U.S. patent application number 13/023671 was filed with the patent office on 2011-09-15 for multi-vitamin and mineral nutritional supplements.
This patent application is currently assigned to Wyeth LLC. Invention is credited to William Bubnis, Richard Cotter, Paul W. Herman, Judith Moreines, Scott W. Poxon, Bruce W. Sutton, Jeffrey V. Vernon, Denise L. Walters, Michael G. Williams, Neil Wittenberg.
Application Number | 20110223250 13/023671 |
Document ID | / |
Family ID | 35064300 |
Filed Date | 2011-09-15 |
United States Patent
Application |
20110223250 |
Kind Code |
A1 |
Bubnis; William ; et
al. |
September 15, 2011 |
MULTI-VITAMIN AND MINERAL NUTRITIONAL SUPPLEMENTS
Abstract
The invention provides a nutritional supplement which includes
micronutrients to facilitate reduction of cholesterol, and/or
reduction of homocystein and/or reduction of low-density
lipoprotein-cholesterol (LDL-C) oxidation in humans. In one
embodiment the supplement is a multi-vitamin, a mineral supplement
which includes at least one component known to reduce cholesterol.
The invention further provides a method for tableting one fourth to
one half of the daily effective dosage of a phytosterol containing
nutritional supplement in a practical sized tablet and a method for
reducing blood cholesterol in humans.
Inventors: |
Bubnis; William;
(Mechanicsville, VA) ; Cotter; Richard; (Mendham,
NJ) ; Herman; Paul W.; (Bridgewater, NJ) ;
Moreines; Judith; (Edgewater, NJ) ; Poxon; Scott
W.; (Bridgewater, NJ) ; Sutton; Bruce W.;
(Richmond, VA) ; Vernon; Jeffrey V.;
(Fredericksburg, VA) ; Walters; Denise L.;
(Richmond, VA) ; Williams; Michael G.;
(Midlothian, VA) ; Wittenberg; Neil; (Randolph,
NJ) |
Assignee: |
Wyeth LLC
Madison
NJ
|
Family ID: |
35064300 |
Appl. No.: |
13/023671 |
Filed: |
February 9, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11090486 |
Mar 28, 2005 |
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13023671 |
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60557247 |
Mar 29, 2004 |
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Current U.S.
Class: |
424/474 ;
424/400; 424/464; 424/602; 424/604 |
Current CPC
Class: |
A61K 31/51 20130101;
A61K 9/10 20130101; A23P 10/20 20160801; A61K 31/525 20130101; A61K
33/00 20130101; A61K 31/714 20130101; A61K 31/575 20130101; A61P
3/02 20180101; A61K 9/20 20130101; A61K 31/352 20130101; A61K
31/355 20130101; A61K 9/284 20130101; A23L 33/11 20160801; A23L
33/105 20160801; A23L 33/15 20160801; A23L 33/16 20160801; A61K
31/675 20130101; A61K 45/06 20130101; A61K 31/375 20130101; A61K
31/56 20130101; A23V 2002/00 20130101; A61P 3/06 20180101; A61K
31/355 20130101; A61K 2300/00 20130101; A61K 31/375 20130101; A61K
2300/00 20130101; A61K 31/51 20130101; A61K 2300/00 20130101; A61K
31/525 20130101; A61K 2300/00 20130101; A61K 31/56 20130101; A61K
2300/00 20130101; A61K 31/714 20130101; A61K 2300/00 20130101; A23V
2002/00 20130101; A23V 2250/1592 20130101; A23V 2250/1598 20130101;
A23V 2250/161 20130101; A23V 2250/1642 20130101; A23V 2250/1626
20130101; A23V 2250/1588 20130101; A23V 2250/1612 20130101; A23V
2250/1578 20130101; A23V 2250/1618 20130101; A23V 2250/1608
20130101; A23V 2250/1572 20130101; A23V 2250/1628 20130101; A23V
2250/163 20130101; A23V 2250/1636 20130101; A23V 2002/00 20130101;
A23V 2250/702 20130101; A23V 2250/7044 20130101; A23V 2250/708
20130101; A23V 2250/7052 20130101; A23V 2250/706 20130101; A23V
2250/7056 20130101; A23V 2250/712 20130101; A23V 2250/2136
20130101; A23V 2250/213 20130101; A23V 2200/3262 20130101; A23V
2250/1626 20130101; A23V 2002/00 20130101; A23V 2250/702 20130101;
A23V 2250/708 20130101; A23V 2250/71 20130101; A23V 2250/712
20130101; A23V 2250/714 20130101; A23V 2250/7044 20130101; A23V
2250/304 20130101; A23V 2250/7046 20130101; A23V 2250/7052
20130101; A23V 2250/7056 20130101; A23V 2250/706 20130101; A23V
2250/72 20130101; A23V 2250/705 20130101; A23V 2250/1592
20130101 |
Class at
Publication: |
424/474 ;
424/464; 424/604; 424/602; 424/400 |
International
Class: |
A61K 9/28 20060101
A61K009/28; A61K 9/20 20060101 A61K009/20; A61K 33/42 20060101
A61K033/42; A61P 3/06 20060101 A61P003/06; A61K 9/00 20060101
A61K009/00 |
Claims
1. A nutritional supplement tablet for humans comprising, at least
about 400 mg phytosterol in free form wherein the phytosterol is at
least partially coated with silicon dioxide, at least about 3.5 mg
Zinc, 12 mcg Vitamin K, at least about 15 IU Vitamin E, at least
about 150 IU Vitamin D, at least about 30 mg Vitamin C, at least
about 2 mg Vitamin B.sub.6, at least about 0.8 mg Riboflavin, at
least about 90 mcg Vitamin B.sub.12, at least about 1600 IU Vitamin
A (and Vitamin A precursors), at least about 4.5 mcg Vanadium, at
least about 4.5 mcg Tin, at least about 0.7 mg Thiamin, at least
about 0.9 mg Silicon, at least about 10 mcg Selenium, at least
about 30 mg Potassium, at least about 35 mg Phosphorous, at least
about 5 mg Pantothenic Acid, at least about 10 mg Niacin, at least
about 35 mcg Molybdenum, at least about 1 mg Manganese, at least
about 20 mg Magnesium, at least about 70 mcg Iodine, at least about
200 mcg Folic Acid, at least about 0.35 mg Copper, at least about
60 mcg Chromium, at least about 25 mg Chloride, at least about 50
mg Calcium, at least about 15 mcg Boron, and at least about 15 mcg
biotin per tablet.
2. The nutritional supplement of claim 1, wherein a daily dosage
comprises two tablets.
3. A nutritional supplement for humans comprising multivitamins
and/or multi-minerals and a cholesterol reducing agent comprising a
phytosterol in free form in an amount of at least about 800 mg per
daily dosage wherein the phytosterol is mixed with absorbent to at
least partially coat the phytosterol prior to combination with at
least one additional nutrient selected from the group consisting of
vitamins, minerals and combinations thereof and wherein upon
combination, the supplement is compressed into tablets
disintegratable in user's gastrointestinal track.
4. A nutritional supplement tablet or caplet comprising
multi-vitamins, multi-minerals, an absorbent and a cholesterol
reducing agent of at least 400 mg, said cholesterol reducing agent
comprising phytosterols which comprise beta-sitosterol and
campesterol in free form, wherein said supplement has an oval shape
and disintegrates in the gastrointestinal tract, and wherein the
phytosterol is at least partially coated with the absorbent.
5. A nutritional supplement of a solid dosage form comprising
multi-vitamins, multi-minerals, an absorbent and a cholesterol
reducing agent of at least 800 mg per daily dosage, said
cholesterol reducing agent comprising phytosterols which comprise
beta-sitosterol and campesterol in free form, wherein the
phytosterol is at least partially coated with the absorbent.
6. The nutritional supplement of claim 5, wherein the daily dosage
of the nutritional supplement comprises two tablets and wherein
each of the two tablets has a volume less than about 2 cubic
centimeters.
7. The nutritional supplement of claim 5, wherein the daily dosage
of the nutritional supplement comprises up to four tablets and
wherein each tablet has a volume less than about 1.5 cubic
centimeters.
8. An immediate release nutritional supplement for administration
to humans comprising: an effective amount of phytosterol, wherein
the phytosterol is at least partially coated with an absorbent.
9. The immediate release nutritional supplement of claim 8, wherein
the absorbent is silicon dioxide, calcium silicate, talc, titanium
dioxide, and combinations thereof.
10. The immediate release nutritional supplement of claim 9,
wherein the silicon dioxide is precipitated silicon dioxide.
11. The immediate release nutritional supplement of claim 8 wherein
the nutritional supplement is in a tablet dosage form.
12. The nutritional supplement of claim 11, wherein the tablet is
coated with a film coating comprising polyvinyl alcohol.
14. A method of a nutritional supplementation for a human which
facilitates reduction of serum cholesterol comprising providing a
human an effective amount of the nutritional supplement of claim
8.
15. A method of tableting an immediate release phytosterol
containing nutritional supplement, said method comprising:
providing at least one phytosterol, coating said phytosterol with
an absorbent; granulating the coated phytosterol under high shear
granulation conditions to form a granulation; milling the
granulation.
16. The method of claim 15 wherein the tableted immediate release
phytosterol further comprises a diluent, wherein at least a portion
of the diluent is selected from a calcium compound and a magnesium
compound or a mixture thereof.
