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‘. Patented __ 12,100,054??? ‘ 4 - ~ ; . UNITED .0 i TES- PATENT 1 OFFICE I 2, 2,100,054 ‘ I ’ ‘ I ' , ,, _ _ opkinsong'andAlexander 'ANESTHETICVTANNATE‘ V. Tolstoouhov, “ ‘ v NewijYork',lN. >Y., assignors to Ostro Research Laboratoriealna, New York; N. Y., a corpora tion of‘NewJ/ersey' 1- _ - I‘. ' p ' :No .Dr‘awingJlApplicationOctober 27; 1933,. @ i i ' a - .,~ _ ‘ " - ~ , »>*~‘ ( - ‘.S¢"#1.N0l695,5°6' . 4 Claims. ‘ (Cl. 167-52) 7 p t This invention relates‘to‘newv compound and 9' [In ‘cases- of painful burns,‘ ulcers,' hemorrhoids, ‘ compositions‘ useful‘iini the“ treatment 'o'ti;,scalds, burns,- denuded surfaces‘and‘other painful‘lésions ‘ ' ‘Y of the skint‘or mucous membranes,‘ and; to the‘ a‘ j 5 Process of‘producingthe'mo q ‘ H ‘l ' : a‘ Y‘ ' '3 acid. This can'be accomplished by combining tannic. acldand‘local anesthetics, or by making . ' Picric acid has :been in .use‘ior‘ a long time'as ‘salts thereof. that have all-thesedesirable proper a disinfectant 'andprotein ‘precipitant in the treatment of ‘burns?usually in‘ the ‘form of a ties- Tannates of. local anesthetics generally are fairly insoluble fat the pH or body ?uids. » This water solution. Itr'has some-anesthetic proper- 101 gtieswhich are-of courseioftgreatwbene?t in the ‘ 0‘ etc; it is desirableto add anesthetic action to the astringent and Jantiseptic ‘properties of tannic treatment of burnsmI-Iowever, it has-several drawbacks, the most important .of which is a relatively high general ‘ toxicity, especially when used on large areas. It also produces some local l5“ irritation to the tissue cells due to the fact that i it is a fairly strong‘ acid. Furthermore, it pro- duces an objectionablecyellow color‘to the skin property? increases the length‘ of action of I anesthetics and decreases their general toxicity, 10 so'that. they are safe for use ‘on large areas; _ 1' _. The salts of anesthetics‘ and 'tannic acid are, ‘soluble in acid media at pH of about 3.0-4.0.‘ The p ‘ pH at which tannates of di?erentzanesthetics are ' soluble varies widely. For the maximum activity 15 of both the tannic acid and anesthetics thé re-v action of the solutions or ointments ‘containing which is di?i'cult to remove. j Local anesthetics in an oily base or carrier have been used for some time inhthe treatment of ‘,burns principally" for “ the purpose‘ of relieving them should be-just su?iclent to prevent the formation Of .a- heavy‘precipitate- This can be obtained either by adding a. definite excess ‘of. ‘ tannic acid to the Solutions; 01‘ by adding an acid 20 ‘pain, and ithas been‘proposed heretofore ‘to com- Salt Of Phosphoric 61‘ $01118‘ other Weak acidhsuchi bine these two‘ forms’ ofl'treatment by the use of‘ a5 citric acid, tartaricfblfphthalic acid; ' . i . the picrates of certain local anesthetics; ‘(U.' S. ' ‘Tam’lates of ‘anesthetics can 'bQJ’JSOIatGd' only.’ ' 1,596,259_) t ' ' when the ,pH of the solutions .‘are‘abovecertain - , ‘Now \we have discovered that the tannates of certain'local anesthetics'exhibitanumberof prop- ?gures! Usually when‘ Solutions ofjliydrdchlo- 25" Tides of 19°94 aIlESth?iCS" and ?anmd acid'are ‘ erties which render. them vastly superior to the’ mixed thepH Otthle;s0,1uti0ns\are,it0q10w to give? . picrates in the treatment of burns or other painful precipitation Of ' ' Salt 01" htannaté. that .15.. ' ‘I ‘30 lesions. We have also discovered asimple method 'forméd- This‘ may ‘.P9$sib1¥§”eXP1a,1n Why Such ' whereby ‘these tannates, whicliheretofore have Salts'h3V'e<P0t,"DreVi011S1y ‘been. ‘prepared- _ , .30 ' not been known, can be prepared in a su?iciently Tannat'es'bflocal anesthetics may be Prepared ’ . pure state to enable them to be used with safety. in 360011131153 with Fhé‘fpresent inventioneither‘ ‘ ‘ Tannic acid has heretofore