Systems for transport and delivery of nitric oxide

Abstract

The present invention provides a system for transporting and / or delivering nitric oxide into and / or through an epithelial layer (e.g., skin and / or mucosa), the system comprising an alpha-hydroxy acid (AHA) and a nitric oxide source from which nitric oxide (NO) is generated or released. A system according to a first aspect of the invention involves the use of an alpha-hydroxy acid (AHA) as a transport delivery system for NO. The AHA captures NO generated in situ and transports it to deeper layers of the skin (see FIG. 1).

Description

[Technical field]

[0001] Yes2no GmbH Königsallee 27, 40212 Düsseldorf FIELD OF THEINVENTION The present invention generally relates to topical application for medical purposes. The present invention provides a delivery system for nitric oxide for application to body surfaces. In particular, an alpha-hydroxy acid is combined with a nitric oxide source, which provides transport of nitric oxide into and through epithelial layers (e.g., skin and mucous membranes). [Background technology]

[0002] BACKGROUND OF THEINVENTION Nitric oxide (NO) is a potent vasodilator synthesized and released by vascular endothelial cells and plays an important role in regulating vascular local resistance and blood flow (Palmer RM, Ferriege AG, Moncada S, Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor., Nature, 1987;327(6122):524-6). In mammalian cells, NO is produced by the enzymatic oxidation of L-arginine together with L-citrulline. NO is also involved in the inhibition of both platelet and leukocyte aggregation and adhesion, inhibition of cell proliferation, scavenging of superoxide radicals and regulating endothelial layer permeability. Furthermore, NO has also been shown to possess antibacterial properties and immunomodulatory effects, which may have applications for the management of skin disorders, including skin infections, (auto)inflammatory disorders, and wound healing. The beneficial effects of NO on wound repair may be directed to its functional influences on angiogenesis, inflammation, cell proliferation, matrix deposition, and remodeling (Minniti CP, Gorbach AM, Xu D, Hon YY, Delaney KM, Seidel M, et al. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial., Lancet Haematol, 2014;1(3):e95-e103; Fang FC, Perspectives series: host / pathogen interactions, Mechanisms of nitric oxide-related antimicrobial activity., J Clin Invest, 1997;99(12):2818-25). Many dermatological diseases have been associated with alterations in NO activity or may involve inflammatory pathways that can be therapeutically modulated by NO.Therefore, the development of topical NO formulations could have a major impact in the field of dermatology (del Rosso J, Kircik L, Spotlight on the Use of Nitric Oxide in Dermatology:What Is it? What Does it Do? Can It Become an Important Addition to the Therapeutic Armamentarium for Skin Disease?, J Drugs Dermatol, 2017;16(1):s4-10).

[0003] Various systems for the generation of NO in topical formulations have been described in the art, such as pH changes, certain endogenous enzymes, diazeniumdiolates, S-nitrosothiols, and nitrate / nitrite / nitroso compounds that release NO upon exposure to vehicles (e.g., nanoparticles, polymers, dendrimers, micelles, or lipid-based nanocarriers) in combination with NO donors (Liang H, Nacharaju P, Friedman A, Friedman JM, Nitric oxide generating / releasing materials., Future Sci OA, 2015;1(1); Bryan NS, Nitric oxide enhancement strategies., Future Sci / OA, 2015;1(1):FSO48).

[0004] Most of these systems have been unsuccessful because they have various disadvantages, including the formation of harmful by-products, inducing allergic reactions or skin irritation, inconvenient application methods, expensive production processes (Adler BL, Friedman AJ, Nitric oxide therapy for dermatologic disease., Future Sci OA, 2015;1(1):FSO37) and / or unsatisfactory NO delivery (Oplander C, Romer A, Paunel-Gorgulu A, Fritsch T, van Faassen EE, Murtz M, et al., Dermal application of nitric oxide in vivo: kinetics, biological responses, and therapeutic potential in humans., Clin Pharmacol Ther, 2012;91(6):1074-82). Although most of the above disadvantages vary from substance to substance and can be overcome by fine-tuning the materials, the unsatisfactory NO delivery remains a major problem for most of the various NO-generating substances, especially in topical applications. For clinical concerns, a potential drug delivery system that provides the necessary stability and release characteristics of the NO donor, making it an effective and safe topical therapeutic agent that is cost-effective and easy to use, is primarily desired. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Adler BL et al. Future Sci OA(2015)1(1):FSO37 [Non-Patent Document 2] Oplander C et al., Clin Pharmacol Ther (2012) 91(6):1074-82 Summary of the Invention [Means for solving the problem]

[0006] Thus, the present invention comprises a unique transport delivery system that can be used and implemented with any NO-generating substance to enhance NO delivery to a target site.

[0007] (Summary of the invention) As explained above, nitric oxide (NO) is an important mediator in many physiological and pathophysiological mechanisms, for example in the cardiovascular system, immune system, nervous system, and skin. In the latter case, topical application of NO can have anti-inflammatory, immunomodulatory, antibacterial, and vasoactive properties. However, the epidermis of the skin presents a natural barrier, which inhibits the penetration of NO into deeper skin layers (dermis, subcutaneous tissue), especially in high amounts. This requires the application of very high pharmacological local NO concentrations to allow even small amounts of NO to enter the skin.

[0008] To overcome the shortcomings of the prior art, a novel and unique transport delivery system for nitric oxide (NO) for topical application is presented, which ensures the skin penetration and delivery of NO to the deep layers of the skin, and which can be added to any NO generating and NO releasing substances (e.g. authentic NO solution, organic nitrates (mononitrate, dinitrate, trinitrate), acidified nitrite, etc., respectively) to enhance the amount of NO reaching the target site.

[0009] According to a first aspect, the present invention provides a system for transporting and / or delivering nitric oxide into and / or through an epithelial layer (e.g., skin and / or mucosa), the system comprising an alpha-hydroxy acid and a nitric oxide source.

[0010] A system according to a first aspect of the invention involves the use of alpha-hydroxy acids (AHAs) as a transport delivery system for NO, which scavenges NO generated in situ and transports it to deeper layers of the skin (see FIG. 1).

[0011] According to a second aspect, the present invention provides a system according to the first aspect for use in medicine.

[0012] According to a third aspect, the present invention provides a system according to the first aspect for use in the treatment of infection, inflammation, injury, skin disorder and / or vascular disorder (e.g. chronic inflammatory skin disease, acne, eczema, neurodermatitis, psoriasis, scars, wrinkles, abrasions, burns, trauma, hematomas, androgenic alopecia (male pattern baldness and female pattern baldness), blepharitis, Raynaud's syndrome, bacterial skin and soft tissue infections, peripheral vascular disease, chronic venous insufficiency and / or leg ulcers caused by ischemic vasculitis).

