pharmjournalРазработка и регистрация лекарственных средствDrug development & registration2305-20662658-5049LLC «CPHA»10.33380/2305-2066-2025-14-4-2148pharmjournal-2220Research ArticleФАРМАЦЕВТИЧЕСКАЯ ТЕХНОЛОГИЯPHARMACEUTICAL TECHNOLOGYРазработка поликомплексных носителей на основе гидроксипропилцеллюлозы и Carbopol® для гастроретентивной доставки лекарственных средствDevelopment of polycomplex carriers based on hydroxypropyl cellulose and Carbopol® for gastroretentive drug deliveryhttps://orcid.org/0009-0004-8058-8007ЗаболотнаяУ. Н.ZabolotnayaU. N.

420126, Республика Татарстан, г. Казань, ул. Фатыха Амирхана, д. 16

16, Fatykha Amirkhan str., Kazan, Republic of Tatarstan, 420126

https://orcid.org/0000-0002-3690-8905ТимергалиеваВ. Р.TimergalievaV. R.

420126, Республика Татарстан, г. Казань, ул. Фатыха Амирхана, д. 16

16, Fatykha Amirkhan str., Kazan, Republic of Tatarstan, 420126

https://orcid.org/0000-0002-7255-8041НасибуллинШ. Ф.NasibullinS. F.

420126, Республика Татарстан, г. Казань, ул. Фатыха Амирхана, д. 16

16, Fatykha Amirkhan str., Kazan, Republic of Tatarstan, 420126

https://orcid.org/0000-0002-0916-2853МустафинР. И.MoustafineR. I.

420126, Республика Татарстан, г. Казань, ул. Фатыха Амирхана, д. 16

16, Fatykha Amirkhan str., Kazan, Republic of Tatarstan, 420126

ruslan.mustafin@kazangmu.ruИнститут фармации, федеральное государственное бюджетное образовательное учреждение высшего образования «Казанский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияInstitute of Pharmacy. Kazan State Medical UniversityRussian Federation202503122025144108124Copyright © Заболотная У.Н., Тимергалиева В.Р., Насибуллин Ш.Ф., Мустафин Р.И., 20252025Заболотная У.Н., Тимергалиева В.Р., Насибуллин Ш.Ф., Мустафин Р.И.Zabolotnaya U.N., Timergalieva V.R., Nasibullin S.F., Moustafine R.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/2220Введение

Введение. В результате исследования был изучен процесс образования интерполимерного комплекса (ИПК) между парами полимеров: гидроксипропилцеллюлозой (ГПЦ) и разными марками Carbopol® (71G, 971, 974) – при двух порядках смешения в среде этанола 95 % при pH = 3,5 (подкисленной 0,1 M HCl) методами турбидиметрии, ИК-спектроскопии, термогравиметрического анализа (ТГА). Проведенные эксперименты подтвердили образование поликомплекса между данными парами полимеров. По результатам исследований было выбрано оптимальное соотношение пары ГПЦ и Carbopol® 71G в стехиометричном эквимольном соотношении независимо от порядка их смешивания. С использованием метода модулированной дифференциально-сканирующей калориметрии (мДСК), была подтверждена совместимость изучаемых полимеров в составе образующегося поликомплекса. Согласно проведенному элементному анализу полученный ИПК имел стехиометрический состав ГПЦ / Carbopol® 71G 1 : 2 (по молям). Исследование набухаемости матриц, полученных на основе синтезированного ИПК, а также компактов из индивидуальных полимеров и их физической смеси состава, аналогичного поликомплексу, было проведено в среде, имитирующей желудочных сок, в сравнении с исходными компонентами. Изучение высвобождения ацикловира из полученных носителей также проводилось в среде 0,1 М HCl, результаты показали перспективность разработанной системы для создания носителя с направленным высвобождением лекарственных средств (ЛС) в модельную, имитирующую голодный желудок среду. Исследуемые образцы ИПК показали низкие мукоадгезивные свойства по сравнению с индивидуальными полимерами и их физической смесью. Разработка новых носителей для доставки ЛС является одним из ключевых направлений фармацевтической технологии. В связи с этим особое внимание уделяется веществам полимерной природы, носители на основе которых обеспечивают снижение побочных эффектов, повышение биодоступности и пролонгирования действия ЛС. Системы для гастроретентивной доставки представляют интерес при разработке новых лекарственных форм (ЛФ), позволяющих регулировать скорость высвобождения активного фармацевтического ингредиента (АФИ) в желудке.

Цель

Цель. Разработка поликомплексного носителя на основе гидроксипропилцеллюлозы с участием Carbopol® для гастроретентивной доставки ацикловира.

Материалы и методы

Материалы и методы. Подбор условий образования ИПК проводился с использованием методов турбидиметрии, ИК-спектроскопии, ТГА. Полученный оптимальный состав поликомплексного носителя был охарактеризован с использованием методов мДСК и ИК-спектроскопии. Изучение набухаемости матриц на основе синтезированного ИПК проводилось в среде, имитирующей желудочных сок. Изучение высвобождения ацикловира из полимерных матриц в среду растворения проводили по методу 1 «Вращающаяся корзинка» согласно Государственной фармакопее РФ XV издания. Мукоадгезия исследовалась на анализаторе текстуры TA.XTplus (Stable Micro Systems, Великобритания) на компактах из муцина.

