Title: Pharmaceutical composition for muscular anabolism
United States Patent: 6,521,591
Issued: February 18, 2003
Inventors: Smeets; Rudolf Leonardus Lodewijk (Venlo, NL);
Hageman; Robert Johan Joseph (Waddinxveen, NL)
Assignee: N.V. Nutricia (Zoetermeer, NL)
Appl. No.: 500802
Filed: February 10, 2000
A pharmaceutical composition suitable for enhancing muscular anabolism
contains, per daily dose, at least 5 mg of anabolic initiators comprising
anabolic growth factors, at least 0.12 g of protein equivalents of anabolic
substrates and at least 3 g of anabolic facilitators comprising at least 1 g
of creatine or its functional analog. The anabolic initiators may be derived
from a non-denatured animal protein, non-denatured being defined as having
an F0 of less than 3.0.
DESCRIPTION OF THE INVENTION
It has now been found that the simultaneously or sequential administration
1-component that triggers anabolism (initiators),
2-components that provide building blocks (substrates) for biosynthesis of
muscle tissue, and
3-components that facilitate biosynthetic processes (facilitators)
increases, for a certain period of time, lean body mass and/or can prevent
catabolism in periods of rest.
Sequential use means that the different components can be administered
separately during the day, but they must be consumed during the same day. In
this way, for example a product with one or more facilitators is consumed
first, followed by consumption, e.g. 2 hours after consumption of the first
product, of an effective amount of substrate and initiator in the same
product. However, preferably all three types of components are consumed
simultaneously in one product.
The invention pertains to pharmaceutical and/or nutritional compositions
suitable for enhancing muscular anabolism, i.e. production of muscle tissue
or reduction of loss of muscle tissue. The compositions according to the
invention comprise an initiator for muscular tissue production, a
facilitator for biosynthesis, and a substrate. They furthermore comprise a
facilitator, including creatine or a functional equivalent, and optionally
further components facilitating tissue production, and also a substrate
comprising e.g. carbohydrates, amino acids etc.
The products can have a powdered structure, packed in sachets or cans or
similar reservoirs. Other dry forms that are equally suitable are cereals
and bars. The product can also have the form of a drink, e.g., based on a
dairy drink (mil, whey) or fruit juice (orange, apple, grape). For liquid
products it is advantageous to let it have a pH below 4.2 in order to
stabilize some of the active components. The product can also have the form
of a paste or spread or sauce.
The initiators (also referred to as triggering substances or triggers) to be
used in the compositions of the invention are components that start up the
anabolic processes. Examples are anabolic growth factors like Insulin-Like
Growth Factor (IGF-1). These must be present as part of an extract of a
protein-rich food ingredient, in particular in an extract from a
proteinaceous material of animal origin, like mil, blood or egg. Undenatured
whey and especially undenatured colostrum in particular bovine colostrum
comprises a variety of anabolic trigger substances. The high effectivity of
whey and colostrum that was found may also be explained by the presence of
components that increase the bioavailability of the initiator components. In
case of anabolic growth factors, such components are binding proteins.
Specific extracts of animal origin may be used as a source of triggers for
anabolism, providing that the extraction procedures do not affect the
trigger components. The F0 value, defined in the Manual of Common
Methods, defines decimal reductions of germs as a result of heat treatment
of food products. Thus an F0 value of 3.0 defines a thousand-fold
reduction of germs and is achieved by treatment at 121oC. with a Z
value of 10. A heat treatment above F0 =3.0 normally destroys most of
these trigger components. Thus the extracts should not have been subjected
to a heat treatment with an F0 of 3.0 or higher, and preferably any
heat treatment should have an F0 of less than 2.4. Most preferably, a
heat treatment, if any, should not have a F0 of more than 0.2.
Suitable methods for obtaining such products avoiding substantial heat
treatment are described in the art and include filtration and centrifugal
techniques. The amount of extract can be as low as 5 mg per daily dose, if a
high degree of purification of the triggering substances from the
proteinaceous material is obtained. However, when bovine colostrum is used
as sole source for triggering substances, at least 5 g of the product, that
is obtained by using the method disclosed in WO 97/16977, should be included
in a daily dose according to the invention.
The inclusion of insulinotrohic components like digestible carbohydrates and
arginine and lysine can further enhance the triggering activity of extracts
of animal proteins. Arginine and lysine should be included in amounts of
more than 1.0 g and preferably more than 1.5 g per daily dose. Carbohydrates
are preferably glucose polymers like maltodextrines and should be present in
an amount of more than 4 g and preferably more than 8 g.
In order to allow an adequate rate of biosynthesis of muscle tissue, the
presence of sufficient amounts of substrate in the form of a variety of
amino acids is required. It appears that requirements for protein in
athletes are higher than in non-athletes. Daily requirements in strength
athletes are above 120 g protein and in endurance athletes above 100 g
protein. Though it appeared that some amino acids become rate-limiting
earlier in biosynthesis of muscle tissue than other ones, a mixture of all
amino acids, including the essential amino acids is preferably provided
according to the invention. These amino acids should be provided as protein
or hydrolysate thereof; it is especially preferred to use intact protein for
taste reasons and because the amino acids will then be released more slowly.
The latter ensures a constant but sufficient provision of the substrate
amino acids to the tissues and where the amino acids are insulinotrophic, a
longer increase of plasma insulin levels.
In order to provide sufficient amounts of amino acids, typically more than 5
g protein and especially more than 10 or even more than 20 g protein in
included in the formulations. Suitable proteins are all proteins that
comprise high amounts of essential amino acids, especially leucine, lysine
and methionine, such as casein, soy, pea, potato, egg and whey proteins.
However, when undenatured proteins of animal origin like colostrum or whey
from mammal mil, blood or eggs are used, these ingredients also comprise
triggering components for anabolism.
