pharmjournalРазработка и регистрация лекарственных средствDrug development & registration2305-20662658-5049LLC «CPHA»10.33380/2305-2066-2020-9-2-56-66pharmjournal-752Research ArticleФАРМАЦЕВТИЧЕСКАЯ ТЕХНОЛОГИЯPHARMACEUTICAL TECHNOLOGYСовременные технологии модифицированного высвобождения биологически активных веществ в фармацевтической разработке (обзор)Modern Technologies of Controlled Release of Biologically Active Substances in Pharmaceutical Research and Development (Review)СавельеваЕ. И.SavelievaE. I.

Савельева Елена Игоревна – заведующая лабораторией аналитической токсикологии, доктор химических наук

188663, Ленинградская область, Всеволожский район, г.п. Кузьмоловский, ст. Капитолово, корп. № 93

Elena I. Savelieva

build. 93, Kapitolovo station, g/p Kuz’molovsky, Vsevolzskiy district, Leningrad Region, 188663

esavelieva59@mail.ruФГУП «Научно-исследовательский институт гигиены, профпатологии и экологии человека» Федерального медико-биологического агентства (ФГУП «НИИ ГПЭЧ» ФМБА России)Research Institute of Hygiene, Occupational Pathology and Human Ecology Federal State Unitary Enterprise, Federal Medical Biological Agency202019032020925666Copyright © Савельева Е.И., 20202020Савельева Е.И.Savelieva E.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmjournal.ru/jour/article/view/752

Введение В обзоре представлены различные системы, используемые в качестве матриц включения или модификаторов биологически активных веществ для усиления их абсорбции, либо депонирования и последующего высвобождения как равномерного, так и «по требованию» - в ответ на воздействие стимула.

Текст В наибольшей степени разработаны технологии включения активных молекул в наноагрегаты циклодекстринов. На этой основе разработаны модифицированные формы гидрокортизона, глибенкламида, ряда пептидных препаратов. Ацетилцистеин, иммобилизованный на частицах этилцеллюлозы или других полимеров, значительно повышает биодоступность пептидных препаратов при их интраназальном введении. Депонирование активных веществ в организме осуществляется за счет их отсроченного контролируемого растворения, адсорбции, капсулирования или этерификации. Высвобождение депонированных веществ при воздействии эндогенного (изменение рН, температуры) или внешнего (воздействие ультразвука, электрического или магнитного поля, химических активаторов) стимула может быть однократным или многократным в зависимости от способности депонирующей матрицы к самоагрегации.

Заключение  Самоагрегированные пептиды наиболее перспективны для стимул-ориентированных высвобождения/доставки биологически активных веществ. Современные технологии модификации активных веществ повышают эффективность неинвазивных способов их введения, способствуют достижению целевых по локации и времени реализации биологических эффектов.

Introduction

Introduction. The review describes various systems used as inclusion matrices or modifiers of biologically active substances to enhance their absorption or deposition and subsequent release, both continuous or «on demand», i.e. in response to a stimulus.

Text

Text. Technologies for the incorporation of active substances into cyclodextrin nanoaggregates are developed to the greatest extent. Such technologies were used to obtain modified forms of hydrocortisone, glibenclamide, and a number of peptide drugs. Acetylcysteine immobilized on ethyl cellulose or other polymer particles significantly increases the bioavailability of peptide drugs on their intranasal administration. The deposition of active substances in the body takes place by way of their delayed controlled dissolution, adsorption, encapsulation, or esterification. The release of deposited substances upon exposure to an endogenous (change in pH, temperature) or external (exposure to ultrasound, electric or magnetic field, chemical activators) stimulus can be single or multiple, depending on the ability of the accommodating matrix for self-aggregation.

Conclusion

Conclusion. Self-aggregated peptides are most promising for stimulus-induced release/delivery of biologically active substances. Modern technologies for the modification of active substances increase the efficiency of their administration and favor targeted location and implementation time of biological effects.

