Translation. Region: Russian Federation –
Source: Novosibirsk State University –
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Scientists from Novosibirsk State University, in collaboration with specialists from STM-Cosmetics, are studying the delivery systems and mechanisms of penetration of medicinal and cosmetic products into the body through the skin. To evaluate their effectiveness and study their pharmacokinetics, the method of accelerator mass spectrometry will be used for the first time in Russia. This method involves introducing the isotope carbon-14 into the composition of the substance whose transdermal permeability efficiency needs to be determined, instead of carbon-12. To verify the reliability of the data obtained using AMS, the scientists decided to use radiocarbon-labeled nicotine, known for its high transdermal permeability. For this purpose, tobacco was grown in laboratory conditions, watered with urea with an increased proportion of radiocarbon. The first harvest of "radioactive" tobacco has already been obtained, and an in vitro study of the penetration of nicotine obtained from it through the skin of a snake and a laboratory mouse has been conducted. A similar procedure will follow with the skin of pigs. The next stage will be studies with harmless nicotine derivatives in vivo on laboratory animals. This work is being carried out at the Institute of Medicine and Medical Technologies NSU in the NSU-NSC Accelerator Mass Spectrometry Shared Use Center with the support of the programPriority 2030".
— There are many methods of delivering drugs into the body, both invasive and non-invasive. Transdermal belongs to the latter, and is of great research interest to us. It is very convenient to use, but there are a number of difficulties. The skin is the largest human organ; it perfectly performs a barrier function, reliably protecting the body from all kinds of xenobiotics – substances foreign to living organisms and not included in the natural cycle, which come from the environment and can cause negative consequences, disrupt metabolism, undermine the immune system and accumulate in tissues. The skin effectively rejects substances with high molecular weight, as well as hydrophilic and charged substances. In general, science has already come up with a lot of different transdermal systems for delivering drugs to the body, including liposomal and niosomal. Some of them are already used in clinical practice, while others still exist only at the development level. However, there is a problem: you need to understand how effective this process is and what its pharmacokinetics are, how deeply the substance penetrates into organs and tissues and how exactly it acts inside them. Often, not the entire dose of medicine enters the body; most of it remains outside, cut off by the stratum corneum of the epidermis. Until now, it has not been possible to determine how much of a substance has passed this barrier and reached its target, unlike oral or injection methods of administering drugs into the body. A study using the accelerator mass spectrometry method will answer this question, said Anton Astanin, executive director of STM-Cosmetics.
The transdermal method of administering drugs or cosmetics involves their penetration into the body to certain depths of the skin, into the circulatory system or into internal organs. It has some advantages – some drugs lose their properties when administered orally into the body. For this reason, they are administered by injection. For example, insulin, which often has to be administered regularly. However, this method carries some risks and discomfort for the patient. An alternative could be a transdermal method of drug administration, but first it is necessary to quantitatively assess the effectiveness of drug penetration into the body. However, methods for such assessment do not currently exist. NSU scientists proposed using the method of accelerator mass spectrometry using radiocarbon-labeled compounds to solve this problem. Currently, scientists have identified reference substances that are 100% permeable through the layers of the skin – nicotine, caffeine and others. These substances should become an internal standard for quantitative measurements of the permeability of drugs into the body through the skin. Expert chemist Anton Astanin, candidate of chemical sciences Ksenia Babina and student of the Faculty of Natural Sciences of NSU Olga Kondakova are working on the development of niosomes – means of delivering substances to the body. Reference substances labeled with C-14 will be encapsulated in niosomes for studies using accelerator mass spectrometry and confirmation of the effectiveness of delivery vehicles. This work is being carried out at the Center for Shared Use “Accelerator Mass Spectrometry NSU-NSC” for the first time.
