Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups

Definitions

• Another object of the present invention is to provide highly eifective anesthetic preparations which can be pressure-dispensed and which have a much higher anesthetic effect than heretofore attained by conventional preparations of this type.
• a further object of the present invention is to provide highly effective and non-irritating injectable preparations containing a local anesthetic agent.
• Still another object of the present invention is to provide a simple and effective process of making such improved local anesthetic preparations.
• a further object of the present invention is to provide a highly effective method of locally and topically anesthetizing mucous membranes and other parts of the animal and human body.
• these objects of the present invention are achieved by producing solutions of a local anesthetic base of the acid amide type which contain an excess of carbon dioxide over the stoichiometrically required amount.
• carbon dioxide is introduced into a suspension of the local anesthetic base, preferably under pressure, and at a low temperature, and the resulting solution is poured into the dispensing containers such as vials, ampoules, pressure resistant dispensers, and the like.
• the present invention is useful in the preparation of local anesthetics of the acid amide type, it has proved of special value in the preparation of solutions of the local anesthetic known as lidocaine.
• the base dissolves gradually and slowlyand a clear solution is obtained.
• a pressure resistant atomizer or dispenser When filling such a solution into a pressure resistant atomizer or dispenser and adding thereto additional pharmaceutically acceptable driving agent or propellant, for instance, excess carbon dioxide, nitrogen, propellants of the halogenated hydrocarbon type which contain one or more fluorine atoms in addition to other halogens in their molecule, such as dichloro difluoro methane, chloro trifluoro methane, chloro difluoro methane, sym. dichloro tetrafluoro ethane, and others, or a mixture of such agents, pressure dispensable local anesthetic solutions are obtained which can readily be applied topically to the body of animals and humans.
• additional pharmaceutically acceptable driving agent or propellant for instance, excess carbon dioxide, nitrogen, propellants of the halogenated hydrocarbon type which contain one or more fluorine atoms in addition to other halogens in their molecule, such as dichloro difluoro methane, chloro trifluoro methane
• a pharmaceutically acceptable acid addition salt of the local anesthetic is dissolved in water.
• injectable solutions of the local anesthetic of the acid amide type by proceeding as pointed out hereinabove, either by suspending the base of the local anesthetic in water and solubilizing the same by the addition of carbon dioxide, or by dissolving the water soluble, pharmaceutically acceptable, acid addition salt of the local anesthetic and adding thereto a water soluble, pharmaceutically acceptable hydrogen carbonate.
• the resulting solutions are then filled into arnpoules or other containers for application by injection and are kept therein under a certain carbon dioxide pressure.
• This process may be modified by using a suspension of the local anesthetic base in a solution of its hydrochloride or other water soluble, pharmaceutically acceptable acid addition salt and introducing carbon dioxide and an amount of a pharmaceutically acceptable, water soluble hydrogen carbonate into the suspension, said hydrogen carbonate being added in anamonut sufl'lcient to neutralize the acid moiety of the acid addition salt.
• Sodium bicarbonate which is the preferred hydrogen carbonate used in this process may be replaced by equimolecular amounts of other neutralizing agents, such as sodium carbonate, sodium hydroxide, and others. Addition of sodium bicarbonate is of advantage because it yields additional amounts of carbon dioxide as is evident from the following equation:
• the further advantage is achieved that first the base is precipitated in finely divided form which is solubilized more readily and rapidly by the addition of carbon dioxide than when suspending the base as such in water and then introducing carbon dioxide into the resulting suspension.
• the salt solution may be added to the hydrogen carbonate solution, or the two solutions may be introduced simultaneously in equimolecular amounts into the reaction vessel.
• the process of reacting the base with carbon dioxide and the process of reacting the acid addition salt of the base with sodium bicarbonate or the like compounds may be combined and carbon dioxide may be introduced into the mixture of base, acid addition salt, and water soluble hydrogen carbonate.
