Journal of Steroid Biochemistry and Molecular Biology: Vaibhav Kumar Maurya, Khalid Bashir, Manjeet Aggarwal T

Journal of Steroid Biochemistry and Molecular Biology 196 (2020) 105489
Contents lists available at ScienceDirect
Journal of Steroid Biochemistry and Molecular Biology

journal homepage: www.elsevier.com/locate/jsbmb
Review
Vitamin D microencapsulation and fortification: Trends and technologies T

a b a,
Vaibhav Kumar Maurya , Khalid Bashir , Manjeet Aggarwal *
a
Department of Basic and Applied Sciences, National Institute of Food Technology, Entrepreneurship and Management, Kundli, Sonepat, 131028, Haryana, India
b
Department of Food Technology, JamiaHamdard University, New Delhi, 110062, India
A R T I C LE I N FO A B S T R A C T
Keywords: Today, as per the latest medical reports available, majority of the population throughout globe is facing vitamin
Vitamin D D (Vit D) deficiency. Even in sub-tropical countries like India and many others Vit D deficiency is highly pre-
Fortification valent despite the exuberant available sunshine (a major source of Vit D) throughtout the year. The reason could
Encapsulation be attributed to an array of factors including socioeconomical, cultural and religious. Further, other than the
Bioavailability
sunlight, there are very limited sources of Vit D to fulfil the recommended dietary allowance of Vit D (RDA:
Micro-/nano-encapsulation
400–800 IU per day). A large proportion of Vit D is lost during food processing and storage due to environmental
Functional food
stress conditions such as temperature, pH, salt, oxygen and light. Vita D, an important micronutrient, is es-
sentially required for the prevention of disorders such as neurodegenerative diseases, cardiovascular diseases,
cancer etc. in addition to its traditional role in bone metabolism. Therefore, in order to meet the daily re-
quirements of Vit D for human body, WHO has recognized fortification as the most efficient and safest method to
address malnutrition. But there are innumerable chellenges involved during food fortification using Vit D as
fortificants such as homogeneity into the food matrix, physico-chemical/photochemical degradation, loss during
processing and storage, interactions with other components of food matrix resulting into change in taste, texture
and appearance thus affecting acceptability, palatability and marketability. Fortification of Vit D into food
products especially the ones which have an aqueous portion, is not simple for food technologist. Recent advances
in nanotechnology offer various microencapsulation techniques such as liposome, solid-lipid particles, nanos-
tructured lipid carriers, emulsion, spray drying etc. which have been used to design efficient nanomaterials with
desired functionality and have great potential for fortification of fortificants like Vit D. The present review is an
undate on Vit D, in light of its fortification level, RDA, factors affecting its bioavailability and various micro-
encapsulation techniques adopted to develop Vit D-nanomaterials and their fate in food fortification.
1. Introduction diabetes etc. The recent research has further elaborated the role of Vit D
in prevention of cancer, cardiovascular diseases, diabetes, cellular
The role of vitamin D (Vit D) in bone health (calcium and phos- growth, cellular differentiation, embryonic development, fertility, im-
phorus metabolism) is well reported in literature [2,10,45]. This is in- munological disorder, liver disorder, neurological, renal and respiratory
stantiated by the fact that between 1991 and 2019, there have been disorders [1–5]. Millions of preschool-aged children are found to be Vit
approximately 80,000 published articles, listed in PubMed, which D deficient [10]. As per the mortality reports of WHO, Vit D deficiency
contain the term “Vit D” in their title and there has been continuous is one of the major contributors to total deaths (0.8 million deaths) per
scientific activity to overcome the elusiveness of Vit D. Accruing evi- annum [6–9]. In infants and young children, a concentration of 25-OH-
dences clearly show the role of Vit D in different physiological functions D in serum below about 11 ng/L, 20–30 ng/L, ≥ 30 ng/L, and 300 ng/L
of the human body apart from bone health and calcium-phosphorus is an indication of deficiency, insufficiency, sufficiency and toxicity of
metabolism [45]. Hence, its insufficient intake may result into complete Vit D respectively [9–12]. Vit D exists majority in two forms: (i) Vit D2
or partial inhibition of those functions which may lead to osteoporosis, (ergocalciferol), synthesized only by plants and not by human body and
rickets, calcium-phosphorus imbalance, parathyroid imbalance, (ii) Vit D3 (cholecalciferol) synthesized by the human body, especially
Abbreviations: WHO, World Health Organization; FAO, Food and Agriculture Organization; IOM, Institute of Medicine; EC, European commission; UK, United
Kingdom; NNR, nordic nutrition recommendations; CMCS, carboxymethyl chitosan; SPI, soy protein isolate; WPI, whey protein isolate; WPC, whey protein con-
centrate; HACS, high amylose corn starch; MCT, medium chain triglycerides; DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine; PC, phosphatidylcholine
⁎
Corresponding author.
E-mail addresses: [email protected], [email protected] (M. Aggarwal).
https://doi.org/10.1016/j.jsbmb.2019.105489
Received 3 March 2019; Received in revised form 31 July 2019; Accepted 30 September 2019
Available online 02 October 2019
0960-0760/ © 2019 Published by Elsevier Ltd.
V.K. Maurya, et al. Journal of Steroid Biochemistry and Molecular Biology 196 (2020) 105489
Table 1
Effect of processing practices on vitamin D.
Food processing Food Impact on vitamin D Reference
Baking Fish, meat Significant reduction in [23,24]

cholecalciferol
Bread 24-31% loss in ergocalciferol [22]
Boiling Egg Significant loss in25- [23]
hydroxycholecalciferol
22-24% loss in vitamin D [22]
Frying Mushroom Significant loss in ergocalciferol [23]
Egg and 22-24% loss in vitamin D [22]
Margarine
Cooking Beef 35–42% of the original vitamin D [21]
Pasteurization Milk No significant loss [25]
Sterilization Milk No significant loss [25]
Solar Drying Fish meat Significant loss [26]
Steaming Fish oil Significant loss [27]
Oven Drying fish meal Significant loss [28]
Smoking Fish Significant loss [29]
Roasting Beef Significant loss [21]
obesity, genetic variation etc.) have been comprehensively discussed in

