TOTAL PARENTERAL AND ENTERAL NUTRITION COMPOSITION

COMPOSE POUR NUTRITION PARENTERALE ET ENTERALE TOTALE

English Abstract

ABSTRACT

A stable fat emulsion composition for parenteral or enternal nutrituion
is disclosed containing amino acids, fat and carbohydrates. The emulsion is
stabilized by a combination of co-emulsifiers comprising a phosphatide such
as egg or soybean phosphatide and a fatty acid-amino acid peptide wherein
the fatty acid component of the peptide is a saturated or unsaturated fatty
acid having from 16 to 22 carbon atoms.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A stable aqueous fat emulsion comprising a fat suitable for human
nutrition, one or more nutritive amino acids and two or more co-emuisifiers
wherein at least one of said co-emulsifiers is a pharmaceutically acceptable
phosphatide and at least one other of said co-emulsifiers is a fatty
acid-amino acid peptide or a pharmaceutically acceptable salt thereof and
wherein the fatty acid component of said peptide is selected from the group
consisting of saturated and unsaturated fatty acids having from 16 to 22
carbon atoms and the amino acid component of said peptide is a pharma-
ceutically acceptable amino acid.


2. An emulsion according to Claim 1 wherein said fatty acid com-
ponent of said peptide is selected from the group consisting of palmitic acid,
stearic acid, arachidic acid, lignoceric acid, palmitoleric acid, oleic acid,
linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid.


3. An emulsion according to Claim 1 wherein said amino acid com-
ponent of said peptide is selected from the group consisting of leucine,
isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine,
arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine,
aspartic acid, glutamic acid, and glycine.


4. An emulsion according to Claim 1 wherein said fatty acid com-
ponent of said peptide is linoleic acid.


5. An emulsion according to Claim 1 wherein said amino acid com-
ponent of said peptide is glutamic acid.


6. An emulsion according to Claim 1 wherein at least one of said
co-emulsifiers is disodium linoleoyl-L-glutamate.


7. An emulsion according to Claim 1 wherein said phosphatide is
selected from the group consisting of egg phosphatide and soybean
phosphatide.



8. An emulsion according to Claim 1 wherein one of said nutritive
amino acids is L-arginine.


9. An emulsion according to Claim 1 wherein one of said nutritive
amino acids is L-lysine.


10. An emulsion according to Claim 1 wherein said fat is a vegetable
oil.


11. An emulsion according to Claim 1 wherein said emulsion is
non-pyrogenic, has a pH range of about 5 to 9, and is suitable for
intravenous administration to humans.


12. An emulsion according to Claim 1 wherein said fat, said peptide,
said phosphatide, and said amino acids are present in approximately the
following relative weight proportions:

Image


13. An emulsion according to Claim 12 wherein said relative weight
proportions are:

Image


16

14. A stable aqueous fat emulsion suitable for human nutrition
comprising 3-30 w/v% based on the emulsion of a fat suitable for human
nutrition, 0.05-0.5 w/v% of a fatty acid-amino acid peptide or a pharma-
ceutically acceptable salt thereof, 0.5-5.0 w/v% of a phosphatide and
2-24 w/v% of one or more nutritive amino acids.


15. An emulsion according to Claim 14 wherein the fatty acid com-
ponent of said peptide is selected from the group of saturated and
unsaturated fatty acids having from 16 to 22 carbon atoms.


16. An emulsion according to Claim 15 wherein said fatty acid
component is selected from the group consisting of palmitic acid, stearic
acid, arachidic acid, lignoceric acid, palmitoleric acid, oleic acid, linoleic
acid, linolenic acid, arachidonic acid, and clupanodonic acid.


17. An emulsion according to Claim 14 wherein the amino acid com-
ponent of said peptide is selected from the group consisting of leucine,
isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine,
arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine,
aspartic acid, glutamic acid, and glycine.


18. An emulsion according to Claim 14 wherein said fatty acid com-
ponent of said peptide is linoleic acid.


19. An emulsion according to Claim 14 wherein said amino acid com-
ponent of said peptide is glutamic acid.


20. An emulsion according to Claim 14 wherein said peptide is
disoldium linoleoyl-L-glutamate.


21. An emulsion according to Claim 14 wherein said phosphatide is
selected from the group consisting of egg phosphatide and soybean
phosphatide.



