NZ729004B2 - Method of inducing satiety - Google Patents

Abstract

The invention provides a method of inducing satiety in a subject comprising a step of orally administering a composition comprising an effective amount of a first agent capable of inducing satiety (e.g. a medium or long chain fatty acid compound, said fatty acid compound being comprised in a first lipid component), and of a second agent capable of augmenting the satiety-inducing effect of the first agent (e.g. a water-swellable or water-soluble polymeric component). Also disclosed are compositions for carrying out the method, and a body weight management system comprising such compositions in combination with a device configured for the collection, storage and/or display of information relating to a subject's response to a predefined therapeutic regimen of orally administering the composition. The composition may, for instance, be an ingestible particle having a sieve diameter in the range from 0.05 to 3 mm, wherein a water-swellable or water-soluble polymeric component is embedded within, and/or coated with, a lipid component. ipid component), and of a second agent capable of augmenting the satiety-inducing effect of the first agent (e.g. a water-swellable or water-soluble polymeric component). Also disclosed are compositions for carrying out the method, and a body weight management system comprising such compositions in combination with a device configured for the collection, storage and/or display of information relating to a subject's response to a predefined therapeutic regimen of orally administering the composition. The composition may, for instance, be an ingestible particle having a sieve diameter in the range from 0.05 to 3 mm, wherein a water-swellable or water-soluble polymeric component is embedded within, and/or coated with, a lipid component.

Description

TITLE: METHOD OF INDUCING SATIETY Description FIELD The present invention relates to oral compositions for the delivery of bioactive agents to the gastrointestinal tract.

OUND In the field of oral drug delivery it is of interest to develop gastroretentive dosage forms for bioactive substances. Substances associated with bioactivity are typically synthetic compounds, so called small molecules. Often such synthetic nds require a slow release from their dosage form after oral stration to minimise side effects and maximise cy. For this purpose drug substances may be incorporated in a matrix comprising lipids. Due to the hobic nature of the lipidic components of such a formulation, a lipophilic or amphiphilic bioactive substance may be released more slowly into the gastrointestinal lumen as compared to a standard tablet matrix comprising highly water-soluble excipients. Due to the fact that the release from a sustained release matrix may proceed over the course of up to six or eight hours but the typical time of gastric emptying is limited to only two hours, there is a need for ering gastroretentive properties into such a slow release formulation in order to maximise the effective time of drug delivery. Gastroretention may be achieved by rendering the formulation mucoadhesive. A gastric mucoadhesive system will bind to the mucosa of the gastric wall and prolong the residence time of the system, providing for a more extended release period. The combination of mucoadhesive properties and slow-release lipid matrix has been addressed. US 2006/0134144 details mucoadhesive compositions for solubilisation of insoluble drugs. Here, pharmaceutical compounds are formulated with monoglycerides and oil. WO03/037355 to Reckitt Benckiser Healthcare mentions polyacrylate itions for use in ting . In addition to the mucoadhesive r, such compositions se Vitamins and oil. EP 0580861 to Nippon ku Company claims a sustained release capsule for adhesion in the gastrointestinal tract.

Hard capsules were filled with drug substance, adhesion polymer and filler polymers and liquid paraffin. US 5,571,533 to Recordati discloses controlled-release mucoadhesive compositions for the oral administration of drug substance furosemide. In this , furosemide-lipid granules were coated with mucoadhesive rs. US 6,368,635 to Takeda Chemical Industries describes gastrointestinal mucosa-adherent matrices. High- melting triglyceride was mixed with drug substance and acryl acid polymer, and solid dosage forms were prepared with hesive properties. From recent research in the area of anti-obesity, it has emerged that triglycerides or their digestive degradation products, free fatty acids, may act as bioactive substances in their own right. For instance, it is well documented that the infusion of lauric acid or oleic acid into the duodenum by means of a feeding tube provides for strong satiety signalling. Consequently, there is a need to provide sustained release formulations of free fatty acids.

WO 36975A1 describes a method and system for displaying gastric band information, and more specifically gastric band ation which can t adjustment of a gastric band. The adjustment of the gastric band may be dependent on l pieces of data. Such data may include satiety state date.

Alternative non-invasive approaches for the treatment of obesity may infer satiety or the g of fullness or satisfaction through a variety of different ingestible compositions such as gelling s or certain nt compositions. s for gastric banding, satiety state information may be of relevance to the healthcare professional to monitor efficacy of the device, for non-invasive satiety compositions it may be useful to collect and display y state information in order to support administration of the satiety-inducing composition and to increase compliance.

Such satiety-state information are conventionally collected as hand written nts, or typed data entry into computer spreadsheets or forms. More preferably, such satiety-state data may be collected in real-time by means of a software application running on a computer or a mobile device such as a smartphone or a wearable device.

It is an object of the t invention to provide an effective method for delivering agents capable of ng satiety, such as fatty acids and lipids based on fatty acids, to the gastrointestinal tract. A further object is to provide means for the delivering such fatty acids and lipids to specific regions within the gastrointestinal tract, such as the stomach or the duodenum. A further object is to provide compositions, dosage forms and/or formulations which are useful for the oral delivery of fatty acids and lipids based on fatty acids. Alternatively or additionally, an object of the present invention is to provide the public with a useful choice.Further objects will become apparent on the basis of the following description including the examples, and the patent claims.

SUMMARY OF THE INVENTION In a first aspect, the invention provides an oral ition comprising an effective amount of (a) a first agent capable of inducing satiety, (b) a second agent capable of augmenting the satiety-inducing effect of the first agent, and optionally (c) an amino acid, (d) a vitamin, and/or (e) a micro-nutrient; wherein the composition is an ible particle having a sieve diameter in the range from 0.05 to 3 mm, wherein the first agent is a medium or long chain fatty acid compound, said fatty acid compound being comprised in a first lipid component, wherein the second agent is a water-swellable or water-soluble polymeric component, and wherein the weight ratio of the first lipid component to the water-swellable or watersoluble polymeric component is in the range from 1 to 3, and wherein the water-swellable or water-soluble polymeric component is embedded within the lipid component.

In a second aspect, the invention es a method of inducing y in a t for cosmetic purposes, said method comprising a step of orally stering the composition of the first aspect of the invention.

In a third aspect, the invention es a body weight ment system comprising the composition of the first aspect of the invention and a programmed electronic device configured for the collection, storage and/or display of information relating to a subject's adherence, or the effectiveness of, a predefined ent regimen of orally administering the composition.

In a fourth aspect, the invention relates to the use of a composition of the first aspect of the invention, in the manufacture of a medicament for use in (a) the prevention and/or treatment of obesity; (b) the prevention and/or treatment of a disease or condition associated with obesity; (c) the induction of satiety; and/or (d) controlling or reducing body .

BRIEF DESCRIPTION OF THE INVENTION Described is an oral composition comprising an effective amount of a first agent e of inducing satiety, a second agent capable of augmenting the satiety-inducing effect of the first agent, and optionally an amino acid, a vitamin and/or a nutrient.

The first agent which is capable of inducing satiety may be selected from medium or long chain fatty acid compounds. The second agent may represent a r capable of sing the ilability or the residence time of the first agent in the gastrointestinal tract.

Also described is an ible particle having a sieve er in the range from 0.05 to 3 mm, comprising a water-swellable or water-soluble polymeric component, a first lipid component, and optionally an amino acid, a vitamin and/or a micro-nutrient.

The first lipid component comprises a medium or long chain fatty acid compound. The particle is further characterised in that the water-swellable or water-soluble polymeric component is embedded within, and/or coated with, the lipid component.

The first lipid component in/by which the water-swellable or water-soluble polymeric component is ed or coated may represent the active core of the ingestible particle. The particle may further be coated with a coating layer that comprises a second lipid component and/or a hydrophilic ent. Optionally, the coating layer is substantially free of the water-swellable or water-soluble polymeric component.

Alternatively, the ingestible particle may comprise an inert core, e.g. composed of an inert material, and the first lipid component in/by which the water-swellable or water-soluble polymeric component is embedded or coated may be designed as a coating covering the inert core. Moreover, the particle may further comprise a second coating layer covering the first coating. The second g comprises a second lipid component and/or a hydrophilic component. Optionally, the second g layer is substantially free of the water-swellable or water-soluble polymeric component.

Preferably, the first lipid component comprises at least one medium or long chain fatty acid compound with a melting range below 37 °C, either per se or in the hydrated state.

Also described are compositions for oral administration which comprise the ingestible particles or which are ed from them, such as bottle, s, stick packs, capsules or tablets or other dosage units.

Also described is the use of the particles and of the compositions based on the particles for the prevention and/or treatment of obesity, or a disease or condition associated with obesity. Moreover, the use in appetite suppression and induction of satiety is provided. er, described is a method for inducing satiety in a subject; a method of treating or preventing overweight, y, or a disease or condition ated with ight or obesity in a t; and a method of controlling or reducing the body weight of a subject; which s comprise a step of orally administering a composition sing an effective amount of the first agent capable of inducing satiety and of the second agent capable of augmenting the satiety-inducing effect of the first agent.

Furthermore, described is a body weight management system comprising such composition and a device configured for the collection, storage and/or display of information relating to a subject's adherence, or the effectiveness of, a predefined therapeutic regimen of orally administering the composition.

DETAILED DESCRIPTION OF THE INVENTION Described is an oral composition comprising an effective amount of a first agent capable of inducing satiety, a second agent e of augmenting the satiety-inducing effect of the first agent, and optionally an amino acid, a vitamin and/or a micro-nutrient.

The first agent may be any compound or mixture of compounds which, after oral ingestions by a subject, triggers a signal or signalling cascade causing the subject to experience a feeling of satiety, or a reduced feeling of hunger or appetite. The second agent, on the other hand, may be any compound or mixture of compounds which, given by itself, does not induce a feeling of satiety, but when co-administered with the first agent, is e of augmenting the y-inducing effect of the first agent.

The augmentation may be achieved by a direct or indirect interaction, and effected via any pharmacological, physiological, or physical means. For example, a compound or mixture of compounds may be selected as the second agent which is capable of increasing the bioavailability of the first agent which s satiety. Alternatively, the second agent may be selected such as to g the gastric residence time and/or the small intestinal residence time of the first agent.

For the avoidance of doubt, it should be understood that the presence of the amino acid, the vitamin and/or the micro-nutrient in the particles described herein (and/or mixtures for the preparation of said particles) is optional in all embodiments, unless where explicitly stated otherwise. This means that, as used herein, listings including the amino acid, the vitamin and/or the micro-nutrient simply refer to the specific embodiments in which the optional amino acid(s), vitamin(s) and/or micro-nutrient(s) are present, while not excluding those embodiments without these optional components. r, the incorporation of the amino acid, the n and/or the nutrient into the particles described herein are independent of each other; i.e. the les may be free of all these components, comprise only one, two or three of the four, or they may comprise all four of them.

It should also be tood that, as used , the terms ‘a’ or ‘an’ or ‘the’ or features bed in their singular form do not exclude a ity of the respective features. Unless explicitly stated or described otherwise, expressions such as “an amino acid”, “a first agent”, “a vitamin”, “the micro-nutrient”, “the second agent” or the like are chosen solely for reasons of simplicity and are meant to encompass one or more agent(s), amino acid(s), vitamin(s), micro-nutrient(s), polymer(s) etc.; e.g. in the form of blends, or mixtures, of two or more of the respective components.

The increase in bioavailability and/or residence time of the first agent in the upper gastrointestinal tract may optionally be effected by the second agent in that the second agent increases the strength or on of contact of the first agent to the gastrointestinal mucosa. Optionally, the bioavailability and/or residence time of the amino acid, the vitamin and/or the micro-nutrient (if present) is also sed by the second agent in the same manner. Depending on the actual compounds selected as first and second agents, respectively, this may best be accomplished by ing a composition for oral administration in which effective amounts of the first agent and the second agent are incorporated as an intimate mixture, optionally also incorporating the amino acid, the vitamin and/or the nutrient (if present) in said intimate mixture.

In a preferred embodiment, the first agent is a medium or long chain fatty acid compound, as defined below, or a mixture of two or more medium or long chain fatty acid compounds. The second agent is preferably a water-swellable or water-soluble polymeric ent, as described in more detail below.

In a ic embodiment, described is an ingestible particle having a sieve diameter in the range from 0.05 to 3 mm, comprising a water-swellable or soluble polymeric component, a first lipid component, and optionally an amino acid, a vitamin and/or a micro-nutrient. The first lipid component comprises a medium or long chain fatty acid compound. The particle is further characterised in that the water-swellable or water- e polymeric component is embedded within, and/or coated with, the lipid component.

The ors have found that the ingestible particles as defined herein, and in ular oral compositions sing or prepared from a plurality of the particles, are capable of effectively inducing satiety, of suppressing the appetite, and thereby may be used to prevent or treat obesity or conditions associated with obesity; e.g. by using the ingestible particles as defined herein and/or compositions comprising or prepared from a plurality of these particles for body weight reduction. Without wishing to be bound by theory, it is currently believed that upon oral administration, the fatty acid or fatty acid ester comprised in the particle is more effectively delivered to the mucosa of the gastrointestinal tract, such as the stomach or duodenum, by virtue of the water-swellable or water-soluble polymeric component, which may be mental in providing a ged or otherwise increased interaction of the fatty acid material with target structures in the mucosa. Furthermore, the water-swellable or water-soluble polymeric component may be instrumental in providing a prolonged or otherwise increased interaction of the amino acid, the vitamin and/or the nutrient (if present) with target structures in the mucosa. ly, the water-swellable or water-soluble polymeric component prolongs the ity of the particle after ion as compared to a lipid particle without the wellable or water-soluble polymeric component. Prolonged integrity of the ontaining particle may result in more rapid gastric emptying of the particles and therefore more rapid interaction of particle-derived fatty acids or fatty acid esters with the intestinal . Prolonged integrity of the lipid-containing particle may also result in the delivery of fatty acids or fatty-acid esters to the more distal parts of the small intestine such as the jejunum or ileum.

Possibly, the water-swellable or water-soluble polymer component increases the digestibility of a lipid component of otherwise limited ibility such as a hard fat such as for instance tristearin. In a published rat feeding study, tristearin (Dynasan® 118, melting range 72-75 °C) was found to provide an energy t of only 3 kcal/g, corresponding to a true digestibility of stearic acid from arin of only 0.15 g/g independent from intake. Possibly, the water-swellable or water-soluble polymer ent enhances the particle´s surface wetting properties and/or facilitates water and bile acid access and subsequent emulsification and lipase-mediated hydrolysis of the lipid.

Possibly, the water-swellable or water-soluble polymeric component provides the particle with mucoadhesive properties, in particular in combination with a prolonged integrity of the particle.

As used herein, an ingestible particle is a particle which is in principle le for oral ingestion, or oral administration. A particle which by virtue of its composition, size and morphology would be le as a food component or a component of a pharmaceutical composition for oral use is an example of an ingestible particle.

The particle has a sieve diameter in the range from about 0.05 mm to about 3 mm, which means that it would normally pass through a sieve having an aperture or opening size of about 3 mm, but not through a sieve having an aperture or opening size of about 0.05 mm or less. The particle may also have a diameter in the range from about 0.1 mm to about 2.5 mm, or from about 0.1 mm to about 2 mm, such as about 0.25 ± 0.20 mm, about 0.5 ± 0.25 mm, about 1.0 ± 0.25 mm, about 1.05 ± 0.25 mm, or about 2.0 ± 0.25 mm, respectively. Within a composition comprising a plurality of particles described herein, these particle sizes should be interpreted to characterise the preferred mass median sieve diameters of the ingestible particles.

The water-swellable or water-soluble polymeric component is a hydrophilic or amphiphilic polymeric material capable of swelling in an aqueous environment. The material may se a mucoadhesive compound or mixture of mucoadhesive nds, or it may be capable of inducing mucoadhesiveness to the particle. If it is a mixture, it may also comprise one or more constituents which are themselves not waterswellable or mucoadhesive, as long as the mixture is water-swellable.

As used herein, swelling by water, or in an s environment, typically means the volume increase of a solid body caused by an influx, or diffusion process of water accompanied by hydration, i.e. g and absorption of moisture.

The water-soluble polymeric ent is a hydrophilic or amphiphilic polymer of a solubility in water of at least 1 mg/L.

Prolongation of particle integrity is the prolongation of time during incubation under in vivo or simulated in vivo conditions in which the majority (more than 50 %) of les do not decrease their volume or mass or melt into droplets. Particle integrity may be readily inferred by visual inspection by the naked eye or by means of a microscope or through g technology, including microscopic imaging, and subsequent computer-aided image processing.

Mucoadhesiveness is the lity of adhering to a mucosa, or mucosal membrane.

Various conventional methods are ble to determine mucoadhesiveness, such as tensile strength measurements, ellipsometry, or rheological measurements (D. Ivarsson et al., Colloids Surf B Biointerfaces, vol. 92, pages 353-359, 2012). Even though these s may not provide absolute values for mucoadhesiveness as such, they indicate the presence and ve magnitude of mucoadhesiveness of a material.

To determine mucoadhesiveness in the context of the ion, it is preferred that a modified g liquid film method ibed among other method in Mucoadhesive drug delivery systems, Carvalho F.C. et al., Brazilian Journal of Pharmaceutical Sciences 46 (2010)) is employed. According to the method, the selected mucous membrane (e.g. from pig stomach) is placed in a petri dish together with simulated gastric fluid at a controlled temperature of 37 °C. The petri dish is placed on a table undergoing a tilting movement. Both tilting movement and volume of buffer are ed so that small waves of buffer continuously run over the surface of the mucous tissue. In the falling liquid film method, a similar agitation is achieved by pumping buffer over mucosal tissue tilted at a 45° angle. The amount of particles remaining on the mucous membrane after a ied time interval can be fied by various methods. For instance, particles can be counted, optionally using a magnifying glass or cope, or they may be collected, dried and measured gravimetrically.

In the context of the invention, the water-swellable or water-soluble polymeric component may have, or induce, sufficient mucoadhesive strength to cause ment to a mucosal membrane upon contact with, and to cause the particle or a component thereof to stay attached for a period of time which is significantly longer than a material which is not mucoadhesive, such as a solid triglyceride or a lipophilic polymer, e.g. polytetrafluoroethylene. In one preferred embodiment, the water-swellable or water- e polymeric ent comprises a mucoadhesive polymer. In particular, it may comprise at least one polymeric material selected from poly(carboxylates), chitosan, cellulose ethers, and xanthan gum.

In a further preferred embodiment, the water-swellable or water-soluble polymeric component is a plant fibre. In the context of the ion, a plant fibre includes selected dual components of plant fibres or derived therefrom, as well as their mixtures. For example, a suitable water-swellable or water-soluble polymeric component is psyllium seed husk, or psyllium seed husk fibres, also referred to as psyllium husk or simply psyllium. Psyllium seed husk are the seed coats of the seeds of Plantago ovata, also known as Desert Indianwheat or Blond Psyllium. A major ent of psyllium seed husk is soluble but indigestible polysaccharide fibers which are highly ble in water.

Psyllium is known as a source of dietary fibre and as a mild laxative or stool softener.

If a poly(carboxylate) is used, this is preferably selected from poly(acrylic acid), poly(methacrylic acid), copolymers of acrylic and methacrylic acid, and ydroxyethyl methacrylic acid). The ose ether is preferably selected from hydroxyethyl cellulose, hydroxypropyl cellulose (also known as hyprolose), hydroxypropyl methylcellulose (also known as hypromellose), and methylcellulose. If an ionic polymer is used such as a poly(carboxylate) and/or a carboxymethylcellulose, this may be partially or entirely neutralised, preferably as sodium or potassium salt, most preferably as the sodium salt. er, the polymeric material may be at least partially crosslinked.

In a further preferred embodiment, the mucoadhesive r is a copolymer of acrylic acid and methacrylic acid, or of acrylic or methacrylic acid and maleic acid. The copolymer may be crosslinked with small amounts of a polyalkenyl polyether. Such copolymers are highly hydrophilic and capable of absorbing large amounts of water which causes their swelling.

Particularly suitable for carrying out the invention are, for e, carbomers.

Carbomers resins are high molecular weight, crosslinked acrylic acid-based polymers.

Commercial ns of carbomers are sold as e.g. Carbopol®, Noveon®, Pemulen®, Polygel®, Synthalen®, Acritamer®, or Tego Carbomer®. Most of these brands include s carbomer grades.

