WO2024092335A1

WO2024092335A1 - Cosmetic, dermatological and/or pharmaceutical composition; method for increasing radio-efficiency in radiotherapy procedures and/or for improving the resolution and/or quality of diagnostic images; method for attenuating or minimising the reactive species formed after radiotherapy sessions, or for reducing cell damage from exposure to radiation; and process for producing said composition

Info

Publication number: WO2024092335A1
Application number: PCT/BR2023/050370
Authority: WO
Inventors: Marcos MOISES GONCALVES
Original assignee: Moises Goncalves Marcos
Priority date: 2022-10-31
Filing date: 2023-10-31
Publication date: 2024-05-10

Abstract

The present invention aims to solve the problems of the prior art by means of a new dermatological, pharmaceutical and/or cosmetic composition comprising sulphur derivatives, which is particularly useful for topical application before radiotherapy to aid radio-efficiency in radiotherapy procedures to combat cancerous tumours, or to reduce damage resulting from exposure to radiation, or to improve the resolution and/or quality of diagnostic images resulting from the use of radiation, and/or post-radiotherapy to attenuate or minimise the amount of reactive oxygen species and/or reactive nitrogen species formed after radiotherapy sessions.

Description

DESCRIPTIVE REPORT OF THE INVENTION PATENT

COSMETIC, DERMATOLOGICAL AND/OR PHARMACEUTICAL COMPOSITION; METHOD FOR INCREASING RADIOEFFICIENCY IN RADIOTHERAPY PROCEDURES AND/OR IMPROVING THE RESOLUTION AND/OR QUALITY OF DIAGNOSTIC IMAGES; METHOD TO ATTITUDE OR MINIMIZE REACTIVE SPECIES FORMED AFTER RADIOTHERAPY SESSIONS; OR; TO REDUCE CELLULAR DAMAGE FROM EXPOSURE TO RADIATION; AND; COMPOSITION PRODUCTION PROCESS

Field of invention

[0001] The invention describes new dermatological, pharmaceutical and/or cosmetic compositions comprising sulfur derivatives. In one embodiment, said compositions are useful, among other uses, for pre-radiotherapy topical application to aid radioefficiency in radiotherapy procedures, preferably those combating cancerous tumors. Furthermore, processes for developing and obtaining the aforementioned compositions and dermatological products are presented. This invention is inserted in the technical sector of dermatological, pharmaceutical and/or cosmetic compositions, including dermatological supplies.

Fundamentals of the invention

[0002] Every year, millions of people around the world die from cancer due to ineffective treatments or lack of adherence due to adverse effects.

[0003] In 2020, there were approximately 20 million deaths from cancer in the world and, in Brazil, 250 thousand, where more than 2.5 trillion reais were spent on the pathology.

[0004] One of the pillars of cancer treatment is the association of surgical processes, chemotherapy and ionizing radiotherapy. [0005] More than 50% of cancer treatment procedures use radiotherapy. The total dose of ionizing radiation can vary from 45 to 60 Gy depending on the location and severity of the tumor and can usually be divided into equal daily doses.

[0006] In ionizing radiotherapy whose objective is to combat tumor tissues, the ionizing beams that pass through the tissues promote cellular apoptosis, death of mitotic cells, necrosis or cellular senescence.

[0007] Energy absorption depends on the abundance of material in the radiation path. When the energy of ionizing radiation is deposited in a macromolecule associated with observable biological effects, such as DNA, it is called a direct radiation effect. Photons can also be absorbed by the body's water, causing excitation and ionization of these molecules. As water makes up approximately 80% of the mass of living cells, the largest proportion of the radiation energy deposited in the cell will be absorbed in its water, and the pore water will also interact with the radiation through the process of radiolysis. Energy is also deposited in locations rich in gas 02 molecules such as the connective tissue of the skin creating reactive chemical species (radicals) that in turn interact with the target molecules. Approximately 2/3 of biological damage occurs when x-rays carry out linear energy transfer (TLE) or by scattered ionizing radiation, due to indirect action.

[0008] Ionizing electromagnetic radiation, when interacting with tissues, gives rise to free electrons that ionize the environment and create chemical effects such as the breakdown of water and O2 molecules and the rupture of DNA chains.

[0009] Direct damage to DNA causes the breaking of its structural bonds. In indirect injury, there is electron displacement (e-) from the water molecule (H2O), which becomes a positive water ion (H2O+). The electron will react with another water molecule forming H2O-, which dissociates into hydroxyl ion (OH-) and hydrogen free radical (H«). The positive water ion (H2O+) dissociates into positive hydrogen ion (H+) and hydroxyl free radical (OH«). Ions and free radicals are highly reactive with cellular structures. Ionizing radiation induces various types of DNA damage, such as base damage, single-strand breaks (QFS), double-strand breaks (QFD), and cross-links. Because cells have biological repair pathways corresponding to each type of radiation-induced DNA damage, they are able to recover from this radiation-induced damage. [0010] Persistent or unrepaired QFD can determine the antitumor effects of ionizing radiation by inducing apoptosis, necrosis, mitotic catastrophe or permanent growth arrest. About 40 QFD/cell are generated by irradiation with 1 Gy. In theory, if just one QFD remains on an important gene, the cell could be sterilized or even die. Therefore, the efficiency of a cell's QFD repair capacity is a very important factor in radiotherapy.

[0011] Cell death can occur through different mechanisms, from the inactivation of vital systems for the cell to its inability to reproduce. [0012] The response of tissues to radiation depends on several factors, such as the sensitivity of the tumor to radiation, the location and oxygenation of the cells, as well as the dose and fractionation prescribed.

[0013] In external radiotherapy (TEN) treatments, there is often a need to treat superficial lesions in patients with tumor disease, these lesions may be located on the skin or adjacent to it.

[0014] When the radiation beam enters the patient, it deposits a certain dose of radiation on the surface, increasing until it reaches a maximum value at a depth called zmax and then decreases almost exponentially until it reaches a value at the patient's exit point ( zex), according to the depth dose percentage profile.

[0015] When internal tumors are treated by radiotherapy, the skin that stands in the way ends up being injured by the process. The severity of the skin's reaction to radiation is classified and varies from erythema, dry scaling, more severe moist scaling, and eventually ulceration. [0016] Skin reactions induced by ionizing radiation have an impact on the level of pain, promoting discomfort and impairing the quality of life of those undergoing treatment, which may require changes to the radiotherapy schedule, delaying the patient's improvement.

[0017] Radiation dermatitis can limit the therapeutic dose administered to patients and sometimes lead to an interruption in treatment, therefore potentially compromising local control and survival outcome.

[0018] Acute radiation dermatitis, called radiodermatitis, is a common side effect that occurs within hours to weeks after starting radiotherapy and affects more than 90% of patients.

[0019] The release of molecules is associated with the damage of ionizing radiotherapy that activates the innate and adaptive immune systems allowing additional antitumor responses.

[0020] The local erythematous reaction is intensified by increased vascular permeability and vasodilation, promoted by ionizing radiation, which activates inflammatory processes and causes the overproduction of cytokines and chemokines by irradiated skin cells.

[0021] Skin cells have a high proliferation rate and are highly sensitive to damage caused by ionizing radiation and respond quickly to injury.

[0022] Ionizing radiation inhibits the skin's self-renewal property, as it damages the mitotic capacity of the basal stem cells of the epidermis, which try to compensate for the radiation damage by increasing their mitotic activity. Thus, the cells reproduce faster than old cells, causing dry, scaly skin (i.e., dry peeling).

[0023] As ionizing radiotherapy continues, the basal layer cannot produce enough new cells to replace the old ones and, therefore, the outer layer of the epidermis will become fissured, edematous with exudation (i.e., moist desquamation). [0024] Radiation also acts on other molecules inside cells, such as water, to generate reactive oxygen species (ROS), such as superoxide, hydrogen peroxide and hydroxyl radical, which indirectly cause further damage to DNA and other cellular components such as proteins and lipids.

