Pro-molecules, method for obtaining same, and uses thereof

Abstract

The present invention relates to pro-molecules having a mono-, oligo-, or polysaccharide as a carrier, which allow the controlled delivery of their active ingredients, to the method for obtaining the pro-molecules and to uses thereof. The present invention has applications in the field of chemistry, especially in fragrances, flavors (edible), pharmaceuticals, dietary supplements, and agricultural actives (pesticides and fertilizers, inter alia).

Description

[0001] Promolecules, methods for obtaining them, and their uses.

[0002] Field of invention

[0003]

[0001] The present invention relates to promolecules with at least one mono-, oligo- or polysaccharide as a carrier for the intelligent delivery of an active ingredient, to the method of obtaining the promolecules and to their uses.

[0004] [2] The field of application of the present invention is the field of chemistry, more specifically fragrances, flavors (edible), pharmaceuticals, food supplements and agricultural actives (pesticides, fertilizers, among others).

[0005] Fundamentals of the invention

[0006] [3] The fragrance industry presents a number of challenges, some of which are in constant and progressive development. One of these challenges is the development of new technologies that enable higher performance, such as increasing its retention time on a surface (skin, hair, floor, fabric, among others), and increasing its stability in a product base, susceptible to degradation or oxidation processes, which are facilitated by increased temperature.

[0007] [4] Frequently, the efficiency of a fragrance is measured by its duration on the surface where it was applied - the longer the retention time, the greater the efficiency. Therefore, some technologies are employed to try to meet this recurring demand, such as the use of microcapsules, which utilize a physical mechanism: a polymeric shell that encapsulates the olfactory molecules, keeping them more stable and preventing them from evaporating / volatilizing. After the disintegration of its membrane, the fragrance is released, obtaining greater control over fragrance delivery, increasing the fragrance retention time on the applied surface (A. Herrmann, 2015 GY Zhu et al., 2012.).

[0008] [5] Another type of technology employed is the use of pro-fragrances, also known as fragrance precursors (MJB Osés et al, 2007; A. Haetzelti et al, 2020), where fragrance delivery occurs through a chemical mechanism: the fragrance binds to a carrier via a covalent bond which, when exposed to the environment, breaks the bond and releases the fragrance. This effect gives the user the possibility of experiencing a fragrance for longer, which, in addition to providing olfactory value, may contain aromatherapy raw materials capable of improving physical and mental health, such as citral, with stress and depression relief effects (Z. Lu et al., 2020) and limonene with anti-anxiety effects, improved learning and memory (Z. Lu et al., 2020).

[0009] [6] In the same way that pro-fragrances are molecules that can deliver fragrance in a more controlled manner, there are several other pro-molecules that can deliver their molecule of interest, the active ingredient, in a more controlled manner. Pro-fragrances are included in the universe of pro-molecules, a very broad, interdisciplinary and very common topic in the context of intelligent delivery of bioactives. Pro-molecules are capable of releasing the active ingredient through different mechanisms, for example stimulated by increased temperature, changes in pH, light exposure, redox reactions, enzymatic action, hydrolysis or oxidation.

[0010] [7] Promolecules can be formed from covalent bonds, for example through a reaction between actives containing an aldehyde group with carriers containing a primary amine group, forming imine (Schiff base), hydrazone, acylhydrazone or oxime type promolecules (S. Ulrich, 2019).

[0011] [8] Schiff bases are widely used in the fragrance industry, as is the case with aurantiol: a Schiff base formed from hydroxycitronellal and methyl anthranilate. In this case, it is a promolecule classified as a pro-fragrance, formed from the inaction between two fragrances. The carrier can be understood as one of the fragrances. Methyl anthranilate has a vapor pressure four times greater than aurantiol. Since vapor pressure is directly related to volatility, aurantiol is much less volatile than methyl anthranilate. Aurantiol is used both as an olfactory raw material in itself (without the need to release the reacting fragrances) since it has olfactory value, showing excellent performance in laundry products (fabric softeners and laundry detergents); and as a pro-fragrance, since it can undergo hydrolysis and simultaneously release hydroxycitronellal and methyl anthranilate.

[0012] [9] Another example of promolecules formed through covalent bonding is the reaction of actives containing a thiol group with a carrier also containing a thiol, forming a promolecule containing a disulfide group. Another example is formed by the reaction of actives containing a hydroxyl group with a carrier containing boron acid, forming borate esters (S. Ulrich, 2019).

[0013]

[0010] Promolecules can also be formed by crosslinking. Crosslinking occurs through intermolecular interactions and van der Waals forces between the molecules of a polymeric system (composed of one or more chemical species of polymers). These interactions can occur between the molecules of the polymeric system themselves or under the action of an added crosslinking agent. This results in the creation of a kind of three-dimensional network, a matrix, altering the physicochemical properties of the material. Crosslinking can occur naturally or be induced through chemical or physical processes, such as heat emission, radiation, or the insertion of crosslinking agents. It is one of the techniques used in the manufacture of materials such as plastics, rubbers, adhesives, and resins, and can offer greater mechanical strength, durability, and thermal stability.In this type of active delivery system, the active ingredient is the crosslinking agent, forming covalent bonds or interacting with certain polymer chains in this system. Thus, the carrier is the polymeric system, the active ingredient is the crosslinking agent, and the pro-molecule is the crosslinked system. An example of such a pro-molecule is the prodrug PSPA-PEG-Cisplatin (PSPA-PEG-Pt), formed in two steps: (1) the active ingredient cisplatin is incorporated into a polyethylene glycol (PEG) polymer as a linker, which is then integrated into a copolymer with a poly[(p-iodomethyl)styrene] core and polyacrylic acid (PSPA) arms; (2) the active ingredient cisplatin is then added as a crosslinking agent, interacting between the PSPA chains. Cisplatin (Pt) has a dual role in the structuring of this prodrug: as a linker between PEG and PSPA (first step) and as a crosslinking agent (second step). In both steps, it is an integral part of the system, forming bonds / interactions between polymers.Cisplatin is a chemotherapeutic agent used in cancer treatment, which has significant side effects due to its systemic toxicity in its free form. Thus, PEG-Pt and PSPA-PEG-Pt present an alternative for treatments with fewer side effects and sustained release of the chemotherapeutic agent (E. Stoyanova et al, 2013).

[0014]

[0011] Promolecules can also be formed by matrix trapping. In matrix trapping, the active ingredient is incorporated within a matrix, such as a polymeric system (usually cross-linked), hydrogels, liposomes, microspheres, or nanoparticles. This matrix forms a kind of three-dimensional "network" where the active ingredient will be accommodated / incorporated. An example of this system is the use of prodrugs in the form of nanogels: hyper-branched and cross-linked polyglycerol with disulfide bonds, biodegradable and biocompatible, which can be degraded under reductive intracellular conditions (X. Zhang et al, 2014).

