CZ38639U1 - A preparation to treat herpes labialis and a plaster with such preparation - Google Patents

Description

A remedy for treating cold sores or herpes labialis and a patch containing this remedy

Technical area

The technical solution relates to a means for treating cold sores or herpes labialis.

The technical solution also relates to a patch with a remedy for treating cold sores or herpes labialis.

State of the art

Cold sores are a viral infection caused by the Herpes simplex virus, specifically HSV 1. The incubation period of cold sores is approximately 2 to 6 days. During this time, the viral infection is asymptomatic and the virus infiltrates and multiplies. In the next phase, cold sores are manifested by itching, which usually turns into blisters on the second day, which can burn and hurt. After a few days, the swollen blister bursts and a scab forms. Cold sores on the lip usually last for 7 to 10 days, when the immune system deals with the viral infection and the associated skin injury heals. This occurs due to the multiplication of the virus in the host's skin cells. In the event of complications, the treatment period may be extended. Such complications include the spread of the infection through transmission. This usually occurs due to scratching the itchy blisters. Furthermore, complications can occur due to reduced immunity, which leads to a prolongation of the infection and the formation of extensive foci around the mouth. The result is also a combined infection, when the cold sore wound is infiltrated by a bacterial infection, which further complicates and prolongs healing. For this reason, it is necessary that the products for treating cold sores should not only target the treatment of the viral infection and the resulting purulent skin defect, but also allow the exudate to escape from the blisters and at the same time protect the cold sore environment from secondary infection from the external environment. Furthermore, they should actively support healing so that the wound closes as quickly as possible. These requirements should therefore include biocompatibility with the skin and harmlessness to the digestive tract, given the possibility of swallowing/licking the product.

There are currently a number of solutions on the market designed for the treatment and cure of cold sores, but none of them combine all of the above properties into one product.

Currently known solutions mainly use creams, ointments and gels with an admixture of antivirals. These provide an active substance for the treatment of viral infection, but do not allow the drainage of exudate (in the later stages of infection) and do not allow simultaneous gas exchange with the environment. Another known solution is hydrocolloid patches or plasters. These are applied to the cold sore in liquid form and solidify at the indicated site. Their function is to protect the cold sore and possibly support healing if they contain active substances (mostly vitamins). Their structure does not allow the drainage of exudate and they are intended for application in the initial stages of cold sore development.

Utility model CZ 35177 U1 (2021-38671) describes the preparation of a spinning solution for the preparation of chitosan nanofibers with antibacterial effects for the healing of generally contaminated wounds. The antibacterial effect is achieved by incorporating antibacterial substances. Chitosan is chemically modified with a methacrylate group and subsequently crosslinked by UV radiation using an auxiliary crosslinking agent (e.g. Irgacure). Patent CZ 307059 B6 (2016-688) then describes the preparation of nanofibers containing chitosan chemically modified with a methacrylate group and crosslinked by UV radiation. Modification with methacrylate is necessary for UV crosslinking of nanofibers. Nanofibers do not exhibit antiviral activity.

Utility model CZ 36586 U1 (2022-39980) describes a composition for cosmetic or dermatological purposes, which contains a non-woven textile as a carrier substrate and a nanofiber layer containing chitosan in combination with gelatin. The composition does not contain active substances, does not show antibacterial activity, is not crosslinked and has not been proven to have antiviral activity.

- 1 CZ 38639 UI

Utility model CZ 34674 U1 (2020-38245) describes the preparation of a textile composite with an antibacterial effect containing a nanofiber layer. It is intended for hygienic sorption aids. The material of the nanofiber layer is polyamide 6 (PA6), polyvinyl butyral (PVB) or polyvinylidene fluoride (PVDF). The substance with an antibacterial effect is dodecyltrimethylammonium bromide or chlorhexidine. The composite is not biodegradable, hydrophilic and its antiviral activity has not been proven.

Utility model CZ 34532 U1 (2020-37826) describes an antibacterial patch with an electrostatically spun nanofiber layer, where the nanofiber layer is made of polyurethane and the antibacterial effect is achieved by surface treatment with nanoparticles.

Patent CZ/EP 2 306 999 T3 describes cosmetic formulations (creams/gels) based on chitosan and Ce-Cn dicarboxylic acids for dermal applications with a focus on the treatment of rosacea. It does not exhibit a highly porous structure or antiviral activity.

Patent CZ/EP 2 922 581 T3 describes an aqueous gel formulation containing chitosan and hyaluronic acid for the treatment of mucosal lesions by topical administration. It does not exhibit a highly porous structure or antiviral activity.

Utility model CZ 16196 U1 (2005-17310) describes a preparation for treating cold sores based on pink powder with aloe vera.