For example, the Carbopol® polymer series encompasses homopolymers, mers, interpolymers as exemplified by Carbopol® Aqua SF-1 (acrylate copolymer, a y cross-linked te copolymer), Carbopol® Aqua SF-2 (acrylate crosspolymer-4), Carbopol® Aqua CC (polyacrylate-1 crosspolymer), Carbopol® 934 (carbomer, acrylate homopolymer cross-linked with allyl ethers of e), Carbopol® 940 (carbomer), Carbopol® 941 mer), Carbopol® 971P (carbomer, lightly crosslinked with allyl pentaerythritol), Carbopol® 71G (a free-flowing granular form of Carbopol® 971P for use in direct compression formulations), Carbopol® 974P (carbomer, highly crosslinked), Carbopol® 980 (carbomer), Carbopol® 980 (carbomer), Carbopol® 981 mer, allyl pentaerythritol crosslinked), Carbopol® 1342 (acrylates/C 10-30 alkyl acrylate crosspolymer, mer of acrylic acid and C1O-C30 alkyl acrylate crosslinked with allyl pentaerythritol), Carbopol® 1382 (acrylates/C10-30 alkyl acrylate crosspolymer, copolymer of c acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol), Carbopol® 2984 (carbomer), Carbopol® 5984 (carbomer), Carbopol®Ultrez 10 (carbomer), ol® Ultrez 20 (acrylates/ C10-30 alkyl acrylate crosspolymer), Carbopol® Ultrez 21 (acrylates/ C10-30 alkyl acrylate crosspolymer), ol® Ultrez 30 (carbomer), Carbopol® ETD 2001, Carbopol® ETD 2020 (acrylates/ C10-30 alkyl acrylate crosspolymer, interpolymer containing a block copolymer of polyethylene glycol and a long chain alkyl acid ester), Carbopol® ETD 2050 mer).

Polymer grades approved for pharmaceutical use are preferred among these, such as those which comply with a copoeial monograph, such as the aph "Carbomer" of the European Pharmacopoeia (Ph. Eur. 8) or the aphs in the US copoeia/National Formulary (USP-NF) with the titles, mer 910", "Carbomer 934","Carbomer 934P","Carbomer 940","Carbomer 941", "Carbomer Homopolymer", "Carbomer Copolymer", "Carbomer Interpolymer", or "Carbomer 1342".

Also particularly suitable are polycarbophils (USP-NF), which represent high molecular weight acrylic acid polymers crosslinked with divinyl glycol. They provide excellent bioadhesive properties. An example of a preferred grade of polycarbophil is NOVEON® AA-1.

Optionally, the water-swellable or water-soluble polymeric component comprises at least one ccharide approved for oral use as excipient or food additive or food ingredient. The at least one polysaccharide may be selected from the groups of cationic polysaccharides, anionic polysaccharides and non-ionic polysaccharides.

Suitable cationic polysaccharides include, but are not limited to, chitosan, polysaccharides modified by means of nary ammonium groups (for example cationic guar gum, cationic ose, cationic hydroxyethyl cellulose, and cationic starch), derivatives thereof, or mixtures of two or more thereof.

Alternatively, the cationic polysaccharide is a polymeric material with basic amino groups which are at least partially protonated in a neutral environment. The ic polysaccharide may be provided or incorporated as a free base, as a quantitatively protonated salt form, or any mixture of the two forms.

The "free base" form refers to a polymer such as polyglucosamine san) comprising amino side chains in the base form, e.g. -NH2. The "salt form" refers to a polymer such as polyglucosamine (chitosan) comprising amino side chains in the salt form, e.g. -NH3+ Cl- for chloride salts of ammonium groups. It is understood that the salt form may refer to mixtures of salts, e.g. the salt form may be composed of es of different salts such as -NH3+ Cl- and -NH3+ CH3-COO-. "Any mixture of the two forms" refers to a polymeric material comprising amino groups, where a fraction of the amino groups is present in the free base form, e.g. as -NH2 for primary amino , and a fraction of those side chains is present in the salt form, e. g. -NH3+ Cl-. For ce, such a mixture may be referred to as l chloride salt of chitosan.

“Chitosan” for the purpose of the invention is defined as chitosan derived from fungi or derived by deacetylation of chitin, wherein the average degree of deacetylation is preferably more than about 75 %, more than about 80 %, more than about 90 %, or more than about 95 %, respectively. The degree of deacetylation refers to the percentage of the chitin´s amino groups that are ylated. A particularly preferred chitosan is derived from fungal biomass selected from the group consisting of a Guillermondii, Aspergillus niger, Aspergillus terreus, and combinations thereof, the chitosan ning material having greater than 85 percent deacetylation of N-acetyl groups in the chitin and exhibiting a viscosity of less than 25 centipoise (mPas) at 25 °C in 1 percent aqueous acetic acid.

Suitable anionic polysaccharides include, but are not limited to, sulphated amino glycans including heparans, heparansulfates, heparins; alginates; propylene glycol alginates; carrageenans; cellulose sulfate; carboxymethyl cellulose; fucoidan; galactans containing glucuronic acid or galacturonic acid; chondroitins or chondroitin sulphates; gellan gums; onans and hyaluronic acids; modified starches such as octenyl succinate starches or monostarch phosphates, ed starches or carboxymethylated es; pectic acids, pectins including amidated pectins, homogalacturonans, substituted galacturonans, rhamnogalacturonans, their methyl and ethyl esters; porphyrans; sulphated galactanes; anth or gum karaya; xanthan gums and .

One particularly suitable polycarboxylate polysaccharide is alginic acid. c acid is a linear copolymer with homopolymeric blocks of (1-4)-linked β-D-mannuronate (M) and its C-5 epimer luronate (G) residues, respectively, covalently linked together in different sequences or blocks. The monomers can appear in homopolymeric blocks of utive G-residues (G-blocks), consecutive M-residues (M-blocks) or alternating M and G-residues (MG-blocks).

The anionic polysaccharide may be incorporated in the form of a free acid, or as the neutralised salt form of the acid, or as a mixture of these, i.e. as a partially neutralised salt. The "free acid" form refers to a ric al comprising acid groups in the non-ionised, protonated acid form, e.g. -COOH or -SO4H2. The "salt form" refers to a polymeric material with acid groups in the ionised form, or salt form, e.g. -COO- Na+ for sodium salts of carboxylates or -SO42- 2Na+ for sodium salts of sulphates. It is tood that the salt form may refer to mixtures of salts, e.g. the salt form may be composed of mixtures of -COO- Na+ and -COO- K+ or -COO- Ca2+ -COO- salts. "Any mixture of the two forms" refers to a polymeric material comprising acid , where a fraction of those groups is present in the non-ionised acid form, e.g. as -COOH for carboxylic acids, and another fraction of the acid groups is present in the ionised salt form, e.g. -COO- Na+ for sodium salts of carboxylic acids. For instance, such a mixture may be referred to as l sodium salt of alginic acid.

Preferably, the anionic polysaccharide is an anionic dietary fibre. Dietary fibres, for the purpose of the invention, are carbohydrate polymers with ten or more monomeric units which are not hydrolysable by endogenous enzymes in the small intestine of humans. They typically ent carbohydrate polymers which have been obtained from food raw material by physical, enzymatic or chemical means, or synthetic carbohydrate polymers. ably, the anionic ccharide is alginic acid, carboxymethylcellulose, hyaluronan, sodium alginate, propylene glycol alginate, carrageenan, gellan gum, pectin, tragacanth or xanthan gum. Particularly preferred is that the at least one anionic polysaccharide is carboxymethylcellulose, sodium alginate or propylene glycol alginate, pectin, xanthan gum, or hyaluronan. ally, a combination of anionic polysaccharides is employed, such as sodium alginate and xanthan, or sodium te and pectin.

Pectic polysaccharides ns) are rich in galacturonic acid. Several distinct polysaccharides have been identified and characterised within the pectic group.

Homogalacturonans are linear chains of α-(1–4)-linked D-galacturonic acid. Substituted galacturonans are characterised by the presence of saccharide appendant residues (such as D-xylose or se in the respective cases of xylogalacturonan and apiogalacturonan) branching from a backbone of D-galacturonic acid residues.

Rhamnogalacturonan I pectins (RG-I) contain a backbone of the repeating disaccharide: 4)-α-D-galacturonic acid-(1,2)-α-L-rhamnose-(1). From many of the rhamnose residues, sidechains of s l sugars may branch off. The neutral sugars are mainly D- galactose, L-arabinose and D-xylose, with the types and proportions of neutral sugars varying with the origin of pectin. Another structural type of pectin is rhamnogalacturonan II (RG-II). Isolated pectin has a molecular weight of typically 60– 130,000 g/mol, varying with origin and extraction conditions. In nature, around 80 percent of carboxyl groups of galacturonic acid are esterified with methanol. This proportion is decreased to a varying degree during pectin extraction. The ratio of esterified to non-esterified galacturonic acid determines the behaviour of pectin in food applications. This is why pectins are classified as high- vs. low-ester s (short HM vs.

LM-pectins), with more or less than half of all the galacturonic acid esterified. The non- esterified galacturonic acid units can be either free acids (carboxyl groups) or salts with sodium, ium, or calcium. The salts of partially esterified pectins are called pectinates; if the degree of esterification is below 5 percent the salts are called pectates; the insoluble acid form pectic acid. Amidated pectin is a modified form of pectin. Here, some of the galacturonic acid is converted with ammonia to carboxylic acid amide. Most preferred s are high ester pectins.

Suitable non-ionic polysaccharides include, but are not limited to, agaroses; ectins; amyloses; arabinoxylans; beta glucans including e, curdlan, chrysolaminarin or leucosin, rin, lentinan, lichenin, pleuran, schizophyllan, n; capsulans; celluloses including hemicelluloses, cellulose esters such as cellulose acetate, cellulose triacetate, cellulose nate, cellulose acetate propionate and cellulose e butyrate; cellulose ethers such as cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose (hypromellose), hydroxyethyl cellulose, hydroxypropyl cellulose (hyprolose), hydroxyethyl hydroxypropyl cellulose, methyl ethyl cellulose or alkoxy hydroxyethyl hydroxypropyl cellulose, wherein the alkoxy group is unbranched or branched and comprises 2 to 8 carbon atoms; chitins; cyclodextrins; dextrans; dextrins (for example cially ble as Nutriose® or Benefiber®); galactoglucomannans; galactomannans including fenugreek gum, guar gum, tara gum, locust bean gum or carob gum; glucomannans including konjac gum; ns including inulin, levan, sinistrin or phlein; extrins; glycogens; pullulans; starches including resistant starches, modified starches such as acetylated starch, hydroxypropylated starch or hydroxyethyl starch; polydextroses; welan gum and xyloglycans.

Preferably, the non-ionic polysaccharide is a nic dietary fibre. Preferably, the non-ionic polysaccharide is selected from the group consisting of beta glucans, cellulose ethers, guar gums, galactomannans, glucomannans, inulins and dextrins. Preferably, the non-ionic polysaccharide is hydroxypropyl methylcellulose (hypromellose) or locust bean gum, or oat or barley beta glucan or konjac gum or ant dextrin. Among the particularly preferred non-ionic polysaccharides are hydroxypropyl methylcellulose (hypromellose), hydroxypropylcellulose, beta glucan from oat or barley and resistant dextrin from starch.

Resistant dextrins are short chain glucose polymers without sweet taste which are relatively resistant to the hydrolytic action of human digestive s. They can be made for instance from wheat (NUTRIOSE® FB range or Benefiber®) or maize starch (NUTRIOSE® FM , using a highly controlled process of dextrinisation followed by a tographic onation step. During the dextrinisation step, the starch undergoes a degree of hydrolysis followed by repolymerisation that converts it into fibre: in addition to the typical starch α-1,4 and α-1,6 digestible linkages, non-digestible glycosidic bonds such as β-1,2 or β-1,3, are formed, which cannot be cleaved by enzymes in the digestive tract.

Optionally, the water-swellable or water soluble polymeric component according to the invention comprises more than one ccharide. Preferred is in particular the ion of an anionic polysaccharide and a nic polysaccharide, especially the combination of xanthan gum and hydroxypropyl methylcellulose (hypromellose).

Optionally, the water-swellable or water soluble polymeric component according to the invention ses a synthetic water swellable or water e ric material such as polyvinyl alcohol, polyvinyl acetate, polyethylene glycols (PEG), polypropylene glycols (PPG) or polyvinylpyrrolidones (PVP). Such polymer may be linear, ed or crosslinked, as for instance in crospovidone (crosslinked polyvinylpyrrolidone), or a PEG hydrogel.

Optionally, the water-swellable or water-soluble polymeric component comprises a thiolated polymer such as anthiobutylamidine, a chitosan-thioglycolic acid conjugate, a chitosan-cysteine ate, a an glutathione conjugate, a polycarbophil-cysteine ate, a rylic acid-cysteine conjugate, a carboxymethyl ose-cysteine conjugate, or any mixture or combination of two or more of these.

The first lipid ent comprises a medium or long chain fatty acid compound. A fatty acid compound, as used herein, may refer to a free fatty acid, a partially or completely neutralised fatty acid, i.e. the salt of a fatty acid, such as a sodium, potassium or calcium salt, or an esterified fatty acid. An esterified fatty acid may have, as alcohol residue, a glycerol, so that the esterified fatty acid is a mono-, di- or ceride. The acyl chain of the fatty acid may be saturated or unsaturated.

A medium chain fatty acid is understood as fatty acid with an acyl residue of 6 to 12 carbon atoms, whereas a long chain fatty acid means a fatty acid with an acyl chain of 13 to 21 carbon atoms. Among the preferred medium chain fatty acids are caprylic acid, capric acid, and lauric acid, including their esters and salts, in particular their mono-, diand triglycerides and their sodium, potassium and calcium salts. In the case of di- and triglycerides, these may also have different fatty acid residues per glyceride molecule.

Examples of preferred long chain fatty acids include myristic acid, palmitic acid, stearic acid, arachidic acid, c acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, linoleic acid, and linolenic acid, and the respective salts and glycerides.

In one of the preferred embodiments, the first lipid component comprises one or more l glycerides of a medium or long chain fatty acid, in particular monoglycerides of a medium or long chain fatty acid. For example, monoolein or monolaurin are very suitable for carrying out the invention, individually or in combination with each other. As used herein, a monoglyceride such as monoolein or monolaurin may be incorporated as a substantially pure nd or as a mixture of mono- and diglycerides or even mono-, di- and triglycerides with various fatty acids, but with a high content ("enriched") of a particular monoglyceride compound. For example, a monoolein grade may be used which comprises at least about 40 % (or at least about 50 %, or 60 % or 70 % or 80 % or 90 %) of the actual monoglyceride of oleic acid.

The first lipid component may of course represent a mixture incorporating two or more fatty acids, and/or fatty acid esters or salts. For example, the component may comprise one or more a fatty acids, which may be partially or completely lised, in combination with one or more glycerides, such as triglycerides.

The constituent(s) of the first lipid component may represent a native, synthetic or semisynthetic material. For example, cocoa butter may be used, which is itself a mixture of various lipid nds, most of which represent fatty acid compounds as defined herein. Another preferred constituent of the first lipid component is palm stearin or palm kernel stearin. Palm stearin is the solid on of palm oil that is produced by partial llization at controlled temperature.

In one embodiment, the first lipid component comprises one or more free fatty acids. For example free oleic acid or lauric acid may be part of the lipid component. Other preferred free fatty acids are mixtures of unsaturated fatty acids such as the led omega fatty acids or conjugated linoleic acids. ated ic acids (CLA) are a family of isomers of linoleic acid. Conjugated linoleic acid is both a trans fatty acid and a cis fatty acid as the double bonds of CLAs are conjugated and separated by a single bond between them. Brands of CLAs are marketed as dietary supplements (Tonalin®, BASF, and Clarinol®, Stepan). Omega-3 fatty acids are polyunsaturated fatty acids (PUFAs) with a double bond (C=C) at the third carbon atom from the end of the carbon chain. Examples of omega-3 fatty acids are α-linolenic acid (ALA) (found in plant oils), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (both commonly found in marine oils). If the first lipid component comprises an unsaturated fatty acid, it may also comprise an antioxidant such as n E or a derivative thereof.

In one of the preferred embodiments, the medium or long chain fatty acid compound in the first lipid component, either per se in vitro or in the hydrated state in vivo, has a melting range of below 37 °C. As used herein, the melting range is understood as being below 37 °C if the lower (but not arily the upper) limit of the range is below 37 °C. In other words, a compound having a melting range of 35 °C to 38 °C is an example of a al with a melting range of below 37 °C according to the invention. In other words, at least some of the fatty acid material in the lipid component should melt at the physiological ature of the human body according to this embodiment.

Moreover, the specified melting range is also met if the lipid component is capable of hydration, wherein the melting range in the hydrated state is below 37 °C. Such behaviour of some lipids has also been described as "melting by hydration".

According to a further preference, the first lipid component comprises a medium or long chain fatty acid compound having a melting range, or lower limit of the melting range, between about 10 °C and 37 °C, or between about 25 °C and 37 °C, respectively.

It has been surprisingly found by the inventors that particles containing the waterswellable or water-soluble polymeric component embedded in, or coated with, a lipid component comprising such low-melting fatty acid compound(s) are capable of exhibiting a prolonged integrity of the particles. ly, mucoadhesive properties are inferred to the particles, depending on the nature of the polymeric component. Possibly, these effects alone or in combination also contribute to, or are related to, the prolonged gastric residence time of the particles, the increased bioavailability of the lipid(s) and the induction of satiety caused by the particles’ administration.

It has further surprisingly been found by the inventors that particles ning the water-swellable or water-soluble ric ent embedded in, or coated with, a lipid ent sing such low-melting fatty acid compound(s) is capable of forming a viscous emulsion in the gastrointestinal tract. Possibly, this effect also butes, or is related to, the prolonged gastric residence time of the particles and the induction of satiety caused by their administration.

Optionally, the first lipid ent may se one or more further tuents which may have entirely ent melting ranges. For example, a mixture of oleic acid, which has a melting range of 13 °C to 14 °C, and a hard fat (i.e. a e of triglycerides) having a melting range of 42 °C to 45 °C may be used as the first lipid component. As an alternative to the hard fat, myristic acid (mp 54 °C to 55 °C) or lauric acid (mp 43 °C to 44 °C) may be used in such mixture. It may also be advantageous to combine a fatty acid with the salt of a fatty acid at a selected ratio such as to adjust the melting range to a desired optimum.

In one of the preferred embodiments, the fatty acid compound in the first lipid component, either per se in vitro or in the hydrated state in vivo, has a melting range of above 37 °C. As used herein, the melting range is understood as being above 37 °C if the lower limit of the range is above 37 °C. In other words, a compound having a melting range of 40 °C to 44 °C is an example of a al with a melting range of above 37 °C according to the invention. er, the specified melting range is also met if the lipid component is capable of hydration, wherein the melting range in the hydrated state is still above 37 °C. A particularly preferred first lipid component having a melting range of above 37 °C is fractionated but non-hydrogenated palm stearin or palm kernel stearin.

Palm stearin is the solid fraction of palm oil that is produced by partial crystallization at controlled temperature. An example of a preferred commercial quality is Prifex® 300 from Sime Darby Unimills.

According to the invention, the water-swellable or water-soluble polymeric component is embedded within, and/or coated with, the lipid component. As used herein, the term ‘embedded’ means that the water-swellable or water-soluble polymeric ent is largely dispersed within the lipid component, whether molecularly, colloidally or in the form of a solid suspension. The lipid component forms a continuous phase in which the water-swellable or water-soluble polymeric component is discontinuous and in dispersed form. For the avoidance of doubt, this does not exclude that some of the al representing the water-swellable or water-soluble polymeric component - typically a small fraction - is not fully embedded, but positioned at the outer e of the lipid component.

Typically, ‘embedded’ also means in the context of the invention that the lipid component and the swellable or water-soluble polymeric ent are mixed so intimately that the porosity of the resulting lipid-polymer composition is y reduced as compared to the particles formed from the water-swellable or water-soluble polymer itself, for instance as formed by roller compaction or agglomeration. le porosity may be determined by porosimetry, an analytical technique used to determine s quantifiable s of a material's porous nature, such as pore diameter, total pore volume, and surface area. The technique es the ion of a non-wetting liquid at high pressure into a material through the use of a porosimeter.

The term ‘coated’ means that a particle comprising the water-swellable or watersoluble polymeric material is substantially surrounded with a layer of the lipid material representing the first lipid component. In practice, both forms dded in’ or ‘coated with’) may co-exist to some degree, depending on the method of preparation.

In one of the preferred embodiments, the particle described herein may be designed to exhibit an active core and a coating covering the core, wherein the active core comprises the first lipid component with the ed or coated water-swellable or water soluble polymeric component, whereas the coating comprises a second lipid component and/or a hydrophilic component. The coating may be substantially free of the swellable or water-soluble polymeric component.

This embodiment is particularly useful in that the coating allows for convenient oral administration without the swellable or water-soluble polymeric component interacting with the mucosa of the mouth or oesophagus during ingestion, as the coating acts as a protective layer. The g also provides protection against agglomeration and sintering during manufacture, storage and shipping, and contributes to achieving an acceptable shelf life.

In other words, in this group of embodiments, the active core may be coated with a physiologically inactive coating, such as a polymeric film coating or a lipid coating. The polymeric film coating, which is based on a hydrophilic component, may be free of lipid, or it may comprise some relatively small amount of lipid e.g. as a ciser. The lipid coating may be solely composed of the second lipid component, or it may contain some amount of the hydrophilic component, e.g. as a disintegration enhancer.

