Lipid matrix-based particles

Abstract

The invention relates to non-liposomal lipid matrix-based particles of nutrients, particularly of water-soluble vitamins, showing a continuous release of the nutrient throughout the small intestine, and a method of manufacturing it. The non-liposomal lipid matrix-based particles of nutrients are intended for use in food, agricultural, personal care, cosmetic, manufacturing, or pharmaceutical applications, and particularly in supplementation applications.

Description

[0001] LIPID MATRIX-BASED PARTICLES

[0002] TECHNICAL FIELD

[0003] The present invention relates to non-liposomal lipid matrix-based particles of a water-soluble or fat-soluble nutrient providing a modified or sustained release of such nutrient, manufacturing processes for such particles, delivery systems and compositions incorporating these particles for use in food, agricultural, personal care, cosmetic, manufacturing, and pharmaceutical applications. The present invention further relates to the use of the non-liposomal lipid matrixbased particles in nutritional supplementation formulations and products.

[0004] BACKGROUND

[0005] It is known that intravenous administration of vitamin C, also known as ascorbic acid, reduces oxidative stress and can improve immune function in animals and humans. Vitamin C has several essential functions in the human body. It is supporting the immune system, acting as an antioxidant, and maintaining healthy skin and bones. Oral vitamin C has much lower bioavailability than intravenous administration of vitamin C due to degradation in digestive pathways which reduce the effective amounts of vitamin C reaching the blood stream. Cellular uptake of vitamin C is limited due to saturation of the active transport system, causing excess of ingested vitamin C to be secreted from the body. Therefore, there is an increased interest and need, and currently a high research and development activity in the industry on enhancing oral delivery of vitamin C, and thus increasing bioavailability, using dedicated formulation technology, such as liposomal delivery, enabling sustained release allowing a more consistent absorption and achieving higher plasma levels.

[0006] The number of liposomal nutrients, i.e. nutrients embedded in liposomes, particularly vitamin C supplementation products on the market steadily grow. Such products aim at reducing degradation and enhancing bioavailability of e.g., vitamin C, particularly by avoiding early degradation in the Gl tract which can done by providing a continuous or a sustained release of vitamin C, evenly released throughout the Gl tract.

[0007] Liposomes are spherical lipid vesicles (50-500 nm) composed of a lipid bilayer. They are produced by creating lipid bilayers in an organic solvent, evaporating the solvent, and breaking the bilayer into liposomes in an aqueous medium by homogenization, followed by a washing and a drying process in case the powder is desired for further processing. Liposomal formulations are complex as many different steps or operations and / or many different ingredients are required to obtain and stabilize liposomes, all of which makes liposomal formulations expensive, and the manufacturing processes elaborate and effortful. Examples of liposomal vitamin C formulations can be found in CN 1698643, CN 101239040, US2014141066A1 , US2016367480A1 , CN105902996, WO2018172511A1 , WO2019221598A1 , WO2021176327A1 , WO2023141658A1 , or KR20230027971A.

[0008] The inventors intended to provide alternatives to the available liposomal formulations of nutrients, in particular liposomal formulations of vitamin C, having similar release profiles and effects, but which are not as elaborate, effortful, and expensive. Liposomal formulations have several disadvantages. Most of the various formulations on the market are liquid and therefore face long-term stability issues, leaking the payload too early, whereas solid forms of liposomal formulations face different challenges. The solid liposomal formulations require a reliant drying process on the one hand, as such drying processes often lead to leakage of the payload from the liposomes eventually, and a reliant re-hydration step of the solid liposomal formulation on the other hand, providing a ready-to-use formulation.

[0009] The inventors have surprisingly found that the same effect of a liposomal formulation providing continuous release of vitamin C throughout the Gl tract can be reached with less sophisticated compositions and obtained by a less complex formulation technique, by providing a nutrient, such as vitamin C, in non-liposomal lipid matrix-based particles having a water content of less than 10 wt% (weight %), less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, preferably of less than 8 wt%, more preferably of between 6 and 1 wt%, most preferably of between 5 and 2 wt% of the total weight of the non-liposomal lipid matrix-based particle formulation according to the present invention as described hereinafter.

[0010] It has further been found that the same delivery method and formulation technique can be applied to other water-soluble nutrients, such as water-soluble vitamins of the group of B vitamins, its precursors, or derivatives thereof, minerals, or amino acids, but also to fat-soluble vitamins, such as vitamins A, D, E and K, or to carotenes, including its precursors, or derivatives, or to mixtures thereof.

