WO2025202994A1 - Uses of compositions containing cyclic oligosaccharides with antibiofilm and/or antifungal activity - Google Patents

Abstract

The present invention consists of the use of cyclic oligosaccharides as modulators of the activity of antiseptic active ingredients, causing a synergistic effect in antimicrobial compositions; more specifically, the present invention presents the ability of cyclic oligosaccharides to alter or modulate the spectrum of antimicrobial activity of an antiseptic active ingredient, enabling efficacy against microorganisms against which the active ingredient is not effective in its isolated form or increasing its efficacy against fungi, resistant microorganisms, such as resistant fungi, and microorganism biofilms. The present invention also presents the novelty of a composition that hinders the development of resistant microorganisms and/or eliminates resistant microorganisms, thanks to the specific characteristic of the cyclic oligosaccharide and the slow and continuous release of the antiseptic active ingredient. For resistant microorganism biofilms, the prolonged antiseptic action obtained has a significant impact on combating the complex defences created by biofilms.

Description

USES OF COMPOSITION CONTAINING CYCLIC OLIGOSACCHARIDES WITH ANTIBIOFILM AND/OR ANTIFUNGAL ACTIVITY

TECHNICAL DOMINION

[0001] The present disclosure refers to the use of an inclusion compound, also called an inclusion complex, with antibiofilm and/or antifungal activity, applicable in therapeutic, agronomic, and food contexts, as well as hygiene, disinfection, and/or sanitization processes.

BACKGROUND

[0002] Antimicrobial resistance (AMR) is among the top global threats to health and human development. The World Health Organization calls for urgent multisectoral action to achieve the Sustainable Development Goals (SDGs) and considers multidrug-resistant microorganisms (or "superbugs") as one of the greatest challenges humanity will face.

[0003] This threat could become a new pandemic, potentially more deadly than COVID-19. Associated with five million deaths per year, antimicrobial resistance (AMR) becomes the third leading underlying cause of death worldwide.

[0004] The excessive, incorrect and insufficient use of several classes of antibiotics and their intended elimination or inadequate treatment in various sectors, including agriculture, veterinary and health care, has led to an increase in the resistance of microorganisms to antibiotics. The need to develop new generations of antibiotics has economic, social and medical consequences, including increased mortality rates and financial burdens.

[0005] Resistant microorganisms have been declared a matter of global concern by the Centers for Disease Control and Prevention (CDC), the Infection Disease Society of America (Infection Disease Society of America), the World Economic Forum (World Economic Forum), and the World Health Organization (WHO).

[0006] The common action of drugs against bacteria is: inhibition of deoxyribonucleic acid (DNA) replication, translational activity, and cell wall synthesis. Once the antibiotic is eliminated regularly, the mutation will continue to exist and transmit resistance through vertical and horizontal transfer. Among the resistance mechanisms of microorganisms are: alternating membrane permeability, excess drug efflux, and enhanced efflux. genetic modifications that affect or protect target areas, deactivation of the drug molecule by covalent binding, transmission of resistance by plasmids and the development of biofilms.

[0007] Biofilm is a complex, highly dynamic microbial ecosystem that acts in a coordinated manner, adhered to biotic and/or abiotic surfaces or suspended in solution, whose cells may or may not be surrounded by a matrix of exopolymers, and may be formed from a single or multiple species. It is important to note that microbial biofilms are produced by pure cultures of bacteria and by combinations of microorganisms, which may include fungi, protozoa and algae (SCHNEIDER, R. P. Biofilmes Microbianos. Microbiologia em Foco, n 2, vol 1, p 4 - 12. 2007).

[0008] Bacteria and fungi form biofilms as part of their survival mechanisms, and therefore, biofilms are ubiquitous in nature. Although certain constituents are common to all biofilms, the host's contribution to the microorganisms, such as immunological components and physical weathering, impacts this structure. Among the various functions of biofilms, they are used by microorganisms for communication through the release of substances within this structure, a process called density-dependent communication between microorganisms (quorum sensing) (Pena RT, Blasco L, Ambroa A, González-Pedrajo B, Fernández-García L, López M, Blériot I, Bou G, Garcia-Contreras R, Wood TK and Tomás M (2019) Relationship Between Quorum Sensing and Secretion Systems Front Microbiol. 10:1100).

Biofilms have a protective effect on microorganisms, making them a resistant source of contamination. This leads to continued unresponsiveness to removal treatments such as pH changes, ultraviolet radiation, osmotic pressure variations, scraping, and antimicrobial agents. Within these biofilms, only nutrients enter and wastes exit, protecting them from the action of antibiotics, antifungals, and some components of the immune system (when there is contamination in the animal organism). As a result, these microorganisms become even more resistant to the action of antibiotics or surface disinfectants (Ramage G, Mowat E, Jones B, Williams C, Lopez-Ribot J. Our current understanding of fungal biofilms. Crit Rev Microbiol. 2009;35(4):340-55). The collaboration within the microcommunity of a biofilm structure contributes to substrate change, the flow of metabolic products, and the elimination of metabolic waste. This microcommunity is organized to ensure that a minimal bacterial structure survives in anaerobic environments (anaerobic digestion) and when organic materials break down into CH4 and CO2. These surviving bacteria are considered the most resilient, as they resist attack by biofilms and, for a period, close themselves off from receiving food and oxygen.

[0010] The biofilm offers a favorable environment for the establishment of a syntrophic association, which is an affiliation of two or more metabolically distinct bacteria, which exchange substrates for their energy needs. [0011] Biofilms pose a serious public health problem because these microorganisms can cause infections in patients by establishing themselves on internal medical devices. Their organized structure helps reduce their susceptibility to antiseptic active ingredients, resulting in greater survival and permanence on surfaces and increasing the risk of cross-contamination.

[0012] In hospitals, biofilm formation on surgical equipment and surfaces in general makes it difficult to maintain a sterile environment. Studies indicate that biofilms also tend to form more quickly on hydrophobic materials such as Teflon and other plastics than on glass and metal (Xiaobo Liu, Bo Tang, Qjuya Gu, Xiaobin Yu, Elimination of the formation of biofilm in industrial pipes using enzyme cleaning technique, Methods X, vol. 1, p. 130 - 136, 2014).

[0013] The impacts caused by biofilms are estimated to be around 1% of gross domestic product (GDP) in industrialized countries. The formation of microbial biofilms affects everything from building pipes to supertankers, generating high costs associated with periodic maintenance to remove and treat the affected area. In manufacturing industries, the main source of damage is heat exchangers, as their rapid formation causes these devices to increase their resistance to heat transfer, as a thick layer of biofilm impedes the normal exchange process. Water supply system pipes also suffer from biofilm formation, directly impacting human health. It is very difficult to reach internal structures and properly sanitize them. Humidity and lack of light contribute to the increased proliferation of resistant microorganisms.

[0014] Considering that the formation of the biofilm structure depends on the presence of flagella or fimbriae, the exopolysaccharide production capacity, and the cell's hydrophobicity, some microorganisms are more likely to form biofilms than others. Among the many microorganisms, such as various fungi and bacteria, some are more relevant in biofilm contamination in hospital settings, such as Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus viridans, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and mycobacteria. These microorganisms can come from the skin of patients, healthcare professionals, water, and environmental sources.

[0015] Even in individuals with excellent cellular and humoral immune responses, biofilm infections are rarely resolved by host defense mechanisms because antibodies are not effective in killing microorganisms within biofilms and can cause damage to immune complexes in surrounding tissues (Cochrane D.M.G. Immune response to bacterial biofilms. Med Microbiol J 1988;27:255).

[0016] Still in biofilm structures, whose complexity of interactions between different types of microorganisms creates a barrier that is highly difficult to access, there are few alternatives to effective antiseptic active ingredients. Eliminating microorganisms located in the deepest layers of biofilms is the biggest challenge in combating them.

[0017] Among the different classes of microorganisms, fungi are a key factor in society's treatment of fungal-related diseases, especially in patients with weakened immune systems. One challenge is late diagnosis and the ineffectiveness of existing antifungals, such as fluconazole, significantly increasing the mortality rate among people infected with fungi.

[0018] The same fungus can cause different diseases depending on the organism in which it resides. A single species can include distinct species with different levels of drug resistance, as is the case with Candida parapsilosis, reclassified into three species: C. parapsilosis sensu stricto, C. orthopsilosis, and C. metapsilosis. All three can be found on the hands of medical staff in hospitals, resulting in infections associated with the handling of catheters and other devices commonly used in intensive care units.

[0019] The virulence of fungi and their ability to cause infection and drug resistance are not obvious. Fungi have great genotypic plasticity and a high capacity for adaptation to different environments. For example, acute and chronic pneumonias of fungal origin are not treated properly, often due to late diagnosis.

[0020] The World Health Organization (WHO) has released a list of 19 fungi that exhibit pathogenic characteristics in humans and have demonstrated resistance to conventional treatments and high mortality rates. This rate is estimated to be around 1.7 million deaths annually and over 150 million serious infections worldwide. In most cases, fungal diseases occur in people who are already ill from other causes and are vulnerable to infections due to weakened immune systems, such as those with cancer, acquired immunodeficiency syndrome (AIDS), or respiratory diseases such as tuberculosis and COVID-19.

[0021] Among the list presented by the WHO, the fungi Aspergillus fuminatus, Cryptococcus neoformans, Candida albicans, and Candida auris are in the critical priority group. The fungus Aspergillus fuminatus produces spores that spread through the air, can threaten the lung health of people with compromised immune systems, and is present, for example, in animal feed. The fungus Cryptococcus neoformans is a leading cause of disease in patients with the human immunodeficiency virus (HIV/AIDS) and kills at least 180,000 people annually.

[0022] Species of the genus Candida spp. are known to cause diseases in humans, such as candidiasis, and are common in hospital settings. Candida albicans (C. albicans) is commonly Found in the human intestine, it can cause invasive infections in immunocompromised individuals, potentially leading to asthma-like conditions, pulmonary fibrosis, or non-cancerous tumors. Most manifestations of candidiasis are associated with the formation of Candida biofilms on surfaces and are also associated with mucosal and systemic infections.

Candida sp. biofilms share several properties with bacterial biofilms, as they have the ability to adhere and form biofilms with structural heterogeneity and typical microcolony and water channel architecture similar to bacterial biofilms. C. albicans biofilm formation has 3 distinct developmental phases: early, intermediate, and mature. Antifungal drug resistance is rapidly becoming a major problem. The main genes contributing to drug resistance in C. albicans are the CDR genes (CDR 1 and CDR 2) and the MDR genes. These genes have been shown to be upregulated during biofilm formation and development (Khosravi Rad K, Falahati M, Roudbary M, Farahyar S, Nami S. Overexpression of MDR-1 and CDR-2 genes in fluconazole resistance of Candida albicans isolated from patients with vulvovaginal candidiasis. Curr Med Mycol. 2016).

