Cosmetic and pharmaceutical preparations containing captopril, whether or not presented as liquid crystal nanoparticles, with a brightening effect.

Description

"COSMETIC AND PHARMACEUTICAL PREPARATIONS CONTAINING CAPTOPRIL, WHETHER OR NOT IN LIQUID CRYSTAL NANOPARTICLES, WITH A BRIGHTENING ACTION" Field of invention

[001] The present invention falls within the dermatological, pharmaceutical and cosmetic fields and relates to the skin-lightening properties of captopril in its free form or incorporated into nanoformulations. Captopril has been shown to be capable of inhibiting the tyrosinase enzyme in vitro, one of the main enzymes involved in melanin formation (melanogenesis). The cosmetic preparations resulting from this invention are for topical use and can be in powder, liquid, solid and semi-solid form, such as solution, suspension, aerosol, foam, soap, lotion, gel, serum, cream, gel-cream, stick, powder, and are used for the treatment of hyperpigmentation. A nanoformulation containing captopril was developed in order to increase its stability and ensure better performance. Fundamentals of the invention

[002] Pigmentation disorders, such as melasma, are the third most frequent report in dermatological consultations, varying according to age group, sex and region of the country, affecting millions of people worldwide. Although melasma is a pathological alteration with only an aesthetic connotation, it can generate a great social, family and professional impact on affected individuals, causing a decrease in both quality of life and emotional well-being. Studies show that 30 to 60% of patients diagnosed with melasma are affected by significant psychosocial disorders, which can lead to feelings of sadness, anxiety, or even depression (HANDOG, EVANGELINE B. et al. MELASMA AND VITILIGO IN BROWN SKIN. SPRINGER INDIA, 2017; BALKRISHNAN, R. et al. DEVELOPMENT AND VALIDATION OF A HEALTH-RELATED QUALITY OF LIFE INSTRUMENT FOR WOMEN WITH MELASMA. BRITISH JOURNAL OF DERMATOLOGY, V. 149, N. 3, P. 572-577, 2003).

[003] Melanin is the main pigment that constitutes skin color. Excess melanin production by melanocytes causes melasma. This pathology is characterized by asymptomatic hyperpigmentation ranging in color from light brown to brown. Petition 870250095180, dated 10 / 17 / 2025, page 3 / 13 2 / 10 dark, with irregular borders and symmetrical arrangement. The most affected part of the face is the central region, with spots on the forehead, nasal bridge, cheekbones, and chin areas. It can be caused by endogenous or exogenous stimuli such as genetic predisposition, solar elastosis, photoaging, UV radiation, comorbidities, hormonal factors, basement membrane damage, among others (HANDOG, EVANGELINE B. et al. MELASMA AND VITILIGO IN BROWN SKIN. SPRINGER INDIA, 2017; NASCIMENTO, DB ET AL. ETIOLOGY AND MEDICAL TREATMENT OF MELASMA DURING PREGNANCY. JOURNAL OF SCIENTIFIC INITIATION AND EXTENSION, V. 2, N. 3, P. 176-180, 2019; PIÇTOWSKA, Z. et al. UNDERSTANDING MELASMA - HOW CAN PHARMACOLOGY AND COSMETOLOGY PROCEDURES AND PREVENTION HELP TO ACHIEVE OPTIMAL TREATMENT RESULTS? A NARRATIVE REVIEW. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH, V. 19, N. 19, P. 12084, 2022).

[004] After identifying the type of melasma, the therapy is chosen. Its treatment, topical or oral, is long-term, with recurrence and resistance, whose objective is to reduce melanin synthesis, inhibit melanosome formation, and promote their degradation. Recommended treatments for melasma include the use of topical depigmenting agents and the use of sun protection (PIÇTOWSKA, PIÇTOWSKA, Z. et al. UNDERSTANDING MELASMA-HOW CAN PHARMACOLOGY AND COSMETOLOGY PROCEDURES AND PREVENTION HELP TO ACHIEVE OPTIMAL TREATMENT RESULTS? A NARRATIVE REVIEW. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH E SAÚDE PÚBLICA, V. 19, N. 19, P. 12084, 2022).