[0013] Alpha-hydroxy acids (eg, glycolic acid) increase skin moisturization and skin turgor, and normalize epidermal differentiation. Alpha-hydroxy acids have been shown in several studies to interfere with intercellular ionic bonds in the stratum corneum of the epidermis, resulting in keratolysis and reduced thickness, and to diffuse through the skin (Tang SC, Yang JH, Dual Effects of Alpha-Hydroxy Acids on the Skin., Molecules, 2018;23(4); Babilas P, Knie U, Abels C, Cosmetic and dermatologic use of alpha hydroxy acids., J Dtsch Dermatol Ges, 2012;10(7):488~91; Jiang M, Qureshi SA, Assessment of in vitro percutaneous absorption of glycolic acid through human skin sections using a flow-through diffusion cell system., Journal of Dermatological Science, 1998;18(3):181~188; Kraeling MEK, Bronaugh RL, In vitro percutaneous absorption of alpha hydroxy acids in human skin., J Soc Cosmet Chem, 1997;48:187-197; Van Scott EJ, Yu RJ, Hyperkeratinization, corneocyte cohesion, and alpha hydroxy acids. Journal of the American Academy of Dermatology, 1984;11(5):867-879). The system according to the invention can be used in all kinds of preparations to increase the amount of NO that reaches the target site, enhancing the effectiveness of other NO-generating formulations to offset their poor NO delivery.

[0014] Alpha-hydroxy acids that can be used for this purpose (especially at low nano to molar concentrations) include, but are not limited to, lactic acid, citric acid, citric acid monohydrate, mandelic acid, glycolic acid, tartaric acid, and malic acid. The inventors have found that when alpha-hydroxy acids are added to topical NO applications, NO transport is significantly increased.

[0015] The present disclosure relates to the addition of a transport delivery system to a formulation, which can be applied to the skin and used for dermatological or cosmetic purposes, but is not limited by its application method. The formulation with added alpha-hydroxy acid can be applied (but is not limited to) to all kinds of skin dressings, including patches, plasters, bandings, pads, compresses, folios, etc., especially for use on damaged (e.g., by trauma or disease) and non-damaged (e.g., wrinkled) skin. The formulation can further be applied as a gel or aqueous solution without a skin dressing. Depending on the application method, its wide applicability includes a range of fluidities from jelly-like to aqueous solutions.

[0016] According to a fourth aspect, there is provided a dressing comprising a system according to the first aspect.

[0017] According to a fifth aspect, the present invention provides a method for enhancing transport and / or delivery of nitric oxide into and / or through an epithelial layer (e.g., skin and / or mucosa), the method comprising: (i) combining a nitric oxide source with an alpha-hydroxy acid; (ii) applying the nitrate source to the epithelial layer; (iii) activating the nitrate source to produce and / or release nitric oxide. Includes.

[0018] According to a sixth aspect, the present invention provides the use of an alpha-hydroxy acid to enhance the transport and / or delivery of nitric oxide into and / or through an epithelial layer (e.g., skin and / or mucosa). Other objects, features, advantages and aspects of the present application will become apparent to those skilled in the art from the following description and the appended claims. [Brief description of the drawings]

[0019] [Figure 1] Figure 1: Illustrative depiction of NO penetration or lack thereof through the epidermis of the skin. Without the transporter delivery system described in this invention, NO molecules do not reach the deeper layers of the skin (dermis, subcutaneous tissue), because the epidermis provides a natural barrier. The transporter (alpha-hydroxy acid) transports the generated NO through the epidermis of the skin to the target site (adapted from Servier Medical Art by Servier (licensed under Creative Commons Attribution 3.0 Unported License)).

[0020] [Diagram 2] Figure 2: Graph of time (seconds) vs. NO concentration (parts per billion, ppb) showing the amount of NO produced by mixing Gel A and Gel B.

[0021] [Diagram 3] Figure 3: (A) Patient skin before (left) and 8 weeks after (right) application of NO-generating gel via a transport delivery system. (B) Changes in Global Acne Grading System (GAGS) scores in the above patient group after 4 and 8 weeks. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description of the Invention Various aspects and embodiments of the invention disclosed herein represent important contributions to the art, as also described below.

[0023] (System according to the first aspect) According to a first aspect, there is provided a system for transport and / or delivery of nitric oxide into and / or through an epithelial layer (e.g., skin and / or mucosa), the system comprising an alpha-hydroxy acid and a nitric oxide source.

[0024] As mentioned above, alpha-hydroxy acid increases epidermal penetration. According to the first aspect, alpha-hydroxy acid is used to transport and deliver nitric oxide through epithelial layers that inhibit or impair nitric oxide penetration into deeper tissue layers. In particular, nitric oxide is generated and / or released from a nitric oxide source. The generation and / or release of nitric oxide from a nitric oxide source can be induced by acidic pH. The pH can be adjusted by adding an acid (e.g., alpha-hydroxy acid or other acid (e.g., sulfuric acid)) to the nitric oxide source. Other nitric oxide sources that induce the generation and / or release of NO by other mechanisms are also included.

[0025] According to one embodiment, the system may be a one-component system that includes an alpha-hydroxy acid and a nitric oxide source in one composition. According to this embodiment, the system may include additional additives and / or a suitable nitric oxide source to prevent the production and / or release of nitric oxide until the system is applied to the epithelial layer.

[0026] According to an alternative embodiment, the system is a two-component system comprising a first composition comprising an alpha-hydroxy acid and a second composition comprising a nitric oxide source. According to this embodiment, nitric oxide is generated and / or released upon contact of the first and second compositions.

[0027] As used herein, the term "epithelial layer" refers in particular to any surface of the body, particularly the human body, including the external surface (e.g., skin) and the internal surface (e.g., mucosa). The epithelial layer is generally characterized by a reduced permeability for nitric oxide. According to one embodiment, the epithelial layer is the epidermis of the skin. Nitric oxide is transported and / or delivered to the dermis and / or subcutaneous tissue (i.e., deeper skin layers) by the alpha-hydroxy acids. As explained in the Summary of the Invention, the epidermis presents a natural barrier that inhibits the penetration of nitric oxide into the deeper skin layers (dermis and subcutaneous tissue). Thus, the system according to the first aspect may be advantageously used to transport and / or deliver nitric oxide through the epidermis, in particular into the dermis and / or subcutaneous tissue. According to an alternative embodiment, the epithelial layer is a mucosa. The mucosa may be provided by any mucosa (e.g., oral mucosa, nasal mucosa, intestinal mucosa, or visceral mucosa). According to one embodiment, the system enables the transport and delivery of nitric oxide by alpha-hydroxy acids into and / or through a variety of epithelial layers, including the skin and mucosa described above.

[0028] Specific features and preferred embodiments of the system according to the first aspect will now be described in detail.

