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Patented Jan. 16, 1934 1,943,467 UNITED STATES PATENT OFFICE _ 1,943,467 PHARMACEUTICAL PREPARATION Rudolph S. Bley; Washington, D. O. No Drawing. Application February 8, 1932v Serial No. 591,755 1.8 Claims. (Cl. 167-93) ' This invention‘relates to an improved anti 1 pounds exert a more powerful germicidal effect septic dentifrice. I am well aware that numerous than those used up to date in dentifrices. antiseptics have been already incorporated into ‘ In my copending applications I have claimed a dentifrices as a means to check pyorrhuea process of producing reaction products of all 5 alveolar-is, a dental disease of bacterial origin. phatic and aromatic acids with monohydric, di However all these well-known antiseptics are hydric and trihydric phenols. highly poisonous to animal tissue especially to By condensng carboxylic or fatty acids of the the tender mucous membranes, and it is for this type CnH2n+1.(COOI-I):c with monohydric, di— reason that all of these antiseptics can be used mrdric or trihydric phenolsin presence of con 10 only in very small percentages in dentifrices, densing agents such as zinc chloride and reduc thus decreasing greatly their germicidal value. ing the intermediate reaction product with zinc The phenol coef?cient of most of the well-known amalgam, powerful antiseptics oi’ the following 70' dentifrices is therefore extremely low. structure are evidently obtained. The primary object of the present invention 15 is to incorporate into dentifrices antiseptics of i such type which are non-poisonous to human wherein It represents a hydroxybenz‘ene. The beings even when swallowed in small quantities. CnH2n+1 radical may be evidently linked to the Another object of the present invention is to benzol nucleus in the ortho, meta or para posi incorporate into dentifrices a highlyconcentrated. 2o antiseptic or a mixture of highly concentrated By condensing for example caproic acid with m antiseptics without having any harmful effect diphydroxybenzene and reducing the 1,3-dioxy tion. upon human teeth and their surrounding tis . sues. _ A further object of this invention is to incorpo 25 rate into dentifrires such antiseptics which are I up ' phenyl-lA-alkylketones, n-hexyl-2,4-dihydroxy 80 benzene is ?nally obtained. The puri?ed, crys talline reaction product is soluble in‘ water, alco hol or ether. It has a speci?c gravity of about characterized by a low surface tension, thus in 1.282, a melting point of about 116° C. and a boil creasing the property of penetration of said anti ing point of about 276° 0. Its phenol coe?iclent septics into the cavities of teeth and tissues is 45-55 and its surface tension in aqueous solu to which such dentifrices are applied. Anti tion 35-40 dynes per centimeter. By condensing 30 septics of low surface tension penetrate readily other fatty acids with m-dihydroxybenzene and small crevices and spaces which may harbour reducing the intermediates, a series of ?nal re microorganisms and moreover they diduse into action compounds may be obtained for example: 90 bacterial cells more readily, thus more rapidly C-propionyl-m- dihydroxybenzen?e. destroying the same. Under equivalent condi C-butyl-m-dihydroxybenzene. 35 tions the efficiency of a germicide is increased the C-heptyl-m-dihydroxybenzene. more its surface tension is reduced. Dentifrices C-octyl-m-dihydroxybenzene. 95 having incorporated therein compounds of low surface tension are characterized by a better wetting property which promotes the cleansing 40 action of such dentiirices. u l have discovered that reaction products of C-dodecyl-m-dihydroxybenzene. C-isobutyl-m-dihydroxybenzene. C-isoamyl-m-dihydroxybenzene. C-isohexyl-m-dihydroxybeiizene, etc. aliphatic and aromatic acids with monohydric, Instead of m-dihydroxybenzene, o-dihydroxy 100 dihydric and‘trihydric phenols exert a powerful benzene or p-dihydroxybenzene may be used to germicidal action and that they are harmless produce ortho and para compounds respectively. 4.5 to animal tissue even in concentrated form. Such~ reactions may also be carried out with When swallowed in small quantities by human hydroxybenzenes or trihydroxybenzenes. beings they are non-poisonous, but on the con Instead of reacting aliphatic acids with hy 105 trary some of these compounds, especially n droxybenzenes and reducing the intermediates, hexyl-m-dihydroxy-benzene, have a bene?cial ef aromatic acids may be reacted upon in a similar 60 feet upon the urinary organs when the same are infected by bacilli of the Coli group. I prefer to use such reaction products as in gredients in dentifrices which have a low surface tension in order to increase the germicidal co “ efficient of such dentifrices. However I wish to state that satisfactory results may also be ob manner. . . ‘ I have moreover found that especially hetero cyclic compounds of the furane group yield reac .110 tion‘ products with hydroxybenzenes which are splendid antiseptics for dentifrices. . . By condensing for example furoic acid or py romucic acid with hydroxybenzenes and reducing the intermediate products, preferably in "statu 115 tained with reaction compounds which do not nascendi”, ?nal reaction products having high have a very low surface tension. Even such com phencl coef?cients are obtained. 