Composition comprising methanesulfonic acid and a non-aqueous proton acceptor for use in a method for the treatment and management of various diseases characterized by a range of chronic and / or recurrent conditions

Abstract

The present invention further relates to a composition comprising methanesulfonic acid and a non-aqueous proton acceptor for use in a method for the treatment and management of one or more of fistula, pilonidal sinus, herpes labialis, pyogenic granuloma, fungal nail infection and onicocriptosis.

Description

[0001] Composition for use in a method for the treatment and management of various diseases characterized by a range of chronic and / or recurrent conditions

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a composition and use thereof in a method for the treatment and management of various diseases characterized by a range of chronic and / or recurrent conditions, selected from one or more of fistula, pilonidal sinus, herpes labialis, pyogenic granuloma, fungal nail infection and onicocriptosis. The present invention further relates to a composition comprising a sulphonic acid derivative, in particular methanesulfonic acid, and a non-aqueous proton acceptor for use in the said method for the treatment and management of one or more of fistula, pilonidal sinus, herpes labialis, pyogenic granuloma, fungal nail infection and onicocriptosis.

[0004] BACKGROUND ART

[0005] It is well-known that the chronic and recurrent medical conditions are long-term health issues that can flare up periodically, vary widely in terms of their severity, frequency of symptoms, and impact on daily life. These conditions generally persist for extended periods, often over a year, and may require continuous management. Particularly, some conditions are both chronic and recurrent, as they persist long-term but involve periodic flare-ups or acute episodes. Living with these conditions often means navigating medical treatments, adjusting lifestyles, and maintaining regular health check-ups to manage symptoms, prevent flare-ups, and maintain quality of life.

[0006] A fistula is an abnormal connection joining two hollow spaces / two epithelialized surfaces that do not usually connect. Based on the connection tissues / organs, the fistulas are categorized into different fistulas, such as vestibular fistula / oroantral fistula, anal fistula, colovaginal fistula, urinary tract fistula, vesicouterine fistula, vesicovaginal fistula, urethrovaginal fistula, enteroenteral fistula, cutaneous fistula, enterocutaneous fistula, colocutaneous fistula. Fistulas can occur due to various underlying conditions, including trauma, infection, or surgery. They often present with chronic discharge and can become sites of persistent infection and inflammation. Standard treatments include drainage, antibiotics, and surgical closure; however, these approaches are often associated with recurrence and post-operative complications (Reference: Parks AG et al., “A Classification of Fistula-in-Ano,” Br J Surg., 1976). The treatment of anal fistulas is usually complex and burdened by a high rate of failure and / or relapses. This is related to the fact that fistulas, although surgically cleaned, have a high probability of reinfection.

[0007] A pilonidal disease is a chronic inflammatory condition characterized by cystic lesions or sinus tracts often located in the sacrococcygeal region. The condition typically arises from hair follicle infection, leading to cyst formation near the tailbone. The cavity under the skin has a connection through the skin to the outside. This can be seen as a small hole or a small retraction in the skin, known as pilonidal sinus (PNS). It is more prevalent among young adults, particularly those with sedentary lifestyles or occupations that involve prolonged sitting. Conventional treatments involve incision, drainage, and sometimes excision, which can require long recovery periods and may not prevent recurrence (Reference: Bascom J., “Pilonidal disease: long-term results of follicle removal,” Diseases of the Colon & Rectum, 1983). This involves a high risk of re-infection and the need for the patient to be medicated 2-3 times a week with consequent impaired quality of life and prolonged suffering.

[0008] A herpes labialis is commonly known as cold sore and characterized by the development of a rash in the skin or mucous membranes, primarily in the lips, which causes erythema and blisters frequently accompanied by a burning sensation of pain. It is caused by the herpes simplex virus (usually herpes simplex virus type 1 (HSV-1) and occasionally herpes simplex virus type 2 (HSV-2). While antiviral agents like acyclovir and famciclovir are available, their effectiveness is limited, and repeated outbreaks remain a common issue. Long-term use of antiviral drugs may also contribute to resistance (Reference: Corey L et al., “Herpes Simplex Viruses,” in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 2005).

[0009] A pyogenic granulomas (PGs) is characterized by a common and benign vascular proliferation that occurs on both mucosa, skin or subcutaneous tissue and appears as an overgrowth of tissue. Based on the location of the occurrences, PGs are categorized into different types, such as periungual or subungual, oral, eye, face and limbs. A subungual granulomas are inflammatory lesions that form beneath the nail plate, often due to chronic trauma, infection, or the presence of foreign material under the nail. Similarly, a periungual granulomas are inflammatory lesions that develop around the nail. These granulomas can cause pain, swelling, lifting of the nail plate and are prone to bleeding, and they can become sites for secondary bacterial or fungal infections. Current treatments include topical or systemic antimicrobials, and in several cases surgical removal of the nail or granuloma, which can be uncomfortable, lead to prolonged recovery, and carry a risk of recurrence (Reference: Baran R et al., “Nail Disorders: Diagnosis and Treatment,” Dermatol Clin., 2006; Haneke E., “Periungual Granulomas: Diagnosis and Therapy,” Clin Dermatol., 2013). In addition, improper antibiotic treatments are often administered systemically, contributing to the problem of antibiotic resistance.

[0010] A fungal nail infection, also known as onychomycosis is a chronic condition occurring due to dermatophytes and fusarium fungus. This leads to white or yellow nail discoloration, thickening, and deformation of the nail plate. The condition can cause pain, restrict mobility, and cellulitis of the lower leg. Treatment typically involves oral antifungals, topical agents, or, in severe cases, nail removal. However, treatment is often lengthy, and recurrence rates are high (Reference: Gupta AK et al., “Onychomycosis: Pathogenesis, Diagnosis, and Management,” Clin Microbiol Rev., 2000).

[0011] An ingrown nail, also known as onicocriptosis occurs when the nail grows into the surrounding skin, causing inflammation, pain, and sometimes infection. Treatments range from conservative approaches, such as soaking and lifting the nail, to more invasive measures like partial nail avulsion or complete removal in severe cases. Unfortunately, ingrown nails are prone to recurrence, and patients often experience prolonged discomfort (Reference: Heidelbaugh JJ et al., “Management of the Ingrown Toenail,” Am Fam Physician, 2009).

[0012] These conditions, while diverse in their pathologies, share a common need for effective, long term treatment and management due to issues such as chronic inflammation, infection, pain, and high recurrence rates. The existing therapeutic options may provide temporary relief but are often limited by adverse effects, recurrence, and incomplete remission. Thus, an improved therapeutic composition is needed to address these challenges.

[0013] Given the limitations of current treatments, the present invention addresses the need by providing a composition that effectively targets the conditions, which are characterized by a range of chronic and / or recurrent conditions and further providing said composition for use in a method for the treatment and management of one or more of fistula, pilonidal sinus, herpes labialis, pyogenic granuloma, fungal nail infection and onicocriptosis. SUMMARY OF THE INVENTION

[0014] The invention concerns a composition comprising a sulphonic acid having the general formula (A):

[0015]

[0016] wherein R is

[0017] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0018] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring.

[0019] The PCT publications: WO2020 / 165628, WO2021 / 148124 and W02023 / 057098 disclose the compositions comprising sulphonic acids, in particular methane sulphonic acid, ethane sulphonic acid, propane sulphonic acid or 4-dodecylbenzene sulphonic acid, which compositions have been incorporated herein by reference and which can be used in the medical indications of the invention.

[0020] In one aspect, the invention concerns the use of said composition for use in a method of the treatment or management of various diseases or conditions selected from one or more of fistula, pilonidal sinus, herpes labialis, pyogenic granuloma, fungal nail infection and onicocriptosis.

[0021] In an aspect the invention concerns a composition comprising a sulphonic acid having the general formula (A):

[0022]

[0023] wherein R is

[0024] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0025] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0026] for use in a method for the treatment or management of a fistula.

[0027] In an aspect the invention concerns a composition for use in a method for the treatment of a fistula, the composition comprising a sulphonic acid selected from: methanesulfonic acid, ethanesulfonic acid, 1 -propanesulfonic acid, 4- dodecylbenzenesulphonic acid and mixtures thereof, wherein the composition further comprises a non-aqueous proton acceptor.

[0028] In a preferred embodiment, the sulphonic acid is methanesulfonic acid. In a more preferred embodiment, the amount of methanesulfonic acid is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition. In a preferred embodiment, the non-aqueous proton acceptor comprises or consists essentially of dimethyl sulfoxide. In a more preferred embodiment, the non-aqueous proton acceptor is in an amount of 5% to 50% w / w, preferably 10% to 40% w / w, based on the total weight of the composition.

