Note: Descriptions are shown in the official language in which they were submitted.
STABLE EMULSIFIED VITAMIN AND OMEGA FATTY ACID COMPOSITIONS AND
PROCESS FOR PREPARING SAME
FIELD OF THE INVENTION
[0001] The present invention pertains to the field of pharmaceutical
compositions and in
particular to stable emulsions of oil-soluble vitamins and fatty acids.
BACKGROUND
[0002] Vitamins and fatty acids are organic compounds that humans need in
small quantities.
Many of them need to come from food because our body either does not produce
them or
produces very little.
[0003] Vitamins D, E, and K are fat-soluble vitamins. The body stores fat-
soluble vitamins in
fatty tissue and the liver.
[0004] Vitamin D is a group of fat-soluble secosteroids. Several forms
(vitamers) of vitamin D
exist. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or
cholecalciferol.
Chemically, the various forms of vitamin D are secosteroids, i.e., steroids in
which one of the
bonds in the steroid rings is broken. The structural difference between
vitamin D2 and vitamin
D3 is the side chain of D2 that contains a double bond between carbons 22 and
23, and a
methyl group on carbon 24. Vitamin D without a subscript refers to either D2
or D3 or both.
[0005] Vitamin D (also referred to as "calciferol") is a fat-soluble vitamin
that is naturally
present in a few foods, added to others, and available as a dietary
supplement. It is also
produced endogenously when ultraviolet (UV) rays from sunlight strike the skin
and trigger
vitamin D synthesis.
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[0006] Vitamin D obtained from sun exposure, foods, and supplements is
biologically inert and
must undergo two hydroxylations in the body for activation. The first
hydroxylation, which occurs
in the liver, converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known
as "calcidiol." The
second hydroxylation occurs primarily in the kidney and forms the
physiologically active 1,25-
dihydroxyvitamin D [1,25(OH)2D], also known as "calcitriol".
[0007] Vitamin D is essential for strong bones, because it helps the body use
calcium from the
diet. Traditionally, vitamin D deficiency has been associated with rickets, a
disease in which the
bone tissue doesn't properly mineralize, leading to soft bones and skeletal
deformities. But
increasingly, research is revealing the importance of vitamin D in protecting
against a host of
health problems.
[0008] Vitamin D has been shown to be useful for the prevention and treatment
multiple
sclerosis, the prevention and treatment type 1 and type 2 diabetes, the
prevention and
treatment hypertension, the prevention and treatment glucose intolerance, the
decreased risk of
some types of cancer, and for to decrease the risk of death from
cardiovascular disease.
[0009] Vitamin E is a group of eight fat-soluble compounds that include four
tocopherols and
four tocotrienols. There are also water-soluble derivatives of Vitamin E.
Vitamin E is a fat-
soluble vitamin. It is found in many foods including vegetable oils, cereals,
meat, poultry, eggs,
fruits, vegetables, and wheat germ oil. It is also available as a supplement.
[0010] Vitamin E can be used for treating vitamin E deficiency, as well as for
treating,
preventing or managing many other conditions such as: Alzheimer disease, low
levels of red
blood cells in people with long-term illness (anemia of chronic disease), a
blood disorder that
reduces levels of protein in the blood called hemoglobin (beta-thalassemia),
leakage of
intravenous (IV) drug from the vein into the surrounding skin and tissue
(extravasation),
menstrual cramps (dysmenorrhea), scarring or hardening of blood vessels in the
kidney
(glomerulosclerosis), an inherited disorder that causes red blood cells to
break down in
response to stress (G6PD deficiency), a type of non-cancerous skin sore
(granuloma annulare),
an inherited brain disorder that affects movements, emotions, and thinking
(Huntington
disease), bleeding within the skull (intracranial hemorrhage), bleeding into
or around the fluid-
filled areas (ventricles) of the brain (intraventricular hemorrhage),
conditions in a man that
prevent him from getting a woman pregnant within a year of trying to conceive
(male infertility),
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reduced benefit of nitrate therapy that happens when nitrates are used all day
(nitrate
tolerance), swelling (inflammation) and buildup of fat in the liver in people
who drink little or no
alcohol (nonalcoholic steatohepatitis or NASH), Parkinson's disease, recovery
from laser eye
surgery (photoreactive keratectomy), premenstrual syndrome (PMS), physical
performance in
elderly adults, scarring of tissue caused by radiation therapy, rheumatoid
arthritis (RA),
movement disorders often caused by antipsychotic drugs (tardive dyskinesia),
and swelling
(inflammation) of the eye (uveitis).
