Patent Description:
There is a general need for nutritional compositions providing a high amount of calories and nutrients in a relatively low volume of formula.

Such nutritional compositions are particularly needed for elderly patients having reduced appetite, for patients with reduced tolerance to high or even normal amounts of food, patients in need of more than normal calorie and nutrient supply (e.g. patients suffering from (chronic) wasting diseases).

One issue in feeding patients at risk of or with malnutrition is low compliance with the nutritional therapy. Patients often do not tolerate high or even normal volumes of food and / or nutritional compositions.

Typically, the need for a high amount of calories in relatively low volume is met by increasing the amount of lipid and/ or carbohydrate in nutritional compositions. Increasing the protein content is difficult. In particular in compositions comprising minerals and vitamins, such as nutritionally complete compositions, interactions between minerals and proteins make it often impossible to obtain a stable, homogeneous composition.

However, there is often a medical need for compositions being high in protein and calories in a low volume of formula. And still, for mainly technical reasons, nutritional compositions having a high amount of protein typically have a lower caloric density. Also, compositions high in protein are often devoid of or at least low in lipids and/ or carbohydrates.

Thus, the protein density of a nutritional composition is typically not simultaneously increased with the caloric density as such an increase typically poses problems in terms of processability, homogenization, sterilization, fouling, instable emulsions and/or high viscosity. These issues are most pronounced for nutritionally complete compositions, i.e. compositions providing minerals and vitamins in amounts rendering them suitable as sole source of nutrition.

Therefore, when it comes to ready to use nutritional compositions and in particular nutritionally complete compositions, the patient / caregiver typically has to choose one of two options: <NUM>. high caloric nutrition or <NUM>. nutrition high in protein.

<CIT> discloses a liquid high-fat protein composition for persons who are unable to meet their nutritional requirements. The composition comprises non-micellar casein, a heat stabilization system and a high amount of fat. <CIT> relates to enteral formula containing a mixture of caseinate and stabilizing protein, which is either whey or vegetable. The formula exhibits reduced creaming compared to formula containing caseinate as sole protein source. <CIT> concerns an enteral nutritional product for persons with neurological injury. The product is low in carbohydrate and high in fat with a ratio n-<NUM> to n-<NUM> fatty acids from <NUM>-<NUM>. <CIT> discloses a liquid enteral nutritional product with a protein system of <NUM>-90wt. % soy protein hydrolysate and not more than <NUM> wt% of intact protein sources.

Accordingly, there is a need for nutritional compositions simultaneously providing a high caloric density and a high amount of protein. In particular there is a need for such a composition being additionally adaptable to be nutritionally complete.

The inventors found that the use of a protein component comprising at least two different protein sources, wherein low molecular weight protein having a molecular weight (Mw) of from <NUM> Da to <NUM> Da is the first protein source and present from <NUM>-90wt% based on the total weight of the protein component, and the second protein source is selected from milk protein and present from <NUM>-<NUM> wt% based on the total weight of the protein component it is possible to provide homogeneous nutritional compositions having both: high caloric density of at least 2kcal/mL and a high amount of protein (at least <NUM> EN% based on the total energy of the nutritional composition) in a low volume.

Moreover, the inventors found that such nutritional compositions can be supplemented with minerals and vitamins in sufficient amounts to render them nutritionally complete and still be stable and homogeneous.

In a first aspect, the present disclosure relates to nutritional compositions comprising a protein component, a lipid component, a carbohydrate component, minerals, vitamins and water, wherein the protein component comprises at least two different protein sources; wherein the nutritional composition has a caloric density of at least 2kcal/mL, the nutritional composition has a pH of <NUM>-<NUM>, and the protein component provides at least <NUM> EN% % based on the total energy of the nutritional composition, and wherein the first protein source is low molecular weight protein having a molecular weight (Mw) of from <NUM> Da to <NUM> Da, the lipid component provides at least <NUM> EN % of the total energy of the composition, the first source of protein represents <NUM>-<NUM> wt% based on the total weight of the protein component, the second protein source is selected from milk protein, wherein the milk protein represents <NUM>-<NUM> wt% based on the total weight of the protein component and wherein the nutritional composition comprises at least <NUM> protein per <NUM> product.