[0024] According to a warning from the National Health Surveillance Agency (Anvisa), some strains of Candida auris (C. auris) are resistant to polyenes, azoles, and echinocandins, the three main classes of antifungal drugs. Furthermore, these strains are resistant to most disinfectants used in hospitals and can persist in the environment for weeks or months. Anvisa reports that 39% of hospital mortality in Brazil is associated with the fungus C. auris, which has led to the deaths of between 30% and 60% of hospitalized patients.

[0025] The first record of infection by this fungus was made in 2009, in the ear of a patient in Japan. In the last decade, the microorganism has spread to more than 30 countries and infected more than 4,700 people (Chen, J., Tian, S., Han, X. et al. Is the superbug fungus really so scary? A systematic review and meta-analysis of global epidemiology and mortality of Candida auris. BMC Infect Dis 20, 827 (2020), (Calvo B, Melo AS, Perozo-Mena A, Hernandez M, Francisco EC, Hagen F, Meis JF, Colombo AL. First report of Candida auris in America: Clinical and microbiological aspects of 18 episodes of candidemia. J Infect. 2016 Oct;73(4):369-74).

[0026] WHO encourages countries to follow a stepwise approach, starting with strengthening their laboratory and surveillance capacities for fungal and bacterial diseases, and ensuring equitable access to existing quality therapeutics and diagnostics.

[0027] Because biofilms contaminate industrial piping, dental water lines, catheters, ventilators, and medical implants, they act as a source of disease for humans, animals, and plants. Given this, it is not surprising that a staggering number of chronic bacterial and fungal infections involve biofilms, which are not easily eradicated by conventional antibiotic therapy. [0028] The three main drugs used to treat fungi are fluconazole, amphotericin B, and drugs belonging to the echinocandin group. However, these drugs have side effects. Fluconazole is generally well tolerated, but there are reports of severe cases of hepatotoxicity (namely, necrosis, hepatitis, cholestasis, and fulminant hepatic failure) and death, with the most common symptoms being abdominal pain, nausea, vomiting, constipation, and flatulence. The most common side effects of amphotericin B are chills, tremors, headache, seizures, tachycardia, arrhythmia, hyper or hypotension, increased serum creatinine, pyrexia, hypokalemia, nausea, vomiting, and abdominal pain. Echinocandins have low toxicity compared to other antifungals; however, their intravenous administration presents reactions such as fever, chills, hives and/or rash, hypokalemia, anemia, flushing, nausea, vomiting, diarrhea, and phlebitis.

[0029] The types of fungi considered pathogenic are those that cause systemic mycoses, such as fungi of the genus Cryptococcus, Histoplasma and Coccidioides; opportunistic mycoses, such as fungi of the genus Candida, Aspergillus and Penicillium; and those that cause cutaneous and subcutaneous mycoses, such as fungi of the genus Sporothrix, Trichophyton, Trichosporon, Epidermophyton, Microsporum, Fusarium, Fonsecaea, Cladosporium, Exophiala and Malassezia.

[0030] Among the fungi that cause pathogenic diseases in humans, we have: Aspergillus fumigatus as one of the most dangerous, as it mainly affects the lungs, as well as Histoplasma capsulatum and Penicillium marneffei, which in addition to the lungs can reach vital areas such as the liver and kidneys, especially in HIV-positive people and those with low immunity, and can lead to death. Another fungus that only 20% of affected people survive is Lomentospora prolificans.

[0031] Species of the genus Candida spp. are known to cause diseases such as candidiasis and are common in hospital settings. Candida albicans is commonly found in the human intestine but can cause invasive infections in immunocompromised individuals, potentially leading to asthma-like conditions, pulmonary fibrosis, or non-cancerous tumors. The WHO suggests that overcrowding and scarcity of resources for infection control practices, such as prolonged use of personal protective equipment due to lack of availability, could create fertile ground for microorganisms such as C. auris to spread, colonize invasive devices, and trigger healthcare-associated infections.

[0032] Regarding fungal or mycotic skin infections in humans, these can be superficial or deep. The agents frequently involved are from the Microsporum and Trychophyton species. Scalp mycoses, such as Tinea capitis, affect the scalp and hair, causing scaling and patchy alopecia. For body mycoses, diseases related to fungi of the genera Sporothrix, Trichophyton, Trichosporon, and Epidermophyton are known. Microsporum, Fusarium, Fonsecaea, Cladosporium, Exophiala, and Malassezia. These diseases require prolonged treatment, with topical or even systemic medication in more severe cases.

[0033] Among the most common diseases in animals caused by fungi, there is also candidiasis, the same genus of fungus present in the human microbiota (Candida spp.); dermatophytosis, caused by the fungi Microsporum spp., Trichophyton spp. and Epidermophyton spp.; and malasseziosis, a disease associated with the fungus Malassezia spp. In particular, malassezia causes hair loss, severe itching, skin hyperpigmentation and redness, and this fungus is almost always accompanied by bacteria or an allergic reaction (Nobre, M.; Meireles, M.; Gaspar, L.F.; Pereira, D.; Schramm, R.; Schuch, L.F.; Souza, L; Souza, L, Malassezia pachydermatis and other infectious agents in external otitis and dermatitis in dogs, Ciência Rural, 28(3), 2008, p. 447-452.).

[0034] The cure for these diseases usually requires a long period of treatment. The veterinary drugs used are sold in the form of ointments, sprays, creams, soaps, and specific shampoos, and the choice of application method is usually based on the size and location of the lesion or the animal's age. For systemic infections, the animal often requires oral or injectable dosing.

[0035] Animal feed is one of the main sources of animal nutrition; however, it can also be subject to microbial contamination, primarily by mycotoxin-producing fungi that pose health risks to the animal, depending on the amount of contaminated feed ingested, the species, and the life stage of the animal. For this reason, feed mills for these segments pay close attention to quality throughout the entire process, from the receipt and storage of raw materials to the production, transportation, and final storage of the feed. Animal feed is based on plant-based raw materials, such as cereals and grains, which require special attention due to the high risk of fungal contamination, leading to the presence of mycotoxins.

[0036] Contamination of food by mycotoxins causes several damages to the quality of the feed, such as changes in organoleptic characteristics and a reduction in the nutrients available in the animal's diet. Consequently, they can negatively influence and affect the performance indices of animals.

Bovine mastitis is an inflammation of the mammary gland that is the most important disease associated with dairy farming worldwide. It is estimated to cause annual losses of US$1.8 billion in the United States of America (USA) alone (Souza GN et al., Mastitis, Embrapa Dairy Cattle, 2021. Accessed on: April 5, 2023). Mastitis is associated with contamination by colonies of microorganisms in the udder region of dairy cows. Research shows that udder contamination is associated with milking equipment used contaminated with non-aureus staphylococcus, Staphylococcus epidermidis, and especially biofilms, indicating contagious transmission between cattle. Therefore, one way to avoid cross-contamination is to properly clean milking equipment. These equipments should be cleaned using products that are easy to apply and remove, act quickly, and do not contaminate the milk (Almeida, LM; De Almeida, MZP; Mendonça, CLD; Mamizuka, EM Comparative analysis of agr groups and virulence genes among subclinical and clinical mastitis Staphylococcus aureus isolates from sheep flocks of the Northeast of Brazil. Braz J Microbiol. 44, 2013, 493-498).

[0038] Still on diseases in large animals, data indicate that the average incidence of hoof disease in beef cattle is 5% to 20% per year, and in dairy cattle it is 15% to 35%. In horses, it reaches around 20%. Treatment of hoof diseases occurs, in many cases, through footbaths.

[0039] One way to prevent the proliferation of fungi in animal consumption materials is to use antifungals as preservatives, increasing the shelf life of products. Currently, the most commonly used active ingredients for this purpose are citric acid, propionic acid, sorbic acid, and calcium propionate, used individually or in combination.

[0040] The impact of fungi on the agricultural sector is also very relevant. Fungi are microorganisms that cause the largest number of plant diseases and food spoilage. They are linked to crop damage or reduced shelf life of foods. Fungi such as Penicillium expansum, Botrytis cinerea, Colletotrichum musae, Colletotrichum lindemuthianum, Stemphyllium spp., Rhizoctonia solani, Fusarium oxysporum fsp., Verticillium dahliae, Alternaria solani, Sclerotium rolfsii, Phytophthora infestans, and Septoria lycopersici are some of the fungi responsible for this negative impact.

[0041] Postbloom fruit drop (PFD), also known as citrus flower rot, is a disease caused by a fungus of the Colletotrichum family. It is one of the most important fungal diseases of citrus crops in the Americas due to the enormous damage it causes. Production reductions in sweet orange groves can be as much as 80% due to premature fruit or flower drop.

[0042] Asian soybean rust, caused by the fungus Phakopsora pachyhizi, is considered one of the most severe diseases affecting the crop. The cost of controlling the disease in Brazil is estimated at an average of US$2.8 billion per harvest, and when contamination occurs, producers can lose up to 90% of their crops.

[0043] Cyclodextrins (CDs) are widely used in various matrices due to their high commercial availability, relatively low acquisition cost, low toxicity, known use in formulation of inclusion compounds and for their use as excipients in drug delivery vehicles and antiplatelet agents.

[0044] For many years, cyclodextrins were limited to excipients. However, more recent research has shown that these oligosaccharides can no longer be considered solely as excipients in formulations. By serendipity, it was discovered that the use of hydroxypropyl-betacyclodextrin helps reduce the progression of Niemann-Pick disease type C. Based on studies that showed similar results, cyclodextrins were recently classified as active ingredients by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

[0045] Cyclodextrins are used to encapsulate compounds.

[0046] Generally, the inclusion compound formed occurs through weak interactions in the internal cavity of the cyclodextrin, which makes the guest-host interaction, i.e., compound-cyclodextrin, reversible. Due to its toroidal structure, the hydrophobic character cavity of the cyclodextrins and its more hydrophilic external surface, a favorable interaction occurs between the compound to be encapsulated and the cyclodextrin cavity.

[0047] Chlorhexidine is a broad-spectrum antimicrobial agent. However, its main action is antibacterial and directed at Gram-positive bacteria, with good action also against Gram-negative bacteria, yeasts and viruses, with the mechanism of action of this active ingredient against bacteria already reported in the state of the art (Silva, D. A. R.; Costa, M. M.; Vargas, A. C.; Alievi, M.M.; Schossler, J.E.W.; Silva, T.R. Chlorhexidine gluconate or alcohol-iodine-alcohol in the antisepsis of surgical area in dogs, Ciência Rural, Santa Maria, 30 (3), 2000, p. 431-437.).

