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Патент USA US3085943

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3,085,933
United States Patent
Patented Apr. 16, ‘19563
2
1
3,085,933
stance and a salt of a cationic surfactant. The-net result
of this combination is an increased feed e?i'ciency and
,
GROWTH PROMOTANT SUBSTANCES
Maurice A. Schooley and Byron M. Shinn, Western
Springs, 111., assignors, by mesne assignments, to
Armour & Company, Chicago, Ill, a corporation of
Delaware
No Drawing. Filed ‘Oct. 3, 1958, Ser. No. 765,045
14 Claims. (Cl.‘167—53)
promotion of growth in animals into which it is intro
duced.
.
r
In accordance with the present invention, certainclasses
of surfactants which have been chemically‘ modi?ed. so
as to display substantially'nosurface activity in‘ water,
when combined with a minor amount of an estrogenic
substance, demonstrate superior growth promoting prop
This invention relates to a novel composition which is 10 erties while at the same time eliminating the disadvantages
resulting from the use of the estrogenic substance alone.
useful as a growth promotant. More particularly this in
The'mechanism o? the'action of‘this combination has
vention relates to an improved growth promoting factor
not been elucidated, but the net effect is demonstratable
comprising a combination of an estrogenic substance and
a salt of a cationic surfactant.
It has been found that a number of so-called growth
promoting substances when introduced into an'animal
and pronounced.
Whilea vraiety of active estrogenic substances may be
employed to achieve‘ the advantages of this inventi'omthe
either orally, by skin implantation, or otherwise, result in
accelerated growth of the animal. Perhaps the best es
stilbene derivatives are particularly suited.
These, pre—
Since these substances apparently are not a normal nutri
hexane; and esters such as dienestrol diacetate.
tional requirement of animals, it is believed that their
principal effect is to suppress diseases of the animals in
contemplated by this invention are estrogen derivatives
such as those comprising 4,4’-oxygenated stilbenederiv
ferred derivatives include such compounds as-diethyl
stilbestrol, dienestrol, hexestrol; their lower alkyl ethers
tablished of these substances are certain growth-stimu
lating antibiotics such as, for example, aureomycin. 20 such as dianisylhexene, dianisylhexadiene and dianisyl
Also
atives or'4,4'-oxygenated diphenylhexane derivatives, said
cluding those subclinical diseases which are not manifest.
Animal-s .thus treated, therefore, are more healthy and 25 derivatives having. at least two substituents in the aromatic.
nuclei, the substituents being made‘up, of aliphatic straight
will tend to. grow and gain weight at an increased rate.
In addition, as reported in the literature in this ?eld,
chains containing at least two carbon atoms, branch»
there are indications that other non-nutritional substances,
chains, aromatic rings, and cyclic and heterocyclic rings.
biotics.
Another class of substances which fall within the cate
ferred to as stilbestrol, is a well-known synthetic organic
gory of growth promotants are estrogenic compounds.
principally as a therapeutic agent in medicine, where it
Speci?c examples of this last mentioned class of estrogen
principally surfactants, under certain conditions may also
stimulate growth. It has been postulated that the growth 30 derivatives are 3,3'-diallyldiethylstilbestrolj. 3,r3’.-diallyl-.
hexestrol; 3,3'-dipropylhexestrol; and 3,3.’-dipropyldiethyl-‘
promoting properties of surfactants may be related to
stilbestrol. Of thederivatives de?ned, diethylstilbestrol
their bactericidal and basteriostatic characteristics, and
is particularly effective. This compound, commonly re
that, therefore, theirrtaction is similar tofthat of the anti
chemical possessing estrogenic activity. It has been‘ used.
The growth and weight aceclerating' advantages of these
is employed for its estrogenic properties.
such an extent'th‘at even though‘ more pounds of edible
ammonium halides, dialkyldimethyl-ammoniurn halides,
grading. However, at the lower levelsthe growth pro
moting‘results achieved ‘may be substantially reduced.
Still another problem'in' the use of estrogenic sub
stances arises in connection withtheir implantation in
livestock destined for. themarket place. When thus in
troduced intoan animal, some ofthe estrogenic material
may remain in the edibleportions, ofl the animal, and, if
suchis the case, when ulti'matelyconsumed could pro
such compounds as alkylbenzyldimethylam-monium ha
lides. We mention, for example, such speci?c cationic.
