Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
WO91/11117 2~ 7 PCT/US91/00719
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TIME RELEASE FORM~LATION OF VITAMINS, MINERALS
AND OTH2R-BENEFICIAL SUPPLEMENTS
Vitamins and minerals may be broadly defined as -
substances that are essential for the maintenance of normal
metabolic function but are not synthesized in the body.
These substances must be furnished from an exogenous
source. A healthy individual ingesting a well-balanced
diet receives adequate amounts of vitamins and minerals ;-
from food. Vitamins obtained in this manner are not
generally regarded as drugs.
However, there are many situations in which the
concentration of one or more vitamins or minerals in the
body tissues may be suboptimal. When such circumstances
arise or can be anticipated, it is the common practice to
administer vitamins or minerals in a chemically pure form.
When employed in this manner, vitamins and minerals may be
regarded as drugs and a knowledge of their pharmacological
properties is desirable. For example, large doses of
various vitamins are frequently employed for the treatment
of disorders that are not etiologically related to vitamin
deficiency. The implication is that such large doses may
exert pharmacodynamic actions that are useful in therapy.
' '' ' .
It should be noted, however, that excessive
administration of certain vitamins, notably vitamin A, can
cause untoward toxic effects.
In today's fast paced society many physicians and
dieticians believe that a daily dietary vitamin and mineral
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WO91/11117 - PCT/US91/00719-
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supplement acts prophylactically to prevent pathologies
associated ~ith vitamin and mineral deficiencies. These
supplements typically include several vitamins and
minerals, and are referred to as multi-vitamin
formulations. Examples of these preparations include One-
A-Day~ and Centrum~ multi-vitamins. Researchers have
suggested that multi-vitamins which include large
quantities of vitamins and minerals are effective both for
prophylactic purposes and for the treatment of an enormous
variety of illnesses. Many millions of individuals living
in the United States regularly ingest multi-vitamin
preparations.
Some of these multi-vitamin preparations contain
amounts of vitamins and minerals that are in excess of the
RDA daily requirements. In the case of the water-soluble
vitamins, there is little harm done to the body because of
the low toxicity of this class of compounds. The low
toxicity of the water-soluble vitamins is attributable to
the fact that excess quantities of these substances are
rapidly excreted in the urine. In the case of the lipid-
soluble vitamins, the compounds accumulate in the body fat
and can cause untoward toxic effects.
It is extremely important to distinguish between
supplemental and therapeutic vitamin preparations. The
latter contains much larger quantities of the individual
vitamins and minerals than do the supplemental
preparations. The present invention is directed to
supplemental preparations.
The use of dietary multi-vitamin supplements should be
considered by the physician in a wide variety of
situations. Such situations may result from (l) inadequate
vitamin intake, (2) mal-absorption syndromes, and (3)
increased tissue requirements.
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Vitamin deficiency due to an inadequate intake arises
in a variety of circumstances. There are still large parts
of the world and even considerable areas in the United
States where, owing to poverty, the population eats a diet
inadequate in terms of vitamin content. Moreover, there
are areas where the prevalence in the diet of one
particular type of food results in a relatively high
incidence of vitamin deficiencies. Eccentric diets
resulting from psychiatric disturbance, individual
idiosyncrasies, religious beliefs, or food fads are other
major causes of vitamin deficiency. A decrease in food
consumption because of excess use of alcoholic beverages,
poor appetite, dieting to combat obesity, or restricted
diets prescribed by physicians for the management of
specific diseases represents a further group of situations
in which vitamin deficiency can arise.
A disturbance in absorption of vitamins is also seen
in a variety of conditions. Examples are diseases of the
liver and biliary tract, prolonged diarrhea from any cause,
hyperthyroidism, pernicious anemia, and a variety of other
disorders of the digestive system. Moreover, since a
substantial proportion of certain vitamins is provided by
the bacteria of the gastrointestinal tract, treatment with
antimicrobials that alter the intestinal bacterial flora
may lead inevitably to a decreased vitamin absorption.
Increased tissue requirements for vitamins also occur
under a variety of conditions so that a nutritional defi-
ciency may develop on a diet that had previously been
adeguate. Such situations can occur in both health and
disease. In healthy individuals, for example, there is a
greater requirement for various nutrients, including vita-
mins, during growth, during periods of hard physical work,
exercise, during pregnancy, lactation, and menstruation.
Diseases associated with an increased metabolism, such as
hyperthyroidism, and conditions accompanied by fever or
..
WO91/11117 PCT/US91/00719
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2~ 7 - 4
tissue wasting also increase the body~s requirements for
vitamins. There is also good evidence that vitamin
requirements increase during stress and after injury.
Multiple-vitamin therapy, using supplemental dietary
multi-vitamins, is desirable in a variety of situations.
Since deficiency of a single vitamin is rarely encountered
clinically, it is customary practice in cases of suspected
vitamin deficiency, as well as in prophylactic treatment,
to recommend that multiple-vitamin therapy be administered.
Typical of the multi-vitamins available are One-A-Day and
Centrum multi-vitamins. (Table 1). Multi-vitamins such as
these provide a great number of the essential vitamins and
minerals needed by healthy individuals. Further, these
preparations include electrolytes, and trace elements.
Recently, it has been determined that antioxidants, and
free radical scavenging agents are protective against the
development of certain cancers. Although, multi-vitamin
preparations currently available include many needed vita-
mins and minerals, they do not include the antioxidants
and/or free radical scavengers which have been shown to
enhance the immune system and to prevent certain cancers,
cardiovascular disorders, inflammatory diseases and to slow
ageing. Further, currently available multi-vitamin
preparations do not include cardio-protective inositol or
Omega-3 fish oils. Still further, several enzymes, amino
acids, and dietary supplements which are known to be neces-
sary and beneficial in supplementing an individual's diet
are not included in presently available multi-vitamins.
Accordingly, a new multi-vitamin dietary supplement is
needed which incorporates many of these beneficial ingredi-
ents into a stable pharmaceutical preparation.
The present invention concerns development of a
multi-vitamin dietary supplement formulation which includes
several dietary supplements which are cardio- and cancer-
protective as well as immunostimulatory. By including
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these cardio- and cancer-protective immunostimulatory
compounds into a multi-vitamin formulation, the present
invention advantageously provides the general population
the benefits of recent scientific research which has
S discovered that several agents are, for example, cardio-
and cancer-protective. Accordingly, it is believed that
the inventive methods and formulations will provide the
general population with an improved multi-vitamin
formulation capable of reducing the incidence of diseases
such as heart disease and cancer while enhancing longevity
and the immune system.
The present invention is directed to a formulation
including vitamins, minerals and other beneficial
supplements. More specifically, the invention is directed
to a formulation and methods of manufacturing an*
administering a formulation containing vitamins and
minerals in association with antioxidants, fish oils, food
concentrate containing naturally occurring anti-oxidizing
enzymes such as catalase and superoxide dismutase, for
example, and amino acids. The formulations of the present
invention exploit synergistic relationships which have not
previously been reported.
One aspect of the present invention is directed to a
multi-vitamin and mineral supplement which includes at
least one antioxidant selected from the group consisting of
BHT, BHA, propyl gallate, and sodium benzoate.
Several of the antioxidants, vitamins and minerals
contained in the formulation have been shown to inhibit the
induction of cancer at several stages in the multistage
process. For example, B-carotene, glutathione, cysteine,
8HA, BHT, Vitamins A, C and E, as well as selenium, inhibit
the tumor initiation, promotion and progression stages of
cancer. The synergistic effects of BHA and Vitamin E, for
example, are related to the observations that BHA inhibits
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W091/11117 PCT/US91tO0719
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tumor promoter-induced polyamine synthesis, and Vitamin E
inhibits promoter-induced hyperplasia, thus leading to a
synergistic effect. Furthermore, Vitamins A, C and E,
selenium, BHA, BHT, and propyl gallate have been shown to
inhibit tumor initiation by counteracting the covalent
binding of carcinogen to DNA and the mutagenic effect of
carcinogens.
A further aspect of the present invention is directed
to a multi-vitamin and mineral supplement including
antioxidants in combination with certain preferred amino
acids selected from the group consisting of glutathione,
cysteine, methionine, glutamine, and taurine. According to
a preferred embodiment, the inventive formulation further
includes at least one of the following beneficial
ingredients: omega-3 fish oil, para-aminobenzoic acid,;
superoxide dismutase, catalase (these two enzymes being
preferably in food concentrates), bioflavonoids, and
inositol.
-
Preferably, the supplement of the present invention
includes (but is not limited to) the following vitamins and
minerals in an amount equal to or greater than the minimum
daily requirement in man: vitamin C, folic acid, vitamin Bl,
vitamin B2, niacinamide, vitamin B6, vitamin Bl2, vitamin D3,
biotin, pantothenic acid, vitamin Kl, calcium, iodine,
potassium, iron, magnesium, copper, zinc, manganese,
chromium, molybdenum, selenium, vanadium, silicon, and
boron.
An important aspect of the present invention is
directed to a method for preventing cancer and
cardiovascular disorders as well as increasing longevity
and augmenting the immune system in a human subject. The
method including the step of administering daily an oral
sustained release tablet including the dietary multi-
.
WO91/11117 2~ ~5~7 PCT/US91/00719
. ~,. ' ' ' ~ --' t
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vitamin and mineral supplement including antioxidants and
other beneficial substances of the present invention.
! ~ '
A still further aspect of the present invention is
directed to the production of a sustained-release tableted
dietary supplement which is intended to be administered one
to three times daily.
FIG. l graphically represents, as a function of %
potassium released versus time, the dissolution of Centrum
tablets in gastric juice. ;
FIG. 2 graphically represents, as a function of %
potassium released versus time, the dissolution of the
sustained release tablets of the present invention in
intestinal juice.
