Skip to main content

Advertisement

SpringerLink
Log in

QbD Based Formulation Development and Optimisation of Ozenoxacin Topical Nano-Emulgel and Efficacy Evaluation Using Impetigo Mice Model

  • Research Article
  • Novel Skin Drug Delivery Technology
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

To formulate and optimize Ozenoxacin nano-emulsion using Quality by Design (QbD) concept by means of Box–Behnken Design (BBD) and converting it to a gel to form Ozenoxacin nano-emulgel followed by physico-chemical, in-vitro, ex-vivo and in-vivo evaluation. This study demonstrates the application of QbD methodology for the development and optimization of an effective topical nanoemulgel formulation for the treatment of Impetigo focusing on the selection of appropriate excipients, optimization of formulation and process variables, and characterization of critical quality attributes. BBD was used to study the effect of “% of oil, % of Smix and homogenization speed” on critical quality attributes “globule size and % entrapment efficiency” for the optimisation of Ozenoxacin Nano-emulsion. Ozenoxacin loaded nano-emulgel was characterized for “description, identification, pH, specific gravity, amplitude sweep, viscosity, assay, organic impurities, antimicrobial effectiveness testing, in-vitro release testing, ex-vivo permeation testing, skin retention and in-vivo anti-bacterial activity”. In-vitro release and ex-vivo permeation, skin retention and in-vivo anti-bacterial activity were found to be significantly (p < 0.01) higher for the nano-emulgel formulation compared to the innovator formulation (OZANEX™). Antimicrobial effectiveness testing was performed and found that even at 70% label claim of benzoic acid is effective to inhibit microbial growth in the drug product. The systematic application of QbD principles facilitated the successful development and optimization of a Ozenoxacin Nano-Emulsion. Optimised Ozenoxacin Nano-Emulgel can be considered as an effective alternative and found to be stable at least for 6 months at 40 °C / 75% RH and 30 °C / 75% RH.

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

Similar content being viewed by others

Data Availability

All the relevant data are reported within the paper and or supplementary file. For additional details, data are available on request to the authors.

References

  1. Nardi NM, Schaefer TJ. Impetigo. [Updated 2023 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430974/.

  2. May PJ, Tong SYC, Steer AC, Currie BJ, Andrews RM, Carapetis JR, Bowen AC. Treatment, prevention and public health management of impetigo, scabies, crusted scabies and fungal skin infections in endemic populations: a systematic review. Trop Med Int Health. 2019;24(3):280–93. https://doi.org/10.1111/tmi.13198.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Galli L, Novelli A, Ruggiero G, Stefani S, Fortina AB. Pediatric impetigo: an expert panel opinion about its main controversies. J Chemother. 2022;34(5):279–85. https://doi.org/10.1080/1120009X.2021.1961185.

    Article  PubMed  Google Scholar 

  4. Sahu JK, Mishra AK. Ozenoxacin: A Novel Drug Discovery for the Treatment of Impetigo. Curr Drug Discov Technol. 2019;16(3):259–64. https://doi.org/10.2174/1570163815666180502165014.

    Article  CAS  PubMed  Google Scholar 

  5. Vila J, Hebert AA, Torrelo A, et al. Ozenoxacin: a review of preclinical and clinical efficacy. Expert Rev Anti Infect Ther. 2019;17(3):159–68. https://doi.org/10.1080/14787210.2019.1573671.

    Article  CAS  PubMed  Google Scholar 

  6. Koulenti D, Xu E, Yin SMI, Song A, Karageorgopoulos DE, Armaganidis A, Lipman J, Tsiodras S. Novel Antibiotics for Multidrug-Resistant Gram-Positive Microorganisms. Microorganisms. 2019;7:270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barbieri E, Cavagnis S, Boracchini R, Scamarcia A, Testa A, Ciarniello MG, Martinelli B, Cantarutti L, Giaquinto C, Cantarutti A. Retrospective Analysis of the Real-World Use of Topical Antimicrobials in the Paediatric Population with Impetigo in Italy: Focus on the Role of Ozenoxacin 1% Cream. Children. 2023;10(3):547. https://doi.org/10.3390/children10030547.

    Article  PubMed  PubMed Central  Google Scholar 

  8. National Center for Biotechnology Information. PubChem Compound Summary for CID 9863827, Ozenoxacin. https://pubchem.ncbi.nlm.nih.gov/compound/Ozenoxacin. Accessed Feb. 24, 2024.