Результаты и обсуждение

Результаты и обсуждение. Формирование ИПК происходит посредством образования водородных связей между —OH-группами макромолекулярных звеньев линейной ГПЦ и —COOH-группами редкосшитой полиакриловой кислоты (рПАК) в составе используемых марок карбополов. Смещение характеристической полосы влево до 1730 см–1 на ИК-спектрах поликомплексов подтверждает образование ИПК. ИПК характеризуются единственной температурой стеклования (Тс = 91,0 ± 2,1 °C). Элементный анализ выявил двухкратный мольный избыток редкосшитого полимера (Carbopol® 71G) над линейным (ГПЦ). На протяжении всего эксперимента по изучению кинетики набухаемости компактированные матрицы сохраняют свою форму, увеличиваясь в размерах. С использованием термического анализа образцов поликомплексных матриц в процессе оценки их набухаемости был проведен мониторинг возможных структурных преобразований, подтвердивший устойчивость поликомплекса в кислой среде. По результатам исследования кинетики высвобождения модельного АФИ максимальная концентрация ацикловира, перешедшего в среду, наблюдается на 30-й мин эксперимента и составляет 98,5 %. Тогда как для ГПЦ-матриц максимальная концентрация достигается по истечении 2 ч, а для матриц на основе Carbopol® 71G и их физической смеси (ФС) – только в заключительной части эксперимента. Синтезированный ИПК характеризовался низкой способностью к мукоадгезии к компактам из муцина по сравнению с индивидуальными полимерами и ФС.

Заключение

Заключение. В результате исследования были подобраны оптимальные условия образования ИПК между парами полимеров – ГПЦ и изучаемыми марками Carbopol® (71G, 971 и 974). Методами турбидиметрии, ИК-спектроскопии и ТГА доказано образование поликомплексов на основе ГПЦ и различных марок Carbopol®. ИПК ГПЦ / Carbopol® 71G стехиометрического состава, подтвержденный элементным анализом, был охарактеризован с использованием термических и спектральных методов. Изучение высвобождения ацикловира из полученных матриц показало перспективность применения разработанной системы для пероральной гастроретентивной его доставки.

Introduction

Introduction. As a result of the study, the process of formation of interpolymer complex (IPC) between pairs of polymers was studied between hydroxypropyl cellulose (HPC) and different brands of Carbopol® 71G, 971, 974 at two mixing orders in 95 % ethanol at pH = 3,5 (acidified with 0,1 M HCl) by turbidimetry, IR-spectroscopy, thermogravimetric analysis (TGA). The performed experiments confirmed the formation of an interpolymer complex (IPC) between these pairs of polymers. According to the research results, the prospective ratio of a pair of HPC and Carbopol® 71G was selected in a stoichiometric equimolar ratio regardless of the mixing order. The compatibility of the studied polymers in the composition of the resulting polycomplex was confirmed, using the method of modulated differential scanning calorimetry (mDSC). The obtained IPC had a stoichiometric composition of Carbopol® 71G / HPC 2 : 1 (by moles), according to the elemental analysis. Swelling of matrices based on the synthesized IPC, as well as matrices from individual polymers and their physical mixture (PM), was carried out in a medium simulating stomach acid in comparison with the original polymers. The analysis of the of acyclovir release from the produced carriers was also carried out in a 0.1 M HCl media and showed the prospects of the developed system for creating a carrier with targeted release of drugs into a model environment simulating an empty stomach. The IPC samples showed low mucoadhesive properties compared to individual polymers and their physical mixture. The development of new carriers for drug delivery is one of the key areas of pharmaceutical technology. In this regard, special attention is paid to polymeric substances, carriers based on which provide a reduction in side effects, increased bioavailability and prolongation of the drug action. Gastroretentive delivery systems are of interest in the development of new dosage forms that allow regulating the rate of release of the active pharmaceutical ingredient (API) in the stomach.

Aim

Aim. Development of a polycomplex carrier based on hydroxypropyl cellulose with Carbopol® for gastroretentive delivery of acyclovir.

Materials and methods

Materials and methods. The selection of IPC – formation conditions was carried out using the methods of turbidimetry, IR-spectroscopy, and TGA. The obtained optimal polycomplex carrier composition was characterized using modulated differential scanning calorimetry (mDSC) and IR-spectroscopy. The swelling of the matrices based on the synthesized polycomplex was studied in an environment that imitating stomach acid. The acyclovir release from the resulting matrices was studied in modeling media using method 1 (USP I) "basket method". Mucoadhesion was studied using a TA.XTplus texture analyzer (Stable Micro Systems, Surrey, UK) on mucin compacts.

Results and discussion

Results and discussion. The formation of IPC occurs through the formation of hydrogen bonds between the —OH groups of macromolecular units of linear HPC and —COOH groups of rare-crosslinked polyacrylic acid (rPAA) in the composition of the used brands of Carbopol’s. The leftward shift of the characteristic band to 1730 cm–1 in the FTIR spectra of the polycomplexes confirms the formation of IPCs. The IPCs are characterised by a single glass transition temperature (Tg = 91,0 ± 2,1 ºC). Elemental analysis revealed a two-fold molar excess of the rare cross-linked polymer (Carbopol® 71G) over the linear one (HPC). Throughout the entire experiment to study the kinetics of swelling, the compacted matrices retain their shape, increasing in size. Monitoring of possible structural transformations was carried out, using thermal analysis of samples of polycomplex matrices in the process of assessing their swelling, to confirm the stability of the polycomplex in an acidic environment. According to the results of the model API release kinetics, the maximum concentration of acyclovir released into the media is observed at 30 minutes of the experiment and equal 98.5 %. Whereas for HPC matrices, the maximum concentration is achieved after 2 hours, and for matrices based on Carbopol® 71G and their PM only in the final part of the experiment. The synthesized IPC was characterized by low mucoadhesion capacity on mucin compacts compared to individual polymers and the PM.

