US 2948684 A
Description (OCR text may contain errors)
Unite DISINFECTANT AND DEODORANT SOAP COMPOSITION Frederik August Johan Thiele, Vlaardingen, Netherlands, assignor to Lever Brothers Company, New York, N.Y., a corporation of Maine This invention relates to detergent and cosmetic compositions having disinfectant and deodorant properties, which compositions may be in the form of a solution, a semi-solid, such as for example a cream, or a solid, such as for example a tablet or a powder. The compositions in general tend to prevent the deleterious effects often caused sky skin-flora.
With respect to compositions within the detergent and cosmetic field special reference is made to soaps, lotions or powders. Specific disinfectant compositions may fall within the surgeons field, for example preoperative glove powders.
Although the compositions according to the invention are effective as combating agents for the transient bacteria which reside on the skin, the compositions were especially developed for reducing that other part of the skin-flora, the so-called resident bacteria which are beneath the surface of the skin and reside in sub-surface skin layers.
It is well-known that the normal skin-flora contributes to the decomposition of sebum and perspiration. The products of this decomposition are mainly the cause of offensive odours. By reducing the skin-flora these odours can be effectively reduced or even prevented. Since the skin-flora may also be responsible for skin-infections a reduction in the skin-flora will tend to prevent skin-infection or, when already present, reduce or cure it.
For combating the skin-flora thiuram sulphides have previously been used. Thiuram sulphides which show a strong antibacterial potency are of the general formula where Z, and Z each denote a single bivalent cycloaliphatic radical or two monovalent aliphatic radicals, and n is an integer from 2 to 4. Z and Z are preferably saturated, straight chain lower aliphatic radicals such as methyl, ethyl or propyl. These aliphatic thiuram sulphide compounds have been incorporated in detergent compositions, based on soap or anionic and/or nonionic soapless detergents. Into these known detergent compositions, Iwhich combine detergent properties with antibacterial properties, other germicides, such as 2.2'-dihydroxy halogenated diphenylmethanes may be incorporated.
It has now been found that when an aliphatic thiuram sulphide is combined with one of the compounds listed hereafter a synergistic antibacterial potency towards the flora of the human skin is obtained. Compositions containing a mixture of active compounds according to the invention are so effective that once the skin-flora is reduced substantially recovery of the flora proceeds remarkably slowly. Therefore on using the compositions according to theinvention, a prolonged antibacterial effect is obtained. Even after prolonged use the composi- States Farent ice 2. tions according to the invention do not give rise to irritations or other skin sensitisations.
The compositions of the present invention are most reliable in their antibacterial properties. This is obviously of great advantage since, for example, persons who show no or a poor response towards conventionalantibacterial preparations all show a 'good response towards compositions according to the present invention.
According to the'invention the following compounds are combined with an aliphatic thiuram sulphide:
(1) 3.3.S.5'.6.6' -hexach1oro-2.2' dihydroxydiphenylmethane (2) 18.104.22.168' -tetrachloro-2.2' dihydroxydiphenylsulphide (3) 3.4.4-trichloro-N.N'-diphenylurea (4) 4.3'.4-trichlorosalicylanilide (5 l.1-bis-(5'-chloro-2'-hydroxy-phenyl) -ethan (6) 1.1-bis-(5 -chloro-2" hydroxy 6' nitro phenyl) ethane (7) 5-nitro-2-furaldehyde semi-carbazone As examples of aliphatic thiuram sulphides which are preferably used according to this invention reference is made to alkylated thiuramdisulphides, for example tetraalkyl thiuramdisulphide, especially tetra-methylthiuramdisulphide. I J Only small amounts of mixtures of a thiuram sulphid and one of the .above listed compounds are required in View of the very high antibacterial potency obtained.
The amount to be incorporated in the composition de- I pends of course on the type of composition and on the purpose for which it is meant.
In the case of soap the amount of the antibacterial 1 mixture may vary from 1 to 5% based on the weight of the soap; preferably about 3% is used for medical soaps and 1% for deodorant soaps. However, if a smaller antibacterial effect is considered suflicient, or if the composition is to be used in larger amounts, as for example a soap po wder, the amount of the mixture of antibacterial compounds may be reduced to, for example 0.1 to 0.9%;even less of the mixture, for example 0.01
to 0.9% may in certain instances be incorporated in the composition. Similar considerations apply to powders or liquid compositions (which need not possess detergent properties, only disinfectant or deodorant properties), such as for example toilet powders or 10- t-ions.
By soap is meant the usual alkali metal soap of saturated or unsaturated higher fatty acids, for example the sodium soap derived from acids naturally occurring in tallow and/ or coconut-oil.
