NZ729003B2 - Formulation comprising particles - Google Patents
Formulation comprising particles Download PDFInfo
- Publication number
- NZ729003B2 NZ729003B2 NZ729003A NZ72900315A NZ729003B2 NZ 729003 B2 NZ729003 B2 NZ 729003B2 NZ 729003 A NZ729003 A NZ 729003A NZ 72900315 A NZ72900315 A NZ 72900315A NZ 729003 B2 NZ729003 B2 NZ 729003B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- water
- test
- lipid
- particles
- component
- Prior art date
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- 235000013618 yogurt Nutrition 0.000 description 1
- 235000010930 zeaxanthin Nutrition 0.000 description 1
- 239000001775 zeaxanthin Substances 0.000 description 1
- 229940043269 zeaxanthin Drugs 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N α-D-galactose Chemical class OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
Abstract
The invention provides ingestible particles comprising a water-swellable or water-soluble polymeric component, a lipid component, and optionally an amino acid, a vitamin and/or a micro-nutrient. The polymeric component may be embedded in the lipid component. The particle may further comprise an inert core and/or an outer layer which rapidly disintegrates after oral ingestion. The invention further provides methods for preparing the ingestible particles and uses thereof. t core and/or an outer layer which rapidly disintegrates after oral ingestion. The invention further provides methods for preparing the ingestible particles and uses thereof.
Description
TITLE: FORMULATION COMPRISING PARTICLES
Description
FIELD
The present invention relates to oral itions for the delivery of bioactive
agents to the gastrointestinal tract.
BACKGROUND
In the field of oral drug delivery it is of interest to develop gastroretentive dosage
forms for ive substances. Substances ated with bioactivity are typically
synthetic compounds, so called small molecules. Often such synthetic compounds require
a slow release from their dosage form after oral administration to minimise side effects
and maximise efficacy. For this purpose drug substances may be orated in a matrix
comprising lipids. Due to the hydrophobic 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 engineering
gastroretentive ties into such a slow release formulation in order to maximise the
ive time of drug delivery. Gastroretention may be achieved by ing the
ation 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 sed. US 2006/0134144 details mucoadhesive compositions for
solubilisation of insoluble drugs. Here, pharmaceutical compounds are formulated with
monoglycerides and oil. WO 03/037355 to Reckitt Benckiser Healthcare mentions
rylate compositions for use in protecting mucosa. In addition to the mucoadhesive
polymer, such compositions comprise Vitamins and oil. EP 1 to Nippon Shinyaku
Company claims a sustained release capsule for adhesion in the gastrointestinal tract.
Hard es were filled with drug substance, adhesion polymer and filler polymers and
liquid in. US 533 to ati discloses controlled-release mucoadhesive
compositions for the oral administration of drug substance furosemide. In this patent,
furosemide-lipid granules were coated with mucoadhesive polymers. US 6,368,635 to
Takeda Chemical Industries describes gastrointestinal mucosa-adherent es. Highmelting
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 ations of free fatty acids.
A1 describes a method and system for displaying gastric band
information, and more specifically gastric band information which can support
adjustment of a gastric band. The adjustment of the gastric band may be dependent on
several pieces of data. Such data may include satiety state date.
Alternative non-invasive approaches for the treatment of obesity may infer satiety
or the feeling of fullness or satisfaction through a variety of different ingestible
compositions such as gelling systems or certain nutrient 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 satiety state information in order to
support administration of the satiety-inducing composition and to increase compliance.
Such y-state information are conventionally collected as hand written
documents, 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 re application
running on a computer or a mobile device such as a smartphone or a wearable device.
Described is an effective method for delivering fatty acids and lipids based on fatty
acids to the gastrointestinal tract. Also described are means for the delivering such fatty
acids and lipids to specific regions within the gastrointestinal tract, such as the stomach
or the um. An object of the ion is to provide ingestible les,
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 .
Further objects will become apparent on the basis of the ing description
including the examples, and the patent .
SUMMARY OF THE INVENTION
In a first aspect, the invention provides an ingestible particle having a sieve
diameter in the range from 0.05 to 3 mm, comprising
(a) a swellable or water-soluble polymeric component, and
(b) a first lipid component,
and optionally
(c) an amino acid,
(d) a vitamin, and/or
(e) a micro-nutrient;
wherein
- the first lipid component comprises a medium or long chain fatty acid compound,
and
- the weight ratio of the first lipid component to the water-swellable or water-soluble
polymeric component is in the range from 1 to 3, and
- the water-swellable or water-soluble polymeric component is embedded
within the lipid component; and
wherein the ingestible particle is free of a synthetic drug nce.
In a second aspect, the invention provides a method for the preparation of the
particle according to the first aspect of the invention, comprising a step of sing a
mixture comprising the first lipid component and the water-swellable or water-soluble
polymeric component by
(a) extruding the mixture using a screw extruder;
(b) spray ling the mixture, optionally 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;
(f) spray coating of the e onto inert cores.
In a third aspect, the invention provides an ingestible particle obtained by the
method of the second aspect of the invention.
In a fourth aspect, the invention provides a solid composition for oral
administration comprising a plurality of particles of the first or third aspects of the
invention, wherein the particles in the composition optionally have a mass median sieve
diameter in the range from 0.1 mm to 3 mm, and/or wherein the dynamic angle of repose
of a sion prepared from suspending the composition in water at a weight ratio of 1
is less than 30°.
In a fifth aspect, the invention provides a solid composition for oral administration
obtained by compressing a plurality of particles of the first or third aspect of the
invention into s.
In a sixth aspect, the invention provides a single dose unit or package comprising
the composition of the fourth or fifth aspects of the invention, wherein the amount of the
composition is from 3 g to 20 g, and/or wherein the amount of the first lipid component
in the composition is at least 2 g.
BRIEF DESCRIPTION OF THE INVENTION
Described is an ingestible le 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 ally an amino acid, a vitamin and/or a micro-nutrient. The first
lipid component comprises a medium or long chain fatty acid nd. 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 soluble
polymeric component is embedded or coated may represent the active core of the
ible particle. The particle may further be coated with a coating layer that comprises
a second lipid component and/or a hydrophilic component. 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 ric 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 coating comprises a second lipid component
and/or a hydrophilic component. Optionally, the second coating layer is substantially free
of the 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 prepared from them, such as bottles, sachets, stick
packs, capsules or tablets or other dosage units.
Also described is the use of the particles and of the compositions based on the
les for the prevention and/or treatment of obesity, or a disease or condition
associated with obesity. Moreover, the use in appetite suppression, induction of y
and/or body weight reduction is described.
DETAILED DESCRIPTION OF THE INVENTION
bed is an ingestible particle having a sieve diameter 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 ent 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.
For the avoidance of doubt, it should be understood that the ce of the amino
acid, the vitamin and/or the micro-nutrient in the particles according to the ion
(and/or mixtures for the preparation of said les) is optional in all embodiments,
unless where explicitly stated otherwise. This means that, as used , listings
including the amino acid, the vitamin and/or the micro-nutrient simply refer to the
specific embodiments in which the optional amino acids, vitamins and/or micro-
nutrients are present, while not excluding those ments without these optional
components.
Further, the incorporation of the amino acid, the vitamin and/or the micro-nutrient
into the particles of the invention are independent of each other; i.e. the particles 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 understood that, as used herein, the terms ‘a’ or ‘an’ or ‘the’ or
es described in their singular form do not exclude a plurality of the respective
features. Unless explicitly stated or described ise, expressions such as “an amino
acid”, “a vitamin”, “the micro-nutrient”, “the polymer” or the like are chosen solely for
reasons of city and are meant to encompass one or more amino acid(s), n(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 inventors have found that the ingestible particles as defined , and in
particular oral compositions comprising or prepared from a plurality of the particles, are
capable of effectively ng 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 red to the mucosa of the
gastrointestinal tract, such as the stomach or duodenum, by virtue of the water-swellable
or soluble polymeric component, which may be instrumental in providing a
prolonged or ise increased interaction of the fatty acid material with target
structures in the mucosa. Furthermore, the water-swellable or soluble polymeric
component may be instrumental in providing a prolonged or otherwise increased
interaction of the amino acid, the vitamin and/or the micro-nutrient (if present) with
target structures in the mucosa.
Possibly, the swellable or water-soluble polymeric component gs the
integrity of the particle after ingestion as compared to a lipid particle without the water-
swellable or water-soluble polymeric component. Prolonged integrity of the lipid-
containing particle may result in more rapid c emptying of the particles and
ore more rapid interaction of particle-derived fatty acids or fatty acid esters with
the intestinal mucosa. ged 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 digestibility 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 content of only 3 kcal/g,
corresponding to a true digestibility of stearic acid from tristearin 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 uent emulsification and lipase-mediated hydrolysis of the
lipid.
Possibly, the water-swellable or water-soluble ric 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 suitable for
oral ingestion, or oral stration. A particle which by virtue of its composition, size
and morphology would be suitable as a food component or a component of a
pharmaceutical composition for oral use is an example of an ible particle.
The le has a sieve diameter in the range from about 0.05 mm to about 3 mm,
which means that it would ly 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 1.5 ± 0.25 mm, or about 2.0 ± 0.25 mm,
respectively. Within a composition comprising a plurality of particles according to the
invention, 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 al capable of dissolving or swelling in an aqueous
nment. The al may comprise a mucoadhesive compound or mixture of
mucoadhesive compounds, or it may be capable of ng mucoadhesiveness to the
particle. If it is a mixture, it may also comprise one or more constituents which are
lves not water-swellable or mucoadhesive, as long as the mixture is waterswellable.
As used herein, swelling by water, or in an aqueous environment, typically means
the volume increase of a solid body caused by an influx, or diffusion process of water
anied by hydration, i.e. wetting and absorption of moisture.
The water-soluble polymeric component is a hydrophilic or amphiphilic polymer of
a solubility in water of at least 1 mg/L.