[0029] (α-hydroxy acid) The system according to the first aspect comprises an α-hydroxy acid. According to one embodiment, the system may comprise one or more α-hydroxy acids. An α-hydroxy acid comprises a hydroxyl group on the carbon atom adjacent to its carboxyl group, and the α-hydroxy acid may be naturally occurring (e.g., in fruits, sugar cane and milk) or synthetic.

[0030] According to one embodiment, the alpha-hydroxy acid has the general formula: [ka] It is of the following.

[0031] In particular, R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, hydroxy, carboxy, and carbonyl, and the alkyl, alkenyl, and aryl can be optionally substituted with one or more of alkyl, alkenyl, aryl, hydroxy, carboxy, and carbonyl.

[0032] Alkyl particularly refers to C1 alkyl to C5 alkyl, in particular C1 alkyl to C3 alkyl. Alkenyl particularly refers to C2 alkenyl to C5 alkenyl, in particular C2 alkenyl to C3 alkenyl. Aryl particularly refers to phenyl. According to one embodiment, R1 is H and R2 has one of the following characteristics: (i) R2 is H (glycolic acid); (ii) R2 is CH3 (lactic acid); (iii) R2 is C2H3O2 (malic acid); (iv) R2 is C6H5 (mandelic acid); (v) R2 is C2H3O3 (tartaric acid); or (vi) R2 is C4H5O4 (isocitric acid).

[0033] According to one embodiment, R1 and R2 are both C2H3O2 (citric acid).

[0034] According to one embodiment, the alpha-hydroxy acid is provided in one isomer (e.g., stereoisomer or enantiomer). According to one embodiment, the alpha-hydroxy acid is provided in a combination of isomers.

[0035] According to one embodiment, the α-hydroxy acid is selected from the group consisting of, but not limited to, glycolic acid, lactic acid, citric acid, isocitric acid, citric acid monohydrate, mandelic acid, tartaric acid, malic acid, tartronic acid, hydroxycaprylic acid, hydroxycapric acid and mixtures thereof. Glycolic acid is known to have the smallest molecular size of α-hydroxy acids and the greatest bioavailability and skin penetration. According to an advantageous embodiment, the α-hydroxy acid is glycolic acid. As shown by the examples, glycolic acid is a suitable α-hydroxy acid for transporting and delivering nitric oxide through the epidermis of the skin to the deeper layers of the skin. Those skilled in the art can select a suitable α-hydroxy acid for the system according to the first aspect.

[0036] (Nitric oxide source) The system further includes a nitric oxide source from which nitric oxide can be generated and / or released. Such a nitric oxide source can be a salt of nitrous acid, HNO2 (M + NO2 - , where M is a monovalent cation) and esters (RON=O, where R is an organic radical). Examples of salts are potassium nitrite (KNO2), sodium nitrite (NaNO2) or calcium nitrite (Ca(NO2)2). Suitable nitric oxide sources for clinical topical formulations exhibiting good biocompatibility are well known in the prior art and the skilled artisan will be able to select a suitable nitric oxide source for the system according to the first aspect of the invention.

[0037] According to one embodiment, the nitric oxide source is selected from the group consisting of standard nitric oxide, nitric oxide solutions, organic and inorganic nitrates (e.g., mono-, di- and tri-nitrates), acidified nitrites, nitrogen oxides, and mixtures thereof. "Acidified nitrite" refers to any nitrite that reacts with acids, including alpha-hydroxy acids, to form unstable nitrous acid (HNO2), which decomposes to, among other things, nitric oxide (NO).

[0038] NO is generated and / or released from the nitric oxide source. According to one embodiment, this can be achieved by an acidic pH. For example, the pH of the first composition of a two-component system can be in the acidic range (e.g., due to its alpha-hydroxy acid), so that when the first composition and the second composition are combined, nitric oxide is released from the nitric oxide source of the second composition. The pH of the first composition can be adjusted according to the ratio of the first composition and the second composition to be mixed to ensure a pH in the acidic range after mixing, which results in the generation and release of nitric oxide from the nitric oxide source. As shown by the examples, an acidic pH results in the generation and release of nitric oxide from a suitable nitric oxide source.

[0039] According to one embodiment, the nitric oxide source is an acidified inorganic nitrite. According to a preferred embodiment, the nitric oxide source is sodium nitrite (NaNO2). As shown by the examples, sodium nitrite is a suitable nitric oxide source for the production of nitric oxide under physiological conditions.

[0040] (Further components of the system) According to one embodiment, the system further comprises an activator that initiates the release of nitric oxide from the nitric oxide source. Such an activator can be an acid that provides an acidic pH, resulting in the production and release of nitric oxide from the nitric oxide source. According to one embodiment, the activator can be provided by the alpha-hydroxy acid of the system. According to one embodiment, the activator can be an acid different from the alpha-hydroxy acid. According to a further embodiment, two or more acids can be included in the system as activators, optionally one of the two or more acids being an alpha-hydroxy acid. As shown in the examples, two or more acids (e.g., ascorbic acid and an alpha-hydroxy acid) can provide an activator that initiates the release of the nitric oxide source of the system. Any activator can be used to initiate the release of nitric oxide from the nitric oxide source of the system according to the first aspect.

[0041] According to one embodiment, the system further comprises a solvent. Suitable solvents are known in the art, such as non-polar solvents, polar aprotic solvents and polar protic solvents, such as water, alcohol, polyol or multi-component solvents. The solvent can also be provided by a mixture of two or more solvents. Those skilled in the art can select a suitable solvent that exhibits good biocompatibility and low toxicity depending on the desired formulation, including gel, cream, lotion, foam or spray. According to an advantageous embodiment, the solvent is water.

[0042] According to one embodiment, the system further comprises at least one thickening agent. According to one embodiment, the thickening agent is a gelling agent. According to this embodiment, the solvent and thickening agent provide for the preparation of the system according to the first aspect for various formulations, including gels, creams, lotions, foams, and sprays. Thus, the system can be prepared for all kinds of formulations, which can be applied to epithelial layers, such as skin and / or mucous membranes. The thickening agent can be natural or synthetic. Various biocompatible thickening agents, including gelling agents, suitable for topical application are known in the art, such as polyacrylic acid (PAA), polyethylene glycol, cellulose-derived thickening agents (e.g., hydroxyethyl cellulose), gelatin, xanthan gum, and hyaluronic acid. Thus, a person skilled in the art can select any biocompatible and non-toxic thickening agent and / or combination of solvent and thickening agent depending on the desired formulation.

[0043] According to one embodiment, the system includes a PAA.

[0044] According to one embodiment, the system comprises hyaluronic acid. According to an advantageous embodiment, the hyaluronic acid is provided by hyaluronic acid of various molecular weights.

[0045] According to one embodiment, the system may include one or more additional skin penetration enhancers. Suitable skin penetration enhancers are well described, for example, pyrrolidones, alcohols (e.g., ethanol), alkanols (e.g., decanol), sulfoxides (e.g., dimethylsulfoxide / DMSO), glycols (e.g., propylene glycol), azones (e.g., laurocapram), urea, fatty acids, surfactants, and terpenes.