When preparing detergent compositions anionic and nonionic soapless detergents may be used in addition to or instead of soap.
The ratio in which' the thiuram sulphide compound with strong disinfectant and/or deodorant properties are obtained. Y
The antibacterial etfectiveness of the compositions described in the following examples was measured by one of the following tests, depending on the type of oomp osig tion and its purpose:
(l) Lotions and soaps.Two tests were carried out,
(a) The reduction percentages of skin-flora were measured in vivo according to the Multiple Hand washing Technique described by P. B. Price in: J. Inf. Diss. 63, 301 (1938); J.A'.M.A. 3, 1993 (1938); Drug Standards, 19, 159 (1951); G. F. Reddish, Antiseptics, Disinfectants and Fungicides and Sterilisation, London (1954), page 322 et seq.; A. Manten, Ned. Tijdschrift voor Geneeskunde, 95, 1178 et seq. (1951).
In the examples of this specification this test will be denoted by M.B.H.-test.
(b) The reduction of the intensity of perspirationodours was measured in vivo vitro using theOsmometer by G. M. Fair and, W. F. Wells described by LA. Killian andF. P. Panzerella in: Proc. Sc; Sect. Toilet Goods Ass. 7, 3 (1947); ibid. 13, 34 (1950).
This so-called Olfact'ometer' test is denoted in the examples by O-test.
(2) Ltions.-The antibacterial effect in vitro was measured according to the Lederberg Replica Plating Technique described by S. D. Elek and C. R. F. Hilson in Brit. Med. J. 2, 1298 (1953), hereafter referred to as R.P.T.-test.
In the examples which illustrate further the present invention all percentages are given by weight of the composition.
Example 1 A bar soap was prepared from the following formulation:
Percent Sodium soap of a 4:1 tallow-coconut oil fatty acid mixture 81.9 Glycerine 0.5 Sodium chloride, water and miscellaneous 14.6 Tetramethyl thiuram disulphide 2.0 3.3'.22.214.171.124-hexachloro 2.2 dihydroxy diphenylmethane 1.0
A bar soap of the same composition as that of Example 1 was prepared, but instead of 1% 3.3' .126.96.36.199'-hexachloro-2.2 dihy'clroxyldiphenylmethane, 1% 3.3'.5.5-tetrachloro-2.Z-dihydroxydiphenylsulphide was used.
The M.B.H.-test gave a reduction of over 93% after 5 days, whereas a soap containing 3% of the diphenylsulphide or tetramethylthiuramdisulphide gave in both cases a reduction of about 70% after the same time.
Example 3 A bar soap was prepared from the following formulation:
Percent Sod um soap of a 4:1 tallow-coconut oil fatty acid mixture 82.5 Glycerine 0.5 Sodium chloride, water and miscellaneous :14.0 Tetramethyl thiuram disulphide 1.0 3.4.4-trich.loro-N.N-diphenylurea 2.0
963a M.B.H.-test gave a maximal reductionof over 4 The O-test with regard to armpits gave a loss of odour of about 90%.
Example 4 Three lotions for disinfectant and/or deodorant purposes were prepared by dissolving mixtures of equal parts by weight of tetramethyl thiuram disulphide and 3.3.5 .5 '.6.6' hexachloro2.2'-dihydroxydiphenylmethane in a solvent consisting of 65 parts by volume of acetone and 35 parts by volume of water, in such amounts that the concentrations of the mixture of active compounds amount to 0.2, 0.5 and 1.0% respectively.