  9. López Y, Muñoz L, Gargallo-Viola D, Cantón R, Vila J, Zsolt I. Uptake of Ozenoxacin and Other Quinolones in Gram-Positive Bacteria. Int J Mol Sci. 2021;22(24):13363. https://doi.org/10.3390/ijms222413363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. U.S. Food and Drug Administration; 2022. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208945lbl.pdf. [Last accessed: April / 21 / 2022].

  11. XEPI; 2022. Available from: https://www.xepicream.com/resources/full-prescribing-information. [Last accessed: March / 13 / 2022].

  12. OZANEX; 2022. Available from: https://www.cipherpharma.com/wp-content/uploads/2017/12/Ozanex-PM-English.pdf. [Last accessed: September / 25 / 2022].

  13. Tarragó C, Santos B, Raga M, Guglietta A, Inventor; FERRER INTERNATIONAL, S.A., Assignee. PHARMACEUTICAL TOPICAL COMPOSITIONS. United States patent US 9,180,200 B2. 2015 Nov 10.

  14. Tarragó C, Santos B, Raga M, Guglietta A, Inventor; FERRER INTERNATIONAL, S.A., Assignee. PHARMACEUTICAL TOPICAL COMPOSITIONS. United States patent US 9,399,014 B2. 2016 .

  15. Burki IK, Khan MK, Khan BA, et al. Formulation Development, Characterization, and Evaluation of a Novel Dexibuprofen-Capsaicin Skin Emulgel with Improved In Vivo Anti-inflammatory and Analgesic Effects. AAPS PharmSciTech 2020;21(211). https://doi.org/10.1208/s12249-020-01760-7.

  16. Pinheiro IM, Carvalho IPS, Neto JAT, et al. Amphotericin B-Loaded Emulgel: Effect of Chemical Enhancers on the Release Profile and Antileishmanial Activity In Vitro. AAPS PharmSciTech 2019;20(122). https://doi.org/10.1208/s12249-019-1323-1.

  17. Han HS, Koo SY, Choi KY. Emerging nanoformulation strategies for phytocompounds and applications from drug delivery to phototherapy to imaging. Bioact Mater. 2021. https://doi.org/10.1016/j.bioactmat.2021.11.027.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Latif MS, Nawaz A, Asmari M, Uddin J, Ullah H, Ahmad S. Formulation Development and In Vitro/In Vivo Characterization of Methotrexate-Loaded Nanoemulsion Gel Formulations for Enhanced Topical Delivery. Gels. 2022;9(1):3. https://doi.org/10.3390/gels9010003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pramod K, Tahir MA, Charoo NA, Ansari SH, Ali J. Pharmaceutical product development: A quality by design approach. Int J Pharm Investig. 2016;6(3):129–38. https://doi.org/10.4103/2230-973X.187350.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Akpan S, Dauda M, Kuburi LS, Obada DO. Box-Behnken experimental design for the process optimization of catfish bones derived hydroxyapatite: A pedagogical approach. Mater Chem Phy. 2021;272:124916. https://doi.org/10.1016/j.matchemphys.2021.124916. ISSN 0254-0584.

    Article  CAS  Google Scholar 

  21. Kumari M, Gupta SK. Response surface methodological (RSM) approach for optimizing the removal of trihalomethanes (THMs) and its precursor’s by surfactant modified magnetic nanoadsorbents (sMNP) - An endeavor to diminish probable cancer risk. Sci Rep. 2019;9:18339. https://doi.org/10.1038/s41598-019-54902-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ahmad N, Ahmad R, Buheazaha TM, AlHomoud HS, Al-Nasif HA, Sarafroz MD. A comparative ex vivo permeation evaluation of a novel 5-Fluorocuracil nanoemulsion-gel by topically applied in the different excised rat, goat, and cow skin. Saudi J Biol Sci. 2020;27(4):1024–40. https://doi.org/10.1016/j.sjbs.2020.02.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Niyaz A, Ahmad R, Al-Qudaihi A, Alaseel SE, Fita IZ, Khalid MS, Pottoo FH. Preparation of a novel curcumin nanoemulsion by ultrasonication and its comparative effects in wound healing and the treatment of inflammation. RSC Advances. 2019;9:20192–206. https://doi.org/10.1039/C9RA03102B.

    Article  Google Scholar 

  24. Orange Book; 2022. Available from: https://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=208945#34904. [Last accessed: March / 13 / 2022].

