U.S. patent number 5,066,500 [Application Number 07/418,948] was granted by the patent office on 1991-11-19 for infant formulas and nutrition products enriched with nucleosides and/or nucleotides and processes for their preparation.
This patent grant is currently assigned to Union Industrial y Agro-Ganadera, S. A. (UNIASA). Invention is credited to Angel H. Gil, Daniel V. Morales, Eduardo R. Valverde.
United States Patent |
5,066,500 |
Gil , et al. |
November 19, 1991 |
Infant formulas and nutrition products enriched with nucleosides
and/or nucleotides and processes for their preparation
Abstract
Nucleosides and/or nucleotides are added to non-milk based
infant formulas, to provide a formula having enhanced physiological
properties and also closely resemble human milk. Additionally,
nutritionally balanced diet formulations are described having
nucleosides and/or nucleotides incorporated therein.
Inventors: |
Gil; Angel H. (Granada,
ES), Morales; Daniel V. (Granada, ES),
Valverde; Eduardo R. (Granada, ES) |
Assignee: |
Union Industrial y Agro-Ganadera,
S. A. (UNIASA) (Granada, ES)
|
Family
ID: |
8251143 |
Appl.
No.: |
07/418,948 |
Filed: |
October 6, 1989 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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55858 |
Jun 1, 1987 |
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Foreign Application Priority Data
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May 29, 1987 [ES] |
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8701601 |
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Current U.S.
Class: |
426/72;
426/801 |
Current CPC
Class: |
A23L
33/13 (20160801); A23L 33/40 (20160801); Y10S
514/885 (20130101); Y10S 426/801 (20130101) |
Current International
Class: |
A23L
1/30 (20060101); A23L 1/29 (20060101); A23C
009/00 () |
Field of
Search: |
;426/801,471,72,73,74,587,519,522,2 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
21 CFR 105 Apr. 1, 1982..
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Primary Examiner: Paden; Carolyn
Attorney, Agent or Firm: Cushman, Darby & Cushman
Parent Case Text
This is a continuation of application Ser. No. 07/055,858, filed
June 1, 1987, which was abandoned upon the filing hereof.
Claims
We claim:
1. A non-milk based infant formula comprising carbohydrates, a
source of amino acids, vegetable oils, minerals, vitamins, wherein
the formula contains at least one of uridine, uridine phosphate or
mixtures thereof; guanosine, guanosine phosphate or mixtures
thereof; adenosine, adenosine phosphate or mixture thereof;
cytidine, cytidine phosphate or mixtures thereof or inosine,
inosine phosphate or mixtures thereof.
2. An infant formula according to claim 1, which comprises (on a
dry basis per 100 g):
a) up to 17.40 mg uridine, uridine phosphate or mixture
thereof;
b) up to 3.32 mg guanosine, guanosine phosphate or mixtures
thereof;
c) up to 3.75 mg adenosine, adenosine phosphate or mixtures
thereof;
d) up to 4.58 mg cytidine, cytidine phosphate or mixtures thereof;
and
e) up to 1.92 mg of inosine, inosine phosphate or mixtures
thereof.
3. An infant formula according to claim 2 containing in mg per 100
g total weight:
uridine and/or uridine phosphate: 17.40-1.86 mg;
guanosine and/or guanosine phosphate: 3.32-0.27 mg;
adenosine and/or adenosine phosphate: 9.50-4.25 mg;
cytidine and/or cytidine phosphate: 10.16-3.52 mg; and
inosine and/or inosine phosphate: 1.92-0.00.
4. An infant formula according to claim 3 containing L-cystine.
5. An infant formula according to claim 3 containing carnitine.
6. An infant formula according to claim 2 containing L-cystine.
7. An infant formula according to claim 2 containing carnitine.
8. An infant formula according to claim 6 in powdered form.
9. A formulation according to claim 8 in powder form containing for
each 100 g;
uridine: 1-300 mg;
guanosine: 1-300 mg;
adenosine: 1-300 mg;
cytidine: 1-300 mg; and
inosine: 1-300 mg.
10. A powdered formulation according to claim 9 containing:
uridine: 50-250 mg;
guanosine: 50-250 mg;
adenosine: 50-250 mg;
cytidine: 50-250 mg; and
inosine: 50-250 mg.
11. An infant formula according to claim 1 in liquid form.
12. An infant formula according to claim 11, containing per dl:
uridine and/or uridine phosphate: 2.62-0.28 mg;
guanosine and/or guanosine phosphate 0.50 -0.04 mg;
adenosine and/or adenosine phosphate: 1.43-0.64 mg;
cytidine and/or cytidine phosphate: 1.53-0.53 mg; and
inosine and/or inosine phosphate: 0.29-0.00.
13. A process for the preparation and aseptic packaging of a liquid
infant formula or a liquid nutritionally balanced diet formulation
comprising a composition as set forth in claim 1, said process
comprising the steps of:
a) mixing aqueous liquid and non-fat solids of said composition in
the absence of any vitamins, nucleosides and nucleotides;
b) preheating the mixture to a temperature ranging from about
75.degree. to 80.degree. C. and then deaerating the heated mixture
followed by adding the vegetable oils to the deaerated mixture;
c) homogenizing the mixture under pressure and then cooling;
d) standardizing the mixture by addition of any vitamins, minerals,
nucleosides, nucleotides and other components not added in step a),
and adjusting the pH in the range of about 6.8 to about 7.1;
e) UHT (ultra-high temperature) sterilizing the standardized
mixture and subsequently homogenizing the mixture under
pressure;
f) cooling the homogenized mixture and aseptically packaging
same.
14. A process for the preparation and bottling of a liquid infant
formula or a liquid nutritionally balanced diet formulation
comprising a composition as set forth in claim 1, said process
comprising the steps of:
a) mixing aqueous liquid and non-fat solids of said composition in
the absence of any vitamins, nucleosides and nucleotides;
b) preheating the mixture to a temperature ranging from about
75.degree. to about 80.degree. C. and then deaerating the heated
mixture followed by adding the vegetable oils to the deaerated
mixture;
c) homogenizing the mixture under pressure and then cooling;
d) adjust the pH of the mixture under pressure and then
cooling;
e) standardizing the UHT sterilized mixture by the addition of any
vitamins, minerals, nucleosides, nucleotides and other components
not added in step a) and reheating the standardized mixture to a
temperature ranging from about 30.degree. C. to about 70.degree. C.
and bottling the heated mixture;
f) sterilizing the bottled mixture a second time to obtain a final
bottled product in a liquid form.
15. A process for the preparation in powder form of an infant
formula or a nutritionally balanced diet formulation comprising a
composition as set forth in claim 1, said process comprising the
steps of:
a) mixing water with the non-fats of said composition in the
absence of the vitamins, nucleosides and nucleotides;
b) preheating the mixture to a temperature ranging from about
75.degree. to about 80.degree. C. and then deaerating the heated
mixture and then adding the vegetable oils to the deaerated
mixture;
c) homogenizing the mixture under pressure and then cooling;
d) standardizing the mixture by addition of any vitamins, minerals,
nucleosides, nucleotides and other components not added in step a),
and adjusting the pH in the range of about 6.8 to about 7.1;
e) reheating the standardized mixture to between about 65.degree.
C. and 70.degree. C.;
f) homogenizing the reheated mixture and drying the homogenized
mixture in a spray drier to obtain a final dry powder product;
and
g) packaging the dry powder product.
16. A formulation according to claim 1 in liquid form containing
per dl:
uridine: 0.2-60 mg;
guanosine: 0.2-60 mg;
adenosine: 0.2-60 mg;
cytidine: 0.2-60 mg; and
inosine: 0.2-60 mg.
17. A liquid formulation according to claim 16 containing:
uridine: 10-50 mg;
guanosine: 10-50 mg;
adenosine: 10-50 mg;
cytidine: 10-50 mg; and
inosine: 10-50 mg.
Description
BACKGROUND OF THE INVENTION AND PRIOR ART
The present invention relates to the composition of, and processes
for making, products for infant formulas and for nutritional
products suitable for both infants and adults, and particularly for
clinical nutrition. These products may be administered orally or by
enteral feeding tubes. These products are enriched with specific
nucleosides, nucleotides, or mixtures thereof.
Infant formulas are derived, to a large extent, from cow's milk.
After being diluted, the cow's milk is enriched with whey proteins,
diverse carbohydrates, such as lactose, dextrin, maltose and
starches, different mixtures of vegetable and animal fats, vitamins
and minerals. These components are present in suitable amounts to
meet the requirements of low birth weight newborns or those of at
term healthy infants during the first and second semester of
life.
Sometimes, infant formulas contain isolated milk proteins, isolated
vegetable proteins or protein hydrolyzates, from different origins
such as casein, lactalbumin, soy and meat. Also, these infant
formulas have one or more carbohydrates (sucrose, dextrin, maltose
and starch), mixtures of diverse kind of fats, minerals and
vitamins, to meet not only the healthy newborns' nutritional
requirements, but also of infants and children with clinical
symptoms of lactose intolerance, protein intolerance and, in
general, with diverse malabsorption-malnutrition syndromes.