17. The method of claim 15 wherein the absorbent is selected from
the group consisting of silicon dioxide, calcium silicate, talc,
titanium dioxide, and combinations thereof.
18. The method of claim 15, said method further comprising film
coating the tablet.
19. An aqueous suspension composition comprising an immediate
release phytosterol, wherein said phytosterol is at least partially
coated with an absorbent.
20. A method of nutritional supplementation for a human which
facilitates the lowering of serum cholesterol comprising
administering the composition of claim 19.
Description
CROSS REFERENCE TO RELATED APPLICATION(S)
[0001] This application claims priority from U.S. Provisional
Application 60/557,247 filed Mar. 29, 2004 entitled "Multi-Vitamin
and Mineral Nutritional Supplements" the content of which is
incorporated herein in its entirety to the extent that it is
consistent with this invention and application.
BACKGROUND OF THE INVENTION
[0002] This invention relates to nutritional supplements. Features
of the invention include the provision in multi-vitamin and/or
mineral supplements of ingredients and micro-nutrients to
facilitate reduction of cholesterol, and/or reduction of
homocysteine, and/or reduction of low-density
lipoprotein-cholesterol (LDL-C) oxidation in humans. In particular,
the invention relates to multi-vitamin and/or mineral supplements
which include at least one component known to reduce
cholesterol.
[0003] It has long been established that a number of chemical
compounds typically referred to as vitamins and minerals provide
significant value to maintaining an individual in a healthy state
and/or treating specific medical conditions even when supplied in
relatively small amounts. Over the years a number of such vitamins
and minerals have been identified. For example, vitamins include A,
C, D, E and the family of B vitamins and minerals include iron,
zinc, calcium and chromium. The human body does not synthesize most
of these compounds which are essential to maintaining the health of
the human body. Thus these necessary vitamins and minerals must be
obtained from an external source. The two most common external
sources are foods and nutritional supplements. Food is typically
the primary source of obtaining the necessary nutrients; however,
the majority of people do not eat foods that consistently provide
the necessary daily requirements of vitamins and minerals. Thus,
vitamin and mineral nutritional supplementation has become a
recognized method of meeting accepted medical and health
standards.
[0004] While certain vitamins and minerals have been shown to be
essential for maintaining an individual's health, the use of
vitamin and mineral nutritional supplementation has afforded the
possibility to include micro-nutrients which, although not
absolutely essential to maintaining health, provide significant
benefit towards maintaining health. For example, U.S. Pat. No.
6,361,800 to Cooper et al. provides for a multi-vitamin supplement
preparation with a composition of micro-nutrients which is
purported to decrease plasma homocysteine levels and plasma glucose
levels.
[0005] A significant health concern to many individuals is the
problem of high cholesterol. While many medications are available
for treating this problem, most of the common medications require
doctor's supervision for use and are relatively expensive.
Certainly a doctor's care and use of these medications in cases of
highly elevated or chronically elevated cholesterol are very
important but the medications are used when the cholesterol level
is a serious health threat.
[0006] Some herbal/natural vitamin and/or mineral and/or
nutritional compositions that contain phytosterols, compounds which
are believed to facilitate cholesterol reduction, are commercially
available. However, the efficiency of these herbal/natural product
compositions for reducing cholesterol is questionable as they
typically contain 20 to 50 mg of phytosterol per dose. This is
substantially below the amount that the FDA (Food and Drug
Administration) recognizes as an efficacious dose of phytosterol
for reducing cholesterol levels. In 21 CFR 101.83 dated Feb. 14,
2003, the FDA indicates that 800 mg/day is the lowest effective
intake of the phytosterols to reduce risk of coronary heart
disease.
[0007] Accordingly, it would be desirable to have a convenient,
practical and relatively inexpensive way to facilitate reducing
cholesterol levels, and/or reducing homocysteine, and/or decreasing
LDL-C oxidation in humans before the cholesterol reaches a level to
become a serious health threat.
SUMMARY OF THE INVENTION
[0008] The present invention provides a nutritional supplement
which facilitates providing an adequate intake of vitamins,
minerals and other micro-nutrients desirable for disease
prevention, protection against nutritional losses and deficiencies
due to inadequate dietary intake patterns and life style factors
and provides micro-nutrients to facilitate reduction of
cholesterol, and/or reduction of homocysteine, and/or reduction of
LDL cholesterol in humans. The invention also provides a method of
preparing an efficacious dosage of the nutritional supplement in a
practical dosage form and a method for reducing cholesterol levels
and/or LDL cholesterol and/or homocystine in humans.
[0009] In one embodiment the invention provides a nutritional
supplement for administration to humans comprising: an effective
amount of at least one vitamin selected from the group consisting
of Vitamin A; Vitamin C; Vitamin E, Vitamin B.sub.6, Vitamin
B.sub.2, folate and Vitamin B.sub.12 and an effective amount of at
least one cholesterol reducing agent selected from the group
consisting of phytosterols, phytostanols, policosanols, and
statins.
[0010] In one embodiment the invention provides a nutritional
supplement for administration to humans comprising: an effective
amount of at least one mineral selected from the group consisting
of selenium, chromium and zinc, and an effective amount of at least
one cholesterol reducing agent selected from the group consisting
of phytosterols, phytostanols, policosanols, and statins.
[0011] In one embodiment the invention provides a multi-vitamin and
mineral nutritional supplement for administration to humans
comprising at least one cholesterol reducing agent from the group
consisting of phytosterols, phytostanols, policosanols and statins
in an amount effective to reduce cholesterol and an effective of
amount of vitamins A, B.sub.2, B.sub.6, B.sub.12, folate (folic
acid), and E. The composition may further comprise at least one of
an effective amount of lycopene and an effective amount of
selenium.
[0012] In another embodiment the invention provides a multi-vitamin
and mineral nutritional supplement for administration to humans
comprising pharmaceutically acceptable forms of the following: at
least about 800 mg of phytosterols; at least about 3500 I.U. of
vitamin A and/or vitamin A precursors; at least about 60 mg of
vitamin C; at least about 400 I.U. of vitamin D; at least about 30
I.U. of vitamin E; at least about 25 mcg of vitamin K; about 1.5 mg
of thiamin; at least about 1.7 mg of vitamin B.sub.2 (riboflavin);
at least about 20 mg of niacin; at least about 5 mg of vitamin
B.sub.6; at least about 800 mcg of folic acid; at least about 200
mcg of vitamin B.sub.12; at least about 30 mcg of biotin; at least
about 10 mg of pantothenic acid; at least about 6 mg of iron; about
150 mcg of iodine; at least about 210 mg of magnesium; at least
about 7.5 mg of zinc; at least about 20 mcg of selenium; at least
about 0.7 mg of copper; at least about 2 mg of manganese; at least
about 108 mg calcium; at least about 80 mg of phosphorus; at least
about 75 mcg of molybdenum; at least about 320 mcg boron; at least
about 5 mcg nickel; at least about 2 mg silicon; at least about 10
mcg tin; at least about 10 mcg vanadium; at least about 120 mcg of
chromium; at least about 64 mg of potassium; at least about 78 mg
of chloride; at least about 300 mcg of lycopene; and at least about
250 mcg lutein.
[0013] Another embodiment of the invention provides a multi-vitamin
and mineral nutritional supplement for administration to humans
comprising pharmaceutically acceptable forms of the following: at
least one ingredient to facilitate reduction of cholesterol, at
least one ingredient to facilitate reduction of homocysteine or
facilitate reduction of low-density lipoprotein-cholesterol (LDL-C)
and about 1300 I.U. to about 10,000 I.U. of vitamin A and/or
vitamin A precursors; about 200 I.U. to 2000 I.U. of vitamin D;
about 0 mcg to about 50 mcg of vitamin K; about 1.2 mg to about 4.5
mg of thiamin; about 5 mg to about 40 mg of niacin; about 0 mg to
about 550 mg of choline; about 0 mcg to about 1400 mcg of folic
acid; about 0 mcg to about 300 mcg of biotin; about 0 mg to about
16 mg of pantothenic acid; about 0 mg to about 18 mg of iron; about
0 mcg to about 300 mcg of iodine; about 0 mg to about 100 mg of
magnesium; about 3 mg to about 15 mg of zinc; about 0 mg to about 2
mg of copper; about 0 mg to about 6 mg of manganese; about 0 to
about 200 mg calcium; about 0 mg to about 750 mg of phosphorus;
about 0 mcg to about 250 mcg of molybdenum; about 0 mcg to about
150 mcg boron; about 0 mcg to about 100 mcg nickel; about 0 mg to
about 40 mg silicon; about 0 mcg to about 35 mcg tin; about 0 mcg
to about 25 mcg vanadium; about 0 mcg to about 300 mcg of chromium;
about 0 mg to about 125 mg of potassium; about 0 mg to about 120 mg
of chloride; about 0 to 3 g of Omega-3 fatty acids; about 0 to 3 g
lycopene; about 0 to 3 g zeaxanthin; and about 0 mcg to about 3 g
lutein.
[0014] Ingredients to facilitate reduction of cholesterol may
comprise one or more of the following ingredients in an amount
effective to reduce cholesterol: phytosterols, phytostanols, or
their equivalents, in free or esterified form, policosanol and
statins. Suitable statins include, for example, atorvastatin,
provastatin, simvastatin, lovastatin or flavastatin. Typically
about 0.8 grams to about 3 grams of phytosterols, stanols, or their
equivalents, may be used in the multi-vitamins and mineral
nutritional supplements. Amounts of policosanol of up to about 200
mg may be used in the multi-vitamins and mineral nutritional
supplements. Statins may be used in amounts of up to 80 mg and
typically are used in amounts of about 40 mg to about 80 mg. More
particularly with regard to statins, provastatin and simvastatin
are preferably used in amounts of about 40 mg, and atorvastatin,
lovastatin and fluvastatin are typically used in amounts of about
80 mg.