17,048,467 2 saponins, quinine, quinine derivatives, Two isomers are evidently obtainable having‘ starches, glucosides, peppermint oil, peppermint‘ oil sub probably the following structures: , (1) alpha-furfurylhydroxybenzenes: , stitutes, clove oil, eucalyptol, terpenyl acetate. cassia oil, cinnamon oil, thyme oil, nutmeg oil, anethol, camphor, eugenol, phenethyl alcohol, H/ xHJI Caraway oil, orris root powder, alcohols, berga mot oil, rose-geranium oil, neroli oil, citronellol, HIS-J11. benzaldehyde. ‘albumins, myrrh powder, menthol, methyl, salicylate, thymol, geraniol, ‘lavender oil, lemon oil, citral, cosine, salol, phloxine, magenta crystas, erythrosine, sodium-benzoate, carmine, saffron, glycerine, glycerine of starch, glycerine wherein It represents a \hydr (2) beta-furfurylhyroxybenzenes: 10 substitutes, honey, syrup, molasses, lrevulose, gums, vitamins, irradiated vitamins, radioactive sébstances, 15 wherein R represents also a hydroxybenzene. ' e ferments, bu?er salts, . . . . About 2-100% of the finely ground antiseptic Evidently the furane nucleus may be linked to is added to'the dentifrices as follows. The addi the benzol nucleus in theortho, meta or para tion of enzymes may vary between l/4--5 per position. ‘ ' thousand; though more of the same may be in 95 A further object of my invention is to incorpo 20 rate my antiseptics together with enzym_ , for corporated at will. Example 1: Acid tooth powder example diastase, into dentifrices. I am aware that it has been already proposed to use enzymes, for example pepsin, in dentifrices. Enzymes Cream of tartar-.. _______________ _i__ 400 grams 100 have also been combined with certain antiseptics, Kieselguhr ............ _.'. _________ _- 600 grams 25 ' such as thymol, alcohol, phenol, etc.. without de Erythrosine ______________________ __ 0.5 grams creasing their activity considerably. However Oilof peppermint ________________ __ 10 cc. all these antiseptics mustbe used in very dilute form, otherwise enzymic action is inhibited. I have found that antiseptics produced by re 30 acting aliphatic or aromatic acids upon hydroxy benzenes and reducing the intermediates in the described manner do not inhibit enzymic action‘ ' even when added to enzymes in concentrated 35 form. Citral ____________________________ __ 1.5 cc. N-hexyl-m-dihydroxybenzene for example in Antiseptic-- 2-100 per thousand of the total mix 135 Example 2: Alkaline toothpowder sodium bicarbonate ___________ _-_-_- 50 grams Borax 50 grams Magnesium carbonate ............ _- 400 grams 111) Precipitated chalk _____________ _,__ 500 grams Eucalyptol ____________________ Q... 5 cc 50% aqueous solution does not decrease the en Terpenyl acetate _______________ -zymic action of diastase upon carbohydrates, such Soluble saccharine ______________ .3. as starches. By incorporating, for example, diastase in its natural-or isolated form together 40 with n-hexyl-m-dihydroxybenzene into a denti frice, a splendid commer product is obtained. The antiseptic ingredient instantaneously kills pathogenic microorganisms without aifecting the ‘ 5 cc. 1 g. Antiseptic __________________ _- as in Example 1‘ 115 Example 3: Antacid toothpowder Precipitated chalk ________________ -_ 700 grams um carbonate ____________ __ 225 grams tissue, its germicidal action being greatly s\ip—‘ Borax ___________________________ __ 45 ported by its low surface tension. The diastatic Eosine ___________________________ __ oil ________________________ _. ingredient, on the other hand, rapidly hydrolizes Cassia , oil starchy food particles clinging to crevices and ‘Rose 120 75 grams 1 g. 8 cc. 2 cc. __________________ _- as in Example 1 cavities of teeth or vtheir surrounding tissues. Antiseptic By this hydrolysis soluble and digestible sugars Diastase at will; preferably V4-5 per thousand 125, 50 are obtained. Such a dentifrice has not only‘ Example 4: Saponaceous toothpouider high germicidal, but also therapeutical proper Powdered castile soap _____________ __ 200 grams ties. My antiseptics may be used in combination Chalk precipitated _______________ __ 400 grams 13o with neutral, alkaline, acid‘or foaming denti Magnesium carbonate _______ __._.'-___ ‘400 grams frices. Gluside (600) ____ -._ ______________ _- ‘ “ 1 g. I wish to point out that r am not limited to Peppermint oil ___________________ _.. 1 cc. speci?c tooth paste combinations, but my anti Lemon oil ______________________ _-__ 9 cc. septics may be added to any known commercial Antiseptic as in Example 1 or antiseptic plus dias- 135 tooth paste composition. They may be combined 60 , also with dry tooth powders or antiseptic chew gums. _ tase as in Example 3 . Example 5: White toothpaste As a base for tooth powders or tooth pastes I Precipitated chalk. _______________ __ 500 grams 65 may use: precipitated chalk, amorphous prepared Tricalcium orthophosphate ________ .. 400 grams chalk, calcium phosphate, kieselguhr, clay, kao Soluble saccharine?m ____________ __ 0.5 g. . lin, magnesium carbonate, pumice, cattle ?sh Soap powder....