[0011] "Vitamin K" is the generic name for a family of fat-soluble compounds
with a common
chemical structure of 2-methyl-1,4-naphthoquinone, that is naturally present
in some vegetables
like spinach, asparagus, and broccoli or in eggs and also is available as a
dietary supplement.
[0012] "Vitamin K" include several chemical compounds. These are similar in
structure in that
they share a quinone ring, but differ in the length and degree of saturation
of the carbon tail and
the number of repeating isoprene units in the side chain. Plant-sourced forms
are primarily
vitamin K1, whereas animal-sourced forms are primarily vitamin K2.
[0013] Vitamin K plays a key role in helping the blood clot, preventing
excessive bleeding.
Unlike many other vitamins, vitamin K is not typically used as a dietary
supplement.
[0014] Matrix Gla-protein, a vitamin K-dependent protein present in vascular
smooth muscle,
bone, and cartilage, is the focus of considerable scientific research because
it might help reduce
abnormal calcification. Osteocalcin is another vitamin K-dependent protein
that is present in
bone and may be involved in bone mineralization or turnover
[0015] In the circulation, vitamin K is carried mainly in lipoproteins.
Compared to the other fat-
soluble vitamins, very small amounts of vitamin K circulate in the blood.
Vitamin K is rapidly
metabolized and excreted. This rapid metabolism accounts for the relatively
low levels of
vitamin K in blood and tissue stores compared to those of the other fat-
soluble vitamins.
[0016] Low levels of vitamin K can raise the risk of uncontrolled bleeding.
While vitamin K
deficiencies are rare in adults, they are very common in newborn infants. A
single injection of
vitamin K for newborns is standard. Vitamin K is also used to counteract an
overdose of the
blood thinner coumadin.
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[0017] The omega-fatty acids include, for example, omega-3-, omega-6- and
omega-9-fatty
acids.
[0018] Fatty acids are long-chain (monounsaturated, polyunsaturated, and
saturated) acids
found mainly in plants and fish. Fatty acids are organic, meaning that they
contain both carbon
and hydrogen molecules. Chemically, fat molecules are made up of four parts: a
molecule of
glycerol on one end of the molecule chain, and three molecules of fatty acids
on an opposite
end of the molecule chain. Each fatty acid consists of a hydrocarbon chain
with a carboxyl
group at one end. Fatty acids are typically referred to as omega fatty acids
and the number
following the term "omega-" represents the position of the first double bond,
counting from the
terminal methyl group on the molecule.
[0019] Omega 3 is a polyunsaturated fatty acid found primarily in fish, nuts
and vegetable oils.
The most common recommendation for adults is to eat at least 900 milligrams of
it per day.
Children need around half of this amount. It is also useful for pregnant
women. There are three
types of omega 3: DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), and
ALA (alpha-
linolenic acid). Even though the emphasis is usually on the former two, in
fact, you require all
three. Both lemon juice and fish oil provide the body with numerous minerals
and health benefits
that strengthen the heart and kidneys and cardiovascular and other systems.
[0020] Pregnant women, in particular, have an increased need for omega-3 fatty
acids.
Studies have shown that fatty acids are needed for fetal growth, brain
development, learning,
and behavior. Thus, lactating women are encouraged to increase their intake of
fatty acids since
infants receive their essential fatty acids through breast milk as more
research is undertaken,
people become more aware of the possible health benefits of omega-3 fatty
acids and there is
added incentive to supplement a person's diet with omega-3 fatty acids. Some
medical experts
recommend at least 500 mg per day of combined EPA and DHA.