[0046] According to one embodiment, the system may include additional adjuvants, such as substances to reduce or prevent skin irritation.

[0047] According to one embodiment, the system includes one or more vitamins.

[0048] In an advantageous embodiment, the combination of an alpha-hydroxy acid, a nitric oxide source and the above-mentioned further ingredients exhibits good biocompatibility, and the combination reduces or prevents irritation of the epithelial layer to which the system is applied.

[0049] (Final composition) According to one embodiment, the system is for forming a final composition comprising an alpha-hydroxy acid and a nitric oxide source on an epithelial layer.

[0050] According to one embodiment, the final composition is a viscous solution (e.g., a gel) or a liquid solution. Thus, the final composition can be provided in any formulation (e.g., a gel, a cream, a lotion, a foam, or a spray).

[0051] According to one embodiment, the alpha-hydroxy acid is present in the final composition at a concentration ranging from 0.05% (w / w) to 20% (w / w), preferably from 0.1% (w / w) to 15% (w / w), more preferably from 1% (w / w) to 10% (w / w), most preferably from 3% (w / w) to 6% (w / w). In a particular embodiment, the alpha-hydroxy acid is present in the final composition at a concentration of at least 2.5%, in particular at least 3%.

[0052] According to one embodiment, the concentration of the nitric oxide source in the final composition is in the range of 0.0001% (w / w) to 1% (w / w), preferably 0.001% (w / w) to 0.1% (w / w), more preferably 0.001% (w / w) to 0.01% (w / w).

[0053] The pH value of the final composition may in particular be in the range from 1 to 7.4, in particular in the range from 3.5 to 6.

[0054] (Two-component system) In certain embodiments, the system of the first aspect is a two-component system comprising a first composition comprising an alpha-hydroxy acid and a second composition comprising a nitric oxide source.

[0055] According to one embodiment, the system comprises: (a) a first composition, the first composition comprising an alpha-hydroxy acid; and (b) a second composition, the second composition comprising a source of nitric oxide. Includes.

[0056] (First composition) According to one embodiment, the first composition of the two-component system is a viscous or liquid solution (e.g., an aqueous solution), which is particularly advantageous when the system is to be used in a formulation (e.g., a gel, cream, lotion, foam, or spray).

[0057] According to one embodiment, the concentration of alpha-hydroxy acid in the first composition ranges from 1% (w / w) to 50% (w / w), preferably from 3% (w / w) to 20% (w / w), more preferably from 5% (w / w) to 10% (w / w). In a particular embodiment, the concentration of alpha-hydroxy acid in the first composition is at least 5%, in particular at least 6%. According to these embodiments, the alpha-hydroxy acid is preferably glycolic acid.

[0058] According to one embodiment, the first composition may comprise further components, which are described above in conjunction with the system, and which may be advantageously incorporated into the first composition of the two-component system.

[0059] According to one embodiment, the first composition further comprises one or more of the following components: (a) Ascorbic acid; (b) at least one hyaluronic acid (optionally, the hyaluronic acid is provided by at least one low molecular weight hyaluronic acid and at least one high molecular weight hyaluronic acid); (c) a composition comprising one or more vitamins (preferably, the composition is a liquid solution); (d) polyacrylic acid; and / or (e) Water.

[0060] According to one embodiment, the first composition comprises all of the additional ingredients described above.

[0061] According to one embodiment, the at least one hyaluronic acid is provided by at least one low molecular weight hyaluronic acid, for example, the low molecular weight hyaluronic acid may have a molecular weight in the range of 20 kDa to 200 kDa, and / or the high molecular weight hyaluronic acid may have a molecular weight in the range of 500 kDa to 2000 kDa.

[0062] According to one embodiment, the one or more vitamins are provided by a composition that includes Vitamin A, Vitamin C and Vitamin E. Preferably, the composition is a liquid solution.

[0063] According to one embodiment, the first composition comprises: (i) ascorbic acid at a concentration ranging from 0.1% (w / w) to 1.0% (w / w), preferably from 0.3% (w / w) to 0.5% (w / w); (ii) low molecular weight hyaluronic acid at a concentration ranging from 0.1% (w / w) to 2% (w / w), preferably from 0.5% (w / w) to 1.5% (w / w), and high molecular weight hyaluronic acid at a concentration ranging from 0.001% (w / w) to 1% (w / w), preferably from 0.01% (w / w) to 0.2% (w / w); (iii) a liquid solution containing vitamin A, vitamin C and vitamin E at a concentration ranging from 0.001% (w / w) to 1% (w / w), preferably from 0.01% (w / w) to 0.2% (w / w); and (iv) polyacrylic acid at a concentration ranging from 1% (w / w) to 10% (w / w), preferably from 2% (w / w) to 5% (w / w); It is an aqueous solution comprising:

[0064] (Second Composition) According to one embodiment, the second composition of the two-component system is a viscous or liquid solution (e.g., an aqueous solution), which is particularly advantageous when the system is to be used in a formulation (e.g., a gel, cream, lotion, foam, or spray).

[0065] According to one embodiment, the concentration of the nitric oxide source in the second composition is in the range of 0.0001% (w / w) to 0.1% (w / w), 0.001% (w / w) to 0.01% (w / w), preferably 0.002% (w / w) to 0.005% (w / w), and the nitric oxide source is preferably sodium nitrite (NaNO2).

[0066] According to one embodiment, the second composition may comprise additional components. Such additional components are described above in conjunction with the system, and such additional components may be advantageously incorporated into the second composition of the two-component system, except for the activator. In particular, the second composition may comprise a solvent and a thickener.

[0067] According to one embodiment, the second composition further comprises one or both of the following components: (a) polyacrylic acid; and / or (b) Water.

[0068] According to one embodiment, the second composition comprises polyacrylic acid in a concentration ranging from 0.1% (w / w) to 10% (w / w), preferably from 0.5% (w / w) to 2.5% (w / w).

[0069] As shown by the examples, combination of such a second composition with the first composition described above results in the production and release of nitric oxide, which is then transported and delivered into and through the epidermis of the skin to deeper layers of the skin by the alpha-hydroxy acid (e.g., glycolic acid) contained in the first composition.

[0070] As disclosed herein, the first composition and the second composition are combined to generate and release nitric oxide from the nitric oxide source, which is then transported and delivered through and into various skin layers by alpha-hydroxy acids. This is accomplished, for example, by topically applying the first composition and the second composition to the same area on an epidermal layer (e.g., skin). Alternatively, the first composition and the second composition are mixed before topical application on the epidermal layer. In certain embodiments, the first composition is contacted with the second composition in a ratio of the first composition to the second composition selected from the range between 10:1 to 1:10, preferably 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, or 2:1 to 1:2, more preferably 1:1.

