Skip to main content

Advertisement

SpringerLink
Log in

Deep Eutectic Solvents Based on L-Arginine and 2-Hydroxypropyl-β-Cyclodextrin for Drug Carrier and Penetration Enhancement

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract 

By selecting L-arginine as the hydrogen bond acceptor (HBA) and 2-hydroxypropyl-β-cyclodextrin (2HPβCD) as the hydrogen bond donor (HBD), deep eutectic solvents (DESs) with various water content were prepared at the 4:1 mass ratio of L-arginine to 2HPβCD with 40 to 60% of water, and were studied for its application in transdermal drug delivery system (TDDS). The hydrogen bond networks and internal chemistry structures of the DESs were measured by attenuated total reflection Fourier transform infrared (ATR-FTIR) and 1H-nuclear magnetic resonance spectroscopy (1H-NMR), which demonstrated the successful synthesis of DESs. The viscosity of DES was decreased from 10,324.9 to 3219.6 mPa s, while glass transition temperature (Tg) of the DESs was increased from − 60.8 to − 51.4 °C, as the added water was increased from 45 to 60%. The solubility of ibuprofen, norfloxacin, and nateglinide in DES with 45% of water were increased by 79.3, 44.1, and 3.2 times higher than that in water, respectively. The vitro study of transdermal absorption of lidocaine in DESs showed that the cumulative amounts of lidocaine reached 252.4 µg/cm2, 226.1 µg/cm2, and 286.1 µg/cm2 at 8 h for DESs with 45%, 50%, and 60% of water, respectively. The permeation mechanism of DES with lower content of water (45%) was mainly by changing the fluidization of lipids, while changing the secondary structure of keratin in stratum corneum (SC) at higher water content (50% and 60%). These nonirritant and viscous fluid like DESs with good drug solubility and permeation enhancing effects have broad application prospect in the field of drug solubilization and transdermal drug delivery system.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Data Availability

Data available on request from the authors.

References

  1. Ramadon D, McCrudden MT, Courtenay AJ, Donnelly RF. Enhancement strategies for transdermal drug delivery systems: current trends and applications. Drug Deliv Transl Re. 2022;12(4):758–91.

    Article  Google Scholar 

  2. Zaid Alkilani A, McCrudden MT, Donnelly RF. Transdermal drug delivery: innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum. Pharmaceutics. 2015;7(4):438–70.

    Article  PubMed Central  Google Scholar 

  3. Qindeel M, Ullah MH, Ahmed N. Recent trends, challenges and future outlook of transdermal drug delivery systems for rheumatoid arthritis therapy. J Control Release. 2020;327:595–615.

    Article  CAS  PubMed  Google Scholar 

  4. Roohnikan M, Laszlo E, Babity S, Brambilla D. A snapshot of transdermal and topical drug delivery research in Canada. Pharmaceutics. 2019;11(6):256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Peña-Juárez M, Guadarrama-Escobar OR, Escobar-Chávez JJ. Transdermal delivery systems for biomolecules. J Pharm Innov. 2022;17(2):319–32.

    Article  PubMed  Google Scholar 

  6. Leppert W, Malec-Milewska M, Zajaczkowska R, Wordliczek J. Transdermal and topical drug administration in the treatment of pain. Molecules. 2018;23(3):681.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Jiang T, Xu G, Chen G, Zheng Y, He B, Gu Z. Progress in transdermal drug delivery systems for cancer therapy. Nano Res. 2020;13(7):1810–24.

    Article  CAS  Google Scholar 

  8. Kováčik A, Kopečná M, Vávrová K. Permeation enhancers in transdermal drug delivery: benefits and limitations. Expert Opin Drug Del. 2020;17(2):145–55.

    Article  Google Scholar 

  9. Dragicevic N, Maibach H. Combined use of nanocarriers and physical methods for percutaneous penetration enhancement. Adv Drug Deliv Rev. 2018;127:58–84.

