Block Copolymers of Ethylene Oxide and Propylene Oxide: Prospects for Medical and Pharmaceutical Application in Russia
https://doi.org/10.30895/1991-2919-2023-530
Abstract
Block copolymers of ethylene oxide and propylene oxide (EO/PO block copolymers) are polymeric non-ionic surfactants with a high hydrophilic–lipophilic balance also referred to as pluronics, poloxamers, or proxanols. These compounds are among the most demanded modern excipients for the production of medicines. EO/PO block copolymers are used both in the production of traditional (liquid, semi-solid, and solid) dosage forms and as part of targeted delivery systems. The extensive application of EO/PO block copolymers is due to the diverse array of their properties, including not only solubilising, emulsifying, gelling, and other effects but also thermoreversibility, which is essential for developing in situ delivery systems and 3D printing technologies.
The aim of the study was to evaluate the potential of EO/PO block copolymers for medicinal use and to assess the range of medicinal products approved in the Russian Federation that contain EO/PO block copolymers.
This review presents an analysis of the register of poloxamer-containing medicines approved in the Russian Federation, a list of the largest manufacturers of EO/PO block copolymers in the world, and a study of the possibility to use copolymers for medical purposes. Currently, there are more than 10 chemical manufacturers producing EO/PO block copolymers for the pharmaceutical, biotechnology, and other industries around the world. EO/PO block copolymers are included in more than 60 medicinal products present in the Russian pharmaceutical market; this observation indicates the need to phase out the import of poloxamers.
Keywords
About the Authors
E. O. BakhrushinaRussian Federation
Elena O. Bakhrushina, Cand. Sci. (Pharm.), Associate Professor
8/2 Trubetskaya St., Moscow 119991
V. S. Pyzhov
Russian Federation
Victor S. Pyzhov
8/2 Trubetskaya St., Moscow 119991
P. S. Sakharova
Russian Federation
Polina S. Sakharova
8/2 Trubetskaya St., Moscow 119991
N. B. Demina
Russian Federation
Natalia B. Demina, Dr. Sci. (Pharm.), Professor
8/2 Trubetskaya St., Moscow 119991
D. A. Chizhova
Russian Federation
Diana A. Chizhova, Cand. Sci. (Biol.)
3 Rakhmanovsky Ln., GSP-4, Moscow 127994
T. V. Tabanskaya
Russian Federation
Tatiana V. Tabanskaya
8/2 Trubetskaya St., Moscow 119991;
8/2 Petrovsky Blvd, Moscow 127051
M. F. Lutfullin
Russian Federation
Marsel F. Lutfullin
3 Rakhmanovsky Ln., GSP-4, Moscow 127994
References
1. Vorob’ev AM. Selection of mixtures of wetting agents for cleansing the skin of radioactive contamination. Gig Sanit. 1967 1967;(7):45–9 (In Russ.). PMID: 5603613
2. Dmitriev MT, Kitrosskiĭ NA, Erofeeva ZA. Ionization-chromatographic separate determination of detergents in water with preliminary pyrolysis. Gig Sanit. 1971;(8):77–82 (In Russ.). PMID: 5145470
3. Linse P, Malmsten M. Temperature-dependent micellization in aqueous block copolymer solutions. Macromolecules. 1992;25(20):5434–9. https://doi.org/10.1021/ma00046a048
4. Schillén K, Glatter O, Brown W. Characterization of a PEO-PPO-PEO block copolymer system. In: Laggner P., Glatter O, eds. Trends in Colloid and Interface Science VII. Progress in Colloid and Polymer Science. 2008;93:66–71. https://doi.org/10.1007/BFb0118476
5. Alexandridis P, Holzwarth JF, Hatton TA. Micellization of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers in aqueous solutions: thermodynamics of copolymer association. Macromolecules. 1994;27(9):2414–25. https://doi.org/10.1021/ma00087a009
6. Cendejas G, Arreguín F, Castro LV, Flores EA, Vazquez F. Demulsifying super-heavy crude oil with bifunctionalized block copolymers. Fuel. 2013;103:356–63. https://doi.org/10.1016/j.fuel.2012.08.029
7. Liu D, Yang M, Wang D, Jing X, Lin Y, Feng L, Duan X. DPD study on the interfacial properties of PEO/ PEO-PPO-PEO/PPO ternary blends: effects of pluronic structure and concentration. Polymers (Basel). 2021;13(17):2866. https://doi.org/10.3390/polym13172866
8. Kabanov AV, Batrakova EV, Alakhov VYu. Pluronic® block copolymers as novel polymer therapeutics for drug and gene delivery. J Control Release. 2002;82(2–3):189–212. https://doi.org/10.1016/s0168-3659(02)00009-3
9. Schmolka IR. A review of block polymer surfactants. J Am Oil Chem Soc. 1977;54(3):110–116. https://doi.org/10.1007/BF02894385
10. Schmolka IR. The molecular basis for toxicity of surfactants in surgical wounds. 1. EO:PO block polymers. J Surg Res. 1973;14(4):277–284. https://doi.org/10.1016/0022-4804(73)90029-2
11. Schmolka IR, Raymond AJ. Micelle formation of polyoxyethylene-polyoxypropylene surfactants. J Am Oil Chem Soc. 1965;42:1088–91. https://doi.org/10.1007/BF02636916
