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Wellness Europe

THE MAGAZINE FOR , FUNCTIONAL FOODS & BEVERAGES AND SUPPLEMENTS

Zinc citrate – a highly bioavailable source

Reprint from Wellness Foods Europe issue 3/2014 Wellness Foods Europe Special

Zinc citrate – a highly bioavailable zinc source

Markus Gerhart, Jungbunzlauer Ladenburg GmbH

Zinc, the versatile , is about to be- Zinc is a component of about 300 and come the next star in the catego- 2000 transcriptional factors, and 10 % of the ry. Profiting from its various health benefits human proteome contain zinc-binding motives. and its relatively low cost in use, zinc sales Impairment of intestinal zinc absorption results in supplements have shown a double digit in severe clinical manifestations like skin lesions, growth in 2012 and are starting to catch up developmental retardation, stunted growth and with , and , the cate- immune deficiency. gory leaders. Its importance for human health was empha- sised by the European health claim regu­lation, Zinc is an essential transition that is where zinc received more positive opinions (18 directly or indirectly involved in a wide varie- in ) than any other mineral. The range of ty of physiological processes. After discover- claims (Table 1) includes, amongst others, im- ing the necessity of zinc for , it portant health benefits like immunity, took another 100 years before its relevance for health, cognitive function and healthy vision. humans was recognised, when the zinc deficien- These health benefits can be clearly defined and cy syndrome was described for the first time by are easy for the consumer to understand. Even Prasad and his co-workers at the beginning of if the EU regu­lations are not valid outside Eu- the 1960s. rope, they influence other regions in the world

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because they represent the first comprehensive proportion of animal products and particularly evaluation of health claims, while the respective meat in the . Nevertheless, people with spe- dossiers can be used by other authorities as well. cialised diets like vegetarians, as well as elderly people and individuals in which gastric dysfunc- Table 1: Authorised health claims in the EU ac- tions (e. g., gastric atrophy and achlorhydria), cording to latest wording (status 01.01.2014) of are at higher risk of suffering from zinc defi- Art. 13.1 health claims list of Regulation (EC) ciency. No 1924/20061. Characteristics of > A wide – Normal function of the immune system vari ­ety of zinc salts are available for use in func- – Normal DNA synthesis tional foods, dietary supplements and – Role in the process of cell division products. The most common forms are zinc – Protection of cells from oxidative stress oxide, zinc sulphate and , the lat- – Maintenance of normal ter two (together with ) being re­ – Normal cognitive function commended by the WHO for use in syrups or – Normal fertility and reproduction dispersible tablets for diarrhoea treatment in in- – Normal macronutrient and fants. There are various properties that need to be – Normal acid-base metabolism considered when formulating with zinc salts. – Normal metabolism of A Taste and , in particular, limit the use – Normal metabolism of fatty acids of some compounds in specific applications. – Maintenance of normal vision However, costs and bioavailability are further – Maintenance of normal skin factors that need to be considered (Table 2). – Maintenance of normal hair – Maintenance of normal nails Table 2: Commonly used zinc salts approved – Normal synthesis for fortification in the EU according to Regula- – Maintenance of normal testosterone levels in tion (EC) No. 1825/2006. blood

Good dietary sources for zinc are primarily foods of animal origin, e. g., meat, , fish, as well as and . Concerning plant origin, high levels are reported for wholemeal products and . However, plant-derived zinc generally displays low bioavailability, as The recommended daily allowance (RDA) of intestinal zinc absorption is in many cases im- zinc is only 10 mg in the EU and the daily value paired by anti-nutritive factors like . (DV) is 15 mg in the US, so only small amounts The global prevalence of was are needed for typical formulations, thus estimated at 31 %, ranging from 4–73 % across making the usage of zinc very cost efficient. The sub-regions. Based on these estimates, zinc de- large variation of mineral content has a huge ficiency in children aged below five years was impact on dosage of the specific zinc form and estimated to cause 176,000 diarrhoea deaths, may thus provide some benefit on overall for- 406,000 pneumonia deaths and 207,000 ma- mulation cost. Additionally, for formulations laria deaths per year. Zinc deficiency is rather with limited space (e. g., multi-vitamin or multi-­ uncommon in populations with predominant- mineral formulations) compounds with high ly Western style nutrition because of the high zinc content may be preferred.