  25. Namjoshi S, Dabbaghi M, Roberts MS, Grice JE, Mohammed Y. Quality by Design: Development of the Quality Target Product Profile (QTPP) for Semisolid Topical Products. Pharmaceutics. 2020;12(3):287. https://doi.org/10.3390/pharmaceutics12030287.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Testas, M., da Cunha Sais, T., Medinilha, L.P. et al. An industrial case study: QbD to accelerate time-to-market of a drug product. AAPS Open 2021. 7(12). https://doi.org/10.1186/s41120-021-00047-w.

  27. Yu LX, Amidon G, Khan MA, et al. Understanding Pharmaceutical Quality by Design. AAPS Journal. 2014;16:771–83. https://doi.org/10.1208/s12248-014-9598-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lakshmikanth RP, Shanmugasundaram S. QBD Approach for Design and Characterization of Pramlintide Microspheres for Controlled Drug Release. J Pharm Innov. 2023;18:2325–47. https://doi.org/10.1007/s12247-023-09795-6.

    Article  Google Scholar 

  29. Amarnath Reddy R, Dilip KB. Analytical Method Validation on Simultaneous Estimation of Ozenoxacin and Benzoic Acid in Pharmaceutical Formulation. Acta Chromatogr. 2022;35(3):278–85. https://doi.org/10.1556/1326.2022.01064.

    Article  CAS  Google Scholar 

  30. USP General chapter<1724> Semisolid drug products-performance tests. pp. 5778–5788. United States Pharmacopoeia and National Formulary. USP36-NF31, Rockville, MD, 2013b.

  31. Ma H, Yu M, Tan F, Li N. Improved percutaneous delivery of azelaic acid employing microemulsion as nanocarrier: Formulation optimization, in vitro and in vivo evaluation. RSC Adv. 2015;5:28985–95. https://doi.org/10.1039/C5RA00713E.

    Article  CAS  Google Scholar 

  32. Jonsdottir F, Snorradottir BS, Gunnarsson S, Georgsdottir E, Sigurdsson S. Transdermal Drug Delivery: Determining Permeation Parameters Using Tape Stripping and Numerical Modeling. Pharmaceutics. 2022;14(9):1880. https://doi.org/10.3390/pharmaceutics14091880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lademann J, Jacobi U, Surber C, Weigmann H-J, Fluhr JW. The tape stripping procedure – evaluation of some critical parameters. Eur J Pharm Biopharm. 2009;72(2):317–23. https://doi.org/10.1016/j.ejpb.2008.08.008.

    Article  CAS  PubMed  Google Scholar 

  34. McRipley RJ, Whitney RR. Characterization and Quantitation of Experimental Surgical-Wound Infections Used to Evaluate Topical Antibacterial Agents. Antimicrob Agents Chemother. 1976;10:38–44. https://doi.org/10.1128/aac.10.1.38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Boon RJ, Beale AS. Response of Streptococcus pyogenes to therapy with amoxicillin or amoxicillin-clavulanic acid in a mouse model of mixed infection caused by Staphylococcus aureus and Streptococcus pyogenes. Antimicrob Agents Chemother. 1987;31:1204–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gisby J, Bryant J. Efficacy of a New Cream Formulation of Mupirocin: Comparison with Oral and Topical Agents in Experimental Skin Infections. Antimicrob Agents Chemother. 2000;44:255–60. https://doi.org/10.1128/aac.31.8.1204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Berry V, Page R, Satterfield J, Singley C, Straub R, Woodnutt G. Comparative efficacy of gemifloxacin in experimental models of pyelonephritis and wound infection. J Antimicrob Chemother. 2000;45:87. https://doi.org/10.1093/jac/45.suppl_3.87.

    Article  CAS  PubMed  Google Scholar 

  38. Rittenhouse S, Singley C, Hoover J, Page R, Payne D. Use of the Surgical Wound Infection Model to Determine the Efficacious Dosing Regimen of Retapamulin, a Novel Topical Antibiotic. Antimicrob Agents Chemother. 2006;50:3886–8. https://doi.org/10.1128/AAC.00183-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Håkansson J, Björn C, Lindgren K, Sjöström E, Sjöstrand V, Mahlapuu M. Efficacy of the Novel Topical Antimicrobial Agent PXL150 in a Mouse Model of Surgical Site Infections. Antimicrob Agents Chemother. 2014;58:2982–4. https://doi.org/10.1128/AAC.00143-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tarragó C, Esquirol LP, Arañó A, Lachamp L, D’Aniello F, Zsolt I. Therapeutic efficacy of ozenoxacin in animal models of dermal infection with Staphylococcus aureus. Futur Microbiol. 2018;13:21–30. https://doi.org/10.2217/fmb-2017-0290.

