COMPOSIÇÃO E USO DE MICROCÁPSULA À BASE DE ÓLEO DE EUTERPE OLERACEA (AÇAÍ), PECTINA E DOCETAXEL PARA APLICAÇÃO CONTRA LEUCEMIA PROMIELOCÍTICA

Description

/ 14 COMPOSITION AND USE OF A MICROCAPSULE BASED ON Euterpe oleracea (Açaí) OIL, PECTIN AND DOCETAXEL FOR APPLICATION AGAINST PROMYELOCYTIC LEUKEMIA

[001] The present invention relates to the field of Biotechnology, directed to the pharmaceutical industry, and concerns the composition and use of a powdered microcapsule, based on açaí pulp oil (Euterpe oleracea), pectin and docetaxel for application against acute promyelocytic leukemia, characterized by comprising: pectin, Euterpe oleracea pulp oil, docetaxel and triblock copolymer of poly(oxide) ethylene poly(oxide) propylene.

[002] The proposed system, the subject of the present invention, shows potential against acute promyelocytic leukemia and has the advantage of promoting the controlled release of docetaxel and increasing its bioavailability in aqueous systems. The claimed material has as a differentiating factor the strategic association of açaí oil, which has proven anti-tumor and anti-inflammatory properties, with docetaxel in the form of a microcapsule containing an oily core on a nanometric scale. In addition, the polymer used to form the microcapsule was the polysaccharide pectin extracted from orange pulp and albedo, which has favorable physicochemical characteristics to promote resistance to the direct and uncontrolled release of docetaxel.

[003] According to the National Cancer Institute (INCA), cancer can be defined as a set of malignant diseases that encompasses more than 100 types, representing the uncontrolled growth of cells, which tend to invade neighboring tissues and organs, promoting the formation of tumors that can extend to other areas of the body.

[004] Leukemia is the name given to cancer of the blood cells in the bone marrow, the site where cells that give rise to leukocytes (white blood cells), erythrocytes (red blood cells), and platelets are generated. In this process, an immature blood cell undergoes some genetic mutation, transforming it into a cancerous cell that, Petition 870250006506, dated 01 / 27 / 2025, page 9 / 28 / 14 due to its malfunction, it multiplies more rapidly, replacing healthy blood cells. Leukemia types are classified based on their growth (acute and chronic leukemia) and the type of cell affected (lymphoid or myeloid). According to INCA (2022), the estimate in Brazil for the three-year period from 2023 to 2025 is 11,540 cases of leukemia, corresponding to a risk of 5.33 per 100,000 inhabitants.

[005] Docetaxel (DTX) is a drug belonging to the taxane class (Paclitaxel and Docetaxel) that exhibits antineoplastic activity (IMRAN et al., 2020) and has been extensively explored for its importance in the treatment of a range of cancers (KAUSHIK et al., 2020).

[006] DTX has very low solubility in water (2.5 pg / L) (YI; KOSEL, 2017), the main limiting characteristic regarding its pharmacokinetics (SILVA et al., 2018), it has high lipophilicity (logP = 4.1), low bioavailability and high toxicity (ROCHA et al., 2020).

[007] Its commercial formulation (Taxotere®) contains Tween 80 (polysorbate 80; P80), and for administration and better solubilization of this drug, dilution of this mixture with a 13% ethyl alcohol solution is necessary (ZHANG; ZHANG, 2013). The pharmaceutical industry developed these formulations as a strategy to circumvent the pharmaceutical problems in the administration of DTX (ROCHA et al., 2020), even though this is the reason for some side effects (ZHANG; ZHANG, 2013).

[008] Given the characteristics that limit the administration of docetaxel for cancer therapy and knowing about nanoemulsions and microcapsules as drug carriers, polymeric microcapsules were developed using pectin extracted from orange peel (Citrus sinensis (L.) Osbeck) to encapsulate the nanoemulsion prepared with açaí oil (Euterpe Oleracea) containing DTX, as a strategy to increase its water solubility, provide controlled release, increase its bioavailability and reduce its toxicity. Petition 870250006506, dated 01 / 27 / 2025, page 10 / 28 / 14

[009] A variety of natural and synthetic polymers have been used for the development of drug delivery systems (PECORINI; FERRARO; PUPPI, 2023). The biological and physicochemical properties of polysaccharides, such as biocompatibility, biodegradability, and their low immunogenicity, make these natural polymers suitable for the development of drug delivery systems, since polysaccharide-based carriers can increase the residence time of the drug in the gastrointestinal tract, and thus, increase its bioavailability (PECORINI; FERRARO; PUPPI, 2023).

