A study on toxicity, local irritative effect of and allergic response to a novel intranasal medication containing N-phenylacetyl-L-prolylglycine ethyl ester
Keywords:N-phenylacetyl-L-prolylglycine ethyl ester, medication for intranasal delivery, pharmacology, acute toxicity, allergic reaction
Development of novel medications for delivery of active ingredients with systemic absorption and high bioavailability is an actual challenge for modern pharmaceutical and medical science. Nowadays, the number of diseases of the central nervous system is continuously growing. These conditions lead to impairment of mnestic and intellectual brain functions, to a decrease in mental alertness and memory in particular, which results in deterioration in the quality of life, sometimes in disability and patients’ partial or complete dependence on other people.
The existing variety of nootropics does not fully respond to modern criteria of clinical science and practice due to insufficient effectiveness and neuroavailability. Recently, scientists have drawn attention to the potential of intranasal administration for delivery of active ingredients with systemic effect to human blood flow. Intranasal administration for delivery of active ingredients will enhance neuroavailability and, thus, a therapeutic effect of drugs.
At the Departments of Medicines Technology, Pharmacology and Medical Formulation of ZSMU, a composition of the novel medication containing N-phenylacetyl-L-prolylglycine ethyl ester for intranasal delivery was developed as the result of complex physical and chemical, microbiological and biopharmaceutical experiments. The medication contains 1 % of N-phenylacetyl-L-prolylglycine ethyl ester, 5 % of Glycerin and Poltava Bischofite (standardized solution prepared at the Department of Medicines Technology of ZSMU), Sodium carboxymethyl cellulose solution and Tween 80 (1 %). Given the above, the urgent task is to study some safety parameters of the developed dosage form.
The aim of the research is to study some toxicological parameters, local irritative effect of and allergic response to an effective dose of created medication containing N-phenylacetyl-L-prolylglycine ethyl ester for intranasal delivery.
Materials and methods. The created medications for intranasal delivery were used as materials for each test. These medications contained N-phenylacetyl-L-prolylglycine ethyl ester (Noopept) 1 %, Glycerin and standardized Poltava Bischofite (5 % each), Sodium carboxymethyl cellulose solution, and Tween 80 (1 %). N-phenylacetyl-L-prolylglycine ethyl ester (CAS №157115-85-0, obtained from Shijiazhuang Prosperity Import and Export Co., Ltd., China. Purity: ≥98 %), Poltava Bischofite (standardized solution prepared at the Department of Medicines Technology of ZSMU), Polysorbate 80 (obtained from Limited liability company “Synbias”, Kyiv), Sodium carboxymethyl cellulose (obtained from Limited liability company “Synbias”, Kyiv), Glycerin (obtained from Limited liability company “Synbias”, Kyiv), Benzalkonium chloride (obtained from Limited liability company “Istok-Plus”, Zaporizhzhia). A study of acute toxicity, allergic response and irritating effect on skin, and cutaneous anaphylaxis reaction was conducted on white rats. Local irritative effect (Conjunctival allergen provocation test, CAPT) of created medication containing N-phenylacetyl-L-prolylglycine ethyl ester for intranasal delivery was determined on guinea pigs in accordance with recommendations of the State Pharmacological Center of the Ministry of Health of Ukraine and other recommendations.
Results were statistically processed by means of the standard statistical package of the licensed program Statistica for Windows 13 (StatSoft Inc., № JPZ804I382130ARCN10-J). For all analysis types the P-value <0.05 (95 %) was considered statistically significant.
Results. One-time intranasal delivery of the maximum allowable volume of the medication under research (0.4 ml) to the rats weighing 100 g in a dose of 40 mg/kg did not result in death of any of 6 animals of the experimental group overnight.
In the course of studying potential local irritative effect of the intranasal gel containing N-phenylacetyl-L-prolylglycine ethyl ester, two experimental animals out of 10 developed a slight reddening of the conjunctiva immediately after the administration. No changes in mucous membrane of the eyes were observed in other eight experimental animals. Daily application of the studied medication for intranasal delivery (0.5 g) to a shaved area of the lateral surface of the animals’ bodies (4 × 4 cm) during 5 days, and consequent one-time application of the intranasal gel containing N-phenylacetyl-L-prolylglycine ethyl ester (0.3 g), did not result in anaphylactic shock development. No visible reactions were detected in the experimental animals after 20 more skin applications of the intranasal gel containing N-phenylacetyl-L-prolylglycine ethyl ester during 4 weeks (5 times per week). The skin area exposed to application in animals of the control and experimental groups looked the same.
Conclusions. Complex studies of some toxicological parameters (such as mortality, dynamics of body weight change, local irritative effect and allergic response to the effective dose of a novel medication containing N-phenylacetyl-L-prolylglycine ethyl ester for intranasal delivery) have been performed. Summarizing obtained results, it can be confirmed that the medication under study does not cause any local irritative effect and allergic response and does not demonstrate general toxic effects in case of its intranasal delivery. Thus, further research of the novel medication containing N-phenylacetyl-L-prolylglycine ethyl ester for intranasal administration has a potential perspective.
