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 - Google Patents
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 Download PDFInfo
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- WO2024092335A1 WO2024092335A1 PCT/BR2023/050370 BR2023050370W WO2024092335A1 WO 2024092335 A1 WO2024092335 A1 WO 2024092335A1 BR 2023050370 W BR2023050370 W BR 2023050370W WO 2024092335 A1 WO2024092335 A1 WO 2024092335A1
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- radiotherapy
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
Definitions
- the invention describes new dermatological, pharmaceutical and/or cosmetic compositions comprising sulfur derivatives.
- said compositions are useful, among other uses, for pre-radiotherapy topical application to aid radioefficiency in radiotherapy procedures, preferably those combating cancerous tumors.
- 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.
- One of the pillars of cancer treatment is the association of surgical processes, chemotherapy and ionizing radiotherapy.
- 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.
- the ionizing beams that pass through the tissues promote cellular apoptosis, death of mitotic cells, necrosis or cellular senescence.
- 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.
- Direct damage to DNA causes the breaking of its structural bonds.
- e- electron displacement
- H2O water molecule
- H2O+ positive water ion
- 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.
- 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.
- Cell death can occur through different mechanisms, from the inactivation of vital systems for the cell to its inability to reproduce.
- 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.
- TEN external radiotherapy
- the radiation beam 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.
- 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.
- 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.
- 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.
- Skin cells have a high proliferation rate and are highly sensitive to damage caused by ionizing radiation and respond quickly to injury.
- 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.
- the cells reproduce faster than old cells, causing dry, scaly skin (i.e., dry peeling).
- ROS reactive oxygen species
- ROS ROS
- 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.
- neutrophils 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.
- cytokines such as tumor necrosis factor-a, interleukin-1 and interleukin-6
- 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.
- TGF-[3 a potent profibrotic factor that is elevated in the early stages of radiation damage and strongly implicated in the pathogenesis of
- 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.
- bolus 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- curcumin (1,7-bis-(4hydroxy3-methoxyphenyl)-heptadien-3,5-dione)
- demethoxy-curcumin and bis-demethoxy-curcumin.
- 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.
- 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.
- 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.
- RT radiotherapy
- 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.
- 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.
- 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.
- 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.
- 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 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.
- 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.
- 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.
- the document is categorical in indicating that the compounds revealed do not interfere with the efficiency of radiotherapy (example 8).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- R1 is selected from H or CH3;
- 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.
- R3 is selected from:
- said application is topical.
- 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%).
- the glycolic compound is ethoxydiglycol.
- 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.
- 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.
- the radiation treatment session is treatment with external beam radiation therapy.
- 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.
- 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.
- compositions 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.
- a new process for producing a composition as previously defined is also presented, characterized by comprising the following steps:
- 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).
- 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 Ind ⁇ stria.
- 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 Ind ⁇ stria.
- 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 Ind ⁇ stria.
- 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.
- FIG. 6 Doppler SMI analysis of tissue perfusion before use of the invention (RTP).
- Figure 8 Spectral Doppler analysis of follicular arteriole before use of the invention (RTP) showing arteriolar flow.
- FIG. 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.
- 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.
- 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.
- 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.
- the formulation of the invention transposes the layers of the epidermis and enters the connective tissue.
- 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.
- 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.
- 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.
- 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.
- 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.
- K the electron binding energy
- 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.
- 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.
- the atomic attenuation coefficient at T is proportional to Z 4 /(hv) 3
- the mass attenuation coefficient Tm is proportional to (Z/hv) 3 , where Z is the atomic number of the attenuator.
- 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.
- 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).
- 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.
- 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 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Table 1 Standard device conditions (200mA, 20mA.s 1 , 76 kVp)
- 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.
- 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.
- 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.
- 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.
- 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.
- the present invention by reducing Compton scatters, by altering biological spaces, increases the efficiency of radiotherapy.
- said thiols are biothiols and which can be selected from at least one compound: on what:
- 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.
- 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%).
- cream oil from 15 to 30% cetostearyl alcohol/sodium cetearyl sulfate, from 1 to 5% cetyl alcohol
- water from 2 to 6% propylene glycol, from 0.3 to 0.7 % nipagim and demineralized water qsp 100%.
- 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.
- 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:
- 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.
- 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:
- Formula 1 aminothiol (L-Cysteine) from 1%: start of pilot clinical trial tests.
- 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.
- Formula 2 aminothiol (L-Cysteine) from 3%: demonstrated to be able to optimize prophylaxis of side effects in the pilot clinical trial.
- Formula 4 Aminothiol (L-Cysteine) in an anionic base demonstrated high skin diffusion power: it caused marked hypoxia in scalp skin.
- Formula 5 aminothiol (L-Cysteine) from 5%: shown to be able to optimize x-ray images (hospital experiment).
- 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.
- Oxygen 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.
- 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 varies between 1 and approximately 3, respectively, when moving from hypoxic conditions (without oxygen) to normoxic irradiation conditions.
- OER 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.
- 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).
- 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.
- 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.
- 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.
- hypoxia increases the efficiency of radiotherapy.
- hypoxia is also desirable as it is strongly associated with its radioresistance.
- 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.
- these vascular smooth muscles experience vasoconstriction.
- 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.
- Pilot Test - Population Women aged between 24 and 70 years old, diagnosed with breast cancer.
- 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.
- 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
- 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:
- 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.
- DMEM Dubelcco Modified Eagle Medium
- FBS Fetal Bovine Serum
- 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.
- CN negative control
- CCT cytotoxic control
- 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).
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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
RELATÓRIO DESCRITIVO DA PATENTE DE INVENÇÃO DESCRIPTIVE REPORT OF THE INVENTION PATENT
COMPOSIÇÃO COSMÉTICA, DERMATOLÓGICA E/OU FARMACÊUTICA; MÉTODO PARA AUMENTO DA RADIOEFICIÊNCIA EM PROCEDIMENTOS RADIOTERÁPICOS E/OU PARA MELHORIA DA RESOLUÇÃO E/OU QUALIDADE DE IMAGENS DIAGNÓSTICAS; MÉTODO PARA ATENUAR OU MINIMIZAR AS ESPÉCIES REATIVAS FORMADAS APÓS AS SESSÕES DE RADIOTERAPIA; OU; PARA REDUÇÃO DE DANOS CELULARES DA EXPOSIÇÃO À RADIAÇÃO; E; PROCESSO DE PRODUÇÃO DA COMPOSIÇÃO 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
Campo da invenção Field of invention
[0001] A invenção descreve novas composições dermatológicas, farmacêuticas e/ou cosméticas compreendendo derivados de enxofre. Em uma concretização, as referidas composições são úteis, entre outros usos, para aplicação tópica pré-radioterapia para auxiliar a radioeficiência em procedimentos radioterápicos, preferencialmente aqueles de combate a tumores cancerígenos. Ainda, são apresentados processos de desenvolvimento e obtenção das mencionadas composições e produtos dermatológicos. Esta invenção está inserida no setor técnico de composições dermatológicas, farmacêuticas e/ou cosméticas, incluindo insumos dermatológicos. [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.
Fundamentos da invenção Fundamentals of the invention
[0002] Anualmente milhões de pessoas no mundo todo morrem de câncer pela ineficiência dos tratamentos ou pela falta de adesão devido aos efeitos adversos. [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] Em 2020 houve no mundo, aproximadamente 20 milhões de mortes por câncer e, no Brasil 250 mil, onde se gastou mais de 2,5 trilhões de reais com a patologia. [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] Um dos pilares do tratamento do câncer é a associação de processos cirúrgicos, quimioterapia e radioterapia ionizante.
[0005] Mais de 50% dos procedimentos de tratamento de câncer fazem uso da radioterapia. A dose total de radiação ionizante pode variar de 45 a 60Gy dependendo da localização e gravidade do tumor e, habitualmente, pode ser fracionada em doses diárias iguais. [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] Na radioterapia ionizante cujo objetivo é combater os tecidos tumorais, os feixes ionizantes que passam através dos tecidos, promovem apoptose celular, morte de células mitóticas, necrose ou senescência celular. [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] A absorção de energia depende da abundância de material no caminho da radiação. Quando a energia da radiação ionizante é depositada em uma macromolécula associada a efeitos biológicos observáveis, como o DNA, ela é chamada de efeito direto da radiação. Os fótons podem também ser absorvidos pela água do organismo causando excitação e ionização destas moléculas. Como água é aproximadamente 80% da massa das células vivas, a maior proporção da energia da radiação depositada na célula irá ser absorvida em sua água, e a água intersticial também interagirá com a radiação pelo processo de radiólise. A energia também é depositada em locais ricos em moléculas de gás 02 tais como o tecido conectivo da pele criando espécies químicas reativas (radicais) que por sua vez interagem com as moléculas alvo. Aproximadamente 2/3 dos danos biológicos se dá quando os raios-x fazem transferência linear de energia (TLE) ou por radiação ionizante esparsa, devido à ação indireta. [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] As radiações eletromagnéticas ionizantes ao interagirem com os tecidos dão origem a elétrons livres que ionizam o meio e criam efeitos químicos como a quebra das moléculas da água e O2 e a ruptura das cadeias de DNA. [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] A lesão direta do DNA ocasiona a quebra de suas ligações estruturais. Na lesão indireta, há deslocamento de elétron (e-) da molécula de água (H2O), que se torna um íon água positivo (H2O+). O elétron reagirá com outra molécula de água formando H2O-, que se dissocia em ion hidroxila (OH-) e radical livre hidrogênio (H«). O íon água positivo (H2O+) se dissocia em íon hidrogênio positivo (H+) e radical livre hidroxila (OH«). Os íons e radicais livres
são altamente reativos com as estruturas celulares. A radiação ionizante induz vários tipos de danos ao DNA, como danos à base, quebras de fita simples (QFS), quebras de fita dupla (QFD) e ligações cruzadas. Como as células têm vias de reparo biológico correspondentes a cada tipo de dano ao DNA induzido por radiação, elas são capazes de se recuperar deste dano induzido por radiação. [0010] As QFD persistentes ou não reparadas podem determinar os efeitos antitumorais da radiação ionizante induzindo apoptose, necrose, catástrofe mitótica ou parada permanente do crescimento. Cerca de 40 QFD/célula são gerados por irradiação com 1 Gy. Em teoria, se apenas um QFD permanecer em um gene importante, a célula pode ser esterilizada ou até mesmo morrer. Portanto, a eficiência da capacidade de reparo do QFD de uma célula é um fator muito importante na radioterapia. [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] A morte celular pode ocorrer por diferentes mecanismos, desde a inativação de sistemas vitais para a célula até à sua incapacidade de reprodução. [0012] A resposta dos tecidos às radiações depende de diversos fatores, tais como a sensibilidade do tumor à radiação, a localização e oxigenação das células, assim como a dose e o fracionamento prescrito. [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] Nos tratamentos de radioterapia externa (RTE), existe frequentemente a necessidade de se tratar lesões superficiais em pacientes com doença tumoral, estas lesões podem situar-se na pele ou serem adjacentes à mesma. [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] Quando o feixe de radiação entra no paciente, deposita uma determinada dose de radiação à superfície, aumentando até atingir um valor máximo numa profundidade denominada zmax e, em seguida, diminui quase exponencialmente até atingir um valor no ponto de saída do paciente (zex), de acordo com o perfil de percentagem de dose em profundidade. [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] Quando tumores internos são tratados pela radioterapia a pele que se interpõe neste caminho acaba por ser injuriada pelo processo. A gravidade da reação da pele à radiação é classificada e varia de eritema, descamação seca, descamação úmida mais severa e, eventualmente, ulceração.