[0029] In an aspect the invention concerns a composition comprising a sulphonic acid having the general formula (A):

[0030]

[0031] wherein R is

[0032] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0033] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0034] for use in a method for treatment or management of a pilonidal sinus.

[0035] In an aspect the invention concerns a composition for use in a method for treatment or management of a pilonidal sinus, the composition comprising a sulphonic acid selected from: methanesulfonic acid, ethanesulfonic acid, 1 -propanesulfonic acid, 4-dodecylbenzenesulphonic acid and mixtures thereof, wherein the composition further comprises a non-aqueous proton acceptor. In a preferred embodiment, the sulphonic acid is methanesulfonic acid. In a more preferred embodiment, the amount of methanesulfonic acid is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition. In a preferred embodiment, the non-aqueous proton acceptor comprises or consists essentially of dimethyl sulfoxide. In a more preferred embodiment, the non-aqueous proton acceptor is in an amount of 5% to 50% w / w, preferably 10% to 40% w / w, based on the total weight of the composition.

[0036] In an aspect the invention concerns a composition comprising a sulphonic acid having the general formula (A):

[0037]

[0038] wherein R is

[0039] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0040] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0041] for use in a method for the treatment or management of a herpes labialis.

[0042] In an aspect the invention concerns a composition for use in a method for treatment or management of a herpes labialis, the composition comprising a sulphonic acid selected from: methanesulfonic acid, ethanesulfonic acid, 1 -propanesulfonic acid, 4-dodecylbenzenesulphonic acid and mixtures thereof, wherein the composition further comprises a non-aqueous proton acceptor.

[0043] In a preferred embodiment, the sulphonic acid is methanesulfonic acid. In a more preferred embodiment, the amount of methanesulfonic acid is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition. In a preferred embodiment, the non-aqueous proton acceptor comprises or consists essentially of dimethyl sulfoxide. In a more preferred embodiment, the non-aqueous proton acceptor is in an amount of 5% to 50% w / w, preferably 10% to 40% w / w, based on the total weight of the composition.

[0044] The inventors have surprisingly found that the composition according to the invention, for example based on a combination of methanesulfonic acid and the non-aqueous proton acceptor, is effective in treating the virus infection caused by a herpes labialis associated virus, such as herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). and to support a fast healing of the wound, which is infected or caused by the herpes labialis virus. This surprising activity has not been described before in relation to said virus, and was not anticipated.

[0045] Safe application of the composition is provided by a controllable topical administrating and maintaining the composition at the wound location of herpes labialis, in particular when using the gel composition.

[0046] In an aspect the invention concerns a composition comprising a sulphonic acid having the general formula (A):

[0047]

[0048] wherein R is

[0049] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0050] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0051] for use in a method for the treatment or management of a fungal nail infection.

[0052] In an aspect the invention concerns a composition for use in a method for treatment or management of a fungal nail infection, the composition comprising a sulphonic acid selected from: methanesulfonic acid, ethanesulfonic acid, 1 -propanesulfonic acid, 4-dodecylbenzenesulphonic acid and mixtures thereof, wherein the composition further comprises a non-aqueous proton acceptor.

[0053] In a preferred embodiment, the sulphonic acid is methanesulfonic acid. In a more preferred embodiment, the amount of methanesulfonic acid is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition. In a preferred embodiment, the non-aqueous proton acceptor comprises or consists essentially of dimethyl sulfoxide. In a more preferred embodiment, the non-aqueous proton acceptor is in an amount of 5% to 50% w / w, preferably 10% to 40% w / w, based on the total weight of the composition. The inventors have surprisingly found that the composition according to the invention, for example based on a combination of methanesulfonic acid and the non-aqueous proton acceptor, is effective in treating the fungal nail infection and to support a fast healing of the wound, which is caused by a chronic condition occurring due to dermatophytes and fusarium fungus. This surprising activity of the composition has not been described before in relation to said fungal nail infection. The advantage of the treatment, compared to standard care of using antifungal topical creams treatment (such as clotrimazole topical agent and miconazole topical agent) is that these standard topical treatments are often lengthy (days / weeks), and recurrence rates are high, while the treatment of the invention is only a short time treatment necessary to effectively treat the chronic wound and manage, and prohibit the effects of the fungal infection on the wound area.

[0054] In an aspect the invention concerns a composition comprising a sulphonic acid having the general formula (A):

[0055]

[0056] wherein R is

[0057] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0058] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0059] for use in a method for the treatment or management of onicocriptosis.

[0060] In an aspect the invention concerns a composition for use in a method for treatment or management of onicocriptosis, the composition comprising a sulphonic acid selected from: methanesulfonic acid, ethanesulfonic acid, 1 -propanesulfonic acid, 4-dodecylbenzenesulphonic acid and mixtures thereof, wherein the composition further comprises a non-aqueous proton acceptor.

[0061] In a preferred embodiment, the sulphonic acid is methanesulfonic acid. In a more preferred embodiment, the amount of methanesulfonic acid is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition. In a preferred embodiment, the non-aqueous proton acceptor comprises or consists essentially of dimethyl sulfoxide. In a more preferred embodiment, the non-aqueous proton acceptor is in an amount of 5% to 50% w / w, preferably 10% to 40% w / w, based on the total weight of the composition.

[0062] The invention concerns a composition comprising a sulphonic acid having the general formula (A):

[0063]

[0064] wherein R is

[0065] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0066] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0067] for use in a method for the treatment or management of a pyogenic granuloma.

[0068] In an aspect the invention concerns a composition for use in a method for treatment or management of a pyogenic granuloma, the composition comprising a sulphonic acid selected from: methanesulfonic acid, ethanesulfonic acid, 1 -propanesulfonic acid, 4-dodecylbenzenesulphonic acid and mixtures thereof, wherein the composition further comprises a non-aqueous proton acceptor.

[0069] In a preferred embodiment, the sulphonic acid is methanesulfonic acid. In a more preferred embodiment, the amount of methanesulfonic acid is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition. In a preferred embodiment, the non-aqueous proton acceptor comprises or consists essentially of dimethyl sulfoxide. In a more preferred embodiment, the non-aqueous proton acceptor is in an amount of 5% to 50% w / w, preferably 10% to 40% w / w, based on the total weight of the composition.

[0070] Given that a pyogenic granuloma (granuloma pyogenicum) is a noncancerous (benign), raised tumor on your skin or mucous membranes, it is found surprising that the composition according to the invention is effective in treating the pyogenic granuloma. In one aspect, the invention concerns a composition comprising a sulphomc acid having the general formula (A):

[0071]

[0072] wherein R is

[0073] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0074] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0075] for use in a method for the treatment or management of anal fistula.

[0076] In one aspect, the invention concerns a composition comprising a sulphonic acid having the general formula (A):

[0077]

[0078] wherein R is

[0079] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0080] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0081] for use in a method for the treatment or management of periungual granuloma.

[0082] In one aspect, the invention concerns a composition comprising a sulphonic acid having the general formula (A):

[0083]

[0084] wherein R is (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0085] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0086] for use in a method for the treatment or management of subungual granuloma.

[0087] In one aspect, the invention concerns a kit comprising:

[0088] a. a composition comprising a sulphonic acid having the general formula (A):

[0089]

[0090] wherein R is

[0091] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0092] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0093] b. optionally an applicator, preferably a syringe or a catheter;

[0094] c. an instruction for application of the composition.

[0095] Preferably, the kit is designed for home care.

[0096] In one aspect, the invention concerns a kit comprising:

[0097] a. a composition comprising a sulphonic acid having the general formula (A):

[0098]

[0099] wherein R is

[0100] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0101] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0102] b. optionally an applicator, preferably a syringe or a catheter;

[0103] c. an instruction for application of the composition;

[0104] for use in a method for the treatment or management of one or more of fistula, pilonidal sinus, herpes labialis, pyogenic granuloma, fungal nail infection and onicocriptosis.

[0105] In one aspect, the invention concerns a kit comprising:

[0106] a. a composition comprising a sulphonic acid having the general formula (A):

[0107]

[0108] wherein R is

[0109] (i) an alkyl group, preferably a methyl or ethyl or propyl; or

[0110] (ii) an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring;

[0111] b. optionally an applicator, preferably a syringe or a catheter;

[0112] c. an instruction for application of the composition;

[0113] for use in a method for the treatment or management of one or more of wounds, for use in removing a bacterial biofilm and / or necrotic or infected tissue from acute or chronic, preferably chronic, skin lesions or from oral cavities, for use in disinfecting acute or chronic skin lesions, or for use in the treatment or management of a pathology selected from the group consisting of: chronic cutaneous ulcer, periodontal disease, perimplantitis and aphtha.