Conclusion

Conclusion. As a result of the study, optimal conditions for IPC – formation between pairs of polymers HPC and different brands of Carbopol® (71G, 971 and 974) were selected. Turbidimetry, IR-spectroscopy and TGA methods proved the formation of polycomplexes based on HPC and various brands of Carbopol®. The IPC HPC / Carbopol® 71G of stoichiometric composition, confirmed by elemental analysis, was characterized using thermal and spectral methods. The study of the release of acyclovir from the obtained matrices has shown the promise of using the developed systems for oral gastroretentive delivery.

интерполимерные комплексыпроизводные целлюлозыносителиконтролируемая доставкагидроксипропилцеллюлозапроизводные редкосшитой полиакриловой кислотыCarbopol®interpolymer complexescellulose derivativescarrierscontrolled deliveryhydroxypropyl cellulosederivatives of crosslinked polyacrylic acidCarbopol®Исследование было выполнено при финансовой поддержке Российского научного фонда (научный проект № 23-15-00263).The research was carried out with the financial support of the Russian Science Foundation (scientific project № 23-15-00263).ReferencesKhutoryanskiy V. V., Dubolazov A. V., Mun G. A. pH- and ionic strength effects on interpolymer complexation via hydrogen-bonding. In: Khutoryanskiy V. V., Staikos G., editors. Hydrogen-bonded interpolymer complexes: Formation, structure and applications. Singapore: World Scientific Publishing Co. Pte. Ltd.; 2009. P. 1–21. DOI: 10.1142/9789812709776_0001.Khutoryanskiy V. V., Dubolazov A. V., Mun G. A. pH- and ionic strength effects on interpolymer complexation via hydrogen-bonding. In: Khutoryanskiy V. V., Staikos G., editors. Hydrogen-bonded interpolymer complexes: Formation, structure and applications. Singapore: World Scientific Publishing Co. Pte. Ltd.; 2009. P. 1–21. DOI: 10.1142/9789812709776_0001.Smyslov R. Y., Gorshkova Y. E., Nekrasova T. N., Makhayeva D. N., Mun G. A., Irmukhametova G. S., Khutoryanskiy V. V. Dynamic and structural insights into hydrogen-bonded interpolymer complexes of poly (2-alkyl-2-oxazolines) with poly (carboxylic acids). Journal of Colloid and Interface Science. 2025;699(1):138185. DOI: 10.1016/j.jcis.2025.138185.Smyslov R. Y., Gorshkova Y. E., Nekrasova T. N., Makhayeva D. N., Mun G. A., Irmukhametova G. S., Khutoryanskiy V. V. Dynamic and structural insights into hydrogen-bonded interpolymer complexes of poly (2-alkyl-2-oxazolines) with poly (carboxylic acids). Journal of Colloid and Interface Science. 2025;699(1):138185. DOI: 10.1016/j.jcis.2025.138185.Kopishev E., Jafarova F., Tolymbekova L., Seitenova G., Sаfarov R. Interpolymer Complexation Between Cellulose Ethers, Poloxamers, and Polyacrylic Acid: Surface-Dependent Behavior. Polymers. 2025;17(10):1414. DOI: 10.3390/polym17101414.Kopishev E., Jafarova F., Tolymbekova L., Seitenova G., Sаfarov R. Interpolymer Complexation Between Cellulose Ethers, Poloxamers, and Polyacrylic Acid: Surface-Dependent Behavior. Polymers. 2025;17(10):1414. DOI: 10.3390/polym17101414.Khutoryanskiy V. V. Pharmaceutical applications of interpolymer complexes. In: Khutoryanskiy V. V., Staikos G., editors. Hydrogen-bonded interpolymer complexes. Formation, structure and applications. Singapore: World Scientific Publishing Co. Pte. Ltd.; 2009. P. 235–258. DOI: 10.1142/9789812709776_0009.Khutoryanskiy V. V. Pharmaceutical applications of interpolymer complexes. In: Khutoryanskiy V. V., Staikos G., editors. Hydrogen-bonded interpolymer complexes. Formation, structure and applications. Singapore: World Scientific Publishing Co. Pte. Ltd.; 2009. P. 235–258. DOI: 10.1142/9789812709776_0009.Khutoryanskiy V. V. Hydrogen-bonded interpolymer complexes as materials for pharmaceutical applications. International Journal of Pharmaceutics. 2007;334(1–2):15–26. DOI: 10.1016/j.ijpharm.2007.01.037.Khutoryanskiy V. V. Hydrogen-bonded interpolymer complexes as materials for pharmaceutical applications. International Journal of Pharmaceutics. 2007;334(1–2):15–26. DOI: 10.1016/j.ijpharm.2007.01.037.Keldibekova R., Suleimenova S., Nurgozhina G., Kopishev E. Interpolymer Complexes Based on Cellulose Ethers: Application. Polymers. 2023;15(15):3326. DOI: 10.3390/polym15153326.Keldibekova R., Suleimenova S., Nurgozhina G., Kopishev E. Interpolymer Complexes Based on Cellulose Ethers: Application. Polymers. 2023;15(15):3326. DOI: 10.3390/polym15153326.Adeleke O. A. Premium ethylcellulose polymer based architectures at work in drug delivery. International Journal of Pharmaceutics. 