FIG. 3 graphically represents, as a function of %
ascorbic acid released versus time, the dissolution of the
sustained release tablets of the present invention in
intestinal juice.
: .
FIG. 4 graphically represents, as a function of %
niacinamide released versus time, the dissolution of the
sustained release tablets of the present invention in
intestinal juice.
~,
FIG. 5 graphically represents, as a function of
pyridoxine % released versus time, the dissolution of the
sustained release tablets of the present invention in
intestinal juice.
The present invention concerns a formulation of vita-
mins, minerals and other beneficial supplements. It is
believed that the formulations of the present invention
will not only extend longevity but also protect against
certain cancers, immunological disorders and cardiovascular
,
WO91/11117 ~ PCT/US91/00719
2~ 8
disorders in humans. Generally, the invention is directed
to a formulation and methods of manufacturing and
administering a formulation containing vitamins and
minerals in association with antioxidants, fish oils, anti-
oxidizing enzymes preferably contained in food
concentrates, and amino acids. It is believed that the
formulations of the present invention will be beneficial in
treating or preventing several pathologies, including
various vitamin deficiencies, certain cancers,
immunological disorders, and cardiovascular disease.
The formulations of the present invention exploit some
synergistic relationships which have not previously been
reported. The formulations of the present invention are
particularly well adapted as a daily dietary supplement.
The present invention further involves a method for
administering the formulations of the present invention to
a person in need thereof. The preparation of the present
formulations is also a component of the present invention.
Table l shows the anti-cancer effects of various
components of the present formulation, individually and in
synergistic combination.
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WO91/11117 PCT/US91/00719
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Table 1
Effects of antioxidant~ on 8kin Tumor Promotion-
Antioxidant Tumor Response
(mg) (% Inhibition)
Control (DMBA + TPA) o
BHA (0.5) 35
BHT (0.5) 32
Propyl gallate (0.5) 40
Vitamin E (0.1) 25
Vitamin C (0.5) 30
B-carotene (0.5) 20
Selenium (0.004) 23
BHA (0.5) + BHT (0.5) 92
BHA (0.5) + Vit E (0.1) 86
BHA (0.5) + Vit C (0.5) 98
Vit E (0.1) + Selenium (0.004) 94
Vit E (0.1) + B-carotene (0.5) 94
BHA (0.5) + B-carotene (0.5) 87 -
BHA(O.l)+BHT(O.l)+Vit E(O.l)+B-carotene(0.1) 97
^30 female mice (SENCAR) per group were used. The mice were
initiated with 10 nmoles of 7,12-dimethylbenzanthracene and
promoted with 1 ug of TPA 2x/~k. The antioxidants were
applied simultaneously with TPA for the duration of
experiment (30 weeks).
Table 2 illustrates the effects of certain antioxidant
components of the present formulation on all the known
spontaneous tumor formations and longevity in mice.
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WO91/11117 PCT/US91/00719
2~ o -
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Effects of Antioxidants on Aging and
~pontaneou~ Tumor Formation in ~ice- -
Antioxidantsb Spontaneous Tumor Formation Increase in
(% of Control) Lifespan (%~
1 0
Normal Diet lOO
BHA 46 132
BHT 56 124
Propyl gallate 62 127
~100 mice (SENCAR) (50 males and 50 females) were used for
each group. The groups receiving the antioxidants had them
introduced in the normal laboratory chow (Wayne Research
Animal Diet) at 0.5%.
Core ingredients in the most preferred formulation of
the present invention are antioxidants and/or free radical
scavenging agents of different types which protect against
many kinds of free radicals and unstable molecules. In
some cases, they work synergistically with other
antioxidants, vitamins, and minerals. The following are
the Core ingredients:
bioflavonoids
L-glutathione (reduced)
L-Cysteine
Potassium sorbate/sorbic acid
BHA
BHT
Propyl gallate
Sodium benzoate
Taurine
D L-Methionine
L-glutamine
SOD and Catalase
(preferably contained in food
concentrate)
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The significance and content of the Core ingredients may
be described as follows: -
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Bioflavonoids are ~iologically active compounds that
have been shown to act as antioxidants, protecting vitamin
C and other components from oxidation. certain
bioflavonoids have been shown to have a protective effect
against some cancers. The dosage of the bioflavonoid
included is from about 2 to 200 mg, more preferably, from
about 25 to about 150 mg, and most preferably, about 50 mg.
Preferable sources of bioflavonoid include citrus ;
bioflavonoid, vitamin P, vitamin P complex, rutin, orange
peel bioflavonoid, grapefruit peel bioflavonoid, lemon
bioflavonoid, lime bioflavonoid, flavonoids, kaempferol,
narigenin, apigenin, naringin, naringenis, myricetin,
delphinidin, quercetin, phloretin, cyanic, catechin, morin,
phloridzin, phloretin, 3-hydroxyflavones, 3-deoxyflavonols,
isorhamnetin, luteolin, tricin, chrysoeriol, hesperitin,
eriodictyon, techtrochrysin, silybin, taxifolin,
pinocembrim, galangin, robinin, diosmetin, kaempferide,
fisetin, rhamnetin, and 3-0-methyl catechin. The most
preferable source is, however, citrus bioflavonoid.
It is believed that glutathione may protect normal cells
against radiation, free radicals and other toxic materials,
and certain cancers. Functionally, glutathione is the
proton donor used by glutathione peroxidase to remove free -
radicals. Forms of glutathione useful in the practice of
the present invention include: L-glutathione, S-
ethylglutathione, S-butylglutathione, S-decylglutathione,
S-heptylglutathione, S-methylglutathione, S-
propylglutathione, S-pentylglutathione, S-octylglutathione
and S-nonylglutathione. However, most preferably,
glutathione is included in the formulations of the present
invention as reduced L-glutathione. The dosage of
glutathione included to the inventive formulation is
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WO91/11117 PCT/US91/0071~ ~
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preferably from about l to about 29 mg, and most
- preferably, about lO mg.
L~Cysteine is an amino acid which has antioxidant
propertieC and plays an important role in glutathione
peroxidase activity. Cysteine also appears to have certain
anticancer activity. Preferably, cysteine is included in
the present invention as L-cysteine HCl, L-cysteine, L-
acetyl cysteine, L-cysteine ethylester monohydrochloride,
DL-cysteine, DL-cysteine HCl, L-cysteine methylester.
However, it is most preferred, that cysteine is included as
L-cysteine HCl, in a dosage of from about 5 to about lOo
mg, and more preferably, about 50 mg.
::
Potassium sorbate and/or Sorbic acid are useful as a
mold and yeast prohibitor. Sorbic acid has been shown to
increase the effectiveness of antioxidant mixtures by
acting synergistically with them. The sorbic acid dosage
is preferably from about lO to 500 mg as potassium sorbate,
sorbic acid, or sodium sorbate. Most preferably, however,
the dosage of sorbic acid is about 200 mg as potassium
sorbate.
In one important aspect of the present invention, the
formulation includes at least one antioxidant. The
antioxidant is preferably selected from the group
consisting of butylated hydroxyanisole, butylated
hydroxytoluene, propyl gallate, and sodium benzoate. The
inventive formulation may include one, or, more preferably,
several of the preferred antioxidants in combination.
According to one embodiment, the inventive formulation
includes butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), sodium benzoate, and propyl gallate.
Sodium benzoate, BHA, BHT and propyl gallate are all
antioxidants used to -stabili~e cosmeticj pharmaceutical,
and food products. It has been reported that these agents
protect normal cells against radiation, free radicals,
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WO91/11117 ~ PCT/US91/00719
- 13 - ~ .
toxic chemicals and chemical carcinogens. It has also beën
reported that these agents are protective against the
induction of cancer by many cancer-causing agents in almost
every tissue of the body. Further, the preferred
antioxidants of the present invention have been reported to
protect against cardiovascular disorders, enhance immune
function and increase longevity. The preferred
antioxidants of the present invention work synergistically
with several vitamins, minerals, amino acids, enzymes, and
other antioxidants or free radial scavengers included in
the formulation of the present invention as will be
described in detail below.
According to one embodiment, BHA is included in a daily
dietary multi-vitamin and mineral formulation for humans
administered on a 1-3 times daily basis. Preferably, from
about l to amount 300 mg of BHA is included in combination
with a number of vitamins and minerals. More preferably,
however, the formulation includes from about lO to about
150 mq of BHA, and most preferably, about 50 mg of BHA.
BHA may be included in the inventive formulation as
butylated hydroxyanisole, 3-tert-butyl-4-hydroxyanisole, or
2-tert-butyl-4-hydroxyanisole, but most preferably is
butylated hydroxyanisole.
According to another preferred embodiment, BHT is
included in a daily dietary multi-vitamin and mineral
formulation. Preferably, from about l to amount 300 mg of
BHT is included in combination with a number of vitamins
and minerals. More preferably, however, the formulation
includes from about lO to about 150 mg of BHT, and most
preferably, about 50 mg of BHT.
According to further embodiment, propyl gallate is
included in the daily dietary multi-vitamin and mineral
formulation. Preferably, from about l to amount 300 mg of
propyl gallate is included in combination with a number of
WO91/11117 PCT/~S91/~0719
- 14 -
2~7 ~ P~
vitamins and minerals. More preferably, however, the
formulation includes from about lO to about 150 mg of
propyl gallate, and most preferably, about 50 mg of propyl
gallate.
Sodium benzoate, an antioxidant used to stabilize food
and pharmaceutical products, according to another
embodiment, is included in a d~ily dietary multi-vitamin
and mineral formulation. Preferably, from about l to
amount 300 mg of sodium benzoate is included in combination
with a number of vitamins and minerals. More preferably,
however, the formulation includes from about l to about 150
mg of sodium benzoate, and most preferably, about 4 mg of
sodium benzoate. As described above, one embodiment of the
inventive formulation includes sodium benzoate. However,
it has been determined that potassium benzoate, benzoic
acid, calcium benzoate, cuprous benzoate, cupric benzoate,
manganese benzoate, nickel benzoate, magnesium benzoate are
all also useful in the practice of the present invention.