Also disclosed herein is a process for making such a nutritional composition.

Additionally, the use of such a composition is disclosed herein.

Further disclosed herein is a dose unit comprising the nutritional composition.

A dosage regime for applying the nutritional composition is also disclosed herein.

"High protein" as used herein refers to nutritional compositions wherein the protein component provides at least <NUM> EN%, preferably at least <NUM> EN%, most preferred at least <NUM> EN% based on the total energy of the nutritional composition. In preferred embodiments, such nutritional compositions comprise at least <NUM> wt% of protein based on the total weight of the composition. According to the present disclosure, there may be an upper limit to protein content such as at most <NUM> EN%, preferably at most <NUM> EN%, more preferred at most 28EN%.

"High caloric" as used herein refers to nutritional compositions having a caloric density of at least <NUM> kcal/mL, preferably at least <NUM> kcal/ml, more preferably at least <NUM> kcal/mL, most preferably at least <NUM> kcal/mL.

"Low molecular weight protein" as used herein refers to protein for example obtainable by hydrolysis by procedures known to the skilled artisan. Low molecular weight proteins herein have an average molecular weight Mw of from <NUM> Da to <NUM> Da. Methods for determining the average molecular weight are well known in the art. An exemplary method is given hereinbelow.

"Nutritional composition" herein refers to a synthetically produced food composition. Thus, nutritional compositions are artificial nutritional products obtained by mixing / dissolving bulk ingredients whereby said ingredients are typically provided in solid form (e.g. powders) or liquid from (e.g. oils, water, syrup). The term "nutritional composition" excludes "food", i.e. nonmodified natural food products, such as meat, vegetables, fruits in their natural form and conventionally prepared (e.g. cooked) meals or drinks like tea, coffee or juices.

For the present disclosure, "nutritional compositions" are limited to liquid or semi-solid compositions.

"Patient nutrition" as used herein refers to nutrition intended for individuals suffering from a medical condition. Patient nutrition as defined herein excludes the provision of nutrients in the form of conventionally prepared meals ("food"). Patient nutrition therefore only refers to the provision of nutrients in form of nutritional compositions as defined above. Herein, patient nutrition is intended for patients having high caloric needs and high protein needs.

"Nutritionally complete" refers to nutritional compositions suitable as sole source of nutrition. To be nutritionally complete, it is required that a nutritional composition comprises - in addition to the lipid, carbohydrate and protein components - minerals and vitamins. In order to be nutritionally complete, vitamins and minerals should be present in sufficient amounts as known to the man skilled in the art, i.e. in accordance with established nutritional guidelines. The recommended nutrient requirements, in particular with respect to minerals and vitamins, can be found in standard nutritional guidelines such as EU commission directive <NUM>/<NUM>/EC.

(see table <NUM> hereinbelow). Suitable nutrients according to the present disclosure fulfil the requirements of / are listed in REGULATION (EU) No <NUM>/<NUM>.

"Malnutrition" as used herein refers to one or both of Option I: body mass index (BMI, kg/m2) <<NUM>; Option II: the combined finding of unintentional weight loss (mandatory) and at least one of either reduced BMI or a low fat free mass index (FFMI). Weight loss is defined as either ><NUM>% of habitual weight indefinite of time, or ><NUM>% over <NUM> months. Reduced BMI is <<NUM> or <<NUM>/m2 in subjects younger and older than <NUM> years, respectively. Low FFMI is <<NUM> and <<NUM>/m2 in females and males, respectively.

A composition "consisting of" a number of ingredients or components is to be understood as comprising no other than the named ingredients or components. In case ranges for amounts of ingredients or components are given, the individual amount of all ingredients or components within the composition has of course also to be adapted such that the sum of all amounts of all present ingredients or components adds up to 100wt%.

"Homogenization" as used herein refers to the process of diminishing the size of the fat globules in a nutritional emulsion. A preferred homogenization process herein comprises two homogenization steps. The first homogenization step may be carried out at a pressure of 100bar and the second homogenization step may be carried out at <NUM> bar. Both steps may be carried out at a temperature of <NUM>-<NUM>, such as <NUM>-<NUM>, for example <NUM>.

