Experiment planning at the pharmaceutical development of liposomal cytostatics

A. V. Stadnychenko, Yu. M. Krasnopolskiy, T. G. Yarnykh

Abstract


At present, there is an increasing interest in developing new ways of drug delivery and targeted therapy, using nanotechnology and nanomaterials.
Aim – to study the order of carrying out of pharmaceutical development of liposoms with cytostatics. Propose the scope of the experiment to optimize the planned quality indicators and technological parameters.
Materials and methods. Analysis of normative documents, scientific literature and also the results of previous personal experimental studies, which became the basis for determining the methodology for the creation of liposomal drugs based on oxaliplatin and irinotecan. Lipids manufactured by Lipoid, Germany, were used to make liposomes. The lipid film was produced on a Buchi 210 rotary evaporator with a vacuum controller, at a residual pressure of 0.02 atm. For homogenization, a high pressure extrusion method was used, which was carried out on a Microfluidiser M-110P (Microfluidics, USA).
Results and discussion. With the development of the pharmaceutical industry, there is a growing interest to the use of nanotechnology and nanomaterials. One of the practical implementation of nanotechnology is liposomes with cytostatics. Concentration of the active substance; pH and salt API; method of loading for API into liposomes; lipid to lipid ratio, lipids concentration; particle size and internal volume; lipid solubility in the step of lipid film preparation; stability testing of of finished products are factors that need to be studied and solved for the successful implementation of the development. Planning an experiment in the pharmaceutical development of liposomal oxaliplatin and liposomal irinotecan are complex studyes with using the principles of Quality by Design (QbD).                                                                                            Conclusions. The requirements of normative documentation for creating liposomal forms of medicinal products are considered. At pharmaceutical development it is necessary to use the complex approach as the majority of the put questions can not be solved separately. An experiment planning system for the pharmaceutical development of liposomal preparations of irinotecan and oxaliplatin is proposed.


Keywords


irinotecan; oxaliplatin; liposomes; a lipid bilayer; pharmaceutical development; chromatography; freeze drying

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References


Tyner, K. M., Zou, P., Yang, X., Zhang, H., Cruz, C. N., Lee, S. L. (2015). Product quality for nanomaterials: current U.S. experience and perspective.

Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 7 (5), 640–654. doi: 10.1002/wnan.1338

Brown, S. C., Palazuelos, M., Sharma, P., Powers, K. W., Roberts, S. M., Grobmyer, S. R., Moudgil, B. M. (2010). Nanoparticle Characterization for

Cancer Nanotechnology and Other Biological Applications. Cancer Nanotechnology, 39–65. doi: 10.1007/978–1–60761–609–2_4

Baer, D. R., Amonette, J. E., Engelhard, M. H. et al. (2008). Characterization challenges for nanomaterials. Surf Interface Anal., 40, 529–537.

Stadnychenko, A. V. Krasnopolskyiб Yu. M., Shvetc, V. I. (2015). Biofarmatcevticheskii zhurnal, 1 (7), 53–55.

Feng, S.–S., Mu, L., Win, K., Huang, G. (2004). Nanoparticles of Biodegradable Polymers for Clinical Administration of Paclitaxel. Current Medicinal

Chemistry, 11 (4), 413–424. doi: 10.2174/0929867043455909

Pharmaceutical development Q8 (R2). (2009). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals

for Human use. (4), 28. Available at: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/

Q8_R2_Guideline.pdf

Development and Manufacture of Drug Substances Q11. (2012). International Conference on Harmonisation of Technical Requirements for Registration

of Pharmaceuticals for Human use, 36. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf

Liposome Drug Products. Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation.

(2015). Guidance for Industry. Food and Drug Administration, 17.

Guideline for the Development of Lposome Drug Products. (2016). Ministry of Health, Labour and Welfare (MHLW), Japan. Available at: http://

www.nihs.go.jp/drug/section4/160328_MHLW_liposome_guideline.pdf

Toh, M.–R., Chiu, G. N. C. (2013). Liposomes as sterile preparations and limitations of sterilisation techniques in liposomal manufacturing. Asian

Journal of Pharmaceutical Sciences, 8 (2), 88–95. doi: 10.1016/j.ajps.2013.07.011

Yu, B., Lee, R. J., Lee, L. J. (2009). Microfluidic Methods for Production of Liposomes. Methods in Enzymology, 129–141. doi: 10.1016/s0076–

(09)65007–2

Huwyler, J., Drewe, J., Krahenbuhl, S. (2008). Tumor targeting using liposomal antineoplastic drugs. Int J Nanomedicine, 3, 21–29.