[0021] In addition to omega-3 fatty acids, other fatty acids such as omega-6
and omega-9
fatty acids are also known to provide health benefits. Omega-6 fatty acids are
a family of
unsaturated fatty acids having in common a final carbon-carbon double bond in
the n-6 position;
i.e., the sixth bond from the methyl end of the fatty acid. There are nine
members in this family
of fatty acids, with the two most important being linoleic acid (LA), which
may be found in
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Date recue/date received 2021-10-21
soybean oil, corn oil, safflower oil, peanut oil, cottonseed oil, and rice
bran oil; and Arachidonic
acid (AA), which may be found in certain meats, eggs, and dairy products. Like
omega-3 fatty
acids, omega-6 fatty acids are polyunsaturated fats that cannot be produced in
the human body.
Thus, omega-3 and omega-6 fatty acids are classed as essential fatty acids
(EFAs) to the
human diet that can only be obtained by consuming foods such as meat, poultry
and eggs, as
well as nut and plant-based oils.
[0022] Omega-9 fatty acids are a family of unsaturated fatty acids having in
common a final
carbon-carbon double bond in the n-9 position; i.e., the ninth bond from the
methyl end of the
fatty acid. There are five members in this family of fatty acids, with the two
most important being
oleic acid (OA), which is commonly found in olive oil, canola oil, and other
monounsaturated
fats; and erucic acid (EA), which can be extracted from rapeseed, wallflower
seed, and mustard
seed.
[0023] The most widely available source of fatty acids, namely EPA and DHA, is
cold-water
oily fish, such as mackerel, herring, tuna, salmon, anchovies, and sardines.
Most people in the
Western world do not get enough omega fatty acids in their diet, especially
those with low fish
diets. Therefore, there is a need to supplement the human diet with the omega
fatty acids.
[0024] The omega fatty acids in the form of fish oil are safe for most people
when used
appropriately. However, fish oil can have a "fishy" aftertaste and can also
cause belching,
nosebleeds, nausea, and loose stools. A major concern with fish oil is that
because fish do not
produce the omega fatty acids themselves but accumulate it in their bodies
from the ingestion of
microalgae and seaweed, the fish oil may contain traces of heavy metals, in
particular, mercury
and other contaminants. Thus, a need exists for a safe, easily digestible, and
palatable dietary
supplement that will directly supply a sufficient dosage of the omega fatty
acids to the human
body, without the drawbacks of fish oil mentioned above.
[0025] As a result, the rate of oxidation of EPA/DHA fatty acids added to the
aqueous
suspension via the supplementation oil can be reduced at least two-fold or
even much more
compared to the rate of oxidation of an equal quantity of the same EPA/DHA
fatty acid-
containing enriching oil homogenized into the same aqueous suspension without
having been
first combined and diluted with the oxidative stabilization oil.
Date recue/date received 2021-10-21
[0026] Omegas can be dissolved in normal non-carbonated beverages (drinks)
with varying
degrees of good stability and shelf life. Historically, omegas when put into a
carbonated drink
have significant time limited taste and short shelf-life issues. By time
limited taste, it is meant
that over time the taste changes and becomes unsatisfactory for the taster. By
short shelf life, it
is mean that in certain cases the carbonated drink product may not survive 48
hours after
production.
[0027] US2008/274175 describes emulsions or liquids in which are mixed oils
comprising
omega-3 fatty acids. These compositions may optionally contain vitamin B3 and
iron but without
using oil-soluble Vitamins.
[0028] WO 2011/060084 describes stable, water soluble formulations comprising
omega-type
fatty acids in combination with stabilizing agents and one or more additives
selected from metal
chelators, water-soluble reducing agents, water-insoluble reducing agents,
bisulfite and
metabisulfite salts, or mixtures thereof.
[0029] EP3188715B1 describes oil-in-water emulsion comprising omega-3 fatty
acids,
chelated iron, vitamin B and an emulsifier, however without density control
agent.