the literature available [18].
Based upon anti-rachitic discoveries, initially it was belived that Vit
D2 and Vit D3 were equipotent and could be used interchangeably.
Nevertheless, recent scientific evidences clearly highlight the variation
between their bioefficacy which is attributed to high metabolism and
Fig. 1. Vitamin D synthesis pathway. clearance of Vit D2 than that of Vit D3 in liver and kidney respectively
[19]. Further, the processing methods and conditions have also been
found to have significant influence on the availability of Vit D [21–28].
via skin, when it exposed to sunlight (Fig. 1).
Vit D is prone to degradation when exposed to heat, light, moisture,
There are several factors which contribute to Vit D deficiency. These
or oxygen during processing as well as storage. Thermal processing of
includes geographical location (altitude and latitude), angle of the sun
foods such as boiling, pressure cooking, frying, steaming, baking and
and length of the sun exposure, pollution [13,14] and the limitation of
sterilization can significantly affect the final level of Vit D in food
naturally occurring Vit D rich foods. Only a few wild varieties of
[21,22]. These factors ultimately affect the actual availability of Vit D
mushroom, certain varieties of algae from plant kingdom and foods
to the human body and must be considered while addressing the
such as egg, Cod liver oil, salmon and other fatty fish from animal
bioavailability of Vit D present in any food matrix. The impact of var-
kingdom are the major sources of Vit D [15,16]. In order to meet the
ious food processing methods on Vit D content in some food products is
RDA requirements for Vit D, several countries have now permitted
presented in Table 1.
fortification of food with Vit D such as milk, margarine, certain edible
Several methods have been adopted to determine the bioavailability
oils, cereals etc. In addition to this, currently certain pharmaceutical
such as animal model, in vitro test and bioassays [30–34]. The con-
supplements are also majorly being used as source of Vit D [15]. Despite
clusion of bioassay generally relies on absorption/serum 25(OH)D
the availability of Vit D fortified food, Vit D deficiency is prevailing
while balance studies calculate the difference between feed (input) and
across the globe which could be attributed to the low bioavailability of
excretion (output). The measurement of solubility, dispersibility, frac-
Vit D (fortified as well as naturally occurring foods) in the food as well
tional permeability across the muscous membrane of GIT and Vit D
as in human gastro intestinal tract (GIT) [17].
uptake in the experimental animals can also be considered while se-
lecting the in vitro studies [34,35]. Furthermore, in vitro method is
1.1. Bioavailability of Vit D preferred over other methods due to its cost effective and rapid as
compared to other methods and offers better control of experimental
The biological accessibility or bioavailability of Vit D to human variables as compared to an animal or human model. However, scien-
body is defined as the proportion of the ingested Vit D that eventually tific attempts are continuously in progress to develop and refine tech-
ends in systemic blood circulations and consequently imparts related niques to determine dietary Vit D absorption in the body. The analytical
physiological functions [18]. The mechanism of absorption of Vit D (Vit methods such as high performance liquid chromatography and liquid
D2 and Vit D3) is believed to be concentration independent unsaturable chromatography mass spectroscopy have been extensively used for
passive diffusion process [17]. The total quantity of Vit D present in accurate evaluation and detection of low levels of Vit D during the
food system does not reflects its bioavailable amount since a significant bioavailability studies [36,37]
proportion remaines bound to the food matrices [18]. Unavailability of
literature on the aspects of absorption and actual bioavailability of Vit 2. Supplementation and fortification of Vit D: which is the better
D in upper GIT in human, makes it a subject of major concern. Though option?
an array of factors influences the bioavailability of Vit D in the food
system; such as variation in the physiochemical forms of the Vit D (Vit Vit D2 or ergocalciferol comes from Vit supplements, fortified food
D species and the physiological linkages), the complexity of food ma- and some plant foods like mushrooms. Vit D3 or cholecalciferol is
trice (variety and quantity of fatty acids, dietary fibers etc., doses of Vit synthesized and is found in animal foods like salmon, cod liver and egg
D, location of Vit D in animal as well as plant tissue, processing con- yolk. It has been found that Vit D3 more effective as compared to Vit D2
dition and size of food particles) and absence/presence of Vit D en- for raising Vit D level in blood since the binding protein has a higher
hancer/inhibitor), interaction among fat-soluble nutrients available in affinity towards Vit D3 [11]. Supplementation and fortification are
food and host-associated factors (surgery, age, disease, fed condition, considered as the most viable options to combat Vit D deficiency [49].
2
Table 2
Vitamin D fortified foods and fortification level across the globe, where * is signifies to mandatory fortification.
Country Category Food name Fortification level Reference
For adults
USA Dairy Fluid milk 400 IU/ 946 mL [52,61,65,222]