The European Society of Pediatric Gastroenterology and Nutrition
(ESPGAN), the American Academy of Pediatric (AAP), the Codex
Alimentarius Mundi, and the European Community Council, among other
organizations, have given general rules for the composition of
infant formulas (ESPGAN Committee on Nutrition, Acta Paed Scand,
Supl 262, 1977; ESPGAN Committee on Nutrition, Acta Paed Scand,
Supl 287, 1981; ESPGAN Committee on Nutrition, Acta Paed Scand,
Supl 302, 1982; ESPGAN Committee on Nutrition, Acta Paed Scand,
Supl 330, 1987; AAP Committee on Nutrition, Pediatric Nutrition
Handbook, 1979; AAP Committee on Nutrition, Pediatrics, 75, 976,
1985; EEC Council, 85/C 28/05 COM (84) 703 final, 1985; EEC
Council, 86/C 124/06 COM/86 91 final, 1986; Codex Alimentarius
Mundi, Codex Stan 72-1981).
As used herein, the term "infant formulas" is intended to refer to
the well established understanding as defined by ESPGAN Committee
on Nutrition, Acta Paed Scand, supl 262, pg 3, supra, and also the
American Academy of Pediatrics (Pediatrics, Vol 57 no 2, pg 281,
February 1976).
In general, infant formulas tend to have a composition
qualitatively and quantitatively as similar as possible to human
milk. Nevertheless, despite the efforts made by several
researchers, infant formulas still have a number of differences in
their composition compared to human milk. This is because the
latter has many substances, such as immunoglobulins, free amino
acids, polyamines, nucleotides, polyunsaturated fatty acids, etc,
which are not present in cow's milk. Thus, it would be desirable
that infant milk formulas have most of the substances present in
human milk so as to produce the same physiological effects as human
milk.
Nutritional products, such as those currently used in hospitals,
special or for dietary purposes, are based on the utilization of
diverse protein sources (casein, sodium and calcium caseinate,
isolated soy protein, protein hydrolyzates and/or crystalline amino
acids) mixtures of vegetable and animal fats, carbohydrates
(basically glucose polymers), vitamins and minerals to meet, at
least, the dietary intakes recommended for healthy individuals
(Committee on Dietary Allowances, Food and Nutrition Board, Nat
Acad Sci, 9th Ed, 1980).
Protein energy malnutrition (PEM) is found in many patients
admitted to hospitals. This happens not only in developing
countries, but also in those with a high socioeconomic level where
the percentages of medical-surgical patients vary between 40-50%
(Bistrian et al. JAMA, 235, 1567, 1976; G. Hill et al. Lancet, 1,
689, 1977; Gassull et al. Human Nutr: Clin Nutr, 38C, 419, 1984).
Proper nutritional support for such patients, while not a primary
mode of treatment is, nevertheless, an important factor for therapy
and recovery. It is, therefore important to administer a
nutritionally balanced diet given orally, enterally or
parenterally, adequate to the needs of the patient. This is
especially true for those patients where conventional feeding is
contraindicated (gastroenterological patients) or is insufficient
(hypercatabolic patients). The enteral or oral mode of
administration of foods is preferably to parenteral modes (E. Cabre
and M. A. Gassull, J. Clin Gastroenterol Nutr, 1, 97, 1986) because
of the lower morbidity, trophic effect upon the intestinal mucose,
lower necessity for instruments and lower costs.
Nutritional products for proper diets associated with parenteral
administration should be formulated to meet the requirements of the
individual needs in specific situations. Thus, complete balanced
diets with an energy content between 130-150 Kcal/g nitrogen, are
recommended for the preventive and repletive therapy in cases of
PEM due to nervous anorexy, esophageal stenosis, maxillofacial
surgery, chronic vasculo-cerebral disease, long evolution
neurological syndromes, vascular surgery postoperative period,
malabsorption syndromes, preoperative period, complete intestinal
oclusion, preparation of colon (surgery, radiology and endoscopy)
and, in general, in all cases when it is necessary to take a
balanced diet of nutrients. Diets with a high content of nitrogen
(80-120 Kcal/g nitrogen) are recommended for the nutritional
therapy of burn patients or patients suffering cranial trauma,
multiple trauma, open fractures, Crohn disease, ulcerous colitis,
digestive fistula, sepsis, oncology surgery, oncological
radiotherapy and chemotherapy, pre- and postoperative periods,
orthopedic surgery, and, in general, for catabolic patients.
Diets containing protein hydrolyzates as a source of amino nitrogen
are specially made for the nutritional support of patients with
diverse malabsorption-malnutrition syndromes, such as short bowel,
acute celiac disease, Crohn disease, chronic pancreatic
insufficiency, cystic fibrosis, intestinal fistulas, postoperative
nutrition, and the like.
Furthermore, such products can be made as specific clinical diets
for specific diseases, such as hepatopathies, chronic renal
disease, and chronic obstructive pulmonary disease.
In addition, there is a variety of dietary products marketed to
meet the nutritional needs of various individuals. For example,
many individuals desirous of achieving verifying degrees of weight
loss, may benefit from the use of a special nutrition diet
formulations to provide specific nutrients otherwise provided by a
normal diet. Likewise, many people find it necessary to supplement
their daily diet with additional nutrients due to age, allergy or
physical afflictions.
As used herein, the term "nutritionally balanced diet formulations"
is intended to refer to the above type of products.
Currently marketed nutrition products do not contain nucleic acids
or their simpler compounds, either nucleosides and/or nucleotides,
which are normally present in foods and carry out fundamental
physiological functions, described further on.
In relation to the nutritional importance of nucleotides, some
relevant aspects of these compounds such as their content in human
milk, physiological effects in newborns, intestinal absorption,
tissue utilization and effects upon cell immunity are shown
below.
U.S. Pat. No. 4,544,559 teaches that human milk has a specific
nucleotide content, very different from cow's milk. Human milk
contains, at least, twelve different nucleotides, predominating
cytidine monophosphate (CMP), adenosine monophosphate (AMP),
uridine monophosphate (UMP), guanosine monophosphate (GMP), inosine
monophosphate (IMP) and uridine derivatives, whereas cow's milk has
very low amounts of CMP and AMP; it lacks the other nucleotides and
has high amounts of orotic acid, which is absent in human milk.
Also, U.S. Pat. No. 4,544,559 teaches that a humanized milk
enriched with nucleotides AMP, CMP, GMP, UMP and IMP in the same
range as human milk, stimulates the development of Bifidobacterium
bifidum Ti at the intestinal level. This bacterium comprises 80% of
the total bifidobacteria present in the feces of breast-fed
newborns. Furthermore, this humanized milk promotes serum fatty
acid profile very similar to that found in newborns fed with human
milk.
Ziro et al. U.S. Pat. No. 3,231,385 describes infant milk formulas
supplemented with certain nucleotides to simulate human milk,
improve the milk taste and lower the curd tension.
Nucleotides can be synthesized in most tissues by two processes: a)
de novo synthesis from the precursors which include
pyrophosphoribosilphosphate, glutamine, aspartate, glycine,
formiate and carbon dioxide and b) utilization of bases and the
nucleosides liberated through the catabolism of nucleotides and
nucleic acids contained in foods by the "salvage pathway" (S.
Leleiko et al. J Pediatr Gastroenterol Nutr, 2, 313, 1983). This
last way is an important alternative in the synthesis of
nucleotides when the biosynthetic de novo pathway is hindered by an
insufficient supply of precursors. Tissues such as bone marrow,
intestine and the liver are heavily dependent on the salvage
pathway. The activity of the "salvage pathway" has also been shown
demonstrated in kidney, brain and retina (P. Mandel, Traite de
biochemie generale, Polonovski, Boulanger, Lemoigne, Wurmser, eds,
Masson et Cie, Paris, 1972).
The intestinal mucosa needs a continuous supply of nucleotides or
their precursors from dietary origin, apart from the hepatic supply
by the vascular system, in order to maintain continuous synthesis
of RNA.
It has been confirmed in cuts made in the small intestine of rats
that the exogenous adenosine triphosphate (ATP) increases the
intracellular concentration of this nucleotide and it has been
observed that at temperatures over 20.degree. C. the marked
exogenous ATP is absorbed by everted sacs of rat small intestine
(J. Bronk and H. Leese, J. Physiol. 235, 183, 1973; J. Blair, M.
Lucas and A. Matty, J. Physiol., 245, 333, 1975). Also, it has been
shown in rabbit's ileum "in vitro" that, at low concentrations, the
ATP as well as the nucleoside adenosine are absorbed through a
carrier associated to the enterocyte membrane.
Since the carrier system works for ATP and adenosine, it is likely
that the system also works for other purine nucleotides, because
competitive inhibition measures have proved that any compound with
a purine ring united to a ribose molecule is absorbed. (V. Harms
and C. Stirling, Am. J. Physiol., 233, E-47, 1977).
It has also been shown that the purines and pyrimidines in the RNA
and DNA, present in the diet, are absorbed by mice, preferably as
nucleosides. Between 2-5% of the nucleosides are used for nucleic
acid synthesis in intestinal tissue, and citosine nucleosides are
used for DNA synthesis, specially in the spleen (F. Sonoda, M.
Tatibana, Biochem. Biophys. Acta, 521, 55, 1978).
It has also been shown that purine bases, such as adenine, guanine,
hypoxanthine and xanthine are almost completely absorbed by rats,
4.5-6.5% being incorporated in tissues and in a greater proportion
by the liver and intestine.
The absence of pyrimidine or purine derivatives in the diet is
known to supress the normal function of T lymphocytes (F. Rudolph
et al. Adv. Exp. Med. Biol, 165, 175, 1984), and to increase the
mortality in experimental animals by staphylococcus sepsis. The
addition of pyrimidine and purine derivatives to the diet decreases
the suceptibility of animals to infection (A. Kulkarni et al, JPEN,
10, 169, 1986). Thus, the effect of purines and pyrimidines on the
immune function can be of great importance in a number of clinic
situations, such as transplants of organs in patients, malnutrition
recovery, in diverse chemotherapeutic regimens and in the treatment
of leukemias derived from T cells.