"UHT-treatment" aims at killing of microorganisms. Preferred UHT treatment may be carried out with a pre-heat treatment at <NUM> for <NUM> followed by UHT at <NUM> for <NUM> seconds, followed by a (third) homogenization step requiring homogenization at less than <NUM> with a pressure that can oscillate between <NUM>-<NUM> bar.

"Protein component" as used herein refers to the entirety of ingredients of the nutritional composition declarable as "protein".

"Lipid component" as used herein refers to the entirety of ingredients of the nutritional composition declarable as "fat".

"Carbohydrate component" as used herein refers to the entirety of ingredients of the nutritional composition declarable as "carbohydrate".

"EN%" refers to the contribution of a certain component or of a specific ingredient to the total nutritional energy of an edible composition, e. g the nutritional composition.

"Ready-to-use" refers to the final form of the nutritional composition as administered to a patient. Typically, the nutritional compositions herein are pre-packed in a ready to use format. sold in separately packed dose units that do not require any further dilution etc..

The nutritional compositions herein comprise nutrients in predetermined and controllable amounts. A nutritional composition according to the present disclosure comprises a protein component, a lipid component, a carbohydrate component, minerals, vitamins and water. Optionally, such a nutritional composition may further comprise dietary fibres and/or further ingredients known as food additives.

The nutritional compositions herein typically are liquid or semi-solid and will typically be provided in an oil-in-water emulsion (O/W).

The nutritional compositions are adapted to have a high caloric density of at least <NUM> kcal/mL, preferably at least <NUM> kcal/ml, more preferably at least <NUM> kcal/mL, most preferably at least <NUM> kcal/mL. Typically, the nutritional compositions will have a caloric density of at most <NUM> kcal/mL, preferably at most <NUM> kcal/ml, most preferred at most <NUM> kcal/mL. For example, the compositions herein have a caloric density of <NUM>-<NUM> kcal/mL.

The nutritional composition herein may comprise a lipid component, a protein component, a carbohydrate component, wherein.

Preferably, in the nutritional compositions according to the present disclosure comprises a lipid component, a protein component, a carbohydrate component, wherein.

In preferred embodiments, the amount of water comprised in the present composition represents <NUM>-<NUM> wt% based on the total weight of the nutritional composition, preferably <NUM>-<NUM> wt%.

The nutritional composition of the present disclosure is administered enterally, preferably orally.

The protein component comprises at least two different protein sources, wherein the first protein source is low molecular weight protein and represents <NUM>-<NUM> wt%, preferably <NUM>-<NUM> wt% based on the total weight of the protein component.

The first protein source is selected form proteins with low average molecular weight, i.e. an average molecular weight Mw of <NUM> Da - <NUM> Da. In view of patient compliance, low molecular weight proteins with reduced or masked bitter taste are preferred.

The second protein source is selected from milk protein, such as total milk protein, milk protein isolate, milk protein concentrate, whey, casein and mixtures thereof, preferably total milk protein and / or milk protein concentrate.

Within the second protein source, proteins having different average molecular weights (Mw ) may be used. Preferred average molecular weights of the proteins used within the second protein source lie in the range of <NUM>-60kDa. In such a range properties of the nutritional composition can be well balanced in terms of heat stability and/ or viscosity.

For example, within the range of <NUM>-60kDa, a second protein source comprising a high amount of a protein having a relatively lower molecular weight will lead to a reduced viscosity of the nutritional composition. Therefore, a preferred second protein source comprises more than <NUM> wt%, preferably more than <NUM> wt% of a protein having an average molecular weight of <NUM>-<NUM> kDa (based on the total weight of the second protein source).

A preferred protein component comprises low molecular weight protein having a molecular weight (Mw) of from <NUM> Da to <NUM> Da as the first protein source and milk protein as the second protein source, wherein the first source of protein represents <NUM>-<NUM> wt% based on the total weight of the protein component. Such a protein component is particularly suitable as it can be adapted such that it provides an amino acid distribution suitable to meet current international recommendations for daily intake (e.g. when the nutritional compositions of the present disclosure are used as sole source of nutrition), even without addition of free amino acids, di- or tri-peptides. Such an exemplary international recommendation has been published by the WHO (Technical Report Series <NUM>, <NUM>, p. Particularly preferred is a protein component comprising <NUM>-<NUM> wt% of low molecular weight protein having a molecular weight (Mw) of from <NUM> Da to <NUM> Da as the first protein source and <NUM>-10wt% milk protein as the second protein source, such as <NUM> wt% low molecular weight protein having a molecular weight (Mw) of from <NUM> Da to <NUM> Da with <NUM> wt% milk protein (each based on the total weight of the protein component).

