U.S. patent application number 10/037573 was filed with the patent office on 2003-07-10 for stable aqueous suspension.
Invention is credited to Milley, Christopher J., Peters, Scott E..
Application Number | 20030129253 10/037573 |
Document ID | / |
Family ID | 21895069 |
Filed Date | 2003-07-10 |
United States Patent
Application |
20030129253 |
Kind Code |
A1 |
Milley, Christopher J. ; et
al. |
July 10, 2003 |
Stable aqueous suspension
Abstract
An aqueous suspension of a hydrophobic nutrient is disclosed. In
particular, the nutrient, in ester form, is combined with a
selected dispersion aid and a dispersion agent(s), and then
dispersed in an aqueous medium to form the suspension.
Inventors: |
Milley, Christopher J.;
(Orrville, OH) ; Peters, Scott E.; (Wooster,
OH) |
Correspondence
Address: |
FROMMER LAWRENCE & HAUG
745 FIFTH AVENUE- 10TH FL.
NEW YORK
NY
10151
US
|
Family ID: |
21895069 |
Appl. No.: |
10/037573 |
Filed: |
January 3, 2002 |
Current U.S.
Class: |
424/523 ;
424/725; 424/736 |
Current CPC
Class: |
A61K 36/185 20130101;
A61K 36/61 20130101; A61K 31/122 20130101; A61K 36/752 20130101;
A61K 47/46 20130101; A61K 31/56 20130101; A61K 31/352 20130101;
A61K 36/534 20130101; A61P 3/02 20180101; A61K 36/28 20130101; A61K
31/047 20130101; A61K 47/24 20130101; A61K 9/08 20130101; A61K
36/48 20130101; A61K 31/235 20130101; A61K 35/60 20130101; A61K
36/53 20130101; A61K 36/54 20130101; A61K 47/44 20130101; A61K
36/48 20130101; A61K 36/63 20130101; A61K 36/63 20130101; A61K
36/28 20130101; A61K 36/534 20130101; A61P 7/00 20180101; A61P 9/10
20180101; C12Y 110/02002 20130101; A61K 47/34 20130101; A61K 38/44
20130101; A61K 36/185 20130101; A61K 36/54 20130101; A61K 36/61
20130101; A23D 7/003 20130101; A61K 36/752 20130101; A61K 31/575
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 36/53 20130101 |
Class at
Publication: |
424/523 ;
424/725; 424/736 |
International
Class: |
A61K 035/60; A61K
035/78 |
Claims
We claim:
1. An aqueous suspension of a hydrophobic nutrient which comprises,
the nutrient in ester form associated with a dispersion aid
selected from the group consisting of a triglyceride, an essential
oil extractive, night primrose oil, fish oil, and a mixture of any
of the foregoing dispersion aids; a dispersion agent: and an
aqueous medium into which said associated nutrient is
suspended.
2. The suspension as defined in claim 1, wherein said associated
nutrient is in a fully dispersed, uniform form in the aqueous
medium.
3. The suspension as defined in claim 2, wherein the particles size
of said fully dispersed, uniform form ranges from 50 to 400 nm.
4. The suspension as defined in claim 1, wherein said ester is an
ester of a nutritional compound selected from the group consisting
of (a) a phytosterol selected from the group consisting of
stigmasterol, sitosterol, fucosterol, brassicasterol, campesterol,
clionasterol, desmosterol, chalinosterol, poriferasterol, and any
mixture of the foregoing phytosterols; (b) a phytostanol, selected
from the group consisting of e.g. .alpha. sitostanol or .beta.
sitostanol, campestanol, brassicastanol, clionastanol,
stigmastanol, desmostanol, chalinostanol, poriferastanol, 22, 23
dihydrobrassicastanol and any mixture of the foregoing
phytostanols; (c) lutein, (d) Coenzyme Q.sub.10, (e) isoflavones,
(f) and a mixture of any of the foregoing esters.
