FOOD ADDITIVES AND CLINICAL NUTRITION

II. FOOD ADDITIVES AND CLINICAL NUTRITION

A. Nutrition

The regulatory environment for food additives is subject to continuous change and evolu- tion; there are also significant differences in approach and detail between U.S. regulations and those developed, for examples, within the European Union. These are the subject of extensive discussion elsewhere in this book. In general, additives as defined by EU law provide a technological rather than nutritional function, whereas under U.S. law compo- nents described as additives may have a nutritional element. The long-running debate regarding the ‘‘additive’’ status of complex carbohydrates (such as inulin and oligosaccha- rides) highlights some of the difficulties which have been faced in this context.

B. Palatability

The primary function of a clinical nutrition product is its therapeutic or health maintaining performance. It is also crucially important that the product is designed to optimize compli- ance by individuals who may have a reduced appetite or interest in food. The main design criterion is to ensure that all nutrients and dietary supplements required for each particular medical condition are added to their functional level as indicated by clinical or physiologi- cal data. It is only once these constraints are met that the technologist can intervene to improve palatability and general acceptability. Nutritionally complete products for inborn errors of metabolism and a range of gastrointestinal derangements may have their protein requirements partially or wholly provided by amino acids or by protein hydrolysates. Amino acids have their own individual sensoric characteristics (1,2), while protein hydro- lysates often have characteristic bitter tastes.

In an amino acid–based nutritional product, these amino acids in the final, diluted, unflavored product are added well above their threshold level; the taste is therefore pre- dominantly a mixture of their sensoric characteristics. The unique flavor properties of L- glutamic acid (2) and the sulphurous persistent off taste of L-methionine (3) and L-cysteine (2) contribute toward an obnoxious, meaty lingering flavor profile and a predominantly bitter taste. It has also been suggested that a further reason for unpalatability of amino In an amino acid–based nutritional product, these amino acids in the final, diluted, unflavored product are added well above their threshold level; the taste is therefore pre- dominantly a mixture of their sensoric characteristics. The unique flavor properties of L- glutamic acid (2) and the sulphurous persistent off taste of L-methionine (3) and L-cysteine (2) contribute toward an obnoxious, meaty lingering flavor profile and a predominantly bitter taste. It has also been suggested that a further reason for unpalatability of amino

There are several ways in which a product of this type can be rendered palatable. (From a clinical point of view this is very important, since dietary compliance is more likely to be achieved if the product is pleasant tasting). These include

1. Addition of flavors and food acids

2. Chemical derivatization, substitution, and purification of key unpleasant tasting amino acids

3. Microencapsulation of key unpleasant tasting components

4. Addition of bitterness inhibitors

1. Addition of Flavors and Food Acids Most amino acid–containing products are flavored using sweet fruity notes. One reason

for this is that the addition of a sweetener helps to mask and reduce the bitter note which predominates in these products. One of the best tasting sweeteners on the market at present is aspartame (L-aspartyl-L-phenylalanine); however, its addition into products for phenyl- ketonurics is forbidden due to the phenylalanine element of the sweetener. In this case saccharin is added, which, with its bitter secondary note,is a far from perfect alternative. There has also been concern, especially in the United States, regarding possible carcino- genic effects of saccharin, based on early animal toxicity data. Intensity of flavor is the main criterion for choice of flavor.

The addition of food acids may also play an important role. Apart from the reported function of enhanced fruity taste (5), food acids also seem to play a pivotal role in improv- ing palatability. One such reason may be their reported ability to chelate metal ions (6). In this respect the acid could act as a shield in preventing the metal ion from reaching flavor receptors. DL-malic acid has been reported to reduce the intensity of off flavors and bitterness in soybean protein hydrolysates (7). It has also been reported that at pH 5.7,

7.5 mg of mercaptons renders formulations containing amino acids unpalatable, whereas at

a pH of 3.7, twice the level of mercaptons is required before the formulation becomes unpalatable (4). The specific taste characteristics of food acids differ considerably: whereas citric acid has an initial burst of acid taste, with intensity descending rapidly with time, DL- malic acid has been reported to have a taste profile which lingers far longer (5). This can

be used to the flavorist’s advantage: if both acids are added to the product, citric acid will help mask the initial burst of off flavor, while the malic acid will help mask the lingering aftertaste. As reported, the addition of sweetness and acidity will help mask bitterness (4).

