COMPOSIÇÃO E PROCESSO DE OBTENÇÃO DE NANOCARREADOR LIPÍDICO À BASE DE ISOQUERCITRINA E ÓLEO DE SYAGRUS CEARENSIS PARA CANDIDÍASE

Description

1 / 14 COMPOSITION AND PROCESS FOR OBTAINING A LIPID NANOCARRIER BASED ON ISOQUERCITRIN AND SYAGRUS CEARENSIS OIL FOR CANDIDIASIS

[001] The present invention relates to the field of Biotechnology, directed to the pharmaceutical industry, and concerns the composition and process for obtaining a lipid nanocarrier based on isoquercitrin and catolé coconut oil (Syagrus cearensis) for candidiasis, characterized by comprising: Anthophila (bee) wax, catolé coconut kernel oil (Syagrus cearensis), poly(ethylene oxide) stearate, isoquercitrin and water.

[002] The system proposed in the present invention has potential as an antifungal drug and the advantage of being in nanostructured form. Its distinguishing feature is the use of a bioactive strategically associated with beeswax and babassu coconut oil.

[003] Currently, hospital-acquired fungal infections have been studied due to their higher prevalence, in addition to high mortality rates, which vary between 40 and 70%, this percentage being linked to the risk factor involved (CORZOLEÓN et al., 2015). Among clinically important yeasts, those of the genus Candida are relevant, opportunistic pathogens found in hospitalized patients, particularly immunocompromised individuals (PFALLER et al., 2014).

[004] Antifungal drugs, including azoles, amphotericin B, allylamines, and echinocandins, are widely used to treat candidiasis. However, the continuous use of these antifungal drugs has led to fungal species belonging to the genus Candida developing resistance to multiple administered drugs. In addition, the production of biofilms by fungi contributes to a reduction in drug concentration at the microbial site, therefore requiring new effective anti-Candida agents (GUPTA; YVAS, 2012), (SILVA et al., 2023). Petition 870250006183, dated 01 / 27 / 2025, page 9 / 29 2 / 14

[005] From this treatment perspective, natural products are an important source of anti-infective agents (RAJESHKUMAR; SUNDARARAMAN, 2012). Isoquercitrin or quercetin-3-O-β-D-glucopyranoside is one of the main glycosidic forms of the flavonoid species quercetin, being found in various types of plant sources. It also occurs in foods derived from these plants, such as teas and wines (HASUMURA ​​et al., 2004).

[006] Among the physicochemical properties of isoquercitrin, the increased solubility it possesses due to the glycosylation process stands out, having a solubility equal to 206 pmol / L (MAKINO et al., 2009), the (log P) of the described bioactive has a magnitude determined between 0.76 and 0.77. The spectral properties of the compound indicate that the absorption bands in the UV-VIS spectrum are located from the beginning of the spectrum up to 400 nm; in terms of color, isoquercitrin presents a yellow color.

[007] The listed biological properties of isoquercitrin are based on its action in combating free radicals, reactive oxygen species (ROS), and reducing prostaglandin levels. Based on studies of the bioactive's mechanisms of action, its use in in vivo tests is directed towards research that evaluates: bioavailability, metabolism, safety, and subsequently, assays are focused on potential antioxidant, anti-inflammatory, anticarcinogenic, cardioprotective, antidiabetic, antiallergic, and neuropharmacological activities (VALENTOVÁ et al., 2014).

[008] However, due to structural complexity, its use becomes limited, making it necessary to use intelligent delivery systems that minimize the problems related to the use of natural products, such as low solubility in water and low availability via oral route (TABOSA et al., 2018). Petition 870250006183, dated 01 / 27 / 2025, page 10 / 29 3 / 14

[009] The use of nanostructured systems emerges as a viable alternative in the process of carrying hydrophobic actives, since these systems possess properties that can enhance the biological effect of these bioactives due to increased bioavailability in the physiological environment. Within the field of nanostructured systems, nanostructured lipid carriers (NLCs) have stood out due to their potential, such as: high encapsulation efficiency, sustained release of bioactives, high storage stability, enhanced biocompatibility, and improved bioavailability compared to other nanocarrier systems (PATIL et al., 2018).

[010] CLNs consist of a mixture of solid and liquid lipids in a ratio that can vary from 70 / 30 to 99.9 / 0.1. By mixing solid and liquid lipids in different proportions, more space can be obtained for encapsulation of the active component, forming a less ordered lipid matrix.