been'used chie?y as iv 35 an astringent for ‘ mucous membranes‘ of the; ,iby'mixingan alcohol solutionlof va local anesthetic ‘ in‘the form qfyth'e ‘free, base anda solution of 1- ~ - * " and mouth disinfectant and intestinal in the tract preparation and as‘anofastringent the skin ‘ of patients or hands of surgeons for Surgiéa] 0p_ ‘ solution 'Of_ tannic acid»; MOther vSCVJIVGDJJS’(Liitl'l. also erations. It has also been usedfor the treat-‘9 be Used instead“ 31cbh°1,..b1‘- Water-I To isolate , 40“ ment of burns with good results; . ‘t ‘ a‘local tar'm'ic‘ acid; anesthetic or‘by hydrochloride mixing-‘ah aqueous and‘an solution aqueous‘! or i Tannlc .acid has a .very‘ low general'toxlcity. It is completely oxidized in the body, whether the tannates .in dry for‘ ' ,iti'S preferable ‘2,0 use 40 the ‘aqueous solu-tio _' adjust the pH ‘in'each particular ‘case,v 'otasto-givethe ‘maximum'pre- . ‘taken by mouth or» intravenously. ‘This vlow ' cipitation oflthe ztannate' consistent with purity fgeneral toxicity of .tannic acid gives it a very : of the.product.i_;_Thepligljis adjusted by adding ‘is 3 +45‘ important advantage in comparison with plcrie . an alkali, such‘astsodiumfhydroxide, for example. 45 ' ‘ acid. ‘Picric acid‘ has ‘the disadvantage that ‘it The. precipitated tann'ate' may be- removed by ‘ is sooner or later absorbed in the body and causes ,' ?lteringand is then ‘ ied. ' ‘ - vv‘poisoning. . This disadvantage is not present ,In- carrying out‘ his invention it has. been 1 ‘ with tannic acid as it forms protein. tannates found that tannates that are produced by causing ‘ 50 ‘which act as a protection. These vtann'ate's'h’av'e '-tannic acid to react vwith local anestheticsthat ‘ no poisonous propertiea}Tannicaacid has also have basic properties are ‘very e?ective. We . bactericidal properties. ' , The "combination of _.have. also found that tannates produced by caus astringentand antiseptic properties together with ~ ing tannic acid to react with local anesthetics negligible toxicity make tannic acid very useful . that have basic properties ‘dueto the factthat'r ' ootforthehuman‘beingh1.1» " I t » a " they contain an aminov group or-a, substituted 55 ' 2 2,100,054 amine are particularly useful in treating vburns and other skin lesions. More particularly, local anesthetics that have basic properties and have an aromatic nucleus, such as a naphthalene nucleus and others, can be used to form the tan nate when reacted with tannic acid’, thus produc ing products veryuseful for the purposes of this invention. . i v ' The precipitate is a brownish powder that ‘is very di?icultly soluble in H2O, alcohol, and weak alkalies, but is soluble in dilute acids. Its melting point is 107-109" C. The smallest visible precipitation of salt starts from N/ 100 solutions of the hydrochloride of this anesthetic and free tannic acid at about pH 4.38. Maximum precipitation takes place at about e The tannates of anesthetics prepared in ac 10 cordance with this invention can be incorporated into ointments, suppositories, pastes, etc. We pH 7.08. ‘ Example 3.——Preparation of cz-blltYlOXYCiil 10 choninic acid diethyl-ethylenediamide tannate: 15 15 coin, N 20 20 prefer to use 1 to 5% by weight of the tannate in such vehicles depending on the strength of the particular local anesthetic that is used in mak ing the tannate. 25 » i - The following are given for illustrative purposes as speci?c examples for preparing the tannates of some local anesthetics, but it is to be under stood that the invention is not restricted to these examples. ' r ‘ Example 1.