[0015]

[0012] Promolecules can also be formed by encapsulation. In this method, the active ingredient is completely enclosed by a protective capsule / membrane / shell / wall, which prevents its immediate release. This capsule can be made from different materials, but is usually formed from polymers. Furthermore, it can be on a microscopic scale (microcapsules) or nanoscopic scale (nanocapsules). This technique can be used in various sectors, such as food, pharmaceuticals, and fragrances. In the food industry, aromas have their flavor preserved in microcapsules (usually made of starch), being released by mechanical force induced by teeth grinding and hydrolysis (by saliva) during chewing. In the fragrance industry, it is very common to use this technique to microencapsulate fragrance compositions in fabric softener formulations, allowing the deposition of these capsules on the fabric fibers of clothing.These microcapsules can be formed from different polymers, such as polyacrylates, polyurea, chitosan, alginate, and melamine. When the fabric is dry and mechanical force is applied (friction with the fabric), the capsules break and the fragrance is released, allowing for a long-lasting effect. If the garment is stored in a regular drawer, for example, the fragrance may remain protected for months within these microcapsules (K. Bruyninckx et al., 2019).

[0013] Promolecules can also be formed by adsorption. Adsorption is the result of intermolecular interactions (van der Waals forces) between the active ingredient and the carrier. The carrier can be composed of different materials, such as polyacrylate resins, cyclodextrins, silicas, and modified chitosan. A lipase enzyme can be immobilized on a macroporous polyacrylate resin, such as Novozym® 435 (Candida antarctica CAL-B lipase B immobilized on Lewatit® VP OC 1600).This process facilitates enzyme separation after a (bio)catalyzed reaction, reduces processing costs, allows for reuse, and increases stability against organic solvents and high temperatures (C. Ortiz et al., 2019). Cyclodextrin can be used as a carrier for fragrance molecules, increasing their water solubility and reducing their evaporation rate, resulting in more controlled release. Cyclodextrins belong to a class of cyclic oligosaccharides that contain a relatively hydrophobic central cavity and a hydrophilic outer surface, allowing interactions between fragrances and their hydrophobic portion. This phenomenon is reversible and leads to an equilibrium between the free and immobilized active ingredient.The disadvantage of using cyclodextrins in the fragrance industry is that this balance is not usually easily controlled, meaning that many fragrances can be released within a product, thus compromising its stability. Furthermore, it is common for other hydrophobic molecules in the product's composition to compete with fragrance molecules to interact with the hydrophobic portion of the cyclodextrin, further favoring the formation of free fragrance (U. Numanoglu et al., 2007). Some authors consider the use of cyclodextrins as encapsulation; however, unlike capsules, cyclodextrin is not a system that completely encloses the active ingredient.

[0016]

[0014] Promolecules can also be formed using nanomagnets. Nanomagnets are a class of nanoparticles that are sensitive to magnetic fields. They commonly have two components: a magnetic material, usually made from iron, nickel, and cobalt, and a chemical component that has functionality (SH Bossmann et al., 2017), which binds to the active component. A hypothetical example of a nanomagnet could be formed from a core made of FesC that has superparamagnetic properties (it exhibits magnetization in the presence of an external magnetic field) and a shell of SiO2 or biopolymers, such as carboxymethylcellulose and chitosan. The representation for this system (core plus shell) is written as Fe3O4@SiO2. Then, it is still possible to add ligands, for example containing primary amine groups at the external terminals (L-NH2), which then bind to an enzyme. Thus, an enzyme is immobilized by Fe3O4@SiO2@-NH2@enzyme.In other words, a nanomanet can be represented as a magnetic material@coating / shell@ligands@active. In the area of ​​prodrugs, nanomanets can perform magnetic drug targeting (MDT), and are being studied for the development of different types of treatments for cancer and arterial diseases, such as atherosclerosis (MKD Manshadi et al., 2018). Superparamagnetic iron oxide nanoparticles are widely used for prodrug design (DS Parimi et al., 2022).

[0017]

[0015] Promolecules containing at least one active drug can be understood as a prodrug. A prodrug can be defined as a chemical derivative that is pharmacologically inactive until it is converted in vivo into the active portion of the drug (B. Wang et al., 2016). A prodrug does not necessarily use a covalent bonding system to deliver an active ingredient. Prodrugs are compounds that, after administration, are metabolized (converted by the body) into a pharmacological active ingredient. This type of action replaces the direct introduction of the pharmacological active ingredient, so that, by being released in a controlled manner, there is better absorption of the active ingredient, allowing for greater treatment efficiency with lower dosages of the active ingredient applied (J. Rautio et al., 2018 / J. Stella et al., 1985).An example of a prodrug is acetylsalicylic acid, Aspirin (analgelic, antipyretic, and anti-inflammatory), developed by Felix Hoffman for the Bayer company in 1897: it undergoes a hydrolysis reaction, facilitated by esterase enzymes in the intestinal region, releasing salicylic acid as the active product (JO Miners et al., 1989). Other examples include Enalapril (treatment of hypertension) and Valacyclovir (antiviral for the treatment of herpes) (B. Wang et al., 2016). For pharmacological agents to exert their action, they commonly face several challenges before reaching the specific site where they should act. Some examples of these challenges are: the intestinal barrier, the blood-brain barrier, and metabolic reactions that can inactivate them (B. Wang et al., 2016). Most drugs disperse randomly throughout the body, so that only a small amount reaches the site of action.For an effective amount to reach the desired site without causing serious systemic side effects, the drug must possess certain physical and chemical characteristics that facilitate its passage through various biological membranes, thus avoiding metabolic inactivation by enzymes and retention in body tissues, which can result in undesirable long-term effects. These desirable physical and chemical characteristics are not always present in pharmacologically active compounds. One strategy that allows for a greater amount of drug action is to increase the drug dosage; however, this can increase side effects and the final cost of the drug formulation (B. Wang et al., 2016). There are different mechanisms of activation / release of a prodrug – two common examples are: metabolic release mediated by enzymes present in the biological system and hydrolysis (B. Wang et al., 2016).It is worth noting that the present invention presents an ester-type promolecule, which can fit into both of these delivery systems. The advantages of prodrugs can include: increased bioavailability, pain relief at the injection site, reduction of unpleasant drug taste, decreased toxicity or side effects, decreased metabolic inactivation, increased chemical stability, and prolonged action of the active ingredient (B. Wang et al., 2016). Its benefit is not limited to ingestion, as it can facilitate processes such as formulation, handling, and shelf life (stability) of the pharmacological active ingredient. It is important to emphasize that the present invention is a promolecule that can be classified as a prodrug and may, for example, offer these aforementioned benefits.

[0018]

[0016] Promolecules containing at least one fragrance active can be understood as a pro-fragrance. The general concept of pro-fragrance technology is centered on the idea of ​​achieving the temporary immobilization of an olfactory molecule through a carrier, forming a fragrance precursor. It is not usual to find the term pro-fragrance using delivery systems other than through the breaking of a covalent bond, unlike prodrugs which can be presented in different forms.