5. The suspension as defined in claim 1, wherein said triglyceride
is selected from the group consisting of sunflower oil, soy bean
oil, olive oil, a medium chain triglyceride, selected from the
group containing fatty acids ranging from C.sub.6 to C.sub.12, and
a mixture of any of the foregoing triglycerides.
6. The suspension as defined in claim 1, wherein said essential oil
extractive is one selected from the group consisting of orange oil,
lime oil, clove oil, oregano oil, peppermint oil, cinnamon oil, and
a mixture of any of the foregoing extractives.
7. The suspension as defined in claim 1, wherein said dispersion
agent is selected from the group consisting of (a) a lecithin, (b)
a hydrocolloid, (c) a surfactant and (d) a mixture of any of the
foregoing dispersion agents.
8. The suspension as defined in claim 7, wherein said lecithin is
selected from the group consisting of lecithin derived from soybean
and lecithin derived from egg.
9. The suspension as defined in claim 7, wherein said hydrocolloid
is selected from a group consisting of xanthan gum, starch, pectin,
gelatin, guar gum, carrageenan, methylcellulose, hydroxypropyl
cellulose and a mixture of the foregoing hydrocolloids.
10. The suspension as defined in claim 7, wherein said surfactant
is selected from the group consisting of cetylpyridinium chloride,
polysorbate 80, sorbitan monostearate, a polyglycerol ester, a
block copolymer of propylene oxide, ethylene oxide and a mixture of
any of the foregoing surfactants.
11. A method of rendering a hydrophobic nutritional compound water
dispersible, which comprises: (a) treating an ester form of the
compound with a dispersion aid selected from the group consisting
of a triglyceride, an essential oil extractive, night primrose oil,
fish oil, and a mixture of any of the foregoing dispersion aids, to
form a modified nutrient compound; (b) combining a dispersion agent
with said modified nutrient compound in an aqueous medium to form
an aqueous suspension; and treating said aqueous to a high shear
force to form a stable aqueous suspension.
12. The method as defined in claim 11, wherein said stable
suspension has a mean particle size ranging from 50 to 400 nm.
13. The method as defined in claim 11, wherein said ester is an
ester of a nutritional compound selected from the group consisting
of (a) a phytosterol, selected from the group consisting of
stigmasterol, sitosterol, fucosterol, brassicasterol, campesterol,
clionasterol, desmosterol, chalinosterol, poriferasterol, and any
mixture of the foregoing phytosterols; (b) a phytostanol selected
from the group consisting of .alpha. sitostanol, .beta. sitostanol,
campestanol, brassicastanol, clionastanol, stigmastanol,
desmostanol, chalinostanol, poriferastanol, 22, 23
dihydrobrassicastanol, and any mixture of the foregoing
phytostanols; (c) lutein, (d) Coenzyme Q.sub.10, (e) isoflavones,
(f) and a mixture of any of the foregoing esters.
14. The method as defined in claim 11, wherein said triglyceride is
selected from the group consisting of sunflower oil, soy bean oil,
olive oil, a medium chain triglyceride selected from the group
containing fatty acids ranging from C.sub.6 to C.sub.12 and a
mixture of any of the foregoing triglycerides.
15. The method as defined in claim 11, wherein said essential oil
extractive is one selected from the group consisting of orange oil,
lime oil, clove oil, oregano oil, peppermint oil, cinnamon oil and
a mixture of any of the foregoing extractives.
16. The method as defined in claim 11, wherein said dispersion
agent is selected from the group consisting of (a) a lecithin, (b)
a hydrocolloid, (c) a surfactant and (d) a mixture of any of the
foregoing dispersion agents.
17. The method as defined in claim 11, wherein said lecithin is
selected from the group consisting of a lecithin derived from
soybean and a lecithin derived from egg.
18. The method as defined in claim 17, wherein said hydrocolloid is
selected from a group consisting of xantham gum, starch, pectin,
gelatin, guar gum, carrageenan, methylcellulose, hydroxypropyl
cellulose and a mixture of the foregoing hydrocolloids.