• preparations according to the present invention i.e., preparations which contain, in solution, the reaction product of carbon dioxide and lidocaine or other local anesthetic bases of the acid amide type in the presence of an excess of carbon dioxide, have a much higher local anesthetic potency than the heretofore used preparations which contain acid addition salts and especially the hydrochlorides of such bases in solution.
• the potency of solutions according to the present invention is increased about two to three times over that of hydrochloride solutions as can be demonstrated by the rabbit cornea test. When the isolated nerve action potential technique is employed, a fivefold to tenfold increase in potency over that of solutions of the hydrochloride is observed.
• preparations according to the present invention over known preparations consists in the possibility of preparing solutions of the local anesthetic agent which are highly effective, even at a pH-value below 6.0. While, for instance, lidocaine hydrochloride solutions are substantially ineffective at a pH-value below 6.0, the lidocaine-carbon dioxide solu tion according to the present invention has a very substantial potency even at a pH of about 5.0 as can be demonstrated by the high lidocaine concentration in the isolated nerve.
• a further advantage of preparations according to the present invention is their reduced toxicity. This is due to the precipitation of the base from its carbon dioxidecontaining solution upon release of the carbon dioxide on administration. The precipitated base is more slowly absorbed than, for instance, the hydrochloride. Thus, for instance, in certain anesthetic procedures solutions of a lower concentration of lidocaine can be used than heretofore possible. Spraying solutions containing solvents as they were heretofore employed conventionally, produced concentrations of the local anesthetic in excess of 20% at the site of application.
• preparations according to the present invention produce effective concentrations of only about 4% and less of the local anesthetic after release of the driving agent.
• concentrations of the local anesthetic at the site of application as produced heretofore is, of course, more apt to cause toxic manifestations and side reactions than the low concentration produced by preparations according to the present invention.
• EXAMPLE 1 40 g. of lidocaine base are placed into an Erlenmeyer side-arm pressure flask provided with a glass tube extending to the bottom of the fiask. Distilled water is added thereto to make up to 1000 cc. Carbon dioxide is introduced into the solution at a pressure of 10 p.s.i. As soon as absorption of carbon dioxide ceases, the mixture is cooled to about 4 C. Charging with carbon dioxide at said pressure and temperature is repeated until all of the lidocaine is dissolved. The time required to effect solution depends on the frequency of charging. If charged three times during an eight hour working day, solution is effected within three to four days.
• the resulting solution is filled into pressure spray containers using either nitrogen at a pressure of p.s.i. or a mixture of 20% of dichloro difiuoro methane and 80% of sym. dichloro tetrafluoro ethane as propellant.
• the solution may also be filled into glass ampoules, if desired, after addition of epinephrine.
• EXAMPLE 2 24.64 g. of lidocaine hydrochloride (with one mole of water of crystallization) are dissolved in 350 cc. of distilled water. A solution of 7.2 g. of sodium bicarbonate dissolved in cc. of distilled water is added slowly and with stirring to said lidocaine hydrochloride solution. No etfervescence is observed but lidocaine base is precipitated in finely divided form. The resulting suspension is diluted with distilled water to a volume of 500 cc. The pH of the resulting suspension is 7.15. It is placed into a 2 liter tubulated Erlenmeyer flask.
• Carbon dioxide is introduced through a tube extending to the bottom of the flask at a pressure of 10 p.s.i. and room temperature.
• the precipitated lidocaine base goes into solution within four days of repeated charging of carbon dioxide at a pressure of 10 p.s.i. and room temperature.
• the pH of the resulting solution is 6.72.
• the solution contains 4.0% of lidocaine base and about 1.0% of sodium chloride formed in the reaction. It is filled in dispensing containers as described in Example 1.