The coating may be designed to be rapidly disintegrating so that the active core of the particle is ed rapidly after wing. Preferably, the second lipid component, i.e. that which is incorporated in the coating of the particle, comprises one or more lipids having a melting point or g range below about 37 °C, as defined above, such as a melting range between about 25 °C and about 37 °C. The composition of the second lipid component may optionally be the same as that of the first lipid component. Alternatively, it may be different.

As said, the coating of the particle according to this embodiment may se a hydrophilic component. This hydrophilic material may be embedded or dispersed within the second lipid al and may act as a disintegration enhancer for the coating layer. egration enhancement may be achieved by various mechanisms, depending on the choice of the hydrophilic component. For example, a egrant - such as e.g. crospovidone, croscarmellose, low-substituted hypromellose or even ion-exchange resins may rapidly take up water, expand in volume and thereby cause the tion of the coating. Non-swelling, highly water-soluble excipients such as sugars or sugar alcohols, on the other hand, may predominantly act as pore formers by which water channels are rapidly created by which egration is also enhanced. Optionally, the hydrophilic component comprises a e of hydrophilic compounds. Preferably, the hydrophilic component is different from the water-swellable or water soluble polymeric component and has no or only a low degree of mucoadhesiveness.

If the g only contains the hilic component but no lipid component, the hydrophilic component preferably represents a film-forming agent such as a water soluble polymer. Examples of potentially suitable film-forming polymers include methylcellulose, hyprolose, hypromellose, polyvinyl alcohol, povidone, polyvinyl acetate, (meth)acrylate copolymer, and the like. Optionally, the composition may comprise further ingredients such as one or more plasticisers, pH-modifying agents, pore formers, colouring agents, sweetening agents, flavours, anti-tack agents, or dispersion aids.

In this group of embodiments, where the particle bed herein ts an active core sing the first lipid component with the embedded or coated waterswellable or water-soluble polymeric component and nded by a coating, it is furthermore preferred that the active core contributes at least about 50 % to the weight of the total particle. Optionally, the weight of the active core is at least about 60 %, or even at least about 70 % of the total particle's weight.

In a related embodiment, the particle described herein comprises an inert core, a first coating covering the inert core, and a second coating covering the first g. In this case, the first coating comprises the water-swellable or water-soluble polymeric component and the first lipid component, the second coating comprises a second lipid component and optionally a hydrophilic ent, and the second coating is also ntially free of the water-swellable or water-soluble polymeric component. The hydrophilic ent may be selected as described above. As in the previously discussed embodiment, the first lipid component with the embedded or coated waterswellable or water soluble polymeric component is surrounded with a coating layer comprising the second lipid component. The ence is that the first lipid component and the water-swellable or water soluble polymeric component do not form the core of the particle, but a layer on an inert core having a different composition.

The inert core may be composed of a pharmacologically inert material such as sucrose, starch or microcrystalline cellulose. Specific examples of suitable inert cores include spheroids with average diameters in the range of about 100 or 200 µm based on microcrystalline cellulose which are e.g. commercially available as Cellets® 100 or Cellets® 200; nonpareils of starch and sugar of similar diameter; or sugar crystals of similar diameter, e.g. as obtainable by g.

With respect to the ition and further optional features of the lipid components, the water-swellable or soluble polymeric component and the hydrophilic component, reference is made to the discussion above.

In the context of this embodiment, the inert core should preferably not contribute more than about 70 % to the weight of the total le. More preferably, the weight of the core is not higher than about 60 %, or not higher than about 50 % of the total particle weight. In other embodiments, the weight of the core is from about 10 % to about 50 %, or from about 10 % to about 40 %, or from about 15 % to about 35 % of the total particle weight.

As already discussed, it is a key feature of the ion that the water-swellable or water-soluble ric component is embedded within, or coated by, the first lipid component, which appears to effect an improved and/or prolonged interaction of the fatty acid with its target at the gastrointestinal mucosa. A target structure may, for example, be represented by G-protein d receptors (GPCRs) involved in the sensing of intestinal lipids such as GPR120.

In some embodiments, this may also result in an increased bioavailability of the first lipid component. It may also result in an increased ilability of the amino acid, the vitamin and/or the micro-nutrient if present. In this context, bioavailability should be broadly understood such as to include the availability of e.g. the first lipid component, or the biologically active constituents thereof, at a biological target site, such as the gastric or intestinal mucosa, in terms of the extent and/or duration of availability. ally, the particle may further contain an amino acid, a n, a micronutrient , or any combinations of these.

As used herein, an amino acid is an organic compound having an amino group and a carboxyl group, mostly in the generic structure of NH2-CHR-COOH wherein R represents the side chain which is specific to each amino acid. Optionally, the carboxylic group is partially or fully neutralised. The amino acid may be provided in its L- form, its D-form or in its racemic form. In a preferred embodiment, the amino acid is a proteogenic amino acid, i.e. an amino acid which is a potential precursor of a n in that it may be incorporated into a protein during its translation, or biosynthesis.

Proteogenic o acids as currently fied are L-alanine, L-arginine, L-asparagine, L-aspartic acid, eine, L-glutamic acid, amine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L- tryptophan, L-tyrosine, L-valine, L-selenocysteine, L-pyrrolysine, and N-formyl-L- methionine. In another embodiment, the amino acid is selected from the 20 amino acids which form the genetic code, which group consists of L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, onine, L- phan, L-tyrosine, and L-valine.

In another preferred embodiment, the amino acid is selected from the group of the so-called essential amino acids which consists of those amino acids which the human organism cannot synthesise, i.e. L-histidine, L-isoleucine, L-leucine, ne, L- methionine, L-phenylalanine, L-threonine, L-tryptophan, and L-valine.

In a further preferred embodiment, the amino acid is selected from the group consisting of L-isoleucine, L-valine, L-tyrosine, L-methionine, ne, L-arginine, L- cysteine, L-phenylalanine, L-glutamate, L-glutamine, L-leucine, and L-tryptophan. From these, the group consisting of L-phenylalanine, ine, amine, L-glutamate, and L-tryptophan is particularly preferred. In another preferred embodiment, the amino acid is L-tryptophan.

Optionally, the particle comprises two or more amino acids. Such mixture or combination of amino acids should preferably comprise at least one amino acid as described above, i.e. a genic amino acid, or an amino acid from the group of amino acids forming the genetic code, or from the essential amino acids, or the group of amino acids consisting of eucine, L-valine, L-tyrosine, L-methionine, L-lysine, L-arginine, L- ne, L-phenylalanine, L-glutamate, L-glutamine, L-leucine, and L-tryptophan. ularly preferred particles with mixtures or combinations of amino acids comprise at least one amino acid from the group consisting of L-phenylalanine, L-leucine, L- ine, L-glutamate, and L-tryptophan. In particular, L-tryptophan is a preferred constituent of a combination of two or more amino acids.

Also preferred are mixtures or ations of amino acids in which at least two amino acids are s of one of the red groups as previously defined. Moreover, mixtures or combinations of amino acids may be used in the particles described herein in which essentially all incorporated amino acids are members of one of the preferred groups as previously defined.

As used herein, vitamins are vital nutrients required in small amounts, which e.g. humans (or other organisms) lly cannot synthesise in sufficient quantities and which therefore must be taken up with the diet. The term ‘vitamin’ is conditional in that it depends on the particular organism; for instance ascorbic acid is a n for humans, while many other animals can synthesise it. ns are organic compounds classified by their biological and chemical activity, not by their structure. Each vitamin refers to a number of vitamers, all having the biological activity of the particular vitamin, convertible to the active form of the vitamin in the body, and grouped together under alphabetised generic descriptors, such as ‘vitamin A’. Universally recognised vitamins are preferred for the present invention (related vitamers(s) in brackets): vitamin A (retinol, retinal, and the carotenoids, ing beta carotene, xanthin, lutein, ne, zeaxanthin), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin, niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine, pyridoxamine, pyridoxal), vitamin B7 (biotin), vitamin B8 (ergadenylic acid), vitamin B9 (folic acid, folinic acid), vitamin B12 (cyanocobalamin, hydroxycobalamin, methylcobalamin), vitamin C bic acid), vitamin D (cholecalciferol (D3), ergocalciferol (D2)), vitamin E (tocopherols, tocotrienols), vitamin K (phylloquinone, menaquinones). The ns according to the invention may be provided as semisynthetic and synthetic-source supplements and/or as supplements of natural origin; such as in the form of plant extracts.

As used , the term ‘micro-nutrients’ refers to nutrients required by humans and/or other organisms in small quantities for a variety of their physiological functions, their proper growth and development; including, for instance, dietary micro-minerals or trace elements in amounts generally less than 100 mg/day (as opposed to macrominerals ). The micro-minerals or trace elements include at least boron, cobalt, um, calcium, copper, de, iodine, iron, magnesium, manganese, molybdenum, selenium, zinc. Micronutrients also e phytochemicals, such as terpenoids or polyphenolic compounds, as well as ns (i.e. some compounds may qualify for both categories, vitamins and micro-nutrients).

Preferred micro-nutrients according to the invention may be selected from organic acids, such as acetic acid, citric acid, lactic acid, malic acid, choline and taurine; and trace minerals such as salts of boron, cobalt, chromium, calcium, copper, fluoride, iodine, iron, magnesium, manganese, molybdenum, selenium, zinc, sodium, potassium, phosphorus, or chloride; and cholesterol.

The optional components, i.e. the amino acid, the vitamin and/or the micro-nutrient may be incorporated within the particles described herein in different ways. For example, hydrophilic compounds such as amino acids, water-soluble vitamins and water-soluble micro-nutrients may be incorporated in admixture with the water-soluble or waterswellable polymer, whereas lipophilic compounds may be incorporated in admixture with the first and/or second lipid component.

To further enhance the cial effects of the le, it is preferred that the weight ratio of the first lipid component to the water-swellable or soluble polymeric component is in the range from about 0.1 to about 10. In some embodiments, the weight ratio is from about 0.1 to about 5, from about 0.1 to about 3, from about 0.1 to about 2, or from about 0.1 to about 1. In further embodiments, this weight ratio is from about 0.2 to about 1.5, from about 0.25 to about 1.2, from about 0.25 to about 1.0, such as about 0.3, about 0.5., about 0.75, or about 1, respectively. Particularly red is a weight ratio from about 0.5 to about 5, or from about 0.75 to about 4, or from about 1 to about 3, respectively.

The inventors have found that the satiety-inducing effect of a free or fied fatty acid is enhanced if red in the form of the particle described herein, which allows appetite suppression and the prevention and/or treatment of obesity even without pharmacological ention using a synthetic drug. It is therefore a preferred embodiment that the particle is also free of a synthetic drug substance. In other words, the particle may ntially consist of the water-swellable polymeric or water-soluble component and the first lipid component, and optionally the second lipid ent, the amino acid, the vitamin and/or the micro-nutrient and optionally one or more pharmacologically inert excipients such as the hydrophilic component or an inert core material.

The particle described herein may be in the form of a granule, a pellet, or a minitablet. More preferably, the particle is a granule and/or a pellet.

As used herein, a granule refers to an erated particle which has been prepared from a plurality of smaller, primary particles. Agglomeration, or granulation, for the purpose of preparing a granule, may involve the use of a dry, wet or melt granulation technique.

A pellet, as used herein, is understood as a particle with a relatively spherical or spheroidal shape. If prepared by an agglomeration process, a pellet is a special type of granule. However, pellets (i.e. spherical or idal particles) may also be prepared by other processes than agglomeration. For the avoidance of doubt, the degree of sphericity of a pellet may differ in s technical fields. In the context of the invention, the sphericity of a pellet is in the typical range of pellets used in pharmaceutical formulations for oral use.

A minitablet, often also referred to as a microtablet, is a unit formed by the compression or compaction of a powder or of granules. Typically, the compression is done on tablet presses using punches.

Minitablets, tablets or capsules comprising the particles bed herein are preferably formulated and processed in such a way that they y disintegrate after oral administration. As used herein, disintegration is understood as a substantial physical change to the blet, tablet or capsule logy, such as the e or detachment of the tablet's coating, the dissolution of a capsule or the disintegration of a tablet or minitablet to release particles or pellets or granules described herein. For the detection of such tablet, minitablet or capsule disintegration behaviour, a microscope may be used. With respect to the apparatus, the ynamic conditions, and the temperature, the method <701> of the United States copeia 29 (USP29) may be used, except that water may be used as test medium and that the wire mesh may be adapted with respect to the mesh size or aperture to take the sieve er of the tablet, minitablet or capsule into account. When tested according to this method, the minitablets or tablets or capsules comprising particles described herein ably disintegrate within not more than about 15 minutes. More preferably, they disintegrate within about minutes or less. According to another embodiment, they disintegrate within about 8 minutes or less, or within about 5 minutes or less, respectively.

Particles described herein may be prepared by a method comprising a step of processing a mixture comprising the first lipid component, the water-swellable or watersoluble polymeric component and optionally the amino acid, the vitamin and/or the micro-nutrient by (a) extruding the mixture using a screw extruder; (b) spray congealing the e, ally using a jet-break-up technique; (c) melt granulating the mixture; (d) compressing the mixture into minitablets; (e) melt injection of the mixture into a liquid medium; or (f) spray coating of the mixture onto inert cores.

The preparation of the mixture comprising the first lipid ent, the waterswellable or soluble polymeric component and ally the amino acid, the vitamin and/or the micro-nutrient may be accomplished by conventional means such as blending or high-shear mixing. Optionally, the mixture is prepared using the same equipment which is also utilised for the subsequent step in which the particles are . For example, for preparing a melt to be used for melt congealing, melt ation or melt injection, it may not be required to prepare a dry premix prior to melting the constituents of the melt, but the mixing and melting can be performed simultaneously in one step. Therefore, the mixture to be processed according to steps (a) to (f) above should be broadly reted to cover any form of combining the materials required for preparing the particles.

In one embodiment, the mixture is extruded using a screw extruder. Optionally, a twin-screw extruder is used for carrying out the extrusion step. The er should have a screen with an aperture that is useful for producing an extrudate with appropriate diameter, such as 0.5 mm or 1.0 mm. The screw speed may be selected in consideration of the lity of the extruder and on the processability of the mixture. For e, it may be useful to select a screw speed in the range from about 20 to about 100 rpm.

Preferably, the extrusion step is carried out without the use of a solvent and at a relatively low temperature, such as below about 35 °C, or below about 30 °C, e.g. at room temperature. It is also preferred that the extrusion step is d out at a temperature which is lower than the lower limit of the melting range of the lowest-melting constituent of the mixture.

It is also preferred that the ients used for preparing the particles by ion are mixed or blended before they are fed to the er.

As mentioned above, the ingredients may also be mixed using the same equipment which is utilised for the extrusion step. Thus, it is also preferred that the ingredients used for preparing ed particles are provided to the extruder by co-feeding, using appropriate feeding equipment, and optionally recycled within the extruder (e.g. via internal bypass-loops) until a uniform mixture is obtained which is ready for subsequent extrusion.

Subsequent to the extrusion step, the extrudate may be spheronised in order to obtain approximately cal particles. For this purpose, any conventional spheroniser may be used. The temperature of the spheroniser jacket should preferably be set to be lower than the lower limit of the melting range of the lowest-melting constituent of the mixture. The speed of the spheronisation plates may be set n about 200 and about 2,000 rpm, such as about 500 to about 1,500 rpm. uent sieving may be performed in order to select an optimal particle size of the product.

In a particular embodiment, the particles are prepared from the mixture by spray congealing. This process may also be ed to as spray chilling or spray cooling. In this process, a liquid melt is atomised into a spray of fine droplets of approximately spherical shape inside a spray cooling chamber. Here, the droplets meet a stream of air or gas which is sufficiently cold to solidify the droplets. The air or gas stream may have a ent , mix-current or counter-current direction of flow.

To improve the formation of droplets of appropriate size and shape, a heatable rotary spray nozzle or a fountain nozzle may be used. In the context of the invention, a high speed rotary nozzle is one of the preferred nozzle types for preparing the particles.

Optionally, the uniformity of the atomised droplets may be further enhanced by using a jet break-up technique, such as electrostatic droplet generation, jet-cutting, jet excitation or flow ng. In general, jet up refers to the disintegration of a liquid/gas jet due to forces acting on the jet.

In electrostatic droplet formation processes, a nozzle equipped with an electrode is used which applies an electrical charge to the melt spray. In jet cutting, the spray is directed h a cutter similar to e.g. a rotary disc with apertures of defined size. Jet excitation means the excitation of the melt spray by onic waves, causing vibration and facilitating the separation of droplets.

Flow focusing results from combining hydrodynamic forces with a specific geometry, which may be achieved by using a pressure chamber pressurised with a continuous focusing fluid supply. Inside, a focused fluid is injected h a capillary feed tube whose ity opens up in front of a small e linking the r with the or ambient. The focusing fluid stream moulds the fluid meniscus into a cusp giving rise to a microjet exiting the r through the orifice. Capillary instability breaks up the stationary jet into homogeneous droplets.

In another specific embodiment, the particles are prepared by injecting the melted mixture into a liquid. The liquid may be cooled to a temperature below room temperature, or preferably to substantially below the lower limit of the melting range of the lowest-melting constituent of the lipid component. The liquid should be selected taking the composition of the mixture into consideration, but also with an eye on safety and physiological tolerability. In many cases, ethanol is a suitable liquid.

In another embodiment, the particles may be formed by melt agglomeration, or melt granulation. In the context of the invention, agglomeration and granulation may be used interchangeably. For this e, the constituents of the mixture are mixed or blended and agglomerated, or granulated, in a suitable type of equipment, such as a heatable granulator, a high-shear mixer/granulator or a fluid bed granulator. Depending on the type of equipment, the granulation may be carried out by heating the e to a ature at which at least one of its constituents softens or melts, under continuous ng or mixing. In a conventional granulator, this may lead to larger agglomerates which are then passed through a sieve to obtain the desired particle size. If fluid bed equipment is used, the complete mixture may be fluidised and heated carefully up to the melting temperature of the lowest-melting constituent. Alternatively, the lowest-melting constituent may be melted and sprayed onto the sed powder mixture comprising the remaining tuents.

Optionally, the melt granules may be further sed and ssed into minitablets. For this purpose, it is preferred that the granules are first blended with one or more tablet fillers/binders to enhance the plasticity of the mixture. Moreover, conventional excipients to improve the flow of the granules and reduce their tackiness may also be added before compression. Tableting may be carried out using any conventional pharmaceutical tablet press, such as an ric press or a rotary press.

Optionally, the press may be equipped with multi-punch tooling so that each compression yields a plurality of minitablets. Punches for very small tablet diameters are preferred, such as between about 1 mm and about 3 mm, such as about 1.5 mm.

In a further embodiment, the particles are prepared by spray coating the mixture comprising the first lipid component and the swellable or water-soluble polymeric component onto inert cores. As used herein, an inert core is a particle from a physiologically able material which is suitable for being coated, and which itself does not ntially contribute to the physiological effect of the particles described herein, i.e. the induction of satiety. Examples of suitable cores include crystals of appropriate size and shape, such as sugar (sucrose) crystals. In one of the preferred embodiments, spherical beads or non-pareils made from sugar, starch, cellulose, in particular microcrystalline cellulose (e.g. Cellets®) are spray coated with the mixture.

The spray coating of the inert cores may, for example, be performed in a fluid bed apparatus. The mixture of the first lipid ent and the water-swellable or watersoluble polymeric component may be melted and sprayed onto the fluidised core particles. Optionally, the amino acid, the vitamin and/or the micro-nutrient if present may also be added to this mixture. Alternatively, an aqueous or c dispersion (or suspension, which is understood as a sub-type of a dispersion) of the mixture is sprayed onto the fluidised cores in such a way that the water or solvent evaporates and the mixture of the first lipid component and the water-swellable or water-soluble polymeric component - and ally the amino acid, the vitamin and/or the micro-nutrient if present - forms a g on the inert core particles.

As in all other processes mentioned above, a subsequent step of classifying the resulting particles using a sieve in order to obtain a more uniform particle size distribution may be useful.

For the preparation of particles described herein which further exhibit a g (or second coating covering the first coating) comprising a second lipid component and/or a hydrophilic component but not the water-swellable or water-soluble polymeric ent, such second coating may also be applied using conventional pharmaceutical spray coating techniques. In one of the preferred ments, fluid bed coating is used for this purpose, using particles described herein prepared as described above as active cores which are fluidised, and onto which either a melt or a dispersion/suspension of the second lipid component, or a solution or dispersion/suspension of the hydrophilic component is sprayed. If both the second lipid component and the hydrophilic component are present, they may be applied together in the form of a dispersion/suspension in water or solvent, or as a melt of the lipid in which the hydrophilic component is sed.