2C Taurine is an amino acid used by the liver for
conjugation with bile acids. It has also been suggested
that taurine strengthens and stabilizes cellular membranes.
High concentrations of taurine are found in the brain.
Taurine, it is believed, acts in concert with the preferred
antioxidants of the present invention to provide increased
protection against cancer and certain cardiovascular
diseases. Preferably, taurine is included in the
formulations of the present invention in a dosage of from
about l to about 20 mg, and most preferably, about lO mg.
Methionine is an essential amino acid which has antioxi-
dant properties. Methionine is the principal source of
methyl groups which are, in turn, transferred to many
diverse acceptors in important physiological reactions,
such as, methyl transferases. Methionine is preferably
include in the formulations of the present invention as DL-
methionine, L-methionine, S-adenosylmethionine, N-acetyl-
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WO91/11117 2f~ 5~ 7 PCT/US91/00719
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- 15 -
methionine, S-methyl-DL-methionine-sulfonium chloride.
However, more preferably, methionine is included as DL-
methionine, in a dosage of from about l to about 20 mg, and
most preferably, about l0 mg.
Glutamine is an amino acid which serves as an amino
donor in many reactions. Glutamine is critical for the de
novo synthesis of purine and pyrimidine nucleotides. These
nucleotides are critical to normal cell function and
replication. Preferably, glutamine is included in the
formulations of the present invention as L-glutamine, DL-
glutamine, or N-acetyl-L-glutamine. However, most
preferably, glutamine is included as L-glutamine, in a
dosage of from about l to about 20 mg, and most preferably,
about l0 mg.
Superoxide dismutase (SOD) stabilizes the formulations
of the present invention and is an antioxidant. SOD
prevents the formation of singles oxygen, hydroxyl radicals
and other reactive oxygen species. It is believed that SOD
can protect against cancer, cardiovascular disorders and
increase longevity. The dosage included of SOD (superoxide
dismutase) is preferably from about 20 to about 500 units,
more preferably, from about l00 to about 300, and most
preferably about 150 units (i.u.) (McCord/Fridovich units).
Preferable sources of SOD for the formulation of the
present invention include purified liver SOD, bovine SOD,
intercellular SOD, bovi~e liver SOD, erthrocytic SOD,
extracellular SOD, vegetable culture SOD, vegetable SOD,
bovine lyophilized liver SOD, fractionated liver SOD,
fractionated erythrocyte SOD, and bacterial SOD. The most
preferable source of SOD is, however, vegetable SOD,
particularly as a food concentrate.
.
Catalase also stabilizes the formulations of the present
invention and compliments SOD. Catalase converts hydrogen
peroxide into water and oxygen. It is believed that
,
WO91/11117 PCT/US91/00719
2~ J7 - l6 -
catalase protects against diseases such as cancer and
cardiovascular disorders as well as increasing longevity.
The dosage of catalase included is from about 5 mg to 500
units, more preferably, from about lOO to about 300 units,
and most preferably, about 150 units (i.u.) (Baker Units).
Preferable sources of catalase include that purified from
bovine liver, fractionated liver, bacteria, Aspergillus
niger, and vegetables. The most preferable source is,
however, vegetables, particularly as a food concentrate.
~ ~:
The core antioxidants can also interact synergistically
with the following components, vitamins and minerals which
are antioxidants additionally included in the preferred
formulation (Core II):
Vitamin A
B-carotene (beta-carotene~
Vitamin E
Ca Ascorbate
Copper
Zinc
Manganese
Selenium
omega-3 fish oil
inositol
PABA
Due to their importance both in the prevention of cancer
and cardiovascular disorders, omega-3 fatty acid, PABA and
inositol are also an important part of the Core II
formulation.
The Core II ingredients may be described as follows:
Vitamin A is a fat soluble vitamin essential in cell
differentiation, vision, immunity, healthy skin, hair, and
mucous membranes. This vitamin is also necessary for
proper reproduction, bone growth and development of teeth.
Deficiencies have been associated with a higher incidence
of certain cancers. Vitamin A appears to work
synergistically with several other vitamins, as well as
minerals and antioxidants, to lower cancer rates and to
WO91/11117 2~ PCTtUSg1/00719
- 17 -
increase longevity. The dose of vitamin A preferably
included is from about 1,000 to 3,000 i.u., and more
preferably, about 2,000 i.u. Preferably, the vitamin A
source included in the formulation is vitamin A acetate,
vitamin A palmitate, retinol, and retinal. The source of
vitamin A may be water soluble, fat soluble, or emulsified.
Most preferably, however, the vitamin A source is
emulsified vitamin A acetate.
Beta carotene or, provitamin A is a precursor to vitamin
A. Beta carotene must be converted by the body into active
retinol-type vitamin A to be utilized. Beta carotene is
also a potent antioxidant and may prevent certain types of
cancer. Beta carotene appears to work synergistically with
several vitamins, minerals and antioxidants to lower cancer
rates and to increase longevity. Although Vitamin A and
other retinoids have been shown to inhibit the induction of
skin cancer in mice, an unexpected result has been the lack
of an inhibitory activity by B-carotene (beta carotene) in
the mouse skin carcinoqenesis system. However, if B-
carotene is given with low doses of vitamin E, BHA or BHT,
it very effectively enhances their activity in a
synergistic manner. The dosage of beta carotene included
is preferably from about 2,500 to 7,500 provitamin A units
as water soluble beta carotene, or emulsified beta
carotene, and most preferably 5,000 provitamin A units as
emulsified beta carotene.
Vitamin E is a fat soluble vitamin which functions as an
antioxidant protecting lipid membranes against oxidation.
Deficiencies in vitamin E can increase the tendency of
blood to clot. Vitamin E appears to work synergistically
with several vitamins, minerals, e.g., selenium, and
antioxidants to lower cancer rates and to increase
longevity. The dosage of vitamin E included is preferably
from about 10 to 100 units as DL-alpha tocopheryl acetate,
DL-alpha tocopheryl succinate, water soluble DL-alpha
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WO91/11117 PCT/US91/00719
2~ 18
tocopheryl acetate or succinate, emulsified DL-alpha
tocopheryl acetate, D-alpha tocopheryl acetate, D-alpha
tocopheryl succinate, mixed tocopherols, emulsified D-alpha
tocopheryl acetate, emulsified mixed D-tocopherols, water
soluble D-alpha tocopheryl acetate, water soluble mixed D-
tocopherols, D-alpha tocopherol, emulsified D-alpha
tocopherol, water soluble D-alpha tocopherol, or alpha
tocopheryl nicotinate. Most preferably, however, the
dosage of vitamin E is about lO0 units as vitamin E, DL-
alpha tocopheryl acetate.
Vitamin C is a water soluble essential vitamin. It is
critical in producing and maintaining collagen, promotes
healing of wounds, aids tooth and bone formation, and is
important in producing hormones that regulate basal
metabolic rate and body temperature. Vitamin C also acts
as an antioxidant and may counteract nitrosamines formed in
the intestinal tract, and, therefore, helps reduce the
rates of certain kinds of cancers. Vitamin C appears to
work synergistically with several other vitamins, as well
as minerals and antioxidants, to lower cancer rates and to
increase longevity. The dosage of vitamin C included is
preferably from about lO to l,000 mg as ascorbic acid, or
salts of ascorbic acid including calcium ascorbate,
magnesium ascorbate, sodium ascorbate, potassium ascorbate,
esterified ascorbic acid, ascorbyl palmitate. Most
preferably, however, the dosage of vitamin C is about 250
mg as calcium ascorbate. -~
Copper is a trace mineral essential for the formation of
red blood cells and the utilization of iron. It also
functions in electron transport, connective tissue
metabolism and the development of the nervous system. ~ ;~
Deficiencies have been linked to nervous system disorders,
bone disorders (spontaneous fractures) and anemia. Copper
may protect against certain types of cancers. Copper
dosage is 0.2 to 20 mg as copper oxide, cupric acetate,
WO91/11117 PCT/US91/00719
- "
-- 1 9 -- ~ ~ ~
cupric butyrate, cupric subcarbonate, cupric chloride,
cupric citrate, cupric formate, cupric gluconate, cupric
glycinate, cupric hydroxide, cupric oxide, cupric stearate,
cupric sulfate, cupric subsulfate, copper gluconate, copper
amino acid chelate, copper salicylate, copper proteinate,
cupric tyrosinate, copper glycerophosphate, and copper
picolinate.
zinc is a trace mineral essential to cell
multiplication, tissue regeneration and wound healing,
sexual maturity, and proper growth. zinc is required for
many enzymatic functions throughout the body, and also
helps regulate the immune system and insulin metabolism.
Preferably, the dosage of zinc included is from about
dosage 2 to about 30 mg as zinc oxide, zinc acetate, zinc
benzoate, zinc caprylate, zinc carbonate, zinc chloride,
zinc citrate, zinc formate, zinc lactate, zinc selenate,
zinc stearate, zinc sulfate, zinc picolinate, zinc
gluconate, zinc sulfate heptahydrate, zinc sulfate
monohydrate, zinc succinate, æinc amino acid chelate, zinc
proteinate, zinc fumarate, zinc aspartate, zinc ascorbate,
and zinc glycerophosphate. Most preferably, however, the
dosage of zinc is about 15 mg as zinc oxide.
