Патент USA US3085943код для вставки
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.