The antibacterial effect of each of the lotions was measured by the M.B.H.-test and compared with the results of tests obtained under comparable conditions with lotions containing tetramethyl thiuram disulphide or 3 .3 '.5 .5 .6.6 hexachloro-Z.2-dihydroxydiphenylmethane respectively. These tests were carried out with 3 testpersons. The results are given in the following table:
Reduction 24 Amount hours Activecompound applied, after mg. application, percent Tetramethyl thluramdisulphlde/188.8.131.52.6.6'- hexachloro-2.2-dihydroxydiphenyl-methane 3 x 2 05 Tetramethyl thiuramdisulphide 3 x 2 73 3.3'.184.108.40.206 hexachloro 2.2 dihydroxydiphenylmethane 3 x 2 49 TEST-PERSON A0.5% LOTION Tetramethyl thiuramdisulphide/220.127.116.11.6.6-hexachlow-2.2-dihydroxydiphenyl-methane 1 x 5 07 Tetramethyl thiuramdisulphide 1 x 5 75 18.104.22.168.6.6 hexachloro 2.2 dihydroxydiphenylmethane 1 x 5 46 TEST-PERSON B 1.0% LOTION Tetramethyl thluramdlsulphide/ 22.214.171.124.6.6-hexschloro-2.2-dihydroxydiphcnyl-methane 1 x 10 72 Tetramethyl thiuramdisulphide 1 x 10 O 126.96.36.199'.6.6 hexaehloro 2.2 dihydroxydiphenylmethane 1 x 10 0 Ammoni APPLICATION or A 0.5% LOTION Tetramethyl thiuramdisulphide/188.8.131.52.6.6-hexa- Tetramethyl thiuramdisulphlde/184.108.40.206'.6.6'-hexachloro-2.2-dihydroxydiphenyl-methaue 1 x 10 86 Tetratuethyl thiuramdisulphide 1 x 10 40 220.127.116.11.6.6' hexachloro 2.2 dihydroxydlphenyl- 1 m 42 methane As can be seen from the above tables the lotions based on tetramethyl thiuramdisulphide/18.104.22.168.6.6'-hexachloro-2.2'-dihydroxydiphenylmethane mixtures show an exceedingly high reduction of skin-flora on the 3 test-persons, whereas lotions based on each of the active compounds alone-if applied under comparable conditionseither result in a relatively small reduction or give no response at all.
For thepurpose of carrying out R.P.T.-tests dilutions were prepared from the tetramethyl thiuramdisulphideand 22.214.171.124'.6.6' hexachloro 2.2'-dihydroxydiphenylmethane-containing lotions respectively, in such a way that per micromil the following amounts (in 'y) of active compounds, separately resp. mixed, as given in the fol- 5 lowing table, were present. These dilutions gave the following zone-diameters (in mm.) onv the replica plate:
Tetramethyl 126.96.36.199.6.6'- thiuramdisulphide Tetramethyl hexachloro-2.2- +188.8.131.52'.6.6- thiuramdisulphide dihydroxydiphenylhexachloro-2.2'-
methane dihydroxydiphenylmethane Zone- Zone- Zone- Arnount/y diameter/ Amount/ diameter] Amount/ diameter] mm. mm. mm.
As appears from the above, the synergistic antibacterial efiect of the tetramethyl thiuramdisulphide/3.3'.5.5'.6.6' hexachloro-2.2'-dihydroxydiphenylmethane mixture is also confirmed "by the R.P.T.-test.
Example 5 Amount and type After addition of soap active compound Before (in mg. per 100 m1. perspiration addition liquid) of soap 1% tetramethyl thiuramdisulphide 1% 184.108.40.206- 6 6 hexachloro-2.2-dil1ydroxy diphenylmethane 8 2 2 2 2 2 2 2% tetrarnethyl thiuramdisulphide B 6 6 5 2 2 2% 3.3 .6.5 .6.6 -hexaohloromethane 8 6 5 5 1 Not determined.
1 Only at 150 mg. a p0=3 is measured.
It is evident that a very small amount of soap containing a combination of tetramethyl thiuramdisulphide and 220.127.116.11.6.6' hexachloro 2.2 dihydroxydiphenylmethane reduces the odour almost completely, whereas with soap containing one only of the active compounds much larger amounts must be applied to obtain the same effect.
Example 6 The doses of =18.104.22.168'.6.6-hexachloro-2.2-dihydroxydiphenylmethane, etc., which gave no, or practically no, zones of inhibition were determined. These inactive dosages were then combined with various quantities of tetramethylthiuramdisulfide, which separately gave a zone on the primary but not on the replica plate. The results are given in the following table. The diameter value equals zone diameter less the diameter of the paper disc (6 mm.). The amount of active substance is expressed in micrograms.
\ Zone- Substance Amount diameter,
35 22.214.171.124'.6.6-hexachloro-2.2'-dihydroxydiphenyl- 5 methane (Ompd, 1) r 2% g 25 9% 12% 1 3.4.4 trichloro-N.N-dipheny1urea (Ompd. 2) 25 134-2 3% 126.96.36.199-tetrachlor0-2.2-dihydroxydlphenyl-sul- 12% 7 phide (Ompd. 3) 25 7 50 9 Tetramethylthiuramdisulphide (Ompd. 4) g 8 NON-SYNERGISTIO COMBINATIONS Zonediameter, mm.