[011] Nanostructured carriers have in their composition a lipid matrix stabilized with surfactant. This matrix has an outer part, which defines the surface characteristics, and an inner part or core, which determines characteristics such as: shape, size and compartment where the drug is located (BUNJES, 2011).

[012] The lipid matrix composed of solid and liquid lipids can exhibit complex crystalline behavior, which depends on the composition of this matrix. The crystallization process begins after cooling during synthesis and can continue during the storage of the nanosystems. This process influences the characteristics of the nanocarriers, such as: particle morphology, drug incorporation, and the stability of this type of colloid (RIBEIRO et al., 2015).

[013] Beeswax (Anthophyla) is a solid lipid matrix, widely used in industry as a thickener and humectant in the manufacture of ointments, creams and lipsticks. It has been obtained from the honeycombs of bees of the genus (Apis mellifera) (ROSIAUX et al., 2014). Petition 870250006183, dated 01 / 27 / 2025, page 11 / 29 4 / 14

[014] Beeswax (Anthophylla) has a chemical composition rich in esters of saturated fatty acids and long-chain alcohols, especially: hydrocarbons, monoesters, diesters, triesters, free myristic acid and varying amounts of hydroxy acids and diols, which give the wax its characteristic solidity at room temperature, a melting point of 65°C and insolubility in water. Considering its high availability and relatively low industrial cost, new forms of application of beeswax are of great interest (SOUZA; DE FREITAS; MAIA CAMPOS, 2017).

[015] Beeswax is a natural product used in the cosmetic, pharmaceutical and food industries. Its highly crystalline nature negatively affects the drug retention capacity, leading to the need for the formation of blends with liquid-phase lipids that can break this crystalline profile, providing an improvement in the encapsulation efficiency of the system (ATTAMA; MÜLLER-GOYMANN, 2008).

[016] In order to solve such problems, the present invention, the subject of the claimed matter, was developed. In this context, the composition and preparation process of a lipid nanocarrier based on isoquercitrin and babassu coconut oil (Syagrus cearensis) for candidiasis becomes a treatment alternative, presenting the advantages of using natural bioactives incorporated into stabilized nanostructured systems, being non-toxic and having greater bioavailability, in addition to being able to solve the problem of Candida resistance to other drugs.

[017] Below are the non-patent documents relating to products and processes most closely related to the present invention, including the following publications: Petition 870250006183, dated 01 / 27 / 2025, p. 12 / 29 5 / 14

[018] The work of (DAHHAM et al., 2016) entitled Development and evaluation of a film-forming system hybridized with econazole-loaded nanostructured lipid carriers for enhanced antifungal activity against dermatophytes, which deals with the use of CLNs as a platform for encapsulating the drug econazole, differs from the present invention by employing a drug that is repeatedly used in the treatment of fungal infections, whereas the present invention proposes the use of an antifungal agent of natural origin that is not being used in conventional treatments, isoquercitrin.

[019] The work of (MENDES et al., 2013) entitled Miconazole-loaded nanostructured lipid carriers (NLC) for local delivery to the oral mucosa: Improving antifungal activity, which deals with the use of miconazole in association with NLCs for the treatment of fungal infections in the oral mucosa, differs from the present invention which will use NLCs to combine the therapeutic action of catolé coconut oil with the action of the drug isoquercitrin for a broader treatment of candidiasis.

[020] The work of (MOAZENI et al., 2024), entitled Lesson from nature: Zataria multiflora nanostructured lipid carrier topical gel formulation against Candida-associated onychomycosis, a randomized double-blind placebo-controlled clinical trial that deals with the association of zataria multiflora essential oil with CLNs, differs from the present invention which uses a drug in solid form, which implies greater efficiency in the incorporation of the drug, given that in this context there will be no losses due to volatilization.