17

22. An emulsion according to Claim 14 wherein one of said nutritive
amino acids is L-arginine.


23. An emulsion according to Claim 14 wherein one of said nutritive
amino acids is L-lysine.


24. An emulsion according to Claim 14 wherein said fat is a vegetable
oil.


25. An emulsion according to Claim 14 wherein said emulsion is
non-pyrogenic and is suitable for intravenous administration to humans.


26. A stable, non-pyrogenic aqueous fat emulsion suitable for parent-
eral administration to humans comprising 3-30 w/v% based on the emulsion
of a fat suitable for human nutrition, 0.05-0.5 w/v% of a fatty acid-amino
acid peptide or a pharmaceutically acceptable salt thereof, 0.5-5.0 w/v% of
a phosphatide and 2-24 w/v% of one or more nutritive amino acids.


27. An emulsion according to Claim 26 wherein the fatty acid com-
ponent of said peptide is selected from the group of saturated and
unsaturated fatty acids having from 16 to 22 carbon atoms.


28. An emulsion according to Claim 26 wherein said fatty acid
component is selected from the group consisting of palmitic acid, stearic
acid, arachidic acid, lignoceric acid, palmitoleric acid, oleic acid, linoleic
acid, linolenic acid, arachidonic acid, and clupanodonic acid.


29. An emulsion according to Claim 26 wherein the amino acid com-
ponent of said peptide is selected from the group consisting of leucine,
isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine,
arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine,
aspartic acid, glutamic acid, and glycine.


30. An emulsion according to Claim 26 wherein said fatty acid com-
ponent of said peptide is linoleic acid.

18



31. An emulsion according to Claim 26 wherein said amino acid com-
ponent of said peptide is glutamic acid.


32. An emulsion according to Claim 26 wherein said peptide is
disoldium linoleoyl-L-glutamate.


33. An emulsion according to Claim 26 wherein said phosphatide is
selected from the group consisting of egg phosphatide and soybean
phosphatide.


34. An emulsion according to Claim 26 wherein one of said nutritive
amino acids is L-arginine.


35. An emulsion according to Claim 26 wherein one of said nutritive
amino acids is L-lysine.


36. An emulsion according to Claim 26 wherein said fat is a vegetable

oil.


37. A method of stabilizing an aqueous fat emulsion containing
nutritive amino acids and suitable for human nutrition comprising including
in said emulsion two or more co-emulsifiers in effective amounts wherein at
least one of said co-emulsifiers is a phosphatide and at least one other of
said co-emulsifiers is a fatty acid-amino acid peptide or a pharmaceutically
acceptable salt thereof and the fatty acid component of said peptide is
selected from the group consisting of saturated and unsaturated fatty acids
having from 16 to 22 carbon atoms and the amino acid component of said
peptide is a pharmaceutically acceptable amino acid.


38. A method according to Claim 37 wherein said fatty acid com-
ponent of said peptide is selected from the group consisting of palmitic acid,
stearic acid, arachidic acid, lignoceric acid, palmitoleric acid, oleic acid,
linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid.


19


39. A method according to Claim 37 wherein said amino acid com-
ponent of said peptide is selected from the group consisting of leucine,
isoleucine, valine, methionine, phenylalanine, tryptophan, threonine. lysine,
arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine,
aspartic acid, glutamic acid, and glycine.


40. A method according to Claim 37 wherein said fatty acid com-
ponent of said peptide is linoleic acid.


41. A method according to Claim 37 wherein said amino acid com-
ponent of said peptide is glutamic acid.


42. A method according to Claim 37 wherein at least one of said
co-emulsifiers is disodium linoleoyl-L-glutamate.


43. A method according to Claim 37 wherein said phosphatide is
selected from the group consisting of egg phosphatide and soybean
phosphatide.