[005] The most common and widely used therapeutic agent for over fifty years is hydroquinone. It frequently includes the administration of hydroquinone or other substances, such as azelaic acid, tretinoin, alpha and beta hydroxy acids, and topical corticosteroids used as monotherapy or in combination. Among topical treatment options, hydroquinone is still considered the most effective treatment; it acts by inhibiting tyrosinase, interrupting melanin formation (MALEK, J. et al. SUCCESS FULL TREATMENT OF HYDROQUINONE-RESISTANT MELASMA USING TOPICAL METHIMAZOLE. DERMATOLOGIC THERAPY, V. 26, N. 1, P. 69-72, 2013; GUPTA, A. et al. Petition 870250095180, dated 10 / 17 / 2025, p. 4 / 13 3 / 10 MELASMA TREATMENT: A REVIEW OF CLINICAL TRIALS. J AM ACAD DERMATOL, 55(6):1048-1065, 2006).

[006] Among the adverse effects of hydroquinone are allergic or irritant contact dermatitis, "confetti" hypopigmentation, post-inflammatory hyperpigmentation, nail discoloration, telangiectasias, epidermal atrophy, and ochronosis. Its use during pregnancy is not indicated, belonging to risk category C according to American regulations - Food and Drug Administration (FDA) (MALEK, J. et al. SUCCESS FULL TREATMENT OF HYDROQUINONE-RESISTANT MELASMA USING TOPICAL METHIMAZOLE. DERMATOLOGIC THERAPY, V. 26, N. 1, P. 69-72, 2013; GUPTA, A. et al. THE TREATMENT OF MELASMA: A REVIEW OF CLINICAL TRIALS. J AM ACAD DERMATOL, 55(6):1048-1065, 2006).

[007] Captopril is a zwitterionic drug with two dissociation constants, pKa1 3.7 and pKa2 9.8, and has an isoelectric point of 6.8. Captopril can be ionized in aqueous solution to affect its percutaneous absorption capacity. The solubility of captopril is independent of pH value. The permeability coefficient as a function of pH showed a maximum rate at pH 5.0 and a minimum rate around the isoelectric point (pH 7.0). Zwitterionic compounds exhibit high melting points and low solubility in lipophilic media, and low permeability through biological membranes. Therefore, transdermal administration of these compounds should be done with the use of skin penetration enhancers to achieve the ideal permeation rate (WU, P. et al. IN VITRO PERCUTANEOUS ABSORPTION OF CAPTOPRIL THROUGH EXCISED RABBIT SKIN. INTERNATIONAL JOURNAL OF PHARMACEUTICS, V. 143, N. 1, P. 119-123, 1996; MAZZENGA, GERARD C. et al.THE TRANSDERMAL DELIVERY OF ZWITTERIONIC DRUGS I: THE SOLUBILITY OF ZWITTERION SALTS. JOURNAL OF CONTROLLED RELEASE, V. 16, N. 1-2, P. 77-88, 1991; SZNITOWSKA, M. et al. IN VITRO PERMEATION OF HUMAN SKIN BY MULTIPOLAR IONS. INTERNATIONAL JOURNAL OF PHARMACEUTICS, V. 99, N. 1, P. 4349, 1993; HATANAKA, T. et al. EFFECT OF PH ON THE SKIN PERMEABILITY OF A ZWITTERIONIC DRUG, CEPHALEXIN. INTERNATIONAL JOURNAL OF PHARMACEUTICS, V. 125, N. 2, P. 195-203, 1995). Petição 870250095180, de 17 / 10 / 2025, pág. 5 / 13 4 / 10

[008] Although captopril is freely soluble in water, it undergoes oxidative degradation, and the rate of degradation is dependent on pH and oxygen concentration. In aqueous solution, captopril has a strong sulfur taste and odor. Its stability is also reduced in contact with metal ions. Its maximum stability occurs at pH below 4 (ANAIZI, NASR H. et al. INSTABILITY OF AQUEOUS CAPTOPRIL SOLUTIONS. AMERICAN JOURNAL OF HOSPITAL PHARMACY, V. 50, N. 3, P. 486-488, 1993; NAHATA, MILAP C. et al. STABILITY OF CAPTOPRIL IN LIQUID CONTAINING ASCORBIC ACID OR SODIUM ASCORBATE. AMERICAN JOURNAL OF HOSPITAL PHARMACY, V. 51, N. 13, P. 1707-1708, 1994; PEREIRA, CONRAD M. et al. 612-615, 1992; PRAMAR, Y. et al. STABILITY OF CAPTOPRIL IN SOME AQUEOUS SYSTEMS. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS, V. 17, N. 3, P. 185-189, 1992).