Manganese is a trace mineral essential to enzyme systems
involved in bone development, insulin production as well as
other enzyme systems. It is also required for the
synthesis of cartilage mucopolysaccharides. Preferably,
the manganese dosage is from about 0.5 to about 5 mg as
manganese gluconate, manganese acetate, manganese
carbonate, manganese chloride, manganese dioxide, manganese
hypophosphite, manganese iodide, manganese silicate,
manganese sulfate, manganese picolinate, manganese
glycerophosphate, manganese lactate, manganese amino acid
chelate, manganese proteinate, manganese ascorbate,
manganese aspartate, manganese citrate, manganese fumarate,
. . : ~ . - .
.. . . .- - . ....................... . - .
. - , , . . , . - , .
-. - . . ~. - -
WO91/11117 PCT/US91/00719
Z~ 7 - 20 -
and manganese glycinate. More preferably, the manganese
dosage i~ about 2.5 mg as manganese gluconate.
Selenium helps maintain proper immune system function.
It is an essential component of glutathione peroxidase, and
as an antioxidant helps protect cells from free radical
damage and toxic effects of certain chemicals.
Deficiencies are linked with increased risk of various
cancers, along with increased risk of stroke, angina and
heart attack. Selenium appears to work synergistically
with several vitamins, minerals and antioxidants to lower
cancer rates and to increase longevity. Preferably, the
dosage of selenium included is from about 2 mcg to about
l00 mcg as sodium selenate, selenous acid, potassium
selenate, selenium oxide, selenomethionine, selenium yeast,
selenium vegetable culture, selenium amino acid chelate,
selenium proteinate, selenium ascorbate, selenium
aspartate, sodium selenite, sodium selenate, potassium
selenite, selenocystine, magnesium potassium selenate,
magnesium selenate, cupric selenate, cupric selenite, zinc
selenate, zinc selenite, calcium selenate, calcium
selenite, selenium picoli~ate, selenium glycinate, and
selenium glycerophosphate. Nost preferably, however, the
dosage of selenium is about 25 mcg as sodium selenate.
Omega-3 (EPA/DHA) are polyunsaturated fatty acids.
Increased dietary levels of polyunsaturated fatty acids
reduces platelet aggregation and has been linked to a lower
incidence of heart disease and cancer. Omega 3 fish oils,
preferably having an EPA:DHA ratio of about 18:12, are
included in the supplement of the present invention in a
dosage of from about l0 to about l,000 mg, more preferably,
however, the dosage is from about 50 to about 800 mg, and
most preferably about 200 mg. The omega-3 fish oil is
preferably included as microencapsulated omega-3 fish oils,
Omega 3 fish oils, cod liver oil, salmon oil,
microencapsulated salmon oil, emulsified cod liver oil,
WO91/11117 PCT/US91/00719
k 5 , ~7 ", ""~
-- 2
emulsified salmon oil, eicosapentaenoic acid,
docosahexenoic acid, emulsified eicosapentaenopic acid,
emulsified docosahexaenoic acid, fish oil, EPA, max EPA
sardine oil, microencapsulated sardine oil, halibut oil, or
microencapsulated halibut oil. Most preferably, however,
the omega-3 fish oil is microencapsulated omega-3 fish oil.
Inositol plays a vital metabolic role at the cellular
level. Inositol is a bipotropic agent and plays a role in
membrane and lipoprotein function. Inositol is preferably
included in a dosage of from 5 to about lOOmg, and most
preferably, about 50 mg.
According to one embodiment, the daily dietary multi-
vitamin and mineral supplement of the present invention
further includes para-aminobenzoic acid (PABA) in
combination with the preferred amino acids and antioxidants
of the present invention. PABA is an essential coenzyme in
the metabolism of proteins and in the formation of red
blood cells. PABA works synergistically with pantothenic
acid. It has been reported that PABA may provide some pro-
tection against hypertension and certain cancers. PABA is
preferably included in the formulations of the present
invention as para-aminobenzoic acid, potassium para-
aminobenzoate, sodium para-aminobenzoate, magnesium para-
aminobenzoate, calcium para-aminobenzoate. Most
preferably, however, PABA is included as the acid in a
dosage of from about lO to about lOO mg, and most
preferably, about 40 mg.
Also, the following vitamins and minerals (Core IIIj,
although not unique, are necessary and important in this
f~ormulation because of their role in normal growth and
general bodily needs. Once vitamins have crossed the
intestinal walls, many function as co-enzymes essential to
all cells. Because they work synergistically, or as a
team, it is better to administer them together. A similar
: . . . .
.
WO91/11117 PCT/US91/00719
~ ,.
- 22 -
synergism is known for many of the minerals. They are as
follows:
Folic Acid
Vitamin B1 l
vitamin B2
Niacinamide
.vitamin B6
Vitamin B12
Vitamin D3
Biotin
Ca Pantothenate
Vitamin K~
Calcium
Iodine
Potassium
Iron
Magnesium
Chromium
Molybdenum
Vanadium
Silicon
Boron ~-;
Compositions of the Core III formulations may be
described as follows.
Folic Acid is an essential water-soluble vitamin. It
is necessary for the synthesis of RNA and DNA, and
therefore, vital in cell growth and division. Folic acid
is important in red blood cell maturation and in other
metabolic processes. The dose of folic acid included is
from about 40 to about l,2000 mcg as folic acid, and most
preferably, about 400 mcg. ;-
Vitamin B1 (thiamine) is an essential water-soluble vita-
min. It is important in the metabolism of carbohydrates
and critical for the transmission of high-frequency
impulses in the central nervous system as well as
maintaining the integrity of the central nervous system.
Preferably, the dosage of vitamin B1 included is from about
l to about 2 mg as thiamine hydrochloride, thiamine ~-
mononitrate, thiamine chloride naphthalene-l, 5-disulfonic
acid salt, thiamine triphosphoriate salt, thiamine
: . : . .; , . . : , ~ .
WO91/11117 PCT/US91/00719
% ~ ~ ~r~ ~
- 23 -
triphosphate ester, thiamine phosphoric acid ester
phosphate salt, thiamine phosphoric acid ester chloride,
and thiamine disulfide. Mos preferably, however, the
dosage of vitamin B~ is about l.50 mg as thiamine
hydrochloride.
Vitamin B2 (riboflavin) is an essential water-soluble
vitamin which is required for the repair and growth of
tissues as well as DNA synthesis. Vitamin B2 assists in
metabolizing nutrients, e.g., proteins, fats and
carbohydrates, and therefore, is critical in the release of
energy. Preferably, the dosage of vitamin B2 is from about
from 170 mcg to about 2 mg as riboflavin, riboflavin
tetrabutyrate, riboflavin 5' phosphate sodium, and
riboflavin monodiethanolamine salt dihydrate. Most
preferably, however, the dosage of vitamin B2 is about l.75
mg as riboflavin.
Niacinamide is critical in the production of energy.
Niacinamide is water-soluble, and is an essential
constituent of coenzymes I and II that occur in a wide
variety of enzyme systems involved in the anaerobic
oxidation of carbohydrates. Niacinamide is necessary for
DNA formation, and important for the integrity of the
central nervous system. Preferably, the dosage of
niacinamide included is from about lO to about 30 mg as
niacinamide, and most preferably, about 20 mg.
Vitamin B6 is a term commonly used for a group of three
vitamins: pyridoxine, pyridoxal and pyridoxamine. They
are important in protein and amino acid metabolism and help
to regulate blood glucose levels. These vitamins are
needed to synthesize hemoglobin and are important in the
proper function of the central nervous system. The dosage
of vitamin 88 is preferably from about 200 mcg to about 3 mg
as pyridoxine hydrochloride, pyridoxal 5-phosphate, calcium
.. . ' ~ : .-, .' , : , .
~ :: -
WO91/11117 PCT/US91/00719
~, .
2~ 24 -
pyridoxine 5-phosphate, pyridoxal. Most preferably,
however, the dosage of vitamin B6 is about 2 mg.
Vitamin B12 is an essential water soluble vitamin. It is
critical for- bone growth, the integrity of the central
nerve tissue, normal blood formation, and cell replication
and DNA synthesis. Vitamin B1z deficiencies are related to
certain anemias. Vitamin B12 is useful especially in the
prevention of pernicious anemia. Preferably the dosage of
Vitamin B12 included is from about 2 to about lO00 mcg as
cyanocobalamin, cobalamin, Co-methylcyanocobalamin, zinc-
vitamin B~2 - tannate, resin bound vitamin B12, and coenzyme
B12-
Vitamin D3 is an oil-soluble vitamin. Vitamin D3 aids
both the absorption of calcium and phosphorus. The primary
role of vitamin D3 is the mineralization of bones and teeth
and the regulation of blood calcium levels. Vitamin D3 is
critical for the growth and differentiation of several
tissues, and, it is believed, reduces the rate of certain
cancers. The dosage of vitamin D3 included is preferably
from about 40 to about 4,000 units as vitamin D3, water
dispersable vitamin D3, water-soluble vitamin D3, and
emulsified vitamin D3. Most preferably, however, the dose
of vitamin D3 is about 600 units. ~
Biotin is a water-soluble vitamin essential in metabol- -
ism. It is a coenzyme in the synthesis of fatty acids and
amino acids. The dosage of biotin is preferably from lO to
lO0 mcg as biotin, and most preferably, about 30 mcg. -
Calcium pantothenate is a source of pantothenic acid, a
water-soluble vitamin. Pantothenic acid is involved with
the metabolism of proteins, fats and carbohydrates in the
form of exoenzyme A, and is involved in the synthesis of
sterols, hormones, porphyrins and acetylcholine. The
... . . . . . .
:, ., : -, . . : .
::.. .. - . : . : : - . . , : , . : : .
WO91tlll17 PCT/US91/00719
2 ~
- 25 - ; -
dosage of calcium pantothenate is preferably from about 1
to about 50mg, and most preferably, about lOmg.
