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F ., 1C6 .. , 2,838,439 passed June 10, 1958, _ 2 anesthetic Another to substancethat be ‘administered has been by subcutaneous found useful asinjection a local is butethamine, the para-aminobenzoic'acid ester‘of 2 isobutylaminoethanol, usually administeredrin the form’ 2,838,439 iNiEcTAnLE LOCAL ANEs'rHErrc SOLUTION§ of an isotonic saline solution of the hydrochloride con COMPRISING Mrxruans or SOLUBLE Pao taining 1.0% to 2.0% by weight of butethamine hydro CAlNE AND BUTETHAMENE SALTS chloride. This substance is particularly useful in nerve Samuel D. Goldberg, West Hempstead, N. Y. block anesthesia, being qualitatively identical in action No Drawing’. Application October s, 1955 with that of procaine, but producing about one third greater anesthetic effect, i. e., a butethamine'hydrochlo ride solution of' three-fourths the concentration of a Serial No. 538,274 11 Claims. (Cl. 167--52) procaine hydrochloride solution is of equal effectiveness. - However, the improvement in the anesthetic power of‘ butethamine over that of procaine is accompanied by the > This invention relates, generally, to compositions of 15 disadvantage ‘that the toxicity of butethamine, also,,is_ about one third greater than that of procaine. For dental or other minor surgery, a 1.0% by weight solu matter useful in medicine and, more particularly, it .re lates to certain novel compositions useful for producing local anesthesia. It is known that certain ‘chemical substances, when applied or administered parenterally to the human body, tion of butethamine hydrochloride with epinephrine (l:75,000) may be injected to obtain nerve block anesthesia; inrmajor surgery or other procedures requir are capable of blocking nerve conduction from the area or region of application or administration and this thus limited blocking eifect is known as local or regional ing nerve block anesthesia equivalent to that produced . anesthesia. Local anesthesia produced by parenterally (l:lO0,000) may be used. by 2.0% by Weight procaine solution, a 1.5% by weight solution of butethamine hydrochloridewith epinephrine ‘ ‘I administrable substances is designated according to the o technique employed or the anatomic site of administra tion: In?ltration anesthesia is injection directly into the . . Other anesthetics, such as tetracaine and dibucaine, have the disadvantage that, when administered with epinephrine and in suf?cient amounts to produce the de sired rapid and profound anesthesia, the anesthesia is area. which is ‘painful or to be subjected to surgical very prolonged and reactions due to the toxicity of the trauma; conductive or nerve block anesthesia is injec tion in proximity to speci?c nerve trunks supplying a 30 anesthetic frequently occur. Moreover, all of the above particular anatomic site. All local anesthetic agents are toxic and the tolerance of individuals varies. Safe dosage is therefore limited for each drug, and administration must be individualized. The choice of the drug to be used, its concentration, rate 3‘) and location of administration, mode of administration, along with the individual’s age, emotional and physical ' mentioned anesthetics, when administered subcutaneous ly, show little tendency to spread into‘ tissues surround ing the situs of administration; hence, the anesthetic eifect is substantially limited to the immediate locality of administration and nerve block anesthesia, rather than in?ltration anesthesia, generally must be relied on to achieve the necessary effects. - must vbe exercised in parenteral administration of local One of the objects of this invention is to provide cer-' tain novel compositions, suitable for subcutaneous ad anesthetics to assure that merely subcutaneous, not in travenous, administration is eifected because these sub stances have profound toxic reactions when administered intravenously. In general, the smallest amount of the least toxic drug that will serve the intended purpos amine but having a materially lesser toxicity. Another object of this invention is to provide local anesthetic agents that, in contrast and comparison with status are a few of the factors involved. should be employed. Great care ~ Of the group of local anesthetic agents suitable for parenteral administration, probably the most widely used is the substance procaine, usually in the form of an isotonic saline solution of procaine hydrochloride at a concentration of about 2% by weight, i. e., the solution contains, in each one hundred cubic centimeters, not less than 1.9 grams and not more than 2.1 grams of pro caine hydrochloride. Solutions containing greater or lesser concentrations of procaine hydrochloride, and so lutions of other procaine salts, such as the borate, which is readily water soluble, and the butyrate, which is solu ble both in water and in vegetable oils, have been found satisfactory for use as local anesthetics. Procaine ministration to produce local anesthesia, qualitatively identical in anesthetic action with procaine and buteth procaine and butethamine preparations heretofore known, are suited for use in in?ltration anesthesia and that, when administered subcutaneously, readily and rapidly spread into tissue surrounding the situs of administration, pro- ‘ ducing profound anesthesia therein. A further object of this