Ecobiological treatment of radiation therapy side effects

Abstract

The present invention relates to a three-dimensional bipolymer matrix exerting biological and biomechanical activity capable of neutralizing various physiopathological parameters involved in the development and exacerbation of skin lesions and / or sores, which combines: - a first polymer network comprising a first colloid (Col-1) non-covalently bound to a cross-linked non-sulfated polysaccharide; and - a second polymer network comprising a second colloid (Col-2) covalently or non-covalently bound to a sulfated polysaccharide.

Description

[Technical Field]

[0001] The present invention relates to a three-dimensional bipolymeric matrix with biomechanical activity that is capable of counteracting various physiopathological parameters involved in the development and exacerbation of skin lesions and / or sores, particularly radiation dermatitis. [Background technology]

[0002] According to the latest estimates from the International Agency for Research on Cancer, based on data collected from 185 countries, there were 18.1 million new cases of cancer diagnosed worldwide in 2018.

[0003] In France, the overall number of new cancer cases has been increasing every year for 30 years, mainly due to an aging population and improved diagnostic methods. According to the US National Cancer Institute, there were an estimated 400,000 new cancer cases in the France metropolitan area in 2017.

[0004] This means that cancer remains a major public health problem in France and around the world.

[0005] Depending on the nature of the tumor, its molecular profile and / or its location, numerous treatments are implemented to limit or stop the progression of the disease. A classical distinction is made between surgery, radiotherapy, immunotherapy, hormonal therapy, targeted therapy or chemotherapy, whether performed alone or in combination within the framework of multidisciplinary care.

[0006] These treatments are particularly aggressive to the body and usually come with side effects.

[0007] In particular, radiation therapy (or irradiation) involves the use of high-energy rays to destroy or damage cancer cells. The primary biological effect of ionizing radiation is to break DNA strands in tumor cells, either directly or through the formation of free radicals, resulting in the death of these cells.

[0008] However, exposure to ionizing radiation can induce side effects such as radiation dermatitis, which are skin lesions whose severity is graded according to the international Common Terminology Criteria for Adverse Events: - Grade 1: Erythema occurring within a few days to a maximum of 3 weeks after the radiation therapy period, especially in subjects with light skin phototype. It is often accompanied by a tingling sensation and edema. It occurs frequently, but when treatment is stopped, it rapidly regresses after a stage of desquamation and often transient hair loss caused by damage to the skin appendages (hair follicles, sweat glands, or sebaceous glands). - Grade 2: Moderate erythema and edema, exudative patches limited to the irradiated area. - Grade 3: Exudative radiodermatitis, usually followed by erythema as the radiation therapy progresses. Characterized by desquamation and confluent ulcers leaving the dermis exposed several weeks after the radiation therapy. Epithelialization (or re-epithelialization) occurs over weeks to months, depending on the site of the lesion, resulting in pigmentation disorders and alopecia, which are almost always permanent. Radiation therapy must usually be stopped to allow time for healing. - Grade 4: Acute radiation necrosis, evidence of excessive radiation, which currently occurs exceptionally except in cases of very extensive superficial or infiltrating tumors (high doses in a very short time), manifests within a few days as a very painful, inflammatory plaque, which progresses to necrotic and hemorrhagic phenomena and deep necrosis, which may expose muscle, tendons, and bone.

[0009] Thus, ranging from simple dry erythema (erythema sicca) to tissue necrosis, with more or less exudative intermediate stages, radiation dermatitis is not amenable to specific treatment protocols. Although radiation dermatitis is highly variable, the therapies commonly used to treat this type of skin lesion are similar to those used in burns (emollients, dermal corticoids, dressings such as petrolatum gauze, hydrogels, hydrocolloids, or charcoal- or silver-coated dressings).

[0010] The choice of the best treatment depends directly on the type of lesion being treated, i.e., dry, weeping, severely weeping, infected, etc. For example, hydrogel-type dressings tend to promote healing of dry lesions by maintaining a moist environment, whereas their application to exudative radiation dermatitis tends to cause the phenomenon of maceration, which in turn inhibits healing and may lead to infection or superinfection.

[0011] More generally, skin can be damaged by means other than ionizing radiation from radiotherapy.

[0012] A skin sore or lesion is a break in the continuity of tissue. A wound exists when the skin or mucous membrane is broken, cut, or torn. The severity of a sore is characterized by its location, appearance, and cause (burn, bite, cut, etc.).

[0013] Skin lesions can be classified based on biological and clinical characteristics such as hydration / nutrition needs and occlusion needs. Lesions can be divided into three families: - Exudative lesions: These are lesions that are susceptible to maceration and need to be dried with non-occlusive care to allow air to pass through. These include, for example, diaper rash with exudative lesions or blisters, maceration of the folds, and chickenpox. - Type I non-exuding lesions: These are superficial to medium-sized lesions that require semi-occlusive breathable care and hydration. These include, for example, sutures, cuts, abrasions from everyday life after the sore has dried, chickenpox in the healing stage, lesions after cosmetic procedures (peeling, laser, permanent hair removal, tattooing, tattoo removal, etc.), or non-exuding diaper rash. - Type II non-exuding lesions: These are medium to large lesions that require occlusive care and lipid supplementation to create a barrier against the external environment. These include, for example, chapped skin, sores, pulpitis, burns, and abrasions.

[0014] The skin insulates and protects the body from the external environment. When a sore develops, the body triggers a natural biological phenomenon: healing. This is a complex repair process in which the body must stop possible bleeding, protect, cleanse, and seal the wound. Damaged tissue must be remodeled as close to the original tissue as possible.

[0015] The natural healing process of a lesion is a series of biochemical, biological, and cellular steps, all of which are essential for healing.

