WO2014209106A1

WO2014209106A1 - Induced viscosity fibre system for the treatment or prevention of gastro-oesophageal reflux (gor)

Info

Publication number: WO2014209106A1
Application number: PCT/NL2013/050448
Authority: WO
Inventors: Fabien Naomie BELLE; Leunis Forrinus Harthoorn; Paul Venema; Wai Ming Claudia CHOI
Original assignee: Nutricia NV
Current assignee: Nutricia NV
Priority date: 2013-06-24
Filing date: 2013-06-24
Publication date: 2014-12-31
Anticipated expiration: 2015-12-24
Also published as: EP3013156A1

Abstract

The invention pertains to the use of pectin and alginate in the manufacture of a liquid nutritional composition in the treatment or prevention of gastro-oesophageal reflux in a patient, said composition comprising pectin and alginate, said composition exhibiting a maximum gel strength at a pH in the range between 3.5 and 5, said gel strength expressed as storage modulus G' between 200 and 10,000 Pascal. A combination of low methylated pectin and (sodium) alginate was found to have the strongest thickening effect directly after entry in the stomach, which initial increase in viscosity (at the beginning of the stomach)is decreased later when the pH becomes lower than 4 (i.e. the pH at the end of the stomach). This decrease in viscosity at the lower part (antrum and pylorus) of the stomach stimulates the gastric emptying time of the food consumed.

Description

Induced viscosity fibre system for the treatment or prevention of gastro-oesophageal reflux (GOR)

Background of the invention

Gastro-oesophageal reflux is a chronic symptom of mucosal damage caused by gastric acid coming up from the stomach into the oesophagus. Feeding patients with enteral nutrition (tube or sip feed) may result in gastro-oesophageal reflux disease (GORD). This is particularly a problem with feeding neurologically impaired patients where the swallowing reflex is disturbed or other problems exist with retaining the food in the stomach.

Between 30 and 45% of neurologically disabled children, e.g. children with Cerebral Palsy (CP), have faltering growth and undernourishment, while growth is a proxy marker for health and social well-being. The cause of poor growth in these CP children is complex and influenced by many factors. CP is characterised as a permanent disorder of muscle control or coordination resulting from non-progressive disturbances in brain development of the infant.

An important contributing factor to poor growth is an imbalance between nutritional

requirements and actual intake due to oromotor dysfunction. Oromotor dysfunction leads to prolonged and difficult feeding times and has a huge impact on convenience and quality-of-life of both the child and caregiver. Gastrointestinal motility is affected by the impaired neurological status and consequently results in more swallowing difficulties (dysphagia) and gastro- oesophageal reflux (GOR: regurgitation of gastric content into the distal oesophagus), which negatively impacts food intake and worsens nutritional status. The incidence of GOR among CP children ranges from about 30 to 75%. Furthermore, tone and involuntary movements can increase energy needs by up to 10%, however, total energy expenditure is typically near to or lower than predicted by age and weight.

Depending on the severity of the underlying condition (i.e. at different stages of dysphagia) and impairment of the nutritional status in CP children, enteral tube feeding (both naso-gastric (NG), percutaneous endoscopic gastrostomy (PEG) and transpyloric) has shown benefits over oral feeding and has become a major strategy to manage and overcome CP -related malnutrition, failure to thrive, unsafe swallowing and severe oral aversion, and to improve quality-of-life in this target group of children with neurologic impairment. However, also in tube fed children the occurrence of gastro-oesophageal reflux is still high. Reflux episodes not only cause

gastrointestinal symptoms, such as episodes of regurgitation or vomiting, haematemesis, and reflux oesophagitis, but also respiratory problems, such as recurrent respiratory infections, persistent cough, life-threatening apnoeic episodes, and respiratory failure during fairly minor respiratory infections. Without intervention, chronic GOR can contribute to respiratory problems, such as recurrent pneumonias, persistent cough, life-threatening apnoeic episodes, and even respiratory failure if refluxed material is being aspirated. Respiratory problems play a major role in the quality-of-life and life expectancy of these children.

Thickening food to prevent GOR has been suggested for infants. For example Nutrilon AR is an infant formula thickened with locust bean gum specifically designed for babies with reflux problems. The prior art describes also the use of pre-thickened food using pectin for the treatment of GOR in cerebral palsy patients. [Effects of pectin liquid on gastro-oesophageal reflux disease in children with cerebral palsy, Reiko Miyazawa et al. BMC Gastroenterology 2008, 8: 11].

The problem with these pre-thickened foods is that their composition is not suitable for consumption through a straw (sip feed) or administration through a tube using a standard pump due to the high viscosity of these pre-thickened foods. In addition, it is known that the use of thickeners has a satiating effect and results in increased gastric emptying times. This is an unwanted side effect in the treatment of GOR(D) with thickeners. Nishiwaki et all (J Parenter Enternal Nutr. 2009;33 : 513-519) suggests that there may be a relation between GOR and the viscosity of percutaneous endoscopic gastrostomy tube feeding. While it is suggested that although semi-solid nutrition may improve the GOR symptoms, it has the problem of decreased gastric distribution and decreased gastric emptying times. Therefore, there still is a need for improving the nutritional compositions of the prior art for use in the treatment of GOR(D), with less or without any unwanted side-effects such as decreased gastric distributions and without disadvantageously affecting gastric emptying times. Summary of the invention

The inventors surprisingly found that a combination of low methylated pectin and (sodium) alginate has the strongest thickening effect directly after entry in the stomach, and which initial increase in viscosity at the beginning of the stomach is decreased later when the pH becomes lower than 4 (i.e. the pH at the end of the stomach). This decrease in viscosity at the lower part (antrum and pylorus) of the stomach advantageously stimulates (i.e lowers) the gastric emptying time of the food consumed.