2019;1:100023. DOI: 10.1016/j.ijpx.2019.100023.Adeleke O. A. Premium ethylcellulose polymer based architectures at work in drug delivery. International Journal of Pharmaceutics. 2019;1:100023. DOI: 10.1016/j.ijpx.2019.100023.Nurkeeva Z. S., Mun G. A., Khutoryanskiy V. V. Interpolymer complexes of water-soluble nonionic polysaccharides with polycarboxylic acids and their applications. Macromolecular Bioscience. 2003;3(6):283–295. DOI: 10.1002/chin.200408305.Nurkeeva Z. S., Mun G. A., Khutoryanskiy V. V. Interpolymer complexes of water-soluble nonionic polysaccharides with polycarboxylic acids and their applications. Macromolecular Bioscience. 2003;3(6):283–295. DOI: 10.1002/chin.200408305.Satoh K., Takayama K., Machida Y., Suzuki Y., Nakagaki M. Nagai T. Factors affecting the bioadhesive property of tablets consisting of hydroxypropyl cellulose and carboxyvinyl polymer. Chemical and Pharmaceutical Bulletin. 1989;37(5):1366–1368. DOI: 10.1248/cpb.37.1366.Satoh K., Takayama K., Machida Y., Suzuki Y., Nakagaki M. Nagai T. Factors affecting the bioadhesive property of tablets consisting of hydroxypropyl cellulose and carboxyvinyl polymer. Chemical and Pharmaceutical Bulletin. 1989;37(5):1366–1368. DOI: 10.1248/cpb.37.1366.Mangazbaeva R. A., Mun G. A., Nurkeeva Z. S., Khutoryanskiy V. V. Interpolymer complexes of hydroxypropylmethylcellulose with polycarboxylic acids in aqueous solutions. Polymer International. 2006;55(6):668–674. DOI: 10.1002/pi.2012.Mangazbaeva R. A., Mun G. A., Nurkeeva Z. S., Khutoryanskiy V. V. Interpolymer complexes of hydroxypropylmethylcellulose with polycarboxylic acids in aqueous solutions. Polymer International. 2006;55(6):668–674. DOI: 10.1002/pi.2012.Mun G. A., Nurkeeva Z. S., Khutoryanskiy V., Dubolazov A. V. Effect of pH and ionic strength on the complex formation of poly (acrylic acid) with hydroxyethylcellulose in aqueous solutions. Polymer Science. 2003;45(12):2091–2095.Mun G. A., Nurkeeva Z. S., Khutoryanskiy V., Dubolazov A. V. Effect of pH and ionic strength on the complex formation of poly (acrylic acid) with hydroxyethylcellulose in aqueous solutions. Polymer Science. 2003;45(12):2091–2095.Şakar-Deliormanli A. Flow behavior of hydroxypropyl methyl cellulose/polyacrylic acid interpolymer complexes in aqueous media. Polymer International. 2012;61(12):1751–1757. DOI: 10.1002/pi.4266.Şakar-Deliormanli A. Flow behavior of hydroxypropyl methyl cellulose/polyacrylic acid interpolymer complexes in aqueous media. Polymer International. 2012;61(12):1751–1757. DOI: 10.1002/pi.4266.Negim E. S. M., Nurpeissova Z. A., Mangazbayeva R. A., Khatib J. M., Williams C., Mun G. A. Effect of pH on the physico-mechanical properties and miscibility of methyl cellulose/poly (acrylic acid) blends. Carbohydrate Polymers. 2014;101:415–422. DOI: 10.1016/j.carbpol.2013.09.047.Negim E. S. M., Nurpeissova Z. A., Mangazbayeva R. A., Khatib J. M., Williams C., Mun G. A. Effect of pH on the physico-mechanical properties and miscibility of methyl cellulose/poly (acrylic acid) blends. Carbohydrate Polymers. 2014;101:415–422. DOI: 10.1016/j.carbpol.2013.09.047.Khutoryanskaya O. V., Morrison P. W., Seilkhanov S. K., Mussin M. N., Ozhmukhametova E. K., Rakhypbekov T. K., Khutoryanskiy V. V. Hydrogen-bonded complexes and blends of poly (acrylic acid) and methylcellulose: nanoparticles and mucoadhesive films for ocular delivery of riboflavin. Macromolecular Bioscience. 2014;14(2):225–234. DOI: 10.1002/mabi.201300313.Khutoryanskaya O. V., Morrison P. W., Seilkhanov S. K., Mussin M. N., Ozhmukhametova E. K., Rakhypbekov T. K., Khutoryanskiy V. V. Hydrogen-bonded complexes and blends of poly (acrylic acid) and methylcellulose: nanoparticles and mucoadhesive films for ocular delivery of riboflavin. Macromolecular Bioscience. 2014;14(2):225–234. DOI: 10.1002/mabi.201300313.Zhang X., Lin F., Yuan Q., Zhu L., Wang C., Yang S. Hydrogen-bonded thin films of cellulose ethers and poly (acrylic acid). Carbohydrate Polymers. 2019;215:58–62. DOI: 10.1016/j.carbpol.2019.03.066.Zhang X., Lin F., Yuan Q., Zhu L., Wang C., Yang S. Hydrogen-bonded thin films of cellulose ethers and poly (acrylic acid). Carbohydrate Polymers. 2019;215:58–62. DOI: 10.1016/j.carbpol.2019.03.066.Khutoryanskiy V. V., Cascone M. G., Lazzeri L., Barbani N., Nurkeeva Z. S., Mun G. A., Dubolazov A. V. Morphological and thermal characterization of interpolymer complexes and blends based on poly (acrylic acid) and hydroxypropylcellulose. Polymer International. 