Patent CZ/EP 2509586 (2010-792884) describes buccal tablets for the treatment of herpes and patent EP 2723385 (2012-731592) describes a film-forming mixture for the treatment of herpes.

None of the known solutions describes a single device that would cover all the necessary functions for the treatment of cold sores, drainage of exudate (in the later stages of infection), and neither do they allow simultaneous gas exchange with the environment, which is the main disadvantage of the prior art.

The aim of the technical solution is to eliminate or at least minimize the disadvantages of the prior art.

The essence of the technical solution

The objective of the technical solution is achieved by a means for treating cold sores (herpes labialis), which allows the creation of a bioactive patch for cold sores, because this means takes into account the specific requirements imposed on means for treating cold sores - i.e. purulent lesions on the skin caused by infection with the Herpes simplex 1 virus (HSV 1). The essence of the technical solution is that the means contains a nanofibrous layer carrying at least one active substance in its mass. The hydrophilic, biocompatible and biodegradable nanofibrous layer is based on partially cross-linked chitosan with an admixture of polyethylene oxide, which facilitates the process of processing by electrostatic spinning and ensures increased hydrophilicity of the nanofibers. The nanofibrous layer contains an antiviral agent as an active substance, preferably acyclovir (acyclovir, CAS 59277-89-3). The active substance, i.e. antiviral, may be supplemented with an excipient to increase wound hydration and to improve the kinetics of release of the active substance, in particular the excipient is formed by glycerol. Alternatively, the active substance is supplemented with other additives, in particular to improve healing and to reduce itching and/or is supplemented with fragrances. The active substance is incorporated directly into the mass of nanofibers, which ensures its homogeneous distribution in the nanofiber layer and gradual release.

The technical solution is intended for short-term application, e.g. using a patch, directly to the area of the cold sore, and in addition to its antiviral effect, it is characterized by the ability to stimulate wound healing due to the content of partially cross-linked chitosan. The nanofibrous structure, thanks to its small dimensions and high porosity, protects the area of the cold sore from secondary infection and at the same time allows the drainage of exudate. The technical solution is

-2CZ 38639 UI is characterized by good biocompatibility towards skin epithelium and digestive tract cells. The technical solution also describes a method of manufacturing this composite strip for a patch.

The combination of a partially cross-linked hydrophilic biocompatible nanofibrous layer and an antiviral active substance is characterized by good biocompatibility with the skin and the digestive tract and with a good antiviral effect. Thanks to the combination of structure and chemical composition, it accelerates the healing of herpes and reduces the risk of spreading the infection. The technical solution also describes a method of manufacturing fibrous structures.

The biocompatible nanofibrous layer is characterized by a nanofiber diameter in the range of 150 nm to 600 nm depending on the proportion of additives and the conditions of the production process. The nanofibrous layer is a homogeneous mixture of nanofibers with the content of both polymer components evenly distributed in the mass of the nanofibers. Chitosan is contained in the range of 70 to 92% by weight, and polyethylene oxide (PEO) in the range of 6 to 10% by weight, dry matter. The average molecular weight of polyethylene oxide is in the range of 300,000 to 500,000 g/mol, preferably 400,000 g/mol. To ensure better solubility in an aqueous environment, polyethylene oxide with a hydroxyl end group is preferably used. The nanofibrous layer is preferably prepared by electrostatic spinning from an aqueous solution of acetic acid onto a suitable compatible collector. The antiviral agent and any additives are incorporated directly into the spinning solution, which leads to their uniform distribution in the cross-section and area of the nanofiber layer. The antiviral agent is preferably acyclovir and is incorporated in the nanofibers in the range of 1 to 20% of the dry weight of the nanofibers, preferably 5 to 10%. The addition of glycerol or another moisturizing agent preferably constitutes a proportion of 0.1 to 5% of the weight of the nanofibers. Furthermore, it is possible to support the bioactivity of the nanofibers by incorporating natural substances with a soothing effect on the skin (e.g. aloe vera extract), fragrances or flavorings. The final dose of active substances on the area of the treated lip and surrounding tissue is determined by a combination of their concentration in the spinning solution and the final surface weight of the nanofiber layer. Depending on the spinning process conditions, this ranges between 0.5 and 10 g/m ² , preferably 3 to 6 g/m ² . The nanofiber layer thus created and the bioactive patch with it are effective against infections with the Herpes simplex virus 1 (HSV 1) and, thanks to its softness and hydrophilicity, which allows good adhesion to the wound, it is a suitable agent for the treatment of cold sores (herpes labialis).

