Field of the invention

This invention is in the field of nutritional compositions that contain dietary fats, vegetable proteins and casein proteins. In particular this invention concerns the digestion in the upper gastro-intestinal tract of nutrients comprised by such

compositions. This invention aims to control the postprandial digestion of dietary fats comprised by a nutritional composition that further contains casein proteins and vegetable proteins and preferably aims to improve the digestion thereof.

Background of the invention

Inclusion of casein and/or caseinate in liquid enteral nutritional compositions is important and beneficial for several reasons. It is a commonly used, widely accepted protein source which is safe to use and still relatively cheap compared to other available animal protein sources. The amino acid profile of these animal proteins closely resembles those as needed by the human body, making this an excellent protein source for inclusion in nutritional compositions.

Caseins and/or caseinates can be included at quite high protein levels in enteral nutritional compositions of medium to high caloric content while remaining of sufficiently low viscosity to provide a liquid composition suitable for tube feeding purposes.

These proteins are furthermore sufficiently heat-stable to withstand heat- sterilization and/or pasteurizing conditions such that shelf-stable nutritional compositions can be obtained.

However, inclusion of caseins and/or caseinates in liquid enteral nutritional compositions also has disadvantages. The main disadvantage is that, due to the prevailing acidic conditions encountered in the stomach, these proteins form a coagulate which is reported to delay its gastric emptying (Boirie et al., PNAS 1997).

Nutritional compositions containing casein, in particular sodium caseinate and vegetable proteins such as soy and/or pea protein are well known.

For example US 2003/0104033 teaches enteral formulations comprising 40 - 95 weight% of caseinate and 5 - 60 weight% of a stabilizing protein, selected from the group of whey and a one or more vegetable proteins, selected from the group of soy, corn, potato, rice and pea, the most preferred vegetable protein being soy protein. The document is concerned with the reduction of creaming in enteral formulae and is silent with respect to improving digestibility properties of the composition.

WO 2007/063142 (EP 1 972 346) discloses a pea-based protein mixture comprising 50 weight% caseinate, 25 weight% whey proteins and 25 weight% pea protein. The document mentions that the protein mixture described therein has a high protein quality combined with high digestibility making the protein mixture easily convertible. No attention is drawn to improving digestibility of dietary fats.

In WO2010/131952A1 it is disclosed that inclusion of vegetable proteins, such as pea protein, in nutritional compositions with casein proteins leads to an unexpected reduction in coagulation of casein proteins. It suggests that such compositions could treat or prevent a delay in gastric emptying. However, this document is silent with respect to the postprandial fate of fats included in liquid enteral nutritional

compositions.

Summary of the invention

The present invention is based on the finding that the postprandial digestion of a fat fraction comprised by a liquid enteral nutritional composition that further contains a casein protein can be improved by including a vegetable protein in said nutritional composition.

In particular, the present inventors have shown that the fat fraction of a liquid enteral nutritional composition that comprises casein protein can be made better digestible upon exposure to the gastric environment of a human subject, by including a vegetable protein in said nutrition. When a vegetable protein was added to the casein comprising liquid enteral nutrition, conversion of dietary fats, preferably those that are sensitive to the enzymatic action of gastric lipase, such as triacylglycerides, into free fatty acids was found to be improved over similar compositions that are free of vegetable protein.

Hence, the present invention relates to the use of a vegetable protein in improving postprandial or gastric digestion of fat in a subject (preferably a human subject), said subject having consumed a liquid enteral nutritional composition comprising said fat, said vegetable protein and casein protein. Furthermore, the present invention relates to a method of improving digestibility properties of a liquid enteral nutritional composition that comprises a fat fraction and casein protein, comprising the step of including a vegetable protein in the protein fraction of the nutritional composition.

Furthermore, the present invention relates to a method of improving the digestion of a fat fraction present in a casein protein comprising liquid nutritional composition for enteral use, which method comprises the inclusion of a vegetable protein in the composition and administering the composition to a subject. Preferably, an effective amount of the vegetable protein is added to the nutritional composition to improve the digestion of the fat fraction.

Furthermore, the present invention relates to a liquid enteral nutritional composition that comprises a casein protein, a vegetable protein and a (dietary) fat, wherein the vegetable proteins are included for use in improving the postprandial digestibility properties of the nutritional composition. In particular, the vegetable proteins are added to the enteral nutritional composition for improving the digestibility or digestibility properties of the fat fraction of the composition. In particular, the digestibility of fats comprised by the nutritional composition is enhanced in such a manner that increased amounts of free fatty acids are released from the fat fraction as a consequence of consumption of the composition by a subject or administering of the composition to a subject. In particular, fats become increasingly available as a consequence of gastric digestion of the nutritional composition.

The present invention further relates to the use of a vegetable protein in the manufacture of liquid enteral nutritional compositions that comprise a fat fraction and casein proteins, for use in improving digestibility properties of said fat fraction as contained in the nutritional composition. In particular, the vegetable proteins are included in the nutritional composition for enhancing the gastric digestibility of the fat fraction. More in particular, conversion of dietary fat into free fatty acids in the stomach and/or gastric emptying of fats into the small intestine is increased.

