Selection of excipients for the purpose of creating an intranasal gel of interleukin-1 receptor antagonist β (IL-1ra)
Keywords:interleukin-1β (IL-1ra) receptor antagonist, release, nasal dosage form
There is a negative dynamic of the spread of cerebrovascular diseases, which often lead to disability or death in patients in the world, today. Such diseases are characterized by acute disorders of cerebral metabolism and blood circulation, against the background of other chronic pathologies. More than one hundred thousand cases of stroke are registered in Ukraine every year, with more than thirty percent of patients dying within the first month of the disease according to the Center for Medical Statistics of the Ministry of Health of Ukraine.
The nasal route of administration is a promising method of transporting active substances for systemic action, various pharmacotherapeutic groups, both small and large molecules. The created nasal preparations of hormones, antibiotics, analgesics, exhibit a quick therapeutic effect due to the branched capillary system in the nasal cavity. In addition, the nasal route of administration is the most promising non-invasive method for delivering active substances to the brain for cerebroprotective drugs, due to the anatomical features of the location of the nerves.
According to published data, the researchers found that the receptor antagonist of interleukin-1 (IL-1ra) exhibits neuroprotective properties in brain ischemia by blocking excess IL-1 and activating the anti-inflammatory cytokine cascade, in order to reduce local inflammation and neuronal loss.
Therefore, in order to expand the range of pharmacotherapeutic drugs – neuroprotectors, the development of a new intranasal form with the active pharmaceutical ingredient - receptor antagonist interleukin-1 (IL-1ra) is an urgent problem of modern medicine and pharmacy.
The aim of work was to substantiate the choice of excipients for the new intranasal gel of the receptor antagonist of interleukin-1 (IL-1ra).
Materials and methods. The studies were carried out according to the plan of two-way analysis of variance with repeated observations. Factors that were investigated: factor A (type of polymer) – A1 – chitosan 3 %, A2 – sodium carboxymethyl cellulose 0.3 %, A3 – sodium hyaluronate 0.7 %, A4 – sodium alginate 0.5 %; factor B (type of alcohol): B1 – without alcohol, B2 – sorbitol, B3 – glycerin, B4 – D-panthenol. A prefabricated solution of the receptor antagonist of interleukin-1 (IL-1ra) was used as an active substance. A portion of the active substance was taken considering the calculations, to ensure a concentration of 0.5 % IL-1ra in each composition.
The release of the active pharmaceutical ingredient was determined by equilibrium dialysis according to Kruvchinsky at 37.0 ± 0.5 °C through a semi-permeable membrane – “Cuprofan” for all compositions. Dialysis was performed in Franz cells at a nine-position station (PermeGear, Inc., USA). The concentration of IL-1ra, after 30 minutes, was determined by UV spectrophotometry at a wavelength of 280 nm on a UV-2600 spectrophotometer (Shimadzu Corporation, Japan).
Results. We studied the effect of pharmaceutical factors (polymers and alcohols) on the intensity of the release of IL-1ra from the nasal form to justify the choice of excipients for the nasal gel of the receptor antagonist interleukin-1 β. The results of the analysis of variance of pharmaceutical factors (polymers and alcohols) showed that hydrophilic polymers and humectants had a significant effect on the release of the active substance from the experimental compositions. It is advisable to use a mucoadhesive polymer – sodium salt of carboxymethylcellulose, as well as alcohol-moisturizer D-panthenol for the new nasal form of IL-1ra, as excipients.
Conclusions. Excipients were selected for a liquid intranasal gel with the receptor antagonist interleukin-1 (IL-1ra). It was found that the type of mucoadhesive polymers and alcohols, to moisten the mucous membrane, had a significant effect on the release of the active pharmaceutical ingredient from nasal dosage forms. As a result of research, it was found that the optimal release of IL-1ra from nasal compositions was provided by excipients - hydrophilic mucoadhesive component - sodium carboxymethylcellulose with the addition of humectant alcohol – D-panthenol.
Zozulia, I. S., & Zozulia, A. I. (2011). Epidemiolohiia tserebrovaskuliarnykh zakhvoriuvan v Ukraini [Epidemiology of cerebrovascular diseases in Ukraine]. Ukrainskyi medychnyi chasopys, (5), 38-41. [in Ukrainian].