[0030] Therefore there is a need for emulsions of omega fatty acids and oil-
soluble vitamins
that are shelf-stable for long periods of time under ambient storage
conditions.
[0031] This background information is provided to reveal information believed
by the applicant
to be of possible relevance to the present invention. No admission is
necessarily intended, nor
should be construed, that any of the preceding information constitutes prior
art against the
present invention.
SUMMARY OF THE INVENTION
[0032] An object of the present invention is to provide a stable emulsified
vitamin and omega
fatty acid compositions and process for preparing same. In accordance with an
aspect of the
present invention, there is provided an emulsified oil-soluble vitamin and
omega fatty acid
composition comprising: one or more oil-soluble vitamins; one or more omega
fatty acids; at
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least one emulsifying agent; a density control agent; an antioxidant and/or a
preservative agent;
and water, wherein the composition is a stable water-in-oil emulsion or oil-in-
water emulsion.
[0033] In accordance with another aspect of the present invention, there is
provided an oral
dosage form comprising the emulsified composition of the present invention.
[0034] In accordance with another aspect of the present invention, there is
provided a
process for preparing a stable emulsified oil-soluble vitamin and omega fatty
acid composition
comprising the following steps: providing a mixture comprising one or more oil-
soluble vitamins,
one or more omega fatty acids, and an antioxidant and/or preservative agent
and blending the
combination to provide a first blended mixture; adding at least one
emulsifying agent to the first
blended mixture and blending to provide a second blended mixture; adding water
to the second
blended mixture and blending in a high shear mixer to provide a third blended
mixture; adding a
density control agent to the third blended mixture and blending to provide a
fourth blended
mixture; and passing the fourth blended mixture through a high-pressure
homogenizer to
provide the emulsified oil-soluble vitamin and omega fatty acid composition.
DETAILED DESCRIPTION OF THE INVENTION
[0035] The present invention provides a stable, oil-in-water (or water-in-oil)
emulsion
formulation comprising one or more oil-soluble vitamins; one or more omega
fatty acids; at least
one emulsifying agent; a density control agent; an antioxidant and/or a
preservative agent; and
water.
[0036] The term "emulsion" as used herein refers to a lipophilic molecule of
the present
application emulsified (solubilized) in an aqueous medium using a solubilizing
agent of the
present application. In one example, the emulsion includes micelles formed
between the
lipophilic molecule(s) and the solubilizing agent. When those micelles are
sufficiently small, the
emulsion is essentially clear. Typically, the emulsion will appear clear
(e.g., transparent) to the
normal human eye, when those micelles have a median particle size of about 100
nm. In one
embodiment, the micelles in the emulsions of the present invention have median
particle sizes
between about 30 nm to about 170 nm, preferably between about 30 nm to about
130 nm, more
preferably between about 40 nm to about 100 nm.
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Date recue/date received 2021-10-21
[0037] Emulsions are not thermodynamically stable, so achieving stable
emulsified
compositions is of great commercial interest, particularly oil-in-water
emulsions comprising both
fat-soluble vitamins and fatty acids that can be stored for long periods of
time under ambient
conditions. A stable emulsion is one in which separation between the aqueous
phase and the
lipophilic component does essentially not occur (e.g., the emulsion stays
clear).
[0038] The term "micelle" is used herein according to its art-recognized
meaning and includes
all forms of micelles, including, for example, spherical micelles, cylindrical
micelles, worm-like
micelles and sheet-like micelles, and vesicles, formed in water, or mostly
water.
[0039] The terms "fat-soluble" and "oil-soluble" are used herein
interchangeably and refer to
molecules that are generally hydrophobic and soluble in nonpolar solvents and
insoluble in polar
solvents.
[0040] As used herein, the term "weight percent" or "wt%" refers to the weight
of a component
relative to the weight of the total composition.
[0041] As used herein, the term "about" refers to a +/-10% variation from the
nominal value. It
is to be understood that such a variation is always included in a given value
provided herein,
whether or not it is specifically referred to.