Acidified milk 400 IU/ 946 mL
Cultured milk 400 IU/ 946 mL
Concentrated milk 400 IU/ 946 mL
Evaporated milk, fortified 89 IU/100 g
Evaporated milk 89 IU/100 g
Dry whole milk 89 IU/100 g
Yogurt 89 IU/100 g
Low fat yogurt 89 IU/100 g
Nonfat yogurt 89 IU/100 g
Margarine 89 IU/100 g
Cheese and cheese products (excluding cottage cheese, ricotta 81 IU/30g
cheese, and hard grating cheeses)
Calcium-fortified fruit juices and drinks 100 IU/RACC
Cereals Enriched Farina > 350 IU/100 g
Enriched rice 550–2200 IU/kg
Ready-to-eat breakfast cereals 350 IU/100 g
Enriched macaroni products 89 IU/100 g
Enriched farina ≥550 IU/kg
Enriched noodle 90 IU/100 g
products
Enriched vegetable 550–2200 IU/kg
macaroni products
Enriched vegetable 550–2200 IU/kg
noodle products
Other foods Special dietary meal replacement bars or other type bars 100 IU/ 40g
Beverages Orange juice 100 IU/240 ml
Malted drink mix and powder 123 IU/g
Special dietary soy-protein based meal replacement beverages 140 IU /240 ml
Canada Dairy Milk, milk powder, sterilized milk, (naming the flavour) milk* 300-400 IU/100 g [52,66,67,68,69,222]
Condensed milk Optional
*Skim milk with added milk solids, partly skimmed milk with 300-400 IU/100 g
added milk solids, (naming the flavour) skim milk, (naming the
flavour) partly skimmed milk, (naming the flavour) skim milk with
added milk solids, (naming the flavour) partly skimmed milk with
added milk solids, skim milk, partly skimmed milk, skim milk
powder
*Evaporated skim milk, concentrated skim milk, evaporated partly 300-400 IU/100 g
skim milk, concentrated partly skimmed milk
Food represented for use in a very low-energy diet* 300-400 IU/100 g
*Meal replacements and nutritional supplements* 300-400 IU/100 g
Goat's milk, goat's milk powder Optional
Partly skimmed goat's milk, skimmed goat's milk, partly skimmed 300-400 IU/100 g
goat's milk powder, skimmed goat's milk powder
Evaporated goat's milk Optional
Evaporated partly skimmed goat's milk, evaporated skimmed goat's Optional
milk
Margarine* 530 IU/100 g
҂
Other foods Liquid whole egg, dried whole egg, frozen whole egg, liquid yolk, Optional
dried yolk, frozen yolk, liquid egg white (liquid albumen), dried
egg white (dried albumen), liquid whole egg mix, dried whole egg
mix, frozen whole egg mix, liquid yolk mix, dried yolk mix, frozen
yolk mix
Infant formulas and formulated liquid diets 530 IU/100 g
Latin America
Brazil Dairy Dried skimmed milk 2000–2400 IU/kg [52,66,67,68,69]
Guatemala Dairy Skim milk 400–600 IU/L
Whole milk 400–600 IU/L
Honduras Dairy Milk 400 IU/L
Margarine 1500 IU/kg
Mexico Dairy Sterilized low-fat 400 IU/L [52,66,67,68,69]
milk
Pasteurized low-fat 400 IU/L
Milk NA
Evaporated whole 400 IU/L
Margarine/Spreads 2000 IU/kg
Argentina Dairy Fluid and dried 400 IU/L [65]
Panama Dairy Margarine 1500 IU/kg [70]
Ecuador Dairy Margarine 2000-4000 IU/kg [52,66,67,68,69]
Peru Dairy Margarine 3000 IU/kg [70]
Venezuela Dairy Dried milk powder 400 IU/L [70]
Chile Dairy Margarine 3000 IU/kg [70]
(continued on next page)
3
Table 2 (continued)

For adults
Colombia Dairy Margarine* 200-400 IU/100 g [69,70]

Uruguay Cereals Rice NA [69]
Ecuador Dairy Margarine* 200-400 IU/100 g [69]
Australia and New Zealand

New Zealand Dairy Edible oils and spreads Edible oil spreads and margarine: 40-164 IU/10 g [71]
Beverages Formulated Beverages 100 IU/10 g
Beverages containing no less than 3% m/m protein derived from 40-164 IU/200ml
legumes
Analogues of yoghurt and dairy desserts containing no less than
3.1% m/m protein derived from legumes
Analogues of cheese containing no less than 15% m/m protein 40-164 IU /150g
derived from legumes
Analogue Beverages Orange juice 44-123 IU/g
Analogues derived Beverages 40-164 IU/25g
from cereals
Australia Dairy Edible oil spreads 220-640 IU/100 g
Cereals Breakfast cereals 100 IU/serving
Europe
UK Beverage Orange beverage 1000 IU/240 ml [69,72,73,74,75,222]
Dairy Margarine 282–352.8 IU/
100 g
Cereals Bread 200 IU/100 g
Infant formula NA
Austria Dairy Milk NA
Bulgaria Dairy Milk NA
Estonia Dairy Milk NA
France Dairy Milk NA
Germany Oil D-fluorette in first NA
few months of life
Iceland Dairy (Voluantary) 1.5% fat milk 20 IU/100 g
0.3% fat milk 15.2 IU/100 g
Sweden Dairy *Milk with, 3% fat 38-44 IU/100 g
*Lactose free/vegetable based milk alternative 38-44 IU/100 g
*Sour milk products with < 3% fat 11-44 IU/100 g
*Lactose free/vegetable based sour milk alternative 11-44 IU/100 g
*Margarine, fat spread and fluid margarines 780-840 IU/100 g
Norway Diary Extra low fat milk 16 IU/100 g
Lactose free milk 16 IU/100 g
Butter 32 IU/100 g
The Netherlands Cereals Porridge cereals 200 IU–649 IU/
100 g
Breakfast cereals 68 IU–400 IU/
100 g
Cookies Infant cookies 120 IU–400 IU/
100 g
Dairy (Fruit) fromagefrais 38 IU–50 IU/
100 g
Ready-to-drink milk porridge 40 IU-80 IU/100 g
Yoghurt drink 30 IU/g
Toddler milk 38–38 IU/g
Drinks Instant cacao powder 320 IU/100 g
Soja drink junior 29.6 IU/100 g
Finland Dairy Milk (except organic milk)* 40 IU/100 g
Sour milk* 40 IU/100 g
Yoghurt* 40 IU/100 g
Vegetable based milk alternative 40 IU/100 g
Fat spreads 800 IU/100 g
Turkey Rice NA [69]
Asia
Philippines Dairy Filled milk, sweetened ≥973IU/L [76,77,78,79]
Margarine 3300 IU/kg
Saudi Arabia Cereals Enriched wheat and ≥551.15 IU/kg [80]
Bahrain Cereals Enriched and enriched ≥551.15 IU/kg
Morocco Margarine 250-300 IU/100 g [79]
Rice NA [69]
Sri Lanka Margarine 300 IU/100 g [69]
(continued on next page)
4
Table 2 (continued)