The present invention furthermore relates to a method of increasing gastric emptying of fats and/or increasing gastric digestion of fat, comprising the step of including a vegetable protein in a fat and casein protein comprising liquid enteral nutritional composition. Even though liquid nutritional compositions for enteral use that comprise mixtures of vegetable and casein protein with dietary fats are known, to date the effects of the inclusion of vegetable protein to casein protein with respect to the postprandial fate of dietary fat of such nutrition as described herein are unreported.

The invention will now be further elucidated by describing a number of embodiments of the present invention.

Detailed description of the invention

The present invention thus concerns the use of a vegetable protein in improving postprandial digestion of fat in a subject, said subject having consumed a liquid enteral nutritional composition comprising said fat and a casein protein.

Hence, preferably the improving of the postprandial digestion is or comprises improving digestion in the stomach of said fat. More preferably, the improving of digestion is or comprises enhancing digestion of said fat, in particular enhancing the production of free fatty acids from said fat fraction. A consequence of enhanced gastric fat digestion is that the content of the stomach effluent comprises higher free fatty acid levels, which can be used to the benefit of certain target groups, such as subjects with pancreatic insufficiency or subjects suffering from or experiencing dyspepsia, in particular subjects suffering from or experiencing dyspepsia related to maldigestion of fats, defective lipolysis or subjects suffering from or experiencing reduced lipolysis.

Free fatty acid production occurs in the gastro-intestinal tract by the enzymatic action of lipases acting, i.a. on (dietary) triacylglycerides. One class of lipases acting on triacylglyceride containing fats are gastric lipases. These enzymes are responsible for up to 30% of fat digestion processes occurring in human digestion. Gastric lipases hydrolyze the ester bonds of triglycerides under acidic pH conditions, thereby releasing diacylglycerides which are subsequently converted into free fatty acids. They are secreted by gastric chief cells in the fundic mucosa of the stomach. Thus, not only can gastric lipases contribute quite significantly in healthy subjects to total lipolytic digestion activity in the gastro-intestinal tract of humans, the initiation of gastric lipid digestion facilitates the subsequent action of pancreatic lipases in the duodenum in further fat digestion. Moreover, in subjects suffering from pancreatic insufficiency, the role of gastric lipase is quantitatively much more important. Consequently, in a preferred embodiment, the fat fraction of the nutritional composition comprises dietary fats that are sensitive to the enzymatic action of lipases, in particular gastric lipase. Such dietary fats comprise a glycerol to which one, two or three fatty acids are attached via an ester bond. The term "fat" is meant to include fats that are suitable and meant for human consumption (typically and herein also named "dietary fats"). They include fish oils, vegetable oils and animal fats. Such fats comprise fats that contain short-chain fatty acids (with an aliphatic carbon tail of less than 6 atoms), medium-chain fatty acids (with an aliphatic carbon tail of 6-12 carbon atoms) and long-chain fatty acids (with an aliphatic carbon tail of between 14 atoms and about 24 carbon atoms). Preferably, the fat fraction of the nutritional composition of the invention comprises or consists of a mixture of dietary fats such as, fish oil, vegetable oil and animal fat.

A problem that has become apparent during research that led to the present invention, is that inclusion of a casein protein in fat- and carbohydrate containing liquid enteral nutrition not only leads to the retaining of these proteins in the stomach, but that also dietary fats comprised by the liquid enteral nutrition are retained in the stomach. Since the protein and fat fraction of these nutritional compositions are selectively retained in the stomach, other (macro)nutrients are first emptied from the stomach.

It has thus been surprisingly found that inclusion of vegetable proteins

(preferably pea and/or soy) in a liquid nutritional composition for enteral use that comprises casein protein and a fat fraction leads to higher release rates of fats from the stomach as evidenced in the herein described in vitro gastric digestion model, compared to such nutrition that does not contain vegetable protein or less vegetable protein. In such nutritional compositions that contained casein protein as the sole protein source, proteins and fats are selectively retained in the stomach, while other components (mainly carbohydrates) are released first from the stomach. One valuable insight of the present invention is that the use of a combination of vegetable proteins, casein proteins and a fat fraction in a liquid enteral nutrition is that the release of macronutrients, in particular proteins and fats, occurs in a more concerted, more simultaneous manner than without the presence of vegetable proteins.

Hence, in one embodiment of the present invention, improving digestion is or comprises the improvement of a more balanced gastric emptying of said fat and said casein protein. In one embodiment, improving digestion is or comprises preventing undue (simultaneous) retention of protein and fats in the stomach and improving their release from the stomach. In another embodiment, improving digestion is or comprises the enhanced gastric emptying of the fat fraction of the liquid enteral nutritional composition. In one embodiment, improving digestion is or comprises enhancing gastric emptying of the fat fraction such that fat, in particular free fatty acids, and proteins are more simultaneously released from the stomach compared to liquid enteral compositions based on casein proteins or without sufficient vegetable protein levels.

In one embodiment, improving digestion is or comprises enhancing gastric emptying of the fat fraction such that a more balanced release of fat and proteins from the stomach is achieved.

In a preferred embodiment, the casein protein comprises or consists of micellar casein and/or caseinate. Preferably, caseinate includes sodium caseinate, potassium caseinate, magnesium caseinate and/or calcium caseinate.