A preferred embodiment according to the invention is a liquid nutritional composition comprising pectin and alginate, for use in improving gastric emptying time and/or for use in the treatment or prevention of gastro-oesophageal reflux and gastro-oesophageal reflux disease. The pectin and alginate provide a controlled thickening effect in stomach conditions. Worded differently, a preferred embodiment according to the invention relates to the use of pectin and alginate in the manufacture of a liquid nutritional composition for improving gastric emptying time and/or in the treatment or prevention of gastro-oesophageal reflux and gastro-oesophageal reflux disease. Also, the invention pertains to a method for improving gastric emptying time and/or for treating or preventing (i.e. reducing the risk of) gastro-oesophageal reflux and gastro- oesophageal reflux disease in patient, said method comprising administering a liquid nutritional composition comprising pectin and alginate. In a preferred embodiment, the above composition is a tube or sip feed (nutritional supplement), preferably a tube feed. The pectin preferably comprises or consists of low-methylated pectin; the alginate preferably comprises or consists of alginate with monovalent counterions, more preferably sodium alginate.

In a preferred embodiment the composition has a gelling behaviour expressed as storage modulus G' between 200 and 10,000 Pascal. In a preferred embodiment according to the invention the composition further comprises a non-coagulating protein that does not coagulate in the stomach. Preferably the non-coagulating protein is selected from the group consisting of whey protein, pea protein and soy protein, and combinations thereof. In a preferred embodiment according to the invention the composition is low in casein, preferably comprising less than 50wt% casein based on the total protein content, and preferably casein is used in combination with one or more non-coagulating protein selected from the group consisting of pea, soy and whey. In the context of this paragraph, the term 'casein' includes micellar casein and caseinates.

List of embodiments

1. Use of pectin and alginate in the manufacture of a liquid nutritional composition in the treatment or prevention of gastro-oesophageal reflux in a patient, said composition comprising pectin and alginate, said composition exhibiting a maximum gel strength at a pH in the range between 3.5 and 5, said gel strength expressed as storage modulus G' between 200 and 10,000 Pascal.

2. Use according to embodiment 1 , wherein the storage modulus G' of the composition is between 200 and 7500 Pascal, preferably between 350 and 5000 Pascal.

3. Use according to embodiment 1 or 2, wherein the patients are infants or children with or at risk of faltering growth.

4. Use according to any of the preceding embodiments, wherein the patients are neurologically disabled, including cerebral palsy patients.

5. Use according to any of the preceding embodiments, wherein the storage modulus G' of the composition increases to at least 125% of the original value at pH 6, when the pH decreases from about pH 6 to about pH 4.

6. Use according to any of the preceding embodiments wherein the storage modulus G' of the composition decreases going from pH 4 to pH 2.

7. Use according to any of the preceding embodiments, wherein the weight ratio pectin: alginate is at least 1, preferably between 1 and 3.

8. A liquid nutritional composition comprising protein, digestible carbohydrates, optionally fat, and a viscosity or gelling fibre system consisting of pectin and alginate, wherein pectin is present in a concentration between 0.1 mg/ml and 10 mg/ml, and alginate is present in a concentration between 0.1 mg/ml and 1 mg/ml. 9. The composition according to embodiment 8 wherein the protein comprises a non- coagulating protein source selected from whey, soy, pea, hydrolysed proteins, and combinations thereof.

10. The composition according to any of the embodiments 8 - 9, wherein the energy content is at least 0.7 kcal per ml.

11. The composition according to any of embodiments 8 - 10, comprising protein, fat, digestible and indigestible carbohydrates and nucleotides wherein the composition has

a. an energy density of 0.7-2.0 kcal/ml; and

b. a protein component providing at least 9 % of the total calories; and

c. between 0.1 - 5 wt% long chain polyunsaturated fatty acids based on total fatty acids in the composition; and

d. between 0.2 - 0.4 wt% indigestible carbohydrate based on the dry weight of the composition; and optionally

e. at least 3 nucleotides selected form the group consisting of cytidine 5'-monophospate (CMP), uridine 5'-monophospate (UMP), adenosine 5'-monophospate (AMP), guanosine 5'-monophospate (GMP), and inosine 5'-monophospate (IMP) present in an amount of at least 1.10-4 wt% based on the dry weight of the composition.

12. The composition according to any of embodiments 8 - 11, wherein the weight ratio pectin: alginate is at least 1, preferably between 1 and 3.

13. Use of a composition according to any of embodiments 8- 12 as tube feed or sip feed.

14. A liquid nutritional composition comprising pectin and alginate, said composition exhibiting a maximum gel strength at a pH in the range between 3.5 and 5, said gel strength expressed as storage modulus G' between 200 and 10,000 Pascal, for use in the treatment or prevention of gastro-oesophageal reflux in a patient.

Detailed description of the invention

Many patients suffer from malnutrition. It is estimated that about 1 in 4 adult patients in hospital are at risk of malnutrition or are already malnourished. More than 1 in 3 patients in care homes are malnourished or at risk of malnutrition, as many as 1 in 3 older people living independently are at risk of malnutrition, and almost 1 in 5 children admitted to Dutch hospitals have acute or chronic malnutrition. The malnutrition in these groups is often treated with specialized medical foods, in the form of sip feeds or tube feeds e.g. if the patients are unable to swallow properly. The invention pertains to provide treatment to both infants and adults (e.g. elderly patients), particularly those addressed here above who are in need of such treatment. Gastro-oesophageal reflux (GOR) is often seen during nutritional treatment with liquid nutrition and may also occur after sip or tube feed consumption. GOR is particular prominent in patients with dysphagia and/or neurodisabilities (e.g. cerebral palsy). Hence, in one embodiment, the patient suffering from or is at (immediate) risk of developing dysphagia and/or neurodisabilities such as cerebral palsy. Without being bound by theory the inventors believe that inappropriate functioning of the oesophageal sphincter allows fluids from the stomach to flow back

(regurgitation) causing the reflux reflex, expulsion of gastric content or even vomiting.

