Skip to main content
SpringerLink
Log in

Incorporating sodium deoxycholate endorsed the buccal administration of avanafil to heighten the bioavailability and duration of action

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

A Correction to this article was published on 10 April 2023

This article has been updated

Abstract

The highly effective phosphodiesterase type 5 inhibitor (avanafil; AVA) is routinely prescribed to treat erectile dysfunction. The drug has poor oral bioavailability and undergoes a significant first-pass metabolism. Therefore, altering AVA’s solubility and choosing a different delivery method may boost its effectiveness. Nine different solid dispersion formulations utilizing polyvinylpyrrolidone (PVP) at three different ratios were prepared and characterized. The Box-Behnken design was employed to optimize AVA–buccal tablets. The pre-compression and post-compression characteristics of the tablets were assessed. The mucoadhesion strength of the optimized tablet was investigated using cow buccal mucosal tissue. In vivo performance of the optimized tablets was examined on human volunteers compared to the commercial tablets. PVP K90 at 2:1 drug to polymer ratio showed the highest solubilization capacity. The mucoadhesive polymer type and percentage and the mucopenetration enhancer percentage were significantly affect the mucoadhesion strength, tablet hardness, and the initial and cumulative AVA released from the prepared tablets. The optimized AVA–buccal tablet showed 4.96 folds increase in the mean residence time, higher plasma exposure, and an improvement in the relative bioavailability of AVA by 1076.27% compared with the commercial tablet. Therefore, a successful approach to deal with AVA first-pass metabolism and low bioavailability could be to employ buccal tablets containing a solubility-enhanced form of AVA.

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

Similar content being viewed by others

Data availability

Not applicable.

Change history

References

  1. Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. 2007;120:151–7.

    PubMed  Google Scholar 

  2. Mulhall JP, Luo X, Zou KH, Stecher V, Galaznik A. Relationship between age and erectile dysfunction diagnosis or treatment using real-world observational data in the USA. Int J Clin Pract. 2016;70:1012–8.

    CAS  PubMed  Google Scholar 

  3. Fahmy U. Nanoethosomal transdermal delivery of vardenafil for treatment of erectile dysfunction: optimization, characterization, and in vivo evaluation. Drug Des Devel Ther. 2015;9:6129–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. El-Sakka AI. Erectile dysfunction in Arab countries. Part I: Prevalence and correlates. Arab J Urol. 2012;10:97–103.

  5. Alamoudi AA, Ahmed OAA, El-Say KM. Investigating the potential of transdermal delivery of avanafil using vitamin e-tpgs based mixed micelles loaded films. Pharmaceutics. 2021;13:739.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hackett G, Kirby M, Wylie K, Heald A, Ossei-Gerning N, Edwards D, et al. British Society for Sexual Medicine Guidelines on the Management of Erectile Dysfunction in Men—2017. Elsevier Inc. J Sex Med. 2018;15:430–57.

  7. Al-hejaili OD, Alamoudi AA, Ahmed OAA, El-Say KM. Transdermal Film loaded with avanafil ultra-deformable nanovesicles to enhance its percutaneous absorption and bioavailability. AAPS PharmSciTech. AAPS PharmSciTech. 2022;23:46.

  8. Evans J, Burke R. Avanafil for treatment of erectile dysfunction: review of its potential. Vasc Health Risk Manag. 2012;8:517–23.

    PubMed  PubMed Central  Google Scholar 

  9. Hosny KM, Ahmed OAA, Fahmy UA, Alkhalidi HM. Nanovesicular systems loaded with a recently approved second generation type-5 phospodiesterase inhibitor (avanafil): I. Plackett-Burman screening and characterization. Elsevier. J Drug Deliv Sci Technol. 2018;43:154–9.

  10. Patel VF, Liu F, Brown MB. Advances in oral transmucosal drug delivery. Elsevier B.V. J Control Release. 2011;153:106–16.

  11. Pather SI, Rathbone MJ, Şenel S. Current status and the future of buccal drug delivery systems. Expert Opin Drug Deliv. 2008;5:531–42.

    CAS  PubMed  Google Scholar 

  12. Lesch CA, Squier CA, Cruchley A, Williams DM, Speight P. The Permeability of human oral mucosa and skin to water. J Dent Res. 1989;68:1345–9.

    CAS  PubMed  Google Scholar 

  13. Takahashi Y, Takeda C, Seto I, Kawano G, Machida Y. Formulation and evaluation of lactoferrin bioadhesive tablets. Int J Pharm. 2007;343:220–7.