In a preferred embodiment, the total amount of protein of the liquid enteral nutritional composition is between 1 and 10 g/100 ml of the composition, of which the weight ratio casein protein to vegetable protein lies between 95:5 and 5:95, preferably between 90: 10 and 10:90, more preferably 85: 15 to 25:75, most preferably 80:20 to 40:60.

In another preferred embodiment, total protein in said nutritional composition provides 10 to 40 En% of the total caloric value of the composition and fats provide 20 to 60 En% of said total caloric value. In another preferred embodiment, carbohydrates are included representing between 20 and 60 En% of the nutritional composition. In further preferred embodiments, the protein provides 12 to 24 En% of the total caloric value of the composition and/or fats provide 24 to 48 En% of the total caloric value and/or carbohydrates provide 36 to 54 En% of the nutritional composition

In yet another preferred embodiment, the vegetable protein comprises or consists of one or more proteins derived from plants. The term "vegetable" herein is interchangeable with the terms "vegetal", "plant-derived" or "of plant origin". Suitable examples of vegetable proteins include wheat, rice, corn, bean and soy proteins. In particular, the term encompasses vegetable proteins obtained from legume plants, i.e. from the Fabaceae family, including beans, peas, soybeans lentils, alfalfa, lupins etc. Most preferred vegetable proteins according to the invention in comprise or consist of pea (Pisum, especially P. sativum), soy (Glycine max) or a combination thereof. Further details about preferred peas and soy proteins are given below.

In addition to the casein and the vegetable, in particular leguminous, protein, the protein fraction to be used according to the invention may contain further proteins, in particular animal or microbial proteins. A particularly useful further protein comprises whey protein or fractions or derivatives thereof, which may constitute 5-50, especially 10-40 wt.% of the total protein fraction. A suitable protein composition comprises 10- 80 wt.%, especially 20-65 wt.% casein, and 25-75, especially 30-50 wt.% vegetable protein, in particular leguminous, more in particular pea and/or soy protein, and 0-20 wt.%), especially 5-15 wt.%, of a further protein.

In a preferred embodiment, the fat, dietary fat or fat fraction according to the present invention comprises a combination of canola oil (low-erucic rapeseed oil), high oleic sunflower oil, fish oil and MCT oil. More in particular are combined: 30-45 wt.%, in particular about 37 wt% of canola oil, about 35-50 wt.%, in particular 42 wt% of high oleic sunflower oil, 0.5-5 wt.%, in particular about 2 wt% of fish oil and 10-25 wt.%), in particular about 17 wt%> of MCT oil.

In a preferred embodiment, the pH of the liquid enteral composition lies between pH 5 and 8, preferably between 5.5 and 7.5, more preferably between 6.0 and 7.5 or 6.5 and 7.5.

Clinical relevance

Within the framework of the present invention that postprandial fat digestion of fats comprised by a liquid enteral nutritional composition that further comprises casein and vegetable protein is enhanced and that gastric emptying of fats proceeds faster, the following clinically relevant but distinct embodiments can be discerned.

Enhanced postprandial gastric digestion of fats into free fatty acids

One aspect of the present invention relates to the use of a vegetable protein in improving postprandial digestion of fat in a subject, said subject having consumed a liquid enteral nutritional composition comprising said fat, said vegetable protein and a casein protein.

Within this aspect, improved postprandial fat digestion encompasses at least the herein reported finding of increased enzymatic conversion of fats, in particular dietary fats that comprise triglycerides, into free fatty acids by the enzymatic action in the stomach of a gastric lipase.

In a preferred embodiment, the improving of postprandial fat digestion is or comprises enhanced postprandial gastric fat digestion, more in particular the production of free fatty acids by the enzymatic action of gastric enzymes, preferably by gastric lipase.

Since inclusion of a vegetable protein in a liquid enteral nutritional composition, that further comprises casein protein and a fat fraction, results in enhanced gastric digestion of dietary fats into free fatty acids, use of vegetable proteins in this composition improves the digestibility properties of the composition better, allowing easier digestion of said liquid nutritional composition. Thus, in another embodiment the liquid enteral composition has improved digestibility properties.

In a preferred embodiment, improving free fatty acid production in the stomach is preferably established for subjects suffering from dyspepsia, functional dyspepsia, dyspepsia associated with fat consumption or pancreatic insufficiency. Pancreatic insufficiency, or also referred to as exocrine pancreatic insufficiency, herein is defined as a condition characterized by inadequate production and secretion of pancreatic enzymes that are needed for digestion, in particular pancreatic enzymes that exhibit lipolytic activity. It is a major consequence of pancreatic diseases leading to a loss of pancreatic parenchyma, obstruction of the main pancreatic duct, decreased pancreatic stimulation, or acid-mediated inactivation of pancreatic enzymes. Nutritional malabsorption, anorexia, poorly localized upper abdominal or epigastric pain, malaise, and severe weight are often associated with this condition. So far, supportive care, specific treatment of the cause, and replacement or augmentation of the absent or lacking substances are recommended as therapy for pancreatic insufficiency.

In a preferred embodiment, the liquid nutritional composition comprising casein protein, a vegetable protein and a fat fraction is used to compensate for loss of pancreatic lipase (or lipolytic) activity in subjects suffering from pancreatic

insufficiency.