[0016] Healing can be defined as a phenomenon involving three successive stages characterized by specific cellular activities that follow a precise, overlapping temporal sequence to advance the repair process.

[0017] Phase 1 - Inflammation or Debridement Phase: Immediately after lesion formation, local blood vessels dilate, causing increased vascular permeability and plasma leakage. This vasodilation is quickly followed by vasoconstriction, followed by the formation of a thrombus at the base of the lesion, particularly due to the action of platelets, which suppresses bleeding. Subsequently, attracted by chemotactic substances, proinflammatory cells (leukocytes and macrophages) arrive from surrounding tissues to cleanse the lesion by removing dead tissue, pathogens, and bacteria. This phase begins between 12 and 24 hours and produces an inflammatory response characterized by redness (erythema), swelling (edema), pain, and local temperature elevation.

[0018] Although necessary, it is important that this inflammatory state not last longer than three days, otherwise the subsequent stages of cell proliferation and new epithelial formation (or epithelialization) may be delayed. However, in some cases, inflammation can be stimulated and sustained by the presence of free radicals, such as reactive nitrogen species (RNS) and reactive oxygen species (ROS). These compounds naturally induce the oxidation of newly synthesized biomolecules in the lesion, thereby delaying the cell regeneration and healing process.

[0019] Stage 2: Sprouting or granulation tissue formation stage: During this stage, connective tissue cells, fibroblasts, appear in large numbers after stimulation and recruitment by macrophages. Fibroblasts produce large amounts of collagen, elastin, and other components of the dermal cellular matrix. At the same time, endothelial cells form sprouts at the ends of damaged capillaries. This overgrowth ceases when granulation tissue compensates for the loss of material and the fibroblasts reach the edge of the lesion.

[0020] Step 3: Epidermalization or Epithelialization: Around day 25 or 30, once the primary scar forms, collagen begins to significantly degrade and remodeling of the primary scar begins. During this stage, the edges of the lesion continue to slowly contract due to the action of myofibroblasts and strengthening of the junction between the epidermis and dermis. As a result, the scar gradually becomes more flexible, smoother, and softer to the touch. This remodeling results in the final scar forming six months to a year or more later.

[0021] The quality of the final scar depends on its size, its location, and especially on the progress of early healing, so care and follow-up during the formation of the primary scar is important.

[0022] Alterations in the primary healing process of acute lesions can lead to the formation of chronic, complex lesions that require specialized care with dressings and materials that allow so-called "directed" healing, or to the formation of abnormal, unsightly scars that may even leave functional sequelae.

[0023] Improperly treated lesions present a significant risk of infection, which in turn affects the healing process. The term "contamination" is used when the damaged tissue is inhabited by bacteria that have not yet multiplied. In contrast, the "colonization" stage involves bacterial proliferation within the lesion. Colonization can progress to "critical colonization" and then to a local infection of the lesion. The bacteria then penetrate deeper into the damaged tissue, where they multiply and cause an inflammatory response. Common symptoms of such infections are fever, rash, pain at the site of the lesion, or increased leukocytosis. By entering the bloodstream, the local infection can develop into a "systemic infection," which can spread throughout the body and, in some cases, develop into acute sepsis, which can lead to the death of the subject.

[0024] In the field of wound care, the choice of dressing plays a decisive role in ensuring the therapeutic effect and in carrying out the care under the required sterile conditions.

[0025] It is clear that the choice of the best treatment will directly depend on the type of wound being treated. To achieve maximum effectiveness, a dressing should ideally combine a number of properties and functions, such as being able to prevent the risk of infection, being able to absorb excess exudate and blood, being able to create or maintain a moist environment around the lesion, being able to promote leukocyte migration, being able to maintain good insulation or being breathable.

[0026] Today, no single dressing has been found that offers such diverse properties, making it necessary to tailor the dressing to the type of lesion or even to change it as the healing process progresses.

[0027] Therefore, there remains a clear need to develop a unique dressing that is capable of treating all types and / or severity grades of skin lesions, particularly radiation dermatitis, with maximum effectiveness. Summary of the Invention [Means for solving the problem]

[0028] The applicant has recognized that a three-dimensional bipolymer matrix is ​​capable of configuring and controlling the conditions (humidity, temperature, pH, oxygen supply) essential for the healing of the lesion, regardless of the type of lesion, its state of development, and / or its state of healing.

[0029] The present invention overcomes the above-mentioned problems of the prior art.

[0030] According to a first aspect, the present invention relates to a three-dimensional bipolymer matrix with biomechanical activity capable of counteracting various physiopathological parameters involved in the development and exacerbation of skin lesions and / or wounds, comprising: - a first polymer network comprising a first colloid (Col-1) non-covalently bound to a cross-linked non-sulfated polysaccharide; and - a second polymer network comprising a second colloid (Col-2) covalently or non-covalently bound to the sulfated polysaccharide; For the purposes of the present invention, the term "colloid" is understood to mean crystalline particles (non-amorphous form) resulting from the ordered stacking of the molecules that compose it. These colloids are sometimes called "quantum dots" or nanocrystals. They may also be in the form of a suspension of colloids in an aqueous medium.

[0031] The concept of binding between Col-1 and Col-2 colloids is part of the general knowledge of those skilled in the art. Binding is the formation of a non-covalent or covalent bond.

[0032] Of course, the non-covalent or covalent bond is not limited to the attachment of a single compound, but may be the attachment of multiple molecules of at least one compound on each nanocrystal.

[0033] The formation of Col-2 / sulfated polysaccharide complexes, particularly the formation of covalent or non-covalent bonds, is carried out according to the knowledge of those skilled in the art.

[0034] In certain embodiments, the second colloid (Col-2) is covalently bound to the sulfated polysaccharide.