[0019]

[0017] After the condensation reaction between the carrier and the olfactory molecule, the product with the higher molecular mass provides a significant reduction in volatility, as it has greater intermolecular interactions (Van der Waals forces) dipole-dipole or dipole-induced, due to its larger surface area. The reduction in volatility can be verified by the reduction in vapor pressure (which is directly related to volatility) between the target fragrance molecule and the pro-fragrance. For this technology to be effective, the reverse reaction must occur after the pro-fragrance is exposed to the environment where the user will encounter the fragrance. In other words, the covalent bond between the carrier and the olfactory molecule must break, triggering and releasing the fragrance, which can occur through increased temperature, enzymatic action, pH change, or the presence of water / oxygen (hydrolysis / oxidation) (T. Kuhnt et al., 2014', F. Flachsmann et al., 2005 B. Indradas et al., 2018).The present invention is a promolecule model that can release the active ingredient through hydrolysis and / or enzymatic action. In one example of the present invention, more specifically, this promolecule can be an ester-type profragrance whose release can occur on human skin, which contains microbiota with a certain moisture content (presence of water) and a certain concentration of lipase enzymes, capable of releasing the fragrance in a more controlled manner compared to free fragrance.

[0020]

[0018] Fragrance promolecules, also called pro-fragrances, can be obtained from various types of molecules. One type that is little explored in the literature refers to polysaccharide derivatives, which are abundant on the planet. An example of the misuse of these compounds is the fate of biomass generated by the agricultural industry, such as orange peel, which is largely destined for landfills, use as livestock feed, or burning for non-clean energy generation (MA Marino et al., 2021).

[0019] Orange peel is an example of biomass that fits this innovation, since two examples of new promolecules developed use D-glucuronic acid as a carrier, which is the major monomer of pectin, a polysaccharide abundant in orange peel.

[0021]

[0020] Glucuronic acid is a model monosaccharide derived from pectin or D-glucose that can have its value added by being esterified with fragrance molecules, contributing to a higher performance of fragrances containing hydroxyl groups. Furthermore, it is a non-toxic and biodegradable compound, and can be widely used in cosmetic and food products. It is important to highlight that Brazil is a world leader in orange production, generating a large amount of bagasse (agro-industrial residue), which contains pectin as its major polysaccharide, opening up possibilities for reusing this biomass to, for example, add value to the fragrance industry.

[0022]

[0021] Due to its comprehensive nature, the knowledge acquired in the project is not limited to the area of ​​fragrances, and can be applied in other sectors, such as the synthesis of prodrugs, food supplements, more sustainable agrochemicals, pest control, among others. The development of new promolecules allows a range of sectors important to society to have more options for how to deliver an active ingredient more efficiently.

[0023]

[0022] The state of the art describes some technologies for fragrance release, such as the Scentaurus® line of pro-fragrances (from Givaudan) and the HaloScent® line (from Firmenich-DSM). The Givaudan line works mainly with pro-fragrances that are accords, that is, two molecules of olfactory value with functional groups that react with each other are condensed so that two fragrances are released simultaneously. Currently, Firmenich also works with this approach. This information can be found on the companies' websites.

[0024]

[0023] Hexarose® is an ester pro-fragrance, formed from geraniol (a fragrance with a hydroxyl group) and palmitic acid. This molecule can be used in laundry detergent formulations, where, during washing, it is deposited on the fabric fibers along with lipase enzymes contained in fabric softeners. After contact between the softener enzymes and the laundry detergent pro-fragrance, it undergoes enzymatic hydrolysis, releasing geraniol (A. Herrmann, 2015; W. Paget et al., 1995). Although this technology is also an ester-type pro-fragrance, it does not explore the use of saccharides as a carrier, as is the objective of this proposal.

[0025]

[0024] Patent WO2019147742 A1 describes acetal-type pro-fragrances that can be activated by hydrolysis: fragrances with hydroxyl groups (such as geraniol and phenethyl alcohol) can condense with a salt derived from pyridoxal salt (derived from vitamin B6) and form pro-fragrances (GR Boyce, 2019; K. L. Weeks et al., 2018). Although this technology is a pro-fragrance that, like the present invention, can release fragrance by hydrolysis, it does not exploit the use of saccharides as a carrier and the molecule is not of the ester type.

[0025] Patent WO2010105874A1 describes a cyclamoxazolidine as a bicyclic oxazolidine-type pro-fragrance, used for the release of two cyclamen aldehyde units, which has a floral-muguet note. This pro-fragrance can be released by contact with air or moisture (undergoing hydrolysis or oxidation), releasing two molecules of cyclamen aldehyde ( / V. Armanino et al., 2020 U. Huchel et al., 2010).Although this technology is a pro-fragrance that, like that of the present invention, can release fragrance by hydrolysis, it does not exploit the use of saccharides as carriers and the molecule is not of the ester type.

[0026]

[0026] Patent W02005077881A1 describes Scentaurus Tonkarose® as a pro-fragrance activated by light-based photolysis, which induces trans (E) to cis (Z) isomerization, followed by spontaneous lactonization, releasing coumarin (sweet, coconut and freshly cut hay nuances) and 9-decen-1-ol (fresh, green, greasy, waxy-floral-pink). Lactonization is the formation of a cyclic ester, in this case occurring through intramolecular esterification, spontaneous by forming a stable ring (spontaneous process when the structure formed is 5 or 6 members) (F. Flachsmann et al., 2005; S. Derrer et al., 2007). Although this technology is a pro-fragrance, it does not explore the use of saccharides as a carrier.

[0027]

[0027] Patent EP1460994B1 describes the pro-fragrance Haloscent D® as a conjugated addition product between the thiol dodecane and the fragrance γ-damascone, which has an α,[3-unsaturated] carbonyl group. Upon exposure to air (presence of moisture / water or oxygen), this pro-fragrance can be activated through a 1,4-retro-addition mechanism. The fragrances released are γ-damascone (fruity, floral-rose) and lauric aldehyde (aldehyde, citrus) (C. Fehr et al., 2005; C. Fehr et al., 2002). Although it reports on a pro-fragrance, it does not explore the use of saccharides as carriers; furthermore, this is not a molecule formed from the esterification of a carrier with a fragrance containing at least one hydroxyl group.

[0028]

[0028] Another pro-fragrance model is found in patent document EP2438908 which discloses an amphiphilic copolymer that can be used in film-forming compositions for dermal applications. The amphiphilic copolymer is characterized by having a defined structure with a hydrophilic polymeric structure and pendant hydrophobic groups. When applied to the skin, the copolymer rearranges itself in contact with the lipid-rich domains of the outermost layer of the skin, resulting in the formation of a stable film. The amphiphilic copolymer contains covalently linked active ingredients, such as sunscreens, humectants or colorants, resulting in the immobilization of the active ingredient on the skin.Amphiphilic copolymers can also contain other active agents, such as fragrances, cosmetics, or dermatologically active drugs, covalently linked through a chemical bond that can be degraded under the physiological conditions found on the skin, resulting in the sustained release of the immobilized active ingredient. However, the aforementioned European prior art document does not explore a pro-fragrance comprising a saccharide, for example, derived from orange pomace, which is a biodegradable and non-toxic carrier for pharmaceutical and dermato-cosmetic use, as well as D-glucuronic acid.

