Compositions for Acute and Chronic Wounds

Abstract

The present invention relates to a compound of general formula (A) for use in removing bacterial biofilms and / or necrotic or infected tissue from acute or chronic, preferably chronic, skin lesions or from the oral cavity or for use in disinfecting acute or chronic skin lesions JPEG2024536395000017.jpg42149 wherein R is an arene group, preferably a benzene group, and the arene group or the benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, e.g., methoxy, and the substituents are preferably alkyl having a number of 1 to 20 carbon atoms, and the alkyl chain is in the 3- or 4-position of the benzene ring.

Description

FIELD OF THEINVENTION

[0001] The present invention relates to compositions which can be used in particular by medical staff (doctors / nurses) or also directly by the patients themselves (or their caregivers) for cleaning and / or disinfecting both acute and chronic skin wounds and for the removal of biofilms present in superficial body lesions, in particular wounds and chronic ulcers, or for the removal of necrotic or infected tissue from the oral cavity, in particular periodontal pockets, peri-implant pockets or from wounds. [Background technology]

[0002] It is well known that both acute and chronic skin wounds contain microorganisms, especially bacteria, that replicate and cause a persistent inflammatory response. In chronic lesions, the continued presence of viral microorganisms leads to a severe and persistent inflammatory response, which ultimately causes damage to the host organism. In fact, there is a continuous production of inflammatory mediators and a constant migration of neutrophil granulocytes, which releases cytolytic enzymes and free radicals into the wound, which are the main cause of tissue damage. Furthermore, macrophages are inhibited, and as a result, chronic lesions are unable to auto-regenerate. Moreover, localized thrombosis can occur, and metabolic products with vasoconstrictive effects are released, which induce tissue hypoxia, causing further bacterial proliferation and tissue damage. Due to the considerable invasiveness of some infectious bacterial species, microbial components can be responsible for exacerbating the lesion and increasing the biofilm layer.

[0003] The term "biofilm" is defined as a thin layer of polysaccharide, nucleic acid, protein, lipid and glycoprotein materials produced by active but slowly replicating bacteria and attached to the lesion bed. Biofilms formed in infected wounds are responsible for delayed healing. In fact, in the presence of biofilms, conditions are created for individual microorganisms to interact with each other with nutrients and metabolic products exchanged, thus establishing a truly organized bacterial population. Thus, biofilms act as a protection against infection and may emerge in wounds as bacterial resistance, which may protect them from the action of antimicrobial agents, such as antibiotics and antiseptics. Usually, biofilms consist of multiple layers of microorganisms, and communication between microbial cells is an essential factor for the development and maintenance of the biofilm itself.

[0004] The term "chronic skin ulcer" defines a skin lesion that does not progress towards healing after at least 6 weeks of appropriate treatment. Regardless of the etiology (indeed, diabetic, venous, arteriopathy, vasculitic and post-traumatic chronic ulcers exist), chronic skin ulcers show several common pathogenic mechanisms that make them chronic. Among these pathogenic mechanisms, the best known are the excessive presence of inflammatory proteins (cytokines and proteases) in the exudate, the persistent colonization of the lesion base by pathogenic microorganisms, and the development of biofilms that make the lesion base inaccessible for drugs and dressings. These characteristics of chronic skin ulcers slow down or stop the autolytic process of removal of non-viable material, the proliferation of new blood vessels that are essential for the formation of granulation tissue, and the proliferation of dermal and epidermal cells.

[0005] Chronic skin ulcer, for example chronic skin ulcer of lower limbs, is a worldwide problem.In fact, it is estimated that 1.5% of the world population suffers from such pathology.Age is a significant risk factor, so the prevalence of said chronic skin ulcer is low in pediatric age and very high in elderly. In addition to those highlighted above with particular reference to the problem of chronic skin ulcers, it will be observed that the phenomenon of microbial proliferation also causes or is involved in pathologies related to the oral cavity, such as periodontal disease and peri-implantitis.

[0006] The term "periodontal disease" is defined as a group of inflammatory pathologies that attack the tooth-supporting tissues or periodontal system, and can be differentiated into superficial (gingiva) and deep (periodontal ligament, root cementum and alveolar bone) periodontal diseases. The most frequent causes of periodontal disease are microbial, especially bacterial, and the microorganisms involved are those normally present in bacterial plaque. Infection occurs when the normal equilibrium that keeps the tissues healthy is lost due to excessive bacterial proliferation and / or a decrease in the organism's defense mechanisms. If the inflammation is only superficial to the periodontal tissues, the clinical picture is gingivitis, whereas if (without appropriate treatment) the inflammation spreads beyond the gingival area and affects the deeper zones of the periodontium (alveolar bone, periodontal ligament and cementum), the clinical picture is periodontitis. Gingivitis attacks the gums near the teeth (marginal gingiva) and symptoms (which are completely reversible after appropriate therapeutic treatment) include redness of the gingival margin, edema and bleeding after mechanical stimulation. Periodontitis destroys the tooth-supporting system and is manifested by attachment and bone loss, pocket formation and gingival shrinkage. A typical sign of periodontitis is the formation of periodontal pockets associated with dental looseness. The destruction of the tooth-supporting tissues is irreversible in most cases. Gingivitis always precedes periodontitis, so it is possible to prevent periodontitis by preventing gingivitis.