[009] Captopril is able to prevent melanin formation by inhibiting the enzyme tyrosinase. Increased captopril concentrations caused a concomitant decrease in tyrosinase activity, which may be explained by the presence of L-proline in its chemical structure (ESPÍN, JC et al. EFFECT OF CAPTOPRIL ON MUSHROOM TYROSINASE ACTIVITY IN VITRO. BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY, 1544(1-2), 289-300, 2001).

[010] Nanotechnology has also investigated ways to overcome biological barriers, facilitating the transport of therapeutic molecules to the sites of action. With the use of nanosystems, it is possible to encapsulate a range of substances with different solubilities, improving their release and increasing efficacy, while reducing the risks of adverse effects (TAVARES LUIZ, M. et al. THE USE OF TPGS IN DRUG DELIVERY SYSTEMS TO OVERCOME BIOLOGICAL BARRIERS. EUROPEAN POLYMER JOURNAL, V. 142, P. 110129, JAN. 2021A).

[011] Among the nanosystems under study, nanocarriers made of liquid crystals stand out for their great potential in pharmaceutical formulations. They offer advantages such as biocompatibility, similarity to biological membranes, biodegradability, and protection of water-soluble and lipid-soluble drugs. Their unique architecture attracts interest from various fields, including biology, medicine, and chemistry. Petition 870250095180, dated 10 / 17 / 2025, page 6 / 13 5 / 10 and nanotechnology. The use of these nanocarriers aims to improve drug stability, increase their bioavailability in the skin, and enhance photodynamic efficiency (SILVESTRINI, AVP et al. ADVANCES IN LYOTROPIC LIQUID CRYSTAL SYSTEMS FOR SKIN DRUG DELIVERY. EXPERT OPINION ON DRUG DELIVERY, V. 17, N. 12, P. 1781-1805, 1 DEC. 2020).

[012] Liquid crystals possess a particular positional and directional order, combining the fluidity of the liquid phase with the characteristic organization of the solid state. A liquid crystal is a state of matter that exhibits mechanical and symmetrical properties intermediate between those of a crystalline solid and an isotropic liquid (SINGH, S. PHASE TRANSITIONS IN LIQUID CRYSTALS. PHYSICS REPORT, V. 324, N. 2-4, P. 107-269, 2000).

[013] Liquid crystals can be produced by thermal methods (thermotropic) or by the addition of solvents (lyotropic). Lipid-based lyotropic systems have been studied as options for drug delivery due to their unique properties resulting from a thermodynamically regular and stable internal structure, allowing for the controlled release of active substances. These lyotropic systems are formed by the combination of at least two elements: an organic component, called a mesogen (such as a surfactant), and a solvent. The variation in the concentration of the mesogen within the solvent causes a phase change at a specific temperature, resulting in the formation of a lyotropic crystal (CHEN, Y.; MA, P.; GUI, S. CUBIC AND HEXAGONAL LIQUID CRYSTALS AS DRUG DELIVERY SYSTEMS. BIOMED RESEARCH INTERNATIONAL, V. 2014, 2014. SINGH, S. PHASE TRANSITIONS IN LIQUID CRYSTALS. PHYSICS REPORT, V. 324, N. 2-4, P. 107-269, 2000. FORMARIZ ET AL., 2005; LEU ET AL., 2023).

[014] The present invention is innovative because the skin lightening activity attributed to the active ingredient captopril is unprecedented. The incorporation of captopril into nanoformulations also represents a differentiating factor, justified by increasing its performance in terms of its lightening action, ensuring the stability of the active ingredient during its shelf life and its gradual release. Petition 870250095180, dated 10 / 17 / 2025, page 7 / 13 6 / 10

[015] Extensive research was conducted in the scientific literature and no studies were found that correlate the topical use of captopril with the lightening of skin blemishes.

[016] In the patent field, no document related to the topical use of captopril was found in the INPI patent database nor in the PATENTSCOPE database of the World Intellectual Property Organization. Summary of the invention

[017] The present invention describes the topical use of captopril as a whitening agent in the treatment of hyperpigmentation using it in its free form or in nanostructured systems carried in cosmetic or pharmaceutical preparations. It also describes the preparation and composition of formulations in liquid, solid or semi-solid forms, which may be presented as lotion, gel, serum, cream, gel-cream, stick or powder.