    CAS  PubMed  Google Scholar 

  14. El-Say KM, Ahmed TA. Buccal route of drug delivery. In: Talevi A, editor. ADME Encycl. Cham: Springer International Publishing; 2022. p. 222–31.

    Google Scholar 

  15. Zaki NM, Awad GAS, Mortada ND, Abd ElHady SS. Rapid-onset intranasal delivery of metoclopramide hydrochloride. Part I. Influence of formulation variables on drug absorption in anesthetized rats. Int J Pharm. 2006;327:89–96.

  16. Ludwig A. The use of mucoadhesive polymers in ocular drug delivery. Adv Drug Deliv Rev. 2005;57:1595–639.

    CAS  PubMed  Google Scholar 

  17. Megahed MA, El-Sawy HS, Reda AM, Abd-Allah FI, Abu Elyazid SK, Lila AE, et al. Effect of nanovesicular surface-functionalization via chitosan and/or PEGylation on cytotoxicity of tamoxifen in induced-breast cancer model. Elsevier Inc. Life Sci. 2022;307:120908.

  18. El-Say KM, El-Sawy HS. Polymeric nanoparticles: promising platform for drug delivery. Int J Pharm. 2017;528:675–91.

    CAS  PubMed  Google Scholar 

  19. Sinha S, Ali M, Baboota S, Ahuja A, Kumar A, Ali J. Solid dispersion as an approach for bioavailability enhancement of poorly water-soluble drug ritonavir. AAPS PharmSciTech. 2010;11:518–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. El-Say K, Al-Subaie M, Hosny K, Ahmed T, Aljaeid B. Utilization of nanotechnology to enhance percutaneous absorption of acyclovir in the treatment of herpes simplex viral infections. Int J Nanomedicine. 2015;10:3973.

    PubMed  PubMed Central  Google Scholar 

  21. Alotaibi FO, Alhakamy NA, Omar AM, El-Say KM. Clinical pharmacokinetic evaluation of optimized liquisolid tablets as a potential therapy for male sexual dysfunction. Pharmaceutics. 2020;12:1187.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Desoqi MH, El-sawy HS, Kafagy E, Ghorab M, Gad S. Fluticasone propionate – loaded solid lipid nanoparticles with augmented anti-inflammatory activity : optimisation, characterisation and pharmacodynamic evaluation on rats. J Microencapsul Taylor & Francis. 2021;38:177–91.

    CAS  Google Scholar 

  23. Kassem MA, El-Sawy HS, Abd-Allah FI, Abdelghany TM, El-Say KM. Maximizing the therapeutic efficacy of imatinib mesylate–loaded niosomes on human colon Adenocarcinoma using box-behnken design. J Pharm Sci. 2017;106:111–22.

    CAS  PubMed  Google Scholar 

  24. Soliman MS, Abd-Allah FI, Hussain T, Saeed NM, El-Sawy HS. Date seed oil loaded niosomes: development, optimization and anti-inflammatory effect evaluation on rats. Drug Dev Ind Pharm. 2018;44:1185–97.

    CAS  PubMed  Google Scholar 

  25. El-Say KM, Ahmed TA, El-Sawy HS. Transdermal film formulations and methods of use. KSA: United States Patent. 2021.

  26. Gardouh AR, Ewedah TM, Abd-allah FI, Ghorab MM, Omran MM, El-sawy HS. Enhanced efficacy , cellular uptake , and antiangiogenic activity of the optimized imatinib mesylate-loaded proniosomal-derived nanovesicles. Elsevier B.V. J Drug Deliv Sci Technol. 2021;61:102267.

  27. Yan X, Gurtler J, Fratamico P, Hu J, Gunther NW, Juneja V, et al. Comprehensive approaches to molecular biomarker discovery for detection and identification of Cronobacter spp. ( Enterobacter sakazakii ) and Salmonella spp. Appl Environ Microbiol. 2011;77:1833–43.

  28. Nair AB, Kumria R, Harsha S, Attimarad M, Al-Dhubiab BE, Alhaider IA. In vitro techniques to evaluate buccal films. J Control Release. 2013;166:10–21.

    CAS  PubMed  Google Scholar 

  29. Ahmed TA, Bawazir AO, Alharbi WS, Safo MK. Enhancement of simvastatin ex vivo permeation from mucoadhesive buccal films loaded with dual drug release carriers. Int J Nanomedicine. 2020;15:4001–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ahmed TA, Alotaibi HA, Alharbi WS, Safo MK, El-Say KM. Development of 3D-printed, liquisolid and directly compressed glimepiride tablets, loaded with black seed oil self-nanoemulsifying drug delivery system: In Vitro and In Vivo Characterization. Pharmaceuticals. 2022;15:68.