Thickened nutritional products are conjectured to give some relief to patients suffering from GOR. However, knowing that so many patients need enteral nutrition, e.g. sip or tube nutrition, the problem solved by the invention is to design a product that is a low-viscosity liquid product when consumed through a straw or tube, and instantly increases viscosity when entering the stomach, while at the same time this increased viscosity should not lead to a longer gastric emptying time. An increase in gastric emptying time is associated with an increase in GOR.

If gastro-oesophageal reflux (GOR) persist for a longer time, this may lead to gastro-oesophageal reflux disease (GORD), characterised by mucosal damage in the oesophagus. In a preferred embodiment the composition according to the invention is for use in the treatment or prevention of GOR and/or GORD. In one embodiment, the composition is for use in improving gastric emptying in a patient suffering from or at risk of GOR and/or GORD. Thickeners

The rheological behaviour of hydrocolloids can be modified by changing pH value, ionic strength, and protein concentration. Because of the viscosity limitations of enteral feeding tubes, opportunities lie in the acid-induced thickening or gelation of hydrocolloids. The food system remains fluid at neutral pH, but shows partial solid-like (elastic) behaviour upon acidification in the stomach. A network is formed by chains connected to each other by non-covalent and covalent bonds in which water is entrapped. The thickness of gels is usually described by viscoelastic properties, which describe the ability of a system to react to an applied stress, by partially storing the corresponding energy in the network. This elastic response is measured by the storage modulus (G'), whereas part of the energy is also lost (loss modulus, G") due to viscous dissipation. When the elastic energy (G') is larger than the viscous dissipation (G"), the system is a gel by definition. Unless indicated otherwise, G' and G' ' are determined at 20 °C.

The composition of the invention preferably comprises pectins. Pectins are carbohydrates generally obtained from dilute acid extracts of citrus or apple pulp. Besides that they are also present in the cellular walls of vegetables and fruits as well as in root crops (carrots and beetroot) and tubers (potatoes). The general structure of pectins is a main chain of homogalacturonan ((l,4)-a-D-galacturonic acid units) and rhamnogalacturonan, with side chains of arabinan, galactan, or arabinogalactan. The exact chemical composition and molecular weight varies among sources. Another varying factor that has large influence on interactions is the degree of esterification (DE). Galacturonic acids may be esterified with methyl (-CH3) or acetyl (- COCH3) groups. Most commonly, a distinction is made between high methylated (HM) pectin and low methylated (LM) pectin, with a degree of methylation (DM) of >50% and <50%, respectively. High methylated pectin is commonly used for its ability to gel in foods with a sugar content higher than 55% and a pH below approximately 3.5, whereas LM pectin is used for gelling with divalent cations (mainly calcium). To change their physical properties, pectins are often modified, such as in degree of substitution and charge density. In the present invention, the composition preferably comprises at least low-methylated (LM) pectin, ie. Pectin with a degree of methylation of less than 50 %. The degree of polymerization is preferably in the range of DP 15- 1000. The composition preferably also comprises an alginate salt, preferably sodium alginate. In the context of the invention, alginates are desired because of their pH-dependent gelling behaviour. Alginate could be regarded as a true block copolymer composed of homopolymeric regions of mannuronic acid (M) and guluronic acid (G), termed M- and G-blocks, respectively, interspersed with regions of alternating structure ('MG'). Its building blocks mannuronic acid (M) and guluronic acid (G) have pKa values (acid dissociation constants) of 3.38 and 3.65, respectively. The pKa value of the alginate polymer will vary slightly, depending on the monomeric residue composition. Below this pKa value (approx. pH 3.5), gelation will take place, but the exact gelation behaviour does not just depend on pH, but also on the amounts of divalent ions present in the composition. Blocks of guluronic acid (G-blocks) participate in the formation of 'egg-box' models with divalent ions similar to LM pectin to form a gel.

Surprisingly, a synergistic gelation effect has been found when alginate and pectin are mixed in the context of the invention, enabling gelling in absence of calcium ions or in systems with high water activity. Without being bound by theory, the inventors believe this effect is based on interactions between G-blocks of alginate and methylated parts of pectin, preferably present in low-methylated pectins. Preferably the weight ratio pectin: alginate is at least 1, preferably between 1 and 10, more preferably between 1 and 8, more preferably between 1 and 5, even more preferably between 1 and 2.5, even more preferably between 1.5 and 2.5, most preferably between 1.8 and 2.2 especially at about 2. These ranges give the optimal increase in storage modulus (see example 8). The above weight ratios and ranges particularly apply to pectin being low-methylated or LM pectin, the alginate being alginate having monovalent counterions, more preferably sodium alginate.

In addition to the pectin and alginates in the aforementioned ratios, the composition may comprise additional fibres, for instance to further increase viscosity levels. As example 2 indicates, such additional fibres will not affect the acid-induced gelation effect observed for the mixture of hydrocolloids of the invention, with optimum gelling at or around pH 4. The fibres do not substantially change the maximum gelling effects in the range between pH 3 and 5, preferably between 3.5 and 5, more preferably at about pH 4 - 4.5 which are due to the hydrocolloid mixture according to the present invention. The advantageous decrease in gelling towards pH 2 is maintained. If additional fibres are present, it is preferred that the amounts of additional fibres is less than 5 g/lOOml, preferably at least 0.05 g/100 ml but less than 5 g/100 ml.