2. Chemical Derivatization Substitution, and Purification of Unpleasant Amino Acids

Cysteine and methionine have sulfur-containing side chains resulting in taste profiles which are very odorous and lingering. Protection of these side chains by derivatization can lead to vast taste improvement. One example is N-acetyl-L-methionine, where the acetyl group blocks the sulfur groups passage to flavor receptors. This material has been approved for food use in the United States, where it is classed as an additive. However, it has been reported that other N-acetylated amino acids are poorly utilized in humans Cysteine and methionine have sulfur-containing side chains resulting in taste profiles which are very odorous and lingering. Protection of these side chains by derivatization can lead to vast taste improvement. One example is N-acetyl-L-methionine, where the acetyl group blocks the sulfur groups passage to flavor receptors. This material has been approved for food use in the United States, where it is classed as an additive. However, it has been reported that other N-acetylated amino acids are poorly utilized in humans

Glutamic acid has a meaty/acidic flavor, which is considered to have flavor-enhanc- ing properties in some situations. In cases where this is not so, its offensive taste can be removed by substitution with an alternative amino acid which can functionally replace glutamic acid on a nutritional basis. L-glutamine (4) has been offered as an alternative, although glutamine is susceptible to hydrolysis in aqueous solution and is therefore not suitable for liquid formulations (9).

3. Microencapsulation of Key Unpleasant Tasting Components The coating of functional food additives to change their diffusional properties, thus con-

trolling their release into the food matrix, is not a new idea (10). In clinical nutrition, one approach to improve palatability using encapsulation techniques is to coat offending molecules, such as amino acids, with a hardened fat or wax. Such a coating has to function as a physical barrier preventing the amino acids from contacting taste and flavor receptors. The fat used must therefore be insoluble in an aqueous solution, solid at oral cavity temper- atures, and degradable by stomach/intestinal enzymes. The fat matrix must also be imper- meable to the guest molecule. The use in clinical nutrition of fat coated amino acids has been limited, partly due to the expense of the raw material and its limited applicability (for example, the difficulty of stabilization in liquid products).

4. Addition of Bitterness Inhibitors There are many compounds which have been listed as potential bitterness inhibitors. How-

ever, as yet no food additive solely functioning as a bitterness inhibitor has been used in clinical nutrition products. This may be due to bitterness inhibitors being specific to one particular sapophore or the strictness in food regulations. Clinical nutrition products could

be classified into one category where a strong need for a bitterness inhibitor could be shown. One particular type of product which has earned a great amount of attention is the chemical group of compounds called cyclodextrins. These synthetic structures are able to form inclusion complexes with ‘‘guest’’ molecules. The most common cyclodextrins are α, β, and γ cyclodextrins, which consist of 6, 7, and 8 (1–4) linked α-D-glucosyl residues, respectively. The central cavity of the cyclodextrin is hydrophobic and it is this characteris- tic which enables hydrophobic guest molecules, such as amino acids (11) to become en- trapped within its ring structure.