In view of this, this embodiment of the invention can also be worded as the use of a vegetable protein, preferably pea and/or soy, in the manufacture of a liquid nutritional composition for enteral use that further comprises casein protein and a fat fraction, for use in preventing or reducing of postprandial dyspepsia, functional dyspepsia, dyspepsia associated with fat consumption or pancreatic insufficiency. Alternatively, this embodiment of the invention can be worded as the use of liquid nutritional composition for enteral use comprising a vegetable protein, preferably pea and/or soy, a casein protein and a fat fraction, for preventing or reducing of

postprandial dyspepsia, functional dyspepsia, dyspepsia associated with fat

consumption or pancreatic insufficiency.

The invention can also be worded as the use of a vegetable protein, preferably pea and/or soy, in the manufacture of a liquid nutritional composition for enteral use that further comprises casein protein and a fat fraction, for use in enhancing

postprandial gastric digestion of fats into free fatty acids. Alternatively, this

embodiment of the invention can be worded as the use of a liquid nutritional composition for enteral use comprising a vegetable protein, preferably pea and/or soy, a casein protein and a fat fraction for enhancing postprandial gastric digestion of fats into free fatty acids.

Improved postprandial gastric emptying of fat into the small intestine

Another aspect of the invention relates to the use of a vegetable protein in improving postprandial gastric emptying of fat or providing an improved balance in postprandial gastric emptying of macronutrients in a subject, said subject having consumed a liquid enteral nutritional composition comprising said fat, said vegetable protein and a casein protein.

In a preferred embodiment, the present invention is thus for improving postprandial gastric emptying of fat into the small intestine. More preferably, improving gastric emptying of fat includes faster gastric emptying of fats out of the stomach of a subject into the duodenum, wherein the fats are comprised by a nutritional composition that also comprises vegetable protein and a casein protein.

In WO2010131952A1 it is suggested that inclusion of vegetable proteins, such as pea protein, in nutritional compositions with casein proteins in general terms may lead to faster gastric emptying of casein proteins. The currently described effects of faster gastric emptying of fats by the inclusion of pea or soy protein have not been disclosed therein.

Faster gastric emptying of dietary fat is preferably established for subjects suffering from disorders wherein retaining of fat in the stomach is associated with intestinal discomfort, aspiration pneumonia, high gastric residual volume (GRV) , vomiting, nausea, bloating, and delayed gastric emptying, especially in vulnerable persons, such as hospitalized patients. Simultaneous postprandial gastric emptying of macronutrients

Unbalanced digestion and gastric processing may result in macronutrients (fats, proteins and carbohydrates) entering the intestines for further digestion at different paces. In particular an undue retention of fats and proteins in the stomach may result in digestion of (digestible) carbohydrates preceding digestion of the further macro- nutrients, and hence in an unbalanced metabolic pattern, including an excessive or premature postprandial glucose response. This is undesired, especially for diabetic or obese or potentially obese persons.

The mechanical forces and biochemical enzymatic actions that simulate the gastric environment and hence gastric digestion, that are exerted onto a liquid nutritional composition for enteral use that comprises a fat fraction, a carbohydrate fraction, with casein as a protein source and substantially free of vegetable proteins, is herein shown to result in selective retaining of the casein protein and fat fraction in the stomach model as used herein. Inclusion of vegetable protein in said liquid composition results in alleviation of this selective blockade, having the effect that the protein fraction, the fat fraction and the carbohydrate fraction are emptied from the stomach in a simultaneous or more concerted manner than without vegetable proteins being present in said liquid nutrition.

Thus, a preferred embodiment of the invention concerns the provision of an improved balance in postprandial gastric emptying of macronutrients in a subject, said subject having consumed a liquid enteral nutritional composition comprising said fat, said vegetable protein and a casein protein.

Another preferred embodiment of the invention concerns the use of a vegetable protein, preferably pea and/or soy, in the manufacture of a liquid nutritional

composition for enteral use that further comprises casein protein and a fat fraction, for use in improving postprandial gastric emptying of macronutrients, in particular said fats and said proteins, more in particular fats, protein and carbohydrates. Alternatively, this embodiment of the invention can be worded as the use of a liquid nutritional composition for enteral use comprising a vegetable protein, preferably pea and/or soy, a casein protein and a fat fraction for improving the balanced postprandial gastric emptying of fats and proteins, preferably fats, proteins and carbohydrates.

One valuable insight that was found by of the present inventors is that milk proteins (in particular caseins) as well as fats that are present in liquid nutritional compositions, which is substantially free of vegetable proteins, are selectively retained in the stomach during gastric digestion and that the principle macronutrient fraction that empties first from the stomach is the carbohydrate fraction. This insight can be used in the dietary management of subjects that would suffer from imbalanced gastric emptying of macronutrients, more in particular subjects that would suffer from undue emptying of carbohydrates from the stomach while dietary fats and proteins are retained therein. For instance, simultaneous gastric release of macronutrients can be established in the duodenum of diabetics as part of the reduction, prevention of the symptoms of diabetics or in the treatment of diabetics. Also, this is based on the fact that the protein availability is seen as an important driver for insulin release after gastric transit.