биологически активные веществамодифицированные формынаноагрегатыстимул-ориентированное высвобождениедепоbiologically active substancesmodified formsnanoaggregatesstimulus-induced releasedepotReferencesDemina N. B. Current Trends in the Development of Technologies for Matrix Formulations with Modified Release. Pharmaceutical Chemistry Journal. 2016; 50(7): 475–480. DOI: 10.1007/s11094-016-1472-4.Demina N. B. Current Trends in the Development of Technologies for Matrix Formulations with Modified Release. Pharmaceutical Chemistry Journal. 2016; 50(7): 475–480. DOI: 10.1007/s11094-016-1472-4.Краснюк (мл.) И. И., Овсянникова Л. В., Степанова О. И., Беляцкая А. В., Краснюк И. И., Харитонов Ю. Я., Грих В. В., Кошелева Т. М., Король Л. А. Применение твердых дисперсий с нестероидными противовоспалительными средствами в фармации. Разработка и регистрация лекарственных средств. 2016; 2(15): 40–44. DOI: 10.1007/s11094-018-1799-0.Krasnuk (Junior) I. I., Ovsyannikova L. V., Stepanova O. I., Belyatskaya A. V., Krasnuk I. I., Kharitonov Y. Y., Grikh V. V., Kosheleva T. M., Korol L. A. Application of solid dispersions with non steroidal anti inflammatory drugs in pharmacy. Drug development & registration. 2016; 2(15): 40–44. DOI: 10.1007/s11094-018-1799-0 (in Russ.).Кузнецова И. Г., Дубовик Е. Г., Дубовик Н. С., Комаров Т. Н., Медведев Ю. В., Меньшикова Л. А., Северин С. Е., Шохин И. Е., Ярушок Т. А. Биораспределение полимерной транспортной формы рифабутина. Вестник РАМН. 2015; 70(3): 366–371. DOI: 10.15690/vramn.v70i3.1335.Kuznetsova I. G., Dubovik E. G., Dubovik N. S., Komarov T. N., Medvedev Yu. V., Men’shikova L. A., Severin S. E., Shohin I. E., Yarushok T. A. Biodistribution of the polymer transport form of rifabutin. Bulletin of RAMS. 2015; 70 (3): 366–371. DOI: 10.15690/vramn.v70i3.1335 (in Russ).Loftsson T., Brewster M. E. Pharmaceutical applications of cyclodextrins: basic science and product development. J PharmPharmacol. 2010; 62(11): 1607–1621. DOI: 10.1111/j.2042-7158.2010.01030.x.Loftsson T., Brewster M. E. Pharmaceutical applications of cyclodextrins: basic science and product development. J PharmPharmacol. 2010; 62(11): 1607–1621. DOI: 10.1111/j.2042-7158.2010.01030.x.Грачева И. М. Биотехнология биологически активных веществ. Учебное пособие для студентов высших учебных заведений. – М.: Издательство НПО «Элевар». 2006: 453.Gracheva I. M. Biotechnology of biologically active substances. Textbook for students of higher educational institutions. – M.: Publishing house of NPO «Elevar». 2006: 453 (in Russ).Кедик С. А., Панов А. В., Тюкова В. С., Золотарева М. С. Циклодекстрины и их применение в фармацевтической промышленности (обзор). Разработка и регистрация лекарственных средств. 2016; 3(16): 68–75.Kedik S. A., Panov A. V., Tyukova V. S., Zolotareva M. S. Cyclodextrins and their application in pharmaceutical industry. Drug development & registration. 2016; 3(16): 68–75 (in Russ).Morrison P. W. J., Connon Ch. J., Khutoryanskiy V. V. CyclodextrinMediated Enhancement of Riboflavin Solubility and Corneal Permeability. Molecular Pharmaceutics. 2013; 10(2): 756–762. DOI:10.1021/mp3005963.Morrison P. W. J., Connon Ch. J., Khutoryanskiy V. V. CyclodextrinMediated Enhancement of Riboflavin Solubility and Corneal Permeability. Molecular Pharmaceutics. 2013; 10(2): 756–762. DOI: 10.1021/mp3005963.Scantlebery A. M., Ochodnicky P., Kors L. et al. β-cyclodextrin counteracts obesity in western diet-fed mice but elicits a nephrotoxic effect. Scientific Reports. 2019; 9: 17633. DOI: 10.1038/s41598-019-53890-z.Scantlebery A. M., Ochodnicky P., Kors L. et al. β-cyclodextrin counteracts obesity in western diet-fed mice but elicits a nephrotoxic effect. Scientific Reports. 2019; 9: 17633. DOI: 10.1038/s41598-019-53890-z.Messner M., Kurkov S. V., Brewster M. E., Jansook P., Loftsson T. Selfassembly of cyclodextrin complexes: Aggregation of hydrocortisone/ cyclodextrin complexes. International Journal of Pharmaceutics. 2011; 407: 174–183. DOI: 10.1016/j.ijpharm.2011.01.011.Messner M., Kurkov S. V., Brewster M. E., Jansook P., Loftsson T. Selfassembly of cyclodextrin complexes: Aggregation of hydrocortisone/ cyclodextrin complexes. International Journal of Pharmaceutics. 2011; 407: 174–183. DOI: 10.1016/j.ijpharm.2011.01.011.Wu Ch., Xie O., Xu W., Tu M., Jiang L. Lattice self-assembly of cyclodextrin complexes and beyond Current. Opinion in Colloid & Interface Science. 2019; 39: 76–85. DOI: 10.1016/j.cocis.2019.01.002Wu Ch., Xie O., Xu W., Tu M., Jiang L. Lattice self-assembly of cyclodextrin complexes and beyond Current. Opinion in Colloid & Interface Science. 