F, as well as PVA, from the moviol series from the manufacturer Clariant, in particular, Mowiol 4-88.
[121] In an alternative embodiment, the intermediate layer containing NOD contains at least one hydrophobic polymer. Examples of suitable hydrophobic polymers are polytetrafluoroethylene or polytrifluorochlorethylene.
[122] The middle layer can consist, for example, essentially of fibers, which can be configured as fabric or fleece.
[123] The inner layer is configured, in one embodiment, as a self-adhesive matrix. It preferably has sufficient solubility and permeability / transmissibility for nitrogen monoxide. Preferably, this is impervious to NOD precursors.
[124] As "permeable to NO" in the sense of the present invention, a layer is designated, which is permeable to NO under application conditions, therefore, under conditions on the patient's skin.
[125] The inner layer may have, for example, one or more membranes permeable to NO. Such membranes are published, for example, in US document 2002/0026937. In a preferred embodiment, the membrane is a selectively permeable membrane, as prepared, for example, by a copolymer of 70% polyester and 30% polyether (for example, SipatexTM, 10 μm membrane, see Hardwick and collaborators, Clinical Science 100: 395-400 (2001)).
[126] In addition, the inner layer can also be applied over the intermediate layer as a permeable coating to NO. Such NO permeable coatings are known from US application no 2003/0093143 or US application no 2005/0220838.
[127] The self-adhesive matrix as an inner layer may preferably comprise a solid or semi-solid semipermeable polymer, preferably a pressure sensitive adhesive (adhesive, PSA) or a mixture of these adhesives. The pressure sensitive adhesive / adhesive (s) (s) form / form the matrix, in which optionally other auxiliary or additive substances are incorporated.
[128] The adhesive agent is preferably pharmaceutically acceptable in the sense that it is biocompatible, non-sensitizing and non-irritating to the skin. Adhesion agents particularly advantageous for use in the present invention must also satisfy the following requirements: 1. constant adhesion agents and properties of co-adhesion agents in the presence of moisture or perspiration at usual temperature fluctuations, 2. good compatibility with NO, NOD, as well as with other auxiliary substances, which are used in the formulation of the plaster.
[129] Although various types of pressure sensitive reaction adhesion agents can be used in the present invention, the use of hydrophobic adhesion agents is preferred, which have both a low absorption capacity of the active substance and also a low ability to water absorption.
[130] In one embodiment, the inner layer contains at least one hydrophobic polymer. In the case of at least one hydrophobic polymer, it may preferably be a polyisobutylene (PIB) or a mixture of several polyisobutylene (PIBs), polybutylene, butyl rubber, a styrene copolymer, block copolymer of styrene and butadiene and styrene, a copolymer of styrene and isoprene, styrene and isoprene, a silicone polymer or a mixture of various silicone polymers, ethylene vinyl acetate (EVA) copolymers or a mixture or copolymer of the themselves.
[131] In particular, a PIB, a mixture of several PIBS, a silicone polymer, as well as a mixture of various silicone polymers are preferred. Particularly preferred are a GDP, as well as a mixture of several GDPs.
[132] According to one embodiment, a GDP with a higher molecular weight is used.
[133] The highest molecular weight GDP in this case has a weighted average molecular weight Mw of 100,000 to 1,000,000 g / mol, preferably 150,000 to 800,000 g / mol, more preferably 200,000 to 700,000 g / mol and particularly preferably, from 250,000 to 600,000 g / mol.
[134] For example, a GDP with a Mw of around 250,000 g / mol or a GDP with a Mw of about 600,000 g / mol can be used.
[135] According to another embodiment, a mixture of two PIBs of different molecular weight is used. Preferably, in this case, a mixture of a higher molecular weight GDP with a lower molecular weight GDP is used.
[136] The lowest molecular weight GDP in this case preferably has a weighted average molecular weight Mw of 10,000 to 100,000 g / mol, preferably from 20,000 to 50,000, more preferably from 30,000 to 40,000, and particularly preferably, of about 36,000 g / mol.
[137] Advantageously, a low molecular weight polybutylene is added to this mixture.
[138] For example, PIB from the BASF manufacturer's opanol series and / or from the Henkel manufacturer's Durotak series can be used. For example, Oppanol 10, Oppanol 100, Oppanol 200, Durotak 87-6908, as well as Durotak 618a can be mentioned here. The PIBs of the Durotak series, however, can also be easily mixed by the specialist himself, for example, those of the Oppanol series, such as B100, B10 and so on.
[139] Preferably, the silicone polymers used in the inner layer of the medical patch are of the type, which form a soluble polycondensed polydimethylsiloxane (PDMS) / resin network, with hydroxy groups being capped, for example, with trimethylsilyl groups (TMS ). Preferably, the weight ratio of resin to PDMS amounts to 85:15 to 35:65, preferably 75:25 to 45:55 and particularly preferably 65:35 to 55:45. Preferred silicone polymers of this type are pressure sensitive BIO-PSA silicone glues, produced by Dow Corning, in particular, 07-420x and 07-430x qualities, in this case, x represents a manufacturer's numeric code, which characterizes the solvent used of the respective glue (x = 1: heptane, x = 2: ethyl acetate, x = 3: toluene). However, other silicone glues can also be used. BIO-PSA 420x with a resin-PDMS weight ratio of 65:35 is of medium stickiness, BIO-PSA 07-430x, on the contrary, with a 55:45 ratio is of high stickiness.
[140] In another and particularly preferred aspect, two or more silicone glues are used as the main components of the glue. It may be advantageous if such a mixture of silicone glues contains a mixture of pressure sensitive glues, strongly adhesive, which comprise PDMS with a resin (eg 07-430x) and pressure sensitive silicone glues, of medium adhesion, comprising PDMS with a resin (for example, 07-420x).
[141] Such a mixture, which comprises a pressure sensitive silicone glue with high and medium tackiness, which comprises PDMS with a resin, is advantageous, since it provides an excellent balance between good adhesion and low cold flow. Excessive cold flow can result in a patch that is too soft, which remains slightly sticky on the patient's packaging or garments. Furthermore, such a mixture can be useful in a very particular way, to obtain higher plasma levels. A mixture of the 07-420x (medium tackiness) mentioned above and 07-430x (high tackiness), therefore, is particularly useful for the medical plaster according to the present invention. In this case, mixing ratios between the medium sticky silicone glue are preferred to the high stickiness silicone glue from 1:50 to 50: 1, particularly preferably from 1:10 to 10: 1 and, in particular, from 1: 1.
[142] It is also possible that the hydrophobic polymers and copolymers mentioned above contain other hydrophilic monomers, the proportion of which hydrophilic monomers being a maximum of 50% by mol, preferably a maximum of 30% by mol, particularly preferably a maximum of 10% in mol.
[143] In another aspect of the invention, “SxS self-adhesive” is used for the inner layer. SxS self-adhesives are glue based on styrene block copolymers, which do not carry elastomeric styrene blocks on the ends and elastomeric blocks in the middle. The elastomeric blocks can consist, for example, of polyethyleneobutylene, polyethylenepropylene, polybutadiene, polyisobutylene or polyisopropene.
[144] Suitable SxS adhesives are described, for example, in US 5,559,165 or US 5,527,536 and stand out for their good adhesive properties, easy production and processing, as well as for good compatibility with the skin.
[145] SxS self-adhesives can be referred to commercially (for example, as Duro Tak 378-3500 by National Starch & Chemical), while they can also be produced with hot melt extrusion equipment in the production of the multilayer NOM itself. For this, for example, corresponding amounts (at least the following components) of a styrene block copolymer (eg Shell Kraton GX1657 or Kraton D-1107CU) with an aliphatic and / or aromatic resin (eg Keyser Mackay Regalite R1090 or Regalite R1010 or Regalite R1100) and an oil (eg Shell Ondina 933 or Ondine 941) are dosed in the extruder from the individual dosing stations, where they are mixed and melted. In the last stage, the active substance of the extruder is dosed in the self-adhesive produced in this way and the mass is laminated to form films. Typical exemplary parts of polymer: resin: oil are, for example, 100: 120: 20 or 100: 200: 50. By varying these quantitative parts, the properties of the SxS self-adhesive can be adjusted respectively to the desired properties of the medical patch (adhesive strength, minimum cold flow, duration of the adhesion time, release profile of the active substance and so on).
[146] Advantageous combinations of intermediate and inner layer polymers are listed in the table below.
[147] In this table they mean:
[148] “TH-PVA”: particularly hydrolyzed polyvinyl alcohol, preferred examples for TH-PVAs are Mowiol 3-85, Mowiol 4-88, Mowiol 5-88, Mowiol 8- 88, Mowiol 13-88, Mowiol 18-88, Mowiol 23-88, Mowiol 26-88, Mowiol 32-88, Mowiol 40-88, Mowiol 47-88 and Mowiol 30-92
[149] “VH-PVA”: fully hydrolyzed polyvinyl alcohol, preferred examples for TH-PVAs are Mowiol 4-98, Mowiol 6-98, Mowiol 10-98, Mowiol 20-98, Mowiol 30-98, Mowiol 56-98 , Mowiol 15-99 and Mowiol 28-99.
[150] “sol.-PVP”: soluble polyvinylpyrrolidone derivatives. Preferred examples for sol-PVAs include Kollidon 12 PF, Kollidon 17 PF, Kollidon 25, Kollidon 30, Kollidon 30 LP and Kollidon 90 F.
[151] “CL-PVP”, crosslinked insoluble cross-linked polyvinylpyrrolidone derivatives. Preferred examples for Cl-PVAs include Kollidon CL, Kollidon Cl-F, Kollidon Cl-SF and Kollidon CL-M.
[152] "VP / Vac", copolymers of 1-vinyl-2-pyrrolidone and vinyl acetate, preferably in a 6: 4 mass ratio. Preferred examples for VP / Vac comprise Kollidon VA64 and Kollidon VA64 fine.
[153] “SxS Self-Adhesives”, copolymer-based adhesives in styrene block, which carry non-elastomeric styrene blocks at the ends and elastomeric blocks in the middle (see above).
[154] "Polysaccharides" are molecules, in which at least monosaccharide molecules are linked through a glycosidic bond. Preferred examples include alginates, agar-agar, carrageenan, guar seed flour, konjak gum, locust bean flour, oat beta-glucan, pectin, xanthan, hydroxypropyltrimony guar chloride and sodium hyaluronate.