[0016] As reações cutâneas induzidas pela radiação ionizante têm um impacto sobre o nível da dor, promovendo desconforto e prejudicando a qualidade de vida daqueles que se submetem ao tratamento, o que pode exigir mudanças no cronograma de radioterapia, postergando a melhora do paciente. [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] A dermatite de radiação pode limitar a dose terapêutica administrada aos pacientes e, às vezes, levar a uma interrupção no tratamento, portanto, potencialmente comprometendo o controle local e o resultado de sobrevivência. [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] A dermatite aguda por radiação, denominada radiodermite, é um efeito colateral comum que ocorre dentro de horas a semanas após o início da radioterapia e afeta mais de 90% dos pacientes. [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] A liberação de moléculas é associada aos danos da radioterapia ionizante que ativa os sistemas imunológicos inatos e adaptativos permitindo respostas antitumorais adicionais. [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] A reação eritematosa local é intensificada por aumento da permeabilidade vascular e da vasodilatação, promovidos pela radiação ionizante que ativa os processos inflamatórios e causa a superprodução de citocinas e de quimiocinas pelas células da pele irradiada. [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] As células da pele têm uma alta taxa de proliferação e possuem alta sensibilidade aos danos causados pela radiação ionizante e respondem rapidamente à injúria. [0021] Skin cells have a high proliferation rate and are highly sensitive to damage caused by ionizing radiation and respond quickly to injury.
[0022] A radiação ionizante inibe a propriedade de auto renovação da pele, pois danifica a capacidade mitótica das células-tronco basais da epiderme, as quais tentam compensar o dano da radiação aumentando sua atividade mitótica. Assim, as células se reproduzem mais rápido do que as células antigas, ocasionando uma pele seca e escamosa (ou seja, descamação seca). [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] Conforme a radioterapia ionizante continua, a camada basal não pode produzir células novas em quantidade suficiente para substituir as velhas e, portanto, a camada externa da epiderme ficará fissurada, edemaciada com exsudação (ou seja, descamação úmida).
[0024] A radiação também atua sobre outras moléculas no interior das células, como a água, para gerar espécies reativas de oxigênio (ERO), como superóxido, hidrogênio peróxido e radical hidroxila, que indiretamente causam mais danos ao DNA e em outros componentes celulares como por exemplo em proteínas e lipídios. [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] A geração das ERO é considerada responsável por mais de 60% do total dos danos induzidos por radiação ionizante. [0025] The generation of ROS is considered responsible for more than 60% of the total damage induced by ionizing radiation.
[0026] A dermatite crônica fibrótica, denominada radiodermite fibrótica, é um efeito colateral tardio, marcada por fibrose, com enrijecimento dérmico e epidérmico substancial, cicatrizes e retração do tecido, com evidência histológica de extensa hialinização do colágeno reticular. [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] Após a entrada na área irradiada, os neutrófilos são estimulados e liberam citocinas pró-inflamatórias, como o fator de necrose tumoral-a, interleucina-1 e interleucina-6, que perpetuam a inflamação e aumentam a formação das ERO. Os monócitos e os linfócitos subsequentemente migram para a pele irradiada. Os monócitos se diferenciam em macrófagos e liberam o fator de crescimento derivado das plaquetas, que estimula a angiogênese e a migração de fibroblastos. Os macrófagos, e as células endoteliais, fibroblastos e células epidérmicas secretam o fator crescimento [3 (TGF-[3), um fator pro- fibrótico potente, que é elevado nas fases iniciais do dano por radiação e fortemente implicado na patogênese da radiodermite crônica fibrótica. [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] A radiodermite crônica fibrótica normalmente se desenvolve de quatro a dozes meses após a terapia, mas pode continuar por muitos anos de maneira progressiva, e, em alguns casos, se faz necessária a cirurgia para a reconstrução da pele danificada. [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] Portanto, o gerenciamento de reações cutâneas é uma importante prioridade no cuidado de quem se submete ao tratamento por radiação. [0029] Therefore, managing skin reactions is an important priority in the care of those undergoing radiation treatment.
[0030] Existem várias inconsistências nos tratamentos por radiação em todo o mundo no que diz respeito à prática e às recomendações dadas por profissionais de saúde para prevenir e controlar os efeitos colaterais dolorosos
do tratamento com radiação ionizante. [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] Atualmente não existem procedimentos consensuais ou protocolos que utilizam preparados por via oral ou tópica eficazes para prevenir ou gerenciar as reações adversas da pele induzidas pela radioterapia. Os procedimentos e produtos são meramente paliativos e, em sua totalidade, objetivam reparar os danos já causados, sem a capacidade de preveni-los. [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] Estudos de revisão sistemática indicam que não há evidências clínicas para apoiar a superioridade das intervenções químicas de uso tópico na profilaxia da radiodermite, como a trolamina, corticosteroides tópicos, ácido hialurônico, ácido ascórbico, dexpantenol, sucralfato tópico, creme Cavilon, creme Theta, curativo de folha de prata, calêndula, enzimas proteolíticas, Aloe vera, entre outros. [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] Na radioterapia ionizante quando é exigida uma superficialização do ponto de dose máxima, seja para maximizar a dose no tumor ou mesmo para limitar a penetração do feixe, utiliza-se uma camada de um material que mimetiza o tecido humano, chamado de bólus, com espessura variável, que serve também para corrigir as irregularidades anatômicas quando colocados sobre a área a irradiar. [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] O bólus permite uma alteração na profundidade onde o máximo de energia depositada ocorre no interior do paciente, permitindo um aumento de dose à pele. No entanto, estes bólus, por não serem individualizados ao contorno externo da área a tratar, podem não ter um ajuste perfeito, comprometendo a distribuição de dose calculada pelo planejamento da radioterapia. [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] Apesar da radioterapia ser essencial no combate ao câncer, este procedimento possui algumas restrições e o gerenciamento das reações cutâneas é prioridade no cuidado de quem se submete ao tratamento por radiação. [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] Os tumores profundos são uma séria limitação ao tratamento, pois é comum que apenas 5% dos raios os atinjam. Boa parte do feixe paralelo de radiação (FPR) desvia e se espalha ao encontrar a pele e outros tecidos,
injuriando-os seriamente e reduzindo a radioeficiência da terapia. A literatura científica encontrada aponta a impossibilidade de redução estes espalhamentos não conseguindo manter o feixe colimado. [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] Por outro lado, em países com menos recursos, a limitação na disponibilidade das instalações destinadas ao protocolo radioterápico resulta em acúmulo de pessoas seminuas à espera da sessão, onde o impacto desta objetificação, vai além dos efeitos colaterais, minando-as psicologicamente. [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] As interrupções durante os ciclos de tratamento, devido ao aparecimento de efeitos adversos, podem comprometer o resultado do tratamento e diminuir a probabilidade de resposta do tumor. [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] As evidências clínicas reforçam a importância tecnológica desta invenção, realçando sua relevância quanto ao aumento de radioeficiência no tratamento, reduzindo o risco de recidiva local e a radiodermite. [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] Desta forma, realizaram-se buscas pelo estado da técnica e alguns documentos patentários foram detectados visando atuar neste problema técnico, os quais serão descritos a seguir. [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] O documento PI0005352 descreve uma loção preparada com produtos nacionais. A invenção descrita nesse documento é composta Aloe vera, colágeno, vitamina E, lanolina e alantoína. As soluções descritas neste documento diferem consideravelmente da descritas pela invenção, uma vez que utiliza de uma composição totalmente distinta do da presente invenção, bem como não cita os efeitos de radioeficiência. [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] O documento BR102015009017 descreve um processo de obtenção de nanopartículas lipídicas sólidas contendo curcuminoides. A invenção descrita nessa patente é composta por curcumina (1 ,7-bis-(4 hidroxi3- metoxifenil)-heptadien-3,5-diona), demetoxi-curcumina e bis-demetoxi- curcumina. Assim, a composição revelada neste documento difere consideravelmente da revelada pela invenção bem como não trata do uso pré- radioterapia, não cita efeitos de radioeficiência. [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] O documento EP3459534 correspondente ao documento
WO201 9057874 descreve uma composição da pravastatina para a redução das radiodermites e da fibrose no tratamento de câncer de mama com radioterapia. As informações reveladas no presente documento diferem consideravelmente da descrita pela invenção, tanto na composição e seu componente ativo como por não ser concebida para uso pré-radioterapia, não cita efeitos de radioeficiência. [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] O documento EP350760 correspondente ao documento WO201 8041960 define um novo método de diagnóstico para prever o risco de desenvolver um efeito tardio da mama como por exemplo uma pele atrófica, telangiectasia, endurecimento (fibrose) bem como necroses ou ulcerações, caracterizadas como radiodermites, após a radioterapia (RT), usando efeito tardio induzido por radiação citando a apoptose de linfócitos T e parâmetros clínicos. As informações reveladas no documento diferem consideravelmente da descrita pela invenção, uma vez que não cita efeitos de radioeficiência e por não revelarem ou sugerirem a composição e componente ativo da presente invenção. [0045] O documento WO2015087319 descreve alterações de protocolos no atendimento para aumentar a eficiência do tratamento de radioterapia ou da radiocirurgia e, com isto reduzir os efeitos colaterais do tratamento. Estas alterações se referem à fonte de feixe de raios-x convergente para um menor volume no corpo do paciente, reduzindo em média, pelo menos 80% da dose máxima, para que os órgãos internos recebam em média, não mais que 40% da dose máxima. As informações descritas no documento diferem consideravelmente das reveladas pela presente invenção, pois somente a invenção descrita no presente documento versa sobre a radioeficiência devido à ação de composições contendo derivados de enxofre e modificando espaços biológicos enquanto o documento destaca os efeitos benéficos devido a alterações físicas e anatômicas nos protocolos, ou seja, feixes de raios-x convergentes para um menor volume corporal do paciente. [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] O documento US20210369667 descreve o emprego de alguns compostos polifenólicos. A invenção revelada é composta basicamente por