Further amino acids may as well contribute to the second protein source. These may be added in their chemical form or in the form of low molecular peptides, such as di- or tri-peptides. However, in preferred embodiments neither free amino acids nor di- or tri peptides are added to the protein component described herein.

Nutritional compositions herein comprise at least <NUM> wt% of protein based on the total weight of the nutritional composition.

In preferred embodiments, the protein component provides at least <NUM> EN%, preferably at least <NUM> EN%, more preferably at least <NUM> EN% based on the total energy of the nutritional composition. For example the protein component provides <NUM>-<NUM> EN%, preferably <NUM>-<NUM> EN% of the total energy of the composition.

Preferably, the protein to water ratio of the present nutritional composition is at least <NUM>/<NUM> [g/g], preferably at least <NUM>/<NUM> [g/g].

The carbohydrate component may comprise one or more carbohydrate sources. Typical carbohydrate sources may be selected from the list consisting of maltodextrine, glucose syrup, sucrose, fructose, isomaltulose, starch (modified or unmodified), tapioca dextrine, and mixtures thereof.

Typically, in nutritional compositions herein the carbohydrate component provides at least <NUM> EN%, preferably <NUM>-<NUM> EN%, for example <NUM>-<NUM> EN% based on the total energy of the nutritional composition.

A preferred carbohydrate component comprises glucose syrup and, preferably sucrose. The carbohydrate component may comprise <NUM>-95wt% of glucose syrup and <NUM>-95wt% of sucrose based on the total weight of the carbohydrate component. Preferably, the carbohydrate component comprises <NUM>-80wt% glucose syrup and <NUM>-40wt% sucrose, for example <NUM>-75wt% glucose syrup and <NUM>-35wt% sucrose based on the total weight of the carbohydrate component.

The nutritional composition herein may comprise ingredients declarable as dietary fibres. Suitable dietary fibres may be selected from the group consisting of cocoa powder, inulin, wheat dextrine, cellulose, microcrystalline cellulose, soy polysaccharides, tapioca dextrine, xanthan, fructooligosaccharides, galactooligosaccharides, at least partially hydrolysed guar gum, acacia gum, pectin, oat fibre, poly dextrose, resistant starch, hemicellulose and mixtures thereof.

The lipid component may comprise one or more lipid sources, such as lipids of animal and / or vegetable origin. Suitable lipid sources may be selected from oil of marine origin vegetable oils and combinations thereof. Preferably, lipid sources may be selected from fish oil, sunflower oil, safflower oil, soy oil, rapeseed oil, canola oil, linseed oil and combinations thereof. Additionally, the lipid component may comprise MCT in oil or fat form providing C6-C12 fatty acids.

In terms of individual fatty acids, the lipid component typically includes polyunsaturated fatty acids, monounsaturated fatty acids and saturated fatty acids. Suitable fatty acids may be selected from the group consisting of caproic acid (C6:<NUM>), caprylic acid (C8:<NUM>), capric acid (C10:<NUM>), lauric acid (C12:<NUM>), myristic acid (C14:<NUM>), palmitic acid (C16:<NUM>), palmitoleic acid (C16:1w7), stearic acid C18:<NUM>, oleic acid (C18:1w9), linoleic acid (C18:2w6), a-Linolenic acid (C18:3w3), eicosapentaenoic acid (C20:5w3), docosahexaenoic acid C22:6w3 and mixtures thereof.

The lipid component provides at least <NUM> EN%, preferably at least <NUM> EN% of the total energy of the nutritional composition herein.

In preferred embodiments, the lipid component provides at most <NUM> EN%.

Preferably, the lipid component provides <NUM>-<NUM> EN%, for example <NUM> - <NUM> EN% based on the total energy of the nutritional composition.

To be regarded as nutritionally complete, nutritional compositions have to comprise vitamins and minerals.