[155] “Celluloses mod.”: Modified celluloses. Preferred examples are ethyl cellulose (EC), MC (Metolose®, methyl cellulose, methylated cellulose), HPMC (Metolose®, MHPC, hypromellose, hydroxypropyl methyl cellulose), HPMC phthalate (HPMC-P, hypromellose phthalate), AQOAT (HPMC-AS , hypromellose acetate succinate), L-HPC (hydroxypropyl cellulose, low substitution), carboxy methyl cellulose (CMC) and microcrystalline cellulose (MCC).
[156] “Standard silicone glue”, silicone polymer, comprising the following three classes: silicone glue with low adhesive strength (low-tack = indicative 440X), silicone glue with medium adhesive strength (medium-tack = indicative 450X) and silicone glue with high adhesive strength (high-tack = indicative 460X). Selected examples are BIO-PSA 7-4401, BIO-PSA 7-4402, BIO-PSA 7-4501, BIO-PSA 7-4502, BIO-PSA 7-4601 and BIO-PSA 7-4602.
[157] “AK silicone glues” means amine-compatible silicone glues, comprising the following three classes: low-tack silicone adhesive (low-tack = indicative 410X), medium-adhesive silicone adhesive (medium- tack = indicative 420X) and silicone glue with high adhesive strength (high-tack = indicative 430X). Selected examples are BIO-PSA 7-4101, BIO-PSA 7-4102, BIO-PSA 7-4201, BIO-PSA 7-4202, BIO-PSA 7-4301 and BIO-PSA 7-4302.
[158] "HM silicone glues", are called hot melt silicone glues, which are solvent free and become liquid through heat treatment.
[159] “GDP”: mixture of a GDP with a higher molecular weight, in particular, Mw = 250,000 to 600,000 g / mol and a GDP with a lower molecular weight, in particular, Mw = about 36,000 g / mol and preferably with a low molecular weight polybutylene.
[160] "BIB", copolymer of butene and isobutylene, such as, for example, PAR 950.
[161] “Polybutene”: thermoplastic polymer of butene-1, in contrast to the polyisobutylene configured in a branched way, the monomers in PB are arranged in a linear and largely isotactic manner, with a total of 700,000 to 3,000 high molar masses. 000 g / mol. As an example, the indopol is mentioned here.
[162] “EVA”: copolymer of ethylene and vinyl acetate


[163] In an alternative embodiment, the inner layer is not configured in an adhesive way. Thus, and particularly, in the case of open or wet lesions, a non-adhesive plaster is advantageous.
[164] In another preferred embodiment, the inner layer is configured in such a way that it aids healing, in which it absorbs, for example, secretions from the lesion or even forms a non-adhesive gel with the lesion.
[165] Corresponding plasters are known to the skilled person and contain, for example, hydrocolloid, hydrogel, alginates (preferably calcium alginates) or polymeric foam.
[166] Examples of such hydrogel-type materials are described based on the following patent reports: • CA-A 1,180,622: gelatin + polyethylene oxide + polyethyleneimine • DE-C 28 49 570: derived from poly (met) acid hydrophilic acrylic in the presence of polysaccharide / protein • DE-C 30 31 304 base: ethylenically unsaturated hydrophilic monomers, cross-linked with difunctional compounds • EP-B 0.099.758 synthetic collagen or alginates and other biopolymers • EP-B 0.262.405, polysodium acrylate / polyacrylic acid / acryloylamide and other acrylamide derivatives • EP-B 0.272.074 unsaturated monomer copolymers, containing carboxyl group + di- or oligosaccharides • US-A 3,249,109, gelatin, water, polyvalent alcohols, pectin • US-A 4,243,656, polyacrylate dispersion + moisture absorber, gelatin, water • WO 2010/046095 A1: polyurethane gel foam.
[167] In a preferred embodiment, the hydrogel is composed of the following components (see DE 3903672C1): a) 20 to 70% by weight, of at least one polyvalent alcohol b) 10 to 35% by weight, of at least a natural gelling agent (biopolymers) c) 0.05 to 12% by weight of at least one unbranched copolymer from one or more vinylcarboxylic acids and their salts (synthetic polymer) d) 0.05 to 10% in weight, of a cross-linking agent e) 0 to 50% by weight, of water or physiological sodium chloride solution.
[168] As polyvalent alcohol, glycerin is preferred in this case, which can be used alone or in a mixture with other polyvalent alcohols. Other polyvalent alcohols are ethylene glycol, diethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, 1,4-butanediol, glycerin monoacetate or a mixture of those alcohols. As a natural gelling agent (biopolymers), in this case, gelatin alone or in the mixture with other biopolymers, preferably alginates, is used in the first line. A combination of gelatin and sodium alginates in a weight ratio of 5: 1 to 30: 1 is particularly preferred. Like other biopolymers, which are used alone or in a mixture with gelatin, collagens and pectins can be mentioned. The unbranched copolymer used as a synthetic polymer is formed from at least one vinylcarboxylic acid and at least one of its alkali or ammonium salts. As vinylcarboxylic acids, acrylic acid, methyl acrylic acid and / or e-acryloyloxypropionic acid are preferred. Other suitable vinylcarboxylic acids are vinylacetic acid, maleic acid, fumaric acid, crotonic acid, aconitic acid, itaconic acid and mixtures of these acids. The crosslinking agents used according to the invention are preferably selected from the group of metal chelates, orthotitanic acid esters, epoxides, aziridines, triazines or melamine and formaldehyde resins. Particularly preferred here are aziridines and the group of metal chelates, for example, acetylacetonate, for example, transition metal acetylacetonates, such as titanium or zirconium acetylacetonate. The cross-linking agent causes cross-linking of biopolymers with synthetic polymer for preferably three-dimensional networks.
[169] In a preferred embodiment, the inner layer is a hydrocolloid. What refers to the term "hydrocolloid", as used in the context of the present invention, then it should be understood very broadly. In general, hydrocolloid is understood to be at least partially water-soluble, natural but also synthetic polymers that form gels or viscous solutions or suspensions in aqueous systems. In this case, these are usually substances, which belong to the substance classes of proteins or polysaccharides, with a large number coming from nature's hydrocolloid, in particular, from terrestrial plants, algae, animals, as well as bacteria. Hydrocolloids are often used as thickeners in cosmetics and food industry products. For more details regarding the hydrocolloid term, reference can be made, in particular, to Rompp Chemielexikon, 10th edition, Georg Thieme Verlag, Stuttgart / New York, keyword: “hydrokolloide”, page 1837, including the literature referred to there, all the relevant content being incorporated in full by reference.
[170] In this case, it is particularly advantageous if the hydrocolloid is gelatin and / or collagen and, in particular, collagen.
[171] In the case of collagen, these are long fiber scleroproteins, linear colloid and high molecular weight of the extracellular matrix, which are present in connective tissue, in particular in the skin, cartilage, as well as in animal tendons vertebrates, but also in phylogenetically early forms of life, such as sponges or sea anemones. The fibrous structure of collagen is conditioned, in particular, by the occurrence of glycine in each third position in the amino acid sequence, since glycine as a space-saving amino acid, conditions a special helical secondary structure in proteins. The amino acids tryptophan and tyrosine also known as helixbreaker, as well as the disulfide-forming amino acid cysteine, on the contrary, are generally not present in collagens. For more details regarding the collagen term, reference can also be made to Rompp, Chemielexikon 10th edition, Georg Thieme Verlag, Stuttgart / New York, keyword: “collagens”, pages 796 and 797, as well as to literature referred to therein, and all relevant content is incorporated herein in full by reference.
[172] What especially refers to the use of collagen within the scope of the plaster according to the invention, so it is able to significantly increase the wound healing process. In particular, collagen has a protease inhibitory effect, which serves to lower the increased protease level in the field of the lesion detrimental to the healing of the lesion. If the level of protease in the field of the lesion is indeed increased, this often leads to uncontrolled healing of the lesion and the destruction of growth factors, as these are degraded by proteases, such as, for example, neutrophilic elastases or metalloproteases matrix (MMPs). In addition, collagen stimulates the formation of vascular structures and connective tissue and, in this way, helps restore the structural stability of the tissue. In this sense, through the use of collagen as a hydrocolloid, healing can be aided in an extremely efficient way and manner.
[173] Similar embodiments also refer to gelatin which, likewise, can be used preferentially in healing as a hydrocolloid: the term "gelatin" means, in the context of the present invention, a polypeptide, which is obtained mainly through hydrolysis of the collagen contained in the skin and bones of animals in acidic or basic conditions. In this case, the obtaining of gelatin takes place under acidic conditions in the so-called gelatin type A. Gelatin initially swells a lot in water, in particular, with the simultaneous influence of heat and dissolves in this forming a viscous solution, which finally solidifies into gelatin below 35 oC. For more details regarding the term gelatine, reference can be made to Rompp, Chemielexikon 10th edition, Georg Thieme Verlag, Stuttgart / New York, keyword: “gelatine”, page 1484, as well as to the literature referred to there, all relevant content is hereby incorporated in its entirety by reference.
[174] What further refers to the hydrocolloid layer, in particular to the collagen layer, then it can be predicted according to the invention that the hydrocolloid, preferably the collagen-containing layer, is based on a fleece of hydrocolloid and / or hydrocolloid foam, preferably in a collagen fleece and / or collagen foam. In this context it can be predicted that the hydrocolloid layer is formed based on hydrocolloid fleece and / or hydrocolloid foam, preferably collagen fleece and / or collagen foam of porcine, bovine and / or equine origin, particularly preferred based on hydrocollagen fleece and / or hydrocollagen foam, preferably collagen fleece and / or collagen foam of porcine origin.
[175] Particularly preferred according to the invention, it can be provided that the hydrocolloid, preferably the collagen-containing layer is formed by a hydrocolloid fleece and / or hydrocolloid foam, preferably collagen fleece and / or a collagen foam , in particular, by a hydrocolloid fleece and / or hydrocolloid foam, preferably collagen fleece and / or a collagen foam of porcine, bovine and / or equine origin, preferably by a hydrocolloid fleece and / or hydrocolloid foam, preferably collagen fleece and / or collagen foam of porcine origin.
[176] The use of hydrocolloid fleece or hydrocolloid foam, preferably collagen fleece or collagen foam, compared to conventional materials for the production of plasters, is particularly associated with the advantage that the material does not stick with the base of the lesion or with the lesion surface, but, however, it is possible to obtain good adhesion to the surface. In addition, it is of particular advantage that plasters based on hydrocolloid foam or hydrocolloid fleece, in particular collagen foam or collagen fleece, do not deposit any fibers or any solid components or particles on the lesion and thus additional penetration or exposure of foreign bodies is avoided.
