U.S. patent application number 13/922863 was filed with the patent office on 2014-08-07 for stability in vitamin and mineral supplements.
The applicant listed for this patent is Wyeth LLC. Invention is credited to Chad Byerley, Steven Dills, Alan M. Goldberg, William Mark, Bruce Sutton.
Application Number | 20140220151 13/922863 |
Document ID | / |
Family ID | 39361442 |
Filed Date | 2014-08-07 |
United States Patent
Application |
20140220151 |
Kind Code |
A1 |
Goldberg; Alan M. ; et
al. |
August 7, 2014 |
Stability in Vitamin and Mineral Supplements
Abstract
The invention provides a multivitamin and mineral nutritional
supplement composition comprising at least one polyvalent metal and
at least one oxidizable vitamin with substantially improved
resistance to reactions that lead to darkening and/or spotting and
reactions that may reduce the potency of oxidizable vitamins. The
composition is a multivitamin and mineral composition comprising at
least one polyvalent metal and at least one oxidizable vitamin
wherein the composition is substantially free of mobile bound
water. The invention also includes methods for making such a
composition and methods of preventing or reducing oxidation,
improving the stability of oxidizable vitamins, and stabilizing the
disintegration time of a multi-vitamin and mineral nutritional
supplement composition.
Inventors: |
Goldberg; Alan M.; (Nutley,
NJ) ; Dills; Steven; (Ashland, VA) ; Mark;
William; (Morgantown, WV) ; Sutton; Bruce;
(Richmond, VA) ; Byerley; Chad; (Midlothian,
VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wyeth LLC |
Madison |
NJ |
US |
|
|
Family ID: |
39361442 |
Appl. No.: |
13/922863 |
Filed: |
June 20, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11706923 |
Feb 15, 2007 |
8491937 |
|
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13922863 |
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Current U.S.
Class: |
424/602 |
Current CPC
Class: |
A61K 31/519 20130101;
A61K 31/4415 20130101; A61K 31/51 20130101; A61P 3/02 20180101;
A61K 31/07 20130101; A61K 31/409 20130101; A61K 33/42 20130101;
A61K 33/00 20130101; A23L 33/16 20160801; A61K 33/26 20130101; A23V
2002/00 20130101; A61K 31/375 20130101; A61K 33/30 20130101; A61K
45/06 20130101; A61K 33/34 20130101; A23L 5/41 20160801; A23V
2250/71 20130101; A61K 33/00 20130101; A61K 33/26 20130101; A61K
31/525 20130101; A61K 33/32 20130101; A23V 2002/00 20130101; A61K
31/375 20130101; A61K 31/197 20130101; A23L 33/15 20160801; A61K
31/59 20130101; A61K 33/06 20130101; A61K 31/455 20130101; A61K
31/355 20130101; A23V 2250/704 20130101; A23V 2250/161 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A23V 2250/702
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A23V
2250/1578 20130101; A23V 2250/1588 20130101; A23V 2250/712
20130101; A23V 2250/1642 20130101; A23V 2250/1592 20130101; A23V
2250/708 20130101; A23V 2250/1612 20130101; A23V 2250/159 20130101;
A61K 33/34 20130101 |
Class at
Publication: |
424/602 |
International
Class: |
A61K 33/42 20060101
A61K033/42; A61K 31/07 20060101 A61K031/07; A61K 31/59 20060101
A61K031/59; A61K 31/355 20060101 A61K031/355; A61K 31/51 20060101
A61K031/51; A61K 31/525 20060101 A61K031/525; A61K 31/455 20060101
A61K031/455; A61K 31/4415 20060101 A61K031/4415; A61K 31/519
20060101 A61K031/519; A61K 31/409 20060101 A61K031/409; A61K 31/197
20060101 A61K031/197; A61K 33/06 20060101 A61K033/06; A61K 33/34
20060101 A61K033/34; A61K 33/26 20060101 A61K033/26; A61K 33/32
20060101 A61K033/32; A61K 33/30 20060101 A61K033/30; A61K 31/375
20060101 A61K031/375 |
Claims
1. A multivitamin and mineral composition comprising at least one
polyvalent metal and least one oxidizable vitamin, wherein the
composition is substantially free of mobile bound water.
2. The multivitamin and mineral composition of claim 1, wherein the
polyvalent metal is selected from the group consisting of iron,
magnesium, zinc, selenium, copper, cobalt, manganese, molybdenum,
vanadium, nickel, tin, chromium and combinations thereof.