Suitable vitamins to be included in the composition in order to render it nutritionally complete according to the present disclosure are Vitamin A, Vitamin D, Vitamin K, Vitamin C, Thiamin, Riboflavin, Vitamin B6, Niacin, Folic acid, Vitamin B12, Pantothenic acid, Biotin and Vitamin E. An example for rendering a nutritional composition complete in vitamins is given in table <NUM>.

Suitable minerals to be included in the composition in order to render it nutritionally complete according to the present disclosure are Sodium, Chloride, Potassium, Calcium, Phosphorus, Magnesium, Iron, Zinc, Copper, Iodine, Selenium, Manganese, Chromium and Molybdenum. Optionally, Fluoride may be included. An example for rendering a nutritional composition complete in minerals is given in table <NUM>.

Nutritional compositions optionally comprise food additives. Additives are typically present in total amount of less than 10wt%, 5wt% or even less than 1wt% based on the total weight of the nutritional composition. Exemplary additives are choline, beta-carotene, lutein, lycopene, caffeine, lecithin, taurine, carnitine, myo-inositol, colorants, aroma and mixtures thereof. Aromas may be caramel, vanilla, yoghurt, chocolate, coffee, cappuccino, fruit aromas and the like.

The additives may include the stabilisers and emulsifiers. Preferably, the stabilisers are selected from gums and mixtures thereof. For example microcrystalline cellulose (E460), sodium carboxymethylcellulose (E466), carrageenan (E407), diacteyl tartaric acid ester of glycerides, cellulose gel (cellulose, microcrystalline). The emulsifiers may be selected from (destilled) monoglycerides such as E471, soy lecithins. For example, stabilizers and emulsifiers are included in the following amounts / ratios monoglycerides (E471, as an emulsifier) <NUM>-<NUM>/L and a stabilizer mixture comprising <NUM>-<NUM>/L, soy lecithin <NUM>-<NUM>/L, diacetly tartaric acid of glycerides (E472, eg. DATEM) <NUM>-<NUM>/L and MCC <NUM>-<NUM>/L.

The nutritional composition of the present disclosure may be used in therapy, for example nutritional therapy. In other words, the nutritional composition herein may be used as patient nutrition.

In one embodiment, the nutritional compositions of the present disclosure are for use in prevention and treatment of nutrient deficiencies associated with malnutrition.

In a further embodiment the nutritional compositions of the present disclosure are for use in prevention and treatment of nutrient deficiencies associated with therapeutic fluid restriction. For example, patients requiring therapeutic fluid restriction may be selected from dialysis patients, patients with cardiac insufficiency and patients with liver insufficiency.

In a further embodiment the nutritional compositions of the present disclosure are for use in prevention and treatment of nutrient deficiencies associated with (chronic) wasting diseases such as catabolism, (cancer) cachexia, HIV, chronic wounds or sarcopenia.

The nutritional compositions of the present disclosure are for use in prevention and treatment of nutrient deficiencies in any condition associated with increased protein needs or overall energy, preferably both. Examples are gastrointestinal conditions associated with protein and / or energy wasting.

Moreover, the nutritional compositions of the present disclosure are for use in prevention and treatment of nutrient deficiencies associated with neurological disorders, anorexia, chronic obstructive pulmonary disease (COPD).

The nutritional compositions described herein are obtainable by a process comprising the following steps:.

In a first step, water is provided and heated to a temperature of <NUM>-<NUM>.

In a second step the carbohydrate component - or a fraction thereof - and, optionally, stabiliser, such as MCC, is added.

In a third step the protein component is added.

In a fourth step the lipid component is added, preferably at an elevated temperature of <NUM>-<NUM>, preferably in combination with a (further) emulsifier and / or stabiliser, such as soy lecithin and / or diacetyl tartric acid of glycerides (e.g. DATEM), and / or (destilled) monoglycerides.

In a fifth step vitamins, minerals and, optionally, the remaining fraction of the carbohydrate component are added. In this step any other powder ingredient may be added. fibres, aroma, and other additives. At any time before, while or after the fifth step, the mixture is allowed to cool to <NUM>-<NUM>.

In a sixth step, the pH of the mixture is adjusted to <NUM>-<NUM>, preferably <NUM>-<NUM>, e.g. <NUM>.