—Preparation of l-ethoxy-‘i-(beta diethyl-amino-ethyl) -naphthalene tannate: This tannate can be prepared in a similar way, i. e., by dissolving 2 mols of a-butyloxycinchoninic acid diethyl-ethylenediamide hydrochloride and 1 mol. of tannic acid in ‘100 cc. of water and adding NaOH. The pH of the solution should not be 25 above 5.0. At higher pH the yields ‘are ‘higher, but the salt is not stable. The salt obtained at this higher'pI-I turns to a dark brown color. This tannate is a brown powder. It is *di?i cultly soluble in water, alcohol, and weak alkalies, 30 and it is soluble in weak‘ acids. Its melting point is 94—96° C. . 0 CIH| 35 40 Dissolve 1.5 gm. of tannic acid '(2 mols) in 100.0 cc. of H20 and 0.9 gm. of 1-ethoxy-4-(beta-di ethyl-amino-ethyl) -*naphthalene - hydrochloride (1 mol.) in 25.0 cc. of H20. Mix the solutions and add 25.0 cc. of N/10 NaOH to bring the 45 pH of solution to 4.6. Filter the precipitate that is formed, wash with H20 and dry in vacuo. As an alternative, powdered tannic acid and hydro chlorides of anesthetics can be dissolved together and-N/lO NaOH can be added to the mixture 50 afterwards. The yield is 92% of the theoretical yield. I The smallest visible precipitate of salt ‘starts 40 from N/ 100 solutions of the hydrochloride of this ' anesthetic and free tannic acid at about pH 3.64. Maximum precipitation takes place at about pH 6.16. i ‘ Example 4.—Preparation of the ‘tannate of methyl. ethyl dimethylamino-methyl carbinol benzoate (stovaine). V ' CH: 1 50 . C O O-(f-CHaNGIHzOaHO O C (OIl)2.Caii2.O.0 C.CcH2(OH): . The precipitate or tannate is a light, creamy powder that is di?icultly soluble in H2O, alcohol, and weak alkalies and is soluble in dilute acids. 55 The melting point is 115-117° C. If the pH of the solution from which the precipitate is formed by‘ adding the alkalies is above 4.6 the precipitate Dissolve gm. of water. of stovaine 1.5To .gm. precipitate hydrochloride of tannicthe acidtannate (1(2mol.) mols)add mice and. 0 turns purplish brown soon after it is formed. The smallest visible precipitation of salt starts 60 from N/100 solutions of the anesthetic hydrochlo ride and free tannic acid at about ,pH 3.53. 65 N . i-GNaOH Maximum precipitation'of the salt takes place at about pH 4.55. Example 2.—-Preparation of diethyl-amino to bring the pH to 5.22. Filter the precipitate that is formed, wash with water and dry in vacuo. ethyl ester of p~amino benzoic acid tannate or very poorly soluble in water, alcohol, and weak alkalies, but is soluble in dilute acids. The smallest visible precipitation of the salt Dissolve 1.5 gm. of tannic acid (‘2 mols) and 0.87 70 gm. of procaine hydrochloride (1 mol.) in 100 cc. of H20, add 20.0 cc. of N / 10 NaOH to'bring the ‘The tannate is a light creamy powder that is starts from _li , 70 100 pH of the solution to 6.0. Filter the precipitate " solutions of the anesthetic hydrochloride and free which forms, wash a few times with H20 and dry tannic acid at about pH-4.'69. Maximum pre cipitation of this salt takes place at about pH 75 75 in vacuo. 2,100,054 5.22. The tannate melts vat .959-100° C. with de composition. v ' “ . ' of water. An alternative method is to dissolve _ one part of the hydrochloride of the local anes Example 5.—Preparation ‘of the tannate‘ of thetic and ?ve parts of tannic acid in 200 parts of water. Part of the tannic acid is immediately ethenyl-p-diethoxydiphenylamidine v (holocaine). . / . CHIC ' V Nn-O-omm \ 10 . ‘Dissolve 1.5 gr. of tannic acidj(2 mols) plus 0.69 . gmseof ethenyl-p#diethoxydiphenylamidine hy ‘ ,rdrochloride' (1 mol.) in 100 cc.’ 01' water. To pre cipitate the tannate add 15 N' .to bring the pH to 4.98.v Filter the precipitate that is formed, wash with water and dry in vacuo. ‘ a The tannate is a light creamy powder that is very poorly soluble in water, alcohol, and weak alkalies, but is ‘soluble in dilute acids. The smallest visible precipitation of the salt .25 starts from , . ' this second method is ease of preparation. This solution can be applied to the denuded area by 1 . a In addition to theadvantage which the tan nates‘ of local anesthetics have over the corre ' ‘ 10 used to form' the tannate.