[0042] Unless defined otherwise, all technical and scientific terms used
herein have the same
meaning as commonly understood by one of ordinary skill in the art to which
this invention
belongs.
[0043] In accordance with the present invention, the emulsified composition
comprises one or
more omega fatty acids.
[0044] The term "omega fatty acid" is used herein to define a family of
polyunsaturated fats
having health benefits, and is intended to include omega-3, -6 and -9 fatty
acids. These fats are
differentiated by the position of the unsaturation. Useful omega fatty acids
include any of those
known in the art. In any of the embodiments described herein, the omega fatty
acids (e.g.,
omega-3, omega-6, and/or omega-9 fatty acids) can be used in the form of fatty
acids or salts
thereof (e.g., free carboxylic acids or sodium salts thereof), esters (e.g., a
methyl ester, an ethyl
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Date recue/date received 2021-10-21
ester, etc.), and/or glycerides (e.g., a triglyceride, a diglyceride, or a
monoglyceride). In some
embodiments, the omega fatty acids are used in the form of triglycerides. In
some
embodiments, the omega fatty acids are used in the form of ethyl esters.
[0045] Accordingly, in one embodiment, the one or more omega fatty acids used
in the
compositions of the present invention are selected from omega-3, -6 and -9
fatty acids, and
pharmaceutically acceptable salts and esters thereof, in any combination.
[0046] Omega-3, -6 and -9 fatty acids are obtained from natural sources like
rapeseed,
almonds, cashews, walnut, soybean, pecans, macadamia nuts, pistachios,
peanuts, perilla
seeds, sesame seeds, flax seeds, chia seeds, camelina seeds, pine nuts, hemp,
sunflower
seeds, pumpkin seeds and olive oils or other oils containing eicosapentaenoic
acid (EPA),
docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), gamma-linolenic acid
(GLA), dihomo-
gamma-linolenic acid (DGLA), conjugated linoleic acid (CLA) and oleic acid.
[0047] In one embodiment, the concentration of omega fatty acids in the
emulsion is at least
about 1 mg/mL and can be as high as about 500 mg/mL.
[0048] In one embodiment, the composition comprises from about 5 to about 15
wt% of the
one or more omega fatty acids.
[0049] In accordance with the present invention, the emulsified composition
comprises one or
more oil-soluble vitamins. In one embodiment, the oil-soluble vitamins are
selected from
vitamins D, E and K. Vitamins D, E and K may be obtained from natural or
synthetic sources. In
a preferred embodiment, vitamins D, E and K are used in their synthetic form.
[0050] As used in the present disclosure, the term "vitamin K" is used to
describe several
chemical compounds that are similar in structure in that they share common
structural feature of
a 2-methyl-1,4-naphthoquinone, but differ in the length and degree of
saturation of the carbon
tail and the number of repeating isoprene units in the side chain. Plant-
sourced forms are
primarily vitamin K1, whereas animal-sourced forms are primarily vitamin K2.
In accordance
with the present disclosure, either form may be employed in the emulsified
compositions of the
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Date recue/date received 2021-10-21
present invention. Vitamin K without a subscript should be interpreted to
refer to either K1 or K2
or both.
[0051] Vitamin E is a group of eight fat-soluble compounds that include a-
tocopherol, 8-
tocopherol, y-tocopherol, 5-tocopherol, a-tocotrienol, 8-tocotrienol, y-
tocotrienol, and 5-
tocotrienol.
[0052] As used in the present disclosure, unless otherwise specified, the term
"vitamin E" may
be understood to refer to any of the eight fat-soluble compounds or any
combination thereof.
[0053] The various forms of vitamin E may be used as food additive in oily
food to deter
rancidity caused by peroxidation. Accordingly, in accordance with the present
disclosure,
vitamin E may be used in the compositions of the present invention as an
antioxidant agent.
[0054] Vitamin D is a group of fat-soluble secosteroids, i.e., steroids in
which one of the bonds
in the steroid rings is broken. The two major forms are vitamin D2 or
ergocalciferol, and vitamin
D3 or cholecalciferol. The structural difference between vitamin D2 and
vitamin D3 is the side
chain of D2 that contains a double bond between carbons 22 and 23, and a
methyl group on
carbon 24. As used in the present disclosure, unless otherwise specified, the
term "vitamin D"
without a subscript refers to either D2 or D3 or both.