[0011] SUMMARY

[0012] In accordance with a first aspect, the invention relates to non-liposomal lipid matrix-based particles comprising a water-soluble or fat-soluble nutrient, preferably a water-soluble vitamin of the group of B vitamins or vitamin C, minerals, or an amino acid, more preferably vitamin C, wherein said water-soluble or fat-soluble nutrient, or a mixture thereof, is embedded in a lipid matrix, and wherein the lipid matrix comprises a lipid, preferably a phospholipid, and more preferably a lecithin; and wherein said non-liposomal lipid matrix-based particles have a water content of less than 10 wt% (weight %), less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, preferably of less than 8 wt%, more preferably of between 6 and 1 wt%, most preferably of between 5 and 2 wt% of the total weight of the non-liposomal lipid matrix-based particle formulation.

[0013] In a second aspect of the present invention, the non-liposomal lipid matrix-based particles according to the first aspect are comprised in a delivery system or a nutritional composition.

[0014] Another aspect of the invention relates to a method of manufacturing such non-liposomal lipid matrix-based particles as described in the first aspect which comprises a water-soluble or a fatsoluble nutrient, preferably a water-soluble vitamin of the group of B vitamins, or vitamin C, its precursors, derivatives thereof, a mineral, or an amino acid, or a mixture thereof, more preferably vitamin C, characterized in that the method comprises three steps: i. wherein the lipid, preferably the phospholipid, more preferably the lecithin, is dissolved or melted in a hydrophobic solvent, preferably in alkyl ethers, alkyl esters, hexane, heptane, dichloromethane, or chloroform, more preferably in alkyl ethers, or alkyl esters, hexane, heptane, most preferably in ethyl acetate, isopropyl acetate, isobutyl acetate, or isopentyl acetate, or mixtures thereof; ii. wherein the solid nutrient, preferably a water-soluble nutrient, preferably in powder form, more preferably vitamin C in powder form, is added to the solubilized lipid slowly, and under stirring until the nutrient is fully dispersed; and then iii. wherein the solvent is evaporated under reduced or atmospheric pressure; and wherein the obtained non-liposomal lipid matrix-based particles preferably have a watercontent of less than 10 wt% (weight %), less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, preferably of less than 8 wt%, even more preferably of between than 6 and 1 wt%, most preferably between 5 and 2 wt% based on the total weight of the non-liposomal lipid matrix-based particle formulation. A further aim of the present invention is to provide a composition comprising the non-liposomal lipid matrix-based particles according to the invention as described herein, further comprising diluents, emulsifiers, surfactants, plasticizer, antioxidants, colorants, or additional lipids suitable for human or animal consumption.

[0015] In a fifth aspect of the invention, the non-liposomal lipid matrix-based particles as described herein are comprised in a consumer product.

[0016] In a sixth aspect of the invention is the use of the non-liposomal lipid matrix-based particles according to the invention as described hereinabove in a formulation for application in food, feed, agriculture, personal care, cosmetic, or in pharmaceutical formulations, preferably in applications for food and feed, more preferably for application in nutritional supplements.

[0017] The details, examples and preferences provided in relation to any particular one or more of the stated aspects of the present invention will be further described herein and apply equally to all aspects of the present invention. Any combination of the embodiments, examples and preferences described herein in all possible variations thereof is encompassed by the present invention unless otherwise indicated herein, or otherwise clearly contradicted by context.

[0018] Brief Description of the Drawings

[0019] Figure 1 : Dissolution of vitamin C as such - measurement of 2 different samples - showing immediate dissolution and degradation of vitamin C over time.

[0020] Figure 2: Dissolution experiments of prototype sample 3 of example 1 (3-fold) having a ratio of vitamin C : lecithin of 30 : 70 - show a sustained release profile that confirms what has been assumed at visual inspection, the vitamin C crystals are embedded completely in the lipid.

[0021] DETAILED DESCRIPTION

[0022] The present inventors studied the characteristics of liposomal formulations of water-soluble and fat-soluble nutrients providing continuous release throughout the small intestine over a prolonged period of time, which is also called sustained release. The manufacture of liposomal formulations of water-soluble and fat-soluble nutrients, particularly of vitamin C, is everything but trivial, this is particularly true for the de-hydrating of liposomes for the delivery in solid forms, and the re-hydrating of the solid form for ready-to-use liquid formulations. Therefore, it is not unusual that dry powder formulations of liposomes can be leaking the very active they are supposed to be protecting. Liposome manufacturing is elaborate, effortful and expensive, and thus there is a need for alternative approaches and formulations providing continuous or sustained release of nutrients, particularly of water-soluble nutrients, such as water-soluble vitamins, its precursors, derivatives thereof, minerals, an amino acid, or mixtures thereof.