For adults
India Oil Vanaspati 44 IU– 64 IU/ [48]

100 g
Edible oil 44 IU– 64 IU/
100 g
Dairy Milk 200 -300 IU/L
Indonesia Margarine* 2500-3500 IU/kg [70,77,78,79,81,82,83,84,85,86,87,88,89]
Thialand Sweetened condensed milk*
Malaysia Dairy Condensed milk 111 IU/100 g
Malted milk Powder 667 IU/100 g
Liquid foods 100 IU/100 g
Dried milk 333 IU/100 g
Cereals Bread 83 IU/100 g
Breakfast cereals 333 IU/100 g
Wheat Flour 167 IU/100 g
Extract of meat 2000 IU/100 g
Other solid food 167 IU/100 g
Singapore Food not specified 400 IU/serving
Brunei Darussalam Food not specified 50 IU/ serving
Africa
Zimbabwe Cooking oil NA [70,90]
Nigeria Margarine NA [69]
Supplementation involves the use of high dose of Vit D formulations. Bank (1993) as the most cost effective way for combating the nutrient
Generally, Vit D3 is administered in the form of cholecalciferol, alfa- deficiency problems among the available health interventions.
calcidiol, and calcitriol as solo ingredient or in combination with cal- Fortification refers as the addition of micronutrients to target foods for
cium and other minerals or vitamins. Vit D supplements containing the purpose of its enrichemnt with respect to a given micronutrient.
alfacalcidiol and calcitriol are generally available in the form of tablets This strategy has resulted in relatively rapid improvements in the mi-
and capsules while the formulations containing cholecalciferol in cronutrient status of a population at a very reasonable cost, particularly
granules in sachets [38,39]. Cholecalciferol is the most favored form for if the existing technology and local distribution networks are exploited
prophylaxis and treatment of Vit D deficient states in not only India [48,49]. Unfortunately, implementation of fortification programs,
[38] but also worldwide [39]. Currently, Vit D supplement intake is especially in the developing world, has been lackadaisical [50]. For
voluntary and its intake is the highest among infants, elderly adults and this, there may be several reasons including (1) lack of knowledge re-
lowest among adolescents, children and young adults who are at high levant to micronutrient deficiency status; (2) lack of understanding of
risk of its deficiency. Further, the distribution of Vit D intake among the significance of micronutrient deficiencies and its concern to the
population is greatly skewed to a small number of high dose supple- healthcare system; (3) inadequate knowledge about food consumption
ments which poses a high risk of excessive intake [38,39]. The pro- patterns; and (4) the consumer acceptance, competitive and costs
curement and purchase of Vit D normally requires quite an expensive concern of the food industry.
pre-packaging, an efficient distribution system and a high level of
consumer compliance (particularly if supplements are to be consumed 2.1. Present status of Vit D fortification
on a long-term basis) [40]. The shortage of supplies and poor com-
pliance are constantly reported in usually adopted supplementation Several Vit D fortification programs have been implemented across
program, which result into main hurdles in its success. Hence, in view the globe. The various foods fortified with Vit D so far include mostly
of public health, food processors need to work on changing the shape of milk, milk products, and edible oil. The food items normally selected for
Vit D intake consumption pattern with the sustainable food based fortification solely depend on the consumption pattern of foods of the
strategies; consequently filling the gap between current and re- country’s population. Many of the foods are being fortified with Vit D in
commended intakes without putting the general population at risk of conjunction with Vit A. Various reports on successful fortification of Vit
habitual either excessive or difficient intake. As on today, several in- D and regulatory compliance adopted for North Americans have been
novative methods have been reported for improving Vit D level in foods published [51–53]. Presently Vit D fortification has become mandatory
by fortification and biofortification. in milk (expect goat milk and condensed milk) and margarine in Ca-
Biofortification relies on enhancing the levels of specific or limiting nada where it is regulated by the Canadian Food and Drug Regulations
micronutrients in edible tissues of plant/animal by combining crop [54–60] while in USA, Vit D fortification is voluntary in fluid milk and
management, breeding, and genetic approaches [16]. Studies have if fortified, needs to be displayed on the label [61,62]. It is also evident
shown that Vit D2 level in fungi can be significantly enhanced by ex- that the majority of the milk-derived products such as butter, cream,
posing them to UVB light [41,42]. Further, the stability of Vit D in these cottage cheese, sour crease, ice cream, hard and soft cheese, and yogurt
irraditated mushroom can be further improved via cold storage [43]. are not routinely fortified with Vit D [52,61,63]. In addition to these
For example, the dried mushrooms are able to retain much of their Vit D products, infant formulations are being fortified globally (40–100 IU/
content even after 2–6 years of cold storage [20]. A significant increase 100 g) [64]. The food products that are being fortified with different
in Vit D content in animal products (pigs, fish and hens) has also been level of Vit D across the globe are listed in Table 2.
reported [44,47]. Vit D3 rich meat and liver can be produced by feeding Today the fortification practices adopted by different countries in
pigs with Vit D3 rich feed [16,44]. Likewise, Vit D content in fish can the world depend upon the country’s regulation. Initially, all margarine
also be enhanced by feeding them Vit D3-rich feed [45] and hens which manufactured for domestic use in the UK and Ireland was subject to
were fed on Vit D3 rich diet have shown to produce eggs with high mandatory fortification but now it become voluntary [91]. Similarly,
content of Vit D [46,47]. other foods like dried and evaporated milk, breakfast cereals, macaroni,
Fortification of food products has been acknowledged by the World noodles, beverages, edible oils, and wheat flour may also be voluntarily
5
fortified with Vit D along with other micronutrients (Table 2). How- of food fortification [113]. The fortification using nanomaterials offers
ever, information pertaining the continuation and compliance of these various advantages over direct addition and emulsification method
fortification regulations is very scanty [92,93]. The stability, dis- such as high stability, better homogeneity and improved physiochem-
pensability, and solubility of Vit D during production and storage of ical as well as organoleptic characteristics [111].
foods are the key concerns for food processors.
3. Use of microencapsulation techniques
2.2. Stability of Vit D in fortified food
The success of microencapsulation of Vit D in pharmaceuticals en-
In general, the success of Vit D fortification mainly depends on the couraged its application in food with the following objectives (i) beats
stability of the fat matrix in the food as Vit D is fat soluble. Fortification solubility barrier between Vit D and the food matrix (ii) shields Vit D
of Vit D has been a challenge to the food industry due to its instability against physiochemical stress such as moisture, oxidation, pH, tem-