[177] In this context it has been proven to be particularly advantageous if the plaster has hydrocolloid foam, in particular collagen foam, that is, hydrocolloid or collagen fixed or expanded forming a foam, in particular, since through the pores contained in the hydrocolloid foam or collagen foam, in addition, efficiently, large amounts of secretion from the lesion can drain from the lesion field, so that the formation of waterlogging, as well as a very long contact of substances contained in the secretion of the lesion and harmful to healing with the injury itself is avoided. In this case, the chemical and physical properties of hydrocolloid or fixed and expanded collagen (i.e., hydrocolloid foam or collagen) prevent, however, the lesion from drying out.
[178] In addition, such foams can be adjusted extremely well to the shape of the lesion base, that is, they can cover the wound surface or the entire width area, without forming lumps or the like. In addition, using a hydrocolloid foam or collagen foam, particularly good gas permeability is possible. This is particularly associated with the advantage that the lesion is well gassed with the NO generated in the plaster, which, on the one hand, promotes the physiological healing process, on the other hand, also prevents the growth of germs.
[179] As a result, therefore, through the presence of the colloidal layer or the collagen layer, on the one hand, the secretion of the lesion is removed efficiently and, on the other hand, a good permeability to NO gas is guaranteed.
[180] In addition, concerning the hydrocolloid layer, in particular, the collagen layer, then it can be predicted according to the invention, that this can be obtained by applying a dispersion or solution of a hydrocolloid, preferably from a collagen on a support and the subsequent drying, in particular lyophilization (freeze drying), preferably with expansion of the hydrocolloid, preferably of the collagen. A suspension or solution of hydrocolloid, preferably of suitable collagen according to the invention can be obtained, in particular, by suspending or solubilizing the hydrocolloid, in particular, collagen, in water, in particular, ultrapure water or in disinfected or sterile water or sterilized. In this case, the hydrocolloid, in particular, collagen, may be contained in the suspension or solution, preferably in an amount in the range of 0.1 to 5% by weight, in particular 0.5 to 4% by weight, preferably 0, 7 to 3% by weight, particularly preferably 1 to 2% by weight, based on the hydrocolloid suspension or solution, preferably the collagen suspension or solution. The hydrocolloid, preferably dried and expanded collagen, can finally be removed from the support and later used to produce the plaster. To guarantee the desired properties, the hydrocolloid or the corresponding layer with the hydrocolloid may have a defined residual moisture content, which is known to the expert.
[181] The hydrocolloid, preferably the collagen of the hydrocolloid layer, in particular the collagen layer, can be, in particular, of porcine, bovine and / or equine origin, preferably of porcine origin, in particular, porcine skin.
[182] Regarding the measurements of at least one layer containing hydrocolloid, preferably collagen, then it has a thickness in the range of 0.01 to 100 mm, in particular, 0.02 to 50 mm, preferably 0.05 to 10 mm. Depending on the severity of the lesion to be treated and the intensity of the exudation of the lesion, it is advantageous, in particular, in the case of a strong secretion of water from the lesion (in particular, for example, in the exudative phase of healing), if the layer containing hydrocolloid, preferably collagen, is formed in a particularly thick manner. In lesions already advanced by the healing process, on the contrary, in most cases it is sufficient to use substantially thinner layers of hydrocolloid or collagen. In this way, according to the invention, it is possible to adjust the thickness of the hydrocolloid or collagen layer to the respective needs.
[183] Advantageous combinations of polymers from the intermediate layer and the healing-promoting inner layer are listed in the table below.



[184] The outer layer provided for in some embodiments preferably comprises at least one hydrophobic polymer. In the case of at least one hydrophobic polymer it may preferably be a polyisobutylene (PIB), a mixture of several polyisobutylene (PIBs), polybutylene, butyl rubber, a styrene copolymer, a styrene block copolymer and butadiene and styrene, a copolymer of styrene and isoprene, styrene and isoprene, a silicone polymer or a mixture of various silicone polymers or a mixture or a copolymer thereof.
[185] Particularly preferred are a PIB, a mixture of several PIBs, a silicone polymer, as well as a mixture of various silicone polymers. Most particularly preferred are a GDP, as well as a mixture of several GDPs.
[186] In addition, for the outer layer reference is made to the data for the inner layer. As already mentioned, the outer and inner layers can have different polymeric compositions. Preferably, the outer layer, however, has the same polymeric composition as the inner layer.
[187] The multilayer NOM of the present invention optionally comprises a back layer, which is inert with respect to the matrix components. The back layer is preferably a film, which is impermeable to the active substances. Such a film may consist of polyethylene terephthalate (PET), polyester, polyamide, polyethylene, polypropylene, polyurethane, polyvinyl chloride or a combination of the two materials mentioned above. These films can optionally be coated with an aluminum film or with an aluminum vapor. The thickness of the back layer can be between 10 and 100 μm, preferably between 15 and 40 μm.
[188] The back layer in at least a partial area is adequately permeable to electromagnetic radiation, which must photolytically dissociate the NOD from the NOM.
[189] The multilayered NOM of the present invention optionally further comprises a protective layer / protective film, which is removed immediately before use, in particular, just before the NOM is brought into contact with the skin. The protective film or sheet may preferably consist of polyester, polyethylene terephthalate (PET), polyethylene or polypropylene, which can optionally be coated with aluminum film or aluminum vapor or fluoropolymers. Typically, the thickness of a protective film or sheet is in the range between 50 and 150 μm. To make it possible to remove the protective film or sheet, when the medical patch is to be used, the protective film or sheet may contain separate protective films or sheets, which have overlapping ends, similar to those used in most conventional plasters.
[190] In a particularly preferred embodiment, the multilayer NOM according to the invention consists of exactly two layers: an intermediate layer containing NOD and an inner layer, the inner layer of which is directly adjacent to the layer containing NOD. This NOM also comprises a back layer and a protective layer.
[191] In an equally preferred embodiment, the multilayered NOM according to the invention consists of exactly three layers: an intermediate layer containing NOD, an inner layer and an outer layer, the inner and outer layer being directly adjacent to the layer containing NOD. This medical plaster comprises, in addition, a back layer and a protective layer.
[192] In another embodiment of the invention, the medical patch is configured in such a way that the release of NO to the environment is reduced or completely avoided.
[193] In another embodiment, the NOM is coupled with a NO sensor, so that the extent of NO generation can be flexibly adjusted as feedback on the measured NO value.
[194] This NO sensor as a measuring device for the quantification of NO can be installed in one of the layers of the NOM, therefore, for example, the back layer, the protective film, the intermediate layer or the inner layer. In addition, it can be installed between the inner layer and the skin or be installed on the outer side (that is, above the back layer or protective film) of the medical patch. In a particular embodiment, the control associated with the NO sensor provides that when exceeding a critical NO value, the SGE fully adjusts the NO generation.
[195] In an embodiment of the invention, the NOM is activated in such a way that the NO content released is kept constant during the treatment period.
[196] In an alternative embodiment of the invention, the NOM is triggered in such a way that the NO content released increases or decreases during the treatment period.
[197] In one embodiment of the invention, the NOM is configured as an easily replaceable consumable item.
[198] In a further preferred embodiment, the NOM is configured in such a way that, from the form, it allows an error-free application in the medical patch. Thus, the shape is preferably configured as a patch or transdermal patch (TTS), which can only be attached to the SEM in just one orientation. This can happen, for example, through a velcro closure, which joins the SEM with the NOM. In addition, the NOM or SEM can be configured with a retention mechanism, which only after a correct connection, that is, perfect fit, allows the production and / or release of electromagnetic radiation on the SEM side. Conveniently, the medical patch, in this case, can be equipped with a sensor, which detects the correct orientation or blocking of the SEM and NOD and shows it to the user.
[199] In this case, the source of the electromagnetic radiation may be an incandescent lamp or a gas discharge lamp (low pressure or high pressure discharge) coated with corresponding fluorochromes, light emitting diodes (LED), organic light emitting diodes light (OLED), LASER or any other source of electromagnetic radiation, which is capable of generating NO from corresponding precursors or chemical substrates.
[200] For optimal dissociation of the photolabile NO precursors dissolved or suspended in the NOM, the SEM light source can emit electromagnetic radiation with wavelengths from 100 to 2000 nm or emit electromagnetic radiation of any other wavelength, which individually or with the support of chemical, physical or biological processes, it can induce a dissociation of nitrogen monoxide precursors and, with that, a release of nitrogen monoxide.
[201] In a preferred way, SEM is so connected with NOM, that the two have a constant distance, defined on their surface. This can be achieved in a preferred way, through a SEM configured in a flexible way, which can be placed in the NOM.
[202] In an alternative embodiment, the SEM is provided with a spacer in the radiation source in a flat form (for example, through an LED panel) which, in this way, can produce a defined distance to the NOM.
[203] To minimize or to avoid or to prevent possible impurities in the ambient air with NO or its oxidative reaction products, the medical patch may have an absorption device, which absorbs the harmful gases that eventually occur, such as NO or NO2 and leads through an activated carbon filter or through another device, which is able to neutralize or eliminate corresponding species of reactive gases.
[204] To ensure a safe application of the device according to the invention, it will have a selection of specific programs for the application, electronically controlled, including a safety shutdown of the medical patch, corresponding temperature sensors and safety of NO, NO2, as well as a remote control and the possibility of connecting equipment to external control applications and documentation. In order to manage security, a specific recognition for application and use is also included and electronically controlled for the specifically loaded NOMs, which are preferably configured as replaceable consumables.
[205] The multilayer NOM of the present invention can be obtained by the fact that (i) a solution containing NOD and at least one hygroscopic polymer or copolymer is smoothed and dried and (ii) the layer thus obtained is coated with a another layer, as well as with a layer, which during treatment is permeable to NO.
[206] Preferably, the solution in step (i) contains at least one hydrophilic solvent, preferably ethanol and / or water.
[207] In the context of the production of the multilayer NOM according to the invention, all layers can be produced using classic techniques of dissolution, mixing, coating and drying resistant to temperature or also by molding marked only by heat.
[208] For this purpose, according to processes long known to the specialist, individual layers can initially be applied to backing films available with adhesive finish, as a rule, polyethylene terephthalate (PET), in the solvent-containing coating process with scraper, spray or roller slotted nozzles in uniform layer thicknesses with preferably 15 to 40 g / m2 application weight after drying for the inner layer and optionally 5 to 40 g / m2 for the outer layer, as well as maximum 40 g / m2 of application weight after drying for the intermediate layer containing NOD. In the case of graduated bilateral silicone polymerization, it can be wound directly on itself with the substrate. Then, the active substance is absorbed in a non-sticky polymeric excipient and a uniform internal phase is produced from the polymer that absorbs water or swells in water through the coating on prepared backing films provided with adhesive in the coating process containing solvent with application with scraper, spray or roller slit nozzles in uniform layer thicknesses with the values above for application weight after drying.