Accordingly, one of the objects of the present invention is to
provide improved nutritionally balanced diet formulations.
Another object of the present invention is to provide non-milk
infant formulas which more closely resemble the human milk of
nursing mothers and also exhibit enhanced properties.
Still yet a further object of the present invention is to provide
improved milk based infant formulas which not only closely resemble
human milk, but which are more readily absorbed by the infant gut
and enhance the infant's immune response.
These and other objects of the present invention will become more
apparent from the discussion which follows.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a range of compositions of infant
formulas and clinical nutrition products enriched with nucleosides,
nucleotides or mixes of these two classes of compounds and the
processes for their preparation. The products are in a liquid ready
to eat form, or concentrated liquid or powder.
According to the invention, adenosine, guanosine, cytidine,
inosine, and uridine or their mixes are used as nucleosides, and
adenosine phosphate, guanosine phosphate, cytidine phosphate,
inosine phosphate and uridine phosphate are used as
nucleotides.
The term uridine phosphate, guanosine phosphate, etc, is intended
herein to refer collectively to the mono, di and/or tri phosphates
as well as the sugar derivatives of the nucleotides mentioned.
However, for various reasons which will be apparent to those
knowledgeable in the art, the 5'-monophosphates are preferred.
The supplementation of nucleosides and/or nucleotides or their
mixes to infant formulas and nutrition balanced diet formulations
gives a better physiological fatty acid tissue membrane composition
to newborns and adult patients, an improved cell immunity and a
better intestinal repair in those patients with intestinal
diseases.
Accordingly, one embodiment of the present invention provides for a
nutritionally balanced diet formulation which comprises a source of
amino nitrogen, carbohydrates, edible fats, minerals, vitamins and
a nucleoside/nucleotide composition containing at least one of:
a) uridine, uridine phosphate or a mixture thereof;
b) guanosine, guanosine phosphate or a mixture thereof;
c) adenosine, adenosine phosphate or a mixture thereof;
d) cytidine, cytidine phosphate or a mixture thereof; or
e) inosine, inosine phosphate or a mixture thereof.
Thus, the formulation must contain at least one of the fifteen
different possible components in an amount (based on 100 grams of
dry product) equal to 1 mg.
Generally, the diet formulation will contain (on a dry weight basis
per 100 g) from 1 to 300 mg of components selected from a), b), c),
d) and e), with a preferred range being from about 50 to about 250
mg. The optimum amount appears to be about 150 mg per 100 grams
product.
On a liquid basis, these ranges correspond to from about 0.2 to 60
mg/dl on a general basis, and preferably about 10 to about 50
mg/dl, with the optimum being about 30 mg/dl.
A further embodiment of our invention provides for improved
non-milk infant formulas. Such non-milk formulas are well known and
generally comprise carbohydrates, a source of amino acids,
vegetable oils, minerals and vitamins. According to this embodiment
of the invention, there is added to such formulas at least one of
uridine, uridine phosphate or mixtures thereof; guanosine,
guanosine phosphate or mixtures thereof; adenosine, adenosine
phosphate or mixtures thereof; cytidine, cytidine phosphate or
mixtures thereof; or inosine, inosine phosphate or mixtures
thereof. As a minimum, at least about 0.27 mg per 100 g of product
of one of the components should be added to the infant formula.
Generally, the non-milk infant formulas according to the present
invention require on a dry weight basis in mg per 100 grams of
total weight approximaterly the following additives:
uridine and/or uridine phosphate. 17.40-1.86 mg;
guanosine and/or guanosine phosphate. 3.32-0.27 mg;
adenosine and/or adenosine phosphate. 9.50-4.25 mg;
cytidine and/or cytidine phosphate. 10-16-3.52 mg; and
inosine and/or inosine phosphate. 1.92-0.00 mg.
On a liquid basis, per dl, these formulation correspond as
follows:
uridine and/or uridine phosphate. 2.62-0.28 mg;
guanosine and/or guanosine phosphate. 0.50-0.04 mg;
adenosine and/or adenosine phosphate. 1.43-0.64 mg;
cytidine and/or cytidine phosphate. 1.53-0.53 mg; and
inosine and/or inosine phosphate. 0.29-0.00 mg.
For reasons discussed more fully below, it may be desirable to add
small amounts of L-cystine and/or carnitine to the non-milk based
infant formulas.
As yet a further embodiment of our invention there is provided an
improved infant milk formula to which is added at least one
nucleoside selected from the group consisting of uridine,
guanosine, adenosine, cytidine and inosine. The added nucleosides
must be present in an amount about 0.27 mg per 100 grams total
product on a dry basis. To provide for a closer simulation of human
breast milk and also enhance absorption by the infant gut, there
should be added to the infant milk formula the following
ingredients for each 100 g of total weight:
uridine and/or uridine phosphate. 17.40-1.86 mg;
guanosine and/or guanosine phosphate. 3.32-0.27 mg;
adenosine and/or adenosine phosphate. 3.75-0.00 mg;
cytidine and/or cytidine phosphate. 4.58-0.00 mg; and
inosine and/or inosine phosphate. 1.92-0.00 mg.
This of course corresponds on a liquid basis (per dl) as
follows:
uridine and/or uridine phosphate. 2.62-0.28 mg;
guanosine and/or guanosine phosphate. 0.50-0.04 mg;
adenosine and/or adenosine phosphate. 0.56-0.00 mg;
cytidine and/or cytidine phosphate. 0.69-0.00 mg; and
inosine and/or inosine phosphate. 0.29-0.00 mg.
Basically, infant formulas, according to the present invention have
a composition adequate for meeting the requirements of low birth
weight infants, at term infants and children with lactose
intolerance.
The infants formulas and nutritionally balanced diet products of
the present invention have been found to stimulate repair and
regeneration of intestinal gut cells, enhance the immune response
of T-cells and provide for specific fatty acid phospholipids
profiles in red blood cell membranes.
The use of nucleosides herein is unique to the formulations of the
present invention. These materials generally have been found to be
at least as effective as their corresponding nucleotides, and even
more effective in providing for enhanced absorption through use of
the salvage pathway in the human body. This apparently may be due
to the higher water solubility of nucleosides as compared to the
corresponding nucleotides. Also, nucleoside stability when used in
the formulations of this invention is greater than that of the
corresponding nucleotides.
When the nucleosides and/or nucleotides or their combinations are
added to infant formulas in concentrations in the same range as
human milk, according to this invention, they stimulate the
conversion of essential fatty acids to their polyunsaturated
derivatives (AGPI), which is reflected in the fatty acid
composition of erythrocyte membrane both in the at-term newborn and
in the preterm newborn as well as in the fatty acids composition of
plasma phospholipids.
In a study carried out by the inventors, 20 at-term newborns were
fed exclusively on human milk, 19 with an infant formula and 19
with the same infant formula supplemented with
nucleoside-5'-monophosphates according to this invention, in
similar concentrations to those of human milk. The relative content
of AGPI, of the w6 series, derived from linoleic acid, as well as
w3 series, derived from linolenic acid, was significantly
decreased, specially in phosphatidylethanolamine and
phosphatidylserine of the erythrocyte membrane in infants fed milk
formula with respect to infants fed nucleoside-5'-monophosphates
supplemented milk formula or human milk. The same happened in the
plasma phospholipids and cholesteryl esters. The arachidonic
(20:4w6) and docosahexaenoic (22:6w3) acids were the most increased
fatty acids in infants fed nucleoside-5'-monophosphates
supplemented milk formula, with respect to those fed milk
formula.
In other study, 19 preterm infants were fed exclusively on human
milk, 18 with an infant milk formula for prematures and 18 with the
same milk formula supplemented with nucleosides-5'-monophosphates
in concentrations similar to those of human milk, according to this
invention. At one month of life, the relative contents of
eicosatrienoic acid (20:3w6), arachidonic acid (20:4w6),
docosatetraenoic acid (22:4w6) and docosapentaenoic acid (22:5w6)
were significantly decreased in the erythrocyte membrane
phospholipids in infants fed milk formula with respect to those fed
nucleoside-5'-monophosphate supplemented milk formula or human
milk. Also, infants fed nucleoside-5'-monophosphate supplemented
milk formula showed an intermediate value of docosahexaenoic acid
(22:6w3) between those fed human milk and those fed milk formula.
The same results were observed in the plasma phospholipids of
preterm newborns.
The modulating effect of nucleosides and nucleotides of the diet
upon cell immunity has been proved through the following
method:
Six groups of BALB/C mice, constituted by 10 mice each, aged four
weeks, weaning period, were feed with a conventional diet (Chow
diet), a nucleosides and nucleotides free diet, a diet supplemented
with nucleosides according to this invention, in the following
proportions 50 mg of uridine, 50 mg of guanosine, 50 mg of
adensine, 50 mg of cytidine and 50 mg of inosine, a diet
supplemented with nucleosides in proportions equivalent to mouse
milk, a diet supplemented with 50 mg of the following nucleotides
UMP, GMP, CMP, UMP according to this invention and a diet
supplemented with nucleotides in proportions equivalent to mouse
milk, respectively. The mice were feed during a period of four
weeks, and with them we proceed with the testing of the cell immune
response "in vitro" as response to allogeneic and syngenetic
antigens using the lymphocyte mixed culture technique and
quantifying the cell proliferation by the incorporation of .sup.3
H-thymidine to DNA and secondly we proceed with the testing of the
proliferation as response to phytohemaglutinin (mitogen agent) to
quantify the state of lymphocyte reactivity, also with the
incorporation of .sup.3 H-thymidine.
