safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2024-12-4-367-379safetyrisk-456Research ArticleГЛАВНАЯ ТЕМА: ТЕНЕВЫЕ СТОРОНЫ ФАРМАКОТЕРАПИИ: НЕЖЕЛАТЕЛЬНЫЕ РЕАКЦИИMAIN TOPIC: THE DARK SIDE OF PHARMACOTHERAPY: ADVERSE DRUG REACTIONSСовременные препараты месалазина: различия кишечнорастворимых лекарственных форм и фармацевтические риски снижения клинической эффективности (обзор)Current Mesalazine Products: Differences in Enteric-Coated Dosage Forms and Pharmaceutical Risks of Clinical Efficacy Reduction (Review)https://orcid.org/0000-0002-7163-7119СереброваС. Ю.SerebrovaS. Yu.

Сереброва Светлана Юрьевна, д-р мед. наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051, 

ул. Трубецкая, д. 8, стр. 2, Москва, 11999

Svetlana Yu. Serebrova, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051, 

8/2 Trubetskaya St., 8, Moscow 119991

serebrova@expmed.ruhttps://orcid.org/0000-0002-6150-5796ЕвтеевВ. А.EvteevV. V.

Евтеев Владимир Александрович

Петровский б-р, д. 8, стр. 2, Москва, 127051

Vladimir A. Evteev

8/2 Petrovsky Blvd, Moscow 127051

evteev@expmed.ruhttps://orcid.org/0000-0003-1972-4386ДемченковаЕ. Ю.DemchenkovaE. Yu.

Демченкова Елена Юрьевна, канд. фарм. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051, 

ул. Трубецкая, д. 8, стр. 2, Москва, 119991

Elena Yu. Demchenkova, Cand. Sci. (Pharm.)

8/2 Petrovsky Blvd, Moscow 127051, 

8/2 Trubetskaya St., 8, Moscow 119991

demchenkova@mail.ruhttps://orcid.org/0000-0002-9198-8661ЖуравлеваМ. В.ZhuravlevaM. V.

Журавлева Марина Владимировна, д-р мед. наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051, 

ул. Трубецкая, д. 8, стр. 2, Москва, 119991

Мarina V. Zhuravleva, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051, 

8/2 Trubetskaya St., 8, Moscow 119991

zhuravleva@expmed.ruhttps://orcid.org/0000-0001-7024-5546ПрокофьевА. Б.ProkofievA. B.

Прокофьев Алексей Борисович, д-р мед. наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051, 

ул. Трубецкая, д. 8, стр. 2, Москва, 119991

Alexey B. Prokofiev, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051, 

8/2 Trubetskaya St., 8, Moscow 119991

prokofiev@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской Федерации; Федеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет им. И.М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский Университет)РоссияScientific Centre for Expert Evaluation of Medicinal Products; Sechenov First Moscow State Medical University (Sechenov University)Russian FederationФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian FederationФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской Федерации; Федеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет им. И.М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский Университет)РоссияScientific Centre for Expert Evaluation of Medicinal Products; Sechenov First Moscow State Medical University (Sechenov University)Russian Federation202411102024124367379Copyright © Сереброва С.Ю., Евтеев В.А., Демченкова Е.Ю., Журавлева М.В., Прокофьев А.Б., 20242024Сереброва С.Ю., Евтеев В.А., Демченкова Е.Ю., Журавлева М.В., Прокофьев А.Б.Serebrova S.Y., Evteev V.V., Demchenkova E.Y., Zhuravleva M.V., Prokofiev A.B.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.risksafety.ru/jour/article/view/456ВВЕДЕНИЕ

ВВЕДЕНИЕ. Препараты месалазина (5-аминосалициловая кислота) для перорального применения широко используются в лечении воспалительных заболеваний кишечника, в частности язвенного колита. Клиническая эффективность таких препаратов напрямую зависит от состава и свойств полимерных соединений, обеспечивающих таргетную доставку месалазина к пораженным участкам толстой кишки. Однако накопленная к настоящему   моменту   информация   позволяет   предположить,   что   высвобождение   месалазина из кишечнорастворимых лекарственных форм в условиях человеческого организма отличается от его поведения в модельных условиях, что требует дополнительного изучения.