44. A method according to Claim 37 wherein one of said nutritive
amino acids is L-arginine.


45. A method according to Claim 37 wherein one other of said
nutritive amino acids is L-lysine.


46. A method according to Claim 37 wherein said fat is a vegetable

oil.


47. A method according to Claim 37 wherein said emulsion is
non-pyrogenic and is suitable for intravenous administration to humans.


48. A method according to Claim 37 wherein said fatty acid-amino
acid peptide is present in an amount of from 0.05 to 0.5 w/v% based on the
emulsion.




49. A method according to Claim 48 wherein said phosphatide is
present in an amount of from 0.5 to 5.0 w/v% based on the emulsion.


50. A method according to Claim 48 wherein said nutritive amino
acids are present in amount of from 2 to 24 w/v% based on the emulsion.


51. A stable aqueous fat emulsion comprising a fat suitable for human
nutrition, and an emulsifier comprising a fatty acid-amino acid peptide or a
pharmaceutically acceptable salt thereof wherein the fatty acid component
of said peptide is selected from the group consisting of saturated and
unsaturated fatty acids having from 16 to 22 carbon atoms and the amino
acid component of said peptide is a pharmaceutically acceptable amino acid.


52. An emulsion according to Claim 51 wherein said fatty acid
component of said peptide is selected fron the group consisting of palmitic
acid, stearic acid, arachidic acid, lignoceric acid, palmitoleric acid, oleic
acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid.


53. An emulsion according to Claim 51 wherein said amino acid
component of said peptide is selected from the group consisting of leucine,
isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine,
arginine, histidine, alanine, proline, serine, crysteine, cystine, tyrosine,
aspartic acid, glutamic acid, and glycine


54. An emulsion according to Claim 51 wherein said fatty acid
component of said peptide is linoleic acid.


55. An emulsion according to Claim 51 wherein said amino acid
component of said peptide is glutamic acid.


56. An emulsion according to Claim 51 wherein said emulsifier is
disodium linoleoyl-L-glutamate.


21

57. An emulsion according to Claim 51 further comprising one or
more nutritive amino acids.


58. A method of stabilizing an aqueous fat emulsion suitable for
human nutrition comprising including in said emulsion an emulsifier in an
effective amount wherein said emulsifier is a fatty acid-amino acid peptide
or a pharmaceutically acceptable salt thereof and the fatty acid component
of said peptide is selected from the group consisting of saturated and
unsaturated fatty acids having from 16 to 22 carbon atoms and the amino
acid component of said peptide is a pharmaceutically acceptable amino acid.


59. A method according to Claim 58 wherein said fatty acid
component of said peptide is selected from the group consisting of palmitic
acid, stearic acid, arachidic acid, lignoceric acid, palmitoleric acid, oleic
acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid.


60. A method according to Claim 58 wherein said amino acid
component of said peptide is selected from the group consisting of leucine,
isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine,
arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine,
aspartic acid, glutamic add, and glycine.


61. A method according to Claim 58 wherein said fatty acid
component of said peptide is linoleic acid.


62. A method according to Claim 58 wherein said amino acid
component of said peptide is glutamic acid.


63. A method according to Claim 58 wherein at least one of said co-
emulsifiers is disodium linoleoyl-L-glutamate.


64. A method according to Claim 58 wherein said fatty acid-amino
acid peptide is present in an amount of from 0.05 to 0.5 w/v% based on the
emulsion.

22

65. A method according to Claim 58 wherein said emulsion further
comprises one or more nutritive amino acids.



23

Description

~5~

TOTAL PARENTERAL AND ENTERAL NUTRITION CC3MPOSITION

., ~ -


This invention relates to an improved composition f or total
parenteral or enteral nutrition, and rnore particularly, to a composition
10 containing amino acids, fat ard carbohydrates and a means for emulsifying
such a composition.

2~ ~

Total parenteral nutrition (TPN) is a technique employed to sustain
life and/or accelerate recovery in patients who cannot consurne foods due to
primary diseases. To provide TPN, a~ueous solutions of amino acids, fat,
carbohydrate, vitamins and electrolytes are typically admixed uncler an
aseptic environment in the pharmacy prior to intraYenous administration in
20 patients. This practice not only increases hospital cost in terms of ordering,
stocking and admixin~, but also introduces a posslbility of microbial
contamination, thereby exposing patients to a higher risk of in~ection.

