Skip to main content

Advertisement

Log in

Tetramethylpyrazine-Loaded Hydrogels: Preparation, Penetration Through a Subcutaneous-Mucous-Membrane Model, and a Molecular Dynamics Simulation

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

Abstract

Tetramethylpyrazine (TMP) was extracted from Ligusticum chuanxiong hort. The compound is known to have a variety of medicinal functions; in particular, it is used for the treatment of cerebral ischemic diseases. TMP-loaded hydrogels offer an excellent preparation with the capacity to bypass the blood-brain barrier, allowing treatment of the brain through intranasal administration. We prepared TMP-loaded hydrogels using carbomer 940 and evaluated the release of TMP from the hydrogel. We determined the release rate using Franz-type diffusion cell experiments with a subcutaneous-mucous-membrane model and also by a molecular dynamics (MD) simulation. In general, the former method was more complicated than the latter was. The dynamic behavior of TMP release from the hydrogel was revealed by analysis of the mean square displacement of the trajectory in the MD simulation. The coefficient of TMP diffusion from the hydrogel was calculated at different temperatures (277, 298, and 310 K) by using MD software. The results showed that the coefficient of diffusion increased with an increase in temperature. This trend was observed both experimentally and in the MD simulation. Therefore, the MD simulation was a complementary method to verify the experimental data.

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

Access this article

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

Similar content being viewed by others

References

  1. Li XY, He JL, Liu T, Li WM, Yua C. Tetramethylpyrazine suppresses interleukin-8 expression in LPS-stimulated human umbilical vein endothelial cell by blocking ERK, p38 and nuclear factor-κB signaling pathways. J Ethnopharmacol. 2009;125:83–9.

    Article  CAS  PubMed  Google Scholar 

  2. Chen L, Lu Y, Wu JM, Xu B, Zhang LJ, Gao M, et al. Ligustrazine inhibits B16F10 melanoma metastasis and suppresses angiogenesis induced by vascular endothelial growth factor. Biochem Biophys Res Commun. 2009;386:374–9.

    Article  CAS  PubMed  Google Scholar 

  3. Sue YM, Cheng CF, Chang CC, Chou Y, Chen CH, Juan SH. Antioxidation and anti-inflammation by haem oxygenase-1 contribute to protection by tetramethylpyrazine against gentamicin-induced apoptosis in murine renal tubular cells. Nephrol Dial Transplant. 2009;24:769–77.

    Article  CAS  PubMed  Google Scholar 

  4. Kang YX, Hu MH, Zhu YH, Gao X, Wang MW. Antioxidative effect of the herbal remedy Qin Huo Yi Hao and its active component tetramethylpyrazine on high glucose-treated endothelial cells. Life Sci. 2009;84:428–36.

    Article  CAS  PubMed  Google Scholar 

  5. Gao X, Zhao XL, Zhu YH, Li XM, Xu Q, Lin HD, et al. Tetramethylpyrazine protects palmitate-induced oxidative damage and mitochondrial dysfunction in C2C12 myotubes. Life Sci. 2011;88:803–9.

    Article  CAS  PubMed  Google Scholar 

  6. Cheng XR, Zhang L, Hu JJ, Sun L, Du GH. Neuroprotective effects of tetramethylpyrazine on hydrogen peroxide-induced apoptosis in PC12 cells. Cell Biol Int. 2007;31:438–43.

    Article  CAS  PubMed  Google Scholar 

  7. Gao C, Liu XZ, Liu W, Shi HZ, Zhao ZH, Chen HR, et al. Anti-apoptotic and neuroprotective effects of Tetramethylpyrazine following subarachnoid hemorrhage in rats. Auton Neurosci Basic Clin. 2008;141:22–30.

    Article  CAS  Google Scholar 

  8. Yang J, Li J, Lu J, Zhang Y, Zhu Z, Wan H. Synergistic protective effect of astragaloside IV-tetramethylpyrazine against cerebral ischemic-reperfusion injury induced by transient focal ischemia. J Ethnopharmacol. 2012;140:64–72.