“Our first priority was to obtain a radiocarbon-labeled substance that would be 100% permeable through the skin. This work was carried out as part of a project supported by the Priority 2030 program, which was scheduled for June-December last year, and such a substance needed to be obtained in a short time, so nicotine, known for its good permeability, was chosen. Tobacco plants reach adulthood at the age of three months from planting. We grew them with the assistance of employees of the Institute of Soil Science and Agrochemistry of the SB RAS, where there are special grow boxes and all the necessary conditions for growing this crop have been created. A month after sowing and until harvest, we watered the plants with a radiocarbon-tagged preparation; this is a commercial reagent for use in medical practice for diagnosing Helicobacter pylori in the stomach of patients. At the same time, at the peak of plant growth, the overall background radiation in the premises, according to our measurements, was below the permissible level. After harvesting, we made about 60 measurements aimed at determining the kinetics of C-14 accumulation in various plant organs – roots, stems, lower and upper leaves. An interesting point was the question of the plant’s absorption of carbon from urea, which cannot be solved without the use of a radiocarbon tag. We worked with two varieties of tobacco – “Havana” and “Samsun”. It turned out that in “Samsun” more radiocarbon accumulated in the roots, and in “Havana” – in the leaves. We then determined which plant organs contained the most nicotine. It turned out to be in the leaves. Depending on the variety and method of cultivation, they accumulate from 0.2-0.3% to 1-1.5% nicotine per dry biomass. As a result, we isolated half a gram of nicotine labeled C-14. It will become one of the standard substances with 100% permeability through the skin for the development of drug delivery vehicles. In parallel, for the same purposes, we synthetically obtained caffeine with a high content of C-14. Caffeine is also known for its 100% permeability through the skin,” said Ekaterina Parkhomchuk, director of the Accelerator Mass Spectrometry Center at NSU-NNSC.
Thus, scientists are currently developing a number of substances that will later be used as internal standards. A graphite target will be created from the resulting drop of labeled nicotine, which will be used to determine the isotope ratio, C-14/C-12, relative to current levels in objects of the biosphere on Earth's land. Currently, the dry biomass of grown C-14-labeled plants has been measured to exceed current levels by 3,000-4,000 times. The scientists were surprised by such an impressive result—the plants absorbed up to 30% of the radioisotope contained in the urea solution they were watered with. They note that this excess, coupled with the high sensitivity of the UMS, will allow them to produce derivatives from labeled nicotine, dilute the substance, and administer it in vivo to quantify its concentration in specific organs and tissues, as well as determine the kinetics of its distribution in the body over time.
In addition to NSU scientists, the study involved researchers from several scientific organizations: the Vorozhtsov Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences, the Institute of Soil Science and Agrochemistry of the Siberian Branch of the Russian Academy of Sciences, and the Boreskov Institute of Catalysis of the Siberian Branch of the Russian Academy of Sciences.
At the engineering center of the Vorozhtsov Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences, tests are being conducted on mouse and snake skin, as well as on pig skin and ears, which are physiologically similar in structure to human skin. Researchers from the Institute of Soil Science and Agrochemistry of the Siberian Branch of the Russian Academy of Sciences were involved in cultivating "radioactive" tobacco plants. This institute has created all the necessary conditions for growing these plants, including grow boxes. The Boreskov Institute of Catalysis has created conditions for working with synthetically produced radioactive substances, such as radiocarbon-labeled caffeine. A setup for graphitizing labeled samples was developed several years ago by specialists from the NSU-NSC Accelerator Mass Spectrometry Shared Use Center to obtain graphite targets from biological tissues, which are analyzed using an accelerator mass spectrometer. The graphitizer used to obtain targets for UMS analysis from archaeological samples cannot be used due to the high risk of cross-contamination of the samples with radiocarbon. Therefore, the NSU-NSC Accelerator Mass Spectrometry Shared Use Center has developed and is operating several graphitizers for various applications.
Currently, scientists are developing a methodology for quantitatively studying the transdermal permeability of drugs and cosmetics. They are confident that their development will be of interest to manufacturers of these products.
"Our company specializes in cosmetics production and raw material supply, so we are interested in developing this area of research. It is crucial for us that biologically active substances penetrate the skin. Together with scientists from the NSU-NSC Accelerator Mass Spectrometry Center, we have begun research to establish a scientific basis for testing the transdermal penetration of substances, studying their pharmacokinetics, and developing more effective means of delivering substances through the skin, which are necessary for the creation of pharmaceuticals and cosmetics," said Anton Astanin.
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