"
Furthermore, the current TPN practice requires a central vein
25 catheter for administration. ~he sur~ical procedures for catheter place-
ment frequently present a problem in many rural and community hospitals.
Patients in these situations may be deprived of optimal medical care. Thus,
the development of a TPN solution which does not require admixlng and can
be administered through a peripheral Yein becomes a vital solution to the
3û problems encountered in small hospitals.

A typical TPN infusate should contain protein sources in the form of
amino acids, together with fat and carbohydrate. Amino acids are used to
synthesi~e body protein, while fat and carbohydrate are sources of energy




~3

` :IL2S~L31

for vital processes. To synthesize body proteins effectively, all of the 20
pro~eln amino acids are required to be present in an optimal proportion in
organs and tissues. Although certain of these amino acids are considered
non-essential, that is they can be synthesized in the body9 it is necessary to
receive from an external source the essential amino acids which cannot be
synthesized in the body ~rom a TPN infusate.

As fat is no~ water soluble, a stable oil-in-wa~ter emulsion is required
for intravenous infusion. It has been found from previous laboratory work
that two amino acids, lysine, which is an essential amino acid, and arginine,
which is a semi-essential amino acid9 destabilize fat emulsions containing
other essential nutrients. Thus, It has been difficult heretofore to manu-
~acture a stable TPN infusate containing these amino acids in a fat
emulsion.
There are currently at least two products known to exist which
include in a single emulsion9 fat, amino acids and carbohydrate. These are
Trieve lO00 TM manufactured by Laboratoire Egic in France and
NutrifundinTM manufactured by B. E~raun in West Germany. Both composi-
tions contain soy bean oil as the fat source and use soy bean phosphatides as
an emulsifier. Use of the soy bean phosphatides as the emulsifier has at
least two drawbacks. First9 the soy bean phosphatide can resul~ in
undesirable side effects and may be nutritionally undesirable. Further, the
use of soy bean phosphatides as the sole emulsifier does not permit the
inclusion of a sufficient amount of ar~inine and thus the amino acid
composition of these two products is lmdesirable due to their very low
concentration or total absence of arginine.

A similar composition has been described in U.S. Patent No.
3,793,450 to Schnell. The composition described in this patent contains
various amino acids, ~a~ and either soy or e~g yolk phosphatide as an
emulsl~ier. Again, however, the use of only the soy or e~g phosphatide is
not sufficient to stabilize a solution containin~ ar~inine with fat. All of the

-
~257~31
examples described in this paten~ include diaminovaleric acid (ornithine),
apparently as a substitute ~or arginine.

U.S. Patent No. 3,873,720 to Suzuki, e~ al., teaches the use of a fa~ty
S acid ~or i~s basic amlno acid salt~ as a co-emulsifier with egg-yQlk
phospholipids. The salt disclosed in Suzuki would dissociate in solution and
is not really different from the use of the ~atty acid alvne in an amino acid
containing emulsion. However, the use of the fatty acid-amino acid
peptide, as opposed to the mere salt which dissociates in solutlon~ has been
10 found to provide additional stabilization advantages, including increased
water solubility and lower requirements for effectiveness. A combination of
f~ty acids together with soybean phosphatides was not able to sufficiently
stabilize a fat emulsion containing arginine together with other nutrients.

The same considerations apply in formulating a composition for oral
and entera! use. Where such a composition contains all o~ the essential
arnino acids ~ogether with fat and carbohydrate, it is necessary to provide a
compatible means for stabilizing a fat/water emulsion, particularly one
containing arginine with fat.
BRIEF SVMMARY OF THE INVENTION

It is therefore an object of this imention to provide a stable
composition for total parenteral and/or enteral nutrition containing fat,
25 amino acids and carbohydrate.

It is a further object of this invention to provide such a composition
which includes the emulsion destabilizing amino acids Iysine and arginine.