The general class of modi?ed surfactants having utility
substances has made their use desirable and pro?table
‘for the purpose of this invention can be designated as the:
even though it has been recognized that their use presents
certain inherent difficulties and hazards. One of the 40 substantially water-insoluble reaction‘ product ofthe cat‘
ionic fragment of a cationic surfactant ‘with the anionic.
problems encountered in the livestock industry, for exam_
fragment of either an anionic surfactant or an anionic,v
ple, in employing estrogenic substances alone as a growth
polyelectrolyte. The cationic fragment of theseagrowth
promotant ‘has been the fact that in many instances their
promotant materials may be derived from surface active;
use will ‘result in a downgrading of an animal into which
quaternary ammonium salts, such as the alkyltrimethyl-l
they are introduced. The downgrading may occur to
trialkylmethylammonium halides, wherein the alkyl group
?esh are produced ‘for each dollar invested in the raising
(or groups) can ‘contain from 8 to 22 carbon atoms andI
ofrthe‘animal, the total'economic return from the sale
of the'animal ‘for food purposes actually will be ‘less than 50 can be saturated or unsaturated. Insteadzof an alkyll
groupof the character‘de'scribed, .the surfaceactive qua‘
that received from animals which‘ have not been treated
ternary ammonium compound cancontain an'aromatic.
with the‘estrogeni‘c‘ substance; Generally, this eifect has
group, such as the benzyl group, and thus the cationic
dictated‘that the estrogens‘be introduced‘into animals at
fragment of this reaction product can be obtained from‘.
suf?ciently low levels to reduce the problemof down
duce an adverse effect in an individual.
It can be seen from this that it would be desirable to
surfactants from which this cationic fragment can 'be de
rived as dimethyldidodecylammonium chloride, trimeth
yldodecylannnonium chloride, dimethyldioctadecylam!
monium chloride, trimethyloctadecylammoniumchloride,
dodecyldirnethylbenzylammonium chloride,. octadecyldi
methyl-benzylamrnonium chloride, (.p-diisobutylphenoxy
ethoxy)ethylbenzenedimethylammonium chloride, tri-a
methyloctylammoniurn chloride, dimethyldodecylbenzyle
diminish‘ the disadvantages encountered in the use of 65 ammonium chloride and methyltrioctadecylammonium1
chloride.‘ Also, mixtures of different cationic surfactants
estrogenic substances-without. adversely affecting their
can be employed, such as the naturaltoccum'ng: mixtures
growth promoting properties. Viewed in a different light,
it ‘would also‘be worth while if these disadvantages could
be reduced and the growth promoting-properties of the
estrogenic substances maintained or even enhanced.
We 70
have discovered that these objects can be accomplished
through the use of a combination of an estrogenic sub
where the vquaternary ammonium compound. is prepared
from alnatural fatty acid source. 'For example trimethyl
“coco”ammonium chloride, dimethy1di“tallow”ammoni-a
um chloride, trimethyl“soya”ammonium chloride,.etc.,
are. suitable sources for the cationic fragment of thisv
reaction product. This cationic frag'mentmay also be
3,085,933
3
A
derived from surface active primary, secondary and terti
ary amines, such as alkylamines, dialkylamines, dimethyl
achieving the growth promotant effects of the combination.
alkylamines, bis(2-hydroxyethyl) alkylamines and N-al
ing examples:
kyLLB-propanediamines, wherein the amines contain at
least one alkyl chain having from 8 to 22 carbon atoms.
EXAMPLE I
A feeding trial lasting 112 days was conducted on
steers and heifers to test the growth promotant properties
of various concentrations of diethylstilbestrol (DES) and
This invention can be further illustrated by the follow
By way of speci?c example, we mention such suitable
amines as octadecylamine, dimethyloctadecylamine, bis(2
hydroxyethyl)octadecylamine, methyldioctadecylamine,
mixture of trialkylhexadecyl and trialkyloctadecylam
dioctadecylamine, dimethyldodecylamine, and N-dodecyl
monium stearate (TAS).
The substances were intro~
1,2-propanediamine. Further, polyamines, such as N 10 duced by skin implants and orally. The results of these
dodecyltrimethylenediamine and cyclic nitrogen com
tests are summarized in Tables I and II below:
pounds such as l-alkylpyridinium halides, for example 1~
Table I
octadecylpyridinium chloride, can be employed to derive
the cationic fragment of this reaction product.
l
2
3
4
5
6
The anionic fragment of the substantially water-insolu
Lot Treatment
DES, DES, TAS, TAS TAS
ble pyrolelectrolyte derivatives of the cationic surfactants
Con 36 mg. 10 mg.
eonD E S, D ES,
having utility for the purpose of this invention may be
trol implant daily
trol
36 mg. 10 mg.