19. The method as defined in claim 17, wherein said surfactant is
selected from the group consisting of celtylpyridinium chloride,
polysorbate 80, sorbitan monostearate, a polyglycerol ester, a
block copolymer of propylene oxide, ethylene oxide and a mixture of
any of the forgoing surfactants.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to a stable aqueous suspension
comprising a nutrient, as well as to a method of rendering a
normally hydrophobic nutritional compound or ingredient dispersible
in water or in an aqueous system.
[0003] 2. Description of the Related Art
[0004] Nutritional compounds, i.e. nutritional supplements, have
been shown to help prevent the onset of undesirable conditions in
man. These substances have been identified as either essential to
human health (e.g. vitamins), or may, based on the increasing
compilation of studies, play a role in maintaining health. For
example, phytosterol and/or phytostanol esters have been shown to
reduce serum cholesterol levels in man (mammals) upon consumption,
and subsequent digestion in the gut. The mechanism for this is not
completely known. Scientists theorize that these compounds block
absorption of cholesterol produced and released from the body
through the normal hepatic function, or consumed as a component of
food. In reducing serum cholesterol levels, current wisdom deduces
that heart and circulatory health may be maintained by preventing
such conditions as arteriosclerosis, myocardial infarction,
etc.
[0005] Nutritional ingredients, such as lutein, are currently
available in tablets or other dry forms because heretofore they
could not be satisfactorily dispersed in water. The nutritional
ingredients, such as the phytosterols, phytostanols, lutein,
isoflavones, Coenzyme Q.sub.10, are typically hydrophobic and are
not ordinarily dispersible in aqueous systems because they are only
slightly water or oil soluble, if to any degree at all.
[0006] The nutritional ingredients are desirable for use in
beverages and cosmetics, in the form of aqueous suspensions,
dispersions, or liposomes. Accordingly, a means for rendering these
ingredients water dispersible or dispersible in an aqueous system
is needed and desired.
SUMMARY OF THE INVENTION
[0007] This invention relates to a stable suspension comprising a
nutrient or nutritional ingredient. In particular, the nutrient is
in an ester form and is associated with a dispersion aid and a
dispersion agent.
DETAILED DESCRIPTION OF THE INVENTION
[0008] This invention involves a stable aqueous suspension which
comprises a nutrient or a nutritional compound or ingredient.
[0009] A suitable nutrient or nutritional ingredient is one which
is suitable for therapeutic treatment of an animal, e.g. a human
being, by ingestion, e.g. via a beverage, or by topical
application, e.g. via a lotion or cream, but which is unfortunately
typically insoluble or only slightly soluble in water at room
temperature, e.g. 20.degree. C. to 25.degree. C., i.e. it is
typically hydrophobic. It is these ingredients which are the
subject of this invention. Some suitable nutrients or nutritional
ingredients include (1) a compound of the formula, 1
[0010] where R is OH, .beta.-glucoside, 6"-O-acetylglucoside, or
6"-O-malonylglucoside; R' is H or OH; and R" is H or OCH.sub.3;
such as isoflavone, e.g. a soybean derived isoflavone, and a
substituted isoflavone, such as daidzein, genistein and glycitein;
(2) lutein, (3) a Coenzyme Q.sub.n, where n is an integer of 1-12,
e.g. Coenzyme Q.sub.10, (4) a phytosterol, e.g. a stigmasterol,
sitosterol, fucosterol, brassicasterol, campesterol, clionasterol,
desmosterol, chalinosterol, poriferasterol, (5) a phytostanol, e.g.
.alpha. or .beta. sitostanol, campestanol, brassicastanol,
clionastanol, stigmastanol, desmostanol, chalinostanol,
poriferastanol, 22, 23 dihydrobrassicastanol, etc. and (6) a
mixture of any of the foregoing ingredients.