[018] Captopril works by inhibiting the enzyme tyrosinase, as demonstrated by an in vitro inhibition assay of this enzyme. Therefore, cosmetic or pharmaceutical products containing captopril in its free or nanostructured form can be used to treat hyperpigmentation such as melasma. Detailed description of the invention

[019] Evaluation of the inhibitory activity of the tyrosinase enzyme

[020] The in vitro tyrosinase enzyme inhibitory activity of captopril was determined using UV / VIS spectrophotometry measured at 492 nm by the modified Khatib (2005) method. Kojic acid was used as a positive control. Inhibition was calculated using the following formula: Inhibition % = [(A - B) / A] x 100%, where A and B are the absorbance of the control and the captopril solution, respectively. (KHATIB, S. ET AL. CHALCONES AS POTENT TYROSINASE INHIBITORS: THE IMPORTANCE OF A 2,4-SUBSTITUTED RESORCINOL MOIETY. BIOORGANIC & MEDICINAL CHEMISTRY. V. 13, P. 433-441, 2005; Sabóia Guerra Diógenes, É. et al. 'Evaluation of the skin whitening and antioxidant Petition 870250095180, dated 10 / 17 / 2025, p. 8 / 13 Activity 7 / 10 of the extract of Myracrodruon urundeuva (aroeira-do-sertão), Natural Product Research, 38(20), pp. 3663-3668, 2023). Table 1: Percentage of enzyme inhibition at concentrations of 50 pL, 100 pL, and 150 pL of captopril and kojic acid after 60 minutes. Concentrations (4L) % Inhibition After 60 Min Captopril Kojic Acid 50 77.23 ± 91.04 ± 100 98.13 ± 98.88 ± 150 98.13 ± 98.88 ±

[021] Comparing the inhibition percentages of kojic acid and captopril at concentrations of 100 and 150 pL, similar values ​​are observed, indicating excellent performance as a whitening agent.

[022] Copper ion chelation assay

[023] A copper ion chelation assay was also performed since the tyrosinase enzyme has two copper ions in its active site and chelation of these ions is one of the enzyme's inhibition mechanisms. Therefore, an in vitro methodology was performed using UV / VIS spectrophotometry, with kojic acid also used as a positive control. A scan was performed at wavelengths from 250 to 500 nm; bathochromic shift indicates chelation. Only kojic acid showed bathochromic shift, suggesting that captopril acts by inhibiting tyrosine through another mechanism (SILVA, AP ET AL. TYROSINASE INHIBITORY ACTIVITY, MOLECULAR DOCKING STUDIES AND ANTIOXIDANT POTENTIAL OF CHEMOTYPES OF LIPPIA ORIGANOIDES (VERBENACEAE) ESSENTIAL OILS. PLOS ONE, V. 12, N. 5, P. 1-17, 2017).

[024] It has been unexpectedly discovered that use in accordance with this invention achieves skin lightening in hyperpigmented areas of mammalian skin. The invention in question is not limited to any particular mechanism of action, but Petition 870250095180, dated 10 / 17 / 2025, page 9 / 13 8 / 10 is believed to work by inhibiting tyrosinase, an enzyme crucial for melanin formation.

[025] Production and analysis of captopril liquid crystalline nanocarriers

[026] For the creation of liquid crystals, the following were used: phosphate buffer solution pH 7.4, Poloxamer 407, PHOSAL® 53 MCT, avocado oil and captopril. Figure 1: Phase diagram used for formula production.

[027] After resting for 24 hours, the samples were analyzed using polarized light microscopy and small-angle X-ray scattering (SAXS) to confirm the formation of a liquid crystalline phase. Figure 2: Pure lamellar phase liquid crystals obtained by polarized light microscopy at a magnification of forty times.

[028] The formulas were sonicated in low-frequency ultrasound in an ice bath for 3 minutes with an amplitude of 20% and then diluted and characterized by DLS. The particle size, polydispersity (PDI) and zeta potential of the liquid nanocrystals were evaluated according to the dynamic light scattering (DLS) technique in a Zetasizer NS 90 device (Malvern Instruments) using a 10mW HeNe laser operating at 633 nm with an incidence angle of 90° and an ambient temperature of 25°C. The analyses were performed in automatic mode, with the samples dispersed 10 times in water and the results (n=3) expressed as mean ± standard deviation (SD).