implant daily
derived from any anionic polyelectrolyte, such as poly
sulfonic acids, e.g., a hexasulfonic acid (Suramin) and
polysulfonic acid resins (Amber-lite IR-IOS); non-poly
No. steers__'__j _____ __
13
meric polysulfonic acids, e.g. acidic azo-dye such as
Trypan Red and ‘Direct Blue BB; polysulfuric esters, e.g.
agar agar and carragheen mucilage; polycarboxylic acids;
e.g. polyacrylic acid, weak cation exchange resins, arabic
acid, alginic acid, pectic acid; polysaccharinic acids such
as carboxymethylcellulose, oxidized starch, mucin, hyal
uronic acid, polyglucuronic acid, and acids derived from
naturally occurring gums such as tragacanth, locust bean,
quince seed, linseed, karaya and acacia; mixed polycar
boxylic acids and polysulfuric acid esters, e.g. heparin and
chondroitin sulfuric acids; polyphosphonic acids, e.g. Duo
12
13
13
12
12
599
880
290
2. 59
595
889
294
2. 63
606
880
274
2. 45
605
925
320
2. 85
575
866
201
2.60
Table II
1
2
3
4
5
6
DES,
DES,
TAS,
TAS
TAS
Con- 18 mg.
24 mg.
eon-
DES,
DES,
trol
18 mg. 24 mg.
Lot Treatment
trol implant implant
impl.
lmpl.
lite C-6l; polyphosphoric acid esters, e.g. Duolite C—65
and phytic acid (hexaphosphoric acid ester); and polysili
cates, e.g. bentonite.
The anionic fragment of the substantially water-insolu
ain ___________ __
ble anionic surfactant derivatives of the cationic surfac
tants contemplated by this invention may be derived from
such compounds as fatty acids and soaps, i.e. sodium or
13
13
12
12
12
595
754
587
763
581
746
572
773
587
782
146
159
176
165
201
195
Daily gain ______ __ 1. 75
1. 89
2. l0
1. 96
2. 40
2. 33
TAS led at rate of 1.5 grams/head/day (steers and heifers).
potassium salts of a higher fatty acid, e.g. sodium stearate,
potassium oleate, potassium octanoate, sodium decanoate,
13
594
740
40
sodium laurate or other salts of fatty acids containing
from 8 to 22 carbon atoms in which the hydrocarbon
chains are either saturated or unsaturated. Also, this
anionic fragment can be derived from such synthetic
anionic surfactants as alkyl sulfates, alkyl sulfonates, alkyl
\aryl sulfonates and dialkyl sulfosuccinates. Further, such
surface active compounds as cyclic acids, e.g. abietic and
cholic, and acyl methyl taurides may be employed in pro
ducing this anionic fragment of the reaction product.
By way of speci?c example of the type of synthetic anionic -
Ration hand ‘fed as follows:
% rolled barley
% dried molasses beet pulp
Grass hay roughage
1# 32% protein supplement pellets as follows:
Pounds/ton
Wheat mixed feed ______________________ -_ 650
Soybean meal __________________________ __ 650
Cottonseed meal ________________________ __ 350
Urea
_________________________________ ..
30
Dehydrated alfalfa ______________________ __ 100
Di-calcium phosphate ____________________ __ 50
surfactants useful in forming the compounds of this
invention, we mention dodecylsulfate, octadecylbenzene
sodium sulfate, the ester of oleic acid, and hydroxy eth
Bone meal---
Salt __________________________________ __
20
ane sodium sulfonate.
Trace minerals _________________________ __
5
_____ __
6
Molasses _
_.__._
__ 140
In practicing this invention, the derivative of the cat
The steers in lot 5 receiving TAS ‘and DES implants
ionic surfactant may be combined with the estrogenic sub
stance merely by mixing them together in suitable pro
gained 22% more than controls, and 10% more than
those implanted with DES alone. The heifers showed
portions. It has been found that the range of concen
a similar pattern for this class of animals.
tration of the components of the combination is rather
wide. Relatively small amounts of the active ingredients, 60
EXAMPLE II
for example, may be incorporated into nutrient materials,
Employing a slightly different ration from that of
such as an animal feed or water, and still produce a
Example I, and a different level of TAS under feed lot
highly desirable result in a short period of time.
conditions, the complementary effect of the combination
Suitable carriers may be employed in the preparation of
of TAS and DES produced the results tabulated below:
concentrates containing the combination of active in
gredients. Examples of such carriers are soybean oil
Group 1 Group 2 Group 3 Group 4
meal, cottonseed oil meal, and linseed oil meal. Bone
meal also may be employed as a diluent when the com
bination is used for animal feeding purposes. The car
rier facilitates uniform distribution of the active agents
in the nutrient material with which the concentrates are
blended.