[0055] In one embodiment, the concentration of vitamins in the emulsion is at
least about 0.1
mg/mL and can be as high as about 50 mg/mL.
[0056] In one embodiment, the composition comprises from about 0.03 to about
0.08 wt% of
the one or more oil-soluble vitamins.
[0057] In accordance with the present invention, the emulsified composition
comprises at
least one emulsifying agent/surfactant.
[0058] The terms "surfactant" and "emulsifier" are used herein interchangeably
and refer to
molecules that have a hydrophobic portion and a hydrophilic portion. A
surfactant is a substance
that stabilizes an emulsion by increasing its kinetic stability. A surfactant
may be non-ionic, ionic
or amphoteric.
[0059] Emulsifying agents/surfactants suitable for this purpose can be chosen
from
Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40
(polyoxyethylene
Date recue/date received 2021-10-21
(20) sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20) sorbitan
monostearate),
Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), sorbitan
monolaurate (Span 20),
sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), lecithin, and
polyethylene
glycol 1000.
[0060] These emulsifying agents/surfactants have HLB value between 2.1 (for
sorbitan
tristearate) to 16.7 (for polysorbate 20). In one embodiment, at least one
surfactant is used in
the emulsified compositions of the present invention. It has been observed
that good stability is
achieved when a combination of surfactants is used. Accordingly, in a
preferred embodiment, a
mixture of surfactants is used in the emulsified compositions of the present
invention.
[0061] In one embodiment, the concentration of emulsifying agents/surfactants
in the
emulsion is at least about 1 mg/mL and can be as high as about 20 mg/mL.
[0062] In one embodiment, the composition comprises from about 1 to about 2
wt% of the
emulsifying agent.
[0063] In accordance with the present invention, the emulsified composition
further comprises
antioxidant and/or preservative agents.
[0064] The phrase "antioxidant agent" as used herein means an agent that can
prevent or
reduce an oxidation, degradation and/or other decomposition that would
otherwise occur to
components or ingredients of the compositions of the invention, such as the
omega fatty acids
or the oil-soluble vitamins.
[0065] Examples of suitable antioxidant and/or preservative agents include,
but are not limited
to, ascorbic acid, citric acid, ascorbic acid palmitate, vitamin E (a-
tocopherol, aT) and water-
soluble precursors of Vitamin E (a-tocopherol, aT), such as its esters with
acetate (aTA),
succinate (aTS), or phosphate (aTP), and synthetic antioxidants, such as
tertiary
butylhydroquinone (TBHQ), butylated hydroxyamisole (BHA), and butylated
hydroxytoluene
(BHT) and combinations thereof. A wide variety of antioxidant agents are
commercially available
from sources known by those of skill in the art.
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Date recue/date received 2021-10-21
[0066] In one embodiment, the concentration of antioxidant in the emulsified
composition is at
least about 0.05 mg/mL and can be as high as about 1 mg/mL.
[0067] In one embodiment, the composition comprises from about 0.01 to about
2.0 wt% of the
antioxidant.
[0068] In accordance with the present invention, in a preferred embodiment,
the emulsified
composition comprises a density control agent. As used herein, the term
"density control agent"
refers to a substance used to control the density of emulsion in order to
ensure stability and
minimize the tendency for the different components to separate due to a
density differential
between micelle and water. In a preferred embodiment, glycerol is employed as
a density
control agent in the compositions of the present invention. When glycerol is
added to the
formulation, stability increases and also the size of the resulting micelles
decreases.
[0069] In one embodiment, concentration of glycerol in the emulsion is at
least about 10 mg/mL
and can be as high as about 1000 mg/mL.
[0070] In one embodiment, the composition comprises from about 1 to about 2
wt% of the
density control agent.