[0035] For example, sulfated polysaccharides can be modified by adding thiol groups (RSH). When Col-2 colloid is placed in the presence of the modified sulfated polysaccharide, a covalent bond is formed between the sulfur atom (S) of the thiol group carried by the sulfated polysaccharide and the metal molecule that constitutes the colloid Col-2.

[0036] In a preferred embodiment, the second colloid (Col-2) is non-covalently bound to the sulfated polysaccharide.

[0037] For example, Col-2 colloids may be covalently bound on their surface to an agent capable of positively charging the colloid, preferably cysteamine, thereby allowing the establishment of non-covalent electrostatic interactions between the second colloid (Col-2) and the negatively charged sulfated polysaccharide.

[0038] For the purposes of the present invention, the terms "positively charged" and "negatively charged" are understood to mean the charge presented on the surface of the colloid at neutral, physiological, or acidic pH (pH 3-7).

[0039] Colloids can be synthesized by conventional techniques, for example by the so-called "bottom-up" approach of growing precursors. This synthetic route, commonly used in the field of nanomaterials, involves nucleation and growth steps from isolated atoms, which allows for control of the size of the colloids.

[0040] Col-1 and Col-2 colloids are different from each other, i.e., they are composed of at least one different chemical element. In fact, they do not have the same properties.

[0041] According to a particular embodiment, the Col-1 colloid consists of chemical elements selected from the group comprising Ce, Si, Ge, Sn, Te, B, N, P, As, Al, Sb, Ga, In, Cd, Zn, Cu, Cl, Pb, Tl, Bi, Ti, U, Ba, Sr, Li, Nb, La, I, Mo, Mn, Ca, Fe, Ni, Eu, Cr, Br, Ag, Pt, Hg, and aggregates thereof.

[0042] According to a particular embodiment, the Col-2 colloid consists of a chemical element, preferably a metal, preferably selected from the group comprising Pt, Au, Ni, Cu, Pd and Ag.

[0043] According to a particular embodiment, the metals that make up the Col-2 colloid exhibit an oxidation state of zero.

[0044] According to a particular embodiment, the Col-1 colloid according to the invention is a cerium dioxide (CeO2) colloid.

[0045] According to a particular embodiment, the Col-2 colloid according to the invention is a platinum (Pt) colloid.

[0046] Preferably, the Col-2 colloid has amine groups on its surface.

[0047] For the purposes of this invention, Col-2 colloids have a core made of metal while having a surface with sulfated polysaccharides covalently or non-covalently bound thereto. This is the core / surface type concept. The term "core" does not relate to the core / shell structure.

[0048] The surface of the Col-2 colloid may optionally have an oxide layer, in which case the colloid has a metal core and an oxide surface, which is covalently bound to a sulfated polysaccharide.

[0049] Preferably, the Col-1 colloid is a cerium dioxide (CeO2) colloid and the Col-2 colloid is a platinum (Pt) colloid in the zero oxidation state, preferably with the core being platinum in the zero oxidation state.

[0050] Generally, the average size of the Col-1 colloid and / or Col-2 colloid is on the order of several nanometers to several tens of nanometers.

[0051] Therefore, the size of the Col-1 colloid and / or Col-2 colloid according to the present invention is preferably between 0.1 nm and 1000 nm, more preferably between 0.3 nm and 100 nm, even more preferably less than 10 nm, or even less than 5 nm, and the size is preferably measured by XRD.

[0052] Preferably, the size of the Col-1 colloid is between 0.4 nm and 2 nm.

[0053] Preferably, the size of the Col-2 colloid is 1 to 5 nm, preferably 2 to 3 nm.

[0054] X-ray diffraction (XRD) is a technique traditionally used to measure crystallite size in the solid state.

[0055] The term "size" is understood to mean the largest dimension of the Col-1 and Col-2 colloids, e.g., the diameter in the case of spherical Col-1 and Col-2 colloids. It refers to the number-average size of the non-covalently bound Col-1 colloids and the covalently bound Col-2 colloids. However, the size of the colloids before non-covalent or covalent binding, optionally coated with a polymer such as dextrose, myo-inositol, or polyvinylpyrrolidone (PVP), also falls within the range of values ​​indicated above. Where appropriate, those skilled in the art will be able to adapt the size of the unbound CeO2 colloids and unbound Pt colloids.

[0056] Coating the colloids according to the invention makes it possible to control their growth during their formation, for example in the Col-1 / dextrose or Col-1 / myo-inositol complexes, where dextrose and myo-inositol are responsible for controlling the size of Col-1 particles during their formation.

[0057] For the purposes of the present invention, the term "controlled colloidal growth" is understood to mean a mechanism by which colloids are smaller in size and less polydispersed, i.e., all particles have sizes sufficiently close together to form a narrow distribution around the mean value.

[0058] The colloids according to the invention are preferably spherical.

[0059] The colloid is undoped. Optionally, the colloid may contain an element, preferably a transition metal, which is introduced during the synthesis of the colloid.

[0060] According to a particular embodiment, the molecular weight of the non-sulfated polysaccharides according to the invention is between 1 kDa and 5 million daltons (MDa), preferably between 5 kDa and 1 MDa.

[0061] According to a particular embodiment, the non-sulfated polysaccharide according to the invention is selected from the group comprising alginic acid, hyaluronic acid, guar gum, xanthan gum, acacia gum, pullulan, dextran, and mixtures thereof, preferably alginic acid.

[0062] Preferably, the first polymer network according to the invention is crosslinked by a crosslinking agent which preferably corresponds to a metal, preferably a divalent metal, even more preferably an alkaline earth metal, such as calcium or magnesium, and in particular calcium.

[0063] Preferably, the polymer network according to the invention corresponds to alginate cross-linked by a metal.