and heterogeneous distribution in food. Loss of Vit D was observed in perature, mechanical etc. (iii) guarantees better bioavailability with the
various food systems fortified with Vit D such as milk [93], cheese controlled and targeted release of encapsulated Vit D (iv) does not
[97,100,101], yogurt [102–104], and other milk based products manipulate appearance, taste, quality of food matrix, thus sustaining
[105,161,224]. The loss is mainly due to oxidation and isomerization customer acceptability.
during processing and storage [105,106]. Similarly, Vit D found to be
susceptible to oxidation with poor retention property in extruded food 3.1. Status of Vit D microencapsulation
products also during storage [107]. Food processing methods such as
baking, cooking, frying and water boiling (fish, mushroom, and egg) The high dispensability of lipophilic drug in aqueous media of
cause significant degradation of Vit D [21,22,25,29]. In addition to the pharmaceutical formulation made research community to assume that
stability, uniform distribution or the homogeneity of Vit D in the for- solubility of these lipophilic drugs can also be improved in the food
tieid food matrix is again one of the major concern for the food in- matrix by microencapsulation. This assumption was evaluated by sev-
dustry. The stability studies in fortified foods other than milk are very eral dedicated studies such as 100-time high solubility was achieved
limited and reports on uniform distribution are even rarer. Thus, studies when tretinoin was encapsulated with β-cyclodextrin [115] while it was
addressing stability, homogenization, and bioavailability of Vit D in the 10000-times for anandamide [116]. However, these cyclic molecules
fortified foods need to be conducted to gain a better understanding in have the ability to host Vit D molecule, but its drug loading capacity
designing the fortified foods. was very poor [116]. To address this problem, nanomaterials have been
introduced that can offer high drug stability and encapsulation effi-
2.3. Methods for Vit D fortification ciency (EE). The potential of nanomaterials to become an efficient
carrier is continuously ested in pharmaceutical and the food industries.
For sustainable fortification, various techniques have been adopted Literature reports about a range of nanomaterials such as emulsion
such as direct addition, emulsification, and microencapsulation. In case [118,119], liposome [100,120–132], niosome [133–137], solid lipid
of Vit D, direct addition is the most widely adopted method for for- nanoparticles [138] and nanostructured lipid carriers [139]. Though
tification of milk and milk products [51,52,54]. In general, these pro- several excellent reviews are available focusing the wall material, mi-
ducts are being spiked with Vit D where Vit D is dissolved in food grade croencapsulation techniques, and nanomaterials for bioactive com-
organic solvent (ethanol) and butter oil, and then homogenized into the pounds [111,114,140,141] but there is a lack of dedicated reports ad-
food matrix to ensure the uniform distribution [94–96]. The deposition dressing microencapsulation techniques which are exclusively used to
of Vit D inside the packaging materials especially the polypacks or develop Vit D nanomaterials for food application (Table 3).
tetrapacks and its degradation in aqueous food matrix leading to the Vit
D instability in food matrix. In emulsification method an oil phase, 3.1.1. Vit D microencapsulation using spray drying technique
having Vit D, is dispersed as fine droplets in water and these fine dro- Spray drying is renowned as one of the oldest technique used for
plets are then mixed with target food material such as cheese, milk and bioactive compounds encapsulation. Vit D is needed to be homogenized
bread [97–99]. Homogenization of Vit D in the food matrix and limited in a dispersion containing wall materials (polymers). Then, the homo-
availability of food grade emulsifiers are major challenges while de- genized dispersion needs to be fed to the spray dryer and atomized by
veloping stable emulsion. hot air that leads to the development of nanomaterials in consequence
The major challenges being faced by food technologists during of water evaporation. The encapsulation process is subjected to a range
fortification of Vit D are its compatibility or suitability with food ma- of factors like homogeneity of dispersion system, quantity, quality and
trix, dispersibility, homogeneity and stability in the food matrix and type of emulsifier used, feed rate, viscosity of dispersion system, pres-
ultimately its bioavailability to the body in required doses for com- sure of hot air, the flow rate of hot air and inlet and outlet temperature.
bating the deficiency. All theses chalanges are the driving forces leading In spite of better control on the shape and size of nanomaterials con-
to the development of various innovative techniques for fortifying Vit D tinuous and reproducible nature, low cost, easy scale-up, spray drying is
in different food matrixs. Recent literature suggests that nano- not quite popular for bioactive compounds exclusively for heat sensitive
technology offers great stability and ensures homogeneity by en- compounds [141,173–175]. Further, several researchers have compre-
capsulation of bioactive core ingredient into a matrix with a size lower hensively described the key factors need to be taken under considera-
than 1000 nm. Microencapsulation is basically insulation of bioactive tion during spray drying while designing nanomaterials for food ap-
core material by secondary wall materials which protect the core from plication [140,141,176–181]. Furthermore, spray drying offers great
its external environment [108–112]. In addition to giving protection to flexibility for choice of wall materials, one or more than one but the use
the bioactive compound, it also helps in controlled release of en- of spray drying in Vit D microencapsulation is even rarer as it mandates
capsulant with high physiochemical stability. Microencapsulation also Vit D to be in water dispersed form. Despite several advantages, the full
promises that the nanomaterials so formed would ensure high bioa- potential of spray drying is still fully unexplored for Vit D encapsulation
vailability, water dispersibility and better homogeneity of the for- which could be accredited to resultant porous nanomaterials that are
tificant in the target food irrespective of complexity of food matrix prone to degradation of encapsulated Vit D hence lacking the aim of
[111]. The rising demand for functional foods has been the major encapsulation [170–172]. Vit D was encapsulated using different
driving force for designing and production of novel nanomaterials that combinations of maltodextrin, gum arabic, modified starch and whey
are suitable for fortifying the food. Literature reports several nanoma- protein concentrate to study the effect of temperature on the physico-
terials, which could be efficient carrier systems for Vit D for the purpose chemical characteristics of spray-dried whey nanoparticles
6
Table 3
Microencapsulation techniques widely adopted for development of vitamin D-nanomaterials.
Microencapsulation techniques Preparation method Matrix composition References
Liposome Homogenization Phosphatidylcholine [97]