[0023] The present inventors surprisingly found that nutrients, preferably water-soluble vitamins, can be released in the small intestine in a continuous manner comparable to liposomal formulations if the solid form of the nutrient is embedded or dispersed in a lipid matrix, such as phospholipids even though the lipids do not form liposomes with the water-soluble nutrient embedded therein.

[0024] The release studies show a sustained release profile and a gradual release of vitamin C in conditions corresponding to the degradation of the lipid matrix in the small intestine by pancreatic enzymes. The release is dependent on the formulation being exposed to bile salts and pancreatic enzymes. Slow release would lead to sustained uptake of vitamin C and would thus lead to lower and more stable vitamin C levels in the blood circulation over time.

[0025] Liposomes are understood as spherical vesicles composed of one or more stable lipid bilayers forming a hydrophobic cavity or core, which can entrap aqueous preparations. Liposomes can thus be loaded with certain ingredients protecting such payload. Due to their structure and similarity to cell membranes, liposomes can be used to deliver drugs, nutrients, or other bioactive substances to specific targets or cells in the body.

[0026] A lipid matrix as described herein shall mean that the nutrient is surrounded by a lipid. Non- liposomal lipid matrix-based particles are particles, wherein the nutrient particles are dispersed in a lipid forming a matrix but wherein the lipids do not form a stable bilayer that assembles to liposomes embedding the nutrient. Thus, the lipid matrix-based particles have not formed stable liposomes and are thus non-liposomal lipid matrix-based particles.

[0027] The lipids suitable for the non-liposomal lipid matrix-based particles of the present invention are any lipids that are not digested by gastric lipase and include hydrophilic or amphiphilic substances that usually are able to form structures such as vesicles, bilayers or multiple layers. The lipid may be any lipid, or at least one lipid as described hereinafter, or a combination of at least two different lipids. Lipids as defined herein can be fatty acids, fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, polyketides, sterol, or prenol lipids. Suitable examples for glycerolipids are mono, di-, and tri-substituted glycerols of fatty acids, preferably triglycerides. Suitable examples for glycerophospholipids are phospholipids such as phosphatidylcholine, also called lecithin, phosphatidylethanolamine, or phosphatidylserine. A suitable example of sterols is cholesterol. Lipids preferably used in the present invention are phospholipids, most preferred is lecithin, such as natural lecithin from e.g., soybeans or sunflowers.

[0028] “Modified release”, herein also called “sustained release”, shall mean the gradual and continuous release throughout the small intestine. This modified release can be measured as described in the art, such as in the USP (US Pharmacopeia) or the Ph. Eur. (European Pharmaceopeia) or according to the methods described hereinafter.

[0029] Organic solvents as used herein are preferably hydrophobic solvents. Suitable hydrophobic solvents include alkyl ethers, such as diethyl ether, alkyl esters, such as ethyl acetate, isopropyl acetate, isobutyl acetate, isopentyl acetate, chloroform, or dichloromethane, hexane, heptane, or mixtures thereof. Preferred hydrophobic solvents are alkyl ethers, alkyl esters, hexane, or heptane, and even more preferred are alkyl esters, such as ethyl acetate, isopropyl acetate, isobutyl acetate, or isopentyl acetate, or mixtures thereof.

[0030] The non-liposomal lipid matrix-based particles of a nutrient may further comprise other nutrients, such as water-soluble or fat-soluble vitamins, its precursors, or derivatives thereof, minerals, and an amino acid, or mixtures thereof.

[0031] Other ingredients may be added to the non-liposomal lipid matrix-based particles of a nutrient to enhance the release properties or to stabilize the formulation such as suitable diluents or bulking agents, emulsifiers, surfactants, plasticizer, additional lipids, or colorants. Such other ingredients are not to be added during the formation of the non-liposomal lipid matrix-based particles, only after the non-liposomal lipid matrix-based particles have been obtained.

[0032] The delivery system or the nutritional composition may further comprise other ingredients to enhance the release properties, or to stabilize the delivery system or the nutritional composition by adding suitable diluents or bulking agents, emulsifiers, surfactants, plasticizer, antioxidants, additional lipids, or colorants, whereas such other ingredients are added to the non-liposomal lipid matrix-based particles. Such other ingredients are not added during the manufacture of the non-liposomal matrix-based particles, but only after the non-liposomal lipid matrix-based particles have been obtained.