polifenóis incluindo-se os ácidos fenólicos, flavonóides, estibenos (por exemplo, resveratrol), diferuloilmetanos (curcuminas), taninos e lignana, na composição com ácido hialurônico. As informações reveladas pelo documento diferem consideravelmente da descrita pela invenção pois não cita uma composição como as reveladas pela presente invenção, não revela os efeitos de radioeficiência., bem como não foi projetada para ser utilizada antes das sessões de radioterapia para modificar o ambiente biológico previamente à aplicação dos raios x e/ou gama. [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] O documento US20210338756 descreve o emprego de composições que contêm óleo de semente de romã, óleo de rosa mosqueta e oleorresina de Inula viscosa (ou seu extrato) e/ou óleo de Citrus medica vulgaris (ou seu extrato). As composições reveladas são compostas basicamente por preparações cosméticas com óleo e extratos vegetais. Assim, diferem consideravelmente do revelado pela presente invenção, não cita efeitos de radioeficiência e principalmente pelo fato da invenção aqui descrita se tratar de composições a base de compostos contendo enxofre e projetadas para serem também utilizadas antes das sessões de radioterapia para modificar o ambiente biológico previamente à aplicação dos raios gama. [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] O documento US20210315861 descreve uma composição que compreende a conjugação de compostos análogos do sulfurafano e da melatonina, como a 6-hidroximelatonina e o isotiocianato de 6-metilsulfinilhexila, respectivamente, para o emprego na redução das radiodermites. O complexo Sulforano-Melatonina é utilizado de forma a reagir com cisteínas presentes em Keapl para liberar Nrf2, estes agindo para serem conjugados com GSH dentro das células para gerar um composto conjugado com efeito antioxidante. A invenção, em contrapartida, é decorrente da utilização de compostos que interagem diretamente para a remoção do oxigênio livre no ambiente que será exposto à radiação, gerando a hipóxia das células e reduzindo / minimizando espalhamentos Compton e permitindo que mais raios continuem colimados na direção do tumor a ser combatido evitando que o dano decorrente da formação
de radicais livres sequer ocorra, ou seja substancialmente atenuado. [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] O documento US20190134156 descreve uma composição que compreende a formulação de medicamento (injetáveis, nasais e à base de peptídeos e derivados de peptídeos). Os compostos constantes no documento são peptídeos formados por aminoácidos agrupados em arranjos específicos em que a sua ação está associada com a tridimensionalidade e se diferem dos compostos da invenção que são compostos tiólicos capazes de reduzir os espalhamentos Compton e, com isso, proporcionar radioeficiência. [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] O documento US7314959 descreve sobre amino tióis e poliamidas e composições farmacêuticas para administração em conjunto com quimioterapia ou radioterapia contra câncer. As moléculas apresentadas diferem estruturalmente das reveladas pelo presente pedido de patente e não compreendem a conjugação de grupos funcionais e estruturas moleculares tais como as da presente invenção. Ainda, o documento é taxativo em indicar que os compostos revelados não interferem na eficiência da radioterapia (exemplo 8). [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] O documento US20200360476 descreve uma composição que compreende peptídeos derivados da eritropoetina. As informações reveladas no documento diferem consideravelmente da descrita pela invenção, uma vez que, não cita os efeitos de radioeficiência e por se tratar de composições distintas. Outro aspecto que difere a invenção é o fato dela ter sido projetada para ser também utilizada antes das sessões de radioterapia de forma a modificar o ambiente biológico previamente à aplicação dos raios gama. [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] O documento US20160168199 descreve uma composição de peptídeos que incluem fragmentos, quimeras, bem como peptídeos projetados para imitar a localização espacial dos principais resíduos de aminoácidos dentro dos ligantes do receptor protetor da eritropoetina. O presente documento difere substancialmente sobre a invenção aqui revelada uma vez que o documento não descreve a mesma composição nem os efeitos de radioeficiência. O documento também não revela informações sobre suas composições poderem ser utilizadas antes das sessões de radioterapia de forma a modificar o ambiente biológico
previamente à aplicação dos raios gama. [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] O documento US5716608 descreve uma composição de polímeros biocompatíveis. A invenção revelada na patente acima difere consideravelmente da descrita no presente documento, uma vez que a primeira não cita efeitos de radioeficiência e principalmente por não se tratar de composição de bioderivados de enxofre. Outro aspecto que difere a invenção é o fato dela ter sido projetada para ser também utilizada antes das sessões de radioterapia de forma a modificar o ambiente biológico previamente à aplicação dos raios x e/ou gama. [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] Portanto, a invenção apresentada neste documento de patente de invenção preenche o requisito da novidade, pois até o presente momento nenhum trabalho científico ou técnico compreendido no estado da técnica revela integralmente o conteúdo reivindicado por este documento de patente. Destaca- se ainda que a invenção proposta neste documento de patente apresenta também os outros critérios de patenteabilidade: atividade inventiva, uma vez que nenhum documento pode ser considerado como tornando evidente ou óbvia a presente invenção, e, possuí aplicação industrial. [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.
Breve descrição da invenção Brief description of the invention
[0055] Dessa forma, a presente invenção tem por objetivo resolver os problemas constantes no estado da técnica a partir de uma nova composição dermatológica, farmacêutica, e/ou cosmética, que compreende derivados de enxofre sendo particularmente útil para aplicação tópica: pré-radioterapia para auxílio da radioeficiência em procedimentos radioterápicos de combate a tumores cancerígenos, ou, para redução de danos celulares decorrentes da exposição à radiação, ou; para melhoria da resolução e/ou qualidade de imagens diagnósticas decorrentes de utilização de radiação; e/ou; pós-radioterapia para atenuar ou minimizar a quantidade de espécies reativas de oxigênio e/ou espécies reativas de nitrogênio formadas após sessões de radioterapia. [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] Assim, é apresentada uma nova composição cosmética,
dermatológica e/ou farmacêutica, para aplicação pré-radioterapia para auxílio da radioeficiência em procedimentos radioterápicos de combate a tumores cancerígenos, ou, para redução de danos celulares decorrentes da exposição à radiação, ou; para melhoria da resolução e/ou qualidade de imagens diagnósticas decorrentes de utilização de radiação; e/ou; pós-radioterapia para atenuar ou minimizar a quantidade de espécies reativas de oxigênio e/ou espécies reativas de nitrogênio formadas após sessões de radioterapia; caracterizada por compreender ao menos um composto tióico de fórmula geral:
em que: [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 é um entre H, alquila, alquenila, alquinila, lineares ou ramificados; R1 is one of H, alkyl, alkenyl, alkynyl, linear or branched;
R2, é um entre H, alquila, alquenila, alquinila lineares ou ramificados; R2, is one of linear or branched H, alkyl, alkenyl, alkynyl;
R3 é um entre H, alquila, alquenila, alquinila lineares ou ramificados; molécula com 1 a 20 átomos de carbono, linear, ramificada, ou linear ou ramificada e contendo um ou mais grupos cíclicos, aromáticos, não-aromáticos e/ou heterocíclicos, compreendendo pelo menos um grupo hidroxila, cetona, aldeído, carboxila, carbonila, carboalcoxila, éter, carboxiamida, aminas primárias, secundárias ou terciárias, imina, imida, tióis ou tio éter; ou seus sais, esteroisômeros cosmética, dermatológica e/ou farmacêuticamente aceitáveis. 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] Em uma concretização da presente invenção R1 é selecionado entre H ou CH3;
[0057] In an embodiment of the present invention R1 is selected from H or CH3;
ou, ao menos um dos compostos conforme definidos a seguir:
or, at least one of the compounds as defined below:
[0058] Em uma concretização da presente invenção R3 é uma molécula com 1 a 20 átomos de carbono linear ou ramificada e contendo: pelo menos um grupo carboxila e; pelo menos um grupo amina primária ou secundária, ou, amida. [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] Em uma concretização da presente invenção R3 é selecionado entre:
[0059] In an embodiment of the present invention R3 is selected from:
[0060] Em uma concretização da presente invenção a referida aplicação é tópica. [0060] In an embodiment of the present invention, said application is topical.
[0061] Em uma concretização da presente invenção a referida composição compreende entre 0,1% e 10,0% do ao menos um composto tióico, 0,1% a 5% de pelo menos um composto glicólico e creme base óleo-água (qsp. 100%). [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] Em uma concretização da presente invenção o composto glicólico ser etoxidiglicol. [0062] In one embodiment of the present invention the glycolic compound is ethoxydiglycol.
[0063] Em uma concretização da presente invenção a referida composição compreende adicionalmente entre 0,1 a 3,0% de vitamina C e seus derivados; entre 0,1 a 5,0% de antioxidantes polifenólicos e seus derivados; entre 0,1 a 5,0% de glicosaminoglicanas; ou uma combinação entre estes.
[0064] É também apresentado um método para aumento da radioeficiência em procedimentos radioterápicos de combate a tumores cancerígenos e/ou para melhoria da resolução e/ou qualidade de imagens diagnósticas decorrentes de utilização de radiação compreendendo a administração tópica pré-sessão de diagnóstico ou tratamento por radiação em um indivíduo de uma composição conforme definida anteriormente, em uma concentração radioeficiente da referida composição. [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] Em uma realização da presente invenção a sessão de tratamento por radiação é o tratamento com radioterapia de feixe externo de radiação. [0065] In one embodiment of the present invention the radiation treatment session is treatment with external beam radiation therapy.
[0066] Em uma concretização da presente invenção a administração tópica ocorre pelo menos em uma dose entre 45 e 3 minutos antes do início da sessão de radioterapia. Em uma concretização, a administração tópica ocorre pelo menos em uma dose entre 30 e 5 minutos antes do início da sessão de radioterapia. [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] É também apresentado um método para atenuar ou minimizar as espécies reativas de oxigênio e/ou espécies reativas de nitrogênio eventualmente formadas após as sessões de radioterapia; ou; para redução de danos celulares da exposição à radiação compreendendo a aplicação em um indivíduo pós-radioterapia ou pré-radioterapia de uma composição conforme definida anteriormente. [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] É também apresentado um nosso uso de uma composição, conforme definida anteriormente, para a produção de um medicamento, produto cosmético ou produto dérmico para uso tópico em um método: pré-radioterapia para auxílio da radioeficiência em procedimentos radioterápicos de combate a tumores cancerígenos, ou, para redução de danos celulares decorrentes da exposição à radiação, ou; para melhoria da resolução e/ou qualidade de imagens diagnósticas decorrentes de utilização de radiação; e/ou; pós-radioterapia para atenuar ou minimizar a quantidade de espécies reativas de oxigênio e/ou espécies reativas de nitrogênio formadas
após sessões de radioterapia. [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] É também apresentado um novo processo de produção de uma composição conforme definida anteriormente, caracterizado por compreender as seguintes etapas: [0069] A new process for producing a composition as previously defined is also presented, characterized by comprising the following steps:
- misturar os componentes de fase água e submetê-los a aquecimento em uma temperatura entre 70 SC e 90 SC; - mix the water phase components and subject them to heating at a temperature between 70 S C and 90 S C;
- misturar os componentes da fase óleo em tempo suficiente para as ceras se fundirem e homogeneizarem a aquecimento em uma temperatura entre 70 SC e 90 SC; e - 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
- misturar a fase água à fase óleo para a formação de uma emulsão óleo em água, sob agitação. - mix the water phase with the oil phase to form an oil-in-water emulsion, under stirring.