[0011] For purposes of the dispersions of this invention, which are
intended for therapeutic use or as additives in association with a
therapeutic treatment of animals, e.g. a human, a particular
nutrient or mixture of nutritional ingredients is present in the
inventive aqueous dispersions or suspensions in an effective
nutritional amount, that is an amount which causes its desired
nutritional or therapeutic effect.
[0012] The term "amount" as used herein refers to quantity or
concentration as appropriate to the context. The amount of nutrient
that constitutes a nutritional amount varies according to factors
such as potency of the particular ingredient or mixture of
ingredients, the mode of administration and the mechanical system
used to administer the dispersion. A normally effective amount of a
particular nutrient can be selected by those of ordinary skill in
the art with due consideration of such factors. Generally, a
nutritionally effective amount will be from 0.005 parts by weight
to about 25 parts by weight based on 100 parts by weight of the
dispersion or suspension.
[0013] A suitable aqueous system or medium is selected. A suitable
aqueous system or medium for the dispersions or suspensions of this
invention include water and an aqueous solution of an organic
alcohol of 1 to 6 carbon atoms, e.g. ethanol, propylene glycol,
glycerin, etc., and a mixture of the foregoing; present in an
amount of up to 10 percent (10%) by weight. The aqueous system is
one which will permit a stable dispersion or suspension to be
formed therein when combined with the selected nutrient or mixture
of nutrients, which in turn is destined to be in the form of at
least a mono-ester associated with a suitable dispersion aid. The
aqueous system is present in an amount which affords the desired
dispersion and is dependent upon the selected nutrient or mixture
of nutritional ingredients with the selected dispersion aid.
Typically, the aqueous system comprises 55 to 95 weight percent of
the dispersion or suspension.
[0014] The selected nutrient must first be converted to an ester,
e.g. a mono-, di-, tri-ester, etc., if it does not already exist as
at least a mono-ester. Such conversion, if required, is
conventionally carried out. In this regard, reference is made to
such standard text as Briehler, and Pearson, "Survey of Organic
Synthesis", Volumes 1 and 2, John Wiley & Sons.
[0015] Additionally, reference is made to Ingmar Westar et al., WO
09956558; M. P. van Amerongen et al., EP 00911385 A1 which
describes the preparation of stanol, phytosterol and phytostanol
esters.
[0016] A suitable dispersion aid is selected, i.e. an agent which
when combined or associated with the nutrient ester modifies such
ester from its crystalline form or morphous form to a dissolved
form. The then modified nutrient compound, i.e. ester, can then be
further formulated or treated, e.g. pulverized, particularized,
homogenized, liquefied, dispersed in oil carrier, whereby it can be
easily dispersed in water or an aqueous medium as a suspension.
[0017] A suitable dispersion aid includes (1) a triglyceride, such
as sunflower oil, soy bean oil, olive oil; a medium chain
triglyceride i.e. triglycerides with mixed fatty acids of C.sub.6
to C.sub.12 lengths, such as sn-glyceryl-1-caprylate, -2-caprate,
-3-caprylate, etc., and a mixture of any of the foregoing, (2) an
essential oil extractive, such as orange oil, lime oil, clove oil,
oregano oil, peppermint oil, cinnamon oil, etc., and a mixture of
the foregoing; (3) night primrose oil; (4) fish oils; (5) and a
mixture of any of the foregoing aids.
[0018] The nutrient in ester form is combined or mixed with the
dispersion aid, typically at a temperature ranging from 20 to
80.degree. C., e.g. 70-75.degree. C., for 2 to 10 minutes to form
the nutrient ester associated with the dispersion aid. By
"associate" or "associated" means that the nutrient ester has
either reacted with the dispersion aid or has physically interacted
with the dispersion aid whereby it is either mixed therewith,
encapsulated, wholly or partially, thereby, or becomes part of the
interstices thereof, solubilized or diluted.