One compound being used at present as a fruity flavor enhancer has also been re- ported as having bitterness inhibitor activity. This compound is ethyl maltol/maltol (E636, E635) and is at present being used in some flavoring preparations for synthetic diets in the management of inflammatory bowel disorders. It has been claimed to mask the bitterness associated with B complex vitamins and high intensity sweeteners (12).

a. Protein Hydrolysates. Protein hydrolysates are being used increasingly in clinical nutrition because of their superior absorption by deranged or dissected gut (13), although they are often exceedingly bitter and unpalatable. These are manufactured by the addition of proteolytic enzymes to a protein such as whey or casein, resulting in a mixture of peptides and free amino acids. Peptide size or range can be defined by the extent of hydro- lysis and choice of molecular separation techniques. Protein hydrolysates currently avail- a. Protein Hydrolysates. Protein hydrolysates are being used increasingly in clinical nutrition because of their superior absorption by deranged or dissected gut (13), although they are often exceedingly bitter and unpalatable. These are manufactured by the addition of proteolytic enzymes to a protein such as whey or casein, resulting in a mixture of peptides and free amino acids. Peptide size or range can be defined by the extent of hydro- lysis and choice of molecular separation techniques. Protein hydrolysates currently avail-

Proteolytic enzymes used for hydrolysate production are either endo- or exopepti- dases. Endopeptidases internally break down the protein molecule at specific amino acid sequence points, whereas exopeptidases split individual amino acids from the C- and N- terminal ends of the peptides, and show affinity for hydrophobic amino acids. The bitter- ness of hydrolysates is partly due to the formation of oligopeptides (1000–5000 daltons), but the hydrophobicity of the oligopeptide also plays a part: increased hydrophobicity leads to increased bitterness. Enzyme combinations have been devised which specifically contain large amounts of exopeptidases to produce less bitter hydrolysates (14). In princi- ple, palatability may be further improved by the application of the plastein reaction, in which amino acids are linked onto peptides, but the cost of this process at present renders it uneconomic.

Currently, there is no community-wide EEC legislation on the use of enzymes for food processing and the regulation of these products as food additives or processing aids varies on a country-by-country basis.

C. Manufacture

The majority of clinical nutrition products are considered most presentable for dietitians/ patients in the form of either a ready-made drink or as a powder to be dissolved in water. Due to the inherent insolubility of amino acids such as tyrosine, cystine, histidine, and glutamine (15) there is a need to study ways in which elemental diets and PKU diets can

be made more appealing by improving the solubility of individual components without compromising the nutritional efficacy of the product. For example, tyrosine’s inherent insolubility (0.045g/100 mL of water at 25 °C) causes problems when designing products for PKU patients. Tyrosine is an essential component of the diet as it replaces nutritionally the phenylalanine, which is toxic to PKU sufferers.

More soluble alternatives for tyrosine, glutamine, and histidine can be added. In the case of glutamine, it has been known for some time that this amino acid represents an important fuel for the cells lining the gastrointestinal tract (16), and there is a perceived requirement to supplement glutamine in many enteral feeds. However, as discussed earlier, the possibility of glutamine incorporation into a ready-made drink is limited due to its tendency to undergo quantitative aqueous hydrolysis with formation of cyclic products and ammonia (9), and reported limited solubility. Thus it has been recommended that to avoid the risk of precipitation, glutamine concentrations in feeding solutions should not exceed 1–1.5% (8). Options for amino acid derivatives include use of the hydrochloride form or conversion to the ester. They are claimed by the author to be biologically safe and available for absorption. However, currently this approach is little used. Alternatively soluble peptide could be used. This route is normally very expensive as well as increases the bitterness of the final product. As yet, no satisfactory solution has been offered.

Emulsifiers are also used to stabilize the emulsion of any essential fats added into the formula. The absence of protein, which contributes to emulsion formation in other circumstances, presents particular challenges in amino acid–based systems.

1. Osmolarity The osmolarity of products designed for clinical applications is a matter of some impor- 1. Osmolarity The osmolarity of products designed for clinical applications is a matter of some impor-

Although administration of hyperosmolar solutions has been associated with adverse symptoms such as ‘‘osmotic’’ diarrhea, this can often be overcome by appropriate dilution or slowing down of the rate of administration of the feed. It should be borne in mind that the normal digestive process will naturally break down protein to smaller components in the gut, and it may not be simply product osmolarity which is the significant factor in this.