Although many hydrocolloids are used to stabilise a food system, the addition of polysaccharides to milk proteins may often result in undesirable ingredient interactions. Phase separation between the aqueous phase and polymers (or polymer complexes) may happen when e.g. attraction between protein - polysaccharide is stronger than between protein - protein and polysaccharide - polysaccharide. For example segregative phase separation may occur, caused by

thermodynamic incompatibility of different biopolymers. Heat treatments may further enhance these interactions by lowering kinetic barriers. An enteral feed with a shelf-life of one year should not show instabilities such as phase separation or flocculation, as it may be visually unappealing to users or cause tube occlusion. Especially since enteral feed is generally administered over a longer time span (i.e. 1.25 - 5 h for one pouch of 500 ml), nutrients should be delivered homogeneously to prevent hyperosmolar gastric content. In view thereof, in the search for an optimal blend or mix of hydrocolloids in a nutritional matrix comprising dairy proteins, wherein such hydrocolloids have a strong thickening effect in the beginning (pH 5 - 4) and decreased thickening at the end of the stomach (pH 4 - 2) the inventors surprisingly found that nutritional compositions comprising a mixture of pectin and alginate as described above have the required effect in a model system, See Example 2.

Gelling and Viscosity

To get an estimate for the viscosity, a consistometer was used before and after acidification. In this method the distance the thickened fluid travels across a plate in a standard time (Adams and Birdsall, 1946) is taken as a measure for the viscosity. Measurements were made with an Adams consistometer suited in the field of rheology to straightforwardly measure diameter of spreading or consistency of semifluid foods. The Adams consistometer method involves a cone containing a defined sample volume which is placed in the center of a sheet with concentric circles, with a 5 mm scale, and lifted. The extent of flow or distance of spreading at four equidistant points on the disk is recorded 30 seconds after vertically raising the cone. The four values are averaged, and this average value represents the consistency of the product. The entire measurement is carried out in duplicate. The Adams consistometer measurements are typically indexed (as a measure of viscosity, spreading or consistency) as X = 100 / (averaged distance of spreading). The measurements are preferably carried out at use conditions, preferably 20 °C. In a preferred embodiment, the viscosity or spreading [according to the Adams consistometer index] at pH 4 is significantly higher than that observed at pH 2 and pH 6. The Adams consistometer index preferably decreases with more than 50 % going from pH 6 to pH 4, and preferably the index at pH 2 is lower than the index at pH 4, more preferably ranges between the index measured at pH 4 and pH 6. The alginate and pectin as discussed in detail here above are therefore present in amounts resulting in viscosity or spreading requirements as defined here above. The thickness of gels may be described in terms of viscoelastic properties, which describe the ability of a system to react to applied stress, thereby storing part of the applied energy in the form of recoverable elastic deformation of the gel. In the field, such viscoelastic behaviour is measured as the storage modulus (G'), whereas part of the energy is also lost (loss modulus, G"). When the elastic modulus (G') is larger than the viscous modulus (G"), by definition the system is considered a gel. As in the examples, viscoelastic properties during acidification may be determined by measuring the storage modulus (G'), the loss modulus (G"), and the loss tangent (tan δ = G'VG') with small deformation oscillatory measurements. Such measurements are considered to fall within the ambits of the skilled person routine experimentation skills, for instance using a controlled stress rheometer (Physica MCR 301, Anton Paar, Austria) with a concentric cylinder or a titanium double gap geometry (Anton Paar, Austria). In the context of the invention, G' and G" are measured at 20°C. As guidance to the skilled person, G', G", and tan delta measurements could be reproducibly carried out using a sample recovery period of 5 min in the geometry, to allow structure recovery and temperature equilibrium. For

reproducibility, small-deformation oscillatory measurements may be performed for 10 min, in which G' and G" were recorded every 2 sec (strain deformation of 0.1%, at a frequency of 0.1 or lHz). In the context of the invention, 'gel formation' is defined when G' is larger than G" (a 'gel' thus implies that G' is larger than G"); stronger gels having a lower tan δ value.

In a preferred embodiment the nutritional composition according to the invention has a storage modulus (G') that is higher at about pH 4 than at about pH 2. Preferably the G' at pH 4 and at 20 °C is at least 200 Pa, preferably between 200 and 10,000 Pascal, even more preferably between 250 and 7,500 Pa. In terms of absolute values, the storage modulus G' at 20 °C is preferably between 200 and 7,500 Pascal, preferably between 350 and 5,000 Pascal. However, these absolute numbers should be treated with care as the actual G' values are affected by various other ingredients which may be present in the composition, such as minerals and fibers. Reference is made to examples 7 and 8 attached. The alginate and pectin are thus preferably present in the composition in amounts effective to obtain the above-defined storage modulus.

The hydrocolloid mixtures according to the present invention particularly contribute in terms of introducing acid-induced (pH-dependent) gelling behaviour. It is preferred that the storage modulus G' of the composition of the invention decreases going from pH 4 to pH 2, and preferably G' decreases over this range with at least 10 %. Additionally or alternatively, preferably additionally, the storage modulus G' of the composition will at least increase to 125% (of the original value at pH 6) when the pH decreases from about pH 6 to about pH 4. At these G' values the products are expected to have an optimal effect on GORD, because of the benefits of such pH-dependent behaviour in stomach conditions. The alginate and pectin are thus preferably present in the composition in amounts effective to obtain the above-defined storage modulus. While the alginate and pectin are preferably present in amounts effective to obtain any if not all of the above effects, it is preferred that the sum of alginate and pectin present in the composition is at least 0.1 wt%, more preferably 0.1 - 10wt%, even more preferably 0.1 - 8 wt%, more preferably 0.1 - 5 wt%, most preferably at least 0.15 - 5 wt%, in terms of total weight of the composition. However, as said above, the actual amounts could readily be determined by the skilled person taking the above into account, also considering other components. Additionally or alternatively, pectin is preferably present in a concentration between 0.05 and 10 mg/ml, preferably between 0.08 and 10 mg/ml, more preferably between 0.1 mg/ml and 10 mg/ml, preferably between 0.2 - 8 mg/ml, more preferably 0.3 - 5 mg/ml;, and alginate is present in a concentration between 0.05 and 3 mg/ml, preferably between 0.05 and 1 mg/ml. In one embodiment, the alginate is preferably present in a concentration between 0.1 mg/ml and 3 mg/ml, more preferably 0.1 - 1 mg/ml, even more preferably 0.2 - 1 mg/ml , most preferably 0.3 - 1 mg/ml. The above weight amounts and ranges particularly apply to pectin being low- methylated or LM pectin, the alginate being alginate having monovalent counterions, more preferably sodium alginate. Protein