[0015] Ingredients to facilitate reduction of homocystine may
comprise one or more of the following: up to about 40 mg of vitamin
B.sub.2 (riboflavin); up to about 10 mg of vitamin B.sub.6; up to
about 1 mg of folate, and up to about 2 mg of vitamin B.sub.12.
Ingredients to facilitate reduction of homocysteine, may more
preferably comprise one or more of the following: about 1.3 mg to
about 5.1 mg of vitamin B.sub.2 (riboflavin); up to about 1400
about 800 mcg folate; about 1 mg to about 6 mg of vitamin B.sub.6;
and about 2.4 mcg to about 200 mcg of vitamin B.sub.12.
[0016] Ingredients to facilitate reduction of low-density
lipoprotein-cholesterol cholesterol (LDL-C) oxidation, which may
comprise one or more of the following: up to about 2 grams of
vitamin C; up to about 800 I.U. of vitamin E; up to about 6 grams
of lycopene; and up to about 350 mcg of selenium. Ingredients to
facilitate reduction of low-density lipoprotein-cholesterol
cholesterol (LDL-C) oxidation, may more preferably comprise one or
more of the following: about 45 mg to about 250 mg of vitamin C;
about 20 I.U. to about 200 I.U. of vitamin E; about 0 mcg to about
3 g of lycopene; and about 0 mcg to about 75 mcg of selenium.
[0017] The composition described herein may further include a
diluent such as, for example a calcium compound, magnesium
compound, microcrystalline cellulose, starch or a combination
thereof.
[0018] The composition described herein may also include an
absorbent such as silicon dioxide, for example. In some embodiments
the silicon dioxide may be precipitated, fumed or a mixture
thereof.
[0019] The invention further provides a method of reducing
cholesterol levels, reducing homocysteine, and decreasing
low-density lipoprotein-cholesterol (LDL-C) oxidation in humans by
administering the composition of the invention to a human.
[0020] The invention further includes a method of tableting
nutritional supplements comprising at least one phytosterol, the
method comprising: providing at least one phytosterol and at least
one diluent; granulating the phytosterol and the at least one
diluent under high shear granulation conditions to form a
granulation; milling the granulation; and adding an absorbent to
the granulation.
[0021] For wet granulation methods, the method may further comprise
drying the granulation and the absorbent is preferably added after
drying. A fluid bed dryer is exemplary of a suitable dryer for
drying the granulation.
[0022] The method may comprise compressing the granulation to form
a tablet. The tableting may be coated with a film coat comprising
polyvinyl alcohol (PVA), for example.
[0023] In one embodiment a daily efficacious amount of nutritional
supplement comprises two tablets, each of the two tablets having a
volume less than 2 cubic centimeters.
[0024] In one embodiment a daily efficacious amount of the
nutritional supplement comprises four tablets or fewer. Each tablet
having a volume less than 1.5 cubic centimeters.
[0025] In some embodiments the tablets may have an oblong, oval,
modified oval, or capsule shape.
[0026] Alternatively a daily efficacious amount of the nutritional
supplement may comprise one or more capsules, one or more chewable
delivery unit, a powder, or a sachet.
BRIEF DESCRIPTION OF THE FIGURES
[0027] FIG. 1 is an end view of an exemplary embodiment of a tablet
of the composition of the invention.
[0028] FIG. 2 is a top view of an exemplary embodiment of a tablet
of the composition of the invention;
[0029] FIG. 3 is a side view of an exemplary embodiment of a table
of the composition of the invention;
[0030] FIG. 4 is a graph showing tablet disintegration data for
tablets of two exemplary embodiments of the composition of the
invention in water; and
[0031] FIG. 5 is a graph showing tablet disintegration data for
tablets of two exemplary embodiments of the invention in acid.
DETAILED DESCRIPTION OF THE INVENTION
[0032] The invention provides a nutritional supplement which in one
embodiment is a multi-vitamin and mineral nutritional supplement
for administration to humans, having at least one ingredient to
facilitate reduction of cholesterol. The cholesterol reducing
ingredient may include phytosterols and/or stanols, and/or statins,
and/or policosanol. In some embodiments the nutritional supplement
further includes at least one ingredient for reduction of
homocysteine and/or reduction of low-density
lipoprotein-cholesterol (LDL-C). The multi-vitamin and mineral
nutritional supplement may comprise one or more of: vitamin A
and/or vitamin A precursors; vitamin C; vitamin D; vitamin E;
vitamin K; thiamin; vitamin B.sub.2 (riboflavin); niacin; vitamin
B.sub.6; folic acid; vitamin B.sub.12; biotin; pantothenic acid;
iron; iodine; magnesium; zinc; selenium; copper; manganese;
calcium; phosphorus; molybdenum; boron; nickel; silicon; tin;
vanadium; chromium; potassium; chloride; choline; lycopene; and
lutein. When administered to a human on a regular basis (for
example, daily), the composition of the invention facilitates
adequate intake of vitamins and minerals and provision of other
micro-nutrients to promote good health including micro-nutrients
which facilitate the lowering of cholesterol levels, and/or
reduction of homocysteine, and/or decrease of low-density
lipoprotein-cholesterol (LDL-C) oxidation in humans. In other
embodiments, the nutritional supplement may include one or more
vitamins in combination with at least one cholesterol lowering
ingredient, or at least one mineral in combination with at least
one cholesterol-lowering ingredient. The terms "nutritional
supplement" or "supplement" should be taken to refer to any or all
of the embodiments (e.g. a multi-vitamin and mineral supplement
with at least one cholesterol lowering agent, a composition
comprising at least one vitamin and at least one cholesterol
lowering agent, or a composition comprising at least one mineral
and at least one cholesterol lowering agent). The nutritional
supplement may in some embodiments further comprise other actives
such as for example, homocystine lowering actives or one or more
other actives that provide a nutritional and/or health benefit. A
preferred embodiment of the invention is a multi-vitamin and
mineral supplement with at least one cholesterol lowering agent, as
such supplement provides a simple method for addressing nutritional
deficiencies and promotes compliance in usage by an individual in
need of nutritional supplementation.
[0033] The invention further provides a method for preparing solid
dosages forms comprising nutritional supplement components in
efficacious amounts in a unit or units compatible with convenient
human consumption. (For example, in a dosage form in which a daily
efficacious amount of at least one vitamin and/or mineral
supplement and at least one cholesterol reducing ingredient is
contained in 2-4 tablets of a size that an adult human can
practically swallow.) Typically the number and amount of vitamin
and mineral components needed to provide a efficacious daily dosage
to generally supplement nutritional deficiencies constitutes a
substantial tablet volume. Provision of an additional component(s)
in the supplement to facilitate the reduction of cholesterol
further increases the volume of material to be included in a dosage
form.
[0034] Preparing a solid dosage form containing efficacious amounts
of a significant number of vitamins and minerals and phytosterol in
a practical dosage unit, for example, is particularly challenging
in that a minimum of 800 mg of phytosterol per day is needed to
meet the FDA standard for efficacy and phytosterol is a waxy
material with a low bulk density. The inventors have addressed
these problems by developing a preparation method (e.g.
manufacturing process) that employs granulation techniques and/or
the use of diluent and/or the use of absorbent excipients to
prepare a tableted dosage form comprising efficacious daily amounts
of the components of the nutritional supplement in preferably 2-4
tablets of a tablet size suitable to be swallowed by a human.
[0035] As used herein, the phrase "cholesterol lowering agent" or
"cholesterol reducing agent" means any compound, combination of
compounds, including any extract or plant component, naturally
found or processed, or synthetic compound that has the property of
lowering cholesterol levels when administered in an effective
amount.
[0036] All amounts specified herein are based on milligrams unless
otherwise indicated. The term "I.U." represents International
Units. The term "mcg" means micrograms, "mg" means milligrams, and
"g" means grams. Further, it should be understood that the amounts
of components disclosed herein are for a daily dosage and that a
daily dosage may comprise one dosage unit or a plurality of dosage
units.
[0037] "An efficacious dosage" of a nutrient is at least the
minimum amount of the nutrient needed on a daily basis recognized
by the United States Food and Drug Administration (FDA) for
providing a health or nutritional benefit. We further note that in
some guidelines the FDA recommends that daily dosages of
multivitamin and mineral supplements be divided and administered in
two dosage units taken at spaced intervals during the day.
Typically, with meals or food, for example such as twice daily with
meals. Accordingly amounts are given for daily dosages but it
should be understood that the daily dosage may be in multiple
dosage units and consumption of these units may occur at the same
time or different times during the day.
[0038] Typically, sterols and stanols derived from plant sources
are termed phytosterols and phytostanols. Phytosterols and
phytostanols are natural compounds that can be consumed regularly
as a part of a healthy diet. Accordingly, while plant derived
materials are the preferred source of these compounds, equivalent
synthesized stanols and sterols, or stanols and sterols from other
sources, may be used in the practice of the invention. Any
reference to use of phytosterol or phytostanols herein should be
taken to apply to equivalent sterols or stanols from alternative
sources. It should be understood in terms of discussing amounts of
the composition that sterols or phytosterols may be used in like
amounts or vice-versa. It should be understood in terms of
discussing amounts of the composition, that stanols or phytostanols
may be used in like amount or vice-versa.