[209] The production of these thin layers is possible today by the specialist with the usual coating, drying and extrusion processes. In this case, the addition of NOD can be in one or more layers - intermediate layer or separate layers - both containing solvent, according to intermediate drying processes, or also without solvent, if the NOD is liquid at the processing temperature or if a another solvent remaining in the formulation is added. In each case, due to the low diffusion pathways, a distribution of the active substance in the system components is easily possible, if desired within hours to days after production.
[210] The layers can be produced in any sequence and laminated overlapping according to processes known to the specialist. Without remaining in the system during application, a back layer essentially impermeable to NO can be provided, which protects the NOM against adhesion with textiles. In addition, a separable protective layer can be provided, which is removed before applying the NOM on the skin.
[211] In a preferred embodiment, the production of the multilayer NOM according to the invention is carried out with the processes described in documents DE 101 47 036 A1 and DE 10 2008 038 595 A1. With the processes described there, substrates coated with a protective film can be coated in a particularly advantageous manner, whereby an application with particularly uniform adhesive is obtained.
[212] In alternative embodiments, however, the following application and lamination systems can also be used to produce the NOMs according to the invention:
[213] Knife System - cylinder and air knife; Double Side system - double spatula system; Commabar system - Commabar system; Case Knife system - box knife system; Engraved Roller system - application with engraved cylinder; 2-cylinder system; 3-cylinder system; Micro Roller System - microcylinder system; 5 cylinder system; reverse cylinder system; Rotary Screen System - nozzle / casting technology; Curtain Coating System - curtain coating system; Hotmelt Slot Die System - hot melt wide slit nozzle system; Powder Scattering System - powder dispersion system.
[214] In a preferred embodiment, the NOM according to the invention is produced through the so-called slot die system, which is based on a nozzle technology. In this case, the nozzle represents a closed application system, which consists of a nozzle chamber, to which the coating raw material to be applied is poured. The nozzle geometry, which is specially determined for each coating raw material with respect to its flow chart, ensures a uniform output of the coating raw material from the outlet slot. A (micro) pump transports the coating medium with great dosing precision to the nozzle. In addition, the exit gap as well as the speed of the goods guarantee the application weight. Thus, depending on the viscosity of the raw material, very thin layers below 5 μm are possible.
[215] In an embodiment of the invention, NO is produced by a plasma chemical method. In addition to the use of “technical” NO gases for medical application, there are processes for the plasma chemical production of nitrogen monoxide. From WO 95/07610 A, US 5,396,882 A and DE 198 23 748 A, processes for the plasma chemical production of NO are known, in which NO is produced by the action of a light discharge, spark or arc flash in an operational gas containing nitrogen (N2) and oxygen (O2). A gas discharge of the type described leads, when it is carried out at very low temperatures (as can be seen in the light discharge), to a low efficiency of NO production in a gas mixture. Furthermore, under these conditions, the unwanted NO2 (NO2 *) radical is produced for inhalation purposes. To remove the NO2 radical from the inhalation gas, the use of expensive absorbent technology is required. The disadvantage of an absorbent is, in particular, that the absorbent material must often be replaced or recycled. The discharge of sparks or arc flash richer in energy compared to a light discharge, causes a comparatively strong gas heating, so a correspondingly efficient NO production is obtained. The high thermal load of the electrodes, in particular, at the starting point of the spark, however, disadvantageously leads to strong erosion of the electrodes, that is, to a progressive decomposition of the electrode material. Due to this erosion of the electrodes, the process, on the one hand, has an intense maintenance, since the electrodes are very susceptible to wear. On the other hand, it must be avoided that the small particle electrode material eroded in the gas reaches the patient. This requires expensive gas purification.
[216] In the context of the present invention, NO generation is carried out through the photolysis of a photolabile substance. Then, for example, the nitrite ions (NO2-) contained in a solution containing nitrite (for example, sodium nitrite) are dissociated by means of electromagnetic radiation (for example, UVA radiation with wavelengths between 320 and 440 nm ) (photolysis), with which NO is generated. Under reducing conditions or under protective gas (eg nitrogen), the decomposition of nitrite induced by electromagnetic radiation takes place through different channels, partly also parallel, in a thermodynamic way, however, weighted differently. It can be assumed that in channel 1 (reactions 1 to 5), UVA radiation (with an optimum at 354 to 366 nm) dissociates nitrite to form the nitrogen monoxide radical (NO *) and the anion of the oxygen radical ( O * - (equation 1) The product mentioned last starts, in aqueous solutions, the formation of the reactive hydroxyl radical (OH *) (equation 2) .The hydroxyl radical reacts with nitrite, which leads to the formation of the nitrogen dioxide radical (NO2 *) (equation 3). This can continue to react with nitrogen monoxide for dinitrogen trioxide (N2O3) (equation 4). NO- + hv ^ NO * + O * - (1) O * - + H2O ^ OH * + OH- (2) NO2- + OH * ^ NO2 * + OH- (3) NO2 * + NO * ^ N2O3 (4) N2O3 + H2O ^ 2 NO2- + 2 H + (5)
[217] In channel 2 (equations 6 to 10), hydroxyl radicals do not appear to have any important role in the mentioned conditions, however, a “quantized” electron (e-aq) is formed, as well as a nitrogen dioxide radical (equation 6). The electron, in the case of an excess of nitrite, is transferred to it and the resulting nitrite anion (equation 7) is reduced in water in the radical NO (equation 8). The following reactions in equations (9) and (10) correspond to those in equations (4) and (5). The weighting of channel 1 to channel 2 forms, in this case, a proportion of approximately 40:60. NO2- + hv ^ NO2 * + e-aq (6) e-aq + NO2- ^ NO2- (7) NO2- + H2O ^ NO * + 2 OH- (8) NO * + NO2 * ^ N2O3 (9) N2O3 + H2O ^ 2 NO2- + 2 H + (10)
[218] As is evident from reactions 1 to 10, photolytic decomposition of nitrite is accompanied by a parallel production of reactive and cytotoxic chemical species. From the reactions in equations (4) and (9) it is also evident that the NO2 radicals (NO2 *) can react again with the NO formed in equation (1).
[219] It has been recognized (EP1903003A1) that through the use of at least one system, which degrades or neutralizes NO2 radicals or oxygen species, during the generation of nitrogen monoxide the formation of the mentioned reactive intermediate products of nitrite decomposition induced by light (NO2 *, O * -, OH *, e-aq) is suppressed or eliminated, while, at the same time, the generation of nitrogen monoxide is not reduced. In this way, the yield of freely available NO and the purity of the gas increases.
[220] The increase in the release of NO, as well as the high degree of purity are based on an elimination of the reactive intermediate products conditioned by the reaction, for example, according to the following reactions (11) to (17). N2O3 + RS- ^ NO2- + RSNO (11) RSNO + hv ^ NO * + RS * (12) NO2 * + RS- ^ NO2- + RS * (13) NO * + RS ^ RSNO (14) BA + OH * ^ BA-OH (15) VitC + NO2 * ^ NO2- + VitC * - (16) Trol + NO2 * NO2- + Trol * - (17) (Abbreviations: RS-, thiol; RSNO, S-nitrous-thiol ; RS-, thioyl radical; BA, benzoic acid; VitC, vitamin C, ascorbate, ascorbic acid; VitC *, the VitC radical; trol, trolox; trol *, the trolox radical).
[221] This process (EP1903003A1) makes possible, through the presence of these or other functionally identical systems during the formation of nitrogen monoxide, a high yield of nitrogen monoxide, while, at the same time, the formation of nitric oxides (several undesirable oxidized substances, in particular, from NO2 *, as well as from hydroxyl radicals and quantized reactive electrons, are efficiently avoided or these substances are eliminated after their formation or else they can be produced only at such a low rate that they remain in solution and cannot pass to the gas phase. In this way, these substances, for example, cannot cause any pathologically relevant damage as a result of inhaling the inhalation gases.
[222] As systems, which degrade or neutralize reactive nitric oxide species (for example, nitrogen dioxide radicals or reactive oxygen species, substances that degrade or neutralize reactive oxygen species or nitric oxide species (ROS or RNS) (antioxidants) In addition, it is preferably ascorbic acid, ascorbate, vitamin E and its derivatives, thiols, other antioxidants, radical scavengers or enzymes that degrade ROS and RNS.
[223] In addition, it has been found that the binding or elimination of the mentioned reactive intermediate products from light-induced nitrite decomposition (NO2 *, O * -, OH-, e-aq) can also be carried out in a range of Neutral pH, maximum NO release with maximum purity can be obtained.
[224] Under acidic conditions (pH <7.0) the “spontaneous” decomposition of nitrite is favored in aqueous solutions. According to equations 18 to 20, the nitrite anion (NO2-) is found in aqueous solutions in equilibrium with its conjugated acid, with nitric acid (NHO2). HNO2, in turn, is in equilibrium with dinitrogen trioxide (N2O3), which decomposes spontaneously to NO * and NO2 *. NO2- + H + HNO2 (18) 2 HNO2 N2O3 + H2O (19) N2O3 NO * + NO2 * (20)
[225] In an embodiment of a described process (EP1903003A1), the UVA-induced generation of nitrogen monoxide is preferably carried out, with this, in a pH range of 0 to 12, in particular, from 1 to 10, particularly preferably from 1.5 to 6, especially from 2 to 6, especially from 2.5 to 4.
[226] Depending on the concentration of nitrite or antioxidant used, as well as depending on the height of the physical decompensation stimulant, which leads to the decomposition of nitrite, a high concentration of nitrogen monoxide can be obtained through the mentioned process (EP1903003A1).
[227] In a solution, the amount of nitrogen monoxide generated can be controlled, through the concentration used of the agents that release nitrogen monoxide and through physical and / or chemical induction, which is responsible for the release of nitrogen monoxide from the agents .
[228] In this case, by the term “physical and / or chemical induction”, in addition to the intensity of electromagnetic radiation, as well as the duration of exposure, to which the reaction solution is exposed, the reaction parameters are also generally understood, which have an influence on the formation of nitrogen monoxide in and on the concentration of nitrogen monoxide. These include, in general, the pH value of the reaction solution, the redox state of the reaction solution, the temperature of the reaction solution, the irradiated area exposed, the action time for an induction size on the agents nitrogen monoxide releasers, the removal of the source of electromagnetic radiation for the reaction solution, the spectrum of the source of electromagnetic radiation, the absorption, transmission, reflection properties of the reaction solution, the concentration of biological or chemical catalysts or mediating substances , which also outside the "typical" physical-chemical conditions of an optimal release of NO, however, enable such NO-generating substances through catalysis or corresponding receptor properties. In particular, chromophores and other substances are understood, with the help of which, for example, also electromagnetic radiation outside the UVA spectrum range would be able to enable the release of NO from the corresponding NO-forming agents.