[0048] Regarding its toxic activity in eukaryotic cells, chlorhexidine presents different levels of toxicity depending on the type of cell affected. Epidermal, endothelial, mucosal cells and osteoblasts are more susceptible to this effect, while it has little effect on cell proliferation. In osteoblast culture, exposure to 0.12% chlorhexidine caused lysis in 80% of the cells, including DNA fragmentation damage (Gendron et al., 1999; Gianelli et al., 2008).

[0049] Obtaining an antimicrobial agent that acts against biofilms and resistant microorganisms, is less toxic, fast-acting, has fewer side effects, or its combination with another active ingredient that optimizes its action, becomes strategic for the study and development of the pharmaceutical area, both human and veterinary.

[0050] The need to use active ingredients that can degrade the protection formed in the biofilm, which provides greater resistance to the structure, is still lacking in the literature of active ingredients with broad, effective, fast and low-toxicity action, or that do not cause damage to the material on which the biofilm is found.

[0051] The prior art contains some disclosures that demonstrate the use of antiseptic active ingredients against bacterial and fungal biofilms. Patent application WO2021174284, "Combination treatment for microorganisms," describes the combination of antiseptics such as chlorhexidine, alcohols, peroxides, and other organic groups within a method for use in the treatment of bacterial and fungal infections, as well as the treatment of biofilm formation. The patent also describes the use of transition metal cations within inorganic complexes in the formulation for combined action against microorganisms. This combination can create complexity in product stabilization and a risk of loss of activity over time. This application highlights the fact that there is activity against the most resistant structures without the need for a combination of active ingredients, and the mechanism of action differs from that already known for the active ingredient in its free state.

[0052] Prior art WO2022041352, "Feed additive for preventing diarrhea and improving immunity, and preparation method therefor and application thereof, provides an application in animal feed of cyclodextrin as a feed additive for preventing diarrhea and improving immunity, a preparation method and an application thereof. The feed additive is prepared by uniformly mixing compound amino acids, probiotic powder, nicotinamide, chitosan, P-cyclodextrin and fulvic acid; the preparation is used for adding to animal feed, especially for feeding poultry and livestock.

[0053] Document WO2017074285, "Antimicrobial surface coating material", also addresses the application of chlorhexidine against fungi, which addresses the application of chlorhexidine in composite polymeric surfaces that have antimicrobial and antiviral properties. The invention presents polymeric composites containing additives, in which combinations of boron and/or zinc pyrithione compounds made with chlorhexidine gluconate and/or triclosan are used. The invention prevents the occurrence of biodegradation or biocontamination on surfaces. The technology for which protection is sought aims to control pathogenic factors (bacteria, yeasts, fungi, and viruses), which are the causes of surface hygiene, allergies, and infectious diseases, in sectors (particularly agriculture, health, food, and defense) where polymeric composites are widely used.

[0054] Document W02021205075A1 reports the use of macrocyclic structures associated with antibiotics and their systemic use, which aims to sensitize bacteria, reducing the amount of active ingredient required for elimination, while inhibiting, treating and preventing the formation of biofilms of pathogenic bacteria for human use. The study carried out by this prior art is the macrocyclic structure in inclusion compound with pillararene, which acts to attenuate the virulence of bacteria by binding a positively charged functional group to interact with the liposaccharide structures. present in the membrane. They further state that, according to the present invention, the macrocyclic structure enables the use of previously used antimicrobial agents because it makes the bacteria susceptible to them again. They cite the fact that the presence of the structure hinders the formation of biofilms and state that such a structure, due to its size, cannot penetrate the bacteria, which is an advantage, since it would not contribute to microbial resistance.

[0055] Document US2018325117, entitled "Probiotic compositions and uses thereof, describes compositions useful in removing, decreasing, eliminating or preventing the presence of biofilm on any surface. Also included are methods of using the compositions to remove, decrease, eliminate or prevent the presence of biofilm on any surface using in their formulation chlorine, chlorine dioxide, alcohol, hydrogen peroxide, sodium hypochlorite, an oxidant, quaternary ammonium, chlorhexidine, glutaraldehyde, a phenol, a pine oil or a derivative of any of the foregoing. The combination of active ingredients is a practice that has been widely used in the market, since the active ingredients, in their isolated form, in lower concentrations, can contribute to the formation of resistant microorganisms or biofilms and in high concentrations it becomes toxic to cells.

[0056] Chlorhexidine as an antifungal active ingredient is difficult to use due to its low antibiofilm and antifungal action against resistant fungi and because there are better cost-benefit drugs on the market. However, its study and application in different matrices and systems is very common, mainly due to its low toxicity and good stability in environments with neutral to slightly acidic pH.

[0057] These facts are described in order to illustrate the technical problem solved by the achievements of this document.

GENERAL DESCRIPTION

[0058] The present invention consists of the uses of a composition comprising an inclusion compound (also called an inclusion complex) as a modulator of the activity of antiseptic active ingredients, causing a synergistic antimicrobial effect. More specifically, the present invention presents the ability of cyclic oligosaccharides, namely cyclodextrins, to alter or modulate the spectrum of antimicrobial activity of an antiseptic active ingredient, enabling effectiveness against microorganisms for which the active ingredient is not effective in its isolated form or increasing its effectiveness against fungi, resistant microorganisms, resistant fungi and biofilms of microorganisms. The present invention also presents the novelty of the composition eliminating or hindering the development of resistant microorganisms, thanks to the specific characteristic of the cyclic oligosaccharide and its slow and continuous release. For resistant microorganisms that form biofilm, The prolonged antiseptic action obtained has a significant impact on combating the complex defenses created by the biofilm.

[0059] The composition indicated in the present invention is capable of preventing or eliminating biofilms, associating the physicochemical characteristics of the cyclic oligosaccharide, its nanometric size, its capacity to form inclusion compounds with a wide variety of antimicrobial and/or antibiotic active ingredients and its interaction with the same compounds through weak and temporary bonds provides greater effectiveness, in addition to the release occurring gradually and continuously.

[0060] The present disclosure relates to a new mechanism of action, which uses known antiseptic active ingredients, in a compound, or inclusion complex, to achieve effectiveness in the elimination of microorganisms, namely fungi and fungal biofilms.

[0061] In the present disclosure, the inclusion compound formed occurs by weak interactions between the active ingredient (guest) and the internal cavity of the host, the cyclic oligosaccharide, which makes the guest-host interaction reversible. The formation of the inclusion compounds is the result of the relationship of weak bonds between the free guest and the cyclic oligosaccharide, related by the formation (Kf) and stability (Ka) constants, in an aqueous medium. Because these are weak bonds in the inclusion compounds, the strategy of encapsulation at first and the release of the guest only at a second moment creates a sequence of activities fundamental to the effectiveness of the present invention.

[0062] The properties of cyclodextrins are fully utilized in the present invention. Due to their toroidal structure, their hydrophobic cavity and the more hydrophilic external surface, a favorable interaction occurs between the active ingredient to be encapsulated and the cyclodextrin cavity. The present invention uses active ingredients whose interaction occurs between the active ingredient and the cyclodextrin cavity, however, this interaction is less stable when compared to the interaction that occurs naturally between the structure of the microorganism and the cyclodextrin cavity, which allows the controlled release of the active ingredient in the biofilm.

[0063] Among the possible active ingredients used as antiseptics that can be combined with cyclodextrin (CHX) may be chlorhexidine and its various salts.

[0064] The present invention consists of the use of compositions that utilize an inclusion compound comprising at least one cyclic oligosaccharide and at least one antiseptic active ingredient, for the elimination of resistant microorganisms, including fungi and biofilms of resistant microorganisms, and the application of the inclusion compound in various formulations and/or matrices. More specifically, the present invention is related to the use of compositions with high efficiency activity against biofilms of fungi, spores, viruses, mycobacteria, bacteria and polymicrobial biofilms of resistant fungi and resistant bacteria, having as main agents the cyclic oligosaccharide, the cyclodextrins, which act as activity-modulating agents in combined action with inclusion compounds formed by the same cyclic oligosaccharide and one or more antiseptic active ingredients, presenting an increase in spectrum and a highly efficient synergistic effect for the elimination of resistant or non-resistant microorganisms, even in biofilms, using a low concentration of the antiseptic active ingredient, quickly and safely for human, veterinary and agricultural use.

[0065] With the formation of the inclusion compound as proposed in the present invention, it is possible to significantly reduce the concentration of the antiseptic active ingredient, reducing the toxicity of the compositions and expanding the application of the active ingredient.

[0066] The present invention for which protection is sought hinders the formation of resistant microorganisms, even with a single antimicrobial active ingredient present in the solution, thanks to its specific characteristic, combined with the residual action of the nanocompound, which enables a significant reduction in concentration and consequent reduction in toxicity.

[0067] The technology for which protection is sought uses betacyclodextrin as a cyclic structure, whose size is 7.8 Angstrom, falling within the nanoscale, being smaller than the size of bacteria, allowing entry into the cell wall and enabling the new mechanism of action. The spectrum of activity is another distinguishing feature of the present invention, since the compound formed, regardless of the antiseptic active ingredient used, allows the creation of activity previously non-existent in the free antiseptic active ingredient, including activity against fungi and biofilms. Another distinguishing feature of the present invention is the broad applicability of the inclusion composition, including addition to material bases and compositions intended for veterinary, agricultural, and sanitizing use, in addition to therapeutic application for human and veterinary use, systemic or otherwise.

[0068] The physical characteristic of cyclodextrin in terms of size is an advantage, which, associated with the fact that it is a sugar, creates a favorable environment, which facilitates the access of the active ingredient to more fragile regions of the microorganism, increasing the effectiveness of compounds formed by this structure and antimicrobial actives.

[0069] In one embodiment, among the possible active ingredients used as antiseptics that can be combined with cyclodextrin, there may be chlorhexidine and its most varied salts.

[0070] In the present invention, cyclodextrin is used in the formation of an inclusion compound with antimicrobial active ingredients to act in the prevention of infections caused by fungi present in animal feed.

[0071] The technology that is claimed for protection aims to control pathogenic factors (bacteria, yeasts, fungi and viruses), which are the causes of surface contamination, allergies and infectious diseases, with its application being particularly relevant in sectors such as agriculture, health, food and defense where polymer composites are widely used. [0072] In one embodiment of the present invention, the macrocyclic structure in the inclusion compound formed with pilararene has a size compatible with entry through the cell wall of the microorganism. The inclusion composition of the present disclosure comprises a macrocyclic structure that has a size compatible with penetration through the cell wall of the microorganism, which, surprisingly, provides a complementary action to the antiseptic active ingredients used, increasing the effectiveness of the antimicrobial action, namely the antibiofilm and antifungal action.