  31. Silva CO, Rijo P, Molpeceres J, Figueiredo IV, Ascensão L, Fernandes AS, et al. Polymeric nanoparticles modified with fatty acids encapsulating betamethasone for anti-inflammatory treatment. Elsevier B.V. Int J Pharm. 2015;493:271–84.

  32. Mulik RS, Mönkkönen J, Juvonen RO, Mahadik KR, Paradkar AR. ApoE3 mediated polymeric nanoparticles containing curcumin: apoptosis induced in vitro anticancer activity against neuroblastoma cells. Elsevier B.V. Int J Pharm. 2012;437:29–41.

  33. Aldawsari HM, Fahmy UA, Abd-Allah F, Ahmed OAA. Formulation and optimization of avanafil biodegradable polymeric nanoparticles: a single-dose clinical pharmacokinetic evaluation. Pharmaceutics. 2020;12:596.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Absolute A-EL-S, Bioavailability R. In: Hock FJ, Gralinski MR, editors. Drug Discov eval methods clin pharmacol. Cham: Springer International Publishing; 2018. p. 1–7.

    Google Scholar 

  35. El-Say KM, Al-hejaili OD, Alamoudi AA, Ahmed OAA. Transfersome-containing transdermal film formulations and methods of use. United States Pat Trademark Off KSA. 2021.

  36. Mosli HAM, Atteiah SAG, Omar KMH, El-Bassossy HMAE-M, Helal MHAM. In situ gel loaded with phosphodiesterase type V inhibitors nanoemulsion. United States Pat Appl Publ KSA. 2015.

  37. Broman CT, Sheu E. Orally disintegrating dosage form for administration of avanafil, and associated methods of manufacture and use. United States. 2018.

  38. Fossel ET, Gutman L. Transdermal delivery of sildenafil and other phosphodiesterase type 5 inhibitors. USA: United States Pat. Appl. Publ; 2016.

    Google Scholar 

  39. Ahmed OAA, Badr-Eldin SM. Development of an optimized avanafil-loaded invasomal transdermal film. United States Pat. Trademark Off. 2020.

  40. Ahmed OAA, Badr-Eldin SM. Development of an optimized avanafil-loaded invasomal transdermal film: Ex vivo skin permeation and in vivo evaluation. Elsevier. Int J Pharm. 2019;570:118657.

  41. Kurakula M, Naveen N. R, Patel B, Manne R, Patel DB. Preparation, optimization and evaluation of chitosan-based avanafil nanocomplex utilizing antioxidants for enhanced neuroprotective effect on PC12 cells. Gels. 2021;7.

  42. Fahmy UA, Ahmed OAA, Hosny KM. Development and evaluation of avanafil self-nanoemulsifying drug delivery system with rapid onset of action and enhanced bioavailability. AAPS PharmSciTech. 2015;16:53–8.

    CAS  PubMed  Google Scholar 

  43. Soliman KAB, Ibrahim HK, Ghorab MM. Formulation of avanafil in a solid self-nanoemulsifying drug delivery system for enhanced oral delivery. Elsevier B.V. Eur J Pharm Sci. 2016;93:447–55.

  44. Gardouh AR, Elhusseiny S, Gad S. Mixed Avanafil and Dapoxetin Hydrochloride cyclodextrin nano-sponges: Preparation, in-vitro characterization, and bioavailability determination. Elsevier B.V. J Drug Deliv Sci Technol. 2022;68:103100.

  45. Kurakula M, Ahmed OAA, Fahmy UA, Ahmed TA. Solid lipid nanoparticles for transdermal delivery of avanafil: optimization, formulation, in-vitro and ex-vivo studies. J Liposome Res. 2016;26:288–96.

    CAS  PubMed  Google Scholar 

  46. Asbahr ACC, Franco L, Barison A, Silva CWP, Ferraz HG, Rodrigues LNC. Binary and ternary inclusion complexes of finasteride in HPβCD and polymers: preparation and characterization. Bioorg Med Chem Elsevier Ltd. 2009;17:2718–23.

    CAS  Google Scholar 

  47. Soliman KA, Ibrahim HK, Ghorab MM. Effect of different polymers on avanafil–β-cyclodextrin inclusion complex: in vitro and in vivo evaluation. Elsevier B.V. Int J Pharm. 2016;512:168–77.