• EXAMPLE 3 24.64 g. of lidocaine hydrochloride (with one mole of water of crystallization) are dissolved in 500 cc. of distilled water. The pH of the solution is 4.08. A solution of 7.2 g. of sodium bicarbonate in 200 cc. of distilled water of a pH of 7.86 is added to the lidocaine hydrochloride solution slowly and with stirring. No effervescence is observed. The pH of the resulting suspension is 7.1. It is placed into a calibrated 2 l. tubulated Erlenmeyer flask. 20.0 g. of lidocaine base, 5.01 g. of sodium chloride, and 200 cc. of distilled water are added thereto.
• Carbon dioxide is introduced into the mixture at a pressure of 10 p.s.i. and at room temperature. The carbon dioxide pressure is maintained until all the lidocaine base is dissolved. Usually 5 days are required to effect complete solution. The solution is then diluted to a volume of 1,000 cc. Its pH is 6.3 and it contains 4.0% of lidocaine base and 1.0% of sodium chloride, one-half of which was formed in the reaction.
• EXAMPLE 4 Distilled water is first charged at 4 C. with carbon dioxide at a pressure of 10 p.s.i. until saturated with carbon dioxide. Its pH is then 3.4.
• lidocaine hydrochloride (with one mole of water of crystallization) are dissolved in 500 cc. of said carbon dioxide-saturated water of 4 C.
• the resulting solution has a pH of 3.5.
• 5.87 g. of sodium bicarbonate are dissolved at 4 C. in 200 cc. of carbon dioxide-saturated water to yield a solution of a pH of 6.8.
• Said sodium bicarbonate solution is added to the lidocaine hydrochloride solution slowly and with stirring while maintaining the temperature at 4 C. No effervescence is observed.
• the resulting suspension is then diluted to a volume of 1000 cc.
• EXAMPLE 5 The water used in the preparation of the following lidocaine solution is prepared by saturating distilled water at 25 C. with carbon dioxide at a pressure of 10 p.s.i.
• lidocaine hydrochloride (with one mole of water of crystallization) are dissolved in 350 cc. of said carbon dioxide-saturated water.
• the resulting solution has a pH of 3.75.
• a solution of 2.935 g. of sodium bicarbonate in 125 cc. of said carbon dioxidesaturated water having a pH of 7.03 is added slowly and with stirring to the lidocaine hydrochloride solu tion. No eifervescence is observed.
• the resulting suspension is diluted with carbon dioxide-saturated water to a volume of 500 cc., is then placed in a tubulated Erlenmeyer flask, and is charged at room temperature with carbon dioxide at a pressure of 10 p.s.i.
• EXAMPLE 6 300 g. of lidocaine base are added to 2.5 liters of distilled water in a 4 liter tubulated Erlenmeyer filter flask. A Teflon coated magnet is also placed in the flask.
• the flask is equipped with a #12 one hole rubber stopper and with a piece of glass tubing extending through the hole in the stopper and reaching almost to the bottom of the flask.
• the other end of the tubing has a 90 bend with a piece of rubber tubing fitted thereover and extending about 10 beyond its end.
• the tubulated side arm has a piece of rubber. tubing over it that extends 2" beyond its end.
• the stopper is tied in securely and then the rubber tubing from the long glass tube is connected to a tub from a tank of carbon dioxide. Carbon dioxide is allowed to bubble through the Water slowly for about three minutes whereafter the rubber tubing on the tubulated side arm is closed by means of a Hoifman clamp. The carbon dioxide pressure is then raised to 10 p.s.i., and the rubber tubing connected to the carbon dioxide source is closed with a Hoffman clamp. The flask is kept refrigerated at 5 .C. for two hours. Thereafter, more carbon dioxide is introduced through the long tube to bring the pressure up to 10 p.s.i. The flask is then placed on a magnetic stirrer and stirred for about one hour, after which it is gassed again and then refrigerated.
• Equal volumes of said lidocaine-carbon dioxide solution (10%) and a 2.6% solution of cal-boxy methyl cellulose are mixed with each other.