[0114] In one aspect, the fistula is selected from one or more of: anal fistula, colovaginal fistula, urinary tract fistula, vesicouterine fistula, vesicovaginal fistula, urethrovaginal fistula, enteroenteral fistula, cutaneous fistula, enterocutaneous fistula and colocutaneous fistula. In one aspect, the pyogenic granuloma occurs on skin and / or mucous membranes, preferably on one or more sites selected from the group consisting of periungual skin (periungual pyogenic granuloma), subungual site (subungual pyogenic granuloma), oral cavity (oral pyogenic granuloma), eyelid (conjunctival pyogenic granuloma), face and limbs.

[0115] In one aspect, the composition is anhydrous, preferably the composition contains less than 5 wt.% water, more preferably the composition is substantially free from water.

[0116] The effective treatment or management of the diseases conditions as provided by the present invention is advantageous over the standard care or currently existing treatments by following means:

[0117] • increase in treatment success rates;

[0118] • avoiding the need for systemic antibiotics;

[0119] • possible to carry-out the treatment even by non-medical person and suitable for homecare;

[0120] • speeding up the healing time;

[0121] • simplified procedure over the surgical treatment;

[0122] • cost effective.

[0123] DEFINITION

[0124] The term “management” as used herein refers to overall management of intended diseases condition(s). The management would include pre- and post-operative management of said disease condition. Particularly, the individuals with chronic conditions require appropriate management and interventions to ensure optimal health outcomes. The management includes performing required treatment steps, which would result to: improved safety and quality of care, improved access to care, reducing health care costs and improving quality of life for individuals patients with chronic conditions as it would prevent or minimizing the effects of the disease through integrated care and treating chronic conditions more quickly and more effectively.

[0125] The term "biofilm" defines the thin layer of polysaccharides, nucleic acids, proteins, lipids and glycoprotein material that is produced by bacteria in active, albeit slow, replication and that adheres to the lesion bed. The biofilm that is formed in an infected wound contributes to delaying its healing. Indeed, in the presence of biofilm, the conditions are created in order for the individual microorganisms to interact reciprocally exchanging nutrients and metabolites, so that to establish actual organized bacterial communities. Therefore, biofilms act as protected infection and bacterial resistance outbreaks within the wound and they are able to protect bacteria from the action of antimicrobial agents, such as antibiotics and antiseptics. Biofilms usually consist of a plurality of layers of microorganisms and communication between microbial cells is a crucial factor for the development and maintenance of the biofilm itself.

[0126] The term “necrotic tissue” defines a body tissue wherein tissue necrosis has occurred. Tissue necrosis is a pathological response that results in loss of organ function due to cell death. Cell death can be caused by external factors such as toxicants and is recognized microscopically by changes in the nucleus, including pyknosis, karyorrhexis, and karyolysis. These changes may include swelling of the nucleus, which is followed by condensation of the nuclear chromatin (pyknosis), and finally by dissolution of the nucleus (karyolysis).

[0127] The term “granuloma” defines an area of inflammation (the way your body protects itself from something harmful) in your body. Granulomas are clusters of white blood cells that “wall off’ bacteria, a foreign object or something else it thought was harmful from the rest of your body. The term "pyogenic granuloma” (granuloma pyogenicum) is a noncancerous (benign), raised tumor on your skin or mucous membranes. Pyogenic granulomas tend to ooze, and they break and bleed easily.

[0128] DETAILED DESCRIPTION OF THE INVENTION

[0129] The alkyl sulphonic acids and aryl sulphonic acids in general have reasonable strong acidities, however which are dependent on the substituents. Exemplary sulphonic acids according to the invention and their p Taand acid dissociation constant Kaare given in Table 1.

[0130] The composition further comprises a non-aqueous proton acceptor. The inventors have found that combining a sulphonic acid with a non-aqueous proton acceptor, in particular using specific amounts or ratios with respect to one another, provides a surprising combined effect of providing a strong dehydrating and decontaminating functionality, including removing bacterial biofilm and necrotic and / or infected tissues when present at the relevant topical site of the body of treatment, while preventing any damage to the topical site of treatment and the surrounding area caused by the acidic activity of the sulphonic acid, due to the proton balancing activity of the non-aqueous proton acceptor.

[0131] A composition containing the sulphonic acid and a non-aqueous proton acceptor, preferably as the main constituents, has proven particularly useful in effectively decontaminating and in removing bacterial biofilm and necrotic and / or infected tissues present in the topical sites of infection of the body at the same time, without the need of further mechanical treatments and / or without the need of longer treatment procedures to obtain the desired effect.

[0132] However, it is surprising that the composition of the invention is effective in treating several indications, which are either due to a viral infection of Herpes labialis, or are due to a fungal nail infection, also known as onychomycosis occurring due to dermatophytes and fusarium fungus.

[0133] It is surprising that a pyogenic granuloma wound can effectively be treated with the composition according to the invention, as the main components of the pyogenic granuloma wound are clusters of white blood cells that “wall off’ bacteria, and no relation to an occurrence or presence of a biofilm is known for a pyogenic granuloma wound. As such, the effectiveness of the composition according to the invention is a surprising effect.

[0134] The combination of a strong sulphonic acid and a non-aqueous proton acceptor is explained as following: especially in case of a strong sulphonic acid the strong acidic action, which may provide aggressive action, is desirably compensated or controllably adjusted in the composition by adding the non-aqueous proton acceptor.

[0135] It has furthermore been found by the inventors, that when adding water to the composition, instead of the non-aqueous proton acceptor, considerably obstructs the composition of being effective in removing the biofilm and necrotic and / or infected tissues present in topical sites of infection of the body.

[0136] Antimicrobial effects have been reported in general for several sulphonic acid compounds and compositions thereof. However, given that these known compositions contain water in a considerable amount (at least 10 wt.% or more) and they do not contain a non-aqueous proton acceptor in reasonable amounts, these compositions are not effective towards removing the biofilm and necrotic and / or infected tissues present in topical sites of infection of the body. In those cases, additional mechanical, i.e. surgical actions have been found to be needed to remove the biofilms or necrotic or infected tissue. In particular, when infections are partly or completely embedded in biofilms or body tissues, common antimicrobial compositions, which contain water as a main carrier or solvent, have shown not to be effective to treat said infections.

[0137] Common decontamination strategies (for example using Dermacyn; acetic acid solution, etc.) have shown to be effective only when extensively used in several medical applications (let’s say: apply the product; leave it there for 10-20 minutes; repeat the procedure 3 -times per weeks; extent treatment for several weeks). That means that you may require several weeks before reaching full decontamination.

[0138] In preferred embodiments, the non-aqueous proton acceptor is at least one component, selected from: dimethyl sulfoxide, isopropyl alcohol, 3 -methoxy-3 -methyl- 1 -butanol, propylene carbonate, anhydrous sodium carbonate, ethylenediaminetetraacetic acid tetrasodium salt, sodium gluconate, polyethylene glycol and mixtures thereof. Preferably, the non-aqueous proton acceptor is dimethyl sulfoxide.

[0139] The composition according to the invention, comprising the sulfonic acids, can be formulated as a solution, gel or cream and can be easily applied topical sites of infection of the body. A surprisingly unexpected property of all compositions, according to the invention, is that the latter are able to act on the biofilm and on the necrotic or infected tissues, causing a rapid desiccation thereof (for example within seconds or 1 to 5 minutes) and enabling the substantially complete removal thereof (through washing or sterile gauze) within a few seconds or a few minutes after the application and thus avoiding complicated, painful and costly surgical procedures (debridement).

[0140] The compositions according to the invention are preferably in a gel form. Such gel compositions include one or more gelling agents, preferably including the gelling agents SiCh and / or TEOS. For example, formulations may include the gelling agent SiCh and are in gel form, without the inclusion of (supportive) gelling agent TEOS.

[0141] The gel compositions provide advantages of controllable application and maintaining a suitable amount of the gel composition at a wound location, which is to be treated. This provides in particular advantages for locations of wounds, which for safety reasons desire a proper control of maintaining the composition within desired areas, such as close to mouth, eye or other sensitive organs of the body. The gel compositions according to the invention support said safe application of the compositions. In this way, its activity is controllably located at the desired locations.

