Advertisement

Pharmaceutical Research

, 36:117 | Cite as

MOF Capacitates Cyclodextrin to Mega-Load Mode for High-Efficient Delivery of Valsartan

  • Wei Zhang
  • Tao Guo
  • Caifen Wang
  • Yuanzhi He
  • Xi Zhang
  • Guangyu Li
  • Yizhi Chen
  • Jun Li
  • Yangjing Lin
  • Xu Xu
  • Li WuEmail author
  • Suxia ZhangEmail author
  • Jiwen ZhangEmail author
Research Paper
  • 190 Downloads

Abstract

Purpose

To investigate the mechanism of enhancing solubility and bioavailability of water-insoluble drug, valsartan (VAL), with being mega-loaded by cyclodextrin metal organic framework (CD-MOF).

Methods

VAL was successfully mega-loaded into CD-MOF by magnetic agitation of VAL in ethanolic solution. Characterizations including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), synchrotron radiation-based Fourier transform-infrared spectroscopy (SR-FTIR) 13C solid-state nuclear magnetic resonance spectroscopy ( 13C SS-NMR), nitrogen gas adsorption, and small-angle X-ray scattering (SAXS) were carried out to confirm the mechanism and incorporation behavior of VAL in CD-MOF. Ball milling process combined with molecular modeling was also used to confirm the mechanism. Improvement of bioavailability in vivo was confirmed by pharmacokinetic experiment in beagles.

Results

As a carrier with payload 150% higher than conventional CD complexation, CD-MOF included molecules of VAL as complexations in the chambers of (γ-CD)2, and nanoclusters in the confined spherical cages of (γ-CD)6 confirmed by SAXS and 13C SS-NMR. Ball milling combined with molecular modeling inferred that the reduced release rate of the milled CD-MOF with ultrahigh drug payload was mainly due to the partial aggregation of the VAL nanoclusters. The molecules of VAL as nanoclusters in the cages of (γ-CD)6 are critical in dramatically improving the apparent solubility (39.5-fold) and oral bioavailability (1.9-fold) of VAL in contrast to γ-CD inclusion.

Conclusions

The new understanding of drug nanoclusters in CD-MOF will help to design more efficient drug delivery systems using CD-MOF carrier with nanocavities.

Key Words

Bioavailability cyclodextrin metal-organic framework solubility valsartan 

Abbreviations

13C SS-NMR

13C solid-state nuclear magnetic resonance spectroscopy

CD

Cyclodextrin

CD-MOF

Cyclodextrin metal-organic frameworks

DSC

Differential scanning calorimetry

PXRD

Powder X-ray diffraction

SAXS

Small-angle X-ray scattering

SEM

Scanning electron microscopy

SR-FTIR

Synchrotron radiation-based Fourier transform-infrared spectroscopy

VAL

Valsartan

VAL/CD

Valsartan cyclodextrin inclusion complex

VAL/CD-MOF

Valsartan loaded by cyclodextrin metal-organic frameworks

Notes

Supplementary material

11095_2019_2650_MOESM1_ESM.docx (534 kb)
ESM 1 (DOCX 534 kb)