[0070] Estes e outros objetos da invenção poderão ser imediatamente reconhecidos pelos versados na área e a seguir serão providas descrições em detalhes suficientes para sua reprodução por um técnico no assunto. [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.
Breve descrição dos desenhos Brief description of the drawings
[0071] Com o intuito de melhor definir e esclarecer o conteúdo do presente pedido de patente, são apresentadas as figuras a seguir: [0071] In order to better define and clarify the content of this patent application, the following figures are presented:
[0072] Figura 1 : refere-se à representação esquemática das interações das radiações (raios-x ou raios-y) com a matéria, resultando em (1 ) Efeito Thompson (7 = 7’), (2) Efeito Fotoelétrico e (3) Espalhamento Compton (7 < 7’). 7: fóton incidente, 7’: fóton espalhado. [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] Figura 2: refere-se as imagens que foram elaboradas com dois diferentes ajustes do aparelho com exposição ao não à uma das possíveis composições da invenção (RTP). (a) AJUSTE 1 (condições-padrão do equipamento, 200mA, 20mA.s’1, 76 kVp) e (b) AJUSTE 2 (200mA, 14mA.s’1, 76 kVp). Especificações do Aparelho: equipamento tipo B, 60Hz, 2 fases, potência de entrada 200VA, potência de saída 110W, tensão de entrada 200Vac, modo de operação contínua com carga intermitente, da empresa Marpe Indústria. [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] Figura 3: refere-se as imagens radiográficas e seus respectivos histogramas de pixels que foram elaboradas com três quadriláteros regulares da
mesma região anatômica, com o AJUSTE 1 do aparelho (condições-padrão do equipamento, 200mA, 20mA.s-1 , 76 kVp), Especificações do Aparelho: equipamento tipo B, 60Hz, 2 fases, potência de entrada 200VA, potência de saída 1 10W, tensão de entrada 200Vac, modo de operação contínua com carga intermitente, empresa 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] Figura 4: refere-se as imagens radiográficas e seus respectivos histogramas de pixels que foram elaboradas com quatro quadriláteros regulares da mesma região anatômica, com o AJUSTE 2 do aparelho (200mA, 14mA.s-1 , 76 kVp). Especificações do Aparelho: equipamento tipo B, 60Hz, 2 fases, potência de entrada 200VA, potência de saída 1 10W, tensão de entrada 200Vac, modo de operação contínua com carga intermitente, da empresa Marpe Indústria. [0076] Figura 5: frações de sobrevida celular para raios-x, nêutrons e partículas a. As curvas pontilhadas demonstram as células bem oxigenadas e as curvas contínuas para células em hipóxia. [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] Figura 6: Análise Doppler SMI da perfusão tecidual antes do uso da invenção (RTP). [0077] Figure 6: Doppler SMI analysis of tissue perfusion before use of the invention (RTP).
[0078] Figura 7: Doppler SMI evidenciando significativa redução da perfusão tecidual [0078] Figure 7: Doppler SMI showing significant reduction in tissue perfusion
[0079] Figura 8: Análise com Doppler espectral de arteríola folicular antes do uso da invenção (RTP) mostrando fluxo arteriolar. [0079] Figure 8: Spectral Doppler analysis of follicular arteriole before use of the invention (RTP) showing arteriolar flow.
[0080] Figura 9: Análise com Doppler espectral de arteríola folicular 5 minutos após o uso da invenção (RTP) a 3% do princípio ativo mostrando claramente ausência dos fluxos arteriolares. [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] Figura 10: Resultados do tratamento após protocolo com formulação de 3% do aminotiol. Pode-se verificar a ausência de efeitos da radiodermite em graus elevados e o efeito protetor das formulações da presente invenção. [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.
Descrição detalhada da Invenção Detailed description of the Invention
[0082] Entre os diversos contextos apresentados no presente pedido de patente, pode-se entender que a invenção apresenta uma nova modalidade de
aumento a eficiência do tratamento radioterápico, aumenta casos de sucesso da radioterapia, minimiza/elimina dores insuportáveis, evita queimaduras sérias e danos crônicos de pele, reduz a desistência e a mortalidade dos indivíduos sob tratamento, em suma, promove uma humanização inédita aos pacientes. O fundamento da invenção reside no fato de que, quanto menos radiossensível é uma região biológica, menos interações ocorrerão entre o feixe de radiação que passa e a região em questão, ou seja, a região interagirá menos com a radiação incidente. [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] Diferentemente dos procedimentos paliativos atuais, quando a invenção é aplicada minutos antes das sessões de radioterapia, os tióis da presente invenção interagem quimicamente com os espaços biológicos modificando-os de forma inédita, de modo a criar uma condição que minimiza as interações com a radiação incidente e, como resultado desse processo, tem-se um ganho de radioeficiência no procedimento radioterápico, além da redução das reações da pele induzidas pela radiação. [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] Inicialmente para interagir com a derme, a formulação da invenção transpõe as camadas da epiderme e adentra no tecido conectivo. Assim o sistema de liberação transepidérmico da formulação permite que o produto possa inicialmente atingir o espaço biológico dérmico, em seguida, os ativos são liberados para modificar este ambiente tornando-o menos radiossensível. [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] Por prova de conceito, a invenção se aplica para procedimentos de radioterapia em que se quer combater tumores que se dispõem em regiões biológicas abaixo da pele. Nestas situações a pele fica no caminho como um obstáculo entre as radiações incidentes e as regiões tumorais a serem bombardeadas. Esta invenção promove o aumento da eficiência da radioterapia pois diminui o espalhamento indesejável do FPR, fazendo com que este consiga atingir, com maior potência, os tumores profundos principalmente nas terapias em que as doses de radiação são mais intensas, e que implicariam em danos ainda maiores. [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] A invenção promove um estado fisiológico modificado que permite
redução das doses de radiação, do número de sessões, poupa das injúrias, principalmente das queimaduras, reduzindo o desvio do feixe incidente, mantendo-o na direção e sentido do tumor, aumentando a eficiência da radioterapia. [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] Para demonstrar alguns fundamentos da invenção deve-se descrever as interações que os fótons experimentam com os tecidos biológicos desde as energias presentes nas imagens de raios-x até o intervalo de energias característico da radioterapia. Ao contrário das partículas carregadas, os fótons são eletricamente neutros e não perdem energia de forma constante à medida que penetram na matéria. Em vez disso, eles podem viajar alguma distância antes de interagir com um átomo, estes efeitos podem ser compreendidos com o auxílio da figura 1 . [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] O efeito fotoelétrico ocorre com elétrons da camada K, de modo que a energia do fóton é próxima ou igual à energia desse elétron. Como o efeito fotoelétrico é muito específico para a energia de ligação da camada K, ocorrerá ionização do átomo, ou seja, o elétron que foi ejetado agora é chamado de fotoelétron e o fóton de raios-x foi completamente atenuado neste ponto. Assim, a energia que ele emitiu foi capturada exclusivamente por esse fotoelétron. Como a interação depende da energia de ligação do elétron K, ela se relaciona com o número atômico Z do tecido. Na interação fotoelétrica, toda energia do fóton incidente é transferida para o elétron, retirando-o da órbita. Este efeito ocorre para fótons de energias relativamente pequenas e é relevante para a radiologia diagnóstica. O fóton interage com um elétron orbital fortemente ligado de um átomo atenuador e desaparece, enquanto o elétron orbital é ejetado como um fotoelétron com uma energia cinética Ec (Ec = hv - EL) onde, hv energia do fóton incidente e EL energia de ligação do elétron. [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] Para estabilizar o átomo, um elétron da camada externa preenche a vaga na camada interna. A energia que é perdida por esse elétron quando cai para a camada interna, pode ser emitida como radiação característica, ou seja, fóton de raio-x. Para o efeito fotoelétrico, o coeficiente de atenuação atômica aT é
proporcional a Z4/(hv)3, enquanto o coeficiente de atenuação de massa Tm é proporcional a (Z/hv)3, onde Z é o número atômico do atenuador. [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] A probabilidade deste efeito fotoelétrico é máxima quando a energia do fóton incidente é igual ou apenas ligeiramente maior que a energia de ligação do elétron em sua camada, ou seja, a borda K correspondente à camada K em que o elétron está fortemente ligado. O elétron que é removido é então chamado de fotoelétron e o fóton incidente é completamente absorvido no processo. À medida que o número atômico do meio atenuante aumenta, a probabilidade de ocorrência do efeito fotoelétrico também aumenta de forma cúbica. Este efeito é proporcional à densidade física do meio atenuante (p) e inversamente proporcional ao cubo da energia do fóton incidente (E). Assim, a probabilidade geral de absorção fotoelétrica pode ser resumida da seguinte forma: absorção fotoelétrica ~ p (Z3/E3). À medida que se aumenta a energia do tubo de raios-x em picos de quilo voltagem, diminui a probabilidade de ocorrer o efeito fotoelétrico. [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] A interação Compton se manifesta de forma diferente com perda da energia dos raios incidentes devido ao processo de choque com elétrons livres (não ligados aos átomos) ou elétrons das camadas externas ou camada de valência fracamente ligados. A ionização ocorre com o átomo interagente liberando um elétron e um fóton com um comprimento de onda maior (X < X’). Assim, o fóton entra no corpo humano e interage com um átomo e a sua energia é parcialmente absorvida pelo elétron da camada externa. Como efeito deste choque, o elétron é arrancado de sua órbita caracterizando um processo de ionização e ele passa a ser denominado de elétron Compton uma vez que foi criado por esta interação. O restante da energia permanece no fóton espalhado (E’= hc/À’) mas sua direção foi modificada sensivelmente por isso o termo “espalhamento”. A energia e o momento são conservados neste processo. O efeito Compton é um processo de absorção parcial onde o fóton original perdeu energia, e este processo é denominado deslocamento Compton (ou seja, um deslocamento do comprimento de onda/frequência). A mudança de comprimento