2019; 39: 76–85. DOI: 10.1016/j.cocis.2019.01.002Lucio D., Martinez-Oharriz M. C., Gonzalez-Navarro C. J., NavarroHerrera D., Gonzalez-Gaitano G., Radulescu A., Irache J. M. Coencapsulation of cyclodextrins into poly (anhydride) nanoparticles to improve the oral administration of glibenclamide. A screening on C. elegans. Colloids and surfaces Biointerfaces. 2017. (163): 64–72. DOI: 10.1016/j.colsurfb.2017.12.038.Lucio D., Martinez-Oharriz M. C., Gonzalez-Navarro C. J., NavarroHerrera D., Gonzalez-Gaitano G., Radulescu A., Irache J. M. Coencapsulation of cyclodextrins into poly (anhydride) nanoparticles to improve the oral administration of glibenclamide. A screening on C. elegans. Colloids and surfaces Biointerfaces. 2017. (163): 64–72. DOI: 10.1016/j.colsurfb.2017.12.038.Lucio D., Martinez-Oharriz M. C., Gu Z., He Y., Aranaz P., Vizmanos J. L., Irac he J. M. Cyclodextrin-grafted poly (anhydride) nanoparticles for oral glibenclamide administration. In vivo evaluation using C. elegans. Int J Pharm. 2018; 547(1-2): 97–105. DOI: 10.1016/j.ijpharm.2018.05.064.Lucio D., Martinez-Oharriz M. C., Gu Z., He Y., Aranaz P., Vizmanos J. L., Irac he J. M. Cyclodextrin-grafted poly (anhydride) nanoparticles for oral glibenclamide administration. In vivo evaluation using C. elegans. Int J Pharm. 2018; 547(1-2): 97–105. DOI: 10.1016/j.ijpharm.2018.05.064.Srinivasan M., Rajabi M., Mousa S. A. Multifunctional Nanomaterials and Their Applications in Drug Delivery and Cancer Therapy. Nanomaterials. 2015; 5(4): 1690–1703. DOI: 10.3390/nano5041690.Srinivasan M., Rajabi M., Mousa S. A. Multifunctional Nanomaterials and Their Applications in Drug Delivery and Cancer Therapy. Nanomaterials. 2015; 5(4): 1690–1703. DOI: 10.3390/nano5041690.Chaves P. D., Ourique A. F., Frank L. A., Pohlmann A. R., Guterres S. S., Beck R. C. Carvedilol-loaded nanocapsules: Mucoadhesive properties and permeability across the sublingual mucosa. European journal of pharmaceutics and biopharmaceutics. 2017; 114: 88–95. DOI: 10.1016/j.ejpb.2017.01.007.Chaves P. D., Ourique A. F., Frank L. A., Pohlmann A. R., Guterres S. S., Beck R. C. Carvedilol-loaded nanocapsules: Mucoadhesive properties and permeability across the sublingual mucosa. European journal of pharmaceutics and biopharmaceutics. 2017; 114: 88–95. DOI: 10.1016/j.ejpb.2017.01.007.Vega E., Egea M. A., Garduno-Ramirez M. L., Garcia M. L., Sanchez E., Espina M., Calpena A. C. Flurbiprofen PLGA-PEG nanospheres: role of hydroxy-beta-cyclodextrin on ex vivo human skin permeation and in vivo topical anti-inflammatory efficacy. Colloids and surfaces. B, Biointerfaces. 2013; 110: 339–346. DOI: 10.1016/j.colsurfb.2013.04.045.Vega E., Egea M. A., Garduno-Ramirez M. L., Garcia M. L., Sanchez E., Espina M., Calpena A. C. Flurbiprofen PLGA-PEG nanospheres: role of hydroxy-beta-cyclodextrin on ex vivo human skin permeation and in vivo topical anti-inflammatory efficacy. Colloids and surfaces. B, Biointerfaces. 2013; 110: 339–346. DOI: 10.1016/j.colsurfb.2013.04.045.Li I., Zhang J., Wang Z., Yao Y., Han X., Zhao Y., Liu J., Zhang S. Identification of a cyclodextrin inclusion complex of antimicrobial peptide CM4 and its antimicrobial activity. Food Chemistry. 2017; 221: 296–301 DOI: 10.1016/j.foodchem.2016.10.040.Li I., Zhang J., Wang Z., Yao Y., Han X., Zhao Y., Liu J., Zhang S. Identification of a cyclodextrin inclusion complex of antimicrobial peptide CM4 and its antimicrobial activity. Food Chemistry. 2017; 221: 296–301. DOI: 10.1016/j.foodchem.2016.10.040.Демина Н. Б. Биофармацевтическая классификационная система как инструмент разработки дизайна и технологии лекарственной формы. Разработка и регистрация лекарственных средств. 2017; 2(19). 56–60.Demina N. B. Biopharmaceutical classificatiom system as a tool for the development of drug formulations and their designs. Drug development & registration. 2017; 2(19): 56–60 (in Russ.).Shingaki T., Hidalgo I. J., Furubayashi T., Sakane T., Katsumi H., Yamamoto A., Yamashita S. Nasal Delivery of P-gp Substrates to the Brain through the Nose–Brain Pathway. Drug Metabolism and Pharmacokinetics. 2011; 26(3): 248–255. DOI: 10.2133/dmpk.dmpk-10-rg-108.Shingaki T., Hidalgo I. J., Furubayashi T., Sakane T., Katsumi H., Yamamoto A., Yamashita S. Nasal Delivery of P-gp Substrates to the Brain through the Nose–Brain Pathway. Drug Metabolism and Pharmacokinetics. 2011; 26(3): 248–255. DOI: 10.2133/dmpk.dmpk-10-rg-108.Bitter C., Suter-Zimmermann K., Surbera C. Nasal Drug Delivery in Humans. Current Problems in Dermatology. 2011; 40: 20–35. DOI: 10.1159/000321044.Bitter C., Suter-Zimmermann K., Surbera C. Nasal Drug Delivery in Humans. Current Problems in Dermatology. 2011; 40: 20–35. DOI: 10.1159/000321044.Привалова А. М., Гуляева Н. В., Букреева Т. В. Интраназальное введение. Перспективный способ доставки лекарственных веществ в мозг. Нейрохимия. 