[0029] Another document found in the state of the art is WO9730687A2, entitled “Fragrance Precursors,” which refers to fragrance precursors that can act in cosmetic products, such as deodorants and antiperspirants. These compounds are normally odorless or nearly odorless, but upon contact with the skin, for example, in skin care compositions or personal care compositions, they produce fragrances through the release of an odorous alcohol. However, the patent document in question does not disclose an ester-type promolecule such as that of the present invention, and does not concern the specific use of mono-, oligo-, or polysaccharide carriers, which are biodegradable and commonly non-toxic carriers for pharmaceutical and dermato-cosmetic use.Furthermore, the prior art does not reveal a method for obtaining promolecules such as those of the present invention under suitable pressure, temperature and time conditions in a solvent evaporation process.

[0029]

[0030] Another patent document, BR112021025470-6, describes long-lasting fragrance compositions that may include a fragrance compound and a glycoside selected from a steviol glycoside, derivatives thereof, or combinations thereof. Thus, although glycosides such as steviol have groups like carboxylic acid and fragrances may have -OH (hydroxyl) groups, the prior art document describes the use of glycoside carriers that, unlike the present invention, do not form ester-type covalent bonds with the active ingredients, such as fragrances. Furthermore, the document does not disclose a differentiated method of obtaining the technology or the operating format / mechanism that allows these bonds.

[0030]

[0031] Another patent document, EP2747742B1, discloses a composition comprising a distribution particle of an agent comprising at least one of hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl guar, hydroxyethyl ethyl cellulose, or methyl cellulose. The invention also provides a process for manufacturing particles in which perfume oil is encapsulated using emulsion polymerization to form core-shell particles (alternatively, the perfume may be subsequently adsorbed) and an additional polymer layer is formed on the outside. Although this is a mechanism that allows for increased fragrance retention time in use, this mechanism does not involve preserving the fragrance through a covalent ester bond between the fragrance and the carrier.

[0031]

[0032] Another patent document, EP2012 / 064898, also refers to the distribution of the agent (preferably perfume), for example, to the fabric during washing, or to the substrate surfaces of the human body, such as the skin or, more preferably, the hair. However, unlike the present invention, the prior art document does not teach a pro-fragrance comprising a saccharide, such as a pectin derivative, for the controlled release of an active ingredient.

[0032]

[0033] Another patent document, US2020 / 0170895, describes the composition of a microcapsule for the release of an active ingredient. This prior art document also describes various products such as shampoo, hair conditioner, detergent, and others containing the microcapsule for the release of an active ingredient. However, the document in question does not teach a promolecule like the one in the present invention, because although it is a mechanism that allows for increased fragrance retention time in use, this mechanism does not involve preserving the fragrance through a covalent ester bond between the fragrance and the carrier.

[0033]

[0034] Furthermore, the aforementioned document US2020 / 0170895 does not describe the use of carriers covalently linked to an active ingredient through an ester-type bond, which implies a completely different mechanism of action for the technology. The state of the art does not teach a promolecule comprising a saccharide (mono-, oligo- or poly-), for example derived from orange peel, and which has a controlled release of the active ingredient. Furthermore, the state of the art does not teach a method for obtaining a promolecule covalently linked to the active ingredient, in which the carrier is a biodegradable mono-, oligo- or polysaccharide.

[0034]

[0035] One of the benefits of the present invention lies in differentiating between two formats for controlling the release of active ingredients: the use of microcapsules and the use of promolecules. In terms of product formulation, the use of promolecules allows for the exploration of more types of applications than microcapsules, since microcapsules are structures that require homogeneous dispersion in the final product, that is, they commonly require another active ingredient that allows this homogeneous dispersion. Furthermore, microcapsules are structures that commonly add a cloudy appearance to the final product, which is undesirable for the end consumer in a range of products such as perfumes, shampoos, scented cleaners, multi-purpose cleaners, laundry detergents, micellar waters, and others. In addition, many microcapsules cannot come into contact with matrices containing large amounts of alcohols such as ethanol, as is the case with perfumes, since their structure may not remain stable in these matrices.Microcapsules are structures that are commonly much larger than promolecules – considering pharmacological, veterinary, and medical applications, there may be greater obstacles in the way a drug contained in microcapsules is delivered to patients, precisely because of the larger particle size. Furthermore, microcapsules are commonly dispersed homogeneously in the final product and not solubilized; while promolecules can commonly be dispersed homogeneously and also solubilized in the final product.

[0035]

[0036] Another advantage of the present invention is the use of saccharides as carriers, since they are commonly biodegradable and non-toxic molecules, and can be exploited in various segments, such as those already mentioned. The use of saccharides also allows for more options for the use of biomass, such as orange bagasse. The misuse of biomass can lead to environmental problems, such as disposal in landfills that require larger areas to support this biomass. In addition, biomass can be burned to generate electricity; however, this is not a sustainable way of obtaining energy, since a large amount of greenhouse gas molecules, such as carbon dioxide, is dispersed into the atmosphere.

[0036]

[0037] Considering the application of fragrance enhancers in media of different polarities, it is desirable to find a carrier with greater solubility in the main solvents used in the industry; for example, in the fragrance industry, where dipropylene glycol, propylene glycol, and ethanol are widely used solvents. Therefore, the present invention involved solubility studies of different carriers (polysaccharides and derivatives, for example, cellulose, pectin, keratin, chitosan, D-glucuronic acid, and glucose) in these different solvents commonly used in the fragrance industry. The same was considered for the aroma industry, where propylene glycol, ethanol, and water are widely used solvents.The present invention also offers a differential and beneficial aspect in terms of solubility, that is, compatibility of use of the technology in products such as fragrances and aromas, with a proposed saccharide-type carrier that may exhibit better solubility in these solvents used in the fragrance and aroma industries.

[0037]

[0038] Another advantage of the present invention is the use of ester-type promolecules, which can be released in a variety of different environments, unlike glycoside-type promolecules, which also use saccharides as carriers. Glycosidic linkages require different release conditions compared to ester linkages. Although both glycosidic and ester linkages can be hydrolyzed (broken in the presence of water), allowing controlled release in the skin and hair, mouth, bloodstream, stomach, intestines, humid environments, and aqueous preparations of food supplements; the presence of lipase enzymes facilitates the breaking of ester-type linkages, and the presence of glycosidase enzymes facilitates the breaking of glycosidic-type linkages.Thus, the present invention allows exploring new ways of using promolecules containing saccharide as a carrier, since there are different concentrations or presence of lipases and glycosidases depending on different environments.

[0038]

[0039] Due to its comprehensive nature, the developments of the present invention are not limited to the area of ​​fragrances, and can be applied in other sectors, such as the synthesis of prodrugs, food supplements, more sustainable agrochemicals, pest control, among others.