[0039] There are multiple specific chemical entities classed as
phytosterols, including but not limited to beta-sitosterol,
campesterol, and stigmasterol, for example. For the nutritional
supplements of this invention either a single specific chemical
species of phytosterol or mixtures comprised of a plurality of
specific chemical species of phytosterols may be employed. For
example, a mixture of phytosterols having beta-sitosterol,
campesterol and sigmasterol as principle components is exemplary of
a mixture suitable for use in the practice of the invention.
Commercial preparations of mixed phytosterols are available from
suppliers such as Cargill and ADM (Archer Daniels Midland), for
example. Likewise, the class phytostanols includes multiple
specific chemical species of phytostanols and a single specific
chemical species of phytostanol or a mixture of a plurality of
specific chemical species of phytostanols may be used in the
practice of the invention. Accordingly, reference to phytosterols
or phytostanols in compositions discussed herein should be taken to
include both single specific chemical species forms as well as
mixtures.
[0040] Foods such as fruits, vegetables, breads and other whole
grain products, and most vegetable oils contain at least some
phytosterols. However, it is difficult to consume enough of these
foods on a daily basis to obtain sufficient phytosterol intake to
have a cholesterol-lowering effect. Based on clinical trial data on
the use of phytosterols in the diet, a daily intake of at least 0.8
grams (800 mg) of phytosterols as part of a diet low in saturated
fat and cholesterol is recommended by the FDA to provide
significant cholesterol lowering benefits. Consuming the
nutritional supplements of this invention is one way to ensure that
an effective daily intake is attained.
[0041] It is believed, but the inventors do not wish to be bound to
the theory, that ingested plant sterols and stanols compete with
the cholesterol to decrease cholesterol absorption and reabsorption
in the small intestine because they are structurally similar to
cholesterol. To a point, the more sterol, such as phytosterol, in
free form that is present in the intestine following a meal, the
less cholesterol absorption and reabsorption will occur. Further,
consumed phytosterols, phytostanols, and their equivalents, are not
absorbed to any appreciable extent. Hence, phytosterols are
believed to inhibit the uptake of cholesterol by the body and are
flushed through the system without absorption. One study showed
that the overall effect may be an average decline in blood levels
of "bad" low-density lipoprotein-cholesterol (e.g. the "LDL-C") of
8-15%, with no observed or identified adverse effects. (See "Plant
Sterol-Fortified Orange Juice Effectively Lowers Cholesterol Levels
In Mildly Hypercholesterolemic Healthy Individuals." Arterioscler.
Thromb. Vasc. Biol. 2004 March; 24(3):e25-8. Epub 2004 Feb 05)
Preferably, the multi-vitamin and mineral nutritional supplement
comprises up to about 3 g of the free form or the esterified form
of phytosterols and more preferably at least about 800 mg of
phytosterols. Most preferably, the supplement comprises about 800
mg of phytosterols in the free form. In some embodiments the
phytosterol may be replaced with phytostanols or a combination of
phytosterols and phytostanols may be used.
[0042] Policosanol is the generic term used for a mixture of
long-chain primary aliphatic saturated alcohols that may reduce
total serum cholesterol and low-density lipoprotein-cholesterol
(LDL-C) levels. Policosanol is also known as polycosanol,
policosanal, policosinal, policosinol, polycosanal, polycosinal and
polycosinol. These alcohols are derived from the waxes of such
plants as sugar cane (Saccharum officinarium) and yams (e.g.
Dioscorea opposita). They are also found in beeswax. The main
long-chain alcohol in policosanol is the 28 carbon 1-octanosol, and
next most abundant is the 30 carbon 1-triacontanol. Other
long-chain alcohols present in much lower concentrations comprise:
1-docosanol (C.sub.22), 1-tetracosanol (C.sub.24), 1-hexacosanol
(C.sub.26), 1-heptacosanol (C.sub.27), 1-nonacosanol (C.sub.29),
1-dotriacontanol (C.sub.32) and 1-tetracontanol (C.sub.34). These
long-chain alcohols are solid waxy substances and are insoluble in
water. They are known collectively as aliphatic alcohols.
[0043] The mechanism of action of reported cholesterol-lowering
activity of policosanol is unknown and the inventors do not wish to
be bound to any theory. Several theories regarding the method of
action of policosanol have been suggested in the literature
including the suggestion from some animal studies that policosanol
may inhibit cholesterol synthesis in the liver by indirectly
down-regulating HMG-CoA reductase. (see "Policosanol Safety Down
Regulates HMG-CoA Reductase--Potential As A Component of the
Esselstyn Regimen." Med. Hypotheses. 2002 Sept; 59(3):268-79.)
Others have suggested Policosanol may impair cholesterol synthesis
between the acetate and mevalonate production steps and/or increase
receptor-dependent LDL-C processing. (see "Policosanol: Clinical
Pharmacology and Therapeutic Significance of a New Lipid-Lowering
Agent." Am. Heart J. 2002 February; 143(2): 356-65). Others have
suggested Policosanol also may reduce lipid peroxidation (see
"Effect of Policosanol on In Vitro and In Vivo Rat Liver Microsomal
Lipid Peroxidation." Arch. Med. Res. 1997 Autumn; 28(3): 355-60).
It is believed that the long-chain not have the same activities as
policosanol and that at least in some instances the combination of
all or some of the alcohols in the policosanol may work
synergistically. In one embodiment policosanol is included in the
multivitamin and mineral nutritional supplement. The multi-vitamin
and mineral nutritional supplement embodiment including polycosanol
comprises up to about 200 mg of policosanol and more preferably
about 10 to about 20 mg of policosanol.
[0044] Statins, including atorvastatin, pravastatin, simvastatin,
lovastatin, and fluvastatin, are believed to be competitive
3-hydroxy-3 methyl glutaryl CoA, hereinafter referred to as HMGCoA
reductase inhibitors. Accordingly, they are believed to be
effective in the reduction of cholesterol, and are believed to be
effective in preventing not only recurrent heart attacks, but also
first heart attacks. In some cases statins may also reduce the risk
of strokes. In one embodiment statins may be included in the
multi-vitamin and mineral nutritional supplement. The nutritional
supplement embodiment including statins may comprise up to about 80
mg of a statin or mixture of statins and more preferably it
comprises about 5 to about 80 mg of a statin or mixture of statins.
Provastatin and simvastatin are preferably used in amounts of about
40 mg, and atorvastatin, lovastatin and fluvastatin are preferably
used in amounts of about 80 mg.
[0045] Several vitamins and minerals are known to facilitate
cholesterol reduction, homocysteine reduction, and/or reduction of
low-density lipoprotein-cholesterol. By providing one of these
agents, or a combination thereof, in a multi-vitamin and
nutritional mineral supplement, this invention provides for a
convenient, practical and relatively inexpensive way to facilitate
reducing cholesterol levels, and/or reducing homocysteine levels,
and/or decreasing LDL-C oxidation in humans.
[0046] Vitamin C, also known as ascorbic acid, is believed to be
necessary for the synthesis of collagen and is used as an
antioxidant. It is believed that Vitamin C fights infection,
reduces inflammation, heals wounds, reduces the risk of heart
disease by reduction of LDL-C oxidation, lowers cholesterol,
reduces the risk of lung, stomach and esophageal cancers, reduces
cervical epithelial abnormalities, inhibits N-nitrosamine, and
reduces the severity of colds. The nutritional supplement may
comprise up to about 2000 mg of Vitamin C, more preferably about 45
mg to about 250 mg, and most preferably about 60 mg of Vitamin
C.
[0047] Vitamin E is needed for the maintenance of cell membranes
and for neurological health. Vitamin E relieves hot flashes,
relieves mastodynia, helps in fighting fibrocystic breast disease,
reduces mammary tumors, reduces the risk of lung cancer, and
reduces the risk of heart disease by reduction of LDL-C cholesterol
oxidation. Vitamin E is the generic term for a group of related
substances, which include alpha-tocopherol, beta-tocopherol,
gamma-tocopherol, and delta-tocopherol. In addition, each of these
four compounds has a "d" form, which is the natural form, and a
"dl" form, which is the synthetic form. All forms of all substances
covered by Vitamin E are included herein. The nutritional
supplement may comprise up to about 1500 I.U. of Vitamin E, and
more preferably about 15 I.U. to about 800 I.U. Most preferably,
the multi-vitamin and mineral nutritional supplement may comprise
about 20 I.U. to 200 I.U. of Vitamin E.
[0048] The nutritional supplement may comprise one or more of B
complex vitamins. The B vitamins included in the nutritional
supplement may include thiamin (Vitamin B.sub.1), riboflavin
(Vitamin B.sub.2), niacin (Vitamin B.sub.3) pantothenic acid
(Vitamin B.sub.5), pyridoxine (Vitamin B.sub.6), biotin, folic
acid, and the cobalamins (Vitamin B.sub.12) or a combination
thereof. The B vitamins are water-soluble. Of these vitamins,
B.sub.2, B.sub.6, and Vitamin B.sub.12 (e.g. or the cobalamins),
are known to reduce homocysteine levels. However, because of the
beneficial nature of the B vitamins in general, all of them are
contemplated for use in one embodiment of the invention.
