Skin-compatible radio-contrast nano-composite hydrogel formulation.

Abstract

The invention specifically relates to a carbomer-based polymeric matrix reinforced with bismuth nanoparticles of high atomic number to selectively absorb X-rays and enhance tissue contrast (visibility), and a hydrogel formulation containing a synergistic antioxidant system (Melatonin and Vitamin E) to neutralize free radicals generated by radiation in the skin, thereby preventing cellular damage and radiation burns, as well as the related formulation production method.

Description

Skin-compatible radio-contrast nano-composite hydrogel formulation. Technical Area The invention is relevant to X-ray based imaging techniques such as mammography, computed tomography, and glossoscopy. used as contrast agents and radioprotectors in diagnostic imaging methods Improving quality while also protecting against the harmful effects of ionizing radiation. providing, externally applied (topical), non-invasive, nano- It relates to a medical hydrogel formulation with a composite structure. The invention specifically improves tissue contrast (visibility) by selectively absorbing X-rays. enhanced with bismuth nanoparticles having a high atomic number to increase its effectiveness a carbomer-based polymeric matrix and free radicals formed by radiation in the skin to neutralize and prevent cellular damage and radiation burns, with synergistic effects. Hydrogel formulation containing antioxidant system (Melatonin and Vitamin E) and related Formulation is related to the production method. State of the Art In the current radiology and clinical radiation diagnostic and treatment sector, there are four fundamental technical problems, and Clinical shortcomings limit patient safety and diagnostic accuracy. These limitations include invasiveness. Systemic risks posed by contrast agents, radioprotection, and diagnostic imaging. The "contrast" paradox between them, the diagnostic inadequacy of existing hydrogels, and ionizing radiation on the skin. These can be listed as oxidative damage on the surface. To detail the systemic risks posed by invasive contrast agents, computerized... In X-ray based imaging methods such as computed tomography (CT) and angiography, soft tissue Current iodine and gadolinium-based agents used to enhance contrast are administered intravenously. It must be administered intravenously. This "invasive" application method is particularly important for the elderly, the risk of "contrast-induced nephropathy (CIN)" in diabetic and renal failure patients While increasing the risk, it can lead to serious allergic reactions, including anaphylactic shock. And Each application requires a painful procedure that reduces patient comfort. The current In applications, it is non-invasive (topical / surface), does not enter the systemic circulation, and only... There is no safe alternative that provides contrast enhancement in the target area. 35 When we examine the "contradiction" paradox between radioprotection and diagnostic imaging, Current radiation protection technologies (lead aprons, bismuth shields) block X-rays. It operates by completely blocking access, resulting in "the protected area being unviewable". This gives rise to the problem. A doctor may examine a specific area of ​​the patient (e.g., thyroid, breast) While imaging, it cannot simultaneously protect that area from the harmful effects of radiation. Current protective coatings show "beam hardening" and metal artifacts in the image. This impairs diagnostic quality. It allows for both diagnostic imaging. (Radiolucent properties) and at the same time reduce the biological damage of radiation. There is a lack of a "hybrid" material (with radioprotective properties). The diagnostic inadequacy of current hydrogels can be explained as follows: They are commonly used in hospitals. Ultrasound gels used as such (e.g., Aquasonic 100) are designed solely to transmit sound waves. These gels have been designed with an X-ray attenuation coefficient equivalent to that of water (approximately 0). Hounsfield Unit). Therefore, in mammography or superficial tissue CT scans They do not provide any contrast enhancement when used. Breast skin, subcutaneous masses. or superficial lesions are indistinguishable from surrounding tissues. In the known technique, topical an "active" hydrogel that can increase tissue contrast (signal-to-noise ratio) when applied. The formulation is not currently available. To elaborate on the limitation of ionizing radiation on oxidative damage to the skin, diagnostic... In radiology and radiotherapy, the "Entrance Skin Dose" (ESD) is the dose to which the skin is exposed. The formation of Free Radicals (Reactive Oxygen Species - ROS) as a result of radiolysis of water. This triggers DNA breaks and leads to acute radiodermatitis (radiation burn). They can open them. Current medical gels contain antioxidants that neutralize these free radicals. It lacks defense mechanisms and only has a hydration function. It is seen but does not provide protection at the cellular level. The solutions offered under the current state of the art are insufficient. Existing practices... either "imaging but not protecting" (invasive contrasts) or "protecting but not protecting" It offers solutions that "block viewing" (lead shields). These two functions benefit the patient. combining them in a single formulation, in a non-invasive way, without compromising safety. a technology does not currently exist. Consequently, due to the aforementioned drawbacks and shortcomings, the relevant technical... The need for innovation in this field has emerged. 