Baricitinib is an antiinflammatory and immunomodulating drug compound used to treat rheumatoid arthritis, severe COVID-19 and autoimmune diseases. However, this substance is poorly soluble in water, which inhibits its intake by the human body. A group of scientists have found a solution to this problem achieving a 7-time increase in the compound solubility. For that purpose, they placed the drug into polymer nanoparticles, the shells of which actively interacted with water. The results of the study funded by a grant of the Russian Science Foundation (RSF) were published in the Journal of Molecular Liquids.
The immune system normally protects our body from a variety of infections but in some cases it may get out of control and attack healthy cells of the body. This, for example, happens in patients with rheumatoid arthritis, an inflammatory disease affecting joints and leading to the destruction of cartilage and bone tissues. An approved preparation for treatment of rheumatoid arthritis in Russia, Europe and the USA is baricitinib. It suppresses synthesis of cytokines, substances causing inflammation during an immune response, which makes it also applicable for suppressing inflammatory reactions in COVID-19 patients. However, baricitinib is poorly soluble in water, which prevents its complete intake in case of oral administration (about 21% of the drug is simply excreted from the body), which reduces the treatment efficiency. All this urges scientists to find ways to increase the bioavailability of baricitinib, for example, by binding the drug molecules with substances improving solubility of poorly soluble compounds.
Quite promising for this purpose are Pluronics – synthetic polymer particles applied in medicine for drug delivery and improvement of drug properties and as components of skincare cosmetics. A special feature of pluronics is that, when in water, their molecules form ball-like structures – micelles. On their surface, micelles always have the hydrophilic molecule parts that actively participate with water and inside them are the hydrophobic parts, i.e. those that are "afraid" of water. It is these micelles that are used as containers for drug molecules when pluronics are applied for drug delivery. However, it remains unknown whether pluronics improve the solubility of baricitinib and, if they do, what is the optimal size of the micelles for this purpose.
A group of ISC RAS scientists together with their colleagues from Ivanovo State University investigated how pluronic molecules affect the solubility of baricitinib. To that effect, the authors used four types of commercial pluronics, the molecules of which differed from each other by the length of the hydrophobic and hydrophilic parts, which made the molecules form micelles of different sizes and chemical activity.
The researchers compared the solubility of pure baricitinib and its mixture with pluronics in solutions similar to the human gastro-intestinal tract media. The solubility of the drug "packed" into micelles turned out to be 7 times higher, with the best result observed in the largest micelles. It is explained by the fact that the latter contained the longest molecule sections on the surface of the micelles and inside them, which actively interacted with the drug facilitating its transition into the particles.
Since only small molecules can penetrate semi-permeable cell membranes, the researchers found whether large micelles would inhibit baricitinib penetration from the intestines to the blood flow. For that purpose, they modelled particle penetration through an artificial membrane with a structure similar to that of a cell membrane. It turned out that at high concentrations, the particles acting as delivery agents cannot penetrate the membranes through the pores well because they are too large, which should be taken into account when using them. A series of experiments allowed the authors to calculate the optimal micelle concentration which would increase the drug solubility and would not inhibit its penetration into the blood flow.
"The approach we propose increased the baricitinib solubility by 7 times and allowed us to exclude the use of high drug concentrations which can be toxic and lead to side effects. We are planning to perform a more detailed study with other compounds increasing solubility to further improve the baricitinib bioavailability", says the head of the project funded by the grant of the Russian Science Foundation Ekaterina Delyagina, a Researcher of the Laboratory of Chemistry of Oligosaccharides and Functional Materials on Their Basis of ISC RAS.