[0007] Gingivitis and periodontitis are pathologies that are bacterial in nature but exhibit a multifactorial etiology, with the interaction of three common factors: host susceptibility, environmental factors and behavioral factors. Bacterial plaque is essential for the development of periodontal disease, but is influenced by its interaction with the host and by a number of local and systemic factors that influence the clinical course, such as diabetes. In Italy, periodontal disease affects approximately 60% of the population, particularly individuals between 35 and 44 years of age. This percentage includes both superficial forms (gingivitis, affecting the parts of the gums near the teeth or the marginal gums) and deep forms (periodontitis proper).

[0008] Treatment of periodontal disease must aim to stop the progression of the disease and prevent or reduce the occurrence of possible relapses. In particular, periodontitis treatment must take into account the multifactorial nature of the pathology and provide clinical treatments that can respond to the complexity of the problem. Control of pathogens is carried out and achieved by mechanical removal of supragingival or subgingival bacterial plaque (e.g. by curettes or ultrasonic devices) and by the possible use of local or systemic drugs. Among the pathogenic periodontal microorganisms, the following species are included in the number: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola.

[0009] From what has been highlighted above, it is clear that in order to effectively prevent periodontal disease, a reduction in the bacterial load in the oral cavity is necessary.

[0010] The term "peri-implantitis" defines an inflammatory process that attacks the tissue adjacent to an osseointegrated implant (an artificial root that acts as a support for a fixed dental prosthesis), resulting in the destruction and loss of alveolar bone tissue. The causes are variable and can be related both to the surgical procedure of implanting the prosthesis and to the accompanying bacterial infection. It should nevertheless be noted that bacterial pathogenic components exacerbate the problems with the surgical implantation of the prosthesis. To protect the osseointegration process, the administration of antibiotics and anti-inflammatory drugs, possible surgical treatment of the involved area (so-called curettage), as well as guided bone regeneration are used.

[0011] All procedures aim to eliminate bacteria from the surface of the implant, both blind techniques (i.e. without piercing the visible gums) and open surgery (i.e. piercing and lifting the gums). Blind technique procedures are less invasive but cannot involve bone regeneration and always require lifting of a gum flap. Moreover, blind technique procedures are procedures that are essentially performed in a "blind" way, and it is not possible to see and see if the microbial load in the treated area has actually been minimized.

[0012] The mechanical type of treatment provides for the use of curettes, sodium bicarbonate or powder jet devices, grinding machines (to remove all surface coils and roughness of the implant). Non-mechanical treatment provides for the use of antiseptic and antibiotic solutions, both as mouthwashes and compositions that slowly release the active principle. Lasers can be used to physically sterilize the surface.

[0013] The drawback of all procedures that are limited to the elimination of bacteria by chemical disinfection or by physical sterilization is that bacteria will recolonize the disinfected or sterilized areas, since bacteria are not only present on the implant but are virtually ubiquitous in the oral cavity.

[0014] It should also be noted that in both moderate to severe peri-implantitis and periodontitis, it is often necessary to achieve surgical treatment (debridement under local anesthesia) to remove the infected tissue adjacent to the implant or tooth. Nevertheless, it is necessary to accompany debridement with the administration of antibiotics and antiseptics, since surgical procedures alone cannot remove the biofilm that forms the lesion from the infection.

[0015] In the context of oral pathology, aphthae must also be mentioned because of their particular frequency. The term "aphthae" defines painful ulcers caused by damage to the mucous membrane inside the oral cavity. These ulcers form periodically and may heal completely between one episode and the next. In the majority of cases, individual aphthae have a duration that varies between 8-10 days. The majority of aphthae appear on the surfaces of the non-keratinized epithelium of the mouth, more specifically, everywhere except the adherent gingiva, the hard palate, and the underside of the tongue. Symptoms of aphthae vary from mild discomfort to difficulty eating and drinking. The condition is very common, affecting approximately 20% of the population. Aphthae formation often occurs during childhood or adolescence, and the condition usually lasts for several years, after which it gradually disappears. Currently, a definitive treatment for aphthae has yet to be identified, and treatments are focused on pain management, reducing healing time, and decreasing the frequency of recurrence.

[0016] From what has been explained above, it is clear that optimal treatment of skin pathologies (chronic skin ulcers) and oral pathologies (periodontal disease, peri-implantitis, aphthae) requires a dramatic reduction of bacterial contamination and then effective removal of biofilms and necrotic or infected tissue. Nevertheless, the most used surgical method for removing necrotic or infected tissue, namely debridement, has a number of drawbacks (risk of bleeding for the patient, need for hospitalization, complexity and high cost of implementation).

[0017] In recent years, a considerable number of studies have highlighted the contribution of lipids to microbial virulence and to the formation of biofilms. These molecules constitute an important component of the extracellular tissue that protects bacterial and fungal biofilms from invasion by their potentially lytic agents. The dense extracellular matrix that surrounds the biofilm consists mainly of glycoproteins (55%), carbohydrates (25%), nucleic acids (5%) and lipids (15%), mainly glycolipids and sphingolipids, the lipids being essential for cell attachment to surfaces and for the formation of biofilms. Considering the aforementioned composition, the use of anionic surfactants, components of soaps and detergents, would allow the solvation and consequent decomposition of the components of the biofilm. However, tests carried out with the application of different types of soaps to chronic wounds never produced the desired results. Indeed, previous studies have revealed the extraordinary activity of sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid and propanesulfonic acid, in disrupting biofilms present in chronic wounds and also in periodontal pockets (International Application PCT / IB2019 / 051146, International Application PCT / EP2020 / 051652). Following the breakdown of the biofilm, spontaneous progressive healing of the subsequently treated wounds is observed.