[0049] Vitamin B.sub.1 or thiamin helps keep collagen-rich
connective and mucous membranes healthy, helps to maintain smooth
muscles, helps in the formation of blood cells, and is necessary
for proper nervous system function. The nutritional supplement may
comprise about 0.9 mg to about 100 mg of, more preferably about 1.2
mg to about 4.5 mg and most preferably about 1.5 mg of thiamin.
[0050] Vitamin B.sub.2 or riboflavin is necessary for healthy hair,
nails and mucous membranes and is involved in red blood cell
formation, homocysteine reduction, antibody production and overall
growth. The nutritional supplement of the invention may comprise up
to about 40 mg of riboflavin, more preferably about 0.9 mg to about
5.1 mg and most preferably about 1.3 to 1.7 mg of riboflavin.
[0051] Vitamin B.sub.3 or niacin helps in the production of most of
the sex hormones, dilates blood vessels and helps maintain blood
circulation. Niacin is the generic name for a group of compounds,
which exhibit niacin activity and includes niacinamide and
nicotinic acid. The nutritional supplement may comprise about 5 mg
to about 500 mg of niacin, more preferably about 5 mg to about 40
mg and most preferably about 20 mg of niacin as niacinamide.
[0052] Vitamin B.sub.6 or pyridoxine is involved in the production
of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA),
homocysteine reduction, and many other reactions in the body.
Pyridoxine refers to and includes three different compounds:
pyridoxine, pyridoxamine, and pyridoxal. The nutritional supplement
may comprise about 1 mg to about 10 mg of Vitamin B.sub.6, more
preferably about 1 mg to about 6 mg, and most preferably about 5 mg
of Vitamin B.sub.6.
[0053] Folic acid is used in the production of red blood cells, the
production of hormones, and the synthesis of DNA. The nutritional
supplement may comprise up to about 1000 mcg of folic acid, more
preferably about 0 mcg to about 800 mcg folate (folic acid), and
most preferably, about 800 mcg of folic acid.
[0054] Vitamin B.sub.12 (e.g. the cobalamins) is necessary for
overall metabolism, the function of the nervous system, metabolism
of folic acid, homocysteine reduction, and the production of red
blood cells. There are at least three active forms of cobalamin:
cyanocobalamin, hydroxocobalamin, and nitrocobalamin. The
nutritional supplement may comprise up to about 2000 mcg of Vitamin
B.sub.12, more preferably about 2.4 mcg to about 200 mcg, and most
preferably, about 200 mcg of Vitamin B.sub.12.
[0055] Biotin is necessary for the metabolism of carbohydrates,
proteins, and fats and is needed for healthy skin and hair. The
nutritional supplement may comprise up to about 900 mcg of biotin
and more preferably about 0 mcg to about 300 mcg, and most
preferably, about 30 mcg of biotin.
[0056] Pantothenic acid, also known as Vitamin B.sub.5, is
important for the production of adrenal gland hormones, increases
overall energy, and helps convert food into energy. The nutritional
supplement may comprise up to about 200 mg of pantothenic acid,
more preferably about 0 mg to about 10 mg, and most preferably,
about 10 mg of pantothenic acid.
[0057] Vitamin A is also contemplated for use in the multi-vitamin
and mineral nutritional supplement of the invention. Vitamin A
prevents night blindness and other eye disorders, keeps skin moist
and elastic, maintains healthy hair, skin, and gums, reduces the
risk of breast cancer, helps alleviate mastodynia, reduces the risk
of lung cancer, maintains cell structure and integrity, works as an
antioxidant to prevent cell aging, helps prevent infection, and
negates skin wrinkling and the effects of sun damage. Vitamin A is
a fat-soluble vitamin. The term Vitamin A is used to include
retinol and other chemically similar compounds referred to as
retinoids.
[0058] In the practice of the invention, Vitamin A may be provided
as a form of Vitamin A, as Vitamin A precursor carotenoids, such as
betacarotene, or as a mixture thereof. For example, in a typical
embodiment 29% of Vitamin A may be provided as beta-carotene, with
the remainder supplied as Vitamin A acetate. The nutritional
supplement of the invention may comprise up to about 10,000 I.U. of
Vitamin A including Vitamin A precursors, more preferably about
1300 I.U. to about 5000 I.U. and most preferably, about 3500 I.U.
of Vitamin A in the form of Vitamin A or Vitamin A and the Vitamin
A precursor beta-carotene.
[0059] Beta-carotene and other carotenoids are provitamins, i.e.,
vitamin precursors, and are converted to vitamins or vitamin-like
substances, as the body requires. Although the carotenoids include
lutein, zeaxanthin and lycopene, amounts of these components are
specified specifically herein and any amounts of Vitamin A
precursors recited herein should not be interpreted to include any
appreciable amount of lutein, zeaxanthin or lycopene.
[0060] Vitamin D is also an essential mineral which assists in the
mineralization and calcification of bone, prevents rickets in
children, prevents osteomalacia in adults, preserves bone and tooth
growth, and lowers blood pressure. Vitamin D is fat-soluble and
cholecalciferol or D.sub.3 is the preferred form. Preferably, the
nutritional supplement may comprise up to about 2000 I.U. of
Vitamin D and more preferably about 200 to about 400 I.U. of
Vitamin D.
[0061] Vitamin K is an active blood clotting agent and assists in
bone formation. It also may help in removing calcium from
atherosclerotic plaques. Phylloquinone or K1 and menoquinone, or K2
are the preferred forms. Preferably, the nutritional supplement may
comprise up to about 1 mg of vitamin K, more preferably about 0 mcg
to about 90 mcg of vitamin K and most preferably about 25 mcg
vitamin K.
[0062] Choline is necessary for nervous system function and brain
function. It is also important for gall bladder and liver function.
Choline helps maintain the structural integrity of membranes
surrounding every cell in the body but also can play a role in
nerve signaling, cholesterol transport, and energy metabolism. In
the nutritional supplement, choline may be provided in the form of
a pharmaceutically acceptable choline salt, such as, for example,
bitartarate. The nutritional supplement may optionally comprise of
up to about 3500 mg choline, and more preferably, of about 50 mg to
about 550 mg of choline in the form of choline bitartarate.
[0063] Iron is used in the production of hemoglobin and myoglobin.
In the nutritional supplement, the iron is dosed in the form of a
pharmaceutically acceptable iron compound. As used herein,
"pharmaceutically acceptable" is a component which is suitable for
use in humans without undue side effects, such as irritation,
toxicity, and allergic response. Useful pharmaceutically acceptable
iron compounds include, but are not limited to, ferrous fumarate,
ferrous sulfate, carbonyl iron, ferrous gluconate, ferrous
chloride, ferrous lactate, ferrous tartrate, ferrous succinate,
ferrous glutamate, ferrous citrate, ferrous pyrophosphate, ferrous
cholinisocitrate, ferrous carbonate, iron-sugar-carboxylate
complexes, and combinations thereof. The nutritional supplement may
comprise up to about 18 mg of iron dosed in a pharmaceutically
acceptable iron compound and more preferably, about 5 mg to about
18 mg of iron.
[0064] Iodine helps to metabolize fats, is necessary for proper
thyroid function, and reduces fibrocystic breast conditions. In the
nutritional supplement of the invention, iodine is dosed in the
form of a pharmaceutically acceptable iodine compound. Useful
pharmaceutically acceptable iodine compounds include, but are not
limited to, potassium iodide, sodium iodide and combinations
thereof. The nutritional supplement may comprise up to about 1100
mcg of iodine dosed in the form of a pharmaceutically acceptable
iodine compound, more preferably up to about 150 mcg, and--most
preferably, about 150 mcg of iodine.
[0065] Magnesium is used in bone formation and growth, prevents
bone loss, relaxes coronary arteries, is used in managing
pre-eclampsia, treating cardiac arrhythmias, and managing diabetes.
In the nutritional supplement, magnesium is dosed in the form of a
pharmaceutically acceptable magnesium compound. Useful
pharmaceutically acceptable magnesium compounds include, but are
not limited to, magnesium stearate, magnesium carbonate, magnesium
oxide, magnesium hydroxide, magnesium sulfate, and combinations
thereof. The nutritional supplement may comprise up to about 400 mg
of magnesium dosed in the form of a pharmaceutically acceptable
magnesium compound, more preferably up to about 350 mg, and most
preferably, about 100 mg of magnesium.
[0066] Zinc is required for proper formation of DNA and RNA and is
needed for growth, immunity and sexual development of women. In the
multi-vitamin and mineral nutritional supplement of the invention,
zinc is dosed in the form of a pharmaceutically acceptable zinc
compound. Pharmaceutically acceptable zinc compounds include, but
are not limited to, zinc sulfate, zinc chloride, zinc oxide, and
combinations thereof. The nutritional supplement may comprise about
3 mg to about 40 mg of zinc dosed in the form of a pharmaceutically
acceptable zinc compound, more preferably about 3 mg to about 15 mg
and most preferably, about 15 mg of zinc.
[0067] Selenium reduces the risk of heart attacks and heart
disease, reduces the risk of cancer, protects against metal
poisoning, and is believed to be synergistic with Vitamin E in
reducing LDL cholesterol oxidation. Pharmaceutically acceptable
selenium compounds include but are not limited to sodium selenate,
selenocysteine, selenomethionine or other amino acid chelates, and
combinations thereof. The nutritional supplement may comprise up to
about 400 mcg of selenium more preferably up to about 75 mcg and
most preferably about 15 mcg to about 75 mcg of selenium dosed in a
pharmaceutically acceptable form.