[0064] According to a particular embodiment, the weight ratio between crosslinker and non-sulfated polysaccharide is 1-10, preferably 1-4.

[0065] According to a particular embodiment, the mass ratio of Col-1 colloid to non-sulfated polysaccharide is 1:50 to 1:1, preferably 1:15 to 1:5, preferably the mass ratio is 1:10.

[0066] According to one embodiment, in the Col-1 colloid / non-sulfated polysaccharide complex according to the present invention, the Col-1 colloid is a cerium dioxide colloid, and the non-sulfated polysaccharide is selected from the group comprising alginic acid, hyaluronic acid, guar gum, xanthan gum, acacia gum, pullulan, dextran, and mixtures thereof, preferably alginic acid.

[0067] According to a particular embodiment, the molecular weight of the sulfated polysaccharide according to the invention is between 1 and 40 million daltons (MDa), preferably between 5 and 30 MDa, preferably between 15 and 25 MDa.

[0068] According to a particular embodiment, the sulfated polysaccharide according to the invention is selected from the group comprising the compound with the INCI name Aphanothece sacrum polysaccharide; sulfated glycosaminoglycans, such as dermatan sulfate, heparin, heparan sulfate or chondroitin sulfate; glucans; fucans; fucoidans; carrageenans; ulvans; pentosan polysulfates, and mixtures thereof, preferably Aphanothece sacrum polysaccharide.

[0069] According to a particular embodiment, the sulfated polysaccharide according to the invention is aphanothece sacrum polysaccharide (INCI name: aphanothece sacrum polysaccharide) modified by adding thiol groups before contacting it with Col-2 colloids.

[0070] Preferably, the second polymer network according to the invention is crosslinked by a platinum colloid covalently bonded at the surface to Col-2 colloid, preferably in oxidation state zero, INCI name aphanothece sacrum polysaccharide, modified by the addition of thiol groups.

[0071] According to another particular embodiment, the Col-2 colloid, preferably a platinum colloid in oxidation state zero, is covalently bound on its surface to an agent capable of positively charging the colloid, preferably cysteamine, which allows the establishment of non-covalent interactions between the amine groups of the Col-2 according to the invention and the sulfate groups of a sulfated polysaccharide, preferably Aphanothece sacrum polysaccharide (INCI name).

[0072] In the two embodiments described above, the Col-2 colloid may act as a cross-linking agent.

[0073] According to a particular embodiment, the mass ratio of Col-2 colloid to sulfated polysaccharide is 1:50 to 1:1, preferably 1:25 to 1:15, preferably the mass ratio is 1:20.

[0074] According to a particular embodiment, the ratio of non-covalently bound Col-1 colloid to covalently or non-covalently bound Col-2 colloid is between 30:1 and 2:1, preferably between 15:1 and 5:1.

[0075] According to one embodiment, in the Col-2 colloid / sulfated polysaccharide complex according to the present invention, the Col-2 colloid is a platinum colloid and the sulfated polysaccharide is selected from the group comprising a compound having the INCI name aphanothece sacrum polysaccharide; a sulfated glycosaminoglycan, such as dermatan sulfate, heparin, heparan sulfate or chondroitin sulfate; a glucan; a fucan; a fucoidan; a carrageenan; an ulvan; a pentosan polysulfate; and mixtures thereof, preferably aphanothece sacrum polysaccharide.

[0076] According to a particular embodiment, the three-dimensional bipolymer matrix according to the invention comprises water.

[0077] According to another particular embodiment, the Col-1 colloid non-covalently bound to the non-sulfated polysaccharide represents 0.01% to 1% by weight of the bipolymer matrix according to the invention, while the Col-2 colloid covalently or non-covalently bound to the sulfated polysaccharide represents 0.001% to 0.1% by weight and the water represents 70% to 99% by weight.

[0078] According to a particular embodiment, the bipolymer matrix according to the invention comprises: - Cerium dioxide colloid; - alginate; - calcium carbonate; - zero-oxide platinum colloid, preferably platinum whose core exhibits the zero oxidation state; - Polyvinylpyrrolidone; gluconic acid or gluconolactone, preferably gluconolactone; - Aphanothece sacrum polysaccharide (INCI name: aphanothece sacrum polysaccharide) modified by adding thiol groups; and - water Contains:

[0079] According to a preferred embodiment, the bipolymer matrix according to the invention comprises: - Cerium dioxide colloid; - alginate; - calcium carbonate; - zero-oxide platinum colloid, preferably platinum whose core exhibits zero oxidation state and which has been modified by the addition of cysteamine; - Gluconolactone; - Aphanothece sacrum polysaccharide (INCI name) and - water Contains:

[0080] According to another aspect, the present invention relates to a matrix as defined above for use as a dressing for preventing and / or healing skin lesions.

[0081] According to other embodiments, the skin lesions are dry or weeping.

[0082] According to another aspect, the present invention relates to a matrix as defined above for use as a dressing for preventing and / or treating radiation dermatitis.

[0083] According to another embodiment, the radiation dermatitis is of the dry to exudative grade.

[0084] In other words, these are grade 1, 2, or 3 radiation dermatitis.

[0085] In particular, the bipolymer matrix according to the invention corresponds to an intertwining of two crosslinked networks, creating a favorable environment (humidity, temperature, pH, oxygen supply, antibacterial and antioxidant functions) around the lesion to prevent its deterioration and / or accelerate its healing.

[0086] Preferably, the bipolymer matrix according to the invention corresponds to a matrix crosslinked by ionic bonds.

[0087] When a lesion is present, the bipolymer matrix of the present invention, when used as a dressing, ensures a moist environment that is favorable to the rate and quality of healing. This moist environment is conducive to the division and migration of newly formed cells, particularly during the epithelialization stage. Moisturizing the lesion also prevents the formation of superficial scabs that delay healing and protects the patient from certain adverse side effects, such as mild sagging at the lesion site.