[0025] The generation of ROS is considered responsible for more than 60% of the total damage induced by ionizing radiation.

[0026] Chronic fibrotic dermatitis, called fibrotic radiodermatitis, is a late side effect, marked by fibrosis, with substantial dermal and epidermal stiffening, scarring and tissue retraction, with histological evidence of extensive hyalinization of reticular collagen.

[0027] After entering the irradiated area, neutrophils are stimulated and release pro-inflammatory cytokines, such as tumor necrosis factor-a, interleukin-1 and interleukin-6, which perpetuate inflammation and increase the formation of ROS. Monocytes and lymphocytes subsequently migrate into the irradiated skin. Monocytes differentiate into macrophages and release platelet-derived growth factor, which stimulates angiogenesis and fibroblast migration. Macrophages, and endothelial cells, fibroblasts, and epidermal cells secrete growth factor[3 (TGF-[3], a potent profibrotic factor that is elevated in the early stages of radiation damage and strongly implicated in the pathogenesis of chronic radiodermatitis. fibrotic.

[0028] Chronic fibrotic radiodermatitis normally develops four to twelve months after therapy, but can continue for many years in a progressive manner, and, in some cases, surgery is necessary to reconstruct the damaged skin.

[0029] Therefore, managing skin reactions is an important priority in the care of those undergoing radiation treatment.

[0030] There are several inconsistencies in radiation treatments around the world with regard to practice and recommendations given by healthcare professionals to prevent and manage painful side effects of treatment with ionizing radiation.

[0031] There are currently no consensual procedures or protocols that use effective oral or topical preparations to prevent or manage adverse skin reactions induced by radiotherapy. The procedures and products are merely palliative and, in their entirety, aim to repair the damage already caused, without the ability to prevent it.

[0032] Systematic review studies indicate that there is no clinical evidence to support the superiority of topical chemical interventions in the prophylaxis of radiodermatitis, such as trolamine, topical corticosteroids, hyaluronic acid, ascorbic acid, dexpanthenol, topical sucralfate, Cavilon cream, cream Theta, silver leaf dressing, calendula, proteolytic enzymes, Aloe vera, among others.

[0033] In ionizing radiotherapy, when a superficialization of the maximum dose point is required, either to maximize the dose to the tumor or even to limit the penetration of the beam, a layer of a material that mimics human tissue is used, called bolus , with variable thickness, which also serves to correct anatomical irregularities when placed on the area to be irradiated.

[0034] The bolus allows a change in the depth where the maximum energy deposited occurs inside the patient, allowing an increase in dose to the skin. However, these boluses, as they are not individualized to the external contour of the area to be treated, may not have a perfect fit, compromising the dose distribution calculated by radiotherapy planning.

[0035] Although radiotherapy is essential in the fight against cancer, this procedure has some restrictions and the management of skin reactions is a priority in the care of those undergoing radiation treatment.

[0036] Deep tumors are a serious limitation to treatment, as it is common for only 5% of rays to reach them. Much of the parallel beam of radiation (FPR) deflects and scatters when it encounters the skin and other tissues, seriously injuring them and reducing the radioefficiency of the therapy. The scientific literature found points to the impossibility of reducing this scattering by not being able to keep the beam collimated.

[0037] On the other hand, in countries with fewer resources, the limitation in the availability of facilities intended for the radiotherapy protocol results in an accumulation of half-naked people waiting for the session, where the impact of this objectification goes beyond the side effects, undermining them psychologically .

[0038] Interruptions during treatment cycles, due to the appearance of adverse effects, may compromise the treatment result and decrease the likelihood of tumor response.

[0039] Clinical evidence reinforces the technological importance of this invention, highlighting its relevance in terms of increasing radioefficiency in treatment, reducing the risk of local recurrence and radiodermatitis.

[0040] In this way, searches were carried out for the state of the art and some patent documents were detected aiming to address this technical problem, which will be described below.

[0041] Document PI0005352 describes a lotion prepared with national products. The invention described in this document is composed of Aloe vera, collagen, vitamin E, lanolin and allantoin. The solutions described in this document differ considerably from those described by the invention, since it uses a composition completely different from that of the present invention, as well as not mentioning the effects of radioefficiency.

[0042] Document BR102015009017 describes a process for obtaining solid lipid nanoparticles containing curcuminoids. The invention described in this patent is composed of curcumin (1,7-bis-(4hydroxy3-methoxyphenyl)-heptadien-3,5-dione), demethoxy-curcumin and bis-demethoxy-curcumin. Thus, the composition disclosed in this document differs considerably from that disclosed by the invention and does not address pre-radiotherapy use and does not mention radioefficiency effects.

[0043] The document EP3459534 corresponding to the document WO201 9057874 describes a pravastatin composition for reducing radiodermatitis and fibrosis in the treatment of breast cancer with radiotherapy. The information revealed in this document differs considerably from that described by the invention, both in the composition and its active component and because it is not designed for pre-radiotherapy use, it does not mention radioefficiency effects.

[0044] Document EP350760 corresponding to document WO201 8041960 defines a new diagnostic method to predict the risk of developing a late effect of the breast such as atrophic skin, telangiectasia, induration (fibrosis) as well as necrosis or ulcerations, characterized as radiodermatitis , after radiotherapy (RT), using radiation-induced late effect citing T lymphocyte apoptosis and clinical parameters. The information revealed in the document differs considerably from that described by the invention, as it does not mention radioefficiency effects and does not reveal or suggest the composition and active component of the present invention. [0045] Document WO2015087319 describes changes in care protocols to increase the efficiency of radiotherapy or radiosurgery treatment and, thereby, reduce the side effects of the treatment. These changes refer to the x-ray beam source converging to a smaller volume in the patient's body, reducing on average at least 80% of the maximum dose, so that the internal organs receive on average no more than 40% of the dose. maximum. The information described in the document differs considerably from that revealed by the present invention, as only the invention described in the present document deals with radioefficiency due to the action of compositions containing sulfur derivatives and modifying biological spaces while the document highlights the beneficial effects due to physical and anatomical in the protocols, that is, x-ray beams converging to a smaller body volume of the patient.

[0046] Document US20210369667 describes the use of some polyphenolic compounds. The disclosed invention basically consists of polyphenols including phenolic acids, flavonoids, stibenes (e.g. resveratrol), diferuloylmethanes (curcumins), tannins and lignan, in the composition with hyaluronic acid. The information revealed by the document differs considerably from that described by the invention as it does not mention a composition such as those disclosed by the present invention, it does not reveal the effects of radioefficiency, and it was not designed to be used before radiotherapy sessions to modify the biological environment previously. to the application of x/or gamma rays.

[0047] Document US20210338756 describes the use of compositions containing pomegranate seed oil, rosehip oil and Inula viscosa oleoresin (or its extract) and/or Citrus medica vulgaris oil (or its extract). The disclosed compositions are basically composed of cosmetic preparations with oil and plant extracts. Thus, they differ considerably from that revealed by the present invention, it does not mention radioefficiency effects and mainly due to the fact that the invention described here involves compositions based on sulfur-containing compounds and designed to also be used before radiotherapy sessions to modify the biological environment previously to the application of gamma rays.