Rafiyath, S. M., Rasul, M., Lee, B., Wei, G., Lamba, G., Liu, D. (2012). Comparison of safety and toxicity of liposomal doxorubicin vs. conventional

anthracyclines: a meta–analysis. Experimental Hematology & Oncology, 1 (1), 10. doi: 10.1186/2162–3619–1–10

Di Bartolomeo, M., Ciarlo, A., Bertolini, A., Barni, S., Verusio, C., Aitini, E., Bajetta, E. (2015). Capecitabine, oxaliplatin and irinotecan in combination,

with bevacizumab (COI–B regimen) as first–line treatment of patients with advanced colorectal cancer. An Italian Trials of Medical Oncology

phase II study. European Journal of Cancer, 51 (4), 473–481. doi: 10.1016/j.ejca.2014.12.020


GOST Style Citations


1. Product quality for nanomaterials : current U. S. experience and perspective / K. M. Tyner, P. Zou, X. Yang et. al. // WIREs Nanomed Nanobiotechnol.
– 2015. – Vol. 7, Issue 5. – Р. 640–654. doi: 10.1002/wnan.1338

2. Nanoparticle characterization for cancer nanotechnology and other biological applications / S. C. Brown, M. Palazuelos, P. Sharma et al. // Methods
Mol. Biol. – 2010. – P. 39–65. doi: 10.1007/978–1–60761–609–2_4

3. Characterization challenges for nanomaterials / D. R. Baer, J. E. Amonette, M. H. Engelhard et al. // Surf Interface Anal. – 2008. – Vol. 40. – P. 529–537.

4. Стадниченко, А. В. Разработка и валидация методики определения степени инкапсуляции иринотекана гидрохлорида в липосомы /
А. В. Стадниченко, Ю. М. Краснопольский, В. И. Швец // Биофармац. журн. – 2015. – Т. 7, № 1. – С. 53–55.

5. Nanoparticles of biodegradable polymers for clinical administration of paclitaxel / S. S. Feng, L. Mu, K. Y. Win et al. // Curr. Med. Chem. – 2004. –
Vol. 11, Issue 4. – P. 413–424. doi: 10.2174/0929867043455909

6. Pharmaceutical development Q8(R2) // International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human use. Version 4. – 2009. – 28 р. – Available at : https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/
Q8_R1/Step4/Q8_R2_Guideline.pdf

7. Development and Manufacture of Drug Substances Q11 // International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human use. – 2012. – 36 р. – Available at : http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/
Quality/Q11/Q11_Step_4.pdf

8. Liposome Drug Products. Chemistry, Manufacturing, and Controls ; Human Pharmacokinetics and Bioavailability ; and Labeling Documentation //
Guidance for Industry. Food and Drug Administration. – 2015. – 17 р.

9. Guideline for the Development of Liposome Drug Products.Ministry of Health, Labour and Welfare (MHLW). – Japan, 2016. – Available at : http://
www.nihs.go.jp/drug/section4/160328_MHLW_liposome_guideline.pdf

10. Toh, M. R. Liposomes as sterile preparations and limitations of sterilisation techniques in liposomal manufacturing / M. R. Toh, G. N. C. Chiu //
Asian J. of Pharmac. Sci. – 2013. – Vol. 8, Issue 2. – P. 88–95. doi : 10.1016/j.ajps.2013.07.011

11. Yu, B. Microfluidic Methods for Production of Liposomes / B. Yu, R. J. Lee, L. J. Lee // Methods in Enzymol. – 2009. – P. 129–141. doi: 10.1016/
s0076–6879(09)65007–2

12. Huwyler, J. Tumor targeting using liposomal antineoplastic drugs / J. Huwyler, J. Drewe, S. Krahenbuhl // Int. J. Nanomed. – 2008. – Vol. 3. – P. 21–29.

13. Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines : a meta–analysis / S. M. Rafiyath, M. Rasul, B. Lee et al. //
Experimental Hematol. & Oncol. – 2012. – Vol. 1, Issue 1. – 10 p. doi: 10.1186/2162–3619–1–10

14. Capecitabine, oxaliplatin and irinotecan in combination, with bevacizumab (COI–B regimen) as first–line treatment of patients with advanced
colorectal cancer. An Italian Trials of Medical Oncology phase II study / M. D. Bartolomeo, A. Ciarlo, A. Ciarlo et al. // Eur. J. of Cancer. – 2015. – Vol. 51,
Issue 4. – P. 473–481. doi: 10.1016/j.ejca.2014.12.020





DOI: https://doi.org/10.24959/ubphj.17.148

Abbreviated key title: Ukr. bìofarm. ž.

ISSN 2519-8750 (Online), ISSN 2311-715X (Print)