2012; 29(2): 93–106.Privalova A. M., Bukreeva T. V., Gulyaeva N. V. Intranasal administration: A prospective drug delivery route to the brain. Neurochemical Journal. 2012; 6(2): 77–88. DOI: 10.1134/s1819712412020080 (in Russ.).Horváth T., Ambrus R., Völgyi G., Budai-Szűcs M., Márki Á., Sipos P., Szabó-Révész P. Effect of solubility enhancement on nasal absorption of meloxicam. European Journal of Pharmaceutical Sciences. 2016; 95: 96–102. DOI: 10.1016/j.ejps.2016.05.031.Horváth T., Ambrus R., Völgyi G., Budai-Szűcs M., Márki Á., Sipos P., Szabó-Révész P. Effect of solubility enhancement on nasal absorption of meloxicam. European Journal of Pharmaceutical Sciences. 2016; 95: 96–102. DOI: 10.1016/j.ejps.2016.05.031.Bartos C., Ambrus R., Sipos P., Budai-Szűcs M., Csányi E., Gáspár R., Márki Á., Seres A. B., Sztojkov-Ivanov A., Horváth T., Szabó-Révész P. Study of sodiumhyaluronate-based intranasal formulations containing micro- or nanosized meloxicamparticles. Int. J. Pharm. 2015; 491(1-2): 198–207. DOI: 10.1016/j.ijpharm.2015.06.046.Bartos C., Ambrus R., Sipos P., Budai-Szűcs M., Csányi E., Gáspár R., Márki Á., Seres A. B., Sztojkov-Ivanov A., Horváth T., Szabó-Révész P. Study of sodiumhyaluronate-based intranasal formulations containing micro- or nanosized meloxicamparticles. Int. J. Pharm. 2015; 491(1-2): 198–207. DOI: 10.1016/j.ijpharm.2015.06.046.Deutel B., Laffleur F., Palmberger T., Saxer A., Thaler M., BernkopSchnürch A. In vitro characterization of insulin containing thiomericmicroparticles as nasal drug delivery system. European Journal of Pharmaceutical Sciences. 2016; 81: 157–161. DOI: 10.1016/j.ejps.2015.10.022.Deutel B., Laffleur F., Palmberger T., Saxer A., Thaler M., BernkopSchnürch A. In vitro characterization of insulin containing thiomericmicroparticles as nasal drug delivery system. European Journal of Pharmaceutical Sciences. 2016; 81: 157–161. DOI: 10.1016/j.ejps.2015.10.022.Matsuyama T., Takahiro M., Horikiri Y. Influence of fillers in powder formulations containing N-acetyl-L-cysteine on nasal peptide absorption. Journal of Controlled Release. 2007; 120(1-2): 88–94. DOI: 10.1016/j.jconrel.2007.04.006.Matsuyama T., Takahiro M., Horikiri Y. Influence of fillers in powder formulations containing N-acetyl-L-cysteine on nasal peptide absorption. Journal of Controlled Release. 2007; 120(1-2): 88–94. DOI: 10.1016/j.jconrel.2007.04.006.Bodor N. The soft drug approach. Chemtech. 1984; 14(1): 28–38.Bodor N. The soft drug approach. Chemtech. 1984; 14(1): 28–38.Matsuyama T., Morita T., Horikiri Y., Yamahara H., Yoshino H. Improved nasal absorption of salmon calcitonin by powdery formulation with N-acetyl-l-cysteine as a mucolytic agent. Journal of Controlled Release. 2006; 115(2); 183–188. DOI: 10.1016/j.jconrel.2006.08.004.Matsuyama T., Morita T., Horikiri Y., Yamahara H., Yoshino H. Improved nasal absorption of salmon calcitonin by powdery formulation with N-acetyl-l-cysteine as a mucolytic agent. Journal of Controlled Release. 2006; 115(2); 183–188. DOI: 10.1016/j.jconrel.2006.08.004.Al-hazmi A. N-acetylcysteine as a therapeutic extract for cardiac, lung, intestine and spleen injuries induced by microcystin-LR in mice. Journal of King Saud University – Science. 2020; 32: 934–938. DOI. 10.1016/j.jksus.2019.06.001.Al-hazmi A. N-acetylcysteine as a therapeutic extract for cardiac, lung, intestine and spleen injuries induced by microcystin-LR in mice. Journal of King Saud University – Science. 2020; 32: 934–938. DOI. 10.1016/j.jksus.2019.06.001.Lee Y., Perry B. A., Labruno S., Lee H. S., Stern W., Falzone L. M., Sinko P. J. Impact of regional intestinal pH modulation on absorption of peptide drugs: oral absorption studies of salmon calcitonin in beagle dogs. Pharmaceutical Research. 1999; 16(8): 1233–1239. DOI: 10.1023/a:1014849630520.Lee Y., Perry B. A., Labruno S., Lee H. S., Stern W., Falzone L. M., Sinko P. J. Impact of regional intestinal pH modulation on absorption of peptide drugs: oral absorption studies of salmon calcitonin in beagle dogs. Pharmaceutical Research. 1999; 16(8): 1233–1239. DOI: 10.1023/a:1014849630520.Ali A., Wahlgren M., Rembratt-Svensson B., Daftani A., Falkman P., Wollmer P., Engblom J. Dehydration affects drug transport over nasal mucosa. Drug Delivery. 2019; 26(1): 831–840. DOI: 10.1080/10717544.2019.1650848.Ali A., Wahlgren M., Rembratt-Svensson B., Daftani A., Falkman P., Wollmer P., Engblom J. Dehydration affects drug transport over nasal mucosa. Drug Delivery. 2019; 26(1): 831–840. DOI: 10.1080/10717544.2019.1650848.He C., Zhuang X., Tang Z., Tian H., Chen X. Stimuli-Sensitive Synthetic Polypeptide-Based Materials for Drug and Gene Delivery. Advanced Healthcare Materials. 