Vitamin K1 is an oil soluble vitamin which is necessary
for the formation of prothrombinogen and other blood
clotting factors. However, vitamin K-dependent protein in
bone suggests a more complex role. Preferably, the dosage
of Vitamin Kl is from about 3 to lOO mcg as trans isomer of
vitamin K1, cis-trans isomers of vitamin Kl, emulsified
trans isomer of vitamin K1, emulsified cis-trans isomers of
vitamin K1, water soluble trans vitamin K1, water soluble
cis-trans isomer of vitamin K1, vitamin K1 oxide, trans
vitamin K1 oxide, emulsified cis-trans vitamin Kl oxide,
water soluble trans vitamin Kl, water soluble cis-trans
vitamin K1 oxide, vitamin K2 (2-methyl -3- all trans-
polyprenyl-1, 4 napthoquinone) and those compounds of
vitamin K2 which may possess side chains varying in length
from C5 (n=1) to C6s (n=13), water soluble vitamin K2 and
water soluble compounds of compounds of K2 which may possess
side chains varying in length from C5 (n=1) to C65 (n=13),
vitamin K5, dihydrovitamin K1, diphosphate ( ol, o4
diphosphoric acid) disodium salt of dihydrovitamin K1,
tetrasodium salt of dihydrovitamin K1, tetrapotassium salt
of dihydrovitamin K1, diphosphate ( ol, o4 - diphosphoric
acid) dipotassium salt of dihydrovitamin K1, vitamin K6,
vitamin K~, vitamin K~ hydrochloride, vitamin K5 (II),
emulsified vitamin K5 (II), water soluble vitamin K5 (II).
Most preferably, however, the dose of vitamin K1 is about 25
mcg.
Calcium is involved with the transmission of nerve
impulses, muscle contraction and relaxation, blood
clotting, structure and function of cell membranes and B12
absorption. Dietary deficiencies are common and have been
~5 associated with accelerated bone loss resulting in alveolar
bone loss and accompanying oral health problems,
",,~..... . - - - , , - . , .............. , , , , . , - . . . .
. : : .. ` . : : : - : -
WO91/11117 PCT/US91/00719
, ~:
. 2~ 26 -
osteoporosis and hypertension. Calcium may also protect
against certain type of cancer such as colon cancer
Preferably, the calcium dosage included is from about 40 to
about l,O00 mg as dicalcium phosphate dihydrate, dicalcium
phosphate, monobasic calcium phosphate, tricalcium
phosphate, calcium carbonate, calcium chloride, calcium
citrate, calcium fluoride, calcium gluconate, calcium
glycerophosphate, calcium hydroxide, calcium lactate,
calcium levulinate, calcium sulfate, calcium succinate,
calcium ascorbate, calcium fumarate, calcium lysinate,
calcium malate, calcium aspartate, calcium amino acid
chelate, calcium caseinate, calcium proteinate, calcium
picolinate, calcium aspartate, calcium alpha ketoglutarate,
calcium caseinate, calcium hydroxide, bone meal, oyster
shell, calcium glycerophosphate, calcium hypophosphite,
calcium ferrous citrate, calcium formate, calcium
hypochlorite, calcium methionate, calcium biphosphate,
calcium stearate, calcium tartrate, hydroxyapatite,
dolomite, calcium sulfate dihydrate, calcium sulfate
hemihydrate, dicalcium phosphate dihydrate, calcium
acetate, calcium pyrophosphate, calcium gycinate. More
preferable sources of calcium include calcium citrate,
calcium carbonate, which act as free radical scavengers,
calcium pantothenate, and dicalcium phosphate dihydrate.
Dicalcium phosphate dihydrate is source of calcium and
phosphorus which functions in almost all aspects of
metabolism, and also aids in the manufacturing (tableting)
process.
Iodine is essential for proper thyroid functioning, and
therefore, the regulation of the basal metabolic rate. The
dosage of iodine included is from about 5 to 500 mcg as
potassium iodide, sodium iodide, iodinated glycerol, kelp,
Atlantic kelp, Pacific kelp, iodine-resublimed, potassium
iodate, ferrous iodide, magnesium iodide, manganese iodide,
iodine picolinate, iodine aspartate, iodine
,.. ,.. ~.. ,, ,., .. , , ~ - ................. , , ~ ,. . . .
.. . . . .. .
WO 9 1 /1 1 1 17 2~ - h5~ PCT/US9l/00719
2 7 ; . ` L . ' '
glycerophosphate. Most preferably, however, the dosage is
about 150 mcg as potassium iodide.
Potassium is a major intracellular electrolyte.
Potassium aids in the transmission of nerve impulses, the
release of insulin, and the proper functioning of digestive
enzymes. Potassium works with sodium to maintain the
balance of body fluids. Preferably, the dosage of 10 to
about 1000 mg potassium is from about as potassium
chloride, potassium acetate, potassium bicarbonate,
potassium carbonate, potassium citrate, potassium
gluconate, potassium glycerophosphate, potassium hydroxide,
potassium nitrate, dipotassium phosphate, potassium
dihydrogen phosphate, tripotassium phosphate, potassium
sorbate, potassium sulfate, potassium proteinate, potassium
amino acid chelate, potassium fumarate, potassium alpha
ketoglutarate, potassium malate, potassium ascorbate,
potassium succinate, potassium aspartate,
potassium/magnesium aspartate, or potassium picolinate.
- Iron is an essential mineral and is needed to transport
oxygen to the tissues throughout the body via hemoglobin
and myoglobin. Iron is involved in the catalysis of many
oxidative reactions within cells and is necessary for the
proper functioning of many biochemical reactions. Iron
plays a role in final steps of energy metabolism. Iron
deficiencies are widespread, especially among women and
children. Preferably, the dosage of iron included is from
about 2 to about 50 mg as ferrous fumarate, ferrous
carbonate mass, ferrous carbonate saccharated, ferrous
chloride, ferrous citrate, ferrous gluconate, ferrous
iodide, ferrous lactate, ferrous oxide, ferrous succinate,
ferrous sulfate,- ferrous ascorbate, iron amino acid
chelate, ferrous aspartate, ferrous peptonate, iron
3S proteinate, iron chloride, iron reduced, iron oxide
saccharated, ferric glycerophosphate, and iron picolinate.
.. .
:.. ::: :
WO91/11117 PCT/US91/00719
2~ ~,~7 - 28 -
Most preferred, however, the dosage of iron is about 18 mg
as iron gluconate.
Magnesium is a mineral essential for every biological
S process including glucose metabolism, protein and nucleic
acid synthesis, electrical balance of cells, and the trans-
mission of nerve impulses. Magnesium effects the function
and structure integrity and contractions of the heart and
all other muscles. Dietary deficiencies are widespread.
Deficiencies have been linked to cardiovascular diseases.
Preferably, the dosage of magnesium included is from about
10 to about 500 mg as magnesium oxide, magnesium benzoate,
magnesium carbonate hydroxide, magnesium chloride magnesium
citrate, di-basic magnesium citrate, magnesium formate,
magnesium hydroxide, magnesium iodide, magnesium lactate,
magnesium peroxide, magnesium hydrogenphosphate,
trimagnesium phosphate, magnesium silicate, magnesium
stearate, magnesium sulfate, magnesium carbonate, magnesium
gluconate, magnesium glycerophosphate, magnesium
trisilicate, magnesium nicotinate, magnesium malate,
magnesium amino acid chelate, magnesium picolinate,
magnesium proteinate, magnesium lysinate, magnesium alpha
ketoglutarate, and magnesium phosphinate hexahydrate. Most
preferably, however, the dosage of magnesium is about 100
mg as magnesium oxide.
Chromium is a cofactor for insulin. Chromium is in-
volved in carbohydrate metabolism, especially the utiliza-
tion of glucose. Low chromium has been linked to diabetes
and hypoglycemia. Low chromium has also been associated
with heart disease. Chromium deficiencies are widespread.
Preferably, the dosage of chromium included is from about
2 to about 50 mcg as chromium ~+3) chloride, chromic
acetate, chromic carbonate, chromic formate, chromic
hydroxide, chromic nitrate, chromic oxide, chromic
phosphate, chromic potassium sulfate, chromic sulfate,
chromic picolinate, chromium polynicotinate, chromium
' ', ' . '
'`. . , ,, ' '
WO 91/11117 2~ PCT/US91/00719
~ . r
2 9 ~ ~. . J.~
soured yeast, chromium vegetable culture, chromium amino
- acid cheIated, chromium proteinate, chromium aspartate,
chromium ascorbate, chromium GTF yeast, chromium glycinate,
and chromium glycerophosphate. Most preferably, the dosage
of chromium is about 25 mcg as chromium (+3) chloride.
Molybdenum is considered to be an essential trace
mineral. Molybdenum plays a role in iron metabolism.
Preferably, the dosage of molybdenum included is from about
2 mcg to lO0 mcg as sodium molybdate, molybdenum amino acid
chelate, molybdenum ascorbate, molybdenum yeast, molybdenum
vegetable culture, molybdenum disulfide, molybdenum
sesquioxide, molybdenum trioxide, sodium phosphomolybdate,
molybdenum picolinate, molybdenum glycinate, and molybdenum
glycerophosphate. Most preferably, however, the dosage of
molybdenum is about 25 mcg as sodium molybdate.
Vanadium is a trace mineral found in the diet. Possible
biochemical and physiological functions for vanadium have
been suggested as including lipid metabolism, glucose
metabolism, bone, and tooth metabolism. Vanadium may serve
a catalytic function or may be an enzyme cofactor.
Preferably, the dosage of vanadium included is from about
2 mcg to about 100 mcg as sodium metavanadate, vanadium
aspartate, vanadium amino acid chelate, vanadium
proteinate, vanadium yeast, vanadium vegetable culture,
potassium metavanadate, calcium vanadate, magnesium
vanadate, ammonium metavanadate, vanadyl sulfate,
oxytartarovanadate, vanadium picolinate, vanadium
glycinate, and vanadium glycerophosphate.