Prolongation of particle ity is the prolongation of time during tion
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 imaging technology, including microscopic imaging, and
subsequent computer-aided image processing.
Mucoadhesiveness is the capability of adhering to a mucosa, or mucosal membrane.
Various conventional s are available to determine mucoadhesiveness, such as
tensile strength measurements, ellipsometry, or rheological measurements (D. Ivarsson
et al., Colloids Surf B erfaces, vol. 92, pages 353-359, 2012). Even though these
s may not provide absolute values for mucoadhesiveness as such, they indicate
the presence and relative magnitude of mucoadhesiveness of a al.
To determine mucoadhesiveness in the context of the invention, it is preferred that
a modified falling liquid film method (described 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 ted 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 selected so that small waves
of buffer uously run over the surface of the mucous tissue. In the falling liquid film
method, a similar ion is achieved by pumping buffer over mucosal tissue tilted at a
45° angle. The amount of particles remaining on the mucous membrane after a specified
time interval can be quantified by various s. For ce, particles can be
counted, ally using a magnifying glass or microscope, 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 , sufficient mucoadhesive strength to cause ment to
a mucosal membrane upon contact with, and to cause the particle or a ent f
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 watersoluble
polymeric component 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 invention, a plant fibre includes selected
individual components of plant fibres or derived therefrom, as well as their mixtures. For
example, a suitable water-swellable or water-soluble polymeric component is um
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 go ovata, also
known as Desert Indianwheat or Blond Psyllium. A major component of psyllium seed
husk is soluble but indigestible polysaccharide fibers which are highly swellable in water.
Psyllium is known as a source of dietary fibre and as a mild laxative or stool softener.
If a arboxylate) is used, this is preferably selected from poly(acrylic acid),
poly(methacrylic acid), copolymers of acrylic and rylic acid, and
poly(hydroxyethyl methacrylic acid), or from alginic acid or pectin or
carboxymethylcellulose. The cellulose ether is preferably selected from yethyl
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. Moreover, the ric material may be at least partially crosslinked.
In a further preferred embodiment, the mucoadhesive polymer is a mer 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 s of water
which causes their swelling.
Particularly suitable for carrying out the invention are, for example, carbomers.
er resins are high molecular weight, crosslinked acrylic acid-based polymers.
Commercial versions of carbomers are sold as e.g. Carbopol®, Noveon®, Pemulen®,
Polygel®, Synthalen®, Acritamer® or Tego Carbomer®. Most of these brands include
various carbomer .
For e, the ol® polymer series encompasses homopolymers,
copolymers, interpolymers as exemplified by Carbopol® Aqua SF-1 (acrylate copolymer, a
lightly linked acrylate mer), Carbopol® Aqua SF-2 (acrylate crosspolymer-4),
Carbopol® Aqua CC (polyacrylate-1 crosspolymer), Carbopol® 934 (carbomer, acrylate
homopolymer cross-linked with allyl ethers of sucrose), Carbopol® 940 (carbomer),
Carbopol® 941 (carbomer), Carbopol® 971P (carbomer, lightly crosslinked with allyl
pentaerythritol), ol® 71G (a free-flowing granular form of Carbopol® 971P for use
in direct compression formulations), Carbopol® 974P (carbomer, highly crosslinked),
Carbopol® 980 mer), Carbopol® 980 (carbomer), Carbopol® 981 mer, allyl
pentaerythritol crosslinked), Carbopol® 1342 (acrylates/C 10-30 alkyl acrylate
crosspolymer, copolymer of c acid and C1O-C30 alkyl acrylate crosslinked with allyl
pentaerythritol), Carbopol® 1382 (acrylates/C10-30 alkyl acrylate olymer,
copolymer of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl
pentaerythritol), Carbopol® 2984 (carbomer), Carbopol® 5984 (carbomer), Carbopol®
Ultrez 10 (carbomer), Carbopol® Ultrez 20 (acrylates/ C10-30 alkyl acrylate
crosspolymer), Carbopol® Ultrez 21 (acrylates/ C10-30 alkyl acrylate crosspolymer),
Carbopol® 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 (carbomer).
Polymer grades approved for pharmaceutical use are preferred among these, such
as those which comply with a pharmacopoeial monograph, such as the monograph
"Carbomer" of the European Pharmacopoeia (Ph. Eur. 8) or the monographs in the US
Pharmacopoeia/National Formulary (USP-NF) with the , "Carbomer 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
lar weight acrylic acid polymers crosslinked with divinyl glycol. They provide
excellent bioadhesive properties. An e of a red grade of polycarbophil is
NOVEON® AA-1.
Optionally, the water-swellable polymeric or water-soluble component comprises
at least one polysaccharide 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 quaternary ammonium groups (for example
cationic guar gum, cationic cellulose, cationic hydroxyethyl cellulose, and cationic starch),
derivatives thereof, or es of two or more thereof.
Alternatively, the ic ccharide is a polymeric material with basic amino
groups which are at least partially ated in a neutral environment. The cationic
polysaccharide may be provided or orated 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 (chitosan)
comprising amino side chains in the base form, e.g. -NH2. The "salt form" refers to a
r such as polyglucosamine (chitosan) comprising amino side chains in the salt
form, e.g. -NH3+ Cl- for de 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 mixtures of
different salts such as -NH3+ Cl- and -NH3+ CH3-COO-. "Any mixture of the two forms"
refers to a ric material sing amino groups, where a fraction of the amino
groups is present in the free base form, e.g. as -NH2 for primary amino groups, and a
fraction of those side chains is present in the salt form, e.g. -NH3+ Cl-. For instance, such a
mixture may be referred to as partial 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 deacetylated. A particularly preferred chitosan is derived
from fungal biomass selected from the group consisting of Candida Guillermondii,
Aspergillus niger, Aspergillus terreus, and combinations thereof, the an containing
material having r than 85 percent deacetylation of N-acetyl groups in the chitin and
exhibiting a viscosity of less than 25 centipoise (mPas) at 25 °C in 1 percent aqueous
acetic acid.
Suitable anionic polysaccharides include, but are not limited to, sulphated
amino glycans including heparans, nsulfates, ns; tes; propylene
glycol alginates; carrageenans; cellulose e; carboxymethyl cellulose; fucoidan;
galactans containing glucuronic acid or galacturonic acid; chondroitins or chondroitin
sulphates; gellan gums; hyaluronans and hyaluronic acids; modified starches such as
octenyl ate starches or monostarch ates, oxidised starches or
carboxymethylated starches; 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. Alginic acid
is a linear copolymer with homopolymeric blocks of (1-4)-linked β-D-mannuronate (M)
and its C-5 epimer α-L-guluronate (G) residues, respectively, covalently linked together
in different sequences or . The monomers can appear in homopolymeric blocks of
consecutive G-residues cks), 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 polymeric material comprising acid groups in the
nised, 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 understood
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 al comprising acid groups, 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 ylic acids. For instance, such a mixture may be referred to as
partial sodium salt of alginic acid.
Preferably, the anionic polysaccharide is an anionic dietary fibre. Dietary fibres, for
the purpose of the ion, are carbohydrate polymers with ten or more monomeric
units which are not hydrolysable by endogenous enzymes in the small intestine of
humans. They typically represent carbohydrate polymers which have been obtained from
food raw material by physical, enzymatic or chemical means, or synthetic carbohydrate
polymers.
Preferably, the anionic polysaccharide is alginic acid, carboxymethylcellulose,
hyaluronan, sodium alginate, ene glycol alginate, carrageenan, gellan gum, pectin,
anth or xanthan gum. Particularly red is that the at least one anionic
polysaccharide is ymethylcellulose, sodium alginate or propylene glycol alginate,
pectin, n gum, or hyaluronan. Optionally, a combination of anionic polysaccharides
is employed, such as sodium alginate and xanthan, or sodium alginate and pectin.
Pectic polysaccharides (pectins) 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 D-apiose in the respective cases of xylogalacturonan and
apiogalacturonan) branching from a backbone of D-galacturonic acid residues.
Rhamnogalacturonan I s (RG-I) contain a backbone of the repeating haride:
4)-α-D-galacturonic acid-(1,2)-α-L-rhamnose-(1). From many of the rhamnose residues,
sidechains of various neutral sugars may branch off. The neutral sugars are mainly D-
galactose, L-arabinose and D-xylose, with the types and tions 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 yl groups of galacturonic acid are fied 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 s are classified as high- vs. low-ester pectins (short HM vs.
LM-pectins), with more or less than half of all the galacturonic acid fied. The nonesterified
galacturonic acid units can be either free acids (carboxyl groups) or salts with
sodium, potassium, or calcium. The salts of partially esterified s are called
pectinates; if the degree of esterification is below 5 percent the salts are called es;
the insoluble acid form pectic acid. Amidated pectin is a ed form of pectin. Here,
some of the galacturonic acid is converted with ammonia to carboxylic acid amide. Most
preferred pectins are high ester pectins.
Suitable nic polysaccharides include, but are not limited to, agaroses;
amylopectins; amyloses; arabinoxylans; beta glucans including callose, curdlan,
chrysolaminarin or leucosin, laminarin, lentinan, lichenin, pleuran, schizophyllan,
zymosan; capsulans; oses ing hemicelluloses, cellulose esters such as cellulose
acetate, cellulose triacetate, cellulose propionate, cellulose acetate propionate and
cellulose acetate te; cellulose ethers such as methylcellulose, hydroxyethyl
methylcellulose, ypropyl 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 commercially available as Nutriose® or Benefiber®);
oglucomannans; omannans including fenugreek gum, guar gum, tara gum,
locust bean gum or carob gum; glucomannans including konjac gum; fructans including
inulin, levan, sinistrin or phlein; maltodextrins; glycogens; pullulans; starches including
ant starches, modified starches such as acetylated starch, hydroxypropylated starch
or yethyl starch; polydextroses; welan gum and xyloglycans.