[0048] Document US20210315861 describes a composition comprising the conjugation of analogous compounds of sulfuraphane and melatonin, such as 6-hydroxymelatonin and 6-methylsulfinlhexyl isothiocyanate, respectively, for use in reducing radiodermatitis. The Sulforan-Melatonin complex is used to react with cysteines present in Keapl to release Nrf2, these acting to be conjugated with GSH inside the cells to generate a conjugated compound with an antioxidant effect. The invention, on the other hand, results from the use of compounds that interact directly to remove free oxygen in the environment that will be exposed to radiation, generating cell hypoxia and reducing/minimizing Compton scattering and allowing more rays to continue collimated in the direction of the tumor to be combated by preventing the damage resulting from the formation of free radicals does not even occur, or is substantially attenuated.

[0049] Document US20190134156 describes a composition comprising the drug formulation (injectable, nasal and based on peptides and peptide derivatives). The compounds contained in the document are peptides formed by amino acids grouped in specific arrangements in which their action is associated with three-dimensionality and differ from the compounds of the invention, which are thiol compounds capable of reducing Compton scattering and, therefore, providing radioefficiency.

[0050] Document US7314959 describes amino thiols and polyamides and pharmaceutical compositions for administration in conjunction with cancer chemotherapy or radiotherapy. The molecules presented differ structurally from those disclosed by the present patent application and do not include the conjugation of functional groups and molecular structures such as those of the present invention. Furthermore, the document is categorical in indicating that the compounds revealed do not interfere with the efficiency of radiotherapy (example 8).

[0051] Document US20200360476 describes a composition comprising peptides derived from erythropoietin. The information revealed in the document differs considerably from that described by the invention, since it does not mention radioefficiency effects and because they are different compositions. Another aspect that differentiates the invention is the fact that it was designed to also be used before radiotherapy sessions in order to modify the biological environment prior to the application of gamma rays.

[0052] Document US20160168199 describes a composition of peptides that include fragments, chimeras, as well as peptides designed to mimic the spatial location of key amino acid residues within the ligands of the protective erythropoietin receptor. The present document differs substantially from the invention disclosed herein since the document does not describe the same composition nor the radioefficiency effects. The document also does not reveal information about whether its compositions can be used before radiotherapy sessions in order to modify the biological environment. prior to the application of gamma rays.

[0053] Document US5716608 describes a composition of biocompatible polymers. The invention disclosed in the patent above differs considerably from that described in this document, since the first does not mention radioefficiency effects and mainly because it is not a composition of sulfur bioderivatives. Another aspect that differentiates the invention is the fact that it was designed to also be used before radiotherapy sessions in order to modify the biological environment prior to the application of x-rays and/or gamma rays.

[0054] Therefore, the invention presented in this invention patent document meets the novelty requirement, as to date no scientific or technical work included in the prior art fully reveals the content claimed by this patent document. It is also noteworthy that the invention proposed in this patent document also presents the other patentability criteria: inventive activity, since no document can be considered as making the present invention evident or obvious, and, it has industrial application.

Brief description of the invention

[0055] Therefore, the present invention aims to solve the constant problems in the state of the art using a new dermatological, pharmaceutical, and/or cosmetic composition, which comprises sulfur derivatives, being particularly useful for topical application: pre-radiotherapy to aid radioefficiency in radiotherapy procedures to combat cancerous tumors, or to reduce cellular damage resulting from exposure to radiation, or; to improve the resolution and/or quality of diagnostic images resulting from the use of radiation; and/or; post-radiotherapy to attenuate or minimize the amount of reactive oxygen species and/or reactive nitrogen species formed after radiotherapy sessions.

[0056] Thus, a new cosmetic composition is presented, dermatological and/or pharmaceutical, for pre-radiotherapy application to aid radioefficiency in radiotherapy procedures to combat cancerous tumors, or, to reduce cellular damage resulting from exposure to radiation, or; to improve the resolution and/or quality of diagnostic images resulting from the use of radiation; and/or; post-radiotherapy to attenuate or minimize the amount of reactive oxygen species and/or reactive nitrogen species formed after radiotherapy sessions; characterized by comprising at least one thioic compound with the general formula:

on what:

R1 is one of H, alkyl, alkenyl, alkynyl, linear or branched;

R2, is one of linear or branched H, alkyl, alkenyl, alkynyl;

R3 is one of linear or branched H, alkyl, alkenyl, alkynyl; molecule with 1 to 20 carbon atoms, linear, branched, or linear or branched and containing one or more cyclic, aromatic, non-aromatic and/or heterocyclic groups, comprising at least one hydroxyl, ketone, aldehyde, carboxyl, carbonyl group, carboalkoxyl, ether, carboxyamide, primary, secondary or tertiary amines, imine, imide, thiols or thio ether; or its salts, cosmetically, dermatologically and/or pharmaceutically acceptable stereoisomers.

[0057] In an embodiment of the present invention R1 is selected from H or CH3;

or, at least one of the compounds as defined below:

[0058] In one embodiment of the present invention R3 is a molecule with 1 to 20 linear or branched carbon atoms and containing: at least one carboxyl group and; at least one primary or secondary amine group, or, amide.

[0059] In an embodiment of the present invention R3 is selected from:

[0060] In an embodiment of the present invention, said application is topical.

[0061] In an embodiment of the present invention, said composition comprises between 0.1% and 10.0% of at least one thioic compound, 0.1% to 5% of at least one glycolic compound and oil-water based cream ( qsp. 100%).

[0062] In one embodiment of the present invention the glycolic compound is ethoxydiglycol.

[0063] In an embodiment of the present invention, said composition additionally comprises between 0.1 to 3.0% vitamin C and its derivatives; between 0.1 and 5.0% polyphenolic antioxidants and their derivatives; between 0.1 and 5.0% glycosaminoglycans; or a combination of these. [0064] A method is also presented for increasing radioefficiency in radiotherapy procedures to combat cancerous tumors and/or for improving the resolution and/or quality of diagnostic images resulting from the use of radiation, comprising topical administration pre-diagnosis or treatment session by radiation to an individual of a composition as defined above, at a radioefficient concentration of said composition.

[0065] In one embodiment of the present invention the radiation treatment session is treatment with external beam radiation therapy.

[0066] In one embodiment of the present invention, topical administration occurs at least in a dose between 45 and 3 minutes before the start of the radiotherapy session. In one embodiment, topical administration occurs at least in a dose between 30 and 5 minutes before the start of the radiotherapy session.

[0067] A method is also presented for attenuating or minimizing reactive oxygen species and/or reactive nitrogen species eventually formed after radiotherapy sessions; or; for reducing cellular damage from radiation exposure comprising applying to an individual post-radiotherapy or pre-radiotherapy a composition as previously defined.

[0068] Our use of a composition, as previously defined, for the production of a medicine, cosmetic product or dermal product for topical use in a method is also presented: pre-radiotherapy to aid radioefficiency in tumor-fighting radiotherapy procedures carcinogenic, or, to reduce cellular damage resulting from exposure to radiation, or; to improve the resolution and/or quality of diagnostic images resulting from the use of radiation; and/or; post-radiotherapy to attenuate or minimize the amount of reactive oxygen species and/or reactive nitrogen species formed after radiotherapy sessions.

[0069] A new process for producing a composition as previously defined is also presented, characterized by comprising the following steps:

- mix the water phase components and subject them to heating at a temperature between 70 ^S C and 90 ^S C;

- mix the components of the oil phase in sufficient time for the waxes to melt and homogenize upon heating at a temperature between 70 ^S C and 90 ^S C; It is

- mix the water phase with the oil phase to form an oil-in-water emulsion, under stirring.

[0070] These and other objects of the invention can be immediately recognized by those skilled in the field and descriptions will then be provided in sufficient detail for their reproduction by a person skilled in the art.

Brief description of the drawings

[0071] In order to better define and clarify the content of this patent application, the following figures are presented:

[0072] Figure 1: refers to the schematic representation of the interactions of radiation (x-rays or y-rays) with matter, resulting in (1) Thompson Effect (7 = 7'), (2) Photoelectric Effect and ( 3) Compton Scattering (7 < 7'). 7: incident photon, 7’: scattered photon.

