US2793155A - Anaesthetic compositions - Google Patents

Description

,May 21, 1957 A, E. w. sMxTH ET AL 2,793,155

'ANAESTHETIC coMPosI'rIoNs Filed Feb.' 24, 195e United States Patent O ANAESTHETIC COMPOSITIONS Arthur Ernest Wilder Smith, Geneva, and Emil Hofstetter, Wolhusen, Switzerland, assignors to Ed. Geistlich Sohne A. G. fur Chemische Industrie, Wolhusen, Switzerland, a corporation of Switzerland Application February 24, 1956, Serial No. 567,580

6 Claims. (Cl. 167-52) This invention relates to improved anaesthetic compositions of particular use in local anaesthesia.

In copending application Serial No. 555,305 tiled December 27, 1955 of Emil Hofstetter there are described certain new compounds of the general formula also described certain new compounds having the general formula 1 y Rx y R-Nny-cofcHr-J-RI RI I 1I (where R is-a monochlorophenyl radical or a dichlorophenyl radical which dichlorophenyl: radical has at leastY one chloro-substituent in the metaor para-position, R1 is hydrogen or an alkyl group having from one to ve carbonv atoms, R2 is an alkyl group having from one to five carbon atoms and R3 is a dialkylamino group containing from two to four carbon atoms or a piperidyl or monoalkyl piperidyl group), which have local anaesthetic activity.

We have now found that an anaesthetic composition having unexpectedly advantageous properties is obtained by mixing together the compound of the Formula I above in which X represents a phenyl radical, that is -diethylamino butyric acid-anilide, or its non-toxic wateror alcohol-soluble salts with the compound of Formula II above in which R is an o,pdichlorophenyl radical, R1 is hydrogen, R2 is methyl and R3 is piperidyl, that is -piperidylbutyric acid-(o,pdich1oro)-anilide or its non-toxic wateror alcohol-soluble salts.

According to the invention, therefore, we provide a local anaesthetic composition comprising a sterile injecable solution of a mixture of a member of the group consisting of -diethylamino butyric acid-anilide and nontoxic waterand alcohol-soluble salts thereof and a member of the group consisting of -piperidyl butyric acid- (o,pdichloro)anilide and non-toxic waterand alcoholsoluble salts thereof.

By the `term non-toxic as applied to the salts of the two compounds mentioned above is meant such salts as are not substantially more toxic under normal conditions of administration than the compounds themselves. Such non-toxic salts specilically include the citrates, tartrates, acetates, sulphates and particularly the hydrochlorides of these compounds.

The local anaesthetic compositions provided according to the invention have important and unexpected advan- 2,793,155 :Ratented May 2l, 1957 'ice tages over either of the component compounds comprising the composition; Thus, a local anaesthetic should have ideally inter alia, the following properties.

(1) It should have a short latent period; that is the period between the injection of the anaesthetic and the time when it takes etect should be as short as possible.

(2) The level of anaesthesia induced should be deep and should be maintained for a suliicient period.

(3) There should be no substantial irritation of lthe tissue on injection, and no substantial ill-etects on the patient. j

Now, it was found that although -diethylamino butyric acid-anilide is a good anaesthetic in many respects it has a long latent period; also anaesthesiav is not maintained for as long a period as might in some cases be desirable. The compound -piperidyl butyric acid-(o,p-dichloro) anilide also has a long latent period, and whilst it is long acting it gives n'se to some tissue irritation in concenhations of greater than about 0.5%.

