Skip to main content

Advertisement

SpringerLink
Log in

Characterization and Systemic Delivery of Dibenzoylmethane via the Intranasal Route

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

Abstract

Intranasal (IN) administration is known to be noninvasive with the potential to carry a drug or vaccine directly to the blood, bypassing first-pass metabolism in the liver and the harsh environment of the gastrointestinal system. Orally administered dibenzoylmethane (DBM) has been shown experimentally to be neuroprotective in animal models of tauopathy and prion disease and effective in the treatment of certain forms of cancers. The purpose of this study was to prepare, characterize, and test formulations of DBM designed for IN administration. DBM was formulated in brain homogenate (BH) and hypromellose and as nanoparticles (NPs). These formulations were detected using UPLC and characterized in solid and suspension states; NPs were also characterized by in vitro cell culture–based studies. Particle size for DBM NP was 163.8 ± 3.2 nm, and in vitro release studies showed 95.80% of DBM was released from the NPs within 8 days. In vitro cell, culture studies suggested no drug uptake until 6 h. A histological analysis of nasal cavity (NC) sections and blood detection studies were carried out 30 min after inhalation. DBM amounting to 40.77 ± 4.93 and 44.45 ± 5.36 ng/mL was detected in the blood of animals administered DBM in polymeric and NP formulation, respectively. Histological studies on NCs confirmed the presence of BH within lymphatic vessels in the lamina propria of each animal; BH was identified traversing the mucosa in 2 animals. Thus, formulations for DBM administered via IN route were successfully designed and characterized and able to cross the nasal mucosa following inhalation.

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

Similar content being viewed by others

References

  1. Grassin-Delyle S, Buenestado A, Naline E, Faisy C, Blouquit-Laye S, Couderc L-J, et al. Intranasal drug delivery: an efficient and noninvasive route for systemic administration. Pharmacol Ther. 2012;134:366–79.

    Article  CAS  Google Scholar 

  2. Agrawal M, Saraf S, Saraf S, Dubey S, Puri A, Gupta U, et al. Stimuli-responsive in situ gelling system for nose-to-brain drug delivery. J Control Release. 2020;327:235–65. https://doi.org/10.1016/j.jconrel.2020.07.044.

    Article  CAS  PubMed  Google Scholar 

  3. Fonseca-Santos B, Chorilli M. The uses of resveratrol for neurological diseases treatment and insights for nanotechnology based-drug delivery systems. Int J Pharm. 2020;589:119832. https://doi.org/10.1016/j.ijpharm.2020.119832.

    Article  CAS  PubMed  Google Scholar 

  4. Kashyap K, Shukla R. Drug delivery and targeting to the brain through nasal route: mechanisms, Applications and Challenges. Curr Drug Deliv. 2019;16(10):887–901. https://doi.org/10.2174/1567201816666191029122740.

    Article  CAS  PubMed  Google Scholar 

  5. Ghardiri M, Young PM, Traini D. Strategies to enhance drug absorption via nasal and pulmonary routes. Pharmaceutics. 2019;11:113–32. https://doi.org/10.3390/pharmaceutics11030113.

    Article  CAS  Google Scholar 

  6. Elder AM, Henderson DM, Nalls AV, Hoover EA, Kincaid AE, Bartz JC, et al. Immediate and ongoing detection of prions in the blood of hamsters and deer following oral, nasal, or blood inoculations. J Virol. 2015;89(14):7421–4.

    Article  CAS  Google Scholar 

  7. Kincaid AE, Bartz JC. The nasal cavity is a route for prion infection in hamsters. J Virol. 2007;81(9):4482–91.

    Article  CAS  Google Scholar 

  8. Kincaid AE, Hudson KF, Richey MW, Bartz JC. Rapid transepithelial transport of prions following inhalation. J Virol. 2012;86(23):12731–40.

    Article  CAS  Google Scholar 

  9. Kincaid AE, Ayers JI, Bartz JC. Specificity, size and frequency of spaces that characterize the mechanism of bulk transepithelial transport of prions in the nasal cavities of mice and hamsters. J Virol. 2016;90:8293–301.