The mice fed on the free nucleoside or nucleotide diets had an
immune response mediated by T cells lower than the other groups
having a diet supplemented with these compounds.
The mice fed on the free nucleoside or nucleotide diets had an
immune response mediated by T cells lower than the other groups
having a diet supplemented with these compounds.
The effect of nucleosides and nucleotides of the diet on the
intestinal cell proliferation and on their enzymatic activity is
proved as follows:
Two groups of Wistar mice, of 20 animals each, from the weaning (21
days of age), are fed during two weeks, the first of them on a diet
(Diet A) containing 167 g of calcium caseinate, 489.5 of corn
starch, 150 g of sugar, 50 g of cellulose, 100 g of soy oil, 3 g of
DL-methionin, 1.1 g of coline chloride, 38.2 g of a mineral mixture
and 1.2 g of a vitamin mixture, per Kg, to satisfy the nutritional
requirements of these animals. The second group was fed with a
similar diet, but with lactose instead of starch (Diet B). In this
second group takes place an osmotic diarrhoea because of lactose
intolerance giving rise to a malnutrition-malabsorption syndrome.
Both groups are divided in two subgroups of 10 animals each, the
first subgroup being fed on Diet A and the second with on Diet A
supplemented with 50 mg of each of the following nucleosides:
uridine, guanosine, adenosine, citidine and inosine, during 4 weeks
or with 50 mg of each of the following nucleotides: UMP, GMP, AMP,
CMP and IMP, according to this invention.
The animals suffering malabsorption syndrome refed on the
nucleoside or nucleotide supplemented diet, according to the
invention, had ileal, jejunal and duodenal mucose weights
significantly superior to those fed on a diet without such
compounds. Also, the proportion of cells in a mitosis state, the
mucose proteins content and the maltase and sucrase enzymatic
activities were significantly higher in animals fed on the
nucleoside or nucleotide supplemented diet than in those fed on a
free purine and pyrimidine diet.
Basic ingredients for infant formulas include cow's milk, protein,
whey proteins, casein and its salts (i.e. calcium caseinate); soy
protein isolates are substituted for milk derived proteins, and are
used in the products made for infants with lactose intolerance
and/or cow's protein intolerance. Protein hydrolyzates (i.e. casein
and lactalbumin hydrolyzates) with low molecular weight, may also
be used for the products
The proportions of the diverse component nutrients are similar to
those of human milk. Thus, the ratio of whey proteins to casein
currently varies from 60:40 to 70:30 in infant formulas based on
milk. The mixture of fats employed is made up of edible fats to
provide an essential fatty acid profile. Lactose is used
exclusively as the carbohydrate source for at-term newborns
infants, except that dextrinmaltose is employed in products used
for the treatment of lactose intolerance and malabsorption
syndromes in infancy.
Infant formulas according to the invention contain minerals
(including calcium, phosphorus, sodium, potassium, chloride,
magnesium, iron, zinc, copper, manganese and iodine) and vitamins
(including vitamin A, vitamin D.sub.3, vitamin C, vitamin B.sub.1,
vitamin B.sub.2, vitamin B.sub.6, vitamin B.sub.12, pantothenic
acid, vitamin E, vitamin K.sub.1, folic acid, biotin) adequate for
the infants' requirements. Also, in the products whose source of
proteins is derived from soy or protein isolates or hydrolyzates,
carnitine is included to satisfy the nutritional requirements for
this compound in infants with malabsorptive syndromes.
The inventors of the present compositions and processes have
demonstrated that the amounts of citosine, adenine, guanine, uracil
and inosine derivatives in human milk vary between 1.53-0.54,
1.43-0.69, 0.50, 2.62 and 0.29-0.00 mg/dl respectively and the
individual contents of CMP, AMP, GMP, UMP and IMP osciallate
between 1.37-0.53, 1.19-0.64, 0.21-0.04, 0.56-0.28, 0.29-0.00
mg/dl, respectively.
The content of nucleosides and/or nucleotides in the infant
formulas of the present invention are in the range of those for
human milk. An examplary nucleoside and/or nucleotide mixture for
infant formulas not containing cow's milk, according to the
invention, is shown in Table I.
The amounts of adenosine and/or adenosine phosphate and cytidine
and/or cytidine phosphate, inosine and/or inosine phosphate added
to cow's milk based infant formulas, according to this invention,
are lower than those shown in Table I, because cow's milk contains
specific amounts of nucleosides and nucleotides.
In Table II an examplary mixture of nucleosides and/or nucleotides
for infant milk formulas containing cow's milk is shown.
The dietary products for balanced nutrition, according to the
present invention, have a composition of nutrients adequate to the
specific requirements of not only healthy human in need of a
balanced nutritional product, but also those individuals in
situations of energy-protein malnutrition and in hypercatabolic
states derived from traumatic, septic, surgical processes and
malabsorption syndromes.
As nitrogenous sources, the following components are preferably
employed: a mixture of dairy proteins (casein or sodium and calcium
caseinates and lactose free lactalbumin) and protein hydrolyzates
with low molecular weight (maximum molecular weight 1,000 daltons,
average molecular weight, 500 daltons). As carbohydrate sources,
glucose polymers are employed, such as dextrinmaltose with a
different grade of dextrose equivalent degree, preferably between
10 and 30 DE. Fats are employed as a mixture of animal and one or
more vegetable fats to meet the essential fatty acids requirements
of patients.
Nutritional products according to the present invention provide
mineral elements which include trace elements and vitamins in
adequate proportions to satisfy the specific requirements of normal
healthy individuals as well as those suffering
malabsorption-malnutrition processes and in a hypercatabolic
state.
The nutritional products are enriched with nucleosides and/or
nucleotides in similar amounts of nucleotides to those present in
foods.
An example of a nucleoside and/or nucleotide mixture for the
enrichment of nutritional products is shown in Table III. On a dry
weight basis, the amount of nucleosides and/or nucleotides may each
vary from about 1 to about 300 mg per 100 grams of product, and
preferably each ranges from about 50 to about 250 mg per 100 grams
of product. On a liquid basis the amount may vary per deciliter of
product from about 0.2 to about 60 mg of each nucleoside and/or
nucleotide, and preferably ranges from about 10 to about 50 mg.
TABLE I
__________________________________________________________________________
Example of a characteristic mixture of nucleosides and/or
nucleotides in infant formulas, not containing cow's milk. Powdered
product Liquid product Preferred Range Preferred Range mg/100 g
mg/100 g mg/dl mg/dl
__________________________________________________________________________
Uridine and/or uridine phosphate 3.42 17.40-1.86 0.51 2.62-0.28
Guanosine and/or guanosine phosphate 1.49 3.32-0.27 0.22 0.50-0.04
Adenosine and/or adenosine phosphate 6.90 9.50-4.25 1.03 1.43-0.64
Cytidine and/or cytidine phosphate 6.87 10.16-3.52 1.03 1.53-0.53
Inosine and/or inosine phosphate 1.00 1.92-0.00 0.15 0.29-0.00
__________________________________________________________________________
TABLE II ______________________________________ Example of a
characteristic mixture of nucleosides and/or nucleotides in infant
formulas based on cow's milk. Powdered Liquid product product Range
Range mg/100 g mg/dl ______________________________________ Uridine
and/or uridine phosphate 17.40-1.86 2.62-0.28 Guanosine and/or
guanosine phosphate 3.32-0.27 0.50-0.04 Adenosine and/or adenosine
phosphate 3.75-0.00 0.56-0.00 Cytidine and/or cytidine phosphate
4.58-0.00 0.69-0.00 Inosine and/or inosine phosphate 1.92-0.00
0.29-0.00 ______________________________________
TABLE III
__________________________________________________________________________
Example of a characteristic mixture of nucleosides and/or
nucleotides in nutritionally balanced diets. Powdered product
Liquid product Preferred Range Preferred Range mg/100 g mg/100 mg
mg/dl mg/dl
__________________________________________________________________________
Uridine and/or uridine phosphate 150 1-300 30 0.2-60 Guanosine
and/or guanosine phosphate 150 1-300 30 0.2-60 Adenosine and/or
adenosine phosphate 150 1-300 30 0.2-60 Cytidine and/or cytidine
phosphate 150 1-300 30 0.2-60 Inosine and/or inosine phosphate 150
1-300 30 0.2-60
__________________________________________________________________________
The invention also includes the process to obtain infant formulas,
as well as specific diets to be used in good nutrition, enriched
with nucleosides and/or nucleotides (FIG. 1 to 4). The products can
be prepared in liquid, ready to be used, concentrated to be diluted
in water before its use, and in powder forms.
This process comprises, in all cases, the preparation of a mixture
containing water and non fat solids, except vitamins, minerals and
nucleosides and/or nucleotides, followed by a preheating to
75.degree.-80.degree. C., deareation of the mixture, injection of
the fat mixture, double homogenization at 70.degree.-75.degree. C.
(usually 150 Kg/cm.sup.2 in the first stage and 50 Kg/cm.sup.2 in
the second) cooling to 4.degree.-6.degree. C. and storage in
standardization tanks.
The liquid products ready for consumption or concentrates to be
diluted before use, are standardized in the said tanks, adapting
the pH to values generally ranging from about 6.8 to about 7.1 and
most preferably ranging from about 6.8 to 7.0 for infant formulas
and from about 6.9 to 7.1 for nutritional products.