The combination may advantageously be administered
orally to both animals and humans as a tablet, capsule,
suspension, etc. Skin implants are also contemplated for
36 mg.
Control
No. steers .................. ..
DES
implant
TAS-+36
2 g. TAS mg. DES
20
20
2O
20
619
018
101
2. 97
616
973
101
3. 54
606
958
101
3. 48
610
976
101
3. 63
3,085,933
5
6
Ration:
Percent
Barley
________________________________ .__
_ EXAMPLE v1
45
. Employing .the ‘same .seli? :fe'ed‘ing techniques was : in Ex.‘
Cull peas _______________________________ __. 17
ample V but using an all pelleted'ration the following'1i12
Cut pulp _______________________________ __ 75
Cane molasses __________________________ _._
day‘ results in" steers were-obtained: .
5
.
Salt ____________________________________ .015
LotNo; ____________________________ __
l 1'
2
3
‘
4-‘
5
Alfalfa ________________________________ _._.. 25
TAS‘alone .(group: 3) gave- 2110.51 pound ‘per :"h'eadilper
Treatment:
day increase over the controls. DES‘ alone:.(group12)
gave a ‘0.57 pound. increase whereas- the-combination‘v
3
Se1f'fe'd_-____'_ ____________ __' ______ __
' Completed pelletedratiom.
X,
0
X
X‘
X~
X
X“
X
Y
X
X
X 0-. -
0
0
0
X
I O‘ I
1 X’
0
X
TAS 200 g./t0n
0 '
0
0
X
X
DES implants, 36
No; steers .... __
0
8
0 '
8
0
8
0
8
X
8
520 ‘
511 '
526
526
'
All‘aliahay long
Straw- ad lib_-__
(group 4) increased gains 0.66‘ pound ‘per head 'perday.
EXAMPLE III
Under field conditions in the summer months,“ the
advantages of the combination of TAS andDESwere
Initial wt;
_
-
527 '
Final-wt.‘ ____ __
__
‘ 861.-
832.
~ Av; daily gain‘.... ___ ________________ __ 2.98
858
2. 84
' s90,
3.09
.
916
3.25
3.49.
shown as follows:
Composition ‘of pelleted ration :7
Lot 1——10
I
‘ mg.‘DES
mg. DES
daily
'
Percent
Lot 2——10
daily, 1 gram 20
'I‘AS daily
Barley 1___
Beef pulp-OM‘
_ 40
l 20
_
Al?alfa'. ground ________________________ .1... 30
No. steers _______________________________ __
19
Av. starting wt;__
__
Av. ?nal wt_____
__ _
Gain/steer _____________________ __
19
731
*
-
1,080
742
1,136
___
349
394
Av. daily gain (May 12—Aug. 31) ________ __
3. 14
3. 55
Wheat mixed ‘ feed_~ _______________________ __
5
Molasses: _______________________________ __-
5
25
EXAMPLE VII '
Finally-1 the. eifeots ': of ‘ .TAS' alone, DESna-lo‘nerzand xthe
conibinationwoffthe 'two drugs were testedsin i steerfscalves
on a constant intake of -a wintering ration, as follows:
Ration: ll6—-32% protein supplement/head/day.
Roughage:
Corn silage, alfalfa hay, 2 lbs. dried beet
pulp plus grain mixture—
Percent
Lot No. ____________ __
Corn ______________________________ __ 25
1
2
3
4
5
6
7
8
Wheat _____________________________ __ 50
Treatment:
Barley _____________________________ __ 25
EXAMPLE IV
35
The same pattern as in the preceding examples was
Yield, percent.
2 g.
TAS
112
767
1022
2.15
61. 79
115
772
1079
2. 60
62.17
10 mg.
DES
2 g. ‘I‘AS
+ 10 mg
daily
X
0
X
0
X
0
71
0
X
72
O
X
72
X
X
69
388
595
207
1.53 1 75
383
570
187
388
568
180
shown with a larger number of animals ‘as follows:
Control
0
X
0
67
1,03
40
363 384
562 580
199 196
1. 58 1.69 1.66
903 1,000
940
954
X
X
X
98
411
616
205
1.74
912
DES daily
118
767
1082
2. 70
61. 91
113
770
1099
2. 84
61. 58 45
In preparing the animal feed materials described in the
above examples, the combination of the estrogenic sub
stance and the salt of a cationic surfactant were intimately
mixed with another feed ingredient such as bone meal or
limestone. An appropriate amount of this “premix” was
then distributed throughout the entire feed in a feed mixer.
