Enhanced stability and clinical absorption of a form of encapsulated vitamin A for food fortification

Food fortification is an effective strategy to address vitamin A (VitA) deficiency, which is the leading cause of childhood blindness and drastically increases mortality from severe infections. However, VitA food fortification remains challenging due to significant degradation during storage and cooking. We utilized an FDA-approved, thermostable, and pH-responsive basic methacrylate copolymer (BMC) to encapsulate and stabilize VitA in microparticles (MPs). Encapsulation of VitA in VitA-BMC MPs greatly improved stability during simulated cooking conditions and long-term storage. VitA absorption was nine times greater from cooked MPs than from cooked free VitA in rats. In a randomized controlled cross-over study in healthy premenopausal women, VitA was readily released from MPs after consumption and had a similar absorption profile to free VitA. This VitA encapsulation technology will enable global food fortification strategies toward eliminating VitA deficiency.

Vitamin A (VitA) plays an essential role in visual health, immune function, and fetal growth and development (1). VitA deficiency (VAD) arises from diets with insufficient fat-soluble micronutrients (MNs) and is currently estimated as the second most common cause of malnutrition, after iron, globally (2). VAD can lead to xerophthalmia (preventable childhood blindness) and weakened host resistance to infection, which can increase the risk of mortality from infectious diseases, such as measles and COVID-19 (3, 4). The WHO estimated that VAD affected 190 million preschool-age children (33.3% of the preschool-age population) and >19 million pregnant women (15.3% of the pregnant population) globally in the period spanning 1995–2005 (5). The most severely affected regions still reached VAD prevalence levels of 48% in sub-Saharan Africa and 44% in South Asia in children in 2013 (6). To reduce the high burden of VAD, a VitA supplementation program was implemented worldwide in 1990 that distributed high-dose VitA capsules every 4–6 mo to over 80% of the total child population in low-income countries (7). This project effectively reduced all-cause mortality caused by severe VAD by 12% (8). However, progress toward VAD elimination was limited to a rate of improvement of only ~0.3% per year from 1990 to 2007, showing that more impactful strategies are required (9, 10).To raise and maintain serum retinol levels, frequent intake of VitA at physiological doses is proven to be more effective than one or two high doses administered over 6 mo (11). However, VitA food fortification is challenging due to its poor stability, which can lead to poor bioavailability after degradation, and fat solubility, which limits the inclusion of VitA in water-based and dry food matrices (12). To prevent VitA degradation and improve miscibility, VitA has previously been encapsulated within matrices composed of polysaccharides (13), proteins (14), and/or lipids (15); however, these materials provide limited protection during storage and cooking (16 –18) and can take up to 3 h to release in the stomach (19). Poor protection and slow release of VitA prevent effective absorption. Therefore, the ideal microparticle (MP) platform for VitA fortification should meet these criteria: i) protect VitA against degradation during storage and cooking; ii) rapidly release VitA in the gastrointestinal tract with high absorption; and iii) readily mix with various food matrices at a tunable concentration to meet the dynamic needs of the target population.We hypothesized that by encapsulating VitA with a pH-responsive hydrophobic polymer, we could enhance stability during storage and cooking and ensure its rapid release in the gastrointestinal tract for subsequent absorption. A commercially available, FDA-approved basic methacrylate copolymer (BMC), also known as either Eudragit® E PO or GRAS-status Eudraguard®, was identified from our previous work (20). BMC is generally regarded as safe with an acceptable daily intake of 20 mg/kg body weight (21). VitA-encapsulated BMC MPs were prepared by emulsion at the laboratory scale and by a commercial process at the kilogram scale. Our VitA-BMC-S MPs readily mix with flour and bouillon cubes and demonstrate enhanced stability under cooking and long-term storage conditions (over 12 mo) in comparison to a leading commercial encapsulated VitA product. The bioavailability of VitA from VitA-BMC MPs was first demonstrated in a rodent model, resulting in a ninefold increase in the accumulation of VitA in the liver from cooked VitA-BMC MPs, as compared to cooked unencapsulated free VitA. In a human clinical study, the absorption of VitA from bread fortified with VitA-BMC-S MPs was investigated, with or without the codelivery of encapsulated iron sulfate (FeSO₄) and folic acid (FA), MNs that children and pregnant women globally are also often deficient in (22, 23). The results indicate that VitA is readily released and absorbed from VitA-BMC-S MPs, and the codelivery of encapsulated iron and free FA does not influence the absorption of VitA. In total, we demonstrated scalable production of MP-encapsulated VitA with enhanced stability and good bioavailability in humans, which could potentially mitigate the high burden of VAD and be codelivered with other MNs.