[0033] Suitable ingredients include such ingredients that are generally recognized as safe (GRAS) and meant for human or animal consumption. Suitable emulsifiers include but are not limited to ascorbylpalmitate, lecithin, citric acid esters, mono- / di-glycerides, polyoxyethylene sorbitan fatty acid esters, phosphates, or hydrocolloids, including modified hydrocolloids such as modified starch. Suitable diluents or bulking agents, include but are not limited to calcium carbonate, pectin, sorbit, silicium dioxide, or polysaccharides, such as starches. Suitable surfactants include but are not limited to polysorbates or salts of fatty acids sulfates, sodium laureth sulfate, sodium lauryl sulfoacetate, sodium cocoyl glycinate, sodium cocoyl glutamate, decyl glucoside, lauryl glucoside. Plasticizers are used to provide more flexibility in the formulation, leading to less leaking. Suitable plasticizers include but are not limited to propylene glycol, glycerol, polyethylene glycols, glycerol triacetate, triethyl citrate, acetyl triethyl citrate. Suitable antioxidants include but are not limited to vitamin C (ascorbic acid) derivatives thereof, citric acid, vitamin E (tocopherols), lactic acid, BHT, BHA, sorbic acid, natural antioxidants extracted from a plant biomass, such as rosemary extract, pomegranate extract, derivatives thereof, or mixtures thereof.

[0034] In the context of the present invention, hydrocolloids may be polysaccharides, gelatin of low bloom, medium bloom or high bloom from fish, pork or bovine, caseins / caseinates, plant- or animal-based protein, other proteinaceous hydrocolloids, and lignosulfonate.

[0035] In the context of the present invention, the term polysaccharide as used herein includes xanthan gum, gum acacia, pectin, guar gum, carob gum, alginates, celluloses, cellulose derivatives, such as starch and starch derivatives. Preferred polysaccharides according to the present invention are gum acacia, starch, starch derivatives, more preferred are gelatinized starch and modified food starch and especially preferred are modified food starches.

[0036] In the context of the present invention, the term "modified food starch" as used herein relates to modified starches that are made from starches substituted by known chemical methods with hydrophobic moieties. For example, starch may be treated with cyclic dicarboxylic acid anhydrides such as succinic and / or glutaric anhydrides, substituted with an alkyl or alkenyl hydrocarbon group.

[0037] A very common and preferred modified starch is starch sodium octenyl succinate (OSA- starch). OSA-starch as used herein denotes any starch (from any natural source such as corn, wheat, tapioca, potato or synthesized) that was treated with octenyl succinic anhydride. The degree of substitution, i.e., the number of esterified hydroxyl groups with regard to the total number of hydroxyl groups usually varies in a range of from 0.1 percent to 10 percent, preferably in a range of from 0.5 percent to 5 percent, more preferably in a range of from 2 percent to 4 percent.

[0038] Preferred diluents or bulking agents that can be used with the present invention are calcium carbonate, pectin, sorbit, silicium dioxide, or polysaccharide, such as starches, particularly potato or maize starch, or mixtures thereof.

[0039] Preferred emulsifiers that are used with the present invention are ascorbylpalmitate, lecithin, citric acid esters, mono- / di-glycerides, polyoxyethylene sorbitan fatty acid esters, phosphates, or modified hydrocolloids such as modified starch, or mixtures thereof.

[0040] Preferred surfactants that can be used with the present invention are polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, or polysorbate 80, salts of fatty acids sulfates, sodium laureth sulfate, sodium lauryl sulfoacetate, sodium cocoyl glycinate, sodium cocoyl glutamate, decyl glucoside, lauryl glucoside, or mixtures thereof. More preferred are polysorbates.

[0041] Preferred plasticizers that can be used with the present invention are glycerol, polyethylene glycols, glycerol triacetate, triethyl citrate, or acetyl triethyl citrate.

[0042] Preferred antioxidants that can be used with the present invention in the delivery system or the nutritional composition is vitamin C, derivatives thereof, citric acid, vitamin E (tocopherols), lactic acid, BHT, BHA, sorbic acid, natural antioxidants extracted from a plant biomass, such as rosemary extract, pomegranate extract, derivatives thereof, or mixtures thereof.

[0043] Preferred colorants include, but are not limited to, natural colorants, colorants identical to natural colorants, and synthetic colorants. Examples for such colorants include carotenoids, such as carotenes, like alpha- or beta-carotene, carotenals, or lycopene, or such as xanthophylls, like lutein, zeaxanthin, astaxanthin, capsanthin, or capsorubin.

[0044] Additional lipids that may be used with the present invention as described hereinabove include preferably oleates. Thus, the non-liposomal lipid matrix-based particles as described herein may be a mixture of a phospholipid and at least one other lipid, preferably an oleate or mixtures of oleates. The non-liposomal lipid matrix-based particles can be used in food, feed, agriculture, personal care, cosmetic, manufacturing, in pharmaceutical formulations, or in nutritional supplementation. Nutritional supplementation means a product that is intended to supplement the normal diet with particular nutrients.