[021] The following documents were found in the patent field:

[022] Patent BR 10 2019 016450 6 A2, filed on 08 / 08 / 2019, which deals with a PROCESS FOR OBTAINING TILAPIA OIL AND ITS USE AS AN INGREDIENT WITH RESTORATIVE ACTION ON SKIN AND HAIR, AND THE USE OF TILAPIA OIL FRACTIONS AS A LIPID NANOCARRIER FOR DRUGS AND COSMETICS, which differs from the present invention by using tilapia oil as a drug, while the present invention combines the antimicrobial properties of catolé coconut oil with the properties of isoquercitrin. Petition 870250006183, dated 01 / 27 / 2025, page 13 / 29 6 / 14

[023] Patent BR 10 2019 013856 4 A2, filed on 04 / 07 / 2019, which deals with SOLID LIPID COMPOSITION FOR THE PRODUCTION OF NANOSTRUCTURED LIPID CARRIER, which differs from the present invention by applying the invention in the cosmetic area, whereas the present invention is intended for application in combating infections caused by species of the genus Candida spp, with consolidated antimicrobial action.

[024] Patent BR 10 2020 015184 3 A2, filed on 07 / 24 / 2020, which deals with a NANOSTRUCTURED LIPID CARRIER COMPRISING HYDROXYMETHYLNITROFURAL AND ITS USE FOR THE PREPARATION OF A MEDICINE TO TREAT LEISHMANIASIS, which differs from the present invention by using nanocarriers for the treatment of leishmaniasis and presenting results related to the compatibility of the nanocarriers, however the present invention has results related to antimicrobial activity.

[025] In view of the references presented, it is demonstrated that the proposed invention is novel because it uses components that have never before been combined in such a way, and it also has inventive activity because it exhibits antifungal activity against pathogens of different fungal species of the genus Candida, such as: Candida parapsilosis, Candida krusei, Candida auris and Candida albicans. In addition, the claimed matter has inventive activity because it proposes the composition of a medicine, which will be used for the treatment of candidiasis, based on isoquercitrin encapsulated in a nanostructured lipid carrier obtained through the association between catolé coconut oil (Syagrus cearensis) and beeswax (Anthophila).

[026] The following is presented with regard to the matter claimed, the composition, the preparation process, the test results of the nanostructured lipid carrier obtained by combining catolé coconut oil (Syagrus cearensis) and beeswax (Anthophila) for the encapsulation of isoquercitrin with antifungal activity against Candida spp. strains. Petition 870250006183, dated 01 / 27 / 2025, page 14 / 29 7 / 14

[027] The invention, the subject of the claim, can be better understood according to the detailed description below:

[028] The claimed subject matter of the present invention is characterized by comprising: Anthophila (bee) wax, oil from the almond of the catolé coconut (Syagrus cearensis), poly(ethylene oxide) stearate, isoquercitrin and water.

[029] The claimed material object of the present invention, characterized by the fact that isoquercitrin is obtained from the aerial parts of Hypericum perforatum L. plants, preferably from the stem.

[030] The subject matter of the present invention is characterized by the fact that catolé coconut oil (Syagrus cearensis) is obtained from the kernel by the Soxhlet extraction method.

[031] The subject matter of the present invention is characterized by the fact that beeswax (Anthophila) is obtained from the wax-producing cells of worker bees in a physiological process of conversion of glucose molecules present in honey.

[032] The claimed material object of the present invention, characterized by the fact that the poly(ethylene oxide) stearate molecule has 20 moles of ethylene oxide.

[033] The claimed material object of the present invention, characterized by the fact that the poly(ethylene oxide) stearate molecule has a molar mass of 1151.56 grams per mole.

[034] The claimed material object of the present invention, characterized by comprising: 2.00 - 4.00% (w / w) of Anthophyla wax; 1.00 - 3.00% (w / w) of Syagrus cearensis oil; 0.40 - 0.90% of poly(ethylene oxide) stearate (w / w); 0.06 - 0.30% of isoquercitrin (w / w) and 92.07 - 96.54% (w / w) of water.

[035] The subject matter of the present invention is characterized by the fact that the nanostructured lipid nanocarrier has an average particle diameter in the range of particle droplets in the range of 101 - 378 nm. Petition 870250006183, dated 01 / 27 / 2025, page 15 / 29 8 / 14

[036] The invention, the subject of the claim, can be better understood according to the detailed description below:

[037] The subject matter of the dispute is characterized by comprising the following stages: a) The oil and wax were heated to 65°C and then isoquercitrin was added until completely dissolved to form solution A; b) Poly(ethylene oxide) stearate was added to water and also heated to 65°C to form solution B; c) Solution B was added to solution A at 65°C and homogenized using a probe ultrasonicator at 70% amplitude with a pulse regime of 10 seconds on and 10 seconds off for 3 minutes to obtain dispersion C; d) At room temperature, dispersion C was cooled to solidify nanoparticles.