2011; 1(1): 48–78. DOI: 10.1002/adhm.201100008.He C., Zhuang X., Tang Z., Tian H., Chen X. Stimuli-Sensitive Synthetic Polypeptide-Based Materials for Drug and Gene Delivery. Advanced Healthcare Materials. 2011; 1(1): 48–78. DOI: 10.1002/adhm.201100008.Kricheldorf H. R. Polypeptides and 100 Years of Chemistry of α-Amino AcidN-Carboxyanhydrides. Angewandte Chemie International Edition. 2006; 45(35): 5752–5784. DOI: 10.1002/anie.200600693.Kricheldorf H. R. Polypeptides and 100 Years of Chemistry of α-Amino AcidN-Carboxyanhydrides. Angewandte Chemie International Edition. 2006; 45(35): 5752–5784. DOI: 10.1002/anie.200600693.Shah A., Malik M. S., Khan G. S., Nosheen E., Iftikhar F. J., Khan F. A., Aminabhavi T. M. Stimuli-responsive peptide-based biomaterials as drug delivery systems. Chemical Engineering Journal. 2018; 353: 559–583. DOI: 10.1016/j.cej.2018.07.126.Shah A., Malik M. S., Khan G. S., Nosheen E., Iftikhar F. J., Khan F. A., Aminabhavi T. M. Stimuli-responsive peptide-based biomaterials as drug delivery systems. Chemical Engineering Journal. 2018; 353: 559–583. DOI: 10.1016/j.cej.2018.07.126.Matson J. B., Zha R. H., Stupp S. I. Peptide self-assembly for crafting functional biological materials. Current Opinion in Solid State and Materials Science. 2011; 15(6): 225–235. DOI: 10.1016/j.cossms.2011.08.001.Matson J. B., Zha R. H., Stupp S. I. Peptide self-assembly for crafting functional biological materials. Current Opinion in Solid State and Materials Science. 2011; 15(6): 225–235. DOI: 10.1016/j.cossms.2011.08.001.Wong S., Shim M. S., Kwon Y. J. Synthetically designed peptide-based biomaterials with stimuli-responsive and membrane-active properties for biomedical applications. J. Mater. Chem. B. 2014; 2(6): 595–615. DOI: 10.1039/c3tb21344g.Wong S., Shim M. S., Kwon Y. J. Synthetically designed peptide-based biomaterials with stimuli-responsive and membrane-active properties for biomedical applications. J. Mater. Chem. B. 2014; 2(6): 595–615. DOI: 10.1039/c3tb21344g.Sankaranarayanan K., Meenakshisundaram N. Micro-viscosity induced conformational transitions in poly-l-lysine. RSC Adv. 2016; 6(78): 74009–74017. DOI: 10.1039/c6ra11626d.Sankaranarayanan K., Meenakshisundaram N. Micro-viscosity induced conformational transitions in poly-l-lysine. RSC Adv. 2016; 6(78): 74009–74017. DOI: 10.1039/c6ra11626d.Ito Y., Park Y. S., Imanishi Y. Nanometer-sized channel gating by a selfassembled polypeptide brush. Langmuir. 2000; 16(12): 5376–5381. DOI: 10.1021/la991102+.Ito Y., Park Y. S., Imanishi Y. Nanometer-sized channel gating by a selfassembled polypeptide brush. Langmuir. 2000; 16(12): 5376–5381. DOI: 10.1021/la991102+.Lee E. S., Shin H. J., Na K., Bae Y. H. Poly(l-histidine) – PEG block copolymer micelles and pH-induced destabilization. Journal of Controlled Release. 2003; 90(3): 363–374. DOI: 10.1016/s0168-3659(03)00205-0.Lee E. S., Shin H. J., Na K., Bae Y. H. Poly(l-histidine) – PEG block copolymer micelles and pH-induced destabilization. Journal of Controlled Release. 2003; 90(3): 363–374. DOI: 10.1016/s0168-3659(03)00205-0.Chang G., Li C., Lu W., Ding J. N-Boc-Histidine-Capped PLGA-PEG-PLGA as a Smart Polymer for Drug Delivery Sensitive to Tumor Extracellular pH. Macromolecular Bioscience. 2010; 10(10): 1248–1256. DOI: 10.1002/mabi.201000117.Chang G., Li C., Lu W., Ding J. N-Boc-Histidine-Capped PLGA-PEG-PLGA as a Smart Polymer for Drug Delivery Sensitive to Tumor Extracellular pH. Macromolecular Bioscience. 2010; 10(10): 1248–1256. DOI: 10.1002/mabi.201000117.Chen P., Qiu M., Deng C., Meng F., Zhang J., Cheng R., Zhong Z. pHResponsive Chimaeric Pepsomes Based on Asymmetric Poly(ethylene glycol)-b-Poly(l-leucine)-b-Poly(l-glutamic acid) Triblock Copolymer for Efficient Loading and Active Intracellular Delivery of Doxorubicin Hydrochloride. Biomacromolecules. 2015; 16(4): 1322–1330. DOI: 10.1021/acs.biomac.5b00113.Chen P., Qiu M., Deng C., Meng F., Zhang J., Cheng R., Zhong Z. pHResponsive Chimaeric Pepsomes Based on Asymmetric Poly(ethylene glycol)-b-Poly(l-leucine)-b-Poly(l-glutamic acid) Triblock Copolymer for Efficient Loading and Active Intracellular Delivery of Doxorubicin Hydrochloride. Biomacromolecules. 2015; 16(4): 1322–1330. DOI: 10.1021/acs.biomac.5b00113.Yan J., Liu K., Zhang X., Li W., Zhang A. Dynamic covalent polypeptides showing tunable secondary structures and thermoresponsiveness. Journal of Polymer Science Part A: Polymer Chemistry. 2014; 53(1): 33–41. DOI: 10.1002/pola.27433.Yan J., Liu K., Zhang X., Li W., Zhang A. Dynamic covalent polypeptides showing tunable secondary structures and thermoresponsiveness. Journal of Polymer Science Part A: Polymer Chemistry. 2014; 53(1): 33–41. DOI: 10.1002/pola.27433.Hassouneh W., Zhulina E. B., Chilkoti A., Rubinstein M. Elastinlike Polypeptide Diblock Copolymers Self-Assemble into Weak Micelles. Macromolecules. 