Coagulation of proteins in the upper gastro-intestinal tract, in particular in the stomach is hypothesized to delay gastric emptying. This can result in upper gastrointestinal complications like reflux, gastrointestinal discomfort, retching and aspiration pneumonia. It has been found that in particular nutritional compositions in which the protein fraction predominantly contains or consists of casein and/or caseinate tend to coagulate under conditions in the stomach.

In cases where it is advantageous for subjects to receive easily digestible nutrition it is desired to administer such a nutrition that does not result in too much coagulation of proteins in the stomach. Controlling digestive coagulation of proteins is preferably established for those subjects wherein it is desired to prevent or reduce upper gastrointestinal conditions or complications such as, e.g. intestinal discomfort, reflux, aspiration pneumonia, high gastric residual volume (GRV), vomiting, nausea, bloating, and delayed gastric emptying, or to make it easily digestible in order to promote digestive comfort, reduce gastrointestinal cramping or colics.

Since in the present invention the viscosity is preferably caused by the dietary fibres, in a preferred embodiment the proteins of the present invention comprises an anti-coagulating protein source, i.e. a protein source that does not coagulate upon acidification in the stomach. Anti- coagulating proteins for example are selected from non-dairy proteins, preferably from vegetable and/or fungal proteins and combinations thereof. Suitable proteins are for example selected from plants such as from rice and wheat, legumes, including beans, lentils, pea and soy, and fungi such as mushrooms or yeast. In the context of this invention "vegetable" relates to protein from plant origin, such as, for instance originating from vegetables such as carrot, pea, chickpea, green pea, cowpea, field pea, kidney bean, lupine, rice, soy, canola, hemp, zein, maize, corn, barley, flax, linseed, and wheat. Equivalent wording may be used, such as "vegetal", "leguminous" or "plant-derived".

Preferably the anti-coagulating protein is selected from pea and soy or a combination thereof. In one embodiment, the protein fraction comprises between 1 and 100 wt% of the sum of pea and soy protein, preferably between 2 and 100% and even more preferably between 4 and 100%, based on the total weight of all proteinaceous matter present in the composition. In a preferred embodiment, the protein fraction - in terms of total protein weight - comprises at least 2 %, more preferably 4 - 80 %, more preferably 6 - 60 % pea protein.

It is also envisaged that hydrolysed dairy or milk protein, in particular hydrolysed casein can act as an anti-coagulating protein. Thus in one embodiment, the anti-coagulating protein is selected from hydrolysed dairy protein, hydrolysed milk protein, hydrolysed whey protein, hydrolysed casein, hydrolysed caseinate or combinations thereof.

Uses

Sick infants and children that need to be fed by tube often suffer from gastro-oesophageal reflux problems. The composition according to the present invention will lead to a decrease in GOR because of the thickening effect in the stomach, while at the same time the composition has a sufficiently low viscosity to be used for tube feeding. A preferred embodiment is the use of the composition according to the claims as a tube feed, preferably for infants.

Infants requiring nutritional support present unique challenges, not only because of their high nutrient requirements for growth, development and organ maturation, but also because of their small body reserves. Infants have fewer body reserves of all nutrients than adults, particularly energy, and these resources can be depleted rapidly during acute and chronic disease. Tissue wasting to meet energy demands proceeds much more rapidly in infants than in older children and adults, which makes them particularly susceptible to the effects of starvation. It has been estimated that an adult has sufficient body reserves for approximately 70 days, compared with 4 days in a preterm baby and 31 days in a full-term baby. The infant preferably has an age up to 4 years of age, more preferably up to 2 years of age, more preferably up to 1 year of age. These infants are particularly at risk of GOR(D) or consequences thereof. Throughout the application, the terms 'infants' and 'children' are used interchangeably.

During acute and chronic disease infants have specific nutritional requirements and often suffer from faltering growth. Therefore these infants will need extra nutrition to compensate for the lack of growth which should have taken place during disease. Normally this is done by giving extra energy. Since infants don't drink large volumes the energy is provided in concentrated drink formula, typically comprising at least 0.75 kcal/ml. These infants also suffer from GOR making it difficult to feed sufficient quantity. A preferred embodiment of the present invention is the composition according to the present invention for use in the treatment of infants with or at risk of faltering growth and for inducing catch-up growth in these infants. The treatment includes the nutritional management of the same patients group.

In one embodiment, the invention relates to malnourished patients, preferably hospitalized human patients, more preferably hospitalized adult humans. It is estimated that about 1 in 4 adult patients in hospital are at risk of malnutrition or are already malnourished. More than 1 in 3 patients in care homes are malnourished or at risk of malnutrition, as many as 1 in 3 older people living independently are at risk of malnutrition, and almost 1 in 5 children admitted to Dutch hospitals have acute or chronic malnutrition. The malnutrition in these groups is often treated with specialized medical foods, in the form of sip feeds or tube feeds e.g. if the patients are unable to swallow properly. In one embodiment, the patient is an elderly patient, preferably a person of at least 45 years of age, more preferably of at least 50 years of age, most preferably of at least 55 years of age.