Further, an ingestible particle is described which is obtainable by the method as described above.

In a further aspect, the invention es a solid composition for oral administration comprising a plurality of the particles as described above, or which has been prepared from a plurality of the particles, such as by compressing the particles into s. If not compressed into s, the particles may in principle be filled into capsules, sachets, stick packs, or ners (e.g. bottles of glass or other materials). In one of the preferred embodiments, the granules are filled into sachets, stick packs, or containers in such a way that a single dose is accommodated in one primary package.

Optionally, the composition may comprise the particles along with one or more further inactive ingredients.

If the particles are to be swallowed as such, it is also preferred that they have a mass median sieve er in the range from about 0.1 mm to about 3 mm. Also red are mass median sieve ers in the range from about 0.5 mm to about 3 mm, or from about 0.75 mm to about 2.5 mm, or from about 1 mm to about 2 mm. In other preferred embodiments, the mass median sieve diameter may be in the range from about 0.1 mm to about 0.4 mm, from about 0.2 mm to about 0.5 mm, or from about 0.2 mm to about 0.4 mm, tively.

The presentation and oral administration in the form of particles in sachets, stick packs or ners is also useful as it is preferred that a relatively large amount of the ition is administered as a single dose. In one of the preferred embodiments, a single dose comprises at least about 2 g of the composition, and more preferably at least about 3 g thereof. In another embodiment, a single dose comprises from about 3 g to about 20 g of the composition. In further embodiments, the amount comprised in a single dose is from about 4 g to about 15 g of the composition, or from about 5 g to about 12 g, or from about 5 g to about 10 g, respectively. It is also preferred that the composition exhibits a high contents of the particles described herein, such as at least about 50 %, or at least about 60 %, or at least about 70 %, or at least about 80 % by weight. Particularly preferred is a particle content in the composition of at least about 90 %, or at least about 95 %, or at least about 98 %, such as about 100 % by weight.

For the purpose of administration, the composition may be suspended in a liquid or semisolid vehicle. The liquid may simply be water or fruit juice or a dairy beverage or any other, preferably non-carbonated, ingestible liquid. It may optionally be provided together with the composition within a kit. This has the advantage that the nature and amount of liquid are controlled and the administration is more reproducible. The ready- to-use drink suspension may have, for example, a volume in the range from about 30 mL to about 300 mL, or from about 50 mL to about 200 mL.

In a preferred ment, the composition of the invention is administered as suspension drink. It was found that the suspension drink described herein is useful for administering large s, such as1 g or more, of the ition while exhibiting good drinkability and mouth feel. Drinkability of such a suspension drink bed herein may be assessed by methods used to determine the flowability of wet granular materials. In particular, dynamic ements of the angle of repose may be taken using a rotating drum apparatus where the whole drum or its bottom and top are transparent or semi-transparent. Such apparatus are commercially available for ce from Mercury Scientific, USA (Revolution Powder Analyzer) and APTIS, Belgium (GranuDruM powder ter). In a suitable experimental set up for dynamic measurements of angle of repose of wet granular material comprising aqueous liquid, the drum is preferably made of PTFE (Teflon®) or coated with PTFE or r anti-adhesive al, and is filled to half of its volume with a suspension of powder or les. After g the drum´s top and bottom along a ntal axis, and repeated tapping for even distribution of the drum´s contents, the suspension forms a horizontal meniscus of an angle of zero. This may be visually observed and measured by standard methods of angle measurements. Rotating the drum along this horizontal axis may displace the meniscus of the powder suspension to a certain angle before the meniscus of the suspension repositions itself to an angle of almost zero. The displacement of the meniscus from the horizontal may be repeated several times, and a mean value of the dynamic angle of repose may be calculated.

Preferably the suspension drink comprises a plurality of the particles described herein and at least one aqueous liquid, and the sum of the volume fractions of the particles and the at least one aqueous liquid makes 100 vol-%. Accordingly, described is a suspension drink, comprising 50 to 75 vol-% of particles described herein; and 25 to 50 vol-% of at least one s liquid; wherein the volume fractions are based on the total volume of the suspension drink. Preferably, the dynamic angle of repose of the suspension drink is less than about 30°.

In a further preferred embodiment, the amounts of particles and liquid are selected such that a densely packed suspension drink is obtained by matching the filling height of the particles settled in a suitably sized container with the filling height of the aqueous liquid in the same container comprising the d les. In other words, the amount of the liquid is chosen in such manner that the meniscus of the liquid is roughly at the on of the upper limit of the settled particles.

The at least one aqueous liquid further may comprise alcohol, flavouring compounds, colouring compounds, preservatives, viscosity enhancers, health ingredients or mixtures of two or more thereof. Suitable flavouring compounds are citric acid, malic acid, phosphoric acid, tartaric acid, natural and synthetic aroma, sweeteners, for example monosaccharides, disaccharides, polyhydric alcohols; including arabitol, erythritol, glycerol, isomalt, ol, maltitol, ol, sorbitol or xylitol; or sugar substitutes, ing cyclamate, rine, stevia, sucralose and/or aspartame. Further suitable flavouring compounds are juices of fruits and/or vegetables. Colouring compounds suitable for the s liquid are for example Allura Red AC, Anthocyanine, azorubine, betanin, Brilliant Blue FCF, carotene, Quinoline Yellow WS, Ponceau 4R, Green S, Patent Blue V and zine, either as such or in the form of the corresponding aluminium lakes.

Suitable preservatives are vitamins A, E or C, l palmitate, ne, methionine, citric acid, sodium citrate, used in amounts of 0.001 to 0.1 % by weight based on the liquid.

The amount of the first lipid component, which is a key ingredient of the composition, should preferably be at least about 1 g per single dose or per package. In another embodiment, a single dose comprises at least about 2 g of the first lipid component, such as about 3 g or about 4 g. In a further preferred embodiment, the content of the first lipid ent per single dose is at least about 5 g.

The amount of the amino acid (or of the total amino acids, if a mixture or combination of amino acids is used) may be about 0.05 g or more per single dose or per package. In another embodiment, a single dose comprises at least about 0.1 g, or at least about 0.2 g, or at least about 0.5 g of amino acid(s), respectively. In further embodiments, the content of the amino acid(s) per single dose is from 0.5 g to about 5 g, or from 0.5 g to about 3 g.

In one of the embodiments, the components of the particles are selected such that the dynamic angle of repose of a suspension prepared from suspending the composition in water at a weight ratio of 1 is less than 30°.

As mentioned, the particles described herein and the compositions of the invention may be used for the ssion of appetite, in particular in human subjects, and for the induction of satiety. Thus, described is a method of ng satiety in a subject, wherein the method comprises a step of orally administering a composition sing an effective amount of a first agent capable of inducing satiety, and a second agent capable of augmenting the y-inducing effect of the first agent, and n the first and the second agent are optionally selected as described above.

Without wishing to be bound by theory, it is currently believed by the inventors that the appetite suppressing effect is at least in part based on the fatty acid compound comprised in the first lipid component, which upon ingestions interacts with physiological targets located in the mucosa of the gastrointestinal tract, such as in the h and/or duodenum, thereby activating one or more signalling cascades which eventually produce a perception of satiety or a reduction of appetite or hunger. Possibly, one of the targets at which the fatty acid acts are the ghrelin cells (or n receptors), large numbers of which are located in the stomach and the duodenum.

If present, the amino acid may further bute to the te suppressing effect, which may be due to a stimulation of chemosensors in the al gastrointestinal tract by which in turn the CCK and glucagon secretion is triggered.

The water-swellable or water soluble polymeric component was found by the inventors to enhance the effect of the fatty acid, which is possibly due to the swelling and/or mucoadhesive properties effecting a prolonged attachment of the les (or components thereof) to the gastric or duodenal mucosa, allowing for an increased interaction of the fatty acid with the target structure. Of , other properties of the particles may also effect or contribute to a prolonged gastric residence time, such as the selected particle size or the low density ing from the high lipid content. In any case, the inventors found that the oral stration of the particles to volunteers induced satiety with the consequence that the ts experienced suppressed appetite and showed a reduced food intake during the meal following the administration of a composition comprising the particles as described herein. This effect was consistent with animal data g the composition leads to a weight loss, or weight reduction, of the test animals.

Also described is a method of treating or preventing overweight, obesity, or a disease or condition associated with overweight or obesity in a subject, wherein the method comprises a step of orally administering a composition comprising an effective amount of a first agent e of inducing satiety, and a second agent capable of augmenting the satiety-inducing effect of the first agent, and wherein the first and the second agent are ally selected as described above. Moreover, described is a method of treating or preventing overweight, obesity, or a disease or condition associated with overweight or obesity in a subject, which method is also characterised by a step of orally administering a composition comprising an effective amount of the first agent and of the second agent.

Of , also the preferred particles and/or compositions as described above may therefore be used clinically, or as dietary ments, for the prevention and/or treatment of obesity and overweight, as well as the prevention and/or treatment of diseases or conditions associated with obesity; e.g. by using the ingestible particles as defined herein and/or compositions comprising or prepared from a plurality of these particles for body weight reduction.

In other words, described is a method for the prevention and/or treatment of obesity and overweight, as well as the tion and/or treatment of diseases or conditions associated with obesity, for appetite suppression, body weight reduction and/or for the induction of satiety, said method comprising a step of orally administering the particles described herein and/or compositions comprising or prepared from a plurality of these particles. Optionally said method comprises the oral administration of the particles and/or compositions at least once a day over a period of at least one week.

In yet other words, described is the use of the particles described herein and/or itions comprising or prepared from a ity of these particles in the manufacture of medicaments for the tion and/or ent of obesity and overweight, as well as the prevention and/or treatment of diseases or conditions associated with obesity, for appetite suppression, body weight reduction and/or for the induction of satiety. Optionally, this comprises the oral administration of the particles and/or compositions at least once a day over a period of at least one week.

As used herein, obesity is a l condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health. Overweight is tood as a borderline condition characterised by a body mass index (BMI) between and below 30. Starting from a BMI of 30, the condition is classified as obesity.

In one embodiment, the particles and/or compositions are administered to normal weight or ight subjects gaining weight over time or otherwise being at risk of developing obesity. In this case, the therapeutical ive is to stop or limit the weight gain and prevent the development of obesity. Another purpose may be to reduce the risk that the subject ps a disease or condition associated with or caused by obesity.

In a further embodiment, the particles and/or itions are administered to obese patients in order to treat or reduce the severity of obesity. Again, the eutic use may also be directed to the reduction of the risk of developing a disease or condition associated with or caused by obesity.

A large number of diseases and conditions are nowadays considered to be associated with or caused by obesity, even though the mechanism by which they are linked to obesity may not always be fully understood. In particular, these diseases and conditions include - t limitation - diabetes mellitus type 2, al hypertension, metabolic syndrome, insulin resistance, hypercholesterolaemia, hypertriglyceridaemia, osteoarthritis, obstructive sleep apnoea, ischaemic heart disease, dial infarction, congestive heart failure, stroke, gout, and low back pain. The prevention and/or reduction of risk for developing any of these conditions is within the scope of the therapeutic use described herein.

Moreover, the therapeutic use preferably involves the at least once daily oral administration of the particles and/or compositions of the invention over a period of at least one week. In this context, the expression "therapeutic use" is understood to also cover the preventive or prophylactic use. In a further preferred embodiment, the particles and/or compositions are administered to a human subject over a period of at least about 2 weeks, or at least about 4 weeks, or at least about 6 weeks, or at least about 2 , respectively. Also preferred is an administration regimen providing for once or twice daily administration.

The time of administration should be selected to maximise the satiety-inducing effect on the amount of food which is uently taken up by the subject that is treated.

For example, it is useful to administer a dose of the ition before a major meal, such as before a lunchtime meal and/or before the evening dinner such as to reduce the amount of food eaten during either of these meals. With respect to the precise timing, it is preferred that the dose is administered within about 5 to 120 minutes prior to the tive meal, in particular about 10 to about 120 minutes prior to the meal, or about 15 to about 90 minutes prior to the meal, such as about 30 or about 60 minutes prior to the meal.

In one of the particularly preferred embodiments, a dose comprising at least about g of the first lipid component is administered to a human subject at least once daily between about 15 and about 90 minutes prior to a meal over a period of at least 4 weeks for the prevention or treatment of obesity or an associated disease.

Further, described is a method of inducing satiety in a subject, or method of treating or preventing overweight, obesity, or a disease or condition associated with overweight or obesity in a subject, or method of controlling or reducing the body weight of a subject, each method comprising a step of orally administering a composition comprising an effective amount of a first agent capable of inducing satiety and a second agent capable of augmenting the satiety-inducing effect of the first agent, wherein the methods r comprise the use of a device for the collection, storage and/or display of information relating to a subject's adherence to, or the effectiveness of, a predefined therapeutic regimen of orally administering the composition.

According to a related aspect, the invention provides a body weight management system comprising the composition comprising effective s of the first agent and the second agent, and a device configured for the collection, storage and/or display of information ng to a subject's adherence, or the effectiveness of, a predefined therapeutic regimen of orally administering the composition.

In more detail, it is contemplated that the particles described herein and/or compositions of the invention are used in combination with the use of a device for the collection, e and/or display of information relating to a subject's adherence to the therapy and/or the effectiveness of the y. As used herein, ation relating to a subject's adherence to the therapy may e, for example, information on whether a dose was administered within a certain period of time (e.g. during a calendar day), or the time at which each dose was administered. The device is ably a programmed electronic device, such as a computer, in particular a microcomputer, and most preferably a le omputer such as a mobile phone ("smartphone"), or a wearable device such as a smart watch, an electronic and, or the like. The information may be received by the device automatically from a sensor, or it may be entered manually by a user, such as the subject or t, the physician, nurse, or by a caregiver, and stored for subsequent analysis or display. For example, the patient may periodically monitor his or her actual compliance or adherence to the therapy.

The device may be programmed to provide the user with a ck signal or reminder in case of non-compliance or lack of adequate adherence to the therapy. The feedback signal may be optical, haptic (e.g. ion), or acoustic.

Information relating to the effectiveness of the therapy may e, for e, the weight of the subject, the degree of hunger or appetite, the number of meals and snacks, or the type or amount of food eaten during any particular period of time (e.g. a calendar day), or even physiological data such as the blood e concentration or blood pressure. Depending on its type, the information relating to the effectiveness of the therapy may be automatically ed by the device or entered manually by the user.

Information with respect to the feeling of satiety or hunger may be usefully entered by the user or patient in a manual mode, whereas logical parameters such as blood glucose or blood pressure may be received from the respective measuring devices used for their determination. In the latter case, the transfer of the data encoding the information generated by the measuring device to the device for the storage and/or display of the information is ably wireless.

In more detail, ation collection may be user-initiated or the device may be programmed with an application (i.e. software) which s an alert calling for the user to input her or his satiety-state information. ably, information collection proceeds in regular time intervals such as 15 or 30 min intervals. In one embodiment, information collection is performed throughout a period of 12, 16 or 18 hours per day. In r ment, information collection is performed in multiple periods of for instance 1 to 3 hours over the day, for instance three times for 3 hours each. Preferably such time periods cover meal times such as breakfast, lunch and dinner. Preferably, users - for a given period of information collection - may not refer to previous satiety ratings when providing the real-time information.

Information collection may proceed in the following fashion. After the user has opened the software application, a satiety state screen is displayed on the colour touch screen using visual analogue scales for the assessment of satiety. Such scales and scores have previously been described in detail [Flint A, Raben A, Blundell JE, Astrup A.

Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord 2000; 24:38-48). In brief, the visual analogue scale (VAS) consists of a ntal, unstructured, 10 cm line with words anchored at each end, describing the extremes ('not at all' or 'extremely') of the ar on, 'How satiated are you right now?' To ensure reliable and valid results, participants rate their feeling of satiation as precisely as possible, and they cannot refer to their previous ratings when marking the VAS.

The satiety state screen may display a query 1 "how hungry do you feel?" combined with an unstructured sliding scale labelled "I am not hungry at all" on one end to "very hungry" on the other hand. The application will wait for the user to touch the sliding scale at one position. Upon touching the scale, a slider may , and the user may adjust its position. The application will determine the position of the slider after the user removed its touching finger from the slider symbol, retrieve the positional value and use it for further processing.

Further potentially useful embodiments are easily derivable on the basis of the guidance ed herein-above and the following examples.

EXAMPLES Example 1: Preparation of particles by spray congealing Particles with a swellable or water-soluble polymeric component embedded within a lipid component may be prepared by spray ling as follows. 250 g of capric acid are melted. 100.0 g of carbomer homopolymer type A NF and 50.0 g of sodium caprate are added to the melt and mixed such as to form a viscous suspension. Under continuous g, the suspension is fed to the heated rotary nozzle of a spray congealing tower. Cold air is continuously introduced into the tower to allow solidification of the resulting droplets. The solid les are then passed through appropriate sieves to allow removal of oversize and undersize particles, and to obtain particles described herein. Optionally, the product may be further processed, e.g. by coating the particles.

Example 2: Preparation of les by spray congealing Similarly, particles may be prepared from polycarbophil and a mixture of fatty acids. For example, 240.0 g of lauric acid and 60.0 g of capric acid are melted, and 100.0 g of polycarbophil (USP) are incorporated into the melt such as to obtain a viscous lipid suspension. Under continuous g, the suspension is fed to the heated rotary nozzle of a spray congealing tower. Again, cold air is uously introduced into the tower to allow solidification of the resulting droplets. Subsequently, the solidified particles are passed through appropriate sieves to allow removal of oversize and undersize particles, and to obtain particles described herein.

Example 3: Preparation of particles by spray congealing using jet break-up techniques As a variation of Example 1, a spray congealing tower may be used which is equipped for a jet break-up spray process to generate monodisperse particles of appropriate size, e.g. electrostatic droplet generation, jet-cutter technology, jet excitation, or flow focusing. 200.0 g of hard fat EP/NF (e.g. Suppocire® A) and 400.0 g of sodium ate are mixed and melted. 100.0 g of carbomer homopolymer type B NF added to the melt and mixed such as to form a viscous suspension. Under continuous heating, the suspension is fed to a nozzle of a spray congealing tower with jet excitation equipment. The vibration excitation is set to provide particles in the range of 200 µm. Cold air is continuously introduced into the tower to allow solidification of the resulting droplets. The uniform, solidified particles are collected as final product.

Example 4: Preparation of particles by melt injection 150.0 g of a mixture of hard fat EP/NF and glyceryl eate (type 40) EP/NF (e.g. Ovucire® WL 2944) and 200.0 g of sodium laurate are mixed and melted. 90.0 g of carbomer interpolymer type A NF added to the melt and mixed such as to form a viscous suspension. Under continuous heating, the suspension is fed to the needle of an tary luidics device, through which droplets are formed and injected into cooled absolute ethanol to provide particles in the 250 µm range. The solidified particles are ted and thoroughly dried to result in the final product.

Example 5: Preparation of particles by solvent-free cold extrusion An intimate mixture of 250.0 g of ed palm oil, 50.0 g of sodium oleate and 110.0 g of carbomer 941 NF is prepared using a V-blender. The blend is fed by a etric powder feeder type KT20 (K-Tron) to the powder inlet g of a Leistritz NANO 16® twin screw extruder and extruded in the first segments at a temperature range between 25 °C and 30 °C. The final segment is cooled to 20 °C. Short rods of approx. 0.8 – 1.5 mm length are obtained by this process. The rods are subsequently spheronised in a Caleva® MBS 120 equipment, with water jacket temperature set to 30-35 °C, until the final product is obtained in the form of ially cal particles.

Example 6: Coating of sugar crystals by melt granulation A premix of 200.0 g of myristic acid, 75.0 g of sodium oleate, 100.0 g of carbomer 941 NF and 250.0 g of sucrose crystals (mean particle size 200 – 250 µm) is prepared. The premix is introduced into a planetary mixer equipped with a heatable . Under continuous operation of the mixer, the temperature is slowly raised until the lipid phase is ghly molten. Again under continuous operation of the mixer, the temperature is cooled to room temperature. The resulting solidified mass is passed through a sieve to break or remove oversized particles, giving the final product.

Example 7: Coating of non-pareil seeds by organic lipid solution A premix of 200.0 g of myristic acid, 75.0 g of sodium oleate, and 100.0 g of carbomer 941 NF is prepared and dispersed in absolute ethanol. 275.0 g of sugar spheres EP/NF (non-pareils) are introduced into an explosion-proof fluid bed equipment with Wurster column and pre-heated to 50-55 °C. Subsequently, the dispersion is slowly sprayed on pre-heated sugar spheres, allowing for evaporation of the ethanol, and taking into account the critical explosion limit of air-ethanol mixtures. At the end, the coated sugar s are cooled to room temperature and flushed with cold air until the limit of residual solvents is within acceptable limits, to e the final product.