[0018] Nonetheless, it would be desirable to provide alternative compositions that can be used in an equally efficient manner to denature present microbial species while at the same time disrupting and removing biofilms and necrotic or infected tissue present in skin ulcers.

[0019] In certain instances, the presence of a contact time-dependent exothermic effect accompanied by a burning sensation due to dissociation of protons with the corresponding sulfonic anions on contact with biofilms composed of 97% water necessitates the application of these preparations by specialized medical nursing staff.

[0020] There is therefore a further need for new compositions that make it possible to modify the microbial species present in a less invasive manner, and therefore perhaps more autonomously by the patient, but equally efficient, while at the same time removing the biofilm and necrotic or infected tissue present in the skin ulcer. Summary of the Invention

[0021] The present invention relates to a compound of general formula (A) for use in removing bacterial biofilms and / or necrotic or infected tissue from acute or chronic, preferably chronic, skin lesions or from the oral cavity [ka] wherein R is an arene group, preferably a benzene group, and the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, e.g., methoxy, the substituents preferably being alkyl having a number of 1 to 20 carbon atoms, and the alkyl chain is in the 3- or 4-position of the benzene ring. The present invention relates to the use of a composition comprising a sulfonic acid having the formula:

[0022] In another aspect, the present invention provides a compound of general formula (A) for use in disinfecting acute or chronic skin lesions [ka] wherein R is an arene group, preferably a benzene group, and the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, e.g., methoxy, the substituents preferably being alkyl having a number of 1 to 20 carbon atoms, and the alkyl chain is in the 3- or 4-position of the benzene ring. The present invention relates to the use of a composition comprising a sulfonic acid having the formula:

[0023] Arylsulfonic acids are generally highly acidic, but the acidity depends on the substituents. Exemplary sulfonic acids according to the present invention, as well as the pK of sulfonic acids are a and acid dissociation constant K a is shown in Table 1.

[0024] Preferably, the composition further comprises a non-aqueous proton acceptor. The inventors have found that combining a sulfonic acid with a non-aqueous proton acceptor provides a surprising combined effect of removing bacterial biofilm and necrotic and / or infected tissue present on the skin lesion while preventing any damage to the skin lesion and surrounding skin caused by the acidic activity of the sulfonic acid.

[0025] Compositions containing sulfonic acids and non-aqueous proton acceptors have proven particularly useful in removing bacterial biofilms and necrotic and / or infected tissue present in skin lesions, preferably in acute or chronic skin ulcers.

[0026] In particular, in the case of strong sulfonic acids, the strong acidity, which can result in aggressive effects, is desirably compensated for in the composition by adding a non-aqueous proton acceptor.

[0027] The inventors have further discovered that adding water to the composition in place of a non-aqueous proton acceptor significantly prevents the composition from being effective in removing biofilm and necrotic and / or infected tissue present on skin lesions.

[0028] Antibacterial effects have been reported for some sulfonic acid compounds and compositions of sulfonic acid compounds. However, considering that these known compositions contain a significant amount of water (at least 10 wt.% or more) and that they do not contain non-aqueous proton acceptors, these compositions are not effective in removing biofilms and necrotic and / or infected tissues present in skin lesions. In these cases, it has been found that additional mechanical, i.e. surgical, debriding actions are necessary to remove biofilms.

[0029] In a preferred embodiment, 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, tetrasodium salt of ethylenediaminetetraacetic acid, sodium gluconate, anhydrous silicon dioxide, tetraethoxysilane, polyethylene glycol, and mixtures thereof. Preferably, the non-aqueous proton acceptor is dimethyl sulfoxide.

[0030] In another aspect, the present invention provides a method for the disinfection and cleaning of acute or chronic skin wounds, the method comprising the steps of: a The present invention relates to the use of a weak sulfonic acid, preferably an alkylbenzene sulfonic acid, having the formula:

[0031] Weak sulfonic acids have also proven to be particularly useful in removing bacterial biofilms present in skin lesions, preferably in acute or chronic skin ulcers, as well as necrotic and / or infected tissue. Experiments carried out by the inventors have demonstrated that weak sulfonic acids are able to penetrate bacterial biofilms with exceptional surfactant effect on their components, allowing their complete removal without causing any sensation of heat or pain.

[0032] Thus, the mild activity of the weak sulfonic acids in particular makes it possible to obtain excellent results of disinfection and removal of biofilms and necrotic and / or infected tissue without causing side effects, such as a burning sensation.As a result, the weak sulfonic acids can be applied independently by the patient without the intervention of specialized staff, such as doctors and nurses, thus overcoming the limitations of known compositions.

[0033] The present invention also relates to a composition comprising a sulfonic acid in a mixture with at least a non-aqueous proton acceptor, preferably a solvent and / or substance / solvent having a basic character and therefore capable of accepting protons, making it possible to adjust, preferably reduce, the acidity of the composition according to the invention. Preferably, the sulfonic acid is a weak sulfonic acid.