.
Silicon functions as a biologic cross-linking agent that
contributes to the structure and resilience of connective
tissues, collagen, elastin and mucopolysaccharide. Silicon
may be required for bone and cartilage collagen
biosynthesis and is apparently involved in bone
calcification. Preferably, the dosage of silicon included
.,u.~...... , , , , ,, , ~ , ,
- , ~ , , ' -.. :
WO91/11117 PCT/US91/00719
2~ ;.,7
- 30 -
is from about 2 mcg to about 50 mcg as sodium metasilicate,
silica amino acid chelate, silicon proteinate, silicon
plant source, silicon vegetable culture, silicon source
trachea, silicon source tendon, silicon source aorta,
silicon source mucopolysaccharide, silicon source pectin,
silicon source alginic acid, silicic acid, silanolate,
silicon dioxide, and silica. More preferably, the dosage
of silicon is about 10 mcg as sodium metasilicate.
Findings suggest that boron influences the metabolism of
calcium, phosphorus, magnesium and cholecalciferol. Boron
may also be involved in the functional efficiency of
membranes. Preferably, the dosage of boron included is
from about dosage 500 mcg to about 2000 mcg as calcium
borogluconate, magnesium borogluconate, sodium borate,
boric acid, potassium borate, sodium metaborage, boron
proteinate, boron amino acid chelate, glyceroborate,
magnesium perborate, sodium perborate, calcium perborate,
and potassium perborate. Most preferably, however, the
dosage of boron is about 1 mg as calcium borogluconate.
With regard to the vitamins and minerals included in the
inventive formulation, each (with the possible exception of
vitamin A, calcium, magnesium and biotin) is included in an
amount equal to or greater than the minimum daily
requirement in man. Further, it is preferred that the
vitamins and minerals included in the inventive formulation
are similar to those included in the multi-vitamin and
mineral preparations Centrum0 or One-A-Day0 (as shown in
Table 3).
WO 91/11117 2~ 7 PCI`/US91/00719
. .
,, , . ., !. ~,
- 31 -
TABLE 3
. CENTRUM~ ONE-A-DAY
Vitamin Amount %USRDA Vitamin Amount ~USRDA
Vitamin A 5000 I.U. 100% Vitamin A 5000 I.U. 100%
(as Acetate . ~a~ Beta
& Beta Carotene) carotens)
Vitamin A 1500 I.U. 3C%
(a~ Acetate)
Vitamin E 30 I.U. 100% Vltamin E 30 I.U. 10
(a~ DL-Alpha
Tocopheryl Acetate)
Vitamin C 60mg 100% Vitamin C 60mg 10~
(a~ Ascorbic Acid) ~:
Folic Acid 400 mcg 100~ Thiamine(Bl) 1.5mg 10~
Vitamin 81 1.5mg100% Riboflavin(B2) L~g
100%
(as Thiamine
Mononitrate) -
Vitamin B2 1.7mg100% Niacin 20mg 100%
(as Riboflavin)
Niacinamide 20mg looe Vitamin D 400 I.U. 100% :.:
vitamin B6 2mg 100% Vitamin B6 2mg 100%
(ac Pyridoxine
Hydrochloride)
Vitamin B12 6mcg 100% Folic Acid 0.4mg 10
~as Cyanocobalamin)
Vitamin D 400 I.~. 100% vitamin Bl2 6mcg 10
Biotin 30mcg100% Biotin 30mcg 10%
Pantothenic Acid 10mg 100% Pantothenic 10mg 100%
Acid
Calcium 162mg 16% Iron 18mg 10D%
(a~ Dibasic
(elemental)
Calcium Phosphate)
Mineral Amount%USRDA Mineral Amount %USRDA
Pho~phorus 125mg 13% Calcium 130mg 13%
(as Dibasic
Calcium Pho~phate)
Iodine 150mcg100% Phocphorun 100mg 10%
~an Potacsium
Iodine)
Iron 18mg 100% Iodine 150mcg 10
(a~ Ferrou~ Fumarate)
W091/11117 PCI`/US91/W7~
2~ ,7
- 32 -
Magne~ium lOOmg 25% Magneuium lOOmg 25%
(a~ Magne~ium
Oxide) . .
Copper 2mg 100% Copper 2mg 10(as Cupric Oxide)
Zinc 15mg 100% Zinc 15mg 10~ ,
(a~ Zinc OxLde)
Mangane~e 2.5mg * Chromium lOmcg
Pota~ium 40mg ~ Selenium lOmcg * `~
(as Potas~ium
Chloride)
Chloride 36.3mg * Molybdenum. lOmcg *
(as Potas~ium
Chloride)
Chromium 25mcg ~ Mangane~e 2.5mg *
(as Chromium
Chloride)
Molybdenum 25mcg ~ Pota~sium 37.5mg *
(a~ Sodium
Molybdate)
Selenium 25mcg ~ Chloride 34mg *
(a~ Sodium
Selenate)
Vitamin ~1 25mcg *
(a~ Phytonadione)
Nickel Smcg *
(a~ Nic~el
Sulfate)
wo 91/11117 2~ PCT/US91/00719
f-
33 ~ i. D ~ '
Mineral Amount ~USRDA Mineral Amount %USRDA
Tin lOmcg ~ .
(aQ Stannous
Chloride)
Silicon lOmcg *
(as Sodium
Meta~ilicate)
Vanadium lOmcg
~as Sodium
Metavanadate)
*No U.S. RDA establi~hed
It is known that certain amino acids are essential for
proper cellular function. However, it has been suggested
by researchers that select amino acids provide some
protection against cancer, and may, in fact, act
synergistically with the preferred antioxidants of the
present invention to protect against cancer. Thus, it is
one important aspect of the present invention to provide a
daily dietary multi-vitamin and mineral supplement
including antioxidants and select amino acids. According
to one embodiment of the invention, the preferred
antioxidants are selected from the group consisting of BHT,
BHA, propyl gallate, and sodium benzoate, and the preferred
amino acids or analogs are selected from the group
consisting of glutathione, cysteine, methionine, glutamine,
and taurine.
Accordingly, one preferred embodiment of the present
invention provides a daily dietary multi-vitamin and
mineral supplement including, in combination:
(a) from about lO to about 300 mg of BHT;
tb) from about lO to about 300 mg of BHA;
(c) from about l to about 300 mg of sodium benzoate;
and
(d) from about lO to about 300 mg of propyl gallate.
(e) from about l to about 20 mg of glutathione;
(f) from about 5 to about lO0 mg of cysteine;
(g) from about l to about 20 mg of methionine;
,
WO91/111~7 ' ' PCT/US91/00719
2~7 '' ~7 ~ . ~
- 34 - '~
~ (h) from about l to about 20 mg of glutamine;
,:' (i) from about 2 to about 200 mg of bioflavonoids;
(j) from about l0 to 500 mg of potassium
sorbate/sorbic acid; .:
(k) from about l to about 20 mg of taurine;
~l) from about 5,to 500 units of catalase as a
food concentrate; and :
(l) from about 20 to about 500 units of SOD, as a
food concentrate.
More preferably, however, the supplement includes:
(a) about 50 mg of BHT; ..
(b) about 50 mg of BHA; .
(c) about 4 mg of sodium benzoate; and
(d) about 50 mg of propyl gallate.
(e) about l0 mg of reduced L-glutathione;
(f) about 50 mg of L-cysteine HCl; ,'
(g) about l0 mg of DL-methionine;
(h) about l0 mg of DL-glutamine; and '
(i) about l00 mg of biofl,avonoids; - .. ~
(j) about 200 mg of potassium sorbate/sorbic acid; ~;
(k) about l0 mg of taurine; .,~
(l) about 150 units of catalase as a foo.d
concentrate; and ~'
(m) about 150 units of SOD as a food concentrate. .~
2~ :
In addition to the antioxidants and amino acids
described above, several other ingredients may be included
in the formulations of the invention, including:
(a) omega-3 fish oil;
(b) para-aminobenzoic acid (PABA); and .
(c) inositol.
'. -
It has been demonstrated that several vitamins and
minerals act synerg~stically in combination with several of
the preferred antioxidants and amino acids of the ~,;
invention; therefore, it is an important aspect of the ~:.
present invention to provide formulation including these . '~
-
.' ' ` , .: : - ;- . .
wo 91/11117 2~ ~ 5~ PCT/US91/00719
... . . .
- 35 -
vitamins and minerals in appropriate amounts. Accordingly,
a preferred embodiment of the present invention provides a
daily dietary multi-vitamin and mineral tablet including,
in combination:
(a) from about 10 to about 300 mg of BHT;
(b) from about lO to about 300 mg of BHA;
(c) from about 1 to about 300 mg of sodium benzoate;
(d) from about 10 to about 300 mg of propyl gallate.
(e) from about 1 to about 20 mg of glutathione;
( f ) from about 5 to about lO0 mg of cysteine;
(g) from about 1 to about 20 mg of methionine;
(h) from about 1 to about 20 mg of glutamine;
(i) from about 1 to about 20 mg of taurine;
(j) from about 1000 to about 3000 i.u. of vitamin A;
lS (k) from about 2500 to about 7500 i.u. of beta
carotene;
(l) from about lO to about 100 i.u. of vitamin E;
(m) from about 10 to about 1000 mg Ca ascorbate; and
(n) from about 10 to about 500 mg potassium sorbate
or sorbic acid.
More preferably, however, the supplement includes:
(a) about 50 mg of BHT;
(b) about 50 mg of BHA;
(c) about 4 mg of sodium benzoate; and
(d) about 50 mg of propyl gallate.