[010] Polymer-based drug delivery systems can be defined as devices that perform the introduction of drugs into the body, improving their safety and efficacy by controlling the rate, time, and location of drug release in the body (SUNG; KIM, 2020).

[011] Emulsions are colloidal dispersions of two immiscible liquids, that is, one of the liquids is distributed in another in the form of very small droplets (SNEHA; KUMAR, 2022). These systems require three basic components: oil or oily liquid, water or aqueous liquid, and an emulsifying substance (protein, peptide, lipid, or low molecular weight surfactant), responsible for the formation and stabilization of the emulsion (SNEHA; KUMAR, 2022).

[012] In addition to conventional emulsions, there are nanoemulsions (5 to 200 nm) which are colloidal systems used for the effective delivery of drugs (KUMAR et al., 2024). Nanoemulsions are formed by oil-in-water, water-in-oil, oil-in-water-in-oil, bi-continuous emulsions and nanoemulgels (SNEHA; KUMAR, 2022). These systems promote greater solubility of hydrophobic compounds and their successful delivery due to the increased drug loading capacity (Jia et al., 2024).

[013] The application of nanoparticles as delivery systems is, among other purposes, the release of bioactive compounds with specific action and location at an ideal therapeutic rate and quantity to promote the desired pharmacological response (GUNASEKARAN et al., 2014). Petition 870250006506, dated 01 / 27 / 2025, page 11 / 28 / 14

[014] Drug delivery systems are used to safely transport the drug throughout the body and achieve the intended therapeutic action, improving its aqueous solubility, providing greater chemical stability to the active agent, increasing its pharmacological activity and reducing side effects (LI et al., 2019).

[015] The literature presents a variety of systems formed by multifunctional microcapsules, given that these systems have wide application in the areas of catalysis, cosmetics and, mainly, in drug delivery (Jia et al., 2017).

[016] Microcapsule synthesis involves incorporating tiny droplets or particles into a heterogeneous or homogeneous matrix (coating material) (BAH; BILAL; WANG, 2019). Thus, polymeric microcapsules are small spheres, formed by a core containing the material of interest and a polymer that forms the coating of the core (BAH; BILAL; WANG, 2019).

[017] Natural polymers such as polysaccharides have stood out in research involving the synthesis of microcapsules due to their wide availability and biocompatibility (WANI et al., 2023). One of the main applications of polysaccharide-based microcapsules is their role as carriers of anticancer drugs, given their high capacity for transporting substances and adjustable properties that favor the supply and delivery of these molecules for cancer therapy, which is only effective through selective targeting of the tumor and controlled release of the drug (JIA et al., 2017).

[018] Açaí pulp oil was used as the oil phase for formulating the microcapsules. Açaí, Euterpe oleracea Martius (Arecaceae), is the fruit of a palm tree cultivated in the Brazilian Amazon region (RABELO et al., 2018). Because it is a highly nutritious food, this fruit has become a highly valued product economically (SANTOS et al., 2024). Petition 870250006506, dated 01 / 27 / 2025, page 12 / 28 / 14

[019] Furthermore, research has been developed to investigate possible pharmacological applications from the specific biological activities of various parts of the plant (fruit, leaves, seeds, roots and oil) (DIAS et al., 2024). Studies carried out by ALESSANDRA-PERINI et al., (2018) demonstrated that açaí is safe and can be used as a chemoprotective agent against cancer, as it exhibits anti-inflammatory, antioxidant, antiproliferative and pro-apoptotic activity. The fatty acid profile of the açaí extract, prepared with supercritical fluid (CO2), showed significantly stearic (C18:0), palmitoleic (C16:1), linoleic (C18:2), oleic (C18:1) and palmitic (C16:0) acids with concentrations of 5.35, 7.08, 15.54, 65.81 and 90.86% (w / w), respectively (BATISTA et al., 2016).