When considering the emptying behavior of proteins, fat and total dry matter (which comprises digestible carbohydrates) in relation to each other for compositions comprising these macronutrients versus such compositions that are free of vegetable proteins, it can be concluded that a more balanced, better concerted or more simultaneous emptying of macronutrients from the composition containing casein, vegetable protein, digestible carbohydrates and dietary fats from the stomach occurs than was found for the composition containing casein and dietary fats, without vegetable protein after a sufficient gastric residence time.

Hence, in a preferred embodiment, the present invention relates to the use of a liquid enteral nutritional composition comprising a vegetable protein, preferably pea and/or soy, a casein protein, a digestible carbohydrate and a fat fraction for improvement in the balanced postprandial gastric emptying of these macronutrients.

Hence, in a more preferred embodiment, the present invention relates to the use of a liquid enteral nutritional composition comprising a vegetable protein, preferably pea and/or soy, a casein protein, a digestible carbohydrate and a fat fraction for improvement in the balanced postprandial gastric emptying of these macronutrients, wherein the ratio in the gastric emptying of the protein : fat : dry matter (or carbohydrates) contained in a composition according to the present invention lies between 0.8-1.3 : 1 : 0.8-1.3 after a physiologically relevant gastric digestion period, more preferably this ratio lies between 1-1.2 : 1 : 1-1.2., most preferably about 1 : 1 : 1.

The "physiologically relevant gastric digestion period" herein is construed as a period of 90 minutes or more, preferably 120 minutes or more, most preferably 150 minutes or more.

Thus, in a more preferred embodiment, the ratio in the gastric emptying of the proteimfat: dry matter (or carbohydrates) contained in a composition according to the present invention lies between 0.8-1.3 : 1 : 0.8-1.3 after 90 minutes gastric digestion, more preferably between 1-1.2 : 1 : 1-1.2, most preferably about 1 : 1 : 1.

In another preferred embodiment, the ratio in the gastric emptying of the protein, fat and total dry matter (or carbohydrates) contained in a composition according to the present invention lies between 0.8-1.3 : 1 : 0.8-1.5 after 120 minutes gastric digestion, preferably between 1-1.2 : 1 : 1-1.4, more preferably about 1 : 1 : 1-1.2, most preferably about 1 : 1 : 1.

Yet in another preferred embodiment, the ratio in the gastric emptying of the protein, fat and total dry matter contained in a composition according to the present invention lies between 0.8-1.3 : 1 : 0.8-1.5 after 150 minutes gastric digestion, preferably between 1-1.2 : 1 : 1-1.4, more preferably about 1 : 1 : 1-1.2, most preferably about 1 : 1 : 1.

Consumption or administration of the liquid enteral nutrition

Due to a variety of reasons, such as diseases, medical conditions, malnutrition, medical disabilities, post-surgery, etc. patients may not be able to obtain the necessary nutrition by ingesting food through the mouth, e.g. by eating or drinking. Therefore, it has been known to provide medical enteral nutrition by oral nutritional supplements or tube feeding. Tube feeding is preferably given to those that need nutritional

supplementation, or to provide nutrition to patients are that are unable to swallow safely, using a device such as a nasogastric feeding tube or by using a percutaneous endoscopic gastrostomy (PEG) feeding system. The present method preferably involves administering the nutritional composition orally, e.g. by drinking, preferably enterally by tube feeding.

Within the context of the invention it should thus be understood that the liquid enteral nutrition comprising a casein protein, a vegetable protein and a fats fraction is received in the stomach from the esophagus, either by tube feeding directly into the stomach or by the natural consumption process involving entering of the nutrition in the oral cavity, followed by swallowing thereof, entry in the stomach after passing the esophagus, such that the nutrition is subjected to the gastric environment.

In the context of this application, the state of being fed by nutritional supplements and/or a by a feeding tube is called enteral feeding, comprising all of the abovementioned tube feeding systems, and the nutrition used in the feeding by nutritional supplements and/or a by a feeding tube is called enteral nutrition.

Use of such enteral nutrition may be temporary for the treatment of acute conditions, long-term or even lifelong in the case of chronic disabilities.

The term "postprandial" is meant in relation to consumption of a meal and herein means "after the consumption of a nutritional composition". With "postprandial gastric digestion" is meant the gastric digestion of a liquid nutritional composition of the invention (i.e. comprising vegetable protein, casein protein and a fat fraction) that has been consumed by or administered to a subject. With "postprandial gastric emptying" is meant the gastric emptying of a liquid nutritional composition of the invention that has been consumed by or administered to a subject. The nutritional composition of the present invention is preferably directly administered into the stomach by tube feeding or is for administration by tube feeding into the stomach directly.

Vegetable proteins, in particular pea and soy protein

For the purpose of the present invention, pea protein and/or soy protein, preferably intact pea protein and/or intact soy protein, are the preferred choices of vegetable proteins.