[0073] Figure 2: refers to the images that were created with two different settings of the device with exposure to one of the possible compositions of the invention (RTP). (a) SETTING 1 (standard equipment conditions, 200mA, 20mA.s' ¹ , 76 kVp) and (b) SETTING 2 (200mA, 14mA.s' ¹ , 76 kVp). Device Specifications: type B equipment, 60Hz, 2 phases, input power 200VA, output power 110W, input voltage 200Vac, continuous operation mode with intermittent load, from the company Marpe Indústria.

[0074] Figure 3: refers to the radiographic images and their respective pixel histograms that were created with three regular quadrilaterals of the same anatomical region, with SETTING 1 of the device (standard equipment conditions, 200mA, 20mA.s-1, 76 kVp), Device Specifications: type B equipment, 60Hz, 2 phases, input power 200VA, output power 1 10W, input voltage 200Vac, continuous operation mode with intermittent load, company Marpe Indústria.

[0075] Figure 4: refers to the radiographic images and their respective pixel histograms that were created with four regular quadrilaterals from the same anatomical region, with SETTING 2 of the device (200mA, 14mA.s-1, 76 kVp). Device Specifications: type B equipment, 60Hz, 2 phases, input power 200VA, output power 1 10W, input voltage 200Vac, continuous operation mode with intermittent load, from the company Marpe Indústria. [0076] Figure 5: Cell survival fractions for x-rays, neutrons and a particles. The dotted curves demonstrate well-oxygenated cells and the solid curves for cells in hypoxia.

[0077] Figure 6: Doppler SMI analysis of tissue perfusion before use of the invention (RTP).

[0078] Figure 7: Doppler SMI showing significant reduction in tissue perfusion

[0079] Figure 8: Spectral Doppler analysis of follicular arteriole before use of the invention (RTP) showing arteriolar flow.

[0080] Figure 9: Spectral Doppler analysis of follicular arteriole 5 minutes after use of the invention (RTP) at 3% of the active ingredient clearly showing absence of arteriolar flows.

[0081] Figure 10: Treatment results after protocol with 3% aminothiol formulation. The absence of radiodermatitis effects at high levels and the protective effect of the formulations of the present invention can be verified.

Detailed description of the Invention

[0082] Among the various contexts presented in the present patent application, it can be understood that the invention presents a new modality of increases the efficiency of radiotherapy treatment, increases success stories of radiotherapy, minimizes/eliminates unbearable pain, avoids serious burns and chronic skin damage, reduces dropout and mortality of individuals undergoing treatment, in short, promotes unprecedented humanization for patients. The basis of the invention lies in the fact that, the less radiosensitive a biological region is, the fewer interactions will occur between the passing radiation beam and the region in question, that is, the region will interact less with the incident radiation.

[0083] Unlike current palliative procedures, when the invention is applied minutes before radiotherapy sessions, the thiols of the present invention interact chemically with biological spaces, modifying them in an unprecedented way, in order to create a condition that minimizes interactions with incident radiation and, as a result of this process, there is a gain in radioefficiency in the radiotherapy procedure, in addition to a reduction in skin reactions induced by radiation.

[0084] Initially to interact with the dermis, the formulation of the invention transposes the layers of the epidermis and enters the connective tissue. Thus, the formulation's transepidermal release system allows the product to initially reach the dermal biological space, then the active ingredients are released to modify this environment, making it less radiosensitive.

[0085] By proof of concept, the invention is applicable to radiotherapy procedures in which we want to combat tumors that are located in biological regions below the skin. In these situations, the skin stands in the way as an obstacle between the incident radiation and the tumor regions to be bombarded. This invention promotes an increase in the efficiency of radiotherapy as it reduces the undesirable scattering of the FPR, making it possible to reach, with greater power, deep tumors, especially in therapies in which the radiation doses are more intense, and which would result in further damage. larger.

[0086] The invention promotes a modified physiological state that allows reducing radiation doses and the number of sessions saves injuries, especially burns, reducing the deviation of the incident beam, keeping it in the direction of the tumor, increasing the efficiency of radiotherapy.

[0087] To demonstrate some fundamentals of the invention, it is necessary to describe the interactions that photons experience with biological tissues, from the energies present in x-ray images to the energy range characteristic of radiotherapy. Unlike charged particles, photons are electrically neutral and do not steadily lose energy as they penetrate matter. Instead, they can travel some distance before interacting with an atom, these effects can be understood with the help of figure 1.

[0088] The photoelectric effect occurs with electrons in the K layer, so that the energy of the photon is close to or equal to the energy of that electron. As the photoelectric effect is very specific to the binding energy of the K layer, ionization of the atom will occur, that is, the electron that was ejected is now called a photoelectron and the x-ray photon has been completely attenuated at this point. Thus, the energy it emitted was captured exclusively by this photoelectron. As the interaction depends on the electron binding energy K, it relates to the atomic number Z of the tissue. In photoelectric interaction, all energy from the incident photon is transferred to the electron, removing it from orbit. This effect occurs for photons of relatively low energies and is relevant for diagnostic radiology. The photon interacts with a tightly bound orbital electron of an attenuating atom and disappears, while the orbital electron is ejected as a photoelectron with a kinetic energy Ec ( _Ec = hv - EL) where, hv energy of the incident photon and EL binding energy of the electron.

[0089] To stabilize the atom, an electron from the outer shell fills the vacancy in the inner shell. The energy that is lost by this electron when it falls to the inner shell, can be emitted as characteristic radiation, that is, x-ray photon. For the photoelectric effect, the atomic attenuation coefficient _at T is proportional to Z ⁴ /(hv) ³ , while the mass attenuation coefficient Tm is proportional to (Z/hv) ³ , where Z is the atomic number of the attenuator.

[0090] The probability of this photoelectric effect is maximum when the energy of the incident photon is equal to or just slightly greater than the binding energy of the electron in its shell, that is, the K edge corresponding to the K shell in which the electron is strongly bound . The electron that is removed is then called a photoelectron and the incident photon is completely absorbed in the process. As the atomic number of the attenuating medium increases, the probability of the photoelectric effect occurring also increases cubically. This effect is proportional to the physical density of the attenuating medium (p) and inversely proportional to the cube of the energy of the incident photon (E). Thus, the general probability of photoelectric absorption can be summarized as follows: photoelectric absorption ~ p (Z ³ /E ³ ). As the energy of the x-ray tube increases in kilovoltage peaks, the probability of the photoelectric effect decreasing.

[0091] The Compton interaction manifests itself differently with loss of energy from the incident rays due to the shock process with free electrons (not bound to atoms) or electrons from the weakly bound outer shells or valence shell. Ionization occurs with the interacting atom releasing an electron and a photon with a longer wavelength (X <X'). Thus, the photon enters the human body and interacts with an atom and its energy is partially absorbed by the electron in the outer shell. As an effect of this shock, the electron is ripped from its orbit, characterizing an ionization process and it becomes called the Compton electron since it was created by this interaction. The remainder of the energy remains in the scattered photon (E'= hc/À') but its direction has been significantly modified, hence the term “scattering”. Energy and momentum are conserved in this process. The Compton effect is a partial absorption process where the original photon has lost energy, and this process is called a Compton shift (i.e. a wavelength/frequency shift). The change in length Wavelength of the scattered photon can be determined by 0.024 (1 -cos 9), where 9 is the angle of the scattered photon. Thus, the energy of the scattered photon decreases with increasing this angle. Compton scattering is the main cause of radiation scattered in a material and can occur at several different energy levels, but becomes the predominant effect at higher energies, including those usual in radiotherapy. The probability of Compton scattering occurring is in direct proportion to the number of electrons in the outer layer, that is, the electronic density, in addition to being directly proportional to the physical density of the material. On the other hand, the Compton effect is very weakly dependent on photon energy, being relatively constant in the range of 10-600 keV. It is known that the effect increases proportionally and smoothly as the peak kilovoltage of the x-ray tube increases.