[0019] A suitable dispersion agent is selected from (1) a lecithin,
derived from soybean or derived from egg which contain a complex
mixture of phospholipids consisting mainly of phosphatidylcholine,
phosphatidylethanolamine, phosphatidylinositol, and phosphatidic
acid combined with varying amounts of other substances such as
triglycerides: the lecithin can be of standard grade or can be
modified or refined lecithin e.g. deoiled, hydrogenated,
hydroxylated, enzyme modified, acetylated, etc.; (2) a
hydrocolloid, e.g. xanthan gum, starch, pectin, gelatin, guar gum,
carrageenan, methylcellulose, hydroxypropyl cellulose; (3) a
surfactant, e.g. cetylpyridinium chloride, polysorbate 80, sorbitan
monostearate, polyglycerol esters, block copolymers of propylene
oxide, ethylene oxide; (4) a mixture of any of the forgoing
dispersion agents.
[0020] An aqueous dispersion of the selected nutrient/aid
combination utilizes the dispersion agent in an amount effective to
form and stabilize the resultant aqueous dispersion relative to an
identical aqueous formulation not containing the dispersion agent,
such that the active ingredient does not settle, cream or
flocculate after agitation so quickly as to prevent
reproducibility, e.g. reproducible dosing. Reproducible
application, e.g. dosing, can be achieved if the resultant aqueous
suspension is substantially uniform for minimally 1 to 2 hours
after agitation thereof. The particular amount of dispersion agent
that constitutes an effective amount is dependent upon the
particular dispersion agent, the particular aqueous system or
medium employed and the particular nutritional ingredient/aid
combination, or mixture of ingredients employed. It is therefore
not practical to enumerate a specific effective amount for use with
specific dispersions or formulations of the invention, but such
amount can readily be determined by those of ordinary skill in the
art with due consideration of the factors set forth above.
Generally, however, the dispersion agent can be present in a
formulation in an amount from about 0.01 percent by weight to about
20 percent by weight, more preferably about 0.05 percent to about
10 percent by weight, most preferably 0.5 percent to 5 percent by
weight, based on the total weight of the dispersion or
formulation.
[0021] Typically, the dispersion aid, e.g. sunflower oil, is
combined with the active ingredient or nutritional agent, e.g.
phytosterol esters, at a temperature of 20.degree. to 80.degree. C.
and is mixed for 2 to 10 minutes. Thereafter the combination is
added to water containing dispersion agents, and is agitated
thereto to form a mixture. The resultant mixture is then subjected
to a high shear treatment using any commercially available
equipment, e.g. Microfluidics M110, at a shear pressure of 6500 to
24,000 psi, and preferably at a shear pressure of 7000 to 20,000
psi, and most preferably at a shear 10,000 to 12,000 psi, whereby a
particle size of the active ingredient typically is less than 500
nm, preferably less than 300 nm, most preferably less than 250 nm,
to form the desired aqueous dispersion or suspension.
[0022] It is noted that the procedure described above can be
modified, namely the order of addition of the nutrient/aid
combination, dispersion agent, and aqueous system to form the
initial aqueous mixture, i.e. preceding to the described high shear
treatment of the mixture.
[0023] The resultant aqueous nutrient dispersion can then be
further formulated and administered to a patient, e.g. a mammal
such as a human being, by any conventional means, such as
topically, orally; etc. Typically the dispersion or suspension is
combined with other drugs, adjuvants, etc. in the form of a cream
or lotion, e.g. a cosmetic, or in the form of a liquid, e.g. a
beverage.
EXAMPLES
Example 1
[0024] SELIN.RTM. brand phytosterol fatty acid esters from Cognis
(6.0 g) was dissolved in 24.0 g of NUSUN.RTM. oil, from Archer
Daniels Midland, a high oleic acid sunflower oil, at 36.degree. C.
The resultant solution was added to an aqueous system comprising
78.5 percent by weight of deionized water (157 g), 4.0 percent by
weight BLENDMAX K.RTM. lecithin from Central Soya (8 g) and 2.5
percent polysorbate 80 (5 g). The resultant mixture was treated two
times with a Microfluidizer.RTM. M110T from Microfluidics at 8,000
psi shear pressure to obtain a stable dispersion.