[0034] In a preferred embodiment, the at least one non-aqueous proton acceptor is selected from dimethyl sulfoxide, isopropyl alcohol, 3-methoxy-3-methyl-1-butanol, propylene carbonate, anhydrous sodium carbonate, ethylenediaminetetraacetic acid tetrasodium salt, sodium gluconate, anhydrous silicon dioxide, tetraethoxysilane, polyethylene glycol, and mixtures thereof.

[0035] The composition of the present invention comprises a sulfonic acid in a concentration between 50 w / w% and 90 w / w%, preferably between 60 w / w% and 80 w / w%.

[0036] The composition of the present invention comprises the non-aqueous proton acceptor in an amount of 5 w / w% to 50 w / w%, preferably 10 w / w% to 40 w / w%.

[0037] In some embodiments, if the sulfonic acid is not completely soluble in the non-aqueous proton acceptor or mixture of non-aqueous proton acceptors, a small amount of water is added, up to 5 w / w%, if necessary.

[0038] The invention can be better understood and practiced with reference to the accompanying drawings which illustrate an exemplary and non-limiting form of implementation thereof. [Brief description of the drawings]

[0039] [Figure 1] FIG. 1 is a photograph of a Petri dish showing a ring of inhibition of microbial growth around the deposition area of ​​a composition according to the invention containing 4-ethylbenzenesulfonic acid (70 w / w%), water (5 w / w%) and DMSO (25 w / w%). [Diagram 2] FIG. 1 is a photograph of a Petri dish showing a ring of inhibition of microbial growth around the deposition area of ​​a composition according to the invention containing 4-methylbenzenesulfonic acid (70% w / w), water (5% w / w) and DMSO (25% w / w). [Diagram 3]Photograph of a Petri dish showing a ring of inhibition of microbial growth around the deposition area of ​​a composition according to the invention containing 70% 4-dodecylbenzenesulfonic acid and 2-propanol (30%). Similar results are obtained using a composition containing 70% 4-dodecylbenzenesulfonic acid and DMSO (30%). [Figure 4] 1 is a photograph showing the effect of treating a chronic wound on the big toe with a composition according to the present invention. [Diagram 5] Photographs showing the effect of treating a chronic wound on a patient's leg with a composition according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] The present invention relates to a compound of general formula (A) for use in removing bacterial biofilms and / or necrotic or infected tissue from acute or chronic, preferably chronic, skin lesions or from the oral cavity [ka] wherein R is an arene group, preferably a benzene group, and the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, e.g., methoxy, the substituents preferably being alkyl having a number of 1 to 20 carbon atoms, and the alkyl chain is in the 3- or 4-position of the benzene ring. The present invention relates to a composition containing a sulfonic acid having the formula:

[0041] The present invention relates to a compound of general formula (A) for use in disinfecting acute or chronic skin lesions [ka] wherein R is an arene group, preferably a benzene group, and the arene group or benzene group is optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, e.g., methoxy, the substituents preferably being alkyl having a number of 1 to 20 carbon atoms, and the alkyl chain is in the 3- or 4-position of the benzene ring. The present invention relates to a composition containing a sulfonic acid having the formula:

[0042] Preferably, the composition further comprises a non-aqueous proton acceptor.

[0043] 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, anhydrous silicon dioxide, tetraethoxysilane, polyethylene glycol, and mixtures thereof.

[0044] Preferably, the non-aqueous proton acceptor is a liquid at room temperature. In one preferred embodiment, the non-aqueous proton acceptor is a solvent selected from dimethylsulfoxide, isopropyl alcohol, 3-methoxy-3-methyl-1-butanol, propylene carbonate, polyethylene glycol, and mixtures thereof.

[0045] More preferably, the non-aqueous proton acceptor is a solvent for the sulfonic acid of the composition.

[0046] Most preferably, the non-aqueous proton acceptor is or includes dimethylsulfoxide.

[0047] In particular, the composition contains up to 5 wt.% water, and preferably is substantially free of water.

[0048] In an embodiment, the sulfonic acid has an acid dissociation constant (K) between 2 and 700, preferably between 2 and 200, more preferably between 2 and 100, even more preferably between 2 and 10, and most preferably between 2 and 5. a ).

[0049] In an embodiment, the sulfonic acid is selected from benzenesulfonic acid, guaiacolsulfonic acid, 2-phenolsulfonic acid, 3-phenolsulfonic acid, 4-phenolsulfonic acid, and alkylbenzenesulfonic acids having the general formula (I):

[0050] In an embodiment, the composition further comprises another sulfonic acid according to general formula (A), where R is an arene group, preferably a benzene group, optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, e.g., methoxy, the substituents being preferably alkyl having a number of 1 to 20 carbon atoms, the alkyl chain being in the 3- or 4-position of the benzene ring, which is different from the other sulfonic acids. The composition contains a mixture of a sulfonic acid according to general formula (A) and another sulfonic acid according to general formula (A).

[0051] In an embodiment, the amount of sulfonic acid or the total amount of sulfonic acid is from 50 w / w % to 90 w / w %, preferably from 60 w / w % to 80 w / w %, based on the total weight of the composition.

[0052] In an embodiment, the non-aqueous proton acceptor component is in an amount of 5 w / w% to 50 w / w%, preferably 10 w / w% to 40 w / w%, based on the total weight of the composition.

[0053] Preferably, the composition is substantially free of sulfuric acid.