[0092] Compton scatters cause a need to increase the dose of radiotherapy. Considering the energy ranges of 100 keV to 10 MeV of the photons used in radiotherapy, the Compton interaction is the main scattering mechanism. Thus, the Compton effect negatively interferes with the dose prescribed for the patient, that is, these doses need to be increased. Furthermore, considering the healthy tissues that are in the path of radiation to the tumor tissue, Compton scattering will result in biological damage, since the process generates free ionized electrons that collide and interact causing biological changes. In turn, the scattered photons can be absorbed by tissues in other biological environments causing further damage. All these effects combined will consume fractions of the incident radiation beam, implying the need for an increase in the patient's dose.

[0093] Compton scatters are also responsible for another negative effect, the so-called bystander dose, that is, for the occupational exposure of professionals who are present in the radiotherapy environment. The reason this happens is because Compton scattering, According to its name, it creates dispersion of photons that leave the patient's body and can easily reach the radiologist. In fact, Compton scatter also impacts the lives of the group of professionals who work with x-rays, being the number one source of exposure dose.

[0094] To prove the radioefficiency action of the invention and its ability to modify the biological environments of the skin, reduce Compton scattering and allow more photons of the radiation beam to remain collimated, x-ray imaging tests were carried out. The images were generated by shooting x-rays directly onto the skin for the two device settings (Adjustment 1 and Adjustment 2).

[0095] Radioimaging procedures with x-rays were carried out without and with the application of one of the compositions of the invention. An x-ray image was prepared without applying the invention. Then, the composition of the invention was applied to the skin, half an hour and five minutes respectively before exposure to x-rays for the two device settings. These effects can be understood with the help of figure 2.

[0096] Pixel histograms were used for quantitative evaluation within a gray scale, from darkest to lightest, to highlight the differences that occurred in the analyzed images.

[0097] By demonstrating that the invention has the ability to reduce the fog effect, it was proven that it reduced the Compton scattering responsible for image distortions. Radioimages that have fog effects appear more diffuse and whiter than those free from these distortions. The fog effect causes an overall increase in radiographic density and results in a decrease in radiographic contrast (scattered radiation creates haze that reduces both contrast and visibility of details). To explore how much the invention (called Pre-Radiotherapy Topical Radioefficiency - RTP) can modify radioimages, an x-ray device was chosen that did not make automatic corrections.

[0098] Comparing the images formed without and with the use of invention, it is clearly noticeable, to the naked eye, that there is a greater fog effect of image whitening for the “no RTP” condition for the 2 settings. Since the fog effect can be attributed to Compton scattering, it is concluded that, when using the invention (RTP), the fog effect was attenuated, proving that it was capable of modifying the biological environment.

[0099] To analyze the pixels of the images, histograms were constructed using the Adobe Photoshop program (versions 2019 and 2022) and comparisons of the pixel averages, two by two, in the conditions without and with the application of RTP. To understand the fog effect, anatomical parts with more homogeneous tones were chosen and analyzed, reducing data dispersion. This is a histogram analysis of pixels of regular quadrilaterals from the same anatomical region under the study conditions. This histogram pixel analysis is based on the fact that monochromatic images are digital where each pixel has only one spectral band. A pixel is characterized by its color intensity value and its location in the image. [0100] The number of tones between the limit values, white and black, that can be represented in tones, depends on how many bits are allocated in the image matrix to store the tone of each pixel. For pixel analysis, the number of gray scale elements (2 ¹ , 2 ² , 2 ³ and 2 ⁴ ) and the limiting shades of gray (0.1 , 0-7, 0-15, 0-254) were considered. ,9), the number of bits required to represent the pixels (1, 2, 3 and 4), respectively. Pixels with a value within the range between 0 - 255 will be assigned the value 255 for white and the value zero for black.

[0101] In the standard conditions of the x-ray device (setting 1), for the 3 quadrilaterals analyzed, it is clear that, when using the invention (designated RTP) previously, the pixel average values were lower compared to the “no RTP” condition, thus demonstrating the effect of the invention in reducing Compton scattering.

Table 1: Standard device conditions (200mA, 20mA.s ¹ , 76 kVp)

[0102] In conclusion, a reduction in Compton scattering demonstrates that the invention is capable of reducing interactions of gamma rays with the skin, increasing the radioefficiency of the therapy and reducing skin radiosensitivity. These effects can be understood with the help of figure 3.

[0103] For adjustment 2, it was possible to prove that the invention reduces the fog effect by detecting a lower average number of pixels for the “with RTP” condition in quadrangle 4. These effects can be understood with the help of figure 4. [ 0104] The invention, by reducing the effects of Compton scattering, potentially promotes a reduction in the Bystander dose and, consequently, reduces the damage from radiation exposure for the radiologist. The reason this happens is because by reducing the effects of Compton scattering, more photons will reach the image receptor, saving the radiologist.

[0105] Compton scatters also have a negative effect on the contrast of the x-ray image and, by reducing the effects of these scatters, the invention provides an improvement in the quality of diagnostic images. So that photonic interactions and the formation of radioimages can be better understood, one must first consider the condition in which x-rays completely penetrate the human body, without any interaction occurring with matter. In this case, without radiation scattering having occurred, the image will take on a very dark color.

[0106] However, when x-rays are absorbed by matter due to With coherent and Compton scattering, its energy is converted into scattered x-rays, generating lighter shades of color and, when the x-rays are blocked by the bones, not reaching the receptor, there is a white image. [0107] The radiation arising from the photoelectric effect, composed of x-ray photons, is referred to as “secondary radiation” due to the fact that it is generated by an electron that jumps to the inner layer, filling the vacancy left by the photoelectron and stabilizing the atom . The radiation coming from the three types of interaction is called “dispersion radiation” or simply “dispersion”. Since coherent scattering occurs at very low energy ranges, outside the energy range used in radioimages, it is mentioned to demonstrate that even at very low kVp levels there will be interactions in the human body. The interactions that produce scatter radiation in radiography occur mainly within the patient. Some scattering also occurs as a result of interactions between the x-ray beam, the Bucky table, the image receptor, and any other material that is within the radiation field. The photoelectric effect contributes to the attenuation of the x-ray beam as it passes through matter and this attenuation ends up being responsible for creating diagnostic images. In short, x-ray images are predominantly due to the photoelectric effect. It is important to highlight that the combination between the photoelectric effect and transmission produces images with good contrast and high quality because there are clear differences in gray tones, differentiating soft tissue from bone. X-rays will experience different attenuation values or absorption differentials due to the fact that the photoelectric effect is directly affected by atomic number and tissue density.

[0108] The photoelectric effect differs from the Compton in some important aspects. The first difference is that the photoelectric effect generally occurs with K-shell electrons and the photon energy is close to or equal to the binding energy of that electron. Thus, this electron is released from the atom and the photon is completely attenuated at this point, extinguishing itself. This photon that would cause a decrease in contrast, as it would exit the collimation condition and, as a result, the image maintains its contrast. The injected electron is now called a photoelectron. The Compton effect can happen in virtually any atom, anywhere in the body. There would be no diagnostic x-rays if the photoelectric effect were not present.

[0109] In x-ray radioimaging, the bones appear opaque white, the subcutaneous tissue and regions with fat, dark gray, soft tissues such as the heart, blood vessels, light gray and the passage of rays through the lung air gives rise to dark color. Bones have higher density and a higher Z, so more photoelectric effect occurs where the x-rays are stopped. Considering lung tissue, where there is lower density and a lower Z number, fewer photoelectric interactions will occur, more x-rays will reach the image receptor, characterizing darker tones.