Preferably, the non-ionic polysaccharide is a non-ionic dietary fibre. Preferably, the
non-ionic polysaccharide is selected from the group consisting of beta glucans, cellulose
ethers, guar gums, galactomannans, glucomannans, s and dextrins. Preferably, the
non-ionic polysaccharide is hydroxypropyl cellulose (hypromellose) or locust
bean gum, or oat or barley beta glucan or konjac gum or resistant dextrin. Among the
particularly preferred non-ionic ccharides are hydroxypropyl methylcellulose
(hypromellose), hydroxypropylcellulose, beta glucan from oat or barley and resistant
dextrin from starch.
Resistant dextrins are short chain e polymers without sweet taste which are
relatively resistant to the hydrolytic action of human ive enzymes. They can be
made for instance from wheat (NUTRIOSE® FB range or Benefiber®) or maize starch
(NUTRIOSE® FM range), using a highly controlled process of dextrinisation followed by a
chromatographic fractionation step. During the dextrinisation step, the starch undergoes
a degree of hydrolysis ed 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 ent according
to the invention comprises more than one polysaccharide. Preferred is in particular the
selection of an anionic polysaccharide and a non-ionic polysaccharide, ally the
combination of xanthan gum and hydroxypropyl methylcellulose (hypromellose).
Optionally, the water-swellable or water-soluble polymeric component ing
to the ion comprises a synthetic water swellable or water-soluble polymeric
material such as polyvinyl alcohol, nyl acetate, polyethylene glycols (PEG),
polypropylene glycols (PPG) or polyvinylpyrrolidones (PVP). Such polymer may be
linear, branched or crosslinked, as for instance in crospovidone (crosslinked
polyvinylpyrrolidone), or a PEG el.
Optionally, the water-swellable or water-soluble polymeric component comprises a
thiolated polymer such as chitosanthiobutylamidine, a chitosan-thioglycolic acid
conjugate, a chitosan-cysteine conjugate, a chitosan glutathione conjugate, a
polycarbophil-cysteine conjugate, a polyacrylic acid-cysteine conjugate, a carboxymethyl
cellulose-cysteine ate, 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 triglyceride. 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, s 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, behenic 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 ses one or
more partial glycerides of a medium or long chain fatty acid, in particular monoglycerides
of a medium or long chain fatty acid. For example, ein or monolaurin are very
le for ng out the invention, individually or in combination with each other. As
used herein, a yceride such as monoolein or monolaurin may be incorporated as a
substantially pure compound or as a mixture of mono- and diglycerides or even mono-,
di- and triglycerides with various fatty acids, but with a high t ("enriched") of a
particular monoglyceride compound. For e, 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 neutralised, 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 e, cocoa butter may be used, which is itself a mixture
of various lipid compounds, most of which represent fatty acid compounds as defined
herein. r preferred constituent of the first lipid component is palm stearin or palm
kernel stearin. Palm stearin is the solid fraction of palm oil that is produced by partial
crystallization 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 rated fatty acids such as the so-called
omega fatty acids or conjugated linoleic acids. Conjugated 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. es
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 vitamin E or a derivative f.
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 tood
as being below 37 °C if the lower (but not necessarily 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 material 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 temperature of the human body according to this embodiment.
Moreover, the ied 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 ng 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, tively.
It has been surprisingly found by the inventors that particles ning the water-
swellable 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 ged integrity of the particles. Possibly, 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 sed 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 containing the
water-swellable or water-soluble polymeric component embedded in, or coated with, a
lipid component comprising such low-melting fatty acid compound(s) is capable of
g a viscous emulsion in the gastrointestinal tract. Possibly, this effect also
contributes, or is related to, the prolonged gastric nce time of the particles and the
ion of satiety caused by their administration.
Optionally, the first lipid component may comprise one or more further
constituents which may have entirely different 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 mixture 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 ageous 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 ments, 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 material with a melting range of above 37 °C
according to the invention. Moreover, the specified g range is also met if the lipid
component is capable of hydration, n 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
lled temperature. An example of a preferred commercial y is Prifex® 300
from Sime Darby Unimills.
According to the invention, the water-swellable or water-soluble ric
component is embedded within, and/or coated with, the lipid ent. As used herein,
the term ‘embedded’ means that the water-swellable or water-soluble polymeric
component is largely dispersed within the lipid component, whether molecularly,
colloidally or in the form of a solid suspension. The lipid ent forms a uous
phase in which the water-swellable or water-soluble polymeric component is
tinuous and in dispersed form. For the avoidance of doubt, this does not exclude
that some of the material representing the water-swellable or water-soluble polymeric
component - typically a small fraction - is not fully embedded, but positioned at the outer
surface 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 component are mixed so
intimately that the porosity of the resulting lipid-polymer composition is greatly reduced
as compared to the particles formed from the water-swellable or soluble polymer
itself, for ce as formed by roller compaction or agglomeration. Particle porosity
may be determined by porosimetry, an analytical technique used to determine various
quantifiable aspects of a material's porous nature, such as pore er, total pore
volume, and surface area. The que involves the intrusion 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 water-
soluble polymeric component is substantially surrounded with a layer of the lipid
material representing the first lipid component. In practice, both forms (‘embedded in’ or
‘coated with’) may co-exist to some degree, depending on the method of preparation.
In one of the preferred embodiments, the particle of the invention 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 embedded or coated water-swellable or
water-soluble polymeric component whereas the coating comprises a second lipid
component and/or a hydrophilic ent. The coating may be substantially free of the
water-swellable or water-soluble polymeric component.
This embodiment is particularly useful in that the coating allows for convenient
oral administration without the water-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 coating 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
logically ve coating, such as a polymeric film coating or a lipid coating. The
polymeric film coating, which is based on a hydrophilic ent, may be free of lipid,
or it may comprise some relatively small amount of lipid e.g. as a plasticiser. The lipid
coating may be solely composed of the second lipid ent, or it may contain some
amount of the hydrophilic component, e.g. as a disintegration enhancer.
The coating may be designed to be rapidly egrating so that the active core of
the particle is released rapidly after swallowing. Preferably, the second lipid ent,
i.e. that which is incorporated in the coating of the particle, comprises one or more lipids
having a melting point or melting range below about 37 °C, as d 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 material and may act as a disintegration enhancer for the coating layer.
Disintegration enhancement may be achieved by various mechanisms, depending on the
choice of the hydrophilic component. For example, a disintegrant such as e.g.
crospovidone, croscarmellose, low-substituted hypromellose or even change resins
may rapidly take up water, expand in volume and thereby cause the disruption of the
coating. Non-swelling, highly water-soluble excipients such as sugars or sugar alcohols,
on the other hand, may predominantly act as pore s by which water channels are
rapidly created by which disintegration 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 ent
and has no or only a low degree of mucoadhesiveness.
If the coating only ns the hydrophilic component but no lipid component, the
hydrophilic component ably represents a film-forming agent such as a watersoluble
polymer. Examples of potentially suitable orming polymers e
methylcellulose, ose, hypromellose, polyvinyl alcohol, povidone, polyvinyl acetate,
(meth)acrylate copolymer, and the like. Optionally, the composition may comprise
further ients 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 of the invention exhibits an active
core comprising the first lipid component with the embedded or coated water-swellable
or water-soluble polymeric component and surrounded 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 according to the invention comprises an inert
core, a first coating covering the inert core, and a second coating ng the first
coating. In this case, the first coating comprises the water-swellable or soluble
polymeric component and the first lipid component, the second coating comprises a
second lipid component and optionally a hilic component, and the second coating
is also substantially free of the water-swellable or water-soluble polymeric component.
The hydrophilic component may be selected as described above. As in the previously
discussed embodiment, the first lipid component with the embedded or coated wellable
or water-soluble polymeric component is surrounded with a coating layer
comprising the second lipid component. The difference 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
e 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
s® 200; nonpareils of starch and sugar of similar diameter; or sugar crystals of
similar er, e.g. as obtainable by sieving.
With respect to the composition and further al features of the lipid
components, the swellable or water-soluble polymeric ent and the
hydrophilic component, reference is made to the sion above.
In the context of this embodiment, the inert core should preferably not contribute
more than about 70 % to the weight of the total particle. 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 polymeric component is embedded within, or coated by, the first lipid
component, which s to effect an improved and/or prolonged interaction of the
fatty acid with its target at the intestinal mucosa. A target structure may, for
example, be represented by G-protein coupled 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 sed bioavailability 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.
Optionally, the le may further contain an amino acid, a vitamin, 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 ed 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 protein in
that it may be orated into a protein during its translation, or biosynthesis.
Proteogenic L-amino acids as currently identified are L-alanine, L-arginine, L-asparagine,
L-aspartic acid, L-cysteine, 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 ed 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, L-threonine, L-
tryptophan, 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 ts of those amino acids which the human
organism cannot synthesise, i.e. L-histidine, L-isoleucine, L-leucine, L-lysine, L-
methionine, L-phenylalanine, L-threonine, L-tryptophan, and L-valine.
In a further preferred embodiment, the amino acid is ed from the group
consisting of L-isoleucine, L-valine, L-tyrosine, L-methionine, L-lysine, L-arginine, L-
cysteine, L-phenylalanine, L-glutamate, L-glutamine, L-leucine, and tophan. From
these, the group ting of ylalanine, L-leucine, L-glutamine, 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 e or
combination of amino acids should ably comprise at least one amino acid as
described above, i.e. a proteogenic amino acid, or an amino acid from the group of amino
acids g the genetic code, or from the essential amino acids, or the group of amino
acids consisting of L-isoleucine, L-valine, sine, L-methionine, L-lysine, L-arginine, L-
cysteine, L-phenylalanine, L-glutamate, L-glutamine, L-leucine, and L-tryptophan.