Cmpd. 2+Ompd. 1:
6%+l2% 8 12$+25 9 25+25 9% Ompd; 3+Ompd. l:
' SYNERGISTIO'GOMBI NA'I IONS Cmpd. 1+Cmpdj 4:
1+4 14 1+s I 15 3+2 l2 Ompd. 2+Cmpd. 4: 25+8 20 Ompd. 3+Ompd. 4: 25+8 14 These experiments show that doses of substances which are themselves inactive, when used in the proper combination according to the present invention, can have an appreciable antibacterial effect. Furthermore, "when a properly selected additive such as Cmpds. 1, 2 and 3 above, are added to tetramethylthiuramdisulphide, bac-- teriostatic activity of tetramethylthiuramdisulphide is turned into a bactericidal one. Such effects must be due to true synergism.
The experiments also show that synergism is not obtained by combinations other than those of the invention.
Example 7 Experiments were run by the replica technique of Elek and Hilson, placing three paper discs side by side on one agar plate. The paper discs had been treated with the antibacterial substances being tested. Care was taken that the zones of inhibition cross-patched each other only in the periphery of the zones. The substances diifused in the agar medium independently. In the area where the zones overlapped, both drugs act on the bacteria. It is very improbable that the extremely low concentrations in the periphery of the zone could result in a bactericidal effect by purely additive efl'ects.
In the experiments, an aliphatic thiuramsulphide was placed on either the central disc or on the two outer discs, and one of the other compounds Was placed on the remainder. The test organisms were staphylococci isolated from the skin.
As a result of these experiments, it was observed that on the replica plates, the combinations of the present invention produced large zones far beyond the original zonesof inhibition. Whereas tetramethylthiuramdisulphide has a bacteriostatic action, in the combinations of the present invention, it is bactericidal. In these experiments, the combination of tetramethylthiuramdisulphide and 3.4.4 trichloro-N.N-diphenylurea was particularly outstanding.
Example 8 Experiments were run to measure the synergistic activity of the combinations of the present invention quantitatively when the materials were applied directly on the skin. The hands of test subjects were brushed four times for three minutes with plain soap, and a bacterial count was then made. The hands were then rinsed with Water and dried in Warm air. The germicide was applied from. a burette, generally in 10 ml. amounts of acetone/ water solution. After this the hands were dried again. Care was taken not to wash the hands within four hours after the application. The next day a bacterial count was made, followed by a renewed application of the germicide. To. exclude additive effects, the total quantities used in the combinations were less than or equal to the quantities used in the control experiments with single substances. Typical results of the oustanding results are in the following table, where Cmpd. 1 is 188.8.131.52'.6.6-hexachloro-2.2- dihydroxydiphenylmethane and Cmpd. 4 is tetramethylthiuramdisulphide. A 1:1 mixture of the two compounds is shown in the table as Mixture A.
Final Remg. mixture 7-10 mg. cmpd. 1;- 32 d.
RDQOECOWOOGJWN ton enecmcnmwtowgocwc naco The above experiments conclusively prove the existence of true synergism with mixtuers of tetramethylthiuramdisulphide and 3.3'.184.108.40.206-hexachl0ro-2.2-dihydroxydiphenyl-methane. By similar experiments the synergistic eifects of the other mixtures of the present invention may be shown.
Example 9 The mixtures of the present invention may be incorporated in soap bars or synthetic detergent preparations and the synergistic anti-bacterial effects observed. The mixtures of the present invention possess an additional advantage over many previously used ingredients in that anti-bacterial action is not lessened by the presence of super fatting agents and/or perfumes in the soap compositions.
The foregoing examples are given solely for purposes of illustration and are not to be considered as limiting the invention to these embodiments. Many modifications will be apparent to those skilled in the art without de parting from the spirit or scope of the invention.
What is claimed is:
A tablet comprising a water-soluble soap and from about 1 to about 5% of a synergistic mixture of one part of tetramethylthiuramdisulfide and from one to three parts of 3.3'.220.127.116.11-hexachloro-2.2'-dihydroxydiphenylmethane.
References Cited in the file of this patent UNITED STATES PATENTS Kunz July 18, 1944 Elliott Nov. 30, 1954 OTHER REFERENCES UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 2,948,684
Frederik August Johan Thiele It is herebi certified that error appears in the-printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 3,, line 14, for "in vivo vitro" read in vivo/vitro line 20, for "in vitro"'read in vitro column 7, line 41 in the table, second column thereof, first item of "Subject N0. 11'', for "5+5+5 mg. cm-pd. 5" read 5+5+5 mg. cmpd. 1
Signed and sealed this 31st day of January 1961.
gSEAL) ttBSti KARL H. AXLINE Attesting Ofiicer ROBERT C. WATSON Commissioner of Patents August 9, 1960