[0073] Surprisingly, the composition of the present disclosure enables modulation of the activity of compounds with low fungal activity, fungal sporicidal or activity against fungal or mixed biofilm.

[0074] One aspect of the present disclosure relates to the use of an antimicrobial composition characterized by being used as an anti-fouling agent (from the English, anti-biofouling; that is, the use as an agent inhibiting the formation of biofilms and/or eliminating biofilms) and/or an agent enhancing the antimicrobial action against resistant microorganisms, fungi, bacteria, fungal biofilms, or algae; in which the composition comprises at least one cyclic oligosaccharide as an encapsulating agent, at least one antiseptic active ingredient; in which the encapsulating agent and the active ingredient form an inclusion compound (or complex).

[0075] In one embodiment, the molar ratio between the antiseptic active ingredient and the encapsulating agent may range from 8:1 to 1:10.

[0076] In another embodiment, the composition of the present disclosure may present a molar ratio between the antiseptic active ingredient and encapsulating agent that ranges from 1:1 to 1:8; preferably from 1:2 to 1:4.

[0077] In another embodiment, the composition of the present disclosure may further comprise a free cyclic oligosaccharide.

[0078] In one embodiment, the mass of free cyclic oligosaccharide, relative to the total mass of the composition, may vary between 0.01% (m _o free cyclic oligosaccharide/m composition) and 20.00% (m o free cyclic oligosaccharide/m composition); preferably 5% (m _o free cyclic _{oligosaccharide} /m composition) and 15% (m o free cyclic oligosaccharide/m composition). That is, in some compositions there is an excess of the encapsulating agent (cyclic oligosaccharide), so that the encapsulating agent may be free in the composition, which allows the modulation of the activity of antimicrobial active ingredients for the elimination of fungi and biofilms of resistant microorganisms, allowing a synergistic effect in the composition.

[0079] In another embodiment, the composition of the present disclosure may comprise encapsulating agents selected from a list consisting of: betacyclodextrin, alphacyclodextrin, or gammacyclodextrin and/or their structural variations or mixtures thereof. These encapsulating agents act when combined with at least one antiseptic active ingredient as an active inclusion compound, this is an active complex, improving the effectiveness of the antimicrobial action and allowing the composition to be used as an antiscaling agent.

[0080] In one embodiment, the concentration of the antiseptic active ingredient may range from 0.005% to 30% (m/v); preferably 0.01% - 10% (m/v).

[0081] In one embodiment, the antiseptic active ingredient may be cationic, anionic, zwitterionic, or neutral; and/or selected from a list consisting of classes of: fa/s-biguanide, antimicrobial agent, essential oil, hydrolate, or mixtures thereof; preferably wherein the antimicrobial agent is an antibiotic, antifungal agent, antiparasitic agent, or mixtures thereof.

[0082] In one embodiment, the β/s-biguanide can be selected from a list consisting of: chlorhexidine, or its acetate, gluconate, or digluconate salts, or mixtures thereof.

[0083] In one embodiment, the antibiotic may be selected from a list consisting of: tetracycline, beta-lactam; aminoglycoside; macrolide; fluoroquinolone; sulfonamide; oxazolidinone; glycopeptide; streptogramin; rifamycins; or mixtures thereof.

[0084] In one embodiment, the antifungal agent may be selected from a list consisting of: azoles, polyenes, echinocandins, or mixtures thereof.

[0085] In one embodiment, the essential oil may be selected from a list consisting of: essential oil from natural bases such as thyme, eucalyptus, oregano, basil, mint, peppermint, levantia, horsetail, mint, rosemary, field rosemary, pequi, geranium, citronella, palmarosa, pitanga, hibiscus, cypress, tea tree, ginger, lemongrass, ora-pro-nobis, moringa, cinnamon, muira puama, amapá, lemongrass or propolis, or mixtures thereof.

[0086] In one embodiment, the concentration of the essential oil may range from 0.05% to 99.00% (w/w).

[0087] In one embodiment, the composition of the present disclosure may further comprise the addition of an organic acid and/or a saturated or unsaturated chain alcohol; preferably wherein the backbone of the organic acid and/or the saturated or unsaturated chain alcohol has a number of carbon atoms between 1 to 10; more preferably between 2 to 8.

[0088] In one embodiment, the composition of the present disclosure may further comprise at least one of the following excipients: humectant, emulsifier, preservative, thickener, sweetener, stabilizer, colorant, antioxidant, surfactant, drug delivery vehicle, or flavorings, or mixtures thereof; preferably polysorbate 20 as the emulsifier.

[0089] In one embodiment, the excipient concentration ranges from 0.02% to 99.00% (w/w); preferably 0.5% to 10% (w/w). [0090] In one embodiment, the composition of the present disclosure may have antimicrobial activity against microorganisms selected from a list consisting of: Clostridioides difficile, Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Proteus mirabilis, Campylobacter spp., Salmonella spp., Klebsiella spp., Pseudomonas spp., Legionella spp., Acinetobacter spp., Enterococcus spp., Enterobacter spp., Aspergillus fumigatus, Candida spp. (Candida albicans, Candida auris, Candida tropicalis, or Candida parapsilose) Cryptococcus neoformans, Talaromyces marneffei, Pneumocystis jirovecii, Paracoccidioides brasiliensis, Histoplasma spp., Madurella spp., Nocardia spp. (associated with Eumycetoma), Nakaseomyces spp., Scedosporium apiospermum, Pseudallescheria spp., Lomentospora prolificans, Pichia kudriavzeveii, Cryptococcus gattii, Phakopsora pachyrizi (Asian soybean rust), Cercospora zeae-maydis, Microsporum spp., Trichophyton spp., Penicillium spp., Coccidioides spp., Epidermophyton spp., Malassezia spp., dermatophytes (such as Microsporum or Trichophyton), fungi of the order Mucorales, coronaviruses, or protozoa (Coccidia) alone or associated with other classes of microorganisms, even bacteria, mycobacteria, or algae.

[0091] In another embodiment, the composition of the present disclosure may have antiseptic antimicrobial activity against Candida auris.

[0092] In one embodiment, the composition of the present disclosure may be for pharmacological application either for systemic use or for local administration.

[0093] In one embodiment, the composition of the present disclosure may be for human or veterinary use on epithelial tissues, skin, mouth, fingers, eyes, nose, ears, nails, hair, mammary glands, perineal region, genitalia, mucous membranes, or wounds.

[0094] In one embodiment, the composition of the present disclosure may be for preparing a medicament for treating hair diseases, preferably for treating dandruff, hair dermatitis, primary cicatricial alopecia, or alopecia Tinea capitis and others.

[0095] In another embodiment, the composition of the present disclosure may be for preparing a medicament to treat candidiasis, preferably fungi of the Sacharomycetaceae family, in particular fungi of the Candida albicans and Candida auris species alone or associated with other types of microorganisms, such as bacteria and/or mycobacteria (resistant or not) in biofilms.

[0096] In another embodiment, the composition of the present disclosure may be for preparing a medicament for treating candidiasis, preferably candidiasis due to Candida auris infection.

[0097] In another embodiment, the composition of the present disclosure may be for preparing a medicament for treating cutaneous and subcutaneous mycoses caused especially by the fungus genus Sporothríx, Trichophyton, Trichosporon, Epidermophyton, Microsporum, Fusarium, Fonsecaea, Cladosporium, Exophiala, or Malassezia.

[0098] In another embodiment, the composition of the present disclosure may be for preparing a medicament for treating bovine mastitis caused by the fungi Non-Aureus Staphylococcus, Staphylococcus epidermidis, or biofilms.

[0099] In another embodiment, the composition of the present disclosure may be for preparing a medicament for treating bovine mastitis caused by the fungi Staphylococcus aureus, Staphylococcus epidermis, Streptococcus dysgalactiae, Streptococcus agalactiae, Streptococcus uberis, Streptococcus bovis, Klebsiella pneumonia, or biofilms.

[00100] In another embodiment, the composition of the present disclosure may be for preparing an antiseptic used in foot bath solutions.

[00101] In another embodiment, the composition of the present disclosure may be for agricultural application; preferably as an agricultural pesticide for crops.

[00102] In one embodiment, said composition may be applied directly to seeds, soil, trunks, leaves, and/or fruits.

[00103] In another embodiment, said composition may be for use in plantations as an agricultural defensive against fungi; preferably Penicillium, Botrytis, Colletotrichum, Colletotrichum, or Phakopsora pachyhizi; more preferably Penicillium expansum, Colletotrichum musae, or Colletotrichum lindemuthianum.

[00104] In another embodiment, said composition may be for use in plantations, as an agricultural defensive against fungi; preferably Penicillium, or Colletotrichum; more preferably Penicillium expansum, Colletotrichum musae, or Colletotrichum lindemuthianum.

[00105] In another embodiment, said composition can be applied as an agricultural defensive against Asian soybean rust.

[00106] In another embodiment, said composition can be applied as an agricultural defensive against post-bloom fruit drop (PFD); preferably against a disease caused by the fungus of the Colletotrichum family; preferably a disease caused by the fungus Colletotrichum musae, or Colletotrichum lindemuthianum.

[00107] In one embodiment, said composition may be for use in foods for human or animal nutrition, and/or packaging to preserve and/or increase the shelf life of foods; preferably the foods are selected from a list of: animal protein, fruits, leaves, vegetables, minimally processed foods, processed cuisine, processed foods, or ultra-processed foods. [00108] In another embodiment, the composition of the present disclosure may be for use as a sanitizer for disinfecting and/or sanitizing surfaces; and/or for producing formulations for treating environments, sanitizing and decontaminating hospital equipment, medical devices, water treatment systems and their structures, air purification systems, or any other critical level sanitization application.

[00109] In one embodiment, the composition of the present disclosure may be for application in plastic polymeric bases (acrylic resin), in organic and/or non-organic matrices, woven and/or non-woven matrices of synthetic, artificial, natural, or mixed composition; preferably cellulosic material (such as cellulosic resin) and/or cotton.

[00110] In one embodiment, said composition may further comprise an organic matrix; preferably cellulosic material; more preferably cellulosic resin.

[00111] In one embodiment, the composition of the present disclosure may be for application to woven and/or nonwoven matrices of synthetic, artificial, natural, or mixed composition.

[00112] In one embodiment, said composition may be in the form of an emulsion, aqueous solution, powder, paste, wet gel, lubricating oil, xerogels, aerosols, spray, foam, tablets, or capsules; preferably an emulsion.