Particularly preferred particles with es or combinations of amino acids comprise
at least one amino acid from the group consisting of L-phenylalanine, L-leucine, L-
glutamine, 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 combinations of amino acids in which at least two
amino acids are s of one of the preferred groups as previously defined. Moreover,
mixtures or combinations of amino acids may be used in the les of the invention 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) typically cannot synthesise in sufficient quantities and
which ore must be taken up with the diet. The term ‘vitamin’ is conditional in that it
s on the particular sm; for ce ascorbic acid is a vitamin for humans,
while many other animals can synthesise it. Vitamins are organic compounds classified
by their biological and chemical activity, not by their structure. Each n refers to a
number of vitamers, all having the biological ty of the particular n,
convertible to the active form of the vitamin in the body, and grouped together under
alphabetised c 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, including beta carotene, cryptoxanthin, lutein, lycopene,
zeaxanthin), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin,
niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine, pyridoxamine,
xal), vitamin B7 (biotin), vitamin B8 (ergadenylic acid), vitamin B9 (folic acid,
folinic acid), vitamin B12 cobalamin, hydroxycobalamin, methylcobalamin),
vitamin C (ascorbic acid), vitamin D calciferol (D3), ergocalciferol (D2)), vitamin E
(tocopherols, tocotrienols), vitamin K (phylloquinone, menaquinones). The vitamins
according to the invention may be provided as nthetic and synthetic-source
supplements and/or as supplements of natural origin; such as in the form of plant
extracts.
As used herein, 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 ts in amounts generally less than 100 mg/day (as opposed to macrominerals
). The micro-minerals or trace elements include at least boron, ,
chromium, calcium, copper, fluoride, iodine, iron, magnesium, manganese, molybdenum,
selenium, zinc. utrients also include phytochemicals, such as terpenoids or
polyphenolic compounds, as well as vitamins (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 n and/or the micro-nutrient
may be incorporated within the particles of the invention 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, s lipophilic compounds may be incorporated in admixture
with the first and/or second lipid ent.
To further enhance the beneficial effects of the particle, it is preferred that the
weight ratio of the first lipid component to the water-swellable or water-soluble
polymeric ent 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 preferred 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 y-inducing effect of a free or fied fatty
acid is enhanced if delivered in the form of the particle of the ion, which allows
appetite suppression and the prevention and/or treatment of obesity even without
pharmacological intervention using a synthetic drug. It is ore 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 or water-soluble polymeric
component and the first lipid component, and optionally the second lipid component, 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 according to the invention 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 agglomerated 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 eration process, a pellet is a special type of
granule. However, pellets (i.e. spherical or spheroidal les) may also be prepared by
other processes than agglomeration. For the avoidance of doubt, the degree of sphericity
of a pellet may differ in various technical . In the context of the invention, the
sphericity of a pellet is in the l range of pellets used in pharmaceutical formulations
for oral use.
A minitablet, often also referred to as a ablet, 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 les of the ion are
preferably formulated and processed in such a way that they rapidly disintegrate after
oral administration. As used herein, disintegration is understood as a substantial physical
change to the minitablet, tablet or capsule morphology, such as the rupture 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 of the invention. For the
detection of such tablet, minitablet or capsule disintegration behaviour, a microscope
may be used. With respect to the apparatus, the hydrodynamic conditions, and the
temperature, the method <701> of the United States copeia 29 ) may be
used, except that water may be used as test medium and that the wire mesh may be
d with respect to the mesh size or aperture to take the sieve diameter of the tablet,
minitablet or e into account. When tested according to this method, the minitablets
or tablets or capsules sing particles according to the invention preferably
disintegrate within not more than about 15 minutes. More preferably, they disintegrate
within about 10 minutes or less. According to another embodiment, they disintegrate
within about 8 minutes or less, or within about 5 minutes or less, respectively.
Particles according to the invention may be prepared by a method comprising a
step of processing a mixture comprising the first lipid ent, the water-swellable or
water-soluble polymeric component and optionally the amino acid, the vitamin and/or
the micro-nutrient by (a) extruding the e using a screw extruder; (b) spray
congealing the mixture, optionally 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 component, the water-
swellable or water-soluble polymeric component and optionally the amino acid, the
vitamin and/or the micro-nutrient may be accomplished by conventional means such as
ng or high-shear mixing. Optionally, the mixture is prepared using the same
ent which is also utilised for the uent step in which the particles are
formed. 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 interpreted 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 extruder should have
a screen with an aperture that is useful for ing an extrudate with riate
diameter, such as 0.5 mm or 1.0 mm. The screw speed may be selected in consideration
of the capability of the extruder and on the processability of the mixture. For example, it
may be useful to select a screw speed in the range from about 20 to about 100 rpm.
Preferably, the ion step is carried out t 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 carried 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 ingredients used for preparing the particles by
extrusion are mixed or blended before they are fed to the extruder.
As mentioned above, the ingredients may also be mixed using the same equipment
which is utilised for the extrusion step. Thus, it is also red that the ingredients used
for ing extruded 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
ion.
Subsequent to the extrusion step, the extrudate may be spheronised in order to
obtain approximately spherical particles. For this purpose, any conventional spheroniser
may be used. The temperature of the niser jacket should ably be set to be
lower than the lower limit of the melting range of the lowest-melting constituent of the
e. The speed of the spheronisation plates may be set between 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 ment, the particles are prepared from the e by spray
congealing. This process may also be referred 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 co-
current, mix-current or r-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 focusing. In general, jet break-up refers to the disintegration of a
/gas jet due to forces acting on the jet.
In electrostatic t 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 through a cutter r to e.g. a rotary disc with apertures of defined size. Jet
excitation means the excitation of the melt spray by ultrasonic waves, causing vibration
and facilitating the separation of ts.
Flow focusing results from combining hydrodynamic forces with a specific
geometry, which may be achieved by using a re chamber pressurised with a
continuous focusing fluid . Inside, a focused fluid is injected through a capillary
feed tube whose extremity opens up in front of a small orifice linking the chamber with
the exterior ambient. The focusing fluid stream moulds the fluid meniscus into a
cusp giving rise to a microjet exiting the chamber through the orifice. Capillary instability
breaks up the stationary jet into neous 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 eration, 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 eration, or
melt granulation. In the context of the invention, agglomeration and granulation may be
used hangeably. For this purpose, the constituents of the e 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 mixture to a
temperature at which at least one of its constituents softens or melts, under continuous
stirring or mixing. In a tional ator, 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 sed 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 fluidised powder mixture comprising
the remaining constituents.
Optionally, the melt granules may be further processed and compressed into
minitablets. For this purpose, it is red 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 eccentric 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 water-swellable or water-soluble polymeric
component onto inert cores. As used herein, an inert core is a particle from a
physiologically acceptable material which is le for being coated, and which itself
does not ntially contribute to the physiological effect of the particles of the
invention, i.e. the induction of satiety. Examples of suitable cores include ls of
appropriate size and shape, such as sugar (sucrose) ls. In one of the preferred
embodiments, spherical beads or non-pareils made from sugar, starch, ose, in
particular microcrystalline cellulose (e.g. s®) 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 component and the water-swellable or watersoluble
polymeric ent may be melted and sprayed onto the fluidised core
particles. ally, the amino acid, the vitamin and/or the micro-nutrient if present
may also be added to this mixture. Alternatively, an aqueous or organic 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 ates and the
mixture of the first lipid component and the water-swellable or water-soluble polymeric
component - and optionally the amino acid, the vitamin and/or the micro-nutrient if
present - forms a coating on the inert core particles.
As in all other processes mentioned above, a uent 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 according to the ion 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 oluble
polymeric component, such second coating may also be applied using
conventional pharmaceutical spray coating techniques. In one of the preferred
embodiments, fluid bed coating is used for this purpose, using particles according to the
invention prepared as bed 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 ent 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 dispersed.
According to a further aspect of the invention, an ingestible particle is provided
which is obtainable by the method as described above.
In a further aspect, the invention provides a solid ition for oral
administration comprising a plurality of the particles as bed above, or which has
been prepared from a ity of the les, such as by compressing the particles into
tablets. If not compressed into tablets, the particles may in principle be filled into
es, sachets, stick packs, or containers (e.g. s of glass or other als). 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 y 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 diameter in the range from about 0.1 mm to about 3 mm. Also
preferred are mass median sieve diameters 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, respectively.
The presentation and oral administration in the form of particles in sachets, stick
packs or containers is also useful as it is preferred that a relatively large amount of the
composition 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 ment, 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 of the invention, 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 ition 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 stration is more ucible. The readyto-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 ition of the invention is administered as
suspension drink. It was found that the suspension drink of the invention is useful for
administering large amounts, such as1 g or more, of the ition while exhibiting
good drinkability and mouth feel. Drinkability of such a suspension drink according to
the invention may be assessed by s used to determine the flowability of wet
granular materials. In particular, dynamic measurements 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 instance
from Mercury Scientific, USA (Revolution Powder Analyzer) and APTIS, Belgium
(GranuDruM powder rheometer). In a suitable experimental set up for c
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 similar anti-adhesive
al, and is filled to half of its volume with a suspension of powder or particles. After
placing the drum´s top and bottom along a horizontal 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 ly 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 les of the
ion 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 according to the invention; and
to 50 vol-% of at least one aqueous 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 ment, 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 ly sized container with the filling height of the aqueous
liquid in the same container comprising the settled particles. In other words, the amount
of the liquid is chosen in such manner that the meniscus of the liquid is roughly at the
position of the upper limit of the settled particles.
The at least one aqueous liquid further may comprise l, flavouring
compounds, colouring nds, preservatives, viscosity enhancers, health ingredients
or mixtures of two or more thereof. Suitable flavouring nds 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, lactitol, maltitol, mannitol, sorbitol or xylitol; or sugar tutes,
including cyclamate, saccharine, stevia, sucralose and/or aspartame. Further suitable
flavouring compounds are juices of fruits and/or vegetables. Colouring compounds
le for the aqueous liquid are for example Allura Red AC, Anthocyanine, azorubine,
betanin, Brilliant Blue FCF, ne, Quinoline Yellow WS, Ponceau 4R, Green S, Patent
Blue V and tartrazine, either as such or in the form of the corresponding ium lakes.