[0045] Water-soluble nutrients shall include, but are not limited to, water-soluble vitamins, such as of the group of B vitamins, B1 (thiamine), B2, (riboflavin), B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine), B7 (biotin), B9 (folate), B12 (cobalamins), or vitamin C, or its precursors, or derivatives thereof, and mixtures thereof; water-soluble nutrients shall further include, but are not limited to, water-soluble minerals, such as calcium salts, magnesium salts, iron salts, essential minerals such as zinc, selenium, copper, or manganese salts, and mixtures thereof; water-soluble nutrients shall further include, but are not limited to, a-amino acids, from which proteins are composed and which are essential to life, such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, selenocysteine, or mixtures thereof.

[0046] Fat-soluble nutrients shall include, but are not limited to, fat-soluble vitamins, such as vitamin A, D, E, K and its precursors, derivatives thereof, or stabilized forms, or mixtures thereof. Fatsoluble nutrients shall further include carotenes, its precursors, derivatives thereof, stabilized forms, or mixtures thereof.

[0047] The delivery systems shall include, but are not limited to, any oral delivery systems including solid and liquid formulations, such as tablets, multi-particulates, capsules, gels, gums, wafers, inhalants, potions, or syrups.

[0048] Nutritional or supplement compositions shall include, but are not limited to, any compositions for supplementation of the natural diet by nutrients that may be deficient or are at risk to be deficient.

[0049] Preferred embodiments of the present invention include non-liposomal lipid matrix-based particles comprising a water-soluble nutrient being selected from the group of B vitamins, or vitamin C, its precursors, derivatives thereof, minerals, or an amino acid as described herein, or mixtures thereof.

[0050] A more preferred embodiment of the present invention shall include non-liposomal lipid matrixbased particles comprising selected from a B vitamin, or vitamin C, its precursors, derivatives thereof, or mixtures thereof, and wherein vitamin C, its precursors, derivatives, or mixtures thereof is most preferred.

[0051] Preferred embodiments of the present invention include non-liposomal lipid matrix-based particles wherein the water-soluble or the fat-soluble nutrient is embedded in a lipid matrix, and wherein the lipid may be at least one lipid, or a mixture of at least two lipids. Preferably, the at least one lipid, or one lipid of the mixture of the at least two lipids, is a phospholipid, or most preferably the at least one lipid, or one lipid of the mixture of the at least two lipids, is a lecithin.

[0052] Preferred embodiments of the present invention include non-liposomal lipid matrix-based particles having a water content of less than 10 wt% (weight %), less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, preferably of less than 8 wt%, more preferably of between 6 and 1 wt%, most preferably between 5 and 2 wt% based on the total weight of the non-liposomal lipid matrixbased particle formulation.

[0053] Embodiments of the present invention as described hereinabove include non-liposomal lipid matrix-based particles wherein the nutrient is comprised in a ratio of lipid : nutrient of between 95 : 5 and 5 : 95, or of between 90 : 10 and 10 : 90, preferably in a ratio of lipid : nutrient of between 80 : 20 and 20 : 80, more preferably in a ratio of lipid : nutrient of between 70 : 30 and 30 : 70.

[0054] With the present invention further advantages achieved are the use of less excipients and fewer steps in the manufacturing process, thus providing a more sustainable product and manufacturing process.

[0055] An additional beneficial effect of the non-liposomal lipid matrix-based particles of the present invention is that it provides an improved shelf-life of the nutrient formulation, and formulations and compositions derived from it, particularly having vitamin C, or derivatives thereof, as water- soluble nutrient.

[0056] The non-liposomal lipid matrix-based particles as described hereinabove are generated from lipids dissolved in suitable organic solvents. Whereas this includes that the lipids are dissolved in solvents and the water-soluble nutrients as described hereinabove are dispersed therein, and whereby preferably the water-soluble nutrients have been added in solid form. The non-liposomal lipid matrix-based particles and preferred embodiments of the present invention, as described and defined hereinabove, can be manufactured in general according to the following method:

[0057] The lipid can be dissolved or melted in a suitable organic solvent. Once the lipid is in a liquid state, the nutrient is slowly added as powder while mixing. The organic solvent may be evaporated while mixing. The resulting non-liposomal lipid matrix-based particles form a dry powder, a wax coated powder, or a solid lipid matrix. The at least one lipid, or the mixture of at least two lipids, or a lipid-excipient combination used must be such that it is in solid form and in ambient temperature.