When the products are going to be UHT sterilized and aseptically
packed in containers made of carton-aluminium-polyethylene, during
the standardization, the vitamins, mineral and nucleotides or
nucleosides mixtures are added as concentrated aqueous solutions
and the content of mineral elements is adjusted by adding the
required salts. The nucleoside and/or nucleotide solutions should
be maintained preferably at pH 6-6.5 to avoid them to
hydrolyze.
Once standardized, the products for consumption in liquid or
concentrated forms, are sterilized through an UHT system at
145.degree.-150.degree. C. for 2-4 seconds and can be either
aseptically packed or bottled in glass or polyethylene bottles. In
the latter case, products are standardized prior to the UHT
sterilization, only in their solids contents, and the pH is
adjusted to values equivalents as noted above; immediately after
they are sterilized, refrigerated at 4.degree.-6.degree. C. and
stored in standardization tanks, the vitamins, minerals and the
nucleoside and/or nucleotide solutions are added; afterwards the
products are reheated at 30.degree.-70.degree. C., packed in
polyethylene or glass bottles, and sterilized in a continuous
sterilizer at 120.degree.-121.degree. C. for 10 minutes.
In the case of powder products, after the phase of concentrated
solids recombination, preheating, deareation, fat mixture
injection, homogenization, refrigeration, final pH standardization,
concentration and addition of vitamins, minerals nucleosides and/or
nucleotides, the mixture is reheated to 65.degree.-70.degree. C.,
homogenized at 100-150 Kg/cm.sup.2 and dried in a spray drier.
Afterwards, the powdered product is packed in
polyethylene-aluminium containers or in cans, internally coated
with varnish, under inert atmosphere, or in other acceptable
containers.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 to 3 are block diagrams illustrating the stages of the
process for the preparation of the products of the invention when
packaged aseptically, in bottles or in powder form.
FIG. 4 is a schematic view of the plant manufacturing process for
preparing products of the present invention.
With reference to FIG. 1, there is depicted a process for the
preparation and aseptic packaging of a liquid infant formula or a
liquid nutritionally balanced diet formulation comprising a
composition as set forth above, said process comprising the steps
of:
a) mixing water and non-fat solids of said composition in the
absence of any vitamins, nucleosides and nucleotides;
b) preheating the mixture to a temperature ranging from about
75.degree. to about 80.degree. C. and then deareating the heated
mixture followed by adding any fats in the composition to the
deareated mixture;
c) homogenizing the mixture under pressure followed by cooling;
d) standardizing the mixture by addition of any vitamins, minerals,
nucleosides, nucleotides and other components not added in step a),
and adjusting the pH in the range of about 6.8 to about 7.1;
e) UHT sterilizing the standardized mixture and subsequently
homogenizing the mixture under pressure;
f) cooling the homogenized mixture and aseptically packaging
same.
With reference to FIG. 2, there is depicted a process for the
preparation and bottling of a liquid infant formula or a liquid
nutritionally balanced diet formulation comprising a composition as
set forth above, said process comprising the steps of:
a) mixing water and non-fat solids of said composition in the
absence of any vitamins, nucleosides and nucleotides;
b) preheating the mixture to a temperature ranging from about
75.degree. to about 80.degree. C. and then deareating the heated
mixture followed by adding any fats in the composition to the
deareated mixture;
c) homogenizing the mixture under pressure followed by cooling;
d) adjust the pH of the mixture in the range of about 6.8 to about
7.1, followed by UHT sterilization;
e) standardizing the UHT sterilized mixture by the addition of any
vitamins, minerals, nucleosides, nucleotides and other components
not added in step a) and reheating the standardized mixture to a
temperature ranging from about 30.degree. C. to about 70.degree. C.
and bottling the heated mixture;
d) sterilizing the bottled mixture a second time to obtain a final
bottled product in liquid form.
With reference to FIG. 3, there is depicted a process for the
preparation in powder form of an infant formula or a nutritionally
balanced diet formulation comprising a composition as set forth
above said process comprising the steps of:
a) mixing water and non-fat solids of said composition in the
absence of any vitamins, nucleosides and nucleotides;
b) preheating the mixture to a temperature ranging from about
75.degree. to about 80.degree. C. and then deareating the heated
mixture followed by adding any fats in the composition to the
deareated mixture;
c) homogenizing the mixture under pressure followed by cooling;
d) standardizing the mixture by addition of any vitamins, minerals,
nucleosides, nucleotides and other components not added in step a),
and adjusting the pH in the range of about 6.8 to about 7.1;
e) reheating the standardized mixture to between about 65.degree.
C. and 70.degree. C.;
f) homogenizing the reheated mixture and drying the homogenized
mixture in a spray drier to obtain a final dry powder product;
and
g) packaging the dry powder product.
Referring to FIG. 4, the process is described in more detail
below:
Through the plate heat exchanger 1, deionized water is fed to
storage tanks 2, at a temperature between 60.degree.-70.degree. C.
Through the centrifugal pump 3 and tri-blender 4 non fat solids
(proteins, carbohydrates and some minerals) are dissolved being
maintained the temperature at 60.degree.-65.degree. C. by means of
a plate heat exchanger 5.
The resulting mixture is fed through positive pump 6 to filters 7
and plate heat exchanger 8 to be heated to 75.degree.-80.degree. C.
for 15-20 s to get the product pasteurized; being immediately
deaerated in a vacuum deaerator 9, lowering the temperature to
70.degree.-75.degree. C. Afterwards, the deaerated product is fed
through centrifugal pump 10 and mixed with fat through fat injector
15. The mixture of fats stored in tank 12 has been fed through
positive pump 13 to plate heat exchanger 14 to be heated at
70.degree.-75.degree. C. before reaching fat inyector 15. A
retention valve 11 prevents the product which contains the non fat
solids and fat to go back to the deaerator.
Immediately after fats are mixed to the non fat solids mixture, the
product is homogenized at 16 and a temperature of about
70.degree.-75.degree. C. and 200-300 Kg/cm.sup.2 of total pressure,
preferably in two stages (1st 150-200 Kg/cm.sup.2, 2nd 50-100
Kg/cm.sup.2).
For liquid products which are to be aseptically packaged, after
homogenization 16, they are cooled to 4.degree. to 6.degree. C. in
plate heat exchanger 17 and fed to isothermal standardizing tanks
18 where the pH is adjusted to from about 6.8 to about 7.1
depending on the product desired. Vitamins, minerals, nucleotides
and/or nucleosides in the required amounts are fed to 18 and the
resulting mixture is fed by pumps 19 and 20 to a UHT sterilizer 21
which is at 145.degree.-150.degree. C., homogenized in 22
(preferably in a double stage at 80.degree. C. and 200-250
Kg/cm.sup.2), then is cooled to 20.degree. to 25.degree. in heat
exchanger 23 and aseptically packaged in 36. The packing is
preferably brick type of cardboard, paperboard, aluminium and
polyethylene.
For liquid products which are to be bottled, the process is the
same as above through the cooling treatment 17. Then the pH is
adjusted in tanks 18 to above noted values. The mixture is fed by
pumps 19 and 20 for UHT sterilization at 21 and homogenization at
22. The sterilized mixture is cooled 23 and fed directly to
standardizing tanks 32 where vitamins, minerals, nucleosides and/or
nucleotides as required are added. From tanks 32, and by means of
pump 33, the mixture is fed to reheater 34 where the temperature is
raised to about 30.degree. C. (for polyethylene bottles) to
70.degree. C. (for glass bottles). The mixture is bottled in a
filling machine 35 and subjected to sterilization 37 at a
temperature of about 120.degree.-121.degree. C. for about 10 to 15
minutes to give a bottled product.
For powder products, the process is the same as first described
above through homogenization 16. As shown by the dotted line, the
product is fed to heat exchanger 24 and cooled to about 4.degree.
to about 6.degree. C. and fed to isothermal standardizing tanks 25,
where the pH is adjusted and the required vitamins, minerals,
nucleosides and/or nucleotides are added. Then the standardized
product is pumped 26 through filters 27 and fed to reheater 28
where the temperature is raised to about 65.degree. to about
70.degree. C., and then finally filtered 29 and homogenized 30
under a pressure of about 100-200 Kg/cm.sup.2. The homogenized
product is fed to a drying tower 31, spray dried and collected for
packaging.
EXAMPLES
The invention is illustrated with the following examples, which are
not to be construed as limiting the scope of the invention.
EXAMPLE I
This example provides a product made to feed preterm and low-birth
weight infants, enriched with nucleosides and/or nucleotides and
according to the invention. Basically, the product is a mixture of
cow'milk, demineralized serum proteins, dextrinmaltose, fat
mixture, mineral, vitamins and nucleosides and/or nucleotides
mixture.
The product has been adapted in the protein, fat carbohydrates,
minerals and vitamins contents to the ESPGAN and AAP international
recommendations as related to the feeding of low-birth weight
infants (ESPGAN, Committee on Nutrition, Acta Paediatr. Scand.,
1987 (in press); AAP, Committe on Nutrition, Pediatrics, 1985).