The anaesthetic compositions of the present invention have the unexpected property of a very short latent period, which is considerably less than that of either -diethyl-v amino butyric acid-anilide or -piperidyl butyric-(op dichloro)anilide. The duration of anaesthesia is also long and a considerable depth of anaesthesia is maintained. l

We have found it particularly advantageous to use a composition in the form of a'sterile injectable solution' containing a mixture of from about 1.5 to 4.0%, preferably 2.0%, of -diethylamino butyricacid-anilide or itsl;

, non-toxic water or alcohol-soluble salts with from about;

0.2 to 0.5%, preferably 0.4%, of -piperidyl butyric acid-v (o,pdichloro)-anilide or its non-toxicwateror'alcohol-` soluble salts the percentages being expressed asa weight' by volume on the-metri'c'sallbased o rithe'volumeof'the. injectable solutions. 'j' Afpiefe'rred infin-*toxic 'salt is 7 the hydrochloride'. When usedin these proportions the irritant properties of l ipiperidyl butyric acid'A ("oipdiiV chloro)v-anilide` 'are'.'not noticeable onv injection of the' composition." "'NVA '.1 f1' The anaestheticcompositions according to 'the inven-' tion are" particularly applicable to'dental' surgery orv sur? gery of a minor nature, although they are also applicableV as ganglionic blocking agents in major surgical intervention. In the case of dental surgery they are conveniently made up in the form of dosage units adapted for parenteral administration each unit conveniently cornprising 1 to 3 ccs. of the anaesthetic composition of our invention. l

According to a feature of the invention we provide alocal anaesthetic composition in dosage unit form adapted for parenteral administration in dental surgery each dosage unit comprising fronil to 3 ccs. of a sterile injectable solution comprising a mixture of about-2`.0% of a member of the group consisting of -diethylamino butyric acidanilide and non-toxic water, and alcohol-soluble *salts-y thereof and about 014%' vof'a member'of'tlie group consisting of -'piperidyl butyric acid (o,pdichloro)-anilide and non-toxic waterand alcohol-soluble salts thereof.

In the case of minor surgery such a dosage unit can conveniently be of the order of 1 to 5 ccs. of the composition having the concentration above-stated.

In the case of -rnajor surgical intervention the composition according to the invention finds application as a ganglionic blocking agent which may be parenterally administered as and where necessary, provided that not more than ccs, of a solution of the above-mentioned concentration is used.

The compositions according to the invention may be made up in any convenient liquid medium which is suitable for injection. Where the components of the cornposition are in the form of their water-soluble salts for example as hydro'chlorid'es, then they' are preferably made up in the form of an aqueous solution. The injectable compositions according to the invention may advantageously contain a vaso-constrictor such as adrenaline.`

In order clearly to demonstrate the unexpectedly short latent period possessed, extensive experiments have been carried out to compare the latent period of the local anaesthetic compositions of our invention with that of -diethylamino butyric acid-anilide and )S-piperidyl butyric aeid-(o,pdiehoro)-anilide In the experiments carried out the persons being studied were injected with a particular anasthetic in aqueous sol'ution the solutions in all cases containing 1`5'-20 y of adrenalin-noradrenalin per ce of solution. The latent period for each anaesthetic solution' was then detenmined, this period being the time elapsing between the moment of injection and the onset of full anaesthesia; the experiments were carried out in all cases on the gums ofV the patients.

The results of these experiments are set' out in the aecompanying drawing which showsthe results in graphical form. Each curve on the graph representsthe results obtained for a particular solution-the composition ofthe various solutions used being as follows:

' Percentage of. Percentage of. -diethylamino -piperidyl Solution and Curve No. butyricacid butyric acid anilide hydro- (o, pdichloro) chloride anilide hydrochloride' 2. u o. 4l 4. 0. 3 2.0 0.3 2. 0 0. 2 1. 5 0. 5 2. 0 0. 5

The results obtained were the averages obtained on treat-- ing a number of people, the number of people treatedY with solution l being 1,100; with solution. 2,. 30; withsolution 3, 50; with solution 4, 40; and with solution 6, 300. In the case of solution 5, people were treated of whom %v complained of tissue irritation, whilst in the case of solution 7 insuicient anaesthesia was produced in the 5 people who were treated.