[0039] Brief description of the invention

[0040]

[0040] The present invention relates to novel promolecules with at least one mono-, oligo- or polysaccharide as a carrier which, in certain applications, can perform the intelligent delivery of an active ingredient (controlled delivery), to the method of obtaining the promolecule and to its uses.

[0041]

[0041] The present invention also relates to novel promolecules with at least one mono-, oligo- or polysaccharide as a carrier which in certain applications can increase the thermal stability of the active ingredient.

[0042]

[0042] In a preferred embodiment of the invention, without however being limited to this embodiment, the present invention relates to pro-fragrances, which are chemical derivatives formed by a carrier that covalently binds to a fragrance in a temporary manner, and may have an olfactory / hedonic value and allow the fragrance to be released in a more controlled manner, as well as potentially increasing its thermal stability.

[0043]

[0043] Also within the scope of the present invention is the method of synthesis by means of esterification using enzymatic catalysis by lipase EC 3.1.1.3 BRENDA (triacylglycerol lipase), and the use of pro-fragrances in the controlled release and increased thermal stability of fragrances.

[0044] Furthermore, the objects of the present invention are two new pro-fragrances formed from D-glucuronic acid (GA) and the fragrances - a) citronellol (CIT) or b) cis-3-hexen-1-ol (HEX), named, respectively, as PRO-CIT and PRO-HEX; which may have olfactory / hedonic value, may allow the release of the fragrance in a more controlled manner and may increase its thermal stability.

[0044] Brief description of the figures

[0045]

[0045] Figure 1A shows the PRO-CIT pro-fragrance derived from citronellol fragrance and D-glucuronic acid saccharide and Figure 1B shows the PRO-HEX pro-fragrance derived from cis-3-hexen-1-ol fragrance and D-glucuronic acid saccharide (1B), obtained according to the synthesis described in Example 1.

[0046]

[0046] Figure 2A presents a graph illustrating the data obtained in the analysis of CIT, GA and PRO-CIT by thermogravimetry expressed as mass as a function of temperature, and Figure 2B shows a graph illustrating the data obtained in the analysis of CIT, GA and PRO-CIT by thermogravimetry and expressed as a derivative of mass as a function of temperature, which describe a greater thermal stability of the fragrance when linked by an ester bond with D-glucuronic acid, according to Example 2.

[0047]

[0047] Figure 3A presents a graph of data obtained from HEX, GA, and PRO-HEX analysis by thermogravimetry expressed as mass as a function of temperature, and Figure 3B shows a graph with data expressed as a derivative of mass as a function of temperature, which describes a greater thermal stability of the fragrance when linked by an ester bond with D-glucuronic acid, according to Example 2.

[0048] Figure 4A illustrates the mean and standard error of fragrance intensity as a function of time from the sensory panel for Example 4; and Figure 4B shows the percentage of votes from the sensory panel for which sample is more intense as a function of time.

[0048]

[0049] Figure 5 shows the relationship between the areas obtained in the partial chromatograms of the base ions corresponding to the CIT and HEX fragrances obtained by HS-SPME-GC-MS, according to Example 3. The area is proportional to the concentration of the free fragrance in the headspace.

[0049]

[0050] Figure 6 presents the assignment of nuclear magnetic resonance (NMR) spectral data for the pro-fragrances of Example 1.

[0050] Detailed description of the invention

[0051]

[0051] According to the present invention, said pro-molecules include a mono-, oligo- or polysaccharide as a carrier for the intelligent delivery of an active ingredient.

[0052]

[0052] The pro-molecules described in the invention may offer benefits during their use, not necessarily related only to the intelligent delivery of an active ingredient, for example the aforementioned pro-fragrances PRO-CIT and PRO-HEX which already have olfactory value.

[0053]

[0053] In a preferred embodiment, without, however, being limited to this embodiment, the present invention provides pro-fragrances that are chemical derivatives formed by a carrier that covalently binds to a fragrance in a temporary manner, releasing it in a more controlled way. It is also an object of the present invention to synthesize, through esterification using enzymatic catalysis by lipase EC3.1.1.3 (triacylglycerol hydrolase), and use them in the controlled release of the pro-fragrances obtained in the present invention.

[0054] The two pro-fragrances are formed from D-glucuronic acid (GA) and the fragrances citronellol (CIT) or cis-3-hexen-1-ol (HEX), named respectively as PRO-CIT and PRO-HEX.

[0054]

[0055] The method for obtaining the promolecule and its uses are detailed further below.

[0055] Examples of embodiments of the invention

[0056] Example 1: Obtaining pro-fragrances from synthesis via esterification between D-glucuronic acid and citronellol (CIT) or cis-3-hexen-1-ol (HEX) fragrance.

[0057]

[0056] In one embodiment of the invention, without, however, being limited to this embodiment, the invention is described in the examples of obtaining the pro-fragrances hereinafter referred to as PRO-CIT and PRO-HEX and their characterizations, wherein the pro-fragrances were obtained through esterification using enzymatic catalysis by lipase EC3.1.1.3 (triacylglycerol hydrolase), with 8.3% and 12.7% yield, according to the innovative method which is presented in accordance with the respective steps and sub-steps described below:

[0058] (i) Dilution of 10 mmol of GA (glucuronic acid) and 10 mmol of CIT (citronellol) or HEX (cis-3-hexen-1-ol) in 50 mL of tert-butyl alcohol in a reaction flask;

[0059] (ii) Addition of 2.5 g of molecular sieve (0.4 nm), magnetic stir bar and, lastly, 0.5 g of lipase enzyme (> 5,000 U / g, recombinant and expressed in Aspergillus niger, EC 3.1.1.3 BRENDA - triacylglycerol lipase) immobilized on macroporous acrylic polymer (L4777-10G - Sigma), with suspension maintained by heating at 55 °C for 48 h, under stirring at 150 rpm; (iii) Then, filtration under reduced pressure occurs and 35 ml of distilled water is added to the filtrate, stirring the mixture at 150 rpm for 2 min;

[0060] (iv) Next, an extraction of four 40 ml portions of dichloromethane is performed, followed by rotary evaporation of the organic phase under reduced pressure at 30 °C;

[0061] (v) The concentrate obtained is used to proceed with the silica gel purification: 3.5% (w / w) distilled water was added to 40.5 g of silica gel (mesh 70-230); chloroform-packed column (containing 0.5% w / w ethanol); final dimensions 22.0 cm x 2.5 cm. The mobile phase was made in a three-phase gradient of 50 ml of different chloroform:methanol ratios: (1) 90:10 (v / v); (2) 80:20 (v / v); (3) 70:30 (v / v); in that respective order.

[0062] (vi) 3 mL fractions were collected from the third mobile phase and the product of interest was identified by thin-layer chromatography, allowing selection of fractions containing the promolecule. The thin-layer chromatography consisted of a stationary phase (Si-60 F254 plate); a mobile phase of chloroform:methanol:water in a 65:15:2 (v / v / v) ratio; and a developer of a methanol solution containing 6.5 mmol. 1(vii) The fractions containing only the product formed were added to a flask and the solvent was evaporated in an evaporative rotary evaporator at reduced pressure and 30 °C until a final volume of approximately 4 mL was reached. (viii) Nitrogen gas was used at low flow rate to evaporate the remaining solvent and, finally, the product was kept in a desiccator for five days until the mass of the product became constant.