[0058] A preferred embodiment of the present invention includes the method of manufacturing the non-liposomal lipid matrix-based particles of a nutrient as described hereinabove, characterized in that the method comprises the following steps: i. wherein the lipid is dissolved or melted in an organic solvent, preferably in a hydrophobic solvent, ii. wherein the solid nutrient, preferably a water-soluble nutrient in powder form, more preferably vitamin C in powder form, is added to the solubilized lipid slowly and under stirring, until the nutrient is fully dispersed in the lipid, and iii. wherein the solvent is evaporated under reduced or atmospheric pressure; wherein the obtained non-liposomal lipid matrix-based particles of the nutrient preferably have a water content of less than 10 wt% (weight %), less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, preferably of less than 8 wt%, more preferably of between 6 and 1 wt%, most preferably between 5 and 2 wt% of the total weight of the non-liposomal lipid matrix-based particles.

[0059] Another embodiment includes that the method as described above preferably comprises a phospholipid as lipid for the non-liposomal lipid matrix-based particles, and more preferably wherein the phospholipid is a lecithin, as described hereinabove. In addition, the lipid may be at least one lipid, or a mixture of at least two lipids. Preferably, the at least one lipid, or the mixture of at least two lipids is a phospholipid, or most preferably the at least one lipid, or one lipid of the mixture of the at least two lipids, is a lecithin. More preferably, the mixture of the at least two lipids is a mixture of a phospholipid and an oleate, or a mixture of oleates. An even further embodiment of the manufacturing method as described above includes the use of a hydrophobic solvent as organic solvent, wherein the hydrophobic solvent is selected from alkyl ethers, such as diethyl ether, alkyl esters, such as ethyl acetate, isopropyl acetate, isobutyl acetate, isopentyl acetate, chloroform, or dichloromethane, hexane, heptane, or mixtures thereof. Preferred hydrophobic solvents are alkyl ethers, alkyl esters, hexane, or heptane, and even more preferred are alkyl esters, such as ethyl acetate, isopropyl acetate, isobutyl acetate, or isopentyl acetate, or mixtures thereof.

[0060] Yet another embodiment of the present invention includes the manufacturing method as described above and requires that the non-liposomal lipid matrix-based particles preferably have a water content of less than 10 wt% (weight %), less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, more preferably of less than 8 wt%, even more preferably of between 6 and 1 wt%, most preferably of between 5 and 2 wt% of the total weight of the non-liposomal lipid matrix-based particle formulation.

[0061] A further embodiment of the manufacturing method of the non-liposomal lipid matrix-based particles as described hereinabove include that the lipid and the nutrient are provided in a ratio of lipid : nutrient of between 95 : 5 and 5 : 95, or of between 90 : 10 and 10 : 90, preferably in a ratio of lipid : nutrient of between 80 : 20 and 20 : 80, more preferably in a ratio of lipid : nutrient of between 70 : 30 and 30 : 70.

[0062] Another embodiment of the present invention includes a composition, such as an oral delivery system, or a nutritional composition, comprising the non-liposomal lipid matrix-based particles of the nutrient as described hereinabove and further comprising diluents, emulsifiers, surfactants, plasticizer, antioxidants, colorants, or additional lipids, all suitable for human or animal consumption.

[0063] Yet another embodiment of the present invention comprises a consumer product comprising the non-liposomal lipid matrix-based particles, compositions, or delivery systems as described hereinabove.

[0064] A further preferred embodiment includes the use of the non-liposomal lipid matrix-based particles in a formulation or composition for application in food, feed, agriculture, personal care, cosmetic, or in pharmaceutical formulations or composition, as described hereinabove, wherein applications for food and feed are preferred, and even more preferred are applications in nutritional supplementation.

[0065] Advantages of the present invention are that the nutrients are protected during the passage through the stomach by the lipid matrix, as the lipid matrix is not digested by the gastric lipases in the stomach. The release process starts then in the small intestine and allows the release of the nutrient evenly throughout the small intestine. By that, a continuous release throughout the small intestine is provided, allowing the nutrient being taken-up by the cell in concentrations that do not overwhelm transportation mechanisms. Therefore, the non-liposomal lipid matrix-based particles provide the same advantages as experienced and postulated for the liposome formulation, but the non-liposomal lipid matrix-based particles of the present invention do not require a sophisticated manufacturing process, storing or handling, and they allow a smaller number of different ingredients to stabilize the formulation. It was surprisingly found by the inventors that the same effect as for liposomal formulations could be achieved but with much less efforts and is thus more cost-efficient and sustainable.