[020] Generally, medium-chain triglycerides are used as an oily core in the encapsulation of substances (ROSA et al., 2019). Given this, açaí oil presents itself as a promising material in the development of microcapsules for improving the delivery of bioactive molecules.

[021] Among citrus fruits, oranges stand out for their greater commercialization (INIGUEZ-MORENO et al., 2024). In the industry, after the production of orange juice, the peels, seeds and moist pulp are considered waste, which makes it extremely important to search for new ways of reusing these residues that present by-products with commercial value such as, for example, essential oils, flavonoids and pectin (ZANELLA; TARANTO, 2015).

[022] Pectin is a polysaccharide widely used in the food industry due to its properties as a gelling, thickening, texturizing, emulsifying, and stabilizing agent for food products (SABERIAN et al., 2017). In plants, pectin plays a structural role in primary cell walls and has a complex structure (HAN et al., 2017), being considered a heteropolysaccharide consisting of distinct sections: homogalacturonan (HG), rhamnogalacturonan I (RGI), and rhamnogalacturonan II (RGII) (HUA et al., 2015). Pectin has been extensively explored for its potential as a carrier of therapeutic agents, in addition to having already demonstrated safety, non-toxicity, and biodegradability (DAS, 2021). Petition 870250006506, dated 01 / 27 / 2025, pp. 13 / 28 / 14.

[023] In view of this information and with the aim of solving the problems related to the low solubility of docetaxel, low bioavailability, and cytotoxicity against healthy cells, the present invention, the subject of the claim, was developed. In this context, the microcapsule, the subject of the claim, becomes an advantageous alternative to existing delivery methods, improved by the strategic association of docetaxel with açaí oil due to the antitumor and anti-inflammatory properties of this oil. Furthermore, it is also a sustainable proposal when using orange pulp as a pectin source.

[024] In a search for non-patented publications relating to products or processes most similar to the present invention, the following publications were found:

[025] The article entitled Docetaxel Loaded Pomegranate Seed Oil Based Nanostructured Lipid Carriers: A Potential Alternative to Current Formulation (TALKAR: KHARKAR: PATRAVALE, 2020) deals with a lipid formulation containing docetaxel and pomegranate oil, differing from the present invention in terms of the formulation components and mainly because it does not contain açaí oil, which has cardioprotective, antioxidant, anti-inflammatory and antitumor properties.

[026] The article entitled Physicochemical characterization and in vivo evaluation of solid self-nanoemulsifying drug delivery system for oral administration of docetaxel (QUAN et al., 2014) deals with dry particles based on docetaxel and capriol 90, colloidal silica, cremophore EL and Transcutol HP. It differs from the claimed material in terms of the formulation components and by not strategically associating docetaxel with açaí pulp oil; this association may confer multifunctional properties in vivo to the claimed formulation, such as antitumor, antioxidant, cardioprotective and anti-inflammatory properties in a single product.

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

[028] Patent PI 0916535-5, filed on 07 / 22 / 2018, which deals with a docetaxel nanoemulsion in water using synthetic triglycerides as the oil phase, differing from the claimed matter in terms of the formulation components and by not strategically associating docetaxel with açaí pulp oil, this association may confer multifunctional properties in vivo to the claimed formulation. Petition 870250006506, dated 01 / 27 / 2025, page 14 / 28 / 14 as an antitumor, antioxidant, cardioprotective and anti-inflammatory agent in a single product.

[029] Patent PI0608173-8, filed on 24 / 02 / 2006, which deals with a composition based on nanoparticulate docetaxel, differs from the present invention in terms of the production process, the specific application for promyelocytic leukemia, and by not strategically associating docetaxel with açaí pulp oil. It is noteworthy that this association can confer multifunctional properties in vivo to the claimed formulation as antitumor, antioxidant, cardioprotective, and anti-inflammatory in a single product.

[030] 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 the form of a microcapsule with a nanostructured core, and also presents inventive activity through the strategic association of the anti-tumor active ingredient docetaxel with açaí oil, which also has anti-tumor potential but mainly due to its anti-inflammatory properties, providing a multifunctional characteristic to the claimed matter.

[031] The following is presented with regard to the matter claimed, the composition, the preparation process, the results of the microcapsule characterization tests and the results of in vitro cytotoxic activity against HL-60 tumor cells.