invention is to provide novel local anesthetic compositions of the type aforesaid that are stable, easy to produce, and that can be produced at costs comparable to those of procaine and butethamine preparations now in use. ' Other objects of this invention will be apparent as the detailed description of the invention proceeds. Regarded in certain broader aspects, the novel local anesthetic agents in accordance with this invention are anesthetics, when administered subcutaneously, induce 60 aqueous solutions containing, in synergistic combination, a soluble procaine salt and a soluble butethamine salt, anesthesia approximately equal to thatv produced by vso proportionated'that there is present in the mixture, cocaine, While being a mere fraction as toxic as cocaine per unit weight of butethamine, one to three units of and virtually free from untoward respiratory and circu weight of procaine. These novel compositions are re- ' latory effects. The chief disadvantage of procaine’ anesthetics is that the anesthesia, although rapidly vin- 65 markable in that their toxicity is materially less than that of a solution containing either procaine or buteth duced, also rapidly disappears; it has been reported that amine in an amount equal to'the total amount of these within two minutes following injection, only faint traces of procaine can be found in the blood. This disadvan tage, to a limited degree, may be overcome by simul substances in the new compositions. For instance, a composition containing two percent by weight of pro taneous administration of a vasoconstrictor, such as ‘70 caine and 1.5 percent by weight of ,butethamine has, at most, about two-thirds the toxicity of a 3.5% by weight epinephrine, which effectively prolongs the anesthetic procaine solution, and ‘even less than two-thirds the effect. 2,838,439 3 '4 toxicity of a 1.5% by weight solution of butethamine salt. The term synergistic combination is herein used in the special and limited signi?cance that it refers to this unexpected and unpredictable phenomenon where lethal dose of this product, determined by subcutaneous injection of white mice, being 325 milligrams per kilo gram of animal body weight. It is found, further, that the intravenous toxicity of by two toxic substances so coact, without loss or im the novel compositions according to this invention is re lated to the intravenous toxicity of the components in pairment of their physiological potencies, that the toxicity of the combination is materially less than the aggregated toxicities of the components. V substantially the same manner as the subcutaneous tox icities above discussed. Using unanesthetized rabbits as test animals, the minimum lethal intravenous dose for toxicity of procaine hydrochloride, administered sub 10 procaine is found to be 45 milligrams per kilogram of cutaneously in the form of an aqueous solution contain animal weight; that for butethamine is found to be 32 Using white mice as test animals, it is found that the ing 2.0% by weight of the salt, is 750 milligrams of the salt per kilogram of test animal weight; and, when tested under the same conditions, it is found that the toxicity milligrams per kilogram; whereas compositions accord ing to this invention containing 2.0% by weight procaine hydrochloride and 1.0% to 1.5% by weight of buteth of butethamine hydrochloride is approximately 550 milli grams of salt per kilogram of test animal weight. These values are the minimum lethal dosages of these drugs, ' amine show minimum lethal dose levels of 35 to 40 i. e., the minimum amounts of these drugs that, when invention may be prepared using any of the water soluble milligrams per kilogram of test animal weight. Compositions embodying the principles of the present administered subcutaneously, result in death ofvthe test salts of procaine and butethamine, the term salts here animal. Likewise, using guinea pigs as thetest animals, 20 signifying the products obtained by treating the free amine it is found that the subcutaneous toxicity of procaine is bases with a mineral or simple, water soluble organic 410-430 milligrams of procaine hydrochloride per kilo carboxylic acid. Although the hydrochlorides are the gram of test animal body weight; while, under the same presently preferred salts, it will be understood that other test conditions, the minimum lethal dose of butethamine hydrochloride is 210—255 milligrams per kilogram. Under comparable test conditions, it is found‘ that the following compositions according to this invention pos sess the toxicity indicated: salts may be used as above indicated. The ratio of butethamine to procaine salt in these products is one part by weight of the former per one to three parts by weight of the latter. As a practical matter, it seldom is necessary or desirable to use either component at a concentration less than about 0.25% of the total weight of solution; Minimum lethal dose (M L D50) Using white mice as test animals and subcutaneously ad ministering to them: butethamine hydrochloride ____________________ -_ (3) Isotonic saline solution containing 2% by weight of procaine hydrochloride and 1.5% by weight of butethamine hydrochloride ____________________ . _ Using guinea pigs as test animals and subcutaneously ad~ ministering to them: (1) Isotonic saline solution containing.r 2% by weight of