[0142] The action of the compositions is due to the release of hydrogen ions (H+) or protons that, possessing a great hydration enthalpy (-1130 KJ / mole), cause the dehydration of the microbial species that make up the biofilm or proliferate in the infected tissues. This action mechanism is now shown to be achieved regardless of the microbial species present and makes the composition according to the invention active against any microbial species, whether bacterial, fungal or viral. See the in vivo data shown for the treatment of herpes labialis, or the in vivo data for the treatment of a fungal nail infection, also known as onychomycosis.

[0143] In the following Table 1, the pKa values are shown (at a temperature of 25°C) of the main strong acids, which dissociate completely, or almost completely, in an aqueous environment. From Table 1 it can be inferred that the trifluoromethanesulfonic acid is the strongest acid (namely, the acid having the highest pKa value), whereas the trifluoroacetic acid is the weakest acid:

[0144] Table 1. Dissociation constants of strong acidic species

[0145]

[0146]

[0147] Considering the volatility of the hydroiodic, hydrobromic, hydrochloric and trifluoroacetic acids, as well as the oxidizing action of the perchloric sulphuric and nitric acids, which can cause undesired effects on the skin and on the mucosa of the oral cavity, the inventors have focused their attention on the Ethanesulfonic, Methanesulfonic, 1 -Propanesulfonic and 4-Dodecylbenzenesulfonic acids which have the lower dissociation constants, exerting therefore a milder (initial) actions in contact with the topical sites of infection of the body. Active sources which have been used as components to prepare the different formulations are the following commercial products:

[0148] Methanesulfonic acid 99%-100% CAS 7575-2 (Abbreviated as MSA)

[0149]

[0150] Ethanesulfonic acid 97 % CAS N. 594-45-6 (Abbreviated as ESA)

[0151]

[0152] 1-Propanesulfonic acid 98%; CAS N. 5284-66-2 (Abbreviated as PSA)

[0153]

[0154] 4-Dodecylbenzenesulfonic acid 99%-100% ; CAS 121-65-3 (Abbreviated as DBSA)

[0155]

[0156] The weaker sulphonic acids have also proven particularly useful in removing bacterial biofilm and necrotic and / or infected tissues present in topical sites of infection of the body. The experiments performed by the inventors demonstrated that the above mentioned sulphonic acids, in particular MSA and DBSA, are able to penetrate the bacterial biofilm with an exceptional surfactant effect towards its components, allowing for its complete removal through the addition of saline or distilled water. In addition its lower acidity constant allows to obtain excellent results of disinfection and removal of the biofilm and necrotic and / or infected tissues without causing side effects, such as the burning sensation. Consequently, these above mentioned sulphonic acids, in particular DBSA, can be applied autonomously by the patient or by a nurse without the intervention of specialised doctors.

[0157] The invention also concerns a composition comprising the sulphonic acids in mixture with at least a non-aqueous proton acceptor, preferably a solvent and / or a sub stance / sol vent with basic characteristics, hence capable of accepting protons which allows to adjust, preferably to reduce, the acidity of the composition according to the invention. Preferably, the sulphonic acid is a weak sulphonic acid.

[0158] In a preferred embodiment, the least one non-aqueous proton acceptor is selected from: dimethyl sulfoxide, 3 -m ethoxy-3 -methyl- 1 -butanol, propylene carbonate, anhydrous sodium carbonate, ethylenedi aminetetraacetic acid tetrasodium salt, sodium gluconate, polyethylene glycol and mixtures thereof, preferably anhydrous dimethylsulfoxide (DMSO).

[0159] Dimethyl sulfoxide or DMSO or (Cff^SO anhydrous, CAS N. 67-68-5

[0160]

[0161] In embodiments, the composition of the invention comprises the sulphonic acid at a concentration between 50% and 95% w / w, preferably between 60% and 90% w / w.

[0162] In embodiments, the composition of the invention comprises the non-aqueous proton acceptor in an amount of 5% to 50% w / w, preferably 10% to 40% w / w. In certain embodiments, the at least one non-aqueous proton acceptor is a liquid or mixture of non-aqueous proton acceptor are liquids.

[0163] In certain embodiments the sulphonic acid and the non-aqueous proton acceptor of the composition, or mixture of non-aqueous proton acceptors, are liquids and form a substantially homogenous mixture and / or the sulphonic acid is substantially completely dissolved in the liquid non-aqueous proton acceptor or in the liquid mixture of liquid non-aqueous proton acceptors of the composition.

[0164] In certain embodiments, the composition is an anhydrous composition or a substantially anhydrous composition.

[0165] In certain embodiments a minor amount of water is added, up to a maximum of 5% w / w, if needed in case the sulphonic acid is not completely soluble in the non-aqueous proton acceptor or mixture of non-aqueous proton acceptors.

[0166] Tables 2 - 7 disclose the qualitative and quantitative composition of six liquid (solution) or gel embodiments of the composition according to the invention:

[0167] Table 2

[0168]

[0169] Table 3

[0170]

[0171] Table 4

[0172]

[0173] Table 5

[0174]

[0175] Table 6

[0176]

[0177] Table 7

[0178]

[0179] Table 8

[0180]

[0181]

[0182] The seventh formulation (Table 8) is an exemplary formulation of the second formulation (Table 3). The in vivo data shown based on the seventh formulation shown in the Examples section are indicative for the effects obtained for the second formulation. The second formulation has the same components and the ranges of the amounts of the second formulation are close to the specific amounts of the seventh formulation.

[0183] Alternative formulations can be based on the formulations of Tables 3 - 6 or 8, without including the gelling agents SiO2and / or TEOS. For example, alternative formulations include the gelling agent SiO2and are in gel form, without the inclusion of (supportive) gelling agent TEOS.

[0184] The procedure for preparing the formulations referred to in the previous Tables 2 - 8 is not disclosed in detail below, because the chemical components of the various formulations can be added to the sulfonic acid according to a variable order and nevertheless without altering the properties of the final solution. In fact, the different chemical components are solubilized without reactions intervening that are able to interfere with the phenomenon of the protonation of the proton acceptors.

[0185] BRIEF DESCRIPTION OF THE FIGURES

[0186] The invention can be better understood and implemented with reference to the attached pictures illustrating exemplary and non-limiting forms of implementation, in which:

[0187] Figures 1A and IB show examples of a case having a clinical wound similar to a pilonidal sinus;

[0188] Figure 2 shows an example of a topical site of herpes labialis which was effective treated using the method described;

[0189] Figures 3 A and 3B show an example of a case having a perinail granuloma; Figures 4A and 4B show an example of a case having onicocriptosis;

[0190] Figures 5A and 5B show another example of a case having onicocriptosis.

[0191] MEDICAL INDICATIONS

[0192] General description of methods for use of the composition in a method of the treatment or management of various diseases or conditions selected from one or more of fistula, pilonidal sinus, herpes labialis, pyogenic granuloma, fungal nail infection and and onicocriptosis.

[0193] Fistula

[0194] The treatment of fistulas, such as anal fistulas, is usually complex and burdened by a high rate of failure and / or relapses. This is related to the fact that fistulas, although surgically cleaned, have a high probability of reinfection. Additionally, cleaning fistulas is more cumbersome than other sites of infection as the fistulas are not easily accessible for treatment and removal of the infections. Especially, when fistulas are infected including necrotic infected tissue, the treatment of the site of infection becomes even more difficult.

[0195] The compositions according to the invention are proposed as an alternative to the standard treatment of fistula, such as anal fistulas, thanks to its characteristics:

[0196] • Being in liquid form, and preferably gel form, it can be easily introduced into the fistula and enter all the cavities / fistulous tracts connected to the main fistula;

[0197] • It has been found that based on its gel form, the composition is suitably retained within the fistula and may act locally within the fistula, while reducing the risk of overspilling the composition outside the fistula.

[0198] • It therefore allows a complete sterilization of the fistulous complex present.

[0199] The proposed treatment methodology is as follows:

[0200] • The treatment can be performed in any surgical clinic

[0201] • Perform adequate anesthesia;

[0202] • Aspirate the composition into a syringe; the amount of composition to be used should be calculated based on the size of the fistula. Ideally the fistula should be completely filled with the composition, but not overfilled;

[0203] • Care must be taken not to get the composition out of the fistula; • Through a special catheter, insert the composition inside the cavity and let it act, for example for 60 seconds;

[0204] • Using a special catheter, rinse and vacuum, removing the denatured material from the composition.

[0205] • The patient must then be followed over time; the treatment can be repeated, if deemed necessary by the clinician.