[0054] In an embodiment, the molar ratio of sulfonic acid to its salt is at least 10:1, more preferably 20:1, and most preferably 50:1, particularly substantially free of its salt. The salt of sulfonic acid can be any salt, including sodium, potassium, ammonium, and the like.

[0055] In an embodiment, the use comprises applying the composition to the bacterial biofilm and / or necrotic or infected tissue of a skin lesion.

[0056] In embodiments, using includes removing the composition from the skin lesion within a time period between 1 second and 30 minutes after applying the composition.

[0057] In certain embodiments, the use includes removing the composition from the skin lesion within a time period between 1 second and 10 minutes, preferably within 5 minutes, more preferably within 1 minute after application of the composition. a In particular, when the sulfonic acid has a K in the range of 10 to 100, a It is preferred when

[0058] By choosing the non-aqueous proton acceptor and adjusting the relative amounts of sulfonic acid and non-aqueous proton acceptor, the time window of application can be adjusted.

[0059] In certain embodiments, the use includes removing the composition from the skin lesion within a time period between 1 second and 30 minutes, preferably between 1 minute and 30 minutes, more preferably between 5 minutes and 30 minutes after application of the composition. a , especially for K below 10 a By selecting the non-aqueous proton acceptor and adjusting the relative amounts of the sulfonic acid and the non-aqueous proton acceptor, the time window of application can be adjusted.

[0060] In one particular embodiment, the present invention relates to a compound of general formula (I) for use in removing bacterial biofilms and / or necrotic or infected tissue from acute or chronic, preferably chronic, skin lesions. [ka] The present invention relates to an alkylbenzene sulfonic acid having the formula:

[0061] In formula (I), n is an integer from 0 to 20, preferably from 1 to 20, preferably from 2 to 13. Preferably, n is equal to 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0062] The alkyl chain can be at the 3- or 4-position of the benzene ring.

[0063] Preferably, the alkylbenzenesulfonic acid of formula (I) has an acid dissociation constant K between 2 and 10, preferably between 2 and 5. a has.

[0064] In a preferred embodiment, the alkyl chain is at the 4-position of the benzene ring.

[0065] In a preferred embodiment, the alkyl chain has n between 0 and 20, preferably between 1 and 13, and is located at the 4-position of the benzene ring.

[0066] In one embodiment of the invention, n is equal to 0, 1 or 11 and the alkyl chain is in position 3 or 4 of the benzene ring, preferably in position 4. In a particularly preferred embodiment, the alkylbenzenesulfonic acid of formula (I) is 4-ethyl-benzene-sulfonic acid.

[0067] In a preferred embodiment, the alkylbenzene sulfonic acid is 4-dodecyl-benzene-sulfonic acid, which is one of the weakest organic sulfonic acids. [ka] 4-Dodecyl-benzene-sulfonic acid has an estimated acid dissociation constant K in the range of 2-3. a This means that approximately 57% of the acid form remains undissociated upon contact with the biofilm (values ​​are calculated using a quadratic equation, X 2 +K a ×X-70×K a= 0 (where X represents the proton (H+) concentration). Thus, the neutral form has the ability to easily penetrate non-polar parts, especially the lipid components of the biofilm. At the same time, the dissociation that occurs in the presence of water leads to a dehydrating effect due to the high hydration energy of the protons, which can capture water molecules present in the biofilm and the microbial species that it contains.

[0068] The effectiveness of dodecylbenzenesulfonic acid against biofilms most likely results from a delicate and unpredictable balance between these two effects.

[0069] This effect was observed in particular for 4-dodecyl-benzene-sulfonic acid, but any weak alkylbenzenesulfonic acid having an acid dissociation constant preferably between 2 and 100 can be substituted.

[0070] Thus, the alkylbenzenesulfonic acids of formula (I) exert a disinfecting effect on acute and / or chronic skin lesions (wounds and / or ulcers), resulting in the removal of biofilms and necrotic and / or infected tissue without causing side effects such as a burning sensation. As a result, the weak sulfonic acids can be applied autonomously by the patient without the intervention of specialized staff, such as doctors and nurses, thus overcoming the limitations of known compositions.

[0071] This effect is due to the surfactant ability of the acid, which is able to penetrate the biofilm present in the lesion and allow the detachment of the necrotic tissue and its complete removal by simple washing with water. Furthermore, the surfactant action, together with the acid dissociation effect, contributes to the elimination of the microorganisms present in the biofilm, in particular bacteria and fungi.

[0072] Other sulfonic acids with acid dissociation constants as high as 600, such as those containing a non-polar group at the 4-position, e.g., 3-methylbenzenesulfonic acid or 4-ethylbenzenesulfonic acid, have significant antimicrobial activity, even though they have lower penetrating efficacy and lower surface activity than 4-dodecylbenzenesulfonic acid due to the reasons listed above and the longer alkyl chain.

[0073] Tests performed on patient biofilms have indeed revealed antibacterial activity that is better, though lower, than that of 4-dodecylbenzenesulfonic acid. [ka]

[0074] In another aspect, the present invention relates to a composition comprising as active principle a sulfonic acid of formula (A), preferably an alkylbenzenesulfonic acid of formula (I), preferably in combination with a suitable non-aqueous auxiliary component, preferably an auxiliary component which acts as a non-aqueous proton acceptor and is able to regulate, in particular reduce, the acidity of the composition.

[0075] The composition according to the invention is capable of removing biofilm and necrotic tissue from infected areas of skin within just a few tens of seconds of application. The composition can be applied directly to the area to be treated by any means suitable to allow its distribution.