Both pea protein and soy protein are relatively cheap (on the average, pea protein may cost about half the price of caseinates) and as it is added to the nutritional composition it increases the protein content while keeping costs quite low. Pea protein is generally tolerated well by most people, it is lactose-free and is not a common allergen. Pea protein is quite high in cysteine content and can therefore compensate the inadequate amount of cysteine in casein proteins. Furthermore, pea protein is quite high in arginine compared to casein, soy or whey protein which is required for muscle metabolism and which facilitates the intake of body mass while reducing body fat; and it is quite high in lysine, when compared to the vegetable proteins, which is needed to build protein muscle and assist in the maintenance of lean body mass.

Soy protein is a vegetable protein that contains the essential amino acids in a relatively high proportion for human health. Soy protein is categorized as a high- quality, complete protein. Soy proteins can be divided into different categories according to their production method. Soy protein isolate (SPI) is the most refined form of soy protein and is mainly used in meat products to improve texture and eating quality. Soy protein isolate contains about 90 percent protein. Soy protein concentrate (SPC) is basically soybean without the water soluble carbohydrates. It contains about 70 percent of protein. Textured soy protein (TSP) is made from soy protein concentrate by giving it some texture. TSP is available as dry flakes or chunks. It will keep its structure when hydrated. Hydrated textured soy protein chunks have a texture similar to ground beef. It can be used as a meat replacement or can be added to meat. Textured soy protein contains about 70 percent protein.

Several pea sources are readily available to the skilled person, for example, from Roquette (Lestrem, France) which markets a pea isolate obtained from the yellow pea (Pisum sativum), and from Cosucra Groupe Warcoing (Warcoing, Belgium). Other pea protein sources may originate from green pea, cowpea, chickpea, and field pea.

Also several soy sources are readily available to the skilled person, for example, from The Solae Company (St. Louis, MO, USA).

In one embodiment according to the invention, the pea protein and/or soy protein is/are substantially in intact form or non-hydrolysed.

In another embodiment according to the invention, the pea protein and/or soy protein is/are is fermented or a protein hydrolysate.

In the context of this invention, a "non-hydrolysed" protein is equivalent to an

"intact" protein, meaning that the protein has not been subjected to an hydrolysis process. However, minor amounts of hydrolysed proteins may be present in the source of non-hydrolysed proteins.

In this context, "minor" should be understood as an amount of about 10 weight% or less. The term "about" should be interpreted as a deviation of plus or minus 10 % of the given value.

The present method preferably involves administering the nutritional composition to humans, preferably to humans that benefit from receiving easily digestible nutrition, preferably to humans with digestive tract complications, preferably to humans with digestive problems, preferably to hospitalized patients, preferably to a person that is in a disease state, a person that is recovering from a disease state, a person that is malnourished. The present method preferably involves administering the nutritional composition orally, by eating or drinking, preferably enterally by tube feeding.

In one embodiment the invention concerns the use of pea protein and/or soy protein in the manufacture of a nutritional composition that further comprises a casein protein and a fat fraction, for use in improving gastric digestion of fat in the stomach of a subject or for improving gastric emptying of fats from the stomach of a subject.

Dosage unit

The nutritional composition according to the invention preferably has the form of a complete food, i.e. it can meet all nutritional needs of the user. As such, the liquid enteral nutritional composition according to the invention preferably contains 1000 to 2500 kcal per daily dosage. Depending on the condition of the patient, a daily dose is about 25 to 35 kcal/kg bodyweight/day. Therefore, a typical daily dose for a 70 kg person contains about 2000 kcal. The complete food can be in the form of multiple dosage units, e.g. from 8 (250 ml/unit) to 2 units (1 1/unit) per day for an energy supply of 2000 kcal/day using a liquid enteral nutritional composition according to the invention of 1.0 kcal/ml. Preferably, the nutritional composition is adapted for tube feeding.

In the case the liquid enteral nutritional composition is an oral food supplement, it can for example to be used in addition to a non-medical food or normal diet.

Preferably, as an oral supplement, the liquid enteral nutritional composition contains per daily dosage less than 1500 kcal, in particular as a supplement, the nutritional composition contains 500 to 1000 kcal per daily dose. The food supplement can be in the form of multiple dosage units, e.g. from 2 (250 ml/unit) to 10 units (50 ml/unit) per day for an energy supply of 500 kcal/day using a liquid enteral nutritional composition according to the invention of 1.0 kcal/ml.

The liquid nutritional composition to be used according to the invention is preferably a composition suitable for sipping or tube feeding. The caloric content may be e.g. between 0.8 and 2.4 kcal/ml, preferably between about 1.0 and 1.8 kcal/ml. Preferably, the nutritional composition is packaged, stored and provided in a container such as plastic bag or a pouch or the like. A variety of such containers is known, for example 500 ml, 1000 ml, and 1500 ml containers are known in the art. It should be noted that any suitable container can be used to package, store and provide the nutritional composition according to the invention.

In one embodiment of the present invention, the nutritional composition is provided in a ready to use liquid form and does not require reconstitution or mixing prior to use. The composition according to the invention can be tube fed or

administered orally. For example, the composition according to the invention can be provided in a can, on spike, and hang bag. However, a composition may be provided to a person in need thereof in powder form, suitable for reconstitution using an aqueous solution or water such that the composition according to the invention is produced. Thus in one embodiment of the present invention, the present composition is in the form of a powder, accompanied with instructions to dissolve or reconstitute in an aqueous composition or water to arrive at the liquid nutritional enteral composition according to the present invention. In one embodiment of the present invention, the present liquid nutritional enteral composition may thus be obtained by dissolving or reconstituting a powder, preferably in an aqueous composition, in particular water.