In a seventh step, the mixture is homogenized, e.g. at <NUM>-<NUM> at a pressure of <NUM>/<NUM> bar,.

In an eighth step, the mixture is sterilized. The eighth step may comprise (<NUM>. a) a preheating step, (<NUM>. b) a heating step and (<NUM>. c) an additional homogenization step. For example:.

The nutritional compositions herein are typically provided in a dose unit.

A dose unit herein refers to <NUM>-<NUM>, preferably <NUM>-<NUM> separately provided in package such as a bottle, tetra brick or bag.

Such a dose unit provides <NUM> - 500kcal, preferably <NUM>-450kcal.

Such a dose unit provides <NUM>-<NUM>, preferably <NUM>-<NUM> of protein, such as <NUM> of protein.

An exemplary dose unit provides 400kcal and <NUM> of protein in a dose unit of <NUM>.

Accordingly, an exemplary daily dose for complete nutrition of <NUM>-2500kcal of the nutritional compositions herein may be provided with <NUM>-<NUM> dose units, for example <NUM> dose units. Accordingly, a daily dose for complete enteral nutrition may be provided by <NUM> dose units each providing <NUM>-450kcal.

A typical daily dose for supplemental nutrition of <NUM>-900kcal of the nutritional compositions herein will be provided by <NUM>-<NUM> dose units. For example by <NUM>-<NUM> dose units each providing <NUM>-450kcal.

Nutritional compositions according to table <NUM> were prepared. After mixing, a homogenization step was conducted.

Example <NUM> is a standard nutritional composition already high in calories with a protein component solely based on milk protein. While being stable and homogeneous at <NUM> kcal and 20EN% protein (Example <NUM>), it was not possible to obtain a sufficiently homogeneous composition when increasing caloric density (Example <NUM>).

Surprisingly, increasing caloric density was possible by adding low molecular weight protein in sufficient amounts to milk protein (Example <NUM> and Example <NUM>). Example <NUM> is a comparative example with insufficient amount of low molecular weight protein.

Example <NUM> further shows that with inclusion of sufficient low molecular weight protein very high energy densities of protein can be reached in a formula that provides high caloric density (Example <NUM>: <NUM> kcal) or very high caloric density (Example <NUM>: <NUM> kcal/mL).

The inventors further observed that fouling during heat treatment could be reduced / prevented when increasing wt% of low molecular weight protein in the protein component (Example <NUM>).

With the nutritional composition, a drinkable viscosity of nutritionally complete compositions can be provided inspite high protein and energy content.

The inventors further observed that bitterness of the product could be reduced by increasing wt% of low molecular weight protein in the protein component. Therefore, the nutritional composition will result in a better patient compliance.

Equipment: GPV/HPLC with UV detector operating at <NUM>. Column: e.g. TSK <NUM> SW XL (Toshoh Biosience GmbH). However, it is understood that the skilled artisan will choose column material as appropriate for the evaluated protein. Isocratic elution using <NUM> mmol/l sodium phosphate buffer (pH <NUM>). Suitable calibration is carried out as known to the skilled artisan, e.g. by means of well-defined fragments. In general, the skilled person is well aware of molecular mass determination via GPC. Another suitable method for determining the Mw of small macromolecules (such as those of the first protein source) is MALDI-MS.

Claim 1:
Nutritionally complete nutritional composition comprising a protein component, a lipid component, a carbohydrate component, minerals, vitamins and water, wherein the protein component comprises at least two different protein sources; wherein the nutritional composition has a caloric density of at least 2kcal/mL, the nutritional composition has a pH of <NUM>-<NUM>, the protein component provides at least <NUM> EN% based on the total energy of the nutritional composition, and wherein
a) the first protein source is low molecular weight protein having a molecular weight (Mw) of from <NUM> Da to <NUM> Da,
b) the lipid component provides at least <NUM> EN % of the total energy of the composition,
c) the first source of protein represents <NUM>-<NUM> wt% based on the total weight of the protein component,
d) the second protein source is selected from milk protein, wherein the milk protein represents <NUM>-<NUM> wt% based on the total weight of the protein component and
e) wherein the nutritional composition comprises at least <NUM> protein per <NUM> product.