BR102017027848A2 - DRUG COMPOSITION FOR THE TREATMENT OF ONICOMICOSES - Google Patents

Abstract

medicament composition for the treatment of onychomycoses The invention describes a topical use medicament for the treatment of onychomycoses which comprises the synergistic association of melaleuca alternifolia essential oil with proven antifungal and antimicrobial properties; a permeation enhancer that interacts with nail keratin, decreasing drug diffusion resistance; a film-forming polymer and solvent, which allow the active to stay in contact with the nail plate much longer, other than the fact that solvent evaporation causes the formation of a film over the entire nail surface which increases the active concentration in the film far beyond the initial concentration, constituting a deposit of the drug and enhancing its penetration by increasing the transungueal gradient.

Description

DRUG COMPOSITION FOR THE TREATMENT OF ONICOMYCOSIS

FIELD OF THE INVENTION [01] The present patent describes a medicamentous composition for the treatment of onychomycosis. More specifically, it comprises a drug composition for topical use with the synergistic association of essential oil of Melaleuca alternifolia, with proven antifungal and antimicrobial properties; a permeation promoter that interacts with the keratin of the nail, decreasing the resistance to drug diffusion; a film-forming polymer and a solvent, which allow the active to remain in contact with the nail plate for a much longer time, apart from the fact that the evaporation of the solvent causes the formation of a film on the entire nail surface which increases the concentration of the active in the film far beyond the initial concentration, constituting a deposit of the drug and potentiating its penetration by increasing the transungeal gradient.

[02] BACKGROUND OF THE INVENTION [03] Onychomycosis is a generic term used to describe pathological processes of fungal etiology that affect the nail unit (Morais OO. Evaluation of the effectiveness of the Erbium-Doped Yttrium Aluminum Garnet (ER: YAG) laser associated with enamel of amorolfine in the treatment of onychomycosis: paired and randomized study. Master's Dissertation. University of Brasilia, 2013).

[04] This chronic disease, which represents more than 30% of all mycotic infections (Summerbell RC. Epidemiology and ecology of onychomycosis. Dermatoly. 1997; 194: S32-36), is considered a

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2/11 important public health problem, given the high prevalence and therapeutic difficulty, associated with high rates of recurrence and evolution to chronic lesions (Zanardi D et al. Evaluation of the diagnostic methods of onychomycosis. An Bras Dermatol. 2008; 83: 119-24; Van Der Schroeff JG et al. A randomized treatment duration-finding study of terbinafine in onychomycosis. Br J Dermatol. 1992; 126: 36-9; Souza EAF et al. Frequency of onychomycosis caused by yeasts in Maringa , Parana, Brazil.An Bras Dermatol. 2007; 82: 1516), in addition to acting as a gateway for other infections.

[05] Onychomycosis can be caused by a diversity of fungal species, which determine a range of morphological changes (Zaias N, Drachman D. A method for the determination of drug effectiveness in onychomycosis. J Am Acad Dermatol. 1983; 9 ( 6): 912-19; Hay RJ, Baran R. Onychomycosis: a proposed revision of the clinical classification. J Am Acad Dermatol. 2011; 65 (6): 1219-27).

[06] Most authors diagnose dermatophytes (80 to 90%) as the most frequent agents, followed by yeasts (5 to 17%) and non-dermatophyte filamentous fungi (2 to 12%) (Perca S et al. A. Prevalence andrisk factors of tinea unguium and tinea pedis in the general population in Spain. J Clin Microbiol. 2000; 38 (9): 3226-30; Haneke E. Fungal infections of the nail. Semin Dermatol. 1991; 10: 4153; Kenna ME , Elewski BE. A US epidemiological survey of superficial fungal diseases. J Am Acad Dermatol. 1996; 35: 539-42; López-Jodra O, Torres-Rodriguez JM. Fungal species with responsible onychomycosis. Rev Iberoam Micol. 1999; 16 (1): 11-15). [07] Considering the implications caused by onychomycosis, its treatment is indicated both from medical and

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Psychosocial 3/11 (Finch JJ, Warshaw E. To enail onychomycosis: current and future treatment options. Dermatol Ther. 2007; 20 (1): 31-46). However, as there is a large therapeutic arsenal available, the management of each patient must be individualized, with the objective of maximizing adherence and achieving therapeutic success (Zaias N, SX Escovar, Rebel G. Opportunistic to enail onychomycosis. The fungal colonization of anavailable nail unit space by non-dermatophytes is produced by the trauma of the closed shoe by an asymmetric gait or other trauma. A plausible theory. European Academy of Dermatology and Venereology. 2014; 28: 002-1006).