  48. El-Say KM, Ahmed TA, Aljefri AH, El-Sawy HS, Fassihi R, Abou-Gharbia M. Oleic acid–reinforced PEGylated polymethacrylate transdermal film with enhanced antidyslipidemic activity and bioavailability of atorvastatin: A mechanistic ex-vivo/in-vivo analysis. Int J Pharm. 2021;608: 121057.

    CAS  PubMed  Google Scholar 

  49. Harbi I, Aljaeid B, El-Say KM, Zidan AS. Glycosylated sertraline-loaded liposomes for brain targeting: QbD study of formulation variabilities and brain transport. AAPS PharmSciTech AAPS PharmSciTech. 2016;17:1404–20.

    CAS  PubMed  Google Scholar 

  50. Liu J, Wang J, Leung C, Gao F. A multi-parameter optimization model for the evaluation of shale gas recovery enhancement. Energies. 2018;11:654.

    Google Scholar 

  51. Basahih TS, Alamoudi AA, El-Say KM, Alhakamy NA, Ahmed OAA. Improved transmucosal delivery of glimepiride via unidirectional release buccal film loaded with vitamin E TPGS-based nanocarrier. Dose-Response. 2020;18:155932582094516.

    Google Scholar 

  52. Hoffmann A, Daniels R. A novel test system for the evaluation of oral mucoadhesion of fast disintegrating tablets. Int J Pharm. 2018;551:141–7.

    CAS  PubMed  Google Scholar 

  53. Avranas A, Tasopoulos V. Aqueous solutions of sodium deoxycholate and hydroxypropylmethylcellulose: dynamic surface tension measurements. J Colloid Interface Sci. 2000;221:223–9.

    CAS  PubMed  Google Scholar 

  54. Guo Y, Wang R, Shang Y, Liu H. Effects of polymers on the properties of hydrogels constructed using sodium deoxycholate and amino acid. RSC Adv Royal Society of Chemistry. 2018;8:8699–708.

    CAS  Google Scholar 

  55. Tank D, Karan K, Gajera BY, Dave RH. Investigate the effect of solvents on wet granulation of microcrystalline cellulose using hydroxypropyl methylcellulose as a binder and evaluation of rheological and thermal characteristics of granules. Saudi Pharm J King Saud University. 2018;26:593–602.

    Google Scholar 

  56. Vila-Jato J, Concheiro A, Seijo B, Viana B. Aging of nitrofurantoin tablets containing Carbopol 934 as a binder. Int J Pharm. 1986;30:229–36.

    CAS  Google Scholar 

  57. De Simone V, Dalmoro A, Lamberti G, Caccavo D, D’Amore M, Barba AA. Effect of binder and load solubility properties on HPMC granules produced by wet granulation process. J Drug Deliv Sci Technol Elsevier. 2019;49:513–20.

    Google Scholar 

  58. Chen C, Lee SH, Cho M, Kim J, Lee Y. Cross-linked chitosan as an efficient binder for Si anode of Li-ion batteries. ACS Appl Mater Interfaces. 2016;8:2658–65.

    CAS  PubMed  Google Scholar 

  59. Kurakula M, Rao GSNK. Pharmaceutical assessment of polyvinylpyrrolidone (PVP): As excipient from conventional to controlled delivery systems with a spotlight on COVID-19 inhibition. Elsevier B.V. J Drug Deliv Sci Technol. 2020;60:102046.

  60. Kapoor B, Gupta R, Gulati M, Singh SK, Khursheed R, Gupta M. The why, where, who, how, and what of the vesicular delivery systems. Elsevier B.V. Adv Colloid Interface Sci. 2019;271:101985.

  61. Attia KAM, Mohamad AA, Emara MS, Abdel-Raoof AM, Hasan MA, Madkour AW, et al. Second derivative synchronous fluorescence determination of avanafil in the presence of its acid-induced degradation product aided by powerful Lean Six Sigma tools augmented with D-optimal design. RSC Adv Royal Society of Chemistry. 2021;11:3834–42.

    CAS  Google Scholar 

  62. Teoh X, Yeoh Y, Yoong L, Chan S. Sustainable dissolution performance of a carrier tailored electrospun. Pharm Res. 2020;37:28.

  63. Rani NS, Sannappa J, Demappa TM. Effects of CdCl2 concentration on the structural, thermal and ionic conductivity properties of HPMC polymer electrolyte films. Ionics (Kiel). 2015;21:133–40.

  64. Ahmed S, Kassem MA, Sayed S. Bilosomes as promising nanovesicular carriers for improved transdermal delivery: construction, in vitro optimization, ex vivo permeation and in vivo evaluation. Int J Nanomedicine. 2020;15:9783–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Bayón R, Rojas E. Feasibility study of D-mannitol as phase change material for thermal storage. AIMS Energy. 2017;5:404–24.