It will be noted from the above results that the latent period for the compositions of our invention, that is those represented by curves -5 is considerably less than that of -diethylamino butyric acid-anilide alone (curve 6) or of Iifi-piperidyl butyric acid (o,p-dichloro)anilide (curve 7) even though this is used at so high a concentration that a certain amount of' tissue irritation results.

The latent period for Xylocaine lies between that of solutions 1-4.whilst that of Procaine has a similar latent periodto that of solution 6.

Whilst only the use of the hydrochlonides of -diethylamino butyric acid anilide and -piperidyl butyric acid (o,pdichloro) -anilide has been exemplified it will be appreciated. by those skilled in the art that other salts can be used, for example,.the citrates, tartrates, acetates or sulphates of these compounds. It will also be appreciated' that whilst'only wafer has been exemplili'ed as the injectable medium any other convenient compatible medium may be used. Thus, for example, the medium used may contain alcohol in which case alcohol-soluble salts of the compounds comprising the composition may conveniently be used.

It is thusseen: that' the new'local anaesthletic compositions of ourinvention possess certain unexpected advantages.A In particular they have azshort" latent and give a long period of deep anaesthesia.'

l. A local anaesthetic composition comprising a sterile injectable solution: of afmxtureV of a'- mernber of' the group consisting, of [.t-diethylamintv butyric acid-anilide and non-toxic waterand alcohol-soluble salts thereof and a member of the group consisting of -piperidyl butyric acid(o,pdichloro)anilide and non-toxic waterand alcoholsolnble salts thereof.

2. A localV anaesthetie composition' comprising a sterile injectable solutionof a mixture of from about 1.5 to 4.0% of: a' member ofjthe group consisting of -diethylamino butyric acid-:militie4v andl non-toxic' waterand alcoholsoluble salts thereof and of' from' about 0.2 to 0.5% of a member of the group consisting of -piperidyl butyric acid-(o,pdichloro)ani1ide and non-toxic waterand alcohol-soluble salts thereof 3. A local' anesthetic-composition comprising a sterile- 'i injectableA solution of amixture of about' 2.0% of the hydrochloride ofTv -ded1ylamino butyrie acid anilidef andi v adapted for parentfnfalliadministration: in dental' surgery each dosage unit comprising from l to 3 ecs, of a-sterile injectable solution comprising a mixture of about 2.0% of a member of the group consisting of -diethylamino butyn'c acid-anilideandiinon-toxic waterand alcoholsoluble salts thereof and about 0.4% of a member of the groupconsisting of -piperidyl. butyric acid-(o,p-dich1oro). anilide. anchl non-toxic. waterand alcohol-soluble salts thereof.

5. A local anaesthetic composition' indosage unit form adapted for'parent'eral administration in dental surgery eachdosage unit comprising from l' to 3 ccs. of an aqueous solution comprising a mixture of about 2.0% of the hydrochloride of -diethylamino butyric aoid-anilide and about 0.4% of the hydrochloride of -piperidyl butyric acid-(o,p-dichloro)anilide.

6. A- localanaesthetic composition 'in dosage unit form adapted for parenteral administration in minor surgery each-dosage: unit comprising. from. 1 to 5 ccs, of a sterile injectable solution comprising a mixture of about 2.0% of a memberl of the group consisting. of -diethylamino butyric acid-anilide and` non-toxic waterand alcohol solution salts thereof and about 0.4% of a member of the group consisting of -piperidyl butyric acid-{0,p-dichloro)anilide and non-toxic water and alcohol-soluble salts thereof.

No, references cited.

Claims (1)

1. A LOCAL ANAESTHETIC COMPOSITION COMPRISING A STERILE INJECTABLE SOLUTION OF A MIXTURE OF A MEMBER OF THE GROUP CONSISTING OF B-DIETHYLAMINO BUTYRIC ACID-ANILIDE AND NON-TOXIC WATER- AND ALCOHOL-SOLUBLE SALTS THEREOF

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