Suitable preservatives are vitamins A, E or C, retinyl palmitate, cysteine, methionine,
citric acid, sodium citrate, used in s of 0.001 to 0.1 % by weight based on the
liquid.
The amount of the first lipid ent, which is a key ingredient of the
composition, should preferably be at least about 1 g per single dose or per e. In
another ment, 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 component 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
e. 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 ed 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 and the compositions of the invention may be used for
the suppression of appetite, in particular in human subjects, and for the induction of
satiety.
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
stomach and/or duodenum, thereby activating one or more ling cascades which
eventually produce a tion of satiety or a ion of appetite or hunger. Possibly,
one of the targets at which the fatty acid acts are the ghrelin cells (or ghrelin receptors),
large numbers of which are located in the stomach and the duodenum.
If present, the amino acid may further contribute to the appetite suppressing effect,
which may be due to a stimulation of chemosensors in the proximal 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 particles (or
components thereof) to the c or duodenal mucosa, allowing for an increased
interaction of the fatty acid with the target structure. Of course, 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 resulting from the high lipid content. In any case,
the inventors found that the oral administration of the particles to volunteers induced
satiety with the consequence that the subjects experienced suppressed te and
showed a reduced food intake during the meal following the administration of a
ition sing the particles as described . This effect was consistent with
animal data showing the composition leads to a weight loss, or weight reduction, of the
test animals.
The particles and/or compositions of the invention may therefore be used
clinically, or as dietary supplements, for the prevention and/or treatment of obesity and
ight, as well as the prevention and/or treatment of diseases or conditions
associated with obesity; e.g. by using the ingestible les 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 prevention and/or treatment of diseases or
conditions associated with y, for appetite suppression, body weight reduction
and/or for the induction of y, said method comprising a step of orally administering
the particles of the invention and/or compositions comprising or ed 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 of the invention and/or
compositions comprising or prepared from a plurality of these particles in the
manufacture of medicaments for the prevention and/or treatment of obesity and
overweight, as well as the prevention and/or treatment of es or conditions
associated with obesity, for appetite suppression, body weight reduction and/or for the
induction of satiety. Optionally, this comprises the oral stration of the particles
and/or compositions at least once a day over a period of at least one week.
As used herein, y is a medical condition in which excess body fat has
accumulated to the extent that it may have an adverse effect on health. Overweight is
understood as a borderline condition characterised by a body mass index (BMI) between
and below 30. ng from a BMI of 30, the ion is classified as obesity.
In one embodiment, the particles and/or compositions are administered to normal
weight or overweight subjects gaining weight over time or otherwise being at risk of
developing obesity. In this case, the therapeutical objective is to stop or limit the weight
gain and prevent the development of obesity. r purpose may be to reduce the risk
that the subject develops a disease or condition associated with or caused by obesity.
In a further embodiment, the particles and/or compositions 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 y.
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 tood. In particular, these es and
conditions include - without limitation - diabetes mellitus type 2, arterial ension,
metabolic me, insulin resistance, hypercholesterolaemia, hypertriglyceridaemia,
osteoarthritis, obstructive sleep apnoea, ischaemic heart disease, myocardial infarction,
congestive heart failure, stroke, gout, and low back pain. The prevention and/or
reduction of risk for ping 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 stered 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 months, 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 subsequently taken up by the subject that is treated.
For example, it is useful to administer a dose of the composition 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
respective meal, in ular about 10 to about 120 minutes prior to the meal, or about
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 sing at least about
5 g of the first lipid component is administered to a human t 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 and/or treatment of y or an associated disease.
It is r contemplated that the particles and/or compositions of the invention
are used in combination with the use of a 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. As used herein, information relating to a subject's adherence to the therapy
may include, for e, ation 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 preferably a programmed onic device, such as a
computer, in particular a microcomputer, and most preferably a portable microcomputer
such as a mobile phone ("smartphone"), or a wearable device such as a smart watch, an
onic wristband, 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 patient, 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. vibration), or acoustic.
Information relating to the effectiveness of the therapy may include, for example,
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 glucose concentration or
blood pressure. Depending on its type, the information relating to the iveness of the
therapy may be automatically received 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 physiological ters such as blood
glucose or blood re may be received from the respective measuring devices used
for their determination. In the latter case, the er of the data encoding the
information generated by the measuring device to the device for the e and/or
display of the information is preferably ss.
In more detail, ation collection may be user-initiated or the device may be
programmed with an application (i.e. software) which creates an alert calling for the user
to input her or his satiety-state ation. Preferably, 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 another
embodiment, 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
s cover meal times such as ast, 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; 48). In
brief, the visual ue 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 unipolar question, 'How satiated are you right now?' To ensure reliable and valid
results, participants rate their feeling of ion as precisely as possible, and they
cannot refer to their previous ratings when marking the VAS.
The y 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 appear, and the user may
adjust its position. The application will ine 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 provided herein-above and the following examples.
EXAMPLES
Example 1: Preparation of particles by spray congealing
Particles with a water-swellable or water-soluble polymeric ent embedded
within a lipid component may be prepared by spray congealing 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 heating, the sion is fed to the heated rotary nozzle of a spray
ling tower. Cold air is continuously introduced into the tower to allow
solidification of the resulting ts. The solid particles are then passed through
appropriate sieves to allow removal of oversize and undersize particles, and to obtain
particles according to the ion. 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 orated into the melt such as to obtain a viscous lipid
suspension. Under continuous heating, the suspension is fed to the heated rotary nozzle
of a spray congealing tower. Again, cold air is continuously introduced into the tower to
allow fication of the resulting droplets. Subsequently, the solidified particles are
passed through appropriate sieves to allow l of oversize and undersize particles,
and to obtain particles according to the invention.
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 t 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 myristate are
mixed and melted. 100.0 g of carbomer homopolymer type B NF added to the melt and
mixed such as to form a s suspension. Under continuous heating, the suspension is
fed to a nozzle of a spray ling 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 ing droplets. The uniform,
solidified particles are collected as final t.
Example 4: Preparation of particles by melt injection
150.0 g of a mixture of hard fat EP/NF and glyceryl monooleate (type 40) EP/NF
(e.g. Ovucire® WL 2944) and 200.0 g of sodium e 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
elementary microfluidics device, h which droplets are formed and injected into
cooled absolute l to e particles in the 250 µm range. The solidified particles
are collected 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 hardened 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
gravimetric powder feeder type KT20 (K-Tron) to the powder inlet opening 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 essentially spherical 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
jacket. Under continuous operation of the mixer, the temperature is slowly raised until
the lipid phase is thoroughly 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 c 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 te 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. uently, the dispersion is slowly
sprayed on pre-heated sugar spheres, allowing for ation of the ethanol, and taking
into account the al ion limit of air-ethanol mixtures. At the end, the coated
sugar spheres are cooled to room temperature and flushed with cold air until the limit of
residual solvents is within acceptable limits, to provide the final product.
Example 8: Coating of reil seeds by aqueous suspension
A premix of 300.0 g of myristic acid and 100.0 g of carbomer 941 NF is prepared
and dispersed in demineralised water (q.s.). In analogy to the us 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 spheres 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: Compression of minitablets from melt granulate
Particles according to the invention may also be prepared in the form of
minitablets, preferably with a small diameter, such as 1.5 mm. For example, 300.0 g of
lauric acid, 50.0 g of sodium laurate, 100.0 g of microcrystalline cellulose
(e.g. Avicel® , and 100.0 g of carbomer 941 NF are mixed to obtain a premix which
is then introduced into a jacketed, heated ary mixer, and agglomerated to result in
a ar material. The melt granulate is then sieved through an appropriate sieve
equipped with knives to result in a fine, granular material. This granular material is
subsequently blended with 75.0 g of microcrystalline cellulose (e.g. Avicel® PH101). The
resulting blend is compressed on a multi-punch eccentric tablet press into biconvex
tablets with a diameter of 1.5 mm and thickness of approx. 2 mm, to provide the final
product. In this example, the microcrystalline ose may also be replaced by lactose
(e.g. e monohydrate NF) or calcium hydrogen phosphate 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
sion (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 ng.
In the next step, 1,000 g of the active cores prepared ing 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 coating dispersion (C) are
slowly sprayed on the active cores, keeping the bed temperature at 25 – 30 °C by
adjusting inlet air temperature and spray rate. The coated active cores are fully dried at
the same temperature 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 polymer 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 l and
55.0 mL of demineralised water. This variation would lead to a more rapid evaporation of
the t during the spray coating process.
Alternatively, a coating dispersion may also be prepared by further incorporating a
plasticiser, a surfactant, and a small amount of ethylcellulose. In this case, a polymer
on (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 ved in 2.5 mL
of demineralised water to form a surfactant solution (A'). A pigment dispersion (B) is
prepared by dispersing 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 r 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.
e 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
standard grade of colloidal silicon dioxide (e.g. AEROSIL® 200) may also be used at the
same amount. In this composition, the silica acts as anti-tacking agent.
Example 12: g 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 l polyoxyl-32 glycerides NF
(e.g. Gelucire® 44/14) in a mixture of 45.0 mL of ethanol and 55 mL of ralised
water. Subsequently, 105 mL of the dispersion is coated on 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. Coated les according to the invention are provided
which exhibit rapid disintegration of the g after oral stration.
As alternatives to the lauroyl polyoxyl-32 glycerides NF, r amounts of
yl polyoxyl-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 on 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. ETHOCEL® 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 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, and taking
into account the critical ion limit of air-acetone-ethanol mixtures. The ure
leads to particles whose coating rapidly releases the active core after oral administration.
Example 15: Coating of active cores with a coating based on olipids
In this Example, the g comprises a lipid component in ation with a
hilic component. A coating sion is prepared by dispersing 10.0 g of partially
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 release coating system (e.g. Opadry®) ning a water-soluble
coating polymer, a plasticiser and pigment. 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 hydrogenated lecithin
(e.g. Lipoid S75-3), or 2.0 g of the fully hydrogenated in may be incorporated in
addition to the 10.0 g of partially hydrogenated soybean lecithin.