2004;53(3):307–311. DOI: 10.1002/pi.140.Khutoryanskiy V. V., Cascone M. G., Lazzeri L., Barbani N., Nurkeeva Z. S., Mun G. A., Dubolazov A. V. Morphological and thermal characterization of interpolymer complexes and blends based on poly (acrylic acid) and hydroxypropylcellulose. Polymer International. 2004;53(3):307–311. DOI: 10.1002/pi.140.Chen Y., Zhang L., Xu J., Xu S., Li Y., Sun R., Huang J., Peng J., Gong Z., Wang J., Tang L. Development of a hydroxypropyl methyl cellulose/polyacrylic acid interpolymer complex formulated buccal mucosa adhesive film to facilitate the delivery of insulin for diabetes treatment. International Journal of Biological Macromolecules. 2024;269:131876. DOI: 10.1016/j.ijbiomac.2024.131876.Chen Y., Zhang L., Xu J., Xu S., Li Y., Sun R., Huang J., Peng J., Gong Z., Wang J., Tang L. Development of a hydroxypropyl methyl cellulose/polyacrylic acid interpolymer complex formulated buccal mucosa adhesive film to facilitate the delivery of insulin for diabetes treatment. International Journal of Biological Macromolecules. 2024;269:131876. DOI: 10.1016/j.ijbiomac.2024.131876.Luo K., Yin J., Khutoryanskaya O. V., Khutoryanskiy V. V. Mucoadhesive and elastic films based on blends of chitosan and hydroxyethylcellulose. Macromolecular Bioscience. 2008;8(2):184–192. DOI: 10.1002/mabi.200700185.Luo K., Yin J., Khutoryanskaya O. V., Khutoryanskiy V. V. Mucoadhesive and elastic films based on blends of chitosan and hydroxyethylcellulose. Macromolecular Bioscience. 2008;8(2):184–192. DOI: 10.1002/mabi.200700185.Khutoryanskiy V. V., Cascone M. G., Lazzeri L., Nurkeeva Z. S., Mun G. A., Mangazbaeva R. A. Phase behaviour of methylcellulose–poly (acrylic acid) blends and preparation of related hydrophilic films. Polymer International. 2003;52(1):62–67. DOI: 10.1002/pi.1004.Khutoryanskiy V. V., Cascone M. G., Lazzeri L., Nurkeeva Z. S., Mun G. A., Mangazbaeva R. A. Phase behaviour of methylcellulose–poly (acrylic acid) blends and preparation of related hydrophilic films. Polymer International. 2003;52(1):62–67. DOI: 10.1002/pi.1004.Brovko O., Palamarchuk I., Gorshkova N. Chukhchin D. Investigation of interpolymer complexes of fucoidan with sodium alginate in solutions and films. Journal of Applied Phycology. 2025;37(1):539–551. DOI: 10.1007/s10811-024-03377-w.Brovko O., Palamarchuk I., Gorshkova N. Chukhchin D. Investigation of interpolymer complexes of fucoidan with sodium alginate in solutions and films. Journal of Applied Phycology. 2025;37(1):539–551. DOI: 10.1007/s10811-024-03377-w.Ramgonda P., Masareddy R. S., Patil A., Bolmal U. Development of budesonide oral colon specific drug delivery system using interpolymer Complexation method. Indian Journal of Pharmaceutical Education and Research. 2021;55(1):164–175. DOI: 10.5530/ijper.55.1s.47.Ramgonda P., Masareddy R. S., Patil A., Bolmal U. Development of budesonide oral colon specific drug delivery system using interpolymer Complexation method. Indian Journal of Pharmaceutical Education and Research. 2021;55(1):164–175. DOI: 10.5530/ijper.55.1s.47.Rahbar N., Darvish S., Farrahi F., Kouchak M. Chitosan/carbomer nanoparticlesladen in situ gel for improved ocular delivery of timolol: in vitro, in vivo, and ex vivo study. Drug Delivery and Translational Research. 2025;15:1210–1220. DOI: 10.1007/s13346-024-01663-1.Rahbar N., Darvish S., Farrahi F., Kouchak M. Chitosan/carbomer nanoparticlesladen in situ gel for improved ocular delivery of timolol: in vitro, in vivo, and ex vivo study. Drug Delivery and Translational Research. 2025;15:1210–1220. DOI: 10.1007/s13346-024-01663-1.Dou H., Jiang M., Peng H., Chen D., Hong Y. pH-Dependent Self-Assembly: Micellization and Micelle–Hollow-Sphere Transition of Cellulose-Based Copolymers. Angewandte Chemie International Edition. 2003;42(13):1516–1519. DOI: 10.1002/anie.200250254.Dou H., Jiang M., Peng H., Chen D., Hong Y. pH-Dependent Self-Assembly: Micellization and Micelle–Hollow-Sphere Transition of Cellulose-Based Copolymers. Angewandte Chemie International Edition. 2003;42(13):1516–1519. DOI: 10.1002/anie.200250254.Dou H., Tang M., Sun K. A Facile One-Pot Synthesis to Dextran-Based Nanoparticles with Carboxy Functional Groups. Macromolecular Chemistry and Physics. 2005;206(21):2177– 2181. DOI: 10.1002/macp.200500326.Dou H., Tang M., Sun K. A Facile One-Pot Synthesis to Dextran-Based Nanoparticles with Carboxy Functional Groups. Macromolecular Chemistry and Physics. 2005;206(21):2177–2181. DOI: 10.1002/macp.200500326.Khutoryanskaya O. V., Williams A. C., Khutoryanskiy V. V. pH-mediated interactions between poly (acrylic acid) and methylcellulose in the formation of ultrathin multilayered hydrogels and spherical nanoparticles. Macromolecules. 