Pandian, J. D., Gall, S. L., Kate, M. P., Silva, G. S., Akinyemi, R. O., Ovbiagele, B. I., Lavados, P. M., Gandhi, D., & Thrift, A. G. (2018). Prevention of stroke: a global perspective. Lancet, 392(10154), 1269-1278. https://doi.org/10.1016/S0140-6736(18)31269-8
Malhotra, K., Gornbein, J., & Saver, J. L. (2017). Ischemic Strokes Due to Large-Vessel Occlusions Contribute Disproportionately to Stroke-Related Dependence and Death: A Review. Frontiers in Neurology, 8, Article 651. https://doi.org/10.3389/fneur.2017.00651
Barbay, M., Taillia, H., Nedelec-Ciceri, C., Arnoux, A., Puy, L., Wiener, E., Canaple, S., Lamy, C., Godefroy, O., Roussel, M., & GRECOGVASC Study Group. (2017). Vascular cognitive impairment: Advances and trends. Revue Neurologique, 173(7-8), 473-480. https://doi.org/10.1016/j.neurol.2017.06.009
Zozulia, A. I., & Zozulia, I. S. (2014). Problema tserebrovaskuliarnykh zakhvoriuvan v Ukraini ta sviti i yii perspektyvy [Issue of cerebrovascular diseases in Ukraine and in the world and its prospects]. Zbirnyk naukovykh prats spivrobitnykiv NMAPO im. P. L. Shupyka, 23(1), 417-432. [in Ukrainian].
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
Jogani, V., Jinturkar, K., Vyas, T., & Misra, A. (2008). Recent Patents Review on Intranasal Administration for CNS Drug Delivery. Recent Patents on Drug Delivery & Formulation (Discontinued), 2(1), 25-40. https://doi.org/10.2174/187221108783331429
Ostrovskaya, R. U., Gudasheva, T. A., Voronina, T. A., & Seredenin, S. B. (2002). Original'nyi nootropnyi i neiroprotektivnyi preparat noopept [The novel nootropic and neuroprotector drug noopept]. Eksperimental'naya i klinicheskaya farmakologiya, 65(5), 66-72. [in Russian].
Belenichev, I. F., Chernii, V. I., Nagornaya, E. A., Pavlov, S. V., Chernii, T. V., Gorchakova, N. A., Bukhtiyarova, N. V., Andronova, I. A., & Kucherenko, L. I. (2014). Neiroprotektsiya i neiroplastichnost' [Neuroprotection and neuroplasticity]. OOO "Poligraf plyus". [in Russian].
Stefanov, A. V. (Ed.). (2001). Doklinichni doslidzhennia likarskykh zasobiv [Preclinical studies of drugs]. Avitsena. [in Ukrainian].
Lapach, S. N., Chubenko, A. V., & Babich, P. N. (2001). Statisticheskie metody v mediko-biologicheskikh issledovaniyakh s ispol'zovaniem EXCEL [Statistical Methods in Biomedical Research Using EXCEL]. Morion. [in Russian].
Mironov, A. N. (Ed.). (2012) Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv. Chast' pervaya [Guidelines for conducting preclinical studies of drugs. Part one]. Grif i K. [in Russian].
Ministry of Health of Ukraine. (2014, September 19). Pro zatverdzhennia standartu "Nastanova. Likarski zasoby. Doklinichni doslidzhennia bezpeky yak pidgruntia klinichnykh vyprobuvan za uchastiu liudyny ta reiestratsii likarskykh zasobiv" [On approval of the standard "Guidelines. Drugs. Preclinical studies of safety as a foundation for clinical trials involving humans and licensing of drugs" (No. 661)]. https://zakon.rada.gov.ua/rada/show/v0661282-14#Text
(2010, October 20). Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes Text with EEA relevance. Europa.eu. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32010L0063
Ministry of Education, Science, Youth and Sports of Ukraine. (2012, March 01). Pro zatverdzhennia Poriadku provedennia naukovymy ustanovamy doslidiv, eksperymentiv na tvarynakh [On approval of the test and experimental procedure carrying out by scientific institutions on animals (No. 241)]. https://zakon.rada.gov.ua/laws/show/z0416-12#Text
Berezovskaya, I. V. (2003). Klassifikatsiya khimicheskikh veshchestv po parametram ostroi toksichnosti pri parenteral'nykh sposobakh vvedeniya [Classification of chemicals based on parameters of acute toxicity in parenteral administration]. Khimiko-faomatsevticheskii zhurnal, 37(3), 32-34. https://doi.org/10.30906/0023-1134-2003-37-3-32-34. [in Russian].
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