Example 8: Coating of non-pareil seeds by aqueous suspension A premix of 300.0 g of myristic acid and 100.0 g of er 941 NF is prepared and dispersed in demineralised water (q.s.). In analogy to the previous example, 275.0 g of sugar s EP/NF (non-pareils) are introduced into a fluid bed equipment with Wurster column and pre-heated to approx. 50-55 °C. Subsequently, the suspension is slowly sprayed on the pre-heated sugar spheres to allow the water to evaporate. At the end, the coated sugar s are cooled to room temperature and flushed with cold air until the limit of residual water is within acceptable , to provide the final product.

Example 9: ssion of minitablets from melt granulate Particles described herein may also be prepared in the form of minitablets, preferably with a small diameter, such as 1.5 mm. For e, 300.0 g of lauric acid, 50.0 g of sodium laurate, 100.0 g of microcrystalline cellulose (e.g. Avicel® PH101), and 100.0 g of carbomer 941 NF are mixed to obtain a premix which is then introduced into a jacketed, heated planetary mixer, and agglomerated to result in a granular material. The melt granulate is then sieved through an appropriate sieve ed with knives to result in a fine, granular material. This granular al is subsequently blended with 75.0 g of microcrystalline cellulose (e.g. Avicel® . The resulting blend is compressed on a multi-punch eccentric tablet press into ex tablets with a diameter of 1.5 mm and thickness of . 2 mm, to provide the final product. In this example, the microcrystalline cellulose may also be replaced by lactose (e.g. lactose monohydrate NF) or calcium hydrogen ate dihydrate (Ph.Eur.).

Example 10: Coating of active cores with a film coating based on hypromellose Active cores prepared according to Examples 1 to 9 may be coated as follows. An aqueous polymer solution (A) is prepared by dissolving 5.0 g of hypromellose type 2910 (e.g. Pharmacoat® 603) in 90.0 mL of demineralised water. Separately, a pigment dispersion (B) is prepared by dispersing 2.0 g of titanium dioxide (e.g. Titanium Dioxide "Anatas") and 1.0 g of a t in 15.0 mL of demineralised water, followed by nisation using a high-shear homogeniser. Subsequently, a coating dispersion (C) is prepared by mixing the polymer solution (A) and the pigment dispersion (B) under continuous stirring.

In the next step, 1,000 g of the active cores prepared according to any one of Examples 1 to 9 are fluidised in a fluidised bed granulation apparatus equipped with a Wurster column at a temperature of 25 – 30 °C. 100 mL of the g dispersion (C) are slowly sprayed on the active cores, keeping the bed ature at 25 – 30 °C by adjusting inlet air temperature and spray rate. The coated active cores are fully dried at the same ature within the fluidised bed, and thereafter cooled to room temperature within the fluidised bed.

In result, coated particles will be obtained whose coating rapidly disintegrates after oral ingestion.

It is noted that the r solution (A) may also be prepared by dissolving 5.0 g of hypromellose type 2910 (e.g. Pharmacoat® 603) in a mixture of 45.0 mL of ethanol and 55.0 mL of demineralised water. This variation would lead to a more rapid evaporation of the solvent during the spray coating process. atively, a coating sion may also be ed by further incorporating a plasticiser, a surfactant, and a small amount of ethylcellulose. In this case, a r solution (A) may be prepared by dissolving 5.0 g of ellose type 2910 (e.g.

Pharmacoat® 603) and 0.5 g of triacetin (glycerol triacetate) in 50.0 mL of demineralised water. In addition, 0.25 g of sodium lauryl sulphate are dissolved in 2.5 mL of demineralised water to form a surfactant on (A'). A pigment dispersion (B) is prepared by sing and homogenising 2.5 g of talc, 3.0 g of titanium dioxide and 0.2 g of colorant pigment in 20.0 mL of demineralised water. Subsequently, the coating dispersion (C) is prepared by mixing the polymer solution (A), the surfactant solution (A'), the pigment dispersion (B), and 5.0 g of an ethylcellulose dispersion (corresponding to 1.5 g dry matter). The coating procedure itself is conducted as described above.

Example 11: Preparation of a composition comprising coated particles A composition comprising the particles of the invention which may easily be filled into stick packs or sachets may be obtained from gently mixing 1,005 g of the coated active cores prepared according to Example 10 with 0.5 g of hydrophobic colloidal silica (NF) (e.g. AEROSIL® R 972) in a rotating drum. Instead of hydrophobic colloidal silica, a rd grade of colloidal n dioxide (e.g. AEROSIL® 200) may also be used at the same amount. In this composition, the silica acts as acking agent.

Example 12: Coating of active cores with a mixture of a lipid component and a hydrophilic component A coating dispersion is prepared by dissolving 5.0 g of hypromellose type 2910 (e.g. Pharmacoat® 603) and dispersing 2.0 g of lauroyl polyoxyl-32 glycerides NF (e.g. Gelucire® 44/14) in a e of 45.0 mL of ethanol and 55 mL of demineralised water. Subsequently, 105 mL of the dispersion is coated on 1,000 g of the active cores prepared according to any one of es 1 to 9, using the same equipment and procedure as in Example 10. Coated particles are described which exhibit rapid disintegration of the coating after oral administration.

As alternatives to the lauroyl polyoxyl-32 glycerides NF, similar amounts of stearoyl yl-32 glycerides NF (e.g. Gelucire® 50/13) or caprylocaproyl polyoxyl-8 glycerides NF (e.g. Labrasol®) may be used.

Example 13: Coating of active cores with a film coating based on povidone A coating solution may be prepared by dissolving 5.0 g of povidone K30 and 1.0 g of polyethylene glycol 4000 (alternatively polyethylene glycol 1000) in a mixture of 60 mL of ethanol and 40 mL of ralised water. 100.0 mL of the solution are then sprayed onto 1,000 g of the active cores prepared according to any one of Examples 1 to 9, using the same equipment and procedure as in Example 10. The procedure leads to particles whose coating rapidly releases the active core after oral administration.

Example 14: Coating of active cores with a film coating based on ethyl cellulose A coating solution may be prepared by dissolving 4.0 g of ethylcellulose NF (e.g. L® 10 FP) and 1.0 g of polyethylene glycol 4000 in a mixture of 25 mL of acetone, 35 mL of ethanol and 40 mL of demineralised water. 100.0 mL of the solution are then sprayed onto 1,000 g of the active cores prepared according to any one of Examples 1 to 9, using the same equipment and ure as in Example 10, and taking into account the critical explosion limit of air-acetone-ethanol es. The procedure leads to particles whose coating rapidly releases the active core after oral administration.

Example 15: Coating of active cores with a coating based on phospholipids In this Example, the coating comprises a lipid component in combination with a hydrophilic component. A coating suspension is prepared by dispersing 10.0 g of lly hydrogenated soybean lecithin (e.g. Lipoid S75-35 or Lipoid S-PC-35) in demineralised water (q.s.), using high shear homogenisation, followed by the addition of a small amount (q.s.) of an immediate e g system (e.g. Opadry®) ning a water-soluble g polymer, a plasticiser and t. 100.0 mL of the dispersion are then sprayed onto 1,000 g of the active cores prepared according to any one of Examples 1 to 9, using the same equipment and procedure as in Example 10. The procedure leads to particles whose coating rapidly releases the active core after oral administration.

To obtain coated particles with reduced stickiness, a portion of the lly hydrogenated soybean lecithin may be replaced by a fully enated lecithin (e.g. Lipoid S75-3), or 2.0 g of the fully hydrogenated lecithin may be incorporated in addition to the 10.0 g of partially enated soybean lecithin.

Example 16: Coating of active cores with a mixture of lecithin and maltodextrin .0 g of a powder mixture of lecithin and maltodextrin (e.g. Soluthin®) is dispersed in 95 mL of demineralised water at room temperature. 1,000 g of the cores prepared according to any one of Examples 1 to 9 are fluidised bed apparatus at a temperature of 20 to 30 °C. Subsequently, 100,0 mL of the dispersion are slowly sprayed on the active cores by the top spraying procedure, keeping the bed temperature at 20 – 30 °C by adjusting inlet air temperature and spray rate. The coated cores are fully dried at the same temperature within the fluidised bed, and thereafter cooled to room temperature within the fluidised bed. Again, coated particles are obtained which release their active core rapidly after oral administration.

Example 17: g of active cores with a sucrose ester A clear solution is prepared by dissolving 15.0 g of sucrose e L-1695 in 90.0 mL of demineralised water at room temperature. 1,000 g of the active cores prepared according to any one of Examples 1 to 9 are fluidised and coated in a similar manner as described in e 16 to obtain coated les with similar properties with respect to their release behaviour.

As an alternative to sucrose e L-1695, sucrose laurate L-1570 may be used, optionally in the form of sucrose laurate LWA-1570, a ready-to-use solution of 40 % L- 1570 in 4 % ethanol and 56 % water. For e, 30.0 g of sucrose laurate LWA-1570 may be diluted with 110.0 mL of demineralised water and 20 mL of ethanol. 150 mL of this coating solution may be used to coat 1,000 g of the cores.

Example 18: Coating of active cores with ethylene glycol/vinyl l graft copolymer Coated particles described herein may also be prepared by using ethylene glycol/vinyl alcohol graft copolymer as an immediate e coating agent. For instance, a polymer on may be prepared from 24.0 g of Kollicoat® which are dispersed 96 mL of ralised water and dissolved under stirring. tely, a pigment suspension is prepared by dispersing 4.5 g of talc, 1.5 g of iron oxide red, and 3.9 g of titanium dioxide in 11.0 mL of demineralised water, followed by homogenisation with a high shear homogeniser. The coating sion is then obtained by mixing 100.0 mL of the polymer solution with 20.0 g of the pigment suspension. 1,000 g of the active cores prepared according to any one of Examples 1 to 9 are sed and coated in a similar manner as described in Example 16 to obtain coated particles with similar properties with respect to their e behaviour. During the whole coating process, the coating suspension is uously stirred to avoid sedimentation.

Example 19: Preparation of les by cryomilling 300 g hard fat (adeps solidus from Caelo, Germany) were brought to a melt at 50 °C. 200 g Carbopol® 971G (Lubrizol) were incorporated into the lipid by means of a a.

The viscous mass was filled into a plastic bag and cooled to -18 °C in a freezer. The frozen material was crushed with a hammer and shredded to a powder in a kitchen blender (Bosch ProfiMIXX, Germany). After drying under vacuum at 25 °C to remove residual condensed water, the obtained particles were classified through a set of wire mesh sieves (VWR International, Germany) to provide a classified powder having a size of below 0.5 mm.

Example 20: Preparation of particles by cryomilling 500 g hard fat (Witepsol® W35 from NRC, Germany) were brought to a melt at 50 °C. 250 g Carbopol® 971G (Lubrizol) were incorporated into the lipid by means of a spatula. The s mass was filled into a plastic bag and cooled to -18 °C in a freezer.

The frozen material was crushed with a hammer and shredded to a powder using an ultra-centrifugal mill (ZM 200, Retsch, Germany). For milling, the material was precooled using dry ice, and a rotation speed of 18000/min was applied for two minutes. The material was quantitatively converted to particles with a diameter (D90) of 0.2 mm. Prior to classifying the particles, they were dried under vacuum at 25 °C to remove residual condensed water, where this was considered expedient.

Example 21: Preparation of particles by fluid-bed granulation 400 g of the classified powder from Example 19 were loaded into a fluid bed device (Ventilus V-2.5/1 from Innojet, Germany) equipped with a IPC3 product reservoir. The powder was fluidised at 32 °C using an air flow of 50 m3/h. The material was ated for 30 min and fied h a set of wire mesh sieves to obtain 240 g of particles of a size n 0.5 and 1.0 mm, and 64 g of particles of a size above 1.0 mm.

Example 22: Animal studies A. General procedures Animals (rats) were kept in cages on rd animal bedding (two animals per cage or individual housing) and were provided with ad libitum access to food and water.

Animal food was provided as pellets in a pellet rack or as a cream or as ate powder in a container attached to the inside of the cage.

Body weight was recorded at ing and end of experiments. Food consumption was documented daily except for weekends. Experiments were performed according to German laws of animal protection.

Rodent chow was purchased from ssniff® Spezialdiäten GmbH, Germany and poly(acrylic acid) (PAA, Carbopol® 971 P NF) was obtained from the Lubrizol Corporation, USA. Cocoa butter chips (Caelo 633B) were from Caesar & Lorentz, Germany. Hard fat (Witepsol®) was from NRC, Germany. All percentages provided are w/w-percentages, unless specifically mentioned otherwise.

B. Standard pellet chow with 5 % fat - reference for normal food uptake and weight gain Twelve male wistar rats having a mean body weight of 319 ± 7 g were fed an experimental diet provided as pellets for seven days. The mixture was composed of standard chow diet (ssniff® EF R/M Control, 5 %) having a fat content of 5 % in the final mixture.

Water was added to the rd chow to e a paste which was ed and cut into s (1 cm x 3 cm) by means of a food processor (Kitchen Aid Classic, USA).

Pellets were dried at 25 °C over night.

At the end of the experiment, food intake, energy intake and body weight change were calculated (± SD). Animals gained 5.0 ± 1.9 % body weight, mean daily food intake was 24.3 ± 2.7 g, representing a mean metabolisable energy intake of 374 ± 40.8 kJ per animal per day.

C. Pellet chow / cocoa butter composition with 11.6 % fat - reference for calorie-adjusted food uptake Six male wistar rats having a mean body weight of 324 ± 6 g were fed an experimental diet provided as pellets for six days. The mixture was composed of standard chow diet (ssniff® EF R/M Control, 5 %) and cocoa butter (7.5 % relative to the standard chow weight), resulting in approx. 11.6 % fat in total (including cocoa butter) and approx. 7.0 % cocoa butter relative to the final mixture. Cocoa butter was melted and blended with standard chow. Water was added to produce a paste which was extruded and cut into pellets (1 cm x 3 cm) by means of a food processor (Kitchen Aid, USA).

Pellets were dried at 25 °C over night.

At the end of the experiment, food intake, energy intake and body weight change were calculated (± SD). Animals gained 3.8 ± 1.3 % body weight, mean daily food intake was 22.5 ± 2.0 g, enting a mean metabolisable energy intake of 382.2 ± 33.7 kJ per animal per day.

D. Cream-or paste chow composition with 50 % fat limited to 10 g/day per animal - reference for weight loss induced by restricted energy supply Four male wistar rats having a mean body weight of 329 ± 7 g were fed an experimental diet provided as a mix of creamy, paste-like texture for five days. The experimental diet was a high-fat chow composition comprising 50 % fat relative to the final mixture, which was prepared by blending three standard chow diets as ed from ssniff®, namely ‘EF R/M Control, 5 %’, ‘EF R/M with 30 % fat’ and ‘EF R/M with 80 % fat’, in a weight ratio of 45, tively.

Chow supply was limited to 10 g per day representing a mean metabolisable energy intake of 236 KJ per day. At the end of the ment, body weight change was evaluated (± SD). s lost 3.6 ± 0.6 % body weight.

E. Pellet chow composition with 4.5 % fat and 9.1 % polymers - example for polymerinduced weight loss due to d uptake Six male wistar rats having a mean body weight of 301.4 ± 9.2 g were fed an mental diet provided as pellets for seven days. The mixture was composed of standard chow diet f® EF R/M Control, 5 %) and in total 10 % polymers (relative to the standard chow weight; specifically 6.2 % Carbopol® 971 NF, 1.5 % Kollicoat® MAE 100P from Sigma-Aldrich, USA, and 2.3 % chitosan from crab shells, Sigma-Aldrich, USA).

This resulted in a pellet chow composition with approx. 4.5 % fat and approx. 9.1 % total polymers relative to the final mixture (specifically, approx. 5.6 % Carbopol®, approx. 1.4 % Kollicoat® and . 2.1 % chitosan).

Standard chow was mixed with polymer powders. Water was added to produce a paste which was extruded and cut into pellets (1 cm x 3 cm) by means of a food processor (Kitchen Aid, USA). Pellets were dried at 25 °C over night.

At the end of the experiment, food intake, energy intake and body weight change were evaluated (± SD). Animals lost 3.9 ± 4.6 % body weight, mean daily food intake was 18.1 ± 2.1 g, enting a mean metabolisable energy intake of 253 ± 29 kJ per animal per day.

F. Pellet chow composition with 4.7 % fat and 5.7 % polymer - example for polymer- induced weight loss due to reduced uptake Six male wistar rats having a mean body weight of 317 ± 14.5 g were fed an experimental diet provided as pellets for seven days. The mixture was composed of standard chow diet (ssniff® EF R/M Control, 5 %) and 6 % Carbopol® 971 NF (relative to the standard chow weight), resulting in a pellet chow composition with approx. 4.7 % fat and approx. 5.7 % Carbopol® relative to the final mixture.

Standard chow was mixed with polymer powder, water was added to produce a paste which was ed and cut into pellets (1 cm x 3 cm) by means of a food processor en Aid, USA). Pellets were dried at 25 °C over night.

At the end of the ment, food , energy intake and body weight change were calculated (± SD). Animals lost 1.8 ± 2.3 % body weight, mean daily food intake was 18.4 ± 5.3 g, representing a mean metabolisable energy intake of 267 ± 77 kJ per animal per day.

G. Powdered pellet chow / Witepsol® composition with 11.0 % fat and 5.3 % polymer - example for polymer-induced weight loss due to reduced uptake Six male wistar rats having a mean body weight of 307 ± 8 g were fed an mental diet provided as powder for five days. The e was composed of standard chow diet (ssniff® EF R/M Control, 5 %) and Witepsol® W25 (7.5 % relative to standard chow weight) and 6 % Carbopol® 971 NF ive to standard chow weight), resulting in . 11.0 % fat in total (including Witepsol®), approx. 6.6 % ol® and approx. 5.3 % Carbopol® relative to the final e.

Molten Witepsol® was mixed with polymer powder, transferred into a zip-loc-bag and cooled to -18 °C in a freezer. The material was crushed by means of a hammer and shredded to a granulate in a kitchen blender (ProfiMIXX, Bosch, Germany). Standard chow diet was added and mixed with the granulate to obtain a powder diet.

At the end of the experiment, food intake, energy intake and body weight change were calculated (SD). Animals lost 2.4 ± 1.8 % body weight, mean daily food intake was 15.1 ± 0.8 g, representing a mean metabolisable energy intake of 245 ± 13 kJ per animal per day.

Example 23: Breath tests on healthy volunteers Gastrointestinal half-life and bioavailability of free fatty acids were assessed using the 13C-octanoic acid breath test. The labelled octanoic acid substrate is rapidly absorbed in the intestine and metabolised in the liver with the production of 13CO2, which is exhaled, thus reflecting uptake of octanoic acid from the gastrointestinal tract and after exit from the stomach. At the beginning of the experiment a reference breath sample was taken from the subject. Subsequently, the subject consumed a load of either lipid granulate as reference sample, or lipid granulate containing polymers as test sample.

Granulate was prepared by melting lipid at 50 °C and adding 100 mg of 13C octanoic acid (Campro Scientific, The Netherlands), and - for test samples - incorporating polymer.

The mixture was subsequently transferred into a zip-loc-bag and cooled to -18 °C in a freezer. The material was crushed by means of a hammer, shredded to a granulate in a kitchen blender (Bosch, Germany), dried under vacuum at 25 °C and classified through a set of wire mesh sieves (VWR International, Germany) to a granulate size of below 1.3 mm and above 0.5 mm.

For sample ingestion, frozen granulate was mixed with 100 g cold yogurt (fruit flavour, ca. 100 calories) and ed within one to two minutes. After ingesting the samples, t exhaled through a mouthpiece to collect an end-expiratory breath sample into a 300 mL foil bag at time intervals. Breath samples were taken over a period of 410 min. During this time , 0.5 - 1.0 L of water were drunk at a rate of approximately one glass per hour, a light lunch was consumed after 180 min, and physical exercise represented daily routine.

After completion of breath bag collection, analysis was performed by means of a FANci2 breath test analyser based on non-dispersive infrared spectroscopy (Fischer Analysen Instrumente GmbH, Germany). 13C nce in breath was expressed as relative difference (‰) from the universal reference standard (carbon from Pee Dee Belemnite limestone). 13C enrichment was defined as the difference between 13C abundance in breath prior to sample ingestion and 13C abundance at the defined time points after sample ingestion and was given in delta over basal (DOB, ‰). From the breath test analyser's operating re (FANci version 2.12.42.14 02/14), values of ted percent dose rate (cPDR, corresponding to ilability), and the time at half the cPDR value (HLF, corresponding to gastrointestinal ife) were taken to protocol.

Hard fat (Witepsol®) was from NRC, y. Cocoa butter was purchased at a local y store. Sodium e and lauric acid, microcrystalline cellulose and HPC qualities were from Sigma-Aldrich, USA. HPMC (Metolose® 90SH) was from Harke, Germany, Xanthan (Xantan Texturas) was from Solegraells Guzman, Spain. Carbopol® was from Lubrizol, USA. Glycerolmonooleate and glycerolmonolaurate were from TCI, Belgium.