[0063]

[0057] Both the final products PRO-CIT and PRO-HEX have the consistency of a colorless to light yellow resin. After purification and obtaining the resins (PRO-CIT citronellol pro-fragrance; PRO-HEX cis-3-hexen-1-ol pro-fragrance), characterizations were performed using spectroscopic and spectrometric techniques.

[0064] Characterization

[0065]

[0058] Infrared spectroscopy experiments were performed on an Agilent Cary 630 FT-IR spectrometer equipped with attenuated total reflection (ATR) monolithic diamond. Each spectrum was obtained by accumulating 128 scans at a resolution of 4 cm⁻¹. -1 , in the wavelength range of 4000 cm -1 400 cm -1 .

[0066]

[0059] Mass spectrometry analyses were performed on a Thermo Q-Exactive Orbitrap with an electron spray ionization system (High Resolution ESI-MS). The experiment was conducted in two modes: full scan (MS) and fragmentation (MS / MS - PRM mode), both with infusion at 20 pL min⁻¹. -1 (Direct by syringe pump), positive field mode (detection of positively charged ions), resolution 70,000, cone voltage 3.5 kV, m / z range 50 to 750. The ionization energy / cone was selected with a value of 50 nce for the PRM fragmentation mode of the ester product. The sample concentration was 50 ppm in methanol. The mass error was calculated according to Equation 1, where _accurate_mass is the experimentally obtained (accurate) ion mass and _r_exact_mass is the exact / theoretical mass calculated considering the mass loss of one electron (0.00055 Da) due to the formation of a positively charged ion.

[0067]

[0060] Equation 1. Mass Error (ppm) = [10 6 (damaged - me xata) / m exata].

[0068]

[0061] Nuclear magnetic resonance analyses were performed on a Bruker Avance III 400 MHz, with a 16-position autosampler (solution analysis), dual broadband resonance (BBI) probe, 1 H (16 scans), and HSQC (12 scans) and HMBC (12 scans). Samples were diluted in DMSO-d for analysis (10 mg of sample to 500 pL of DMSO-d). Also, on a Bruker Avance III 500 MHz, with a 60-position autosampler (solution analysis), dual-resonance broadband probe (BBO), 1 H (16 scans), HSQC (6 scans), and HMBC (8 scans), diluted in DMSO-de (20 mg of sample to 500 pL of DMSO-de).

[0069]

[0062] By infrared spectroscopy a carbonyl-ester band (1726 cm -1 ) was observed. By mass spectrometry, the products had confirmed target ions: (M+Na) + ; (2M+Na) + ; (M+Na-H2O) +; sodium ion minus the fragrance portion; sodium ion minus the fragrance portion and a water molecule; with error modules less than 2 ppm. Nuclear magnetic resonance was used to characterize the chemical structures, with emphasis on the disappearance of the -CH2- signal bound to the hydroxyl group of the free fragrance ( 1 H 3.42 ppm; 13 C 59.27 ppm for CIT; 1 H 3.37 ppm; 13 C 62.91 ppm for HEX) and presence of signal -CH2- linked to the oxygen-ester of the pro-fragrance ( 1 H 4.09 ppm; 13 C 63.21 ppm for PRO-CIT; 1 H 4.05 ppm; 13 C 66.00 ppm for PRO-HEX).

[0070]

[0063] The experimental values ​​and mass assignment for the ions formed in full scan MS and fragmentation MS / MS are summarized in Table 1.

[0071]

[0064] Table 1. Experimental values ​​and mass assignment for ions formed in full scan MS and fragmentation MS / MS for Example 1:

[0072]

[0065] Figure 6A illustrates the assignment of nuclear magnetic resonance chemical shift spectral data for the PRO-CIT fragrances and Figure 6B, PRO-HEX. The chemical shift value is in the format [nuclear chemical shift of 1 H; chemical displacement of the nucleus of 13 W],

[0073] Example 2: Stability and thermal release by thermoquarimetric analysis

[0074]

[0066] The analyses in Example 2 were performed on a TGA-DTA 6200 (Seiko), according to the following parameters:

[0075] • Starting temperature: 25 °C;

[0076] • Final temperature: 545 °C;

[0077] • Rate of temperature increase: 10 °C min -1 ;

[0078] • Gas: Air (Argon);

[0079] • Pan / Stand: Alumina.

[0080]

[0067] Thermogravimetric analysis (TGA) studies showed that the pro-fragrances of Example 1 exhibited greater stability and controlled thermal release of fragrances, showing a difference of more than 94 °C from the onset of volatilization of the free fragrances. The results are illustrated in Figures 2A and 2B for PRO-CIT (PCIT) and in Figures 3A and 3B for PRO-HEX (PHEX).

[0081] Example 3: Controlled release of PRO-CIT and PRO-HEX measured by solid-phase microextraction of the headspace with gas chromatography-mass spectrometry - HS-SPME-GC-MS

[0082]

[0068] The pro-fragrances from Example 1 were used in this example. Samples were prepared using a culture medium as a matrix and an aliquot of the free fragrance (CIT or HEX) or pro-fragrance (PRO-CIT or PRO-HEX). The matrix consisted of a representation of the human forearm microbiota. To prepare the matrix, a tryptone soy broth (TSB) medium was prepared (1.5 g of medium in 50 ml of distilled water) in a glass flask (400 ml), which was then autoclaved at 120 °C, 15 psi for 15 min along with an empty Erlenmeyer flask (250 ml). Next, the medium was transferred to a beaker and a swab sample collected from a human forearm (using a conventional cotton swab autoclaved at 120 °C, 15 psi, 15 min) was added and kept in an incubator at 37 °C for 16 h. Five samples were prepared according to Table 2. The HEX + GA sample was a simple physical mixture of these compounds.The PRO-HEX sample was analyzed a second time, 100 minutes after the first analysis, and will be referred to in the discussion as PRO-HEX-2.

[0083]

[0069] Table 2. Samples used for the HS-SPME-GC-MS study in

[0084] Example 3

[0085]

[0070] For solid-phase microextraction and gas chromatography with a mass spectrometer detector, a 50 / 30 pm divinylbenzene / carboxen / (poly)dimethylsiloxane (DVB / CAR / PDMS) fiber was used. The sample was incubated for 2 min before extraction at 33 °C. Agitation was set to 250 rpm and desorption at the GC inlet was performed at 250 °C for 2 min. The extraction temperature and time were set to 33 °C and 30 min, respectively. GC-MS was performed on a TRACE 1310 gas chromatograph coupled with a Q-Exactive FT-Orbitrap mass spectrometer (ThermoFisher Scientific). The parameters inherent to the chromatographic method, such as dimensions of the chromatographic columns, flow rate of carrier gas and auxiliary gas, temperature programs, among others, are summarized in Table 3.