    Article  CAS  PubMed  Google Scholar 

  10. Roberts M, Mohammed Y, Pastore M, Namjoshi S, Yousef S, Alinaghi A, et al. Topical and cutaneous delivery using nanosystems. J Control Release. 2017;247:86–105.

    Article  CAS  PubMed  Google Scholar 

  11. Abbott AP, Capper G, Davies DL, Rasheed RK, Tambyrajah V. Novel solvent properties of choline chloride/urea mixtures. Chem Comm. 2003;1:70–1.

    Article  Google Scholar 

  12. Zainal-Abidin MH, Hayyan M, Ngoh GC, Wong WF, Looi CY. Emerging frontiers of deep eutectic solvents in drug discovery and drug delivery systems. J Control Release. 2019;316:168–95.

    Article  CAS  PubMed  Google Scholar 

  13. Smith EL, Abbott AP, Ryder KS. Deep eutectic solvents (DESs) and their applications. Chem Rev. 2014;114(21):11060–82.

    Article  CAS  PubMed  Google Scholar 

  14. Hattori T, Tagawa H, Inai M, Kan T, Kimura S-I, Itai S, et al. Transdermal delivery of nobiletin using ionic liquids. Sci Rep. 2019;9(1):1–11.

    Article  Google Scholar 

  15. Daadoue S, Al-Remawi M, Al-Mawla L, Idkaidek N, Khalid RM, Al-Akayleh F. Deep eutectic liquid as transdermal delivery vehicle of Risperidone. J Mol Liq. 2022;345:117347.

    Article  CAS  Google Scholar 

  16. Wang C, Yan T, Yan T, Wang Z. Fabrication of hesperetin/hydroxypropyl-β-cyclodextrin complex nanoparticles for enhancement of bioactivity using supercritical antisolvent technology. J Mol Struct. 2023;1279:134947.

    Article  CAS  Google Scholar 

  17. Donthi MR, Munnangi SR, Krishna KV, Marathe SA, Saha RN, Singhvi G, Dubey SK. Formulating ternary inclusion complex of sorafenib tosylate using β-cyclodextrin and hydrophilic polymers: physicochemical characterization and in vitro assessment. AAPS PharmSciTech. 2022;23(7):254.

    Article  CAS  PubMed  Google Scholar 

  18. Mohandoss S, Velu KS, Stalin T, Ahmad N, Alomar SY, Lee YR. Tenofovir antiviral drug solubility enhancement with β-cyclodextrin inclusion complex and in silico study of potential inhibitor against SARS-CoV-2 main protease (Mpro). J Mol Liq. 2023;377:121544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cai C, Yu W, Wang C, Liu L, Li F, Tan Z. Green extraction of cannabidiol from industrial hemp (Cannabis sativa L.) using deep eutectic solvents coupled with further enrichment and recovery by macroporous resin. J Mol Liq. 2019;287:110957.

    Article  CAS  Google Scholar 

  20. Lv J, Ou X, Fang Y, Wu M, Zheng F, Shang L, et al. The study of deep eutectic solvent based on choline chloride and l-(+)-tartaric acid diethyl ester for transdermal delivery system. AAPS PharmSciTech. 2022;23(7):1–10.

    Article  Google Scholar 

  21. Shang L, Cun D, Xi H, Fang L. An explanation for the difference in the percutaneous penetration behavior of tamsulosin induced by two different O-acylmenthol derivatives. AAPS PharmSciTech. 2014;15(4):803–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kobayashi I, Hosaka K, Ueno T, Maruo H, Kamiyama M, Konno C, et al. Relationship between the amount of propranolol permeating through the stratum corneum of guinea pig skin after application of propranolol adhesive patches and skin irritation. Biol Pharm Bull. 1996;19(6):839–44.