In one embodiment of the present invention, the composition according to the invention is packaged. The packaging may have any suitable form, for example a block-shaped carton, e.g. to be emptied with a straw ; a carton or plastic beaker with removable cover; a small-sized bottle for example for the 80 ml to 200 ml range, and small cups for example for the 10 ml to 30 ml range. Another suitable packaging mode is inclusion of small volumes of liquid (e.g. 10 ml to 20 ml) in edible solid or semi- solid hulls or capsules, for example gelatine-like coverings and the like. Another suitable packaging mode is a powder in a container, e.g. a sachet, preferably with instructions to dissolve or reconstitute in an aqueous composition or water.

The composition to be used according to the invention, can be suitable for any sub-population or age group. In a preferred embodiment, the composition is to be used for improving fat digestion of improving balance of gastric emptying as further described herein, for elderly people, i.e. people of over 65 years of age.

The invention will now be further elucidated by several examples, without being limited thereby. EXAMPLES

Liquid enteral nutritional compositions

The gastric digestion of fats was investigated for two highly similar liquid nutritional compositions, which differed mainly with respect to the choice of proteins being either a mix of vegetable protein and milk protein on the one hand and only milk protein on the other. Both liquid compositions are designed and suitable for tube feeding purposes.

Dynamic Gastro-Intestinal Tract Digestion Model

Gastric digestion of macronutrients of compositions A and B was investigated using a gastro-intestinal tract digestion model, TIM-1 (Minekus et al., 1995). This model allows simulating and investigating gastric digestive processes in a real-time manner. By taking samples on pre-set time points during the gastric digestion process and analyzing the contents of the samples, the gastric digestion of nutritional compositions can be followed over time which closely resembles the in vivo gastric digestion process in humans.

The gastro-intestinal tract digestion model as used herein is based on protocols and the artificial gastrointestinal system as mentioned by Blanquet et al, (2004). Of this gastric-small intestinal system, only the stomach compartment was used. The system was adjusted to mimic gastric digestive condition of elderly using the below mentioned adaptations. The stomach pH curve was based on the average in vivo values of healthy adults, as was the gastric emptying behavior which largely follows a (mirrored) S-curve wherein emptied volume is presented on the y-axis and time on the X-axis (Elashoff et al, 1982, Hellstrom et al, 2006 and Brener et al, 1983). After 100 minutes, half of the contents of the gastric compartment was emptied.

In separate gastric digestion experiments, 300 ml of compositions A and B was added to the artificial gastro-intestinal system, wherein it was first individually mixed with 50 ml human-like artificial saliva (106.1 mM NaCl, 29.5 mM KC1, 2.0 mM CaC12, 14.3 mM NaHC03 and 720 mg/1 a-amylase (A621 1, Sigma, The Netherlands), pH 6.3 at room temperature) and 10 ml gastric enzyme solution (106.1 mM NaCl, 29.5 mM KC1, 2.0 mM CaC12, 130 mg/1 lipase (DF 15, Amano Pharmaceutical Co, Ltd

Nagoya, Japan), 145 mg/1 pepsin (P7012-109, Sigma) and 9.3 mM sodium acetate (pH 5.0). Secretion of gastric enzyme solution during the experiment was 0.5 ml/min. The pH is computer-monitored and continuously controlled by secreting either water or 1.5 M HCl (0.25 ml/min) into the stomach compartment, instead of 1.0 M HCl as described by Blanquet et al, (2004). Over a period of two hours wherein gastric digestion was simulated, the gastric effluent was collected with 30 minute time intervals. The volumes of the samples were measured, as well as the content of the product remaining in the gastric compartment and of the gastric effluent. Protein content, total fat content {i.e. fat soluble in poly-ether), free fatty acid content, dry matter content, and carbohydrate content was determined for each sample. Samples were taken from three independently conducted experiments. For each individual experiment, one

measurement was taken. Protein content measurements on gastric effluent was done based on a standard Dumas method, fat content measurement was conducted according to the Weibull- Stoldt method by CLF (Central Laboratories Friedrichsdorf, Germany). Total free fatty acid content was based on a methodology described by Bligh et al.

Results

Results are shown in Figures 1-3. Figure 1 shows the percentage gastric fat emptying during in vitro gastric digestion of total fat intake ("%OI"). Compositions A and B were subjected to the dynamic in vitro gastric digestion model as mentioned above. The fat fraction of composition A emptied faster from the gastric digestion incubation chamber (which resembles the stomach) than fat comprised by composition B, which retained more in the in vitro stomach. At the 120 minute time point, only 35% of total fat of composition A had not left the gastric compartment, whereas 63% of the dietary fats that entered the system was retained in the gastric compartment of composition B. At t=150, about 20% of total fat comprised by composition A was still located in the gastric incubation chamber (meaning about 80% had emptied). At t=150, 60%) of the fat fraction of composition B was present in the gastric compartment, meaning about 40% of total fat had emptied therefrom. Presented results are average values from three samples.