de onda do fóton espalhado pode ser determinada por 0,024 (1 -cos 9), onde 9 é o ângulo do fóton espalhado. Assim, a energia do fóton espalhado diminui com o aumento deste ângulo. O espalhamento Compton é a principal causa da radiação espalhada num material e pode ocorrer em vários níveis diferentes de energia, mas passa a ser o efeito predominante em energias mais altas, incluindo aquelas usuais da radioterapia. A probabilidade do espalhamento Compton ocorrer está na razão direta do número de elétrons da camada externa, ou seja, a densidade eletrônica além de ser também diretamente proporcional à densidade física do material. Por outro lado, o efeito Compton é muito fracamente dependente da energia do fóton, sendo relativamente constante na faixa de 10-600 keV. Sabe-se que o efeito aumenta proporcionalmente e suavemente à medida em que o pico de quilo voltagem do tubo de raios-x aumenta. [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] Os espalhamentos Compton provocam uma necessidade de aumento da dose de radioterapia. Considerando-se as faixas de energia de 100 keV a 10 MeV dos fótons utilizados na radioterapia, a interação Compton é o principal mecanismo de espalhamento. Assim, o efeito Compton interfere negativamente na dose prescrita para o paciente, ou seja, estas doses necessitam ser aumentadas. Além disto, considerando-se os tecidos sãos que estão no caminho da radiação até o tecido tumoral, os espalhamentos Compton irão resultar em danos biológicos, uma vez que, o processo gera elétrons ionizados livres que colidem e interagem causando alterações biológicas. Por sua vez, os fótons espalhados podem ser absorvidos pelos tecidos em outros ambientes biológicos causando mais danos. Todos estes efeitos somados irão consumir frações do feixe de radiação incidente implicando necessidade de aumento na dose do paciente. [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] Os espalhamentos Compton são responsáveis também por outro efeito negativo, a denominada dose do espectador (bystander dose) ou seja, pela exposição ocupacional dos profissionais que estão presentes no ambiente da radioterapia. A razão pela qual isso acontece é porque a dispersão Compton,
de acordo com seu nome, cria dispersão dos fótons que saem do corpo do paciente e podem facilmente atingir o radiologista. Na verdade, o espalhamento Compton também impacta na vida no grupo de profissionais que trabalha com os raios-x sendo a fonte número um da dose de exposição. [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] Para comprovar a ação de radioeficiência da invenção e sua capacidade de modificar os ambientes biológicos da pele, reduzir os espalhamentos Compton e permitir que mais fótons do feixe de radiação permaneçam colimados, foram realizados testes de imagens de raios-x. As imagens foram geradas disparando-se os raios-x diretamente na pele para os dois ajustes de aparelho (Ajuste 1 e Ajuste 2). [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] Os procedimentos de radioimagem com raios-x foram realizados sem e com a aplicação de uma das composições da invenção. Uma imagem de raios-x foi elaborada sem a aplicação da invenção. Em seguida, a composição da invenção foi aplicada sobre a pele, meia hora e cinco minutos respectivamente antes da exposição aos raios-x para os dois ajustes do aparelho, estes efeitos podem ser compreendidos com o auxílio da figura 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] Os histogramas de pixels foram empregados para a avaliação quantitativa dentro de uma escala de cinza, do mais escuro ao mais claro, para evidenciar as diferenças que ocorreram nas imagens analisadas. [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] Ao se demonstrar que a invenção tem a capacidade de reduzir o efeito fog ou neblina, provou-se que ela reduziu os espalhamentos Compton responsáveis pelas distorções de imagem. As radiomagens que possuem os efeitos fog apresentam-se mais difusas e mais esbranquiçadas do que aquelas livres destas distorções. O efeito fog provoca um aumento geral na densidade radiográfica e resulta numa diminuição do contraste radiográfico (a radiação espalhada cria neblina que reduz tanto o contraste quanto a visibilidade dos detalhes). Para explorar o quanto a invenção (designada Radioeficiência Tópica Pré-Radioterapia - RTP) pode modificar as radioimagens, escolheu-se um aparelho de raios-x que não fizesse correções automáticas. [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] Comparando-se as imagens formadas sem e com a utilização da
invenção percebe-se claramente, a olho nu, maior efeito fog de branqueamento de imagem para a condição “sem RTP” para os 2 ajustes. Uma vez que se pode atribuir o efeito fog aos espalhamentos Compton, conclui-se que, ao utilizar a invenção (RTP), o efeito fog foi atenuado provando-se que ele foi capaz de modificar o ambiente biológico. [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] Para análise dos pixels das imagens foram construídos histogramas utilizando-se o programa Adobe Photoshop (versões 2019 e 2022) e comparações das médias de pixels, duas a duas, nas condições sem e com aplicação do RTP. Para perceber o efeito fog foram escolhidas e analisadas partes anatômicas com tonalidades mais homogêneas reduzindo-se a dispersão dos dados. Trata-se de uma análise de histograma de pixels de quadriláteros regulares da mesma região anatômica nas condições de estudo. Esta análise de pixels de histogramas se fundamenta no fato das imagens monocromáticas serem digitais onde cada pixel possui apenas uma banda espectral. Um pixel é caracterizado pelo valor de intensidade de cor e pela sua localização na imagem. [0100] O número de tons entre os valores limites, branco e preto, que se pode representar em tons, depende de quantos bits são alocados na matriz de imagem para armazenar o tom de cada pixel. Para a análise de pixels considerou-se o número de elementos da escala cinza (21, 22, 23 e 24), os tons limites de cinza (0,1 , 0-7, 0-15, 0-254,9), o número de bits necessários para representação dos pixels (1 , 2, 3 e 4), respectivamente. Aos pixels de valor dentro da faixa entre 0 - 255, será atribuído o valor 255 para branco e, o valor zero, para preto. [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] Nas condições-padrão do aparelho de raios-x (ajuste 1 ), para os 3 quadriláteros analisados, percebe-se que, ao utilizar o a invenção (designada RTP) previamente, os valores das médias de pixels foram inferiores se comparados com a condição “sem RTP”, demonstrando-se assim o efeito da invenção na redução dos espalhamentos Compton.
[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.
Tabela 1 : Condições padrão do aparelho (200mA, 20mA.s 1, 76 kVp) Table 1: Standard device conditions (200mA, 20mA.s 1 , 76 kVp)
[0102] Em conclusão, tem-se que uma redução dos espalhamentos Compton demonstra que a invenção é capaz de reduzir as interações de raios gama com a pele, aumentando a radioeficiência da terapia e reduzindo a radiossensibilidade cutânea. Estes efeitos podem ser compreendidos com o auxílio da figura 3. [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] Para o ajuste 2 conseguiu-se provar que a invenção reduz o efeito fog ao se detectar uma média de pixels menor para a condição “com RTP” no quadrilátero 4, estes efeitos podem ser compreendidos com o auxílio da figura 4. [0104] A invenção, ao reduzir os efeitos do espalhamento Compton, potencialmente promove uma diminuição da dose do Espectador (bystander dose) e, consequentemente, reduz os danos da exposição à radiação para o radiologista. A razão pela qual isso acontece é porque, reduzindo-se os efeitos da dispersão Compton mais fótons atingirão o receptor de imagem poupando o radiologista. [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] Os espalhamentos Compton também têm um efeito negativo no contraste da imagem de raios-x e, a invenção ao reduzir os efeitos destes espalhamentos, propicia uma melhora na qualidade das imagens diagnósticas. Para que as interações fotônicas e a formação de radioimagens possam ser melhor compreendidas, deve-se considerar primeiramente a condição em que os raios-x penetram completamente o corpo humano, sem que nenhuma interação ocorra com a matéria. Neste caso, sem ter ocorrido o espalhamento de radiação, a imagem irá assumir coloração muito escura. [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] Entretanto, quando os raios-x são absorvidos pela matéria devido
aos espalhamentos coerente e Compton, sua energia é convertida em raios-x espalhados gerando matizes de coloração mais claras e, quando os raios-x são bloqueados pelos ossos, não chegando ao receptor, tem-se uma imagem branca. [0107] A radiação proveniente do efeito fotoelétrico, composta por fótons de raios-x é referida como “radiação secundária” devido ao fato de ser gerada por um elétron que pula para a camada interna, preenchendo a vaga deixada pelo fotoelétron e estabilizado o átomo. Para as radiações provenientes dos três tipos interação denomina-se “radiação de dispersão” ou simplesmente “dispersão”. Uma vez que o espalhamento coerente ocorre para faixas de energia muito baixas, fora do intervalo de energia utilizada nas radioimagens, ele é mencionado para demonstrar que mesmo aos níveis muito baixos de kVp existirão interações no corpo humano. As interações que produzem radiação de dispersão na radiografia ocorrem principalmente dentro do paciente. Algum espalhamento também ocorre como resultado de interações entre o feixe de raios-x, a mesa Bucky, o receptor de imagem e qualquer outro material que esteja dentro do campo de radiação. O efeito fotoelétrico contribui para a atenuação do feixe de raios-x ao passar pela matéria e esta atenuação acaba sendo responsável por criar as imagens diagnósticas. Em suma, as imagens de raios-x se devem predominantemente devido efeito fotoelétrico. É importante ressaltar que a combinação entre o efeito fotoelétrico e a transmissão, origina imagens com bons contrastes e alta qualidade porque há diferenças claras nos tons de cinza, diferenciando o tecido mole do osso. Os raios-x experimentarão diferentes valores de atenuação ou diferenciais de absorção devido ao fato do efeito fotoelétrico ser diretamente afetado pelo número atômico e pela densidade tecidual. [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] O efeito fotoelétrico difere do Compton em alguns aspectos importantes. A primeira diferença é que o efeito fotoelétrico geralmente ocorre com elétrons da camada K e a energia do fóton é próxima ou igual à energia de ligação desse elétron. Assim, este elétron é liberado do átomo e o fóton é completamente atenuado neste ponto, se extinguindo. Este fóton que iria