35. Purpose of the Invention 3 The present invention meets the aforementioned requirements while eliminating all disadvantages. a skin-compatible radio-contrast nano-composite structure that removes and offers some additional advantages It relates to hydrogel formulation. The invention is intended to improve X-ray based imaging techniques such as mammography, computed tomography, and glossoscopy. used as contrast agents and radioprotectors in diagnostic imaging methods Improving quality while also protecting against the harmful effects of ionizing radiation. providing, externally applied (topical), non-invasive, nano- The aim is to develop a composite medical hydrogel formulation. The aim of the invention is to create a product containing bismuth nanoparticles that can be applied topically to the skin. X-ray based imaging with a carbomer-based nano-composite hydrogel formulation. methods to increase tissue contrast and also with melatonin and vitamin E a medical compound that helps reduce radiation-induced oxidative skin damage It is about developing. The aim of the invention is to combine imaging and protection functions in a single topical product. A new hydrogel that provides clear diagnosis, less radiation, and higher patient safety. The goal is to present the formulation. The aim of the invention is to combine bismuth nanoparticles with a high atomic number (Z=83). a reinforced, rheologically optimized carbomer-based hydrogel matrix and Hydrogel formulation containing a synergistic antioxidant system (Melatonin and Vitamin E). to provide. The aim of the invention is to use bismuth with a high atomic number (Z=83), unlike traditional passive gels. By enhancing X-ray attenuation in the skin and superficial tissues thanks to its nanoparticles especially in mammography patients with dense breast tissue and in thyroid CT scans The aim is to increase the visibility of the lesion and the sharpness of its boundaries. One aim of the invention is to reduce metal artifacts and ray hardening created by lead shields. (beam hardening) is eliminated. One aim of the invention is to adapt to skin contours at the micron level thanks to its gel form. 35 (conformal coating), a coating that prevents image distortions caused by air gaps. The goal is to obtain a hydrogel formulation. 4 One aim of the invention is to prevent radiation from affecting tissue through its melatonin and vitamin E complex content. It neutralizes the free radicals (ROS) that it produces within seconds, thereby protecting DNA. a molecular-level inhibitor that prevents fractures and the risk of acute radiodermatitis (radiation burns) The goal is to provide a hydrogel formulation. Another aim of the invention is to reduce the risk of renal insufficiency (CIN) by not entering the systemic circulation. A hydrogel formulation was obtained that can be safely used in non-diabetic and elderly patients. to do. Another aim of the invention is that it is painless and does not require needle-based procedures, and uses standard ultrasound gel. The goal is to offer a hydrogel formulation that is easy to apply and clean. To achieve the purposes described above, the invention is used in mammography, computed tomography, Contrast agents and radioprotectors in X-ray-based imaging methods such as glossoscopy. Used to improve diagnostic imaging quality while simultaneously reducing ionizing radiation. Topical (externally applied to the skin) non-invasive drugs that provide protection against harmful effects. It is a non-invasive, nano-composite medical hydrogel formulation with the characteristic of being X- by selectively absorbing light rays to increase tissue contrast (visibility), high a carbomer-based polymeric compound reinforced with bismuth nanoparticles having an atomic number neutralizes free radicals created by the matrix and radiation on the skin, thus preventing cellular damage. and to prevent radiation burns, a synergistic antioxidant system (Melatonin and E) It contains vitamin C. To achieve the purposes described above, the invention is used in mammography, computed tomography, Contrast agents and radioprotectors in X-ray-based imaging methods such as glossoscopy. Used to improve diagnostic imaging quality while simultaneously reducing ionizing radiation. Topical (externally applied to the skin) non-invasive drugs that provide protection against harmful effects. Production of a non-invasive, nano-composite medical hydrogel formulation It is a method, and its characteristic is;  To perform in-situ synthesis of nanoparticles, bismuth nitrate solution, With reducing agents such as sodium borohydride or ascorbic acid at a frequency of 40 kHz and 100 Reacting under ultrasonic cavitation at a power of W for 30 minutes,  By coating nanoparticle surfaces, the zeta potential is increased from +5 mV to +18 mV. To increase the charge to level 35 and ensure steric stabilization, the resulting nanoparticles 3% by weight of polysorbate 80 was added to the suspension and stored at 25 °C for 300 minutes. Mixing at RPM speed for 2 hours, 5  Carbomer to ensure homogeneous distribution of nanoparticles within the polymer network 940 powder (1.5% wt) is left to swell in deionized water for 24 hours. subsequently the stabilized nanoparticle suspension is added to the aforementioned swollen polymer. by adding to the solution at a rate of 10 mL / min and maintaining a speed of 3000 RPM for 15 minutes. processing,  0.5% triethanolamine (TEA) is added to the resulting mixture to raise the pH to 7.0. by bringing it in and initiating the gelling process,  The resulting gel is cooled to +4 °C, and heat-sensitive melatonin and vitamin E are produced. The complex is added to the gel by mixing at 100 RPM, It includes the steps involved in the process. The structural and characteristic features and all the advantages of the invention are described in detail below. This will make it clearer, and therefore the evaluation will also be based on this detail. This should be done taking the explanation into consideration. Detailed Description of the Invention This detailed explanation describes a skin-compatible radio-contrast nano-composite hydrogel. the formulation is solely for the purpose of better understanding the subject and has no limiting effects. It is explained in a way that will not create a problem. The invention is relevant to X-ray based imaging techniques such as mammography, computed tomography, and glossoscopy. used as contrast agents and radioprotectors in diagnostic imaging methods Improving quality while also protecting against the harmful effects of ionizing radiation. providing, externally applied (topical), non-invasive, nano- The invention relates to a medical hydrogel formulation with a composite structure. The characteristic feature of the invention is its high atomic volume. a carbomer-based polymeric compound reinforced with bismuth nanoparticles having the number It contains a matrix and a synergistic antioxidant system (Melatonin and Vitamin E). (Existing) Unlike other applications, it does not need to be administered intravenously but only to the target area. This gel, applied topically, selectively absorbs X-rays, thus providing tissue contrast. While increasing (its visibility), it also protects against radiation thanks to the antioxidants it contains. It neutralizes free radicals formed in the skin, thus preventing cellular damage and radiation. It prevents burns. The invention combines diagnostic clarity and biological protection in a single product. It is a "smart" radiological material. 