[0068] Copper helps keep blood vessels elastic, is needed for the
formation of elastin and collagen, functions as an iron oxidizer,
and is needed for the proper functioning of Vitamin C. In the
nutritional supplement, copper is dosed in a pharmaceutically
acceptable copper compound. Pharmaceutically acceptable copper
compounds include, but are not limited to, cupric oxide, cupric
citrate, cupric sulfate, cupric carbonate, cupric gluconate, and
combinations thereof. The nutritional supplement may comprise up to
about 10 mg of copper dosed in the form of a pharmaceutically
acceptable copper compound, and more preferably, about 1.0 mg of
copper dosed in the form of cupric gluconate, sulfate or
citrate.
[0069] Calcium is needed by the body to build and maintain strong
bones and teeth, facilitate neural transmission, and regulate
muscle contraction and heartbeat. Calcium is lost through shed
skin, nails, hair sweat, urine and feces. If intake is not
sufficient, the body may remove calcium from bone to obtain the
mineral which may adversely affect the bone density and render
bones more susceptible to injury. Pharmaceutically acceptable
calcium compounds include, but are not limited to, calcium
carbonate, dibasic calcium phosphate, tribasic calcium phosphate,
calcium gluconate, calcium lactate, calcium citrate, and
combinations thereof. The nutritional supplement may comprise up to
about 1500 mg calcium, more preferably up to about 200 mg and most
preferably about 100 mg to about 162 mg of calcium dosed in a
pharmaceutically acceptable form.
[0070] A low level of manganese in the body may be associated with
diabetes. Accordingly manganese appears to have a role in the
control of blood sugar levels. Manganese may also have a role in
the metabolism of amino acids and certain vitamins.
Pharmaceutically acceptable manganese compounds include, but are
not limited to, manganese chloride, manganese sulfate, and
combinations thereof. The nutritional supplement may comprise up to
about 12 mg manganese dosed in a pharmaceutically acceptable form
more preferably the nutritional supplement may comprise about 0 mg
to about 4 mg manganese and most preferably about 1 mg
manganese.
[0071] Silicon is believed to be used for the building of collagen
for bones and connective tissue. Pharmaceutically acceptable
silicone compounds include, but are not limited to, sodium
silicate, sodium silicoaluminate, silicon dioxide, and combinations
thereof. The nutritional supplement may comprise about 0 mg to
about 500 mg silicon dosed in a pharmaceutically acceptable form,
more preferably about 0 mg to about 60 mg silicon, and most
preferably about 2 mg silicon.
[0072] Molybdenum may facilitate proper metabolism of fats,
carbohydrate and iron and may protect against certain cancers.
Pharmaceutically acceptable molybdenum compounds include, but are
not limited to, sodium molybdate, molybdenum amino acid chelates,
and combinations thereof. The nutritional supplement may comprise
up to about 2000 mcg molybdenum dosed in a pharmaceutically
acceptable form. More preferably the nutritional supplement may
comprise about 0 mcg to about 75 mcg, and most preferably the
nutritional supplement comprises about 75 mcg molybdenum.
[0073] Vanadium is believed to have a role in the regulation of
sugar levels in the blood. Pharmaceutically acceptable vanadium
compounds include, but are not limited to, ammonium vanadium
tartrate, sodium metavanadate, vanadyl sulfate, and combinations
thereof. The nutritional supplement may comprise up to about 1.8 mg
vanadium in a pharmaceutically acceptable form, more preferably
about 6 mcg to about 18 mcg vanadium and most preferably about 10
mcg vanadium.
[0074] Boron may have a role in mineral metabolism.
Pharmaceutically acceptable boron compounds include, but are not
limited to, sodium borate, boron citrate, boron amino acid
chelates, and combinations thereof. The nutritional supplement may
comprise up to about 20 mg of boron dosed in a pharmaceutically
acceptable form, more preferably about 0 mcg to about 1.35 mg
boron, and most preferably about 150 mcg to about 350 mcg
boron.
[0075] Nickel may activate or inhibit the action of some enzymes or
hormones. Pharmaceutically acceptable nickel compounds include, but
are not limited to, nickel sulphate. The nutritional supplement may
comprise up to about 1.0 mg nickel dosed in a pharmaceutically
acceptable form, more preferably about 0 mcg to about 100 mcg
nickel and most preferably about 5 mcg nickel.
[0076] Tin is known to be found in the human body. In rats a tin
deficiency may depress growth. Pharmaceutically acceptable tin
compounds include, but are not limited to, stannous chloride. The
nutritional supplement may comprise up to about 200 mcg tin dosed
in a pharmaceutically acceptable form, more preferably about 0 mcg
to about 10 mcg tin and most preferably about 10 mcg tin.
[0077] Phosphorus is needed for bone development and is a
constituent in all major classes of biochemical compounds.
Phosphorous, in the form of phosphate in adenosine triphosphate is
a key energy source required for most metabolic processes.
Pharmaceutically acceptable phosphorus compounds include, but are
not limited to, forms of calcium phosphate, sodium phosphate,
potassium phosphate, ammonium phophate, glycerol phosphate, and
combinations thereof. The nutritional supplement may comprise up to
about 1250 mg of phosphorus, more preferably about 0 mg to 750 mg,
most preferably about 109 mg of phosphorous, dosed in a
pharmaceutically acceptable form.
[0078] Chromium assists in the regulation of glucose metabolism, is
used in the synthesis of fatty acids and cholesterol, assists in
transporting proteins, lowers LDL blood levels, and raises' high
density lipoproteins blood levels. In the nutritional supplement,
chromium is dosed in a pharmaceutically acceptable chromium
compound. Useful pharmaceutically acceptable chromium compounds
include, but are not limited to, chromium chloride, yeast-bound
chromium, picolinate, niacin-hound chromium, and combinations
thereof. The nutritional supplement may comprise up to about 10 mg
of chromium dosed in a pharmaceutically acceptable form, more
preferably about 0 mcg to about 150 mcg chromium, and most
preferably about 120 mcg of chromium.
[0079] Potassium is needed to regulate water balance, levels of
acidity, blood pressure and neuromuscular function. Potassium is
also required for carbohydrate and protein metabolism. In the
nutritional supplement, potassium is dosed in the form of a
pharmaceutically acceptable potassium compound. Useful
pharmaceutically acceptable potassium compounds include, but are
not limited to, potassium chloride, potassium sulfate; potassium
glycerophosphate, potassium citrate, potassium gluconate, potassium
phosphate, and combinations thereof. The nutritional supplement may
comprise up to about 3900 mg of potassium dosed in a
pharmaceutically acceptable form of potassium compound, more
preferably about 0 mg to about 80 mg potassium, and most preferably
about 50 mg to about 80 mg of potassium.
[0080] Lycopene has been found to reduce the risk of cancer and it
has also been found to decrease LDL cholesterol oxidation via its
antioxidant capabilities. Lycopene is found primarily in tomatoes,
red grapefruit, watermelon, and other sources, and is a carotenoid.
The nutritional supplement may comprise up to about 6 g lycopene,
more preferably about 0 mcg to about 3 g lycopene and most
preferably about 300 mcg lycopene.
[0081] Lutein and zeaxanthin are carotenoid antioxidants that help
to maintain healthy eyesight, and have been found to reduce the
risk of cancer and heart disease. Lutein has been found to decrease
the risk and prevent the progression of macular degeneration, the
leading cause of blindness in those over the age of 65. Lutein and
zeaxanthin are primarily found in yellow corn, egg yolk, spinach,
broccoli and other green leafy vegetables. The nutritional
supplement may comprise up to about 6 g lutein in a
pharmaceutically acceptable form, more preferably about 0 mcg to
about 3 g lutein and most preferably about 250 mcg lutein. The
nutritional supplement may comprise up to about 6 g zeaxanthin in a
pharmaceutically acceptable form, more preferably about 0 mcg to
about 3 g zeaxanthin and most preferably about 300 mcg
zeaxanthin.
[0082] Epidemiological and intervention trials have demonstrated a
cardio-vascular benefit from increased levels of Omega-3 fatty
acids. In a recent (2002) meta-analysis Bucher et al. looked at the
beneficial effects of Omega-3 fatty acids in randomized controlled
trials. This analysis included 11 trials with 7951 patients. Bucher
et al. "N-3 Polyunsaturated Fatty Acids in Coronary Heart Disearch:
A meta-Analysis of Randomized Control Trials;" Am. J. Med.; March
2002, 112(4): pp 298-304. The trials included both dietary and
supplement sources of Omega-3 fatty acids. They confirmed a
statistically significant 30% reduction in the rate of sudden
cardiac death in the population with increased Omega-3 fatty acid
intakes from both diet and supplement sources. Preferably the
nutritional supplement comprises up to about 6 g of Omega-3 fatty
acids, more preferably about 0 g to about 3 g and most preferably
about 1 g of Omega-3 fatty acids.
[0083] Chloride is needed to help maintain the ionic and fluid
balance in the body, and is an essential component of gastric and
intestinal secretions. Useful pharmaceutically acceptable chloride
compounds include, but are not limited to, sodium chloride,
chromium chloride, stannous chloride and potassium chloride. The
multi-vitamin and mineral nutritional supplement preferably
comprises up to about 100 mg chloride, more preferably about 0 mg
to about 80 mg and most preferably about 50 mg to about 75 mg
chloride.