butethamine hydrochloride ____________________ __ (3) Isotonic saline solution containing 2% by weight of 375 400 grccaine hydrochloride and 1.5% by weight of utethamine hydrochloride _____________________ _ _ 350 From these data, especially the studies conducted with white mice as the test animals, it is evident that the com bination of 2% procaine hydrochloride with 1% buteth amine hydrochloride, or with 1.25% butethamine hydro chloride, results in a product having a toxicity indistin guishable from that of a 2% procaine solution alone, although the anesthetic power is increased to that of a ‘ 31/a% procaine solution, or a 3.6% procaine solution, respectively. These results are the more impressive when compared with the toxicity data found by studies of subcutaneous injection of procaine solutions at con centrations higher than 2.0% by weight: using white mice as the test animals, it is found that the minimum lethal dose, using a solution containing 3.0% procaine hydrochloride, is 700 milligrams per kilogram of animal body weight and, using a 4.0% solution, the minimum lethal dose is 550 milligrams per kilogram. This remark able synergistic action is. limited to combinations of pro caine and butethamine, so far as now known, and it is not exhibited in combinations of procaine with other local anesthetics. Similar use of butethamine hydrochloride in amounts within the range of 1.0% to 1.5% of total weight, and of procaine hydrochloride in the amount of 2.0% of the total weight of ?nished solution presently is preferred. In addition to the improvement in toxicity effected in the novel compositions according to this invention, com pared to anesthetic compositions containing the individual components separately, these new compositions have an procaine hydrochloride and 1% by weight of (2) Isotonic saline solution containing 2% by weight of procaine hydrochloride and 1.25% by weight of concentration for the individual components. considerations set 2.0% of total weight as the effective upper limit of concentration for the butethamine and 6.0% of total weight for the procaine component. The (1) Isotonic saline solution containing 2% by weight procaine hydrochloride and 1% by weight of JVIqsn/kilo. butethamine hydrochloride. ____________________ __ .750 (2) Isotonic saline solution containing 2% by weight of procaine hydrochloride and 1.25% by weight of butethamine hydrochloride _____________________ .. 30 hence, this may be regarded as an eifective minimal For example,,which serves further to em phasize the unexpectedncss of this synergistic action, it is found that the addition of merely 0.15% of tetracaine hydrochloride to a 2.0% procaine hydrochloride solution results in a product more'than twice (ca. 2.3><) as toxic as the procaine hydrochloride solution alone, the minimum other remarkable property: their ability to migrate into surrounding tissue near the situs of injection. This prop erty is of great importance as it permits the anesthetic to be administered by in?ltration rather than restricting its use to block anesthesia as has been necessary with procaine preparations and with butethamine preparations of types heretofore known. This property may be dem onstrated by intracutaneous wheal tests on human sub jects. In these tests, a small amount of the drug under test is injected below the skin surface between the epi dermis and the under-lying tissue, whereby a bleb is produced and the area of this bleb is indicative of the degree of spread of the injected material from the point of injection, and, in this instance, it is indicative of the area of anesthetization. Using a solution containing 1.5% procaine hydrochloride in isotonic saline, no ap~ preciable spreading was observed; using a 1.5% buteth amine hydrochloridc solution, the area of spreading was vfound to be 1.25 centimeters in diameter; and, when epinephrine was included in the butethamine solution, the area of spreading was found to be 1.50 centimeters in diameter. A solution according to the present invention, containing 2.0% by weight procaine hydrochloride and 1.0% to 1.5% by weight of butethamine, but containing no vasoconstrictor, spread over an area 2.0 centimeters in diameter; and, after addition of a vasoconstrictor (epinephrine) to this solution, the area of spread was found to be 3.0 centimeters in diameter. This property of spreading is of great importance in anesthesia as it permits the anesthetist to induce a rapid and profound anesthesia due to in?ltration of the anes thetic throughout the area surrounding the situs of admin istration. In clinical studies of compositions embodying 2,888,439 5 one to three units of weight of procaine. 2. A new composition of matter ‘as de?ned in claim 1 wherein the soluble butethamine salt is present in the aque thesia was established was observed in 500 cases. It was found that complete anesthesia was established immedi ately following injection over a 15-30 second period, whereas, in block or conductive anesthesia, the injection requires 45-60 seconds and anesthesia is not established until about one and one-half minutes thereafter. ous solution in an amount Within the range of 0.25% to 2.0% by weight, based on the total weight of the solution. 