The composition of the present in~ention involves the use of disodium
salts or other cation salts of a fatty acid-amino acld peptide alone and in
combination w;th egg or other phosphatldes as co-emulsif iers. The

~;~57~3~
remainder of the fat emulsion contains fat, amino acids, including lysine and
arginine, and other essential nutrients for TPN and enteral nutritional use.

It has been discovered that the fatty acid-amlno acid peptide may be
S used as an emulsification agent to pro~ide improved stability to a fat
emulsion beyond that provided by the mere salt o thç iEatty acid and the
amino acid. This was surprising in that previous laboratory tests have
indicated that fatty acid-arnlno acid peptides, such as linoleoyl glutamate,
when adrninistered in a saline solution can be hemolytic and ~oxic.
10 However, when included in the fat emulsion of the present invention, the
peptide is physiologically acceptable and combines with the phosphatide to
stabilize the fat emulsion. It has further been discovered that the use of the
fatty acid-amino acid peptide together with a phosphatide proYides a
synergistic emulsification wh;ch pe~mits the preparation of a s~able ~at
15 emulsion containing Iysine and arginine.

The parenteral or enteral composition of the present inven~ion
contains the iollowing ingredients in cssentially the indicated weight
proportions.
~ Wei~ht Proportion
Fat 3-30
Phosphatide 0.5 - 5
Fatty Acid-Amino Acid Peptide 0.05 - 0.5
~-Lysine Acetate 0.2 - 2.0
L-Ar~inine û.2 - ~.0
Remaining Amino Acids * 2 - 20
Sugar Alcohols ** 3 - 30
~ The amino acids used in the invention are the L-isomers and glycine
30 which are utilized for protein synthesis or performing biological functions in
mammals. ~iologically available precusors of these amino acids in the form
of derivatives and peptides may also be included.
~* Sugar alcohols such as glycerol and sorbitol included in the present
35 invention are those which can be metabolized to generate biologically
available energy in the mammalian species, and are chemically compatible
with amino acids durin~ heat sterilization and/or are s~able during shelf life
storage. The reducing su~ars, such as glucose, generally resul~ in undesir-
able reactions with amino acids during heat sterilization.

4 ~
.L~.D f ~

While the composition of the present invention, in order to be
comple~e for total nutrition, preferrably contains carbohydrate as an energy
source, the inclusion or exclusion of such does not affect the use of the
fatty acid-amino acid peptide and e~ phosphatides as co-emulsifiers in oil
in water emulsions.

The fatty acid-amino acid peptide useful with the present invention
is a compound which contains a peptide bond linking the carboxylic group of
lO a long chain fatty acid with the amino g~oup of an amino acid. Examples of
long chain fatty acids useful with the present invention consist of saturated
and unsaturated acids with 16 - 22 carbon atoms including palmitic acid,
stearic acid~ arachidic acid, lignoceric acid; palmitoleic acid, oleic acid,
linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid.
Amino acids which may be used as part of the peptides may
include leucine, isoleucine, valine, methionine, phenylalanine, tryptophan,
threonine, Iysine, arginine, histidine, alanine, proline, serine, cysteine,
cystine, tyrosine, aspartic acid, glutamic acid, and glycine. It is also
20 contemplated that the peptides be used either as the salt or the ~ree acid.

The novel features which are belie~ed to be characteristic of the
present invention, both as to its composition and method of preparation,
to~ether with further objectives and advantages thereof will be better
25 understood from the following description in whish presently preferred
embodiments of the invention are illustrated by way of example. It is to be
expressly understood, however, that the specific embodiments are for the
purposes of illustration and description only, and are not intended as a
de~inition of the limits of the invention.

S~


The total parenteral or enteral nutrition composition of the present
inventlon comprises a combination of amino acids~ Eat and earbohydrates in
S a fat~water emulsion. In particular, it has been surprisingly found that a
fatty acid-amino acid peptide may be used as an emulsifier and that a
combination of co-emulsi~iers can be advantageously used to provide a
stable emulsion even when the amino acids lysine and arginine are included.