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

[033] The microcapsule, the subject of the matter claimed, is characterized by comprising: pectin, oil from the pulp of Euterpe oleracea, docetaxel and a triblock copolymer of poly(oxide) ethylene poly(oxide) propylene.

[034] The microcapsule, the subject of the claimed matter, is characterized by comprising: 15.00-40.00% oil (w / w), 10.00-15.00% copolymer, 44.50-64.90% pectin and 0.10-0.50% (w / w) docetaxel. Petition 870250006506, dated 01 / 27 / 2025, page 15 / 28 / 14

[035] The microcapsule, the subject of the matter claimed, is characterized by the fact that the copolymer comprises in its molecular structure two terminal blocks with 95 ethylene oxide units and a central block with 67 propylene oxide units.

[036] The microcapsule, the subject of the matter claimed, is characterized by the fact that the triblock copolymer of poly(oxide) ethylene poly(oxide) propylene has a molar mass of 12500 grams per mole.

[037] The microcapsule, the subject of the matter claimed, is characterized by the fact that the oil contains 55-65% (m / m) of oleic acid fatty acid esters.

[038] The microcapsule, the subject of the matter claimed, is characterized by the fact that pectin is extracted from orange peel (Citrus sinensis).

[039] The microcapsule, the subject of the matter claimed, is characterized by the fact that the pectin has a degree of methoxylation between 25-75%.

[040] The microcapsule, the subject of the matter claimed, is characterized by the fact that pectin has a molar mass of 10000 to 1000000 grams per mole.

[041] The microcapsule, the subject of the matter claimed, is characterized by the fact that the pectin has a galacturonic acid content between 60-80% (m / m).

[042] The microcapsule, the subject of the matter claimed, is characterized by the fact that the microcapsule has an oily core with a particle diameter between 120 and 250 nm.

[043] The microcapsule preparation process is characterized by comprising the following steps: a) Dissolve the docetaxel at a temperature of 25-30°C until completely dissolved to obtain solution A; b) Prepare a copolymer solution in ultrapure water at 5°C to obtain solution B; c) Add solution B to the previously prepared solution A under vortex stirring and subject to ultrasonication at an amplitude of 70% for 2 min, in 20 s on and 10 s off cycles, at a power of 90-110 W to obtain nanoemulsion C; Petition 870250006506, dated 01 / 27 / 2025, pp. 16 / 28 / 14 d) Dissolve the pectin in water to obtain a solution between 1 and 2% (w / v), stirring for 12 hours at 40-45°C to obtain solution D; e) Add nanoemulsion C to solution D while stirring at 200 RPM to obtain nanoemulsion E; f) Dry the nanoemulsion in a spray dryer at a temperature of 150°C and a flow rate of 3 mL per minute to obtain the powdered microcapsule.

[044] The use of the microcapsules that are the subject of the claim is characterized as being for the preparation of a medicine to treat acute promyelocytic leukemia.

[045] Below are the results of characterization and cytotoxic activity analyses against HL-60 cells (acute promyelocytic leukemia) using the MTT assay:

[046] The powder microcapsules exhibited a spherical shape and an outer particle diameter of 1.6 to 7.0 μM measured by scanning electron microscopy (SEM) and an oily core (inner diameter) of 120 to 250 nm measured by Dynamic Light Scattering.

[047] Microcapsules at a single concentration of docetaxel (equivalent to 20 ppm) reduced the cell viability of HL-60 cells, as measured by the in vitro MTT assay, by between 92.70% and 92.90%.

[048] 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:

[049] Example 1 - Preferred percentage composition (w / w) for the preparation of the nanoemulsion: Docetaxel...............0.07% Oil........................5.28% Copolymer.............3.71% Water.......................90.94% Petition 870250006506, dated 01 / 27 / 2025, page 17 / 28 / 14

[050] Example 2 - Preferred percentage composition (w / w) for the preparation of the nanoemulsion: Docetaxel.................0.12% Oil..........................9.99% Copolymer...............3.51% Water.........................86.38%

[051] Example 3 - Preferred percentage composition (w / w) for preparing the microcapsule from the nanoemulsion after drying: Docetaxel.................0.22% Oil..........................18.03% Copolymer...............12.66% Pectin...........69.09%

[052] Example 4 - Preferred percentage composition (w / w) for preparing the microcapsule from the nanoemulsion after drying: Docetaxel.................0.44% Oil.........................35.75% Copolymer..............12.57% Pectin..................51.25% REFERENCES

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Claims

1 / 3 CLAIMS 1. MICROCAPSULE COMPOSITION BASED ON Euterpe oleracea (AÇAÍ) OIL, PECTIN AND DOCETAXEL characterized by comprising: pectin, oil from the pulp of Euterpe oleracea, docetaxel and triblock copolymer of poly(oxide) of ethylene poly(oxide) of propylene.