[038] The claimed material object of the present invention, characterized by being for preparing a medicament to treat diseases related to candidiasis.

[039] Below are the results of characterization analyses of the synthesized lipid nanocarrier: particle size, polydispersity index, zeta potential, encapsulation efficiency, determination of the minimum inhibitory concentration (MIC) against isolates of different Candida strains and in vivo toxicity test.

[040] The nanostructured lipid nanocarrier containing isoquercitrin showed the following results: particle size in the range of 101 to 378 nm, polydispersity index in the range of 0.214 to 0.382 and zeta potential in the range of -22.7 to -37.4 mV.

[041] The encapsulation efficiency of isoquercitrin in the lipid nanocarrier was 93.9%, demonstrating that the synthesized nanocarriers have a high capacity to incorporate the bioactive isoquercitrin. Petition 870250006183, dated 01 / 27 / 2025, page 16 / 29 9 / 14

[042] The nanostructured lipid carrier subject of the present invention exhibited antifungal activity against Candida parapsilosis, Candida auris, Candida albicans and Candida krusei strains, as shown in Table 1:

[043] Table 1. MIC against Candida parapsilosis ATCC 22019, Candida auris 01256P CDC, Candida albicans 1 and Candida krusei ATCC 6625 strains. Sample Strains C. parapsilosis ATCC 22019 C. krusei ATCC 6258 C. auris 01256 P CDC C. albicans 1 Syagrus cearensis oil >21.04 mg / mL >21.04 mg / mL >21.04 mg / mL >21.04 mg / L Isoquercina 308.1 pg / mL 102.8 pg / mL 462.1 pg / mL 462.1 pg / mL NC-B 0.029% (0.615 pg / mL of OACC) 0.019% (0.41 pg / mL of OACC) 0.312% (0.65 pg / mL of OACC) 0.234% (4.92 pg / mL of OACC) NC-ISQ 0.029% (0.615 pg / mL of OACC and 0.18 pg / mL of ISQ) 0.03% (0.615 pg / mL of OACC and 0.18 pg / mL of ISQ) (0.615% pg / mL of OACC and 3.85 pg / mL of ISQ) 0.468% (9.86 pg / mL of OACC and 2.88 pg / mL of ISQ) ISQ: Isoquercitrin; OACC: Oil from the almond of the catolé coconut (Syagros cearenses); NC-B: Control nanoformulation (blank); NC-ISQ: Nanoformulation containing isoquercitrin. Petition 870250006183, dated 01 / 27 / 2025, page 17 / 29 10 / 14

[044] The results in Table 1 demonstrate that, within the tested concentration range, the activity of isoquercitrin had its potential improved after the encapsulation process.

[045] The result obtained can be justified by a possible synergistic effect between the nanoencapsulation system and isoquercitrin. When compared with the works published by (JANECZKO et al., 2022) and (ALIZADEH; EBRAHIMZADEH, 2022), it can be observed that the antifungal activity of quercetin derivatives has its effect potentiated as the hydrophobicity of the quercetin derivatives increases, which justifies the differences between the results found in this study and those published in the aforementioned works.

[046] The following are examples of embodiments of the invention that serve to illustrate it, but should not be used to limit the scope of the invention:

[047] Example 1 - Preferred composition of the catolé coconut oil-based lipid nanocarrier and: Formulation components % used in the formulation Isoquercitrin 0.07 Poly(ethylene oxide) stearate 0.7 Catolé coconut oil 1.8 Beeswax 3.15 Distilled water 94.28 Petition 870250006183, dated 01 / 27 / 2025, p. 18 / 29 11 / 14

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[065] MENDES, A. I.; SILVA, A. C.; CATITA, J. A. M.; CERQUEIRA, F.; GABRIEL, C.; LOPES, C. M. Miconazole-loaded nanostructured lipid carriers (NLC) for local delivery to the oral mucosa: Improving antifungal activity. Colloids and Surfaces B: Biointerfaces, [s. l.], v. 111, p. 755-763, 2013. Disponível em: <https: / / www.sciencedirect.com / science / article / pii / S0927776513004153>