    Article  CAS  PubMed  Google Scholar 

  23. Roda A, Santos F, Chua YZ, Kumar A, Do HT, Paiva A, et al. Unravelling the nature of citric acid: L-arginine: water mixtures: the bifunctional role of water. Chem Chem Phys. 2021;23(2):1706–17.

    Article  CAS  Google Scholar 

  24. Zhu G, Xiao Z, Zhu G. Fabrication and characterization of ethyl acetate–hydroxypropyl-β-cyclodextrin inclusion complex. J Food Sci. 2021;86(8):3589–97.

    Article  CAS  PubMed  Google Scholar 

  25. Sun C, Cao J, Wang Y, Chen J, Huang L, Zhang H, et al. Ultrasound-mediated molecular self-assemble of thymol with 2-hydroxypropyl-β-cyclodextrin for fruit preservation. Food Chem. 2021;363:130327.

    Article  CAS  PubMed  Google Scholar 

  26. Tanner EE, Curreri AM, Balkaran JP, Selig-Wober NC, Yang AB, Kendig C, et al. Design principles of ionic liquids for transdermal drug delivery. Adv Mater. 2019;31(27):1901103.

    Article  Google Scholar 

  27. Xu LH, Wu D, Zhong M, Wang GB, Chen XY, Zhang ZJ. The construction of a new deep eutectic solvents system based on choline chloride and butanediol: the influence of the hydroxyl position of butanediol on the structure of deep eutectic solvent and supercapacitor performance. J Power Sources. 2021;490:229365.

    Article  CAS  Google Scholar 

  28. Zinov’eva I, Fedorov AY, Milevskii N, Zakhodyaeva YA, Voshkin A. A deep eutectic solvent based on choline chloride and sulfosalicylic acid: properties and applications. Theor Found Chem Eng. 2021;55(3):371–9.

    Article  Google Scholar 

  29. Al-Sadat W, Nasser M, Chang F, Nasr-El-Din H, Hussein I. Rheology of a viscoelastic zwitterionic surfactant used in acid stimulation: effects of surfactant and electrolyte concentration. J Pet Sci Eng. 2014;124:341–9.

    Article  CAS  Google Scholar 

  30. Altamash T, Nasser MS, Elhamarnah Y, Magzoub M, Ullah R, Qiblawey H, et al. Gas solubility and rheological behavior study of betaine and alanine based natural deep eutectic solvents (NADES). J Mol Liq. 2018;256:286–95.

    Article  CAS  Google Scholar 

  31. Rahman MS, Roy R, Montoya C, Halim MA, Raynie DE. Acidic and basic amino acid-based novel deep eutectic solvents and their role in depolymerization of lignin. J Mol Liq. 2022;362:119751.

    Article  CAS  Google Scholar 

  32. Dai Y, van Spronsen J, Witkamp G-J, Verpoorte R, Choi YH. Natural deep eutectic solvents as new potential media for green technology. Anal Chim Acta. 2013;766:61–8.

    Article  CAS  PubMed  Google Scholar 

  33. Mohandoss S, Edison TNJI, Atchudan R, Palanisamy S, Prabhu NM, Napoleon AA, et al. Ultrasonic-assisted efficient synthesis of inclusion complexes of salsalate drug and β-cyclodextrin derivatives for potent biomedical applications. J Mol Liq. 2020;319:114358.

    Article  CAS  Google Scholar 

  34. Preskar M, Vrbanec T, Vrečer F, Šket P, Plavec J, Gašperlin M. Solubilization of ibuprofen for freeze dried parenteral dosage forms. Acta Pharm. 2019;69(1):17–32.

    Article  CAS  PubMed  Google Scholar 

  35. Deaconu M, Pintilie L, Vasile E, Mitran R-A, Pircalabioru GG, Matei C, et al. Norfloxacin delivery systems based on MCM-type silica carriers designed for the treatment of severe infections. Mater Chem Phys. 2019;238:121886.