Example 2
[0025] The procedure of Example 1 was repeated using 15 g of
SELIN.RTM., 15 g of NUSUN.RTM. oil, 157 g of deionized water, 8 g
of BLENDMAX K.RTM., and 5 g of polysorbate 80 to obtain a stable
dispersion.
Example 3
[0026] SELIN.RTM. (6 g) was combined with NUSUN.RTM. oil (24 g) and
heated at 60.degree. C. for 15 minutes to form a solution.
Deionized water (1155.8 g) and polysorbate 80 (5 g) were mixed
together and heated at 60.degree. C. for 15 minutes and then
combined with the solution. BLENDMAX K.RTM. lecithin (8 g), citric
acid (0.6 g) and potassium sorbate (0.6 g) were added to the
combined solution with mixing and then the resultant mixture was
passed through a M110T Microfluidizer.RTM., two times at a shear
pressure of 8,000 psi. A mean particle size of the stable
dispersion of 178.3 nm was obtained.
Example 4
[0027] The procedure of Example 3 was repeated with 10 g of
SELIN.RTM., 20 g of NUSUN.RTM. oil, 155.8 g of deionized water, 8 g
of BLENDMAX K.RTM., 5 g of polysorbate 80, 0.6 g of citric acid and
0.6 g of potassium sorbate. A mean particle size of 194.6 nm of the
stable dispersion was obtained.
Example 5
[0028] An experiment was conducted to see how high a percentage of
the phytosterol esters could be incorporated into a stable
dispersion. The general procedure was to combine BLENDMAX K.RTM.,
Polysorbate 80, NUSUN.RTM. oil and SELIN.RTM. and mix these
components thoroughly at a temperature of 60.degree.-65.degree. C.
To this mix was added deionized water, and the resultant mixture
was mixed with a Silverson.RTM. high shear mixer. While mixing,
citric acid and potassium sorbate were added. Once the mixture
became uniform, it was passed twice through a M110T
Microfluidizer.RTM. at a shear pressure of 8,000 psi. The highest
percentage of the SELIN in a stable dispersion obtained was 10.0
percent by weight, using the following weight percentages of the
ingredients.
1 Deionized Water 72.9 BLENDMAX .RTM. 4.0 Polysorbate 80 2.5 NUSUN
.RTM. Oil 10.0 SELIN .RTM. 10.0 Citric acid 0.3 Potassium sorbate
0.3
Example 6
[0029] The procedure of Example 5 was repeated for lutein
esters
2 A(g) B(g) Deionized Water 72.9 67.9 BLENDMAX .RTM. 4.0 4.0
Polysorbate 80 2.5 2.5 NUSUN .RTM. Oil 19.8 24.75 Citric acid 0.3
0.3 Potassium sorbate 0.3 0.3 Xangold .RTM. Lutein esters 0.2
0.25
[0030] Stable dispersions were obtained.
Example 7
[0031] 7.5 g of Xangold.RTM., a 15% lutein ester suspension in
vegetable oil from Cognis, was dissolved with 17.5 g of orange oil
at 65.degree. C. 4.0 g of BLENDMAX K.RTM., 2.5 g of Polysorbate 80
were added and heated at 65.degree. C. for several minutes. To the
heated mixture was added 67.9 g of Deionized water, 0.3 g citric
acid, and 0.3 g potassium sorbate while mixing with a
Silverson.RTM. high shear mixer. The resultant mixture was then
passed twice through a M110 Microfluidizer.RTM. at a shear pressure
of 10,000 psi to yield a stable dispersion.
Example 8
[0032] The procedure of Example 7 was repeated using 3.75 g of
Xangold.RTM. lutein esters and 21.25 g of olive oil instead of
orange oil to obtain a stable dispersion.
* * * * *