TABLE IV ______________________________________ EXAMPLE I ADAPTED
MILK FORMULA FOR PRETERM INFANTS For 100 g For 100 ml of powder of
liquid ______________________________________ Ingredients Water --
85% Maltodextrines 28.91% 4.33% Vegetab1e oil mixture 20.23% 3.03%
Skim milk (0.05% M.G.) 14.58% 2.19% Lactalbumin 12.13% 1.82%
Lactose 11.92% 1.79% Butterfat 6.45% 0.97% Minerals** 3.26% 0.49%
Calcium caseinate 1.97% 0.296% Lecithin 0.41% 0.061% Vitamins***
0.12% 0.018% Nucleosides and/or nucleotides* 0.0078% 0.0012%
Ascorbile palmitate 0.006% 0.0009% DL-.alpha. Tocopherol 0.001%
0.0001% *Nucleosides and/or nucleotides added Uridine and/or
uridine monophosphate 3.42 mg 515 .mu.g Guanosine and/or guanosine
monophosphate 1.49 mg 225 .mu.g Adenosine and/or adenosine
monophosphate 1.32 mg 200 .mu.g Cytidine and/or cytidine
monophosphate 1.12 mg 170 .mu.g Inosine and/or inosine
monophosphate 0.45 mg 70 .mu.g **Mineral salts added Calcium
lactate 1.74 g 0.26 g Sodium phosphate dibasic 0.65 g 97 mg Calcium
phosphate 0.36 g 54 mg Potasium chloride 0.23 g 34 mg Potassium
phosphate dibasic 0.17 g 26 mg Ferrous lactate 51.7 mg 7.6 mg
Magnesic sulfate 49 mg 7.3 mg Zinc sulfate 7.3 mg 1.1 mg Cupric
sulfate 1.9 mg 285 .mu.g Sodium fluoride 1.5 mg 225 .mu.g Potassium
and chromiun sulfate 510 .mu.g 76 .mu.g Sodium molybdate 265 .mu.g
40 .mu.g Sodium selenite 180 .mu.g 27 .mu.g Manganese sulfate 83
.mu.g 12 .mu.g Potassium iodine 64 .mu.g 10 .mu.g ***Vitamins added
Vitamin A 1.600 UI 240 UI Vitamin D 600 UI 90 UI Vitamin E 5.5 mg
825 .mu.g Vitamin K 60 .mu.g 9 .mu.g Tiamin 0.4 mg 60 .mu.g
Riboflavin 0.45 mg 67 .mu.g Piridoxin 0.25 mg 37 .mu.g Niacin 6.7
mg 1 mg Calcium pantothenate 5.5 mg 825 .mu.g Vitamin B.sub.12 1.1
.mu.g 0.16 .mu.g Biotin 15 .mu.g 2.2 .mu.g Folic acid 350 .mu.g 52
.mu.g Vitamin C 100 mg 15 mg
______________________________________
EXAMPLE II
This example provides a milk formula made to feed at-term infants,
during the first year of life, preferably for the 6 first months of
lactation, suplemented with nucleosides and/or nucleotides in
similar concentrations to those of human milk, according to the
invention.
The product has been adapted in its composition and content of
nutrients to the ESPGAN and AAP international recommendations for
this kind of infants (ESPGAN. Committee on Nutrition, Acta
Paediatr. Scand., supl. 262, 1977; AAP, Committe on Nutrition,
Pediatric Nutrition Handbook, 1979)
TABLE V
__________________________________________________________________________
EXAMPLE II ADAPTED INFANT MILK FORMULA For 100 g For 100 ml
Ingredients of powder of liquid
__________________________________________________________________________
Water -- 87% Lactose 42.61% 5.54% Powdered milk (26% MG) 25.47%
3.31% Vegetable oils 13.37% 1.74% Demineralized whey (65% of
proteins) 9.28% 1.21% Butterfat 7.77% 1.01% Minerals salts* 1.11%
0.14% Lecithin 0.31% 0.04% Vitamins** 0.069% 0.009% Nucleosides
and/or nucleotides*** 0.0078% 0.001% DL-.alpha. tocopherol 0.003%
0.0004% Ascorbile palmitate 0.001% 0.0001% *Mineral salts added
Tripotassium citrate 0.35 g 45 mg Tricalcium citrate 0.1 g 40 mg
Dibasic potassium phosphate 0.24 g 31 mg Calcium chloride 0.16 g 21
mg Ferrous lactate 39 mg 5.1 mg Zinc acetate 8.5 mg 1.1 mg Cupric
sulfate 1.10 mg 143 .mu.g Manganese sulfate 155 .mu.g 20 .mu.g
Potassium iodine 65 .mu.g 8.4 .mu.g **Vitamins added Vitamin C 50
mg 6.5 mg Nicotinamide 6.7 mg 870 .mu.g Vitamin E 5.5 mg 715 .mu.g
Calcium pantothenate 5.5 mg 715 .mu.g Vitamin A 1.600 UI 208 UI
Vitamin B.sub.2 450 .mu.g 58 .mu.g Vitamin B.sub.1 400 .mu.g 52
.mu.g Vitamin B.sub.6 300 .mu.g 39 .mu.g Vitamin K.sub.1 60 .mu.g
7.8 .mu.g Folic acid 25 .mu.g 3.2 .mu.g Biotin 15 .mu.g 1.9 .mu.g
Vitamin D.sub.3 300 UI 39 UI Vitamin B.sub.12 1.1 .mu.g 0.14 .mu.g
***Nucleosides and/or nucleotides added Uridine and/or uridine
monophosphate 3.42 mg 445 .mu.g Guanosine and/or guanosine
monophosphate 1.49 mg 195 .mu.g Adenosine and/or adenosine
monophosphate 1.32 mg 170 .mu.g Cytidine and/or cytidine
monophosphate 1.12 mg 145 .mu.g Inosine and/or inosine
monophosphate 0.45 mg 58 .mu.g
__________________________________________________________________________
EXAMPLE III
This example provides an infant milk formula made to feed healthy
infants from 4-5 months to one year of life, supplemented with
nucleosides and/or nucleotides, according to the invention. The
product has been adapted in its composition and content of
nutrients to the ESPGAN recommendations for these infants ESPGAN,
Committee on Nutrition, Acta Paediatr. Scan. supl. 287, 1981).
TABLE VI
__________________________________________________________________________
EXAMPLE III INFANT ADAPTED FOLLOW-UP MILK FORMULA For 100 g For 100
ml Ingredients of powder of liquid
__________________________________________________________________________
Water -- 85% Full milk 46.61% 6.99% Maltodextrines 23.18% 3.48%
Lactose 19.28% 2.89% Vegetable oils 6.08% 0.91% Demineralized whey
4.22% 0.63% Mineral salts* 0.41% 0.061% Lecithin 0.14% 0.021%
Vitamins** 0.069% 0.01% Nucleosides and/or nucleotides*** 0.0078%
0.0012% DL-.alpha.tocopherol 0.003% 0.0004% Ascorbile palmitate
0.001% 0.0001% *Mineral salts added Monocalcium phosphate 0.36 g 54
mg Ferrous lactate 39 mg 5.8 mg Zinc acetate 8.5 mg 1.3 mg Cupric
sulfate 1.1 mg 165 .mu.g Manganese sulfate 155 .mu.g 23 .mu.g
Potassium iodine 65 .mu.g 9.7 .mu.g **Vitamins added As in Example
II. ***Nucleosides and/or nucleotides added Uridine and/or uridine
monophosphate 3.42 mg 515 .mu.g Guanosine and/or guanosine
monophosphate 1.49 mg 225 .mu.g Adenosine and/or adenosine
monophosphate 1.32 mg 200 .mu.g Cytidine and/or cytidine
monophosphate 1.12 mg 170 .mu.g Inosine and/or inosine
monophosphate 0.45 mg 70 .mu.g
__________________________________________________________________________
EXAMPLE IV
This example provides a lactose free infant formula, containing
protein from milk origin, supplemented with nucleosides and/or
nucleotides in the same quantitites as in human milk, according to
this invention.
The product has been adapted in its composition and content of
nutrients to the international recommendations mentioned
before.
TABLE VII
__________________________________________________________________________
EXAMPLE IV LACTOSE FREE ADAPTED INFANT MILK FORMULA CONTAINING
COW'S PROTEIN For 100 g For 100 ml Ingredients of powder of liquid
__________________________________________________________________________
Water -- 85% Dextrinemaltose 58.03% 8.7% Calcium caseinate
(supplemented 16.7% 2.51% with L-cistine) Butterfat 11.96% 1.79%
Vegetable oils 10.35% 1.55% Mineral salts* 2.18% 0.33% Lecithin
0.69% 0.103% Vitamins** 0.069% 0.01% Carnitine 0.0089% 0.0013%
Nucleosides and/or nucleotides*** 0.0078% 0.0012% DL-.alpha.
tocopherol 0.003% 0.0004% Ascorbile palmitate 0.001% 0.0001%
*Mineral salts added Dibasic potassium phosphate 588 mg 88 mg
Tripotassium citrate 522 mg 78 mg Calcium lactate 272 mg 41 mg
Sodium chloride 389 mg 58 mg Magnesium chloride 260 mg 39 mg
Calcium chloride 90 mg 13.5 mg Ferrous lactate 48 mg 7.2 mg Zinc
acetate 11.2 mg 1.7 mg Cupric sulfate 1.15 mg 0.17 mg Manganese
sulfate 107 .mu.g 16 .mu.g Potassium iodine 65 .mu.g 9.7 .mu.g
**Vitamins added As in Example II. ***Nucleosides and/or
nucleotides and other substances added Uridine and/or uridine
monophosphate 3.42 mg 515 .mu.g Guanosine and/or guanosine
monophosphate 1.49 mg 225 .mu.g Adenosine and/or adenosine
monophosphate 3.32 mg 500 .mu.g Cytidine and/or cytidine
monophosphate 4.98 mg 750 .mu.g Inosine and/or inosine
monophosphate 1.00 mg 150 .mu.g L-cistine 0.1 g 15 .mu.g Carnitine
8.9 mg 1.3 mg
__________________________________________________________________________
EXAMPLE V
This example provides a lactose free adapted infant formula
containing a protein isolate from vegetal origin, supplemented with
nucleosides and/or nucleotides, according to this invention.