    Google Scholar 

  66. Zolotov SA, Demina NB, Zolotova AS, Shevlyagina N V., Buzanov GA, Retivov VM, et al. Development of novel darunavir amorphous solid dispersions with mesoporous carriers. Elsevier B.V. Eur J Pharm Sci. 2021;159:105700.

  67. Ahmed TA. Formulation and clinical investigation of optimized vinpocetine lyoplant-tabs: new strategy in development of buccal solid dosage form. Dove Medical Press Ltd. Drug Des Devel Ther. 2018;13:205–20.

  68. Dadashzadeh S, Haeri A, Daeihamed M, Arzani G, Bakhtiari KH. Niosomal carriers enhance oral bioavailability of carvedilol: effects of bile salt-enriched vesicles and carrier surface charge&nbsp. Int J Nanomedicine. 2015;10:4797.

    PubMed  PubMed Central  Google Scholar 

  69. Davanço MG, Campos DR, Carvalho P de O. In vitro – in vivo correlation in the development of oral drug formulation: a screenshot of the last two decades. Elsevier. Int J Pharm. 2020;580:119210.

  70. Cardot JM, Garrait G, Beyssac E. Use of IVIVC to optimize generic development. Dissolution Technol. 2015;22:44–8.

    Google Scholar 

  71. Kedia GT, Ückert S, Assadi-Pour F, Kuczyk MA, Albrecht K. Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. Ther Adv Urol. 2013;5:35–41.

    PubMed  PubMed Central  Google Scholar 

  72. Hellstrom W, Katz E, Tan R, Rittenberg D. Avanafil for erectile dysfunction in elderly and younger adults: differential pharmacology and clinical utility. Ther Clin Risk Manag. 2014;10:701–11.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge with thanks the Deanship of Scientific Research at King Abdulaziz University, Jeddah, for technical and financial support.

Funding

This project was funded by the Deanship of Scientific Research at King Abdulaziz University, Jeddah, under grant no. (RG-22–166-42).

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia

    Khalid M. El-Say, Omar D. Al-hejaili, Nabil A. Alhakamy & Tarek A. Ahmed

  2. Department of Pharmaceutics and Pharmaceutical Technology, Egyptian Russian University, Cairo, 11829, Egypt

    Hossam S. El-Sawy

  3. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, 11651, Egypt

    Fathy I. Abd-Allah

  4. Department of Medicinal Chemistry and the Institute for Structural Biology, Drug Discovery and Development School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Martin K. Safo

Authors
  1. Khalid M. El-Say
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Omar D. Al-hejaili
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hossam S. El-Sawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nabil A. Alhakamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fathy I. Abd-Allah
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin K. Safo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tarek A. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Khalid M. El-Say: conceptualization, validation, formal analysis, resources, writing—review & editing, supervision, project administration; Omar D. Al-Hejaili: methodology, formal analysis, investigation, writing—original draft; Hossam S. El-Sawy: methodology, validation, formal analysis, investigation, writing—original draft, writing—review & editing, visualization; Nabil A. Alhakamy: formal analysis, writing—review & editing; Fathy I. Abd-Allah: validation, formal analysis, resources, writing—review & editing; Martin K. Safo: Formal analysis, Writing—Review & Editing; Tarek A. Ahmed: Conceptualization, Validation, formal analysis, resources, writing—review & editing, supervision.

Corresponding author

Correspondence to Khalid M. El-Say.

Ethics declarations

Ethics approval

The in vivo investigation was conducted on healthy human volunteers at the International Centre for Bioavailability, Pharmaceutical, and Clinical Research (ICBR), Cairo, Egypt. The purpose, design, conduct, and analysis of the planned study were formally reviewed by the Institutional Review Board/Independent Ethics Committee (IRB/IEC) at ICBR. On July 18, 2019, the committee gave the study procedure its Ethical Approval Code (RESH-007). The Declaration of Helsinki and the International Conference on Harmonization (ICH) of Good Clinical Practices (GCP) were followed in conducting the study. European Medicines Agency (EMA), and Food and Drug Administration (FDA) regulations were followed during the study’s execution.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Competing interests

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

El-Say, K.M., Al-hejaili, O.D., El-Sawy, H.S. et al. Incorporating sodium deoxycholate endorsed the buccal administration of avanafil to heighten the bioavailability and duration of action. Drug Deliv. and Transl. Res. 13, 2297–2314 (2023). https://doi.org/10.1007/s13346-023-01314-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-023-01314-x

Keywords

Search

Navigation