[0071] In view of the significant nutritional, medical and/or other health
benefits provided by
omega fatty acids and oil-soluble vitamins such as vitamins D, E and K, it
would be beneficial to
provide oral dosage forms for oral administration to mammals that disintegrate
upon ingestion,
thereby allowing the oils and oil-soluble vitamins to become bioavailable,
permitting the oils and
oil-soluble vitamins to be absorbed by the body without being substantially or
fully degraded in
the acidic environment of the stomach, and which have a long shelf life under
ambient (room
temperature) storage conditions.
[0072] The phrase "oral dosage forms" as used herein means edible dosage forms
that are
suitable for an oral administration to a mammal. These may include hard or
soft gel or other
capsules, microcapsules and caplets, and the like, containing the emulsified
composition. Such
oral dosage forms may include in their outer structure gelatin or some other
suitable or
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conventional material. Such materials are known by those of skill in the art,
and are
commercially available from sources known by those of skill in the art.
[0073] The oral dosage forms of the present invention may also be provided in
the form of a
beverage or a liquid supplement, or may be incorporated into any suitable
foodstuff.
[0074] In accordance with the present invention, the emulsified compositions
are prepared
using a stepwise process that ensures the complete mixing and emulsification
of the mixture
under conditions that do not damage or degrade the individual components to
provide a final
emulsified composition having the desired long-term stability.
[0075] In a first step, a mixture comprising one or more oil-soluble vitamins,
one or more omega
fatty acids, and an antioxidant and/or preservative agent is blended in a
mixer to provide a first
mixture, then the emulsifying agent(s) is added to the first mixture and
blended to provide a
second mixture. Water is then added to the second mixture, and the resulting
mixture is blended
in a high shear mixer to provide a third mixture. A density control agent is
then added, followed
by a final blending step to provide an emulsified mixture, which is then
passed through a high-
pressure homogenizer to provide the final emulsified oil-soluble vitamin and
omega fatty acid
composition.
[0076] Care is taken at each step of the process to ensure that the
temperature of the mixture
does not exceed 40 C, thereby minimizing degradation of the components of the
composition,
assuring the high quality of the components of the final composition as well
as its long-term
stability.
[0077] The invention will now be described with reference to specific
examples. It will be
understood that the following examples are intended to describe embodiments of
the invention
and are not intended to limit the invention in any way.
EXAMPLES
EXAMPLE 1:
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Date recue/date received 2021-10-21
[0078] A mixture of 625 g of combination of fatty acids (flaxseed oil, olive
oil), 1g of a mixture of
fat-soluble vitamins (2 mg vitamin K, 2 mg vitamin D, and 0.98 g vitamin E)
and 1 g of ascorbic
acid palmitate was mixed at 1000 rpm for 5 minutes with an IKA Eurostar 400
control overhead
mixer, then 100 g of a surfactant blend (50g Tween 20, 40g Lecithin, 10g Span
65) was added
and the resulting mixture was mixed at 1000 rpm for 10 minutes. Then 5000 gram
of water was
added, and the resulting mixture was mixed in a stainless steel container at
2000 rpm for 10
minutes with a high shear SIIverson L5M-A mixer. The temperature was checked
throughout the
process to ensure that it never exceeded 40 C. 100 gram of glycerol was then
added and the
resulting mixture was mixed for another 10 minutes.
[0079] The resulting emulsion was passed one time through a high-pressure
homogenizer
(Homolab 2.20 laboratory homogenizer from FBF ITALIA S.r.I.) under 20000 psi
pressure. The
homogenizer included a cooling system in order to control temperature, to
ensure that it did not
exceed 40 C.
[0080] Then stability of the resulting emulsion was tested by spinning a
sample of the emulsion
in a centrifuge at 3000 rpm for 30 minutes, and by incubating a sample of the
emulsion in an
oven at a temperature of 50 C for 60 days.
[0081] DLS tests showed that the size of micelles in the resulting emulsion
were below 100 nm.
No changed in the size of the micelles was observed after centrifugation. The
emulsion was
also observed to be stable after 60 days in the oven and no separation between
the two phases
of the emulsion occurred.