[0088] Furthermore, the bipolymer matrix for use according to the invention allows the lesion to be maintained at a temperature close to body temperature, i.e., approximately 37°C, ensuring optimal conditions for efficient proliferation of keratinocytes and for enzymatic reactions to occur.

[0089] The bipolymer matrix for use according to the present invention ensures that a pH of 7 to 7.6 is maintained, thus ensuring epithelial proliferation while inhibiting the growth of pathogens in the lesion.

[0090] The bipolymer matrix for use according to the invention functions as a physical barrier, a role that the skin naturally has but which it can no longer perform after injury. The dressing according to the invention provides oxygenation, i.e., gas exchange, between the lesion and the external environment, which is essential for healing.

[0091] The bipolymer matrix for use according to the invention has an effective and importantly high absorption capacity for bleeding and exudate from the lesion, so that the dressing according to the invention does not need to be changed frequently and does not interfere with the process of epidermal remodeling.

[0092] According to the invention, alginic acid and compounds corresponding to the INCI name aphanothece sacrum polysaccharide allow the absorption of fluids and exudates, contribute to mechanical strength and elasticity, and play an insulating role by maintaining the temperature and pH of the lesion.

[0093] At the same time, the complex formed by the Col-1 colloid of CeO2 non-covalently bound to alginate has an antioxidant effect in controlling inflammation without completely suppressing it. In other words, this complex allows eliminating, reducing or inhibiting the synthesis of free radicals of the RNS and / or ROS type, whose continuous synthesis can lead to the chronicity of the lesion.

[0094] Furthermore, the complexes formed by Col-2 colloids, preferably Pt Col-2 colloids, covalently or non-covalently bound to Aphanothece saccharin polysaccharides have antibacterial properties.

[0095] The three-dimensional bipolymer matrix according to the present invention, when used as a dressing, is more effective and longer-lasting in preventing and / or healing skin lesions, particularly radiation dermatitis.

[0096] The three-dimensional bipolymer matrix of the present invention is also more economical to use as a dressing because it requires fewer changes and is therefore less traumatic to the lesion being treated because it reduces tearing of new epithelial cells as they are forming.

[0097] Furthermore, the three-dimensional bipolymer matrix of the present invention, when used as a dressing, offers an alternative to hospitalization of the patient, allowing the patient's healing progress to be monitored remotely by traditional telemedicine means.

[0098] Indeed, in an innovative way, when the lesion becomes infected, the proliferation of the bacterial population causes a change in pH, preferably an increase in pH. This is followed by a change in the valence electron level of the cerium, which causes the matrix to change color from clear to, for example, orange, indicating the need to change the dressing and / or treat the lesion infection to ensure proper healing and reduce the risk of complications (such as sepsis) in the subject.

[0099] Furthermore, the transparent structure of the bipolymer matrix according to the present invention allows the physician to easily monitor the healing progress, possibly remotely, and identify possible complications in real time.

[0100] The three-dimensional bipolymer matrices and dressings according to the present invention are - Non-toxic and non-allergenic - It can effectively protect the lesion from the external environment, - It can prevent the risk of infection, - Absorbs excess exudate and blood, - Create or maintain a moist environment around the lesion, - accelerate and improve healing, - Maintains excellent insulation around the lesion to improve blood flow and epidermal cell migration; - Breathable, allowing gas exchange between the lesion and its environment - Maintaining pH at a level that promotes epithelial growth while suppressing biological growth in the lesion; - Easy to remove without adhering to the lesion, - Providing long-term use, i.e. more economical and less traumatic to the lesion, - Absorption properties intermediate between hydrogel and hydrocolloid dressings; - Protective and - It has antioxidant properties, - It is antibacterial It has several features and functions that allow

[0101] According to another aspect, the present invention relates to a method for preparing a three-dimensional bipolymer matrix as defined above, comprising the steps of: - a solution (A) comprising Col-1 colloid non-covalently bound to a non-sulfated polysaccharide, a source of a divalent metal, preferably an alkaline earth metal, and Col-2 colloid non-covalently bound at its surface to a biocompatible polymer; and - Solution (B) containing an acidifying agent and a sulfated polysaccharide This invention relates to a method for producing a three-dimensional bipolymer matrix using

[0102] According to a preferred embodiment, the present invention relates to a method for producing a three-dimensional bipolymer matrix as defined above, comprising the steps of: - a solution (A) comprising Col-1 colloids non-covalently bound to a non-sulfated polysaccharide, a source of a divalent metal, preferably an alkaline earth metal, and Col-2 colloids covalently bound at their surface to an agent capable of positively charging the colloid, preferably cysteamine; and - Solution (B) containing an acidifying agent and a sulfated polysaccharide This invention relates to a method for producing a three-dimensional bipolymer matrix using

[0103] The bipolymer matrix according to the invention is obtained by mixing solutions (A) and (B).

[0104] Preferably, the two solutions (A) and (B) are mixed in a ratio of 4 / 5 solution (A) and 1 / 5 solution (B).

[0105] According to a particular embodiment, in the solutions (A) and (B) carried out in the method according to the invention, - Col-1 colloid is a cerium dioxide colloid, - Non-sulfated polysaccharides are alginates, the source of divalent metal, preferably alkaline earth metal, is a calcium salt, preferably calcium carbonate; - Col-2 colloid is a platinum colloid in the zero oxidation state, preferably platinum whose core exhibits the zero oxidation state, - the biocompatible polymer is polyvinylpyrrolidone, the acidifying agent is gluconic acid or gluconolactone, preferably gluconolactone; - Sulfated polysaccharides are compounds modified by the addition of thiol groups and have the INCI name aphanothece sacrum polysaccharide.