In one embodiment, the patients are neurologically disabled, including cerebral palsy patients. Examples

Example 1. Induced viscoelastic properties of selected fibre compositions

A low-energy, fibre-containing ready-to-use enteral feed was used as the model product for all thickened enteral feeds (Nutrini Low Energy Multi Fibre, Nutricia, Zoetermeer). Hydrocolloids used were: low methylated and partially amidated pectin (DE~27%, DA~20%; 104-AS-Z, CP Kelco) and sodium alginate (Manugel LB A, FMC Biopolymer), here below addressed as 'LMP' and 'NaAlg', respectively. Concentrations of the selected hydrocolloid blends were between 0.2 and 0.3% w/v. For the specific concentrations and ratios of the blends, see Figure I. To obtain the thickened samples, hydrocolloids were directly dispersed into the model product under continuous stirring for 10 min at 65°C. For the first screening, acidification to pH 2 (± 0.2) was done by drop-wise addition of 1 M hydrochloric acid (HC1) under continuous slow stirring. The thickeners and combinations of thickeners tested are listed in Figure 1.

As an estimate for viscosity, a consistometer was used before and after acidification to measure the distance of spreading at 20°C. Measurements were made with an Adams consistometer suited in the field of rheology to straightforwardly measure diameter of spreading of semifluid foods. The Adams consisotmeter involves a cone containing a defined sample volume which is placed in the center of a sheet with concentric circles, with a 5 mm scale, and lifted. The extent of flow or distance of spreading at four equidistant points on the disk is recorded 30 seconds after vertically raising the cone. The four values are averaged, and this average value represents the consistency of the product. The entire measurement is carried out in duplicate. Viscosity is indexed by dividing 100 by the average distance of spreading. The results for the specific viscosity (100/distance of spreading) and the percentage increase of initial viscosity for the different combinations hydrocolloids are reported in Table 1.

Table 1. Viscosity (100/average distance of spreading) at different pH

Hydrocolloids (concentrations in %w/v) pH6.8 pH4-4.5 pH about 2

NaAlg* I M P** (0.1 0.1 ) 2 4 3 S ( M %) 3. 1 (3 1 %)

NaAlg/LMP/LBG^A (0.08/0.08/0.1) 2.4 4.2 (68%) 3.5 (43%)

Na.Mg I .M P (11.08 0.08 0.1 ) 2.4 .v ^"( 2° o) 3.4 (35%)

Viscosity and percentage increase of initial viscosity at pH about 6.8 for hydrocolloid blends in Nutrini LE MF (% w/v) acidified with 1 M HC1 to pH 4 - 4.5 and pH 2; * NaAlg = sodium alginate; ** LMP = low methylated pectin; ^A LBG = locust bean gum; ^AA GG = guar gum

An unexpected finding was an increase in viscosity around pH 4, followed by a gradual decrease upon further acidification to pH 2. This was observed for blends with LM pectin and Na alginate, and was more pronounced for the latter. LM pectin at a concentration of 0.1% (w/w) in combination with 0.1% guar gum could establish a viscosity increased by 60.0% at pH about 4 and 39.4% at pH about 2. Furthermore, at a concentration of 0.1% (w/v), Na alginate in several combinations gave a viscosity of 50.9 - 61.6 % at pH 4. As before, the increased viscosity effect diminished with further acidification towards pH 2. As shown in the table, the increase at pH 4 and the decrease at pH 2 observed for the mixture of NaAlg and LMP are similar when additional fibers such as LBG and GG are added.

Example 2 Glucono-5-lactone (GPL) acidified compositions gives optimal result for

NaAlg/LMP mixture

Similar hydrocolloids and enteral feed were used as in the first screening, see Example 1.

Hydrocolloids were dispersed in 104.5 g (100 mL) ready-to-use enteral feed at continuous mechanical stirring (low setting) at room temperature for 15 min. Concentrations of the selected hydrocolloid blends were again between 0.16- 0.26% w/v. For the specific concentrations and ratios of the blends, see Table 2.

Table 2 Composition of selected hydrocolloid blends in %w/v per ingredient and in total.

# Hydrocolloid (% w/v) Total (% w/v)

1 Sodium 0.08 LM pectin 0.08 0.16 alginate

2 Sodium Guar gum 0.16 0.24 alginate

Sodium 0.08 Locust bean 0.24 alginate

4 LM pectin 0.08 Guar gum 0.10 Sodium alginate 0.08 0.26

5 LM pectin 0,08 Locust bean gum 0,10 Sodium alginate 0.08 0,26 The samples were covered to prevent evaporation, and heated for 20 min in a water bath of 90°C. Directly after heating the samples were cooled under running tap water for 2 min and

subsequently mechanically stirred for 15-30 sec. After the heat treatment, the samples were cooled to room temperature (RT) and acidified with 6 % (w/w) glucono delta-lactone (D-(+)-Gluconic acid δ-lactone, Sigma-Aldrich) [here below addressed as 'GDL'], as a means to gradually create an acidic environment, and form a homogeneous gel. Upon mixing GDL into pre- warmed samples (10 min at 37°C), small deformation oscillatory measurements were directly performed for 1.5 h (at 37°C). During this time, the pH of the rest of the sample was measured concomitantly in a water bath of 37°C. Acidification and rheology measurements were carried out in at least triplicate, see Table 3. Addition of GDL was able to acidify all samples from their initial pH (mean = 6.74, SD = 0.086) to a mean pH 3.24 (SD = 0.042) in 1.5 h at 37°C.