2015; 48(12): 4183–4195. DOI: 10.1021/acs.macromol.5b00431.Hassouneh W., Zhulina E. B., Chilkoti A., Rubinstein M. Elastinlike Polypeptide Diblock Copolymers Self-Assemble into Weak Micelles. Macromolecules. 2015; 48(12): 4183–4195. DOI: 10.1021/acs.macromol.5b00431.Ward M. A., Georgiou T. K. Thermoresponsive Polymers for Biomedical Applications. Polymers. 2011; 3(3): 1215–1242. DOI: 10.3390/polym3031215.Ward M. A., Georgiou T. K. Thermoresponsive Polymers for Biomedical Applications. Polymers. 2011; 3(3): 1215–1242. DOI: 10.3390/polym3031215.Schwendeman S. P., Shah R. B., Bailey B. A., Schwendeman A. S. Injectable controlled release depots for large molecules. Journal of Controlled Release. 2014; 190: 240–253. DOI: 10.1016/j.jconrel.2014.05.057.Schwendeman S. P., Shah R. B., Bailey B. A., Schwendeman A. S. Injectable controlled release depots for large molecules. Journal of Controlled Release. 2014; 190: 240–253. DOI: 10.1016/j.jconrel.2014.05.057.Rosenthal R. N., Ling W., Casadonte P., Vocci F., Bailey G. L., Kampman K., Beebe K. L. Buprenorphine implants for treatment of opioid dependence: randomized comparison to placebo and sublingual buprenorphine/naloxone. Addiction. 2013; 108(12): 2141– 2149. DOI: 10.1111/add.12315.Rosenthal R. N., Ling W., Casadonte P., Vocci F., Bailey G. L., Kampman K., Beebe K. L. Buprenorphine implants for treatment of opioid dependence: randomized comparison to placebo and sublingual buprenorphine/naloxone. Addiction. 2013; 108(12): 2141– 2149. DOI: 10.1111/add.12315.Narukawa T., Soh J., Kanemitsu N., Harikai S., Ukimura O. Efficacy of combined treatment of intramuscular testosterone injection and testosterone ointment application for late-onset hypogonadism: an open-labeled, randomized, crossover study. The Aging Male. 2019: 1–7. DOI: 10.1080/13685538.2019.1666814.Narukawa T., Soh J., Kanemitsu N., Harikai S., Ukimura O. Efficacy of combined treatment of intramuscular testosterone injection and testosterone ointment application for late-onset hypogonadism: an open-labeled, randomized, crossover study. The Aging Male. 2019: 1–7. DOI: 10.1080/13685538.2019.1666814.Bowersock T. L., Martin S. Vaccine delivery to animals. Advanced Drug Delivery Reviews. 1999; 38(2): 167–194. DOI: 10.1016/s0169-409x(99)00015-0.Bowersock T. L., Martin S. Vaccine delivery to animals. Advanced Drug Delivery Reviews. 1999; 38(2): 167–194. DOI: 10.1016/s0169-409x(99)00015-0.Dubey A., Shami T. Metamaterials in Electromagnetic Wave Absorbers.Defence Science Journal. 2012; 62(4): 261–268. DOI: 10.14429/dsj.62.1514.Dubey A., Shami T. Metamaterials in Electromagnetic Wave Absorbers.Defence Science Journal. 2012; 62(4): 261–268. DOI: 10.14429/dsj.62.1514.Dunn R. L., English J. P., Cowsar D. R., Vanderbelt D. D. Biodegradable in-situ forming implants and methodfor producing the same. US Patent 23 Aug. 1994; 5: 340849.Dunn R. L., English J. P., Cowsar D. R., Vanderbelt D. D. Biodegradable in-situ forming implants and methodfor producing the same. US Patent 23 Aug. 1994; 5: 340849.Saleem M. A., Ahmed S. I. Tephrosiapurpureaameliorates benzoyl peroxides-induced cutaneoustoxicity in mice: diminution of oxidative stress. Pharm Pharmacol Commun. 1999; 5(7): 455–461. DOI: 10.1211/146080899128735162.Saleem M. A., Ahmed S. I. Tephrosiapurpureaameliorates benzoyl peroxides-induced cutaneoustoxicity in mice: diminution of oxidative stress. Pharm Pharmacol Commun. 1999; 5(7): 455–461. DOI: 10.1211/146080899128735162.Wang L., Venkatraman S., Kleiner L. Drug release from injectable depots: two different in vitro mechanisms. J Control Release. 2004; 99(2): 207–216. DOI: 10.1016/j.jconrel.2004.06.021.Wang L., Venkatraman S., Kleiner L. Drug release from injectable depots: two different in vitro mechanisms. J Control Release. 2004; 99(2): 207–216. DOI: 10.1016/j.jconrel.2004.06.021.Paik D. H., Choi S. W. Entrapment of Protein Using Electrosprayed Poly(d,l-lactide-co-glycolide) Microspheres with a Porous Structure for Sustained Release. Macromolecular Rapid Communications. 2014; 35(11): 1033–1038. DOI: 10.1002/marc.201400042.Paik D. H., Choi S. W. Entrapment of Protein Using Electrosprayed Poly(d,l-lactide-co-glycolide) Microspheres with a Porous Structure for Sustained Release. Macromolecular Rapid Communications. 2014; 35(11): 1033–1038. DOI: 10.1002/marc.201400042.Brudno Y., Mooney D. J. On-demand drug delivery from local depots. Journal of Controlled Release. 2015; 219: 8–17. DOI: 10.1016/j.jconrel.2015.09.011.Brudno Y., Mooney D. J. On-demand drug delivery from local depots. Journal of Controlled Release. 