Example 16: Coating of active cores with a mixture of lecithin and maltodextrin
.0 g of a powder e of lecithin and extrin (e.g. Soluthin®) is dispersed
in 95 mL of demineralised water at room temperature. 1,000 g of the cores ed
according to any one of Examples 1 to 9 are fluidised bed apparatus at a temperature of
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 ature at 20 – 30 °C by
adjusting inlet air ature 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: Coating of active cores with a sucrose ester
A clear solution is prepared by dissolving 15.0 g of sucrose laurate 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 Example 16 to obtain coated particles with similar properties
with respect to their release behaviour.
As an alternative to sucrose laurate L-1695, sucrose laurate L-1570 may be used,
optionally in the form of e 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 alcohol graft copolymer
Coated particles according to the invention may also be prepared by using ethylene
glycol/vinyl alcohol graft copolymer as an ate release coating agent. For instance,
a polymer solution may be ed from 24.0 g of Kollicoat® which are dispersed 96 mL
of demineralised water and dissolved under stirring. Separately, 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
niser. The coating dispersion is then obtained by mixing 100.0 mL of the polymer
on 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 fluidised and coated in a similar manner as
described in Example 16 to obtain coated particles with similar properties with respect
to their release behaviour. During the whole coating process, the coating suspension is
continuously stirred to avoid ntation.
Example 19: Preparation of particles by lling
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 spatula.
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 n 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 ational, 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 t to a melt at
50 °C. 250 g Carbopol® 971G (Lubrizol) were incorporated into the lipid by means of a
spatula. 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 using an
ultra-centrifugal mill (ZM 200, Retsch, Germany). For g, the material was precooled
using dry ice, and a rotation speed of 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 les, they were dried under vacuum at 25 °C to remove residual
condensed water, where this was considered expedient.
Example 21: Preparation of les by 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 granulated
for 30 min and classified through a set of wire mesh sieves to obtain 240 g of particles of
a size between 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 standard 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 granulate powder
in a container attached to the inside of the cage.
Body weight was recorded at beginning and end of experiments. Food consumption
was documented daily except for ds. Experiments were performed according to
German laws of animal protection.
Rodent chow was purchased from ssniff® ldiäten 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,
y. Hard fat (Witepsol®) was from NRC, Germany. All percentages provided are
w/w-percentages, unless ically 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 ed as pellets for seven days. The mixture was composed of
standard chow diet f® EF R/M Control, 5 %) having a fat content of 5 % in the final
mixture.
Water was added to the standard chow to produce a paste which was extruded and
cut into pellets (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). s 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 .
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, representing a mean metabolisable energy intake of 382.2 ± 33.7 kJ per
animal per day.
D. 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 ition sing 50 % fat relative to the
final mixture, which was prepared by blending three standard chow diets as obtained
from ®, namely ‘EF R/M Control, 5 %’, ‘EF R/M with 30 % fat’ and
‘EF R/M with 80 % fat’, in a weight ratio of 10:45:45, respectively.
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 experiment, body weight change was evaluated
(± SD). Animals 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 reduced uptake
Six male wistar rats having a mean body weight of 301.4 ± 9.2 g were fed an
experimental 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 rd chow weight; specifically 6.2 % Carbopol® 971 NF, 1.5 % Kollicoat® MAE
100P, Sigma-Aldrich, USA, and 2.3 % chitosan from crab shells, Sigma-Aldrich, USA). This
resulted in a pellet chow ition 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 approx. 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 ment, 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, representing 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 polymerinduced
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 rd chow weight), resulting in a pellet chow composition with approx. 4.7 % fat
and approx. 5.7 % Carbopol® relative to the final e.
Standard chow was mixed with polymer , water was added to produce a
paste which was extruded and cut into s (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 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. ed pellet chow / ol® composition with 11.0 % fat and 5.3 % polymer -
e for r-induced weight loss due to reduced uptake
Six male wistar rats having a mean body weight of 307 ± 8 g were fed an
experimental diet ed as powder for five days. The mixture 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 (relative to standard chow weight),
resulting in approx. 11.0 % fat in total (including Witepsol®), approx. 6.6 % Witepsol®
and approx. 5.3 % Carbopol® ve to the final mixture.
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 ate 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
.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 h. At the beginning of the experiment a reference breath sample was
taken from the subject. Subsequently, the t consumed a load of either lipid
granulate as reference sample, or lipid granulate containing polymers as test sample.
Granulate was ed by melting lipid at 50 °C and adding 100 mg of 13C octanoic
acid (Campro ific, 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 d by means of a hammer, shredded to a ate in a
kitchen blender (Bosch, y), 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, subject exhaled through a mouthpiece to collect an end-expiratory breath
sample into a 300 mL foil bag at time intervals. Breath s 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 ion and 13C abundance at the d time
points after sample ingestion and was given in delta over basal (DOB, ‰). From the
breath test analyser's operating software (FANci version 2.12.42.14 02/14), values of
cumulated percent dose rate (cPDR, corresponding to bioavailability), and the time at
half the cPDR value (HLF, corresponding to gastrointestinal half-life) were taken to
protocol.
Several test compositions with particles according to the invention 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 half-time (test composition 3).
Hard fat (Witepsol®) was from NRC, Germany. Cocoa butter was purchased at a
local grocery store. Sodium laurate and lauric acid, microcrystalline cellulose and HPC
qualities were from Aldrich, USA. HPMC (Metolose® 90SH) was from Harke,
Germany, Xanthan (Xantan Texturas) was from Solegraells Guzman, Spain. Carbopol®
was from Lubrizol, USA. olmonooleate and glycerolmonolaurate were from TCI,
Belgium.
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 Witepsol W25:2 g - 41 232
lauric acid: 2 g
Reference 5 Prifex 300,6 g - 29.0 91.5
Test ition 1 Cocoa butter: 6 g Carbopol 971: 2 g 59 222
Test composition 2 ol W25: 6 g HPC 1 MDa: 2 g 53 176
Test composition3 Witepsol W25:4 g HPC 370 kDa: 1 g 39 243
sodium laurate: 1.25 g
Test composition4 Witepsol W25:2 g HPC 1 MDa: 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, 5.5 g Alginex: 3 g 42.1 65.2
ctin HSRVP
: 1 g
PromOat: 1 g
Example 24: In vitro mucoadhesion and particle integrity assay
Sodium alginate medium viscosity (alginate#1), c acid, sodium laurate and
lauric acid, microcrystalline cellulose (MCC), hydroxypropyl-cellulose (HPC) and
carboxymethyl-cellulose (CMC) qualities, gum arabic, chitosan and calcium 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
(Texturas gellan), te#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, Germany.
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 , amidated low
methoxyl pectin, rapid set high methoxyl pectin, and slow set high methoxyl pectin
qualities were from Modernist Pantry, USA. lucan r fill of Beta glucan
Bio Kapseln) was from Raab Vitalfood, Germany. PromOat® beta-glucan was from
yle, Sweden. Cocoa powder low fat was from Naturata, y. Cocoa powder
high fat was from Cebe, Germany. Inulin was from Spinnrad, Germany. Benefiber®
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. Monoglycerides were from TCI, m. Cocoa butter was
purchased at a local super market. Palm fat was from Peter Kölln, Germany. Palm stearin,
OmegaConcentrate oil and OmegaConcentrate powder 67 were from Bressmer,
Germany. Palm stearin IP and palm n 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
in#1 (powder quality) was from Caelo, Germany. Soy lecithin#2 (Texturas Lecite)
was from Solegraells Guzman, Spain. Cocoa mass was from Homborg, Germany. Cera
flava and alba beeswax were from Heinrich Klenk, Germany. Conjugated linoleic acid
(Tonalin®) was from BASF, Germany. Prifex® 300 palm stearin was from ls, The
lands. Omega-3 fatty acids (Omega-3 1400) were from Queisser Pharma, Germany.
Safflower oil was from Brökelmann, Germany.
Granules were prepared by g one lipid at 50 °C and optionally adding other
lipid components and a few crystals of Oil Red O (Sigma Aldrich, USA) to obtain a
homogenous 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 hammer, shredded to a
granulate in a kitchen r (Bosch IXX, Germany), optionally 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 r) was cut into 3 cm x 3 cm pieces and placed into the
bottom of a glass petri dish (10 cm er). 22 mL fasted-state simulated gastric fluid
(FaSSGF) were added to the petri dish. FaSSGF was prepared by dis-solving 1 g of NaCl
(Sigma-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 h 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 percent of initial granulate weight, representing
binding as a e of mucoadhesiveness. The petri dish containing the remaining
unbound al was agitated at 37 °C for another 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” tegration of less than 50 % of the les, but visible loss of small
amounts of powders from the particles).