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Highly soluble salts like zinc sulphate, zinc relatively low solubility. However, trials in gluconate and zinc acetate have a strong me- the Jungbunzlauer Application Technology tallic, bitter and astringent taste that often Centre have shown that the addition of tripo- needs to be masked. Even at the typically low tassium citrate (or trisodium citrate) can in- dosage levels of zinc salts in fortified foods, crease its solubility and zinc citrate, or a these off-tastes can be noticeable. Particular- combination of zinc citrate and tripotassi- ly in the case of supplements or drug um citrate, results in significantly less bitter products like syrups and dispersible or effer- composition, compared to other soluble zinc vescent tablets, off-tastes can limit the appli- sources like zinc sulphate or zinc gluconate cability of these compounds. However, bet- (Table 3). ter tasting is insoluble and existing data indicates that its bioavailability is at the Bioavailability of zinc salts > Intestinal absorp- lower end of available zinc compounds. In tion of zinc and its adequate utilisation by the contrast to the oxide form, zinc gluconate body – in other words, the bioavailability – de- stands out for its high bioavailability, but its pends on several factors, such as the chemi- low zinc content makes this compound much cal form of the zinc salts, dietary factors and more expensive. An alternative zinc with physio ­logical condition (Table 4). promising sensory properties is zinc citrate. It has been demonstrated in animal and This compound has a high zinc content of human trials that absorbability is strongly 31 %, is slightly soluble in , is odour- related to the specific solubility of zinc com- less, and has relatively low costs. pounds in aqueous solution. Therefore, acidic Its usability in highly concentrated syrups inorganic zinc salts like zinc or zinc as well as in compounds for the beverage in- sulphate, which are very soluble in aqueous so- dustry has often been questioned due to its lution, show suffi­cient bioavailability, where-

Table 3: Taste ranking for bitterness for solutions containing 10 mg Zn2+ per 5 ml each; (Rank: 1= least pronounced bitterness). Values that do not share a common letter are significantly different (p < 0.05)

Zinc sulfate and zinc gluconate have further been described as having a strong metallic and astringent taste (Source: Internal tasting panel (n=10) at Jungbunzlauer Ladenburg GmbH, Germany)

Table 4: Factors affecting bioavailability of zinc

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as zinc absorption from the oxide or carbonate Figure 1: Detailed study procedure (the 3 dif- salt, which are practically insoluble in neutral ferent test supplements were administered in aqueous solution, is significantly lower. Zinc random order) salts with organic anions (zinc acetate, zinc lac- tate) and particularly with amino acid chelates like zinc histidine and other reversibly complex- ing anions (e. g., zinc gluconate or zinc citrate) are thought to have a generally higher bioavail- ability than zinc sulphate. However, human ab- sorption data to support the usage of zinc citrate has so far been very limited. BU: baseline urine; EU: enriched urine. (With kind permission of R. Wegmüller) From the published data on the absorption of zinc from supplements given to humans, it The study showed that there was a significantly would appear that zinc gluconate, zinc citrate, higher absorption of zinc from zinc citrate (me- and zinc sulphate are absorbed at a similar level, dian absorption 61.3 %; P = 0.006) and zinc glu- while zinc oxide is slightly less well absorbed. conate (median absorption 60.9 %; P = 0.009) In order to prove this assumption the ETH when compared with the one from zinc oxide Zurich, Switzerland recently compared the bio­ (median absorption 49.9 %), see figure 2. The availability of two assumed high bioavailable absorption of zinc citrate did not significantly salts (zinc citrate and zinc gluconate) with the differ from that of zinc gluconate. supposed lower bioavailable zinc oxide2. The One further interesting finding was that two goal of this trial was to use the double-isotope (one male, one female) of the 15 participants tracer ratio (DITR) method to compare the ab- did not absorb zinc from zinc oxide and one sorption of these three compounds when they further participant absorbed the zinc oxide at were given as supplements without food. This a low level (14 %). This suggests that there is a procedure is recommended to maximise zinc portion of the population that is not able to ab- absorption and is usually advised for the treat- sorb zinc in its oxide form. It was hypothesised ment of diarrhoea. The isotope tracer technique by the authors that these individuals cannot dis- which was used included the administration of solve zinc oxide in the gastric juice, probably two stable zinc isotopes (one orally and one in- travenously), followed by the quantification of Figure 2: Fractional absorption of zinc from the two isotopes in one spot urine sample four zinc citrate, zinc gluconate, and zinc oxide days later. supplements (n = 15) Fifteen adults were included in this ran- domised, double masked, 3-way crossover study, meaning each participant acting as his/her own control (Figure 1). Healthy male and female par- ticipants aged between 18 and 45 years were se- lected, who were not vegan, smokers, pregnant, or lactating. Zinc gluconate, zinc oxide, and zinc citrate were administered as supplements at a dose of 10 mg of zinc each and consumed with water. Each dose consisted of 9 mg of non-labelled and 1 mg of 67Zn-labelled zinc. Additionally, 70Zn-labelled (With kind permission of R. Wegmüller) ZnCl2 was used for intravenous administration.