    Article  CAS  Google Scholar 

  36. Boddu P, Cherakapu VL, Ponukumati U. Application of solid dispersion technique in solubility and dissolution rate enhancement of nateglinide. Asian J Pharm Clin Res. 2017;10(11):231–8.

    Article  CAS  Google Scholar 

  37. Domańska U, Pelczarska A, Pobudkowska A. Effect of 2-hydroxypropyl-β-cyclodextrin on solubility of sparingly soluble drug derivatives of anthranilic acid. Int J Mol Sci. 2011;12(4):2383–94.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kaushik D, Michniak-Kohn B. Percutaneous penetration modifiers and formulation effects: thermal and spectral analyses. AAPS PharmSciTech. 2010;11(3):1068–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Salimi A, Hedayatipour N, Moghimipour E. The effect of various vehicles on the naproxen permeability through rat skin: a mechanistic study by DSC and FT-IR techniques. Adv Pharm Bull. 2016;6(1):9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kosuge M, Takeuchi T, Nakase I, Jones AT, Futaki S. Cellular internalization and distribution of arginine-rich peptides as a function of extracellular peptide concentration, serum, and plasma membrane associated proteoglycans. Bioconjug Chem. 2008;19(3):656–64.

    Article  CAS  PubMed  Google Scholar 

  41. Ahmadi R, Hemmateenejad B, Safavi A, Shojaeifard Z, Mohabbati M, Firuzi O. Assessment of cytotoxicity of choline chloride-based natural deep eutectic solvents against human HEK-293 cells: a QSAR analysis. Chemosphere. 2018;209:831–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The authors received financial supports from the Key-Area Research and Development Program of Guangdong Province (grant number 2020B1111590001); “Dengfeng Plan” High-level Hospital Construction Opening Project of Foshan Hospital of Traditional Chinese Medicine (grant number 202000192); the Youth Innovation Fund of the Jihua Laboratory, China (grant number X201251XL200); Young Top Talents of Liaoning Xingliao Talents Program (grant number XLYC2007184); and Young and Middle-aged Scientific and Technological Innovation Talents Plan in Shenyang (grant number RC200367).

Author information

Authors and Affiliations

  1. Jihua Laboratory, Jihua Institute of Biomedical Engineering and Technology, Foshan, 528000, People’s Republic of China

    Jianhua Lv, Pan Wu, Yaru Fang, Wenchang Zhang, Mi Wu, Lei Shang & Yan Zhao

  2. Department of Chemistry, College of Sciences, Northeastern University, Shenyang, 110819, People’s Republic of China

    Pan Wu

  3. Foshan Hospital of TCM, Foshan, Guangdong, 528000, People’s Republic of China

    Dongwen Liu & Huaiguo Li

  4. Suzhou Biomedical Research & Development Center, Suzhou, 215000, People’s Republic of China

    Lei Shang

Authors
  1. Jianhua Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yaru Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenchang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dongwen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lei Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huaiguo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Jianhua Lv: conceptualization, methodology, investigation, formal analysis, data curation, writing. Pan Wu: methodology, investigation. Yaru Fang: methodology, investigation. Wenchang Zhang: methodology, investigation. Dongwen Liu: methodology, investigation. Mi Wu: formal analysis, soft ware. Lei Shang: resources, date collection, date analysis, writing—review. Huaiguo Li: resources, writing—review. Yan Zhao: resources, date analysis, writing—review and editing.

Corresponding authors

Correspondence to Mi Wu, Lei Shang, Huaiguo Li or Yan Zhao.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lv, J., Wu, P., Fang, Y. et al. Deep Eutectic Solvents Based on L-Arginine and 2-Hydroxypropyl-β-Cyclodextrin for Drug Carrier and Penetration Enhancement. AAPS PharmSciTech 24, 187 (2023). https://doi.org/10.1208/s12249-023-02638-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-023-02638-0

Keywords

Search

Navigation