(e) about 10 mg of reduced L-glutathione;
(f) about 50 mg of L-cysteine HCl;
(g) about 10 mg of DL-methionine;
(h) about 10 mg of DL-glutamine;
(i) about 10 mg of taurine;
(j) about 2000 i.u. of vitamin A acetate;
(k) about 5000 i.u. of beta carotene;
(l) about 100 i.u. of vitamin E, DL alpha tocopheryl
acetate;
(m) about 250 mg calcium ascorbate; and
(n) about 200 mg of potassium sorbate or sorbic acid.
- .
:' ' .: ':,. ' :''' ' - . , ~ . , :
: ~' " , : . ' `, ~ .`;' ', '
', ' ,-:' . ' .. : ''. ' .', ' ' -
.. . . . . . .
WO91/11117 ~ PCI~U591/U071 ~ ~
2~ 36 -
The inventive supplement includes many vitamins and
minerals which are commonly used in commercially available , -
multi-vitamin and mineral preparations. Preferably, the
supplement of the present invention includes the following
vitamins and minerals in an amount equal to or greater than
the minimum daily requirement in man: '
(a) vitamin C;
(b) folic acid;
(c) vitamin Bl; :
(d) vitamin B2;
(e) niacinamide;
(f) vitamin B6;
(g) vitamin B~2;
(h) vitamin D3;
(i) biotin; -;~
(j) pantothenic acid;
(k) vitamin K~
(1) calcium;
. (m) iodine;
(n) potassium;
(o) iron;
(p) magnesium;
(q) copper;
(r) zinc;
(s) manganese; ~`
(t) chromium;
(u) molybdenum;
(v) selenium;
(w) vanadium;
(x) silicon; and
(y) boron.
~ The formulations of the present invention contain a
. number of vitamins and minerals similar to other multivi$a-
min formulations, e.g, Centrum~. However, the formulation
~ -
-- ... .. . " ., ., . . , ~ . . ,
: -:: - . . . .
WO91/11117 2~ PCT/US91/00719
- 37 -
,~ ~
of the present invention provides those vitamins and miner-
als in amounts which better reflect the scientific data
concerning these agents. For example, the amount of
vitamin A included in the present invention is less than in
other available formulations because it can be toxic to
older people. Further, the amount of beta-carotene
included is greater because it is nontoxic and provides
improved benefits. For the above reasons the vitamins and
minerals included in the present invention offer a broader
base of vitamins a~d minerals than presently available in
the industry; thus, providing the public with a
comprehensive multivitamin useful in the prevention of
heart disease and cancer.
According to one preferred embodiment, the vitamins
and minerals included in the inventive formulation
includes:
VITAMINS
(a) Vitamin A acetate from about lO00 to about
3000iu; (b) Beta carotene from about 3000 to about
6000iu;
(c) Vitamin E, DL alpha tocopheryl acetate from about
20 to about 40 iu;
(d) Calcium ascorbate from about 200 to about 400mg;
(e) Folic acid from about 200 to about 600mcg;
(f) Vitamin Bl from about l.0 to about 2mg;
(g) Vitamin B2 from about l.5 to about 2mg
(h) Niacinamide from about lO to about 30mg;
(i) Vitamin B6 from about l to about 3mg;
(j) Vitamin B~2 from about 4 to about 8mcg;
(k) Vitamin D3 from about 400 to about 800iu;
(l) Biotin from about 20 to about 40mcg;
(m) Calcium pantothenate from about 5 to about 15mg;
and
(n) Vitamin Kl from about 15 to about 35mcg.
- ~ . : . . . ,- - -
. . . .
,, , - - -
: . ., , . ~ - . ~ . .
:, :.: , . - - . ,, , ~, . ., ~ , i. ~ . .
W09ltllll7 PCr/US91/00719
2~ i~;~ 7 -- 38
MINERALS
(a) dicalcium phosphate from about 50 to about 150
mg;
(b) potassium iodide sufficient to supply from about
100 to about 150 mcg of iodine;
(c) potassium chloride sufficient to supply from ~ :
about 20 to about 60mg of potassium; .
(d) ferrous fumarate sufficient to supply from about
16 to about 30mg of iron; ~.
(e) magnesium oxide sufficient to supply from 75 to
about 12Omg of magnesium;
(f) copper oxide sufficient to supply from about 1 to ~:
about 3mg of copper;
(h) zinc oxide sufficient to supply from about 10 to
about 20mg of zinc;
(i) manganese gluconate sufficient to supply from
about 1 to about 3mg of manganese;
(j) chromium (+3)chloride sufficient to supply from
about 15 to about 35mcg of chromium;
(k~ sodium molybdate sufficient to supply from about
15 to about 35 mcg of molybdenum;
(l) sodium selenate sufficient to supply from about
15 to about 35mcg of selenium;
(m) sodium metavanadate sufficient to supply from
about to about 15mcg of vanadium;
(n) sodium metasilicate sufficient to supply from
about 5 to about 15mcg of silicon; and -~
(o) boron from about 1 to about 3mg. ~
~ ':
It should be noted, however, that other vitamins and
minerals not listed above may be added to the formulations
of the present invention without departing from the spirit
of the present invention. ~ :
. .
However, according to the most preferred embodiment,
the vitamins and minerals of the present invention include~
2~ 5~7
WO91/11117 PCT/US91/00719
- 39 -
. ., ~,~,
VITAMINS
(a) about 2000 i.u. of vitamin A acetate;
(b) about 5000 i.u. of beta carotene; ~:-
(c) about 30 i.u. of vitamin E, DL alpha tocopheryl
acetate;
(d) about 250mg of calcium ascorbate;
(e) about 400mcg of folic acid;
(f) about 1.5mg of vitamin B~
(g) about 1.75mg of vitamin B2;
(h) about 20mg of niacinamide; :.
(i) about 2mg of vitamin B6;
(j) about 6mcg of vitamin B12;
(k) about 6bo i.u. of vitamin D3; -::
(l) about 30mg of biotin; '~ --
(m) about lOmg of calcium pantothenate; and ;
(n) about 25mcg of vitamin Kl. ~:
MINERALS :
_ _ .
(a) about lOOmg of dicalcium phosphate; ::
(b) potassium iodide sufficient to supply about 125mg :
iodine;
(c) potassium chloride sufficient to supply about :~ .
40mg of potassium;
(d) ferrous fumarate sufficient to supply about 20mg -.
of iron;
(e) magnesium oxide sufficient to supply about lOOmg
of magnesium;
(f) copper oxide sufficient to supply about 2mg of
copper; ~:
(h) zinc oxide sufficient to supply about 15mg of
zinc;
(i) manganese gluconate sufficient to supply about
2mg of manganese;
(j) chromium (+3)chloride sufficient to supply about :
25mcg of chromium; :~
WO91/11117 PCT/US91/00719
z~7 ~ 5~7 40
(k) sodium molybdate sufficient to suppIy about 25mcg
of molybdenum;
(l) sodium selenate sufficient to supply about
25mcg of selenium;
(m) sodium metavanadate sufficient to supply about
lOmcg of vanadium;
(n) sodium metasilicate sufficient to supply
about lOmcg of silicon; and
(o) about 2mg of boron.
The protective agents included in the inventive
formulations are either already approved by the FDA or
generally regarded as safe (GRAS) by the FDA or are
generally thought to be safe by scientific experts. These
agents include antioxidants, amino acids, and enzymes,
which have been shown to be effective in preventing the
induction of cancer and cardiovascular disorders as well as
extending the life span of experimental animals. Further,
a number of the ingredients have been shown to act
synergistically with other agents in the formulation. This
combined effect should increase their protective effects.
For example, selenium and vitamin E work synergistically
against the induction of breast cancer. Further, in a
number of studies, BHA when given with vitamin A, beta-
carotene and vitamin E was shown to provide a protection
against cancer. Accordingly, the present invention is
directed to a multi-vitamin dietary supplement formulation,
and methods for producing and administering the same to an
individual in need thereof. It is believed that the
present invention provides a formulation which is cardio-
and cancer-protective.
A further aspect of the present invention is directed
to a method for producing the formulations of the present
invention. Preferably, the formulation is tableted, and
most preferably, the formulation is tableted as a sustained
release tablet. The sustained release tablets of the
p~. ,~. , . . . . . , . . ~.
-. :- -. . ~ . .
. : . : . :.: . . . . :
WO91/11117 PCT/~S91/00719
- 41 - : ~
present invention are intended to provide for the extended
action of the ingredients from a single dose. Thus, the
sustained released tablet is a convenient dosage form by
virtue of eliminating the necessity for dosage several
times during the day. Moreover, therapeutic benefits may
also be obtained by the sustained release of the active
ingredients of the inventive formulation. It is believed
desireable that the sustained release dosage form of the
present invention will provide a slow and constant supply
of antioxidants, amino acids, and other beneficial dietary
supplements which will provide protection against cancer
and cardiovascular disease throughout the day.
In order to stabilize the preparations of the present
lS invention, it has been determined that several of the more
reactive constituents are preferably microencapsulated.
The microencapsulation of select constituents prevents
those constituents from reacting with other ingredients if
left unchecked, which would shorten the shelf life of a
commercial product embodying the inventive formulation.
According to one embodiment, the preferred sulfur-
containing amino acids and the polyunsaturated acids are
microencapsulated. More specifically, glutathione,
cysteine, and omega-3 fish oil are preferably
microencapsulated when included in the invented
formulation.
According to one preferred embodiment, hydroxypropyl
methylcellulose is used as a pharmaceutical adjunct which
provides a sustained release of the active constituents of
the tablet. According to this preferred embodiment, based
upon the physical parameters involved in formation of a
tablet which is determined by the nature of the ingredients
(compressibility, adhesion of particles, etc.), up to 20%
of the dry weight could be required for hydroxypropyl
methylcellulose to ensure proper time release tablet.