Temporary stability of the nanofibrous layer while maintaining biodegradability is preferably ensured by partial crosslinking by short-term heat treatment of the nanofibrous layer up to 100 °C. After this treatment, the antiviral efficacy of the nanofibrous layer remains preserved. For application, the nanofibrous layer can be combined with a microfiber carrier or a cellulose-based carrier, etc. to form a patch.

Clarification of drawings

The technical solution is schematically illustrated in the drawing, where Fig. 1 shows the morphology of biocompatible antiviral nanofibers described in embodiment No. 1 with a content of the antiviral agent acyclovir 1%, Fig. 2 the morphology of biocompatible antiviral nanofibers described in embodiment No. 2 with a content of the antiviral agent acyclovir 10% and Fig. 3 the morphology of antiviral partially cross-linked nanofibers with incorporated antiviral agent after application in a humid environment (5 min). Partial preservation of the structure and porosity of the layer is evident.

Examples of implementing a technical solution

The composition for the treatment of cold sores or herpes labialis contains a hydrophilic biocompatible nanofibrous layer, the nanofibers of which are provided with an antiviral active substance in their volume. The nanofibrous layer is preferably formed by an electrostatically spun mixture of chitosan and polyethylene oxide, with the chitosan content in the nanofibers being from 70 to 92% of the dry mass of the nanofibers, i.e. % mass. The antiviral active substance is preferably formed by acyclovir. The antiviral active substance acyclovir has a final proportion in the mass of the nanofibers preferably of 1 to

- 3 CZ 38639 UI % mass, nanofibers, preferably 5 to 10 % mass, nanofibers. The nanofiber layer preferably has a partially cross-linked structure. The nanofiber layer preferably has a surface weight in the range of 0.5 to 10 g/m ² , preferably 3 to 6 g/m ² . The nanofiber layer preferably further contains at least one auxiliary substance for increasing wound hydration and for improving the kinetics of the release of the active substance, in particular it contains glycerol, preferably with a proportion of 0.1 to 5 % mass, nanofibers. The nanofiber layer preferably further contains at least one other additive substance, in particular a substance for improving healing and for reducing itching and/or a fragrance substance. The nanofiber layer preferably has a nanofiber diameter in the range of 150 nm to 600 nm. The polyethylene oxide content in the nanofibers is preferably in the range of 6 to 10% by weight, dry matter of the nanofibers. The polyethylene oxide preferably has an average molecular weight in the range of 300,000 to 500,000 g/mol, preferably 400,000 g/mol. The polyethylene oxide preferably has a hydroxyl end group.

The herpes treatment patch comprises a herpes treatment agent according to the above parameters and description. Preferably, the herpes treatment agent is associated with a patch carrier.

The technical solution will be further described with reference to several very specific examples of implementation, which describe particularly advantageous embodiments, or describe other characteristics and advantages of the technical solution. These specific examples of implementation are a description of advantageous, but not exclusive, embodiments of this technical solution.

Example 1:

A nanofibrous layer is applied to a spun-bond nonwoven fabric, which in this case serves as an auxiliary substrate, by electrostatic solution spinning. The basic polymer matrix of the nanofibrous layer contains chitosan and polyethylene oxide (Mw 400,000 g/mol) with a hydroxyl end group. The nanofibrous layer is prepared from a spinning solution, where the main polymer components are chitosan in a proportion of 7.75% (mass.), polyethylene oxide in a proportion of 0.67% (mass.). Acetic acid is used as the main solvent and constitutes 42.12% mass. Before spinning, the antiviral acyclovir is added to the solution. Other auxiliary substances are optionally added in a specific order in a loose state and/or in an appropriate compatible solvent. The antiviral agent is added to the spinning solution in such a dose that its content in the resulting nanofibrous layer constitutes 1% by mass. The production of nanofibers, for example, took place after dissolving all components and homogenizing the spinning solution on the Nanospider™ 1WS500U Line spinning unit. The substrate feed rate is 30 mm/min. The dose of antiviral agent per unit area is determined by its proportion in the spinning solution and the spinning conditions, which determine the basis weight of the nanofibrous layer. The basis weight of the formed nanofibrous layer is 4.7 g/m ² . The resulting amount of chitosan in the fibers of the nanofibrous layer is approximately 91% (mass.) and polyethylene oxide 9% (mass.). The active nanofibrous layer is subsequently at a temperature below 100 °C. This will improve the stability of nanofibers in an aqueous environment while maintaining biodegradability and without compromising antiviral efficacy.

The nanofibrous layer is made up of smooth nanofibers with minimal defects (see image documentation, Fig. 1). The average diameter value in the nanofibrous layer prepared in this way is 211 nm.