[0206] The potential benefits of treating fistulas with compositions according to the invention are as follows:

[0207] • Simplification of the procedure;

[0208] • Very fast and effective overall treatment of fistula infections including any necrotic tissue within short time (seconds);

[0209] • Safe application of composition by controllably applying the composition inside the fistula, in particular using gel composition;

[0210] • One time application of composition is often sufficient to obtain successful treatment;

[0211] • Increase in treatment success rates;

[0212] • Speeding up healing times;

[0213] • Cost reduction.

[0214] In certain embodiments, the fistula is selected from one or more of: anal fistula, colovaginal fistula, urinary tract fistula, vesicouterine fistula, vesicovaginal fistula, urethrovaginal fistula, enteroenteral fistula, cutaneous fistula, enterocutaneous fistula and colocutaneous fistula.

[0215] In one embodiment, wherein the fistula is vestibular fistula / oroantral fistula and wherein the composition comprises ethanesulfonic, methanesulfonic, 1 -propanesulfonic and 4-dodecylbenzenesulfonic acids or a mixture thereof.

[0216] In certain embodiments, the method comprises applying an amount of the composition into the fistula, wherein the amount of the composition is selected based on the size of the fistula. Preferably wherein the amount of the composition is selected to be sufficient to fill the fistula completely, more preferably without overfilling the fistula.

[0217] In preferred embodiments, the composition is applied into the fistula using a syringe. Pilonidal sinus

[0218] The treatment of sinus pilonidalis is usually surgical. It is about opening the sinus from the skin to the underlying cavity; clean well and remove the infected tissues; then the cavity is left open and healed a little at a time (for second intention)

[0219] This involves a high risk of re-infection and the need for the patient to be medicated 2-3 times a week with consequent impaired quality of life and prolonged suffering.

[0220] The compositions according to the invention are proposed as an alternative to the standard treatment of sinus pilonidalis thanks to its characteristics:

[0221] • Being in liquid or gel form it can be inserted into the sinus pilonidalis using a simple buttoned needle and reach the underlying cavity;

[0222] • Its strong antibacterial activity allows to rapidly sterilize the sinus pilonidalis;

[0223] • Its ability to denature all biological materials within the sinus pilonidalis allows a deep but non-invasive cleaning activity.

[0224] There are two possibilities of treatment of the pilonidal sinus with the compositions according to the invention; one non-invasive (non-surgical) and one more invasive (with surgical incision). The clinician chooses which methodology to use based on the clinic of the sinus pilonidalis (size; infection seriousness; patient type) and based on the location in which he is acting.

[0225] The non-surgical treatment methodology is as follows:

[0226] • The treatment can be performed in any clinical setting;

[0227] • Perform suitable anesthesia based on the size of the sinus and the characteristics of the patient;

[0228] • Aspirate the compositions according to the invention into a syringe; the amount of composition to be used should be calculated according to the size of the sinus pilonidalis. Ideally the cavity should be completely filled by the composition;

[0229] • Using a buttoned needle, insert the composition inside the cavity and let it act, for example for 60 seconds; • Using a syringe and buttoned needle, perform repeated washings of the sinus pilonidalis with physiological solution, trying to get out, even with squeezing maneuvers, the denatured material as a consequence of compositions’ activity;

[0230] • The patient should then be followed over time; the treatment can be repeated, even several times, if the purulent secretions from the sinus pilonidalis persist and / or recur or in the follow-up.

[0231] The surgical treatment methodology is as follows:

[0232] • The treatment must be carried out in the operating room;

[0233] • Perform suitable anesthesia based on the size of the sinus and the characteristics of the patient;

[0234] • Engrave in pilonidal sines along its entire course and up to the cavity;

[0235] • Remove foreign and / or infected materials;

[0236] • Apply the composition according to the invention to the walls of the sinus and cavity for the usual 60 seconds;

[0237] • Wash well with physiological solution, removing all the desiccated material;

[0238] • After drying well, apply vacuum therapy equipment using a foam as a filler;

[0239] • Change the vacuum therapy dressing according to the following schemes until the residual surgical wound is granulated;

[0240] • Then continue standard dressings until complete healing.

[0241] The potential benefits of treatment with the compositions according to the invention of sinus pilonidalis are as follows:

[0242] • Increase in treatment success rates;

[0243] • Speeding up healing times;

[0244] • Cost reduction.

[0245] In certain embodiments, the method for treatment or management of the pilonidal sinus comprises a surgical procedure comprising a surgical incision step.

[0246] In preferred embodiments, the composition is applied into a cavity and / or walls of the pilonidal sinus after the surgical incision step. T1

[0247] In certain embodiments, the method for treatment or management of the pilonidal sinus is a non-surgical procedure. In preferred embodiments, the composition is applied into a cavity and / or walls of the pilonidal sinus.

[0248] In preferred embodiments, the composition is applied into the pilonidal sinus using a syringe.

[0249] Herpes labialis

[0250] A herpes labialis is commonly known as cold sore and characterized by the development of a rash in the skin or mucous membranes, primarily in the lips, which causes erythema and blisters frequently accompanied by a burning sensation of pain. It is caused by the herpes simplex virus (usually herpes simplex virus type 1 (HSV-1) and occasionally herpes simplex virus type 2 (HSV-2).

[0251] The treatment of herpes labialis using the composition of the invention is described in detail in the exemplary section.

[0252] Pyogenic granuloma

[0253] It is a very frequent pathology.

[0254] The treatment of this pathology is usually the competence of podiatrists who, however, cannot perform surgical treatments or perform infiltration anesthesia procedures in some countries. As a result, patients are repeatedly treated with partial, ineffective treatments, with consequent lengthening of the suffering and costs.

[0255] In addition, improper antibiotic treatments are often administered systemically, contributing to the problem of antibiotic resistance.

[0256] The composition according to the invention are proposed as an alternative to the standard treatment of periungual infections / granulomas thanks to its ability to instantly disect and destroy granulomas and to sterilize the infected nail bed.

[0257] The pathology of periungual infections / granulomas (or nail bed pyogenic granuloma) may occur together with an ingrown nail (Onicocriptosis), and may also occur independently.

[0258] The proposed treatment methodology is as follows:

[0259] • The treatment can be carried out in any podiatry;

[0260] • It is usually sufficient to perform a contact / surface anesthesia using a lidocaine cream or spray; • In case an ingrown nail is present, the treatment comprises a step of removing the ingrown nail piece before applying the composition;

[0261] • Apply the composition for 60 seconds;

[0262] • Then rinse with saline solution;

[0263] • Wait a few minutes for the granuloma to be completely dissected;

[0264] • Using a dry gauze, remove the granuloma that will easily detach from the nail fundus and without causing bleeding;

[0265] • Then perform standard dressings until complete healing..

[0266] The potential benefits of the composition according to the invention treatment of periungual infections / granulomas are as follows:

[0267] • Simplification of the procedure;

[0268] • Possibility of carrying out the treatment even by non-medical personnel;

[0269] • Increase in treatment success rates;

[0270] • Speeding up healing times;

[0271] • Cost reduction;

[0272] • No need for systemic antibiotic treatment.

[0273] In certain embodiments of the method, the pyogenic granuloma occurs on skin and / or mucous membranes, preferably on one or more sites selected from the group consisting of periungual skin (periungual pyogenic granuloma), subungual site (subungual pyogenic granuloma), oral cavity (oral pyogenic granuloma), eyelid (conjunctival pyogenic granuloma), face and limbs.

[0274] Fungal nail infection

[0275] This is a very frequent pathology and difficult to eradicate.

[0276] It has very significant aesthetic implications for patients who are ashamed to show their feet. For treatment, the patient is often given antibiotic treatments for both systemic. These treatments are often prolonged for weeks if not months. These drugs are also expensive and potentially burdened by serious, even deadly side effects.

[0277] The compositions according to the invention are proposed as an alternative to the standard treatment of nail mycoses thanks to its ability to instantly kill the fungi responsible for the disease. The proposed treatment methodology is as follows:

[0278] The treatment can be carried out in any podiatry setting.

[0279] • No form of anesthesia is necessary;

[0280] • First, remove the visibly infected piece of nail up to the edge with the healthy nail segment;

[0281] • Then apply the composition both on the nail bed and on the cutting margin of the residual nail;

[0282] • Since in these situations the amount of water present in these tissues (nail bed and margins of the residual nail) is very low, the composition is left to act for more than 60 seconds; the application time is about 5 minutes.

[0283] • Then rinse with saline solution;

[0284] • Then wait for the spontaneous growth of the healthy nail, or reconstruct the missing piece of nail with the available technologies.