[0106] According to another particular embodiment, in the solutions (A) and (B) carried out in the method according to the invention, - Col-1 colloid is a cerium dioxide colloid, - Non-sulfated polysaccharides are alginates, the source of divalent metal, preferably alkaline earth metal, is a calcium salt, preferably calcium carbonate; Col-2 colloid is a platinum colloid in the zero oxidation state, preferably platinum in the core exhibiting the zero oxidation state, covalently bonded to cysteamine at the surface; - The acidifying agent is gluconolactone, - Sulfated polysaccharides correspond to the compound with the INCI name aphanothece sacrum polysaccharide.

[0107] According to the present invention, after mixing of the two solutions (A) and (B), the polymer network crosslinks and entangles without interacting with each other, forming, through a plasticizing effect, a three-dimensional bipolymer matrix in the form of a gel, which covers the lesion to be treated and maintains a protective and breathable film around the lesion.

[0108] Preferably, the bipolymer matrix according to the invention corresponds to a gel crosslinked by ionic bonds.

[0109] According to another aspect, the invention relates to an apparatus for carrying out the method according to the invention.

[0110] According to a particular embodiment, the two solutions (A) and (B) are packaged in a bottle, a sprayer, a syringe, or a single-dose vial.

[0111] According to another particular embodiment, the two solutions (A) and (B) are packaged in a two-compartment container.

[0112] According to a particular embodiment, the device according to the invention comprises: - solution (A) has a pH of 7 and comprises Col-1 colloid non-covalently bound to a non-sulfated polysaccharide, a source of a divalent metal, preferably an alkaline earth metal, and Col-2 colloid covalently bound to a biocompatible polymer; - Solution (B) has a pH of 3 and contains an acidifying agent and a sulfated polysaccharide It is characterized by:

[0113] According to another particular embodiment, the device according to the invention comprises: - solution (A) has a pH of 7 and comprises Col-1 colloid non-covalently bound to a non-sulfated polysaccharide, a source of a divalent metal, preferably an alkaline earth metal, and Col-2 colloid covalently bound to cysteamine; - Solution (B) has a pH of 3 and contains an acidifying agent and a sulfated polysaccharide It is characterized by:

[0114] According to a particular embodiment, in the solutions (A) and (B) implemented in the device according to the invention: - Col-1 colloid is a cerium dioxide colloid, - Non-sulfated polysaccharides are alginates, the source of divalent metal, preferably alkaline earth metal, is a calcium salt, preferably calcium carbonate; - Col-2 colloid is a platinum colloid in the zero oxidation state, preferably platinum whose core exhibits the zero oxidation state, - the biocompatible polymer is polyvinylpyrrolidone, the acidifying agent is gluconic acid or gluconolactone, preferably gluconolactone; - Sulfated polysaccharides are compounds modified by the addition of thiol groups and have the INCI name aphanothece sacrum polysaccharide.

[0115] Examples of dual compartment containers suitable for forming matrices according to the present invention include: - a two-compartment syringe consisting of a 42 ml double syringe (product code: D-KART-050-04) specially designed for a 4:1 ratio, a static mixer L212 (product code: M-50-212), and a 4:1 double syringe gun (product code: PIST-50-4:1) sold by Doseurope, or - Two-compartment Easymix Tube sold by Neopac There is.

[0116] According to a preferred embodiment, in the solutions (A) and (B) implemented in the device according to the invention: - Col-1 colloid is a cerium dioxide colloid, - Non-sulfated polysaccharides are alginates, the source of divalent metal, preferably alkaline earth metal, is a calcium salt, preferably calcium carbonate; Col-2 colloid is a platinum colloid in the zero oxidation state, preferably platinum whose core exhibits the zero oxidation state, covalently bonded to cysteamine; - The acidifying agent is gluconolactone, - Sulfated polysaccharides are compounds that have the INCI name aphanothece sacrum polysaccharide.

[0117] The invention and the advantages arising therefrom will become clearer from the following figures and examples, given to illustrate the invention but not to limit it. [Brief explanation of the drawings]

[0118] [Figure 1] 1 is a graph showing a diffractogram of CeO2 colloid before non-covalent bonding with alginate. [Figure 2] 1 is a graph showing the diffractogram of Pt colloid before covalent bonding with Aphanothece sacrum polysaccharide (INCI name) modified by the addition of thiol groups. [Figure 3] 1 is a graph showing the ABTS degradation activity (in %) of a bipolymer matrix according to the invention as a function of time (in minutes) in comparison with two commercial products. DETAILED DESCRIPTION OF THE INVENTION

[0119] 1 / Synthesis of cerium dioxide colloid (Col-1) according to the present invention Dissolve 0.1-2 mmol of dextrose or myo-inositol and 0.5-5 equivalents of a cerium dioxide precursor, such as cerium chloride, in 10-100 mL of water. Upon dissolution, add 1-10 equivalents of ammonia. Continue stirring the solution for 1-5 hours. Add acetone as an antisolvent and purify by centrifugation. Redisperse the pellet in water to the desired concentration.

[0120] This synthesis method results in cerium dioxide coated with dextrose or myo-inositol, where the dextrose and myo-inositol control the particle size and narrowly distribute the particle sizes around the average size.

[0121] 2 / Synthesis of platinum colloid (Col-2) according to the present invention for covalent binding to sulfated polysaccharides A solution is prepared by dissolving 0.1 to 10 mmol of gluconolactone in 10 to 100 mL of water, and then heating to reflux.

[0122] Once reflux is reached, 0.01-10 mmol of a colloidal platinum precursor salt such as chloroplatinic acid and 0.001-1 mmol of polyvinylpyrrolidone (PVP) dissolved in 10-100 mL of water are added to the reaction medium.