    Article  CAS  Google Scholar 

  41. Håkansson J, Ringstad L, Umerska A, Johansson J, Andersson T, Boge L, Rozenbaum RT, Sharma PK, Tollbäck P, Björn C, et al. Characterization of the in vitro, ex vivo, and in vivo Efficacy of the Antimicrobial Peptide DPK-060 Used for Topical Treatment. Front Cell Infect Microbiol. 2019;9:174. https://doi.org/10.3389/fcimb.2019.00174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sharma N, Madan P, Lin S. Effect of process and formulation variables on the preparation of parenteral paclitaxel-loaded biodegradable polymeric nanoparticles: A co-surfactant study. Asian J Pharm Sci. 2016;11(3):404–16. https://doi.org/10.1016/j.ajps.2015.09.004.

    Article  Google Scholar 

  43. Madhulika P, Singh D, Singh MR. Influence of selected variables on fabrication of Triamcinolone acetonide loaded solid lipid nanoparticles for topical treatment of dermal disorders. Art Cells Nanomed Biotechnol. 2016;44(1):392–400. https://doi.org/10.3109/21691401.2014.955105.

    Article  CAS  Google Scholar 

  44. Amal M. Sindi, Khaled M. Hosny, Waleed Y. Rizg, Fahad Y. Sabei, Osama A. Madkhali, Mohammed Ali Bakkari, Eman Alfayez, Hanaa Alkharobi, Samar A Alghamdi, Arwa A. Banjar, Mohammed Majrashi & Mohammed Alissa. Utilization of experimental design in the formulation and optimization of hyaluronic acid–based nanoemulgel loaded with a turmeric–curry leaf oil nanoemulsion for gingivitis. Drug Delivery 2023;30(1): https://doi.org/10.1080/10717544.2023.2184311.

  45. Pavoni L, Perinelli DR, Bonacucina G, Cespi M, Palmieri GF. An Overview of Micro- and Nanoemulsions as Vehicles for Essential Oils: Formulation, Preparation and Stability. Nanomaterials (Basel). 2020;10(1):135. https://doi.org/10.3390/nano10010135.

    Article  CAS  PubMed  Google Scholar 

  46. Hosny KM, Alhakamy NA, Sindi AM, Khallaf RA. Coconut Oil Nanoemulsion Loaded with a Statin Hypolipidemic Drug for Management of Burns: Formulation and In Vivo Evaluation. Pharmaceutics. 2020;12(11):1061. https://doi.org/10.3390/pharmaceutics12111061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rizg WY, Hosny KM, Elgebaly SS, Alamoudi AJ, Felimban RI, Tayeb HH, Alharbi M, Bukhary HA, Abualsunun WA, Almehmady AM, Khallaf RA. Preparation and Optimization of Garlic Oil/Apple Cider Vinegar Nanoemulsion Loaded with Minoxidil to Treat Alopecia. Pharmaceutics. 2021;13(12):2150. https://doi.org/10.3390/pharmaceutics13122150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gilani SJ, Jumah MNB, Zafar A, Imam SS, Yasir M, Khalid M, Alshehri S, Ghuneim MM, Albohairy FM. Formulation and Evaluation of Nano Lipid Carrier-Based Ocular Gel System: Optimization to Antibacterial Activity. Gels. 2022;8(5):255. https://doi.org/10.3390/gels8050255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fernandez-Campos F, Obach M, Moreno MC, et al. Pharmaceutical development of a generic corticoid semisolid formulation. J Drug Del Sci Technol. 2017;42:227–36. https://doi.org/10.1016/j.jddst.2017.03.016.

    Article  CAS  Google Scholar 

  50. Li C, Liu C, Liu J, et al. Correlation Between Rheological Properties, In Vitro Release, and Percutaneous Permeation of Tetrahydropalmatine. AAPS PharmSciTech. 2011;12(3):1002–10. https://doi.org/10.1208/s12249-011-9664-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Amplitude sweeps. Available from: https://wiki.anton-paar.com/in-en/amplitude-sweeps/. [Last accessed: April / 01 / 2023].