The active nanofibrous layer thus created was confirmed to be biocompatible in vitro with human Hacat keratinocytes, whose viability after 24 hours of exposure was 94%. In vitro biocompatibility (viability higher than 85%) was also demonstrated on intestinal epithelial cells Caco-2. The antiviral efficacy of the sample was 68% (reduction of viral titer).

Example 2:

A nanofibrous layer is applied to a non-textile auxiliary substrate by electrostatic solution spinning. The basic polymer matrix of the nanofibrous layer contains chitosan and polyethylene oxide (Mw 400,000 g/mol). The nanofibrous layer is prepared from a spinning solution, where the main

-4CZ 38639 UI polymer components consist of chitosan in a proportion of 7.75% (mass.), polyethylene oxide in a proportion of 0.67% (mass.). Acetic acid is used as the main solvent and constitutes 42.12% mass. Before spinning, the antiviral acyclovir is added to the solution in such a dose that their content in the resulting nanofibrous layer constitutes 10% mass. The production of nanofibers here took place, for example, after dissolving all components and homogenizing the spinning solution on the Nanospider™ 1WS500U Line spinning unit. The substrate feed rate is 30 mm/min. The dose of antiviral per unit area is determined by its proportion in the spinning solution and the spinning conditions, which determine the basis weight of the nanofibrous layer. The basis weight of the formed nanofibrous layer is 5.3 g/m ² . The resulting amount of chitosan in the fibers of the nanofibrous layer is approximately 82.8% (mass.) and polyethylene oxide 7.2% (mass.). The active nanofibrous layer is subsequently at a temperature of 80 °C. This improves the stability of the nanofibers in an aqueous environment while maintaining biodegradability and without compromising antiviral efficacy.

The nanofibrous layer is made up of smooth nanofibers with minimal defects, which is confirmed by the image documentation (Fig. 2). The average diameter value in the nanofibrous layer prepared in this way is 288 nm.

The active nanofibrous layer thus created was confirmed to be biocompatible in vitro with human Hacat keratinocytes, whose viability after 24 hours of exposure was 88%. In vitro biocompatibility (viability higher than 80%) was also demonstrated with intestinal epithelial cells Caco-2. Antiviral efficacy tested on HSV-1 in vitro reached 99.4% reduction of viral titer.

Industrial applicability

The solution using a hydrophilic biodegradable nanofibrous layer based on chitosan and an antivirally active drug substance allows for the achievement of all required properties and is applicable in all phases of herpes healing.

Claims (14)

1. A composition for treating cold sores or herpes labialis, characterized in that it contains a hydrophilic biocompatible nanofiber layer that contains an antivirally effective active substance that is incorporated into the nanofiber mass. 2. The composition according to claim 1, characterized in that the nanofiber layer is formed by an electrostatically spun mixture of chitosan, polyethylene oxide and an antivirally effective active substance, wherein the chitosan content in the nanofibers is from 70 to 92% by weight of the nanofibers. 3. The composition according to any one of claims 1 or 2, characterized in that the antivirally effective active substance incorporated in the nanofiber mass is acyclovir. 4. The composition according to claim 3, characterized in that the content of acyclovir in the mass of nanofibers is 1 to 20% by weight, preferably 5 to 10% by weight. 5. The composition according to any one of claims 1 to 4, characterized in that the nanofibrous layer has a partially cross-linked structure. 6. The composition according to any one of claims 1 to 5, characterized in that the nanofiber layer has a surface weight in the range of 0.5 to 10 g/m ² , preferably 3 to 6 g/m ² . 7. The composition according to any one of claims 1 to 6, characterized in that the nanofiber layer further comprises at least one excipient for increasing wound hydration and for improving the kinetics of release of the active substance, in particular it comprises glycerol, preferably with a proportion of 0.1 to 5% by weight of the nanofibers. 8. The composition according to any one of claims 1 to 7, characterized in that the nanofibrous layer further comprises at least one additional additive substance, in particular another healing substance, an itch-reducing substance and/or a fragrance substance. 9. The composition according to any one of claims 1 to 8, characterized in that the nanofiber layer has a nanofiber diameter in the range of 150 nm to 600 nm. 10. The composition according to claim 2, characterized in that the polyethylene oxide content in the nanofibers is in the range of 6 to 10% by mass. 11. The composition according to claim 2 or 10, characterized in that the polyethylene oxide has an average molecular weight in the range of 300,000 to 500,000 g/mol, preferably 400,000 g/mol. 12. The composition of any one of claims 2, 10 or 11, wherein the polyethylene oxide has a hydroxyl end group. 13. A medical patch, characterized in that it contains a composition for treating cold sores according to any one of claims 1 to 12. 14. A medical patch according to claim 13, characterized in that the herpes treatment agent is connected to the patch carrier.