2007;40(21):7707–7713. DOI: 10.1021/ma071644v.Khutoryanskaya O. V., Williams A. C., Khutoryanskiy V. V. pH-mediated interactions between poly (acrylic acid) and methylcellulose in the formation of ultrathin multilayered hydrogels and spherical nanoparticles. Macromolecules. 2007;40(21):7707–7713. DOI: 10.1021/ma071644v.Thakker S. P., Rokhade A. P., Abbigerimath S. S., Iliger S. R., Kulkarni V. H., More U. A., Aminabhavi T. M. Inter-polymer complex microspheres of chitosan and cellulose acetate phthalate for oral delivery of 5-fluorouracil. Polymer bulletin. 2014;71(8):2113–2131. DOI: 10.1007/s00289-014-1176-4.Thakker S. P., Rokhade A. P., Abbigerimath S. S., Iliger S. R., Kulkarni V. H., More U. A., Aminabhavi T. M. Inter-polymer complex microspheres of chitosan and cellulose acetate phthalate for oral delivery of 5-fluorouracil. Polymer bulletin. 2014;71(8):2113–2131. DOI: 10.1007/s00289-014-1176-4.Aziz M. S., Sabar M. H. Development and optimization of an innovative raft-forming antiemetic gastro-retentive system. Pharmacia. 2025;72:1–14. DOI: 10.3897/pharmacia.72.e147836.Aziz M. S., Sabar M. H. Development and optimization of an innovative raft-forming antiemetic gastro-retentive system. Pharmacia. 2025;72:1–14. DOI: 10.3897/pharmacia.72.e147836.Park S.-H., Chun M.-K., Choi H.-K. Preparation of an extended-release matrix tablet using chitosan/Carbopol interpolymer complex. International Journal of Pharmaceutics. 2008;347(1–2):39–44. DOI: 10.1016/j.ijpharm.2007.06.024.Park S.-H., Chun M.-K., Choi H.-K. Preparation of an extended-release matrix tablet using chitosan/Carbopol interpolymer complex. International Journal of Pharmaceutics. 2008;347(1–2):39–44. DOI: 10.1016/j.ijpharm.2007.06.024.Zhang F., Meng F., Wang Z. Y., Na W. Interpolymer complexation between copovidone and carbopol and its effect on drug release from matrix tablets. Drug Development and Industrial Pharmacy. 2017;43(2):190–203. DOI: 10.1080/03639045.2016.1230625.Zhang F., Meng F., Wang Z. Y., Na W. Interpolymer complexation between copovidone and carbopol and its effect on drug release from matrix tablets. Drug Development and Industrial Pharmacy. 2017;43(2):190–203. DOI: 10.1080/03639045.2016.1230625.Ershadul Haque S. K., Sheela A. Biocompatible interpolymer complex matrix tablets – an oral sustained release class-III antidiabetic drug. In: IOP Conference Series: Materials Science and Engineering. Bristol: IOP Publishing. 2017;263(2):022030. DOI: 10.1088/1757-899X/263/2/022030.Ershadul Haque S. K., Sheela A. Biocompatible interpolymer complex matrix tablets – an oral sustained release class-III antidiabetic drug. In: IOP Conference Series: Materials Science and Engineering. Bristol: IOP Publishing. 2017;263(2):022030. DOI: 10.1088/1757-899X/263/2/022030.Zhang F., Lubach J., Na W., Momin S. Interpolymer complexation between Polyox and Carbopol, and its effect on drug release from matrix tablets. Journal of Pharmaceutical Sciences. 2016;105(8):2386–2396. DOI: 10.1016/j.xphs.2016.05.020.Zhang F., Lubach J., Na W., Momin S. Interpolymer complexation between Polyox and Carbopol, and its effect on drug release from matrix tablets. Journal of Pharmaceutical Sciences. 2016;105(8):2386–2396. DOI: 10.1016/j.xphs.2016.05.020.Yusif R. M., Hashim I. I. A., Mohamed E. A., El Rakhawy M. M. Investigation and evaluation of an in situ interpolymer complex of carbopol with polyvinylpyrrolidone as a matrix for gastroretentive tablets of ranitidine hydrochloride. Chemical and Pharmaceutical Bulletin. 2016;64(1):42–51. DOI: 10.1248/cpb.c15-00620.Yusif R. M., Hashim I. I. A., Mohamed E. A., El Rakhawy M. M. Investigation and evaluation of an in situ interpolymer complex of carbopol with polyvinylpyrrolidone as a matrix for gastroretentive tablets of ranitidine hydrochloride. Chemical and Pharmaceutical Bulletin. 2016;64(1):42–51. DOI: 10.1248/cpb.c15-00620.Lu X., Hu Z., Schwartz J. Phase transition behavior of hydroxypropylcellulose under interpolymer complexation with poly (acrylic acid). Macromolecules. 2002;35(24):9164–9168. DOI: 10.1021/ma0208842.Lu X., Hu Z., Schwartz J. Phase transition behavior of hydroxypropylcellulose under interpolymer complexation with poly (acrylic acid). Macromolecules. 