35 6 The medical hydrogel formulation described in the invention contains bismuth nanoparticles and is an active radio-contrast agent. phase, carbomer 940 phase forming the polymeric carrier matrix and biological protection complex It has a hybrid structure consisting of the integration of three main phases, including an antioxidant phase. Image contrast is based on the difference in the Linear Attenuation Coefficient (u) between the tissues. The bismuth element used in this invention has a high atomic number, 20-120 keV. It maximizes the photoelectric effect cross-section for photons in the energy range. The photoelectric effect is directly proportional to the cube of the atomic number (Z) (interaction probability Z^3 / E^3). (proportional to). This feature increases the Hounsfield Unit (HU) value and improves soft tissue. It improves contrast. The invention enables the use of nanoparticles with a size range of 1-100 nm, compared to macroscopic materials. It utilizes surface area / volume ratio and quantum effects. Hydrogel formulation, Zeta Potential (absolute value > 30 mV) and Steric Stabilization of Nanoparticles By ensuring homogeneous distribution within the hydrogel matrix using these principles, it prevents artifacts in the image. It prevents the formation of radiation and increases the efficiency of X-ray attenuation. Approximately 70% of the damage caused by ionizing radiation to biological tissues occurs in water. It is known to be caused by free radicals formed as a result of radiolysis. This indirect damage In order to prevent this, the harmful hydroxyl groups that are formed in the hydrogel formulation subject to the invention are eliminated. melatonin, which scavenges (OH) radicals and cell membrane lipid peroxidation. a combined antioxidant defense mechanism containing vitamin E (tocopherol) that blocks It is used. Production of the hydrogel formulation subject to the invention: The production of the hydrogel formulation described in the invention involves the "in-situ" (on-site) application of nanoparticles. synthesis and cold integration technique that preserves the biological activity of active ingredients It consists of 4 basic steps. Step 1: In-situ synthesis of nanoparticles: Bismuth nitrate solution, sodium oxide as a reducing agent. Ultrasonic cavitation with borohydride or ascorbic acid at 40 kHz frequency and 100 W power. The reaction lasts for a few minutes. This process causes particle growth at the nanoscale. It limits. 35 2Bi(NO ) + 3NaBH + 3H O 2Bi(0) + By-products 3 3 4 2 7 Step 2: Surface modification and stabilization: Coating nanoparticle surfaces with zeta increasing the potential from +5 mV to +18 mV and steric stabilization. To achieve this, 3% by weight of polysorbate 80 was added to the resulting nanoparticle suspension. It is added and mixed at 25 °C and 300 RPM for 2 hours. Step 3: Hydrogel integration and homogenization: Carbomr 940 powder (1.5% wt), deionized It is left to swell in water for 24 hours. The stabilized nanoparticle suspension is swollen. It is added to the polymer solution at a rate of 10 mL / min. The resulting mixture is heated at 3000 RPM for 15 minutes. It is processed for minutes. This ensures a homogeneous distribution of nanoparticles within the polymer network. It is provided. Step 4: Neutralization and active loading (cold process): Add 0.5% to the resulting mixture. Gelation is initiated by adding triethanolamine (TEA) and raising the pH to 7.0. The resulting gel... It is cooled to +4 °C and the heat-sensitive melatonin and vitamin E complex is heated at 100 RPM. It is mixed and added to the gel. This process step is called cold integration technique. It prevents the antioxidants from being degraded by the production heat, thus maintaining their biological effectiveness at 95%. It provides protection to a certain extent. The hydrogel formulation obtained within the scope of the invention is a homogeneous, gray-colored and smooth gel. It is in this form. Its viscosity is 35,000 ±5,000 cP, pH 7.0 ±0.2, and it is compatible with skin. Its osmolality is... It has a concentration of 290 mOsm / kg (isotonic), a shelf life of 2 years at 25 °C, and exhibits physical and chemical stability. Radiological performance; contrast enhancement 120 kVp, 200 mAs CT parameters +250 HU Contrast enhancement was achieved. Dose linearity was observed at concentrations of 10 mg / mL to 40 mg / mL. A linear increase in contrast (R-squared = 0.98) was observed between them. Cytotoxicity (ISO 10993-5): IC50 > 5 in MTT test performed on L929 fibroblast cells. The concentration was found to be mg / mL. The product is not cytotoxic. Skin irritation (ISO 10993-10): Irritation Index (Irritation) in tests conducted on rabbits. The irritation index was measured as 0.5. The product is in the minimal irritation class. Systemic toxicity (ISO 10993-11): Oral LD50 value is determined as > 5000 mg / kg. Practical It is classified as toxic. 35 8 Dermal Penetration: In ex-vivo Franz diffusion cell tests, 98% of the nanoparticles were found to penetrate the dermal layer. It remains in the stratum corneum and epidermis layers, with less than 2% penetration into the dermis layer. And it has been proven that there is no risk of systemic absorption. The radioprotective efficacy of the hydrogel formulation described in the invention was also evaluated. according to;  DNA Damage: In Comet Assay tests performed under radiation exposure, the gel DNA damage was reduced by 65% ​​in the treated group.  Lipid Peroxidation: MDA (Malondialdehyde), an oxidative stress marker A 60% reduction in levels has been achieved. 35