[0076] After a contact time of several minutes, the composition can be easily removed from the skin or mucosa by using a simple gauze and washing the treated skin or mucosal surface with a stream of physiological solution or sterile water.

[0077] Thus, by applying the composition according to the invention to skin lesions, it is possible to obtain the same effect as that obtained through a single surgical debridement, without the known drawbacks associated with the procedure of surgical debridement.This new and effective therapeutic possibility is available and has significant benefits even directly to the patient in mild, moderate and severe cases.

[0078] The compositions according to the present invention comprising a sulfonic acid of formula (A), preferably an alkylbenzenesulfonic acid of formula (I), can be formulated as a solution or as a gel and can be easily applied to acute and chronic skin ulcers.

[0079] The surprising and unexpected property exhibited by the compositions according to the invention is that they are able to act on biofilms and necrotic or infected tissue, causing the disintegration of the biofilms and necrotic or infected tissue, allowing easy and painless removal of the biofilms and necrotic or infected tissue using a simple gauze and a stream of water or saline solution a few minutes after application, thus avoiding complex, painful and expensive surgical procedures.

[0080] The action of the composition is apparently due to the penetration and surfactant power of alkylbenzene sulfonic acid on the components of the biofilm, which has a high hydration enthalpy (-1130 KJ / mol) and causes the dehydration of the microbial species that compose the biofilm or grow in the infected tissues, namely hydrogen ions (H + ) or the subsequent release of protons. This mechanism of action occurs regardless of the microbial species present, making the compositions according to the invention active against any microbial species, be it bacteria, fungi or viruses.

[0081] Furthermore, the inventors have foreseen the use of sulfonic acids of formula (A), in particular alkylbenzenesulfonic acids of formula (I), in combination with small amounts of solvents or non-aqueous proton acceptors that can adjust, or more precisely reduce, the acidity of the composition according to the invention. The use of sulfonic acids of formula (A), in particular alkylbenzenesulfonic acids of formula (I), in combination with small amounts of solvents or non-aqueous proton acceptors that can adjust, or more precisely reduce, the acidity of the composition according to the invention can also be efficiently used for the autonomous treatment of acute and chronic skin lesions and ulcers in which biofilms are present, by reducing the concentration of protons released from the sulfonic acid in order to obtain the desired interfering effect while eliminating infectious microbial species, without causing any damage to the healthy surrounding tissue.

[0082] In one embodiment the composition comprises a sulfonic acid, preferably an alkylbenzene sulfonic acid, in an amount between 50 w / w% and 90 w / w%, preferably between 60 w / w% and 80 w / w%.

[0083] Preferably, the composition further comprises a solvent acting as a non-aqueous proton acceptor selected from dimethyl sulfoxide, isopropyl alcohol, 3-methoxy-3-methyl-1-butanol and propylene carbonate, present in the composition in an amount between 10 w / w% and 50 w / w%, preferably between 20 w / w% and 40 w / w%. Optionally, a small amount of water is added as a solvent for the sulfonic acid.

[0084] In one embodiment, the composition comprises a mixture of solvents selected from those listed above, with concentrations of 10% to 50% or 20% to 40% being shared among the solvents used.

[0085] In one embodiment, the composition is formulated as a gel, where amorphous silica is added in an amount between 1% w / w and 10% w / w to a dilute solution of sulfonic acid to obtain a product in gel form.

[0086] In a further embodiment of the composition according to the invention, the rheology of the gel is optimized by the addition of tetraethoxysilane, which acts as a crosslinker.

[0087] Since the chemical components of the various formulations can be added to the sulfonic acid in a variable order without further changing the properties of the final solution, the separation procedures for the various formulations are not detailed below.

[0088] By way of illustration, but not limitation, the following examples of the invention are illustrated by two in vitro antibacterial activity tests (Example 1) and a procedure for the treatment of skin lesions based on the use of a composition according to the invention (Example 2).

[0089] formulation An exemplary formulation of the present invention is as follows: Composition 1: benzenesulfonic acid (70 w / w%), water (5 w / w%) and DMSO (25 w / w%) Composition 2: phenolsulfonic acid (70 w / w%), water (5 w / w%) and DMSO (25 w / w%) Composition 3: Guaiacolsulfonic acid (70 w / w%), water (5 w / w%) and DMSO (25 w / w%) Composition 4: 4-ethylbenzenesulfonic acid (70 w / w%), water (5 w / w%) and DMSO (25 w / w%) Composition 5: 4-methylbenzenesulfonic acid (70 w / w%), water (5 w / w%) and DMSO (25 w / w%) Composition 6: 70 w / w% 4-dodecylbenzenesulfonic acid and 2-propanol (30 w / w%)

[0090] pK of sulfonic acids a and K a The values ​​are shown in Table 1 below.

