混合优化法在基于低聚六亚甲基胍氢化琥珀酸盐的滴眼液剂型的药物开发实施阶段中的应用

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通过离散和持续优化以及随后的风险评估和技术工艺验证，证实了基于支链低聚六亚甲基胍氢化琥珀酸盐物质的滴眼液剂型的药物开发实施阶段的情况。进行了实验样品的开发，确定了关键的工艺和质量参数，进行了工艺特性的测量、参数配给、预测、验证实验、最佳配方的确定、眼药水生产中的风险评估和部分验证。在基于支链低聚六亚甲基胍氢化琥珀酸盐的滴眼液的制药开发过程中，进行了三个周期的优化（包括离散优化和连续优化）。结果确定了活性成分和辅助成分的最佳比例（支链低聚六亚甲基胍氢化琥珀酸盐0.05%、聚乙烯醇1%、磷酸盐缓冲盐水20%、氯化钠0.45%、纯净水 100%）。在对工艺流程进行风险分析审查后，确定了临界点。此外，还进行了部分验证，其积极的结果验证并确认了在制药开发的这 一阶段所做选择的最优性。总的来说，混合优化类型（离散和连续）可用于实施基于支链低聚六亚甲基胍氢化琥珀酸盐的滴眼液的药物开发，并通过一系列实验和风险评估进行了验证，而部分验证则可以验证研究结果。因此，药物开发是一个复杂而耗时的过程，而有限的功能并不总能快速找到最佳药物配方。数学建模方法和各种类型的优化方法可以作为实施药品开发各阶段的有效解决方案。

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作者简介

Denis O. Shatalov

Russian technological university

编辑信件的主要联系方式.
Email: shat-05@mail.ru
ORCID iD: 0000-0003-4510-1721
SPIN 代码: 3453-9987

MD, Сand. Sci. (Pharm.), associate professor

俄罗斯联邦, Moscow

Diana A. Akhmedova

Russian technological university

Email: diana.akhmedova.123@mail.ru
ORCID iD: 0000-0002-0951-939X
SPIN 代码: 4629-8311

assistant

俄罗斯联邦, Moscow

Ivan S. Ivanov

Russian technological university

Email: ivan.ivanov1994@gmail.com
ORCID iD: 0000-0002-1346-7588
SPIN 代码: 1899-6495

Сand. Sci. (Pharm.), researcher

俄罗斯联邦, Moscow

Daria D. Kirillova

Russian technological university

Email: kirillova1541@mail.ru
ORCID iD: 0000-0002-3055-1116
SPIN 代码: 8996-2103

master’s student

俄罗斯联邦, Moscow

Yulia A. Koroleva

Russian technological university; Institute of Pharmaceutical Technologies

Email: jukka.hiden@bk.ru
ORCID iD: 0000-0001-8092-1990
SPIN 代码: 5517-8014

master’s student

俄罗斯联邦, Moscow; Moscow

Dmitry S. Minenkov

Ishlinsky Institute for Problems in Mechanics RAS

Email: minenkov.ds@gmail.com
ORCID iD: 0000-0001-6432-8134
SPIN 代码: 6424-1334

MD, Сand. Sci. (Phyis.), Сand. Sci. (Math.)

俄罗斯联邦, Moscow

Stanislav A. Kedik

Russian technological university

Email: kedik@mirea.ru
ORCID iD: 0000-0003-2610-8493

MD, Dr. Sci. (Tech.), professor

俄罗斯联邦, Moscow

参考

  1. Shilovskikh OV, Ponomarev VO, Kazaykin VN, et al. Bacterial keratitis. Part 1. Epidemiology, etiology, pathophysiology, risk factors, clinic, current aspects of diagnosis. Ophthalmology in Russia. 2023;20(1): 17–23. EDN: BSRWLW doi: 10.18008/1816-5095-2023-1-17-23
  2. Brzheskiy VV. Modern opportunities for the prevention and treatment of inflammatory eye diseases of an infectious nature in children. Ophthalmology reports. 2019;12(4):57–65. EDN: JQDGEV doi: 10.17816/OVI8917
  3. Azari AA, Arabi A. Conjunctivitis: a systematic review. J Ophthalmic Vis Res. 2020;15(3):372–395. doi: 10.18502/jovr.v15i3.7456
  4. Babushkin AE. Local antibiotic therapy of bacterial infectious and inflammatory diseases of the anterior segment of the eye (literature review). Point of view. East-West. 2021. № 2. С. 89–93. EDN: JFYMGR doi: 10.25276/2410-1257-2021-2-89-93
  5. Ivanov IS, Shatalov DO, Kedik SA, et al. Study of the effect of the pharmaceutical substance branched oligohexamethylene guanidine hydrosuccinate in relation to microorganisms. Antibiotics and Chemotherapy. 2019;64(11-12):8–15. EDN: RRPUIR doi: 10.1016/0235-2990-2019-64-11-12-8-15
  6. Kornyushko VF, Nikolaeva OM, Panov AV, et al. Quality management of the chemical-technological process for continuous synthesis of pharmaceutical substances of medicinal compounds in flow microreactors. Fine Chemical Technologies. 2021;16(3):252–266. EDN: GRYFHU doi: 10.32362/2410-6593-2021-16-3-252-266
  7. Ivanov IS. Microfluidic synthesis of hydrosuccinate-oligohexamethyleneguanidine substance and creation of ophthalmic preparation on its basis [dissertation]. Moscow; 2021. 118 p. (In Russ.).
  8. Shatalov DO. Development and standardization of quality control methods for branched oligohexamethyleneguanidine hydrochloride [dissertation]. Moscow; 2015. 137 p. (In Russ.).
  9. McDermott RE, Mikulak RJ, Beauregard MR. The basics of FMEA. 2nd edit. New York: Productivity Press; 2009, 90 р.

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2. Fig. 1. Traditional risk management process

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3. Fig. 2. Algorithmic sequence of optimization cycles for the pharmaceutical development of eye drops

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4. Fig. 3. Viscosity–rate curves of the experimental samples

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5. Fig. 4. Release of the oligohexamethylene guanidine hydrosuccinate substance from samples of the eye drop dosage form

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6. Fig. 5. Diagram of the manufacturing process of eye drops

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7. Fig. 6. Ishikawa diagram for the risk assessment of eye drops

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8. Fig. 7. Technological scheme of the processes for obtaining eye drops: НХ — NaСl; Кт — technological control; Кх — chemical control; Кмб — microbiological control

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