[0285] The potential benefits of the composition of the invention treatment of ungual mycoses are as follows:

[0286] • Simplification of the procedure;

[0287] • Possibility of carrying out the treatment even by non-medical personnel;

[0288] • Increase in treatment success rates;

[0289] • Speeding up healing times;

[0290] • Cost reduction;

[0291] • No need for systemic antibiotic treatment.

[0292] Onicocriptosis

[0293] Onicocriptosis is a painful pathology at the nail bed. Nail removal, full or partly is the most common treatment. The removal of the nail can create infection of the nail bed and the extremity attached. The treatment according to the invention is described in the exemplary section. COMPOSITIONS

[0294] The invention concerns compositions containing a sulphonic acid having the general formula (A):

[0295] o

[0296] R-S-OH

[0297] i i

[0298] O

[0299] (A)

[0300] wherein R is an alkyl group, preferably a methyl or ethyl or propyl or an arene group, preferably a benzene group, wherein the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring.

[0301] In certain embodiments, the sulphonic acid is selected from: methanesulfonic acid, ethanesulfonic acid, 1 -propanesulfonic acid, 4- dodecylbenzenesulphonic acid, phenolsulfonic acid, guaiacolsulfonic acid and mixtures thereof.

[0302] In preferred embodiments, the sulphonic acid is selected from: methanesulfonic acid, ethanesulfonic acid, 1 -propanesulfonic acid, 4- dodecylbenzenesulphonic acid, and mixtures thereof.

[0303] Preferably, the composition further comprises a non-aqueous proton acceptor.

[0304] Preferably, the non-aqueous proton acceptor is at least one component, selected from: dimethyl sulfoxide, isopropyl alcohol, 3 -methoxy-3 -methyl- 1 -butanol, propylene carbonate, anhydrous sodium carbonate, ethylenediaminetetraacetic acid tetrasodium salt, sodium gluconate, polyethylene glycol, preferably anhydrous dimethylsulfoxide and mixtures thereof. More preferably, the non-aqueous proton acceptor consists essentially of dimethyl sulfoxide.

[0305] Optionally, gelling agents can also be used, such as anhydrous silicon dioxide (SiO?), tetraethoxysilane (TEOS). These gelling agents have additional proton acceptor functionality. Preferably, the non-aqueous proton acceptor is a liquid at room temperature.

[0306] More preferably, the non-aqueous proton acceptor is a solvent for the sulphonic acid of the composition.

[0307] Most preferably, the non-aqueous proton acceptor is or comprises anhydrous dimethyl sulfoxide. In particular, the composition contains less than 5 wt.% water, preferably is substantially free from water. A composition substantially without water content is preferred.

[0308] In embodiments, the sulphonic acid has pKa between -1.3 and -0.5.

[0309] In embodiments, the sulphonic acid is selected from methane-sulphonic acid, ethane-sulphonic acid, propane-sulphonic acid, alkylbenzenesulphonic acid having general formula (I).

[0310]

[0311] Formula 1.

[0312] In embodiments, the composition further comprises another sulphonic acid according to general formula (A), wherein R is an arene group, preferably a benzene group, wherein the benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, such as methoxy, wherein the substituent is preferably alkyl having a number of carbon atoms from 1 to 20 and the alkyl chain is at position 3 or 4 of the benzene ring, wherein the sulphonic acid and the other sulphonic acid are different. The composition contains a mixture of the sulphonic acid according to general formula (A) and another sulphonic acid according to general formula (A).

[0313] In embodiments, the amount of sulphonic acid, or the total amount of sulphonic acids, is 50% to 95% w / w, preferably 60% to 90% w / w, more preferably 70% w / w to 90% w / w, based on the total weight of the composition.

[0314] In embodiments, the non-aqueous proton acceptor is in an amount of 5% to 50% w / w, preferably 10% to 40% w / w, even more preferably 10% to 20% w / w, based on the total weight of the composition.

[0315] Preferably, the composition contains substantially no sulphuric acid.

[0316] In embodiments, wherein the use comprises removing the composition from the topical sites of infection within a time between 1 second - 3 minutes after applying the composition. In particular embodiments, the use comprises removing the composition from the topical sites of infection within a time between 1 second - 3 minutes, preferably within 2 minutes, more preferably within 1 minute, after applying the composition. This use is preferred in case the sulphonic acid has a pKa comprised between -1.3 and -0.5. By selecting the non-aqueous proton acceptor and adjusting the relative amounts of sulphonic acid and non-aqueous proton acceptor the application time window can be adjusted.

[0317] In a particular embodiment, the invention concerns an alkylbenzenesulphonic acid having general formula (I)

[0318]

[0319] Formula (I).

[0320] In formula (I) n is an integer from 0 to 20, preferably from 1 to 20, preferably from 2 to 13. Preferably, n equals 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. The alkyl chain can be at position 3 or 4 of the benzene ring.

[0321] Preferably, the alkylbenzenesulphonic acid of formula (I) has an acid dissociation constant pKa between -1 and -0.5. In a preferred embodiment, the alkyl chain has n = 0, 1 or 11. In a preferred embodiment, the alkyl chain is at position 4 of the benzene ring. In a preferred embodiment, the alkyl chain has n from 0 to 20, preferably from 1 to 13, and is positioned at position 4 of the benzene ring. In one embodiment of the invention, n equals 0, 1, or 11 and the alkyl chain is at position 3 or 4 of the benzene ring, preferably at position 4.

[0322] In a preferred embodiment, the alkylbenzenesulphonic acid is 4-dodecyl-benzene-sulphonic acid (which among organic sulphonic acids is one of the weakest):

[0323]

[0324] having an acid dissociation constant, in the order of 3. This means that about 57% of the acid form remains undissociated upon contact with the biofilm. The neutral form therefore has the ability to easily penetrate the non-polar parts and in particular the lipid components of the biofilm. At the same time, the dissociation occurring in presence of water produces a dehydrating effect thanks to the high hydration energy of the proton, able to sequester water molecules present in the biofilm or infected tissue and in the microbial species it contains. The effectiveness of action of dodecylbenzenesulphonic acid most likely results from the delicate and unpredictable balance between these two actions.

[0325] This effect was observed with particular reference to 4-dodecyl-benzene-sulphonic acid but is transferrable to all weak alkylbenzenesulphonic acids, preferably with an acid dissociation constant between 2 and 10. The alkylbenzenesulphonic acid of formula (I) therefore exerts a disinfectant action on topical sites of infection, providing a removal of the biofilm and necrotic and / or infected tissues but without causing side effects, such as the burning sensation. Consequently, the weak sulphonic acid can be applied autonomously by the patient, without the intervention of specialized staff, such as doctors and nurses, thus overcoming the limits of known compositions.

[0326] This action is due to the surfactant capacities of the acid that make it able to penetrate the biofilm present on the site of infection allowing for the detachment of necrotic tissues and the complete removal through simple washing with water. Furthermore, the surfactant action together with the effect of acid dissociation contributes to the elimination of microorganisms, in particular bacteria and fungi, present in the biofilm.

[0327] In another aspect, the invention concerns a composition comprising a sulphonic acid of formula (A), preferably an alkylbenzenesulphonic acid of formula (I), as active principle, preferably in combination with suitable non-aqueous co-formulants, preferably co-formulants acting as nonaqueous proton acceptors and able to adjust, in particular to reduce, the acidity of the composition.

[0328] The composition according to the invention is able to break down / remove the biofilm and necrotic tissues from infected areas within few tens of seconds from the application. The composition can be applied directly to the area to be treated by any mean suitable to allow its distribution. After a contact time of a few minutes, the composition can be readily removed from the topical site by using simple gauze and washing the topical site with a physiological solution or with a stream of sterile water.

[0329] Therefore, by applying the composition according to the invention to a topical site of infection it is possible to obtain the same effects obtainable through one surgical procedure, without however the well-known drawbacks associated with this latter procedure. This new and effective therapeutic possibility is usable, with significant benefit also directly by the patient, in cases of mild, medium and high severity.

[0330] The composition according to the invention, comprising the sulphonic acid of formula (A), preferably the alkylbenzenesulphonic acid of formula (I), can be formulated as a solution or as a gel.

[0331] A surprisingly unexpected property exhibited by the composition according to the invention is that this one is able to act on the biofilm and on necrotic or infected tissues, causing their disintegration and allowing for their easy and painless removal with a simple gauze and a stream of water or saline solution after a few minutes from application and thus avoiding complicated, painful and expensive surgical procedures.