[0086]

[0071] Table 3. Summary of chromatographic parameters used in the HS-SPME-GC-MS fragrance evaluation of Example 3

[0087]

[0072] The result presented in Figure 5 illustrates the results of Example 3. The relative concentration of free fragrance in the headspace was lower for the pro-fragrances compared to the respective free fragrances in a matrix containing human forearm microbiota, suggesting that the release of the fragrances occurred in a more controlled manner, according to the interaction of the microbiota which may contain lipase enzymes.

[0088]

[0073] The HEX + GA sample showed 10.27% more [HEX] than HEX, that is, a relatively close result. The interaction between GA and HEX did not represent a reduction in fragrance evaporation, reinforcing the effect of the PRO-HEX covalent bond in relation to the intermolecular interactions between GA and HEX.

[0089]

[0074] This example shows a snapshot of the first 50 min] of interaction between fragrances and pro-fragrances with a matrix representing the human skin microbiota, allowing comparison of relative fragrance concentrations in the headspace. Free fragrances showed higher concentrations in the headspace compared to pro-fragrances, which can be attributed to the covalent bond between GA and the fragrance. The human skin microbiota contains lipases capable of hydrolyzing the ester covalent bond and, as they do so, more fragrances are released into the liquid matrix and subsequently into the gas phase and the fiber, according to the thermodynamic equilibrium of the three phases.

[0090] Example 4: Controlled release measured via sensory panel

[0091]

[0075] In one embodiment of the invention, without, however, being limited to this application, an example of the application of this technology is perfumes or eau de colognes, in which a dosage of 2% (w / w) of PRO-HEX allowed for a longer duration of the cis-3-hex-1-ol fragrance on human skin, measured in a sensory panel.

[0076] A sensory panel was made with the aim of comparatively evaluating the fragrance intensity in the upper region of each pulse over time. For this purpose, eau de cologne formulations containing HEX and PRO-HEX were prepared.

[0092]

[0077] The cologne formulation was prepared as follows for PRO-HEX:

[0093] I. The fragrance was diluted in dipropylene glycol (DPG);

[0094] II. This dilution was homogenized in water;

[0095] III. Mixture II was diluted with ethanol.

[0096]

[0078] The cologne formulation was prepared as follows for HEX:

[0097] I. The fragrance was diluted in dipropylene glycol (DPG);

[0098] II. This dilution was homogenized in ethanol;

[0099] III. Mixture II was homogenized with water.

[0100]

[0079] The ethanol used was 96 GL (v / v) and the water was deionized. Table 4 shows the final cologne formulations used in the sensory panel.

[0101]

[0080] Table 4. Cologne formulations used for the sensory panel

[0102]

[0081] The HEX 7.25% sample contains an equimolar amount of HEX to the amount of PRO-HEX 20%. The samples used in the sensory panel were prepared up to one day before the evaluation.

[0082] Using a single-channel pipette, 40 pL of each sample was applied to the upper part of the panelists' wrists: PRO-HEX 20% was applied to one wrist and HEX 7.25% to the other. Each panelist was instructed to comparatively evaluate the fragrance intensity immediately after application and every 30 min for 120 min, according to the vertical mixed scale®^ described in Table 5. In addition, the panelists were to indicate which wrist contained the most intense fragrance at each time point.

[0103]

[0083] The panelists were in a typical office environment, room temperature (25 °C), and were allowed to use work computers and walk around the room. The panelists did not apply any perfumed products to their bodies before starting the panel. The panel consisted of eight selected evaluators®^ (minimum duration of one year of panelist training for sensory evaluation of fragrances), each of whom could repeat the evaluation up to three times. The panelists were not informed which sample was applied to which arm. Only one evaluation per period (morning / afternoon) was allowed per panelist. A total of 20 responses (n = 20) were collected.

[0104]

[0084] Table 5. Vertical mixed scale of fragrance intensity for sensory panel evaluation I 10 | Extremely strong |

[0105]

[0085] The following were collected: mean, error, and p-value obtained by the Student's t-test, according to the following Excel formulas:

[0106] • Average: = AVERAGE(value 1 :value n);

[0107] • Error: = STDEV.P(value 1 :value n) / SQRT(=COUNT.NUM(value 1 :value n)-1 );

[0108] • p-value: = TEST.T(value 1:value n;value T:value n';2;2), where value

[0109] 1.value n are the HEX values ​​and value .value n' are the PRO-HEX values.

[0110]

[0086] Table 6 presents the mean, error (n-1) and p-value obtained by the Student's t-test (two-tailed; different variance - check for statistical difference between sample values; does not assume equality of variances) with three decimal places, for each time point.

[0111]

[0087] Table 6. Mean and error (n-1) of intensity as a function of time and p-values ​​(three decimal places) by Student's t-test of the sensory panel

[0112]

[0088] The sensory panel was conducted to evaluate the intensity of fragrance perceived on the skin over 120 min, comparing HEX with PRO-HEX, showing that from 60 min onwards PRO-HEX presented greater intensity.

[0089] The results of the sensory panel indicate that there is a benefit in using a pro-fragrance derived from the cis-3-hexen-1-ol fragrance and the D-glucuronic acid carrier (PRO-HEX) to improve the retention time of the cis-3-hexen-1-ol fragrance (HEX) on human skin.

[0113]

[0090] The fragrance intensity results as a function of time (up to 120 min) show a lower rate of intensity decay for PRO-HEX compared to HEX. After 60 min, there is a statistically significant difference indicating that PRO-HEX was more intense than HEX, with PRO-HEX exhibiting more than three times the olfactory intensity at the last instant (120 min). Furthermore, no panelist rated the HEX sample as more intense than PRO-HEX after 90 min.

Claims

CLAIMS 1. Method for obtaining promolecules characterized by comprising the following steps: a) Diluting (i) GA (glucuronic acid) and (ii) CIT (citronellol) or HEX (cis-3-hexen-1-ol) in tert-butyl alcohol; preferably equimolar amounts of the reagents and preferably an amount of solvent that is, in mL⁻¹, five times the amount in mmol used for each reagent; b) Adding in step “a” molecular sieve (pore size 0.4 nm or 0.3 nm) and lipase enzyme, under heating at 30-80 °C for 4-96 h, under stirring at 50-350 rpm; preferably molecular sieve of size 0.4 nm and an amount of 0.01-0.50 g for each 1 mL⁻¹ of tert-butanol solvent used, more preferably 0.05 g for each 1 mL⁻¹ of solvent used; preferably immobilized lipase enzyme of type EC 3.1.1.