[229] Thus, for example, with induction sizes kept constant through the use of varying concentrations of the nitrogen oxide releasing substance (s), it is possible to release varying amounts of nitrogen monoxide.
[230] In addition, at a constant concentration of the nitrogen oxide releasing substance (s), it is possible to modify the release of nitrogen monoxide by varying the adjustment parameters of the respective induction sizes. In the case of an induction size kept constant, therefore, large amounts of NO can be released through the use of high concentrations of NO releasing substances and vice versa. At a constant concentration of the NO releasing substance, the NO generation can be modified by varying the adjustment parameters of the respective induction sizes. The adjustment parameters, in this case, can be applied alternatively or simultaneously to the regulation of NO generation. In particular, through the simultaneous regulation of NO generation through various adjustment parameters, the process can be advantageously optimized with respect to NO generation, as well as the production of undesirable by-products.
[231] The substance, which is used to release nitrogen monoxide and which is used in the process according to the invention, is not fundamentally subject to any limitation, as long as it is capable of releasing nitrogen monoxide under the influence of electromagnetic radiation . This can be selected, for example, from the group, which consists of (a) pure substances or mixtures of substances, which generate nitrogen monoxide under the action of electromagnetic radiation; (b) mixtures of substances, which in addition to the substances or mixtures of substances mentioned in (a) contain auxiliary substances, which are selected from the group, consisting of photoreceptors, photoamplifiers, transition metals, in particular copper ions, for generate nitrogen monoxide spontaneously or under physical or chemical influence; and (c) substances or mixtures of substances, which only as a result of a chemical reaction carried out previously, with the aid of the substances mentioned in (a) and optionally the auxiliary substances mentioned in (b) under the influence of electromagnetic radiation, generate nitrogen spontaneously or under physical or chemical influence.
[232] In addition, the substances described in (a) may additionally release nitrogen monoxide through changes in temperature and / or changes in humidity and / or changes in the redox state of their solutions.
[233] The release can be made from aqueous solutions of nitrite or S-nitrosothiol. In this case, for practical reasons, the use of an aqueous solution of sodium nitrite or S-nitrosothiols is preferred as a source of NO. The aqueous solution can have a concentration of NO precursors of preferably 0.001 to 10,000 mM, in particular 0.2 to 6000 mM, particularly preferably 0.3 to 5000 mM, especially 0.4 to 2000 mM, very special 0.5 to 1500 mM.
[234] The type of irradiation of starting substrates that generate NO is known to you by the specialist active in the present field. Any electromagnetic radiation can be used, which is capable of decomposing NO derivatives to form nitrogen monoxide. For example, in the context of the present invention, the production of nitrogen monoxide can be carried out by means of photolytic dissociation using UVA radiation with wavelengths of, for example, 310 to 440 nm. However, electromagnetic radiation of any other wavelength can also be used which, individually or with the aid of chemical, physical or biological processes, induces a direct photolytic dissociation, induced or facilitated or catalyzed by other auxiliary substances of NO precursors that generate NO (derived from NO).
[235] The production of nitrogen monoxide can also be carried out in solutions, which are saturated with inert gases. In such solutions saturated with inert gases (nitrogen (N2), helium (H2), argon and so on), the NO dissolved in them has an essentially longer useful life and can also remain in the solution at higher concentrations. In general, it is assumed that the maximum solubility of NO in aqueous solutions is about 2 mM. In this context, as aqueous solutions, culture or infusion media or buffers, serum, blood, gels and all other substances, which are capable of absorbing gases, can also be understood.
[236] The nitrogen monoxide produced by photolysis of photolabile NO precursors can be used, for example, for inhalation purposes. Other specific fields of application are the stimulation of tissue metabolism through external application, the structural modification of organic as well as inorganic surfaces, sterilization or the production of cytotoxicity. The nitrogen monoxide produced by photolysis can also be used to aerate lesions, in particular, to heal chronic, non-healing lesions, eventually infested with bacteria. Nitrogen monoxide can, when produced in saturated liquids, also be used systemically for the treatment of hypertension. Finally, nitrogen monoxide can also be produced in vehicles nitrated with nitrogen monoxide, which spontaneously release NO again. Nitrogen monoxide can also be used to produce different substances that bind NO (for example, NO donors).
[237] The quality of a gas also stored or introduced into solutions for medical applications, must meet high requirements. A small impurity of the gas leads to the formation of undesirable and possibly poisonous by-products. The formation of these by-products in the case of longer storage of gas plugs containing nitrogen monoxide, as well as in the technological production of nitrogen monoxide plasma and the removal of these radicals, represent a major technological as well as financial disadvantage. The advantages of the photolytic process for the production of solutions containing nitrogen monoxide are the simplicity of the production method of the gas containing NO, the particularly high degree of purity of the mixture of NO gas produced, low follow-up costs and no storage costs, particularly simple handling of NO generation, as well as purity control, the incomparably favorable proportion of production costs to the amount of NO gas produced.
[238] Device according to the invention
[239] The present device according to the invention is a modular patch composed of at least two layers and is capable of dissociating photolabile nitrogen monoxide precursors through the emission of electromagnetic radiation from a light module, inserted in a tight absorption module, so that nitrogen monoxide can be produced photolytically, which can be used to assist medical therapies in animals and humans, as well as to generate NO.
[240] The advantages of such a device are evident. Due to the limited dissolution behavior of NO, in the absorption module, in fact, physiologically relevant concentrations of NO can be generated, which, however, are well below those, which could cause damage to human health. In addition, through direct contact of the surface of the human body with the module of the photolytically produced nitrogen monoxide releasing device, an essentially more precise treatment with NO can be obtained than, for example, with gas mixtures containing NO or with donors of NO that decompose spontaneously. Furthermore, the possibility that the device can be used by different end consumers after loading with the corresponding NO precursors, from laymen to the specialist, represents the essential advantage of the device according to the invention over other based therapies. of NO.
[241] The device according to the invention consists of at least one module emitting electromagnetic radiation (in the context of the invention referred to as SEM = module emitting radiation), as well as a module containing the photolabile nitrogen monoxide precursors just ( in the context of the invention designated as NOM = NO module).
[242] SEM generates nitrogen monoxide in the NOM through photolytic dissociation of the photo- or redox-labile nitrogen monoxide precursors inserted in them. In this case, the NOM is an integral component, tightly connected with the SEM of the total device. Alternatively, SEM and NOM can also be used separately from each other and, in fact, in the sense that the irradiation of the NOM is not carried out in direct contact with the SEM, but with a spatial distance of that .
[243] It is important, that the luminous flux of the NOM together with the inserted reaction substances, which release nitrogen monoxide, in the sense of an induced decomposition of material or a release of nitrogen monoxide, is ideal or maximum. For an ideal dissociation of the photolabile NO precursors inserted in the NOM, the SEM can emit electromagnetic radiation with wavelengths from 100 to 2000 nm or electromagnetic radiation of any other wavelength, which individually or with the aid of chemical, physical or biological processes it can induce a dissociation of nitrogen monoxide precursors and thereby generate a release of nitrogen monoxide. The source of the electromagnetic radiation may, in this case, be an incandescent lamp or gas discharge (low pressure or high pressure discharge) coated with corresponding fluorochromes, a light emitting diode (LED), an organic light emitting diode ( OLED), LASER or can be any other source of electromagnetic radiation, which is capable of generating NO from corresponding chemical precursors or substrates.
[244] The source of SEM electromagnetic radiation, which in direct contact or also from some distance induces the release of NO in the NOM, can be installed with the electronic control unit of the light source in a spatially compact way in one piece / box or be spatially separate from that control unit and be connected only via a wired connection or even be completely separate, in which case the light source can be controlled by the light unit using a remote control.
[245] The NOM should be formed of a material / substance / support / medium, which does not influence the energy properties of an electromagnetic radiation source necessary for an optimal release of nitrogen monoxide or, due to its properties, creates or optimizes only the properties of light necessary for a light-induced release of nitrogen monoxide. While the SEM is considered as a constant part of the device, which is not consumed, the NOM is considered as an article of use of the device that can be easily exchanged or replaced. In this case, NOM is considered as a carrier medium, which preferably contains chemically stable or stabilized substances, which potentially store NO and thus potentially release NO again (for example, nitrates, organic or inorganic nitrites, compounds S-, N - or O-nitrous, compounds of NO metals, NO chelating substances), individually or in different combinations, that in pure form or dissolved in different solvents, in a catalyzed reaction, for example, through transition metal ions or in a non-catalyzed reaction, initiated physically and / or chemically, can release nitrogen monoxide from NOM.
[246] The NOM material / medium containing substances that potentially release NO again can be a more or less viscous or fluid or viscous solution / liquid, a gel, a film, a film, foam, textile, fleece, synthetic material, natural substance or a medium carrying any other class of substances, which is capable or can be taken for such, of storing or carrying substances that release NO or its stable precursors and to generate or release NO.
[247] The advantage of using a NOM that can be exchanged or replaced is that by filling a NOM with reactive agents in different combinations and concentrations, different specific NO release samples can be generated in or from the NOM for use and treatment. In this way, it can be achieved that the NO release samples generated through the device through the selection of a specifically equipped NOM enables application optimization adjusted to the technical and responsible competence of the end user. As regards the filling of the NOM, then quantities of preferably 0.001 to 10000 mM are selected there, in particular 0.01 to 6000 mM, particularly preferably 0.1 to 5000 mM, especially 0.4 to 2000 mM , in a very special way 0.5 to 1500 mM of the respective or combined NO precursors (for example, nitrite or S-nitrosothiols).