[066] MOAZENI, M.; KELIDARI, H.; NASIRZADEHFARD, Y.; SHOKOHI, T.; ROOHI, B.; HAJHEIDARI, Z.; KAZEMINEJAD, A.; PARSAY, S.; ASARE-ADDO, K.; NOKHODCHI, A. Lesson from nature: Zataria multiflora nanostructured lipid carrier topical gel formulation against Candida-associated onychomycosis, a randomized double-blind placebo-controlled clinical trial. Medicine in Drug Discovery, [sl], v. 22, p. 100187, 2024. Available at: <https: / / www.sciencedirect.com / science / article / pii / S2590098624000125>

[067] RICARDO et al. Process for obtaining tilapia oil and its use as an ingredient with restorative action on skin and hair, and use of tilapia oil fractions as a lipid nanocarrier for drugs and cosmetics. Applicant: FEDERAL UNIVERSITY OF CEARÁ (BR / CE). Deposit date: August 8, 2019. Publication date: February 9, 2021. https: / / busca.inpi.gov.br / pePI / servlet / PatenteServletController?Action=detail&Cod Pedido=1518890&SearchParameter=NANOCARREADOR%20LIP%CDDICO%20%20%20%20%20%20&Resumo=&Titulo=. Accessed on: June 20, 2024.

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Claims

1 / 2 CLAIMS 1. LIPID NANOCARRIER COMPOSITION BASED ON ISOQUERCITRIN AND BABY COCONUT OIL (SYAGRUS CEARENSIS) FOR CANDIDIASIS characterized by comprising: Anthophila (bee) wax, coconut oil from Syagrus cearensis, poly(ethylene oxide) stearate, isoquercitrin and distilled water.

2. LIPID NANOCARRIER COMPOSITION BASED ON ISOQUERCITRIN AND BABONA COCONUT OIL (SYAGRUS CEARENSIS) FOR CANDIDIASIS according to claim 1, characterized in that the poly(ethylene oxide) stearate molecule has 20 moles of ethylene oxide.

3. A LIPID NANOCARRIER COMPOSITION BASED ON ISOQUERCITRIN AND BABONA COCONUT OIL (SYAGRUS CEARENSIS) FOR CANDIDIASIS according to any of the preceding claims, characterized in that the poly(ethylene oxide) stearate molecule has a molar mass of 1151.56 grams per mole.

4. A LIPID NANOCARRIER COMPOSITION BASED ON ISOQUERCITRIN AND BABÃO COCONUT OIL (SYAGRUS CEARENSIS) FOR CANDIDIASIS according to any of the preceding claims, characterized in that the coconut oil from Syagrus cearensis is obtained from the kernel of the catolé coconut.

5. LIPID NANOCARRIER COMPOSITION BASED ON ISOQUERCITRIN AND BABY COCONUT OIL (SYAGRUS CEARENSES) FOR CANDIDIASIS according to any of the preceding claims, characterized as comprising: 2.00-4.00% (w / w) of Anthophyla wax; 1.00-3.00% (w / w) of Syagrus cearensis oil; 0.40-0.90% of poly(ethylene oxide) stearate (w / w); 0.06-0.30% of isoquercitrin (w / w) and 92.07-96.54% (w / w) of distilled water.

6. PROCESS FOR OBTAINING A LIPID NANOCARRIER BASED ON ISOQUERCITRIN AND BABÃO COCONUT OIL (SYAGRUS CEARENSES) FOR CANDIDIASIS as defined in the preceding claims, characterized by comprising the following steps: a) The oil and wax were heated to 65°C and isoquercitrin was added until completely dissolved to form solution A; b) Poly(ethylene oxide) stearate was added to water and also heated to 65°C to form solution B; c) Solution B was added to solution A at 65°C and homogenized using an ultrasonic probe at 70% amplitude with a pulse regime of 10 seconds on and 10 seconds off for 3 minutes to obtain dispersion C; d) At room temperature, dispersion C was cooled to solidify nanoparticles.

7. USE OF A LIPID NANOCARRIER BASED ON ISOQUERCITRIN AND BABY COCONUT OIL (SYAGRUS CEARENSES) FOR CANDIDIASIS as defined in the preceding claims, characterized by being for preparing a medicament to treat candidiasis. Petition 870250006183, dated 01 / 27 / 2025, p. 24 / 29