3. The multivitamin and mineral composition of claim 1, wherein the
oxidizable vitamin is selected from the group consisting of Vitamin
C, Vitamin E, Vitamin A, Vitamin A precursors. Vitamin B6, Vitamin
D3, Vitamin K, folic Acid and combinations thereof.
4. The multivitamin and mineral composition of claim 1, further
comprising anhydrous dicalcium phosphate.
5. The multivitamin and mineral composition of claim 1, further
comprising a carotinoid.
6. The multivitamin and mineral composition of claim 1, wherein the
composition is in a solid dosage form.
7. A multivitamin and mineral composition of claim 6, wherein the
solid dosage form is selected from the group consisting of tablets,
caplets, capsules, chewable dosage forms, powder, sachet and
combination thereof.
8. A method for reducing oxidation induced spotting in a in a
multivitamin and mineral tablet and for stabilizing disintegration
behavior of multivitamin and mineral tablets over time comprising:
combining at least one polyvalent metal selected from the group
consisting of iron, magnesium, zinc, selenium, copper, cobalt,
manganese, molybdenum, vanadium, nickel, tin, chromium and
combinations thereof, and at least one oxidizable vitamin selected
from the group consisting of Vitamin C, Vitamin E, Vitamin A,
Vitamin A precursors, Vitamin B6, Vitamin D3, folic acid and
combinations thereof to form a composition, wherein the composition
is substantially free of mobile bound water; and forming the
composition into tablets.
9. The method of claim 8, further comprising combining anhydrous
dicalcium phosphate with the at least one polyvalent metal and at
least one oxidizable vitamin.
10. A multivitamin and mineral composition comprising at least 150
mg of elemental calcium per dosage unit, at least one polyvalent
metal, and at least one oxidizable vitamin, wherein the composition
is substantially free of mobile bound water.
11. The multivitamin and mineral composition of claim 10, wherein
the polyvalent metal is selected from the group consisting of iron,
magnesium, zinc, selenium, copper, cobalt, manganese, molybdenum,
vanadium, nickel, tin, chromium and combinations thereof.
12. The multivitamin and mineral composition of claim 10, wherein
the oxidizable vitamin is selected from the group consisting of
Vitamin C, Vitamin E, Vitamin A, Vitamin A precursors, Vitamin B6,
Vitamin D3, Vitamin K, folic acid and combinations thereof.
13. The multivitamin and mineral composition of claim 12, wherein
the oxidizable vitamin is Vitamin C.
14. The multivitamin and mineral composition of claim 10, wherein
the composition is in a solid dosage form.
15. The multivitamin and mineral composition of claim 14, wherein
the solid dosage form is selected form the group consisting of
tablets, caplets, capsules, chewable dosage forms, powder, sachet
and combination thereof.
16. The multivitamin and mineral composition of claim 15, wherein
the solid dosage form is a tablet.
17. The multivitamin and mineral composition of claim 10, wherein
the elemental calcium is provided in the form of anhydrous
dicalcium phosphate.
18. The multivitamin and mineral composition of claim 15, wherein a
first portion of the elemental calcium is provided in the form of
anhydrous dicalcium phosphate.
Description
FIELD OF INVENTION
[0001] This invention relates to nutritional supplement
compositions. More particularly this invention provides a
composition and method to reduce the degradation in vitamin and
mineral supplements associated with darkening and/or spotting of
multi-component nutritional supplement tablets over time.
BACKGROUND OF THE INVENTION
[0002] 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. The human body cannot synthesize most of
the vitamins and minerals that are essential to maintaining the
health of the human body. Thus, vitamins and minerals must be
obtained from an external source. The two most common external
sources are foods and nutritional supplements. As most people do
not eat foods that consistently provide the necessary daily
requirements of vitamins and minerals, vitamin and mineral
nutritional supplementation has become a recognized method of
meeting accepted medical and health standards.
[0003] Vitamin and mineral preparations may be administered to
treat specific medical conditions or as general nutritional
supplements. As there are a number of vitamins and minerals needed
and the daily amounts needed are relatively small, it is convenient
to administer mixtures of vitamins and minerals in tablet or
capsule form as a general supplement. Typical daily dosages of
commercially available multivitamin and mineral supplements are one
or two tablets or capsules per day. It is not unusual for such
compositions to include two dozen or more nutrients in addition to
the excipients needed to make the dosage form.
[0004] Accordingly, it is not surprising that undesirable chemical
interactions can occur in these complex mixtures. The most common
of these reactions are degradation reactions that lead to a reduced
potency of the impacted nutrients and may also cause the
composition to darken or develop unsightly dark spots. Oxidation
reactions are exemplary of a common form of degradation reactions.