Several test itions with particles described herein were administered. As shown in the table below, it was found that the particles lead to an increase in bioavailability (test compositions 1, 2, 4, 5 and 6) or to an increased gastrointestinal halftime (test composition 3).

Sample Lipid (g) Polymer (g) cPDR HLF (%) (min) Reference 1 Cocoa butter: 6 g - 37 219 Reference 2 Witepsol W25: 6 g - 32 189 Reference 3 Witepsol W25: 4 g - 32 180 sodium laurate:1.25 g Reference 4 WitepsolW25:2 g - 41 232 lauric acid: 2 g Reference 5 Prifex 300:6 g - 29.0 91.5 Test composition 1 Cocoa butter: 6 g Carbopol 971: 2 g 59 222 Test composition 2 Witepsol W25: 6 g HPC 1MDa: 2 g 53 176 Test composition 3 Witepsol W25: 4 g HPC 370 kDa: 1 g 39 243 sodium laurate:1.25 g Test composition 4 WitepsolW25:2 g HPC 1MDa:2 g 57 172 lauric acid: 2 g Test composition 5 Glycerolmonooleate:3 g, HPMC: 1.3 g 59 165 Glycerolmonolaurate: 3 g Xanthan: 0.7 g Test composition 6 Prifex 300: 6 g Alginex: 3 g 42.1 65.2 Aglupectin HSRVP : 1 g PromOat: 1 g Example 24: In vitro mucoadhesion and le integrity assay Sodium alginate medium viscosity (alginate#1), alginic acid, sodium laurate and lauric acid, microcrystalline ose (MCC), hydroxypropyl-cellulose (HPC) and ymethyl-cellulose (CMC) qualities, gum arabic, chitosan and m salts were from Sigma-Aldrich, USA. Alginate#3 was from Dragonspice, Germany. Alginate#4 (Satialgine® S 1600) was from Cargill, France. Alginate#5 (Manucol® DH) was from IMCD, Germany. te#6 (Protanal® LF) and alginate#7 (Protanal® PH) were from FMC, UK.

Alginate#8 (Alginex® HH) and Alginate#9 (Algin LZ-2) were from Kimica, Japan.

Carbopol® qualities were from Lubrizol, USA. Xanthan (Texturas Xantan), gellan gum ras gellan), alginate#2 (Texturas Algin) were from Solegraells Guzman, Spain.

HPMC (Metolose® 90SH) was from Harke, Germany. Psyllium ies (99 %; 100 Mesh) and guar gum were from Caremoli, Germany. Carob bean gum was from Werz, y.

Coconut flour was from Noble House, Belgium. Apple pectin, apple pectin low esterified and lysolecithin were from Dragonspice, Germany. Pectin#1 (Pektin Classic AU202) was from Herbstreith & Fox, Germany. Pectin#2 (Aglupectin® HS-RVP) and Tara gum (AgluMix® 01) were from Silva Extracts, Italy. Low methoxyl pectin, ed low methoxyl pectin, rapid set high methoxyl pectin, and slow set high methoxyl pectin qualities were from Modernist Pantry, USA. lucan (powder fill of Hafer-Beta glucan Bio Kapseln) was from Raab Vitalfood, Germany. PromOat® beta-glucan was from Tate&Lyle, Sweden. Cocoa powder low fat was from Naturata, Germany. Cocoa powder high fat was from Cebe, Germany. Inulin was from Spinnrad, Germany. ber® resistant dextrin (also known as Benefiber® Nutriose®) was from Novartis, UK.

Witepsol® hard fat qualities were from NRC, Germany. Gelucire® 43/01 hard fat was from Gattefossé, France. ycerides were from TCI, Belgium. Cocoa butter was purchased at a local super . Palm fat was from Peter Kölln, Germany. Palm stearin, OmegaConcentrate oil and OmegaConcentrate powder 67 were from Bressmer, Germany. Palm n IP, and palm stearin MB were from Henry Lamotte, Germany.

Coconut oil and coconut fat qualities were from Dr. Goerg, Germany. Shea butter#1 was from Gustav Hees, Germany. Shea butter#2 was from Cremer Oleo, Germany. Soy lecithin#1 (powder quality) was from Caelo, Germany. Soy lecithin#2 (Texturas Lecite) was from Solegraells Guzman, Spain. Cocoa mass was from g, Germany. Cera flava and alba beeswax were from Heinrich Klenk, y. Conjugated linoleic acid (Tonalin®) was from BASF, Germany. ® 300 palm stearin was from Unimills, The Netherlands. Omega-3 fatty acids (Omega-3 1400) were from Queisser Pharma, Germany.

Safflower oil was from Brökelmann, Germany.

Granules were prepared by melting one lipid at 50 °C and optionally adding other lipid ents and a few crystals of Oil Red O (Sigma Aldrich, USA) to obtain a nous melt or suspension. For test samples polymer(s) were incorporated by mechanical mixing. Each composition was transferred into a zip-loc-bag and cooled to - 18 °C in a freezer. The material was first crushed by means of a , shredded to a granulate in a n blender (Bosch IXX, Germany), ally dried under vacuum at 25 °C and then classified through a set of wire mesh sieves (VWR International, Germany) to a granulate size of below 2.0 mm and above 1.3 mm. Fresh pork stomach (from a local butcher) was cut into 3 cm x 3 cm pieces and placed into the bottom of a glass petri dish (10 cm diameter). 22 mL fasted-state simulated gastric fluid (FaSSGF) were added to the petri dish. FaSSGF was prepared by dis-solving 1 g of NaCl -Aldrich) in 450 mL of water, adding 30 mg of SIF powder (biorelevant.com), adjusting the pH to 2.0 with 0.1 N HCl (Sigma-Aldrich) and adding water to a final volume of 500 mL. The petri dish was covered and placed onto a petri dish shaker (ST5 from CAT, Germany) set to a tilt angle of 12° and a speed of 50/min. The shaker was placed into an oven heated to a temperature of 37 °C. After 30 minutes, 350 mg granulate were added to the contents of the petri dish without interrupting agitation. After 5 min, the samples were removed from the oven, and the piece of pork stomach was rinsed three times with water (3 mL each). The material bound to the stomach surface was removed by means of a spatula, transferred into a weighing dish, and dried to constant weight (electronic moisture meter MLB 50-3N, Kern & Sohn, Germany). Dry weight of the mucoadhesive material was recorded and calculated as t of initial granulate weight, representing binding as a measure of mucoadhesiveness. The petri dish containing the remaining d material was agitated at 37 °C for r 15 min, and particle integrity was classified by visual inspection as "low" (complete disintegration or disintegration of at least 50 % of the particles), or "high" (disintegration of less than 50 % of the particles) or “medium” (disintegration of less than 50 % of the particles, but e loss of small amounts of powders from the particles).

In result, it was found that certain test compositions with particles described herein showed a substantially increased binding to the mucosa and/or high particle integrity, as shown in the table below.

Particle Sample Lipid (g) Polymer (g) Binding integrity Test 1 Witepsol W25, 4 g HPC 1MDa, 2 g 75 % high Particle Sample Lipid (g) Polymer (g) Binding integrity Test 2 ol W25, 4 g HPC 1MDa, 1 g 69 % high CMC ultra high viscosity, 1 g Test 3 Witepsol W25, 4 g CMC ultra high viscosity, 2 g 53 % high Test 4 Cocoa butter, 2 g HPC, 1 g 91 % high Lauric acid, 2 g CMC, 1 g Test 5 Cocoa butter, 2 g Carbopol 971, 2 g 92 % high Glycerolmonolaurate, 2 g Test 6 Cocoa butter, 2 g Carbopol 971, 2 g 64 % high Glycerolmonostearate, 2 g Test 7 Cocoa butter, 4 g HPC, 1 g 35 % n.d.

CMC, 1 g Test 8 Cocoa butter, 4 g HPC, 1 g 69 % high Carbopol 971, 1 g Test 9 Cocoa butter, 4 g Carbopol 971, 2 g 77 % high Test 10 Cocoa butter, 2 g Carbopol 971, 2 g 49 % n.d.

Lauric acid, 2 g Test 11 Cocoa butter, 4 g HPC 1MDa, 2 g 44 % n.d.

Test 12 Cocoa butter, 2 g HPC 1MDa, 2 g 55 % n.d.

Glycerolmonolaurate, 2 g Test 13 Cocoa butter, 2 g HPC 1MDa, 2 g 84 % high olmonostearate, 2 g Test 14 Glycerolmonooleate, 2 g HPMC, 2 g 50 % n.d.

Lauric acid, 2 g Test 15 Glycerolmonooleate, 2 g HPMC, 2 g 52 % n.d.