[0071] Further embodiments of the system according to the first aspect According to one embodiment, the system is a viscous or liquid solution. This is particularly advantageous when the system is used in a formulation (e.g., gel, cream, lotion, foam, or spray). According to this embodiment, the one-component system may contain additional additives to prevent the production, decomposition, and / or release of nitric oxide until the system is applied to the epidermal layer. For example, nitric oxide may be produced when contacting with oxygen contained in the air and / or when contacting with the skin.

[0072] According to one embodiment, the system comprises a first composition comprising an alpha-hydroxy acid and a second composition comprising a nitric oxide source, the first composition being a viscous solution (e.g., a gel) or liquid solution, and the second composition being a viscous solution (e.g., a gel) or liquid solution. This embodiment is particularly preferred when the system is applied directly to an epithelial layer (e.g., skin and / or mucosa). For example, the first composition is provided by a first gel comprising an alpha-hydroxy acid, and the second composition is provided by a second gel comprising a nitric oxide source. Preferred embodiments of the first and second compositions are described elsewhere herein, and are incorporated by reference in their respective disclosures. The two gels may be applied to the same area on an epithelial layer (e.g., skin or mucosa) and thereby brought into contact (i.e., mixed). Upon contact, nitric oxide is generated from the nitric oxide source contained in the second gel and is scavenged by the alpha-hydroxy acid contained in the first gel. Nitric oxide-carrying alpha-hydroxy acids transport the nitric oxide across the epidermal layer and deliver it to deeper tissue layers (eg, the dermis and / or subcutaneous tissue).

[0073] According to one embodiment, the system comprises: (a) a first composition, the first composition comprising at least one alpha-hydroxy acid as defined in combination with an alpha-hydroxy acid according to the first aspect above, the first composition is a viscous or liquid solution, preferably the first composition is a gel; Preferably, the at least one α-hydroxy acid in the first composition is glycolic acid, and the concentration of glycolic acid in the first composition is in the range of 1% (w / w) to 20% (w / w), 5% (w / w) to 15% (w / w), preferably 5% (w / w) to 10%; and (b) a second composition comprising at least one nitric oxide source as defined in accordance with the first aspect above, said first composition being a viscous or liquid solution, preferably said second composition being a gel; Preferably, the at least one nitric oxide source in this second composition is sodium nitrite (NaNO2), and the concentration of sodium nitrite (NaNO2) in this second composition is in the range of 0.0001% (w / w) to 0.1% (w / w), 0.001% (w / w) to 0.01% (w / w), preferably 0.002% (w / w) to 0.005% (w / w). Includes.

[0074] The first and second compositions of the two-component system according to the first aspect are kept separately until use.As shown by the examples, such two-component system is suitable for generating and releasing nitric oxide when the first and second compositions contact each other, especially under physiological conditions at 37°C.Furthermore, the alpha-hydroxy acid contained in the two-component system transports and delivers the generated nitric oxide through and into the epidermis of skin to the deeper layers of skin, which is demonstrated in the examples by improving the skin condition of acne vulgaris.

[0075] The system according to the first aspect can be provided in any suitable container. The first composition and the second composition of the two-component system can be provided in separate containers or in separate compartments of the same container. For example, the system can be stored in a syringe, tube or flask. Thus, when the system is provided as a two-component system, the first composition and the second composition can each be provided in separate syringes, tubes or flasks, or in one syringe, tube or flask with two compartments. This can be particularly advantageous when the first composition and the second composition are provided as viscous or liquid solutions.

[0076] In certain embodiments, the system according to the first aspect is provided in a dressing or as part of a dressing. When the two-component system is provided in a dressing, the dressing can have two compartments. The barrier between the two compartments of the dressing can be broken when the dressing is prepared for application (e.g., when the protective sheet is removed) so that the first composition and the second composition can be mixed.

[0077] The container can be designed according to the type of formulation in which the system is provided, i.e., the system can be included in any formulation or preparation for topical administration (e.g., gel, cream, lotion, foam, or spray). The formulation can also be provided as a powder or lyophilizate that can be reconstituted in a solvent prior to topical application.

[0078] (medical application) According to a second aspect, the system according to the first aspect is provided for use in medicine. In an embodiment, the medicine includes human medicine and veterinary medicine. As explained above, nitric oxide is involved in many physiological and pathophysiological processes, including vasodilation, platelet and leukocyte aggregation and adhesion, cell proliferation, endothelial layer permeability, scavenging of superoxide radicals, antibacterial effect, immunomodulatory effect, and wound repair. Therefore, the system according to the first aspect is suitable for regulating such processes by providing nitric oxide and transporting and delivering it to target sites.

[0079] According to a third aspect, there is provided a system according to the first aspect for use in the treatment of infections, inflammations, injuries, skin disorders and / or vascular disorders (e.g. chronic inflammatory skin diseases, acne, eczema, neurodermatitis, psoriasis, scars, wrinkles, abrasions, burns, trauma, hematomas, androgenic alopecia (male pattern baldness and female pattern baldness), blepharitis, Raynaud's syndrome, bacterial skin and soft tissue infections, peripheral vascular disease, chronic venous insufficiency and / or leg ulcers caused by ischemic vasculitis). The subject to be treated may be a human or an animal, in particular a human. As shown by the examples, the system of the invention is particularly suitable for use in the treatment of human skin disorders (e.g. acne). Thus, the system may be used in the treatment of infections, inflammations, injuries, skin disorders and / or vascular disorders in any mammal (e.g. dog, cat, horse, cow, sheep, pig, etc.).

[0080] According to one embodiment, the system is administered topically to the epithelial layer (e.g., skin and / or mucosa). According to this aspect, the system according to the first aspect can be administered topically or applied to the epithelial layer located at the site of the physiological or pathophysiological process to be regulated. As shown by the examples, the system according to the first aspect can be used for topical administration on human skin. The system can be administered directly to the target area on the epithelial layer. According to an advantageous embodiment, the system is a viscous or liquid solution as described elsewhere herein. When a two-component system is used, the first composition and the second composition can be administered in any order, i.e., either the first composition is first topically administered to an area of ​​the epithelial layer and then the second composition is administered to the same area, or the second composition is first administered and then the first composition is administered. It is advantageous to distribute the two compositions evenly on the area of ​​the epithelial layer to ensure optimal mixing of both compositions and, as a result, optimal nitric oxide production. As a result, the amount of nitric oxide transported and delivered by the alpha-hydroxy acids is maximized.

[0081] According to one embodiment, the system induces vasodilation, increases blood flow and / or increases angiogenesis. As explained above, nitric oxide is a potent vasodilator and plays an important role in regulating vascular local resistance, which is often compromised during infection, inflammation, injury, and skin and vascular disorders.