The presence of water may also contribute to degradation either
directly or by facilitating reactions such as oxidation reactions,
for example.
[0005] Both water and fat-soluble vitamin components such as
ascorbic acid (vitamin C) and alpha tocopheryl acetate (vitamin E),
for example, have been found to be susceptible to moisture induced
chemical degradation in multi component supplement compositions.
Ascorbic acid oxidation, promoted by the interaction of ascorbic
acid with polyvalent metal ions in a dietary supplement composition
and facilitated in the presence of water, can cause tablet
darkening and/or spotting and prolonged disintegration times that
may impact availability of components for utilization in the
body.
[0006] Conventionally, it has been believed that the water that
contributes to degradation, is water in the environment proximate
the composition (e.g. environmental water) and/or water that is
loosely associated with the surface or interfacial areas of the
composition. For example, the commercially available nutritional
supplementation product, One-A-Day.RTM. Active, includes a storage
statement which reads, "If excess moisture enters the bottle, the
iron may cause spotting on the tablet."
[0007] Accordingly, desiccants have been employed to improve
stability. However, there are several problems with desiccants:
First, desiccants can be physically removed from a package by the
consumer negating the beneficial effect. Secondly, a desiccant may
lose efficacy over time and/or have limitations in its ability to
remove bound water. Thirdly, desiccants add expense to the final
product.
[0008] Limiting the contents of tablets to exposure to
environmental water by employing tablet coating has also been used.
While this method may mask problems from a consumer's view, the
polymeric film coatings used to date do not appreciably reduce
spotting and/or darkening problems. Examination of aged coated
tablets often reveals spotting or core darkening under the
coating.
[0009] Shah et al. in "A Study of the Chemical and Physical
Stability of Ascorbic Acid, Folic Acid, and Thiamine Hydrochloride
Tablets Formulated With Emcompress Standard.RTM." reported that
Emcompress Standard.RTM. (directly compressible dicalcium phosphate
dihydrate granulation) induced ascorbic acid chemical degradation
and physical degradation (with regard to disintegration times) in
ascorbic acid and thiamine hydrochloride tablets. (Shah, D. H.
& Aramblo, A., 1975, Drug Devel. & Ind. Pharm., 1, 459-505)
The reference attributed these instabilities to the moisture
associated with environmental water or water that is loosely
associated with the surface or interfacial areas of the
composition.
[0010] Accordingly as moisture promoted degradation reactions lead
to a loss of potency and/or unappealing discoloration of
multi-component nutritional supplements containing mineral ions and
oxidizable vitamins, a composition and/or methods are needed to
reduce moisture promoted degradation in multi-component nutritional
supplements.
SUMMARY OF THE INVENTION
[0011] The present invention provides a pharmaceutical composition
comprising a multivitamin and mineral composition comprising at
least one polyvalent metal and at least one oxidizable vitamin
wherein the composition is substantially free of mobile bound
water. In an exemplary embodiment the at least one polyvalent metal
is selected from the group consisting of iron, magnesium, zinc,
selenium, copper, cobalt, manganese, molybdenum, vanadium, nickel,
tin and chromium and combinations thereof, and the oxidizable
vitamin is selected from the group consisting of Vitamin C, Vitamin
E, Vitamin A, Vitamin A precursors, Vitamin B.sub.6, Vitamin
D.sub.3, Vitamin K, Folic Acid and combinations thereof.
[0012] In a preferred embodiment, the composition further comprises
anhydrous dicalcium phosphate and is in a tablet dosage form.
[0013] A method for preparing a multivitamin and mineral
composition of the invention is provided. The method comprises
providing at least one oxidizable vitamin, at least one polyvalent
metal ion and anhydrous dicalcium phosphate; and combining the at
least one polyvalent mineral ion, the at least one oxidizable
vitamin and anhydrous dicalcium phosphate to form a composition,
wherein the composition is substantially free of mobile bound
water.
[0014] A method for reducing oxidation induced spotting in a
multivitamin and mineral composition supplement tablet is provided.
The method comprises combining at least one polyvalent metal
selected from the group consisting of iron, magnesium, zinc,
selenium, copper, cobalt, manganese, molybdenum, vanadium, nickel,
tin and chromium and combinations thereof, and at least one
oxidizable vitamin selected from the group consisting of Vitamin C,
Vitamin E, Vitamin A, Vitamin A precursors, Vitamin B.sub.6,
Vitamin D.sub.3, Vitamin K, folic acid and combinations thereof to
form a composition wherein the composition is substantially free of
mobile bound water.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The invention provides a nutritional supplement composition
comprising at least one polyvalent metal and at least one
oxidizable vitamin with substantially improved resistance to
reactions that lead to darkening and/or spotting and reactions that
may reduce the potency of oxidizable vitamins. The invention also
includes methods for making such a composition and methods of
preventing or reducing oxidation, improving the stability of
oxidizable vitamins, and stabilizing the disintegration time of a
multi-vitamin and mineral nutritional supplement composition.