Claims

1. The invention relates to X-ray based imaging techniques such as mammography, computed tomography, and glossoscopy. used as contrast agents and radioprotectors in diagnostic imaging methods Improving quality while also protecting against the harmful effects of ionizing radiation. providing, externally applied (topical), non-invasive, nano- It is a composite medical hydrogel formulation whose characteristic is that it selectively blocks X-rays. to increase tissue contrast (visibility) by absorbing it, having a high atomic number A carbomer-based polymeric matrix reinforced with bismuth nanoparticles and radiation It neutralizes free radicals formed in the skin, thus preventing cellular damage and radiation. A synergistic antioxidant system (Melatonin and Vitamin E) to prevent sunburn. It includes.

2. The invention relates to X-ray based imaging techniques such as mammography, computed tomography, and glossoscopy. used as contrast agents and radioprotectors in diagnostic imaging methods Improving quality while also protecting against the harmful effects of ionizing radiation. providing, externally applied (topical), non-invasive, nano- It is a method for producing a composite medical hydrogel formulation, the characteristic of which is;  To perform in-situ synthesis of nanoparticles, bismuth nitrate solution, With reducing agents such as sodium borohydride or ascorbic acid at a frequency of 40 kHz and 100 Reacting under ultrasonic cavitation at a power of W for 30 minutes,  By coating nanoparticle surfaces, the zeta potential is increased from +5 mV to +18 mV. to increase the load to the level and to ensure steric stabilization, the resulting nanoparticles 3% by weight of polysorbate 80 was added to the suspension and stored at 25 °C for 300 minutes. Mixing at RPM speed for 2 hours,  Carbomer to ensure homogeneous distribution of nanoparticles within the polymer network 940 powder (1.5% wt) is left to swell in deionized water for 24 hours. subsequently the stabilized nanoparticle suspension is added to the aforementioned swollen polymer. by adding to the solution at a rate of 10 mL / min and maintaining a speed of 3000 RPM for 15 minutes. processing,  0.5% triethanolamine (TEA) is added to the resulting mixture to raise the pH to 7.

0. by bringing it in and initiating the gelling process,  The resulting gel is cooled to +4 °C, and heat-sensitive melatonin and vitamin E are produced. The 35 complexes are added to the gel by mixing at 100 RPM. It includes the steps of the process.