__';._-_ ______________ __'100 g. bone, strontium oxide, soap, catechu, tin oxide, Tragacanth -_ 1 g. barium sulphate, camphorated chalk, charcoal. zinc oxide, zinc carbonate, etc. . . . In other words, 70 75 I may use any inorganic or organic base known in the tooth paste art. Peppermint oil ___________________ __ Spearmint oil __________ __.. _______ __ Methyl salicylate _________________ __ 5 g. 1 g. 2 g. 140 V 145 ' ‘ honey, Other modifying and ?avoringcompounds may Clari?ed proper consistency be incorporated, such as cream of tartar, sodium Antiseptic or antiseptic plus enzyme as in Ex bicarbonate, borax, saccharine, sodium chloride, ampleslanda boric ‘acid, milk sugar, glucose, higher sugars, 150 3 Example 6; Pink toothpaste 6. An antiseptic dentifrice which does not dele Add to composition, Example 5, proper amount teriously affect animal tissue comprising a fur furyl-m-mrdroxybenzene andan enzyme in active of erythrosine or the like state. I wish to point out that the above examples are 7. A dentifrice comprising n-hexyl-m-dihy merely illustrative, and I do not wish to be limited. droxybenzene and active diastase. _ to the exact proportions set forth above, which 8. A composition of matter comprising a con are typical combinations, as certain of these in gredients may be omitted or replaced by others 10 of similar nature, and the proportions within limits may be varied. In other words, while I have found that the ingredients and proportions above mentioned give the desired results, I do not‘ wish to be limited to the use of all of these in 15 gredients, to these ingredients and no others, nor to the exact proportions and concentrations set forth above, as the omission of some ingre dients or a slight variation of proportions will centrated solution of an antiseptic and an enzyme in active state suspended therein, said antiseptic having the structure R.CnH:n+1.‘wherein R repre sents a hydroxybenzene. 9. A composition of matter comprising a con centrated solution of a furfuryl-hydroxybenzene which acts as a disinfectant and an enzyme in active state dispersed therein. 10. The method of preserving the activity of enzyme suspensions which comprises adding thereto ?nal, reaction products. which are not not adversely affect the ?nal dentifrice, although deleterious to animal tissue, of an aliphatic acid 20 it may vary somewhat the relative characteristics with a hydroxybenzene having probably the struc 95 of such dentifrice. resulting from such variations. ture R.CnH2n+1, wherein R represents a hydroxy Moreover I wish to point out that I may combine one or more different types of my antiseptics in benzene. ' 11. The method of preserving the activity of one dentifrice. with other words I may combine, enzyme suspensions which comprises . adding 25 for example the hexyl-m-dihydroxybenzene with thereto final reaction products of an aromatic 100 the furi'uryl-m-dihydroxybenzene etc. . . ., to acid with a hydroxybenzene having probably the obtain the desired germicidal action. structure R.R1, wherein R1 represents a phenyl What I claim and desire to secure by Letters radical and R a hydroxybenzene. ‘ 12. The method of preserving the activity of 1. An antiseptic dentifrice, which does not enzyme suspensions which comprises adding 105' 30 deleteriously affect animal tissue comprising ?nal thereto ?nal reaction products of a furane deriva Patent is: reaction products of organic acids with hydroxy tive with a hydroxybenzene. ' benzenes and an enzyme in active state. 13. The method of preserving the activity of 2. An antiseptic dentifrice which does not dele diastase suspensions which comprises, adding 35 teriously affect animal tissue comprising a ?nal thereto hexyl resorcinol. " 110 reaction product of an aliphatic acid with a hy 14. The method of preserving the activity of droiwbenzene, having probably the structure enzyme suspensions which comprises adding R.CnH:n+1, wherein R represents a hydroxyben thereto hexyl resorcinol. zene and an enzyme in active state. 40 15. The method of preserving the activity of 3. An antiseptic dentifrice which does not dele enzyme suspensions which comprises adding 115 teriously affect animal tissue comprising a ?nal thereto a furfuryl-m-Mdroxybenzene. reaction product of an aromatic acid with a hy 16. The method of preserving the activity of droxybenzene, having probably the structure diastase which comprises adding thereto furfuryl BB1, wherein R represents a hydroxybenzene, R: m-dihydroxybenzene. a phenyl radical, and an enzyme in active state. 17. A composition of matter comprising an 120 4. An antiseptic dentifrice which does not dele alkylresorcinol which acts as an antiseptic and an teriously affect animal tissue comprising a ?nal enzyme in active state dispersed therein. reaction product of a furane derivative with a 18. A composition of matter comprising hydroxybenzene and an enzyme in active state. alkylresorcinol and active diastase. ‘ ' 5. An antiseptic dentifrice which does not dele 125 teriously affect animal tissue comprising n-hexyl m-ghydroxybenzene and an enzyme in active LRUDOLPH 8. BLEY. 135. no 70 76