3. BRENDA immobilized on macroporous acrylic polymer and a quantity of 0.001 - 0.500 g of immobilized enzyme for each 1 mmol of reagent, more preferably 0.05 g of enzyme for each 1 mmol of one of the reagents; preferably heating at 55 °C for 48 h under magnetic stirring at 150 rpm; c) Filter the product from step “b”, preferably under reduced pressure; d) Add distilled water to the filtrate obtained in step “c” under stirring for a few minutes; preferably 0.1 - 1.0 ml of distilled water for each 1 ml of tert-butanol solvent, stirring. preferably magnetic at 50-300 rpm, for 0.5-5.0 min; more preferably 0.7 ml of distilled water for each ml of tert-butanol solvent, 150 rpm and 2 minutes of stirring; e) Extract the product from step “d” by adding portions of organic solvent; preferably more than 3 portions of 0.1-1.0 ml of organic solvent for each 1 mL of tert-butanol solvent used; more preferably 4 portions of 0.8 mL of the organic solvent dichloromethane for each 1 mL of tert-butanol solvent used; f) Evaporate the product obtained in step “e” by rotary evaporation under reduced pressure at 30 °C of the organic phase; g) Purify the concentrate obtained in step “f” using a silica gel column in a proportion of 0.1-5% (w / w) distilled water, 20-100 g of silica gel (mesh 70-230), in a packed column) with an organic solvent; with a mobile phase composed of a certain proportion of a non-polar organic solvent and a polar solvent;preferably a silica gel column containing distilled water in a proportion of 3.5% (w / w), 40.5 g of silica gel packed with chloroform, mobile phase being a gradient composed of chloroform:methanol proportions: (1) 90:10 (v / v); (2) 80:20 (v / v); (3) 70:30 (v / v).

2. Promolecule, obtained as defined in claim 1, characterized by comprising a carrier and one or more active molecules; the carrier being a saccharide, selected from mono-, oligo- or polysaccharide with at least one carboxylic acid, and the active molecules containing one or more hydroxyl groups.

3. Promolecule according to claim 2, characterized in that the saccharide is a monosaccharide.

4. Promolecule according to claim 2, characterized in that the saccharide is selected from hyaluronic acid, alginate, xanthan gum, pectin, heparin, ulvan, fucoidan, agarose, carboxymethyl cellulose, D-mannuronic acid, L-guluronic acid, glycyrrhizic acid, cupric tartrate, D(+)-malic acid, potassium D-erythronate, disodium tartrate dihydrate, ammonium L-tartrate, sodium D-glucuronic acid, D-tartaric acid, magnesium gluconate, L-malic acid, potassium tartrate, mucic acid, sodium glucoheptonate, potassium gluconate, D-glucuronic acid.

5. Promolecule according to claim 2, characterized in that the saccharide is D-glucuronic acid.

6. Promolecule according to claim 2, characterized in that the active ingredient is selected from fragrances, flavorings, food supplements, pharmaceuticals or agricultural actives.

7. Promolecule according to claim 6, characterized by fragrances to be selected from among linalool, citronellol, geraniol, menthol, vanillin, ethyl vanillin, eugenol, isoeugenol, anethole, thymol, terpineol, phenylethyl alcohol, salicylaldehyde, lavandulol, cis-3-hexen-1-ol, 3-octanol, 9-decen-1-ol, 10-undecen-1-ol, 4-methyl-3-decen-5-ol, amyl alcohol, isoamyl alcohol, hexyl alcohol, 2-hexyl alcohol, heptyl alcohol, octyl alcohol, nonyl alcohol, decyl alcohol, undecyl alcohol, lauryl alcohol, myristic alcohol, raspberry ketone, cinnamyl alcohol, nerol, trans-2-hexenol, farnesol, benzyl alcohol, among others.

8. Promolecule according to claim 6, characterized in that the aromas are selected from linalool, citronellol, geraniol, menthol, vanillin, eugenol, cinnamaldehyde, anethole, isoeugenol, thymol, carvone, terpineol, phenylethyl alcohol, salicylaldehyde, lavandulol, cis-3-hexen-1-ol, 3-octanol, 9-decen-1-ol, 10-undecen-1-ol, 4-methyl-3-decen-5-ol, among others.

9. Pro-molecule according to claim 6, characterized in that the dietary supplements are selected from resveratrol, silymarin, vitamin C (ascorbic acid), vitamin E (tocopherol and tocotrienol), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B9 (folic acid), vitamin D (cholecalciferol), vitamin A (retinol), vitamin P (rutin), among others.

10. Pro-molecule according to claim 6, characterized in that the drugs are selected from among paracetamol (acetaminophen), morphine, codeine, propranolol, warfarin, salbutamol (albuterol), acyclovir, atenolol, clindamycin, rosuvastatin, lorazepam, among others.

11. Pro-molecule according to claim 6, characterized by the agricultural actives being selected from among cellulose, hemicellulose, lignin, humic acid, fulvic acid, pectin, tannin, ferulic acid, salicylic acid, catechin, gibberellin, abscisic acid (ABA), chlorogenic acid, betulinic acid, resorcinol, caffeic acid, arabinoxylan, alginates, tannic acid, among others.

12. Promolecule according to claim 6, characterized in that the fragrance is citronellol.

13. Promolecule according to claim 6, characterized in that the fragrance is cis-3-hexen-1-ol.

14. Promolecule characterized by comprising a carrier and at least one active ingredient, the carrier being a saccharide with at least one carboxylic acid, preferably D-glucuronic acid, and an active ingredient with at least one hydroxyl group, selected from citronellol and cis-3-hexen-1-ol.

15. Promolecule according to claim 2 characterized by comprising GA (glucuronic acid) and CIT (citronellol), preferably in a 1:1 molar ratio during its production by catalyzed synthesis.

16. Promolecule according to claim 2 characterized by comprising GA (glucuronic acid) and HEX (cis-3-hexen-1-ol) in a preferred ratio of 1:

1.

17. Use of the promolecule as defined in any one of claims 2 to 15, characterized by being in the controlled release of the active ingredient.

18. Use of the pro-molecule as defined in any of claims 2 to 15, characterized by being in the preparation of cosmetics, pharmaceuticals, food supplements, and agricultural actives.

19. Use of the promolecule as defined in any one of claims 2 to 15, characterized by being for preparing a cosmetic product (perfumes, colognes, lotions, shampoos, conditioners, among others), a laundry cleaning product (fabric softeners, laundry detergents, among others), household cleaning products (multi-purpose cleaners, scented cleaners, degreasers, among others), and other products that may contain fragrances.

20. Use of the promolecule as defined in any one of claims 2 to 15, characterized by being for preparing a hedonic, olfactory, gustatory or flavor-enhancing product for a food product (candies, beverages, yogurts, snacks, among others) or animal feed.

21. Use of the promolecule as defined in any of claims 2 to 15, characterized by being for the preparation of a pharmaceutical product, for medical or veterinary purposes (serums, injectables, medicines, generics, among others).

22. Use of the promolecule as defined in any one of claims 2 to 15, characterized by being for preparing an agricultural product that contributes to soil health, plant structure, and various plant growth and development processes.

23. Use of the promolecule as defined in any of claims 2 to 15, characterized by being for preparing a product with nutritional benefits conferred to a nutritional product, food supplement (human or animal).

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