[0084] The multi-vitamin and mineral nutritional supplement of the
invention is intended for oral administration and may be provided
in a solid form. In addition to the active material, the
multi-vitamin and mineral nutritional supplement may further
comprise excipients and processing aides such as: absorbents,
diluents, flavorants, colorants, stabilizers, fillers, binders,
disintegrants, lubricants, wetting agents, glidants, antiadherents,
sugar or film coating agents, preservatives, buffer, artificial
sweeteners, natural sweeteners, dispersants, thickeners,
solubilizing agents and the like or some combination thereof.
[0085] The dosage forms of the present invention are typically
considered to be solid. However, they may contain liquid or
semi-solid components. Suitable "solid dosage forms of the present
invention includes, but are not limited to, tablets, caplets,
capsules including soft gel capsules, chewable dosage forms of and
sachets and the like. The daily dosage may be included in a single
delivery unit or may comprise multiple delivery units. Dividing the
daily dosage among multiple delivery units may be desirable if a
tablet is used, for example, to provide a tablet size that is
convenient to swallow. If multiple delivery units are used, they
may be administered at one time or administered at intervals during
the dosage period (e.g. typically a day) if desired. Present FDA
guidelines recommend that the daily dosage be divided and
administered in two dosage units taken at spaced intervals.
However, we note that at least three current clinical studies
indicate that once daily dosing of phytosterols is efficacious.
(See Plat J, et al. Effects On Serum Lipids, Lipoproteins and Fat
Soluble Antioxidant Concentrations of Consumption Frequency of
Margarines and Shortenings Enriched With Plant Sterol Esters. Eur J
Clin Nutr 2000, 54:671-677; Matvienko O A et al. A Single Daily
Dose of Soybean Phytosterols in Ground Beef Decreases Serum Total
Cholesterol and LDL Cholesterol in Young Mildly
Hypercholesterolemeic Men. Am J Clin Nutr 2002, 76:57-64; and
Volpe, R. et al. Effects of Yogurt Enriched With Plant Sterols on
Serum Lipids in Patients With Moderate Hypercholesterolemia.
British Journal of Nutrition. 2001; 86:233-39.)
[0086] Accordingly it should be understood that the amounts of the
vitamins, minerals and cholesterol reducing agents disclosed herein
are for a daily dosage and that dosage may be delivered in a single
delivery unit or multiple delivery units. In some embodiments
packaging design may be used to facilitate identification of the
proper daily dosage to the consumer. For example, a blister pack
with labeling to indicate a daily dosage may be used.
[0087] Tableting compositions containing sterols such as
phytosterol presents challenges. Phytosterol has a waxy nature, is
hydrophobic, typically does not flow well in micronized form and
has a low bulk density. These properties cause problems during the
tablet making (tableting) process, which include, but are not
limited to picking and sticking of materials to tooling, materials
sticking to the press turntable during compression and poor tablet
weight control. Further, phytosterol is difficult to mill because
it tends to clog the mill screen unless cryo-milled. Prior to the
present invention tablets high in phytosterol typically exhibited
poor compressibility and once compressed had slow tablet
disintegration adversely impacting delivery of the phytosterol upon
ingestion. Timely disintegration is believed to be important for
efficacy. As inventors believe, without wishing to be held to any
theory, phytosterol acts in primary particle form in the
gastrointestinal lumen.
[0088] The inventors have surprisingly discovered that use of
certain granulating methods can yield a tablet containing at least
one half the daily efficacious dose of phytosterol and at least one
other vitamin or mineral in a single tablet which is a size that
may be swallowed by a human. Further, the tablet of the invention
disintegrates into primary particles in a time consistent with
gastric emptying time, e.g. the compacted phytosterol containing
tablet of the invention is believed to substantially disintegrate
before reaching the gastrointestinal lumen. In one embodiment at
least one half the daily efficacious dose of phytosterol and at
least one half the daily efficacious dose of a plurality of
vitamins and minerals are tableted in a single tablet that may be
swallowed by a human and which disintegrates in time consistent
with gastric emptying. In an embodiment in which a daily
efficacious dose of the nutritional supplement is contained in two
tablets it is preferable that the volume of each tablet is less
than about 2 cubic centimeters.
[0089] In another embodiment an efficacious daily dose of the
nutritional supplement of the invention is tableted in four tablets
or less each of a size that can be swallowed by a human. Preferably
when a daily efficacious dosage is contained in three or four
tablets each tablet has a volume of about 1.5 cubic centimeters or
less.
[0090] Tablet shape of a nutritional supplement is believed to
contribute to several factors that may improve user compliance. The
inventors believe, without being held to the theory, that oblong,
oval, modified oval, and capsule shaped compacts of about 1.5 cubic
centimeters in volume or less, for example are easier for a
consumer to swallow than, for example, round compacts of about 1.5
cubic centimeters or less, for example. In some instances tablets
that are easier to swallow may improve user compliance with the
dosing regimen. FIGS. 1 to 3 show an exemplary embodiment of a
tablet shape. As one skilled in the art will appreciate this shape
is exemplary and any of many other shapes may be equally suitable
in the practice of the invention.
[0091] In one embodiment, tablets may be prepared using a high
shear wet-granulation method. In an exemplary high shear wet
granulation method phytosterol is granulated with at least one
diluent. The diluent may comprise one or more of the inorganic
mineral nutrients described herein, such as, for example, a
magnesium compound, or calcium compound, other active agents;
inactive diluents such as, for example celluloses, cellulose
derivatives, lactose or other sugars, polyols, starches, starch
derivatives, polymers or mixture thereof. Utilizing one or more of
the inorganic mineral nutrients as the diluent or a portion of the
diluent has the advantage of minimizing added excipients and
facilitates forming a smaller tablet. Dibasic calcium phosphate,
and magnesium oxide are exemplary of specific magnesium and calcium
compounds which both act as a nutrient and are useful as diluents.
These diluents are exemplary and other diluents and granulation
components or mixtures thereof known to those skilled in the art
may be used for the granulation. Other granulation excipients known
to those skilled in the art may be added such as povidone,
disintegrants, co-disintegrants, super-disintegrants, surfactants,
glidants, lubricants and binders. Further, other actives such as
low dose mineral actives may be included in the granulation
mixture. Inclusion of other low dose activities in the granulation
may contribute only modestly to the granulation properties but
addition to the granulation mixture facilitates uniform
distribution of these low dose actives. In one exemplary embodiment
the mixture subjected to granulation comprised the phytosterol,
diluents, the binder polyvinyl pyrrolidone (PVP), the excipient
crosprovidone, and water. The water was added slowly to the
remaining ingredients while they were mixed in a high-shear
granulator.
[0092] Optionally the granulation may be dried. The drying may be
performed in a fluid bed dryer, for example. The granulation is
milled to a suitable particle size. In one exemplarily embodiment a
0.05 screen was used. However, as one skilled in the art will
appreciate this is exemplary and other sizes may be employed. After
milling, the milled granulation is mixed with an absorbent. Silicon
dioxide is exemplary of a suitable absorbent. Other materials known
to these skilled in the art as absorbents may also be used in the
practice of the invention.
[0093] Other vitamins, minerals and cholesterol reducing agent may
be blended into the milled granulation with an absorbent preferably
in an ordered blending after a portion of the absorbent is combined
with the granulation. These additional components may be added as
single ingredients, preformed mixes or a combination thereof. Other
excipients such as flavorants, colorants, stabilizers, fillers,
binders, disintegrants, lubricants, milling agents, glidants,
antiadherents, preservatives, buffers, sweeteners, dispersants,
thickness, solubilizing agent and the like or combination thereof
may optionally be included.
[0094] After blending the composition may be formed into tablets
using compression methods, for example. Optionally the tablets may
be coated using tablet coating materials and methods such as those
known to those skilled in the art. The waxy nature of the phyto
sterols has been discovered to make adherence of a film-coating
material to the tablet core difficult. The inventors have
discovered that satisfactory adherence may be obtained using an
aqueous based film-coating system comprising polyvinyl alcohol.
Further, the inventors believe without wishing to be held to the
theory, that using a film-coating comprising polyvinyl alcohol may
improve patient compliance by yielding a tablet that is easier to
swallow.
[0095] The inventors believe without wishing to be bound to the
theory that their discovery of ordered blending of the phytosterol
granulation with absorbent to coat or partially coat the granules
facilitates disintegration of the tablet. Thus the inventors'
discovery addresses the problem that untreated waxy phytosterols
tend to form compacts with long disintegration times which are
undesirable. The untreated compact compounds likely pass through
the gastrointestinal track with minimum, if any, disintegration to
primary particles which are believed to be necessary for
efficacy.
[0096] The inventors further believe that the physical nature and
size of the absorbent particle may modify the disintegration rate
of the tablet. For example, the inventors have discovered that when
the absorbent silicon dioxide was used at a 1:8 w/w ratio with
phytosterols, slower disintegration was seen with a fumed silicon
dioxide of about 0.2-0.3 micron particle size and about 200 meter
squared per gram surface area than with a precipitated silicon
dioxide of about 7 micron particle size and about 300 meter squared
per gram surface area. The inventors believe that it is preferable
to use precipitated silicon dioxide as described above as the
absorbent for an immediate release phytosterol nutritional
supplement and that a fumed silicon dioxide as described above as
the absorbent may be used to modulate disintegration rate. As the
physical nature and size of the absorbent appear to impact the rate
of disintegration in some embodiments it may be desirable to use a
mixture of absorbent types and/or particle size to facilitate
obtaining the desired disintegration profile. Although silicon
dioxide is referred to as an absorbent herein, the inventors note
that the silicon dioxide may also function as an adsorbent (e.g. it
may be a sorbent). For the purposes of this disclosure the
distinction between absorbent and adsorbent is not critical and
reference to absorbent should be taken to include absorbent,
adsorbent, sorbents or combination thereof.