Thin film hydration method L-α-Phosphatidylcholine, [120]
L-αphosphatidyl - DL glycerol sodium salt
Thin film hydration method 1-O-Octadecyl-2-O-benzyl-3-methylthio-1,2-propanediol [121]
Supercritical antisolvent-based Technology Hydrogenated phosphatidylcholine [123]
Film hydration-sonication technique Soybean phosphatidylcholine [127]
Homogenization Methylparaben and propylparaben and disodium edetate [129]
Film hydration-sonication technique 1,2-dimyristoyl-sn-glycero-3-phosphocholine [130]
Hydration Xanthan and guar gums [142]
Solid lipid nanoparticles Hot homogenization technique Glyceryl tri palmitate, [138]
Polyoxyethylene and
Sorbitanmonolaurate
Nanostructured lipid carriers Phase-inversion temperature Capric and caprylic acid triglyceride, [139]
Polyethylene glycol hydroxyl stearate and
Soybean lecithin
Phase-inversion temperature Oleic acid, [143]
Glycerol monostearate and
Tween 80
Emulsion system Microchannel emulsification Tween 20 and decaglycerolmonolaurate (Sunsoft A-12) or β-lactoglobulin. [119]
Homogenizing Oleoyl alginate ester [144]
Homogenizing Quillajasaponin, Triglycerides in MCT [118]
Homogenization method Sodium caseinate, [145]
Lecithin, Decaglycerolmonooleate
Wash out Tween 20, [146]
Method followed by ultrasonication Fish oil
Solvent evaporation assisted lyophilization N,N-dimethylhexadecylcarboxymethyl chitosan. [223]
Sonication High amylose corn starch and [147]
Alpha-amylase
Acidification assisted with ultrasonication Whey protein isolate [108]
High pressure treatment Casein [148]
Microfluidization Whey protein concentrate, [98]
Calcium caseinate and
Sodium caseinate
Acidification B-casein [149]
Ultra-high-pressure homogenization Tween-80 and Casein [112]
Phase Zein and Carboxymethyl chitosan [150]
Separation method assisted lyophilization
Isoelectric precipitation Carboxymethyl chitosan and [151]
Soy protein isolate
Micro fluidization Tween 20, 60 or 80 and [110]
Medium chain triglycerides
Spontaneous emulsification MCT oil, Tween- 20, 40, 60, 80 and 85 [152]
Sonication Pea protein isolate [153]
High pressure homogenization Orange oil, starch and miglyol 812 [154]
High pressure homogenization Soybean oil/ olive oil/or medium chain triglyceride and Tween 20 [155]
High-pressure homogenization Cellulose [156]
Ultra-high-pressure homogenization Casein [157]
Microfluidization Corn oil and tween 80 [158]
High pressure homogenization Polysorbate 20, tween 20 and soybean lecithin [159]
High-pressure homogenization Corn/fish/ flaxseed oil and pea protein [160]
Phase inversion Caprylic-/capric triglyceride, Leciva S70, Kolliphor® HS 15 [161]
pH-shifting and sonication combined treatment Pea protein isolate [162]
Sonication and ph-shifting Pea protein isolate [153]
Homogenization Corn oil and whey protein isolate [163]
Molecular complexes Chemical modification Cyclodextrin, [164]
Strontium salt
Solvent evaporation method β-cyclodextrin [165]
Chemical modification Bisphosphonate, [167]
cyclodextrin
Sonication Amylose and amylopectin [168]
Complex coacervation Carbohydrate (cress seed mucilage, CSM) and a protein (gelatin) [162]
Electrospinning – Polyvinylpyrrolidone [169]