  52. Arya KR, Wadhwa S, Singh SK, Kumar B, Gulati M, Kumar A, Almawash S, Saqr AA, Gowthamarajan K, Dua K, Singh H, Vishwas S, Khursheed R, Parveen SR, Venkatesan A, Paudel KR, Hansbro PM, Chellappan DK. Topical non-aqueous nanoemulsion of Alpinia galanga extract for effective treatment in psoriasis: In vitro and in vivo evaluation. Int J Pharm. 2022;624:121882. https://doi.org/10.1016/j.ijpharm.2022.121882.

    Article  CAS  Google Scholar 

  53. Russell J. Wilson, Yang Li, Guangze Yang, Chun-Xia Zhao. Nanoem Drug Del Particuol. 2022;64:85–97. https://doi.org/10.1016/j.partic.2021.05.009.

    Article  CAS  Google Scholar 

  54. Simona M, Manconi M, Valenti D, Sinico C, Vila AO, Fadda AM. Transcutol containing vesicles for topical delivery of minoxidil. J Drug Target. 2011;19(3):189–96. https://doi.org/10.3109/1061186X.2010.483516.

    Article  CAS  Google Scholar 

  55. Liu L, Mao K, Wang W, et al. Kolliphor® HS 15 Micelles for the Delivery of Coenzyme Q10: Preparation, Characterization, and Stability. AAPS PharmSciTech. 2016;17:757–66. https://doi.org/10.1208/s12249-015-0399-5.

    Article  CAS  PubMed  Google Scholar 

  56. Ritika A, Aggarwal G, Harikumar SL, Kaur K. Nanoemulsion Based Hydrogel for Enhanced Transdermal Delivery of Ketoprofen. Adv Pharm. 2014;2014:1–12. https://doi.org/10.1155/2014/468456.

    Article  Google Scholar 

  57. Chen H, Chang X, Danrong Du, Li J, Huibi Xu, Yang X. Microemulsion-based hydrogel formulation of ibuprofen for topical delivery. Int J Pharm. 2006;315(1–2):52–8. https://doi.org/10.1016/j.ijpharm.2006.02.015.

    Article  CAS  PubMed  Google Scholar 

  58. Osborne DW, Musakhanian J. Skin Penetration and Permeation Properties of Transcutol®-Neat or Diluted Mixtures. AAPS PharmSciTech. 2018;19(8):3512–33. https://doi.org/10.1208/s12249-018-1196-8.

    Article  CAS  PubMed  Google Scholar 

  59. Shukla T, Upmanyu Neeraj, Agrawal Mukta, Saraf S, Saraf S, Alexander A. Biomedical applications of microemulsion through dermal and transdermal route. Biomedicine & Pharmacotherapy. 2018;108:1477–94. https://doi.org/10.1016/j.biopha.2018.10.021.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Authors are thankful to Optimus Pharma Private Limited, Hyderabad and Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapur for providing facilities to perform this research. One of the authors Amarnath Reddy Ramireddy is thankful to the Jawaharlal Nehru Technological University, Anantapur, for enrolling as a research scholar.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Jawaharlal Nehru Technological University Anantapur (JNTUA), Ananthapuramu, Andhra Pradesh, 515002, India

    Amarnath Reddy Ramireddy

  2. Chemical Engineering, JNTUA College of Engineering (Autonomous), Jawaharlal Nehru Technological University Anantapur (JNTUA), Ananthapuramu, Andhra Pradesh, 515002, India

    Dilip Kumar Behara

Authors
  1. Amarnath Reddy Ramireddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dilip Kumar Behara
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Amarnath Reddy Ramireddy: The acquisition, analysis, interpretation of data for the work and drafting of the work. Dilip Kumar Behara: The conception, design of the work and final approval of the version to be published.

Corresponding author

Correspondence to Amarnath Reddy Ramireddy.

Ethics declarations

Ethical Approval

This article contains animal studies performed by the authors. The established guidelines by the Institutional Animal Ethical Committee of the Indian government (Approval No.: IAEC/III/02/RIPER/2023) were followed when handling the animals.

Conflict of Interest

The authors declare that no potential conflicts of interest.

Additional information

Communicated by Nisarg Modi, Yousuf Mohammed, and Lakshmi Raghavan

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 501 KB)

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

Ramireddy, A.R., Behara, D.K. QbD Based Formulation Development and Optimisation of Ozenoxacin Topical Nano-Emulgel and Efficacy Evaluation Using Impetigo Mice Model. AAPS PharmSciTech 25, 90 (2024). https://doi.org/10.1208/s12249-024-02805-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-024-02805-x

Keywords

Search

Navigation