2002;35(24):9164–9168. DOI: 10.1021/ma0208842.Volkova I. F., Grigoryan E. S., Shandryuk G. A., Gorshkova M. Y. Hydrogels Based on Interpolymer Complexes of Sodium Alginate and Synthetic Polyacids. Polymer Science, Series A. 2023;65(1):85–95. DOI: 10.1134/S0965545X23700803.Volkova I. F., Grigoryan E. S., Shandryuk G. A., Gorshkova M. Y. Hydrogels Based on Interpolymer Complexes of Sodium Alginate and Synthetic Polyacids. Polymer Science, Series A. 2023;65(1):85–95. DOI: 10.1134/S0965545X23700803.Gorshkova M. Y., Volkova I. F., Grigoriyan E. S., Molchanov S. P. Structure and properties of hydrogels based on sodium alginate and synthetic polyacids. Mendeleev Communications. 2024;34(3):372–375. DOI: 10.1016/j.mencom.2024.04.019.Gorshkova M. Y., Volkova I. F., Grigoriyan E. S., Molchanov S. P. Structure and properties of hydrogels based on sodium alginate and synthetic polyacids. Mendeleev Communications. 2024;34(3):372–375. DOI: 10.1016/j.mencom.2024.04.019.Schmidt R. F., Lutzki J., Dalgliesh R., Prévost S., Gradzielski M. pH-Responsive Rheology and Structure of Poly (ethylene oxide)–Poly (methacrylic acid) Interpolymer Complexes. Macromolecules. 2025;58:321–333. DOI: 10.1021/acs.macromol.4c02726.Schmidt R. F., Lutzki J., Dalgliesh R., Prévost S., Gradzielski M. pH-Responsive Rheology and Structure of Poly (ethylene oxide)–Poly (methacrylic acid) Interpolymer Complexes. Macromolecules. 2025;58:321–333. DOI: 10.1021/acs.macromol.4c02726.Насибуллин Ш. Ф., Ван Дуонг T., Николакакис И., Какриманис K., Ван Ден Мутер Г., Мустафин Р. И. Разработка и исследование гранул методом реактивной термоэкструзии на основе интерполимерных сочетаний сополимеров Eudragit® для доставки индометацина. Разработка и регистрация лекарственных средств. 2025;14(1):223–244. DOI: 10.33380/2305-2066-2025-14-1-1983.Nasibullin S. F., Van Duong T., Nikolakakis I., Kachrimanis K., Van den Mooter G., Moustafine R. I. Development and study of reactive hot-melt extruded granules based on interpolymer combinations of Eudragit® copolymers for indomethacin delivery. Drug development & registration. 2025;14(1):223–244. (In Russ.) DOI: 10.33380/2305-2066-2025-14-1-1983.Гордеева Д. С., Насибуллин Ш. Ф., Карпов А. Г., Хуторянский В. В., Мустафин Р. И. Eudragit® EPO, модифицированный группами 4-фенилбороновой кислоты, как новый полимерный носитель с улучшенными мукоадгезивными свойствами. Разработка и регистрация лекарственных средств. 2024;13(3):93–102. DOI: 10.33380/2305-2066-2024-13-3-1866.Gordeeva D. S., Nasibullin S. F., Karpov A. G., Khutoryanskiy V. V., Moustafine R. I. Eudragit® EPO, modified with 4-phenylboronic acid groups, as a novel polymeric excipient with enhanced mucoadhesive properties. Drug development & registration. 2024;13(3):93-102. (In Russ.) DOI: 10.33380/2305-2066-2024-13-3-1866.Гордеева Д. С., Ситенкова (Буховец) А. В., Мустафин Р. И. Интерполиэлектролитные комплексы на основе сополимеров Eudragit® как носители для систем биоадгезивной гастроретентивной доставки метронидазола. Разработка и регистрация лекарственных средств. 2020;9(2):72–76. DOI: 10.33380/2305-2066-2020-9-2-72-76.Gordeeva D. S., Sitenkova (Bukhovets) A. V., Moustafine R. I. Interpolyelectrolyte Complexes Based on Eudragit® Copolymers as Carriers for Bioadhesive Gastroretentive Metronidazole Delivery System. Drug development & registration. 2020;9(2):72–76. (In Russ.). DOI: 10.33380/2305-2066-2020-9-2-72-76.Викторова А. С., Елизарова Е. С., Романова Р. С., Тимергалиева В. Р., Хуторянский В. В., Мустафин Р. И. Интерполимерные комплексы на основе Carbopol® и поли(2-этил-2-оксазолина) как носители для трансбуккальной доставки метформина. Разработка и регистрация лекарственных средств. 2021;10(1):48–55. DOI: 10.33380/2305-2066-2021-10-1-48-55.Viktorova A. S., Elizarova E. S., Romanova R. S., Timergalieva V. R., Khutoryanskiy V. V., Moustafine R. I. Interpolymer complexes based on Carbopol® and poly(2-ethyl-2-oxazoline) as carriers for buccal delivery of metformin. Drug development & registration. 2021;10(1):48–55. (In Russ.). DOI: 10.33380/2305-2066-2021-10-1-48-55.Nasibullin S. F., Dunaeva J. V., Akramova L. A., Timergalieva V. R., Moustafine R. I. Characteristics of interpolyelectrolyte complexes based on different types of pectin with Eudragit® EPO as novel carriers for colon-specific drug delivery. International Journal of Molecular Sciences. 2023;24(24):17622. DOI: 10.3390/ijms242417622.Nasibullin S. F., Dunaeva J. V., Akramova L. A., Timergalieva V. R., Moustafine R. I. Characteristics of interpolyelectrolyte complexes based on different types of pectin with Eudragit® EPO as novel carriers for colon-specific drug delivery. International Journal of Molecular Sciences. 