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Development and Validation of Discriminatory In-vitro Release Method for Intramammary Drug Product

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Abstract

Purpose

Intramammary (IMM) formulations are locally acting and delivered intracisternally into the udder. No pharmacopeial in-vitro release method is available to differentiate between the IMM formulations. Our research aim is to develop in-vitro release methods that discriminate different IMM formulations (SPECTRAMAST® LC and in-house formulations).

Methodology

Different in-house formulations were developed to simulate SPECTRAMAST® LC generics. SPECTRAMAST® LC and the in-house formulations were characterized for physicochemical attributes, such as particle size, rheology, drug content, sedimentation rate, and flocculation rate. The in-vitro release method was optimized by evaluating drug release using USP apparatuses 1, 2 (with and without enhancer/customized cells), and 4. Various test parameters, including medium effect (whole homogenized bovine milk versus aqueous buffer), medium volume (200–900 mL), and rotational speed (50–200 rpm) were investigated.

Results

Two potential in-vitro systems can be used as discriminatory methods for IMM formulations: USP apparatus 2 with the IMM formulation loaded into two containers a) customized formulation container (83.1 cm in height and 56.4 cm in width) or b) enhancer cells with their top adapted with mesh #40 (rotation speed:125 rpm and 900 mL of whole homogenized bovine milk). The release profile of SPECTRAMAST® LC at 1 h (99.8%) was not significantly different from formulations with similar physicochemical characteristics F-01 (99.1%) and F-02 (100.5%). Formulation with different physicochemical characteristics F-03 (44.3%) and F-04 (57.2%) showed slower release (1 h) than SPECTRAMAST® LC (98.8%).

Conclusion

The developed in-vitro release methods can be used as a potential tool for in-vitro comparability evaluations for IMM formulations.

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References

  1. Hogeveen H. Mastitis in dairy production: Current knowledge and future solutions. 1st ed. Wageningen: Academic Publisher; 2005.

  2. Gianneechini R, Concha C, Rivero R, Delucci I, Moreno LJ. Occurrence of clinical and sub-clinical mastitis in dairy herds in the West Littoral Region in Uruguay. Acta Vet Scand. 2002;43(4):221–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Huma ZI, Sharma N, Kour S, Lee SJ. Phenotypic and molecular characterization of bovine mastitis milk origin bacteria and linkage of intramammary infection with milk quality. Front Vet Sci. 2022;9: 885134.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Blowey RW, Edmondson P. Mastitis control in dairy herds. 2nd ed. CABI; 2010.

  5. U.S. Food & Drug Adminstraton (FDA). Approved animal drug products (Green Book). Maryland, U.S.A. 2023.

  6. U.S. Food & Drug Administration (FDA). Dry-Clox® intramammary infusion-cloxacillin benzathine gel Boehringer lngelheim Animal Health USA Inc. (NADA: N55058). 2017.

  7. U.S. Food & Drug Administration (FDA). SpectraMast® LC sterile suspension- ceftiofur hydrochloride liquid suspension, Zoetis Inc. (NADA: 141–238). 2018.

  8. U.S. Food & Drug Administration (FDA). TOMORROW®- cephapirin benzathine gel Boehringer lngelheim Animal Health USA Inc. (NADA: N108114). 2022.

  9. U.S. Food & Drug Administration (FDA). TODAY®- cephapirin sodium gel Boehringer lngelheim Animal Health USA Inc. (NADA: N97222). 2022.

  10. U.S. Food & Drug Administration (FDA). Orbenin DC™- cloxacillin benzathine liquid suspension Intervet Inc. (NADA: N55069). 2022.

  11. U.S. Food & Drug Administration (FDA). Generic Animal Drug and Patent Term Restoration Act (GADPTRA). 2023.

  12. Abebe R, Hatiya H, Abera M, Megersa B, Asmare K. Bovine mastitis: prevalence, risk factors and isolation of Staphylococcus aureus in dairy herds at Hawassa milk shed, South Ethiopia. BMC Vet Res. 2016;12(1):270.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Arruda AG, Godden S, Rapnicki P, Gorden P, Timms L, Aly SS, et al. Randomized noninferiority clinical trial evaluating 3 commercial dry cow mastitis preparations: I. Quarter-level outcomes. J Dairy Sci. 2013;96(7):4419–35.

    Article  CAS  PubMed  Google Scholar 

  14. U.S. Food & Drug Administration (FDA). Administrative Applications and the Phased Review Process: Guidance for Industry. 2018, Document number 132. https://www.fda.gov/media/70029/download.

  15. Schall R, Endrenyi L. Bioequivalence: Tried and tested. Cardiovasc J Afr. 2010;21(2):69–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Krishnaiah YS, Xu X, Rahman Z, Yang Y, Katragadda U, Lionberger R, et al. Development of performance matrix for generic product equivalence of acyclovir topical creams. Int J Pharm. 2014;475(1–2):110–22.

    Article  CAS  PubMed  Google Scholar 

  17. ElAgouri G, ElAmrawy F, ElYazbi A, Eshra A, Nounou MI. Male enhancement nutraceuticals in the Middle East market: Claim, pharmaceutical quality and safety assessments. Int J Pharm. 2015;492(1):109–19.