• the mixture is placed in a tubulated Erlenmeyer filter flask as used to make the initial solution. Carbon dioxide is bubbled 6 slowly through the mixture. Then the side vent is clamped and the pressure of carbon dioxide is raised to 10 p.s.i.
• .EXAMPLE 7 17.3 g. of lidocaine base are mixed with about 800 cc. of water. The mixture is placed in an Erlenmeyer flask as described in Example 6. 6.0 g. of sodium chloride are added thereto and the mixture is filled up to a volume of 1000 cc. The flask is then charged with carbon dioxide at a pressure of 10 p.s.i. and cooled to 4 C. Charging with carbon dioxide is repeated until solution is effected. The pressure is released, the stopper is removed, and 0.5 g. of sodium metabisulfite and 0.01 g. of epinephrine are added quickly. The stopper is placed back and secured in the flask.
• the flask is immediately charged with carbon dioxide at a pressure of 10 p.s.i. and charging is repeated. Complete solution is eifected after several hours.
• the solution is filled into ampoules which are sealed. It contains lidocaine base in an amount equivalent to that of a 2% lidocaine hydrochloride solution.
• the epinephrine concentration is 0.01 mg./cc.
• the process according to the present invention has proved of special advantage in preparing solutions of the local anesthetic lidocaine, it can also be applied to other local anesthetics possessing amino groups and especially to local anesthetics of the acid amide type. It has been found, for instance, that it is of great value in the preparation of solutions of mepivacaine, i.e., dl-N- methyl pipecolyl-2,6-xylidide of the following formula Preparations with said local anesthetic base, for instance, are produced according to the present invention as described hereinafter.
• EXAMPLE 8 22.58 g. of mepivacaine hydrochloride and 5.94 g. of sodium bicarbonate in about 475 cc. of distilled water are treated with carbon dioxide as described in Example 2. The resulting solution is made up with distilled water to 500 cc.
• EXAMPLE 9 20.0 g. of mepivacaine base, 22.58 g. of mepivacaine hydrochloride, 5.94 g. of sodium bicarbonate, 4.13 g. of sodium chloride, and 900 cc. of distilled water are treated with carbon dioxide as described in Example 3. The resulting solution is made up with distilled water to 1000 cc.
• EXAMPLE 10 22.37 g. of mepivacaine hydrochloride, 5.87 g. of sodium bicarbonate, and 700 cc. of carbon dioxide-saturated water are treated at 4 C. with carbon dioxide as described in Example 4. The resulting solution is made up with carbon dioxide-saturated water to 1000 cc.
• EXAMPLE 11 11.19 g. of mepivacaine hydrochloride, 2.94 g. of sodium bicarbonate, and'475 cc. of carbon dioxide-saturated water are treated with carbon dioxide at room temperature as described in Example 5. The resulting solution is made up to 500 cc. with carbon dioxide-saturated water. 0.25 g. of sodium metabisulfite and 8 mg. of epinephrine are added thereto, whereafter treatment with 7 carbon dioxide is continued as described in Example 5.
• Another local anesthetic of the acid amide type which may also be used for producing valuable local anesthetic preparations according to the present invention is the a-(n propylamino) propionyl toluidide-(Z) of the following formula which, in contrast to lidocaine and mepivacaine, contains a secondary amino group.
• the following example serves to illustrate the preparation of solutions of said local anesthetic agent according to the present invention.
• EXAMPLE 12 3.4 g. of e-(n-propylamino) propionyl toluidide-(Z) base are placed into an Erlenmeyer side-arm pressure flask provided with a glass tube extending to the bottom of the flask. Distilled Water is added thereto to malte up to 200 cc. Carbon dioxide is introduced thereinto at a pressure of psi. As soon as absorption of carbon dioxide ceases, the mixture is cooled to about 4 C. Charging with carbon dioxide at said pressure and temperature is repeated until the base is completely dissolved. The time required to effect solution depends on the frequency of charging. If charged three times during an eight hour working day, solution is effected within three to four days. The resulting solution is filled into 30 cc. ampoules. It contains 1.71% of the base corresponding to 2% of its hydrochloride.