Spray drying – Chitosan [170]
– Casein [171]
– Whey protein [172]
7
encapsulating Vit D [172]. Higher stability and greater bioavailability loading capacity, higher encapsulation efficiency, and better chemical
of Vit D2 were achieved when it was encapsulated in casein micelles stability against physiochemical stress. The literature describes the
using spray drying [171]. Similarly sustained release of Vit D2 in si- preparation methods for solid lipid nanoparticles (SLN)
mulated GIT conditions was demonstrated by ethylcellulose coated [136,137,193–201]. The ability of SLN to encapsulate and protect Vit D
spray dried nanomaterials containing chitosan [170]. The stability issue is still untapped and the only single report has been generated till date
can be resolved by proper selection of wall materials and association in which Vit D-SLN was prepared using molten tripalmitin [201].
with other microencapsulation techniques.
3.1.5. Vit D microencapsulation using nanostructured lipid carriers (NLC)
3.1.2. Vit D microencapsulation using emulsification technique NLC generally encompasses unstructured solid lipid matrix com-
This system involves at least two immiscible phases (lipid and prised of a mixture of liquid and solid lipid blend and an aqueous phase
water) where one phase needs to be dispersed as small spherical dro- consisting of a surfactant or a mixture of surfactants. Typically, liquid
plets within another phase. On the basis of the spatial arrangement of and solid lipids are blended in a ratio that could vary from 70:30 to
two phases, the emulsion system is generally classified into two classes 99.90:0.10 while the surfactant content is kept between 1.5–5% (W/V)
i.e. oil in water (O/W) or water in oil (W/O). Then, these two im- [202]. The unstructured/partially solid matrix creates interesting na-
miscible phases need to be stabilized by surfactants and emulsifiers nostructures, which enhance the stability of the entrapped bioactive
[182]. Several complex emulsion system like oil-in-water-in-oil (O/W/ compound, facilitate high loading capacity and offers controlled/target
O), water-in-oil-in-water (W/O/W), water-in-oil-in-oil (W/O/O) or release. Literature dictates various methods for NLC preparations
water-in-oil-in-oil-in-water (W/O/O/W), are reported in literature [202–205]. Despite being the most promising technique for drug de-
[183–185]. Several researchers have explored emulsion techniques to livery, NLC is among the least explored method for Vit D encapsulation.
develop Vit D-nanomaterials using food grade materials such as whey Till date, only three dedicated studies were reported addressing Vit D
protein isolate (WPI) [108], casein [149], Medium chaing triglycerides encapsulation in NLC [139,143,224]. In the first report, Vit D loaded
(MCT) and Tween 20, 40, 80, 85 [152], MCT and Tween 20, 60, 80 NLC was formulated by phase-inversion temperature method displayed
[110], carboxymethyl chitosan and SPI [151], zein and carboxymethyl high physical and chemical stability for NLC as well as Vit D and was
chitosan [150], Tween 20 and casein [151,213], WPI, calcium caseinate found to be a suitable vehicle for milk fortification [139]. While the
and sodium caseinate [98], casein [148], HACS and α-amylase [147], second report was conducted to evaluate the drug release kinetic of Vit
Tween 20 and fish oil [146], sodium caseinate and lecithin [145], D loaded NLC and were fabricated with oleic acid, glycerol monosterate
quilajapaponin [118] and oleoyl alginate ester [144] and PPI [153]. Vit and Tween 80 using hot high-pressure homogenization [143]. NLC
D emulsion fabricated with sodium caseinate, calcium caseinate, nonfat particles displayed biphasic kinetic release (burst effect) resulting in
dry milk, and whey protein have found to be stable during cheddar almost 50% of the Vit D released during the first 2 h and 80% released
cheese preparation [98]. The selection of emulsion method for Vit D after 4 h of digestion, followed by a sustained release until 90.9% of the
encapsulation depends on various factors such as absence/presence of Vit D during 8 h [143].
antioxidants, quantity and type of carrier oils and surfactant. It was
observed that the stability of encapsulated Vit D is highly correlated to 3.1.6. Vit D microencapsulation using molecular complex
the stability of emulsion system. Further, it is also evident that the In general, the molecular complex is formed with the use of cyclo-
presence of an antioxidant in the emulsion system also enhances the dextrin which can host bioactive agents within its void. Cyclodextrin is
stability of Vit D. usually applied for encapsulation of Vit D in pharmaceutical formula-
tions to assess its chemical stability against various physiochemical
3.1.3. Vit D microencapsulation using liposome stresses [117,119,144,153,167].
Literature reveled about various preparation methods for liposome
which are comprehensively discussed by researchers in their excellent 3.1.7. Vit D microencapsulation using electrospinning
reviews [131,136,186–192]. In general, liposomes are referred to the It is a fiber producing technique which exertes electric force to draw
spherical liquid structures in which an aqueous core bounded by a charged fiber of polymer solutions or polymer melts up to diameters of
single (unilamellar liposomes) or multiple lipid bilayers (multilamellar nanoscale. This continuous process is performed by extruding disper-
liposomes). The ability to host both hydrophilic and hydrophobic sion of polymer through the needle on rotating drums to impact charge
bioactive ingredients individually or simultaneously makes liposome on fibers. The literature describes electrospinning as the most suitable
the most adopted encapsulation technique for Vit D. In addition to techniques for thermo-sensitive bioactive agents, but its use for Vit D
flexibility in composition and size, liposome also promises high bio- encapsulation is very scant. Till date single report is documented in
compatibility with animal tissue as it mimics with the natural plasma which Vit D-nanofiber fabricated using poly (vinyl pyrrolidone) [169].
membrane [188]. Several researchers have fabricated liposome for
encapsulation of Vit D using 1,2-dimyristoyl-sn-glycero-3-phos- 3.2. The fate of Vit D-nanoscale materials in GIT
phocholine (DMPC) [130], methylparaben and propylparaben and the
di-sodium edentate [129], L-α-phosphatidylcholine and L-α phospha- The small intestine is recognized as the site of absorption of Vit D
tidyl-DL glycerol [120], 1-O-Octadecyl-2-O-benzyl-3-methylthio-1,2- after its oral ingestion [206,207]. Fig. 2 illustrates the main routes of
propanediol [121], phosphatidylcholine [100], hydrogenated phos- Vit D absorption in small intestine. Nanomaterials encapsulating Vit D
phatidylcholine [123] and soybean phosphatidylcholine [127]. have demonstrated its improved absorption [114,122,139,161] and the
Though, Vit D shows high chemical stability when it is integrated mechanism how nanomaterials improve its oral bioavailability has al-
within liposome but its application in food fortification is still not fully ready been reviewed in the previous article [114]. Generally, mixed
explored. The limited use of liposome in Vit D fortification could be micelles are generated as a result of digestion of lipid as well as na-
attributed to its dependency on soya derived lecithin which carries nomaterials and facilitate Vit D passage passing through the aqueous
intense smell. This issue can be easily resolved by replacing soya de- mucous layer to make it bioavailable to brush bordered enterocytes.
rived lecithin with milk-based lecithin or hydrogenated lecithin. The absorbed Vit D is then encased into chylomicrons within the en-