[0091] [Table 1]

[0092] pK a and Ka Values ​​are based on literature references including: E. P. Serjeant and B. Dempsey (eds.), Ionization Constants of Organic Acids in Solution, IUPAC Chemical Data Series, Volume 23, Pergamon Press, Oxford, UK, 1979; Part of Journal of Research of the National Bureau of Standards.Volume 31, December 1943, pH VALUES OF ACID.SALT MIXTURES OF SOME AROMATIC SULFONIC ACIDS AT VARIOUS TEMPERATURES AND A CRITERION OF COMPLETENESS OF DISSOCIATION, Walter j.Hamer.Gladys D.Pinching and SFAcree; Guthrie, J.P. Hydrolysis of esters of oxy acids: pKa values ​​for strong acids. Can. J. Chem. 1978, vol. 56, pp. 2342-2354;

[0093] Example 1 - In vitro antibacterial activity test The antibacterial activity of the formulation of the composition according to the invention was tested against the following microbial strains (purchased from Diagnostic International Distribution SpA): Pseudomonas aeruginosa ATCC 15442, Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 10536, Enterococcus hirae ATCC 10541, Candida albicans ATCC 10231. 1.5×10 for each species. 12 ~5.5×10 12A mixture of different strains of microorganisms was prepared, with concentrations expressed in colony forming units (CFU) ranging from 0.1 to 0.1. A sample of 100 μl of the mixture was plated on a Petri dish containing a TSA (tryptone soy agar) solid culture medium. The seeding was carried out by known standardized analytical methods, namely by depositing the liquid sample on the surface of the agar with a micropipette and distributing the liquid sample on the surface of the agar using sterile glass beads. Subsequently, 50 μl aliquots of the six formulations of the composition according to the invention were deposited on the central area of ​​the agar of each Petri dish. The plates were then incubated at 37° C. for 24 hours.

[0094] FIG. 1 shows a Petri dish marked X1 onto which a 50 μl aliquot of a formulation containing 4-ethylbenzenesulfonic acid (70 w / w%), water (5 w / w%) and DMSO (25 w / w%) was deposited.

[0095] FIG. 2 shows a Petri dish marked X2 onto which a 50 μl aliquot of a formulation containing 4-methylbenzenesulfonic acid (70 w / w%), water (5 w / w%) and DMSO (25 w / w%) was deposited.

[0096] FIG. 3 shows a Petri dish marked X3 onto which a 50 μl aliquot of a formulation containing 70% 4-dodecylbenzenesulfonic acid and 2-propanol (30%) was deposited.

[0097] Similar results were obtained with a formulation containing 70% 4-dodecylbenzenesulfonic acid and DMSO (30%).

[0098] After incubation, the plates were examined to assess microbial growth (colony formation) and the width of the ring of inhibition (i.e. the size of the area where microbial growth was inhibited) around the agar area where the samples of the six formulations were deposited. As can be seen, a clear zone of inhibition of microbial growth around the area of ​​deposition of the formulations according to the invention was observed in all Petri dishes. The ring was larger for composition 6. The analytical results obtained showed that the various formulations showed a significant increase in the inhibition of microbial growth over a 10-day period. 11We show that it is possible to inhibit the growth of CFU of gram-positive bacteria, gram-negative bacteria and the fungal species Candida albicans.

[0099] Example 2 - Treatment of patients with chronic skin ulcers The composition according to the invention was tested on more than 20 volunteer patients by applying a treatment protocol comprising the following steps: a) preparing the wound by rinsing and drying the wound prior to application of the formulation; b) applying the formulation; c) Wait for about 5 to 10 minutes. d) Removal of the formulation from the wound using simple gauze and a stream of water or saline solution.

[0100] Tests carried out with compositions 4 and 5 gave poor results, despite the antibacterial activity confirmed in vitro. The difference between the in vitro and in vivo tests is related to the presence of biofilms, against which composition 6 of the invention shows better activity.

[0101] An example of the effectiveness of composition 6 containing 4-dodecylbenzenesulfonic acid and 30% isopropyl alcohol on a patient is reported in FIGS.

[0102] Figure 4. The image on the left shows a chronic ulcer on the radius of the left foot of a diabetic patient. The base of the ulcer is entirely covered with a yellowish soft scab, which is thicker on the left side. On the right is the same part of the foot after treatment with composition 6 of the invention (containing 70% 4-dodecylbenzenesulfonic acid and 30% 2-propanol). The base of the ulcer appears completely cleaned because the scab has been removed.

[0103] Figure 5. The left image shows a chronic medial malleolar ulcer of venous origin. The base is almost entirely covered with a hard yellowish scab. The right image shows the base of the ulcer, which appears clean and granular due to the removal of the scab, after treatment with composition 6 of the invention (containing 70% 4-dodecylbenzenesulfonic acid and 30% 2-propanol).

[0104] Granulation of the base of the lesion was achieved in all treated patients.

[0105] Even further improved results are obtained with Formulations 7 and 8 below which contain 4-dodecylbenzenesulfonic acid and 2-propanol or dimethylsulfoxide (DMSO).

[0106] [Table 2]

[0107] [Table 3]

[0108] The composition includes amorphous silica SiO2 and tetraethoxysilane (TEOS) and is formulated as a gel. The composition in gel form remains stationary on the wound during application, enhancing topical treatment of the wound.

[0109] Thus, the application of the composition 6 according to the invention, containing 4-dodecylbenzenesulfonic acid diluted in a suitable solvent, resulted in complete recovery of the affected tissue in all cases and promoted its healing. Such a treatment protocol may be applicable to all patients, thus avoiding complicated, expensive and potentially risky surgical procedures. Furthermore, treatment with the composition according to the invention may substantially reduce the need for antibiotic therapy, which is expensive and associated with the increasingly emerging phenomenon of antibiotic resistance.