• lidocaine, mepivacaine, and ot-(n-propylamino) propionyl toluidide-(2) which are the preferred local anesthetics to be used as starting materials in the production of preparations according to the present invention, there may be employed other local anesthetic agents of the acid amide type.
• Such acid amide local anesthetics correspond in principle to the following formula wherein R represents lower alkyl, especially methyl;
• R represents halogen, when R is lower alkyl and R is hydrogen, or lower alkoxy, when R and R are lower alkyl, or hydrogen or lower alkyl, especially methyl;
• R represents a carballtoxy group, when R is lower alkyl, or halogen, when R is lower alkyl, or hydrogen, or lower alkyl, especially methyl;
• R and R represent hydrogen or lower alkyl or, together with the nitrogen and the -CH-group to which they are attached, forming a piperidine ring;
• R represents lower alkyl
• This group of acid amides as is evident comprises not only lidocaine but also mepivacaine which is a piperidino compound wherein R and R of the above given formula represent butylene-CH -CH CH -CH forming a piperidine ring with the nitrogen atom and the neighboring CH-group, and the secondary amino compound a-(n-propylamino) propionyl toluidide-(Z) of the preceding examples.
• acid amides of the above given formula which are useful components of local anesthetic compositions according to the present invention are, for instance, Ot-(l'lbutylamino) acetyl-2-methyl-6-chloro anilides, a-diethyl- & amino acetyl-2,6-dimethyl-4-butoxy anilide, and the like compounds.
• lidocaine preparations according to the present invention. They clearly demonstrate the superiority of such preparations over the heretofore used solutions of lidocaine hydrochloride.
• the test method consists in the introduction of a sciatic nerve sensory block in the frog.
• the sciatic nerve preparation of a green frog was immersed in the test solutions of varying molarity of 10 minutes. The preparation was then rinsed for 40 seconds in Ringers solution. After homogenization, the amount of lidocaine absorbed by the sciatic nerve was determined. The results are given in Table III.
• Solution a is a lidocaine base solution treated with carbon dioxide under a pressure of 15 p.s.i., i.e., a solution according to the present invention of a pH between 5.68 and 6.23.
• Solution b is an equimolecular lidocaine hydrochloride solution in Ringers solution, the pH of which was adjusted to a pH of 7.20, i.e., to optimum pH-conditions.
• Solution 0 is an equimolecular lidocaine hydrochloride solution in Ringers solution of a pH of 6.00.
• lidocaine base solution is far better absorbed by the sciatic nerve tissue than lidocaine hydrochloride and that this absorption at a pH of about 6.0 considerably exceeds even the absorption of lidocaine from a solution of a pH of about 7.2, i.e., under conditions which, heretofore, were considered to be optimum conditions. It may be pointed out that such superior results are not achieved when replacing carbon dioxide by other weak acids of about the same dissociation constant, such as lactic acid, tartaric acid, citric acid, and the like, but are apparently due to the administration of the local anesthetic base in the form of its hydrogen carbonate in the presence of an excess of carbon dioxide.
• the preparations according to the present invention can also be applied to the ear. Preparations as heretofore available did not produce satisfactory anesthesia in the ear.
• solutions of lidocaine, mepivacaine, and other local anesthetics of the acid amide type according to the present invention can be pressure-dispensed by spraying or can be parenterally administered for infiltration and nerve block anesthesia, for peridural and spinal anesthesia.
• Jellies of this type are advantageously used for providing profound anesthesia of accessible mucous membranes, particularly in the male and female urethra, and in the ear, nose, and throat.
• compositions according to the present invention are prepared in accordance with the examples given hereinabove and in a conventional manner.