[248] The production of NO in or from the NO of the device according to the invention, is preferably regulated based on the manipulation of different adjustment parameters in the SEM or also NOM. In this case, as adjustment parameters, the concentration used of the agents that release NO, the intensity of electromagnetic radiation and the properties of the other sizes of physical and / or chemical induction, which are responsible for the release of NO from the agents, are applied. In addition, as possible sizes of induction of a NO release from substances that potentially generate NO individually or in different combinations, the following parameters can vary and be used: - the pH value, - the redox state (presence of reducing substances or oxidants), - the temperature, - current flow and / or voltage, - the surrounding pressure, - the intensity of the electromagnetic radiation and duration of exposure, to which the NOD is exposed in the NOM, - the exposed irradiation surface, - the exposure time of an induction size on the agents that release NO, - the removal of the source of electromagnetic radiation into the reaction solution, - the spectrum of the source of electromagnetic radiation, - the properties of absorption, transmission, reflection of the layers of NOM, - or the concentration of catalysts or biological or chemical promoter substances, which also outside the “typical” physicochemical conditions of an optimal release of NO enable such a substance s NO-generators through catalysis or corresponding receptor properties (for example, with the aid of chromophores and other substances, with the help of which, for example, electromagnetic radiation outside the UVA spectrum range might be able to enable the release of NO from corresponding NO-forming agents).
[249] Regarding the last point mentioned, reference should be made to the fact that, particularly in the presence of transition metal ions, for example, Cu2 +, nitrite solutions can absorb with essentially longer wavelengths than solutions of pure nitrite and, in this way, the nitrite ion can also be dissociated through light at wavelengths from 400 to 450 nm with NO release.
[250] Regarding the control variables mentioned above, then, in the device according to the invention with an induction size kept constant, varying amounts of nitrogen monoxide could be produced through the use of varying concentrations of the substances that release nitrogen oxide. On the other hand, at a constant concentration of substances that release nitrogen monoxide, the release of nitrogen monoxide in the carrier medium could be altered by varying the parameters for adjusting the respective induction size.
[251] The device according to the invention has a reliable sensor relevant to safety and treatment (for example, for NO, NO2, temperature, light intensity, erythema, time limit and so on), as well as possibilities connection and connection to external equipment, such as, for example, computers, smartphones and so on). In addition, all functions of the device can be controlled remotely directly or through applications controlled by software and, in addition, the device can “communicate” with all external equipment in the sense of feedback.
[252] The NO generated with the aid of the device according to the invention described here, can be used to stimulate the metabolism of tissues through external application, in the area of dermatology for the treatment of surgical injuries or due to accidents, chronic, non healing or difficult to heal and / or bacterial or fungal attacks, as well as for the treatment of dermatological diseases in the formation of inflammatory diseases, immunologically controlled or autoimmune. Examples of possible fields of application would be: • treatment of diabetic feet and injuries; • treatment of neuropathic pain in diabetes and other diseases, • treatment of varicose veins; • treatment of superficial as well as deep local ischemias and thrombotic tissue diseases; • acute and chronic skin inflammations, • skin allergies, • parasitic skin infection, • atopic dermatitis, in particular, neurodermatitis, • dermatomyositis, • pemphigus vulgaris and / or other local and systemic infections and / or situations of acute and chronic, • injury defects, such as chronic diabetic-neuropathic ulcer, • venous foot ulcer, • decubitus injuries, • infected secondary scarring injuries, • non-irritating primary scarring injuries, such as, in particular, lacerations or ablative abrasions, • transplants (skin), • treatment of diabetic pain in the lower extremities (foot or leg); and treatment of poorly perfused skin plastic surgery.
[253] In addition, it could be possible, through the treatment of larger areas of the body, to also link systemic diseases, such as, for example, increased blood pressure (hypertonia) and related hemodynamic diseases.
[254] For the purpose of a treatment, the NOM is placed over the area to be exposed and preferably exposed in direct contact or also at a distance from the electromagnetic radiation emitted from the SEM. The treatment time can last between a few seconds and many hours.
[255] In a preferred embodiment of the invention, the treatment time is between 5 to 30 minutes, preferably between 7.5 and 20 minutes and particularly preferably between 10 to 15 minutes.
[256] In an embodiment of the invention, the medical patch is used for the treatment of diseases. In that case, the medical patch is conveniently placed over the area of the body to be exposed, therefore, for example, over a part of the trunk or a part of the extremity, and then through the release induced by UV radiation or a release of NO from NOM caused by a redox reaction, that corresponding area is exposed to NO.
[257] In this way, the medical plaster according to the invention cannot be used only for the treatment of chronic or acute diseases, but also for the possible prevention of these diseases. Unless otherwise indicated, the term "therapy" or "treatment" includes all measures for the relief, cure or prevention of the diseases relevant here.
[258] Such a plaster treatment can be applied at intervals of 1, 2, 3, 4, 5, 6 or 7 days or even several times a day, with an application of 2 to 3 times a day being preferred.
[259] In this case, the NOM remains conveniently on the skin and by applying the SEM for a dimensioned time it can be stimulated again to generate NO and release NO. This is possible through an “excess” of NOD in the NOM, which allows multiple irradiation intervals.
[260] To control the duration of treatment, the medical patch may preferably contain a timing unit, which after a certain period of time or preferably a flexible programmable time, switches off the radiation source from the SEM and, with this prevents the generation of NO.
[261] In addition, the medical plaster may contain a dye, which after a certain time experiences a color change, so that the user is informed about the end of the treatment time.
[262] In addition, the medical patch may also comprise a device for measuring blood circulation which, based on the success of the therapy, allows for particularly good control over the duration of treatment and / or the intensity of treatment. The specialist knows numerous devices for measuring blood circulation. Examples for this purpose include vascular tachometers or the microsensors published in WO 97/46853. This sensor comprises an insertion permeable to the indicator, which is arranged in an opening of an indicator container, which is formed by a container, whereby the insertion forms a permeable wall part of the container.
[263] As alternative parameters for skin circulation, other vasculogenic measurement parameters, such as skin erythema or in time of the skin, may be used, for which the corresponding measurement methods and equipment are known from the current state of the art.
[264] In another aspect, the invention provides a process for treating a patient, which comprises the following steps: a. application or adhesion of a medical patch according to the invention on the part of the body to be treated; and b. generation and release of NO by linking the UV radiation source of the SEM.
[265] In a preferred embodiment, in this process the treatment is selected from the group containing: • stimulation of tissue metabolism through external application in humans and animals; • treatment of surgical injuries or due to accidents; • treatment of chronic, non-healing or difficult-to-heal injuries; • treatment of bacterial and / or fungal infested lesions; • treatment of dermatological diseases in the circle of formation of immune-controlled or autoimmune inflammatory diseases; • treatment of diabetic feet and injuries; • treatment of neuropathic pain; • treatment of varicose veins; • treatment of superficial and deep local ischemias and thrombotic tissue diseases; • treatment of acute and chronic skin inflammations; • treatment of skin allergies; • treatment of parasitic skin infections; • treatment of atopic dermatitis, in particular, neurodermatitis, dermatomyositis and pemphigus vulgaris; • treatment of injury defects, such as chronic diabetic-neuropathic ulcer, venous foot ulcer, decubitus injuries; • treatment of larger areas of the body for the treatment of systemic diseases, such as, for example, increased blood pressure (hypertonia) and related hemodynamic diseases; • treatment of patients with (skin) transplants; • treatment of diabetic pain in the lower extremities (foot or leg); and • treatment of poorly widespread skin plastic surgery.
[266] In a preferred embodiment, the process is applied for the treatment of chronic lesions of the lower extremities of diabetics.
[267] Conveniently, the process is characterized by the fact that the treatment is carried out through the application or adhesion of the medical patch on a part of the trunk or end part with the release of NO induced by UV radiation. Such a treatment, in this case, can last between a few seconds and many hours.
[268] Preferably, the treatment through the release of NO induced by UV radiation lasts between 5 to 30 minutes, preferably between 7.5 to 20 minutes and particularly preferably between 10 to 15 minutes.
[269] In a particularly preferred embodiment, the medical patch according to the invention is used for the treatment of chronic lesions of the lower extremities, and in this case, in particular, in diabetics. In this case, moreover, through treatment towards prophylaxis, the risk of forming chronic injuries, as well as the number of medical amputations, can be reduced. Thus, the reduction of neuropathic pain in the leg and the production of a better healing environment for the lesion occur together with a significantly better quality of life for patients. In addition, a significant decrease in treatment costs can be expected by reducing injury care.
[270] In an embodiment of the invention, the medical patch is used for the therapy of difficult-to-heal lesions. Poor arterial circulation and / or disorders of venous return are decisive causes in the formation, as well as the chronicity of lesions of the lower extremities. An arterial vasodilation induced by NO improves the circulation of the affected tissue and through the antithrombogenic effect of NO, a venous return of the blood is essentially stimulated or facilitated. The NO-dependent improvement of the two hemodynamic parameters represents the relevant decisive aspect of therapy for a local as well as a systemic effect, which significantly reduces the risk of lesion formation or essentially accelerates its healing. The NO supplied to the body by means of the medical patch in a form locally limited to the part of the extremity or the part of the trunk to be treated can, therefore, be applied successfully for the therapy of difficult to heal lesions.
[271] In a particular embodiment, the medical patch according to the invention is used to treat diabetic pain in the lower extremities, therefore, of the foot and / or leg. Diabetic pain is a very common event in the course of a diabetes disease. Diabetic foot / leg pain is an event of long-term high concentrations of glucose, which is the fundamental cause of nerve damage, as well as vascular damage seen during diabetes disease. An arterial vasodilation induced by NO improves the circulation of the affected tissue and aids in the transmission of pain in order to influence pain attenuation. The NO supplied from the outside to the foot and / or leg with the medical patch can therefore be applied successfully for diabetic foot / leg pain therapy.
[272] In a special embodiment of the invention, the medical plaster according to the invention is used for the treatment of patients with (skin) transplants and, in this case, in particular, for the treatment of badly skin plastic surgery perfused. The two hemodynamic variables mentioned above, arterial circulation, as well as venous return are also essential parameters for the success of skin plastic surgery therapy. Plastic skin surgeries are called plastic-surgical techniques, which take skin and / or tissue from a location (essential) of the same individual to a new desired location. As a rule, these are clean skin flaps, however, any tissue with or without skin can be transplanted, both complete (therefore, with their respective vessels that supply blood and nerves), as well as free (that is, with connection blood vessels to the blood supply of the new medium). The functional acceptance of the transplanted tissue, in this case, depends exclusively on the supply of arterial blood, as well as regulated venous drainage. NO-induced arterial vasodilation improves circulation and, thus, the necessary supply of skin plastic surgery and venous drainage or blood return is stimulated or facilitated through the NO's antithrombogenic effect. NO preparations used from the outside can therefore guarantee or stimulate the success of a therapy option based on skin plastic surgery.