[08] In general, the treatment of onychomycosis consists of the use of oral antifungal agents. Oral therapy, however, takes months to become effective, since it requires high concentrations of drug in the circulation to achieve therapeutic levels at the site of infection (Palliyil B, Lebo DB, Patel PR. A preformulation strategy for the selection of penetration enhancers for a transungual formulation. AAPS Pharm Sci Tech. 2013; 14 (2): 682-691; Brown MB et al. Overcoming the nail barrier: A systematic investigation of ungual chemical penetration enhancement. Int J Pharm. 2009; 370 (1): 61-7). In addition, due to the side effects associated with systemic antifungal therapy, which requires monitoring of liver functions and blood cell counts in some cases, it may become contraindicated (Murdan S. Drug delivery to the nail following topical application. Int J Pharm. 2002; 236 (1-2): 1-26).

[09] The main drugs with systemic action used in the treatment of onychomycosis are of synthetic origin and belong to the groups of alkylamines and azole antifungals, among which is

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4/11 possible to mention griseofulvin, ketoconazole, fluconazole, terbinafine and itraconazole. A meta-analysis carried out showed average cure rates of 76% for terbinafine, 63% for itraconazole, 61% for griseofulvin and 48% for fluconazole (Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol. 2004; 150 (3): 537-44). [010] Topical therapy is advantageous for maximizing the exposure of the affected area, enabling the increase in the degree of penetration and permanence of the drug at the site of infection, and minimizing systemic exposure, thus reducing the chances of adverse effects and drug interactions (Palliyil B, Lebo DB, Patel PR. A preformulation strategy for the selection of penetration enhancers for a transungual formulation. AAPS Pharm Sci Tech. 2013; 14 (2): 682-691; Brown MB et al. Overcoming the nail barrier: A systematic investigation of ungual chemical penetration enhancement. Int J Pharm. 2009; 370 (1): 61-7; Murdan S. Drug delivery to the nail following topical application.Int J Pharm. 2002; 236 (1-2) : 1-26 However, in order for it to be successful, it is necessary to choose a potent antifungal to ensure that effective concentrations reach the site of action, in order to eradicate the infection. nail, drug and formulation should be taken into account to improve the diffusion of the asset. [011] Topical treatment approved in Brazil includes the drugs amorolfine, ciclopirox and tioconazole. Such therapeutic options are of synthetic origin, have a high cost and are often ineffective in eradicating the infection. Thus, safer, more efficient and affordable alternatives must be envisaged.

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5/11 [012] The state of the art describes several drug compositions for the treatment of onychomycosis, such as document PI1106123, by the same holder, which comprises a formulation for topical use based on tea tree oil (M elaleuca altemifolia) between 45 , 0 to 55.0%, between 0.20 to 0.25% of chitosan, between 0.08 to 0.10% of 2,6-di-tert-butyl-4-methyl phenol (BHT), between 0 , 05 to 0.15% sodium metabisulfite, between 2.0 to 3.0% benzyl alcohol, sodium hydroxide qs ph 5.0 and isopropyl alcohol q.s.p.

[013] The document BRPI1003691 describes a phytotherapic formulation with indication for the treatment of onychomycosis, whose active ingredient is Alijum cepa 5%, whose chemical constituents are thiopropionic acid, aliine, gliocoquinine, atylpropyl disulfide. methylaline, cycloaline, gitonin F and quercetin.

[014] BRPI9915394 describes an antifungal therapeutic preparation to cure fungal nail infections that comprises the combination of an antifungal agent (miconazole), DMSO and a secondary anti-inflammatory agent (ibuprofen) in polyglycol.

[015] BRPI0713002 describes single-phase pharmaceutical compositions, for topical application, comprising a biologically active agent, a delivery vehicle comprising at least one non-polymeric crystallization inhibitor and a film former, and a volatile solvent.

[016] BRPI9904662 describes pharmaceutical compositions for the treatment of dermatoses, comprising extracts, juices and essential oils from the leaves and aerial parts of Erigeronbonariensis (Asteraceae).

[017] The document BRPI9200786 describes a

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6/11 dermatological composition comprising at least one antifungal agent selected particularly from those of the allylamine family, at least one hydrophilic penetrating agent and a hydroalcoholic medium that solubilizes said antifungal agent (s) and with which said penetrating agent (s) is (are) at least partially miscible.

[018] BR112015022590 describes a pharmaceutical composition for the treatment of fungal infections that comprises a urea-based component, a diol component, an organic acid component, and a triol component.

[019] The document BR102015022081 refers to a formulation for topical use containing curcumin and / or curcuminoids in carbopol gel and / or emulsion O / A, as vehicles for incorporation, aiming at the treatment of onychomycosis.

[020] BR112016099223 describes a topical antifungal composition, in the form of enamel, for the treatment of onychomycosis, which essentially consists of cyclopirox as an antimycotic agent, hydroxypropyl chitosan as a film-forming agent, water and a lower alkanol as a solvent .