[0016] The inventors believe without wishing to be held to the
theory that minimization of bound water traditionally believed to
be unavailable for participation in chemical reactions at ambient
or near ambient conditions is important to minimization of spotting
and/or darkening of multi-vitamin and mineral compositions
comprising polyvalent metal ions and an oxidizable vitamin.
[0017] In a preferred embodiment, the composition comprises vitamin
C and a polyvalent metal ion, and anhydrous dicalcium phosphate
wherein the composition is substantially free of mobile bound
water. The invention is directed to solving a problem in
conventional commercial multivitamin and mineral tablets which to
the observer appear to be dry and which are prepared from well
characterized vitamins, minerals and related substances.
[0018] In addition to improved chemical stability, the composition
of the invention typically has improved consistency of tablet
disintegration times over time and is resistant to darkening and/or
spotting of the tablet over time frames consistent with commercial
product shelf life.
[0019] Polyvalent metal cations are believed to serve as catalysts
for oxidation of vitamins and the process appears to be facilitated
by the presence of water. Traditionally, environmental water or
loosely associated surface or interstitial water have been believed
to be the source of water that facilitates the oxidation of
vitamins in the presence of polyvalent metal ions. An observation
supported by the fact that vitamin oxidation is accelerated by
increasing humidity, and to a lesser extent by increasing
temperature. However, while this source of water can be a factor,
spotting can still occur when these sources provide negligible
amounts of water.
[0020] Certainty, preventing multi-vitamin and mineral supplement
tablets having a plurality of vitamins and minerals from being
exposed to moisture will help maintain both chemical and physical
stability, but it is frequently insufficient to prevent spotting
over the commercial shelf life of multi-vitamin and mineral
supplements and/or make a significant impact on the lengthening of
disintegration times over a time. The inventors have discovered
that water of hydration of a crystalline structure traditionally
believed to be unavailable for reaction at ambient or near ambient
conditions, may play a role in the vitamin oxidation reactions in
the presence of polyvalent metal cations that lead to spotting of
multi-vitamin and mineral supplement tablets. The present invention
provides for minimization of internal bound water available for
reaction in a solid dosage form, e.g. mobile bound water. In one
exemplary embodiment the propensity for ascorbic acid (e.g. Vitamin
C) to interact with polyvalent metal cations is minimized by using
anhydrous dicalcium phosphate as a mineral/excipient (e.g., as a
source of calcium and phosphorus and as a diluent and/or binder)
and avoiding using calcium salts having water of hydration.
[0021] As used herein, the term "degradation" means the change of a
given chemical species to a different chemical species (e.g.
chemical change). Chemical changes which produce spotting and/or
decrease the potency of a component or compound or both are of
particular interest in relation to this invention.
[0022] As used herein, the phrase "disintegration time" means the
amount of time it takes for a tablet dosage unit of a nutritional
supplement to disintegrate under controlled laboratory conditions.
One of ordinary skill in the art is familiar with methods and
procedures for determination of disintegration times.
[0023] As used herein, the term "stability" may refer to chemical
stability and/or physical stability. As used herein, the phrase
"chemical stability" means the ability of a compound to maintain
its chemical identity over time. Accordingly, stability implies the
ability of a chemical species to resist oxidation or other
degradation, for example. As used herein, the phrase "physical
stability" means the ability of a composition to maintain
consistent physical properties over time. The ability of a
composition to maintain a consistent disintegration time over time
is exemplary of physical stability.
[0024] As used herein, the phrase "mobile bound water" means bound
water which is attached to a chemical entity via some form of
bonding and that may become available to facilitate chemical
reactions under ambient or near ambient conditions. Water of
hydration, particularly water of hydration in the crystalline
structure of dicalcium phosphate dihydrate is exemplary. Although
generally considered to be bound and stable under ambient or near
ambient conditions (e.g. typical conditions of shipping, storage
and use), in the presence of oxidizable vitamins and polyvalent
metal ions the water bound as water of hydration can facilitate the
oxidation reaction. As used herein the term "substantially free of
mobile bound water" means less than 0.3% by weight of the
composition can be attributed to water of hydration or other
formally bound water that may become available for reaction under
ambient or near ambient conditions. Accordingly, the use of a
component that has mobile bound water is preferably avoided, but
substantially free of mobile bound water recognizes that very small
amounts of water of hydration associated with nutrients may be used
and/or that trace amounts of hydrated forms may be present in
compositions designated as anhydrous.