12. Schmolka IR. Polyoxyethylene-polyoxypropylene aqueous gels. US Patent No. US3740421A; 1966.
13. Jeon SW, Yoon YJ, Park SM, Jang JD, Kim TH. Unusual self-assembly of amphiphilic block copolymer blends induced by control of hydrophobic interaction. J Phys Chem B. 2022;126(34):6511–9. https://doi.org/10.1021/acs.jpcb.2c03043
14. Cappuccio de Castro K, Cedran Coco J, Mendes Dos Santos E, Artem Ataide J, Miliani Martinez R, Monteiro do Nascimento MH, et al. Pluronic® triblock copolymer-based nanoformulations for cancer therapy: a 10-year overview. J Control Release. 2023;353:802–22. https://doi.org/10.1016/j.jconrel.2022.12.017
15. Singla P, Garg S, McClements J, Jamieson O, Peeters M, Mahajan RK. Advances in the therapeutic delivery and applications of functionalized Pluronics: a critical review. Adv Colloid Interface Sci. 2022;299:102563. https://doi.org/10.1016/j.cis.2021.102563
16. Hou X, Liang J, Yang X, Bai J, Yang M, Qiao N, et al. Poloxamer 188 -based nanoparticles improve the anti-oxidation and anti-degradation of curcumin. Food Chem. 2022;375:131674. https://doi.org/10.1016/j.foodchem.2021.131674
17. Nguyen NT, Bui QA, Nguyen HH, Nguyen TT, Ly KL, Tran HL, et al. Curcuminoid co-loading platinum heparin-poloxamer P403 nanogel increasing effectiveness in antitumor activity. Gels. 2022;8(1):59. https://doi.org/10.3390/gels8010059
18. Gao J, Shi Y, Han Y, Tang X, Bi R, Pan L, Lai X. One-way intestinal perfusion of PVP/VA–poloxamer 188 –Curcuma longa L. extract solid dispersion in rats in vivo and its effect on HSC-T6 cell proliferation. AAPS PharmSciTech. 2022;23(3):83. https://doi.org/10.1208/s12249-022-02228-6
19. Sunoqrot S, Aliyeh S, Abusulieh S, Sabbah D. Vitamin E TPGS-poloxamer nanoparticles entrapping a novel PI3Kα inhibitor potentiate its activity against breast cancer cell lines. Pharmaceutics. 2022;14(9):1977. https://doi.org/10.3390/pharmaceutics14091977
20. Kim J, Francis DM, Sestito LF, Archer PA, Manspeaker MP, O’Melia MJ, Thomas SN. Thermosensitive hydrogel releasing nitric oxide donor and anti-CTLA-4 micelles for anti-tumor immunotherapy. Nat Commun. 2022;13(1):1479. https://doi.org/10.1038/s41467-022-29121-x
21. Yang Y, Alencar LMR, Pijeira MSO, Batista BDS, França ARS, Rates ERD, et al. [ 223 Ra] RaCl 2 nanomicelles showed potent effect against osteosarcoma: targeted alpha therapy in the nanotechnology era. Drug Deliv. 2022;29(1):186–91. https://doi.org/10.1080/10717544.2021.2005719
22. De Souza MVF, Shinobu-Mesquita CS, Meirelles LEF, Mari NL, Cesar GB, Gonçalves RS, et al. Effects of hypericin encapsulated on Pluronic F127 photodynamic therapy against triple negative breast cancer. Asian Pac J Cancer Prev. 2022;23(5):1741–51. https://doi.org/10.31557/apjcp.2022.23.5.1741
23. Nugraha DH, Anggadiredja K, Rachmawati H. Effect of the surfactant charge on the characteristics and anticancer effects of docetaxel-loaded poloxamer polymeric micelles. Pharm Nanotechnol. 2023. https://doi.org/10.2174/2211738511666221103152156
24. Mishra S, Streeter PR. Micelle-based nanocarriers for targeted delivery of cargo to pancreas. Methods Mol Biol. 2023;2592:175–84. https://doi.org/10.1007/978-1-0716-2807-2_12
25. Kempe S, Mäder K. In situ forming implants — an attractive formulation principle for parenteral depot formulations. J Control Release. 2012;161(2):668–79. https://doi.org/10.1016/j.jconrel.2012.04.016