Thus, according to one embodiment, a total formulation
. ~,
. : ~ . , . - :,. .: .
W~91/11117 PCT/US91/00719
z~ ~5,, ~ - 42 -
weight range, including time released material, would have
a weight range of from about 4090 mg to about 3526 mg.
Because of the bulk of the formulation, the formulation is
preferably produced and administered as 1-3 tablets daily.
,
The following examples are presented to describe
specific preferred embodiments and utilities of the present
invention and are not meant to limit the present invention
unless otherwise stated in the claims appended hereto.
EXAMPLES
In vitro disintearation characteristics
A comparison was made between the relative
disintegrations of Centrum tablets and the sustained
release tablets of the present invention.
As a measurement of disintegration, the release of
four different vitamins, potassium, vitamin C, niacinamide,
and pyridoxine was measured. The results, summarized in
Figs. 1-6, show that the sustained release tablet of the
present invention provides for uniform disintegration over
at least seven hours.
As a general procedure, gastric and intestinal juices
were prepared according to the United States Pharmacopeia
XVIII. The dissolution tests were conducted using the
apparatus specified for such procedures in the National
Formulary XIII. The apparatus generally consisted of a
horizontal rotating shaft to which was attached clamps for
holding round cylinders approximately 150mm long and having
a diameter of approximately 30 mm wherein the tablets were
contained. The apparatus then submerges the tablets in the
appropriate dissolution fluid. The temperature of the
dissolutions fluid was maintained at 37+ 2 C throughout the
study. Eight tablets were used to generate the dissolution
.: : . : ~ . ~ : .: . -: : .
WO91~11117 PCT/US91/00719
1 2~ ~ ~ 43 _ ,~
data. Six Centrum (UDC0005-4239-13 Lederle Laboratories
Division American Cyanamid Company) and two sustained
release tablets of the present i~vention, which were
prepared as follows.
The following shows the content and instructions for
preparing a most preferred formulation (300,000 tablets 3
tablet/dose) of the present invention.
Weight Range Per Do~e
~dose = 1 dav su~lv) G _
vitamins
5.4 mgVitamin A acetate 2000 iu from 500,000 iu/gm
beadlet~ with 35% overage 540
40.5 mgBeta carotene 5000 iu = 30 mg with 35% overage
from 10% beadlets 405
231 mg Vitamin E DL alpha tocopheryl acetate 100 iu from
50% 2.1 mg finished material with 10% overage 23,100
300 mg Calcium ascorbate = 250 mg with 20% overage 30,000
mg Follc acid as 10% trit = 400 mcg/do~e with 25%
overage 500
1.73mg Vitamin Bl dose = 1.5 mg with 15~ overage173
1.87mg Vitamin B2 dose = 1.7 mg with 10% overage187
3022 mg Niacinamide dose = 20 mg with 10% overage2,200
2.67mg Vitamin B6 dose = 2 mg with 10% overage 267
0.75mg Vita~in B12 dose = 6 mcg from 1% trit on re~in with
25% overage 75
8.1 mg Vitamin D3 dose = 600 iu from 100,000 iu/gm with
35% overage 810
403.3 mg BiotLn do~e = 30 mcg from 1% trit with 10% overage 330
14 mg Calcium pantothenate dose = 10 mg with 30~ overage 1,400
3.4 mg Vitamin ~1 dose = 25 mcg from 1% trit with 35%
overage 340
100 mg Dicalcium phosphate dihydrate10,000
(use in granulations)
S0 0.20mg Pota~ium iodide supplies 150 mcg iodine 20
76.3 mg Pota6~ium chloride supplies 40 mg pota~ium 7,630
155 mg Ferrous gluconate supplies 18 mg iron 15,550
166 mg Magnesium oxide supplies lO0 mg magne~ium16,660
WO9]/11117 PCr/US91/00719
~` .
2~7~ 44 -
2.503mg Copper oxide supplies 2 mg copper 250
18.75mg Zinc oxide supplies 15 mg zinc1,875
22.7 mg Manganese gluconate supplies 2.5 mg manganese 2,270
0.08mg Chromium (+3) chloride supplie~ 25 mcg chromium 8Z
0.06mg Sodium molybdate supplies 25 mcg molybdenum 63
0.06mg Sodium selenate supplies 25 mcg ~elenium 64
0.038mg S o d i u m
metavanadate supplies 10 mcg vanadium 3.86
0.044mg S o d i u m
metasilicate supplies 10 mcg silicon 4.45
22.3 mg Calcium borogluconate supplies 1 mg boron 2,230
100 mg Citrus bioflavonoids from 50~ material supplying
50 mg per dose 10,000
4 mg Sodium benzoate 25,000
250 mg Calcium carbonate 25,000
100 mg Calcium citrate 10,000
10 mg L-glutathione ~reduced) (microencapsulated) 2,500
50 mg L-cysteine HC1 (microencapsulated) 5,000
200 mg Potassium sorbate/sorbic acid 20,000
3540 mg PABA 4,000
50 mg BHA 5,000
50 mg 8BT 5,000
571 mg Omega 3 fish oils supplying 200 mg Omega 3 oils
from microencapsulated material which is 35%
omega 3 having an EPA:DHA ratio of 18:12 57,100
4550 mg Inositol 5,000
150 mg Vegetable source SOD 200 units (mfu)
Vegetable source catalase 200 units (bsu) 15,000
50 mg Propyl gallate 5,000
10 mg Taurine 1,000
10 mg DL methionine 1,000
10 mg L glutamine 1,000
hydroxypropylmethylcellulose
(e.g. Methocel X, Dow Chem.)61,162
Magnesium Stearate 1,500
Total weight of ingredients = 376,102
Tablet Weight = 1.1667 grams
. .. . .
WO 91/111l7 PCl`tUS9l/00719
2~
The KI was dissolved in 50 ml H20 with about 2000 gm
of the dicalcium phosphate dihydrate. The mixture was
dried at 120-F for 48 hours and then milled. The CrCl3 was
also dissolved in 50 ml H20 with about 2000 gms dicalcium
phosphate dihydrate. This mixture was also dried at 120`F
for about 48 hours and was then milled. The sodium
molybdate was dissolved in 50 ml H2O with about 2000 gm of
dicalcium phosphate dihydrate. The mixture was dried at
120`F for about 48 hours and then milled. The sodium
selenate was dissolved in 50 ml H2O with 2000 gms dicalcium
phosphate dihydrate and dried at 120-F for about 48 hours
and then was milled. The sodium metasilicate was mixed
with 2000 gms dicalcium phosphate dihydrate and added to
the sodium metavandate which was dissolved in 50 ml H2O.
This mixture was then dried at 120-F for about 48 hours and
then was milled. All of the above milled ingredients were
then mixed.
All the remaining ingredients were weighed separately
and added to a stainless steel ribbon blender and blended
for 10 minutes. Tablets were then compressed on a rotary
tablet press machine. Tablets weighed 1.2537 grams 1 2%.
The tablets were oblong measuring 0.75 inches (height) x
0.35 inches ~width) x 0.30 inches (depth). The tablets
were produced at 4 tons pressing force per square inch. It
was determined that these tablets disintegrated uniformly
over an 8 hour period. The tablets are also suitable for
an aqueous film coating, such as with riboflavin, in a
conventional film coating pan.
: .
The dissolution data was collected at 1/2 hr, 1 and
1/2 hr, 2 and 1/2 hr, 3 and 1/2 hr, 4 and 1/2 hr, 5 and
1/2 hr, 6 and 1/2 hr, and 7 and 1/2 hr. Data for Centrum
was obtained for 6 tablets under identical conditions.
However, the total dissolution occurred for Centrum at
approximately 20 minutes. Therefore, Centrum was only
WO91/11117 PCT/US91/00719
2 ~ ~r;~ 7 - 46 - _
observed in gastric test solution. This data is
summarized in Fig. 1.
.
The release of potassium from the tablet of the
present invention was monitored using a Perkin Elmer
spectrophotometer. To do this monobase sodium phosphate
was used in place of H2KPO4 in the intestinal liquid.
Replacement of H2KPO4 with H2NaPO~ allowed accurate
measurement of potassium from the tablet without
interferences.
Measurements of potassium were made at 766.5 lambda
using atomic absorption. Results:
Time %K released during observed interval
0 - 1/2hr 11.54
lt2 - 2 1/2hr 14.61
1/2 - 2 1/2hr 14.61
2 1/2 - 3 1/2hr 14.61
3 1/2 - 4 1/2hr 13.15
4 1/2 - 5 1/2hr 13.15
5 1/2 - 6 1/2hr 10.96
6 1/2 - 7 1/2hr 7.30
25To obtain interval values intestinal fluid was replaced
hourly. The above data is summarized in Fig. 2.
Data for ascorbic acid, niacinamide, and pyridoxine
HCl were generated using a Bausch and Lomb
30spectrophotometer (Model 21). The wavelengths used for
analysis were: -
245mm Ascorbic Acid
261mm Niacinamide
29imm Pyridoxine
Samples were taken from 1/2hr, 1/2hr, 2 1/2hr, 3 1/2hr, 4
1/2hr, 5 1/2hr, 6 1/2hr, 7 1/2hr periods. ~his data is
: . . ~ ~ : - ,
W091/~1117 PCTtUS9ltO0719
5~
,
- 47 -
summarized in Figs. 3, 4, and 5 respectively. The data
collected showed that the tablet of the present invention
provided for the sustained release of the constituents of
the inventive formulation.
While the invention is susceptible to various
modifications and alternative forms, a specific embodiment
thereof has been shown by way of example and therein was
described in detail. It should be understood, however,
that it is not intended to limit the invention to the
particular forms disclosed, but on the contrary, the
intention is to cover all modifications, equivalents, and
alternatives falling within the spirit and scope of the
invention as defined by the appended claims.
: . : . . . . . . .
