Research ArticleDrug Delivery

A heat-stable microparticle platform for oral micronutrient delivery

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Science Translational Medicine  13 Nov 2019:
Vol. 11, Issue 518, eaaw3680
DOI: 10.1126/scitranslmed.aaw3680
  • Fig. 1 Particle synthesis and characterization.

    Schematic representations of the (A) one-step and (B) two-step processes for formulating MPs. SEM images of (C) HA MPs, (D) HA-BMC MPs, (E) the cross section of an HA-BMC MP (inset, confocal image of an HA-BMC MP with fluorescently labeled HA), and (F) the cross section of a BMC MP. Scale bars, 100 μm, unless otherwise noted.

  • Fig. 2 Controlled release of micronutrients.

    (A) Percent cumulative release of 11 different individually encapsulated micronutrients in 37°C SGF, pH 1.5 (blue lines), and RT water (black lines) or boiling water (red lines). Schematic shows micronutrients encapsulated via one-step process (red text) versus two-step process (black text). (B and C) Representative bright-field images and time-lapse release of (B) vitamin A from BMC MPs and (C) iron from HA-BMC MPs in SGF (insets, SEMs). (D) Schematic of four co-encapsulated micronutrients [folic acid (purple), B12 (brown), vitamin A (red), and vitamin D (black)] and percent cumulative release in (E) 37°C SGF, (F) RT water, and (G) boiling water. Error bars represent SD of the mean (n = 3). Scale bars, 200 μm.

  • Fig. 3 Protection from heat, light, and chemical interactions.

    Recovery of individually encapsulated versus unencapsulated (free) micronutrients after exposure to (A) boiling water and (B) light. (C) Recovery of co-encapsulated micronutrients after boiling in water. (D) Time history of color change (ΔE), an indication of a chemical reaction between iron and polyphenols present in banana milk, of laboratory-scale Fe-HA-BMC MPs versus unencapsulated (free) iron. (E) Time-lapse release of iron from HA-BMC MPs after boiling in water for 2 hours at RT and upon immersion in RT SGF. Error bars represent SD of the mean (n = 3). *P < 0.05 as determined by Student’s t test.

  • Fig. 4 In vivo release of a model dye and absorption of vitamin A.

    (A) Representative IVIS images (logarithmic scale) of explanted murine gastrointestinal tract harvested after oral administration of dye-loaded BMC MPs showing encapsulated dye (purple) and released dye (green) over 60 min. (B) Quantitative analysis of encapsulated dye in the stomach (solid purple bars), released dye in the stomach (solid green bars), encapsulated dye in the intestines (hatched purple bars), and released dye in the intestines (hatched green bars). Error bars represent SD of the mean (n = 3). (C) Blood content of radiolabeled vitamin A over a 6-hour period after oral gavage of free vitamin A (blue lines) or VitA-BMC MPs (red lines). Error bars represent SEM (n = 6).

  • Fig. 5 Bioavailability of iron in humans and iron transport in an in vitro intestinal barrier model.

    (A) Iron bioavailability as assessed by erythrocyte iron incorporation in young women (n = 20) after ingestion of unencapsulated (free) uncooked iron as FeSO4 (red circles), encapsulated uncooked iron (black squares), and encapsulated cooked iron (blue triangles) and expressed as a percentage of the total amount that was ingested. Iron transported across a human in vitro intestinal barrier model after addition of iron in the presence of varying amounts of MP constituents (B) HA and (C) BMC and expressed as a percentage of transported free iron. Error bars in (A) represent geometric means (n = 20) with 95% CI. *P < 0.05, free Fe and each encapsulated group as determined by post hoc paired Student’s t test with Bonferroni correction. Error bars in (B) and (C) represent SD of the mean (n = 3). NSD, no significant difference.

  • Fig. 6 Process development and scale-up.

    (A) Schematic showing the process for the scaled synthesis of 1 kg of Fe-HA-BMC MPs. SEM images of (B) the Fe-HA MP intermediate product and (C) the Fe-HA-BMC final product. (D) Iron release from scaled Fe-HA-BMC MPs in 37°C SGF, pH 1.5 (blue line), RT water (black line), and boiling water (red line). Error bars represent SD of the mean (n = 3).

  • Fig. 7 Bioavailability of iron in humans from higher loaded Fe-HA-BMC MPs.

    Iron bioavailability as assessed by erythrocyte iron incorporation in young women (n = 24) after ingestion of free iron as FeSO4 (red circles), 3.19% Fe-HA-BMC MPs (black squares), and 18.29% Fe-HA-BMC MPs (blue triangles) and expressed as a percentage of the total amount of iron that was ingested. Error bars represent geometric means (n = 24) and 95% CI. *P < 0.05 and **P < 0.01. Significant effect of meal on iron absorption determined by linear mixed models, participants as random intercept, meal as repeated fixed factor, and post hoc paired comparisons with Bonferroni correction P < 0.05.

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/11/518/eaaw3680/DC1

    Materials and Methods

    Fig. S1. Laboratory-scale co-encapsulation of micronutrients.

    Fig. S2. Vitamin B12 release as a function of pH.

    Fig. S3. HA-BMC MP electron micrograph after 2 hours in boiling water.

    Fig. S4. Spectral fingerprinting of DiR-loaded MPs.

    Fig. S5. Release, electron micrographs, and time history of color change for 3.19 and 18.29% Fe-HA-BMC MPs.

    Fig. S6. Evaluation of iron absorption from 3.19% Fe-HA-BMC MPs in humans when co-administered with VitA-BMC MPs and free folic acid.

    Fig. S7. Comparison of iron absorption from 3.19% Fe-HA-BMC MPs with each MP constituent both individually and in combination.

    Table S1. Polymers evaluated as potential MP matrix materials.

    Table S2. Formulation parameters and loadings for laboratory-scale MPs.

    Table S3. Subject characteristics of human studies 1 and 2.

    Table S4. Process design formulation parameters and loadings for MPs used in the second human study.

    Table S5. Quality control tests for MPs used in both human studies.

    References (6592)

  • This PDF file includes:

    • Materials and Methods
    • Fig. S1. Laboratory-scale co-encapsulation of micronutrients.
    • Fig. S2. Vitamin B12 release as a function of pH.
    • Fig. S3. HA-BMC MP electron micrograph after 2 hours in boiling water.
    • Fig. S4. Spectral fingerprinting of DiR-loaded MPs.
    • Fig. S5. Release, electron micrographs, and time history of color change for 3.19 and 18.29% Fe-HA-BMC MPs.
    • Fig. S6. Evaluation of iron absorption from 3.19% Fe-HA-BMC MPs in humans when co-administered with VitA-BMC MPs and free folic acid.
    • Fig. S7. Comparison of iron absorption from 3.19% Fe-HA-BMC MPs with each MP constituent both individually and in combination.
    • Table S1. Polymers evaluated as potential MP matrix materials.
    • Table S2. Formulation parameters and loadings for laboratory-scale MPs.
    • Table S3. Subject characteristics of human studies 1 and 2.
    • Table S4. Process design formulation parameters and loadings for MPs used in the second human study.
    • Table S5. Quality control tests for MPs used in both human studies.
    • References (6592)

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