Claims

1. For use in removing bacterial biofilms and / or necrotic or infected tissue from acute or chronic skin lesions or from the oral cavity, a composition comprising a sulfonic acid having the general formula (A): 【Chemical 1】 wherein R is an arene group or a benzene group, said arene group or benzene group being optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy.

2. A composition for use according to claim 1, further comprising a non-aqueous proton acceptor.

3. The composition for use according to claim 2, wherein the non-aqueous proton acceptor is at least one component selected from dimethyl sulfoxide, isopropyl alcohol, 3-methoxy-3-methyl-1-butanol, propylene carbonate, sodium carbonate anhydrous, ethylenediaminetetraacetic acid tetrasodium salt, sodium gluconate, silicon dioxide anhydrous, tetraethoxysilane, polyethylene glycol and mixtures thereof.

4. The composition for use according to claim 2 or 3, wherein the non-aqueous proton acceptor is dimethyl sulfoxide or comprises dimethyl sulfoxide.

5. A composition for use according to claim 1 or 2, containing up to 5 wt.% of water or substantially free of water.

6.

7. The sulfonic acid has an acid dissociation constant (K ａ ) between 2 and 700, a composition for use according to claim 1 or 2. A composition for use according to claim 1 or 2, further comprising another sulfonic acid of the general formula (A) wherein R is an arene group or a benzene group, said arene group or benzene group being optionally substituted with one or more substituents independently selected from alkyl, OH and alkoxy, and wherein the sulfonic acid is different from the other sulfonic acid.

8. The composition for use according to claim 1 or 7, wherein the amount or the total amount of the sulfonic acid is 50 w / w% to 90 w / w% based on the total weight of the composition.

9. The composition for use according to claim 2, wherein the non-aqueous proton acceptor component is in an amount of 5 w / w% to 50 w / w% based on the total weight of the composition.

10. A composition for use according to claim 1 or 2, substantially free of sulfuric acid.

11. The composition for use according to claim 1 or 2, wherein the molar ratio of the sulfonic acid to its salt is at least 10:1 or the salt is substantially absent.

12. The sulfonic acid is of the formula (I) ​ [Chemical 2] (wherein n is an integer from 0 to 20, and the alkyl chain is at the 3-position or 4-position of the benzene ring) The composition for use according to claim 1 or 2, which is an alkylbenzene sulfonic acid having the formula:

13. The composition for use according to claim 12, wherein the alkyl chain is at the 4-position of the benzene ring.

14. The composition for use according to claim 13, wherein n is equal to 0, 1, 2 or 12, and the alkyl chain is at the 4-position of the benzene ring.

15. The composition for use according to claim 12, wherein the alkylbenzene sulfonic acid has an acid dissociation constant between 2 and 5.

16. The composition for use according to claim 12, wherein the sulfonic acid is selected from 4-dodecyl-benzenesulfonic acid, methyl-benzenesulfonic acid and ethyl-benzenesulfonic acid.

17. The composition for use according to claim 1 or 2, wherein the use comprises applying the composition to the bacterial biofilm of the skin lesion and / or necrotic or infected tissue.

18. The composition for use according to claim 1 or 2, wherein the use comprises removing the composition from the skin lesion within a time period of 1 second to 30 minutes after applying the composition.

19. The composition for use according to claim 1 or 2, for disinfecting acute or chronic skin lesions.

20. The composition for use according to claim 1 or 2, further comprising amorphous silica and formulated as a gel.

21. General formula (A) 【Chemical Formula 3】 (wherein R is an arene group or a benzene group, the arene group or benzene group is optionally substituted with one or more substituents, and the substituents are independently selected from alkyl, OH and alkoxy) A composition comprising a sulfonic acid having the formula: wherein the sulfonic acid is in an amount of 50 w / w% to 90 w / w%, and further comprising at least one non-aqueous proton acceptor selected from dimethyl sulfoxide, isopropyl alcohol, 3-methoxy-3-methyl-1-butanol, propylene carbonate, sodium carbonate anhydrous, ethylenediaminetetraacetic acid tetrasodium salt, sodium gluconate, polyethylene glycol, silicon dioxide anhydrous, tetraethoxysilane and mixtures thereof, and the non-aqueous proton acceptor is in an amount of 5 w / w% to 50 w / w%.

22. The composition according to claim 21, wherein the non-aqueous proton acceptor is dimethyl sulfoxide or contains dimethyl sulfoxide.

23. The composition according to claim 21 or 22, wherein the molar ratio of the sulfonic acid to its salt is at least 10:1, or the salt is substantially absent.

24. The sulfonic acid is of formula (I) 【Chemical Formula 4】 (wherein n is an integer from 0 to 20, and the alkyl chain is at the 3-position or 4-position of the benzene ring) The composition according to claim 21 or 22, which is an alkylbenzene sulfonic acid having the same.

25. The composition according to claim 24, wherein the sulfonic acid is selected from 4-dodecyl-benzenesulfonic acid, methyl-benzenesulfonic acid and ethyl-benzenesulfonic acid.

26. The composition according to claim 21 or 22, further comprising amorphous silica and formulated as a gel.

27. A composition for use in disinfecting acute or chronic skin lesions, of general formula (A) [Chemical Formula 5] (wherein R is an arene group or a benzene group, the arene group or benzene group is optionally substituted with one or more substituents, and the substituents are independently selected from alkyl, OH and alkoxy) containing a sulfonic acid having the same.

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