[0082] According to one embodiment, the system is first applied to a skin and / or mucosal dressing (e.g., a patch, plaster, band, pad, compress, and bi-fold) and then topically administered to the epithelial layer (e.g., skin and / or mucosa). This embodiment is advantageous when the dressing needs to cover the area of ​​the target site. This may be the case when bleeding occurs and absorption of blood, pus, and / or lymph is required, or when the target area needs to be protected (e.g., from pathogens in case of injury).

[0083] According to one embodiment, upon topical administration of the system at the epithelial layer, nitric oxide is generated and / or released. Suitable conditions (e.g., acidic pH) that result in the generation and / or release of nitric oxide from the nitric oxide source of the system are described elsewhere herein, and are incorporated by reference in their respective disclosures. The generated nitric oxide is then scavenged by the alpha-hydroxy acids of the system of the present invention, transported into and / or through the epithelial layer, and delivered to the target site in the deeper tissue layer.

[0084] In certain embodiments, the use in medicine is (i) optionally, when a two-component system is used, mixing the first and second components of the two-component system; (ii) applying the system to an epithelial layer; and (iii) activating the nitrate source to produce and / or release nitric oxide. Includes.

[0085] The steps of the above method may be carried out in any order. The above three steps are particularly initiated shortly after or even simultaneously with each other, particularly within 30 minutes, preferably within 5 minutes, more preferably within 1 minute. In particular, when a two-component system is used, the nitric acid source is activated to generate and / or release nitric oxide by mixing the first composition with the second composition.

[0086] (Bandage) According to a fourth aspect, there is provided a dressing comprising a system according to the first aspect. As explained above, the dressing may be used to absorb bodily fluids (e.g., blood) or to protect a target area on an epithelial layer.

[0087] According to one embodiment, the dressing is selected from the group consisting of a patch, a plaster, a band, a pad, a compress, and a bi-fold.

[0088] In certain embodiments, the two-component system described herein is used in a dressing.In these embodiments, the two components of the system, the first composition and the second composition, are present in separate compartments of the dressing and are mixed only when the dressing is applied to the skin and / or mucous membrane of a subject or when the dressing is prepared for application.

[0089] Methods and Uses for Enhancing Nitric Oxide Transport and / or Delivery According to a fifth aspect, the present invention provides a method for enhancing transport and / or delivery of nitric oxide into and / or through an epithelial layer (e.g., skin and / or mucosa), the method comprising: (i) combining a nitric oxide source with an alpha-hydroxy acid; (ii) applying the nitrate source to the epithelial layer; (iii) activating the nitrate source to produce and / or release nitric oxide. Includes.

[0090] The transport and / or delivery of nitric oxide into and / or through the epithelial layer is enhanced by the presence of an alpha-hydroxy acid, as compared to the same method without step (i).

[0091] The steps of the above method can be carried out in any order. It is preferred to carry out the steps in the order (i), (ii) and (iii). If another order is used, the three steps are particularly started shortly after or even simultaneously with each other, particularly within 30 minutes, preferably within 5 minutes, more preferably within 1 minute.

[0092] According to a sixth aspect, there is provided a use of an alpha-hydroxy acid to enhance transport and / or delivery of nitric oxide into and / or through an epithelial layer (e.g., skin and / or mucosa).

[0093] The system features, characteristics and embodiments described herein apply equally to methods and uses of alpha-hydroxy acids for enhancing nitric oxide transport and / or delivery.

[0094] According to one embodiment, the alpha-hydroxy acid is selected from the group consisting of glycolic acid, lactic acid, citric acid, isocitric acid, citric acid monohydrate, mandelic acid, tartaric acid, malic acid, tartronic acid, hydroxycaprylic acid, hydroxycapric acid and mixtures thereof. Preferred embodiments of the alpha-hydroxy acid are described elsewhere herein and are incorporated by reference in their respective disclosures.

[0095] As used in this specification, sections, and claims, the singular forms "a", "an" and "the" include multiple aspects unless the context clearly indicates otherwise. The terms "include", "have", "comprise" and variations thereof are used synonymously and are to be construed as open-ended. Additional components and steps may be present. Throughout this specification, when a composition is described as comprising an ingredient or material, it is further contemplated that the composition may also, in embodiments, consist essentially of or consist of any combination of the recited ingredients or materials, unless otherwise stated. References such as "the disclosure" and "the invention" include single or multiple aspects taught herein; and the like. The aspects taught herein are encompassed by the term "invention".

[0096] Selection and combination of the preferred embodiments described herein are preferred, and specific subject matter resulting from each combination of the preferred embodiments also belongs to the present disclosure.

[0097] (Specific embodiment) In the following, specific embodiments of the present invention are described.

[0098] (Embodiment 1) A system for transport and / or delivery of nitric oxide into and / or through an epithelial layer (e.g., skin and / or mucosa), the system comprising an alpha-hydroxy acid and a nitric oxide source.

[0099] (Embodiment 2) 2. The system of embodiment 1, wherein the epithelial layer is the epidermis of the skin.

[0100] (Embodiment 3) 3. The method of embodiment 2, wherein the nitric oxide is transported and / or delivered into the dermis and / or subcutaneous tissue.

[0101] (Embodiment 4) The system of any one of the preceding embodiments, wherein the alpha-hydroxy acid is selected from the group consisting of glycolic acid, lactic acid, citric acid, isocitric acid, citric acid monohydrate, mandelic acid, tartaric acid, malic acid, tartronic acid, hydroxycaprylic acid, hydroxycapric acid, and mixtures thereof.

[0102] (Embodiment 5) 5. The system of embodiment 4, wherein the alpha-hydroxy acid is glycolic acid.

[0103] (Embodiment 6) The system of any one of the preceding embodiments, wherein the nitric oxide source is selected from the group consisting of standard nitric oxide, nitric oxide solutions, organic and inorganic nitrates (e.g., mononitrates, dinitrates and trinitrates), acidified nitrites, nitrogen oxides, and mixtures thereof.

[0104] (Embodiment 7) 7. The system of embodiment 6, wherein the nitric oxide source is an acidified inorganic nitrite.

[0105] (Embodiment 8) The system of embodiment 6 or 7, wherein the nitric oxide source is sodium nitrite (NaNO2).

[0106] (Embodiment 9) The system of any one of embodiments 1 to 8, further comprising an activator that initiates the release of nitric oxide from the nitric oxide source.

[0107] (Embodiment 10) The system of any one of the preceding embodiments, further comprising a solvent and optionally a thickening agent (eg, a gelling agent).

[0108] (Embodiment 11) The system according to any one of the preceding embodiments, for forming a final composition comprising an alpha-hydroxy acid and a nitric oxide source in an epithelial layer.

[0109] (Embodiment 12) The system of embodiment 11, wherein the final composition is a viscous solution (e.g., a gel) or a liquid solution.