Viscoelastic properties were determined by measuring the storage modulus (G'), the loss modulus (G"), and the loss tangent (tan δ = G'VG') with small deformation oscillatory measurements. G' and G" of the samples were measured at 20°C. Samples were kept for 5 min in the geometry to allow structure recovery and temperature equilibrium. Small-deformation oscillatory measurements were performed for 10 min, in which G' and G" were recorded every 2 sec (strain deformation of ε = 0.1%, at a frequency of f = 0.1 Hz). A controlled stress rheometer was used (Physica MCR 301, Anton Paar, Austria) with a concentric cylinder geometry (CC27, Anton Paar, Austria). Table 3 Mean peak and final storage moduli for several hydrocolloid blends in nutritionally complete enteral feed (Nutrini LEMF) during acidification with GDL at a temperature of 20°C

# Blend N Peak G' (Pa) Final G' (Pa)

(mean ± SD) (mean ± SD)

0 Control: Nutrini LEMF 3 42 0 (±0, 1) 20 (±0.1)

1 NaAlg/LMP 3 254 0 (±2.7) 193 0 (±3.3)

2 NaAlg/GG 7 42 (± 11.0) 21 0 (±5.9)

3 NaAlg/LBG 4 30 0 (±3.6) 17 0 (±2.9)

4 NaAlg /LMP/GG 3 166 (± 10.3) 148 0 (±8.2)

5 NaAlg LMP/LBG 3 150 (± 14.9) 136 (± 14.1)

A slow acidification process comparable to that of Example 1 yields a more homogeneous gelation compared to direct addition of concentrated acid, thus improving data reproducibility. Such slow acidification is also believed to more closely resemble real-time stomach conditions where stomach motion avoids strong increase in acidity locally. From these data it is observed that Pectin and Na alginate are mixtures of hydrocolloids that increase the storage modulus significantly. It is concluded that the pectin and alginate not only result in a viscosity increase upon acidification (see Example 1) but also advantageously yield high storage modulus directly after entering the stomach.

Example 3A; Enteral nutritional tube feed composition suitable for younger children

Tube feeding for children of 1 to 6 years of age comprising per 100 ml: 100 kcal, 2.8 g protein (including casein and whey), 12.3 g digestible carbohydrates (including maltodextrin), 4.4 g fat (including vegetable and fish oil), 0.80 g fibre mixture, and 0.24 g hydrocolloids mixture (NaAlg;LMP 1 : 1 weight ratio). The composition further comprises minerals, trace elements, vitamins as known in the art, 2 mg carnitine, 20 mg choline, 7.5 mg taurine and has an osmolarity of 235 mOsmol/1. The hydrocolloid mixture comprises per g hydrocolloid: 0.16 g low methylated and partially amidated pectin (DE~27%, DA~20%; 104-AS-Z, CP Kelco) and 0.08 g sodium alginate (Manugel LB A, FMC Biopolymer). Example 3B Composition with an energy density of 1 kcal/ml suitable for inducing catch-up growth in children older than 1 year of age.

g/lOOml

Protein 9.7 en% 2.5

Carbohydrate 49.3 en% 12.5

Fat 39.5 en% 4.5

Indigestible carbohydrates 1.5 en% 0.8

Vitamins/minerals/trace elements according to EC directive FSMP 1999/21. The composition comprises 0.24 g hydrocolloids mixture per 100 ml, with NaAlg:LMP in 1 : 1 weight ratio. Example 4 Low energy enteral nutritional composition suitable for adults

Tube feeding for adults comprising per 100 ml: 78 kcal, 3 g protein (including casein and soy), 9.2 g digestible carbohydrates (including maltodextrin), 2.9 g fat (including vegetable oil), 1.5 g fibre mixture and 0.36 g hydrocolloid mixture of example 3. The composition further comprises minerals, trace elements, vitamins as known in the art, 28 mg choline and has an osmolarity of 195 mOsmol/1.

Example 5 High energy enteral nutritional tube feed composition suitable for adults

High energy tube feeding for adults comprising per 100 ml: 153 kcal, 6 g protein (including casein, whey, pea and soy), 18.4 g digestible carbohydrates (including maltodextrin), 5.8 g fat (including vegetable oil), 1.5 g fibre mixture and 0.36 g hydrocolloid mixture of example 3. The composition further comprises minerals, trace elements, vitamins as known in the art, 55 mg choline and has an osmolarity of 390 mOsmol/1.

Example 6 Protein composition with anti-coagulating properties Protein composition including both animal and vegetable sources. The protein composition comprises per g protein: 0.35 g whey, 0.25 g casein, 0.20 g soy and 0.20 g pea protein. The protein composition is close to a normal diet, and complies fully with the amino acid profile recommendations (WHO/FAO UNU Expert Consultation, 2007).

Example 7 Induced viscoelastic properties of selected fibre and protein isolate compositions Predetermined protein and hydrocolloids concentrations were prepared from 8% protein dispersions by diluting with demineralised water and dissolved hydrocolloid mixture. In preparation, only the vegetable protein dispersions, comprising soy and pea protein, had to be homogenised with an industrial homogeniser (lx at p about 550 bar, Niro-Soavi) to achieve an acceptable stability of the blended preparations. The protein dispersions were not heat-treated before blending.

Two stock solutions of the hydrocolloids mixtures were prepared - one with 1 : 1 weight ratio and concentration of 5mg NaAlg & 5mg LMP/g, one with 1 :2 weight ratio and concentrations of 3.33 mg NaAlg & 6.67 mg LMP/g. Both solutions were prepared at temperature 50-60°C. The pH was adjusted prior to addition to the milk protein dispersions (pH about 7) and the vegetable protein dispersions (pH about 7.5) to prevent instabilities due to pH fluctuations. The blended protein dispersions were sealed in 20 mL glass containers to prevent evaporation and placed in an aluminium heating plate for 20 minutes. The content of the containers was stirred continuously to ensure an optimal heat transfer. The temperature fluctuated between 92 and 95°C during the heat treatment. The preparations were cooled down and stored in a fridge (6- 10°C) until use. The samples were characterised within one week after preparation.