Figure 2 shows the cumulative free fatty acid (FFA) amount during in vitro gastric digestion of emptied contents in mg FFA of the emptied gastric substance. Compositions A and B were subjected to the dynamic in vitro gastric digestion model as mentioned above. A clear trend was visualized wherein the FFA content of composition A was higher than determined for composition B. Presented results are average values of three samples.

When the outcome of Figures 1 and 2 are combined, it can be concluded that the gastric fat digestion of composition A was more efficient than that of composition B. The total amount of fat that was emptied from the gastric chamber at t=120 was 11.3 g (65 % of 17.4 g intake), of which 2 grams was converted into FFA, meaning 18% of all emptied fat was converted into FFA. For composition B, the percentage of converted FFA from the total amount of emptied fat was a mere 13%.

Figure 3 shows the percentage dry matter emptying during in vitro gastric digestion of total dry matter intake ("%OI"). Compositions A and B were subjected to the dynamic in vitro gastric digestion model as mentioned above. Dry matter of composition A emptied faster from the gastric digestion incubation chamber (which resembles the stomach) than dry matter of composition B, which retained more in the in vitro stomach. At the 120 minute time point, only about 29% of total dry matter of composition A had not left the gastric compartment, whereas about 38% of dry matter that entered the system was retained in the gastric compartment of composition B. At t=150, about 12%) of total protein comprised by composition A was still located in the gastric incubation chamber (meaning about 88%> had emptied). At t=150, still 29%> dry matter of composition B was present in the gastric compartment, meaning about 71%> of total dry matter had emptied therefrom. Presented results are average values from three individually taken samples.

Gastric emptying of proteins was also measured during the experiments (figure not shown). At t=120 minutes, 71%> of all proteins had emptied from the stomach compartment when composition A was subjected to the dynamic gastro-intestinal tract digestion model, versus merely 43%> for composition B. At t=150 this was 87%> for composition A and 48%> for composition B.

Summary

Liberation of free fatty acids from the fat fraction of nutritional composition A by the gastric digestion model was demonstrated to be significantly more pronounced than for comparable composition B. Another outcome of the study is that gastric emptying of the dietary fat fraction, as well as casein protein, is faster for composition A than B. Furthermore, gastric emptying of the contents as measured by total dry matter content of the gastric incubation chamber is faster for composition A than B. Also, fat digestion into FFA of the fat fraction contained in composition A progressed more efficiently than the fat fraction of composition B.

When considering the emptying behavior of proteins, fat and total dry matter in relation to each other for both compositions A and B, it can be concluded that a more balanced, better concerted emptying of nutrients from composition A from the stomach occurs than was found for composition B after a sufficient gastric residence time. The ratio of emptying for composition A for proteins, fat and dry matter is 71%>:65%>:71%>, compared to 43%>:37%>:62%> after 2 hours gastric digestion. At t=90 these ratios are 50:46:50 and 36:33 :45 for compositions A and R, respectively. At t=150 these ratios are 87:80:88 and 48:40:70 for compositions A and R, respectively. Based on these values, the following table can be presented wherein also the ratios in the amounts of protein, fat and dry matter is presented. Table 1. Values of columns A and B indicate the emptied amounts of indicated constituents after 90, 120 and 150 minutes gastric digestion, as a percentage of the amount of starting material for compositions A and B, respectively. Percentages of emptied constituents are also expressed as ratios relative to the percentage emptied fat. Prot. = protein, DM = dry matter.

These results allow the conclusion to be drawn that at least from 90 minutes of gastric digestion onwards, a more balanced gastric emptying of macronutrients occurs or at least more balanced gastric emptying of proteins, fat and total dry matter occurs.

It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the invention and without diminishing its advantages. It is therefore intended that such changes and modifications are covered by the appended claims.

CITED LITERATURE

Blanquet, S., et al., A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions. Pharm Res, 2004. 21(4): p. 585-91.

Boirie Y et al, Slow and fast dietary proteins differently modulate postprandial protein accretion. Proc. Natl. Acad. Sci. USA, December 1997, Vol. 94, pp. 14930-14935,. Brener, W., T.R. Hendrix, and P.R. McHugh, Regulation of the gastric emptying of glucose. Gastroenterology, 1983. 85(1): p. 76-82.

Elashoff, J.D., T.J. Reedy, and J.H. Meyer, Analysis of gastric emptying data.

Gastroenterology, 1982. 83(6): p. 1306-12.

Feldman M, Cryer B, McArthur KE, Huet BA, Lee E (1996) Effects of aging and gastritis on gastric acid and pepsin secretion in humans: A prospective study.

Gastroenterology 110 (4): 1043-1052. Hellstrom, P.M., P. Gryback, and H. Jacobsson, The physiology of gastric emptying. Best Pract Res Clin Anaesthesiol, 2006. 20(3): p. 397-407.

Horowitz, M., et al., Role and integration of mechanisms controlling gastric emptying. Digestive diseases and sciences, 1994. 39(12 Suppl): p. 7S-13S.

Minekus M, Marteau P, Havenaar R, Huis in 't Veld JHJ (1995) Multicompartmental dynamic computer-controlled model simulating the stomach and small intestine. Altern Lab Animals 23 : 197-209.