[0110] (Embodiment 13) 13. The system according to embodiment 11 or 12, wherein the alpha-hydroxy acid is present in the final composition at a concentration ranging from 0.05% (w / w) to 20% (w / w), preferably from 0.1% (w / w) to 15% (w / w), more preferably from 1% (w / w) to 10% (w / w), and most preferably from 3% (w / w) to 6% (w / w).

[0111] (Embodiment 14) 13. The system of embodiment 11 or 12, wherein the alpha-hydroxy acid is present in the final composition at a concentration of at least 2.5%.

[0112] (Embodiment 15) 13. The system of embodiment 11 or 12, wherein the alpha-hydroxy acid is present in the final composition at a concentration of at least 3%.

[0113] (Embodiment 16) The system according to any one of embodiments 11 to 15, wherein the concentration of the nitric oxide source in the final composition is in the range of 0.0001% (w / w) to 1% (w / w), preferably 0.001% (w / w) to 0.1% (w / w), more preferably 0.001% (w / w) to 0.01% (w / w).

[0114] (Embodiment 17) (a) a first composition comprising an alpha-hydroxy acid; and (b) a second composition comprising nitric oxide The system according to any one of embodiments 1 to 16, comprising:

[0115] (Embodiment 18) 18. The system according to embodiment 17, wherein the concentration of alpha-hydroxy acid in the first composition is in the range of 1% (w / w) to 20% (w / w), preferably 5% (w / w) to 15% (w / w), more preferably 5% (w / w) to 10% (w / w).

[0116] (Embodiment 19) 18. The system of embodiment 17, wherein the concentration of alpha-hydroxy acid in the first composition is at least 5%.

[0117] (Embodiment 20) 18. The system of embodiment 17, wherein the concentration of alpha-hydroxy acid in the first composition is at least 6%.

[0118] (Embodiment 21) The system of any one of embodiments 17-20, wherein the alpha-hydroxy acid is glycolic acid.

[0119] (Embodiment 22) 22. The system according to any one of embodiments 17 to 21, wherein the concentration of the nitric oxide source in the second composition is in the range of 0.0001% (w / w) to 0.1% (w / w), 0.001% (w / w) to 0.01% (w / w), preferably 0.002% (w / w) to 0.005% (w / w).

[0120] (Embodiment 23) The system of any one of embodiments 17-22, wherein the nitric oxide source is sodium nitrite (NaNO2).

[0121] (Embodiment 24) The system of any one of embodiments 17 to 23, wherein the first composition is a viscous solution (e.g., a gel) or a liquid solution, and the second composition is a viscous solution (e.g., a gel) or a liquid solution.

[0122] (Embodiment 25) 25. The system according to any one of embodiments 17 to 24, wherein the first composition and the second composition in the system have a volume ratio in the range of 10:1 to 1:10, preferably 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, or 2:1 to 1:2, more preferably 1:1.

[0123] (Embodiment 26) The system according to any one of embodiments 1 to 25 for use in medicine.

[0124] (Embodiment 27) The system of any one of embodiments 1-25 for use in treating infections, inflammation, injuries, skin disorders and / or vascular disorders (e.g., chronic inflammatory skin diseases, acne, eczema, neurodermatitis, psoriasis, scars, wrinkles, abrasions, burns, trauma, hematomas, androgenic alopecia (male pattern baldness and female pattern baldness), blepharitis, Raynaud's syndrome, bacterial skin and soft tissue infections, peripheral vascular disease, chronic venous insufficiency and / or leg ulcers caused by ischemic vasculitis).

[0125] (Embodiment 28) 28. The system for use in medicine according to embodiment 26 or 27, which is administered locally to an epithelial layer (e.g., skin and / or mucosa).

[0126] (Embodiment 29) A system for use in medicine according to any one of embodiments 26 to 28, which induces vasodilation, increases blood flow and / or increases angiogenesis.

[0127] (Embodiment 30) The system for use in medicine according to any one of embodiments 26 to 29, which is first applied to a skin and / or mucosal dressing (e.g., a patch, plaster, band, pad, compress, and bi-fold) and then administered topically to the epithelial layer (e.g., the skin and / or mucosa).

[0128] (Embodiment 31) The system for use in medicine according to any one of embodiments 26 to 30, wherein nitric oxide is produced and / or released when the system is topically administered to an epithelial layer.

[0129] (Embodiment 32) The use in medicine is (i) optionally, when a two-component system is used, mixing the first and second components of the two-component system; (ii) applying the system to an epithelial layer; and (iii) activating the nitrate source to produce and / or release nitric oxide. A system for use in medicine according to any one of embodiments 26 to 31, comprising:

[0130] (Embodiment 33) A dressing comprising a system according to any one of embodiments 1 to 25.

[0131] (Embodiment 34) The dressing of embodiment 33, which is selected from the group consisting of a patch, a plaster, a band, a pad, a compress, and a bi-fold.

[0132] (Embodiment 35) 1. A method for enhancing transport and / or delivery of nitric oxide into and / or through an epithelial layer (e.g., skin and / or mucosa), comprising: (i) combining a nitric oxide source with an alpha-hydroxy acid; (ii) applying the nitrate source to the epithelial layer; (iii) activating the nitrate source to produce and / or release nitric oxide. A method comprising:

[0133] (Embodiment 36) The method according to embodiment 35, having one or more of the features defined in any one of embodiments 2 to 25.

[0134] (Embodiment 37) Use of alpha-hydroxy acids to enhance the transport and / or delivery of nitric oxide into and / or across epithelial layers (e.g., skin and / or mucosa).

[0135] (Embodiment 38) The use according to embodiment 37, wherein the alpha-hydroxy acid is selected from the group consisting of glycolic acid, lactic acid, citric acid, isocitric acid, citric acid monohydrate, mandelic acid, tartaric acid, malic acid, tartronic acid, hydroxycaprylic acid, hydroxycapric acid, and mixtures thereof.

[0136] (Embodiment 39) The use according to embodiment 37 or 38, having one or more of the features as defined in any one of embodiments 2 to 25. EXAMPLES

[0137] (Example) It should be understood that the following examples are for illustrative purposes only and that the following examples are not to be construed as limiting this invention in any manner.

[0138] Typically, we describe herein the use of the transport delivery system of the present invention in a two-component system using an acidified inorganic nitrite, which has been described for the production of NO in topical applications.

[0139] Example 1: Preparation of acidified nitrite gel for localized release of NO

[0140] The following non-limiting example shows the use of the transport delivery system in a two-component system for topical application.It is a two-component gel (Gel A and Gel B), which includes glycolic acid as a suitable AHA, a reducing agent, a granulating agent and a penetration enhancer (Gel A) and a nitric oxide source (Gel B).After mixing Gel A and Gel B, controlled in-situ NO production is initiated, and the induced AHA transports the NO through the skin layer to the target site.

[0141] The two components, Gel A and Gel B (A containing AHA and B containing nitrite), were mixed individually and kept separate until use.