[0110] Compton scattering is bad for the x-ray diagnostic technique because it is noise that negatively interferes with image formation, causing distortions. Scattering occurs from the energy level of 40 kVp. By increasing the kVp values, the amount of Compton scattering is proportionally increased and, therefore, the total image contrast is reduced. By increasing kVp to a certain value, the Compton effect overcomes the photoelectric effect. By continuing to increase kVp, the photoelectric effect reduces to the point of practically disappearing and the Compton effect intensifies proportionally. When reaching 200 kVp, only the Compton effect will exist, that is, only noise will remain for image formation. Furthermore, a greater thickness of the biological path also interferes by increasing Compton scattering.

[0111] As Compton scatters reduce the efficiency of radiotherapy by reducing collimated rays that end up not reaching the cancerous tumor, the present invention, by reducing Compton scatters, by altering biological spaces, increases the efficiency of radiotherapy.

[0112] Therefore, based on all of the above, it is presented for purposes examples, the homologous series of thiol compounds used as active principles of pre-radiotherapy formulations to modify the biological environment with reduction of Compton scattering.

[0113] In an embodiment of the present invention, said thiols are biothiols and which can be selected from at least one compound:

on what:

[0114] An additional aspect of the present invention is understood to be the fact that the transepidermal dermatological-based preparation is capable of carrying thiols, inducing modification of the cutaneous biological environment with a reduction in Compton scattering of incident photons.

[0115] Thus, the preparation of the dermatological base refers to a composition may also comprise cream oil (from 15 to 30% cetostearyl alcohol/sodium cetearyl sulfate, from 1 to 5% cetyl alcohol), in water (from 2 to 6% propylene glycol, from 0.3 to 0.7 % nipagim and demineralized water qsp 100%).

[0116] As an example of the production of a possible composition within the context of the present invention, in a container the components of the water phase are mixed and subjected to heating until reaching 80 ^s C. In another container, hot, the components of the oil phase until the waxes melt, providing homogenization of the ingredients and the system temperature reaches 78 ^S C. Under more intense mixing, a small portion of the water phase is poured onto the oil phase until a water-in-oil emulsion is formed. Then, the remainder of the water phase is added and mixed intensely so that phase inversion occurs, characterizing the final oil-in-water emulsion. As the temperature drops, stirring must be slower, just enough to keep the system in an emulsified state and to avoid aeration.

[0117] An additional aspect of the present invention is the final pre-radiotherapy dermatological preparation capable of carrying thiols inducing skin modification with reduction of Compton scattering of incident photons.

[0118] Thus, the final preparation phase of the invention may refer to the incorporation of solid thiol compounds (from 0.1 to 10% of solid thiols are crushed until obtaining a very fine powder) or liquids (from 0.1 to 10 % of liquid thiols) in the oil-in-water cream:

[0119] In a container, the thiols and ethoxydiglycol (from 1 to 5%) are mixed until a homogeneous mixture is formed.

[0120] This mixture is then added geometrically to the oil-in-water emulsion, until a homogeneous system is obtained.

[0121] An additional aspect of the present invention is the basis of the dosage of the pre-radiotherapy preparation providing radioefficiency considering the fact that the dermis is a dynamic space that can gradually reoxygenate.

[0122] Thus, a dosage was developed that guides the application of the formula in two moments prior to radiotherapy. With clean and sanitized skin, apply RTP for 30 minutes and reapply 5 minutes, before the start of each radiotherapy session.

[0123] Examples

[0124] Therefore, in the context of the present patent application, it must be understood that the composition with pre-radiotherapy topical radioefficiency (RTP) that generated the results contained in figures 2, 3 and 4 is a composition with the following qualitative parameters general:

[0125] Formula 1: aminothiol (L-Cysteine) from 1%: start of pilot clinical trial tests.

[0126] Proof of Concept of the Property of the Invention (RTP) in Increasing the Efficiency of Radiotherapy

[0127] To prove the radioefficiency action of the invention and its ability to modify the biological environments of the skin, reduce Compton scattering and allow more photons of the radiation beam to remain collimated, x-ray imaging tests were carried out. Radioimaging procedures with x-rays were carried out with and without the application of the invention. To demonstrate the effects of Compton scattering a composition with L-Cysteine was applied to the skin at 5%, half an hour and five minutes before exposure to x-rays, these effects can be understood with the help of figures 2, 3 and 4.

[0128] Pixel histograms were used for quantitative evaluation within a gray scale, from darkest to lightest, to highlight the differences that occurred in the analyzed images. By demonstrating that the invention has the ability to reduce the fog effect, it was proven that it reduced the Compton scattering responsible for image distortions. Radioimages that have fog effects appear more diffuse and whiter than those free from these distortions. The fog effect causes an overall increase in radiographic density and results in a decrease in radiographic contrast (scattered radiation creates haze that reduces both contrast and visibility of details). To explore how much the invention (RTP) can modify radioimages, an x-ray device was chosen that did not make automatic corrections.

[0129] Comparing the images formed with and without the use of the invention (RTP) one can clearly see, with the naked eye, a greater fog effect of image whitening for the “without RTP” condition. Since the fog effect can be attributed to Compton scattering, it is concluded that, when using the invention (RTP), the fog effect was attenuated, proving that it was capable of modifying the biological environment.

[0130] To analyze the image pixels, histograms were constructed using the Adobe Photoshop program (2019 and 2022 versions) and comparisons of the pixel averages, two by two, in conditions with and without applying the composition of the present invention (RTP) . To understand the fog effect, anatomical parts with more homogeneous tones were chosen and analyzed, reducing data dispersion. This is a histogram analysis of pixels of regular quadrilaterals from the same anatomical region under the study conditions. This histogram pixel analysis is based on the fact that monochrome images are digital where each pixel has only a spectral band.

[0131] In the standard conditions of the x-ray device (setting 1), for the 3 quadrilaterals analyzed, it is clear that, when using the RTP invention previously, the pixel average values were statistically lower compared to the condition “without RTP”, thus demonstrating the effect of the invention in reducing Compton scattering. In conclusion, there is a reduction in Compton scattering, demonstrating that RTP is capable of reducing x-ray interactions with the skin, increasing the radioefficiency of the therapy and reducing skin radiosensitivity.

[0132] The invention, by reducing the effects of Compton scattering, potentially promotes a reduction in the Bystander dose and, consequently, reduces the damage from radiation exposure for the radiologist. The reason this happens is because by reducing the effects of Compton scattering, more photons will reach the image receptor, saving the radiologist.

[0133] Other examples of compositions within the context of the present invention can be found below.

[0134] Formula 2: aminothiol (L-Cysteine) from 3%: demonstrated to be able to optimize prophylaxis of side effects in the pilot clinical trial.

[0135] Formula 3: Aminothiol (L-Cysteine) on a non-ionic basis demonstrated moderate cutaneous diffusion power: it caused partial hypoxia in skin of scalp.

[0136] Formula 4: Aminothiol (L-Cysteine) in an anionic base demonstrated high skin diffusion power: it caused marked hypoxia in scalp skin.

[0137] Formula 5: aminothiol (L-Cysteine) from 5%: shown to be able to optimize x-ray images (hospital experiment).

[0138] Proofs of Concept of the invention.

[0139] Beneficial effects of the invention.

[0140] A very beneficial and fundamental property of the invention is its ability to cause hypoxia in the skin space. Hypoxia is characterized when concentrations of oxygen gas (molecular oxygen) reach levels lower than those commonly found in biological tissues. Hypoxia, in turn, confers at least two categories of benefits: Radioefficiency of Therapy and Tissue Radioprotection or Reduction of Tissue Damage.