provocar diminuição de contraste, pois sairia da condição de colimação é extinto e, como resultado, a imagem mantém o contraste. O elétron injetado é agora chamado de fotoelétron. O efeito Compton pode acontecer praticamente em qualquer átomo, em qualquer lugar do corpo. Não existiriam os raios-x diagnósticos se o efeito fotoelétrico não estivesse presente. [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] Na radioimagem por raios-x, os ossos aparecem na cor branca opaca, o tecido subcutâneo e regiões com gordura, cinza escuro, tecidos moles tais como coração, vasos sanguíneos, cinza claro e a passagem dos raios pelo ar pulmonar originam a cor escura. Os ossos têm densidade maior e um Z maior, assim mais efeito fotoelétrico ocorre em que os raios-x são parados. Considerando-se o tecido pulmonar, onde há menor densidade e um número Z menor, menos interações fotoelétricas irão ocorrer, mais raios-x chegarão ao receptor de imagem, caracterizando tons mais escuros. [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] O espalhamento Compton é ruim para a técnica diagnóstica por raios-x por ser um ruído que interfere negativamente na formação das imagens, causando distorções. O espalhamento ocorre a partir do nível de energia de 40 kVp. Aumentando-se os valores de kVp, aumenta-se proporcionalmente a quantidade de espalhamento Compton e, portanto, diminui-se o contraste total da imagem. Aumentando-se os kVp a um determinado valor, o efeito Compton supera o fotoelétrico. Continuando-se a aumentar os kVp, o efeito fotoelétrico se reduz a ponto de praticamente desaparecer e o efeito Compton vai se intensificando proporcionalmente. Ao se atingir 200 kVp só existirá o efeito Compton, ou seja, somente permanecerá o ruído para a formação da imagem. Além disto, uma espessura maior de caminho biológico também interfere aumentando os espalhamentos Compton. [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] Como os espalhamentos Compton reduzem a eficiência da radioterapia pela redução dos raios colimados que acabam por não atingir o tumor cancerígeno, a presente invenção ao reduzir os espalhamos Compton, pela alteração de espaços biológicos, aumentam a eficiência da radioterapia. [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] Assim, com base em todo o acima referido, apresenta-se para fins
exemplificativos, a série homóloga de compostos tiólicos usados como princípios ativos das formulações pré-radioterápicas para a modificação do ambiente biológico com redução dos espalhamentos Compton. [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] Em uma concretização da presente invenção os referidos tióis são biotióis e que podem ser selecionados entre ao menos um composto:
em que:
[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] Entende-se como aspecto adicional da presente invenção o fato que a preparação de base dermatológica transepidérmica é capaz de carrear tióis induzindo a modificação do ambiente biológico cutâneo com redução dos espalhamentos Compton dos fótons incidentes. [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] Assim, a preparação da base dermatológica se refere a uma
composição pode também compreender creme óleo (de 15 a 30 % de álcool cetoestearílico/cetearil sulfato de sódio, de 1 a 5 % de álcool cetílico), em água (de 2 a 6% de propilenoglicol, de 0,3 a 0,7% de nipagim e água desmineralizada qsp 100%). [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] Como um exemplo da produção de uma possível composição dentro do contexto da presente invenção, em um recipiente os componentes da fase água são misturados e submetidos a um aquecimento até atingir 80sC. Em outro recipiente são misturados, a quente, os componentes da fase óleo até as ceras se fundirem propiciando uma homogeneização dos ingredientes e a temperatura do sistema atingir 78SC. Sob mistura mais intensa, verte-se uma pequena porção da fase água sobre a fase óleo até formar uma emulsão água em óleo. Em seguida, o restante da fase água vai sendo adicionado e mistura- se de forma intensa para que ocorra a inversão de fases, caracterizando-se a emulsão final óleo em água. À medida que a temperatura vai abaixando, a agitação deve ser mais lenta, só o suficiente para manter o sistema sob estado emulsionado e para se evitar sua aeração. [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] Um aspecto adicional da presente invenção é a preparação dermatológica pré-radioterápica final capaz de carrear os tióis induzindo à modificação cutânea com redução dos espalhamentos Compton dos fótons incidentes. [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] Assim, a fase final de preparo da invenção pode se referir a incorporação de compostos tiólicos sólidos (de 0,1 a 10% de tióis sólidos são triturados até obtenção de um pó finíssimo) ou líquidos (de 0,1 a 10% de tióis líquidos) no creme óleo em água: [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] Num recipiente, os tióis e o etoxidiglicol (de 1 a 5%) são misturados até formar uma mistura homogênea. [0119] In a container, the thiols and ethoxydiglycol (from 1 to 5%) are mixed until a homogeneous mixture is formed.
[0120] Em seguida esta mistura é adicionada geometricamente à emulsão óleo em água, até obtenção de um sistema homogêneo. [0120] This mixture is then added geometrically to the oil-in-water emulsion, until a homogeneous system is obtained.
[0121] Um aspecto adicional da presente invenção é o fundamento da posologia da preparação pré-radioterápica propiciando radioeficiência
considerando-se o fato de que derme é um espaço dinâmico que pode gradativamente se reoxigenar. [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] Assim desenvolveu-se uma posologia que orienta a aplicação da fórmula em dois instantes prévios à radioterapia. Com a pele limpa e higienizada aplicar RTP 30 minutos e reaplicar 5 minutos, antes do início de cada sessão de radioterapia. [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] Exemplos [0123] Examples
[0124] Desta forma, no contexto do presente pedido de patente, deve-se entender que a composição com rádioeficiência tópica pré-radioterapia (RTP) que gerou os resultados contidos nas figuras 2, 3 e 4 é uma composição com os seguintes parâmetros qualitativos gerais: [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] Fórmula 1 : aminotiol (L-Cisteína) a partir de 1 %: início dos testes do ensaio clínico piloto.
[0125] Formula 1: aminothiol (L-Cysteine) from 1%: start of pilot clinical trial tests.
[0126] Prova de Conceito da Propriedade da invenção (RTP) em Aumentar Eficiência da Radioterapia [0126] Proof of Concept of the Property of the Invention (RTP) in Increasing the Efficiency of Radiotherapy
[0127] Para comprovar a ação de radioeficiência da invenção e sua capacidade de modificar os ambientes biológicos da pele, reduzir os espalhamentos Compton e permitir que mais fótons do feixe de radiação permaneçam colimados, foram realizados testes de imagens de raios-x. Os procedimentos de radioimagem com raios-x foram realizados com e sem a aplicação da invenção. Para evidenciar os efeitos de espalhamento Compton
uma composição com L-Cisteína foi aplicada sobre a pele a 5%, meia hora e cinco minutos antes da exposição aos raios-x, estes efeitos podem ser compreendidos com o auxílio das figuras 2, 3 e 4. [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] Histogramas de pixels foram empregados para a avaliação quantitativa dentro de uma escala de cinza, do mais escuro ao mais claro, para evidenciar as diferenças que ocorreram nas imagens analisadas. Ao se demonstrar que a invenção tem a capacidade de reduzir o efeito fog ou neblina, provou-se que ela reduziu os espalhamentos Compton responsáveis pelas distorções de imagem. As radiomagens que possuem os efeitos fog apresentam- se mais difusas e mais esbranquiçadas do que aquelas livres destas distorções. O efeito fog provoca um aumento geral na densidade radiográfica e resulta numa diminuição do contraste radiográfico (a radiação espalhada cria neblina que reduz tanto o contraste quanto a visibilidade dos detalhes). Para explorar o quanto a invenção (RTP) pode modificar as radioimagens, escolheu-se um aparelho de raios-x que não fizesse correções automáticas. [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] Comparando-se as imagens formadas com e sem utilização da invenção (RTP) percebe-se claramente, a olho nú, maior efeito fog de branqueamento de imagem para a condição “sem RTP”. Uma vez que se pode atribuir o efeito fog aos espalhamentos Compton, conclui-se que, ao utilizar o a invenção (RTP), o efeito fog foi atenuado provando-se que ele foi capaz de modificar o ambiente biológico. [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] Para análise dos pixels das imagens foram construídos histogramas utilizando-se o programa Adobe Photoshop (versões 2019 e 2022) e comparações das médias de pixels, duas a duas, nas condições com e sem aplicação da composição da presente invenção (RTP). Para perceber o efeito fog foram escolhidas e analisadas partes anatômicas com tonalidades mais homogêneas reduzindo-se a dispersão dos dados. Trata-se de uma análise de histograma de pixels de quadriláteros regulares da mesma região anatômica nas condições de estudo. Esta análise de pixels de histogramas se fundamenta no fato das imagens monocromáticas serem digitais onde cada pixel possui apenas
uma banda espectral. [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] Nas condições-padrão do aparelho de raios-x (ajuste 1 ), para os 3 quadriláteros analisados, percebe-se que, ao utilizar a invenção RTP previamente, os valores das médias de pixels foram estatisticamente inferiores se comparados com a condição “sem RTP”, demonstrando-se assim o efeito da invenção na redução dos espalhamentos Compton. Em conclusão, tem-se que uma redução dos espalhamentos Compton demonstrando que o RTP é capaz de reduzir as interações de raios-x com a pele, aumentando a radioeficiência da terapia e reduzindo a radiossensibilidade cutânea. [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] A invenção, ao reduzir os efeitos do espalhamento Compton, potencialmente promove uma diminuição da dose do Espectador (bystander dose) e, consequentemente, reduz os danos da exposição à radiação para o radiologista. A razão pela qual isso acontece é porque, reduzindo-se os efeitos da dispersão Compton mais fótons atingirão o receptor de imagem poupando o radiologista. [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] Outros exemplos de composições dentro do contexto da presente invenção podem ser encontrados a seguir. [0133] Other examples of compositions within the context of the present invention can be found below.
[0134] Fórmula 2: aminotiol (L-Cisteína) a partir de 3%: demonstrou conseguir otimizar profilaxia dos efeitos colaterais no ensaio clínico piloto.
[0134] Formula 2: aminothiol (L-Cysteine) from 3%: demonstrated to be able to optimize prophylaxis of side effects in the pilot clinical trial.
[0135] Fórmula 3: Aminotiol (L-Cisteína) em base não iônica demonstrou moderado poder de difusão cutânea: provocou hipóxia parcial em pele de
escalpo.
[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] Fórmula 4: Aminotiol (L-Cisteína) em base aniônica demonstrou elevado poder de difusão cutânea: provocou hipóxia acentuada em pele de escalpo.
[0136] Formula 4: Aminothiol (L-Cysteine) in an anionic base demonstrated high skin diffusion power: it caused marked hypoxia in scalp skin.
[0137] Fórmula 5: aminotiol (L-Cisteína) a partir de 5%: demonstrou conseguir otimizar imagens de raios-x (experimento no hospital).
[0137] Formula 5: aminothiol (L-Cysteine) from 5%: shown to be able to optimize x-ray images (hospital experiment).
[0138] Provas de Conceito da invenção. [0138] Proofs of Concept of the invention.
[0139] Efeitos Benéficos da invenção. [0139] Beneficial effects of the invention.