[273] In a particular aspect, the invention provides the following embodiments:
[274] Embodiment 1: A device made up of at least two modules of any size and area, which by means of the emission of electromagnetic radiation from at least one of the modules (hereinafter referred to as SEM = emission module of radiation) may preferentially photolytically decouple photolabile or redox-labile nitrogen monoxide precursors (hereinafter referred to as NOD = NO derivatives) contained in a second module preferably just for that purpose (hereinafter referred to as NOM = NO module), so that in the NOM nitrogen monoxide (NO) is generated and preferably from which the NOM can be released.
[275] Embodiment 2: Device according to Embodiment 1, characterized by the fact that the NOM is preferably an integral component, tightly connected with the SEM of the entire device, which includes the possibility that the SEM and the NOM, however, can also be spatially separated from each other, so that the irradiation of the NOM is not done in direct contact applied in the SEM, but with a spatial distance to it.
[276] Embodiment 3: Device according to Embodiment 1 and 2, characterized by the fact that for an ideal dissociation of the photolabile NO precursors inserted in the NOM, the SEM can emit electromagnetic radiation with wavelengths, which individually or with the support of chemical, physical or biological processes, it can induce a dissociation of nitrogen monoxide precursors and, with that, a release of nitrogen monoxide, and through the presence of other substances with catalytic properties or specific receptor properties of light, NO generation can be facilitated or even made possible (for example, with the aid of transition metals, such as, for example, Cu2 + ions, chromophores and other substances, with whose aid, for example, also radiation Electromagnetic radiation outside the UVA spectrum range may be able to enable the release of NO from the corresponding NO-forming agents).
[277] Embodiment 4: Device according to Embodiments 1 to 3, characterized by the fact that the source of electromagnetic radiation integrated in the SEM can be an incandescent lamp or discharge lamp (low pressure discharge or high pressure) coated with corresponding fluorochromes, a light emitting diode (LED), an organic light emitting diode (OLED) or LASER or also another source of electromagnetic radiation, which is capable of generating NO from corresponding precursors or chemical substrates .
[278] Embodiment 5: Device according to Embodiments 1 to 4, characterized by the fact that the source of SEM electromagnetic radiation can be installed with an electronic control unit the light source in a spatially separate way and it can only be connected via a wired connection or it can even be completely separate, in which case the light source can be controlled by the light unit using a remote control.
[279] Embodiment 6: Device according to Embodiments 1 to 5, characterized by the fact that the generation of NO in or from the NOM is subject to an electronically regulated safety management, which 1.) is preferably regulated based on the manipulation of various physical or chemical technical adjustment parameters in SEM or also NOM, 2.) it has sensors relevant to safety and treatment (for example, for NO, NO2, temperature, light intensity, erythema, time limit and so on, 3.) has possibilities of connection and connection to external equipment (for example, computers, smartphones and so on), as well as could be controlled remotely and controlled through software-controlled applications, one of which essential part of device security management is application-specific and electronically controlled recognition and acceptance of use of the NOM specifically loaded with NO Ds or their parts that can be exchanged or replaced and that contain photolabile NO derivatives.
[280] Embodiment 7: characterized by the fact that it can be used to stimulate tissue metabolism through external application, in the area of dermatology and surgery it can be used for the treatment of surgical injuries or due to accidents, chronic injuries not healing or difficult to heal and / or bacterial and / or fungal infested, for the treatment of dermatological diseases in the circle of formation of inflammatory diseases, immunologically controlled or autoimmune, thus, for example, for the treatment of feet or injuries in diabetics, neuropathic pain in diabetes and other diseases, from varicose veins, superficial and deep local ischemia and thrombotic tissue diseases, acute and chronic inflammation of the skin, skin allergies, parasitic skin infections, atopic dermatitis, in particular, neurodermatitis, dermatomyositis, pemphigus vulgaris and / or other local and systemic infections and / or situations of acute and chronic inflammation, injury defects s, such as chronic diabetic-neuropathic ulcer, venous foot ulcer, decubitus injuries, infected secondary scarring injuries, non-irritating primary scarring injuries, such as, in particular, ablative lacerations or abrasions, (skin) transplants, but also for the treatment of larger areas of the body for the treatment of systemic diseases, such as, for example, increased blood pressure (hypertonia) and related hemodynamic diseases, with individual treatment lasting between a few seconds and many hours, with for the purpose of a treatment, the NOM is placed over the area to be exposed and is exposed in direct contact or, also, from a spatial distance to the electromagnetic radiation emitting from the SEM, and such treatment can last between a few seconds and many hours.
[281] REFERENCE INDEX 1 inner layer 2 intermediate layer 3 outer layer 4 back layer 5 transparent window on the back layer 6 fixing device for SEM 7 non-adhesive part of an inner layer 8 hollow space in the inner area of the plaster 9 radiation source 10, 10 'spacer
[282] FIGURES
[283] The invention is explained in detail below, based on the figures, without restricting the invention to them. These show:
[284] Figure 1: the application for the treatment of the injury, in which the NOM is placed on the leg injury as a flexible patch and an SEM positioned above the patch is irradiated with UV radiation, so that the NOM releases NO from the side of the body.
[285] Figure 2: an exploded schematic view of an embodiment of the NOM of the medical plaster with internal layer (1), intermediate layer (2) and external layer (3).
[286] Figure 3: a schematic representation of a multilayered NOM seen with the inner layer (1) and the back layer (4) in (A), with an additional transparent area as an activation window in (B) and with a fixing device (for example, as a Velcro fastener) for the SEM in (C).
[287] Figure 4: a schematic representation of a two-layer NOM seen in cross section with the intermediate layer (2) and the posterior layer (4) in (B), with an additional transparent area as an activation window in (A ).
[288] Figure 5: a schematic representation of a three-layer NOM seen in cross section with the inner layer (1), with the middle layer (2) and with the back layer (4) in (A), with an area additional transparent as an activation window in (B), with the inner layer inserted flatly in (C), with a non-adhesive inner layer in the middle layer area in (D) and with a hollow space wrapped on all sides below of the intermediate layer in (E).
[289] Figure 6: a schematic representation of the medical plaster in cross section with a three-layer NOM t with the inner layer (1), the middle layer (2) and the back layer (4) with a transparent activation window (5 ) and the radiation source placed with SOM in (A), with spacers (10, 10 ') in (B).
[290] LITERATURE [1] K.D. Kroncke, K. Fehsei, and V. Kolb-Bachofen, Inducible nitric oxide synthase in human diseases. Clin Exp Immunol 113 (1998) 147-56. [2] K. Matsunaga, and R.F.Furchgott, Responses of rabbit aorta to nitric oxide and Superoxide generated by ultraviolet irradiation of Solutions containing inorganic nitrite. J Pharmacol Exp Ther 259 (1991) 1140-6. [3] M. Fischer, and P. Warneck, Photodecomposition of nitrite and undissociated nitrous acid in aqueous solution. J.Phys.Chem. 100 (1996) 18749-18756. [4] H. Strehlow, and I. Wagner, Flash photolysis in aqueous nitrite Solutions. Z. Phys. Chem. NF 132 (1982) 151-160. [5] S. Frank, H. Kampfer, C. Wetzler, and J. Pfeilschifter, Nitric oxide drives skin repair: novel functions of an established mediator. Kidney Int 61 (2002) 882-8. [6] S. Frank, B. Stallmeyer, H. Kampfer, N. Kolb, and J. Pfeilschifter, Nitric oxide triggers enhanced induction of vascular endothelial growth factor expression in cultured keratinocytes (HaCaT) and during cutaneous wound repair. Faseb J 13 (1999) 2002-14. [7] S. Frank, H. Kampfer, M. Podda, R. Kaufmann, and J. Pfeilschifter, Identification of copper / zinc Superoxide dismutase as a nitric oxide-regulated gene in human (HaCaT) keratinocytes: implications for keratinocyte proliferation. Biochem J 346 Pt 3 (2000) 719-28. [8] K. Yamasaki, H.D. Edington, C. McClosky, E. Tzeng, A. Lizonova, I. Kovesdi, D.L. Steed, and T.R. Billiar, Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J Clin Invest 101 (1998) 967-71. [9] J. Pfeilschifter, W. Eberhardt, and A. Huwiler, Nitric oxide and mechanisms of redox signalling: matrix and matrix-metabolizing enzymes as prime nitric oxide targets. Eur J Pharmacol 429 (2001) 279-86. [10] Y. Ishii, T. Ogura, M. Tatemichi, H. Fujisawa, F. Otsuka, and H. Esumi, Induction of matrix metalloproteinase gene transcription by nitric oxide and mechanisms of MMP-1 gene induction in human melanoma cell lines . Int J Cancer 103 (2003) 161-8. [11] M.B. Witte, F.J. Thornton, D.T. Efron, and A. Barbul, Enhancement of fibroblast Collagen synthesis by nitric oxide. Nitric Oxide 4 (2000) 572-82. [12] F. Verrecchia, and A. Mauviel, TGF-beta and TNF-alpha: antagonistic cytokines Controlling type I Collagen gene expression. Cell Signal 16 (2004) 873-80. [13] D.A. Siwik, and W.S. Colucci, Regulation of matrix metalloproteinases by cytokines and reactive oxygen / nitrogen species in the myocardium. Heart Fail Rev 9 (2004) 43-51. [14] V.M. Darley-Usmar, R.P. Patel, V.B. O'Donnell, and B.A. Freeman, Antioxidant actions of nitric oxide. in: L.J. Ignarro, (Ed.), Nitric Oxide: Biology and Pathobiology, Academic Press, San Diego, 2000, pp. 265-276. [15] S.P. Goss, B. Kalyanaraman, and N. Hogg, Antioxidant effects of nitric oxide and nitric oxide donor compounds on low-density lipoprotein oxidation. Methods Enzymol 301 (1999) 444-53. [16] D.A. Wink, J.A. Cook, R. Pacelli, J. Liebmann, M.C. Krishna, and J.B. Mitchell, Nitric oxide (NO) protects against cellular damage by reactive oxygen species. Toxicol Lett 82- 83 (1995) 221-6. [17] B. Brüne, A. von Knethen, and K.B. Sandau, Nitric oxide (NO): an effector of apoptosis. Cell Death Differ6 (1999) 969-75. [18] D. Moellering, J. McAndrew, R.P. Patel, T. Cornwell, T. Lincoln, X. Cao, J.L. Messina, H.J. Forman, H. Jo, and V.M. Darley-Usmar, Nitric oxide- dependent induction of glutathione synthesis through increased expression of gamma-glutamylcysteine synthetase. Arch Biochem Biophys 358 (1998) 74-82. [19] U. Forstermann, M. Nakane, W.R. Tracey, and J.S. Pollock, Isoforms of nitric oxide synthase: functions in the cardiovascular System. Eur Heart J 14 Suppl I (1993) 10-5. [20] P. He, M. Zeng, and F.E. Curry, Effect of nitric oxide synthase inhibitors on basal microvessel permeability and endothelial cell [Ca2 +] i. Am J Physiol 273 (1997) H747-55. [21] M. Toborek, and S. Kaiser, Endothelial cell functions. Relationship to atherogenesis. Basic Res Cardiol 94 (1999) 295-314. [22] M. Keim, and B. Strauer, Endotheliale Dysfunktion; Therapeutische und prognostische Relevanz. Internist. 