    Article  CAS  Google Scholar 

  10. Dibenzoylmethane. Pubchem.ncbi.nlm.nih.gov. 2019. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Dibenzoylmethane

  11. Liao Y-F, Tzeng Y-M, Hung H-C, Liu G-Y. Dibenzoylmethane, hydroxydibenzoylmethane and hydroxymethyldibenzoylmethane inhibit phorbol-12-myristate 13-acetate-induced breast carcinoma cell invasion. Mol Med Rep. 2015;11(6):4597–604. https://doi.org/10.3892/mmr.2015.3304.

    Article  CAS  PubMed  Google Scholar 

  12. Huang M-T, Lou Y-R, Xie JG, Ma W, Lu Y-P, Yen P, et al. Effect of dietary curcumin and dibenzoylmethane on formation of 7,12- dimethylbenz[a]anthracene-induced mammary tumors and lymphomas/ leukemias in Sencar mice. Carcinogenesis. 1998;19(9):1697–700.

    Article  CAS  Google Scholar 

  13. Khor TO, Yu S, Barve A, Hao X, Hong J-L, Lin W, et al. Dietary feeding of dibenzoylmethane inhibits prostate cancer in transgenic adenocarcinoma of the mouse prostate model. Cancer Res. 2009;69(17):7096–102.

    Article  Google Scholar 

  14. Shishu AKS, Kaur IP. Inhibitory effect of dibenzoylmethane on mutagenicity of food-derived heterocyclic amine mutagens. Phytomedicine. 2003;10:575–82.

    Article  CAS  Google Scholar 

  15. Singeltary K, MacDonald C, Iovinelli M, Fisher C, Wallig M. Effect of the β-diketones diferuloylmethane (curcumin) and dibenzoylmethane on rat mammary DNA adducts and tumors induced by 7,12-dimethylbenz[a]anthracene. Carcinogenesis. 1998;19(6):1039–43.

    Article  Google Scholar 

  16. Cheung KL, Khor TO, Huang M-T, Kong A-N. Differential in vivo mechanism of chemoprevention of tumor formation in azoxymethane/dextran sodium sulfate mice by PEITC and DBM. Carcinogenesis. 2010;31(5):880–5.

    Article  CAS  Google Scholar 

  17. Takano K, Kitao Y, Tabata Y, Miura H, Sato K, Takuma K, et al. A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress. Am J Phys Cell Phys. 2007;293(6):C1884–94.

    Article  CAS  Google Scholar 

  18. Halliday M, Radford H, Zents KAM, et al. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain. 2017;140(6):1768–83.

    Article  Google Scholar 

  19. Vora D, Heruye S, Kumari D, Opere C, Chauhan H. Preparation, characterization and antioxidant evaluation of poorly soluble polyphenol-loaded nanoparticles for cataract treatment. AAPS PharmSciTech. 2019;20(5).

  20. Meng F, Gala U, Chauhan H. Classification of solid dispersions: correlation to (i) stability and solubility (ii) preparation and characterization techniques. Drug Dev Ind Pharm. 2015a;41(9):1401–15.

    Article  CAS  Google Scholar 

  21. Meng F, Trivino A, Prasad D, Chauhan H. Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions. Eur J Pharm Sci. 2015b;71:12–24.

    Article  CAS  Google Scholar 

  22. Chien TW, Chang SF. Intranasal drug delivery for systemic medications. Crit Rev Ther Drug Carrier Syst. 1987;4(2):67–194.

    CAS  PubMed  Google Scholar 

  23. Tong G, Qin N, Sun L. Development and evaluation of desvenlafaxine loaded PLGA-chitosan nanoparticles for brain delivery. Saudi Pharma J. 2017;25(6):844–51.

    Article  Google Scholar 

  24. Pardeshi C, Rajput P, Belgamwar V, Tekade A, Surana S. Novel surface modified solid lipid nanoparticles as intranasal carriers for ropinirole hydrochloride: application of factorial design approach. Drug Deliv. 2013;20(1):47–56.

    Article  CAS  Google Scholar 

  25. Alshweiat A, Ambrus R, Csoka I. Intranasal nanoparticulate systems as alternative route of drug delivery. Curr Med Chem. 2019;26(35):6459–92. https://doi.org/10.2174/0929867326666190827151741.