[0140] Uma propriedade muito benéfica e fundamental da invenção é a sua capacidade de provocar hipóxia no espaço cutâneo. A hipóxia se caracteriza quando as concentrações de gás oxigênio (oxigênio molecular) atingem níveis inferiores ao comumente encontrados em tecidos biológicos. Hipóxia, por sua vez, confere pelo menos duas categorias de benefícios: Radioeficiência da Terapia e Radioproteção Tecidual ou Redução de Dano Tecidual. [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 ] Hipóxia é Radioprotetora Porque Reduz Dano Tecidual [0141 ] Hypoxia is Radioprotective Because It Reduces Tissue Damage
[0142] Ao se considerar o momento da sessão de radioterapia em que os raios-x estão sendo aplicados no paciente pode-se afirmar que a hipóxia cutânea, ao reduzir as concentrações de gás oxigênio no ambiente da pele, diminuirá sensivelmente a formação dos radicais livres uma vez que a interação dos raios- x com gás oxigênio é muito conhecida e denominada de “efeito oxigênio”. [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] Efeito Oxigênio versus Dano Tecidual [0143] Oxygen Effect versus Tissue Damage
[0144] A presença ou ausência de oxigênio molecular dentro de uma célula influencia no efeito biológico da radiação ionizante: quanto maior a oxigenação celular acima da anóxia, maior é o dano ou efeito biológico da radiação ionizante. O oxigênio, portanto, é um dos agentes modificadores de dose mais eficazes, sensibilizando as células à radiação. O oxigênio causa uma “amplificação” dos danos ao DNA induzidos pela radiação. Especialmente para
os raios-x que são mais penetrantes e liberam pouca energia linear aos tecidos que interage, ou seja, baixos valores de TLE, quanto maior a oxigenação celular acima da anóxia, maior será o efeito biológico até que ocorra a saturação do efeito do oxigênio. Como mostrado na figura abaixo, o efeito é bastante dramático para radiações de baixa TLE (esparsamente ionizantes) como os raios-x, enquanto para radiações de alta TLE (densamente ionizantes) é muito menos pronunciado. A proporção de doses sem e com oxigênio (células hipóxicas versus células bem oxigenadas) para produzir o mesmo efeito biológico é chamada de taxa de aumento de oxigênio, OER (Oxygen Enhancement Rate). [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 °se Para Pr° uzir determinado efeito sem oxigênio dose para produzir determinado efeito com oxigênioOER ° if To P r ° use a certain effect without oxygen dose to produce a certain effect with oxygen
[0145] Dano Celular. [0145] Cellular Damage.
[0146] OER varia entre 1 e aproximadamente 3, respectivamente, ao passar de condições hipóxicas (sem oxigênio) para condições normóxicas de irradiação. Para os raios-x, se a OER é de 2,5 significa dizer que, para matar determinado percentual de células em ambiente hipóxico será necessária uma dose duas vezes e meia maior do que para ambientes abundantemente oxigenados. Para os nêutrons a presença de oxigênio molecular impacta menos no dano celular e as partículas a são as que sofrem a menor influência do meio oxigenado (figura 5). [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] Hipóxia da Pele Aumenta a Eficiência da Radioterapia [0147] Skin Hypoxia Increases the Efficiency of Radiotherapy
[0148] Radioterapia é um dos principais recursos terapêuticos utilizados para o combate aos tumores cancerígenos. Para tratar os tumores mais internos são utilizados raios mais penetrantes tais como os raios-x. Porém para atingir tais alvos o feixe colimado de raios-x é obrigado a passar pelas barreiras biológicas que são, em realidade, tecidos sadios que interpõem no caminho até o tumor. Desafortunadamente, ao se deparar principalmente com a pele e outros tecidos sãos, uma fração dos raios-x incidentes experimentam desvios do tipo espalhamentos Compton. Tais raios desviados, além de não atingirem o tecido- alvo, irão causar danos à pele além de contaminar o ambiente de tratamento
provocando uma exposição conhecida como bystander dose ou dose do espectador atingindo os radiografistas e técnicos e expondo desnecessariamente outras regiões anatômicas do paciente. Provocar hipóxia nos tecidos cutâneos significa dizer que considerável quantidade de oxigênio molecular foi retirada destes locais. Assim, os raios-x do feixe colimado ao passar através da pele experimentarão menos hits ou interações e assim, menos energia será depositada, ou seja, menos ionizações ocorrerão. Tais raios que não sofreram os espalhamentos Compton podem prosseguir em frente em direção ao tumor. Isto significa dizer que mais raios atingirão o tecido-alvo de forma colimada aumentando a capacidade de bombardeio do tumor cancerígeno. Pode-se dizer então que a hipóxia cutânea aumenta a eficifiência da radioterapia. Em se tratando do ambiente da pele a hipóxia também é desejável uma vez que está fortemente associada à sua radiorresistência. [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] Invenção é Capaz de Provocar Hipóxia Tecidual - Prova de Conceito [0149] Invention is Capable of Causing Tissue Hypoxia - Proof of Concept
[0150] É muito conhecido e notório que o estabelecimento de quadros de hipóxia em ambientes biológicos tem sido relacionado com eventos de vasoconstricção de arteríolas que se encontram próximas a esses ambientes. [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] Segundo Malvin e Walker (2001 ) um quadro de hipóxia na região alveolar altera o potencial redox nas células musculares lisas de vasos arteriais diminuindo a condutância de K+ da membrana causando uma despolarização que aumenta a probabilidade de abertura dos canais de Ca2+ do tipo L facilitando a entrada de Ca2+ nas células. Como resultado, esses músculos lisos vasculares experimentam uma vasoconstrição. [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] Para comprovar categoricamente o fato da invenção ser capaz de provocar hipóxia utilizou-se a análise multiparamétrica de ultrassonografia com aparelho Canon Aplio i800 transdutores de 24 e 33 MHz operados por médico especialista em ultrassonografia. Em experimentos de ultrassonografias com efeitos Doppler em couro cabeludo, o preparado dermatológico da invenção contendo 3% do princípio ativo L-Cisteína foi aplicado e foi capaz de causar
marcadamente vasoconstricção de arteríolas. [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] Inicialmente foi feita a ultrassonografia sem aplicação da invenção evidenciando atividade normal de perfusão tecidual. [0153] Initially, ultrasound was performed without applying the invention, showing normal tissue perfusion activity.
[0154] Em seguida aplicou-se uma composição contendo L-Cisteína a 3%, após 5 minutos, foi efetuada a análise de ultrassonografia demonstrando drástica redução de perfusão sanguínea tecidual (figura 7). [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] A figura 7 ao evidenciar intensa redução de perfusão sanguínea tecidual demonstra claramente o quadro hipóxico. [0155] Figure 7, showing an intense reduction in tissue blood perfusion, clearly demonstrates the hypoxic condition.
[0156] Para corroborar com o estabelecimento de hipóxia tecidual demonstrou-se que houve, de fato, vasoconstricção das arteríolas. Assim, as arteríolas foram analisadas nas situações antes e depois da aplicação do produto. Sem a influência do RTP o Doppler evidencia claramente atividade das arteríolas com o gráfico em formato de “serra” em que as linhas inclinadas descendentes demonstram as diferenças entre sístole e diástole. Cinco minutos após a utilização da invenção contendo L-Cisteína a 3% a análise com Doppler espectral evidenciou o desaparecimento de fluxos arteriais, permanecendo apenas fluxos de retorno venoso (Figuras 8 e 9). [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] Propriedades Radioprotetoras da invenção - Prova de Conceito[0157] Radioprotective Properties of the invention - Proof of Concept
[0158] A invenção conseguiu comprovar as suas propriedades radioprotetoras por meio de estudo piloto, aberto e randomizado com mulheres portadoras de neoplasia de mama tratadas em um Centro de Radioterapia, com planos terapêuticos que envolveram apenas o tratamento das mamas e drenagens (CAAE - 65217722.0.0000.5373). As pacientes foram divididas dois grupos de cinco mulheres e a composição da presente invenção foi aplicada nas concentrações de 1 % ou 3% de L-Cisteína antes das frações diárias de radioterapia. O tratamento radioterápico foi realizado com Acelerador Linear de Elétrons com dose total entre 40 e 48 Gy. Os dados foram coletados através de consultas, fotografias, questionário próprio de avaliação das radiodermatites e consenso entres escalas de classificação de radiodermatites. As pacientes foram avaliadas até 15 dias após o término da radioterapia. As pacientes com aplicação
da composição com L-Cisteína a 1% apresentavam apenas três fatores de risco que aumentam a incidência de radiodermatite grau II, idade avançada, IMC de sobrepeso e CTV acima de 794,14 cm3, além de receberem dose de 44,6 Gy; três desenvolveram radiodermatite grau II e duas, grau I. Já as pacientes aplicadas com uma composição com L-Cisteína a 3% apresentavam IMC de sobrepeso, doenças cardiovasculares concomitantes, estadiamento clínico de risco moderado, quimioterapia neoadjuvante e dose de 46,4 Gy; entretanto todas desenvolveram apenas radiodermatite grau I. Os sinais de eritema e descamação seca apareceram por volta da terceira semana de tratamento com a composição contendo L-Cisteína a 3%. Houve atraso no tempo de aparecimento dos sintomas, principalmente a minimização da sensibilidade. A radiodermatite grau III não foi observada em nenhum dos grupos. A composição da presente invenção apresentou atividade de radioproteção em pacientes com câncer de mama submetidas à radioterapia e essa proteção é dose dependente. [0159] Desfecho primário [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] Proteção da pele que receberá a radiação, redução dos efeitos deletérios induzidos pelo tratamento por radioterapia, redução de dores e desconforto durante e após o tratamento, maior redução da possível descontinuidade do tratamento devido às lesões. [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] Desfecho secundário [0161] Secondary outcome
[0162] Maior adesão ao tratamento, redução de possíveis intervalos entre doses causados pela lesão, melhoria da qualidade de vida das pacientes. [0162] Greater adherence to treatment, reduction of possible intervals between doses caused by the injury, improvement in patients' quality of life.
[0163] Delineamento do estudo [0163] Study design
[0164] Tratou-se de um ensaio piloto, aberto e de braço único, para a avaliação da exposição a um agente de proteção dermatológica. O estudo é aberto pois tanto as pacientes como o médico responsável saberão o que está sendo empregado para a proteção. Pesquisa de braço único, pois o controle será a evolução de possíveis queimaduras da própria paciente. [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 e métodos [0165] Material and methods
[0166] Ensaio Piloto - População
[0167] Mulheres na faixa etária entre 24 e 70 anos, com diagnóstico de câncer de mama. [0166] Pilot Test - Population [0167] Women aged between 24 and 70 years old, diagnosed with breast cancer.
[0168] Critérios de Inclusão: Mulheres de 40 a 70 anos, com CA invasivo de mama. Com estadiamento patológico I (TNM T1 N0) ou seja, lesão com tamanho até 2,0 cm unifocais sem acometimento de linfonodos através da amostragem linfonodal da axila ou da pesquisa do linfonodo sentinela. Pacientes com planos terapêuticos que envolvam apenas o tratamento nas mamas. [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] Critérios de exclusão: Mulheres com antecedentes de colagenoses (doenças autoimunes reumatológicas). Pacientes com mamas volumosas, ou seja, com a distância entre o esterno até a linha hemiaxilar média, maior que 25 cm. Planos terapêuticos que envolvam tratamentos de áreas além das mamas como drenagem axilar, drenagem de fossa supraclavicular ou mamária interna. [0170] Benefícios: Proteção da pele ao redor da área a ser radiada, redução de irritações, redução de queimaduras, redução das dores associadas às sessões de radioterapia, poderá auxiliar na redução de desistências ou no espaçamento entre as sessões [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] A seguir as tabelas com os resultados com a aplicação da invenção a 1 % e a 3% do componente ativo tióico L-Cisteína.