Prior to all dynamic oscillation measurements GDL was added for a controlled acidification rate. The amount of GDL (1.5 - 4.5 g GDL/ g protein) was adjusted for each specific hydrocolloid mixtures to obtain a comparable pH gradient so that evaluation of the different mixtures with respect to gel formation would be possible. The temperature of the preparations was controlled between 21 - 23 °C and each sample was stirred for 3-4 minutes after GDL addition to ensure a good distribution. Especially higher protein and hydrocolloids concentrations required an extensive stirring due to poorer GDL dissolution at room temperature. After stirring, a sample for the rheometer was taken. The temperature in the rheometer was set at 25°C. Allowing equilibration time the measurement started 7-8 minutes after GDL addition. Gel formation during acidification was monitored with a controlled stress rheometer (Physica MCR 301, Anton Paar, Austria) using titanium double gap geometry with measuring volume 3.6 mL. All dynamic measurements were performed with a strain deformation ε = 0.1% at a frequency f = lHz. In general, the storage and loss moduli were recorded for 1.5 - 2 hours depending on the system measured. Measurements were performed at least in duplicate and from different batches.

The measured values for the maximum storage modulus at it was found at pH between 3.5 and 5 for NaAlg/LMP mixtures in 2% and 4% soy and whey and sodium caseinate protein isolate and 2% pea protein isolate dispersions during acidification with GDL at a temperature of 25°C are represented in table 4.

Table 4: storage modulus at pH 3.5 - 5 for NaAlg/LMP mixtures in various protein mixtures

The results of Table 4 show that the addition of a combination of pectin (LMP) and alginate (NaAlg) in different protein isolate dispersions results in increased maximum storage modulus G' levels at pH between 3.5 and 5. These increased storage modulus G' levels will have a thickening effect directly after entry in the stomach, after which it will reduce as pH decreases (i.e. the pH at the end of the stomach). Overall the whey protein concentrate and Na-caseinate dispersion showed the highest maximum storage G' levels compared to the soy and pea protein isolate dispersions.

Example 8 Different enteral nutritional compositions show increased storage modulus (G') with NaLg/LMP mixture

The required amount of solid hydrocolloid powder was added to a certain volume of ready-to-use enteral feed:Nutrini Low Energy Multi Fibre (2% protein, 0.7% fibre), Nutrini (2.8% protein), and Nutrini Multi Fibre (2.8% protein, 0.8% fibre), Nutricia, Zoetermeer. All mixtures were covered and dissolved at increased temperature (45 - 60°C) under continuous stirring for at least one hour. The actual dissolution time depended on the hydrocolloid concentration. The blended ready-to-use enteral feeds were also sealed in 20 mL glass containers to prevent evaporation and placed in an aluminium heating plate for 20 minutes.

Further preparation details and rheology measurements are as given in example 7.

The maximum storage modulus at pH between 3.5 and 5 for a range of NaAlg/LMP mixtures in the three nutritionally complete ready-to-use enteral feeds with different levels of protein and protein sources as discussed above during acidification with GDL at a temperature of 25°C is plotted in Figure 1.

Figure 1 shows also that the addition of different combinations of pectin (LMP) and alginate (NaAlg) in ready-to-use enteral feeds with different protein levels and nutritional composition results also in maximum storage modulus G' levels at pH between 3.5 and 5. These maximum levels are reached at a pH level that corresponds to gastric circumstances at the start of food consumption. The storage modulus G' levels will be decreased at the lower part (antrum and pylorus) of the stomach. In contrast to the protein isolate measurements of example 7, the storage modulus G' levels in these nutritionally complete feeds are not directly comparable as nutrients such as minerals and fibre could affect the measurements. However, trends are unmistakably present. A ratio LMP:NaAlg of at least 1, preferably between 1 and 3, even more preferably 2 gives the optimal increase in storage modulus.

Claims

2. Use according to claim 1 , wherein the storage modulus G' of the composition is between 200 and 7500 Pascal, preferably between 350 and 5000 Pascal.

3. Use according to claim 1 or 2, wherein the patients are infants or children with or at risk of faltering growth.

4. Use according to any of the preceding claims, wherein the patients are neuro logically disabled, including cerebral palsy patients.

5. Use according to any of the preceding claims, wherein the storage modulus G' of the composition increases to at least 125% of the original value at pH 6, when the pH decreases from about pH 6 to about pH 4.

6. Use according to any of the preceding claims wherein the storage modulus G' of the composition decreases going from pH 4 to pH 2.

7. Use according to any of the preceding claims, wherein the weight ratio pectin: alginate is at least 1, preferably between 1 and 3.

8. A liquid nutritional composition comprising protein, digestible carbohydrates, optionally fat, and a viscosity or gelling fibre system consisting of pectin and alginate, wherein pectin is present in a concentration between 0.1 mg/ml and 10 mg/ml, and alginate is present in a concentration between 0.1 mg/ml and 1 mg/ml.

9. The composition according to claim 8 wherein the protein comprises a non-coagulating protein source selected from whey, soy, pea, hydrolysed proteins, and combinations thereof.

The composition according to any of the claims 8 - 9, wherein the energy content is at least 0.7 kcal per ml.

The composition according to any of claims 8 - 10, comprising protein, fat, digestible and indigestible carbohydrates and nucleotides wherein the composition has

a. an energy density of 0.7-2.0 kcal/ml; and

b. a protein component providing at least 9 % of the total calories; and

The composition according to any of claims 8 - 11, wherein the weight ratio pectimalginate is at least 1 , preferably between 1 and 3.

13. Use of a composition according to any of claims 8- 12 as tube feed or sip feed.