[0025] The term "multivitamin and mineral" or "multivitamin and
multimineral" supplement(s) should be interpreted to mean
conventional commercial type vitamin and mineral supplements
prepared from specific vitamin and mineral materials. Multivitamin
and mineral supplement includes compositions comprising, at least
one vitamin and at least one mineral and, optionally, related
nutritional agents such as carotinoids. However, as used herein the
term multivitamin and mineral supplement does not include
supplements with complex plant extracts such as for example complex
multi-component herbal extracts and/or compositions with large
amounts of hydrophobic material (e.g. greater than 30% highly
hydrophobic material such as, for example, phytosterois) which add
additional complexities to the supplement composition. In other
words the invention is directed to resolving a problem associated
with conventional mass produced nutritional supplements generally
referred to as multivitamin and mineral supplements that containing
a plurality of vitamins and a plurality of minerals. The terms
"multivitamin and mineral" or "multivitamin and multimineral"
should be interpreted in an equivalent manner herein when they
proceed the terms "nutritional supplement", "tablet", or
"composition".
[0026] The term "potency" relates to the amount of efficacious
component. Typically, as used herein, it refers to the efficacious
amount of a given component at a given time in comparison to the
efficacious amount of the same component at a second time.
Typically, potency is expressed as a percentage. For example, a 20%
reduction in potency of component A after three months means that
the efficacious amount of component A present after a three month
period is 80% of the original efficacious amount of component
A.
[0027] As used herein, the term "polyvalent metal" means a metal
ion having a valance of 2 or higher.
[0028] As used herein, the term "oxidizable vitamin" may apply to
either a fat or water soluble vitamin that is subject to oxidative
degradation, and whose oxidation may be facilitated by the presence
of water and a polyvalent metal. Oxidizable vitamins include, but
are not limited to, Vitamin C, Vitamin E, Vitamin A, Vitamin A
precursors, Vitamin B.sub.6, Vitamin D.sub.3, Vitamin K, and folic
acid.
[0029] As discussed above, the invention addresses the undesirable
interaction of oxidizable vitamins with polyvalent metal ions in
the presence of mobile bound water. Accordingly, the invention is
applicable to a solid form composition containing one oxidizable
vitamin and one polyvalent metal ion whether the oxidizable vitamin
and the polyvalent mineral ion are the sole active agents or part
of a mixture of vitamins and minerals. As noted above, the
invention is particularly directed to complex mixtures of vitamins
and minerals of the type found in commercial multi-vitamin and
mineral supplements. A listing of vitamins and minerals and related
agents that may be included in nutritional supplements and dosage
amounts are set forth in established reference guides such as the
United States Pharmacopeia National Formulary Official Compendium
of Standards (i.e., the U.S.P.-N.F. Official Compendium of
Standards) or European Directive 90/496/EC including amendments
which are incorporated herein by reference. Amounts of vitamins and
minerals may vary in specific embodiments but should typically fall
within the dosage amounts set forth in the U.S.P.-N.F. Official
Compendium of Standards or European Union Directive.
[0030] Vitamins and related entities which may be included in
multivitamin and mineral preparations include but are not limited
to Vitamin C, Vitamin E, thiamin (Vitamin B1), riboflavin (Vitamin
B.sub.2), niacin (Vitamin B.sub.3), pyridoxine (Vitamin B.sub.6),
folic acid, cobalamins (Vitamin B.sub.12), Pantothenic acid
(Vitamin B.sub.5), Biotin, Vitamin A (and Vitamin A precursors),
Vitamin D, Vitamin K, other B complex vitamins, B complex related
compounds such as Choline and Inositol, for example, and
carotinoids such as lutein, lycopene, zeaxanthin, and astaxanthin.
Of these vitamins, Vitamin C, Vitamin E, Vitamin A, Vitamin
B.sub.6, Vitamin D.sub.3, Vitamin K and folic acid are known to be
susceptible to oxidation in multivitamin and mineral preparations.
Any vitamin susceptible to oxidation in the presence of a
polyvalent cation at ambient conditions is within the scope of the
invention; however, of the vitamins listed above, Vitamin C and
vitamin E are particularly susceptible to oxidation in the presence
of polyvalent metal ions.
[0031] Vitamin C is commonly provided as ascorbic acid in
multivitamin-multimineral tablets. As ascorbic acid is particularly
susceptible to oxidation, it commonly is a significant contributor
to spotting and darkening. Alternatively, ascorbyl palmitate, a
hydrophobic ester of Vitamin C which has a reduced affinity for
water may be used. Reduced spotting is observed using ascorbyl
palmitate, but use of ascorbyl palmitate has disadvantages which
need to be carefully considered. Ascorbyl palmitate is relatively
expensive compared to ascorbic acid and is less potent than
ascorbic acid (42.5% vitamin C potency) necessitating higher use
levels and larger tablets for consumers to swallow. Ascorbyl
palmitate also has poor powder flow properties which lead to
processing problems particularly during compression and typically
yields tablets that are subject to substantial increases of
disintegration times over product shelf life time frames.
[0032] Coating or encapsulating ascorbic acid with various barrier
coatings is a possible alternative to preventing or slowing
oxidation. The inventors explored this strategy, but for the
experiments conducted found polymeric film coating to have an
undesirable negative impact on tablet disintegration. Accordingly,
the inventors' discovery that water of hydration can facilitate
oxidation of Vitamin C and that avoiding including components
having mobile bound water in compositions comprising Vitamin C,
provides a practical, cost effective means for reducing degradation
reactions that lead to darkening or spotting.
[0033] Vitamin E is typically provided as DI-alpha tocopheryl
acetate in multivitamin- and mineral tablets. Like Vitamin C,
Vitamin E has been found to be particularly susceptible to moisture
induced chemical degradation in the presence of polyvalent metal
ions. Typically, Vitamin E oxidation does not contribute
significantly to spotting, but the oxidation of Vitamin E leads to
marked decreases in its potency over time. Accordingly, the
oxidation of Vitamin E can impact the quality of the nutritional
supplement over time. Likewise, avoidance of including components
having mobile bound water in compositions comprising Vitamin E
reduces oxidation of Vitamin E.
[0034] Minerals which may be included in multivitamin and mineral
supplements include, but are not limited to, iron, iodine,
magnesium, zinc, selenium, copper, calcium, manganese, silicon,
molybdenum, vanadium, boron, nickel, tin phosphorus, chromium,
cobalt, chloride, and potassium. Mineral components of
multivitamin-multimineral tablets are typically provided in salt
form. The salt form used should be a pharmaceutically acceptable
salt form.
[0035] In some cases the salts may be hydrated forms having bound
water of crystallization. For some hydrated salts such as, for
example, dicalcium phosphate dihydrate, the bound water of
crystallization is mobile bound water that can become available to
facilitate oxidation reactions at ambient or near ambient
conditions. Accordingly, avoiding use of salt forms that contain
mobile bound water removes a significant source of water and
reduces the propensity for moisture facilitated oxidation reactions
to occur. Using anhydrous dicalcium phosphate as a calcium
source/excipient instead of the commonly used dicalcium phosphate
dihydrate is exemplary. Salts with water of hydration may be
generally avoided, or as water of hydration in crystalline
structures has traditionally been considered to be unavailable
under ambient conditions, testing to determine if a hydrated salt
can contribute to the oxidation process may be done. Such testing
could be accomplished in any of several ways. For example, a test
composition comprising the hydrated salt, an oxidizable vitamin and
a polyvalent metal ion could be prepared and subjected to stability
testing.
[0036] Many minerals salts comprise polyvalent metal ions. For
example, typically iron, magnesium, zinc, selenium, copper, cobalt,
manganese, molybdenum, vanadium, nickel, tin and chromium are
provided in a salt form in which the metal is in a polyvalent
state. An polyvalent metal ion may catalyze oxidation reactions;
however, iron and copper ions are known to be particularly
problematic in multivitamin and mineral compositions.
[0037] While water of hydration associated with any salt used in a
multivitamin and mineral composition may potentially be a source of
mobile bound water, the inventors have identified commonly used
hydrated calcium salts to be particularly problematic. Dicalcium
phosphate, dihydrate is commonly used in commercial multivitamin
and mineral preparations because it is a low cost ingredient that
provides several benefits. In addition to providing calcium and
phosphorus nutrients, it is a useful excipient for papering tablets
serving as a binder and/or diluent. Due to its excipient/nutrient
role, dicalcium phosphate often comprises a significant amount of a
commercial multivitamin and mineral tablet.
[0038] Accordingly, for at least the reason of amount used,
eliminating the use of the common hydrated form of dicalcium
phosphate can reduce a significant amount of the mobile bound water
available to facilitate the undesirable oxidation reactions. In one
embodiment, elimination of the mobile bound water associated with
dicalcium phosphate is accomplished by using anhydrous dicalcium
phosphate. Anhydrous dicalcium phosphate provides the calcium and
phosphorus nutrient benefits and excipient benefits without any
mobile bound water to contribute to the undesirable oxidation
reactions. While use of anhydrous dicalcium phosphate is generally
beneficial, it is particularly beneficial in compositions
comprising large amounts of calcium (e.g. compositions comprising
more than 150 mg of elemental calcium per tablet). Further,
anhydrous dicalcium phosphate may be used as the sole source of
elemental calcium in the multi-vitamin and mineral composition or,
alternatively, used in combination with other calcium sources such
as, for example, calcium carbonate.
[0039] The multi-vitamin and mineral nutritional compositions in
accordance with the present invention are intended for oral
administration in a solid form. Accordingly, in order to form a
solid dosage form, the composition may further comprise excipients
and/or processing aides in addition to vitamins and minerals.
Exemplary excipients and processing aids, include but are not
limited to absorbents, diluents, flavorants, colorants,
stabilizers, fillers, binders, disintegrants, lubricants, wetting
agents, glidants, antiadherents, sugar or film coating agents,
preservatives, buffers, artificial sweeteners, natural sweeteners,
dispersants, thickeners, solubilizing agents and the like or some
combination thereof.
[0040] Generally, excipients and processing aids known to those
skilled in the art are suitable for use in multivitamin and mineral
compositions of the invention so long as they do not include water
that can facilitate oxidation reactions. For example, in some
embodiments containing ascorbic acid it may be desirable to avoid
using starch as an excipient for granulating ascorbic acid as
starch is hygroscopic. An exemplary suitable granulating agent for
ascorbic acid is HPMC (hydroxypropylmethylcellulose)
[0041] The dosage form of the compositions of the present invention
is a solid. However, solid dosage form may contain non-aqueous
liquid or semi-solid components. Exemplary solid dosage forms
includes, but are not limited to, tablets, caplets, capsules,
chewable dosage forms, powder, sachet 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 one at a time or
administered at intervals during the dosage period (e.g. typically
a day) if desired. Accordingly, it should be understood that any
amounts of the vitamins, minerals or other related nutritional
agent disclosed herein are for a daily dosage and that dosage may
be delivered in a single delivery unit or multiple delivery units.
Further, dosages are for the amount of the specified species of
nutrient and the mass of any counter ion and/or ligand associated
with the specified species is not included in the specified
amount.
[0042] In a preferred embodiment, the multivitamin and mineral
supplement is a tablet prepared by a direct compression method
avoiding exposing the composition to liquid water in the
manufacturing process. The ingredients of the composition can be
preblended, sequentially combined, or combined through other dry
granulation methods. Alternatively, wet granulation may be used.
However, if wet granulation and/or aqueous based coating is used
processing steps should be designed to limit exposure to water in
processing and provide effective drying upon completion of
granulation and/or coating.
EXAMPLE 1
[0043] Three examples of the composition of exemplary embodiments
of the invention are provided n Tables 1, 2, and 3. These
compositions are representative and examples of the many
compositions that are within the scope of the invention and are
provided for illustrative purposes. The multi-vitamin and mineral
nutritional supplements exemplified in Tables 1-3 are intended to
be a daily dosage and typically would be administered in one or
more dosage units (e.g. one or more tablets). If multiple dosage
units are used they may be taken at one time or spaced intervals
during the day. The amounts indicated are of the specified nutrient
component and do not include the mass of any counter ions.
Accordingly, the specified component may be derived from any
pharmaceutically acceptable compound or salt. Further the examples
give amounts of nutrients (e.g. vitamins or minerals) and it should
be understood that the specified nutrients may be combined with one
or more excipients to prepare a final dosage form.
TABLE-US-00001 TABLE 1 Ingredient Amount/Daily Dosage Vitamin A
(and precursors) 3500 IU Vitamin D 400 IU Vitamin E 30 IU Vitamin C
(ascorbic acid) 60 mg Vitamin B1 (thiamin) 1.5 mg Vitamin B2
(riboflavin) 1.7 mg Niacin 20 mg Vitamin B6 (pyridoxine) 2 mg Folic
Acid 400 mcg Vitamin B12 (cyanocobalamin) 6 mcg Pathothenic Acid 10
mg Calcium 220 mg Phosphorus 110 mg Magnesium 50 mg Copper 1 mg
Iron 18 mg Manganese 2 mg Zinc 15 mg
TABLE-US-00002 TABLE 2 Ingredient Amount/Daily Dosage Vitamin A
(and precursors) 300 IU Vitamin D 400 IU Vitamin E 45 IU Vitamin K
50 mcg Vitamin C (ascorbic acid) 90 mg Vitamin B1 (thiamin) 1.5 mg
Vitamin B2 (riboflavin) 1.7 mg Niacin 20 mg Vitamin B6 (pyridoxine)
2 mg Folic Acid 400 mcg Vitamin B12 (cyanocobalamin) 6 mcg
Pathothenic Acid 10 mg Biotin 30 mg Calcium 200 mg Phosphorus 100
mg Magnesium 100 mg Potassium 40 mg Boron 150 mcg Chromium 120 mcg
Copper 2 mg Sodium 150 mcg Iron 18 mg Manganese 2 mg Molybdenum 25
mcg Selenium 25 mcg Silicon 2 mg Tin 10 mcg Vanadium 10 mcg Zinc 15
mg Nickel 5 mcg Chloride 36 mg Lutein 300 mcg Lycopene 600 mcg
Astexanthin 100 mcg Zeaxanthin 300 mcg Inositol 50 mg Choline 55
mg
TABLE-US-00003 TABLE 3 Ingredient Amount/Daily Dosage Vitamin A
(and precursors) 5000 IU Vitamin D 200 IU Vitamin E 60 IU Vitamin K
25 mcg Vitamin C (ascorbic acid) 120 mg Vitamin B1 (thiamin) 4.5 mg
Vitamin B2 (riboflavin) 5.1 mg Niacin 40 mg Vitamin B6 (pyridoxine)
6 mg Folic Acid 800 mcg Vitamin B12 (cyanocobalamin) 18 mcg
Pathothenic acid 20 mg Biotin 45 mcg Calcium 250 mg Phosphorus 160
mg Magnesium 40 mg Potassium 80 mg Boron 60 mcg Chromium 120 mcg
Copper 0.5 mg Iodine 150 mcg Iron 9 mg Manganese 4 mg Molybdenum 75
mcg Selenium 70 mcg Silicon 4 mg Zinc 7.5 mg Chloride 72 mg
EXAMPLE 2
[0044] Table 4 shows stability data for tablets of an exemplary
embodiment of the invention prepared with anhydrous dicalcium
phosphate as compared to the same combination of ingredients
prepared in the same manner with the exception that dicalcium
phosphate dihydrate was used instead of anhydrous dicalcium
phosphate. Both sets of tablets comprised 60 mg/tablet Ascorbic
Acid (Vitamin C) and 30 IU/tablet Vitamin E and the polyvalent
metal cations of 18 mg/tablet iron (as ferrous fumarate), 100
mg/tablet Magnesium (as magnesium oxide), 2 mg/tablet copper (as
cupric oxide), 15 mg/tablet zinc (as zinc oxide), 2.5 mg/tablet
manganese (as manganese sulfate) 5 mcg/tab Nickel (as nickel
sulfate) and 25 mcg/tablet Chromium (as chromium chloride). As
indicated above, the only distinction between the two sets of
tablets was that one batch was prepared using dicalcium phosphate
dihydrate and the other batch was prepared using anhydrous
dicalcium phosphate. In both batches the amount of calcium per
tablet was 162 mg and the amount of phosphorus per tablet was 125
mg. The tablets were stored under the stressed conditions of 1 week
at 55C/95% Relative Humidity ("RH") plus 3 months at 40C/75% RH.
The tablets were examined and tested initially and at the end of
the test period.
TABLE-US-00004 TABLE 4 Vitamin C Vitamin E Disinte- Disinte-
Stability % Stability % gration gration of initial of initial Time
Time amount amount (Initial) (After) dicalcium 57.4 62.5 2.9-3.9
mins More than phosphate 1 hr dihydrate anthydrous 90.8 94.2
2.9-3.4 mins 8.5-10.2 mins dicalcium phosphate
[0045] As Table 4 shows, under the specified stress conditions,
tablets prepared with anhydrous dicalcium phosphate showed a
substantially higher potency of Vitamins C and E at the end of the
time period than those prepared with dicalcium phosphate dihydrate
(e.g. for Vitamin C 90.8% as compared to 57.4% and for Vitamin E
94.2% as compared to 62.5%). Also the disintegration times for the
tablets prepared with the anhydrous dicalcium phosphate showed
substantially less change over time than the disintegration times
for the tablets prepared using dicalcium phosphate dihydrate.
[0046] Upon visual examination at the end of three month period,
the tablets prepared with anhydrous dicalcium phosphate showed no
evidence of spotting and the tablets prepared with dicalcium
phosphate dihydrate had substantial internal and external
spotting.
[0047] 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 in the art are
intended to be included within the scope of the following
claims.
* * * * *