References

  1. 1.
    Crini G. Review: a history of Cyclodextrins. Chem Rev. 2014;114(21):10940–75.PubMedCrossRefGoogle Scholar
  2. 2.
    Prochowicz D, Kornowicz A, Justyniak I, Lewinski J. Metal complexes based on native Cyclodextrins: synthesis and structural diversity. Coordin Chem Rev. 2016;306:331–45.CrossRefGoogle Scholar
  3. 3.
    Bilensoy E, Hincal AA. Recent advances and future directions in amphiphilic cyclodextrin nanoparticles. Expert Opin Drug Deliv. 2009;6(11):1161–73.PubMedCrossRefGoogle Scholar
  4. 4.
    Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations II: Solubilization, binding constant, and complexation efficiency. Drug Discov Today. 2016;21(2):363–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Harada A, Takashima Y, Yamaguchi H. Cyclodextrin-based supramolecular polymers. Chem Soc Rev. 2009;38(4):875–22.PubMedCrossRefGoogle Scholar
  6. 6.
    Mejia AR, Graña SL, Verboom W, Huskens J. Cyclodextrin-based supramolecular nanoparticles for biomedical applications. J Mater Chem B. 2017;5(1):36–52.CrossRefGoogle Scholar
  7. 7.
    Smaldone RA, Forgan RS, Furukawa H, Gassensmith JJ, Slawin AM, Yaghi OM, et al. Metal-organic frameworks from edible natural products. Angew Chem. 2010;49(46):8630–4.CrossRefGoogle Scholar
  8. 8.
    Singh V, Guo T, Xu H, Wu L, Gu J, Wu C, et al. Moisture resistant and biofriendly CD-MOF nanoparticles obtained via cholesterol shielding. Chem Commun. 2017;53(66):9246–9.CrossRefGoogle Scholar
  9. 9.
    Gassensmith JJ, Furukawa H, Smaldon RA, Forgan RS, Botros YY, Yaghi OM, et al. Strong and reversible binding of carbon dioxide in a green metal-organic framework. J Am Chem Soc. 2011;133(39):15312–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Wu D, Gassensmith JJ, Gouvea D, Ushakov S, Stoddart JF, Navrotsky A. Direct calorimetric measurement of enthalpy of adsorption of carbon dioxide on CD-MOF-2, a green metal-organic framework. J Am Chem Soc. 2013;135(18):6790–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Wang L, Liang X, Chang Z, Ding L, Zhang S, Li B. Effective formaldehyde capture by green Cyclodextrin-based metal-organic framework. ACS Appl Mater Interfaces. 2018;10(1):42–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Michida W, Ezaki M, Sakuragi M, Guan GQ, Kusakabe K. Crystal growth of Cyclodextrin-based metal-organic framework with inclusion of Ferulic acid. Cryst Res Technol. 2015;50(7):556–9.CrossRefGoogle Scholar
  13. 13.
    Moussa Z, Hmadeh M, Abiad MG, Dib OH, Patra D. Encapsulation of curcumin in Cyclodextrin-metal organic frameworks: dissociation of loaded CD-MOFs enhances stability of curcumin. Food Chem. 2016;212:485–94.PubMedCrossRefGoogle Scholar
  14. 14.
    Forgan RS, Smaldone RA, Gassensmith JJ, Furukawa H, Cordes DB, Li Q, et al. Nanoporous carbohydrate metal-organic frameworks. J Am Chem Soc. 2012;134(1):406–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Liu B, Li H, Xu X, Li X, Lv N, Singh V, et al. Optimized synthesis and crystalline stability of gamma-Cyclodextrin metal-organic frameworks for drug adsorption. Int J Pharm. 2016;514(1):212–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Liu B, He Y, Han L, Singh V, Xu X, Guo T, et al. Microwave-assisted rapid synthesis of γ-Cyclodextrin metal–organic frameworks for size control and efficient drug loading. Cryst Growth Des. 2017;17(4):1654–60.CrossRefGoogle Scholar
  17. 17.
    Li H, Lv N, Li X, Liu B, Feng J, Ren X, et al. Composite CD-MOF nanocrystals-containing microspheres for sustained drug delivery. Nanoscale. 2017;9(22):7454–63.PubMedCrossRefGoogle Scholar
  18. 18.
    Li X, Guo T, Lachmanski L, Manoli F, Menendez-Miranda M, Manet I, et al. Cyclodextrin-based metal-organic frameworks particles as efficient carriers for lansoprazole: study of morphology and chemical composition of individual particles. Int J Pharm. 2017;531(2):424–32.PubMedCrossRefGoogle Scholar
  19. 19.
    Xu X, Wang C, Li H, Li X, Liu B, Singh V, et al. Evaluation of drug loading capabilities of gamma-Cyclodextrin-metal organic frameworks by high performance liquid chromatography. J Chromatogr A. 2017;1488:37–44.PubMedCrossRefGoogle Scholar
  20. 20.