[0123] The solution is refluxed for 1 to 5 hours.

[0124] The solution is then cooled to room temperature, acetone is added as an antisolvent, and purified by centrifugation. The pellet is then redispersed in water to the desired concentration.

[0125] This synthesis method results in platinum colloids dispersed in PVP, which can be covalently bound to sulfated polysaccharides according to the invention, such as Aphanothece sacrum polysaccharide (INCI name) modified by the addition of thiol groups, the semisynthesis of which is described in Example 3.

[0126] 3 / Semisynthesis of Aphanothece sacrum polysaccharide (INCI name: aphanothece sacrum polysaccharide) modified by the addition of thiol groups 10~100×10 -7 Dissolve 1 mmol of Aphanothece saccharin polysaccharide in 10-100 mL of water and stir the solution.

[0127] 100,000~100,000,00×10-7 Add 1 mmol of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride. Continue stirring the solution for 10-100 min.

[0128] 1,000,000 to 100,000,000 x 10 -7 Add 1 mmol of cysteine ​​and continue stirring the solution until the solid dissolves. Adjust the pH to 4.

[0129] The solution is stirred for 6 to 24 hours, and then the pH is adjusted to 6.

[0130] To precipitate the Aphanothece saccharin polysaccharides modified by the addition of thiol groups, the solution is poured into approximately 10 times its volume of ethanol, and the compound is recovered by centrifugation. It is then dissolved in a small amount of water (1-5% by weight solution) and freeze-dried.

[0131] 4 / Synthesis of platinum colloid (Col-2) according to the present invention for non-covalent binding with sulfated polysaccharides Dissolve 0.1–10 mmol of gluconolactone in 10–100 mL of water and heat the solution to reflux.

[0132] Once reflux is reached, 0.1 to 1 equivalent of a colloidal platinum precursor salt such as chloroplatinic acid and 0.01 to 0.1 equivalent of polyvinylpyrrolidone (PVP) dissolved in 10 to 100 mL of water are added to the reaction medium.

[0133] The solution is refluxed for 1-5 hours. The solution is cooled to room temperature and 0.1-1 equivalents of cysteamine hydrochloride is added. The solution is stirred for 1-5 hours, and then acetone is added as an antisolvent and purified by centrifugation. The pellet is then dispersed in water to the desired concentration.

[0134] The synthesis method results in platinum colloids dispersed in PVP, modified by the addition of cysteamine. These colloids can non-covalently bind (Coulombic interactions) to sulfated polysaccharides, such as Aphanothece sacrum polysaccharide (INCI name).

[0135] 5 / CeO2 / alginic acid colloid and Pt / Aphanothece saccharin polysaccharide colloid according to the present invention The small size of the CeO2 and Pt particles allows for a large surface area to be covered, thus allowing many molecules to be attached to the surface of each particle.

[0136] The diffractogram was measured by transmitting the powder through an XRD using a Cu-Kα radiation source.

[0137] Figure 1 shows the diffractogram of the CeO2 colloid before non-covalent bonding with alginate.

[0138] Figure 2 shows the diffractogram of Pt colloid before covalent bonding with Aphanothece saccharin polysaccharides modified by the addition of thiol groups.

[0139] 6 / Method for producing the bipolymer matrix according to the invention The two solutions (A) and (B) are mixed in a ratio of 4 / 5 solution (A) and 1 / 5 solution (B).

[0140] Solution (A) comprises the CeO colloid according to the invention obtained from Example 1, alginic acid, calcium carbonate, the Pt / Aphanothece saccharin polysaccharide colloid according to the invention obtained from the mixture of reactions described in Examples 2 and 3, and water.

[0141] Solution (B) contains natural (unmodified) aphanothece sacrum polysaccharide (INCI name: aphanothece sacrum polysaccharide) and gluconolactone dispersed in water.

[0142] Alternatively, solution A contains the CeO2 colloid according to the present invention obtained from Example 1, alginic acid, calcium carbonate, platinum colloid according to Example 4, natural (unmodified) Aphanothece sacrum polysaccharide (INCI name: aphanothece sacrum polysaccharide), and water, and solution B contains the natural (unmodified) Aphanothece sacrum polysaccharide and gluconolactone dispersed in water.

[0143] After mixing, a three-dimensional bipolymer matrix according to the present invention is formed within minutes (1-5 minutes) or seconds (less than 1 minute) by entanglement of the two crosslinked polymer networks according to the present invention.

[0144] 7 / Determination of the antioxidant activity of the three-dimensional bipolymer matrix according to the invention The bipolymer matrix according to the present invention comprises: - Col-1 colloid non-covalently bound to alginate in an amount representing 0.01 to 1% by weight of the matrix; - Col-2 colloid covalently bound to Aphanothece sacrum polysaccharides modified by the addition of thiol groups, in an amount representing 0.001 to 0.1% by weight of the matrix, and - Water in an amount representing 70 to 99% by mass of the matrix Includes.

[0145] A 14 mM stock solution of ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) is incubated with an equal volume of a 4.9 mM aqueous solution of ammonium persulfate to generate cationic ABTS radicals. The reaction mixture is incubated at room temperature in the dark for 16 hours. The resulting solution is diluted 1 / 100 with phosphate buffer (0.2 M, pH 7.4) containing 150 mM NaCl to an absorbance of 1.5 at 734 nm.

[0146] Samples of different masses between 1.2 and 12 mg of the three-dimensional bipolymer matrix according to the invention are dispersed in water at 240 g / L and added to 2970 μL of a 0.07 mM cationic ABTS aqueous solution, then placed in the dark while stirring.

[0147] After 30 minutes of incubation, ABTS is completely degraded.