terocytes depending on their hydrophobicity [208,209]. The chylomi-
3.1.4. Vit D microencapsulation using solid lipid nanoparticles crons and lipid particles are endogenously produced within the en-
It is referred as the most suitable encapsulation technique for vita- terocytes using lipid components (monoacyglycerols, free fatty acids,
mins encapsulation as it has the hybrid structure of liposome and and sterol) of mixed micelles [210]. Then the chylomicrons in-
emulsion system hence tenders a range of advantages like high drug corporating Vit D are transported to the lymphatic circulation system
8
Fig. 2. Physiochemical and physiological processes involved in digestion and absorption of vitamin D in GIT. The fate of vitamin D based nanoscle materials in
intestinal lumen. Where FB: fraction of the encapsulated vitamin D which released from food matrix into the gastric juice in GIT, FA: fraction of the vitamin D which is
transported through the intestinal epithelium and then transported to the portal or lymph, FM: The fraction absorbed vitamin D which is an active form after bypass
the chemical modification by organs such as liver and kidney.
via chylomicron-mediated pathway. but it remained untapped for Vit D encapsulation for fortification
In parallel, it is also assumed that a fraction of Vit D still retained purpose. The first use of microencapsulation technique in the food was
within nanomaterials rather being released during digestion [211,212]. initiated with Indyk’s study where high stability of Vit D was achieved
Vit D-nanomaterials are speculated to pass paracellularly to the portal by encapsulating Vit D in milk powder using spray drying [106]. Fur-
blood via tight junctions or taken up by M cells via Peyer’s patches ther, liposome incorporated with Vit D was applied for fortification for
followed by excretion into the lymph. In addition, it is also supposed cheddar cheese [97,100]. Conversely, the high stability of Vit D was
that the structure and integrity of intestinal border can be modulated reported in soybean phosphatidylcholine based liposome which was
with nanomaterials containing specific compounds hence changing Vit found to suitable nanomaterial for food fortification [127]. Likewise,
D absorption efficiency. The literature reports about these compounds Tippetts’ team has developed Vit D premix and applied it for the pro-
which can modulate the intestinal epithelial integrity such as surfac- duction of Vit D enriched artificial rice [98]. Further, the re-assembled
tants (modulate the integrity of the plasma membrane), EDTA (widens casein based micelles encapsulating Vit A and D displayed great stabi-
intracellular tight junction seals), chitosan (separate the tight junction lity during the storage period and were compatible with milk for-
components) and free fatty acids (increases plasma membrane perme- tification [203]. In addition, Kiani’s team fortified milk with NLC that
ability) [114]. The use of these materials during nanomaterials pre- didn’t change the color and texture of milk [139]. Moreover, Vit D rich
paration may help in achieving the desired functionality. nanoemulsion was developed using phase inversion based method to
evaluate its feasibility in buttermilk fortification [161].
3.3. Vit D fortification with nanomaterials Above observations clearly indicates that desired stability, bioa-
vailability and dispersibility can be achieved by encapsulating Vit D by
To our knowledge, a significant numbers of food products are for- one or more than one encapsulation techniques mentioned above.
tified with Vit D either mandatorily or voluntarily [222]. The current Further, high bioavailability of Vit D is reported when Vit D is ad-
fortification method uses direct addition/mixing of Vit D in food ma- ministered through mushroom [214,215]. Hence, it will be rationale for
trices which may carry various limitations like loss of activity, de- further research exploiting these observations to design Vit D rich food
gradation, irregular distribution, inevitable undesirable interaction, with desired functionalities. Fig. 3 describes the systematic approach
change in appearance and taste, hence affecting the customer accept- for the development of Vit D rich functional foods with its improved
ability. Microencapsulation is a tested technique to address these issues, bioavailability.
9
Fig. 3. Fortification strategy for development of vitamin D enriched food system.
3.4. Safety concerns and risks of Vit D nanoparticles several agencies and government bodies claim to follow the safety
concerns of nanomaterials based food products [221]. The tentative
In general, the nanomaterials are adopted to improve the oral guidelines can be drafted with list of suggestions (i) the physiochemical
bioavailability of poorly soluble drugs. The available reports clearly characterization nanomaterials applied in the food (ii) characterization
indicate that the uptake of nanomaterials from the GIT tract is subject process to assess their hazards characteristic embraced by nanomater-
to its particle size [216] and surface properties [217]. Similarly mod- ials such long and short term toxicity assay (iii) submission of a toxicity
ified characteristics of nanomaterials such as particles size and pene- assessment report to legislative bodies such as FDA, Food Safety and
tration ability to cross the physical barrier and ability to modulate cell Standard Authority of India (FSSAI), European Union (EU) etc. (iv)
integrity may transmit undetected risk to the biological system. Utili- recognize and state a regulatory compliance for the consumption of the
zation of biodegradable or natural materials may limit health hazards nanomaterials derived foods. However, lack of precise guidelines re-
which could generally posed by synthetic polymeric nanomaterials. Due garding the use of nanomaterials in food, demands various legislative
to uncertainty in the long or short term and the direct or indirect effect bodies to come up together to frame universal guidelines which could
of nanomaterials based foods, it is significant to assess the effect of be applicable across the globe.
nanomaterials on human health [218]. In view of food safety, Food and
Drug Administration (FDA) has planned special strategies for mass
4. Conclusion
production of food and food components incorporated with nanoma-
terials [219,220]. Anyway, there are no definite legislative guidelines
Despite the fact that the endogenous synthesis of Vit D can able to
framed addressing the use of nanomaterials in food supply, however,
suffice its daily requirement, its deficiency is prevailing across the globe
10
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Journal of Steroid Biochemistry and Molecular Biology 196 (2020) 105489

Contents lists available at ScienceDirect

Journal of Steroid Biochemistry and Molecular Biology

Vitamin D microencapsulation and fortiﬁcation: Trends and technologies T

Baking Fish, meat Signiﬁcant reduction in [23,24]

obesity, genetic variation etc.) have been comprehensively discussed in

USA Dairy Fluid milk 400 IU/ 946 mL [52,61,65,222]

Country Category Food name Fortiﬁcation level Reference

Colombia Dairy Margarine* 200-400 IU/100 g [69,70]

Australia and New Zealand

Country Category Food name Fortiﬁcation level Reference

India Oil Vanaspati 44 IU– 64 IU/ [48]

Liposome Homogenization Phosphatidylcholine [97]

Electrospinning – Polyvinylpyrrolidone [169]

Fig. 3. Fortiﬁcation strategy for development of vitamin D enriched food system.

foodchem.2014.08.087. ingredients—a review, Food Bioprocess. Technology 5 (2012) 3–14, https://doi.

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