In result, it was found that certain test compositions with particles according to the
invention 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
Test 2 Witepsol 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
Particle
Sample Lipid (g) Polymer (g) Binding
integrity
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 , 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 , 4 g HPC, 1 g 69 % high
Carbopol 971, 1 g
Test 9 Cocoa butter, 4 g ol 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
Glycerolmonostearate, 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 Glycerolmonooleate, 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
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
Glycerolmonooleate, 1.1 g Xanthan, 0.1 g
Witepsol W25, 1 g
Particle
Sample Lipid (g) Polymer (g) Binding
integrity
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
Glycerolmonooleate, 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
Witepsol 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
ol 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 n, 0.1 g
ol W25, 1 g
Test 29 Glycerolmonolaurate, 1.9 g HPMC, 2.4 g 75 % high
Glycerolmonooleate, 0.6 g n, 0.1 g
Glycerol, 0.5 g
Witepsol W25, 1 g
Particle
Sample Lipid (g) r (g) Binding
integrity
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 Xanthan, 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
Witepsol 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
olmonooleate, 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
olmonooleate, 1.1 g HPMC, 1 g
MCT, 0.55 g Xanthan, 0.5 g
Witepsol W25, 1 g
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
Particle
Sample Lipid (g) Polymer (g) Binding
integrity
Test 39 olmonolaurate, 1.9 g HPMC, 1.9 g 83 % high
Imwitor 990, 1.1 g Xanthan, 0.1 g
Witepsol W25, 1 g
Test 40 olmonolaurate, 3.2 g PromOat, 1.5 g 87 % high
olmonooleate, 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
Imwitor 990, 1.1 g Xanthan, 0.1 g
ol 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 PromOat, 3 g 83 % high
Glycerolmonooleate, 1.3 g HPMC, 3 g
Witepsol W25, 3.7 g n, 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
Witepsol 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
Test 49 Witepsol W25, 4 g HPMC, 2 g 47 % high
Test 50 Glycerolmonolaurate, 4 g HPMC, 2 g 45 % high
Particle
Sample Lipid (g) Polymer (g) Binding
integrity
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
n, 0.1 g
Test 53 Glycerolmonolaurate, 3 g HPMC, 1.9 g 83 % high
Witepsol W25, 1 g n, 0.1 g
Test 54 Glycerolmonolaurate, 2 g HPMC, 1.9 g 75 % high
Witepsol 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
ol W25, 3 g Xanthan, 0.1 g
Test 61 re 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
Test 63 Gelucire 43/01, 2 g PromOat, 1 g 78 % high
Witepsol W25, 6 g HPMC, 2.9 g
Xanthan, 0.1 g
Particle
Sample Lipid (g) Polymer (g) Binding
integrity
Test 64 Glycerolmonolaurate, 1 g HPMC, 2 g 80 % high
Witepsol W25, 3 g
Test 65 Glycerolmonolaurate, 2 g t, 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 olmonolaurate, 2 g Psyllium (99 %; 100 Mesh), 60 % high
ol W25, 2 g 3 g
Shea butter, 4 g HPMC, 1 g
Test 69 Glycerolmonolaurate, 2 g PromOat, 1 g 90 % high
Witepsol W25, 6 g Apple pectin, 1 g
HPMC, 2 g
Test 70 Glycerolmonolaurate, 2 g PromOat, 1 g 55 % high
Witepsol 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 olmonolaurate, 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 pectin, 1.5 g
HPMC, 1 g
Test 74 Witepsol W25, 2 g HPMC, 2 g 88 % high
Cocoa powder (high-fat), 2 g
Test 75 Glycerolmonolaurate, 2 g HPMC, 3 g 85 % high
Witepsol W25, 4 g Cocoa powder (high-fat), 4 g
Particle
Sample Lipid (g) Polymer (g) Binding
integrity
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 re 43/01, 2 g Apple pectin, 1 g 77 % high
Witepsol W25, 4 g HPMC, 3 g
Cocoa powder (high-fat), 4 g
Test 79 Gelucire 43/01, 2 g HPMC, 4 g 90 % high
Witepsol 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 re 43/01, 2 g Psyllium (99 %; 100 Mesh), 25 % high
ol W25, 4 g 1 g
HPMC, 2 g
Xanthan, 1 g
Cocoa powder (low-fat), 4 g
Test 83 Gelucire 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
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
Particle
Sample Lipid (g) Polymer (g) Binding
integrity
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 olmonolaurate, 1 g Alginate#1, 1 g 88 % high
ol W25, 3 g HPMC, 1 g
Test 89 Glycerolmonolaurate, 1.33 g Alginate#1, 1 g 60 % high
Witepsol W25, 1.33 g HPMC, 1 g
Coco fat, 1.33 g
Test 90 Glycerolmonolaurate, 1.33 g te#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 (strong 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 olmonolaurate, 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 Calcium L-lactate hydrate,
0.6 g
Test 95 Glycerolmonolaurate, 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
ol 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 olmonolaurate, 1 g Amidated low methoxyl 74 % high
Witepsol W25, 3 g pectin, 2 g
Test 103 Glycerolmonolaurate, 1 g Rapid set high methoxyl 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 yl 85 % high
Witepsol W25, 3 g pectin, 4 g
Test 106 Glycerolmonolaurate, 1 g Apple , 2 g 66 % high
Witepsol W25, 3 g
Test 107 Glycerolmonolaurate, 1 g Apple pectin, 4 g 90 % high
Witepsol W25, 3 g
Test 108 Glycerolmonolaurate, 2 g Apple , 3 g 70 % high
Witepsol W25, 4 g
Test 109 Glycerolmonolaurate, 2 g Apple pectin, 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) Binding
integrity
Test 112 Glycerolmonolaurate, 1 g Carob bean gum, 2 g 46 % medium
Witepsol W25, 3 g
Test 113 Glycerolmonolaurate, 1 g t,1 g 63 % high
Witepsol W25, 3 g n, 1 g
Test 114 Glycerolmonolaurate, 1 g um (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 Glycerolmonolaurate, 1 g Psyllium (99 %; 100 Mesh 70 % high
Witepsol 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
Witepsol W25, 3 g
Test 125 Glycerolmonolaurate, 1 g c 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) r (g) Binding
integrity
Test 127 Glycerolmonolaurate, 1 g Alginate#2, 1 g 95 % high
Witepsol 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 pectin, 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 te#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 Glycerolmonolaurate, 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 methoxyl
pectin, 2 g
Test 137 olmonolaurate, 1 g Alginate#2, 2 g 78 % high
Witepsol W25, 3 g Rapid set high yl
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) Polymer (g) Binding
integrity
Test 140 Gelucire 43/01, 5 g Alginate#2, 2 g 86 % high
Coco oil, 2 g Apple , 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 Alginate#2, 2 g 93 % high
Soy lecithin #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 n, 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 te#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 Alginate#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 te#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 n, 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 , 2 g
Coco oil, 3 g
Soy lecithin #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 te#2, 2.7 g 91 % high
1598 Soy lecithin #1, 1 g Apple , 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 pectin, 1.3 g
m 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 stearin 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 pectin, 1.3 g
, 1 g
Test 169 Palm stearin, 6.5 g Alginate#2, 2.7 g 65 % high
Soy in #1, 1.5 g Apple pectin (low fied),
1.3 g
Test 170 Palm stearin, 7 g Alginate#2, 2.7 g 70 % high
Lysolecithin 1, 1 g Apple pectin, 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 in #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 n, 4 g Alginate#4, 7.5 g 85 % high
Soy lecithin #2, 1 g
Particle
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 Alginate#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 lecithin #2, 0.5 g
Test 185 Palm stearin, 5 g Alginate#5, 7.5 g 68 % high
Test 186 Palm stearin, 5 g te#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 te#9, 7.5 g 31 % high
Test 190 Palm n, 8 g te#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 Alginate#8, 6 g 78 % no
Test 195 Palm stearin, 6 g Alginate#8, 5 g 76 % yes
Pectin#1, 1 g
Test 196 Palm stearin, 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 n, 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 Alginate#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 te#4, 3 g 89 % high
Apple pectin, 1 g
t, 1 g
Test 209 Palm stearin, 5 g Alginate#4, 3 g 87 % high
Apple pectin, 1 g
PromOat, 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 te#4, 3 g 89 % high
Apple pectin, 1 g
PromOat, 1 g
Particle
Sample Lipid (g) Polymer (g) g
integrity
Test 212 Palm stearin, 6 g te#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
PromOat, 1 g
Test 214 Prifex 300, 5.5 g te#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 stearin, 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
Benefiber, 3 g
Test 220 Palm stearin, 5.5 g Alginate#4, 2.5 g 78 % high
Benefiber, 2.5 g
Test 221 Palm stearin, 5.5 g Alginate#4, 2 g 82 % high
Benefiber, 3 g
Test 222 Palm n, 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) g
integrity
Test 226 Palm stearin, 5 g Pectin 2, 1 g n.d. medium
Benefiber, 2.5 g
PromOat, 1.5 g
Test 227 Prifex 300, 3.5 g Alginate 8, 3 g 86 % high
Safflower 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
Omega-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
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
PromOat, 1.5 g
Test 231 Prifex 300, 3.5 g Alginate 8, 3 g 83 % high
wer 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
d 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 , 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 uous mixing operation at 80 rpm, the temperature in the vessel was raised
to 60 °C and until the lipid components were completely molten. With continued mixing,
heating was stopped and 2 kg of crushed dry ice were added within 5 min. The resulting
granulate was removed from the vessel after evaporation of the carbon dioxide used as
premix for ion experiments. 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 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, Germany)
equipped with a heating . Under continuous mixing operation at 80 rpm, the
temperature in the vessel was raised to 60 °C and until the lipid ents were
completely molten. With continued , g was stopped and 3.0 kg of psyllium
seed husks (Carepsyllium, Caremoli, Germany) were added and after 5 min, 2 kg of
crushed 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 ate les were dried
under vacuum at 25 °C to remove al condensed water; e.g. prior to fying
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 (Lödige, Germany) equipped 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 completely molten. With continued mixing,
heating was stopped and 1 kg of crushed dry ice was added within 5 min. The resulting
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. 51 % (w/w) of the material were obtained
as particle size fraction of 1.0 - 3.15 mm.
e 28: Preparation of a granulate by high-shear granulation
900 g alginate (Satialgine®, l, Germany), 60 g soy lecithin (powder quality,
Golden Peanut, Germany) and 540 g of palm stearin (Palm Stearin 54, er,
Germany) were introduced into a Ploughshare mixer e, 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 components were completely molten. With
continued mixing, heating was stopped and 440 g of crushed dry ice were added within
min. The resulting granulate was removed from the , 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, Belgium) and 300 g um 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 DE-40/10, Gabler, Germany) and
extruded at a temperature range of 30-35 °C to strands of 1.0 mm diameter. Extruded
strands were cut to granules by means of rotating 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 ol monooleate
(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, rland) were fed via
volumetric dosing system (Volumetric Single Screw , Thermo Fisher, Germany) to
the powder inlet opening of the extruder, and the mixture was extruded at a temperature
range of 30-35 °C to strands of 1.5 mm diameter and subsequently broken and rounded
in a niser (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 es 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 overhead stirrer. The hot melt was sprayed onto the
granulate using a peristaltic pump and a top spraying ure at a spray rate of
6.5 g/min. Samples 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 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 t
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 stirrer. The hot melt d onto the
granulate using a peristaltic pump and a top spraying ure at a spray rate of
6.5 g/min. Samples of different amounts of coating were taken at time intervals,
corresponding to 15 and 25 % (w/w).