[021] The document BRPI1000338 describes a compound for application in the treatment of onychomycosis, whose formulation has acetic acid as its main asset, which through some preparation steps originates a product for topical use.

[022] BRPI0704809 describes a topical formulation for the treatment of superficial mycoses containing Piper regnellii extract, incorporated in a cosmetic enamel.

[023] The document BRPI0617576 describes a pharmaceutical composition for nail and nail application intended for

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7/11 treatment and / or prevention of dermatological conditions, in particular onychomycosis, comprising an antimycotic agent of the morpholines family and a water-soluble filmogen agent.

[024] The document BRPI0301913 describes a curative formula for nail ringworm, whose formula comprises enamel and silver nitrate (AgNO ₃ ).

[025] BRPI9904780 describes a nail polish for the treatment or prevention of fungal infections, such as onychomycosis, which includes an efficient fungicidal proportion of cyclopirox, econazole or other fungicidal agent in a film-forming enamel, which includes a forming polymer water-insoluble film, 2-n-nonyl-1,3-dioxolane or similar penetration enhancer and volatile solvent.

[026] Most state-of-the-art documents describe compositions for the treatment of onychomycosis and other fungal infections that comprise the use of synthetic active ingredients for topical application or in the form of cosmetic enamel. [027] Among the compositions that use plant-based actives, phytotherapeutic formulations are foreseen for topical use or in the form of enamels, which, however, may have mutagenic or genotoxic potential.

[028] However, given the fact that the nail plate is extremely hard and impermeable, due to the physical and chemical stability of the disulfite and hydrogen bonds found in keratin (Chohuan P, Saini TR. Hydratation of nail plate: A novel screening model for transungueal drug permeation enhancers. Int J Pharm. 2012; 436 (1-

2): 179-82), the access of the drug to the agents that cause onychomycosis is restricted. Although topical formulations allow a

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8/11 greater proximity to the infection site, some areas may still remain relatively inaccessible, making it difficult to maintain effective concentrations of antifungals.

[029] Formulating antifungals to achieve transungueal penetration, ideal for the active ingredient, has been a challenge.

[030] Antifungal formulations focused on obtaining a greater concentration gradient on the nail surface through the use of delivery systems that comprise the active, a film-forming polymer and a solvent, allow the active to remain in much longer contact with the nail plate, favoring therapeutic success (Kircik LH. Enhancing transungual delivery ans spreading of efinaconazole under the nail plate through a unique formulation approach. J Drugs Dermatol. 2014; 13 (12): 1457-61; Rajendra et al. Transungual drug delivery: an overview J App Pharm Sci. 2012; 2 (1): 203-9).

[031] When applied, the solvent evaporates, forming a film over the entire nail surface. The evaporation process increases the concentration of the active ingredient in the film far beyond the initial concentration, constituting a deposit of the drug and enhancing its penetration by increasing the transungual gradient (Murdan S. Drug delivery to the nail following topical application. Int J Pharm. 2002; 236 (12): 1-26). The formation of the film also reduces the loss of water from the nail surface, resulting in a super-hydration that intensifies the diffusion of the drug. This type of delivery is considered safe (Akhtar N, Sharma H, Pathak K. Onychomycosis: Potential of nail lacquers in transungual delivery of antifungals. Scientifica. 2016; 2016: 112), easy to use and excellent tolerance and acceptance, increasing, thus, the patient's adherence to treatment (Kircik

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9/11

LH. Enhancing transungual delivery ans spreading of efinaconazole under the nail plate through a unique formulation approach. J Drugs Dermatol. 2014; 13 (12): 1457-61; Miron D. Evaluation of the antifungal activity of monoterpenes and development of analytical methods and topical formulation. Doctoral thesis. Federal University of Rio Grande do Sul, Porto Alegre, 2013).

[032] Thus, the object of the present invention is a drug composition for the treatment of onychomycosis, for topical use, with the synergistic association of essential oil of Melaleuca alternifolia, with potential antifungal activity, demonstrated in vivo and in vitro by several studies ( Buck DS, Nidorf DM, Addino JG. Comparison of two topical preparations for the treatment of onychomycosis: Melaleuca alternifolia (teatree) oil and clotrimazole. J Farm Pract. 1994; 38 (6): 601-5; Carson CF, Riley TV, Cookson BD. Efficacy and safety of tea tree oil as a topical antimicrobial agent. J Hospi Infect. 1998; 40 (3): 175-8; Syed et al. Treatment of to enail onychomycosis with 2% butenafine and Melaleuca alternifolia (teatree) oil in cream. Trop Med Int Health. 1999; 4 (4): 284-7; Hammer KA, Carson CF, Riley TV. In vitro activity of Melaleuca alternifolia (teatree) oil against dermatophytes and other filamentous fungi. J Antimicrob Chemother. 2002; 50: 195-99); a permeation promoter that interacts with the keratin of the nail, decreasing the resistance to drug diffusion; a film-forming polymer and a solvent, which allow the active to remain in contact with the nail plate for a much longer time, apart from the fact that the evaporation of the solvent causes the formation of a film on the entire nail surface which increases the concentration of the active in the film far beyond the initial concentration, constituting a deposit of the drug and enhancing its penetration by the

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10/11 increase in the transungeal gradient.