[0148] The product was mixed with 3000 μL of the ABTS solution prepared above in a polymethyl methacrylate ultraviolet (UV) spectrophotometer vessel. The reaction mixture was incubated at room temperature in the dark for 30 minutes. The absorbance was then measured every 20 minutes.

[0149] The antioxidant properties of the bipolymer matrix according to the present invention were compared with two commercially available products: Nu-Gel® dressings, which correspond to hydrogels containing sodium alginate, for dry, fibrotic or necrotic sores; Flaminal Hydro® dressing, which corresponds to a gel containing alginic acid and an antibacterial enzyme system Compare with.

[0150] The data are shown in Figure 3.

[0151] The results show that after 120 hours, approximately 85% of ABTS is degraded by the bipolymer matrix according to the present invention, while the Nu-Gel® and Flaminal Hydro® dressings degrade approximately 18% and 27% of ABTS, respectively.

[0152] In conclusion, the antioxidant activity of the solution containing the bipolymer matrix according to the invention is exponentially greater than that of the two commercial dressings.

[0153] 8 / Determination of the absorption capacity of exudates by the three-dimensional bipolymer matrix according to the invention The ability of the bipolymer matrix of the present invention to absorb exudate was compared to various commercially available products indicated for the treatment of exudative or highly exudative sores.

[0154] The exudate solution is prepared by mixing 50 mL of fetal bovine serum with 50 mL of diluent containing 0.1% peptone and 0.9% sodium chloride. The sheet dressing is 1.98 cm 2 The gel dressing is cut to an area of ​​1.98 cm 2 Pour to cover the area.

[0155] Each sample is placed in a 3 cm diameter Petri dish and weighed (m0). Each dressing is covered with 4 mL of exudate, the Petri dish is sealed, and it is stored at 21°C for 72 hours. Any remaining exudate is removed from each dish, and each sample is reweighed (m1).

[0156] The exudate absorption capacity of each dressing was calculated using the following formula:

[0157]

number

[0158] is determined by.

[0159] The results are shown in Table 1 below.

[0160] [Table 1]

[0161] The results showed that hydrofiber and hydrocellular dressings, which are indicated for exudative or highly exudative sores, absorbed 65-100 g / cm of exudate. 2 and has better absorbency.

[0162] Hydrogel type sheet dressings are 10-35g / cm 2 Absorbs exudates.

[0163] Hydrocolloid-type dressings, indicated for the treatment of poorly exuding sores, are available in a dose of 20-30 g / cm 2 Absorbs exudates.

[0164] The bipolymer matrix according to the present invention has a density of 15 g / cm 2 The exudate is absorbed and placed into a hydrogel-type sheet dressing. The two commercially available hydrogels evaluated (Intrasite Conformable and Hydrotac) were partially or completely dissolved in the exudate, making this the only liquid-form sheet hydrogel that survived the exudate absorption test.

[0165] This is because the cross-linking of the bipolymer matrix according to the present invention allows the dressing to absorb exudate while maintaining its shape.

[0166] Furthermore, absorption of exudate occurs slowly and gradually, allowing for reorganization of the bipolymer matrix. In contrast, the commercial products tested absorb exudate like a sponge. As a result, after saturation, these products can no longer absorb exudate and are therefore no longer effective.

Claims

1. - a first polymer network comprising a first colloid (Col-1) non-covalently bound to a cross-linked non-sulfated polysaccharide; and - a second crosslinked polymer network comprising a second colloid (Col-2) covalently or non-covalently bound to the sulfated polysaccharide; A three-dimensional bipolymer matrix combining The Col-1 colloid is a cerium dioxide colloid, the non-sulfated polysaccharide is alginic acid, The Col-2 colloid is a platinum colloid, and the sulfated polysaccharide is a compound whose INCI name is aphanothece sacrum polysaccharide. Three-dimensional bipolymer matrix.

2. 2. The matrix according to claim 1, characterized in that a second colloid (Col-2) is non-covalently bound to the sulfated polysaccharide.

3. 3. A matrix according to claim 1 or 2 for use as a dressing for preventing and / or healing skin sores.

4. 4. A matrix for use according to claim 3, characterized in that the lesions are dry or exudative.

5. 3. A matrix according to claim 1 or 2 for use as a dressing for preventing and / or treating radiation dermatitis.

6. 6. The polymer matrix for use according to claim 5, wherein the radiation dermatitis is of dry to exudative grade.

7. 5. A method for producing a three-dimensional bipolymer matrix according to any one of claims 1 to 4, comprising the steps of: a solution (A) comprising Col-1 colloids non-covalently bound to a non-sulfated polysaccharide, a source of a divalent metal, and Col-2 colloids covalently bound to cysteamine at their surface; and - Solution (B) containing an acidifying agent and a sulfated polysaccharide The method is characterized in that it is obtained by mixing

8. the non-sulfated polysaccharide is alginic acid; the source of the divalent metal is a calcium salt; - Col-2 colloid is a zero oxidation state platinum colloid with a zero oxidation state core and covalently bonded cysteamine to the surface; - the acidifying agent is gluconolactone, - The sulfated polysaccharide is a compound that corresponds to the INCI name Aphanothece sacrum polysaccharide.

8. The method according to claim 7.

9. 9. The method according to claim 7 or 8, characterized in that the two solutions (A) and (B) are mixed in a ratio of 4 / 5 of solution (A) to 1 / 5 of solution (B).

10. A two-compartment container, - one compartment comprises Col-1 colloid non-covalently bound to a non-sulfated polysaccharide, a source of a divalent metal, and Col-2 colloid covalently bound to cysteamine; - Other compartments contain acidifiers and sulfated polysaccharides Apparatus for carrying out the method according to any one of claims 7 to 9, characterized in that

11. - Solution (A) has a pH of 7, - Solution (B) has a pH of 3 11. The device according to claim 10, characterized in that

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