The product has been adapted, as in example IV, in its composition
and content of nutrients to the suckling children and newborns.
TABLE VIII
__________________________________________________________________________
EXAMPLE V LACTOSE-FREE ADAPTED INFANT FORMULA CONTAINING VEGETAL
PROTEIN For 100 g For 100 ml Ingredients of powder of liquid
__________________________________________________________________________
Water -- 85% Dextrinemaltose 57.20% 8.58% Soy protein isolate
16.67% 2.5% Butterfat 11.96% 1.79% Vegetable oils 10.35% 1.55%
Mineral salts* 3.04% 0.46% Lecithin 0.69% 0.103% Vitamins** 0.069%
0.01% Carnitine 0.0089% 0.0013% Nucleosides and/or nucleotides***
0.0078% 0.0012% DL-.alpha. tocopherol 0.003% 0.0004% Ascorbile
palmitate 0.001% 0.0001% *Mineral salts added Dibasic potassium
phosphate 450 mg 67.5 mg Tripotassium citrate 628 mg 94.2 mg
Calcium chloride 370 mg 55.5 mg Calcium carbonate 400 mg 60 mg
Magnesium chloride 260 mg 39 mg Calcium lactate 873 mg 131 mg
Ferrous lactate 48 mg 7.2 mg Zinc acetate 11.2 mg 1.7 mg Cupric
sulfate 1.18 mg 0.18 mg Magnesium sulfate 107 .mu.g 25 .mu.g
Potassium iodine 65 .mu.g 9.7 .mu.g **Vitamins added As in Example
II. ***Nucleosides and/or nucleotides and other substances added
Uridine and/or uridine monophosphate 3.42 mg 515 .mu.g Guanosine
and/or guanosine monophosphate 1.49 mg 225 .mu.g Adenosine and/or
adenosine monophosphate 3.32 mg 500 .mu.g Cytidine and/or cytidine
monophosphate 4.98 mg 750 .mu.g Inosine monophosphate or inosine
1.00 mg 150 .mu.g Carnitine 8.9 mg 1.3 .mu.g
__________________________________________________________________________
EXAMPLE VI
This example provides a lactose-free infant formula which contains
a mixture of lactalbumin and casein hydrolizates with a low
molecular weight, supplemented with nucleosides and/or nucleosides,
as specified in the invention.
The composition and content of nutrients are adapted to the
suckling children and newborns' requirements, as in examples IV and
V.
TABLE IX
__________________________________________________________________________
EXAMPLE VI HYPOALERGENIC ADAPTED INFANT FORMULA For 100 g For 100
ml Ingredients of powder of liquid
__________________________________________________________________________
Water -- 85% Maltodextrines 52.48% 7.87% Vegetable oil mixtures
16.98% 2.55% Lactalbumin enzymatic hydrolyzate 12.31% 1.85% Casein
enzymatic hydrolyzate 5.16% 0.77% Corn starch 4.87% 0.73% Butterfat
4.29% 0.64% Minerals** 3.19% 0.48% Emulsifier 0.60% 0.09%
Vitamins*** 0.069% 0.01% Lecithin 0.0231% 0.0035% Carnitine 0.0089%
0.0013% Nucleosides and/or nucleotides* 0.0078% 0.0012% DL-.alpha.
Tocopherol 0.0038% 0.0006% Ascorbile palmitate 0.0015% 0.0002%
*Nucleosides and/or nucleotides and other substances added Uridine
and/or uridine monophosphate 3.42 mg 515 .mu.g Guanosine and/or
guanosine monophosphate 1.49 mg 225 .mu.g Adenosine and/or
adenosine monophosphate 3.32 mg 500 .mu.g Cytidine and/or cytidine
monophosphate 4.98 mg 750 .mu.g Inosine and/or inosine
monophosphate 1.00 mg 150 .mu.g Carnitine 8.9 mg 1.3 mg **Mineral
salts added Calcium phosphate 0.86 g 0.13 g Tripotassium citrate
0.85 g 0.13 g Calcium chloride 0.49 g 73 mg Sodium phosphate
dibasic 0.38 g 57 mg Potassium chloride 0.24 g 36 mg Magnesium
sulfate 0.20 g 30 mg Potassium phosphate dibasic 0.12 g 18 mg
Ferrous lactate 39 mg 5.8 mg Zinc acetate 10 mg 1.5 mg Cupric
sulfate 2.2 mg 330 .mu.g Sodium fluoride 310 .mu.g 46.5 .mu.g
Manganese sulfate 307 .mu.g 46 .mu.g Potassium chromium sulfate 115
.mu.g 17 .mu.g Sodium molybdate 83 .mu.g 12 .mu.g Potassium iodine
65 .mu.g 9.7 .mu.g Sodium selenite 37 .mu.g 5.5 .mu.g ***Vitamins
added As in Example II.
__________________________________________________________________________
The products in examples IV, V and VI contain carnitine in similar
concentration to that found in human milk, to satisfy the newborns
requirements of this compound.
The products in examples I to VI are presented as liquid products,
ready to use, as liquid concentrate products, to be used with the
addition of water and as powdered products.
EXAMPLE VII
Example VII provides a complete product and nutritionally balanced
to be used in clinical nutrition orally or by feeding tubes, with
an energy ratio of 146 Kcal/g nitrogen, enriched with nucleosides
and/or nucleotides in agreement with the invention.
The composition and content of nutrients have been adapted to the
specific nutritional requirements of ill adults suffering
energy-protein malnutrition.
TABLE X
__________________________________________________________________________
EXAMPLE VII NORMOPROTEIN DIET FOR USE IN CLINICAL NUTRITION For 100
g For 100 ml COMPOSITION of powder of liquid
__________________________________________________________________________
Water -- 78.7% Maltodextrines 52.13% 11.2% Vegetable oils 12.1%
2.5% Lactalbumin 11.63% 2.48% Calcium caseinate 10.05% 2.14%
Butterfat 8.84% 1.88% Minerals* 3.79% 0.79% Nucleosides and/or
nucleotides*** 0.75% 0.15% Soy lecithin 0.66 -- Emulsifier --
0.136% Stabilizer -- 0.02% Vitamins** 0.026% 0.005% Ascorbile
palmitate 0.0232% 0.0008% DL-.alpha. Tocopherol 0.0008% 0.0002%
*Mineral salts added Sodium phosphate dibasic 1.1 g 270 mg
Potassium chloride 0.99 g 210 mg Magnesium sulfate 1.014 g 203 mg
Calcium chloride 0.31 g 58 mg Potassium phosphate dibasic 0.28 g 34
mg Sodium chloride 50 mg 6 mg Ferrous lactate 21 mg 4 mg Zinc
acetate 14 mg 3 mg Manganese sulfate 4 mg 760 .mu.g Cupric sulfate
3 mg 640 .mu.g Sodium fluoride 2.2 mg 442 .mu.g Potassium chromium
sulfate 480 .mu.g 96 .mu.g Sodium molybdate 315 .mu.g 63 .mu.g
Sodium selenite 166 .mu.g 33 .mu.g Potassium iodine 49 .mu.g 10
.mu.g **Vitamins added Vitamin C 15 mg 3 mg Niacin 4.75 mg 0.95 mg
Vitamin E (mg. -TE) 2.5 mg 0.5 mg Pantothenic acid 1.75 mg 0.35 mg
Vitamin B.sub.6 550 .mu.g 110 .mu.g Vitamin B.sub.2 425 .mu.g 85
.mu.g Vitamin B.sub.1 375 .mu.g 75 .mu.g Vitamin A (mg Re) 250
.mu.g 50 .mu.g Folate 100 .mu.g 20 .mu.g Biotin 50 .mu.g 10 .mu.g
Vitamin K.sub.1 35 .mu.g 7 .mu.g Vitamin D 2.5 .mu.g 0.5 .mu.g
Vitamin B.sub.12 0.75 .mu.g 0.15 .mu.g ***Nucleosides and/or
nucleotides added Adenosine and/or adenosine monophosphate 150 mg
30 mg Cytidine and/or cytidine monophosphate 150 mg 30 mg Guanosine
and/or guanosine monophosphate 150 mg 30 mg Uridine and/or uridine
monophosphate 150 mg 30 mg Inosine and/or inosine monophosphate 150
mg 30 mg
__________________________________________________________________________
EXAMPLE VIII
This example provides a complete product and nutritionally balanced
with a high protein content (91 Kcal/g nitrogen), enriched with
nucleosides and/or nucleotides in agreement with the invention.
The composition and content of nutrients have been adapted to meet
the specific nutritional requirementes of ill adults in
hypercatabolic state.