[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] A figura 10 apresenta os surpreendentes resultados que puderam ser alcançados mediante a aplicação das formulações descritas neste pedido de patente. Pode-se verificar claramente que nenhum dos pacientes que passou pelo protocolo de forma correta sofreu os efeitos mais graves da radiodermite. Principalmente nos pacientes que tiveram a aplicação da invenção em 3% do composto tióico ativo foram reportados somente radiodermites de grau I ou ausência de radiodermite. Exemplos do estado da técnica e graus de radiodermites esperadas de serem encontradas podem ser verificadas nos documentos exemplificativos: [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, L. L. ; CAMARGOS, M. G. ; CADAMURO, S. A. ;
LUIZE, P. B. . Tratamento do radiodermite aguda em paciente oncológico: relato de caso. In: XVI Encontro Latino Americano de Iniciação Científica, 2012, São José dos Campos. XVI Encontro Latino Americano de Iniciação Científica, 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. [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. [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] Avaliação de segurança da invenção - teste de citotoxicidade (MTT) [0177] O teste MTT foi empregado para avaliação citotoxicidade e comprovação da segurança de uma composição de L-Cisteína (produzida conforme os conhecimentos revelados por este pedido de patente), em cultura de fibroblastos imortalizados do estroma do rim de macaco verde africano (COS1 ), nas concentrações de 5pg, 30pg, 11 Opg, 230pg e 500pg. As análises mostraram que houve menos que 1% de morte celular em todos os testes, com as porcentagens de células vivas nas concentrações de 230 pg e 500 pg de 99,87% e 99,14%, respectivamente. Portanto, os resultados obtidos indicam segurança das composições da presente invenção, avaliada no Teste de citotoxicidade MTT em cultura de células COS1 . [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] O teste empregado para a avaliação da segurança in vitro de I- Cisteína foi o Teste de MTT - [3-(4,5-dimetiltiazol— 2yl)-2,5-difenil brometo de tetrazolina]. O teste foi realizado em cultura de células de fibroblastos imortalizados do estroma do rim de macaco verde africano (COS1 ), com meio de cultura “Dubelcco Modified Eagle Medium” (DMEM), suplementado com 10% de Soro Fetal Bovino (SFB) contendo antibióticos, incubados por 24h em estufa a 37°C contendo 95% ar e 5% CO2. Após a tripsinização para destacamento das
células, o conteúdo foi transferido para tubos Falcon e centrifugado. O pellet foi diluído e homogeneizado para ser adicionado a câmara de Neubauer previamente montada para então contagem das células. Foram colocadas 2,0 x 104 células em cada poço, com 200 pL de meio em cada poço, com as seguintes concentrações do princípio ativo do RTP: 30pg, 5pg, 110pg, 230pg e 500pg. Para a avaliação de morte celular, foram empregados um controle negativo (CN) e um controle citotóxico (CCT). A placa foi novamente incubada por 24 horas. Após, a placa foi retirada da estufa, a solução de MTT foi adicionada e, o meio de cada poço foi retirado, para adição DMSO. Após agitação no thermomixer, usou-se o leitor para detecção da absorbância (570 nm). [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] Finalmente, independente de todos os dados até então providos, verifica-se que simulações computacionais (in silico) demonstraram que a aplicação dos compostos da presente invenção e a subsequente hipóxia diminui a interações do espalhamento Compton. [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] Os exemplos aqui revelados possuem o intuito de somente exemplificar algumas das inúmeras formas de realização e utilização da presente invenção, sem limitar a interpretação de seu escopo e amplitude, bem como, sobre eventuais formas alternativas e variações configuracionais da mesma que serão definidas a partir das reivindicações aqui apresentadas.
[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 . Composição cosmética, dermatológica e/ou farmacêutica, para aplicação pré-radioterapia para auxílio da radioeficiência em procedimentos radioterápicos de combate a tumores cancerígenos, ou, para redução de danos celulares decorrentes da exposição à radiação, ou; para melhoria da resolução e/ou qualidade de imagens diagnósticas decorrentes de utilização de radiação; e/ou; pós-radioterapia para atenuar ou minimizar a quantidade de espécies reativas de oxigênio e/ou espécies reativas de nitrogênio formadas após sessões de radioterapia; caracterizada por compreender ao menos um composto tióico de fórmula geral:
em que: 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 é um entre H, alquila, alquenila, alquinila, lineares ou ramificados; R1 is one of H, alkyl, alkenyl, alkynyl, linear or branched;
R2, é um entre H, alquila, alquenila, alquinila lineares ou ramificados; R2, is one of linear or branched H, alkyl, alkenyl, alkynyl;
R3 é um entre H, alquila, alquenila, alquinila lineares ou ramificados; molécula com 1 a 20 átomos de carbono, linear, ramificada, ou linear ou ramificada e contendo um ou mais grupos cíclicos, aromáticos, não-aromáticos e/ou heterocíclicos, compreendendo pelo menos um grupo hidroxila, cetona, aldeído, carboxila, carbonila, carboalcoxila, éter, carboxiamida, aminas primárias, secundárias ou terciárias, imina, imida, tióis ou tio éter; ou seus sais, esteroisômeros cosmética, dermatológica e/ou farmacêuticamente aceitáveis. 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.
2. Composição, de acordo com a reivindicação 1 , caracterizado por: 2. Composition, according to claim 1, characterized by:
R1 ser selecionado entre H ou CH3;
R1 be selected between H or CH3;
ou, ao menos um dos compostos conforme definidos a seguir:
or, at least one of the compounds as defined below:
3. Composição, de acordo com a reivindicação 1 , caracterizada por R3 ser uma molécula com 1 a 20 átomos de carbono linear ou ramificada e contendo: pelo menos um grupo carboxila e; pelo menos um grupo amina primária ou secundária, ou, amida. 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. Composição, de acordo com a reivindicação 3, caracterizada por R3 ser
4. Composition, according to claim 3, characterized in that R3 is
, ou, , or,
5. Composição, de acordo com qualquer uma das reivindicações anteriores, caracterizado por ser para aplicação tópica. 5. Composition, according to any of the previous claims, characterized in that it is for topical application.
6. Composição, de acordo com qualquer uma das reivindicações anteriores, caracterizada por compreender entre 0,1% a 10,0% do ao menos um composto tióico de fórmula geral 1 , 0,1% a 5% de pelo menos um composto glicólico e creme base óleo-água (qsp. 100%). 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. Composição, de acordo com qualquer uma das reivindicações anteriores, caracterizada pelo composto glicólico ser etoxidiglicol. 7. Composition, according to any of the previous claims, characterized in that the glycolic compound is ethoxydiglycol.
8. Composição, de acordo com qualquer uma das reivindicações anteriores, caracterizada por compreender adicionalmente entre 0,1 a 3,0% de vitamina C e seus derivados; entre 0,1 a 5,0% de antioxidantes polifenólicos e seus derivados; entre 0,1 a 5,0% de glicosaminoglicanas; ou uma combinação entre estes.
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. Método para aumento da radioeficiência em procedimentos radioterápicos de combate a tumores cancerígenos e/ou para melhoria da resolução e/ou qualidade de imagens diagnósticas decorrentes de utilização de radiação caracterizado por compreender administração tópica pré-sesssão de diagnóstico ou tratamento por radiação em um indivíduo de uma composição conforme definida em qualquer uma das reivindicações 1 a 8, em uma concentração radioeficiente da referida composição. 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. Método, de acordo com a reivindicação 9, caracterizado pela sessão de tratamento por radiação ser o tratamento com radioterapia de feixe externo de radiação. 10. Method according to claim 9, characterized in that the radiation treatment session is treatment with external beam radiotherapy.
1 1. Método, de acordo com a reivindicação 9 ou 10, caracterizado pela administração tópica ocorrer pelo menos em uma dose entre 45 e 3 minutos antes do início da sessão de radioterapia. 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. Método para atenuar ou minimizar as espécies reativas de oxigênio e/ou espécies reativas de nitrogênio eventualmente formadas após as sessões de radioterapia; ou; para redução de danos celulares da exposição à radiação caracterizado por compreender a aplicação em um indivíduo pós-radioterapia ou pré-radioterapia de uma composição conforme definida em qualquer uma das reivindicações 1 a 8. 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. Uso de uma composição, conforme definida em qualquer uma das reivindicações 1 a 8, caracterizada por ser para a produção de um medicamento, produto cosmético ou produto dérmico para uso tópico em um método: pré-radioterapia para auxílio da radioeficiência em procedimentos radioterápicos de combate a tumores cancerígenos, ou, para redução de danos celulares decorrentes da exposição à radiação, ou; para melhoria da resolução e/ou qualidade de imagens diagnósticas decorrentes de utilização de radiação; e/ou; pós-radioterapia para atenuar ou minimizar a quantidade de espécies reativas de oxigênio e/ou espécies reativas de nitrogênio formadas após sessões de radioterapia.
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. Processo de produção de uma composição conforme definida em qualquer uma das reivindicações 1 a 8, caracterizado por compreender as seguintes etapas: 14. Process for producing a composition as defined in any one of claims 1 to 8, characterized in that it comprises the following steps:
- misturar os componentes de fase água e submetê-los a aquecimento em uma temperatura entre 70 SC e 90 SC; - mix the water phase components and subject them to heating at a temperature between 70 S C and 90 S C;
- misturar os componentes da fase óleo em tempo suficiente para as ceras se fundirem e homogeneizarem a aquecimento em uma temperatura entre 70 SC e 90 SC; e - 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
- misturar a fase água à fase óleo para a formação de uma emulsão óleo em água, sob agitação.
- mix the water phase with the oil phase to form an oil-in-water emulsion, under stirring.
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EP1532976A2 (en) * | 2003-11-18 | 2005-05-25 | John Alfred Gorton Holt | Compositions comprising organic disulfides, cysteine sulfoxides, sulfones, sulfoximines or other sulfur containing substances and their use in therapy in combination with radiation |
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EP1532976A2 (en) * | 2003-11-18 | 2005-05-25 | John Alfred Gorton Holt | Compositions comprising organic disulfides, cysteine sulfoxides, sulfones, sulfoximines or other sulfur containing substances and their use in therapy in combination with radiation |
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