[00113] Another aspect of the present disclosure relates to a composition characterized by comprising at least one cyclic oligosaccharide as an encapsulating agent, at least one antiseptic active ingredient; in which the encapsulating agent and the active ingredient form an inclusion compound (or complex), in which the composition is used for the treatment of diseases caused by biofilm in an individual or animal.

[00114] In one embodiment, the biofilm-caused disease may be selected from a list of: recurrent urinary tract infections (associated with catheters), lung infections (in patients with cystic fibrosis, such as infections caused by Pseudomonas aeruginosa), periodontitis (biofilms in the oral cavity), gingivitis (biofilms in the oral cavity), chronic wounds (such as diabetic ulcers), infective endocarditis (when biofilms form on heart valves), infections associated with medical devices (such as orthopedic prostheses, pacemakers, and venous catheters).

[00115] In another embodiment, the biofilm disease may be caused by a Candida auris biofilm.

[00116] In another embodiment, the composition of the present disclosure may comprise at least one cyclic oligosaccharide as an encapsulating agent, at least one antiseptic active ingredient; wherein the encapsulating agent and the active ingredient form an inclusion compound (or complex), wherein the composition is used as a coating on a medical device for use in the preventative treatment of biofilm-mediated medical device-associated infections in a subject. [00117] In one embodiment, the medical device-associated infection is caused by Candida auris; preferably, said medical device-associated infection is a catheter-associated infection.

[00118] In one embodiment, the molar ratio between the antiseptic active ingredient and the encapsulating agent may range from 8:1 to 1:10.

[00119] In another embodiment, the composition of the present disclosure may present a molar ratio between the antiseptic active ingredient and encapsulating agent that ranges from 1:1 to 1:8; preferably from 1:2 to 1:4.

[00120] In one embodiment, the composition of the present disclosure may further comprise a free cyclic oligosaccharide.

[00121] In one embodiment, the mass of free cyclic oligosaccharide, relative to the total mass of the That is, in some compositions there is an excess of the encapsulating agent (cyclic oligosaccharide) so the encapsulating agent can be found free in the composition, which allows the modulation of the activity of antimicrobial active ingredients to eliminate fungi, biofilms of resistant microorganisms, allowing a synergistic effect in the composition.

[00122] In one embodiment, the composition of the present disclosure may comprise encapsulating agents selected from a list consisting of: betacyclodextrin, alphacyclodextrin, or gammacyclodextrin and/or their structural variations or mixtures thereof. These encapsulating agents act when combined with at least one antiseptic active ingredient as an active inclusion compound, i.e. an active complex, improving the efficacy of the antimicrobial action and allowing the composition to be used as an antifouling agent.

[00123] In one embodiment, the concentration of the antiseptic active ingredient ranges from 0.005% to 30% (m/v); preferably 0.01% - 10% (m/v).

[00124] In one embodiment, the antiseptic active ingredient is cationic, anionic, zwitterionic, or neutral; and/or selected from a list consisting of classes of: b/s-biguanide, antimicrobial agent, essential oil, hydrolate, or mixtures thereof; preferably wherein the antimicrobial agent is an antibiotic, antifungal agent, antiparasitic agent, or mixtures thereof.

[00125] In one embodiment, the b/s-biguanide may be selected from a list consisting of: chlorhexidine, or its acetate, gluconate, or digluconate salts, or mixtures thereof.

[00126] In one embodiment, the antibiotic may be selected from a list consisting of: tetracycline, beta-lactam; aminoglycoside; macrolide; fluoroquinolone; sulfonamide; oxazolidinone; glycopeptide; streptogramin; rifamycins; or mixtures thereof. [00127] In one embodiment, the antifungal agent may be selected from a list consisting of: azoles, polyenes, echinocandins, or mixtures thereof.

[00128] In one embodiment, the essential oil may be selected from a list consisting of: essential oil from natural bases such as thyme, eucalyptus, oregano, basil, mint, peppermint, levantia, horsetail, mint, rosemary, rosemary, pequi, geranium, citronella, palmarosa, pitanga, hibiscus, cypress, tea tree, ginger, lemongrass, ora-pro-nóbis, moringa, cinnamon, muira puama, amapá, lemongrass or propolis, or mixtures thereof.

[00129] In one embodiment, the concentration of the essential oil may range from 0.05% to 99.00% (w/w).

[00130] In one embodiment, the composition of the present disclosure may further comprise the addition of an organic acid and/or a saturated or unsaturated chain alcohol; preferably wherein the backbone of the organic acid and/or the saturated or unsaturated chain alcohol has a number of carbon atoms between 1 to 10; more preferably between 2 to 8.

[00131] In one embodiment, the composition of the present disclosure may further comprise at least one of the following excipients: humectant, emulsifier, preservative, thickener, sweetener, stabilizer, colorant, antioxidant, surfactant, drug delivery vehicle, or flavorings, or mixtures thereof; preferably polysorbate 20 as the emulsifier.

[00132] In one embodiment, the excipient concentration may range from 0.02% to 99.00% (w/w); preferably 0.5% to 10% (w/w).

[00133] In one embodiment, said composition may further comprise an organic matrix; preferably cellulosic material; more preferably cellulosic resin.

[00134] In one embodiment, said composition may be in the form of an emulsion, aqueous solution, powder, paste, wet gel, lubricating oil, xerogels, aerosols, spray, foam, tablets, or capsules; preferably an emulsion.

[00135] In one embodiment, the disease is a medical device-associated infection and is caused by Candida auris; preferably, said medical device-associated infection is a catheter-associated infection.

[00136] Another aspect of the present disclosure relates to a coated surface or coated article, wherein the coating is on a medical device and comprises the composition described in the present disclosure, for use in the preventative treatment of biofilm-mediated medical device-associated infections in an individual.

[00137] In one embodiment, the coated surface or article may further comprise at least 0.01% (w/v) of the composition described in the present disclosure. [00138] In another embodiment, the coated surface or article may be a medical device, preferably selected from the list consisting of a catheter, a syringe, a stent, a tube, a medical package, a dialysis device, a dental prosthesis, a dental implant, an orthodontic device, a mask, or clothing.

BRIEF DESCRIPTION OF THE FIGURES

[00139] For easier understanding, the figures are attached, which represent preferred embodiments that are not intended to limit the scope of this description.

Figure 1. Illustration of the results, in millimeters, of the average readings of the halos obtained in each of the samples, in relation to the tested microorganism Penicillium expansum, being in a) sample A6, b) sample A2 and in c) sample A7.

DETAILED DESCRIPTION

[00140] The present invention consists of the uses of cyclic oligosaccharides as modulators of the activity of antiseptic active ingredients, causing a synergistic effect in antimicrobial compositions. More specifically, the present invention presents the ability of cyclic oligosaccharides to alter or modulate the spectrum of antimicrobial activity of an antiseptic active ingredient, enabling effectiveness against microorganisms in which the active ingredient is not effective in its isolated form or increasing its effectiveness against fungi, resistant microorganisms, such as resistant fungi, and biofilms of microorganisms. The present invention also presents the novelty of the composition hindering the development of resistant microorganisms and/or eliminating resistant microorganisms, thanks to the specific characteristic of the cyclic oligosaccharide and slow and continuous release of the antiseptic active ingredient. For biofilms of resistant microorganisms, the prolonged antiseptic action obtained has a significant impact in combating the complex defenses created by biofilms.

[00141] The present invention presents as a novelty the positive modulation of the activity of antiseptic active ingredients, which do not present, in their isolated form, satisfactory antifungal, fungal sporicidal and/or antibiofilm activity and which, after encapsulation with betacyclodextrin in varied molar concentrations, become antifungal, antibiofilm and fungal sporicidal active ingredients with application in low concentration and safe for human, veterinary and agricultural use.

[00142] Chlorhexidine and its salts are not significantly active against resistant fungi, fungal spores and biofilms. In one embodiment, the combination of chlorhexidine or its salts with betacyclodextrin, in varying molar concentrations, obtaining inclusion compounds presented modulation of chlorhexidine activity, allowing application in low concentrations in systems now sensitive to chlorhexidine, enabling application in safe concentrations for use.

[00143] The modulation of activity that occurs in the present invention is related to the fact that the compound/inclusion complex formed by the antiseptic active ingredient with the cyclic oligosaccharide has activity against fungal biofilms, resistant fungi, bacterial biofilms and resistant bacteria or polymicrobial biofilms, even when the antiseptic active ingredient does not present activity in its free form, even in high concentrations.

[00144] The characteristics of cyclodextrins, as a nano-sized cyclic oligosaccharide, differentiate them from other larger macrocyclic structures; the nanostructure allows physical permeation and positively contributes to their use as an activity modulator in antiseptic compositions. Dextrins, like sugars, are able to permeate the structures of microorganisms, easily accessing their interiors, as they are mistaken for food by the microorganisms. Another distinguishing feature is their ability to form inclusion compounds with different active ingredients or functional groups of antiseptic actives, hiding them, in order to alter the reading method used by microorganisms, including those that have already been able to create special defense mechanisms, such as biofilms or resistant microorganisms.

[00145] The resistance of microorganisms is related to their ability to survive the antiseptic or antibiotic active ingredients commonly used to combat them, with one of the triggers being the "closure" of all oxygen and food receiving channels, when there is the presence of any antiseptic functional group that can be recognized as a threat.

[00146] Thus, in the present disclosure, with nanoencapsulation, it was possible for the cyclodextrins to interact with the functional groups of the antiseptic active ingredients, in order to temporarily hide them. There is an inclusion compound and the bacteria are no longer able to read the presence of the antiseptic active ingredient; it will not close, allowing the penetration of the compounds into the most sensitive layers of the microorganisms.

[00147] In the present invention, considering the weak and temporary bonds that are created between the functional groups of the antiseptic active ingredient and the internal cavity of the cyclodextrin, there will be a subsequent release of this same active ingredient after the penetration of the inclusion compound, allowing, in low concentrations, effectiveness against the pathogenic agent.

[00148] This technology also highlights the differential antiseptic action, achieved through gradual release, enabling prolonged action. For structures such as biofilms, where the deeper layers are responsible for ensuring their survival, the differential residual action becomes decisive for satisfactory antibiofilm activity. [00149] The resilience of cyclodextrins also contributes positively to the combination of different antiseptic active ingredients for the development of inclusion compounds/compositions that enable a synergistic effect. In the present invention, chlorhexidine stands out as an example of an active ingredient; however, any antiseptic active ingredient that forms an inclusion compound with cyclodextrins can be used and be an option for the novelty of the invention.

