PerspectivePharmacology

“Inactive” ingredients in oral medications

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Science Translational Medicine  13 Mar 2019:
Vol. 11, Issue 483, eaau6753
DOI: 10.1126/scitranslmed.aau6753
  • Fig. 1 Active versus inactive ingredients and complexity of formulations.

    (A) Number of publications in PubMed containing the search terms “excipient allergy” (green circles) or “excipient irritation” (black triangles) per year. (B) Percentage of the mass of a medication corresponding to inactive (dark green) versus active (light green) ingredients. (C) Correlation analysis between the mass and the percentage of inactive ingredients in a given medication. Green shading denotes dose. Different formulations for the same API and dose are grouped together [for example: valsartan, 40 mg (I); cyclosporine, 100 mg (II); and amoxicillin, 1 g (III)]. (D) Distribution of inactive ingredients in oral solid dosage forms. The median 8 is highlighted in black. Inset: Distribution of 596 pills/capsules with 20 inactive ingredients or more. (E) Frequency of inactive ingredients. Gini coefficient = 0.95. (F) Formulation heterogeneity for the 18 most prescribed single-agent oral medications in 2016 (14). Green triangles denote the number of different available formulations; the mean and standard deviation of the distribution of the number of inactive ingredients contained in these formulations are depicted by black circles and lines, respectively. (G) Formulation network highlighting the complexity of formulation space. Each node corresponds to a specific combination of inactive ingredients; two nodes are connected when at least one API has been commercially formulated with each of these separate combinations of inactive ingredients. Node color corresponds to the frequency of formulation usage, and edge thickness corresponds to the number of APIs that have been formulated with either of the two inactive ingredient combinations. Few clusters of inactive ingredients are exclusively applied to certain drugs (periphery), whereas other formulations are heavily applied to many different APIs and form a complex relationship (central region). The red box highlights the region of valproic acid formulations. (H) Enlarged valproic acid region from (G). Network for three different combinations of inactive ingredients currently used to formulate valproic acid. Darker green indicates more frequent use.

  • Fig. 2 ARAIIs in drugs.

    (A) Pie chart depicting the percentage of medications containing potential allergen classes (or excipients with the potential to be contaminated with allergens). Gray bar: Percentage of medications without any potential allergens. Colors correspond with classes in (B). (B) Percentage of APIs with potential allergens. Black bars: All formulations of the API contain a specific allergy-associated inactive ingredient. Dark gray bars: All formulations of the API are devoid of the allergen inactive ingredient. Light gray bars: Some formulations of the API contain the potential allergen. (C) Heat map showing the ARAII content of different GI therapeutics, grouped by medication class. Numbers in parentheses indicate number of available formulations. PPI, proton pump inhibitor; H2B, histamine 2 blockers; IBS, inflammatory bowel syndrome treatments. (D) Analysis of fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) content in gastrointestinal therapeutics.

  • Table 1 List of critical inactive ingredients that can act as allergens or are potentially contaminated with allergens.

    Percentage occurrence refers to fraction of all formulations of medications (solid oral dosage forms) that contain the critical ingredient. PEG, polyethylene glycol.

    IngredientClassificationPercentage occurrence in
    medications
    LactoseFood44.82%
    Corn starchFood36.54%
    PEGPolymer36.03%
    PovidonePolymer35.80%
    CarboxymethylcelluloseOther21.38%
    GelatinFood16.93%
    Brilliant blueDye14.47%
    Sunset yellow FCFDye12.27%
    Allura redDye11.20%
    Propylene glycolOther11.14%
    Indigo carmineDye10.63%
    MannitolSugar7.20%
    SucroseSugar5.21%
    Sodium benzoateOther1.72%
    ParabensOther1.48%
    AspartameOther1.46%
    ErythrosineDye1.03%
    TartrazineDye0.95%
    SaccharinOther0.81%
    PoloxamerPolymer0.76%
    Soybean oilFood0.44%
    Benzyl alcoholOther0.43%
    VanillaFood0.38%
    Castor oilFood0.30%
    Cetyl alcoholOther0.19%
    SulfiteOther0.19%
    PEG castor oilsFood0.13%
    Peanut oilFood0.08%
    Benzoic acidOther0.07%
    Corn syrupFood0.05%
    Sesame oilFood0.05%
    Starch wheatFood0.04%
    CaseinFood0.03%
    Banana essenceFood0.01%
    MilkFood0.01%
    GlucosamineFood0.00%
    New coccineDye0.00%
    Stearyl alcoholOther0.00%

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/11/483/eaau6753/DC1

    Materials and Methods

    Fig. S1. Summary statistics for different allergen classes of potential allergens.

    Fig. S2. Flowchart of data curation strategy for Pillbox extraction.

    Table S1. Piece weight analysis of different versions of most commonly prescribed medications.

    Table S2. Top 10 most common inactive ingredients in Pillbox.

    Table S3. List of publications analyzed for identification of reports of allergic reactions or gastrointestinal side effects through inactive ingredients in medications.

    Table S4. Lactose content of various medications.

    Table S5. Corrected and identified misspellings or alternative spellings in the Pillbox database.

  • This PDF file includes:

    • Materials and Methods
    • Fig. S1. Summary statistics for different allergen classes of potential allergens.
    • Fig. S2. Flowchart of data curation strategy for Pillbox extraction.
    • Table S1. Piece weight analysis of different versions of most commonly prescribed medications.
    • Table S2. Top 10 most common inactive ingredients in Pillbox.
    • Table S3. List of publications analyzed for identification of reports of allergic reactions or gastrointestinal side effects through inactive ingredients in medications.
    • Table S4. Lactose content of various medications.
    • Table S5. Corrected and identified misspellings or alternative spellings in the Pillbox database.

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