Historical Evolution and Provider Awareness of Inactive Ingredients in Oral Medications

Abstract

Purpose

A multitude of different versions of the same medication with different inactive ingredients are currently available. It has not been quantified how this has evolved historically. Furthermore, it is unknown whether healthcare professionals consider the inactive ingredient portion when prescribing medications to patients.

Methods

We used data mining to track the number of available formulations for the same medication over time and correlate the number of available versions in 2019 to the number of manufacturers, the years since first approval, and the number of prescriptions. A focused survey among healthcare professionals was conducted to query their consideration of the inactive ingredient portion of a medication when writing prescriptions.

Results

The number of available versions of a single medication have dramatically increased in the last 40 years. The number of available, different versions of medications are largely determined by the number of manufacturers producing this medication. Healthcare providers commonly do not consider the inactive ingredient portion when prescribing a medication.

Conclusions

A multitude of available versions of the same medications provides a potentially under-recognized opportunity to prescribe the most suitable formulation to a patient as a step towards personalized medicine and mitigate potential adverse events from inactive ingredients.

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Abbreviations

API:

Active Pharmaceutical Ingredient

FDA:

Food and Drug Administration

IRB:

Institutional Review Board

NDC:

National Drug Code

NIH:

National Institute of Health

References

  1. 1.

    FDA. 21 CFR 210.3(b)(7). 2018.

  2. 2.

    Best over-the-counter (OTC) drugs for common ailments - Consumer Reports [Internet]. 2013. Available from: https://www.consumerreports.org/cro/2013/07/compare-over-the-counter-drugs-for-common-ailments-consumer-reports/index.htm

  3. 3.

    Abrantes CG, Duarte D, Reis CP. An overview of pharmaceutical excipients: safe or not safe? J Pharm Sci. 2016;105:2019–26.

    CAS  Article  Google Scholar 

  4. 4.

    Reker D, Blum SS, Steiger C, Anger KE, Sommer JM, Fanikos J, et al. ‘Inactive’ ingredients in oral medications. Sci Transl Med. 2019;11:eaau6753.

  5. 5.

    Kelso JM. Potential food allergens in medications. J Allergy Clin Immunol. 2014;133:1509–20.

    CAS  Article  Google Scholar 

  6. 6.

    Nagel-Edwards KM, Ko JY. Excipient choices for special populations. Int J Pharm Compd [Internet]. 2008;12:426–30 Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-77949515503&partnerID=40&md5=ad64acc85bd473f3414d22d483088011.

    Google Scholar 

  7. 7.

    Brandstetter RD, Conetta R, Glazer B. Lactose Intolerance Associated with Intal Capsules. New Engl J Med [Internet]. Massachusetts Medical Society; 1986 [cited 2018 Apr 12];315:1613–4. Available from: http://www.nejm.org/doi/abs/10.1056/NEJM198612183152515

  8. 8.

    FDA. Gluten in Drug Products and Associated Labeling Recommendations. Draft Guid. 2017;

  9. 9.

    King AR. Gluten Content of the Top 200 Medications: Follow-Up to the Influence of Gluten on a Patient’s Medication Choices. Hosp Pharm [Internet]. SAGE Publications; 2013 [cited 2018 Apr 13];48:736–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24421547.

  10. 10.

    Gibson PR. Use of the low-FODMAP diet in inflammatory bowel disease. J Gastroenterol Hepatol. 2017;32(Suppl 1):40–2.

    CAS  Article  Google Scholar 

  11. 11.

    NLM. Pillbox [Internet]. Available from: pillbox.nlm.nih.gov

  12. 12.

    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res [Internet]. Oxford University Press; 2018 [cited 2018 Dec 5];46:D1074–82. Available from: http://academic.oup.com/nar/article/46/D1/D1074/4602867

  13. 13.