EXAMPLE V
The growth promotant substances described herein not
Employing ‘a ration high in concentrates and self feed
only speed up the growth of the animal, but also maintain
ing the following results were obtained in a 160 day 50 the “grade” of the animal and improve the e?iciency of
study:
feed conversion. This is an important advantage since
it makes the growing process economical for [animal raisers
by requiring less feed per pound of weight gain while pro
36 mg. DES
36 mg. DES
implant
implant
+ 200 g.
TAS/ton feed 55
No. animals _____________________________ __
14
12
704
1114
2. 79
24.4
875
3. 57
60. 90
657.7
28.15
304.07
708
1157
3.10
28.2
908
4. 36
62. 71
710.8
29. 51
334. 51
4
Av. carcass grade:
ducing a high grade animal.
While in the foregoing speci?cation various embodi
ments of this invention have been set forth and speci?c
details thereof elaborated for the purpose of illustration,
it will be apparent to those skilled in the art that the
invention is susceptible to other embodiments and that
many of these details may be varied widely without de
parting from the basic concept and spirit of the invention.
We claim:
1. A ‘growth promoting composition of matter compris
ing a synthetic estrogenic substance and a substantially
water-insoluble salt of a cationic surfactant said salt hav
ing substantially no surface activity in water.
Choice +
1
Choice..._
4
Choice —-
4
1
Good +.
2
0
2. A growth promoting composition of matter compris~
Good ________________________________ __
1
0
ing a synthetic estrogenic substance and a substantially
5
waterdnsoluble compound composed of a cationic frag
Ration:
Percent 70 ment of a cationic sur?actant and the anionic fragment
Rolled shelled corn _____________________ __ 67.5
Soybean oil meal _______________________ __ 10.0
Ground alfalfa hay _____________________ __ 20.0
meal ____________________________ __
1.5
Trace mineral salt ______________________ __
Bone
1.0
of an anionic surfactant.
3. A composition as claimed in claim 2 in which the
e‘strogenic substance is a stilbene derivative and the
cationic surfactant is a quaternary ammonium surfactant.
4. A composition of matter as claimed in claim 3, in
75
3,085,933
7
which said quaternary ammonium surfactant is a rtrimethyl
alkyl ammonium compound in which the alkyl group con
tains from 8 to 22 carbon atoms.
5. A growth promoting composition of matter compris
ing a synthetic es-trogenic substance and a substantially
water-insoluble compound composed of a cationic frag
ment of a cationic surfactant and the anionic fragment
of an anionic polyelectrolyte.
8
prising a synthetic estrogenic substance and mixtures of
substantially water-insoluble salts of cationic surfactants
said salts having substantially no surface activity in water.
12. A growth promoting composition of matter com
prising diethylstilbestrol and a mixture of trimethylhexa
decylammonium stearate and trimethyloctadecylam
monium stearate.
13. An animal nutrient material characterized by con
rtaining as its essential active ingredients the combination
6. A composition as claimed in claim 5 in which the
estrogen’ic substance is a stilbene derivative and the 10 of a synthetic estrogenic substance and mixtures of sub
stantially water-insoluble salts of cationic surfactants said
cationic surfactant is a quaternary ammonium surfactant.
‘salts having substantially no surface activity in water.
7. A growth promoting composition of matter compris
14. A nutrient material characterized by containing
ing a stilbene estrogenic derivative and a substantially
as its essential :active ingredients the combination of
water-insoluble salt of a trimethyloctadecylammoniinn
surfactant said salt having substantially no surface activity
in water.
8. A growth promoting composition of matter compris
diethylstilbestrol and a mixture of trimethylhexadccyl
ammonium stearate and trimethyloctadecylammonium
stearate.
ing diethylstilbestrol and trimethyloctadecylammonium
References Cited in the ?le of this patent
9. An animal nutrient material characterized by con 20
UNITED STATES PATENTS
taining as its essential active ingredient a combination of
Cunkelman ___________ __ May 1, 1951
2,550,914
a synthetic estrogenic substance and a substantially water
Rogers _______________ _._ July 22, 1958
2,844,466
insoluble salt of a cationic surfactant said salt having
OTHER REFERENCES
substantially no surface activity in water.
10. An animal nutrient material characterized by con
O’Mary: J. of Animal Science, vol. 11, No. 4, Novem
taining as its essential active ingredients :a combination
ber 1952, pages 656-659.
stearate.
of diethylstilbestrol and trimethyloctadecylammonium
stearate.
11. A growth promoting composition of matter com
Stern: Poultry Science, vol. 32, No. 1, January 1953,
pages 26-28.
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