[029] Composition of the formula for topical use containing captopril Table 2: Raw materials and their respective percentages used in the formulation of captopril serum. FORMULATION RAW MATERIAL CONCENTRATION (%) Aristoflex AVL 0.01 - 20.00 Petition 870250095180, dated 10 / 17 / 2025, p. 10 / 13 9 / 10 Xanthan gum 0.10-10.00 Glycerin 0.1 - 20.00 Phenoxyethanol, Ethylhexylglycerin 1.00 Disodium EDTA 0.10 BHT 0.05 Captopril 0.10-30.00 Deionized water q.s. Qsp. - sufficient quantity for Table 3: Raw materials and their respective percentages used in the formulation of captopril gel-cream. FORMULATION RAW MATERIAL CONCENTRATION (%) Non-ionic cream 0.10-95.00 Xanthan gum 0.10-10.00 Glycerin 0.10-20.00 Phenoxyethanol, Ethylhexylglycerin 1.00 Disodium EDTA 0.10 BHT 0.05 Captopril 0.10-30.00 Deionized water q.s. Qsp. - sufficient quantity for

[030] Serum preparation process: a) Add Aristoflex AVL to half of the water and stir until a homogeneous mixture is obtained. Set aside; b) To the remaining water, add the xanthan gum and stir until a homogeneous mixture is obtained; c) Mix the two previous phases and stir until a homogeneous mixture is obtained; d) Add the other ingredients and mix.

[031] Gel-cream preparation process: a) Disperse the xanthan gum in water while stirring. Keep stirring until the mixture is homogeneous; b) Add the non-stick cream Petition 870250095180, dated 10 / 17 / 2025, page 11 / 13 10 / 10 ionic acid in the previous mixture and homogenize; c) Add the other ingredients and keep stirring until a homogeneous mixture is obtained.

[032] Listing and description of the figures

[033] Figure 1 is a phase diagram showing possible formulas for creating liquid crystals using the aqueous phase (composed of phosphate buffer solution pH 7.4 and Poloxamer 407), PHOSAL® 53 MCT, avocado oil and captopril.

[034] Figure 2 shows the formation of pure lamellar phase liquid crystals obtained by polarized light microscopy at a magnification of forty times.

Claims

CLAIMS 1. Cosmetic and pharmaceutical preparations containing captopril for skin lightening action, characterized by containing captopril as an active agent or adjuvant, alone or in combination, for skin lightening and / or depigmenting action.

2. Cosmetic and pharmaceutical preparations containing captopril for skin lightening action according to Claim 1, characterized by containing nanometric liquid crystals composed of phosphate buffer solution pH 7.4, Poloxamer 407, PHOSAL® 53 MCT, avocado oil, captopril.

3. Cosmetic and pharmaceutical preparations containing captopril for skin-lightening action according to Claims 1 and 2, characterized by being for topical administration, and may be in powder, liquid, solid, semi-solid form, in the form of a solution, suspension, aerosol, foam, soap, lotion, gel, serum, cream, gel-cream, emulgel, stick, powder or any other forms for topical use, in its free or nanostructured form.

4. Cosmetic and pharmaceutical preparations containing captopril for skin-lightening action according to Claims 1 to 3, characterized by containing 0.01 to 95% captopril, associated or not with 0.1 to 95% of an oil-phase viscosity agent, gelling and emulsifying agent, associated or not with 0.1 to 95% of humectants, emollients, associated or not with 0.1 to 5% of hydrophilic and lipophilic preservatives and a chelating agent, carried in conventional or nanostructured cosmetic and pharmaceutical systems.

5. Cosmetic and pharmaceutical preparations containing captopril for skin lightening action according to Claims 1 to 4, characterized by being for the treatment of hyperpigmentation.

6. Cosmetic and pharmaceutical preparations containing captopril for whitening action according to Claims 1 to 5, characterized by having the preparation process of the liquid crystalline nanocarriers containing 0.1% to 99% buffer solution and / or 0.1% to 99% surfactant / emulsifier and / or 0.1% to 99% vegetable oil and / or 0.1% to 99% captopril. Petition 870250081727, dated 11 / 09 / 2025, page 4 / 18 2 / 2 7. Cosmetic and pharmaceutical preparations containing captopril for skin lightening and / or depigmenting action according to Claims 1 to 6, characterized by being carried in any nanotechnology system to improve its stability, permeation and skin penetration and / or protection of its metabolites.

8. Topical use of captopril as a whitening and / or depigmenting agent according to Claims 1 to 7, characterized by being used in its free form or in nanostructured systems carried in cosmetic or pharmaceutical preparations.

9. Topical use of captopril as a whitening and / or depigmenting agent characterized by being in accordance with Claims 1 to 8, and may also be in combination with another active agent, whether in the form of plant extract or fractions, vegetable oil, essential oil or even isolated substances, whether natural or not.

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