[0066] As used in this application and in the claims, derivatives are understood as modifications of a parent substance through chemical reaction like substitution, addition, elimination, or rearrangement of atoms or groups of atoms, typically retaining most of the structural features of the parent substance but also exhibiting new properties introduced by the chemical modification, such as e.g. esters, amides, halogenated derivatives, ketones etc. One example is ascorbyl palmitate which is ascorbic acid derivatized by esterification with a palmitate to make ascorbic acid fat-soluble, to obtain ascorbyl palmitate which would then be considered a derivative of ascorbic acid and a derivative of palmitate.

[0067] As used in this application and in the claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise, whereas the term "includes" means "comprises." The methods and compositions of the present disclosure, including components thereof, can comprise, consist of, or consist essentially of the essential elements and limitations of the embodiments described herein, as well as any additional, or optional ingredients, components, or limitations described herein or otherwise useful in nutritional compositions. Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, percentages, and so forth, as used in the specification or claims are to be understood as being modified by the term "about." EXAMPLES

[0068] Example 1 : Manufacturing of the non-liposomal lipid matrix-based particles:

[0069] Materials used:

[0070] - Vitamin C USP / Ph. Eur (Lot TL02108285, DSM-Firmenich)

[0071] - Sodium deoxycholate (Lot D6750-25G, Sigma)

[0072] Basic method:

[0073] Lecithin was weighed and dissolved or melted in the hydrophobic solvent with a magnetic stirrer. Once lecithin has fully dissolved in the solvent, Vitamin C in powder form is slowly added while mixing, dispersing the vitamin C fully in the lecithin solution. The solvent is evaporated overnight while stirring. Alternatively, the solvent is evaporated in the vacuum at a temperature of about 50°C for several hours.

[0074] Table 1 : Examples and comparative examples

[0075] Example 2: Dissolution experiments:

[0076] Materials used:

[0077] - Phosphate buffer as described below,

[0078] - Bile salt as described below,

[0079] - Lipazym capsules

[0080] Phosphate buffer (pH 7.3) preparation:

[0081] - For 1 L, 2.48g KH2PO4+ 8.62g Na2HPO4+ IL distilled water.

[0082] Bile salt incorporation:

[0083] - Preparation at least 1 day in advance (slow solvation).

[0084] - For 3 mM, add 124.3mg Sodium deoxycholate to lOOmL phosphate buffer.

[0085] - Strong stirring for at least one day prior the experiment. Lipase incorporation (done just before the experiment):

[0086] - Open capsules to get the small beadlets inside.

[0087] - For the low lipase / bile salt content Test medium, 600mg Lipazym required for 20mL buffer (one Lipazym capsule contains 16'000 U of pancreatic lipase).

[0088] - 10-30 min magnetic stirring prior the dissolution experiment.

[0089] Equiment used:

[0090] - Miniaturized dissolution setup (water bath on multi position magnetic stirrer)

[0091] - 20 ml brown volumetric flasks (x6)

[0092] - Camera

[0093] - Micropipettes with long tips: 100 pL (for sample) and 5000 pL (for dilution)

[0094] - Syringe mini filters (0.22pm 0 0.4 cm or similar)

[0095] - 2 mL Eppendorf tubes for sampling

[0096] - 1 mL disposable syringes

[0097] - Centrifuge Eppendorf Minispin Plus

[0098] - 0.350 mL HPLC brown vials with integrated insert

[0099] Basic method:

[0100] Water bath at 37°C under magnetic stirring (~ 300 rpm) was provided.

[0101] Place 6 volumetric flasks (triplicate for vitamin C-Lecithin 70:30 and triplicate for Vitamin C-Lecithin 50:50) containing 20mL phosphate buffer.

[0102] Weight each sample to get 20mg vitamin C in each flask (28.57mg for vitamin C: Lecithin 70:30 and 40mg for vitamin C: Lecithin 50:50). Try to compress it to get small tablets.

[0103] Introduce the tablets in each flask and start the timer.

[0104] Collect lOOpL samples after 10 min, 30 min, 1 h, 2 h, 3 h, 4 h and 6h in 2mL Eppendorf tubes.

[0105] Dilution into 2mL phosphoric acid buffer (target range of concentration for HPLC : 30-60 pg / mL).

[0106] Check turbidity. If clear, collect the clear part with ImL syringe and filter it in HPLC vial.

[0107] If not clear, centrifugation for 30 sec at 14000 rpm.

[0108] Collect the clear part with 1 mL syringe and filter it in HPLC vial.

[0109] Results of the example 1 listed in table 1 are shown in Fig. 2.