    Berthold MR, Cebron N, Dill F, Gabriel TR, Kötter T, Meinl T, et al. KNIME: The Konstanz information miner. Data Anal Mach Learn Appl [Internet]. Springer; 2008;319–326. Available from: https://www.knime.com/

  14. 14.

    Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42:377–81.

    Article  Google Scholar 

  15. 15.

    FDA. Inactive Ingredient Search for Approved Drug Products [Internet]. Available from: https://www.accessdata.fda.gov/scripts/cder/iig/

  16. 16.

    Thimerosal in Vaccines Thimerosal | Concerns | Vaccine Safety | CDC. 2018.

  17. 17.

    Aitken M, Kleinrock M. The global use of medicine in 2019 and outlook to 2023. Data Sci: IQVIA Inst. Hum; 2019.

    Google Scholar 

  18. 18.

    AAM. Generic Drug Access & Savings Report. 2018:2018.

  19. 19.

    Eadala P, Waud JP, Matthews SB, Green JT, Campbell AK. Quantifying the ‘hidden’lactose in drugs used for the treatment of gastrointestinal conditions. Aliment Pharmacol Ther. 2009 Mar;29(6):677–87.

    CAS  Article  Google Scholar 

  20. 20.

    Aungst BJ. Absorption enhancers: applications and advances. APPS J [Internet]. Springer; 2012 [cited 2017 Jul 18];14:10–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22105442.

  21. 21.

    Reker D, Shi Y, Kirtane AR, Hess K, Zhong GJ, Crane E, et al. Machine learning uncovers food-and excipient-drug interactions. Cell Rep. 2020 Mar 17;30(11):3710–6.

    CAS  Article  Google Scholar 

  22. 22.

    Pottel J, Armstrong D, Zou L, Fekete A, Huang XP, Torosyan H, et al. The activities of drug inactive ingredients on biological targets. Science. 2020 Jul 24;369(6502):403–13.

    CAS  PubMed  Google Scholar 

  23. 23.

    Kesselheim AS, Gagne JJ, Eddings W, Franklin JM, Ross KM, Fulchino LA, et al. Prevalence and predictors of generic drug skepticism among physicians: Results of a national survey. JAMA Intern. Med. 2016. p. 845–7.

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was funded in part by: Swiss National Science Foundation Fellowships P2EZP3_168827 and P300P2_177833 (DR), the Department of Medicine Residency Program (SB), MGH Cancer Center T32 2T32CA071345-21A1 (SB), the Alexander von Humboldt Foundation Feodor Lynen Fellowship (CS), the NIH grant EB000244 (GT), the Division of Gastroenterology at Brigham and Women’s Hospital, the Department of Mechanical Engineering at MIT and Karl van Tassel (1925) Career Development Professorship (GT), and the MIT-IBM Watson AI Lab (DR, CS, GT). We are grateful to Professor R. Langer for invaluable guidance and comments on this work. Complete details of all relationships for profit and not for profit for G.T. can be found at the following link: www.dropbox.com/sh/szi7vnr4a2ajb56/AABs5N5i0q9AfT1IqIJAE-T5a?dl=0. S.M.B. has a consulting relationship with Two River Consulting, Third Rock Ventures and is an equity holder in Kronos Bio Inc. C.S. is employed by Bayer AG, Berlin, Germany. D.R. acts as a consultant for the pharmaceutical and biotechnology industry and a mentor for the German Accelerator Life Sciences. D.R., S.B., and G.T. are co-inventors on a provisional patent application 62/811, 502 encompassing systems and algorithms capable of quantifying and providing inactive ingredient burden in medications.

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Correspondence to Giovanni Traverso.

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Reker, D., Blum, S.M., Wade, P. et al. Historical Evolution and Provider Awareness of Inactive Ingredients in Oral Medications. Pharm Res 37, 234 (2020). https://doi.org/10.1007/s11095-020-02953-2

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Key words

  • dosage forms
  • excipients
  • oral solid
  • pharmacometrics