‘ ‘The advantage of means of tampons or swabs. . ENaOl-I ‘ l 20 3 15 sponding picrates in being non-toxic,‘ colorless and non-staining, there is another important ad vantage. Tannic acid is an'oxygen absorbent ‘and therefore acts to prevent the decomposition , 20 of the readily oxidizable local anesthetics when exposed to air. On the other hand, picric acid does not prevent this oxidation. The tannates of local anesthetics have been found to be much more stable than the corresponding picrates. .25 3!. Examplesof other local anesthetics, the tan 100 nates of which are useful in the treatment of solutions of the anesthetic hydrochloride and‘ burns, denuded areas and other painful lesions I free tannic acid at about pH 4.20. Maximum are: precipitation of salt takes place at about pH 4.98. Cocaine ‘l 80 . The tannate melts at 1509-155° with decomposi tion. For application to painful lesions, the tan nates described above, and other similar tan-r nates, can be dissolved in water that is slightly 1 j acidi?ed; or theymay be incorporated into oint ments by methods well-known in the art; or they ‘ ‘ may be incorporated in‘ a “areaseless cream”. We 40 prefer to use about 1 to 5% of the tannate in any of the‘above bases or carriers. - r A particularly ‘useful ointment for ‘serious ~burns, scalds,'etc. can be prepared by mixing 2 ‘ parts by weight of 1-.ethoxy-4-(beta-diethyl ‘ 745‘ amino-ethyll-naphthalene tannate, 90 parts ‘white Vaseline and 10v parts lanolin. 2 parts of ; tannic acid may be added to the above if'desired. A‘ very satisfactory creainfor the treatment of ‘sunburn can be prepared by mixing one or two parts by weight of l-ethoizy-4-‘(beta-diethyl amino-ethyl),-naphthalene tannate with 20 parts of glycerol mono stearate and 80 parts of water at 70° C. and allowing the mixture to cool while stirring. This produces a cooling greaseless cream having a neutral reaction. Several parts . of Vaseline, lanolin or petrolatum may be added to the above if desired. _ , Tropacocaine v ' Trimethyl-benzoxy-piperidine (eucaine) , - Occasionally, physicians, prefer in the treat ment of large burns to use an aqueous solution 60 and to leave the areas uncovered until the nat ural formation of ‘a protective covering. An ex cellent wash can be prepared for this purpose by dissolving one part by weight of 1-ethoxy-4 (beta-diethyl -. amino-ethyl) -naphthalene tan V65 nate and two parts of tannic acid in 100 parts Benzoxy-dimethylamino-methyl dimethyl-amij no butane (alypine) p-Amino-benzoyl dimethyl-amino-methyl-bu tanol (tutocaine) ‘ .p - Amino - benzoyl - gamma - amino propanol (butyn). dinormal - butyl vWe claim: - 1. A composition for treating'skin lesions hav ing therein a compound in the list consisting of 1-ethoxy-4-(beta- diethyl - amino-ethyl) - naph thalene tannate, diethyl-amino-ethyl ‘ester of p-amino benzoic acid tannate, a-butylox'y cincho ninic acid diethyl-ethylenediamine tannate, methyl ethyl dimethylamino-methyl carbinol benzoate tannate, ethenyl-p-diethoxydiphenyl tannate, ‘ tropacooaine tannate, tri methyl-benzoxy-piperidine tannate, benzoxy dimethyl-amino-methyl dimethyl-amino butane amidine tannate, p - amino - benzoyl '50 dimethyl - amino methyl-butanol tannate, and p-amino-benzoyl gamma-dinormal~butylamino propanol tannate.‘ 2. A composition for treating skin lesions hav ing therein 1-ethoxy-4-(beta-diethyl-amino 55 benzoic acid tannate. 4. A composition for treating skin lesions hav 60 ethyl) -naphthalene tannate. 3. A composition fortreating‘skin lesions hav ing therein diethyl-amino-ethyl ester of p-amino ing therein a—butyloxy. cinchoninic acid diethyl ethylenediamide tannate. RUSSELL HOPKINSON. ALEXANDER V. TOLSTOOUHOV.