Claims

Claims1. Non-liposomal lipid matrix-based particles, wherein the non-liposomal lipid matrix-based particles comprise a water-soluble nutrient selected from the group of B vitamins, or vitamin C, its precursors, derivatives thereof, minerals, an amino acid, or a mixture thereof, wherein said water-soluble nutrient is embedded in a lipid matrix and, wherein the lipid matrix is preferably generated by a phospholipid, preferably lecithin, characterized in that the non-liposomal lipid matrix-based particles have a water content of less than 10 wt% (weight %), less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, preferably of less than 8 wt%, more preferably of between than 6 and 1 wt%, most preferably between 5 and 2 wt% of the total weight of the non-liposomal lipid matrix-based particle formulation.

2. Non-liposomal lipid matrix-based particles according to claim 1 , wherein the water-soluble nutrient is vitamin C or a B vitamin, its precursors, derivatives thereof, or a mixture thereof.

3. Non-liposomal lipid matrix-based particles according to claim 1 or 2, wherein the water- soluble nutrient is vitamin C, its precursors, derivatives thereof.

4. Non-liposomal lipid matrix-based particles according to claim 1 to 3, wherein the non- liposomal lipid matrix-based particles are generated by adding said water-soluble nutrient in solid form to said lipids dissolved in suitable organic solvents.

5. Non-liposomal lipid matrix-based particles according to claim 1 to 4, wherein the lipid matrix can be a mixture of a phospholipid and at least one other lipid, preferably an oleate or mixtures of oleates.

6. Non-liposomal lipid matrix-based particles according to any of the preceding claims, wherein the water content of the non-liposomal lipid matrix-based particle formulation is between 6 and 1 wt%.

7. Non-liposomal lipid matrix-based particles according to any of the preceding claims, wherein the nutrient is comprised in a ratio of lipid : nutrient of between 95 : 5 and 5 : 95, preferably 90 : 10 and 10 : 90, more preferably in a ratio of lipid : nutrient of between 80 : 20 and 20 : 80, more preferably in a ratio of lipid : nutrient of between 70 : 30 and 30 : 70.

8. Non-liposomal lipid matrix-based particles according to any of the preceding claims, wherein further agents such as emulsifiers, surfactants, plasticizer, colorants, or additional lipids suitable for human or animal consumption, or mixtures thereof, are added to said non-liposomal matrix-based particles.

9. Delivery system or nutritional composition comprising the non-liposomal lipid matrix-based particles according to any of the preceding claims.

10. Delivery system or nutritional composition according to claim 9, wherein the delivery system or the nutritional composition further comprise emulsifiers, surfactants, plasticizer, antioxidants, colorants, or additional lipids suitable for human or animal consumption, or mixtures thereof.

11. Method of manufacturing non-liposomal lipid matrix-based particles of a water-soluble or a fat-soluble nutrient, preferably vitamin C, its precursors, derivatives thereof, a mineral, or an amino acid, or mixtures thereof, as referred to in the preceding claims, characterized in that the method consists of the following steps: i. wherein the lipid, preferably the at least one lipid, preferably being a phospholipid, more preferably being lecithin, is dissolved or melted in a hydrophobic solvent, preferably in alkyl ethers, alkyl esters, hexane, heptane, dichloromethane, or chloroform, more preferably in alkyl ethers, or alkyl esters, hexane, heptane, most preferably in ethyl acetate, isopropyl acetate, isobutyl acetate, or isopentyl acetate, or mixtures thereof; ii. wherein the solid nutrient, preferably a water-soluble nutrient in powder form, more preferably vitamin C in powder form, is added to the solubilized lipid slowly and under stirring until the nutrient is fully dispersed, and iii. wherein the solvent is evaporated under reduced or atmospheric pressure; wherein the obtained non-liposomal lipid matrix-based particles preferably have a watercontent of less than 10 wt% (weight %), less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, preferably of less than 8 wt%, more preferably of between 6 and 1 wt%, most preferably between 5 and 2 wt% based on the total weight of the non-liposomal lipid matrix-based particle formulation.

12. Non-liposomal lipid matrix-based particles obtained by the method of claim 11 .

13. Composition comprising the non-liposomal lipid matrix-based particles according to claims 1 to 10 or 12, and further comprising diluents, emulsifiers, surfactants, plasticizer, antioxidants, colorants, or additional lipids suitable for human or animal consumption, or mixtures thereof.

14. Consumer product comprising the non-liposomal lipid matrix-based particles according to claims 1 to 10, or 12 to 13.

15. Use of the non-liposomal lipid matrix-based particles according to claims 1 to 10, 12 to 14 in a formulation for application in food, feed, agriculture, personal care, cosmetic, or in pharmaceutical formulations, preferably in applications for food and feed, more preferably for application in nutritional supplementation.

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