Example 33: Mucoadhesion assay of coated granulate
Granulate prepared according to experiment 30 were coated ing to
experimental procedure 31 to different coating thickness and ted to the
mucoadhesion assay protocol described above, except that binding kinetics were
ed up to 30 min.
Pork stomach binding of the granulate sample carrying 10 % (w/w) coating was
maximal after 6 min. Pork stomach binding of the granulate sample carrying 15 % (w/w)
g was maximal after 9 min. Pork stomach binding of the granulate sample carrying
% (w/w) coating was l after 12 min. Pork stomach binding of the granulate
sample carrying 25 % (w/w) coating was maximal after 25 min.
Example 34: Mucoadhesion assay of coated granulate
Granulate prepared according to experiment 30 were coated ing to
experimental procedure 32 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 binding of the granulate sample ng 15 % (w/w) g was
maximal after 14 min. Pork stomach binding of the granulate sample carrying 20 %
(w/w) coating was maximal after 25 min.
Example 35: Preparation of granulate by ion
A premix prepared according to the protocol of experiment 26, comprising 224 g
palm stearin (Palmstearin 54, , Germany), 96 g alginate (Satialgine®, Cargill,
France), 32 g pectin (Aglupectin® HS-RVP, Silvateam, Italy) and 32 g oat beta glucan
(PromOat®, Tate & Lyle, Sweden), 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 7 rpm) and extruded 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
ted into extrudate within less than 5 min.
Example 36: 10 kg batch of coated granulate
A premix was prepared my g 8.25 kg palm stearin (Palm Stearin 54,
Bressmer, Germany) in a g pot over an induction plate. When the melt had a
temperature of 60 °C, 4.5 kg sodium alginate (Satialgine®, Cargill, France), 1.5 g oat fibre
ation (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 c 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 les 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 der DE-40/10,
Gabler, Germany, operating at 10 rpm) and extruded 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. The extrudate was transferred 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 ate. Subsequently, granules
were ally 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 aliquots 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 r. The hot melt was tatively sprayed onto the granulate using a
peristaltic pump and a top spraying procedure at a spray rate of 6.5 g/min. ts were
combined and a total of 10 kg of coated ate was obtained and stored in a plastic
container.
Example 37: Coated granulate
Fourteen kg of a premix were ed 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, Makana, 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
alginate ex®, Kimica, Japan), 0.1 kg oat fibre preparation (PromOat®, Tate&Lyle,
Sweden) and 0.1 kg pectin (Aglupectin® HS-RVP, Silva, Italy) were incorporated by means
of a cooking spoon. The mixture was transferred in aliquots into zip-loc c 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® sional 750, Vita-Mix Corp., USA). The obtained
premix was fed via a volumetric dosing system ex DO-50 Gabler, Germany) into a
powder inlet of a twin screw extruder (Extruder DE-40/10, Gabler, Germany, ing
at 10 rpm) and extruded 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
rotating blades (running at 100 rpm). The extrudate was transferred into plastic bags in
aliquots and stored at -18 °C. Subsequently, granules were optionally dried under
vacuum at 25 °C and subjected to classification using a wire mesh sieves (Atechnik,
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 sieves. 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
n (Prifex® 300, Unimills, The Netherlands) were molten in a beaker on a hot plate
(at 100 °C) ed with an overhead stirrer. The hot melt was tatively 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
obtained and stored in a plastic container.
Example 38: Preparation of tryptophan-containing es
Granules was prepared by melting 2 g glycerol monolaurin (Mosselman, m)
and 2 g glycerol monoolein 40 (TCI, Belgium) at 55 °C. L-Tryptophan (1 g, TCI, m),
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 c-bag and cooled to -18 °C in a freezer. The
al was first crushed by means of a hammer, shredded into a granulate 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, y) to a
granule size of below 1.0 mm and above 0.5 mm.
A sample of 200 mg of tryptophan-containing es 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 minutes.
A sample of 200 mg of tryptophan-containing granules was suspended in 22 mL
fasted-state simulated intestinal fluid (FaSSIF) 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 -Aldrich) and 1.98 g sodium dihydrogen phosphate monohydrate
(Sigma-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 phan concentration
was determined by absorption measurement at a wavelength of 280 nm in a
NanoDrop® 2000 device (Thermo Scientific, USA). phan release ed firstorder
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). Tryptophan
was tatively dissolved after 10 minutes.
The term “comprising” as used in this ication and claims means “consisting at
least in part of”. When interpreting statements in this specification and claims which
include the term “comprising”, other features besides the features prefaced 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
ing a context for discussing the features of the invention. Unless specifically stated
otherwise, nce to such al documents is not to be construed as an admission
that such nts, or such sources of information, in any jurisdiction, are prior art, or
form part of the common general knowledge in the art.
In the ption in this specification reference may be made to subject matter that
is not within the scope of the claims of the current application. That subject 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 (19)
1. An ingestible particle having a sieve diameter in the range from 0.05 to 3 mm, comprising (a) a water-swellable or water-soluble polymeric ent, and (b) a first lipid component, and optionally (c) an amino acid, (d) a vitamin, and/or (e) a nutrient; wherein - the first lipid component comprises a medium or long chain fatty acid compound, and - the weight ratio of the first lipid component to the water-swellable or watersoluble polymeric ent is in the range from 1 to 3, and - the water-swellable or water-soluble polymeric component is embedded within the lipid component; and wherein the ingestible particle is free of a synthetic drug substance.
2. The particle of claim 1, comprising an active core and a coating, wherein - the active core comprises the water-swellable or water-soluble polymeric component and the first lipid component, - the coating comprises a second lipid component and/or a hydrophilic component, n the coating may be substantially free of the water-swellable or water-soluble polymeric component, and wherein the composition of the second lipid component may be the same as, or different from, the ition of the first lipid component.
3. The particle of claim 1, comprising - an inert core, - a first coating covering the inert core, and - a second coating covering the first coating, wherein the first coating ses the water-swellable or soluble polymeric component and the first lipid component, and n the second coating comprises a second lipid ent and/or a hydrophilic component, wherein the second coating is substantially free of the water-swellable or watersoluble polymeric component, and wherein the ition of the second lipid ent may be the same as, or different from, the composition of the first lipid component.
4. The particle of any one of the preceding claims, wherein the water-swellable or water-soluble polymeric ent comprises at least one polymeric al selected from poly(carboxylate), chitosan, cellulose ethers, and xanthan gum; wherein the poly(carboxylate) is optionally partially or entirely lised; and wherein the polymeric material is optionally at least partially inked.
5. The particle of claim 4, 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).
6. The le of claim 4, wherein the cellulose ether is selected from hydroxyethyl cellulose, hydroxypropyl ose, hydroxypropyl methylcellulose, methylcellulose, and carboxymethylcellulose; wherein the carboxymethylcellulose is optionally partially or entirely neutralised.
7. The particle of any one of the preceding claims, essentially consisting of the waterswellable or water-soluble polymeric component, the first lipid component, and optionally the amino acid(s), the vitamin(s), the nutrient(s), a second lipid component, and optionally one or more pharmacologically inert excipients.
8. The particle of any one of the preceding claims, being in the form of a granule, a pellet, or a minitablet.
9. A method for the preparation of the particle according to any one of claims 1 to 8, comprising a step of processing a mixture comprising the first lipid component and the water-swellable or water-soluble ric component by (a) extruding the mixture using a screw extruder; (b) spray congealing the mixture, optionally 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; (f) spray coating of the mixture onto inert cores.
10. An ingestible particle obtained by the method of claim 9.
11. A solid ition for oral administration comprising a plurality of particles of any one of claims 1 to 8 or claim 10, wherein the particles in the composition optionally have a mass median sieve diameter in the range from 0.1 mm to 3 mm, and/or wherein the dynamic angle of repose of a sion prepared from suspending the composition in water at a weight ratio of 1 is less than 30°.
12. A solid composition for oral administration obtained by compressing a plurality of particles of any one of claims 1 to 8 or claim 10 into tablets.
13. The solid composition of any one of claims 11 to 12, essentially consisting of the particles of any one of claims 1 to 8 and claim 10, and optionally one or more pharmacologically inert excipients.
14. A single dose unit or package comprising the composition of any one of claims 11 to 13, wherein the amount of the composition is from 3 g to 20 g, and/or wherein the amount of the first lipid component in the composition is at least 2 g.
15. An ingestible particle according to any one of claims 1 to 8 and 10, ntially as herein described with nce to any example thereof.
16. A method according to claim 9, substantially as herein described with reference to any example thereof.
17. A solid ition according to any one of claims 11 to 13, substantially as herein described with reference to any example thereof.
18. A single dose unit or package according to claim 14, ntially as herein described with reference to any example thereof.
19. An ingestible particle according to claim 15, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14180566.3 | 2014-08-11 | ||
EP14180566 | 2014-08-11 | ||
EP14183861 | 2014-09-06 | ||
EP14183861.5 | 2014-09-06 | ||
EP15175571.7 | 2015-07-07 | ||
EP15175571 | 2015-07-07 | ||
PCT/EP2015/068501 WO2016023923A1 (en) | 2014-08-11 | 2015-08-11 | Formulation comprising particles |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ729003A NZ729003A (en) | 2021-01-29 |
NZ729003B2 true NZ729003B2 (en) | 2021-04-30 |
Family
ID=
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