Derzhavnyi zaklad «Tsentr medychnoi statystyky Ministerstva okhorony zdorovia Ukrainy» [Center for Health Statistics Ministry of Health of Ukraine]. http://medstat.gov.ua/
Belenichev, I. F., Cherniy, V. I., Nagorna, E. A., Pavlov, S. V. & Buhtiyarova, N. V. (2015). Neyroprotektsiya i neyroplastichnost [Neuroprotection and Neuroplasticity]. Kiev : Logos. [in Russian].
Suprun, E. V., Chekman, I. S., Bielenichev, I. F., Horchakova, N. O., Svintsitskyi, A. S., Zahorodnyi, M. I., & Burlaka, B. S. (2017). Tsytokinova terapiia v kompleksnomu likuvanni tserebrovaskuliarnykh zakhvoriuvan: stan, perspektyvy doslidzhen [Cytokine therapy in the complex treatment of cerebrovascular diseases: status, research prospects]. Ratsionalna farmakoterapiia, (1), 19-30. [in Ukrainian].
Suprun, E. V., Gromov, L. A., & Belenichev, I. F. (2010). Korrekcija antagonistom receptorov interlejkina-1 nevrologicheskih i kognitivnyh narushenij pri jeksperimental’nom ishemicheskom insulte [Correction receptor antagonist for interleukin-1 of neurological and cognitive disorders in experimental ischemic stroke]. Ukrainskyi visnyk psykhonevrolohii, 18(2), 40-43. [in Russian].
Prajapati, N., Srivastava, P., & Bhargava, S. (2012). Recent advances in nasal drug delivery using natural polymers. Current Drug Therapy, 7(3), 170-178. https://doi.org/10.2174/157488512803988076
Wang Z., Xiong G., Tsang W. C., Schätzlein A. G., & Uchegbu I. F. (2019) Nose-to-Brain Delivery. Journal of Pharmacology and Experimental Therapeutics, 370(3), 593-601. https://doi.org/10.1124/jpet.119.258152
Kumar, H., Mishra, G., Sharma, A. K., Gothwal, A., Kesharwani, P., & Gupta, U. (2017). Intranasal Drug Delivery: A Non-Invasive Approach for the Better Delivery of Neurotherapeutics. Pharmaceutical nanotechnology, 5(3), 203-214. https://doi.org/10.2174/2211738505666170515113936
Rogachev, I. O., Gladyshev, V. V., Burlaka, B. S., & Kechin, I. L. (2011). Sravnitel’nye issledovaniya strukturno-mekhanicheskikh kharakteristik intranazal’nykh myagkikh lekarstvennykh form nimodipina [Comparative studies of the structural and mechanical characteristics of intranasal soft dosage forms of nimodipine]. Zaporozhye medical journal, 13(3), 92-94. [in Russian].
Suprun, E. V., Ishchenko, A. M., Simbirtsev, A. S., Belenichev, I. F., & Suprun, А. S. (2014). Vliyanie retseptornogo antagonista interleikina-1 na sootnoshenie pokazatelei tiol-disul’fidnoi sistemy, okislitel’noi modifikatsii belkov i energeticheskogo metabolizma v kletkakh golovnogo mozga krys na fone eksperimental’noi giperglikemii i tserebral’noi ishemii [Influence of the receptor antagonist of interleukin-1 on the relation of influence of thiol-disulphide system, oxidative modification of protein and energetic metabolism in cells of rats’ brain on the background of experimental hyperglycemia and cerebral ischemia]. Tsitokiny i vospalenie, 13(2), 82-88. [in Russian].
Hroshovyi, T. A., Martseniuk, V. P., Kucherenko, L. I., & Vronska, L. P. (2008). Matematychne planuvannia eksperymentu pry provedenni naukovykh doslidzhen v farmatsii [Mathematical planning of experiment when conducting scientific research in pharmacy]. Ternopil: TDMU. [in Ukrainian].
Miedviedieva, K. P., Burlaka, B. S., Buhaiova, V. V., Vasyuk, S. O., Belenichev, I. F., & Suprun, E. V. (2019). Rozrobka metodyky spektro-fotometrychnoho vyznachennia rekombinantnoho retseptornoho antahonista interleikinu-1 liudyny v napivfabrykati-rozchyni [The development of method for the spectrophotometric determination of a recombinant human interleukin-1 receptor antagonist in a semi-finished solution]. Farmatsevtychnyi chasopys, (4), 29-36. [in Ukrainian]. https://doi.org/10.11603/2312-0967.2019.4.10685
How to Cite
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access)