The co-emulsifiers of the present invention comprise a combination
of a fatty acid-amino acid peptide together with a phosphatide such as egg
or soybean phosphatide. The use of these c~emulsifiers in combination,
provides a synergistic stability ~o the emulsion not obtainable by using
either emulsifier alone.
The ability to use a fatty acid-amino acid peptide as an emulsifier in
a parenteral solution is unexpected in itself. Tests involvin~ the administra-
tion of disodium linoleoyl glutamate, an example of a peptide pursuant ~o
the present invention, In a saline solution to mice clearly showed the
20 undesirable properties of such parenteral administration of a f atty
acid-amino acid peptide. A saline solution containing 0.1% disodium
linoleoyl glutamate was injected into the tails of laboratory mice.
Hemolysis from this injectate was observed in the tails of ~he animals.
After five days of 50 ml/kg injections, the entire tail was necrotic. The
25 results of these tests clearly su~gested that $he use of a fatty acid-amino
acid peptide in an aqueous parenteral solu$ion would be undesirable.

Tests usin~ disodium linoleoyl glutamate in fat-water emulsions,
however, unexpectedly showed no adverse affects. No hemolysis was
30 observed as with the linoleoyl glutamate in normal saline.




. . .

3~l

A ~at/amino acid emulsion having a composition as stated in Table 1
was prepared. The amolmts of egg yolk phosphatide and disodium
linoleoyl~ glutamate were varied tv assess the stability of the
composi~ion.
S

TAE~LE 1
~ ~ 00 ml
L-Threonine 0O 18
L-Serine 0.,26
L-Proline 0.50
(;lycine 0.63
L-Alanine 0.32
L-V~line Q.30
L-Methionine 0.24
L-lsoleucine 0.3 1
L-l,eucine 0.41
L-Phenylalanine 0.2S
L Tryptophan 0.07
L-Lysine Acetate 0.46
L-Histidine 0.13
L-Ar~inine 0.43
L-Cysteine HCl H2O 0.02
Soybean Oil 5.0
Egg Yolk Phosphatide 0 - 2.0
Glycerol 3-0
Sorbitol 3.0
Disodium Linoleoyl-L-Glutamate 0- 0.4

~ ;~5~131

.
The compositions of Table 1 were placed in vials pur~ed with
nitrogen~ capped and steriliæed statically at 120C for 20 minutes. The
stability of ~he emulsion was determined by measuring the "M-value" of
each sample. The M-values were determined by diluting a 100 ml aliquot
5 with distilled water and obtaining an absorbance reaLding in a 1 cm cuYette
at S00 nm versus a distilled water blank. The actual M-value which is
proportional to the stability of the emulsion is then computed by multiplying
the absorbance reading by the dilution factor. llle results of the study are
set forth in Table 2.

C~e~h~ M-values (X1000) 4 month
LG Conc, EYP* Pre Post storage
15 ~ C
0.0 14006 169 Separated
0.0 2 24.6 120 Separated
0.1 0.539.2 64.1 66.2
0. 1 1 .037.8 53.3 5~ .
0.1 1.538~7 ~6.8 45.7
0.1 2.038.0 40.7 42.0
0.2 0.530.0 44.2 ~4.6
0.2 1.027.6 33.1 31.6
~5 0.~ 1.533.2 33.0 32.2
0.2 2.035.2 34.1 35.0
0.3 0.517.1 39.7 42.8
0.3 1.018.1 20.8 22.2
0.3 1.519.3 18.3 18.9
0.3 2.016.6 18.8 18.6
0.~ 0.514.3 64.3 59.~
0.4 1.010.6 14.8 ~ 15.3
~.4 1.~9.3 10.7 12.1
0.4 2.010.6 1 1.0 1 1.3

*EYP - Egg yolk phosphatide

As can be seen from ~he results o~ the above study, the ~ombination
of the fatty acid amino acid peptide with egg yolk phosphatide as c~
emulsiiers provides a syner~istic effect in stabilizing the fat/amino acid
emulsion. From Table 2 it can be seen that it is desirable to use at least
approximately 1.0 g/100 ml of the egg yolk phosphatide. The stability OI the


~i 2C3~

emulsion increases with an increasing amount of the fa$ty acid-amino acid
peptide. The specific desired amount wDuld depend on a number of factors
including cost and the stability desired. For purposes of parenteral
administration of the emulsion, it is preferred to use approximately 0.1 -
5 0.2 g/100 ml of the pep~ide.