[0141 ] Hypoxia is Radioprotective Because It Reduces Tissue Damage

[0142] When considering the moment of the radiotherapy session in which x-rays are being applied to the patient, it can be stated that cutaneous hypoxia, by reducing the concentrations of oxygen gas in the skin environment, will significantly reduce the formation of radicals free since the interaction of x-rays with oxygen gas is well known and called the “oxygen effect”.

[0143] Oxygen Effect versus Tissue Damage

[0144] The presence or absence of molecular oxygen within a cell influences the biological effect of ionizing radiation: the greater the cellular oxygenation above anoxia, the greater the damage or biological effect of ionizing radiation. Oxygen, therefore, is one of the most effective dose-modifying agents, sensitizing cells to radiation. Oxygen causes an “amplification” of radiation-induced DNA damage. Especially for x-rays, which are more penetrating and release little linear energy to the tissues they interact with, that is, low TLE values, the greater the cellular oxygenation above anoxia, the greater the biological effect until saturation of the oxygen effect occurs. As shown in the figure below, the effect is quite dramatic for low TLE (sparsely ionizing) radiation such as x-rays, while for high TLE (densely ionizing) radiation it is much less pronounced. The ratio of doses without and with oxygen (hypoxic cells versus well-oxygenated cells) to produce the same biological effect is called the oxygen enhancement rate, OER (Oxygen Enhancement Rate).

OER ° ^if ^To P ^r ° ^use ^a certain effect without oxygen dose to produce a certain effect with oxygen

[0145] Cellular Damage.

[0146] OER varies between 1 and approximately 3, respectively, when moving from hypoxic conditions (without oxygen) to normoxic irradiation conditions. For x-rays, if the OER is 2.5 it means that, to kill a certain percentage of cells in a hypoxic environment, a dose two and a half times greater than in abundantly oxygenated environments will be necessary. For neutrons, the presence of molecular oxygen has less impact on cellular damage and the a particles are those that suffer the least influence from the oxygenated medium (figure 5).

[0147] Skin Hypoxia Increases the Efficiency of Radiotherapy

[0148] Radiotherapy is one of the main therapeutic resources used to combat cancerous tumors. To treat more internal tumors, more penetrating rays such as x-rays are used. However, to reach such targets, the collimated beam of x-rays is forced to pass through biological barriers that are, in reality, healthy tissues that stand in the way of the tumor. Unfortunately, when encountering mainly skin and other healthy tissues, a fraction of incident x-rays experience Compton scattering-type deviations. Such deflected rays, in addition to not reaching the target tissue, will cause damage to the skin in addition to contaminating the treatment environment. causing an exposure known as bystander dose or spectator dose, reaching radiographers and technicians and unnecessarily exposing other anatomical regions of the patient. Causing hypoxia in skin tissues means that a considerable amount of molecular oxygen has been removed from these sites. Thus, the x-rays of the collimated beam passing through the skin will experience fewer hits or interactions and thus, less energy will be deposited, that is, fewer ionizations will occur. Such rays that have not undergone Compton scattering can proceed forward towards the tumor. This means that more rays will reach the target tissue in a collimated manner, increasing the bombardment capacity of the cancerous tumor. It can then be said that cutaneous hypoxia increases the efficiency of radiotherapy. When it comes to the skin's environment, hypoxia is also desirable as it is strongly associated with its radioresistance.

[0149] Invention is Capable of Causing Tissue Hypoxia - Proof of Concept

[0150] It is well known and well-known that the establishment of hypoxia in biological environments has been related to vasoconstriction events in arterioles that are close to these environments.

[0151] According to Malvin and Walker (2001), hypoxia in the alveolar region alters the redox potential in the smooth muscle cells of arterial vessels, decreasing the K ⁺ conductance of the membrane, causing depolarization that increases the probability of Ca ² channels opening ⁺ type L, facilitating the entry of Ca ²⁺ into cells. As a result, these vascular smooth muscles experience vasoconstriction.

[0152] To categorically prove the fact that the invention is capable of causing hypoxia, multiparametric ultrasound analysis was used with a Canon Aplio i800 device with 24 and 33 MHz transducers operated by a doctor specialized in ultrasound. In ultrasound experiments with Doppler effects on the scalp, the dermatological preparation of the invention containing 3% of the active ingredient L-Cysteine was applied and was capable of causing markedly vasoconstriction of arterioles.

[0153] Initially, ultrasound was performed without applying the invention, showing normal tissue perfusion activity.

[0154] Then, a composition containing 3% L-Cysteine was applied, after 5 minutes, an ultrasound analysis was carried out demonstrating a drastic reduction in tissue blood perfusion (figure 7).

[0155] Figure 7, showing an intense reduction in tissue blood perfusion, clearly demonstrates the hypoxic condition.

[0156] To corroborate the establishment of tissue hypoxia, it was demonstrated that there was, in fact, vasoconstriction of the arterioles. Thus, the arterioles were analyzed in situations before and after application of the product. Without the influence of RTP, Doppler clearly shows arteriole activity with a “saw”-shaped graph in which the descending inclined lines demonstrate the differences between systole and diastole. Five minutes after using the invention containing 3% L-Cysteine, spectral Doppler analysis showed the disappearance of arterial flows, leaving only venous return flows (Figures 8 and 9).

[0157] Radioprotective Properties of the invention - Proof of Concept

[0158] The invention was able to prove its radioprotective properties through a pilot, open and randomized study with women with breast cancer treated at a Radiotherapy Center, with therapeutic plans that involved only breast treatment and drainage (CAAE - 65217722.0 .0000.5373). The patients were divided into two groups of five women and the composition of the present invention was applied in concentrations of 1% or 3% of L-Cysteine before daily radiotherapy fractions. Radiotherapy treatment was performed with a Linear Electron Accelerator with a total dose between 40 and 48 Gy. Data were collected through consultations, photographs, a radiodermatitis evaluation questionnaire and consensus between radiodermatitis classification scales. Patients were evaluated up to 15 days after the end of radiotherapy. Patients with application of the composition with 1% L-Cysteine had only three risk factors that increase the incidence of grade II radiodermatitis, advanced age, overweight BMI and CTV above 794.14 cm3, in addition to receiving a dose of 44.6 Gy; three developed grade II radiodermatitis and two, grade I. The patients administered a composition with 3% L-Cysteine had an overweight BMI, concomitant cardiovascular diseases, clinical staging of moderate risk, neoadjuvant chemotherapy and a dose of 46.4 Gy; however, all developed only grade I radiodermatitis. Signs of erythema and dry scaling appeared around the third week of treatment with the composition containing 3% L-Cysteine. There was a delay in the onset of symptoms, mainly the minimization of sensitivity. Grade III radiodermatitis was not observed in either group. The composition of the present invention showed radioprotection activity in patients with breast cancer undergoing radiotherapy and this protection is dose dependent. [0159] Primary outcome

[0160] Protection of the skin that will receive radiation, reduction of the harmful effects induced by radiotherapy treatment, reduction of pain and discomfort during and after treatment, greater reduction of possible discontinuation of treatment due to injuries.

[0161] Secondary outcome

[0162] Greater adherence to treatment, reduction of possible intervals between doses caused by the injury, improvement in patients' quality of life.

[0163] Study design

[0164] This was an open, single-arm pilot trial to evaluate exposure to a dermatological protection agent. The study is open because both patients and the responsible doctor will know what is being used for protection. Single-arm research, as the control will be the evolution of possible burns of the patient herself.

[0165] Material and methods

[0166] Pilot Test - Population [0167] Women aged between 24 and 70 years old, diagnosed with breast cancer.