TABLE XI
__________________________________________________________________________
EXAMPLE VIII HYPERPROTEIN DIET FOR USE IN CLINICAL NUTRITION For
100 g For 100 ml COMPOSITION of powder of liquid
__________________________________________________________________________
Water -- 77.28% Maltodextrines 50.6% 11.49% Lactalbumin 15.96%
3.64% Calcium caseinate 13.08% 3.14% Vegetable oils 9.13% 1.99%
Butterfat 6.52% 1.49% Minerals* 3.41% 0.68% Nucleosides and/or
nucletides*** 0.75% 0.15% Soy lecithin 0.5% -- Emulsifier -- 0.11%
Stabilizer -- 0.02% Vitamins** 0.026% 0.005% Ascorbile palmitate
0.0232 0.0008%% DL-.alpha.-Tocopherol 0.008 0.0002%% *Mineral salts
added Potassium chloride 1.01 g 220 mg Magnesium sulfate 1.014 g
203 mg Sodium phosphate dibasic 0.88 g 180 mg Potassium phosphate
dibasic 0.19 g 30 mg Sodium chloride 0.16 g 40 mg Calcium chloride
0.11 g 5 mg Ferrous lactate 21 mg 4 mg Zinc acetate 14 mg 3 mg
Manganese sulfate 4 mg 760 .mu.g Cupric sulfate 3 mg 640 .mu.g
Sodium fluoride 2.2 mg 442 .mu.g Potassium chromium sulfate 480
.mu.g 96 .mu.g Sodium molybdate 315 .mu.g 63 .mu.g Sodium selenite
166 .mu.g 33 .mu.g Potassium iodine 49 .mu.g 10 .mu.g **Vitamins
added As in Example VII ***Nucleosides and/or nucleotides added
Adenosine and/or adenosine monophosphate 150 mg 30 mg Cytidine
and/or cytidine monophosphate 150 mg 30 mg Guanosine and/or
guanosine monophosphate 150 mg 30 mg Uridine and/or uridine
monophosphate 150 mg 30 mg Inosine and/or inosine monophosphate 150
mg 30 mg
__________________________________________________________________________
EXAMPLE IX
This example provides a complete product and nutritionally
balanced, with a high nitrogen content, using as source of this
element a protein hydrolyzate with a low molecular weight to make
easier its absorption, enriched with nucleosides and/or nucleotides
according to the invention. The energy ratio of this product is 100
Kcal/g nitrogen.
The composition and content of nutrients have been adapted to
satisfy the specific nutritional requirements of ill adults
suffering diverse malabsorption-malnutrition syndromes.
TABLE XII
__________________________________________________________________________
EXAMPLE IX PEPTIDE-MCT DIET FOR USE IN CLINICAL NUTRITION For 100 g
For 100 ml COMPOSITION of powder of liquid
__________________________________________________________________________
Water -- 77.83% Maltodextrines 51.62% 11.43% Casein hydrolyzate
25.80% 5.72% Vegetable oils 12.44% 2.76% Minerals* 5.02% 1.11%
Butterfat 3.62% 0.8% Nucleosides and/or nucleotides*** 0.75% 0.17%
Soy lecithin 0.50% -- Emulsifier -- 0.11% L-Cistine 0.20% 0.04%
Stabilizer -- 0.02% Vitamins** 0.026% 0.0058% Ascorbile palmitate
0.0232% 0.0051% DL-.alpha.-Tocopherol 0.0008% 0.0002% *Mineral
salts added Sodium phosphate dibasic 1.05 g 233 mg Magnesium
sulfate 1.014 g 225 mg Calcium chloride 0.84 g 186 mg Tripotassium
citrate 0.83 g 184 mg Potassium phosphate dibasic 0.80 g 177 mg
Sodium chloride 0.44 g 97 mg Ferrous lactate 21 mg 4.6 mg Zinc
acetate 14 mg 3.1 mg Manganese sulfate 4 mg 888 .mu.g Cupric
sulfate 3 mg 665 .mu.g Sodium fluoride 2.2 mg 488 .mu.g Potassium
chromium sulfate 480 .mu.g 106 .mu.g Sodium molybdate 315 .mu.g 70
.mu.g Sodium selenite 166 .mu.g 37 .mu.g Potassium iodine 49 .mu.g
11 .mu.g **Vitamins added As in Example VII. ***Nucleosides and/or
nucleotides and other substances added Adenosine and/or adenosine
monophosphate 150 mg 30 mg Cytidine and/or cytidine monophosphate
150 mg 30 mg Guanosine and/or guanosine monophosphate 150 mg 30 mg
Uridine and/or uridine monophosphate 150 mg 30 mg Inosine and/or
inosine monophosphate 150 mg 30 mg L-Cistine 200 mg 40 mg
__________________________________________________________________________
EXAMPLE X
This example provides a complete product and nutritionally balanced
with a low protein content, supplemented with branched chain amino
acids and enriched with nucleosides and/or nucleotides.
The composition and content of nutrients have been adapted to
satisfy the specific nutritional requirements of ill adults
suffering severe hepatopathy.
TABLE XIII
__________________________________________________________________________
EXAMPLE X COMPLETE DIET FOR USE IN CLINICAL NUTRITION OF PATIENTS
WITH LIVER DISEASE For 100 g For 100 ml COMPOSITION of powder of
liquid
__________________________________________________________________________
Water -- 76.36% Maltodextrines 72.13% 17.04% Vegetable oils 7.48%
1.77% Lactalbumin 7.26% 1.72% Calcium caseinate 6.27% 1.48%
Minerals* 2.94% 0.69% L-Leucine 1.16% 0.27% L-Valine 0.87% 0.21%
L-Isoleucine 0.87% 0.21% Nucleosides and/or nucleotides*** 0.75%
0.18% Soy lecithin 0.22% -- Emulsifier -- 0.05% Stabilizer -- 0.01%
Vitamins** 0.026% 0.006% Ascorbile palmitate 0.0197% 0.005%
DL-.alpha.Tocopherol 0.0003% 0.00007% *Mineral salts added
Magnesium sulfate 1.014 g 225 mg Potassium phosphate dibasic 0.67 g
158 mg Sodium phosphate dibasic 0.60 g 142 mg Calcium chloride 0.49
g 116 mg Sodium chloride 0.12 mg 28 mg Ferrous lactate 21 mg 5 mg
Zinc acetate 14 mg 3.3 mg Manganese sulfate 4 mg 946 .mu.g Cupric
sulfate 3 mg 709 .mu.g Sodium fluoride 2.2 mg 520 .mu.g Potassium
chromium sulfate 480 .mu.g 113 .mu.g Sodium molybdate 315 .mu.g 74
.mu.g Sodium selenite 166 .mu.g 39 .mu.g Potassium iodine 49 .mu.g
11.6 .mu.g **Vitamins added As in Example VII. ***Nucleosides
and/or nucleotides and other substances added Adenosine and/or
adenosine monophosphate 150 mg 30 mg Cytidine and/or cytidine
monophosphate 150 mg 30 mg Guanosine and/or guanosine monophosphate
150 mg 30 mg Uridine and/or uridine monophosphate 150 mg 30 mg
Inosine and/or inosine monophosphate 150 mg 30 mg L-Leucine 1.16 mg
274 mg L-Valine 870 mg 206 mg L-Isoleucine 870 mg 206 mg
__________________________________________________________________________
EXAMPLE XI
This example provides a product considered as a nutritional
supplement for the nutritional repletion of patients with chronic
hepatopathy, constituted by a mixture of proteins from milk origin,
supplemented with branched chain amino acids, carbohydrates,
vitamins and minerals and enriched with nucleosides and/or
nucleotides.
TABLE XIV
__________________________________________________________________________
EXAMPLE XI HYPERPROTENC DIET SUPPLEMENTED WITH BRANCHED CHAIN AMINO
ACIDS FOR USE IN CLINICAL NUTRITION OF PATIENTS WITH LIVER DISEASE
For 100 g For 100 ml COMPOSITION of powder of liquid
__________________________________________________________________________
Water -- 80% Maltodextrines 36.72% 7.32% Lactalbumin 26.26% 5.25%
Sodium caseinate 21.95% 4.39% L-Leucine 4.04% 0.81% Minerals* 3.2%
0.64% L-Valine 3.03% 0.61% L-Isoleucine 3.03% 0.61% Nucleosides
and/or nucleotides*** 0.75% 0.15% Vitamins** 0.026% 0.005% *Mineral
salts added Magnesium sulfate 1.014 g 203 mg Potassium chloride
0.89 g 178 mg Calcium chloride 0.38 g 76 mg Sodium phosphate
dibasic 0.36 g 72 mg Tripotassium citrate 0.34 g 68 mg Potassium
phosphate dibasic 0.17 g 34 mg Ferrous lactate 21 mg 4.2 mg Zinc
acetate 14 mg 2.8 mg Manganese sulfate 4 mg 800 .mu.g Cupric
sulfate 3 mg 600 .mu.g Sodium fluoride 2.2 mg 440 .mu.g Potassium
chromium sulfate 480 .mu.g 96 .mu.g Sodium molybdate 315 .mu.g 63
.mu.g Sodium selenite 166 .mu.g 33 .mu.g Potassium iodine 49 .mu.g
9.8 .mu.g **Vitamins added As in Example VII. ***Nucleosides and/or
nucleotides and other substances added Adenosine and/or adenosine
monophosphate 150 mg 30 mg Cytidine and/or cytidine monophosphate
150 mg 30 mg Guanosine and/or guanosine monophosphate 150 mg 30 mg
Uridine and/or uridine monophosphate 150 mg 30 mg Inosine and/or
inosine monophosphate 150 mg 30 mg L-Leucine 4.04 g 810 mg L-Valine
3.03 g 610 mg L-Isoleucine 3.03 g 610 mg
__________________________________________________________________________
The invention having been thus described, it will be appreciated by
those in the art that variations can occur within the scope of the
claims which follow.
* * * * *