[0332] The action of the composition is evidently due to the penetrating and surfactant power of the alkylbenzenesulphonic acid towards the components of the biofilm and it is also due to the subsequent release of hydrogen ions (H+) or protons which, having a high enthalpy of hydration (-1130 KJ / mole), cause dehydration of the microbial species that make up the biofilm or proliferate in infected tissues. This mechanism of action occurs regardless of the microbial species present and makes the composition according to the invention active against any microbial species, be it bacterial, fungal or viral.

[0333] Furthermore, the inventors have foreseen the use of the sulphonic acid of formula (A), in particular the alkylbenzenesulphonic acid of formula (I), in combination with small quantities of solvents or non-aqueous proton acceptors which allow to adjust, and more exactly to reduce, the acidity of the composition according to the invention. By lowering the concentration of protons released by the sulphonic acid, the latter can be efficiently employed in the also autonomous treatment of topical sites in which the biofilm is present, to yield the desired disruptive effect while eliminating the infective microbial species, without producing any damage to the healthy surrounding tissues. In one embodiment, the composition comprises sulphonic acid, preferably alkylbenzenesulphonic acid, in a quantity between 50% and 90% w / w, preferably between 60% and 80% w / w.

[0334] Preferably, the composition further comprises a solvent acting as non-aqueous proton acceptor selected from: dimethyl sulphoxide, isopropyl alcohol, 3 -methoxy-3 -methyl- 1 -butanol, and propylene carbonate, present in the composition in a quantity between 10% and 50% (w / w), preferably between 20% and 40% w / w. Optionally, a minor amount of water is added as a solvent for the sulphonic acid.

[0335] In one embodiment, the composition comprises a mixture of solvents selected among the ones listed above. In this, the concentration from 10% to 50% or 20% to 40% will be divided among the solvents used.

[0336] In one embodiment, the composition is formulated as a gel. In in this case, amorphous silica is added to the diluted solutions of sulphonic acid, in an amount between 1 and 10% (w / w) to obtain the product in gel form. In a further embodiment of the composition according to the invention - the rheology of the gel is optimized by addition of tetraethoxy silane, which acts as a cross-linking agent.

[0337] The preparation procedure of the different formulations is not described in details below, as the chemical components of the various formulations can be added to sulphonic acid following a variable order and yet without altering the properties of the final solution.

[0338] By way of exemplary, but non-limiting, example of the invention, procedures for the treatment of topical sites of infection based on the use of the composition according to the invention are described in the following examples.

[0339] EXAMPLES IN VIVO / PATIENT DATA

[0340] Fistula

[0341] The following is the first observational data on three patients with necrotizing fasciitis having a fistula within the foot wound area.

[0342] Diabetic foot ulcers (DFUs) are a leading cause of lower-limb amputation and diabetes-related mortality. They affect up to 25% of patients with diabetes during their lifetime. Necrosis and infection perpetuate a self-sustaining cycle of tissue destruction, systemic inflammation, and metabolic dysregulation. Necrotizing fasciitis is the most severe manifestation of this infection, with mortality rates exceeding 20%. This observational pilot trial studied three patients with severe diabetic foot infections, including necrotizing fasciitis.

[0343] At admission (Day 0), patients underwent standard initial management. This management included pressure relief, drainage of exudate, and irrigation of accessible tissues. The composition according to Table 8 was applied intraoperatively to eliminate residual bacterial and necrotic load. Subsequent management followed conservative surgical standards of care.

[0344] To gain access to the infected areas of the fistula channels (located below the skin of the foot), the composition according to Table 8 was applied manually and using a syringe with a canula to access the fistula channels. The treatment methodology is as follows:

[0345] • Aspirate the composition into a syringe; the amount of composition to be used is estimated based on the size of the fistula. Ideally the fistula is completely filled with the composition, but not overfilled;

[0346] • Care must be taken not to get the composition out of the fistula;

[0347] • Through a special catheter, insert the composition inside the cavity and let it act, for example for 60 seconds;

[0348] • Using a special catheter, rinse and vacuum, removing the denatured material from the composition.

[0349] • The patient was then followed over time.

[0350] The following in Table 9 is the data of the three patients:

[0351] Table 9: patient data

[0352]

[0353] The following (Table 10A) shows the indicative levels determined for these three patients for CRP: Table 10A

[0354]

[0355] CRP (C-reactive protein) level is determined according to standard method. C-reactive protein (CRP) is a widely used serum inflammatory marker.

[0356] The following (Table 10B) shows the indicative levels determined for these three patients for WBC:

[0357] Table 10B

[0358]

[0359]

[0360] WBC is white blood cells count as determined according to standard method.

[0361] The following (Table IOC) shows the indicative levels determined for these three patients for creatine:

[0362] Table IOC

[0363]

[0364] The creatine level is determined according to standard method. Pilonidal sinus

[0365] 5 cases were treated with an age ranging from 16 to 35 years. 3 cases were treated using the surgical approach, using negative pressure wound therapy NPWT as post treatment. 2 cases were treated using the composition according to Table 8 according to the following procedure: 1) Direct introduction of the composition according to Table 8 inside the sinus infected using a syringe, thereby controllably applying an amount of the composition to fill the cavity of the sinus;

[0366] 2) Using a syringe and buttoned needle, perform repeated washings of the sinus pilonidalis with physiological solution, trying to get out, even with squeezing maneuvers, the denatured material as a consequence of compositions’ activity; and / or

[0367] 3) Than saffron with silver medicated gouze;

[0368] 4) Post treatment of wound using negative pressure wound technology (NPWT) in agreement to the post treatment as described in Hermans MHE (2022) Combining an Acidic Compound and NPWT: Debridement and Granulation in Leg and Foot Ulcers. Ann Case Report. 7: 1101. DOI: 10.29011 / 2574-7754.101101;

[0369] 5) Healing in all cases was obtained within 2 months.

[0370] Figures 1A and IB show examples of a case having a clinical wound similar to a pilonidal sinus, wherein Figure 1A shows the topical site of infection before the treatment with the composition according to Table 8 and Figure IB shows the topical site after the treatment with the composition according to Table 8, wherein the healing of the site is shown.

[0371] Herpes labialis

[0372] In total 5 cases of herpes labialis were treated as following:

[0373] 1) Application of the composition according to Table 8 for 30 seconds; followed by washing with sterile water

[0374] 2) Application at least twice daily of a moisturizing cream.

[0375] 3) Healing in all cases in few days.

[0376] Safe application of the composition is provided by a controllable topical administrating and maintaining the composition at the wound location, which is infected by herpes labialis. In particular by using the gel composition, which supports controllable topical administration of a suitable amount to cover the local wound and maintaining the composition at the wound location. Figure 2 shows an example of a topical site of herpes labialis which was effectively treated using the method described above.

[0377] Pyogenic granuloma

[0378] First example of clinical data: 20 cases were treated, age ranging from 14 to 72 years. All case treated as described in the methods.

[0379] 1) Application of the composition according to Table 8 (referred to as the seventh formulation);

[0380] 2) Spontaneous immediate detachment of the granulomas without bleeding nor need for using a scalpel.

[0381] 3) Healing in all cases was obtained within 7-10 days.

[0382] Peri- and subungual pyogenic granuloma (PG) is a common pathology which frequently involves the periungual tissues and the bed nail. PG is a common and benign vascular proliferation that develops on the skin or subcutaneous tissue. Non-surgical treatment is topical application of steroids and antibiotics to reduce the inflammatory process. The purpose of this work is evaluating chemical debridement of nail granuloma using composition according to Table 8.

[0383] Second example of clinical data: 7 patients are included with at least one periungual granuloma from onychogryphosis present for more than three weeks. Granuloma is cleaned and then treated with the composition according to Table 8, a cotton swab was used to direct the gel, after 60 seconds the composition is rinsed off with sterile water.

[0384] Results / Discussion: Mean age is 20,1 (range: 18-24), 5 patients were male. 5 patients were treated in a conservative pain treatment and 2 patients with a topical anastatic. At 1 week follow-up all lesions showed almost complete regression.

[0385] Within PG there is often significant bacterial infection and necrotic tissue. As PG is a benign vascular proliferation that causes infection in the nail bed, infection is to be removed and this series shows signs that the compositions according to the invention is effective in management of the regression of PG. Figures 3 A and 3B show an example of a case having a perinail granuloma, wherein Figure 3 A shows the topical site of the perinail granuloma before the treatment with the composition according to Table 8 and Figure 3B shows the topical site of the perinail granuloma after the treatment with the composition according to Table 8, wherein the healing of the site is shown.