[0168] Inclusion Criteria: Women aged 40 to 70 years, with invasive breast CA. With pathological stage I (TNM T1 N0), that is, a unifocal lesion measuring up to 2.0 cm in size without lymph node involvement through lymph node sampling from the axilla or sentinel lymph node research. Patients with therapeutic plans that involve only breast treatment.

[0169] Exclusion criteria: Women with a history of collagenosis (rheumatological autoimmune diseases). Patients with large breasts, that is, with the distance between the sternum and the mid-axillary line greater than 25 cm. Therapeutic plans that involve treatments for areas other than the breasts, such as axillary drainage, supraclavicular or internal mammary fossa drainage. [0170] Benefits: Protection of the skin around the area to be radiated, reduction of irritation, reduction of burns, reduction of pain associated with radiotherapy sessions, may help reduce dropouts or spacing between sessions

[0171] Below are the tables with the results with the application of the invention at 1% and 3% of the thioic active component L-Cysteine.

[0172] Figure 10 shows the surprising results that could be achieved by applying the formulations described in this patent application. It can be clearly seen that none of the patients who underwent the protocol correctly suffered the most serious effects of radiodermatitis. Mainly in patients who had application of the invention in 3% of the active thioic compound, only grade I radiodermatitis or absence of radiodermatitis were reported. Examples of the state of the art and degrees of radiodermatitis expected to be found can be seen in the exemplary documents:

[0173] MANFREDINI, LL ; CAMARGOS, MG; CADAMURO, SA; LUIZE, PB. Treatment of acute radiodermatitis in a cancer patient: case report. In: XVI Latin American Scientific Initiation Meeting, 2012, São José dos Campos. XVI Latin American Scientific Initiation Meeting, 2012. [0174] Kole AJ, Kole L, Moran MS. Acute radiation dermatitis in breast cancer patients: challenges and solutions. Breast Cancer (Dove Med Press). 2017 May 5;9:313-323. doi: 10.2147/BCTT.S109763. PMID: 28503074; PMCID: PMC5426474.

[0175] Ryan JL, Heckler CE, Ling M, Katz A, Williams JP, Pentland AP, Morrow GR. Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients. Radiat Res. 2013 Jul;180(1):34-43. doi: 10.1667/RR3255.1 . Epub 2013 Jun 7. PMID: 23745991 ; PMCID: PMC3998827.

[0176] Safety assessment of the invention - cytotoxicity test (MTT) [0177] The MTT test was used to evaluate cytotoxicity and prove the safety of an L-Cysteine composition (produced according to the knowledge revealed by this patent application), in a culture of immortalized fibroblasts from the stroma of the African green monkey kidney (COS1), at concentrations of 5pg, 30pg, 11 Opg, 230pg and 500pg. The analyzes showed that there was less than 1% cell death in all tests, with the percentages of live cells at concentrations of 230 pg and 500 pg of 99.87% and 99.14%, respectively. Therefore, the results obtained indicate the safety of the compositions of the present invention, evaluated in the MTT cytotoxicity test in COS1 cell culture.

[0178] The test used to evaluate the in vitro safety of I-Cysteine was the MTT Test - [3-(4,5-dimethylthiazol—2yl)-2,5-diphenyl tetrazoline bromide]. The test was carried out in a culture of immortalized fibroblast cells from the stroma of the African green monkey kidney (COS1), with “Dubelcco Modified Eagle Medium” (DMEM) culture medium, supplemented with 10% Fetal Bovine Serum (FBS) containing antibiotics. , incubated for 24 hours in an oven at 37°C containing 95% air and 5% CO2. After trypsinization to detach the cells, the contents were transferred to Falcon tubes and centrifuged. The pellet was diluted and homogenized to be added to the previously assembled Neubauer chamber for cell counting. 2.0 x 104 cells were placed in each well, with 200 pL of medium in each well, with the following concentrations of the active ingredient of RTP: 30pg, 5pg, 110pg, 230pg and 500pg. To evaluate cell death, a negative control (CN) and a cytotoxic control (CCT) were used. The plate was incubated again for 24 hours. Afterwards, the plate was removed from the oven, the MTT solution was added and the medium from each well was removed for DMSO addition. After stirring in the thermomixer, the reader was used to detect absorbance (570 nm).

[0179] Finally, regardless of all the data provided so far, it appears that computational simulations (in silico) demonstrated that the application of the compounds of the present invention and subsequent hypoxia decreases Compton scattering interactions.

[0180] The examples disclosed here are intended to only exemplify some of the countless forms of embodiment and use of the present invention, without limiting the interpretation of its scope and amplitude, as well as any alternative forms and configurational variations thereof that will be defined. from the claims presented here.

Claims

1 . Cosmetic, dermatological and/or pharmaceutical composition, for pre-radiotherapy application to aid radioefficiency in radiotherapy procedures to combat cancerous tumors, or, to reduce cellular damage resulting from exposure to radiation, or; to improve the resolution and/or quality of diagnostic images resulting from the use of radiation; and/or; post-radiotherapy to attenuate or minimize the amount of reactive oxygen species and/or reactive nitrogen species formed after radiotherapy sessions; characterized by comprising at least one thioic compound with the general formula:

on what:

R1 is one of H, alkyl, alkenyl, alkynyl, linear or branched;

R2, is one of linear or branched H, alkyl, alkenyl, alkynyl;

2. Composition, according to claim 1, characterized by:

R1 be selected between H or CH3;

or, at least one of the compounds as defined below:

3. Composition, according to claim 1, characterized in that R3 is a molecule with 1 to 20 linear or branched carbon atoms and containing: at least one carboxyl group and; at least one primary or secondary amine group, or amide.

4. Composition, according to claim 3, characterized in that R3 is

, or,

5. Composition, according to any of the previous claims, characterized in that it is for topical application.

6. Composition, according to any of the previous claims, characterized in that it comprises between 0.1% and 10.0% of at least one thioic compound of general formula 1, 0.1% to 5% of at least one glycolic compound and oil-water based cream (qsp. 100%).

7. Composition, according to any of the previous claims, characterized in that the glycolic compound is ethoxydiglycol.

8. Composition, according to any one of the previous claims, characterized by additionally comprising between 0.1 and 3.0% vitamin C and its derivatives; between 0.1 and 5.0% polyphenolic antioxidants and their derivatives; between 0.1 and 5.0% glycosaminoglycans; or a combination of these.

9. Method for increasing radioefficiency in radiotherapy procedures to combat cancerous tumors and/or for improving the resolution and/or quality of diagnostic images resulting from the use of radiation, characterized by comprising topical administration pre-diagnosis session or radiation treatment in a individual of a composition as defined in any one of claims 1 to 8, in a radioefficient concentration of said composition.

10. Method according to claim 9, characterized in that the radiation treatment session is treatment with external beam radiotherapy.

1 1. Method according to claim 9 or 10, characterized in that topical administration occurs at least in a dose between 45 and 3 minutes before the start of the radiotherapy session.

12. Method to attenuate or minimize reactive oxygen species and/or reactive nitrogen species eventually formed after radiotherapy sessions; or; for reducing cellular damage from exposure to radiation characterized by applying to a post-radiotherapy or pre-radiotherapy individual a composition as defined in any one of claims 1 to 8.

13. Use of a composition as defined in any one of claims 1 to 8, characterized in that it is for the production of a medicine, cosmetic product or dermal product for topical use in a method: pre-radiotherapy to aid radioefficiency in radiotherapy procedures to combat cancerous tumors, or, to reduce cellular damage resulting from exposure to radiation, or; to improve the resolution and/or quality of diagnostic images resulting from the use of radiation; and/or; post-radiotherapy to attenuate or minimize the amount of reactive oxygen species and/or reactive nitrogen species formed after radiotherapy sessions.

14. Process for producing a composition as defined in any one of claims 1 to 8, characterized in that it comprises the following steps: