U.S. patent application number 13/489510 was filed with the patent office on 2012-09-27 for compositions and methods for nutrition supplementation.
This patent application is currently assigned to EVERETT LABORATORIES, INC.. Invention is credited to Charles J. Balzer, John A. Giordano.
Application Number | 20120244229 13/489510 |
Document ID | / |
Family ID | 35800244 |
Filed Date | 2012-09-27 |
United States Patent
Application |
20120244229 |
Kind Code |
A1 |
Giordano; John A. ; et
al. |
September 27, 2012 |
COMPOSITIONS AND METHODS FOR NUTRITION SUPPLEMENTATION
Abstract
The present invention relates to compositions that may be
swallowable, chewable or dissolvable, comprising various vitamins
and minerals, and in a specific embodiment comprising vitamin A,
beta carotene, B-complex vitamins, vitamin C, vitamin D.sub.3,
vitamin E, iron, magnesium and zinc, and methods for using these
compositions for nutritional supplementation in subjects undergoing
physiologically stressful events, such as, for example and without
limitation, pregnancy, lactation or any disease state.
Inventors: |
Giordano; John A.; (West
Orange, NJ) ; Balzer; Charles J.; (Lavalette,
NJ) |
Assignee: |
EVERETT LABORATORIES, INC.
West Orange
NJ
|
Family ID: |
35800244 |
Appl. No.: |
13/489510 |
Filed: |
June 6, 2012 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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11928610 |
Oct 30, 2007 |
8197855 |
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13489510 |
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10916534 |
Aug 12, 2004 |
7560123 |
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11928610 |
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Current U.S.
Class: |
424/643 ; 426/2;
426/73 |
Current CPC
Class: |
A61K 31/4406 20130101;
A61K 31/355 20130101; A61K 31/519 20130101; A61K 33/26 20130101;
A61K 31/51 20130101; A61K 45/06 20130101; A61K 31/355 20130101;
A61K 33/30 20130101; A61K 31/714 20130101; A61K 33/06 20130101;
A61K 31/51 20130101; A61K 31/714 20130101; A61K 31/525 20130101;
A61P 3/02 20180101; A61K 31/375 20130101; A61K 47/34 20130101; A61K
33/26 20130101; A61K 33/06 20130101; A61K 9/0053 20130101; A61K
2300/00 20130101; A61K 31/015 20130101; Y10S 514/904 20130101; A61K
2300/00 20130101; A61K 33/30 20130101; A61K 33/08 20130101; A61K
31/07 20130101; A61K 31/4415 20130101; A61K 31/455 20130101; A61K
31/525 20130101; A61K 9/0056 20130101; A61K 31/593 20130101; A61K
31/715 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/643 ; 426/73;
426/2 |
International
Class: |
A61K 33/30 20060101
A61K033/30; A23L 1/304 20060101 A23L001/304; A23L 1/222 20060101
A23L001/222; A61P 3/02 20060101 A61P003/02; A23L 1/236 20060101
A23L001/236; A23L 1/09 20060101 A23L001/09; A23L 1/30 20060101
A23L001/30; A23L 1/303 20060101 A23L001/303; A23L 1/28 20060101
A23L001/28 |
Claims
1. A composition comprising vitamin A, beta carotene, B-complex
vitamins, vitamin C, vitamin D.sub.3, vitamin E, iron, magnesium
and zinc, wherein said composition is administrable to a
patient.
2. The composition of claim 1, wherein said composition is in a
swallowable form.
3. The composition of claim 1, wherein said composition is in a
chewable form.
4. The composition of claim 1, wherein said composition is in a
dissolvable form.
5. The composition of claim 1, wherein said vitamin A comprises
acetate.
6. The composition of claim 1, wherein said B-complex vitamins
comprise one or more the vitamins selected from the group
consisting of vitamin B.sub.1, vitamin B.sub.2, vitamin B.sub.3,
vitamin B.sub.6, vitamin B.sub.9 and vitamin B.sub.12.
7. The composition of claim 6, wherein said vitamin B.sub.1
comprises thiamine mononitrate.
8. The composition of claim 6, wherein said vitamin B.sub.2
comprises riboflavin.
9. The composition of claim 6, wherein said vitamin B.sub.3
comprises niacinamide.
10. The composition of claim 6, wherein said vitamin B.sub.3
comprises an equivalent molar amount of niacin.
11. The composition of claim 6, wherein said vitamin B.sub.6
comprises pyridoxine hydrochloride.
12. The composition of claim 6, wherein said vitamin B.sub.9
comprises folic acid.
13. The composition of claim 6, wherein said vitamin B.sub.9
comprises folacin.
14. The composition of claim 6, wherein said vitamin B.sub.9
comprises metafolin.
15. The composition of claim 6, wherein said vitamin B.sub.9
comprises folate.
16. The composition of claim 6, wherein said vitamin B.sub.9
comprises one or more natural isomers of folate consisting of
(6S)-tetrahydrofolic acid or a polyglutamyl derivative thereof,
5-methyl-(6S)-tetrahydrofolic acid or a polyglutamyl derivative
thereof, 5-formyl-(6S)-tetrahydrofolic acid or a polyglutamyl
derivative thereof, 10-formyl-(6R)-tetrahydrofolic acid or a
polyglutamyl derivative thereof,
5,10-methylene-(6R)-tetrahydrofolic acid or a polyglutamyl
derivative thereof, 5,10-methenyl-(6R)-tetrahydrofolic acid or a
polyglutamyl derivative thereof and
5-formimino-(6S)-tetrahydrofolic acid or a polyglutamyl derivative
thereof.
17. The composition of claim 6, wherein said vitamin B.sub.12
comprises cyanocobalamin.
18. The composition of claim 1, wherein said vitamin C comprises
ascorbic acid.
19. The composition of claim 1, wherein said vitamin D.sub.3
comprises cholecalciferol.
20. The composition of claim 1, wherein said vitamin E comprises
d-alpha tocopheryl acetate.
21. The composition of claim 1, wherein said vitamin E comprises
d-alpha tocopheryl succinate.
22. The composition of claim 1, wherein said iron comprises ferrous
fumarate.
23. The composition of claim 1, wherein said iron comprises
polysaccharide complex.
24. The composition of claim 1, wherein said magnesium comprises
magnesium oxide.
25. The composition of claim 1, wherein said zinc comprises zinc
oxide.
26. The composition of claim 1, wherein said composition is
substantially free of other added vitamins and minerals.
27. The composition of claim 1, further comprising a
pharmaceutically acceptable carrier.
28. The composition of claim 27, wherein said pharmaceutically
acceptable carrier is selected from one or more of the group
consisting of binders, diluents, lubricants, glidants, colorants,
emulsifiers, disintegrants, starches, water, oils, alcohols,
preservatives and sugars.
29. The composition of claim 1, further comprising a sweetening
agent.
30. The composition of claim 29, wherein said sweetening agent is
selected from one or more of the group consisting of sucrose,
fructose, high fructose corn syrup, dextrose, saccharin sodium,
maltodextrin, aspartame, potassium acesulfame, neohesperidin
dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and
mixtures thereof.
31. The composition of claim 1, further comprising a flavorant.
32. The composition of claim 31, wherein said flavorant is selected
from one or more of the group consisting of a natural flavor oil, a
synthetic flavor oil, a citrus oil, a fruit essence, an extract
from a plant, an extract from a leaf, an extract from a flower, an
extract from a fruit, a synthetic flavor and a combination
thereof.
33. The composition of claim 31, wherein said flavorant is selected
from one or more of the group consisting of anise oil, cinnamon
oil, peppermint oil, oil of wintergreen, clove oil, bay oil, anise
oil, eucalyptus oil, thyme oil, cedar leave oil, oil of nutmeg, oil
of sage, oil of bitter almonds, cassia oil, lemon oil, orange oil,
lime oil, grapefruit oil, grape oil and a combination thereof.
34. The composition of claim 31, wherein said flavorant is selected
from one or more of the group consisting of apple essence, pear
essence, peach essence, berry essence, wildberry essence, date
essence, blueberry essence, kiwi essence, strawberry essence,
raspberry essence, cherry essence, plum essence, pineapple essence,
and apricot essence.
35. The composition of claim 31, wherein said flavorant is selected
from one or more of the group consisting of natural mixed berry
flavor, citric acid, malic acid, vanilla, vanillin, cocoa,
chocolate, and menthol.
36. The composition of claim 1, wherein said composition further
comprises alkyl polysiloxane in an amount of about 0.05 weight
percent to less than about one weight percent of the
composition.
37. The composition of claim 36, wherein said alkyl polysiloxane is
in the form of dimethyl polysiloxane.
38. The composition of claim 1, wherein said composition further
comprises fructose, stearic acid, natural mixed berry flavor,
croscarmellose sodium, citric acid, magnesium stearate, silicon
dioxide, and malic acid.
39. The composition of claim 1, wherein said vitamin A is present
in the range of about 550 IU to about 1650 IU.
40. The composition of claim 1, wherein said beta carotene is
present in the range of about 300 IU to about 900 IU.
41. The composition of claim 6, wherein said vitamin B.sub.1 is
present in the range of about 1 mg to about 3 mg.
42. The composition of claim 6, wherein said vitamin B.sub.2 is
present in the range of about 1 mg to about 3 mg.
43. The composition of claim 6, wherein said vitamin B.sub.3 is
present in the range of about 7 mg to about 23 mg.
44. The composition of claim 6, wherein said vitamin B.sub.6 is
present in the range of about 1 mg to about 4 mg.
45. The composition of claim 6, wherein said vitamin B.sub.9 is
present in the range of about 500 .mu.g to about 1500 .mu.g.
46. The composition of claim 6, wherein said vitamin B.sub.12 is
present in the range of about 2 .mu.g to about 8 .mu.g.
47. The composition of claim 1, wherein said vitamin C is present
in the range of about 30 mg to about 90 mg.
48. The composition of claim 1, wherein said vitamin D.sub.3 is
present in the range of about 200 IU to about 600 IU.
49. The composition of claim 1, wherein said vitamin E is present
in the range of about 15 IU to about 45 IU.
50. The composition of claim 1, wherein said iron is present in the
range of about 14 mg to about 44 mg.
51. The composition of claim 1, wherein said magnesium is present
in the range of about 12 mg to about 38 mg.
52. The composition of claim 1, wherein said zinc is present in the
range of about 7 mg to about 23 mg.
53. The composition of claim 1, wherein said composition comprises
about 550 IU to about 1650 IU vitamin A; about 300 IU to about 900
IU beta carotene; about 1 mg to about 3 mg vitamin B.sub.1; about 1
mg to about 3 mg vitamin B.sub.2; about 7 mg to about 23 mg vitamin
B.sub.3; about 1 mg to about 4 mg vitamin B.sub.6; about 500 .mu.g
to about 1500 .mu.g vitamin B.sub.9; about 2 .mu.g to about 8 .mu.g
vitamin B.sub.12; about 30 mg to about 90 mg vitamin C; about 200
IU to about 600 IU vitamin D.sub.3; about 15 IU to about 45 IU
vitamin E; about 14 mg to about 44 mg iron; about 12 mg to about 38
mg magnesium; and/or about 7 mg to about 23 mg zinc.
54. The composition of claim 1, wherein said composition comprises
about 880 IU to about 1320 IU vitamin A; about 480 IU to about 720
IU beta carotene; about 1.3 mg to about 1.9 mg vitamin B.sub.1;
about 1.5 mg to about 2.2 mg vitamin B.sub.2; about 12 mg to about
18 mg vitamin B.sub.3; about 2 mg to about 3 mg vitamin B.sub.6;
about 800 .mu.g to about 1200 .mu.g vitamin B.sub.9; about 4 .mu.g
to about 6 .mu.g vitamin B.sub.12; about 48 mg to about 72 mg
vitamin C; about 320 IU to about 480 IU vitamin D.sub.3; about 24
IU to about 36 IU vitamin E; about 23 mg to about 35 mg iron; about
20 mg to about 30 mg magnesium; and about 12 mg to about 18 mg
zinc.
55. The composition of claim 1, wherein said composition comprises
about 990 IU to about 1210 IU vitamin A; about 540 IU to about 660
IU beta carotene; about 1.5 mg to about 1.75 mg vitamin B.sub.1;
about 1.6 mg to about 2 mg vitamin B.sub.2; about 13.5 mg to about
16.5 mg vitamin B.sub.3; about 2.3 mg to about 2.8 mg vitamin
B.sub.6; about 900 .mu.g to about 1100 .mu.g vitamin B.sub.9; about
4.5 .mu.g to about 5.5 .mu.g vitamin B.sub.12; about 54 mg to about
66 mg vitamin C; about 360 IU to about 440 IU vitamin D.sub.3;
about 27 IU to about 33 IU vitamin E; about 26 mg to about 32 mg
iron; about 22.5 mg to about 27.5 mg magnesium; and about 13.5 mg
to about 16.5 mg zinc.
56. The composition of claim 1, wherein said vitamin A is present
in the amount of about 1100 IU.
57. The composition of claim 1, wherein said beta carotene is
present in the range of about 600 IU.
58. The composition of claim 6, wherein said vitamin B.sub.1 is
present in the amount of about 1.6 mg.
59. The composition of claim 6, wherein said vitamin B.sub.2 is
present in the amount of about 1.8 mg.
60. The composition of claim 6, wherein said vitamin B.sub.3 is
present in the amount of about 15 mg.
61. The composition of claim 6, wherein said vitamin B.sub.6 is
present in the amount of about 2.5 mg.
62. The composition of claim 6, wherein said vitamin B.sub.9 is
present in the amount of about 1000 .mu.g.
63. The composition of claim 6, wherein said vitamin B.sub.12 is
present in the amount of about 5 .mu.g.
64. The composition of claim 1, wherein said vitamin C is present
in the amount of about 60 mg.
65. The composition of claim 1, wherein said vitamin D.sub.3 is
present in the amount of about 400 IU.
66. The composition of claim 1, wherein said vitamin E is present
in the amount of about 30 IU.
67. The composition of claim 1, wherein said iron is present in the
amount of about 29 mg.
68. The composition of claim 1, wherein said magnesium is present
in the amount of about 25 mg.
69. The composition of claim 1, wherein said zinc is present in the
amount of about 15 mg.
70. The composition of claim 1, wherein said composition comprises
about 1100 IU vitamin A; about 600 IU beta carotene; about 1.6 mg
vitamin B.sub.1; about 1.8 mg vitamin B.sub.2; about 15 mg vitamin
B.sub.3; about 2.5 mg vitamin B.sub.6; about 1000 .mu.g vitamin
B.sub.9; about 5 .mu.g vitamin B.sub.12; about 60 mg vitamin C;
about 400 IU vitamin D.sub.3; about 30 IU vitamin E; about 29 mg
iron; about 25 mg magnesium; and about 15 mg zinc.
71. The composition of claim 1, wherein said patient is
pregnant.
72. The composition of claim 1, wherein said patient is
lactating.
73. The composition of claim 1, wherein said patient has
nutritional deficiencies.
74. The composition of claim 73, wherein said nutritional
deficiencies are a result of pregnancy.
75. The composition of claim 73, wherein said nutritional
deficiencies are a result of lactation.
76. The composition of claim 73, wherein said nutritional
deficiencies are a result of elevated metabolic demand.
77. The composition of claim 73, wherein said nutritional
deficiencies are a result of increased plasma volume.
78. The composition of claim 73, wherein said nutritional
deficiencies are a result of decreased concentrations of
nutrient-binding proteins.
79. The composition of claim 78, wherein said nutrient-binding
proteins comprise one or more of the proteins selected from the
group consisting of serum-ferritin, maltose-binding protein,
lactoferrin, calmodulin, tocopheryl binding protein, riboflavin
binding protein, retinal binding protein, transthyretin, high
density lipoprotein-apolipoprotein A1, folic acid binding protein,
and 25-hydroxyvitamin D binding protein.
80. A method comprising administering a composition comprising
vitamin A, beta carotene, B-complex vitamins, vitamin C, vitamin
D.sub.3, vitamin E, iron, magnesium and zinc, to supplement
nutritional deficiencies in a patient.
81. The method of claim 80, wherein said composition is in a
swallowable form.
82. The method of claim 80, wherein said composition is in a
chewable form.
83. The method of claim 80, wherein said composition is in a
dissolvable form.
84. The method of claim 80, wherein said vitamin A comprises
acetate.
85. The method of claim 80, wherein said B-complex vitamins
comprise one or more vitamins selected from the group consisting of
vitamin B.sub.1, vitamin B.sub.2, vitamin B.sub.6, niacinamide,
folic acid and vitamin B.sub.12.
86. The method of claim 85, wherein said vitamin B.sub.1 comprises
thiamine mononitrate.
87. The method of claim 85, wherein said vitamin B.sub.2 comprises
riboflavin.
88. The method of claim 85, wherein said B.sub.3 comprises
niacinamide.
89. The method of claim 85, wherein said B.sub.3 comprises an
equivalent molar amount of niacin.
90. The method of claim 85, wherein said vitamin B.sub.6 comprises
pyridoxine hydrochloride.
91. The method of claim 85, wherein said vitamin B.sub.9 comprises
folic acid.
92. The method of claim 85, wherein said vitamin B.sub.9 comprises
folacin.
93. The method of claim 85, wherein said vitamin B.sub.9 comprises
metafolin.
94. The method of claim 85, wherein said vitamin B.sub.9 comprises
folate.
95. The method of claim 85, wherein said vitamin B.sub.9 comprises
one or more natural isomers of folate consisting of
(6S)-tetrahydrofolic acid or a polyglutamyl derivative thereof,
5-methyl-(6S)-tetrahydrofolic acid or a polyglutamyl derivative
thereof, 5-formyl-(6S)-tetrahydrofolic acid or a polyglutamyl
derivative thereof, 10-formyl-(6R)-tetrahydrofolic acid or a
polyglutamyl derivative thereof,
5,10-methylene-(6R)-tetrahydrofolic acid or a polyglutamyl
derivative thereof, 5,10-methenyl-(6R)-tetrahydrofolic acid or a
polyglutamyl derivative thereof and
5-formimino-(6S)-tetrahydrofolic acid or a polyglutamyl derivative
thereof.
96. The method of claim 85, wherein said vitamin B.sub.12 comprises
cyanocobalamin.
97. The method of claim 80, wherein said vitamin C comprises
ascorbic acid.
98. The method of claim 80, wherein said vitamin D.sub.3 comprises
cholecalciferol.
99. The method of claim 80, wherein said vitamin E comprises
d-alpha tocopheryl acetate.
100. The method of claim 80, wherein said vitamin E comprises
d-alpha tocopheryl succinate.
101. The method of claim 80, wherein said iron comprises ferrous
fumarate.
102. The method of claim 80, wherein said iron comprises
polysaccharide complex.
103. The method of claim 80, wherein said magnesium comprises
magnesium oxide.
104. The method of claim 80, wherein said zinc comprises zinc
oxide.
105. The method of claim 80, wherein said composition is
substantially free of other added vitamins and minerals.
106. The method of claim 80, further comprising a pharmaceutically
acceptable carrier.
107. The method of claim 106, wherein said pharmaceutically
acceptable carrier is selected from one or more of the group
consisting of binders, diluents, lubricants, glidants, colorants,
emulsifiers, disintegrants, starches, water, oils, alcohols,
preservatives and sugars.
108. The method of claim 80, further comprising a sweetening
agent.
109. The method of claim 108, wherein said sweetening agent is
selected from one or more of the group consisting of sucrose,
fructose, high fructose corn syrup, dextrose, saccharin sodium,
maltodextrin, aspartame, potassium acesulfame, neohesperidin
dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and
mixtures thereof.
110. The method of claim 80, further comprising a flavorant.
111. The method of claim 110, wherein said flavorant is selected
from one or more of the group consisting of a natural flavor oil, a
synthetic flavor oil, a citrus oil, a fruit essence, an extract
from a plant, an extract from a leaf, an extract from a flower, an
extract from a fruit, a synthetic flavor and a combination
thereof.
112. The method of claim 110, wherein said flavorant is selected
from one or more of the group consisting of anise oil, cinnamon
oil, peppermint oil, oil of wintergreen, clove oil, bay oil, anise
oil, eucalyptus oil, thyme oil, cedar leave oil, oil of nutmeg, oil
of sage, oil of bitter almonds, cassia oil, lemon oil, orange oil,
lime oil, grapefruit oil, grape oil and a combination thereof.
113. The method of claim 110, wherein said flavorant is selected
from one or more of the group consisting of apple essence, pear
essence, peach essence, berry essence, wildberry essence, date
essence, blueberry essence, kiwi essence, strawberry essence,
raspberry essence, cherry essence, plum essence, pineapple essence,
and apricot essence.
114. The method of claim 110, wherein said flavorant is selected
from one or more of the group consisting of natural mixed berry
flavor, citric acid, malic acid, vanilla, vanillin, cocoa,
chocolate, and menthol.
115. The method of claim 80, wherein said composition further
comprises alkyl polysiloxane in an amount of about 0.05 weight
percent to less than about one weight percent of the
composition.
116. The method of claim 115, wherein said alkyl polysiloxane is in
the form of dimethyl polysiloxane.
117. The method of claim 80, wherein said composition further
comprises fructose, stearic acid, natural mixed berry flavor,
croscarmellose sodium, citric acid, magnesium stearate, silicon
dioxide, and malic acid.
118. The method of claim 80, wherein said vitamin A is present in
the range of about 550 IU to about 1650 IU.
119. The method of claim 80, wherein said beta carotene is present
in the range of about 300 IU to about 900 IU.
120. The method of claim 85, wherein said vitamin B.sub.1 is
present in the range of about 1 mg to about 3 mg.
121. The method of claim 85, wherein said vitamin B.sub.2 is
present in the range of about 1 mg to about 3 mg.
122. The method of claim 85, wherein said vitamin B.sub.3 is
present in the range of about 7 mg to about 23 mg.
123. The method of claim 85, wherein said vitamin B.sub.6 is
present in the range of about 1 mg to about 4 mg.
124. The method of claim 85, wherein said vitamin B.sub.9 is
present in the range of about 500 .mu.g to about 1500 .mu.g.
125. The method of claim 85, wherein said vitamin B.sub.12 is
present in the range of about 2 .mu.g to about 8 .mu.g.
126. The method of claim 80, wherein said vitamin C is present in
the range of about 30 mg to about 90 mg.
127. The method of claim 80, wherein said vitamin D.sub.3 is
present in the range of about 200 IU to about 600 IU.
128. The method of claim 80, wherein said vitamin E is present in
the range of about 15 IU to about 45 IU.
129. The method of claim 80, wherein said iron is present in the
range of about 14 mg to about 44 mg.
130. The method of claim 80, wherein said magnesium is present in
the range of about 12 mg to about 38 mg.
131. The method of claim 80, wherein said zinc is present in the
range of about 7 mg to about 23 mg.
132. The method of claim 80, wherein said composition comprises
about 550 IU to about 1650 IU vitamin A; about 300 IU to about 900
IU beta carotene; about 1 mg to about 3 mg vitamin B.sub.1; about 1
mg to about 3 mg vitamin B.sub.2; about 7 mg to about 23 mg vitamin
B.sub.3; about 1 mg to about 4 mg vitamin B.sub.6; about 500 .mu.g
to about 1500 .mu.g vitamin B.sub.9; about 2 .mu.g to about 8 .mu.g
vitamin B.sub.12; about 30 mg to about 90 mg vitamin C; about 200
IU to about 600 IU vitamin D.sub.3; about 15 IU to about 45 IU
vitamin E; about 14 mg to about 44 mg iron; about 12 mg to about 38
mg magnesium; and/or about 7 mg to about 23 mg zinc.
133. The method of claim 80, wherein said composition comprises
about 880 IU to about 1320 IU vitamin A; about 480 IU to about 720
IU beta carotene; about 1.3 mg to about 1.9 mg vitamin B.sub.1;
about 1.5 mg to about 2.2 mg vitamin B.sub.2; about 12 mg to about
18 mg vitamin B.sub.3; about 2 mg to about 3 mg vitamin B.sub.6;
about 800 .mu.g to about 1200 .mu.g vitamin B.sub.9; about 4 .mu.g
to about 6 .mu.g vitamin B.sub.12; about 48 mg to about 72 mg
vitamin C; about 320 IU to about 480 IU vitamin D.sub.3; about 24
IU to about 36 IU vitamin E; about 23 mg to about 35 mg iron; about
20 mg to about 30 mg magnesium; and about 12 mg to about 18 mg
zinc.
134. The method of claim 80, wherein said composition comprises
about 990 IU to about 1210 IU vitamin A; about 540 IU to about 660
IU beta carotene; about 1.5 mg to about 1.75 mg vitamin B.sub.1;
about 1.6 mg to about 2 mg vitamin B.sub.2; about 13.5 mg to about
16.5 mg vitamin B.sub.3; about 2.3 mg to about 2.8 mg vitamin
B.sub.6; about 900 .mu.g to about 1100 .mu.g vitamin B.sub.9; about
4.5 .mu.g to about 5.5 .mu.g vitamin B.sub.12; about 54 mg to about
66 mg vitamin C; about 360 IU to about 440 IU vitamin D.sub.3;
about 27 IU to about 33 IU vitamin E; about 26 mg to about 32 mg
iron; about 22.5 mg to about 27.5 mg magnesium; and about 13.5 mg
to about 16.5 mg zinc.
135. The method of claim 80, wherein said vitamin A is present in
the amount of about 1100 IU.
136. The method of claim 80, wherein said beta carotene is present
in the range of about 600 IU.
137. The method of claim 85, wherein said vitamin B.sub.1 is
present in the amount of about 1.6 mg.
138. The method of claim 85, wherein said vitamin B.sub.2 is
present in the amount of about 1.8 mg.
139. The method of claim 85, wherein said vitamin B.sub.3 is
present in the amount of about 15 mg.
140. The method of claim 85, wherein said vitamin B.sub.6 is
present in the amount of about 2.5 mg.
141. The method of claim 85, wherein said vitamin B.sub.9 is
present in the amount of about 1000 .mu.g.
142. The method of claim 85, wherein said vitamin B.sub.12 is
present in the amount of about 5 .mu.g.
143. The method of claim 80, wherein said vitamin C is present in
the amount of about 60 mg.
144. The method of claim 80, wherein said vitamin D.sub.3 is
present in the amount of about 400 IU.
145. The method of claim 80, wherein said vitamin E is present in
the amount of about 30 IU.
146. The method of claim 80, wherein said iron is present in the
amount of about 29 mg.
147. The method of claim 80, wherein said magnesium is present in
the amount of about 25 mg.
148. The method of claim 80, wherein said zinc is present in the
amount of about 15 mg.
149. The method of claim 80, wherein said composition comprises
about 1100 IU vitamin A; about 600 IU beta carotene; about 1.6 mg
vitamin B.sub.1; about 1.8 mg vitamin B.sub.2; about 15 mg vitamin
B.sub.3; about 2.5 mg vitamin B.sub.6; about 1000 .mu.g vitamin
B.sub.9; about 60 mg vitamin C; about 400 IU vitamin D.sub.3; about
30 IU vitamin E; about 29 mg iron; about 25 mg magnesium; and about
15 mg zinc.
150. The method of claim 80, wherein said patient is pregnant.
151. The method of claim 80, wherein said patient is lactating.
152. The method of claim 80, wherein said patient has nutritional
deficiencies.
153. The method of claim 152, wherein said nutritional deficiencies
are a result of pregnancy.
154. The method of claim 152, wherein said nutritional deficiencies
are a result of lactation.
155. The method of claim 152, wherein said nutritional deficiencies
are a result of elevated metabolic demand.
156. The method of claim 152, wherein said nutritional deficiencies
are a result of increased plasma volume.
157. The method of claim 152, wherein said nutritional deficiencies
are a result of decreased concentrations of nutrient-binding
proteins.
158. The method of claim 157, wherein said nutrient-binding
proteins comprise one or more proteins selected from the group
consisting of serum-ferritin, maltose-binding protein, lactoferrin,
calmodulin, tocopheryl binding protein, riboflavin binding protein,
retinal binding protein, transthyretin, high density
lipoprotein-apolipoprotein A1, folic acid binding protein, and
25-hydroxyvitamin D binding protein.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compositions, that may be
swallowable, chewable and/or dissolvable, comprising various
vitamins and minerals, and methods for using these compositions for
nutritional supplementation in, for example, subjects in
physiologically stressful states.
BACKGROUND OF THE INVENTION
[0002] Nutrition plays a critical role in maintaining good health.
Proper nutrition prevents dietary deficiencies, and also protects
against the development of disease. When the body faces
physiological stress, proper nutrition plays an increasingly
important role. For example, pregnancy and lactation are among the
most nutritionally volatile and physiologically stressful periods
and processes in the lifetimes of women. Vitamin and mineral needs
are almost universally increased during these natural processes.
Increased vitamin and mineral needs during these times are almost
always due to elevated metabolic demand, increased plasma volume,
increased levels of blood cells, decreased concentrations of
nutrients, and decreased concentrations of nutrient-binding
proteins.
[0003] When increased nutrient needs occur during pregnancy,
lactation, or any other physiologically stressful state,
nutritional supplementation serves a vital role in maintaining good
health. Nutritional supplementation is especially pertinent to
women contemplating conceiving a child because optimizing specific
nutrients before, during, and after the physiological processes of
pregnancy or lactation can have profound, positive, and
comprehensive impacts upon the overall wellness of the developing
and newborn child as well as on the safety and health of the
mother. The present invention provides compositions and methods
designed to supplement the nutritional needs of individuals in
physiologically stressful states.
[0004] Further, while some patients may prefer swallowable dosage
forms, it is estimated that 50% of the population has problems
swallowing whole tablets. Seager, 50 J. PHARM. PHARMACOL. 375-82
(1998). These problems can lead to poor, or even noncompliance,
with dosing regimens and thus have negative impacts on treatment
efficiency. Id. Administration of vitamins and minerals through
chewable or dissolvable compositions solves this problem because
the compositions need not be swallowed whole.
SUMMARY OF THE INVENTION
[0005] The present invention provides compositions and methods of
using these compositions for both prophylactic and therapeutic
nutritional supplementation. Specifically, for example, the present
invention relates to novel compositions of vitamins and minerals
that can be used to supplement the nutritional deficiencies
observed in patients undergoing physiologically stressful states
such as, for example and without limitation, pregnancy, lactation,
and any disease state. The compositions of the present invention
may be in a swallowable, chewable or dissolvable form according to
an individual patient's preference. Choice in dosage form promotes
ease of administration and compliance with dosing regimens.
[0006] In one embodiment of the present invention, the compositions
may comprise vitamin A, beta carotene, B-complex vitamins, vitamin
C, vitamin D.sub.3, vitamin E, iron, magnesium, and zinc.
[0007] In another embodiment, the compositions of the present
invention may comprise one or more of vitamin A in the form of
acetate; beta carotene; vitamin B.sub.1 in the form of thiamine
mononitrate; vitamin B.sub.2 in the form of riboflavin; vitamin
B.sub.3 in the form of niacinamide or niacin; vitamin B.sub.6 in
the form of pyridoxine hydrochloride; vitamin B.sub.9 in the form
of folic acid, folacin, metafolin, folate and/or one or more
natural isomers of folate including (6S)-tetrahydrofolic acid or a
polyglutamyl derivative thereof, 5-methyl-(6S)-tetrahydrofolic acid
or a polyglutamyl derivative thereof, 5-formyl-(6S)-tetrahydrofolic
acid or a polyglutamyl derivative thereof,
10-formyl-(6R)-tetrahydrofolic acid or a polyglutamyl derivative
thereof, 5,10-methylene-(6R)-tetrahydrofolic acid or a polyglutamyl
derivative thereof, 5,10-methenyl-(6R)-tetrahydrofolic acid or a
polyglutamyl derivative thereof and
5-formimino-(6S)-tetrahydrofolic acid or a polyglutamyl derivative
thereof; vitamin B.sub.12 in the form of cyanocobalamin; vitamin C
in the form of ascorbic acid; vitamin D.sub.3 in the form of
cholecalciferol; vitamin E in the form of d-alpha tocopheryl
acetate or d-alpha tocopheryl succinate; iron in the form of
polysaccharide complex or ferrous fumarate; magnesium in the form
of magnesium oxide; and/or zinc in the form of zinc oxide.
[0008] In another embodiment of the present invention, the
compositions may be substantially free of any other added vitamins
and minerals not described in the preceding paragraph. For example,
the compositions of the present invention may be substantially free
of added alpha carotene; substantially free of added lutein;
substantially free of added lycopene; substantially free of added
zeaxanthin; substantially free of added vitamin B.sub.4;
substantially free of added vitamin B.sub.5; substantially free of
added vitamin B.sub.7; substantially free of added vitamin B.sub.8;
substantially free of added vitamin B.sub.10; substantially free of
added vitamin B.sub.11; substantially free of added calcium;
substantially free of added chromium; substantially free of added
copper; substantially free of added manganese; substantially free
of added selenium; substantially free of added boron; substantially
free of added odorless garlic; substantially free of added coenzyme
Q-10; substantially free of added 1-carnitine; substantially free
of added grape seed extract; substantially free of added green tea
extract; substantially free of added quercetin; substantially free
of added hawthorne berries; and/or substantially free of added
alpha lipoic acid.
[0009] In another specific embodiment, the compositions of the
present invention may be substantially free of added vitamin A;
substantially free of added beta carotene; substantially free of
added vitamin B.sub.1; substantially free of added vitamin B.sub.2;
substantially free of added vitamin B.sub.3; substantially free of
added vitamin B.sub.6; substantially free of added vitamin B.sub.9;
substantially free of added vitamin B.sub.12; substantially free of
added vitamin C; substantially free of added vitamin D.sub.3;
substantially free of added vitamin E; substantially free of added
iron; substantially free of added magnesium; and/or substantially
free of added zinc.
[0010] In another embodiment, the compositions of the present
invention may comprise pharmaceutically acceptable carriers, such
as one or more of binders, diluents, lubricants, glidants,
colorants, emulsifiers, disintegrants, starches, water, oils,
alcohols, preservatives, and sugars.
[0011] In another embodiment of the present invention, the
compositions may comprise sweetening agents such as one or more of
sucrose, fructose, high fructose corn syrup, dextrose, saccharin
sodium, maltodextrin, aspartame, potassium acesulfame,
neohesperidin dihydrochalcone, sucralose, monoammonium
glycyrrhizinate, and mixtures thereof.
[0012] In another embodiment of the present invention, the
compositions may comprise flavorants such as one or more of anise
oil, cinnamon oil, peppermint oil, oil of wintergreen, clove oil,
bay oil, anise oil, eucalyptus oil, thyme oil, cedar leave oil, oil
of nutmeg, oil of sage, oil of bitter almonds, cassia oil, lemon
oil, orange oil, lime oil, grapefruit oil, grape oil, apple
essence, pear essence, peach essence, berry essence, wildberry
essence, date essence, blueberry essence, kiwi essence, strawberry
essence, raspberry essence, cherry essence, plum essence, pineapple
essence, apricot essence, natural mixed berry flavor, citric acid,
malic acid, vanilla, vanillin, cocoa, chocolate, and menthol.
[0013] In another embodiment of the present invention, the
compositions may comprise an alkyl polysiloxane in the form of
dimethyl polysiloxane.
[0014] In another embodiment, the compositions of the present
invention may comprise one or more of about 550 IU to about 1650 IU
vitamin A; about 300 IU to about 900 IU beta carotene; about 1 mg
to about 3 mg vitamin B.sub.1; about 1 mg to about 3 mg vitamin
B.sub.2; about 7 mg to about 23 mg vitamin B.sub.3; about 1 mg to
about 4 mg vitamin B.sub.6; about 500 .mu.g to about 1500 .mu.g
vitamin B.sub.9; about 2 .mu.g to about 8 .mu.g vitamin B.sub.12;
about 30 mg to about 90 mg vitamin C; about 200 IU to about 600 IU
vitamin D.sub.3; about 15 IU to about 45 IU vitamin E; about 14 mg
to about 44 mg iron; about 12 mg to about 38 mg magnesium; and
about 7 mg to about 23 mg zinc.
[0015] In another embodiment, the compositions of the present
invention may comprise one or more of about 880 IU to about 1320 IU
vitamin A; about 480 IU to about 720 IU beta carotene; about 1.3 mg
to about 1.9 mg vitamin B.sub.1; about 1.5 mg to about 2.2 mg
vitamin B.sub.2; about 12 mg to about 18 mg vitamin B.sub.3; about
2 mg to about 3 mg vitamin B.sub.6; about 800 .mu.g to about 1200
.mu.g vitamin B.sub.9; about 4 .mu.g to about 6 .mu.g vitamin
B.sub.12; about 48 mg to about 72 mg vitamin C; about 320 IU to
about 480 IU vitamin D.sub.3; about 24 IU to about 36 IU vitamin E;
about 23 mg to about 35 mg iron; about 20 mg to about 30 mg
magnesium; and about 12 mg to about 18 mg zinc.
[0016] In another embodiment of the present invention, the
compositions may comprise one or more of about 990 IU to about 1210
IU vitamin A; about 540 IU to about 660 IU beta carotene; about 1.5
mg to about 1.75 mg vitamin B.sub.1; about 1.6 mg to about 2 mg
vitamin B.sub.2; about 13.5 mg to about 16.5 mg vitamin B.sub.3;
about 2.3 mg to about 2.8 mg vitamin B.sub.6; about 900 .mu.g to
about 1100 .mu.g vitamin B.sub.9; about 4.5 .mu.g to about 5.5
.mu.g vitamin B.sub.12; about 54 mg to about 66 mg vitamin C; about
360 IU to about 440 IU vitamin D.sub.3; about 27 IU to about 33 IU
vitamin E; about 26 mg to about 32 mg iron; about 22.5 mg to about
27.5 mg magnesium; and about 13.5 mg to about 16.5 mg zinc.
[0017] In another embodiment of the present invention, the
compositions may comprise one or more of about 1100 IU vitamin A;
about 600 IU beta carotene; about 1.6 mg vitamin B.sub.1; about 1.8
mg vitamin B.sub.2; about 15 mg vitamin B.sub.3; about 2.5 mg
vitamin B.sub.6; about 1000 .mu.g vitamin B.sub.9; about 5 .mu.g
vitamin B.sub.12; about 60 mg vitamin C; about 400 IU vitamin
D.sub.3; about 30 IU vitamin E; about 29 mg iron; about 25 mg
magnesium; and about 15 mg zinc.
[0018] In another embodiment of the present invention, the
compositions may be suitable for administration to subjects in
physiologically stressful states, such as those resulting from
pregnancy, lactation or disease states. Such compositions may be
suitable for treating nutritional deficiencies resulting from such
physiologically stressful states, which may result from, for
example and without limitation, elevated metabolic demand,
increased plasma volume, or decreased concentrations of
nutrient-binding proteins such as, for example and without
limitation, serum-ferritin, maltose-binding protein, lactoferrin,
calmodulin, tocopheryl binding protein, riboflavin binding protein,
retinol binding protein, transthyretin, high density
lipoprotein-apolipoprotein A1, folic acid binding protein and
25-hydroxyvitamin D binding protein.
[0019] The present invention also includes methods of administering
the compositions of the invention to patients to supplement
nutritional deficiencies resulting from, for example and without
limitation, pregnancy, lactation, and any disease state.
[0020] In one embodiment of the present invention, the methods may
utilize compositions comprising vitamin A, beta carotene, B-complex
vitamins, vitamin C, vitamin D.sub.3, vitamin E, iron, magnesium
and zinc. In another embodiment of the present invention, the
methods may utilize compositions in a swallowable, chewable, or
dissolvable form.
[0021] In another embodiment of the present invention, the methods
may utilize compositions including vitamin A in the form of
acetate; beta carotene; vitamin B.sub.1 in the form of thiamine
mononitrate; vitamin B.sub.2 in the form of riboflavin; vitamin
B.sub.3 in the form of niacinamide or niacin; vitamin B.sub.6 in
the form of pyridoxine hydrochloride; vitamin B.sub.9 in the form
of folic acid, folacin, metafolin, folate and/or one or more
natural isomers of folate including (6S)-tetrahydrofolic acid or a
polyglutamyl derivative thereof, 5-methyl-(6S)-tetrahydrofolic acid
or a polyglutamyl derivative thereof, 5-formyl-(6S)-tetrahydrofolic
acid or a polyglutamyl derivative thereof,
10-formyl-(6R)-tetrahydrofolic acid or a polyglutamyl derivative
thereof, 5,10-methylene-(6R)-tetrahydrofolic acid or a polyglutamyl
derivative thereof, 5,10-methenyl-(6R)-tetrahydrofolic acid or a
polyglutamyl derivative thereof and
5-formimino-(6S)-tetrahydrofolic acid or a polyglutamyl derivative
thereof; vitamin B.sub.12 in the form of cyanocobalamin; vitamin C
in the form of ascorbic acid; vitamin D.sub.3 in the form of
cholecalciferol; vitamin E in the form of d-alpha tocopheryl
acetate or d-alpha tocopheryl succinate; iron in the form of
polysaccharide complex or ferrous fumarate; magnesium in the form
of magnesium oxide; and zinc in the form of zinc oxide.
[0022] In another embodiment of the present invention, the methods
may utilize compositions substantially free of any other added
vitamins and minerals not described in the preceding paragraph. For
example, the methods may utilize compositions that are
substantially free of added alpha carotene; substantially free of
added lutein; substantially free of added lycopene; substantially
free of added zeaxanthin; substantially free of added vitamin
B.sub.4; substantially free of added vitamin B.sub.5; substantially
free of added vitamin B.sub.7; substantially free of added vitamin
B.sub.8; substantially free of added vitamin B.sub.10;
substantially free of added vitamin B.sub.11; substantially free of
added calcium; substantially free of added chromium; substantially
free of added copper; substantially free of added manganese;
substantially free of added selenium; substantially free of added
boron; substantially free of added odorless garlic; substantially
free of added coenzyme Q-10; substantially free of added
1-carnitine; substantially free of added grape seed extract;
substantially free of added green tea extract; substantially free
of added quercetin; substantially free of added hawthorne berries;
and/or substantially free of added alpha lipoic acid.
[0023] In another specific embodiment, the methods may utilize
compositions that are substantially free of added vitamin A;
substantially free of added beta carotene; substantially free of
added vitamin B.sub.1; substantially free of added vitamin B.sub.2;
substantially free of added vitamin B.sub.3; substantially free of
added vitamin B.sub.6; substantially free of added vitamin B.sub.9;
substantially free of added vitamin B.sub.12; substantially free of
added vitamin C; substantially free of added vitamin D.sub.3;
substantially free of added vitamin E; substantially free of added
iron; substantially free of added magnesium; and/or substantially
free of added zinc.
[0024] In another embodiment of the present invention, the methods
may utilize compositions comprising pharmaceutically acceptable
carriers, such as one or more of binders, diluents, lubricants,
glidants, colorants, emulsifiers, disintegrants, starches, water,
oils, alcohols, preservatives, and sugars.
[0025] In another embodiment of the present invention, the methods
may utilize compositions comprising sweetening agents such as one
or more of sucrose, fructose, high fructose corn syrup, dextrose,
saccharin sodium, maltodextrin, aspartame, potassium acesulfame,
neohesperidin dihydrochalcone, sucralose, monoammonium
glycyrrhizinate, and mixtures thereof.
[0026] In another embodiment of the present invention, the methods
may utilize compositions comprising flavorants such as one or more
of anise oil, cinnamon oil, peppermint oil, oil of wintergreen,
clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar
leave oil, oil of nutmeg, oil of sage, oil of bitter almonds,
cassia oil, lemon oil, orange oil, lime oil, grapefruit oil, grape
oil, apple essence, pear essence, peach essence, berry essence,
wildberry essence, date essence, blueberry essence, kiwi essence,
strawberry essence, raspberry essence, cherry essence, plum
essence, pineapple essence, apricot essence, natural mixed berry
flavor, citric acid, malic acid, vanilla, vanillin, cocoa,
chocolate, and menthol.
[0027] In another embodiment of the present invention, the methods
may utilize compositions comprising an alkyl polysiloxane in the
form of dimethyl polysiloxane.
[0028] In another embodiment, the methods may utilize compositions
comprising one or more of about 550 IU to about 1650 IU vitamin A;
about 300 IU to about 900 IU beta carotene; about 1 mg to about 3
mg vitamin B.sub.1; about 1 mg to about 3 mg vitamin B.sub.2; about
7 mg to about 23 mg vitamin B.sub.3; about 1 mg to about 4 mg
vitamin B.sub.6; about 500 .mu.g to about 1500 .mu.g vitamin
B.sub.9; about 2 .mu.g to about 8 .mu.g vitamin B.sub.12; about 30
mg to about 90 mg vitamin C; about 200 IU to about 600 IU vitamin
D.sub.3; about 15 IU to about 45 IU vitamin E; about 14 mg to about
44 mg iron; about 12 mg to about 38 mg magnesium; and about 7 mg to
about 23 mg zinc.
[0029] In another embodiment of the present invention, the methods
may utilize compositions comprising one or more of about 880 IU to
about 1320 IU vitamin A; about 480 IU to about 720 IU beta
carotene; about 1.3 mg to about 1.9 mg vitamin B.sub.1; about 1.5
mg to about 2.2 mg vitamin B.sub.2; about 12 mg to about 18 mg
vitamin B.sub.3; about 2 mg to about 3 mg vitamin B.sub.6; about
800 .mu.g to about 1200 .mu.g vitamin B.sub.9; about 4 .mu.g to
about 6 .mu.g vitamin B.sub.12; about 48 mg to about 72 mg vitamin
C; about 320 IU to about 480 IU vitamin D.sub.3; about 24 IU to
about 36 IU vitamin E; about 23 mg to about 35 mg iron; about 20 mg
to about 30 mg magnesium; and about 12 mg to about 18 mg zinc.
[0030] In another embodiment of the present invention, the methods
may utilize compositions comprising one or more of about 990 IU to
about 1210 IU vitamin A; about 540 IU to about 660 IU beta
carotene; about 1.5 mg to about 1.75 mg vitamin B.sub.1; about 1.6
mg to about 2 mg vitamin B.sub.2; about 13.5 mg to about 16.5 mg
vitamin B.sub.3; about 2.3 mg to about 2.8 mg vitamin B.sub.6;
about 900 .mu.g to about 1100 .mu.g vitamin B.sub.9; about 4.5
.mu.g to about 5.5 .mu.g vitamin B.sub.12; about 54 mg to about 66
mg vitamin C; about 360 IU to about 440 IU vitamin D.sub.3; about
27 IU to about 33 IU vitamin E; about 26 mg to about 32 mg iron;
about 22.5 mg to about 27.5 mg magnesium; and about 13.5 mg to
about 16.5 mg zinc.
[0031] In another embodiment of the present invention, the methods
may utilize compositions comprising one or more of about 1100 IU
vitamin A; about 600 IU beta carotene; about 1.6 mg vitamin
B.sub.1; about 1.8 mg vitamin B.sub.2; about 15 mg vitamin B.sub.3;
about 2.5 mg vitamin B.sub.6; about 1000 .mu.g vitamin B.sub.9;
about 5 .mu.g vitamin B.sub.12; about 60 mg vitamin C; about 400 IU
vitamin D.sub.3; about 30 IU vitamin E; about 29 mg iron; about 25
mg magnesium; and about 15 mg zinc.
[0032] In another embodiment of the present invention, the methods
may utilize compositions suitable for administration to subjects in
physiologically stressful states, such as those resulting from, for
example and without limitation, pregnancy, lactation or disease
states. Such compositions may be suitable for treating nutritional
deficiencies resulting from such physiologically stressful states,
which may result from, for example and without limitation, elevated
metabolic demand, increased plasma volume, or decreased
concentrations of nutrient-binding proteins such as serum-ferritin,
maltose-binding protein, lactoferrin, calmodulin, tocopheryl
binding protein, riboflavin binding protein, retinol binding
protein, transthyretin, high density lipoprotein-apolipoprotein A1,
folic acid binding protein and 25-hydroxyvitamin D binding
protein.
[0033] Other objectives, features and advantages of the present
invention will become apparent from the following detailed
description. The detailed description and the specific examples,
although indicating specific embodiments of the invention, are
provided by way of illustration only. Accordingly, the present
invention also includes those various changes and modifications
within the spirit and scope of the invention that may become
apparent to those skilled in the art from this detailed
description.
DETAILED DESCRIPTION OF THE INVENTION
[0034] It is understood that the present invention is not limited
to the particular methodologies, protocols, fillers, excipients,
etc. . . . , described herein, as these may vary. It is also to be
understood that the terminology used herein is used for the purpose
of describing particular embodiments only, and is not intended to
limit the scope of the present invention. It must be noted that as
used herein and in the appended claims, the singular forms "a,"
"an," and "the" include the plural reference unless the context
clearly dictates otherwise. Thus, for example, a reference to "a
vitamin" is a reference to one or more vitamins and includes
equivalents thereof known to those skilled in the art and so
forth.
[0035] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this invention belongs. Specific
methods, devices, and materials are described, although any methods
and materials similar or equivalent to those described herein can
be used in the practice or testing of the present invention.
[0036] The term "disease state" as used herein, may comprise any
state in which one or more organs or components of an organism
malfunction. The term "disease state" may refer to any
deterioration of any component of a body. The term "disease state"
may refer to any deficiency of any compound necessary for the
maintenance or function of any component of any organism. The term
"disease state" may refer to any condition in which a body contains
toxins, produced by microorganisms that infect the body or by body
cells through faulty metabolism or absorbed from an external
source. "Disease states" may be adverse states caused by any diet,
any virus, or any bacteria. "Disease states" may comprise disorders
associated with pregnant females such as, for example, osteomalacia
and preeclampsia and disorders associated with a fetus such as, for
example, neural tube defects and various fetal abnormalities.
"Disease states" may comprise any pulmonary disorder such as, for
example, bronchitis, bronchiectasis, atelectasis, pneunomia,
diseases caused by inorganic dusts, diseases caused by organic
dusts, any pulmonary fibrosis and pleurisy. "Disease states" may
comprise any hematological/oncological disorder such as, for
example, anemia, hemophilia, leukemia, and lymphoma. A "disease
state" may comprise any cancer such as, for example and without
limitation, breast cancer, lung cancer, prostate cancer, pancreatic
cancer, liver cancer, stomach cancer, testicular cancer, ovarian
cancer, skin cancer, cancer of the brain, cancer of the mouth,
cancer of the throat, and cancer of the neck. "Disease states" may
comprise any disorder of the immune system such as, for example,
acquired immune deficiency syndrome (AIDS), AIDS-related complex,
infection by any strain of any human immunodeficiency virus (HIV),
and other viruses or pathogens such as bacteria. A "disease state"
may comprise any cardiovascular disorder such as, for example,
arterial hypertension, orthostatic hypotension, arteriosclerosis,
coronary artery disease, cardiomyopathy, any arrhythmia, any
valvular heart disease, endocarditis, pericardial disease, any
cardiac tumor, any aneurysm and any peripheral vascular disorder.
"Disease states" may comprise any hepatic/biliary disorder such as,
for example and without limitation, jaundice, hepatic steatosis,
fibrosis, cirrhosis, hepatitis, any hepatic granuloma, any liver
tumor, cholelithiasis, cholecystitis and choledocholithiasis.
[0037] The term "physiologically stressful state," as used herein,
comprises any state of an organism in which the organism faces one
or more physiological challenges. A "physiologically stressful
state" may comprise, for example and without limitation, pregnancy,
lactation, or conditions in which an organism faces physiological
challenges related to, for example and without limitation, elevated
metabolic demand, increased plasma volume, or decreased
concentrations of nutrient-binding proteins. A "physiologically
stressful state" may result from one or more disease states.
[0038] The term "subject," as used herein, comprises any and all
organisms and includes the term "patient." "Subject" may refer to a
human or any other animal. "Subject" also may refer to a fetus.
[0039] The phrase "pharmaceutically acceptable," as used herein,
refers to those compounds, materials, compositions and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0040] The phrase "swallowable form" refers to any compositions
that do not readily dissolve when placed in the mouth and may be
swallowed whole without any chewing or discomfort. Such
compositions, in one embodiment, may have a shape containing no
sharp edges and a smooth, uniform and substantially bubble free
outer coating.
[0041] The phrase "chewable form" refers to any relatively soft
compositions that are chewed in the mouth after oral
administration, have a pleasant taste and mouthfeel, and quickly
break into smaller pieces and begin to dissolve after chewing such
that they can be swallowed substantially as a solution.
[0042] The phrase "dissolvable form" refers to any compositions
that dissolve into a solution in the mouth. Such compositions, in
one embodiment, may dissolve within about 60 seconds or less after
placement in the mouth without any chewing.
[0043] The term "mouthfeel" refers to non-taste-related aspects of
the pleasantness experienced by a person while chewing or
swallowing a nutritional supplement. Aspects of mouthfeel include,
for example and without limitation, the hardness and brittleness of
a composition, whether the composition is chewy, gritty, oily,
creamy, watery, sticky, easily dissolved, astringent, effervescent,
and the like, and the size, shape, and form of the composition
(tablet, powder, gel, etc. . . . ).
[0044] The term "antioxidant" means an agent which inhibits
oxidation and thus is used to prevent deterioration of preparations
by the oxidative process. Such compounds include, by way of example
and without limitation, ascorbic acid, ascorbyl palmitate,
butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous
acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium
bisulfite, sodium formaldehyde sulfoxylate and sodium metabisulfite
and others known to those of ordinary skill in the art.
[0045] Proper nutrition is essential for maintaining health and
preventing diseases. Adequate nutrition is especially critical
during, for example, nutritionally volatile or physiologically
stressful periods such as those including, by way of example and
without limitation, pregnancy, lactation, or any disease state.
Vitamin and mineral needs are almost universally increased
throughout these periods. Increased needs during physiologically
stressful states such as pregnancy, lactation or disease state may
result from elevated metabolic demand, increased plasma volume,
increased quantities of circulating red blood cells, decreased
concentrations of nutrients, and decreased concentrations of
nutrient-binding proteins such as, for example and without
limitation, serum-ferritin, maltose-binding protein, lactoferrin,
calmodulin, tocopheryl binding protein, riboflavin binding protein,
retinol binding protein, transthyretin, high density
lipoprotein-apolipoprotein A1, folic acid binding protein, and
25-hydroxyvitamin D binding protein. Lapido, 72 (Supp.) AMER. J.
CLIN. NUTR. 280S-90S (2000).
[0046] Optimizing specific nutrients before, during, and after the
physiological processes of pregnancy and lactation can have
profound, positive, and comprehensive impacts on the overall
wellness of the developing and newborn child as well as on the
safety and health of the mother. Black, 85 (Supp.) BRIT. J. NUTR.
S193-97 (2001); Scholl et al., 146 AMER. J. EPIDEM. 134-41 (1997).
Nutrients provided to a mother reach the fetus. Specifically, it is
established that substrates for growth and development, for
example, circulate within the same pathways that carry drugs to and
waste products from the fetus. Exchanges of material between mother
and fetus occur primarily in the placenta, where villi containing
fetal capillaries protrude into sinuses (intervillous spaces).
Maternal arterial blood spurts into these spaces, then drains into
maternal uterine veins to be returned to the maternal systemic
circulation. Solutes in maternal blood cross the epithelial cells
and connective tissue of the villi and the endothelium of the fetal
capillaries; these solutes are then carried to the fetus by
placental veins, which converge into the umbilical vein. THE MERCK
MANUAL OF DIAGNOSIS AND THERAPY 2022 (Mark H. Beers, M.D. &
Robert Berkow, M.D., eds., 17th ed. 1999).
[0047] The compositions and methods of the present invention
provide the means to optimize good health by utilizing vitamin and
mineral nutritional supplementation. The compositions and methods
of the present invention may be administered to or directed to a
subject such as a human or any other organism.
[0048] The compositions and methods of the present invention may
include vitamin A. Vitamin A is involved in physiological processes
that result in cellular differentiation, cellular maturity, and
cellular specificity. Thus, vitamin A is an important component of
a nutritional supplement for subjects in physiologically stressful
states, such as those caused by pregnancy, lactation or disease
state. Zile et al., 131(3) J. NUTR. 705-08 (2001). In a specific
embodiment of the present invention, vitamin A may be included in
the form of acetate. In another specific embodiment, vitamin A may
be included in amounts ranging from about 550 IU to about 1650 IU.
In another specific embodiment, vitamin A may be included in
amounts ranging from about 880 IU to about 1320 IU. In another
specific embodiment, vitamin A may be included in amounts ranging
from about 990 IU to about 1210 IU. In another embodiment, vitamin
A may be included in an amount of about 1100 IU.
[0049] The compositions and methods of the present invention may
include beta carotene. Beta carotene is converted to vitamin A
within the body as needed. Mayne, 10 J. FASEB 690-701 (1996). Beta
carotene also has powerful anti-oxidant properties. Antioxidants
are important during physiologically stressful events for numerous
reasons. For example, lipid peroxidation has been associated with
over 200 disease processes. Rock et al., 96(7) J. AMER. DIET.
ASSOC. 693-702 (1996). Antioxidants are especially important during
pregnancy because in the first trimester, establishment of blood
flow into the intervillous space is associated with a burst of
oxidative stress. The inability to mount an effective antioxidant
defense against this burst results in early pregnancy loss. Myatt
& Cui, HISTOCHEM. CELL BIOL., DOI: 10.1007/s00418-004-0677-x
(Jul. 10, 2004). Further, oxidative stress has been implicated in
the pathophysiology of preeclampsia, a toxemia of pregnancy. Llurba
et al., 37(4) FREE RABIC. BIOL. MED. 557-70 (2004). Finally,
oxidative stress during pregnancy plays an important role in fetal
growth, and healthy antioxidant levels are positively correlated
with birth weight and length. Lee et al., EUR. J. CLIN. NUTR., DOI:
10.1038/sj.ejcn.160 (Mar. 31, 2004). In a specific embodiment of
the present invention, beta carotene may be included in amounts
ranging from about 300 IU to 900 IU. In another specific embodiment
of the present invention, beta carotene may be included in amounts
ranging from about 480 IU to 720 IU. In another specific embodiment
of the present invention, beta carotene may be included in amounts
ranging from about 540 IU to 660 IU. In another embodiment, beta
carotene may be included in an amount of about 600 IU.
[0050] The compositions and methods of the present invention may
comprise or use B-complex vitamins. This class of vitamins
comprises water-soluble nutrients generally not stored in the body.
They play roles in a variety of biological processes critical to
the health of pregnant women, lactating women, and fetuses such as,
for example, the metabolism of homocysteine. The B-complex vitamins
that may be included in the compositions and methods of the present
invention comprise one or more of vitamin B.sub.1, vitamin B.sub.2,
vitamin B.sub.3, vitamin B.sub.6, vitamin B.sub.9 and vitamin
B.sub.12.
[0051] The compositions and methods of the present invention may
comprise or use vitamin B.sub.1. Vitamin B.sub.1 plays a role in
carbohydrate metabolism and neural function. It is a coenzyme for
the oxidative decarboxylation of alpha-ketoacids (e.g.,
alpha-ketoglutarate and pyruvate) and for transketolase, which is a
component of the pentose phosphate pathway. NATIONAL RESEARCH
COUNCIL, RECOMMENDED DIETARY ALLOWANCES 123 (10th ed. 1989)
(hereinafter "RDA"). In a specific embodiment of the present
invention, vitamin B.sub.1 may be included in the form of thiamine
mononitrate. In another specific embodiment, vitamin B.sub.1 may be
included in amounts ranging from about 1 mg to about 3 mg. In
another specific embodiment, vitamin B.sub.1 may be included in
amounts ranging from about 1.3 mg to about 1.9 mg. In another
specific embodiment, vitamin B.sub.1 may be included in amounts
ranging from about 1.5 mg to about 1.75 mg. In another embodiment,
vitamin B.sub.1 may be included in an amount of about 1.6 mg.
[0052] The compositions and methods of the present invention may
comprise or use vitamin B.sub.2. Vitamin B.sub.2 is a component of
two flavin coenzymes, flavin mononucleotide (FMN) and flavin
adenine dinucleotide (FAD). These flavoenzymes are involved in a
number of oxidation-reduction reactions including the conversion of
pyridoxine and niacin. RDA, supra at 132. Flavoenzymes also play a
role in a number of metabolic pathways such as amino acid
deamination, purine degradation and fatty acid oxidation and thus
help to maintain carbohydrate, amino acid and lipid metabolism. In
a specific embodiment of the present invention, vitamin B.sub.2 may
be included in the form of riboflavin. In another specific
embodiment, vitamin B.sub.2 may be included in amounts ranging from
about 1 mg to about 3 mg. In another specific embodiment, vitamin
B.sub.2 may be included in amounts ranging from about 1.5 mg to
about 2.2 mg. In another specific embodiment, vitamin B.sub.2 may
be included in amounts ranging from about 1.6 mg to about 2 mg. In
another embodiment, vitamin B.sub.2 may be included in an amount of
about 1.8 mg.
[0053] The compositions and methods of the present invention may
comprise or use vitamin B.sub.3. Vitamin B.sub.3, or "niacin" is
the common name for two compounds: nicotinic acid (also called
niacin) and niacinamide (also called nicotinamide). Vitamin B.sub.3
is particularly important for maintaining healthy levels and types
of fatty acids. It is also required for the synthesis of
pyroxidine, riboflavin, and folic acid. RDA, supra at 137.
Administration of vitamin B.sub.3 also may effect a reduction in
total cholesterol (LDL) and very low density lipoprotein (VLDL)
levels and an increase in high density lipoprotein (HDL)
cholesterol levels. Nicotinamide adenine dinucleotide (NAD) and NAD
phosphate (NADP) are active coenzymes of niacin. These coenzymes
are involved in numerous enzymatic reactions such as glycolysis,
fatty acid metabolism, and steroid synthesis. Henkin et al., 91 AM.
J. MED. 239-46 (1991). In a specific embodiment of the present
invention, vitamin B.sub.3 may be included in the form of
niacinamide. In another specific embodiment, the present invention
may include an equivalent molar amount of niacin. In another
specific embodiment, vitamin B.sub.3 may be included in amounts
ranging from about 7 mg to about 23 mg. In another specific
embodiment, vitamin B.sub.3 may be included in amounts ranging from
about 12 mg to about 18 mg. In another specific embodiment, vitamin
B.sub.3 may be included in amounts ranging from about 13.5 mg to
about 16.5 mg. In another embodiment, vitamin B.sub.3 may be
included in an amount of about 15 mg.
[0054] The compositions and methods of the present invention may
comprise or use vitamin B.sub.6. The administration of vitamin
B.sub.6 may reduce the levels of homocysteine. Bostom et al., 49
KIDNEY INT. 147-52 (1996). The active forms of vitamin B.sub.6,
pyridoxal-5'-phosphate (PLP) and pyridoxamine-5'-phosphate, are
coenzymes for numerous enzymes and as such, are important for
gluconeogenesis, niacin formation, and erythrocyte metabolism. RDA,
supra at 142-43. Vitamin B.sub.6 is a coenzyme for both
cystathionine synthase and cystathionase, enzymes that catalyze the
formation of cysteine from methionine. Homocysteine is an
intermediate in this process and elevated levels of plasma
homocysteine are recognized as a risk factor for both vascular
disease (Robinson et al., 94 CIRCULATION 2743-48 (1996)) and neural
tube defects (Locksmith & Duff, 91 OBSTET. GYNECOL. 1027-34
(1998)). In a specific embodiment of the present invention, vitamin
B.sub.6 may be included in the form of pyridoxine hydrochloride. In
another specific embodiment, vitamin B.sub.6 may be included in
amounts ranging from about 1 mg to about 4 mg. In another specific
embodiment, vitamin B.sub.6 may be included in amounts ranging from
about 2 mg to about 3 mg. In another specific embodiment, vitamin
B.sub.6 may be included in amounts ranging from about 2.3 mg to
about 2.8 mg. In another embodiment, vitamin B.sub.6 may be
included in an amount of about 2.5 mg.
[0055] The compositions and methods of the present invention may
comprise or use vitamin B.sub.9. This vitamin has demonstrated the
ability to prevent neural tube defects such as spina bifida caused
by disturbed homocysteine metabolism. Vanderput et al., EXP. BIOL.
MED. 243-70 (2001); DeFalco et al., 27 CLIN. EXP. OBSTET. GYNECOL.
188-90 (2000); Eskes, 27 CLIN. EXP. OBSTET. GYNECOL. 157-67 (2000);
Locksmith & Duff, supra. Vitamin B.sub.9 also is important for
the formation of red and white blood cells within bone marrow and
plays a role in heme formation. Further, folate deficiencies
inhibit the activity of vitamin B.sub.1. RDA, supra at 150. In a
specific embodiment of the present invention, vitamin B.sub.9 may
be included in the form of folic acid. In another embodiment,
vitamin B.sub.9 may be included in the forms of folic acid,
folacin, metafolin, folate and/or one or more natural isomers of
folate including (6S)-tetrahydrofolic acid or a polyglutamyl
derivative thereof, 5-methyl-(6S)-tetrahydrofolic acid or a
polyglutamyl derivative thereof, 5-formyl-(6S)-tetrahydrofolic acid
or a polyglutamyl derivative thereof,
10-formyl-(6R)-tetrahydrofolic acid or a polyglutamyl derivative
thereof, 5,10-methylene-(6R)-tetrahydrofolic acid or a polyglutamyl
derivative thereof, 5,10-methenyl-(6R)-tetrahydrofolic acid or a
polyglutamyl derivative thereof and
5-formimino-(6S)-tetrahydrofolic acid or a polyglutamyl derivative
thereof. In another specific embodiment, vitamin B.sub.9 may be
included in amounts ranging from about 500 .mu.g to about 1500
.mu.g. In another specific embodiment, vitamin B.sub.9 may be
included in amounts ranging from about 800 .mu.g to about 1200
.mu.g. In another specific embodiment, vitamin B.sub.9 may be
included in amounts ranging from about 900 .mu.g to about 1100
.mu.g. In another embodiment, vitamin B.sub.9 may be included in an
amount of about 1000 .mu.g.
[0056] The compositions and methods of the present invention may
comprise or use vitamin B.sub.12. Vitamin B.sub.12 can be converted
to the active coenzymes, methylcobalamin and
5'-deoxyadenosylcobalamin. These coenzymes are necessary for folic
acid metabolism, conversion of coenzyme A and myelin synthesis.
Methylcobalamin also catalyzes the demethylation of a folate
cofactor which is involved in DNA synthesis. A lack of
demethylation may result in folic acid deficiency. RDA, supra at
159-160. Deoxyadenosylcobalamin is the coenzyme for the conversion
of methylmalonyl-CoA to succinyl-CoA, which plays a role in the
citric acid cycle. Cobalamin, along with pyridoxine and folic acid,
also are implicated in the proper metabolism of homocysteine, a
breakdown product of the amino acid methionine, which is correlated
with an increased risk of heart disease due to its negative effects
on endothelial function. In one specific embodiment of the present
invention, vitamin B.sub.12 may be included in the form of
cyanocobalamin. In another specific embodiment, vitamin B.sub.12
may be included in amounts ranging from about 2 .mu.g to about 8
.mu.g. In another specific embodiment, vitamin B.sub.12 may be
included in amounts ranging from about 4 .mu.g to about 6 .mu.g. In
another specific embodiment, vitamin B.sub.12 may be included in
amounts ranging from about 4.5 .mu.g to about 5.5 .mu.g. In another
embodiment, vitamin B.sub.12 may be included in an amount of about
5 .mu.g.
[0057] The compositions and methods of the present invention may
comprise or use vitamin C. The major biochemical role of
water-soluble vitamin C is as a co-substrate in metal catalyzed
hydroxylations. Like beta carotene, vitamin C has antioxidant
properties. It interacts directly with superoxide hydroxyl radicals
and singlet oxygen, and also provides antioxidant protection for
folate and vitamin E, keeping vitamin E in its most potent form.
Vitamin C may afford protective effects against preeclampsia by
participating in the scavenging of free radicals. Indeed,
significantly lower levels of vitamin C have been observed in
preeclamptic women than in controls. Woods et al., 185(1) AM. J.
OBSTET. GYNECOL. 5-10 (2001); Kharb, 1 EURO. J. OBSTET. GYNECOL.
REPRO. BIOL. 37-39 (2000); Milczarek et al., 210 MOL. CELL.
BIOCHEM. 65-73 (2000).
[0058] Vitamin C also enhances the absorption of iron. RDA, supra
at 115. In addition, vitamin C is required for collagen synthesis,
epinephrine synthesis, and bile acid formation. Moreover, vitamin C
has been implicated in inhibiting atherosclerosis by being present
in extracellular fluid of the arterial wall and potentiating nitric
oxide activity, thus normalizing vascular function. In a specific
embodiment of the present invention, vitamin C may be included in
the form of ascorbic acid. In another specific embodiment, vitamin
C may be included in amounts ranging from about 30 mg to about 90
mg. In another specific embodiment, vitamin C may be included in
amounts ranging from about 48 mg to about 72 mg. In another
specific embodiment, vitamin C may be included in amounts ranging
from about 54 mg to about 66 mg. In another embodiment, vitamin C
may be included in an amount of about 60 mg.
[0059] The compositions and methods of the present invention may
comprise or use vitamin D.sub.3. Vitamin D.sub.3 is a fat-soluble
"hormone like" substance important for the maintenance of healthy
bones. This vitamin increases the absorption of calcium and
phosphorous from the gastrointestinal tract, and improves mineral
resorption into bone tissue. Vitamin D can be converted to its
active form from exposure of the skin to sunlight. This fact is
among the reasons why vitamin D deficiency is common in the
elderly, notably the institutionalized, who spend little or no time
out of doors. Deficiencies in vitamin D.sub.3 can lead to increased
bone turnover and loss, and when severe, osteomalacia, or softening
of the bones. Supplementation with vitamin D.sub.3 has been shown
to moderately reduce bone loss, increase serum 25-hydroxyvitamin D,
and decrease serum parathyroid hormone levels. Dawson-Hughes et
al., 337 NEW ENG. J. MED. 670-76 (1997); Lips et al., 86 J. CLIN.
ENDOCRINOL. METAB. 1212-21 (2001). Vitamin D.sub.3 also plays a
role in the maintenance of calcium and phosphorus homeostasis, but
it is also active in cell differentiation and immune function. In a
specific embodiment of the present invention, vitamin D.sub.3 may
be included in the form of cholecalciferol. In another specific
embodiment, vitamin D.sub.3 may be included in amounts ranging from
about 200 IU to about 600 IU. In another specific embodiment,
vitamin D.sub.3 may be included in amounts ranging from about 320
IU to about 480 IU. In another specific embodiment, vitamin D.sub.3
may be included in amounts ranging from about 360 IU to about 440
IU. In another embodiment, vitamin D.sub.3 may be included in an
amount of about 400 IU.
[0060] The compositions and methods of the present invention may
comprise or use vitamin E. Vitamin E is a fat-soluble vitamin
antioxidant found in biological membranes where it protects the
phospholipid membrane from oxidative stress. Vitamin E inhibits the
oxidation of unsaturated fatty acids by trapping peroxyl free
radicals. It is also an antiatherogenic agent, and studies have
demonstrated a reduced risk of coronary heart disease with
increased intake of vitamin E. Stampfer et al., 328 NEW ENG. J.
MED. 1444-49 (1993). In addition, vitamin E, like beta carotene and
vitamin C, may afford protective effects against preeclampsia by
participating in the scavenging of free radicals. As with vitamin
C, significantly lower levels of vitamin E have been observed in
preeclamptic women than in controls. Woods et al., supra; Kharb,
supra; Milczarek et al., supra. In a specific embodiment of the
present invention, vitamin E may be included in the form of
d-alpha-tocopheryl acetate. In another specific embodiment, vitamin
E may be included in the form of an equivalent molar amount of
d-alpha tocopheryl succinate. In another specific embodiment,
vitamin E may be included in amounts ranging from about 15 IU to
about 45 IU. In another specific embodiment, vitamin E may be
included in amounts ranging from about 24 IU to about 36 IU. In
another specific embodiment, vitamin E may be included in amounts
ranging from about 27 IU to about 33 IU. In another embodiment,
vitamin E may be included in an amount of about 30 IU.
[0061] The compositions and methods of the present invention may
comprise or use iron. A primary function of iron is to carry oxygen
to bodily tissues via the hemoglobin part of red blood cells.
Supplemental intake of iron is critical to preventing anemia, a
disorder associated with a variety of physiological states
including, for example, pregnancy. Bothwell, 72(Supp.) AM. J. CLIN.
NUTR. 257S-64S (2000). Severe anemia may have adverse effects upon
a mother and a fetus. Specifically, significant depression of
hemoglobin has been associated with poor pregnancy outcome. Black,
supra; Sifakis & Pharmakides, 900 ANN. N.Y. ACAD. SCI. 125-36
(2000). The compositions and methods of the present invention may
include iron in either chelated or nonchelated form. In a specific
embodiment of the present invention, iron may be included in the
form of polysaccharide iron complex. In another specific
embodiment, iron may be included in the form of an equivalent molar
amount of ferrous fumurate. In another specific embodiment, iron
may be included in amounts ranging from about 14 mg to about 44 mg.
In another specific embodiment, iron may be included in amounts
ranging from about 23 mg to about 35 mg. In another specific
embodiment, iron may be included in amounts ranging from about 26
mg to about 32 mg. In another embodiment, iron may be included in
an amount of about 29 mg.
[0062] The compositions and methods of the present invention may
comprise or use magnesium. Magnesium is found primarily in both
bone and muscle and is important for over 300 different enzyme
reactions. A primary function of magnesium is to bind to phosphate
groups in adenosine triphosphate (ATP), thereby forming a complex
that assists in the transfer of ATP phosphate. Magnesium also
functions within cells as a membrane stabilizer. Magnesium plays
roles in nucleic acid synthesis, glycolysis, transcription of DNA
and RNA, amino acid activation, membrane transport, transketolase
reactions, and protein synthesis. James L. L. Groff et al.,
ADVANCED NUTRITION AND HUMAN METABOLISM 341 (2d ed. 1996). It is
also involved in the formation of cAMP, a cytosolic second
messenger that plays a role in cell signaling mechanisms. Magnesium
also functions both synergistically and antagonistically with
calcium in neuromuscular transmission. RDA, supra at 188.
Specifically, magnesium is critical for the maintenance of
electrochemical potentials of nerve and muscle membranes and the
neuromuscular junction transmissions, particularly important in the
heart. Not surprisingly, magnesium deficiency is tied to
cardiovascular disease and hypertension. Agus et al., 17 CRIT. CARE
CLIN. 175-87 (2001). Indeed, oral magnesium therapy improves
endothelial function in patients with coronary disease. Shechter et
al., 102 CIRCULATION 2353-58 (2000).
[0063] Magnesium is available in a variety of salts and can be
included in the compositions and methods of the present invention
in either chelated or nonchelated form. In one specific embodiment
of the present invention, magnesium may be included in the form of
magnesium oxide. In another specific embodiment, magnesium may be
included in amounts ranging from about 12 mg to about 38 mg. In
another specific embodiment, magnesium may be included in amounts
ranging from about 20 mg to about 30 mg. In another specific
embodiment, magnesium may be included in amounts ranging from about
22.5 mg to about 27.5 mg. In another embodiment, magnesium may be
included in an amount of about 25 mg.
[0064] The compositions and methods of the present invention may
comprise or use zinc. Zinc plays a role in numerous metabolic
activities such as nucleic acid production, protein synthesis, and
development of the immune system. There are more than 200 zinc
metalloenzymes including aldolase, alcohol dehydrogenase, RNA
polymerase, and protein kinase C. Zima et al., 17 BLOOD PURIF.
182-86 (1999). Zinc stabilizes RNA and DNA structures, forms zinc
fingers in nuclear receptors, and is a component of chromatin
proteins involved in transcription and replication. Deficiencies of
zinc during pregnancy have been shown to contribute to severe fetal
abnormalities. Srinivas et al., 68(6) INDIAN J. PEDIATR. 519-22
(2001); Yang et al., 13(4) BIOMED. ENVIRON. SCI. 280-86 (2000);
King, 71(Supp.) AM. J. CLIN. NUTR. 1334S-43S (2000). Zinc is
available in many forms and may be included in the compositions and
methods of the present invention in chelated or nonchelated form.
In a specific embodiment of the present invention, zinc may be
included in the form of zinc oxide. In another specific embodiment,
zinc may be included in amounts ranging from about 7 mg to about 23
mg. In another specific embodiment, zinc may be included in amounts
ranging from about 12 mg to about 18 mg. In another specific
embodiment, zinc may be included in amounts ranging from about 13.5
mg to about 16.5 mg. In another embodiment, zinc may be included in
an amount of about 15 mg.
[0065] The compositions and methods of the present invention may
comprise or use a combination of the included vitamins and minerals
just described, in either chelated or non-chelated form. The active
ingredients are available from numerous commercial sources, and in
several active forms or salts thereof, known to those of ordinary
skill in the art. Hence, the compositions and methods of the
present invention are not limited to comprising or using any
particular form of the vitamin or mineral ingredient described
herein.
[0066] In a specific embodiment of the present invention, specific
vitamins and/or minerals may be excluded. For example, in a
specific embodiment, the compositions and methods of the present
invention may be substantially free of added vitamin A;
substantially free of added beta carotene; substantially free of
added alpha carotene; substantially free of added lutein;
substantially free of added lycopene; substantially free of added
zeaxanthin; substantially free of added vitamin B.sub.1;
substantially free of added vitamin B.sub.2; substantially free of
added vitamin B.sub.3; substantially free of added vitamin B.sub.4;
substantially free of added vitamin B.sub.5; substantially free of
added vitamin B.sub.6; substantially free of added vitamin B.sub.7;
substantially free of added vitamin B.sub.8; substantially free of
added vitamin B.sub.9; substantially free of added vitamin
B.sub.10; substantially free of added vitamin B.sub.11;
substantially free of added vitamin B.sub.12; substantially free of
added vitamin C; substantially free of added vitamin D.sub.3;
substantially free of added vitamin E; substantially free of added
calcium; substantially free of added chromium; substantially free
of added copper; substantially free of added magnesium;
substantially free of added manganese; substantially free of added
selenium; substantially free of added zinc; substantially free of
added boron; substantially free of added odorless garlic;
substantially free of added coenzyme Q-10; substantially free of
added 1-carnitine; substantially free of added grape seed extract;
substantially free of added green tea extract; substantially free
of added quercetin; substantially free of added hawthorne berries;
and/or substantially free of added alpha lipoic acid. In another
embodiment of the present invention, the compositions are
substantially free of other added vitamins and minerals.
[0067] A specific embodiment of the present invention may comprise
swallowable compositions. Swallowable compositions are well known
in the art and are those that do not readily dissolve when placed
in the mouth and may be swallowed whole without any chewing or
discomfort. In a specific embodiment of the present invention the
swallowable compositions may have a shape containing no sharp edges
and a smooth, uniform and substantially bubble free outer
coating.
[0068] To prepare the swallowable compositions of the present
invention, each of the active ingredients may be combined in
intimate admixture with a suitable carrier according to
conventional compounding techniques. In a specific embodiment of
the swallowable compositions of the present invention, the surface
of the compositions may be coated with a polymeric film. Such a
film coating has several beneficial effects. First, it reduces the
adhesion of the compositions to the inner surface of the mouth,
thereby increasing the patient's ability to swallow the
compositions. Second, the film may aid in masking the unpleasant
taste of certain drugs. Third, the film coating may protect the
compositions of the present invention from atmospheric degradation.
Polymeric films that may be used in preparing the swallowable
compositions of the present invention include vinyl polymers such
as polyvinylpyrrolidone, polyvinyl alcohol and acetate, cellulosics
such as methyl and ethyl cellulose, hydroxyethyl cellulose and
hydroxylpropyl methylcellulose, acrylates and methacrylates,
copolymers such as the vinyl-maleic acid and styrene-maleic acid
types, and natural gums and resins such as zein, gelatin, shellac
and acacia. Pharmaceutical carriers and formulations for
swallowable compounds are well known to those of ordinary skill in
the art. See generally, e.g., WADE & WALLER, HANDBOOK OF
PHARMACEUTICAL EXCIPIENTS (2.sup.nd ed. 1994).
[0069] In a specific embodiment of the present invention, the
compositions may comprise chewable compositions. Chewable
compositions are those that have a palatable taste and mouthfeel,
are relatively soft and quickly break into smaller pieces and begin
to dissolve after chewing such that they are swallowed
substantially as a solution.
[0070] In order to create chewable compositions, certain
ingredients should be included to achieve the attributes just
described. For example, chewable compositions should include
ingredients that create pleasant flavor and mouthfeel and promote
relative softness and dissolvability in the mouth. The following
discussion describes ingredients that may help to achieve these
characteristics.
[0071] Chewable compositions preferably have a pleasant or
palatable flavor. Palatable flavors may be achieved by including
sweetening agents and/or flavorants. Sweetening agents that may be
included in the compositions of the present invention include, by
way of example and without limitation, sucrose, fructose, high
fructose corn syrup, dextrose, saccharin sodium, maltodextrin,
aspartame, potassium acesulfame, neohesperidin dihydrochalcone,
sucralose, monoammonium glycyrrhizinate, and others known to those
of ordinary skill in the art. As used herein, the term "flavorant"
means natural or artificial compounds used to impart a pleasant
flavor and often odor to a pharmaceutical preparation. Flavorants
that may be used in the present invention include, for example and
without limitation, natural and synthetic flavor oils, flavoring
aromatics, extracts from plants, leaves, flowers, and fruits and
combinations thereof. Such flavorants include, by way of example
and without limitation, anise oil, cinnamon oil, vanilla, vanillin,
cocoa, chocolate, natural chocolate flavor, menthol, grape,
peppermint oil, oil of wintergreen, clove oil, bay oil, anise oil,
eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage,
oil of bitter almonds, cassia oil; citrus oils, such as lemon,
orange, lime and grapefruit oils; and fruit essences, including
apple, pear, peach, berry, wildberry, date, blueberry, kiwi,
strawberry, raspberry, cherry, plum, pineapple, and apricot. All of
these flavorants are commercially available. In a specific
embodiment of the present invention, flavorants that may be used
include natural berry extracts and natural mixed berry flavor, as
well as citric and malic acid. The amount of flavorants used may
depend on a number of factors, including desired taste
characteristics. While not necessary, one or more of these
sweetening agents and/or flavorants also may be included in the
swallowable compositions of the present invention.
[0072] In addition to having a palatable flavor, chewable
compositions also should have a pleasant mouthfeel. A variety of
ingredients can be included in the compositions of the present
invention to enhance mouthfeel.
[0073] In the chewable compositions of the present invention,
sugars such as white sugar, corn syrup, sorbitol (solution),
maltitol (syrup), oligosaccharide, isomaltooligosaccharide,
sucrose, fructose, lactose, glucose, lycasin, xylitol, lactitol,
erythritol, mannitol, isomaltose, dextrose, polydextrose, dextrin,
compressible cellulose, compressible honey, compressible molasses
and mixtures thereof may be added to improve mouthfeel and
palatability. Further, by way of example and without limitation,
fondant or gums such as gelatin, agar, arabic gum, guar gum, and
carrageenan may be added to improve the chewiness of the
compositions. Fatty materials that may be included in the present
invention include, by way of example and without limitation,
vegetable oils (including palm oil, palm hydrogenated oil, corn
germ hydrogenated oil, castor hydrogenated oil, cotton-seed oil,
olive oil, peanut oil, palm olein oil, and palm stearin oil),
animal oils (including refined oil and refined lard whose melting
point ranges from 30.degree. to 42.degree. C.), Cacao fat,
margarine, butter, and shortening.
[0074] Alkyl polysiloxanes (commercially available polymers sold in
a variety of molecular weight ranges and with a variety of
different substitution patterns) also may be used in the present
invention to enhance the texture, the mouthfeel, or both of the
chewable nutritional supplement compositions described herein. By
"enhance the texture" it is meant that the alkyl polysiloxane
improves one or more of the stiffness, the brittleness, and the
chewiness of the chewable supplement, relative to the same
preparation lacking the alkyl polysiloxane. By "enhance the
mouthfeel" it is meant that the alkyl polysiloxane reduces the
gritty texture of the supplement once it has liquefied in the
mouth, relative to the same preparation lacking the alkyl
polysiloxane.
[0075] Alkyl polysiloxanes generally comprise a silicon and
oxygen-containing polymeric backbone with one or more alkyl groups
pending from the silicon atoms of the back bone. Depending upon
their grade, they can further comprise silica gel. Alkyl
polysiloxanes are generally viscous oils. Exemplary alkyl
polysiloxanes that can be used in the swallowable, chewable or
dissolvable compositions of the present invention include, by way
of example and without limitation, monoalkyl or dialkyl
polysiloxanes, wherein the alkyl group is independently selected at
each occurrence from a C.sub.1-C.sub.6-alkyl group optionally
substituted with a phenyl group. A specific alkyl polysiloxane that
may be used is dimethyl polysiloxane (generally referred to as
simethicone). More specifically, a granular simethicone preparation
designated simethicone GS may be used. Simethicone GS is a
preparation which contains 30% simethicone USP. Simethicone USP
contains not less than about 90.5% by weight
(CH.sub.3).sub.3--Si{OSi(CH.sub.3).sub.2}CH.sub.3 in admixture with
about 4.0% to about 7.0% by weight SiO.sub.2.
[0076] To prevent the stickiness that can appear in conventional
chewable compositions and to facilitate conversion of the active
ingredients to emulsion or suspension upon taking, the compositions
of the present invention, may further comprise emulsifiers such as,
by way of example and without limitation, glycerin fatty acid
ester, sorbitan monostearate, sucrose fatty acid ester, lecithin
and mixtures thereof. In a specific embodiment, one or more of such
emulsifiers may be present in an amount of about 0.01% to about
5.0%, by weight of the administered compositions. If the level of
emulsifier is lower or higher than the said range, the
emulsification cannot be realized, or wax value will rise.
[0077] Chewable compositions should begin to break and dissolve in
the mouth shortly after chewing begins such that the compositions
can be swallowed substantially as a solution. The dissolution
profile of chewable compositions may be enhanced by including
rapidly water-soluble fillers and excipients. Rapidly water-soluble
fillers and excipients preferably dissolve within about 60 seconds
of being wetted with saliva. Indeed, it is contemplated that if
enough water-soluble excipients are included in the compositions of
the present invention, they may become dissolvable rather than
chewable composition forms. Examples of rapidly water soluble
fillers suitable for use with the present invention include, by way
of example and without limitation, saccharides, amino acids and the
like. In a specific embodiment, the saccharide may be a mono-, di-
or oligosaccharide. Examples of saccharides which may be added to
the compositions of the present invention include, by way of
example and without limitation, sorbitol, glucose, dextrose,
fructose, maltose and xylitol (all monosaccharides); and sucrose,
lactose, glucose, galactose and mannitol (all disaccharides). Other
suitable saccharides are oligosaccharides. Examples of
oligosaccharides are dextrates and maltodextrins. Other water
soluble excipients that may be used with the present invention
include, by way of example and without limitation, amino acids such
as alanine, arginine, aspartic acid, asparagine, cysteine, glutamic
acid, glutamine, glycine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, proline, serine, threonine, tryptophan,
tyrosine and valine.
[0078] Disintegrants also may be included in the compositions of
the present invention in order to facilitate dissolution.
Disentegrants, including permeabilising and wicking agents, are
capable of drawing water or saliva up into the compositions which
promotes dissolution from the inside as well as the outside of the
compositions. Such disintegrants, permeabilising and/or wicking
agents that may be used in the present invention include, by way of
example and without limitation, starches, such as corn starch,
potato starch, pre-gelatinized and modified starches thereof,
cellulosic agents, such as Ac-di-sol, montmorrilonite clays,
cross-linked PVP, sweeteners, bentonite, microcrystalline
cellulose, croscarmellose sodium, alginates, sodium starch
glycolate, gums, such as agar, guar, locust bean, karaya, pectin,
Arabic, xanthan and tragacanth, silica with a high affinity for
aqueous solvents, such as colloidal silica, precipitated silica,
maltodextrins, beta-cyclodextrins, polymers, such as carbopol, and
cellulosic agents, such as hydroxymethylcellulose,
hydroxypropylcellulose and hydroxyopropylmethylcellulose.
[0079] Finally, dissolution of the compositions may be facilitated
by including relatively small particles sizes of the ingredients
used.
[0080] In addition to those described above, any appropriate
fillers and excipients may be utilized in preparing the
swallowable, chewable and/or dissolvable compositions of the
present invention so long as they are consistent with the
objectives described herein. For example, binders are substances
used to cause adhesion of powder particles in granulations. Such
compounds appropriate for use in the present invention include, by
way of example and without limitation, acacia, compressible sugar,
gelatin, sucrose and its derivatives, maltodextrin, cellulosic
polymers, such as ethylcellulose, hydroxypropylcellulose,
hydroxypropylmethyl cellulose, carboxymethylcellulose sodium and
methylcellulose, acrylic polymers, such as insoluble acrylate
ammoniomethacrylate copolymer, polyacrylate or polymethacrylic
copolymer, povidones, copovidones, polyvinylalcohols, alginic acid,
sodium alginate, starch, pregelatinized starch, guar gum,
polyethylene glycol and others known to those of ordinary skill in
the art.
[0081] Diluents also may be included in the compositions of the
present invention in order to enhance the granulation of the
compositions. Diluents can include, by way of example and without
limitation, microcrystalline cellulose, sucrose, dicalcium
phosphate, starches, lactose and polyols of less than 13 carbon
atoms, such as mannitol, xylitol, sorbitol, maltitol and
pharmaceutically acceptable amino acids, such as glycin, and their
mixtures.
[0082] Lubricants are substances used in composition formulations
that reduce friction during composition compression. Lubricants
that may be used in the present invention include, by way of
example and without limitation, stearic acid, calcium stearate,
magnesium stearate, zinc stearate, talc, mineral and vegetable
oils, benzoic acid, poly(ethylene glycol), glyceryl behenate,
stearyl fumarate, and others known to those of ordinary skill in
the art.
[0083] Glidants improve the flow of powder blends during
manufacturing and minimize composition weight variation. Glidants
that may be used in the present invention include, by way of
example and without limitation, silicon dioxide, colloidal or fumed
silica, magnesium stearate, calcium stearate, stearic acid,
cornstarch, talc and others known to those of ordinary skill in the
art.
[0084] Colorants also may be included in the nutritional supplement
compositions of the present invention. As used herein, the term
"colorant" includes compounds used to impart color to
pharmaceutical preparations. Such compounds include, by way of
example and without limitation, FD&C Red No. 3, FD&C Red
No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green
No. 5, FD&C Orange No. 5, D&C Red No. 8, caramel, and
ferric oxide, red and others known to those of ordinary skill in
the art. Coloring agents also can include pigments, dyes, tints,
titanium dioxide, natural coloring agents, such as grape skin
extract, beet red powder, beta carotene, annato, carmine, turmeric,
paprika and others known to those of ordinary skill in the art. It
is recognized that no colorant is required in the nutritional
supplement compositions described herein.
[0085] If desired, the compositions of the present invention may be
sugar coated or enteric coated by standard techniques. The unit
dose forms may be individually wrapped, packaged as multiple units
on paper strips or in vials of any size, without limitation. The
swallowable, chewable or dissolvable compositions of the present
invention may be packaged in unit dose, rolls, bulk bottles,
blister packs and combinations thereof, without limitation.
[0086] The swallowable, chewable or dissolvable compositions of the
present invention may be prepared using conventional methods and
materials known in the pharmaceutical art. For example, U.S. Pat.
Nos. 5,215,754 and 4,374,082 relate to methods for preparing
swallowable compositions. U.S. Pat. No. 6,495,177 relates to
methods to prepare chewable nutritional supplements with improved
mouthfeel. U.S. Pat. No. 5,965,162, relates to compositions and
methods for preparing multi-vitamin comestible units which
disintegrate quickly in the mouth, especially when chewed. Further,
all pharmaceutical carriers and formulations described herein are
well known to those of ordinary skill in the art, and determination
of workable proportions in any particular instance will generally
be within the capability of the person skilled in the art. Details
concerning any of the excipients of the invention may be found in
WADE & WALLER, HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (2nd ed.
1994). All active ingredients, fillers and excipients are
commercially available from companies such as Aldrich Chemical Co.,
FMC Corp, Bayer, BASF, Alexi Fres, Witco, Mallinckrodt, Rhodia,
ISP, and others.
[0087] Other objectives, features and advantages of the present
invention will become apparent from the following specific
examples. The specific examples, while indicating specific
embodiments of the invention, are provided by way of illustration
only. Accordingly, the present invention also includes those
various changes and modifications within the spirit and scope of
the invention that may become apparent to those skilled in the art
from this detailed description. The invention will be further
illustrated by the following non-limiting examples.
EXAMPLES
[0088] Without further elaboration, it is believed that one skilled
in the art, using the preceding description, can utilize the
present invention to the fullest extent. The following examples are
illustrative only, and not limiting of the remainder of the
disclosure in any way whatsoever.
Example 1
[0089] A composition of the following formulation was prepared in
chewable form:
TABLE-US-00001 Vitamin A (acetate) 1100 IU Beta Carotene 600 IU
Vitamin B.sub.1 (thiamine mononitrate) 1.6 mg Vitamin B.sub.2
(riboflavin) 1.8 mg Vitamin B.sub.3 (niacinamide) 15 mg Vitamin
B.sub.6 (pyridoxine hydrochloride) 2.5 mg Vitamin B.sub.9 (folic
acid) 1000 .mu.g Vitamin B.sub.12 (cyanocobalamin) 5 .mu.g Vitamin
C (ascorbic acid) 60 mg Vitamin D (cholecalciferol) 400 IU Vitamin
E (d-alpha-tocopheryl acetate) 30 IU Iron (polysaccharide complex)
29 mg Magnesium (magnesium oxide) 25 mg Zinc (zinc oxide) 15 mg
Example 2
[0090] A study is undertaken to evaluate the effectiveness of the
compositions of the present invention in the treatment of patients.
The objective of the study is to determine whether oral intake of
the compositions results in an improvement of the nutritional
status of patients with regard to the specific vitamins and
minerals contained in the administered compositions.
[0091] A double-blind, placebo controlled study is conducted over a
six-month period. A total of 120 subjects (60 pregnant women
entering the second trimester of pregnancy and 60 lactating women),
aged 20-35 years, are chosen for the study. An initial assessment
of the nutritional status of each woman is conducted. Vitamin A,
beta carotene and vitamin B.sub.6 are measured using high
performance liquid chromatography. Erythrocyte transketolase
activity is used to measure vitamin B.sub.1 levels. Vitamin B.sub.2
levels are determined by assessment of erythrocyte glutathione
reductase activity. Vitamin B.sub.3 levels are assessed by
measuring urinary excretion of N' methylnicotinamide and its
pyridone. Vitamin B.sub.9 is measured by radioimmunoassay (RIA),
specifically The Solid Phase No Biol Folic Acid Kit (Diagnostic
Products, Los Angeles, Calif.). Vitamin B.sub.12 is measured by RIA
using human intrinsic factor as a binder. Vitamin C levels are
measured by spectrophotometric and colorimetric methods. Vitamin D
is measured using an extraction double-antibody RIA (Dia Sorin,
Inc., Stillwater, Minn.). The peroxide hemolysis test is used to
determine vitamin E status. Iron levels are measured using standard
spectrophotometry. Similarly, magnesium levels are measured by
absorbance of a magnesium chelate with xylidl blue at 660 nM. Zinc
levels are assessed using flame atomic absorption spectrometry
(Perkins Elmer 460, Norwalk, Conn.).
[0092] The 120 subjects are separated into four separate groups of
30 women. In a first group comprising only pregnant women and in a
second group comprising only lactating women, each subject is
administered one dosage form of the composition as described in
Example 1 twice a day. In a third group comprising only pregnant
women and in a fourth group comprising only lactating women, each
subject is administered one placebo dosage form twice a day. Thus,
dosage form administration occurs every 12 hours. No other
nutritional supplements are taken by the subjects during the
assessment period.
[0093] An assessment of the nutritional status of each woman is
conducted utilizing the methods described above at one month
intervals for a six month period. The data is evaluated using
multiple linear regression analysis and a standard t-test. In each
analysis, the baseline value of the outcome variable is included in
the model as a covariant. Treatment by covariant interaction
effects is tested by the method outlined by Weigel & Narvaez,
12 CONTROLLED CLINICAL TRIALS 378-94 (1991). If there are no
significant interaction effects, the interaction terms are removed
from the model. The regression model assumptions of normality and
homogeneity of variance of residuals are evaluated by inspection of
the plots of residuals versus predicted values. Detection of the
temporal onset of effects is done sequentially by testing for the
presence of significant treatment effects at 1, 2, 3, 4, 5, and 6
months, proceeding to the earlier time in sequence only when
significant effects have been identified at each later time period.
Changes from the baseline within each group are evaluated using
paired t-tests. In addition, analysis of variance is performed on
all baseline measurements and measurable subject characteristics to
assess homogeneity between groups. All statistical procedures are
conducted using the Statistical Analysis System (SAS Institute
Inc., Cary, N.C.). An alpha level of 0.05 is used in all
statistical tests.
[0094] A statistically significant improvement in the nutritional
status of all vitamin and mineral levels measured is observed in
the treated subjects over the controls upon completion of the
study. Therefore, the study confirms that oral administration of
the compositions of the present invention is effective in improving
the nutritional status of patients.
[0095] While specific embodiments of the present invention have
been described, other and further modifications and changes may be
made without departing from the spirit of the invention. All
further and other modifications and changes are included that come
within the scope of the invention as set forth in the claims. The
disclosure of all publications cited above are expressly
incorporated by reference in their entireties to the same extent as
if each were incorporated by reference individually.
* * * * *