[00150] In one embodiment, the option of adding free cyclodextrins contributes to the modulation of the activity and synergistic effect previously non-existent for the free antiseptic active ingredient, which is justified by the interaction that occurs between the cyclodextrin cavity and the structure of the microorganism, weakening its defenses and contributing to the action of the nanoencapsulated antiseptic active ingredient.

[00151] In definition, the synergistic or synergistic effect occurs when drugs interact in such a way as to increase or magnify one or more of their effects, or even reduce their side effects. The fact that cyclodextrin has recently been included in the list of active ingredients of the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), allows the inclusion compound of the present invention to no longer be seen only as an excipient. In this disclosure, attention is drawn to the novelty and inventive character of this cyclic oligosaccharide, which presents activity against the structures of the microorganism, even though it does not present effectiveness in isolation, facilitating the action of the inclusion compound and the antiseptic active ingredient.

[00152] In the present disclosure, there is the creation of activity for an active ingredient that, in isolation, does not present activity for certain resistant microorganisms or biofilms with different microorganisms combined.

[00153] In the present disclosure, it was proven that cyclodextrin acts actively with the cellular structure of the resistant or non-resistant microorganism, and can act in the formation of biofilm, weakening it, through mechanisms of action different from those known for the free antiseptic active ingredient. Its special characteristic of weak and temporary bonds, which also provides prolonged action, is a determining factor for the new mechanism of action proposed in this present invention.

[00154] In one embodiment, the inclusion composition comprises free cyclic oligosaccharides, with the purpose of leaving the cyclic oligosaccharide (cyclodextrin) available for interaction with the cell wall of the microorganism and the inclusion compounds formed with the antiseptic active ingredients, creating a more effective antimicrobial environment of activity against resistant microorganisms and biofilms. [00155] In one embodiment, the technology for which protection is sought presents as a novelty the use of an inclusion compound with cyclodextrins as modulating agents of the activity of antiseptic active ingredients, resulting in products that surprisingly present an activity superior to the active ingredients applied individually against fungi, resistant fungi, fungal spores and fungal and bacterial biofilms and for human, veterinary and polymeric or organic matrices application, even in low concentrations.

[00156] In one embodiment, the inclusion composition with antibiofilm and/or antifungal activity used presents encapsulating agents, free or not, being cyclic oligosaccharides, at least one antiseptic active in an inclusion compound with cyclic oligosaccharide and excipients or mixture thereof, being characterized by the modulation of activity of antimicrobial active ingredients for the elimination of fungi, fungal biofilms, algae or bacteria and resistant microorganisms.

[00157] In one embodiment, the encapsulating agents would be, especially, betacyclodextrin and/or its structural variations, or a mixture thereof. Possible structural variations of betacyclodextrin are comprised of the compounds hydroxypropyl-betacyclodextrin, sodium betadexsulfobutylether, hydroxymethyl-betacyclodextrin, methyl-betacyclodextrin, 2,6-dimethyl-betacyclodextrin and hydroxyethyl-betacyclodextrin.

[00158] In another embodiment, the antiseptic active ingredient must be a cationic, anionic, zwitterionic or neutral antimicrobial active ingredient, such as the bis-biguanide class, such as chlorhexidine or its acetate, gluconate, or digluconate salts, and the tetracycline classes, such as doxycycline, eracycline, monocycline, omadacycline, or a combination thereof.

[00159] In one embodiment, the antiseptic active ingredient may be comprised of the unitary addition or mixture of classes of organic acids or alcohols with a saturated or unsaturated chain, with a main chain having a number of carbon atoms between 2 and 8, or a combination thereof, in a concentration between 0.01% and 30.00% (m/v).

[00160] In another embodiment, the antiseptic may also belong to the group of essential oils or hydrolates of essential oils provided with natural bases such as thyme, eucalyptus, oregano, basil, mint, peppermint, levantia, horsetail, mint, rosemary, field rosemary, pequi, geranium, citronella, palmarosa, pitanga, hibiscus, cypress, tea tree, ginger, lemongrass, ora-pro-nóbis, moringa, cinnamon, muira puama, amapá, lemongrass or propolis, or a combination of these in concentrations between 0.05% and 99.00% (w/w).

[00161] In one embodiment, the excipients of the inclusion composition may be selected from a list consisting of: humectants, emulsifiers, preservatives, thickeners, sweeteners, stabilizers, colorants, antioxidants, surfactants, flavorings, or a combination thereof in concentrations between 0.02% and 99% (w/w). [00162] In one embodiment, the antiseptic active ingredient and the encapsulating agent must be in molar ratios between 8:1 and 1:10, respectively.

[00163] In another embodiment, the encapsulating agent, namely betacyclodextrin and/or its structural variations, or a combination thereof, must be in excess in the product in a range of 0.01% to 20% (w/w) in the final composition, being used as a modulator of the activity of antimicrobial active ingredients for the elimination of fungi, biofilms and resistant microorganisms.

[00164] One aspect of the present invention relates to the use of betacyclodextrin and/or its structural variations, or a combination thereof, as a modulator of antifungal and/or antibiofilm activity of active antiseptic agents against microorganisms selected from a list consisting of: Aspergillus fuminatus, Cryptococcus neoformans, Candida, Candida albicans, Candida auris, Histoplasma, Eumycetoma, Candida tropicalis, Nakaseomyces, Candida parapsilosis, Scedosporium apiospermum, Pseudallescheria spp, Lomentospora prolificans, Pichia kudriavzeveii, Cryptococcus gattii, Talaromyces marneffei, Pneumocystis jirovecii and Paracoccidioides brasiliensis, Phakopsora pachyrizi, Cercospora zeae-maydis, Escherichia coli, Staphylococcus aureus, Proteus mirabilis of the genera Microsporum, Sacharomycetaceae, Trichophyton, Coccidioides, Epidermophyton, Malassezia, Enterococcus, Klebsiella, Pseudomonas, Penicillium, Acinetobacter and Legionella, bacillus Enterobacter and the order Mucorales, alone or associated with other classes of microorganisms, even bacteria, mycobacteria or algae.

[00165] One aspect of the present invention relates to the use of the inclusion composition with antibiofilm and/or antifungal activity for the production of a drug for pharmacological application for systemic use, such as an antibiotic in solid, liquid, semi-solid, injectable, and/or related forms.

[00166] One aspect of the present invention also relates to the use for topical treatment of tissues, selected from the group comprising: epithelial tissues, skin, mouth, fingers, nails, hair, mammary glands, perineal region, genitalia, or mucosa.

[00167] One aspect of the present invention relates to veterinary use in the topical dermatological treatment of animals.

[00168] One aspect of the present invention relates to the use and insertion in animal feed.

[00169] Another aspect of the present invention relates to the use in plastic polymeric packaging or in organic matrices, such as cellulosic material or cotton.

[00170] Another aspect of the present invention relates to the use of the antimicrobial composition to prepare a medicine to treat hair diseases, such as dandruff, hair dermatitis, primary cicatricial alopecia, Tinea capitis alopecia, among others. [00171] Another aspect of the present invention relates to the use of the antimicrobial composition to prepare a medicament to treat candidiasis, preferably fungi of the Sacharomycetaceae family, in particular fungi of the Candida albicans and Candida auris species alone or associated with other types of microorganisms, such as bacteria and mycobacteria.

[00172] Another aspect of the present invention relates to the use of the antimicrobial composition to prepare a medicament to treat cutaneous and subcutaneous mycoses caused especially by fungi of the genus Sporothrix, Trichophyton, Trichosporon, Epidermophyton, Microsporum, Fusarium, Fonsecaea, Cladosporium, Exophiala and Malassezia.

[00173] Another aspect of the present invention relates to the veterinary use of the antimicrobial composition that is used to prepare a medicine to treat bovine mastitis, caused by the fungi: Non-Aureus Staphylococcus, Staphylococcus epidermidis and their biofilms.

[00174] Another aspect of the present invention relates to the use of the composition of the present disclosure to prepare an antiseptic used in foot bath solutions.

[00175] Another aspect of the present invention relates to the use for agricultural application, especially as an agricultural pesticide for crops applied to plants or fruits, extending the shelf life of foods. In one embodiment, these applications may be for topical or systemic treatment of diseases caused by fungi of the families Sacharomycetaceae, Malasseziaceae, especially the species Malassezia furfur, the family Arthrodermataceae, especially the species Trichophyton, Microsporum and Epidermophyton.

[00176] Another aspect of the present invention relates to the use of the antimicrobial composition as an agricultural defensive, especially against fungi: Penicillium, Botrytis, Colletotrichum, Colletotrichum, or Phakopsora pachyhizi.

[00177] Another aspect of the present invention relates to the use of the present invention to prepare an agricultural pesticide to treat Asian soybean rust. In one embodiment, the present invention is used especially against post-bloom fruit drop (PFD), also known as citrus leaf rot, a disease caused by the fungus of the Colletotrichum family.

[00178] Yet another aspect of the present invention relates to the use of the antimicrobial composition to be a sanitizer for surface disinfection and/or sanitization, for the production of formulations for topical use, or for environmental treatment, sanitization and decontamination of hospital equipment, medical devices, water treatment systems and their structures, air purification systems, or any other critical level sanitization application, sanitization of air conditioning systems, or in air purification equipment. [00179] In one embodiment, the present invention may be applied in aqueous solution, powder, paste, wet gel, lubricating oil, xerogels, aerosols, spray, foam, tablets, capsules or in adhesives, whether or not inserted into cellulosic, polymeric materials or fabrics.

[00180] In another embodiment, the antimicrobial composition can be applied to plastic polymeric bases or to organic matrices such as cellulosic material or cotton, or woven or non-woven matrices of synthetic, artificial, natural or mixed composition.

[00181] The present technology can be better understood with the following non-limiting examples.

Example 1. Initial processes for preparing inclusion compound compositions in different molar proportions.

[00182] In one embodiment, the process of preparing the solutions with the inclusion compounds was carried out by adding the compound to be encapsulated, such as the chlorhexidine salt, to an aqueous solution containing beta-cyclodextrin encapsulant at 60°C, maintaining the molar proportions at 1:1 (A1), 1:2 (A2), 1:3 (A3) or 1:4 (A4), respectively, following the procedure reported in the literature with minor changes (CORTÉS et al., The chlorhexidine:6-cyclodextrin Inclusion compounds: preparation, characterization and microbial evaluation. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 40, 2001, 297-302).

Table 1. Compositions of inclusion compounds/complexes in different molar ratios.

Example 2. Processes for preparing emulsions of inclusion compounds in different molar proportions.