[0386] Fungal nail infection

[0387] 1) Resection of the portion of the nail infected close to the border with healthy nail;

[0388] 2) Application of the composition according to Table 8 for up to 5 minutes (related to a minimal amount of water present in this situation); no anesthesia is required for this application

[0389] 3) Washing with water

[0390] 4) No medication needed thereafter

[0391] Onicocriptosis

[0392] Onicocriptosis is a painful pathology at the nail bed. Nail removal, full or partly is the most common treatment. The removal of the nail can create infection of the nail bed and the extremity attached. Treatment of the nail bed to remove infection is evaluated in this case series with the use of the composition according to Table 8.

[0393] Method: 5 patients have been included that suffer from onicocriptosis and nail bed infection. Mean age of the patients 25,4 (range 18-48) including 3 female. At first visit Phenolization is performed to remove the piece of nail that causes the onicocriptosis. One week later the composition according to Table 8 is performed to remove infection.

[0394] The advantage of the composition according to Table 8 compared to simple mechanical cleaning of the lesion seems less pain for the patient, greater compliance and simple home management. The antimicrobial effect of the composition contributed to reducing post-surgical complications of the site of infections, favoring a faster healing.

[0395] Figures 4A and 4B show an example of a case having onicocriptosis, wherein Figure 4A shows the topical site of the onicocriptosis before the treatment with the composition according to Table 8 and Figure 4B shows the topical site of the onicocriptosis after the treatment with the composition according to Table 8, wherein the healing of the site is shown. Figures 5A and 5B show another example of a case having onicocriptosis, wherein Figure 5A shows the topical site of the onicocriptosis before the treatment with the composition according to Table 8 and Figure 5B shows the topical site of the onicocriptosis after the treatment with the composition according to Table 8, wherein the healing of the site is shown.

[0396] Conclusion

[0397] The application of the compositions according to the invention containing one of MSA, ESA and DBSA diluted with a non-aqueous proton acceptor, such as anhydrous DMSO, as shown in the Tables 2 - 8, provided in all cases a complete restoration of the tissues in the topical sites of infection, promoting its healing. The treatment protocol described above can potentially be applied to all patients, thus avoiding complicated, expensive and potentially risky surgical procedures. Furthermore, the treatment with the composition according to the invention can reduce the need for antibiotic therapies, which are substantially expensive and associated with the increasingly emerging phenomenon of antibiotic resistance.

Claims

42CLAIMS1. A composition for use in a method for the treatment of a fistula, said composition comprising methanesulfonic acid, wherein the composition further comprises a nonaqueous proton acceptor, and wherein preferably the amount of methanesulfonic is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition.

2. The composition for use according to claim 1, wherein the fistula is selected from one or more of: anal fistula, colovaginal fistula, urinary tract fistula, vesicouterine fistula, vesicovaginal fistula, urethrovaginal fistula, enteroenteral fistula, cutaneous fistula, enterocutaneous fistula and colocutaneous fistula.

3. The composition for use according to claim 2, wherein the fistula is cutaneous fistula.

4. The composition for use according to any one of claims 1-3, wherein the method comprises applying an amount of the composition into the fistula, wherein the composition is applied into the fistula using a syringe, wherein the amount of the composition is selected based on the size of the fistula, and wherein the amount of the composition is selected to be sufficient to fill the fistula completely, more preferably without overfilling the fistula.

5. A composition for use in a method for treatment of a pilonidal sinus, said composition comprising methanesulfonic acid, wherein the composition further comprises a nonaqueous proton acceptor, and wherein preferably the amount of methanesulfonic is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition.

6. The composition for use according to claim 5, wherein the method for treatment of the pilonidal sinus comprises a surgical procedure comprising a surgical incision step or wherein the method for treatment of the pilonidal sinus is a non-surgical procedure, wherein the composition is applied into a cavity and / or walls of the pilonidal sinus, optionally after the surgical incision step, optionally wherein the composition is applied into the pilonidal sinus using a syringe.

437. A composition for use in a method for the treatment of a pyogenic granuloma, said composition comprising methanesulfonic acid, wherein the composition further comprises a non-aqueous proton acceptor, and wherein preferably the amount of methanesulfonic is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition.

8. The composition for use according to claim 7, wherein the pyogenic granuloma occurs on skin and / or mucous membranes, preferably on one or more sites selected from the group consisting of periungual skin (periungual pyogenic granuloma), subungual site (subungual pyogenic granuloma), oral cavity (oral pyogenic granuloma), eyelid (conjunctival pyogenic granuloma), face and limbs.

9. The composition for use according to claim 7, wherein the pyogenic granuloma is periungual pyogenic granuloma.

10. The composition for use according to claim 7, wherein the pyogenic granuloma is subungual pyogenic granuloma.

11. A composition for use in a method for the treatment of a herpes labialis, said composition comprising methanesulfonic acid, wherein the composition further comprises a nonaqueous proton acceptor, and wherein preferably the amount of methanesulfonic is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition.

12. The composition for use according to any one of the preceding claims, wherein the treatment comprises contacting the composition for at least 20 seconds, preferably for at least 30 seconds, at least 40 seconds, at least 50 seconds, about 60 seconds, less than 120 seconds, or less than 90 seconds, at the site of the intended treatment condition.

13. A composition for use in a method for the treatment of a fungal nail infection, said composition comprising methanesulfonic acid, wherein the composition further comprises a non-aqueous proton acceptor, and wherein preferably the amount of sulphonic acid or the total amount of sulphonic acids is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition.4414. The composition for use according to claim 13, wherein the fungal nail infection is nail mycosis (onychomycosis).

15. A composition for use in a method for the treatment of onicocriptosis, the composition comprising methanesulfonic acid, wherein the composition further comprises a nonaqueous proton acceptor, and wherein preferably the amount of methanesulfonic is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition.

16. The composition for use according to any one of claims 13 - 15, wherein the treatment comprises contacting the composition for at least 2 minutes, preferable for at least 3 minutes, at least 4 minutes or about 5 minutes, at the nail.

17. The composition for use according to any one of the preceding claims, wherein the nonaqueous proton acceptor is selected from: dimethyl sulfoxide, isopropyl alcohol, 3- m ethoxy-3 -methyl- 1 -butanol, propylene carbonate, anhydrous sodium carbonate, ethylenediaminetetraacetic acid tetrasodium salt, sodium gluconate, polyethylene glycol and mixtures thereof.

18. The composition for use according to any one of the preceding claims, wherein the proton acceptor is or consists essentially of dimethyl sulfoxide.

19. The composition for use according to any one of the preceding claims, wherein the treatment comprises applying the composition to the site of intended treatment using buttoned needle or a catheter.

20. The composition for use according to any one of the preceding claims, wherein the treatment further comprises washing the application site using saline solution (0.9% NaCl solution).

21. The composition for use according to any one of the preceding claims, wherein the composition contains less than 5 wt.% water, preferably is substantially free from water.

22. The composition for use according to any one of the preceding claims, wherein the composition contains substantially no free sulphuric acid.

23. The composition for use according to any one of the preceding claims, wherein said methanesulfonic acid is anhydrous sulphonic acid.

24. The composition for use according to any one of the preceding claims, wherein the amount of methanesulfonic acid is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition.

25. The composition for use according to any one of the preceding claims, wherein the proton acceptor is soluble in methanesulfonic acid, or forms a liquid mixture with methanesulfonic acid.

26. The composition for use according to any one of the preceding claims, wherein the proton acceptor is in an amount of 5% to 50% w / w, preferably 10% to 40% w / w, based on the total weight of the composition.

27. The composition for use according to any one of the preceding claims, wherein the composition is a liquid composition.

28. The composition for use according to any one of the preceding claims, wherein the composition is a gel composition.

29. The composition for use according to any one of the preceding claims, wherein the composition comprises a gelling agent selected from anhydrous silicon dioxide, tetraethoxysilane or mixture thereof.

30. The composition for use according to any one of the preceding claims, wherein the composition is selected from:(i) a first formulation comprising the following components:(ii) a second formulation comprising the following components:(vii) a seventh formulation comprising the following components:

31. The composition for use according to any one of the preceding claims, wherein the use comprises providing a kit comprising:a. the composition comprising methanesulfonic acid, wherein the composition further comprises a non-aqueous proton acceptor, wherein the amount of methanesulfonic acid is 50% to 95% w / w, preferably 60% to 90% w / w, based on the total weight of the composition;b. an applicator, which is a syringe or a catheter;c. an instruction for application of the composition.

32. The composition for use according to claim 31, wherein the said composition is in a vial, preferably one vial or more than one vials.

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