EXAMPLE 2:
[0082] The emulsions were prepared using the process as described in Example
1, except
the amount of the fatty acids was varied. The amount of fatty acid and the
resulting micelle size
in the emulsions are summarized in Table 1.
Table 1:
14
Date recue/date received 2021-10-21
Amount Emulsion size
Type
(g) (nm)
rapeseed, oleic acid 600 85
chia, camelina, olive oil 725 100
sunflower, olive oil 650 90
EPA, DHA, olive oil 300 65
alpha-linolenic acid (ALA), olive oil 300 60
[0083] The stability of the resulting emulsions was tested in a centrifuge at
3000 rpm for 30
minutes and also in an oven with temperature of 50 C for 60 days. The
resulting micelle size as
determined using DLS is shown in Table 1. No change in micelle size was
observed after
centrifugation. The emulsions were again shown to be stable after 60 days in
the oven and no
separation between the two phases was observed.
[0084] These results appear to indicate that varying the composition of the
fatty acid
component does not impact the size of micelles but varying the amount of the
fatty acid
component in the composition is important. It was also observed that when
using pure fatty
acids (i.e., not provided as a mixture of fatty acids within an extracted
oil), less oil was used and
the resulting stability of the final emulsions and the size of droplets is
improved.
EXAMPLE 3:
[0085] The emulsions were prepared using the process as described in Example
1, except the
amount of the surfactants was varied. The amounts of each surfactant and the
resulting micelle
size in the emulsions are summarized in Table 5.
Table 2:
Date recue/date received 2021-10-21
Sorbitan Sorbitan Sorbitan
PEG Emulsion
Polysorbate Polysorbate Polysorbate Polysorbate LECITHIN
monolaurate monostearate tristearate 1000 size
20 (g) 40 (g) 60 (g) 80 (g) (9)
(9) (9) (9) (9)
(nm)
20 - - - 5 - 5 - 165
10 10 - 10 - 10 30 -
110
10 - - 20 - 30 - 20 -
100
50 5 8 - - 5 - 50 -
65
50 - - 20 - - 5 29 1
60
50 - - 20 - - 5 29 3
35
[0086] The stability of the resulting emulsions was tested in a centrifuge at
3000 rpm for 30
minutes and also in oven with temperature of 50 C for 60 days. The resulting
micelle size as
determined using DLS is shown in Table 2. No change in micelle size was
observed after
centrifugation. The emulsions were also shown to be stable after 60 days in
the oven and no
separation between the two phases was observed.
[0087] These results appear to indicate that varying the amount of surfactants
is important in
size of micelles, and that with an increase of the overall relative amount of
surfactants, the size
of the micelles is smaller. Polyethylene glycol 1000 was observed to have a
large effect in
reducing the size of the micelles.
EXAMPLE 4:
[0088] The emulsions were prepared using the process as described in Example
1, except
the amount of the glycerol was varied. The amounts of glycerol and the
resulting micelle size in
the emulsions are summarized in Table 3.
Table 3:
Amount Emulsion size
(g) (nm)
50 105
200 80
500 60
1000 40
16
Date recue/date received 2021-10-21
[0089] The stability of the resulting emulsions was tested in a centrifuge at
3000 rpm for 30
minutes and also in an oven with temperature of 50 C for 60 days.
[0090] The resulting micelle size as determined using DLS is shown in Table 3.
No change in
micelle size was observed after centrifugation. The emulsions were also shown
to be stable
after 60 days in the oven and no separation between the two phases was
observed.
[0091] These results appear to indicate that varying the amount of glycerol is
important in the
size of micelles, and that with an increase of the overall relative amount of
glycerol, the size of
the micelles is smaller.
[0092] It is obvious that the foregoing embodiments of the invention are
examples and can be
varied in many ways. Such present or future variations are not to be regarded
as a departure
from the spirit and scope of the invention, and all such modifications as
would be obvious to one
skilled in the art are intended to be included within the scope of the
following claims.
17
Date recue/date received 2021-10-21