[00183] In one embodiment, the emulsion preparation process was carried out by adding the inclusion compound to distilled water, under constant stirring and at room temperature. Then, polysorbate 20 pre-diluted in distilled water was added in an equimolar proportion. The process of Polysorbate 20 was inserted using high pressure and vigorous stirring. The emulsion (A5) was kept stirring for 10 minutes and then transferred to a container and set aside.

Table 2. Composition of emulsion A5.

Example 3. Processes for inserting the inclusion compound into a matrix for Cobb increase in paper.

[00184] In one embodiment, the process of inserting the inclusion compound into cellulosic resin was carried out by adding 3.0g of inclusion compound A2, solubilized in 42.0g of distilled water, to 5.0g of acrylic resin (A6), forming a 10% resin solution (5g/50g) or 3.0g of inclusion compound A2, 3.5g of starch and 43.5g of distilled water (A7), forming a 7% starch suspension (3.5g/50g). Both matrices (resin and starch) are used to increase the Cobb (a measure of the water absorption capacity of a paper). The mixture was vigorously stirred for 20 minutes at room temperature. The mixtures were transferred to containers and set aside.

Table 3. Composition A6.

Example 4. Studies of antifungal activity using inhibition halo analysis against the fungus Penicillium expansum with application of the encapsulated product on a cellulose matrix.

[00185] In one embodiment, in the study, each test microorganism was inoculated into Petri dishes of Mueller Hinton + 2% glucose culture medium. Using sterile scissors and a mold, the samples were marked and cut into 0.8 cm diameter discs. One disc was inoculated onto the surface of the Petri dishes with the inoculated fungal suspensions. The plates were incubated at 25°C. The test The test was performed in triplicate, all accompanied by positive controls (fungal suspension + culture medium) and negative controls (sample + culture medium). The results were read after 10 days of plate incubation, during which the presence or absence of a halo around the inoculated sample was verified. If an inhibition halo formed, its diameter was measured and the result expressed in millimeters.

[00186] In one embodiment, during the test, the formation of a microbial growth inhibition halo was evidenced when the Penicillium expansum fungus was tested (Fig. 1). There was adequate development of the test microorganism on the control plates.

[00187]The methodologies used were: Standardization of Antimicrobial Susceptibility Tests - Anvisa/CLSI Method (M2-A8, Vol. 23 No. 1). Method for evaluating the inhibitory activity of preparations in liquid, creamy and solid forms, Manual of Sanitizing Agents, INCQS/FioCruz, 1992. Agar plate diffusion method. BLOCK, S.S.; Disinfection, Sterilization and Preservation, 4th ed. 1991. The analyses were carried out in the laboratories of the Tropical Culture Collection, André Tosello Foundation.

Table 4: Results, in millimeters, of the average halo readings obtained in each sample, compared to the microorganism tested. Results in Fig. 1.

Example 6. Studies of antifungal activity against the fungus Candida auris.

[00188] In one embodiment, antifungal activity tests were performed for active ingredient A2 against the fungus Candida auris (C. auris) using minimum inhibitory concentration (MIC) methodology. In the test, inclusion compound A2 in distilled water was used as the base solution, having an initial test concentration of 1.5%. The studies showed that the active ingredient had a MIC value of 0.0058% (w/w) against the microorganism.

Example 7. Studies of antibiofilm activity of the fungus Candida auris.

[00189] In one embodiment, for biofilm formation, an inoculum of 10 ⁷ cells/mL in Sabouraud Dextrose (SD) Agar broth (200 pL) was incubated in 96-well polystyrene plates for 24 h at 37° C. The metabolic viability of the biofilm was assessed by the MTT reduction assay (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, Sigma). [00190] In one embodiment, all tested products were effective in inhibiting microbial biofilms, as shown in the tables below.

Table 5. Resulting minimum inhibitory concentration.

[00191] In one embodiment, the final result concludes that both inclusion compounds A2 and A3 are effective in eliminating mature biofilm of the super fungus Candida auris.

Example 8. Studies of inhibitory, antifungal activity of the fungus Colletotrichum musae and Colletotrichum lindemuthianum.

[00192] Determination of minimum inhibitory concentration performed according to USP Methodology XXIII, Antibiotics: Microbial Assays, U.S. Pharmacopeia and Larpent, J. P. Practical Microbiology, Edgard Blücher, p 80. Methodology of Antimicrobial Susceptibility Tests by Dilution for Aerobic Growth Bacteria: Approved Standard - Sixth Edition. National Committee for Clinical Laboratory Standards, 2003. The analysis was performed with samples TNEA21201 (A2) and B2H20I04 (A3) in concentrated powders (98-100%) where the first dilution tested was 50% dilution, from this biserial dilutions (50%) were performed. The test was performed in triplicate and the results are reported in Table 6.

Table 6. Results obtained from the averages of the minimum inhibitory concentration analyses of the sample analyzed, against the selected microorganisms.

[00193] Where ranges are provided, the extremes are included. Further, it is understood that unless otherwise indicated or evident from the context and/or the knowledge of one skilled in the art, values expressed as ranges may assume any specific value within the stated limits, in different embodiments of the invention, with an accuracy of up to one-tenth of a unit. of the lower limit of the interval, unless the context clearly requires otherwise. It is also understood that, unless otherwise indicated or evidenced by the context and/or the knowledge of an expert in the field, values expressed as intervals may encompass any subinterval within the given interval, provided that the extremes of that subinterval are expressed with the same precision (to within one-tenth of a unit of the lower limit of the original interval).

[00194] As used herein, the terms 'treatment' or 'treating' refer to a pharmaceutical regimen or other intervention intended to achieve beneficial or desired results in the recipient. Beneficial or desired results include, but are not limited to, a therapeutic and/or prophylactic benefit. A therapeutic benefit may refer to the eradication or attenuation of symptoms or the underlying condition being treated. Additionally, a therapeutic benefit may be achieved by eradicating or attenuating one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient continues to be affected by the underlying condition. As used herein, the term 'treatment' or 'treating' refers to the therapeutic intervention, management, or alleviation of a disease, disorder, or condition in a patient. Unless otherwise specified, the term encompasses both human and animal patients, hence its use in medicine and/or veterinary medicine. A prophylactic effect includes delaying, preventing, or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination of these actions. For a prophylactic benefit, a patient at risk of developing a particular disease, or a patient exhibiting one or more physiological symptoms of a disease, may undergo treatment even if a formal diagnosis of the disease has not yet been established.

[00195] The term "comprises" or "comprising" when used in this document is intended to indicate the presence of the mentioned features, elements, integers, steps and components, but does not preclude the presence or addition of one or more other features, elements, integers, steps and components, or groups thereof.

[00196] The present invention is, of course, in no way restricted to the embodiments described in this document and a person with average knowledge of the area will be able to foresee many possibilities for modifying it and replacing technical characteristics with equivalent ones, depending on the requirements of each situation, as defined in the attached claims.

[00197] The following claims define additional embodiments of the present description.