2015; 219: 8–17. DOI: 10.1016/j.jconrel.2015.09.011.Kwok C. S., Mourad P. D., Crum L. A., Self-assembled molecular structures as ultrasonically-responsivebarriermembranes for pulsatile drug delivery. J. Biomed. Mater. Res. 2001; 57(2): 151–164. DOI: 10.1002/1097-4636(200111)57:23.0.co;2-5.Kwok C. S., Mourad P. D., Crum L. A., Self-assembled molecular structures as ultrasonically-responsivebarriermembranes for pulsatile drug delivery. J. Biomed. Mater. Res. 2001; 57(2): 151–164. DOI: 10.1002/1097-4636(200111)57:23.0.co;2-5.Laurent S., Forge D., Port M., Roch A., Robic C., Vander E. L., Muller R. N. ChemInform Abstract: Magnetic Iron Oxide Nanoparticles: Synthesis, Stabilization, Vectorization, Physicochemical Characterizations, and Biological Applications. ChemInform. 2008; 39(35). DOI: 10.1002/chin.200835229.Laurent S., Forge D., Port M., Roch A., Robic C., Vander E. L., Muller R. N. ChemInform Abstract: Magnetic Iron Oxide Nanoparticles: Synthesis, Stabilization, Vectorization, Physicochemical Characterizations, and Biological Applications. ChemInform. 2008; 39(35). DOI: 10.1002/chin.200835229.Preiss M. R., Bothun G. D. Stimuli-responsive liposome-nanoparticle assemblies. Expert Opinion on Drug Delivery. 2011; 8(8): 1025–1040. DOI: 10.1517/17425247.2011.584868.Preiss M. R., Bothun G. D. Stimuli-responsive liposome-nanoparticle assemblies. Expert Opinion on Drug Delivery. 2011; 8(8): 1025–1040. DOI: 10.1517/17425247.2011.584868.Харитонов Ю. Я., Черкасова О. Г., Завадский С. П., Цыбусов С. Н., Краснюк И. И. (мл.), Григорьева В. Ю. Контроль качества магнитных наполнителей для магнитных лекарственных форм. Разработка и регистрация лекарственных средств. 2016; 3(16): 112–117.Kharitonov Y. Y., Cherkasova O. G., Zavadskiy S. P., Tsybusov S. N., Krasnyuk (Jr) I. I., Grigorjeva V. Y. Quality control of magnetic fillers for magnetic formulations. Drug development & registration. 2016; 3(16): 100–106 (in Russ.).Харитонов Ю. Я., Черкасова О. Г., Завадский С. П., Шабалкина Е. Ю., Краснюк И. И. (мл.), Григорьева В. Ю., Цыбусов С. Н., Абизов Е. А. Разработка способов и методик контроля качества магнитных лечебных средств (магнитных мазей, магнитных суппозиториев, железоуглеродного компонента для криохирургии). Разработка и регистрация лекарственных средств. 2016; 4(17): 100–106.Kharitonov Y. Y., Cherkasova O. G., Zavadskiy S. P., Shabalkina E. Y., Krasnyuk (Jr.) I. I., Grigorjeva V. Y., Tsybusov S. N., Abizov E. A. Development of the procedures of quality control of magnetic medications (magnetic medical ointments, magnetic suppositories, iron-carbon composite for the cryosurgery). Drug development & registration. 2016; (4): 112–117 (in Russ.).Murdan, S. Electro-responsive drug delivery from hydrogels. Journal of Controlled Release. 2003; 92(1-2): 1–17. DOI: 10.1016/s0168-3659(03)00303-1.Murdan, S. Electro-responsive drug delivery from hydrogels. Journal of Controlled Release. 2003; 92(1-2): 1–17. DOI: 10.1016/s0168-3659(03)00303-1.Murakami Y., Maeda M. DNA-Responsive Hydrogels That Can Shrink or Swell. Biomacromolecules. 2005; 6(6): 2927–2929. DOI: 10.1021/bm0504330.Murakami Y., Maeda M. DNA-Responsive Hydrogels That Can Shrink or Swell. Biomacromolecules. 2005; 6(6): 2927–2929. DOI: 10.1021/bm0504330.Murakami Y., Maeda M. Hybrid Hydrogels to Which Single-Stranded (ss) DNA Probe Is Incorporated Can Recognize Specific ssDNA. Macromolecules. 2005; 38(5): 1535–1537. DOI: 10.1021/ma047803h.Murakami Y., Maeda M. Hybrid Hydrogels to Which Single-Stranded (ss) DNA Probe Is Incorporated Can Recognize Specific ssDNA. Macromolecules. 2005; 38(5): 1535–1537. DOI: 10.1021/ma047803h.Wang Z. H., Wang Z. Y., Sun C. S., Wang C. Y., Jiang T. Y., Wang S. L. Trimethylated chitosan-conjugated PLGA nanoparticles for the delivery of drugs to the brain. Biomaterials. 2010; 31(5): 908–915. DOI: 10.1016/j.biomaterials.2009.09.104.Wang Z. H., Wang Z. Y., Sun C. S., Wang C. Y., Jiang T. Y., Wang S. L. Trimethylated chitosan-conjugated PLGA nanoparticles for the delivery of drugs to the brain. Biomaterials. 2010; 31(5): 908–915. DOI: 10.1016/j.biomaterials.2009.09.104.Sultana Y., Maurya D. P., Iqbal Z., Aqil M. Nanotechnology in ocular delivery: current and future directions. Drugs Today. 2011; 47(6): 441– 455. DOI: 10.1358/dot.2011.47.6.1549023.Sultana Y., Maurya D. P., Iqbal Z., Aqil M. Nanotechnology in ocular delivery: current and future directions. Drugs Today. 2011; 47(6): 441– 455. DOI: 10.1358/dot.2011.47.6.1549023.Patlolla R. R., Chougule M., Patel A. R., Jackson T., Tata P. N., Singh M. Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers. J Control Release. 2010; 144(2): 233–241. DOI: 10.1016/j.jconrel.2010.02.006.Patlolla R. R., Chougule M., Patel A. R., Jackson T., Tata P. N., Singh M. Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers. J Control Release. 