• the step which consists in introducing carbon dioxide under pressure into a suspension of the lidocaine base at a temperature not substantially exceeding room temperature until the lidocaine base is dissolved.
• the step which consists in introducing carbon dioxide under pressure into a suspension of the mepivacaine base at a temperature not substantially exceeding room temperature until the mepivacaine base is dissolved.
• R indicates a member selected from the group consisting of halogen, when R; is lower alkyl and R is hydrogen; lower alkoxy when R and R are lower alkyl; hydrogen, and lower alkyl;
• R indicates a member selected from the group consisting of carbo-lower alkoxy, when R is lower alkyl; halogen, when R is lower alkyl; hydrogen, and lower alkyl;
• R; and R indicate members selected from the group consisting of hydrogen, lower alkyl, and, R and R together with the nitrogen atom and the -CH-group to which they are attached, forming a piperidine ring;
• R indicates lower alkyl
• step which which consists in introducing carbon dioxide under pressure into a suspension of said local anesthetic base of the basically substituted acid amide type at a temperature not substantially exceeding room temperature until the base is dissolved.
• R indicates a member selected from the group consisting of halogen, when R is lower alkyl and R is hydrogen; lower alkoxy when R and R are lower alkyl; hydrogen, and lower alkyl;
• R indicates a member selected from the group consisting of carbo-lower alkoxy, when R is lower alkyl; halogen, when R is lower alkyl; hydrogen, and lower alkyl;
• R; and R indicate members selected from the group consisting of hydrogen, lower alkyl, and, R and R together with the nitrogen atom and the -CH-group to which they are attached, forming a piperidine ring;
• R indicates lower alkyl
• a pharmaceutical preparation comprising a solution of lidocaine base in water saturated with carbon dioxide under pressure, said preparation being kept in pressure resistant containers.
• a pharmaceutical preparation comprising a solution of mepivacaine base in water saturated with carbon dioxide under pressure, said preparation being kept in pressure resistant containers.
• a pharmaceutical preparation comprising a solution of a local anesthetic base of the basically substituted acid amide type of the formula wherein R indicates lower alkyl;
• R indicates a member selected from the group consisting of halogen, when R is lower alkyl and R is hydrogen; lower alkoxy when R and R are lower alkyl; hydrogen, and lower alkyl;
• R indicates a member selected from the group consisting of carbo-lower alkoxy, when R is lower alkyl; halogen, when R is lower alkyl; hydrogen, and lower alkyl;
• R and R indicate members selected from the group consisting of hydrogen, lower alkyl, and, R and R together with the nitrogen atom and the CH-group to which they are attached, forming a pipcridine ring;
• R indicates lower alkyl, in water saturated with carbon dioxide under pressure, said preparation being kept in pressure resistant containers.
• the process of improving the local anesthetic effectiveness of lidocaine which process consists in applying a solution of lidocaine base in water saturated with carbon dioxide under pressure to the part of the body to be anesthetized.
• the process of improving the local anesthetic effectiveness of mepivacaine which process consists in applying a solution of mepivacaine base in water saturated with carbon dioxide under pressure to the part of the body to be anesthetized.
• R indicates a member selected from the group consisting of halogen, when R is lower alkyl and R is hydrogen; lower alkoxy when R and R are lower alkyl; hydrogen, and lower alkyl;
• R indicates a member selected from the group consisting of carbo-lower alkoxy, when R; is lower alkyl; halogen, when R1 is lower alkyl; hydrogen, and lower alkyl;
• R, and R indicate members selected from the group consisting of hydrogen, lower alkyl, and, R and R together with the nitrogen atom and the CH-group 14 to which they are attached, forming a piperidine ring; and R indicates lower alkyl, which process consists in applying a solution of said local anesthetic agent in water saturated with carbon dioxide under pressure to the part of the body to be anesthetized.

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• 1962
  • 1962-03-05 US US177172A patent/US3136691A/en not_active Expired - Lifetime
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