[0142] To prepare the acidic gel, 50 ml of deionized water was heated to 40°C. 0.21 g of ascorbic acid and 4.5 g of glycolic acid were added and the solution was stirred for 2 minutes until the ascorbic acid was completely dissolved. 0.5 g of hyaluronic acid (50 kDa) and 0.05 g of hyaluronic acid (1500 kDa) were added and stirred until completely dissolved. Next, 2 g of polyacrylic acid (PAA) was added and mixed until the PAA was completely gelled. Finally, 0.05 g of Vitamin A / C / E solution was added (Vitamin A and Vitamin E are insoluble in water, so a soluble active complex was used consisting of water, pentylene glycol, lecithin, caprylic / capric triglyceride, tocopherol acetate, retinyl palmitate, sodium phytate, sodium ascorbyl phosphate, and sodium hydroxide).

[0143] To prepare the nitrite gel, 0.055 g of sodium nitrite was dissolved in 50 ml of deionized water and stirred until completely dissolved. Then, 0.7 g of polyacrylic acid (PAA) was added and the mixture was stirred until the PAA was completely gelled.

[0144] After preparation, Gel A and Gel B were loaded into a 10 ml syringe and carefully closed. The same amount of both gels was used to carry out the application to the skin, which resulted in a 1:1 ratio of Gel A and Gel B in the applied mixture. Table 1: Components of Composition A [Table 1]

[0145] Table 2: Components of Composition B [Table 2]

[0146] Example 2: Activated gel-forming NO production

[0147] The in vitro NO generating ability of the two-component gel was investigated using a nitric oxide chemiluminescence detector (CLD). 1 ml of both components was added to an airtight reaction chamber. The reaction chamber contained an inlet port for the inert carrier gas helium (99.996% He; flow rate: 124 ml / min, pressure controlled) and an outlet port leading to the analyzer. To create a physiological environment, the reaction chamber was heated to 37° C. and a magnetic stirrer was used to ensure optimal mixing of both components.

[0148] The resulting NO evolved from this reaction was determined using an ozone-based chemiluminescence assay. NO was actively purged with an inert helium stream in series with a NO chemiluminescence analyzer (ANALYZER CLD 88 sp; Eco Physics) and quantified in the gas phase after reaction with ozone. O3 was supplied in excess to keep reaction conditions constant, and the intensity of the emitted light is directly proportional to the NO concentration.

[0149] (result) A mixture of both components resulted in a steady production of NO, which exceeded the upper limit of detection of 23.847 ppb NO, resulting in a plateau of approximately 15 minutes after an activation time of approximately 60 seconds (Figure 2). NO production decreased but was still detectable 30 minutes after the initial application. When applied to the skin, 2 Measurements in intact skin showed comparable NO production.

[0150] Example 3: Application of a delivery system in an NO-generating gel to acne vulgaris

[0151] Facial acne vulgaris is the most common skin disease in adolescents and adults and is a primary inflammatory disorder of the pilosebaceous region of multifactorial etiology. Within the physiological range, NO has concentration-dependent bimodal antibacterial and immunomodulatory activity. When higher concentrations are used in topical applications, NO exhibits anti-inflammatory and antibacterial properties. The use of the transport delivery system allows for better and deeper transport of NO into the skin layers. The use of the transport delivery system improved acne disease in representative patient cases.

[0152] A total of 10 consecutive patients suffering from mild to moderate facial acne vulgaris were enrolled in the study. Their average age was 34.4 years. The delivery system was applied in a thin layer of gel formulation on the skin twice daily for 8 consecutive weeks. Clinical scores were assessed by trained examiners based on high resolution images.

[0153] (result) Eight weeks of application showed clinical improvement in acne vulgaris. Application reduced the amount of closed and open comedones and inflammatory pustules in moderate acne vulgaris, resulting in a clearer skin texture (Figure 3A).

[0154] Global Acne Grading System (GAGS) scores were reduced by approximately 50% after 8 weeks of treatment (Figure 3B).

Claims

1. A system for the transport and / or delivery of nitric oxide into an epithelial layer, such as the skin and / or mucosa, and / or through an epithelial layer, such as the skin and / or mucosa, the system comprising an α-hydroxy acid and a nitric oxide source.

2. The system according to claim 1, wherein the epithelial layer is the epidermis of the skin and the nitric oxide is transported and / or delivered into the dermis and / or subcutaneous tissue.

3. The system according to claim 1, wherein the α-hydroxy acid is selected from the group consisting of glycolic acid, lactic acid, citric acid, isocitric acid, citric acid monohydrate, mandelic acid, tartaric acid, malic acid, tartronic acid, hydroxycaprylic acid, hydroxycapric acid, and mixtures thereof.

4. The system according to claim 1, wherein the nitric oxide source is selected from the group consisting of standard nitric oxide, nitric oxide solutions, organic nitrates and inorganic nitrates, such as mononitrates, dinitrates and trinitrates, acidified nitrites, nitrogen oxides, and mixtures thereof.

5. wherein the α-hydroxy acid is glycolic acid and the nitric oxide source is sodium nitrite (NaNO ２ ), the system according to claim 1.

6. The system according to claim 1, further comprising an activator substance for initiating the release of nitric oxide from the nitric oxide source and a solvent, and optionally further comprising a thickening agent, such as a gelling agent.

7. The system according to claim 1, for forming the final composition comprising the α-hydroxy acid and the nitric oxide source on the epithelial layer.

8. The system according to claim 7, wherein the α-hydroxy acid is present in the final composition at a concentration in the range of 0.05% (w / w) to 20% (w / w), and the concentration of the nitric oxide source in the final composition is in the range of 0.0001% (w / w) to 1% (w / w).

9. (a)A first composition comprising the α-hydroxy acid; and (b)A second composition comprising the nitric oxide The system according to claim 1, comprising.

10. The system according to any one of claims 1 to 9, for use in medicine.

11. The system according to any one of claims 1 to 9 for use in the treatment of infectious diseases, inflammation, injuries, skin disorders and / or vascular disorders, such as chronic inflammatory skin diseases, acne, eczema, neurodermatitis, psoriasis, scars, wrinkles, abrasions, burns, trauma, hematomas, male hormonal alopecia (male pattern alopecia and female pattern alopecia), blepharitis, Raynaud's syndrome, bacterial skin and soft tissue infections, peripheral vascular diseases, chronic venous insufficiency and / or leg ulcers caused by ischemic vasculitis.

12. The system for use in the pharmaceutical according to claim 11, which is topically administered to the epithelial layer, such as the skin and / or mucosa.

13. A dressing agent comprising the system according to any one of claims 1 to 9.

14. The dressing agent according to claim 13, which is selected from the group consisting of patches, plasters, bands, pads, compression gauzes, and double-folded pieces.

15. The system according to any one of claims 1 to 9 for use in enhancing the transport and / or delivery of nitric oxide into and / or through the epithelial layer, such as the skin and / or mucosa.

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