[033] In addition, Melaleuca alternifolia oil and its components are not mutagenic or genotoxic (Hammer KA, Carson CF, Riley TV, Nielsen JB. A review of the toxicity of Melaleuca alternifolia (teatree) oil. Food Chem Toxicol. 2006 ; 44: 616-625), providing a safe, effective and affordable alternative compared to currently available treatments, acting on the focus of the infection, increasing the concentration in the nail plate and thereby facilitating penetration into the nail plate, with reduced adverse effects.

[034] Additionally, the solvent added to the topical composition undergoes evaporation, resulting in a deposit of the drug on the nail, promoting its penetration to the infection site. In order to intensify this penetration, the composition, object of the present invention, presents in its formulation a permeation promoting agent, which interacts with the keratin of the nail, decreasing the resistance to the diffusion of the drug and improving the dynamic activity of the active principle, increasing its flow (Vieira SPP. Promotion of cutaneous absorption of drugs: state of the art. Master's dissertation. Universidade Fernando Pessoa, Porto, 2013).

DETAILED DESCRIPTION OF THE INVENTION [035] The drug composition for the treatment of onychomycosis, the object of the present invention patent, comprises a topical herbal medicine with the synergistic association of the essential oil of Melaleuca alternifolia, an active agent with antifungal and antimicrobial properties, among 2.0 to 30.0%; between 1.0 to 10.0% of a permeation promoting agent that interacts with the keratin of the nail, decreasing the resistance to the diffusion of the drug;

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11/11 between 5.0 to 20.0% of a film-forming agent and between 1.0 to 15.0% of a plasticizer, said film-forming agent and plasticizer that allow the active to remain much longer in contact with the nail plate; between 2.0 to 80.0% of a solvent that, when evaporating on topical application on the nail, causes the formation of a film on the entire surface of the nail that increases the concentration of the active in the film far beyond the initial concentration, constituting a deposit of the drug and enhancing its penetration by increasing the transungueal gradient; and between 0.005 to 0.20% of an antioxidant agent.

[036] The film-forming agent is a polymer.

[037] Preferably, the plasticizer is triacetin (1,2,3 triacetoxypropane) or glycerin.

[038] The solvent is selected from ethyl acetate, butyl acetate or ethanol, alone or in combination.

[039] The antioxidant agent is selected from BHT (Butylhydroxytoluene) or BHA (Butylhydroxy-anisole), alone or in combination. [040] The permeation promoting agent must have low molecular weight and compounds that interact with disulfide bridges present in the amino acid cysteine, which makes up the keratin molecule, so that the keratolysis induced by this interaction increases the transungueal permeation of the drug.

Claims (6)

CLAIMS: 1. DRUG COMPOSITION FOR THE TREATMENT OF ONICOMYCOSIS characterized by comprising between 2.0 to 30.0% of essential oil of Melaleuca alternifolia, between 1.0 to 10.0% of a permeation promoting agent, between 5.0 to 20 , 0% of a film-forming agent, between 1.0 to 15.0% of a plasticizer, between 2.0 to 80.0% of a solvent and between 0.005 to 0.20% of an antioxidant agent. 2. DRUG COMPOSITION FOR THE TREATMENT OF ONICOMYCOSIS, according to claim 1, characterized by the fact that the plasticizer is triacetin or glycerin. 3. DRUG COMPOSITION FOR THE TREATMENT OF ONICOMYCOSIS, according to claim 1, characterized by the fact that the solvent is selected from ethyl acetate, butyl acetate or ethanol, alone or in combination. 4. DRUG COMPOSITION FOR THE TREATMENT OF ONICOMYCOSIS, according to claim 1, characterized by the fact that the antioxidant agent is selected from BHT (Butylhydroxy-toluene) or BHA (Butylhydroxy-anisol), alone or in combination. 5. DRUG COMPOSITION FOR THE TREATMENT OF ONICOMYCOSIS, according to claim 1, characterized by the fact that the permeation promoting agent has low molecular weight and compounds that interact with disulfide bridges present in the amino acid cysteine. 6. DRUG COMPOSITION FOR THE TREATMENT OF Petition 870170100955, of 12/22/2017, p. 18/20 2/2 ONICOMYCOSIS, according to claim 1, characterized in that the film-forming agent is a polymer.