Claims

1. Use of an antimicrobial composition characterized by being used as an anti-fouling agent and/or agent enhancing antimicrobial action against resistant microorganisms, fungi, bacteria, fungal biofilms, or algae; in which the composition comprises at least one cyclic oligosaccharide as an encapsulating agent, at least one antiseptic active ingredient; in which the encapsulating agent and the active ingredient form an inclusion compound. 2. Use of a composition according to the previous claim, characterized in that the molar ratio between the antiseptic active ingredient and the encapsulating agent varies between 8:1 and 1:10. 3. Use of a composition, according to the previous claims, characterized by presenting a molar ratio between the antiseptic active ingredient and encapsulating agent that varies from 1:1 to 1:8; preferably from 1:2 to 1:4. 4. Use of a composition according to any one of the preceding claims, characterized in that it further comprises a free cyclic oligosaccharide. 5. Use of a composition according to any one of the preceding claims, characterized in that the mass of free cyclic oligosaccharide, relative to the total mass of the composition, varies between 6. Use of a composition according to any one of the preceding claims, characterized in that it comprises encapsulating agents selected from a list consisting of: betacyclodextrin, alphacyclodextrin, or gammacyclodextrin and/or their structural variations or mixtures thereof. 7. Use of a composition according to any one of the preceding claims, characterized in that the concentration of the antiseptic active ingredient varies from 0.005% to 30% (m/v); preferably 0.01% - 10% (m/v). 8. Use of a composition according to any one of the preceding claims, characterized in that the antiseptic active ingredient is cationic, anionic, zwitterionic, or neutral; and/or selected from a list consisting of classes of: £>/s-biguanide, antimicrobial agent, essential oil, hydrolate, or mixtures thereof; preferably wherein the antimicrobial agent is an antibiotic, antifungal agent, antiparasitic agent, or mixtures thereof. 9. Use of a composition according to the preceding claim, characterized in that the b/s-biguanide is selected from a list consisting of: chlorhexidine, or its acetate, gluconate, or digluconate salts, or mixtures thereof. 10. Use of a composition according to claim 8, characterized in that the antibiotic is selected from a list consisting of: tetracycline, beta-lactam; aminoglycoside; macrolide; fluoroquinolone; sulfonamide; oxazolidinone; glycopeptide; streptogramin; rifamycins; or mixtures thereof. 11. Use of a composition according to claim 8, characterized in that the antifungal agent is selected from a list consisting of: azoles, polyenes, echinocandins, or mixtures thereof. 12. Use of a composition according to claim 8, characterized in that the essential oil is selected from a list consisting of: essential oil from natural bases such as thyme, eucalyptus, oregano, basil, mint, peppermint, levantia, horsetail, mint, rosemary, field rosemary, pequi, geranium, citronella, palmarosa, pitanga, hibiscus, cypress, tea tree, ginger, lemongrass, ora-pro-nóbis, moringa, cinnamon, muira puama, amapá, lemongrass or propolis, or mixtures thereof. 13. Use of a composition, according to the previous claim, characterized in that the concentration of the essential oil varies between 0.05% and 99.00% (m/m). 14. Use of a composition according to any one of the preceding claims, characterized in that the composition further comprises the addition of an organic acid and/or a saturated or unsaturated chain alcohol; preferably wherein the main chain of the organic acid and/or the saturated or unsaturated chain alcohol has a number of carbon atoms between 1 and 10; more preferably between 2 and 8. 15. Use of a composition according to any one of the preceding claims, characterized in that it further comprises at least one of the following excipients: humectant, emulsifier, preservative, thickener, sweetener, stabilizer, colorant, antioxidant, surfactant, drug delivery vehicle, or flavorings, or mixtures thereof. 16. Use of a composition according to the previous claim, characterized in that the excipient concentration varies between 0.02% to 99.00% (m/m); preferably 0.5% to 10% (m/m). 17. Use of a composition according to any one of the preceding claims, characterized in that it has antimicrobial activity against microorganisms selected from a list consisting of: Clostridioides difficile, Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Proteus mirabilis, Campylobacter spp., Salmonella spp., Klebsiella spp., Pseudomonas spp., Legionella spp., Acinetobacter spp., Enterococcus spp., Enterobacter spp., Aspergillus fumigatus, Candida spp., Cryptococcus neoformans, Talaromyces marneffei, Pneumocystis jirovecii, Paracoccidioides brasiliensis, Histoplasma spp., Madurella spp., Nocardia spp., Nakaseomyces spp., Scedosporium apiospermum, Pseudallescheria spp., Lomentospora prolificans, Pichia kudriavzeveii, Cryptococcus gattii, Phakopsora pachyrizi, Cercospora zeae-maydis, Microsporum spp., Trichophyton spp., Penicillium spp., Coccidioides spp., Epidermophyton spp., Malassezia spp., dermatophytes, fungi of the order Mucorales, coronaviruses, or protozoa alone or associated with other classes of microorganisms, even if bacteria, mycobacteria or algae. 18. Use of a composition, according to the previous claim, characterized by having antiseptic antimicrobial activity against Candida auris. 19. Use of the composition, according to any of the preceding claims, characterized in that it is for pharmacological application, whether for systemic use or for local administration. 20. Use of the composition, according to the previous claim, characterized by being for human or veterinary use in epithelial tissues, skin, mouth, fingers, eyes, nose, ears, nails, hair, mammary glands, perineal region, genitalia, mucous membranes or wounds. 21. Use of composition, according to any one of the previous claims, characterized in that it is to prepare a medicament to treat hair diseases, preferably to treat dandruff, hair dermatitis, primary cicatricial alopecia, or alopecia Tinea capitis and others. 22. Use of composition according to any one of the preceding claims 1-16, characterized in that it is for preparing a medicament to treat candidiasis, preferably fungi of the Sacharomycetaceae family, in particular fungi of the species Candida albicans and Candida auris alone or associated with other types of microorganisms, such as bacteria and/or mycobacteria. 23. Use of composition, according to the previous claim, characterized in that it is to prepare a medicament to treat candidiasis, preferably candidiasis due to infection by Candida auris. 24. Use of composition according to any one of the preceding claims 1-16, characterized in that it is for preparing a medicament to treat cutaneous and subcutaneous mycoses caused especially by fungi of the genus Sporothrix, Trichophyton, Trichosporon, Epidermophyton, Microsporum, Fusarium, Fonsecaea, Cladosporium, Exophiala, or Malassezia. 25. Use of composition according to any one of the preceding claims 1-16, characterized in that it is to prepare a medicament to treat bovine mastitis caused by the fungi Staphylococcus aureus, Staphylococcus epidermis, Streptococcus dysgalactiae, Streptococcus agalactiae, Streptococcus uberis, Streptococcus bovis, Klebsiella pneumonia or biofilms. 26. Use of composition according to any one of the preceding claims 1-16, characterized in that it is for preparing an antiseptic used in foot bath solutions. 27. Use of composition, according to any one of the previous claims 1-16, characterized by being for agricultural application; preferably as an agricultural pesticide for plantations. 28. Use of composition, according to the previous claim, characterized in that said composition is applied directly to seeds, soil, trunks, leaves and/or fruits. 29. Use of composition according to any one of the preceding claims 27-28, characterized in that said composition is for use in plantations as an agricultural defensive against fungi; preferably Penicillium, Botrytis, Colletotrichum, Colletotrichum, or Phakopsora pachyhizi; more preferably Penicillium expansum, Colletotrichum musae, or Colletotrichum lindemuthianum. 30. Use of composition according to any one of the preceding claims 27-29, characterized in that said composition is applied as an agricultural defensive against post-flowering fruit drop; preferably against a disease caused by the fungus of the Colletotrichum family; preferably a disease caused by the fungus Colletotrichum musae, or Colletotrichum lindemuthianum. 31. Use of composition according to any one of the preceding claims 1-16, characterized in that said composition is for use in foods for human or animal nutrition, and/or packaging to preserve and/or increase the durability of foods; preferably the foods are selected from a list of: animal protein, fruits, leaves, vegetables, minimally processed foods, processed cuisine, processed foods, or ultra-processed foods. 32. Use of composition according to any one of the preceding claims 1-16, characterized in that it is for use as a sanitizer for disinfecting and/or sanitizing surfaces; and/or for producing formulations for treating environments, sanitizing and decontaminating hospital equipment, medical devices, water treatment systems and their structures, air purification systems, or any other critical level sanitization application. 33. Use of composition according to any one of the preceding claims 1-16, characterized in that it is for application on plastic polymeric bases, in organic and/or non-organic matrices, woven and/or non-woven matrices of synthetic, artificial, natural, or mixed composition; preferably cellulose material and/or cotton. 34. Use of composition according to any one of the preceding claims 1-33, characterized in that said composition is in the form of an emulsion, aqueous solution, powder, paste, wet gel, lubricating oil, xerogels, aerosols, spray, foam, tablets, or capsules; preferably an emulsion. 35. Composition characterized by comprising at least one cyclic oligosaccharide as an encapsulating agent, at least one antiseptic active ingredient; in which the encapsulating agent and the active ingredient form an inclusion compound, in which the composition is used for the treatment of diseases caused by biofilm in an individual or animal. 36. Composition, according to the previous claim, characterized in that the disease caused by biofilm is selected from a list of: recurrent urinary infections, lung infections (in patients with cystic fibrosis, such as infections caused by Pseudomonas aeruginosa), periodontitis, gingivitis, chronic wounds, infective endocarditis, infections associated with medical devices. 37. Composition according to any one of the preceding claims 35-36, characterized in that the biofilm disease is caused by a Candida auris biofilm. 38. Composition according to any one of the preceding claims 35-37, characterized in that it comprises at least one cyclic oligosaccharide as encapsulating agent, at least one antiseptic active ingredient; in which the encapsulating agent and the active ingredient form an inclusion compound, in which the composition is used as a coating on a medical device for use in the preventive treatment of biofilm-mediated medical device-associated infections in an individual. 39. Composition according to the preceding claim, wherein the medical device-associated infection is caused by Candida auris; preferably said medical device-associated infection is a catheter-associated infection. 40. Composition according to any one of the preceding claims 35-39, characterized in that the molar ratio between the antiseptic active ingredient and the encapsulating agent varies between 8:1 and 1:10. 41. Composition, according to the previous claim, characterized by presenting a molar ratio between the antiseptic active ingredient and encapsulating agent that varies from 1:1 to 1:8; preferably from 1:2 to 1:4. 42. Composition according to any one of the preceding claims 35-41, characterized in that it further comprises a free cyclic oligosaccharide. 43. Composition according to any one of the preceding claims 35-42, characterized in that the mass of free cyclic oligosaccharide, relative to the total mass of the composition, varies between 44. Composition according to any one of the preceding claims 35-43, characterized in that it comprises encapsulating agents selected from a list consisting of: betacyclodextrin, alphacyclodextrin, or gammacyclodextrin and/or their structural variations or mixtures thereof. 45. Composition according to any one of the preceding claims 35-44, characterized in that the concentration of the antiseptic active ingredient varies from 0.005% to 30% (m/v); preferably 0.01% - 10% (m/v). 46. Composition according to any one of the preceding claims 35-45, characterized in that the antiseptic active ingredient is cationic, anionic, zwitterionic, or neutral; and/or selected from a list consisting of classes of: b/s-biguanide, antimicrobial agent, essential oil, hydrolate, or mixtures thereof; preferably wherein the antimicrobial agent is an antibiotic, antifungal agent, antiparasitic agent, or mixtures thereof. 47. Composition according to the previous claim, characterized in that ab/s-biguanide is selected from a list consisting of: chlorhexidine, or its acetate, gluconate, or digluconate salts, or mixtures thereof. 48. Composition according to claim 46, characterized in that the antibiotic is selected from a list consisting of: tetracycline, beta-lactam; aminoglycoside; macrolide; fluoroquinolone; sulfonamide; oxazolidinone; glycopeptide; streptogramin; rifamycins; or mixtures thereof. 49. Composition according to claim 46, characterized in that the antifungal agent is selected from a list consisting of: azoles, polyenes, echinocandins, or mixtures thereof. 50. Composition, according to claim 46, characterized in that the essential oil is selected from a list consisting of: essential oil of natural bases such as thyme, eucalyptus, oregano, basil, mint, peppermint, levantia, horsetail, mint, rosemary, rosemary of the field, pequi, geranium, citronella, palmarosa, pitanga, hibiscus, cypress, tea tree, ginger, lemongrass, ora-pro-nóbis, moringa, cinnamon, muira puama, amapá, lemongrass or propolis, or mixtures thereof. 51. Composition, according to the previous claim, characterized in that the concentration of the essential oil varies between 0.05% and 99.00% (m/m). 52. Composition according to any one of the preceding claims 35-51, characterized in that the composition further comprises the addition of an organic acid and/or an alcohol with a saturated or unsaturated chain; preferably wherein the main chain of the organic acid and/or the alcohol with a saturated or unsaturated chain has a number of carbon atoms between 1 and 10; more preferably between 2 and 8. 53. Composition according to any one of the preceding claims 35-52, characterized in that it further comprises at least one of the following excipients: humectant, emulsifier, preservative, thickener, sweetener, stabilizer, colorant, antioxidant, surfactant, drug delivery vehicle, or flavorings, or mixtures thereof. 54. Composition according to the previous claim, characterized in that the excipient concentration varies between 0.02% to 99.00% (m/m); preferably 0.5% to 10% (m/m). 55. Composition according to any one of the preceding claims 35-54, characterized in that said composition further comprises an organic matrix; preferably cellulosic material; more preferably cellulosic resin. 56. Composition according to any one of the preceding claims 35-55, characterized in that said composition is in the form of an emulsion, aqueous solution, powder, paste, wet gel, oil lubricant, xerogels, aerosols, spray, foam, tablets, or capsules; preferably emulsion. 57. A coated surface or coated article, characterized in that the coating is on a medical device and comprises the composition described in the preceding claims 35-56, for use in the preventative treatment of biofilm-mediated medical device-associated infections in an individual. 58. Coated surface or article for use according to the preceding claim, characterized in that the coated surface or article additionally comprises at least 0.01% (w/v) of the composition described in the preceding claims 35-56. 59. Coated surface or article for use according to claims 57-58, characterized in that the coated surface or article is a medical device, preferably selected from the list consisting of a catheter, a syringe, a stent, a tube, a medical packaging, a dialysis device, a dental prosthesis, a dental implant, an orthodontic device, a mask, or clothing.