    Article  CAS  PubMed  Google Scholar 

  9. Luo XX, Ogata H, Xu X, Ishitobi F. Protective effect of tetramethylpyrazine on ischemic neuronal damage in the gerbil hippocampus. No To Shinkei. 1994;46:841–6.

    CAS  PubMed  Google Scholar 

  10. Chang Y, Hsiao G, Chen SH, Chen YC, Lin JH, Lin KH, et al. Tetramethylpyrazine suppresses HIF-1alpha, TNF-alpha, and activated caspase-3 expression in middle cerebral artery occlusion-induced brain ischemia in rats. Acta Pharmacol Sin. 2007;28:327–33.

    Article  CAS  PubMed  Google Scholar 

  11. Feng J, Li FZ, Zha YM, Feng YR, Abe Y. Brain pharmacokinetics of tetramethylpyrazine after intranasal and intravenous administration in awake rats. Int J Pharm. 2009;375:55–60.

    Article  CAS  PubMed  Google Scholar 

  12. Rodriguez Vilches S, Séverac C, Thibaut C, Laplatine L, Vieu C, Fitremann J, et al. Nanostructuration of soft hydrogels: synthesis and characterization of saccharidic methacrylate gels. Colloid Polym Sci. 2011;289:1437–49.

    Article  CAS  Google Scholar 

  13. Alsarra IA, Hamed AY, Alanazi FK, Neau SH. Rheological and mucoadhesive characterization of polyvinylpyrrolidone hydrogels designed for nasal mucosal drug delivery. Arch Pharm Res. 2011;34:573–82.

    Article  CAS  PubMed  Google Scholar 

  14. Jin L, Lu P, You H, Che Q, Dong J. Vitamin B12 diffusion and binding in crosslinked polyacrylic acids and polyacrylic acid-co-N-vinyl pyrrolidinones. Int J Pharm. 2009;371:82–8.

    Article  CAS  PubMed  Google Scholar 

  15. Xu L, Li X, Takemura T, Hanagata N, Wu G, Chou LL. Genotoxicity and molecular response of silver nanoparticle NP-based hydrogel. J Nanobiotechnol. 2012;10:16–36.

    Article  CAS  Google Scholar 

  16. Geraths C, Eichstädter L, Gübeli RJ, Christen EH, Friedrich C, Weber W. Synthesis and characterization of a stimulus-responsive L-ornithine-degrading hydrogel. J Control Release. 2013;165:38–43.

    Article  CAS  PubMed  Google Scholar 

  17. Tan XW, Hartman L, Tan KP, Poh R, Myung D, Zheng LL, et al. In vivo biocompatibility of two PEG/PAA interpenetrating polymer networks as corneal inlays following deep stromal pocket implantation. J Mater Sci Mater Med. 2013;24:967–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bysell H, Hansson P, Schmidtchen A, Malmsten M. Effect of hydrophobicity on the interaction between antimicrobial peptides and poly(acrylic acid) microgels. J Phys Chem B. 2010;114:1307–13.

    Article  CAS  PubMed  Google Scholar 

  19. Montheard JP, Chatzopoulos M, Chappard D. 2-Hydroxyethyl methacrylate (Hema)—chemical-properties and applications in biomedical fields. J Macromol Sci Rev Macromol Chem Phys C. 1992;32:1–34.

    Article  Google Scholar 

  20. Charati SG, Stern SA. Diffusion of gases in silicone polymers: molecular dynamics simulations. Macromolecules. 1998;31:5529–35.

    Article  CAS  Google Scholar 

  21. Dieter H, Lydia F, Jens U, Claudia S, Martin B. Detailed-atomistic molecular modeling of small molecule diffusion and solution processes in polymeric membrane materials. Macromol Theory Simul. 2000;9:293–327.