2010; 144(2): 233–241. DOI: 10.1016/j.jconrel.2010.02.006.Slutter B., Bal S., Keijzer C., Mallants R., Hagenaars N., Que I. et al. Nasal vaccinationwith N-trimethyl chitosan and PLGA based nanoparticles: nanoparticle characteristics determine quality and strength of the antibody response in mice against the encapsulated antigen. Vaccine. 2010; 28 (38): 6282–6291. DOI: 10.1016/j.vaccine.2010.06.121.Slutter B., Bal S., Keijzer C., Mallants R., Hagenaars N., Que I. et al. Nasal vaccinationwith N-trimethyl chitosan and PLGA based nanoparticles: nanoparticle characteristics determine quality and strength of the antibody response in mice against the encapsulated antigen. Vaccine. 2010; 28 (38): 6282–6291. DOI: 10.1016/j.vaccine.2010.06.121.Lee P. W., Hsu S. H., Tsai J. S., Chen F. R., Huang P. J., Ke C. J. et al. Multifunctional coreshellpolymeric nanoparticles for transdermal DNA delivery and epidermal langerhans cells tracking. Biomaterials. 2010; 31(8): 2425–2434. Doi: 10.1016/j.biomaterials.2009.11.100.Lee P. W., Hsu S. H., Tsai J. S., Chen F. R., Huang P. J., Ke C. J. et al. Multifunctional coreshellpolymeric nanoparticles for transdermal DNA delivery and epidermal langerhans cells tracking. Biomaterials. 2010; 31(8): 2425–2434. Doi: 10.1016/j.biomaterials.2009.11.100.Barry B. W. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001; 14(2): 101–114. DOI: 10.1016/s0928-0987(01)00167-1.Barry B. W. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001; 14(2): 101–114. DOI: 10.1016/s0928-0987(01)00167-1.Clark S. L., Crowley A. J., Schmidt P. G., Donoghue A. R., Piche C. A. Long-termdelivery of ivermectin by use of poly(D, L-lactic-co-glycolic) acid microparticlesindogs. Am. J. Vet. Res. 2004; 65(6): 752–757. DOI: 10.2460/ajvr.2004.65.752.Clark S. L., Crowley A. J., Schmidt P. G., Donoghue A. R., Piche C. A. Long-termdelivery of ivermectin by use of poly(D, L-lactic-co-glycolic) acid microparticlesindogs. Am. J. Vet. Res. 2004; 65(6): 752–757. DOI: 10.2460/ajvr.2004.65.752.Camargo J. A., Sapin A., Nouvel C., Daloz D., Leonard M., Bonneaux F., Six J. L., Maincent P. Injectable PLA-based in situ forming implants for controlled releaseof Ivermectin a BCS Class II drug: solvent selection based on physico-chemicalcharacterization. Drug Dev. Ind. Pharm. 2012; 39(1): 146–155. DOI: 10.3109/03639045.2012.660952.Camargo J. A., Sapin A., Nouvel C., Daloz D., Leonard M., Bonneaux F., Six J. L., Maincent P. Injectable PLA-based in situ forming implants for controlled releaseof Ivermectin a BCS Class II drug: solvent selection based on physico-chemicalcharacterization. Drug Dev. Ind. Pharm. 2012; 39(1): 146–155. DOI: 10.3109/03639045.2012.660952.Iezzi S., Purslow P., Sara C., Lanusse C., Lifschitz A. Relationship betweenivermectin concentrations at the injection site, muscle and fat of steers treated withtraditional and long-acting preparations. Food and Chemical Toxicology. 2017; 105: 319–321. DOI: 10.1016/j.fct.2017.05.005.Iezzi S., Purslow P., Sara C., Lanusse C., Lifschitz A. Relationship betweenivermectin concentrations at the injection site, muscle and fat of steers treated withtraditional and long-acting preparations. Food and Chemical Toxicology. 2017; 105: 319–321. DOI: 10.1016/j.fct.2017.05.005.Pollock J., Bedenice D., Jennings S. H., Papich M. G. Pharmacokinetics of anextended-release formulation of eprinomectin in healthy adult alpacas and its use inalpacas confirmed with mange. J. Vet. Pharmacol. Ther. 2016; 40(2): 192–199. DOI: 10.1111/jvp.12341.Pollock J., Bedenice D., Jennings S. H., Papich M. G. Pharmacokinetics of anextended-release formulation of eprinomectin in healthy adult alpacas and its use inalpacas confirmed with mange. J. Vet. Pharmacol. Ther. 2016; 40(2): 192–199. DOI: 10.1111/jvp.12341.Chen B. Z., Yang Y., Wang B. B., Ashfaq M., Guo, X. D. Self-implanted tiny needles as alternative to traditional parenteral administrations for controlled transdermal drug delivery. International Journal of Pharmaceutics. 2019; 556: 338–348. DOI: 10.1016/j.ijpharm.2018.12.019.Chen B. Z., Yang Y., Wang B. B., Ashfaq M., Guo, X. D. Self-implanted tiny needles as alternative to traditional parenteral administrations for controlled transdermal drug delivery. International Journal of Pharmaceutics. 2019; 556: 338–348. DOI: 10.1016/j.ijpharm.2018.12.019.Peng H., Qian X., Mao L., Jiang L., Sun Y., Zhou Q. Ultrafast ultrasound imaging in acoustic microbubble trapping. Applied Physics Letters. 2019; 115(20): 203701. DOI: 10.1063/1.5124437.Peng H., Qian X., Mao L., Jiang L., Sun Y., Zhou Q. Ultrafast ultrasound imaging in acoustic microbubble trapping. Applied Physics Letters. 2019; 115(20): 203701. DOI: 10.1063/1.5124437.

The authors declare that there are no conflicts of interest present.