Glycerolmonolaurate, 2 g Test 16 olmonooleate, 2 g HPMC, 2 g 67 % high Witepsol W25, 2 g Test 17 Glycerolmonooleate, 3 g Carbopol 971, 2 g 81 % high Glycerolmonolaurate, 3 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 18 Glycerolmonooleate, 3 g HPMC, 1.3 g 72 % high Glycerolmonolaurate, 3 g Xanthan, 0.7 g Test 19 Glycerolmonolaurate, 1.9 g HPMC, 1.9 g 78 % high olmonooleate, 1.1 g Xanthan, 0.1 g Witepsol W25, 1 g Test 20 Lauric acid, 4 g HPMC, 1.9 g 60 % high Xanthan, 0.1 g Test 21 Lauric acid, 1.9 g HPMC, 1.9 g 75 % high olmonooleate, 1.1 g Xanthan, 0.1 g Witepsol W25, 1 g Test 22 Lauric acid, 1.9 g HPMC, 1.9 g 73 % high Glycerolmonooleate, 1.1 g Xanthan, 0.1 g Test 23 Glycerolmonooleate, 2.05 g HPMC, 1.9 g 57 % Witepsol W25, 1.95 g Xanthan, 0.1 g Test 24 Glycerolmonolaurate, 1.9 g HPMC#2, 1.9 g 85 % high Glycerolmonooleate, 1.1 g Xanthan, 0.1 g Medium chain triglycerides (MCT), 0.55 g Witepsol W25, 0.45 g Test 25 Glycerolmonolaurate, 1.35 g Beta-glucan, 1.95 g 68 % high Glycerolmonooleate, 1.1 g HPMC, 1.6 g MCT, 0.55 g Xanthan, 0.1 g ol W25, 1 g Test 26 Glycerolmonolaurate, 1.9 g HPMC, 2.4 g 75 % high Glycerolmonooleate, 0.6 g Xanthan, 0.1 g Glycerol, 0.5 g Witepsol W25, 1 g Test 27 Glycerolmonolaurate, 1.35 g Chitosan, 0.5 g 66 % high Glycerolmonooleate, 1.1 g HPMC, 2.5 g MCT, 0.55 g Xanthan, 0.1 g Witepsol W25, 1 g Test 28 Glycerolmonolaurate, 1.35 g Beta-glucan, 1.9 g 68 % high Glycerolmonooleate, 1.1 g HPMC, 2.5 g MCT, 0.55 g Xanthan, 0.1 g Witepsol W25, 1 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 29 Glycerolmonolaurate, 1.9 g HPMC, 2.4 g 75 % high Glycerolmonooleate, 0.6 g Xanthan, 0.1 g Glycerol, 0.5 g Witepsol W25, 1 g Test 30 Glycerolmonolaurate, 1.9 g HPMC, 1.9 g 43 % high Glycerol, 0.5 g Xanthan, 0.1 g Witepsol W25, 1 g Test 31 Glycerolmonolaurate, 1.9 g HPMC, 2.5 g 26 % high Glycerol, 1 g n, 0.1 g Witepsol W25, 1 g Test 32 Glycerolmonolaurate, 1.9 g HPMC, 3.15 g 85 % high Glycerolmonooleate, 1.1 g Xanthan, 0.1 g MCT, 0.55 g Witepsol W25, 1 g Test 33 Glycerolmonolaurate, 1.9 g HPMC, 3.15 g 90 % high Imwitor 990, 1.1 g Xanthan, 0.1 g MCT, 0.55 g ol W25, 1 g Test 34 Glycerolmonolaurate, 1.35 g, HPMC, 2.8 g 81 % high Imwitor 990, 1.1 g, Xanthan, 0.1 g MCT, 0.55 g Witepsol W25, 1 g Test 35 Glycerolmonolaurate, 1.35 g Chitosan, 0.5 g 66 % high Glycerolmonooleate, 1.1 g HPMC, 2.5 g MCT, 0.55 g Xanthan, 0.1 g Witepsol W25, 1 g Test 36 Glycerolmonolaurate, 1.35 g PromOat, 1.9 g 61 % high Glycerolmonooleate, 1.1 g HPMC, 1.6 g MCT, 0.55 g Xanthan, 0.1 g Witepsol W25, 1 g Test 37 Glycerolmonolaurate, 1.35 g t, 2.5 g 68 % high Glycerolmonooleate, 1.1 g HPMC, 1 g MCT, 0.55 g Xanthan, 0.5 g Witepsol W25, 1 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 38 Glycerolmonolaurate, 1.95 g PromOat, 1.5 g 90 % high Imwitor 990, 1.6 g HPMC, 2.75 g MCT, 0.8 g Xanthan, 0.15 g Witepsol W25, 1.45 g Test 39 Glycerolmonolaurate, 1.9 g HPMC, 1.9 g 83 % high Imwitor 990, 1.1 g Xanthan, 0.1 g Witepsol W25, 1 g Test 40 Glycerolmonolaurate, 3.2 g t, 1.5 g 87 % high Glycerolmonooleate, 1.8 g HPMC, 2.33 g Witepsol W25, 1.7 g Xanthan, 0.17 g Test 41 Glycerolmonolaurate, 3.2 g PromOat, 1.5 g 65 % high Imwitor 990, 1.8 g HPMC, 2.33 g Witepsol W25, 1.7 g Xanthan, 0.17 g Test 42 Glycerolmonolaurate, 1.9 g HPMC, 2.5 g 85 % high r 990, 1.1 g Xanthan, 0.1 g Witepsol W25, 1 g Test 43 Glycerolmonolaurate, 2.4 g PromOat, 1.5 g 86 % high Glycerolmonooleate, 1.3 g HPMC, 4 g Witepsol W25, 3.7 g Xanthan, 0.1 g Test 44 Glycerolmonolaurate, 2.4 g t, 3 g 83 % high olmonooleate, 1.3 g HPMC, 3 g Witepsol W25, 3.7 g Xanthan, 0.1 g Test 45 Glycerolmonolaurate, 1.9 g HPMC, 1.9 g 72 % high Glycerolmonooleate, 1.1 g Xanthan, 0.1 g Witepsol H35, 1 g Test 46 Glycerolmonolaurate, 1.6 g HPMC, 1.9 g 86 % high Glycerolmonooleate, 1.4 g Xanthan, 0.1 g Witepsol H35, 1 g Test 47 Glycerolmonolaurate, 1.9 g HPMC, 2.5 g 87 % high Glycerolmonooleate, 1.1 g Xanthan, 0.1 g ol H35, 1 g Test 48 Glycerolmonolaurate, 2.6 g PromOat, 1 g 80 % high Glycerolmonooleate, 1.4 g HPMC, 2.9 g Witepsol W25, 4 g Xanthan, 0.1 g Sample Lipid (g) Polymer (g) Binding integrity Test 49 Witepsol W25, 4 g HPMC, 2 g 47 % high Test 50 Glycerolmonolaurate, 4 g HPMC, 2 g 45 % high Test 51 Glycerolmonolaurate, 2.6 g PromOat, 1 g 65 % high Glycerolmonooleate, 1.4 g HPMC, 3 g Witepsol W25, 4 g Test 52 Glycerolmonolaurate, 1.6 g HPMC, 1.9 g 80 % high Xanthan, 0.1 g Test 53 Glycerolmonolaurate, 3 g HPMC, 1.9 g 83 % high ol W25, 1 g Xanthan, 0.1 g Test 54 Glycerolmonolaurate, 2 g HPMC, 1.9 g 75 % high ol W25, 2 g Xanthan, 0.1 g Test 55 Glycerolmonolaurate, 1 g HPMC, 1.9 g 77 % high Witepsol W25, 3 g Xanthan, 0.1 g Test 56 Glycerolmonolaurate, 2 g HPMC, 2.85 g 78 % high Witepsol W25, 4 g Xanthan, 0.15 g Test 57 Glycerolmonolaurate, 4 g PromOat, 1 g 80 % high Witepsol W25, 4 g HPMC, 2.9 g Xanthan, 0.1 g Test 58 Glycerolmonolaurate, 3 g PromOat, 1.125 g 70 % high Witepsol W25, 6 g HPMC, 3.26 g Xanthan, 0.125 g Test 59 Glycerolmonolaurate, 2 g PromOat, 1 g 95 % high Witepsol W25, 6 g HPMC, 2.9 g Xanthan, 0.1 g Test 60 Gelucire 43/01, 1 g HPMC, 1.9 g 81 % high Witepsol W25, 3 g Xanthan, 0.1 g Test 61 Gelucire 43/01, 2 g HPMC, 2,85 g 78 % high Witepsol W25, 4 g Xanthan, 0.15 g Test 62 Gelucire 43/01, 3 g PromOat, 1.125 g 82 % high Witepsol W25, 6 g HPMC, 3.26 g Xanthan, 0.125 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 63 Gelucire 43/01, 2 g PromOat, 1 g 78 % high Witepsol W25, 6 g HPMC, 2.9 g Xanthan, 0.1 g Test 64 Glycerolmonolaurate, 1 g HPMC, 2 g 80 % high Witepsol W25, 3 g Test 65 Glycerolmonolaurate, 2 g PromOat, 1 g 82 % high Witepsol W25, 6 g HPMC, 3 g Test 66 Glycerolmonolaurate, 2 g Psyllium (99 %; 100 Mesh), 93 % high Witepsol W25, 6 g 3 g HPMC, 1 g Test 67 Glycerolmonolaurate, 2 g Psyllium (99 %; 100 Mesh), 85 % high Witepsol W25, 1 g 3 g Shea butter, 5 g HPMC, 1 g Test 68 Glycerolmonolaurate, 2 g um (99 %; 100 Mesh), 60 % high Witepsol W25, 2 g 3 g Shea butter, 4 g HPMC, 1 g Test 69 Glycerolmonolaurate, 2 g PromOat, 1 g 90 % high ol W25, 6 g Apple pectin, 1 g HPMC, 2 g Test 70 Glycerolmonolaurate, 2 g PromOat, 1 g 55 % high ol W25, 6 g Apple pectin, 1 g HPMC, 1.9 g Xanthan, 0.1 g Test 71 Glycerolmonolaurate, 2 g PromOat, 0.5 g 80 % high Witepsol W25, 6 g Apple pectin, 0.5 g HPMC, 3 g Test 72 Glycerolmonolaurate, 2 g PromOat, 0.5 g 65 % high Witepsol W25, 6 g Apple pectin, 1.5 g HPMC, 2 g Test 73 Glycerolmonolaurate, 2 g PromOat, 1.5 g 50 % medium Witepsol W25, 6 g Apple , 1.5 g HPMC, 1 g Test 74 Witepsol W25, 2 g HPMC, 2 g 88 % high Cocoa powder (high-fat), 2 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 75 olmonolaurate, 2 g HPMC, 3 g 85 % high Witepsol W25, 4 g Cocoa powder (high-fat), 4 g Test 76 Glycerolmonolaurate, 2 g PromOat, 1 g 45 % medium Witepsol W25, 4 g HPMC, 2 g Cocoa powder (high-fat), 4 g Test 77 Gelucire 43/01, 2 g HPMC, 4 g 89 % high Witepsol W25, 4 g Cocoa powder (high-fat), 4 g Test 78 Gelucire 43/01, 2 g Apple pectin, 1 g 77 % high ol W25, 4 g HPMC, 3 g Cocoa powder (high-fat), 4 g Test 79 Gelucire 43/01, 2 g HPMC, 4 g 90 % high ol W25, 4 g Cocoa powder (low-fat), 4 g Test 80 Gelucire 43/01, 2 g HPMC, 3 g 70 % high Witepsol W25, 4 g Xanthan, 1 g Cocoa powder (low-fat), 4 g Test 81 Gelucire 43/01, 2 g Psyllium (99 %; 100 Mesh), 75 % high Witepsol W25, 4 g 2 g HPMC, 2 g Cocoa powder (low-fat), 4 g Test 82 Gelucire 43/01, 2 g Psyllium (99 %; 100 Mesh), 25 % high Witepsol W25, 4 g 1 g HPMC, 2 g Xanthan, 1 g Cocoa powder (low-fat), 4 g Test 83 re 43/01, 2 g HPMC, 3.8 g 85 % high Witepsol W25, 3.5 g Xanthan, 0.2 g Glycerolmonooleate, 0.5 g Cocoa powder (low-fat), 4 g Test 84 Gelucire 43/01, 2 g Alginate 1, 2 g 57 % high Witepsol W25, 4 g HPMC, 2 g Cocoa powder (low-fat), 4 g Test 85 Gelucire 43/01, 2 g PromOat, 0.5 g 71 % high Witepsol W25, 4 g HPMC, 3.5 g Palm fat, 2 g Cocoa powder (low-fat), 0.5 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 86 Gelucire 43/01, 2 g PromOat, 0.5 g 72 % high Witepsol W25, 4 g HPMC, 3.3 g Palm fat, 2 g Xanthan, 0.2 Test 87 Gelucire 43/01, 6 g PromOat, 0.5 g 92 % high Palm fat, 2 g HPMC, 3.4 g Xanthan, 0.1 Test 88 Glycerolmonolaurate, 1 g Alginate#1, 1 g 88 % high Witepsol W25, 3 g HPMC, 1 g Test 89 Glycerolmonolaurate, 1.33 g te#1, 1 g 60 % high Witepsol W25, 1.33 g HPMC, 1 g Coco fat, 1.33 g Test 90 Glycerolmonolaurate, 1.33 g Alginate#1, 1 g 80 % high Witepsol W25, 1.33 g HPMC, 1 g Coco oil, 1.33 g Test 91 Glycerolmonolaurate, 1.33 g Alginate#1, 1 g 84 % high Witepsol W25, 1.33 g HPMC, 1 g Coco oil, 1.33 g Cocoa powder g deoiled ), 1 g Test 92 Glycerolmonolaurate, 1.33 g Alginate#1, 1 g 86 % high Witepsol W25, 1.33 g HPMC, 1 g Coco oil, 1.33 g Calcium L-lactate hydrate, 0.006 g Test 93 Glycerolmonolaurate, 1.33 g Alginate#1, 1 g 60 % high Witepsol W25, 1.33 g HPMC, 1 g Coco oil, 1.33 g Calcium L-lactate hydrate, 0.06 g Test 94 Glycerolmonolaurate, 1.33 g Alginate#1, 1 g 49 % high Witepsol W25, 1.33 g HPMC, 1 g Coco oil, 1.33 g m L-lactate hydrate, 0.6 g Test 95 olmonolaurate, 2.67 g Alginate#1, 1 g 60 % high Witepsol W25, 1.67 g HPMC, 1 g Coco oil, 1.67 g Cocoa mass, 4 g Test 96 Glycerolmonolaurate, 1 g Alginate#2, 1 g 92 % high Witepsol W25, 3 g HPMC, 1 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 97 Glycerolmonolaurate, 1 g Alginate#2, 1 g 62 % high Witepsol W25, 3 g HPMC, 1 g Calcium L-lactate hydrate, 0.006 g Test 98 Glycerolmonolaurate, 1 g HPMC, 2 g 80 % high Witepsol W25, 2.5 g Coco oil, 0.5 g Test 99 Witepsol W25, 4 g HPC 1.15MDa, 2 g 92 % high Test 100 Witepsol W25, 4 g HPC 0.85MDa, 2 g 92 % high Test 101 Glycerolmonolaurate, 1 g Low methoxyl pectin, 2 g 45 % medium Witepsol W25, 3 g Test 102 Glycerolmonolaurate, 1 g Amidated low methoxyl 74 % high Witepsol W25, 3 g pectin, 2 g Test 103 Glycerolmonolaurate, 1 g Rapid set high yl 62 % high Witepsol W25, 3 g pectin, 2 g Test 104 Glycerolmonolaurate, 1 g Slow set high methoxyl 81 % high Witepsol W25, 3 g pectin, 2 g Test 105 Glycerolmonolaurate, 1 g Slow set high methoxyl 85 % high Witepsol W25, 3 g , 4 g Test 106 Glycerolmonolaurate, 1 g Apple pectin, 2 g 66 % high Witepsol W25, 3 g Test 107 Glycerolmonolaurate, 1 g Apple , 4 g 90 % high Witepsol W25, 3 g Test 108 olmonolaurate, 2 g Apple pectin, 3 g 70 % high Witepsol W25, 4 g Test 109 Glycerolmonolaurate, 2 g Apple , 4 g 86 % high Witepsol W25, 4 g Test Glycerolmonolaurate, 1 g Xanthan, 2 g 73 % high 1102 Witepsol W25, 3 g Test 111 Glycerolmonolaurate, 1 g Xanthan, 1 g 65 % high Witepsol W25, 3 g Particle Sample Lipid (g) Polymer (g) g integrity Test 112 Glycerolmonolaurate, 1 g Carob bean gum, 2 g 46 % medium Witepsol W25, 3 g Test 113 Glycerolmonolaurate, 1 g PromOat,1 g 63 % high Witepsol W25, 3 g Xanthan, 1 g Test 114 Glycerolmonolaurate, 1 g Psyllium (95 %; 40 Mesh), 3 g 68 % high Witepsol W25, 3 g Test 115 Glycerolmonolaurate, 1 g Psyllium (98 %; 100 Mesh), 46 % medium Witepsol W25, 3 g 3 g Test 116 Glycerolmonolaurate, 1 g Psyllium (99 %; 100 Mesh), 85 % high Witepsol W25, 3 g 3 g Test 117 olmonolaurate, 1 g Psyllium (99 %; 100 Mesh 70 % high ol W25, 3 g Plus), 3 g Test 118 Glycerolmonolaurate, 1 g Psyllium (99 %; 100 Mesh), 52 % medium Witepsol W25, 3 g 2 g Test 119 Glycerolmonolaurate, 1 g Psyllium (99 %; 100 Mesh), 70 % high Witocan H, 3 g 3 g Test 120 Glycerolmonolaurate, 1 g Psyllium (99 %; 100 Mesh), 60 % high Witocan P, 3 g 3 g Test 121 Glycerolmonolaurate, 2 g Psyllium (99 %; 100 Mesh), 50 % medium Shea butter 1.2 g 3 g Test 122 Glycerolmonolaurate, 2 g Psyllium (99 %; 100 Mesh), 42 % medium Shea butter 2.2 g 3 g Test 123 Glycerolmonolaurate, 1 g Guar gum (200 Mesh), 2 g 26 % low Witepsol W25, 3 g Test 124 Glycerolmonolaurate, 1 g Carbopol 971, 2 g 84 % high ol W25, 3 g Test 125 Glycerolmonolaurate, 1 g Alginic acid, 2 g 15 % low Witepsol W25, 3 g Test 126 Glycerolmonolaurate, 1 g Alginate#2, 2 g 86 % high Witepsol W25, 3 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 127 Glycerolmonolaurate, 1 g Alginate#2, 1 g 95 % high ol W25, 3 g Apple pectin, 1 g Test 128 Glycerolmonolaurate, 1 g Alginate#2, 1 g 80 % high Witepsol W25, 3 g Prickly pear pectin, 1 g Test 129 Cera flava, 3.2 g Alginate#2, 2 g 85 % high Coco oil, 4.8 g Apple pectin, 2 g Test 130 Cera alba, 3.2 g Alginate#2, 2 g 84 % high Coco oil, 4.8 g Apple , 2 g Test 131 Gelucire 43/01, 6 g Alginate#2, 2 g 59 % high Coco oil, 2 g Apple , 1.9 g Konjac flour, 0.1 g Test 132 Gelucire 43/01, 6 g Alginate#2, 2 g 75 % high Coco oil, 2 g Apple pectin, 1.9 g Xanthan, 0.1 g Test 133 Glycerolmonolaurate, 1 g Alginate#3, 2 g 75 % high Witepsol W25, 3 g Test 134 Glycerolmonolaurate, 1 g Alginate#2, 2 g 68 % high Witepsol W25, 3 g Amidated low methoxyl pectin, 2 g Test 135 olmonolaurate, 1 g Alginate#2, 2 g 75 % high Witepsol W25, 3 g Low methoxyl pectin, 2 g Test 136 Glycerolmonolaurate, 1 g Alginate#2, 2 g 65 % high Witepsol W25, 3 g Slow set high yl pectin, 2 g Test 137 Glycerolmonolaurate, 1 g Alginate#2, 2 g 78 % high Witepsol W25, 3 g Rapid set high methoxyl pectin, 2 g Test 138 Gelucire 43/01, 4 g Alginate#2, 2 g 91 % high Coco oil, 2 g Apple pectin, 2 g Soy lecithin #1, 2 g Test 139 Gelucire 43/01, 5 g Alginate#2, 2 g 92 % high Coco oil, 2 g Apple pectin, 2 g Soy lecithin #1, 1 g Particle Sample Lipid (g) r (g) Binding integrity Test 140 Gelucire 43/01, 5 g Alginate#2, 2 g 86 % high Coco oil, 2 g Apple pectin, 2 g Soy lecithin #2, 1 g Test 141 Witocan P, 4 g MCC, 2 g <2 % low Test 142 ol W25, 4 g MCC, 2 g <2 % low Test 143 Palm stearin, 7 g te#2, 2 g 93 % high Soy in #1, 1 g Apple pectin, 2 g Test 144 Palm stearin, 8 g Alginate#2, 2 g 70 % high Apple pectin, 2 g PromOat, 2 g Cocoa powder (low fat), 2 g Test 145 Palm stearin, 8 g Alginate#2, 2 g 55 % high Apple pectin, 2 g Test 146 Palm stearin, 7 g Alginate#2, 2 g 56 % high Soy lecithin #1, 1 g Apple pectin, 2 g PromOat, 2 g Test 147 Palm stearin, 7 g Alginate#2, 2 g 48 % high Soy lecithin #1, 1 g Apple pectin, 2 g Cocoa powder (low fat), 2 g Test 148 Palm stearin, 7 g te#2, 2 g 50 % high Soy lecithin #1, 1 g Apple pectin, 2 g Psyllium, 2 g Test 149 Palm stearin, 7 g Alginate#2, 2 g 62 % high Soy lecithin #1, 1 g Apple pectin, 2 g Coco flour, 2 g Test 150 Palm stearin, 7 g Alginate#2, 4 g 70 % high Soy lecithin #1, 1 g Apple pectin, 4 g Test 151 Glycerolmonolaurate, 4 g Alginate#2, 2 g 65 % high Coco oil, 4 g Apple pectin, 2 g Test 152 Glycerolmonolaurate, 3 g Alginate#2, 2 g 65 % high Palm stearin, 1 g Apple pectin, 2 g Coco oil, 4 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 153 Glycerolmonolaurate, 2.67 g Alginate#2, 2 g 67 % high Palm stearin, 2.67 g Apple pectin, 2 g Coco oil, 2.67 g Test 154 olmonolaurate, 3.5 g Alginate#2, 2 g 87 % high Coco oil, 3.5 g Apple pectin, 2 g Soy lecithin #2, 1 g Test 155 Glycerolmonolaurate, 3 g Alginate#2, 2 g 92 % high Palm stearin, 1 g Apple pectin, 2 g Coco oil, 3 g Soy in #2, 1 g Test 156 Palm stearin, 7 g Alginate#2, 4 g 65 % high Soy lecithin #1, 1 g Test 157 Palm stearin, 7 g Alginate#2, 2 g 84 % high Soy lecithin #1, 1 g Apple pectin, 2 g Gum arabic, 1 g Test Palm stearin, 7 g Alginate#2, 2.7 g 91 % high 1598 Soy in #1, 1 g Apple pectin, 1.3 g Test 159 Palm stearin, 7 g Alginate#2, 1.3 g 50 % high Soy lecithin #1, 1 g Apple pectin, 2.7 g Test 160 Palm stearin, 6 g Alginate#2, 2 g 83 % high Cera flava, 1 g Apple pectin, 2 g Soy lecithin #1, 1 g Test 161 Palm stearin, 7 g Alginate#2, 2.7 g 85 % high Soy lecithin #1, 1 g Apple pectin, 1.3 g Calcium carbonate, 0.012 g Test 162 Palm stearin, 7 g Alginate#2, 2.7 g 77 % high Soy lecithin #1, 1 g Apple , 1.3 g Calcium carbonate, 0.12 g Test 163 Palm stearin MB, 7 g Alginate#2, 2.7 g 69 % high Soy lecithin #1, 1 g Apple pectin, 1.3 g Test 164 Palm n IP, 7 g Alginate#2, 2.7 g 45 % high Soy lecithin #1, 1 g Apple pectin, 1.3 g Test 165 Palm stearin, 7 g Alginate#2, 2.7 g 92 % high Soy lecithin #2, 1 g Apple pectin, 1.3 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 166 Palm stearin, 7.5 g Alginate#2, 2.7 g 63 % high Soy lecithin #2, 0.5 g Apple pectin, 1.3 g Test 167 Palm stearin, 6.5 g Alginate#2, 2.7 g 70 % high Soy lecithin #2, 1.5 g Apple pectin, 1.3 g Test 168 Palm stearin, 6.5 g Alginate#2, 2.7 g 80 % high Soy lecithin #1, 1.5 g Apple , 1.3 g Inulin, 1 g Test 169 Palm n, 6.5 g te#2, 2.7 g 65 % high Soy lecithin #1, 1.5 g Apple pectin (low esterified), 1.3 g Test 170 Palm stearin, 7 g Alginate#2, 2.7 g 70 % high Lysolecithin 1, 1 g Apple , 1.3 g Test 171 Palm stearin, 4 g Alginate#2, 10 g 75 % high Soy lecithin #2, 1 g Test 172 Palm stearin, 6.5 g Alginate#2, 7.5 g 85 % high Soy lecithin #2, 1 g Test 173 Palm stearin, 6.5 g Alginate#2, 5 g 70 % high Soy lecithin #2, 1 g Apple pectin, 2.5 g Test 174 Palm stearin, 6.5 g Alginate#2, 3.75 g 59 % high Soy lecithin #2, 1 g Apple pectin, 3.75 g Test 175 Palm stearin, 6.5 g Alginate#4, 7.5 g 80 % high Soy lecithin #2, 1 g Test 176 Palm stearin, 6.5 g Alginate#4, 5 g 82 % high Soy lecithin #2, 1 g Apple pectin, 2.5 g Test 177 Palm stearin, 6.5 g Alginate#4, 3.75 g 82 % high Soy lecithin #2, 1 g Apple pectin, 3.75 g Test 178 Palm stearin, 7.5 g Alginate#4, 7.5 g 60 % high Test 179 Palm stearin, 4 g Alginate#4, 10 g 76 % high Soy lecithin #2, 1 g Test 180 Palm stearin, 4 g te#4, 7.5 g 85 % high Soy lecithin #2, 1 g Sample Lipid (g) Polymer (g) Binding integrity Test 181 Palm stearin, 6.5 g Alginate#4, 3.75 g 73 % high Soy lecithin #2, 1 g Pectin#1, 3.75 g Test 182 Palm stearin, 5 g te#4, 7.5 g 73 % high Test 183 Palm stearin, 4.75 g Alginate#4, 7.5 g 74 % high Soy lecithin #2, 0.25 g Test 184 Palm stearin, 4.5 g Alginate#4, 7.5 g 79 % high Soy in #2, 0.5 g Test 185 Palm stearin, 5 g Alginate#5, 7.5 g 68 % high Test 186 Palm stearin, 5 g Alginate#6, 7.5 g 51 % high Test 187 Palm stearin, 5 g Alginate#7, 7.5 g 32 % Test 188 Palm stearin, 5 g Alginate#8, 7.5 g 72 % high Test 189 Palm stearin, 5 g Alginate#9, 7.5 g 31 % high Test 190 Palm stearin, 8 g Alginate#7, 4 g 19 % medium Test 191 Palm stearin, 8 g Alginate#8, 4 g 73 % high Test 192 Palm stearin, 8 g Alginate#9, 4 g 13 % medium Test 193 Palm stearin, 7.5 g Alginate#8, 5 g 75 % yes Test 194 Palm stearin, 6 g te#8, 6 g 78 % no Test 195 Palm stearin, 6 g Alginate#8, 5 g 76 % yes Pectin#1, 1 g Test 196 Palm n, 6 g Alginate#8, 5 g 82 % high Pectin#2, 1 g Test 197 Palm stearin, 6 g Alginate#4, 5 g 82 % high Pectin#2, 1 g Test 198 Palm stearin, 6 g Alginate#4, 5 g 75 % high Pectin#2, 1 g PromOat, 1 g Test 199 Palm stearin, 6 g Alginate#4, 5 g 83 % high Pectin#2, 1 g PromOat, 0.5 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 200 Palm stearin, 6 g Alginate#4, 4 g 85 % high Pectin#2, 1 g PromOat, 1 g Test 201 Palm stearin, 6 g te#4, 5 g 91 % high PromOat, 1 g Test 202 Palm stearin, 6 g Alginate#4, 4 g 84 % high PromOat, 2 g Test 203 Palm stearin, 7 g Alginate#4, 3 g 92 % high Pectin#2, 1 g PromOat, 1 g Test 204 Palm stearin, 7 g te#8, 3 g 94 % high Pectin 2, 1 g PromOat, 1 g Test 205 Palm stearin, 6.5 g Alginate#4, 3 g 73 % high Conjugated linoleic acid, Pectin#2, 1 g 0.5 g PromOat, 1 g Test 206 Palm stearin, 6 g Alginate#4, 3 g 73 % high Conjugated linoleic acid, 1 g Pectin#2, 1 g PromOat, 1 g Test 207 Glycerolmonolaurate, 1 g HPMC, 2 g 83 % high Witepsol W25, 2.5 g Conjugated linoleic acid, 0.5 g Test 208 Palm stearin, 7 g Alginate#4, 3 g 89 % high Apple pectin, 1 g PromOat, 1 g Test 209 Palm stearin, 5 g Alginate#4, 3 g 87 % high Apple pectin, 1 g t, 1 g Test 210 Palm stearin, 5 g Alginate#4, 3 g 89 % high Pectin 2, 1 g PromOat, 1 g Test 211 Palm stearin, 5.5 g Alginate#4, 3 g 89 % high Apple , 1 g PromOat, 1 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 212 Palm stearin, 6 g Alginate#4, 3 g 89 % high Apple pectin, 1 g PromOat, 1 g Test 213 Palm stearin, 6 g, 3.8 g Alginate#4, 3 g 92 % high Omega-3 fatty acid 1, 1.2 g Apple pectin, 1 g t, 1 g Test 214 Prifex 300, 5.5 g Alginate#4, 3 g 86 % high Apple pectin, 1 g PromOat, 1 g Test 215 Prifex 300, 5.5 g Alginate#4, 3 g 87 % high Pectin 2, 1 g PromOat, 1 g Test 216 Palm stearin, 5.5 g Alginate#4, 3 g 76 % high Benefiber, 2 g Test 217 Palm stearin, 5.5 g Alginate#4, 3 g 81 % high Pectin 2, 1 g Benefiber, 1 g Test 218 Palm n, 5.5 g Alginate#4, 1 g 63 % high Benefiber, 4 g Test 219 Palm stearin, 5.5 g Alginate#4, 2 g 82 % high ber, 3 g Test 220 Palm stearin, 5.5 g Alginate#4, 2.5 g 78 % high Benefiber, 2.5 g Test 221 Palm n, 5.5 g Alginate#4, 2 g 82 % high Benefiber, 3 g Test 222 Palm stearin, 5.5 g Alginate#4, 2.5 g 78 % high Benefiber, 2.5 g Test 223 Palm stearin, 5 g Tara gum, 5 g 62 % high Test 224 Palm stearin, 5 g Gum arabic, 5 g n.d. high Test 225 Palm stearin, 5 g Pectin 2, 1 g n.d. medium Benefiber, 2 g PromOat, 2 g Particle Sample Lipid (g) Polymer (g) Binding integrity Test 226 Palm stearin, 5 g Pectin 2, 1 g n.d. medium ber, 2.5 g PromOat, 1.5 g Test 227 Prifex 300, 3.5 g Alginate 8, 3 g 86 % high wer oil, 2 g Pectin 2, 1 g Omega-3 oil, 0.5 g Benefiber, 2 g Test 228 Prifex 300, 3.5 g Alginate 4, 3 g 77 % high Safflower oil, 2 g Pectin 2, 1 g 3 oil, 0.5 g Benefiber, 2 g Test 229 Prifex 300, 3.5 g Alginate 8, 3 g 60 % high Safflower oil, 2 g Pectin 2, 1 g Omega-3 oil, 0.5 g Benefiber, 3 g Test 230 Prifex 300, 3.5 g Alginate 8, 3 g 71 % high Safflower oil, 2 g Pectin 2, 1 g Omega-3 oil, 0.5 g Benefiber, 3 g t, 1.5 g Test 231 Prifex 300, 3.5 g Alginate 8, 3 g 83 % high Safflower oil, 2 g Pectin 2, 1 g Omega-3 oil, 0.5 g Nutriose FB, 2 g Test 232 Prifex 300, 3.5 g Alginate 8, 3 g 82 % high Safflower oil, 2 g Pectin 2, 1 g Omega-3 oil, 0.5 g Nutriose FM, 2 g Test 233 Prifex 300, 9 g Alginate 8, 3 g 60 % high Linseed oil, 1 g Pectin 2, 1 g PromOat, 1 g Benefiber, 5 g Test 234 Prifex 300, 5.5 g Alginex, 3 g 83 % high Aglupectin HS-RVP, 1 g PromOat 1 g Example 25: Preparation of a premix by high-shear granulation 4.5 kg of hard fat (Witepsol® W25, Cremer Oleo), 1.5 kg of glycerol monolaurate (Mosselman, Belgium), and 3.0 kg HPMC (Metolose 60SH, Shin Etsu, Japan) were introduced into a Ploughshare mixer (Lödige, Germany) equipped with a heating jacket.