26. Thakur RR, McMillan HL, Jones DS. Solvent induced phase inversion-based in situ forming controlled release drug delivery implants. J Control Release. 2014;176:8–23. https://doi.org/10.1016/j.jconrel.2013.12.020
27. Vigani B, Rossi S, Sandri G, Bonferoni MC, Caramella CM, Ferrari F. Recent advances in the development of in situ gelling drug delivery systems for non-parenteral administration routes. Pharmaceutics. 2020;12(9):859. https://doi.org/10.3390/pharmaceutics12090859
28. Dunn RL, Tipton AJ, Southard GL, Rogers JA. Biodegradable polymer composition. US Patent No. 5599552; 1997.
29. Bakhrushina EO, Nikiforova DA, Demina NB. The main aspects of the thermorreversible polycomplexes of poloxamers developing. Health and Education Millennium. 2018;20(5):103–6 (In Russ.) EDN: XOCTJB
30. Cao YL, Lach E, Kim TH, Rodriguez A, Arévalo CA, Vacanti CA. Tissue-engineered nipple reconstruction. Plast Reconstr Surg. 1998;102(7):2293–8. https://doi.org/10.1097/00006534-199812000-00002
31. Yong CS, Choi JS, Quan QZ, Rhee JD, Kim CK, Lim SJ, et al. Effect of sodium chloride on the gelation temperature, gel strength and bioadhesive force of poloxamer gels containing diclofenac sodium. Int J Pharm. 2001;226(1–2):195–205. https://doi.org/10.1016/s0378-5173(01)00809-2
32. Chen LC, Lin SY, Cheng WJ, Sheu MT, Chung CY, Hsu CH, Lin HL. Poloxamer sols endowed with in-situ gelability and mucoadhesion by adding hypromellose and hyaluronan for prolonging corneal retention and drug delivery. Drug Deliv. 2023;30(1):2158964. https://doi.org/10.1080/10717544.2022.2158964
33. Kushwaha SK, Saxena P, Rai A. Stimuli sensitive hydrogels for ophthalmic drug delivery: a review. Int J Pharm Investig. 2012;2(2):54-60. PMID: 23119233
34. Kim HM, Woo SJ. Ocular drug delivery to the retina: current innovations and future perspectives. Pharmaceutics. 2021;13(1):108. https://doi.org/10.3390/pharmaceutics13010108
35. Al Khateb K, Ozhmukhametova EK, Mussin MN, Selikhanov SK, Rakhypbekov TK, Lau WM, Khutoryanskiy VV. In situ gelling systems based on Pluronic F127/Pluronic F68 formulations for ocular drug delivery. Int J Pharm. 2016;502(1–2):70–9. https://doi.org/10.1016/j.ijpharm.2016.02.027
36. Kida D, Zakrzewska A, Zborowski J, Szulc M, Karolewicz B. Polymer-based carriers in dental local healing-review and future challenges. Materials (Basel). 2021;14(14):3948. https://doi.org/10.3390/ma14143948
37. Bakhrushina EO, Demina NB, Shumkova MM, Rodyuk PS, Shulikina DS, Krasnyuk II. In situ intranasal delivery systems: application prospects and main pharmaceutical aspects of development (review). Drug Development and Registration. 2021;10(4):54–63 (In Russ.) https://doi.org/10.33380/2305-2066-2021-10-4-54-63
38. Yap LS, Yang MC. Thermo-reversible injectable hydrogel composing of pluronic F127 and carboxymethyl hexanoyl chitosan for cell-encapsulation. Colloids Surf B Biointerfaces. 2020;185:110606. https://doi.org/10.1016/j.colsurfb.2019.110606
39. Chatterjee S, Hui PC, Kan CW, Wang W. Dual-responsive (pH/temperature) Pluronic F-127 hydrogel drug delivery system for textile-based transdermal therapy. Sci Rep. 2019;9(1):11658. https://doi.org/10.1038/s41598-019-48254-6