[0097] FIGS. 4 and 5 show exemplary disintegration date for two
examples of the composition of the invention in water and acid,
respectively. All examples in FIGS. 4 and 5 have disintegration
times compatible with the timely disintegration in the
gastrointestinal track. However, times do vary depending on the
form of silicon dioxide used as FIGS. 4 and 5 show.
[0098] The high shear granulation method described herein is
exemplary of a suitable method for preparing the composition of the
invention. The inventors' also note that the wet granulation method
described herein does not require expensive cryo-milling.
Alternatively, methods such as dry slugging, dry roller compaction
or extrusion could be used to prepare the compositions of the
invention.
[0099] Optionally the nutritional supplement may be provided in a
liquid and/or semisolid preparation. In addition to the active
material such liquid and/or semisolid preparations may include
excipients and processing aides such as: flavorants, colorants,
stabilizers, buffers, artificial sweeteners, natural sweeteners,
sequestering and/or chelating agents, dispersants, thickeners,
solubilizing agents, humectants, antioxidants, emulsifiers, water,
ethanol, glycerin, propylene glycol and the like or same
combination thereof. The quantity of active material in a unit dose
of the multi-vitamin preparation is varied according to the
particular application and potency of the active ingredients.
[0100] Determination of the proper dosage for a particular
situation is within the skill of the art. Optionally, the
multi-vitamin and mineral nutritional supplement may be presented
in a controlled release formulation.
[0101] Although the composition of the invention is preferably
intended for administration to humans it should be understood that
the formulation may also be utilized in veterinary applications for
animals.
Example 1
Multi-Vitamin and Mineral Nutritional Supplement
[0102] The composition of an exemplary embodiment of the invention
is provided in Table 1. This composition is representative and is
one of many compositions that are within the scope of the invention
and is provided for illustrative purposes. The multi-vitamin and
mineral nutritional supplement exemplified in Example 1 is intended
to be a daily dosage and typically would be administered in one or
more dosage units (e.g. one to four tablets). If multiple dosage
units are used they may be taken at one time or spaced intervals
during the day.
TABLE-US-00001 TABLE 1 Ingredient Amount/Day Zinc 7.5 mg Vitamin K
25 mcg Vitamin E 100 IU Vitamin D 400 IU Vitamin C 60 mg Vitamin
B.sub.6 5 mg Vitamin B.sub.2 (riboflavin) 1.7 mg Vitamin B.sub.12
200 mcg Vitamin A (and Vitamin A precursors) 3500 IU Vanadium 10
mcg Tin 10 mcg Thiamin 1.5 mg Silicon 2 mg Selenium 40 mcg
Potassium 80 mg Phytosterols 800 mg Phosphorous 109 mg Pantothenic
Acid 10 mg Nickel 5 mcg Niacin 20 mg Molybdenum 75 mcg Manganese 2
mg Magnesium 100 mg Lycopene 300 mcg Lutein 250 mcg Iron 6 mg
Iodine 150 mcg Folic Acid 800 mcg Copper 0.7 mg Chromium 120 mcg
Chloride 72 mg Calcium 162 mg Boron 150 mcg Biotin 30 mcg
Example 2
Multi-Vitamin and Mineral Nutritional Supplement
[0103] The composition of another exemplary embodiment of the
invention is provided in Table 2. This is another composition
representative of the composition within the scope of the invention
and is provided for illustrative purposes. The multi-vitamin and
mineral nutritional supplement of Example 2 is intended to be a
daily dosage and typically would be administered in one or more
dosage units (e.g. one to four tablets). If multiple dosage units
are used they may be taken at one time or at spaced intervals
during the day.
TABLE-US-00002 TABLE 2 Ingredient Amount/Day Zinc 7.5 mg Zeaxanthin
300 mcg Vitamin K 25 mcg Vitamin E 45 IU Vitamin D 400 IU Vitamin C
90 mg Vitamin B.sub.6 3 mg Vitamin B.sub.2 (riboflavin) 1.7 mg
Vitamin B.sub.12 25 mg Vitamin A (and Vitamin A precursors) 3500 IU
Vanadium 10 mcg Thiamin 1.5 mg Silicon 2 mg Selenium 55 mg
Potassium 80 mcg Phytosterols 800 mg Phosphorous 100 mg Pantothenic
Acid 10 mg Nickel 5 mcg Niacin 16 mg Molybdenum 45 mcg Manganese
2.3 mg Magnesium 100 mg Lycopene 600 mcg Lutein 500 mcg Iodine 150
mcg Folic Acid 600 mcg Copper 0.7 mg Chromium 50 mcg Choline 55 mg
Chloride 72 mg Calcium 200 mg Boron 150 mcg Biotin 30 mcg
Example 3
Multi-vitamin and mineral nutritional supplement
[0104] The composition of another exemplary embodiment of the
invention is provided in Table 3. This is another composition
representative of the composition within the scope of the invention
and is provided for illustrative purposes. The multi-vitamin and
mineral nutritional supplement of Example 3 is intended to be a
daily dosage and typically would be administered in one or more
dosage units (e.g. one to four tablets). If multiple dosage units
are used they may be taken at one time or at spaced intervals
during the day.
TABLE-US-00003 TABLE 3 Ingredient Amount/Day Zinc 7.5 mg Vitamin K
25 mcg Vitamin E 30 IU Vitamin D 400 IU Vitamin C 60 mg Vitamin
B.sub.6 5.0 mg Vitamin B.sub.2 (riboflavin) 1.7 mg Vitamin B.sub.12
20 mcg Vitamin A (and Vitamin A precursors) 3500 IU Vanadium 10 mcg
Thiamin 1.5 mg Silicon 2 mg Selenium 20 mcg Potassium 64 mg
Phytosterols 800 mg Phosphorous 80 mg Pantothenic Acid 10 mg Nickel
5 mcg Niacin 20 mg Molybdenum 75 mcg Manganese 2.0 mg Magnesium 40
mg Lycopene 300 mcg Lutein 250 mcg Iodine 150 mcg Folic Acid 800
mcg Copper 0.7 mg Chromium 120 mcg Chloride 58 mg Calcium 108 mg
Boron 32 mcg Biotin 30 mcg Iron 6 mg Tin 10 mcg
Example 4
Method of Preparing the Nutritional Supplement
[0105] One exemplary multi-vitamin and mineral nutritional
supplement comprising a plurality of vitamin and mineral
nutritional supplement components and phytosterol was prepared
using the following wet granulation method.
[0106] The phytosterol was delumped using a low energy oscillation
system equipped with a screen. The delumped phytosterol was then
transferred to a high shear granulator and combined with MgO, and
dibasic calcium phosphate diluents (which are also actives), ZnO a
low dose mineral active, microcrystalline cellulose, super
disintegrant and polyvinyl pyrrolidine binder were added to the
granulation bowl. Granulation was begun with a low speed blending
and water was added gradually with mixing to form an acceptable
granulation. One skilled in the art is familiar with the appearance
and physical characteristics of an acceptable granulation.
[0107] Once an acceptable granulation was obtained the granulation
was dried in a fluid bed dryer with air at an airflow inlet
temperature of about 90.degree. C. The granulation was dried to a
moisture content of not more than about 1.5% w/w as determined by
an infrared loss on drying balance.
[0108] The dried granulation was cooled and milled at a medium
speed, with knives forward using a 0.050 screen. Approximately half
of the milled granulation was put into a slant cone blender,
followed by #20 mesh screened silicon dioxide. The remainder of the
milled granulation was added and the mixture was blended.
[0109] Additional active ingredients and excipients including
ascorbic acid and vitamin E acetate, dibasic calcium phosphate (a
second portion), chromium chloride, sodium molybdate, stannous
chloride, sodium metavanadate, nickelous sulfate, sodium selenate,
manganese sulfate, Biotin, vitamin K, riboflavin, thiamine
mononitrate, potassium iodide, niacinamide, copper sulfate, calcium
pantothenate, pyridoxine hydrochloride, folic acid, cyanocobalamin,
potassium chloride, ferrous fumarate, vitamin A acetate, beta
carotene, vitamin D.sub.3, lycopene, lutein, croscarmellose sodium,
crospovidone, and microcrystalline cellulose (second portion) were
added and blended for approximately 10 minutes. Magnesium stearate
screened through a #20 mesh screen was added to the composition and
blending continued for approximately 1.5 minutes.
[0110] The granulation thus obtained was compressed into tablets
using tableting techniques known to those skilled in the art using
a tablet tooling with an oval shape. The inventors believe that
oblong, modified oval, and capsule shaped compacts may be easier
for a consumer to swallow than round compacts of similar volume. In
this embodiment a daily efficacious dosage of phytosterol and the
indicated vitamins and minerals was tableted in two tablets each
tablet having a volume of about 1.2 cm.sup.3.
[0111] The tablets were then coated using an aqueous based
film-coating system comprising polyvinyl alcohol.
[0112] Although the foregoing invention has been described in some
detail by way of illustration and examples for purposes of clarity
of understanding it will be obvious that certain changes and
modifications may be practiced within the scope of the appended
claims. Modification of the above-described modes of practicing the
invention that are obvious to persons of skill or the art are
intended to be included within the scope of the following
claims.
* * * * *