Under continuous mixing operation at 80 rpm, the temperature in the vessel was raised to 60 °C and until the lipid components were completely . With continued mixing, heating was stopped and 2 kg of crushed dry ice were added within 5 min. The resulting granulate was d from the vessel after evaporation of the carbon dioxide used as premix for extrusion experiments. Where ered expedient, the resulting granulate particles were dried under vacuum at 25 °C to remove residual condensed water; e.g. prior to classifying them.

Example 26: Preparation of a premix by high-shear granulation 3.0 kg of hard fat (Witepsol® W25, Cremer Oleo), 1.0 kg of glycerol monolaurate (Mosselman, Belgium) were introduced into a Ploughshare mixer (Lödige, y) ed with a heating jacket. Under continuous mixing operation at 80 rpm, the ature in the vessel was raised to 60 °C and until the lipid components were completely molten. With continued mixing, heating was stopped and 3.0 kg of psyllium seed husks (Carepsyllium, Caremoli, Germany) were added and after 5 min, 2 kg of d dry ice were added within 5 min. The resulting granulate was removed from the vessel after evaporation of the carbon dioxide and used as premix for extrusion experiment 29. Where considered expedient, the resulting granulate les were dried under vacuum at 25 °C to remove residual condensed water; e.g. prior to classifying them.

Example 27: Preparation of a granulate by high-shear granulation 750 g of hard fat (Witepsol® W25, Cremer Oleo), 250 g of glycerol monolaurate (Mosselman, Belgium), and 500 g HPMC (Metolose® 60SH, Shin Etsu, Japan) were introduced into a Ploughshare mixer e, Germany) ed with a heating jacket.

Under continuous mixing operation at 200 rpm, the temperature in the vessel was raised to 54 °C and until the lipid components were tely molten. With continued mixing, heating was stopped and 1 kg of crushed dry ice was added within 5 min. The resulting ate was removed from the vessel, optionally dried under vacuum at 25 °C and passed through a set of wire mesh sieves (1.0 mm (mesh 18) and 2.0 mm (mesh 10) and 3.15 mm, VWR, Germany) to give the t. 51 % (w/w) of the al were obtained as particle size fraction of 1.0 - 3.15 mm.

Example 28: Preparation of a granulate by high-shear granulation 900 g alginate (Satialgine®, Cargill, Germany), 60 g soy lecithin (powder quality, Golden Peanut, y) and 540 g of palm n (Palm Stearin 54, Bressmer, Germany) were introduced into a Ploughshare mixer (Lödige, Germany) equipped with a heating jacket. Under continuous mixing operation at 200 rpm, the temperature in the vessel was raised to 60 °C and until the lipid ents were completely molten. With continued mixing, heating was stopped and 440 g of crushed dry ice were added within min. The ing granulate was removed from the vessel, optionally dried under vacuum at 25 °C and passed through a set of wire mesh sieves (1.0 mm (mesh 18) and 2.0 mm (mesh 10) and 3.15 mm, VWR, Germany) to give the product. 48 % (w/w) of the material were obtained as particle size fraction of 1.0 - 3.15 mm.

Example 29: Preparation of particles by extrusion A premix prepared according to the protocol of experiment 26, comprising 300 g hard fat (Witepsol® W25, Cremer Oleo, Germany), 100 g glycerol monolaurate (Mosselman, m) and 300 g psyllium seed husks (Carepsyllium, Caremoli, Germany), was fed via a volumetric dosing system (Dosimex DO-50, Gabler, Germany) into a powder inlet of a twin screw extruder (Extruder 10, Gabler, Germany) and extruded at a temperature range of 30-35 °C to strands of 1.0 mm diameter. Extruded strands were cut to es by means of ng blades. Granules were subsequently rounded in a spheroniser (Spheronizer 250, Gabler, Germany) to particles of ca. 1 mm diameter.

Example 30: Preparation of particles by extrusion A molten premix of 187.5 g hard fat (Witepsol® W25, Cremer Oleo, Germany), 356.25 g glycerol monolaurate (Mosselman, Belgium) and 206.25 g glycerol eate (Mosselman, Belgium) was prepared in a beaker on a hot plate (at 80 °C) equipped with an ad stirrer and was fed by means of a peristaltic pump (Masterflex®, Thermo Fisher, Germany) to one inlet opening of a twin screw extruder (Pharma 11 HME, Thermo Fisher, Germany). In parallel, a powder premix of 256.25 g HPMC (Metolose® 60SH, Shin Etsu, Japan) and 18.75 g xanthan (Xanthan FF, Jungbunzlauer, Switzerland) were fed via volumetric dosing system (Volumetric Single Screw Feeder, Thermo Fisher, Germany) to the powder inlet opening of the extruder, and the mixture was ed at a temperature range of 30-35 °C to s of 1.5 mm diameter and subsequently broken and rounded in a spheroniser (Caleva MBS 120, Thermo Fisher, Germany) to a granulate of ca. 1-2 mm.

Example 31: Coating of cores with a mixture of lipid and emulsifier 600 g granulate prepared according to one of examples 27-30 were loaded into fluid bed device (Ventilus V-2.5/1, Innojet, Germany, equipped with an IPC3 product reservoir) and fluidised at a bed temperature of 20 °C at an air flow of 90 cubic meters/h. 105.0 g Dynasan® 115 and 45.0 g Polysorbate 65 were molten in a beaker on a hot plate (at 80 °C) equipped with an ad stirrer. The hot melt was sprayed onto the ate using a peristaltic pump and a top spraying procedure at a spray rate of 6.5 g/min. s of different amounts of coating were taken at time intervals, corresponding to 10, 15, 20, and 25 % (w/w).

Example 32: Coating of cores with a mixture of lipid and hydrocolloid 600 g granulate ed according to one of examples 27-30 were loaded into fluid bed device (Ventilus V-2.5/1, Innojet, y, equipped with an IPC3 product reservoir) and fluidised at a bed temperature of 20 °C at an air flow of 90 cubic meters/h. 135 g Dynasan® 116 and 15 g guar gum (Careguar, Caremoli, Germany) were heated on a hot plate (80 °C) equipped with a mechanical r. The hot melt sprayed onto the ate using a peristaltic pump and a top spraying procedure at a spray rate of 6.5 g/min. Samples of different amounts of coating were taken at time intervals, ponding to 15 and 25 % (w/w).

Example 33: Mucoadhesion assay of coated granulate ate prepared according to experiment 30 were coated according to experimental procedure 31 to different coating thickness and subjected to the mucoadhesion assay protocol described above, except that binding kinetics were followed up to 30 min.

Pork stomach g of the granulate sample carrying 10 % (w/w) coating was maximal after 6 min. Pork stomach binding of the ate sample carrying 15 % (w/w) coating was maximal after 9 min. Pork stomach binding of the granulate sample ng % (w/w) coating was maximal after 12 min. Pork stomach binding of the granulate sample carrying 25 % (w/w) coating was maximal after 25 min.

Example 34: hesion assay of coated granulate Granulate prepared according to experiment 30 were coated according to experimental ure 32 to different coating thickness and subjected to the mucoadhesion assay protocol bed above, except that binding kinetics were followed up to 30 min.

Pork stomach binding of the granulate sample carrying 15 % (w/w) coating was maximal after 14 min. Pork stomach binding of the granulate sample carrying 20 % (w/w) coating was maximal after 25 min. e 35: Preparation of granulate by extrusion A premix prepared according to the protocol of ment 26, comprising 224 g palm stearin (Palmstearin 54, Juchem, Germany), 96 g alginate (Satialgine®, Cargill, France), 32 g pectin (Aglupectin® HS-RVP, Silvateam, Italy) and 32 g oat beta glucan (PromOat®, Tate & Lyle, ), was fed via a volumetric dosing system (Dosimex DO- 50, Gabler, Germany) into a powder inlet of a twin screw extruder (Extruder DE-40/10, Gabler, y, operating at 7 rpm) and ed at a temperature range of 10-12 °C to strands of 1.5 mm diameter. Extruded strands were cut to granules of 0.8 - 2.5 mm length by means of rotating blades (running at 100 rpm). The premix was quantitatively converted into extrudate within less than 5 min.

Example 36: 10 kg batch of coated granulate A premix was prepared my melting 8.25 kg palm stearin (Palm Stearin 54, Bressmer, Germany) in a cooking pot over an induction plate. When the melt had a ature of 60 °C, 4.5 kg sodium alginate (Satialgine®, Cargill, France), 1.5 g oat fibre preparation (PromOat®, Tate&Lyle, Sweden) and 1.5 kg pectin (Pektin HV, Golden Peanut, Germany) were incorporated by means of a cooking spoon. The mixture was transferred in aliquots into zip-loc plastic bags and cooled to room temperature to form solid plates. Lipid-polymer plates were further cooled in a freezer set at -18 °C and then ed to particles of ca. 5 mm and smaller by means of a blender (Vitamix®, Vita-Mix Corp., USA). The obtained premix was fed via a volumetric dosing system (Dosimex DO- 50, Gabler, Germany) into a powder inlet of a twin screw extruder (Extruder DE-40/10, Gabler, Germany, operating at 10 rpm) and ed at a temperature range of 10-12 °C to strands of 1.5 mm diameter. Extruded strands were cut to granules of 0.8 - 2.5 mm length by means of rotating blades (running at 100 rpm). The premix was quantitatively converted into ate within less than 5 min. The extrudate was erred into plastic bags in aliquots of 990 g and stored at -18 °C. To each bag, 9.9 g of PromOat® powder were added and thoroughly mixed with the extrudate. Subsequently, es were optionally dried under vacuum at 25 °C and subjected to classification using a wire mesh sieves of 2 mm (mesh 10) and 1.0 mm (mesh 18). The classified granules were mixed and split into ts of 600 g. Aliquots were loaded into a fluid bed device (Ventilus V-2.5/1, Innojet, Germany, equipped with an IPC3 product reservoir) and fluidised at a bed temperature of 20 °C at an air flow of 80 cubic meters/h. 120 g Dynasan® 115 were molten in a beaker on a hot plate (at 90 °C) equipped with an overhead stirrer. The hot melt was quantitatively sprayed onto the granulate using a peristaltic pump and a top spraying procedure at a spray rate of 6.5 g/min. Aliquots were combined and a total of 10 kg of coated granulate was obtained and stored in a plastic container.

Example 37: Coated granulate en kg of a premix were prepared in seven batches of 2 kg each. For each batch, 0.9 kg palm stearin (Prifex® 300, Unimills, The Netherlands) and 0.1 kg linseed oil (manako BIO Leinöl human, , Germany) were brought to a melt in a cooking pot over an induction plate. When the melt had a temperature of 60 °C, 0.3 kg sodium te (Alginex®, Kimica, Japan), 0.1 kg oat fibre preparation at®, Tate&Lyle, ) and 0.1 kg pectin (Aglupectin® HS-RVP, Silva, Italy) were incorporated by means of a cooking spoon. The mixture was transferred in ts into zip-loc plastic bags and cooled to room temperature to form solid plates. Lipid-polymer plates were further cooled in a freezer set at -18 °C and then shredded to particles of ca. 5 mm and smaller by means of a blender (Vitamix® Professional 750, Vita-Mix Corp., USA). The obtained premix was fed via a volumetric dosing system (Dosimex DO-50 Gabler, Germany) into a powder inlet of a twin screw extruder (Extruder DE-40/10, Gabler, Germany, operating at 10 rpm) and ed at a temperature range of ca. 30 °C to strands of 1.0 mm diameter. Extruded strands were cut to granules of 0.8 - 2.5 mm length by means of ng blades (running at 100 rpm). The extrudate was transferred into plastic bags in ts and stored at -18 °C. uently, granules were optionally dried under vacuum at 25 °C and subjected to classification using a wire mesh sieves nik, Germany) of 2 mm (mesh 10) and 1.0 mm (mesh 18). Material retained on the 2 mm sieve was subjected to comminution using a household blending device (MK55300, Siemens, Germany) and re-classified using the set of wire mesh . Granules classified to a range of 1-2 mm were combined to give a yield of 9.0 kg and split into aliquots of 600 g. Batches (one aliquot per run, fifteen runs) were loaded into a fluid bed device (Ventilus V-2.5/1, Innojet, Germany, equipped with an IPC3 product reservoir) and fluidised at a bed temperature of 20 °C at an air flow of 65 m3/h. Per run, 120 kg palm stearin (Prifex® 300, Unimills, The Netherlands) were molten in a beaker on a hot plate (at 100 °C) equipped with an overhead stirrer. The hot melt was quantitatively sprayed onto the granulate using a peristaltic pump and a top spraying procedure at a spray rate of 6.5 g/min. Batches were combined, and a total of 10.67 kg of coated granulate was ed and stored in a plastic container.

Example 38: Preparation of tryptophan-containing granules Granules was prepared by melting 2 g glycerol monolaurin (Mosselman, Belgium) and 2 g glycerol ein 40 (TCI, Belgium) at 55 °C. L-Tryptophan (1 g, TCI, Belgium), hydroxypropyl methylcellulose (Metolose® 90SH-100000SR, Harke, Germany), and xanthan gum (0.5 g, Solegraells, Spain) were incorporated by ical mixing. The composition was transferred into a zip-loc-bag and cooled to -18 °C in a freezer. The material was first d by means of a hammer, shredded into a ate using a kitchen blender (Bosch ProfiMIXX, Germany), optionally dried under vacuum at 25 °C and then classified through a set of wire mesh sieves (VWR International, Germany) to a granule size of below 1.0 mm and above 0.5 mm.

A sample of 200 mg of tryptophan-containing granules was suspended in 22 mL fasted-state simulated gastric fluid (FaSSGF) at 37 °C and agitated (shaker ST5 from CAT, Germany). FaSSGF was prepared by dissolving 1 g of NaCl (Sigma-Aldrich) in 450 mL of water, adding 30 mg of SIF powder lvant.com), adjusting the pH to 2.0 with 0.1 N HCl (Sigma-Aldrich) and adding water to a final volume of 500 mL. Aliquots were removed from the supernatant at time intervals of 15 min, and the tryptophan concentration was determined by absorption measurement at a wavelength of 280 nm in a NanoDrop® 2000 device (Thermo Scientific, USA). Tryptophan release followed first- order kinetics with a half-time of 20 s.

A sample of 200 mg of tryptophan-containing granules was suspended in 22 mL -state simulated intestinal fluid F) at 37 °C and agitated (shaker ST5 from CAT, Germany). FaSSIF was prepared by dissolving 0.21 g NaOH pellets (Sigma-Aldrich), 3.09 g of NaCl (Sigma-Aldrich) and 1.98 g sodium dihydrogen phosphate drate -Aldrich) in 450 mL of water, adding 1.12 g of SIF powder (biorelvant.com), adjusting the pH to 6.5 and adding water to a final volume of 500 mL. Aliquots were removed from the supernatant at time intervals of 15 min, and tryptophan concentration was determined by absorption measurement at a wavelength of 280 nm in a NanoDrop® 2000 device (Thermo Scientific, USA). phan release followed first- order kinetics with a half-time of 15 minutes.

Tryptophan control mg of tryptophan powder were suspended in 22 mL FaSSGF at 37 °C and agitated (shaker ST5 from CAT, Germany). Aliquots were removed at time intervals of min, and tryptophan concentration was quantified using absorption measurement at a wavelength of 280 nm in a NanoDrop® 2000 device (Thermo Scientific, USA). phan was quantitatively dissolved after 10 minutes.

The term ising” as used in this ication and claims means “consisting at least in part of”. When reting statements in this specification and claims which include the term “comprising”, other features besides the features ed by this term in each statement can also be present. Related terms such as “comprise” and “comprises” are to be interpreted in similar manner In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

In the description in this specification reference may be made to t matter that is not within the scope of the claims of the current application. That t matter should be readily identifiable to a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.

Claims (26)

Claims

1. An oral composition comprising an effective amount of (a) a first agent capable of inducing satiety, (b) a second agent capable of augmenting the satiety-inducing effect of the first agent, and optionally (c) an amino acid, (d) a vitamin, and/or (e) a micro-nutrient; wherein the composition is an ingestible particle having a sieve diameter in the range from 0.05 to 3 mm, wherein the first agent is a medium or long chain fatty acid compound, said fatty acid compound being sed in a first lipid component, wherein the second agent is a water-swellable or water-soluble polymeric ent, and wherein the weight ratio of the first lipid component to the water-swellable or soluble polymeric component is in the range from 1 to 3, and wherein the water-swellable or water-soluble polymeric component is embedded within the lipid component.

2. The composition of claim 1, wherein the lipid component forms a continuous phase in which the water swellable or water-soluble polymeric component is discontinuous and in dispersed form.

3. The composition of any one of claims 1 or 2, n the ingestible particle is provided in the form of a granule, a pellet, or a minitablet.

4. The composition of any one of the preceding , wherein the first agent is a free or esterified medium or long chain fatty acid, wherein the free fatty acid is optionally neutralised.

5. The ition of any one of the preceding claims, wherein the water-swellable or water-soluble polymeric component comprises a mucoadhesive polymer.

6. The composition of any one of the preceding claims, wherein the water-soluble polymeric component is a hilic or amphiphilic polymer of a solubility in water of at least 1 mg/L.

7. The composition of any one of the preceding claims, wherein the water-swellable or soluble polymeric component comprises at least one polymeric material selected from poly(carboxylate), chitosan, cellulose ethers, and xanthan gum; wherein the poly(carboxylate) is optionally at least lly neutralised; and wherein the polymeric material is optionally at least partially inked.

8. The composition of claim 7, wherein the poly(carboxylate) is selected from alginic acid, poly(acrylic acid), poly(methacrylic acid), copolymers of acrylic and methacrylic acid, poly(hydroxyethyl methacrylic acid).

9. The composition of claim 7, wherein the ose ether is selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and carboxymethylcellulose; n the carboxymethylcellulose is optionally at least partially neutralised.

10. A method of inducing satiety in a subject for cosmetic purposes, said method comprising a step of orally stering the composition of any one of claims 1 to 9.

11. The method of claim 10, wherein the subject is a human subject having developed, or being at risk of developing, overweight.

12. The method of claim 10 or claim 11, n the oral administration of the ition is med at least once a day over a period of at least one week.

13. The method of any one of claims 10 to 12, further comprising the use of a programmed electronic device for the collection, storage and/or display of information relating to a subject's adherence to, or the effectiveness of, a predefined treatment regimen of orally administering the composition.

14. The composition of any one of claims 1 to 9 for use in a method of treating or preventing overweight, obesity, or a disease or condition associated with ight or obesity in a subject, said method comprising a step of orally administering said composition.

15. The composition of claims 1 to 9 for use in a method of lling or reducing the body weight of a subject, said method comprising a step of orally administering said composition.

16. The composition for use according to any one of claims 14 to 15, wherein the subject is a human subject having developed, or being at risk of developing, overweight, obesity, or a disease or condition associated with ight or obesity.

17. The composition for use according to any one of claims 14 to 16, wherein the oral administration of the composition is med at least once a day over a period of at least one week.

18. The ition for use according to any one of claims 14 to 17, further comprising the use of a programmed electronic device for the collection, e and/or display of information relating to a subject's adherence to, or the effectiveness of, a predefined treatment regimen of orally administering the composition.

19. A body weight management system comprising the composition of any one of claims 1 to 9 and a mmed electronic device configured for the collection, storage and/or display of information relating to a subject's adherence, or the effectiveness of, a predefined treatment n of orally administering the composition.

20. The use of a composition according to any one of claims 1 to 9, in the manufacture of a medicament for use in (a) the prevention and/or treatment of obesity; (b) the tion and/or treatment of a disease or condition associated with (c) the induction of satiety; and/or (d) controlling or reducing body weight.

21. The use of claim 20, wherein the medicament is to be used with a programmed electronic device for the collection, storage and/or display of information relating to a subject's adherence to the therapy and/or the effectiveness of the therapy, n the device is optionally a wearable device.

22. A composition as claimed in any one of claims 1 to 9, substantially as herein described with nce to any example thereof.

23. A method as claimed in any one of claims 10 to 13, substantially as herein described with reference to any example thereof.

24. A composition for use as claimed in any one of claims 14 to 18, substantially as herein described with reference to any example thereof.

25. A body weight management system as d in claim 19, substantially as herein described with nce to any example thereof.

26. A use as claimed in claim 20 or claim 21, substantially as herein described with reference to any example thereof.