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as a result of a high intragastric pH making it While a number of zinc salts are approved poorly absorbable. for the usage in food and food supplements, According to the authors, these results in- many of them have drawbacks regarding dicate that zinc citrate could be a useful com- taste, which limit their usage in taste sensi- pound for zinc supplementation. At the present tive applications or require extensive work time, the WHO recommends the use of the for masking them. Commonly used zinc highly-soluble compounds zinc sulphate, zinc oxide combines a relative low taste impact acetate or zinc gluconate in the form of syrups at a very low price. The assumed lower bio- or dispersible tablets in the management of di- availability was recently confirmed and the arrhoea. Zinc citrate might be a useful addition fact that some individuals can only absorb it to this list and be especially suitable for chew- minimally questions its general usage for zinc able/crushable tablets because it has better sen- fortification or supplementation. sory properties than zinc acetate, zinc sulphate, Zinc citrate combines formulation advan- and zinc gluconate, which have an astringent, tages like preferred sensory properties, relative- bitter, or metallic taste. In relation to price and ly low costs in use due to a high zinc content zinc content, zinc citrate would have an advan- of 31 % as well as sufficient solubility. Com- tage over zinc gluconate, because the costs per bined with the recently proven high bioavaila- kilogram of zinc are $ 30 vs. $ 78, respectively. bility (on the same level as zinc gluconate), this The advantage of zinc citrate over zinc sulphate makes zinc citrate a serious option for zinc-for- is related to its better sensory qualities and the tified foods and zinc supplements. higher zinc content of citrate (31 % vs. 23 %) at Zinc Citrate is part of Jungbunzlauer’s a similar price and presumably for a similarly Special Salts, which are functional minerals high absorption. mainly derived from citric acid or . The fully reacted products are manufactured in The authors conclude > “[…] our results indi- Europe by neutralisation of these acids with the cate that zinc is as well absorbed from zinc ci- appropriate alkaline calcium, magnesium, po- trate as from zinc gluconate and that zinc cit- tassium and zinc sources. The resulting organic rate should be as effective as zinc gluconate in minerals are known for their high bioavailabili­ the prevention of zinc deficiency and presuma- ty, and are used because of their ability to sup- bly also in the treatment of diarrhea. Its higher port human health in different applications of zinc content, good sensory properties, and low- food, beverage, dietary supplements or pharma- er price make it an attractive alternative to zinc ceutical products. gluconate and other water-soluble zinc com- pounds. Zinc oxide appears to be less well ab- 1EFSA; Register of questions http://registerofques- sorbed than other zinc compounds when given tions.efsa.europa.eu/roqFrontend/questionsList without food and may be minimally absorbed Loader?panel=NDA&foodsectorarea=26 by some individuals.” (2; p.136) 2Wegmüller et al. (2014) Zinc Absorption by Young Adults from Supplemental Zinc Citrate Outlook > Awareness of zinc and its various Is omparable with That from Zinc Gluconate beneficial effects on human health has grown and Higher than from Zinc Oxide. J. Nutr. 144: steadily in recent years. Its physiological ver- 132–136, 2014. satility, which offers various options for new Further references are available on request. product concepts, combined with its relative The Author: Markus Gerhart, Product Manager low cost in use, demonstrate why zinc is fore- Special Salts at Jungbunzlauer Ladenburg GmbH, casted to continue its growth within fortified Germany. E-Mail [email protected] foods and supplements. www.jungbunzlauer.com

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