ЦЕЛЬ

ЦЕЛЬ. Систематизация информации о кишечнорастворимых полимерах, применяемых в производстве препаратов месалазина, для оценки фармацевтических рисков снижения эффективности терапии язвенного колита.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Особенности абсорбции и метаболизма месалазина определяют необходимость применения препарата в кишечнорастворимых лекарственных формах для доставки действующего вещества непосредственно к зонам поражения толстой кишки. Установлено, что наиболее часто при изготовлении препаратов месалазина для приема внутрь используют сополимер метакриловой кислоты и метилметакрилата в соотношении мономеров 1:1, который высвобождает действующее вещество при рН 7,0. Также может применяться сополимер метакриловой кислоты и этилакрилата в соотношении мономеров 1:1, растворяющийся при рН 5,5. Показано, что у пациентов с воспалительными заболеваниями кишечника могут быть широкие и перекрывающиеся диапазоны значений рН среды в органах желудочно-кишечного тракта (1,0–7,0 в желудке, 5,0–6,2 в двенадцатиперстной, 6,1–7,1 в тощей, 7,4–7,5 в подвздошной кишках, 5,7–7,5 в толстой кишке с возможностью ее закисления при язвенном колите), кроме того, значительно варьирует скорость транзита кишечного содержимого. Под влиянием этих факторов месалазин может высвобождаться из лекарственных форм в желудке и тонкой кишке, не достигая толстой кишки, что создает риск снижения клинической эффективности препаратов и развития системных нежелательных реакций.

ВЫВОДЫ

ВЫВОДЫ. Cополимер метакриловой кислоты и метилметакрилата обеспечивает таргетную доставку 5-аминосалициловой кислоты из таблеток и гранул при лечении язвенного колита, способствуя реализации ее местного действия в толстой кишке у большинства пациентов. Разработчикам и производителям лекарственных форм месалазина для приема внутрь при выборе кишечнорастворимого полимера следует учитывать фармацевтические риски снижения эффективности препарата.

INTRODUCTION

INTRODUCTION. Oral mesalazine (5-aminosalicylic acid) products are commonly used to treat inflammatory bowel disease, in particular,  ulcerative  colitis.  The  clinical  efficacy  of  these  medicinal  products  depends  directly on the composition and properties of the polymers used to deliver mesalazine to the affected areas of the colon. However, the information that has been accumulated to date suggests that the release of mesalazine from enteric-coated dosage forms in gastrointestinal tract simulations differs from that in the actual human gastrointestinal tract, which necessitates further research.

AIM

AIM. This study aimed to systematise information on the polymers used in the enteric coating of mesalazine products and to assess the pharmaceutical risks associated with the potential reduction in the efficacy of ulcerative colitis therapy.

DISCUSSION

DISCUSSION. The absorption and metabolism of mesalazine dictate the need for enteric-coated dosage forms to deliver the active substance directly to the affected areas of the colon. The most common polymer used in the manufacturing of oral mesalazine products is a methacrylic acid–methyl methacrylate copolymer with a monomer ratio of 1:1, which releases the active substance at pH 7.0. Some manufacturers use a methacrylic acid–ethyl acrylate copolymer with a monomer ratio of 1:1, which dissolves at pH 5.5. The gastrointestinal pH in patients with  inflammatory  bowel  disease  may  vary  in  wide  and  often  overlapping  ranges  depending on the organ (1.0–7.0 in the stomach, 5.0–6.2 in the duodenum, 6.1–7.1 in the jejunum, 7.4–7.5 in the ileum, and 5.7–7.5 in the colon with a possibility of acidification in ulcerative colitis patients). The rate of gastrointestinal transit varies widely as well. These factors may cause premature release of mesalazine in the stomach or the small intestine before the dosage form reaches the colon, which poses the risks of reduced clinical efficacy and systemic adverse effects.

CONCLUSIONS

CONCLUSIONS. In the vast majority of ulcerative colitis patients, the methacrylic acid–methyl methacrylate copolymer provides targeted delivery of 5-aminosalicylic acid from tablets and granules, facilitating its local action in the colon. However, developers and manufacturers selecting the polymer for enteric coating of oral mesalazine dosage forms should consider the pharmaceutical risks associated with reduced clinical efficacy.

месалазинмесаламин5-аминосалициловая кислотаязвенный колитболезнь Кронатолстая кишкавоспалительные заболевания кишечникакишечнорастворимые оболочкикишечнорастворимые лекарственные формысополимер метакриловой кислоты и метилметакрилатаmesalazinemesalamine5-aminosalicylic acidulcerative colitisCrohn’s diseasecoloninflammatory bowel diseaseenteric coatingsenteric-coated dosage formsmethacrylic acid-methyl methacrylate copolymerРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00026-24-01 на проведение прикладных научных исследований (номер государственного учета НИР № 124022200076-2)This study was conducted by the Scientific Centre for Expert Evaluation of Medicinal Products as part of the applied research funded under State Assignment No. 056-00026-24-01 (R&D Registry No. 124022200076-2)ReferencesGBD 2017 Inflammatory Bowel Disease Collaborators. 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The authors declare that there are no conflicts of interest present.