Proteins and amino acids can be expressed as protein equivalents (PE). One
PE can be calculated by multiplying the Kjeldahl nitrogen content of the
substrate by the factor 6.25.
In order to increase the amount of the amino acids that are most critical to
muscle building, methionine, lysine and leucine, additional amounts of these
amino acids can be included. This can be done by including peptides, or
amino acid complexes or free amino acids in the formula. Preferably free
amino acids are used, especially those in the L-form. The amounts of
methionine that are included per daily serving should exceed 0.2 g (9.4% N:
0.12 g PE) and preferably exceed 0.5 g; the preferred range is 1-6 g Met.
Preferably the amount of methionine is more than 2.8 g per 100 g protein
equivalents and in particular in the range 3.0-5.0. The amount of lysine per
daily serving should be more than 1.0 g (19.6% N: 1.3 g PE) and preferably
more than 2.0 g, e.g. 2.5-15.0 g. Calculated per 100 g protein equivalents,
the amount of lysine should be more than 8.3 g, and in particular in the
range 8.5-11. The amount of leucine per daily serving should be more than
2.0 g (10.4% N: 1.3 g PE) and preferably more than 3.0 g, e.g. 3.5-20 g.
Sleeping disorders are often experienced, especially in those persons that
consume large amounts of branched chain amino acids (BCAA valine, isoleucine,
leucine). This is especially undesirable when one wants to maintain
anabolism during a longer period of time. For this reason it is important
that the ratio of L-leucine/BCAA is relatively high. This ratio should be
higher than 0.46 and in particular be in the range 0.5-0.3.
In addition the amount of L-tryptophan should be relatively high. The ratio
Trp/BCAA should be higher than 0.055, preferably in the range of 0.06-0.2
and in particular be in the range of 0.07-0.13. Also persons that suffer
from disease frequently appear to experience problems with maintaining
nitrogen balance. By consuming the above-mentioned types and amounts of
substrates their capacity to synthesize muscle tissue is maximally
According to the invention, lean body tissue can only be synthesized when
sufficient energy is available and sufficient amounts of cofactors are
available as facilitator of the anabolic biochemical processes.
Intracellular energy should be available in the form of adenosine
tri-phosphate (ATP). Creatine phosphate (CP) is able to provide "energized
phosphate" to ADP, which restores ATP levels once they have been used for
labor or biochemical processes. It is therefore especially advantageous to
include in the formulation a source of both energy, in the form of
digestible carbohydrates, and creatine. Instead of creatine, Krebs cycle
intermediates such as citrate and Krebs cycle precursors, such as pyruvate,
glutamate, glutamine, can be used.
The amount of digestible carbohydrates should be above 4 g per daily dose
and preferably more than 10 g per day. That of creatine should be above 1.0
g per daily dose and preferably more than 2.0 g, for example 8 g. Suitable
carbohydrates are maltodextrines, e.g. the one having DE=19, lactose,
sucrose or mixtures thereof. Creatine can be the salt creatine, creatine
phosphate, or functional and stable equivalents thereof.
Because of the high amounts of protein that are digested, consumption of
extra amounts of minerals and vitamins in the diet is desirable. Especially
vitamin B6 should be fortified to ensure to allow a consumption of at least
1.8 mg vit. B6 per 100 g protein that is consumed. The high volume of
protein normally consumed by body building ensures a load of methionine that
should be handled appropriately in order to have only moderate increases in
plasma levels of homocysteine. It is therefore recommended to include folic
acid, vitamin B12, vitamin B6, zine and magnesium in the formula, because
deficiencies of one or more of these compounds frequently occur, while they
are mandatory for homeostasis of homocysteine loads. The levels should be at
least 1 mg vitamin B6, 200 .mu.g folic acid, 1 .mu.g cyanocobalamine, 40 mg
magnesium and 5 mg zinc or the functional equivalents of these components
per daily serving. The prior art discloses which forms of these components
can be advantageously used for nutritional purposes. Vitamin B6 can e.g.
have the form of principles or pyridoxal; folic acid can be in the
monoglutamate form; zinc can be administered as salt, e.g. as zine
carbonate; magnesium can have the form of an inorganic salt like magnesium
A further improvement of the product can be obtained by including in the
product one of the metabolites of leucine, especially beta-hydroxy-beta-methylbutyrate
(HMB). The latter compound can be included in an amount of 1-20 g per daily
serving, in particular in the range 2-5 per day. The component can be
included as pure substance or as inorganic salt such as the calcium salt, or
any other functional equivalent. Other components like yeast, carnitine,
pyruvate, dihydroxyactone, glutamine, ubiquinone (especially CoQ10) and
other vitamins and minerals can be included as well. It is especially
preferred to include melatonin, which supports the anabolic function of the
Table 1 shows the scope of the products according to the invention.
Components according to the invention
Initiators Substrates Facilitators
Undenatured extracts from Proteins Creatine and/or Krebs cycle
proteinacous material of and/or intermediates or precursors
animal origin + L-leucine thereof +
optionally extra: L-methionine optionally
insulinotrophic components L-lysine digestible carbohydrates +
like: optionally extra:
digestible carbohydrates vitamin B6, folic acid,
L-Arginine vitamin B12
L-Lysine magnesium, zinc
Claim 1 of 13 Claims
1. A pharmaceutical composition containing, per daily dose:
at least 5 mg of anabolic initiators comprising anabolic growth factors,
at least 0.12 g of protein equivalents as anabolic substrates, the protein
equivalents comprising a weight ratio of leucine to branched-chain amino
acids between 0.5 and 3.0, and
at least 3 g of anabolic facilitators comprising at least 1 g of creatine or
its functional equivalent.
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