    Lv N, Guo T, Liu B, Wang C, Singh V, Xu X, et al. Improvement in thermal stability of sucralose by gamma-Cyclodextrin metal-organic frameworks. Pharm Res. 2017;34(2):269–78.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang G, Meng F, Guo Z, Guo T, Peng H, Xiao J, et al. Enhanced stability of vitamin a palmitate microencapsulated by γ-Cyclodextrin metal-organic frameworks. J Microencapsul. 2018;35(3):249–58.PubMedCrossRefGoogle Scholar
  22. 22.
    He Y, Zhang W, Guo T, Zhang G, Qin W, Zhang L, et al. Drug nanoclusters formed in confined Nano-cages of CD-MOF: dramatic enhancement of solubility and bioavailability of Azilsartan. Acta Pharm Sin B. 2019;9(1):97–106.PubMedCrossRefGoogle Scholar
  23. 23.
    Cravotto G, Caporaso M, Jicsinszky L, Martina K. Enabling technologies and green processes in Cyclodextrin chemistry. Beilstein J Org Chem. 2016;12:278–94.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Ueda K, Higashi K, Moribe K. Application of solid-state NMR Relaxometry for characterization and formulation optimization of grinding-induced drug nanoparticle. Mol Pharm. 2016;13(3):852–62.PubMedCrossRefGoogle Scholar
  25. 25.
    Ali MH, Navarro AR, Martinez J, Lamaty F, Carboni M, Bantreil X. Synthesis and post-synthetic modification of UiO-67 type metal-organic frameworks by Mechanochemistry. Mater Lett. 2017;197:171–4.CrossRefGoogle Scholar
  26. 26.
    Friščić T, Halasz I, Štrukil V, Eckert MM, Dinnebier RE. Clean and efficient synthesis using Mechanochemistry: coordination polymers, metal-organic frameworks and Metallodrugs. Croat Chem Acta. 2012;85(3):367–78.CrossRefGoogle Scholar
  27. 27.
    Bennett TD, Cheetham AK. Amorphous metal-organic frameworks. Acc Chem Res. 2014;47(5):1555–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Bennett TD, Saines PJ, Keen DA, Tan JC, Cheetham AK. Ball-milling-induced Amorphization of Zeolitic Imidazolate frameworks (ZIFs) for the irreversible trapping of iodine. Chemistry. 2013;19(22):7049–55.PubMedCrossRefGoogle Scholar
  29. 29.
    Han L, Guo T, Guo Z, Wang C, Zhang W, Shakya S, et al. Molecular mechanism of loading sulfur hexafluoride in gamma-Cyclodextrin metal-organic framework. J Phys Chem B. 2018;122(20):5225–33.PubMedCrossRefGoogle Scholar
  30. 30.
    Cole BK, Keller SR, Wu R, Carter JD, Nadler JL, Nunemaker CS. Valsartan protects pancreatic islets and adipose tissue from the inflammatory and metabolic consequences of a high-fat diet in mice. Hypertension. 2010;55(3):715–21.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Sunkara G, Bende G, Mendonza AE, Solar YS, Biswal S, Neelakantham S, et al. Bioavailability of valsartan Oral dosage forms. Clin Pharmacol Drug Dev. 2014;3(2):132–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Chadha R, Bala M, Arora P, Jain DV, Pissurlenkar RR, Coutinho EC. Valsartan inclusion by methyl-beta-Cyclodextrin: thermodynamics, molecular modelling, tween 80 effect and evaluation. Carbohydr Polym. 2014;103:300–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Cappello B, Maio CD, Iervolino M, Miro A. Improvement of solubility and stability of valsartan by Hydroxypropyl-\boldbeta-Cyclodextrin. J Incl Phenom Macro. 2005;54(3–4):289–94.Google Scholar
  34. 34.
    Singh SK, Vuddanda PR, Singh S, Srivastava AK. A comparison between use of spray and freeze drying techniques for preparation of solid self-microemulsifying formulation of valsartan and in vitro and in vivo evaluation. Biomed Res Int. 2013;2013:909045–58.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Yan YD, Sung JD, Kim KD, Kim DW, Kim JQ, Lee BJ, et al. Novel valsartan-loaded solid dispersion with enhanced bioavailability and no crystalline changes. Int J Pharm. 2012;422(1–2):202–10.PubMedCrossRefGoogle Scholar
  36. 36.
    Cao S, Bennett TD, Keen DA, Goodwin AL, Cheetham AK. Amorphization of the prototypical Zeolitic Imidazolate framework ZIF-8 by ball-milling. Chem Commun. 2012;48(63):7805–7.CrossRefGoogle Scholar
  37. 37.
    Wang J, Wang X, Lu L, Mei X. Highly crystalline forms of valsartan with superior physicochemical stability. Cryst Growth Des. 2013;13:3261–9.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Chemical and Environmental EngineeringShanghai Institute of TechnologyShanghaiChina
  2. 2.Center for Drug Delivery Systems Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina
  3. 3.Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghaiChina
  4. 4.Hainan Hualon Pharmaceutical Co., LtdHaikouChina

Personalised recommendations