3. A new composition of matter as de?ned in claim 1 wherein the soluble butethamine salt is present in the It is preferred, in compositions embodying the prin aqueous solution in an amount within the range of 1.0% ciples of this invention, to include a suitable vascoconstric tive sympathomimetic amine, such as epinephrine, phenyl 6 present in the mixture, per unit weight of butethamine, the principles of this invention, the rate at which anes 10 ephrine, laevoarterenol and the like, for the purpose of localizing and prolonging the action of the anesthetic. to 1.5% by weight, based on the total weight of the solution. 4. A new composition of matter as de?ned in claim 1 wherein the soluble procaine salt is present in the aqueous solution in an amount substantially equal to 2.0% of the These substances in amounts of less than 0.02% of the total weight of the solution are effective for this purpose. total weight of the solution. In general, for anesthetics to be used in dentistry, it is pre ferred to use epinephrine in the proportion of 1:50,000 to 5. As a new composition of matter, useful in medicine as a local anesthetic agent, an isotonic aqueous saline solu 1:100,000 parts by weight; phenylephrine, 1:2,500 to tion containing, in synergistic combination, a soluble pro 1:3,500; and laevo-arterenol, 130,000 to 1:60,000. For caine salt and a soluble butethamine salt, so proportion anesthetics to be used in surgery, it is preferred to use somewhat less of the vascoconstrictor, say, for epineph 20 iated that there is present in the solution, per unit weight of butethamine, one to three units of weight of procaine; and rine, 1:130,000 to 1:500,000 parts by weight. a vascoconstrictive sympathomimetic amine in an amount It is to be understood that the term butethamine, as less than 0.02% by weight, based on the total weight of the solution. herein employed, signi?es not only the 2-isobutylamino ethanol ester of para-aminobenzoic acid, but also its iso mer, the 2-isobutylaminoethanol ester of meta-amino lbenzoic acid, which, too, is a potent local anesthetic. The para-isomer is the preferred member of this group for the purposes of this invention. 6. A new composition of matter ‘as de?ned in claim 5 wherein the soluble butethamine salt is present in the aqueous saline solution in an amount within the range of To facilitate a fuller and more complete understanding 0.25% to 2.0% by weight, based on the total weight of the solution. examples follow, provided by way of illustration merely, aqueous saline solution in an amount within the range of of the principles of this invention and of how the products 30 7. A new composition of matter as de?ned in claim 5‘ wherein the soluble butethamine salt is present in the in accordance therewith best may be made, several speci?c 1.0% to 1.5 % by weight, based on the total weight of the not by way of limitation upon the invention de?ned by the subjoined claims. solution. EXAMPLE 1 35 chloride, and the vasoconstrictive sympathomimetic amine is epinephrine. procaine hydrochloride, 2.0% by weight; p-butethamine 40 EXAMPLE 2 A solution is prepared as described in Example 1 ex 9. A new composition of matter as de?ned in claim 8 wherein the butethamine hydrochloride is present in the aqueous saline solution in an amount within the range of 0.25% to 2.0% by weight, based on the total weight of the solution. to produce a concentration of one part per 75,000 parts by weight of ?nished solution. The product has the proper ties hereinabove described. wherein the soluble butethamine salt is butethamine hy~ drochloride, the soluble procaine salt is procaine hydro-' An aqueous solution is prepared containing the follow-' ing substances in substantially the proportions indicated: hydrochloride, 1.25% by weight; sodium chloride, 0.45% by weight; sodium bisul?te, 0.02% by weight; methyl para-hydroxybenzoate, 0.01%; and epinephrine, su?‘icient > 8. A new composition of matter as de?ned in claim 5 45 10. A new composition of matter as de?ned in claim 8 wherein the butethamine hydrochloride is present in the aqueous saline solution in an amount within the range of 1.0% to 1.5% by weight, based on the total weight of the solution. 11. A new composition of matter as de?ned in claim 8 is increased to 1.5% by weight. The product so obtained 50 cept that the proportion of p-butethamine hydrochloride has the properties hereinabove described. EXAMPLE 3 wherein the procaine hydrochloride is present in the aque ous saline solution in an amount substantially equal to 2.0% of the total weight of the solution. A solution is prepared as described in Example 1 except that the proportion of p-butetharnine hydrochloride is de , References Cited in the ?le of this patent creased to 1.0% by weight. The product so obtained has FOREIGN PATENTS the properties hereinabove described. Great Britain _________ __ Mar. 19, 1952 668,502 Having thus described the subject matter of this inven tion, what it is desired to secure [by Letters Patent of the OTHER REFERENCES United States is: 60 Goodman et al.: Pharmacological Basis of Therapeu 1. As a new composition of matter, useful in medicine tics, 2nd ed., 1955, Macmillan Co., New York city, p. 365. as a local anesthetic agent, an aqueous solution containing, Gray et al., Jour. Pharm. and Pharmacol, February in synergistic combination, a soluble procaine salt and a soluble butethamine salt, so proportionated that there is 1954, vol. 6, No. 2, pp. 89-114.