    Article  CAS  PubMed  Google Scholar 

  18. Schukken YH, Bennett GJ, Zurakowski MJ, Sharkey HL, Rauch BJ, Thomas MJ, et al. Randomized clinical trial to evaluate the efficacy of a 5-day ceftiofur hydrochloride intramammary treatment on nonsevere gram-negative clinical mastitis. J Dairy Sci. 2011;94(12):6203–15.

    Article  CAS  PubMed  Google Scholar 

  19. United States Pharmacopeial Convention (USP 2023). (1225) Validation of Compendial Procedures. General Chapter 42(2). Baltimore, MD, USA: United Book Press, Inc: The United States Pharmacopeia (USP 2023–NF 36–38). p. 7665–8166.

  20. Zoetis Inc. SpectraMast® LC (ceftiofur intramammary suspension) sterile suspension (marketing package insert). 2019. https://www.zoetisus.com/content/_assets/docs/dairy/Spectramast-LC-Marketing-Package-Insert.pdf.

  21. United States Pharmacopeial Convention (USP 2023). (905) Uniformity of dosage units. General Chapter, (General tests and assays). 35(3). Baltimore, MD, USA: United Book Press, Inc: The United States Pharmacopeia (USP 2023–NF 36–38). p. 6673–7183.

  22. Patel N, Chotai N, Jayvadan P, Soni T, Desai J, Patel R. Comparison of in-vitro dissolution profiles of oxcarbazepine-hp bcd tablet formulations with marketed oxcarbazepine tablets. Dissolut Technol. 2008;15:28–34.

    Article  CAS  Google Scholar 

  23. Limberg J, Potthast H. Regulatory status on the role of in-vitro dissolution testing in quality control and biopharmaceutics in Europe. Biopharm Drug Dispos. 2013;34(5):247–53.

    Article  CAS  PubMed  Google Scholar 

  24. Dickinson PA, Lee WW, Stott PW, Townsend AI, Smart JP, Ghahramani P, et al. Clinical relevance of dissolution testing in quality by design. AAPS J. 2008;10(2):380–90.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Garg S, Wang W, Song Y, Eats P, Trott DJ, Page SW, et al. Development of intramammary drug delivery systems: Novel in-vitro release method. J Pharm Sci. 2017;106(3):866–71.

    Article  CAS  PubMed  Google Scholar 

  26. Haster PR. An in-vitro dissolution method for the evaluation of an intramammary infusion product “Doctoral dissertation": The University of Mississippi; 1991.

  27. Martinez MN, Fahmy R. Demonstrating comparative in-vitro bioequivalence for animal drug products through chemistry and manufacturing controls and physicochemical characterization: a proposal. AAPS J. 2015;17(2):307–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Martinez MN, Zhao F, Longstaff DG, Gabriel JJ, Coffey MJ. Evaluating the solubility of compounds intended for intramammary infusion based upon tests conducted across a range of milk products using cephapirin sodium and benzathine as model drugs. bioRxiv. 2023:2023.01. 24.525429.

  29. Ishikawa H, Shimizu T, Hirano H, Saito N, Nakano T. Protein composition of whey from subclinical mastitis and effect of treatment with levamisole. J Dairy Sci. 1982;65(4):653–8.

    Article  CAS  PubMed  Google Scholar 

  30. Eros I, Soosne-Csanyi E, Selmeczi B. Influence of viscosity on drug release from ointments, creams, gels and emulsions. Acta Pharm Hung. 1994;64(2):57–61.

    CAS  PubMed  Google Scholar 

  31. Ho MJ, Jeong MY, Jeong HT, Kim MS, Park HJ, Kim DY, et al. Effect of particle size on in-vivo performances of long-acting injectable drug suspension. J Control Release. 2022;341:533–47.

    Article  CAS  PubMed  Google Scholar 

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Funding

This project is funded by the FDA Grant, FDABAA-21–00123, 2022.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M Health Science Center, Texas A&M University, College Station, TX, USA

    Nada A. Helal, Eman M. Mohamed, Ziyaur Rahman, Mansoor A. Khan & Mohammad T. H. Nutan

  2. US FDA Center for Veterinary Medicine, Office of New Animal Drug Evaluation, Rockville, MD, USA

    Marilyn N. Martinez & David G. Longstaff

  3. Kingsville, TX, USA

    Mohammad T. H. Nutan

Authors
  1. Nada A. Helal
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  2. Marilyn N. Martinez
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  4. Eman M. Mohamed
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Correspondence to Mohammad T. H. Nutan.

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The authors report no conflicts of interest in this study.

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The findings and conclusions in this poster have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency endorsement, determination, or policy. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the FDA.

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11095_2023_3609_MOESM1_ESM.jpg

Supplementary file1 (JPG 103 KB) Supporting Fig. 1 Detection of ceftiofur HCl via HPLC analysis using a reversed-phase C18 column (15 cm) along with a gradient mobile system, composed of water and acetonitrile (37 °C, 1.5 mL/min flow rate, 16 min run time)

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Helal, N.A., Martinez, M.N., Longstaff, D.G. et al. Development and Validation of Discriminatory In-vitro Release Method for Intramammary Drug Product. Pharm Res 41, 129–139 (2024). https://doi.org/10.1007/s11095-023-03609-7

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  • DOI: https://doi.org/10.1007/s11095-023-03609-7

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