40. Shriky B, Kelly A, Isreb M, Babenko M, Mahmoudi N, Rogers S, et al. Pluronic F127 thermosensitive injectable smart hydrogels for controlled drug delivery system development. J Colloid Interface Sci. 2020;565:119–30. https://doi.org/10.1016/j.jcis.2019.12.096
41. Giuliano E, Paolino D, Fresta M, Cosco D. Mucosal applications of poloxamer 407-based hydrogels: an overview. Pharmaceutics. 2018;10(3):159. https://doi.org/10.3390/pharmaceutics10030159
42. Dutta SD, Bin J, Ganguly K, Patel DK, Lim KT. Electromagnetic field-assisted cell-laden 3D printed poloxamer-407 hydrogel for enhanced osteogenesis. RSC Adv. 2021;11(33):20342–54. https://doi.org/10.1039%2Fd1ra01143j
43. López-Marcial GR, Zeng AY, Osuna C, Dennis J, Garcia JM, O’Connell GD. Agarose-based hydrogels as suitable bioprinting materials for tissue engineering. ACS Biomater Sci Eng. 2018;4(10):3610–6. https://doi.org/10.1021/acsbiomaterials.8b00903
44. Sodupe-Ortega E, Sanz-Garcia A, Pernia-Espinoza A, Escobedo-Lucea C. Accurate calibration in multi-material 3D bioprinting for tissue engineering. Materials (Basel). 2018;11(8):1402. https://doi.org/10.3390/ma11081402
45. Fu Z, Angeline V, Sun W. Evaluation of printing parameters on 3D extrusion printing of pluronic hydrogels and machine learning guided parameter recommendation. Int J Bioprint. 2021;7(4):434. https://doi.org/10.18063/ijb.v7i4.434
46. Benning L, Gutzweiler L, Trondle K, Riba J, Zengerle R, Koltay P, et al. Assessment of hydrogels for bioprinting of endothelial cells. J Biomed Mater Res A. 2018;106(4):935–47. https://doi.org/10.1002/jbm.a.36291
47. Xu Y, Hu Y, Liu C, Yao H, Liu B, Mi S. A novel strategy for creating tissue-engineered biomimetic blood vessels using 3D bioprinting technology. Materials (Basel). 2018;11(9):1581. https://doi.org/10.3390/ma11091581
48. Hu S, Martinez-Garcia FD, Moeun BN, Burgess JK, Harmsen MC, Hoesli C, de Vos P. An immune regulatory 3D-printed alginate-pectin construct for immunoisolation of insulin producing β-cells. Mater Sci Eng C Mater Biol Appl. 2021;123:112009. https://doi.org/10.1016/j.msec.2021.112009
49. Tracy EP, Gettler BC, Zakhari JS, Schwartz RJ, Williams SK, Birla RK. 3D bioprinting the cardiac Purkinje system using human adipogenic mesenchymal stem cell derived Purkinje cells. Cardiovasc Eng Technol. 2020;11(5):587–604. https://doi.org/10.1007/s13239-020-00478-8
50. Gori M, Giannitelli SM, Torre M, Mozetic P, Abbruzzese F, Trombetta M, et al. Biofabrication of hepatic constructs by 3D bioprinting of a cell-laden thermogel: an effective tool to assess drug-induced hepatotoxic response. Adv Healthc Mater. 2020;9(21):e2001163. https://doi.org/10.1002/adhm.202001163
51. Mozetic P, Giannitelli SM, Gori M, Trombetta M, Rainer A. Engineering muscle cell alignment through 3D bioprinting. J Biomed Mater Res A. 2017;105(9):2582–8. https://doi.org/10.1002/jbm.a.36117
52. Shamma RN, Sayed RH, Madry H, El Sayed NS, Cucchiarini M. Triblock copolymer bioinks in hydrogel three-dimensional printing for regenerative medicine: a focus on Pluronic F127. Tissue Eng Part B Rev. 2022;28(2):451–63. https://doi.org/10.1089/ten.TEB.2021.0026
53. Müller M, Becher J, Schnabelrauch M, Zenobi-Wong M. Printing thermoresponsive reverse molds for the creation of patterned two-component hydrogels for 3D cell culture. J Vis Exp. 2013;(77):e50632. https://doi.org/10.3791/50632
54. Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res. 2004;21(2):201–30. https://doi.org/10.1023/b:pham.0000016235.32639.23
55. Bariev EA, Krasnyuk II, Anurova MN, Bakhrushina EO, Smirnov VV, Bardakov AI, et al. Study of the acute toxicity of a new dosage form of naloxone hydrochloride for intranasal administration. Drug Res (Stuttg). 2019;70(1):23–5. https://doi.org/10.1055/a-0899-4948
56. Bariev EA, Bubelo VD, Lyapunov NA. Pharmaceutical development of a drug «Naloxone nasal spray» to emergency medical care as an antidote to overdose from opioids. Advances in Chemistry and Chemical Technology. 2015;29(10):113–4 (In Russ.). EDN: VDEGUP
57. Anurova MN, Bakhrushina EO, Demina NB. Review of contemporary gel-forming agents in the technology of dosage forms. Pharm Chem J. 2015;49(9):627–34. https://doi.org/10.1007/s11094-015-1342-5
58. Dun J, Osei-Yeboah F, Boulas P, Lin Y, Sun CC. A systematic evaluation of poloxamers as tablet lubricants. Int J Pharm. 2020;576:118994. https://doi.org/10.1016/j.ijpharm.2019.118994
59. Medarević D, Djuriš J, Krkobabić M, Ibrić S. Improving tableting performance of lactose monohydrate by fluid-bed melt granulation co-processing. Pharmaceutics. 2021;13(12):2165. https://doi.org/10.3390/pharmaceutics13122165
60. Narayanappa AT, Mwilu S, Holdread S, Hammett K, Bu G, Dodson EC, Brooks JW. A rapid cell-based assay for determining poloxamer quality in CHO suspension cell culture. Biotechniques. 2019;67(3):98–109. https://doi.org/10.2144/btn-2019-0070
61. Peng H, Hall KM, Clayton B, Wiltberger K, Hu W, Hughes E, et al. Development of small scale cell culture models for screening poloxamer 188 lot-to-lot variation. Biotechnol Prog. 2014;30(6):1411–8. https://doi.org/10.1002/btpr.1967
62. Bandyopadhyay A, Kosanam H, Yang RS, Gupta B, Naralakattu N, Pakhale S, et al. Low-molecular-weight impurity in Poloxamer 188 responsible for atypical cell culture performance for mAb production. J Biotechnol. 2022;351:13–22. https://doi.org/10.1016/j.jbiotec.2022.04.008
63. Zakrzewski R, Lee K, Lye GJ. Development of a miniature bioreactor model to study the impact of pH and DOT fluctuations on CHO cell culture performance as a tool to understanding heterogeneity effects at large-scale. Biotechnol Prog. 2022;38(4):e3264. https://doi.org/10.1002/btpr.3264
64. Bollenbach L, Buske J, Mäder K, Garidel P. Poloxamer 188 as surfactant in biological formulations — an alternative for polysorbate 20/80? Int J Pharm. 2022;620:121706. https://doi.org/10.1016/j.ijpharm.2022.121706
Supplementary files
![]() |
1. Table 2. Medicines containing block copolymers of ethylene oxide and propylene oxide registered in the Russian Federation | |
Subject | ||
Type | Исследовательские инструменты | |
Download
(932KB)
|
Indexing metadata ▾ |
Review
For citations:
Bakhrushina E.O., Pyzhov V.S., Sakharova P.S., Demina N.B., Chizhova D.A., Tabanskaya T.V., Lutfullin M.F. Block Copolymers of Ethylene Oxide and Propylene Oxide: Prospects for Medical and Pharmaceutical Application in Russia. Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. Regulatory Research and Medicine Evaluation. 2023;13(2-1):333-344. (In Russ.) https://doi.org/10.30895/1991-2919-2023-530