    Article  CAS  PubMed  Google Scholar 

  26. Kumar R, Singh A, Garg N, Siril P. Solid lipid nanoparticles for the controlled delivery of poorly water soluble non-steroidal anti-inflammatory drugs. Ultrason Sonochem. 2018;40:686–96.

    Article  CAS  Google Scholar 

  27. Zoubari G, Staufenbiel S, Volz P, Alexiev U, Bodmeier R. Effect of drug solubility and lipid carrier on drug release from lipid nanoparticles for dermal delivery. Eur J Pharm Biopharm. 2017;110:39–46.

    Article  CAS  Google Scholar 

  28. Zhang J, Zhu C, Hu L, Liu H, Pan H. Effect of freeze-drying process on the physical stability and properties of Voriconazole complex system. Dry Technol. 2018;36(7):871–8. https://doi.org/10.1080/07373937.2017.1362648.

    Article  Google Scholar 

  29. Kumar M, Kakkar V, Mishra A, Chuttani K, Kaur I. Intranasal delivery of streptomycin sulfate (STRS) loaded solid lipid nanoparticles to brain and blood. Int J Pharm. 2014;461(1–2):223–33.

    CAS  PubMed  Google Scholar 

  30. Belgamwar A, Khan S, Yeole P. Intranasal chitosan-g-HPβCD nanoparticles of efavirenz for the CNS targeting. Artif Cells Nanomed Biotechnol. 2017;46(2):374–86.

    Article  Google Scholar 

  31. Gänger S, Schindowski K. Tailoring formulations for intranasal nose-to-brain delivery: a review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa. Pharmaceutics. 2018;10(3):116.

    Article  Google Scholar 

  32. Pathak R, Prasad Dash R, Misra M, Nivsarkar M. Role of mucoadhesive polymers in enhancing delivery of nimodipine microemulsion to brain via intranasal route. Acta Pharm Sin B. 2014;4(2):151–60.

    Article  Google Scholar 

  33. Gavini E, Rassu G, Haukvik T, Lanni C, Racchi M, Giunchedi P. Mucoadhesive microspheres for nasal administration of cyclodextrins. J Drug Target. 2009;17(2):168–79.

    Article  CAS  Google Scholar 

  34. Jain A, Jain S. In vitro release kinetics model fitting of liposomes: an insight. Chem Phys Lipids. 2016a;201:28–40.

    Article  CAS  Google Scholar 

  35. Jain A, Jain S. In vitro release kinetics model fitting of liposomes: an insight. Chem Phys Lipids. 2016b;201:28–40.

    Article  CAS  Google Scholar 

  36. Zhao F, Zhao Y, Liu Y, Chang X, Chen C, Zhao Y. Cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials. Small. 2011;7(10):1322–37.

    Article  CAS  Google Scholar 

  37. Katare Y, Piazza J, Bhandari J, Daya R, Akilan K, Simpson M, et al. Intranasal delivery of antipsychotic drugs. Schizophr Res. 2017;184:2–13.

    Article  Google Scholar 

  38. Foster K, Avery M, Yazdanian M, Audus K. Characterization of the Calu-3 cell line as a tool to screen pulmonary drug delivery. Int J Pharm. 2000;208(1–2):1–11.

    Article  CAS  Google Scholar 

  39. Drettner B, Proctor DF, Andersen IB (1982) The Nose-Upper Airway. Physiol Atmos Environ 145–162

  40. Gizurarson S. Anatomical and histological factors affecting intranasal drug and vaccine delivery. Curr Drug Deliv. 2012;9(6):566–82.

    Article  CAS  Google Scholar 

Download references

Funding

This research was supported by a Health Sciences Strategic Investment Fund Faculty Development Grant of Creighton University.

Author information

Authors and Affiliations

  1. Creighton University School of Pharmacy and Health Professionals, Omaha, Nebraska, USA

    Deepal Vora, Anthony E. Kincaid, Justin Tolman & Harsh Chauhan

Authors
  1. Deepal Vora
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony E. Kincaid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Justin Tolman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Harsh Chauhan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harsh Chauhan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vora, D., Kincaid, A.E., Tolman, J. et al. Characterization and Systemic Delivery of Dibenzoylmethane via the Intranasal Route. AAPS PharmSciTech 22, 30 (2021). https://doi.org/10.1208/s12249-020-01904-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-020-01904-9

KEY WORDS

Search

Navigation