    Article  Google Scholar 

  22. Prabha SK, Sathian SP. Determination of accommodation coefficients of a gas mixture in a nanochannel with molecular dynamics. Microfluid Nanofluid. 2012;13:883–90.

    Article  CAS  Google Scholar 

  23. Wang KF, Leng Y, Lu X, Ren FZ, Ge X. Study of protein adsorption on octacalcium phosphate surfaces by molecular dynamics simulations. J Mater Sci Mater Med. 2012;23:1045–53.

    Article  CAS  PubMed  Google Scholar 

  24. Melicherčík M, Holúbeková A, Hianik T, Urban J. Effect of the aminoacid composition of model α-helical peptides on the physical properties of lipid bilayers and peptide conformation: a molecular dynamics simulation. J Mol Model. 2013;19:4723–30.

    Article  PubMed  Google Scholar 

  25. Lee SG, Koh W, Brunello GF, Choi JI, Bucknall DG, Jang SS. Effect of monomeric sequence on transport properties of D-glucose and ascorbic acid in polyVP-co-HEMA. hydrogels with various water contents: molecular dynamics simulation approach. Theor Chem Acc. 2012;131:1206.

    Article  Google Scholar 

  26. Demianenko P, Minisini B, Ortelli G, Lamrani M, Poncin-Epaillard F. Computing thermomechanical properties of dry homopolymers used as raw materials for formulation of biomedical hydrogels. J Mol Model. 2016;22:159.

    Article  PubMed  Google Scholar 

  27. Hong G, Pachter R. Photoactivation of cryptochromes from Drosophila melanogaster and Sylvia borin: insight into the chemical compass mechanism by computational investigation. J Phys Chem B. 2015;119:3883–92.

    Article  CAS  PubMed  Google Scholar 

  28. McQuaid MJ, Sun H, Rigby D. Development and validation of COMPASS force field parameters for molecules with aliphatic azide chains. J Comput Chem. 2004;25:61–71.

    Article  CAS  PubMed  Google Scholar 

  29. Li D, Yang HL, Emmerich H. Phase field model simulations of hydrogel dynamics under chemical stimulation. Colloid Polym Sci. 2011;289:513–21.

    Article  CAS  Google Scholar 

  30. Cui FZ, Tian WM, Hou SP, Xu QY, Lee IS. Hyaluronic acid hydrogel immobilized with RGD peptides for brain tissue engineering. J Mater Sci Mater Med. 2006;17:1393–401.

    Article  CAS  PubMed  Google Scholar 

  31. Djupesland PG. Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review. Drug Deliv Transl Res. 2013;3:42–62.

    Article  CAS  PubMed  Google Scholar 

  32. Hersh DS, Wadajkar AS, Roberts NB, Perez JG, Connolly NP, Frenkel V, et al. Evolving drug delivery strategies to overcome the blood brain barrier. Curr Pharm Des. 2016;22:1177–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kozlovskaya L, Abou-Kaoud M, Stepensky D. Quantitative analysis of drug delivery to the brain via nasal route. J Control Release. 2014;189:133–40.

    Article  CAS  PubMed  Google Scholar 

  34. Djupesland PG, Messina JC, Mahmoud RA. The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview. Ther Deliv. 2014;5:709–33.

    Article  CAS  PubMed  Google Scholar 

  35. Einer-Jensen N, Larsen L. Local transfer of diazepam, but not of cocaine, from the nasal cavities to the brain arterial blood in rats. Pharmacol Toxicol. 2000;87:276–8.

    Article  CAS  PubMed  Google Scholar 

  36. Einer-Jensen N, Larsen L, Deprez S, Starns E, Schwartz S. Intranasal absorption of sumatriptan and naratriptan: no evidence of local transfer from the nasal cavities to the brain arterial blood in male rats. Biopharm Drug Dispos. 2001;22:213–9.