2023;24(24):17622. DOI: 10.3390/ijms242417622.Ngwuluka N. C., Choonara Y. E., Modi G. du Toit L. C., Kumar P., Ndesendo V. M. K., Pillay V. Design of an Interpolyelectrolyte Gastroretentive Matrix for the Site-Specific Zero-Order Delivery of Levodopa in Parkinson’s Disease. AAPS PharmSciTech. 2013;14:605–619. DOI: 10.1208/s12249-013-9945-1.Ngwuluka N. C., Choonara Y. E., Modi G. du Toit L. C., Kumar P., Ndesendo V. M. K., Pillay V. Design of an Interpolyelectrolyte Gastroretentive Matrix for the Site-Specific Zero-Order Delivery of Levodopa in Parkinson’s Disease. AAPS PharmSciTech. 2013;14:605–619. DOI: 10.1208/s12249-013-9945-1.Moustafine R. I., Viktorova A. S., Khutoryanskiy V. V. Interpolymer complexes of Carbopol® 971 and poly (2-ethyl-2-oxazoline): Physicochemical studies of complexation and formulations for oral drug delivery. International Journal of Pharmaceutics. 2019;558:53–62. DOI: 10.1016/j.ijpharm.2019.01.002.Moustafine R. I., Viktorova A. S., Khutoryanskiy V. V. Interpolymer complexes of Carbopol® 971 and poly (2-ethyl-2-oxazoline): Physicochemical studies of complexation and formulations for oral drug delivery. International Journal of Pharmaceutics. 2019;558:53–62. DOI: 10.1016/j.ijpharm.2019.01.002.Gómez-Carracedo A., Alvarez-Lorenzo C., Gómez-Amoza J. L., Concheiro A. Glass transitions and viscoelastic properties of Carbopol® and Noveon® compacts. International Journal of Pharmaceutics. 2004;274(1–2):233–243. DOI: 10.1016/j.ijpharm.2004.01.023.Gómez-Carracedo A., Alvarez-Lorenzo C., Gómez-Amoza J. L., Concheiro A. Glass transitions and viscoelastic properties of Carbopol® and Noveon® compacts. International Journal of Pharmaceutics. 2004;274(1–2):233–243. DOI: 10.1016/j.ijpharm.2004.01.023.Boddupalli Bindu M., Mohammed Z. N. K., Nath R. A., Banji D. Mucoadhesive drug delivery system: An overview. Journal of Advanced Pharmaceutical Technology & Research. 2010;1(4):381–387. DOI: 10.4103/0110-5558.76436.Boddupalli Bindu M., Mohammed Z. N. K., Nath R. A., Banji D. Mucoadhesive drug delivery system: An overview. Journal of Advanced Pharmaceutical Technology & Research. 2010;1(4):381–387. DOI: 10.4103/0110-5558.76436.Gordeeva D. S., Sitenkova (Bukhovets) A. V., Moustafine R. I. New Carriers for Bioadhesive Gastroretentive Drug Delivery Systems Based on Eudragit® EPO/Eudragit® L100 Interpolyelectrolyte Complexes. Scientia Pharmaceutica. 2024;92(1):14. DOI: 10.3390/scipharm92010014.Gordeeva D. S., Sitenkova (Bukhovets) A. V., Moustafine R. I. New Carriers for Bioadhesive Gastroretentive Drug Delivery Systems Based on Eudragit® EPO/Eudragit® L100 Interpolyelectrolyte Complexes. Scientia Pharmaceutica. 2024;92(1):14. DOI: 10.3390/scipharm92010014.Zheng B., Liu D., Qin X., Zhang D., Zhang P. Mucoadhesive-to-Mucopenetrating Nanoparticles for Mucosal Drug Delivery: A Mini Review. International Journal of Nanomedicine. 2025;20:2241–2252. DOI: 10.2147/IJN.S505427.Zheng B., Liu D., Qin X., Zhang D., Zhang P. Mucoadhesive-to-Mucopenetrating Nanoparticles for Mucosal Drug Delivery: A Mini Review. International Journal of Nanomedicine. 2025;20:2241–2252. DOI: 10.2147/IJN.S505427.Donnelly R., Shaikh R., Singh T. R. R., Garland M. J., Woolfson A. D., Donnelly R. F. Mucoadhesive drug delivery systems. Journal of Pharmacy And Bioallied Sciences. 2011;3(1):89–100. DOI: 10.4103/0975-7406.76478.Donnelly R., Shaikh R., Singh T. R. R., Garland M. J., Woolfson A. D., Donnelly R. F. Mucoadhesive drug delivery systems. Journal of Pharmacy And Bioallied Sciences. 2011;3(1):89–100. DOI: 10.4103/0975-7406.76478.Jabbari E., Wisniewski N., Peppas N. A. Evidence of mucoadhesion by chain interpenetration at a poly(acrylic acid)/mucin interface using ATR–FTIR spectroscopy. Journal of Controlled Release. 1993;26(2):99–108. DOI: 10.1016/0168-3659(93)90109-I.Jabbari E., Wisniewski N., Peppas N. A. Evidence of mucoadhesion by chain interpenetration at a poly(acrylic acid)/mucin interface using ATR–FTIR spectroscopy. Journal of Controlled Release. 1993;26(2):99–108. DOI: 10.1016/0168-3659(93)90109-I.Stankovits G., Szayly K., Galata D. L., Móczó J., Szilágyi A., Gyarmati B. The adhesion mechanism of mucoadhesive tablets with dissimilar chain flexibility on viscoelastic hydrogels. Materials Today Bio. 2025;30:101416. DOI: 10.1016/j.mtbio.2024.101416.Stankovits G., Szayly K., Galata D. L., Móczó J., Szilágyi A., Gyarmati B. The adhesion mechanism of mucoadhesive tablets with dissimilar chain flexibility on viscoelastic hydrogels. Materials Today Bio. 2025;30:101416. DOI: 10.1016/j.mtbio.2024.101416.

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