All of the components listed in Table 1 are available commercially
with the exception of disodium linoleoyl-L-glutamate. The synthesis of
linoleoyl glutamate is well known in the art. The particular synthetic
10 process used is described by J. R. Vaughn and R. L. Ostato in the 30urnal of
the American Chemical Socie~y, 74:676 (1952).

As discussed above, a number of variations can be made in the above
composition without departin~ f rom the spirit or scope of the present
15 invention. For example, different sources of fat may be used other than soy
bean oil. These may include corn oil, other vegetable oils or other
nutritionally acceptable fat sources. Further, different phosphatides may be
used o~her than ~hose found in egg. An example is soy bean phosphatide or
lecithin. Various supplemental components such as electrolytes and
20 vitamins may also be added for complete nutrition.

A number of fatty acid-amino acid peptides may be used o~her than
linoleoyl-L-glutamate~ Preferably, the group of long chain fatty acids
which may be used as part of the peptide consists of saturated and
25 unsaturated acids with 16 to 22 carbon atoms. These include palmitlc acid,
stearic acid, arachidic acid, lignoceric acid, palmitoleic acid, oleic acid,
linoleic acid, llnolenic acid, arachidonic acid, and clupanodonic acid~

Amino acids which may be used as part of the peptides may include
30 leucine, isoleucine, valine, methionine, phenylalanine, tryptophan, threonine,
lysine, arginine, histidine, alanine, proline, serine, cysteine, cystine,
tyrosine, aspartic acid, glutamic acid, and glycine. It is preferable to use
the l.-isomer of the amino acids which is biologically active and therefore


~~"
1;~5~
will also have nutritional value. However9 the D~isomer or a racemic mix
may also be used while retaining the desired emulsification characteristics.

It is also contemplated that the peptides may be used e~ther as the
5 salt or the free acid.

The specif ic amino acid cornposition of the emulsion as a whole is not
cri~ical to the present invention. However9 the maximum benefits are
realized by the ability to include arginine and Iys;ne in the fat emulsion.
10 The remaining ingredients are desirable for a total nutritional formulation.
However, their presence is not necessary in order to obtain the specific
benefits of the present imention.

The ranges of proportions of ingredients which may be used in a tota}
15 parenteral or enteral nutrition composition according to the present inven-
tion are set forth in Table 3. Since it is ~he interaction of the various
components which provides the stability of the emulsion, lt is ~he relative
amounts of each ingredient which are important rather than the absolute
arnounts present in the emulsion. In other words, the concentration of the
20 overall composition may vary within pharmaceutically acceptable ranges,
provided that the relative amounts of each component remain within the
ranges stated below.

TABLE 3

Operative Preferred
~ . ~ ~
Fat 3 - 30 4 - 8
3a Phosphatide 0.5 - 5.0 1- 2
Fatty Acid-Amino Acid Peptide 0.05 - 0.5 0.1- û.2
L-Lysine Acetate 0.2 - 2.0 0.40 - 0.52
L-Arginine 0.2 - 2.0 0.37 - 0.49
Remaining Amino Acids 2 - 20 3 - 6
Sugar Alcohols 3 - 30 4 - 8