    Article  CAS  PubMed  Google Scholar 

  37. Wadell C, Björk E, Camber O. Nasal drug delivery—evaluation of an in vitro model using porcine nasal mucosa. Eur J Pharm Sci. 1999;7:197–206.

    Article  CAS  PubMed  Google Scholar 

  38. Fabrizio B, Giulia BA, Fabio S, Paola R, Gaia C. In vitro permeation of desmopressin across rabbit nasal mucosa from liquid nasal sprays: the enhancing effect of potassium sorbate. Eur J Pharm Sci. 2009;37:36–42.

    Article  CAS  PubMed  Google Scholar 

  39. Pund S, Rasve G, Borade G. Ex vivo permeation characteristics of venlafaxine through sheep nasal mucosa. Eur J Pharm Sci. 2013;48:195–201.

    Article  CAS  PubMed  Google Scholar 

  40. Aydt EM, Hentschke R. Swelling of a model network: a Gibbs-ensemble molecular dynamics study. J Chem Phys. 2000;112:5480–7.

    Article  CAS  Google Scholar 

  41. Qiu Y, Park K. Environment-sensitive hydrogels for drug deliver. Adv Drug Deliv Rev. 2001;53:321–39.

    Article  CAS  PubMed  Google Scholar 

  42. Peppas NA, Huang Y, Torres-Lugo M, Ward JH, Zhang J. Physicochemical, foundations and structural design of hydrogels in medicine and biology. Annu Rev Biomed Eng. 2000;2:9–29.

    Article  CAS  PubMed  Google Scholar 

  43. Lin CC, Metters AT. Hydrogels in controlled release formulations: network design and mathematical modeling. Adv Drug Deliv Rev. 2006;58:1379–408.

    Article  CAS  PubMed  Google Scholar 

  44. Amsden B. Solute diffusion within hydrogels. Mech Model Macromol. 1998;31:8382–95.

    CAS  Google Scholar 

  45. Saxton MJ. Anomalous subdiffusion in fluorescence photobleaching recovery: a Monte Carlo study. Biophys J. 2001;81:2226–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Weiss M, Elsner M, Kartberg F, Nilsson T. Anomalous subdiffusion is a measure for cytoplasmic crowding in living cells. Biophys J. 2004;87:3518–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schutz GJ, Schindler H, Schmidt T. Single-molecule microscopy on model membranes reveals anomalous diffusion. Biophys J. 1997;73:1073–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Weiss M, Hashimoto H, Nilsson T. Anomalous protein diffusion in living cells as seen by fluorescence correlation spectroscopy. Biophys J. 2003;84:4043–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Azurmendi HF, Ramia ME. Anomalous diffusion of water in a hydrogel of sucrose and diepoxide monomers. J Chem Phys. 2001;114:9657–62.

    Article  CAS  Google Scholar 

  50. Drazer G, Zanette DH. Experimental evidence of powerlaw trapping-time distributions in porous media. Phys Rev E. 1999;60:5858–64.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This project was financially supported by Anhui Natural Science Fund (1608085MH227), the Natural Science Fund of Anhui University of Traditional Chinese Medicine (2010zr004A), the Natural Science Fund (81274100), the Kangyuan Fund (KYCX201001), and the Anhui province science and technology special fund project (13Z04013).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hongmei Xia.

Ethics declarations

All experimental procedures complied with the requirements of the National Acts on the use of experimental animals and were approved by the Institutional Animal Care (People’s Republic of China).

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xia, H., Xu, Y., Cheng, Z. et al. Tetramethylpyrazine-Loaded Hydrogels: Preparation, Penetration Through a Subcutaneous-Mucous-Membrane Model, and a Molecular Dynamics Simulation. AAPS PharmSciTech 18, 1720–1727 (2017). https://doi.org/10.1208/s12249-016-0645-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-016-0645-5

KEY WORDS

Navigation