2. Microcapsule composition based on Euterpe oleracea (Açaí) oil, pectin and docetaxel according to claim 1, characterized by comprising: 15.00-40.00% oil (w / w), 10.00-15.00% copolymer, 44.50-64.90% pectin and 0.10-0.50% (w / w) docetaxel.

3. A microcapsule composition based on Euterpe oleracea (Açaí) oil, pectin, and docetaxel according to any of the preceding claims, characterized in that the copolymer comprises in its molecular structure two terminal blocks with 95 ethylene oxide units and a central block with 67 propylene oxide units.

4. A microcapsule composition based on Euterpe oleracea (Açaí) oil, pectin, and docetaxel according to any of the preceding claims, characterized by the fact that the triblock copolymer of poly(oxide) ethylene poly(oxide) propylene has a molar mass of 12500 grams per mole.

5. Microcapsule composition based on Euterpe oleracea (Açaí) oil, pectin, and docetaxel according to any of the preceding claims, characterized in that the oil contains 5565% (w / w) of oleic acid fatty acid esters. Petition 870250006506, dated 01 / 27 / 2025, p. 23 / 28 2 / 3 6. Microcapsule composition based on Euterpe oleracea (Açaí) oil, pectin and docetaxel according to any of the preceding claims, characterized in that the pectin is extracted from orange peel (Citrus sinensis).

7. Microcapsule composition based on Euterpe oleracea (Açaí) oil, pectin and docetaxel according to any of the preceding claims, characterized by the fact that the pectin has a degree of methoxylation between 25-75%.

8. Microcapsule composition based on Euterpe oleracea (Açaí) oil, pectin and docetaxel according to any of the preceding claims, characterized in that the pectin has a molar mass of 10,000 to 1,000,000 grams per mole.

9. Microcapsule composition based on Euterpe oleracea (Açaí) oil, pectin and docetaxel according to any of the preceding claims, characterized in that the pectin has a galacturonic acid content between 60-80% (w / w).

10. Microcapsule composition based on Euterpe oleracea (Açaí) oil, pectin and docetaxel according to any of the preceding claims, characterized in that the microcapsule has an oily core with a particle diameter between 120 and 250 nm.

11. PROCESS FOR PREPARING A MICROCAPSULE BASED ON Euterpe oleracea (AÇAÍ) OIL, PECTIN AND DOCETAXEL as defined in the preceding claims, characterized by comprising the steps: a) Solubilizing docetaxel at a temperature of 25-30°C until completely dissolved to obtain solution A; b) Preparing a copolymer solution in ultrapure water at 5°C to obtain solution B; c) Adding solution B to the previously prepared solution A under stirring. Petition 870250006506, dated 01 / 27 / 2025, p.24 / 28 3 / 3 in a vortex mixer and subject to ultrasonication at an amplitude of 70%, 2 min, in 20 s on and 10 s off cycles, at a power of 90-110 W to obtain nanoemulsion C; d) Solubilize the pectin in water to obtain a solution between 1 and 2% (w / v), under stirring for 12 hours at 40-45°C to obtain solution D; e) Add nanoemulsion C to solution D under stirring at 200 RPM to obtain nanoemulsion E; f) Dry the nanoemulsion in a spray dryer at a temperature of 150°C and a flow rate of 3 mL per minute, to obtain the powdered microcapsule.

12. USE OF A MICROCAPSULE BASED ON Euterpe oleracea (AÇAÍ) OIL, PECTIN AND DOCETAXEL as defined in the preceding claims, characterized by being for preparing a medicament to treat acute promyelocytic leukemia. Petition 870250006506, dated 01 / 27 / 2025, p. 25 / 28