~5~

A total parenteral nutrition composition was prepared contairling the
îollowing ingredientst
s 5~me~ ~ ''
L-Threonine Q 18
L-Serine 0~26
L Proline t).50
Glycine 0.63
I 0 L-Alanine 0.3~
L-Valine 1).30
L-Methionine 0.24
~-lsoleucine l).31
L-Leucine 0.41
L-Phenylalanine 0 25
L-Tryptophan 0.07
L-Lysine Acetate 0.46
L-Histidine 0~ 13
L-Arginine 0.43
L-C:ysteine HCl H20 0.02
~Coybean Oil
Egg Yolk Phosphatide 1.0
Glycerol 3-0
Sorbitol 3.0
Disodi~m Linoleoyl-L-Glutamate 0.2
The egg yolk phosphatide was dissolved in soy bean oil by stirring at
600 rpm at 80C for ten minutes. USP grade wa~er warmed to 80C was
then added to the oil mixture under continuous agitation until all egg
30 phospha~ide was dissolved. A primary dispersion was then made by high
shear mixing IJnder nitrogen purge at 8~S00 rpm at ~0C for twenty minutes.
The dispersion was ~hen subjected to high pressure homogenizaSion at 530
kg/cm2 and 50C for ten cycles. An aqueous solution previously made to
contain appropriate amounts of glycerol, sorbitol, amino aclds, in~luding
35 Iysine and arginine, and disodium linoleoyl-L glutamate was then added to
the primary dispersion and further homogenized under high pressure for ten
cycles. After cooling to room temperature, the emulsion was adjusted to an
appropria~e physiological pH (from about S to 9) using means known in the
art and filtered through a û.8 micron filter under O~S kg per square
40 centimeter nitrogen pressure. The emulsion was then placed in appropriate

11

5~3~
containers and may be sterilized using conventional techniques. This may
include heat or f il$er sterilization. The resultin~ emulsion was stable,
non-pyrogenic and suitable ~or intravenous administration to human
patients.




EXAMPI,E 2

A composition useful for enteral nutrition may be prepared using
similar processing steps to those described in Example 1 and containing the
10 following ingredients:
~ ~L~
L-lsoleucine 0.44
L.-Leucine 0.69
L-Methionine 0.69
L-Phenylalanine 0.69
l-Threonine 0.315
I,-Tryptophan 0.157
l-Valine 0.Sû4
1 -Lysine Acetate 0.705
L-Histidine 0. 158
Corn Oil 13.0
I,ecithin 0. 187
Mon~ and Diglycerides 0.373
Maltodextrin 16.0
Sucrose 3.3
- Disodiurn 1 inoleoyl-L-Glutamate 0.109

It should be noted that the amount of heat applied to sterilized
enteral compositions is gençrally less than that required for parenteral
compositions. Furthermore, glucose polymers such as maltodextrins and
starches can be included in enteral compositions to achieve the desired
35 nutritional effecSs. It is possible to sterilize enteral compositions
containing glucose polymers and amino acids without adverse chemical
reactions which may compromise ~he nutritional properties of the
composition.




131
EXA
Another composition suitable for enteral nutrition according to the
present invention also contains a nun ber of vitamins and electrolytes. It
has the following composition:
S ~ ~3~
Disodium Linoleoyl ~;lutamate 148 mg
(::orn Oil 3. 0 g
Medium Chain Triglycerides 2. 0 g
Lecithin 262 mg
Polysorbate 80 39 mg
Maltodextrin 18 . O g
Carrageenan 190 mg
Citric Acid 114 mg
Eg~ ~Ibumin Hydrolysate7.3 g
I,-Valine 1.1 g
L-Leucine 1.8 g
L-Isoleucine 0.95 g
Vitamin A 364 IU
Vitamin D3 27 IU
Vitamin E 4 IU
Vitamin Kl 12 mcg
Vitamin C 13 mg
Thiamine 121 mcg
Riboflavin 121 mcg
Niacinamide 1~34 mg
Vitamin B6 176 mcg
Folic Acid 38 mcg
Vitamin~l2 0.42 mcg
Biotin 21 mcg
3û Pantothenic Acid 791 mcg
Potassium lodide 10 mcg
Chromium Chloride 13 mcg
Sodium Molybdate 20 mcg
Selenium Dioxide 11 mcg
Dicalcium Phosphate113 mg
Monocalcium Phosphate64 mg
Ma~neslum Oxide 2~ mg
Man~anous Sulfate H2O245 mcg
Ferrous Gluconate 7 mg
Copper Gluconate 111 mcg
Zinc Oxide 902 mcg
Sodium Chloride 147 mg
Potassium Citrate H2O307 mg
Potassium Chloride 31 mg
While a wide variety of materials and prepara$ion procedures may be
used in the present invention, it should be understood that changes can be

13

~57~L3~L
made without departing from the spirit or scope thereof. This invention
therefore~ is not ~o be limited to the ~pecific embodiments discussed herein.




14