40 (1999) 1300-1307. [23] T.P. Amadeu, A.B.Seabra, M.G. de Oliveira, and A.M. Costa, S- nitrosoglutathione- containing hydrogel accelerates rat cutaneous wound repair. J Eur Acad Dermatol Venereol 21 (2007) 629-37. [24] R. Weller, and M.J. Finnen, The effects of topical treatment with acidified nitrite on wound healing in normal and diabetic mice. Nitric Oxide 15 (2006) 395-9. [25] A.B. Shekhter, V.A. Serezhenkov, T.G. Rudenko, A.V. Pekshev, and A.F. Vanin, Beneficial effect of gaseous nitric oxide on the healing of skin wounds. Nitric Oxide 12 (2005) 210-9. [26] W.S. McDonald, T.P. Lo, Jr., M. Thurmond, C. Jones, R. Cohen, A. Miller, and D. Beasley, Role of nitric oxide in skin flap delay. Plast Reconstr Surg 113 (2004) 927-31. [27] C. Beige, P.B. Massion, M. Pelat, and J.L. Bailigand, Nitric oxide and the heart: update on new paradigms. Ann N Y Acad Sci 1047 (2005) 173-82. [28] B. Gaston, Summary: systemic effects of inhaled nitric oxide. Proc Am Thorac Soc 3 (2006) 170-2. [29] T.M. Dawson, and S.H.Snyder, Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J Neurosci 14 (1994) 5147-59. [30] C.C. Miller, M.K. Miller, A. Ghaffari, and B. Kunimoto, Treatment of chronic nonhealing leg ulceration with gaseous nitric oxide: a case study. J Cutan Med Surg 8 (2004) 233-8. [31] A. Ghaffari, D.H. Neil, A. Ardakani, J. Road, A. Ghahary, and C.C. Miller, A direct nitric oxide gas delivery System for bacterial and mammalian cell cultures. Nitric Oxide 12 (2005) 129-40. [32] A. Ghaffari, C.C. Miller, B. McMullin, and A. Ghahary, Potential application of gaseous nitric oxide as a topical antimicrobial agent. Nitric Oxide 14 (2006) 21-9. [33] A. Ghaffari, R. Jalili, M. Ghaffari, C. Miller, and A. Ghahary, Efficacy of gaseous nitric oxide in the treatment of skin and soft tissue infections. Wound Repair Regen 15 (2007) 368-77. [34] Z.S. Galis, and J.J. Khatri, Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90 (2002) 251-62. [35] S.C. Tyagi, and M.R. Hayden, Role of nitric oxide in matrix remodeling in diabetes and heart failure. Heart Fail Rev 8 (2003) 23-8. [36] J. Pfeilschifter, W. Eberhardt, and K.F. Beck, Regulation of gene expression by nitric oxide. Pflügers Arch 442 (2001) 479-86. [37] R. Zamora, Y. Vodovotz, K.S. Aulak, P.K. Kim, J.M. Kane, 3rd, L. Alarcon, D.J. Stuehr, and T.R. Billiar, A DNA microarray study of nitric oxide-induced genes in mouse hepatocytes: implications for hepatic heme oxygenase-1 expression in ischemia / reperfusion. Nitric Oxide 7 (2002) 165-86. [38] J. Hemish, N. Nakaya, V. Mittal, and G. Enikolopov, Nitric oxide activates diverse signaling pathways to regulate gene expression. J Biol Chem 278 (2003) 42321-9. [39] M. Ziehe, L. Morbidelli, E. Masini, S. Amerini, HJ Granger, CA Maggi, P. Geppetti, and F. Ledda, Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 94 (1994) 2036-44. [40] S.J. Leibovich, P.J. Polverini, T.W. Fong, L.A. Harlow, and A.E. Koch, Production of angiogenic activity by human monocytes requires an L-arginine / nitric oxide-synthase-dependent effector mechanism. Proc Natl Acad Sei U S A 91 (1994) 4190-4. [41] N.S. Bryan, B.O. Fernandez, S.M. Bauer, M.F. Garcia-Saura, A.B. Milsom, T. Rassaf, R.E. Maloney, A. Bharti, J. Rodriguez, and M. Feelisch, Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues. Nature Chemical Biology 1 (2005) 290-297.

权利要求:
Claims (20)
[0001]
1. Medical patch, characterized by comprising: a. a nitrogen monoxide (NO) module that contains one or more photolabile nitrogen monoxide (NOD) precursors; B. a radiation emitting module (SEM) including a radiation source, referred to as radiation emitting module (SEM) being configured so that the electromagnetic radiation emitted from the source is able to dissociate the nitric oxide precursors in the NO module and, thus, generate NO to release the NO module (NOM); and a configured antioxidant system that degrades or neutralizes one or more reactive intermediate products of light-induced nitric oxide precursor decomposition selected from the group, consisting of poloxed nitrogen oxides, oxygen radical anions, quantized electrons and hydroxyl radicals .
[0002]
Medical patch according to claim 1, characterized in that it additionally contains transition metal cations, which are preferably Cu2 + ions.
[0003]
Medical patch according to claim 2, characterized in that the electromagnetic radiation has a wavelength between 400 to 470 nm and preferably between 400 and 450 nm.
[0004]
Medical patch according to any one of claims 1 to 3, characterized in that the system, which degrades or neutralizes several times oxidized nitric oxides, anions of oxygen radicals, quantized electrons or hydroxyl radicals, is selected from the group, consisting of ascorbic acid, ascorbate, vitamin E, vitamin E derivatives, thiols, antioxidants, enzymes that degrade reactive oxygen species or reactive nitric oxide species.
[0005]
Medical patch according to any one of claims 1 to 4, characterized in that it is a medical patch for injuries.
[0006]
Medical patch according to any one of claims 1 to 5, characterized in that the NOM is firmly joined with the SEM.
[0007]
Medical patch according to any one of claims 1 to 5, characterized in that the radiation emitting module (SEM) is provided with a spacer that produces a defined distance to the NOM.
[0008]
Medical patch according to any one of claims 1 to 7, characterized in that the NOM is configured as an easily replaceable article.
[0009]
Medical patch according to any one of claims 1 to 8, characterized in that the source of electromagnetic radiation from the SEM with the electronic control unit of that source is installed in a box.
[0010]
Medical patch according to any one of claims 1 to 9, characterized in that the source of electromagnetic radiation from the SEM of the electronic control unit of that source is completely separate and the control is carried out via a wired connection or through a Remote Control.
[0011]
Medical patch according to any one of claims 1 to 10, characterized in that the source of electromagnetic radiation is selected from the group containing an incandescent lamp or a gas discharge lamp (low pressure or high pressure discharge) coated with corresponding fluorochromes, a light-emitting diode (LED), an organic light-emitting diode (OLED) and a laser.
[0012]
12. Medical patch according to any one of claims 1 to 11, characterized in that photolabile NOD is selected from the group containing organic nitrates, inorganic nitrates, nitrites, sulfur nitrous compounds, nitrogen or oxygen, NO metal compounds and substances NO chelators.
[0013]
Medical patch according to any one of claims 1 to 12, characterized in that the photolabile NOD is an inorganic nitrite.
[0014]
14. Medical patch according to any one of claims 1 to 13, characterized in that photolabile NOD are selected from the group, consisting of LiNO2, NaNO2, KNO2, RbNO2, CsNO2, FrNO2, Be (NO2) 2, Mg (NO2) 2, Ca (NO2) 2, Sr (NO2) 2, Ba (NO2) 2 or Ra (NO2) 2.
[0015]
Medical patch according to one of claims 1 to 14, characterized in that it contains NaNO2 as a photolabile precursor and ascorbic acid or ascorbate as an antioxidant system.
[0016]
Medical patch according to any one of claims 1 to 15, characterized in that it has a sensor relevant for safety and treatment, preferably for NO, NO2, temperature, light intensity and erythema.
[0017]
17. Use of the medical patch, according to any one of claims 1 to 16, characterized in that it is for application or adhesion on the area to be exposed on the patient's body part for the treatment of diseases.
[0018]
18. Use of the medical patch, according to claim 17, characterized in that the application or adhesion for the treatment of diseases is selected from the group directed to: a. diabetic feet and injuries; B. neuropathic pain; ç. varicose veins; d. superficial or deep local ischemias and thrombotic tissue diseases; and. acute and chronic inflammation of the skin; f. skin allergies; g. parasitic infections of the skin; H. atopic dermatitis, in particular, neurodermatitis, dermatomyositis and pemphigus vulgaris; i. injury defects, such as chronic diabetic-neuropathic ulcer, venous foot ulcer, decubitus sores; j. infected secondary scarring lesions; k. primary healing lesions, such as lacerations or abrasions; l. larger areas of the body for therapy of systemic diseases, such as, for example, increased blood pressure (hypertonia) and related hemodynamic diseases; m. transplant patients (skin); n. diabetic pain and chronic lesions of the lower extremities (foot or leg) of diabetics; it's the. poorly perfused skin plastic surgery.
[0019]
19. Use of the medical patch, according to any one of claims 17 to 18, characterized in that the application or adhesion for the treatment can last between a few seconds and many hours.
[0020]
20. Use of the medical patch, according to claim 19, characterized in that the application or adhesion for the treatment lasts between 5 and 30 minutes, preferably between 7.5 to 20 minutes and particularly preferably between 10 and 15 minutes.

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法律状态:
2018-06-05| B25C| Requirement related to requested transfer of rights|Owner name: BSN MEDICAL GMBH (DE) |

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2018-08-28| B25A| Requested transfer of rights approved|Owner name: BSN MEDICAL HOLDING GMBH (DE) |

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2018-09-18| B25D| Requested change of name of applicant approved|Owner name: BSN MEDICAL GMBH (DE) |

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2019-08-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-06-09| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-10-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-12-29| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/11/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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DE102013018642.0|2013-11-07|

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DE102013018642|2013-11-07|

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PCT/EP2014/074029|WO2015067746A1|2013-11-07|2014-11-07|Medical dressing|

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