US3322624A - Low temperature resistant aerosol anesthetic preparation containing benzocaine - Google Patents

Description

3,322,624 ILQW TEMPERATURE RESISTANT AEROSOL ANESTHETHC KREPARATJIUN CONTAINING BENZOQAHNE Raymond A. Stone, Chicago, ill, assignor to Arnar-Stone Laboratories, Inc, Mount Prospect, 1111., a corporation of lliinois No Drawing. Filed Oct. l, 1964, Ser. No. 400,949

11 Claims. (Cl. 167-52) This application is a continuationin-part of my copending application Serial No. 380,945, filed July 7, 1964, now abandoned, entitled Aerosol Anesthetic Preparation.

This invention relates to an aerosol anesthetic preparation. More particularly, this invention is concerned with a liquid anesthetic preparation in an aerosol container for topical application which is characterized by resistance to low temperatures. The prepartion is designed for relief of surface pain and itching, and provides soothing temporary relief of minor burns, sunburn, cuts, scratches, nonpoisonous insect bites, poison ivy, and minor skin irritations. It may also be used for post-partum care. The preparation is nonstinging and nonchilling even when applied to open cuts and wounds.

In my prior application Serial No. 380,945 there is described an improved aerosol anesthetic preparation which is characterized by being nonstinging and nonchilling even when applied to open cuts and wounds. This prepa ration contains a high concentration of benzocaine dissolved in a polyethylene glycol ester, and contains a liquified ch-lorofiuoroalkane propellant which consists essentially of 70 to 100% by weight of dichlorodifluoromethane and from to 30% of trichlorofluoromethane. In the preferred embodiment, the propellant consists of 80 to 100% by weight of dichlorodifluoromethane and from 0 to of trichlorofluoromethane. From 1.5 to- 2.5 parts of the propellant are employed per part by weight of the polyethylene glycol ester. The solution of the benzocaine in the polyethylene glycol ester contains at least 10% by weight of benzocaine. The liquified propellant is miscible with the polyethylene glycol solvent solution, and the preparation preferably consists of a substantially single phase system, although the benzocaine is not appreciably soluble in the propellant. A high proportion of the propellant, particularly the high proportion of the dichlorodifluoromethane, makes it difficult to maintain the desired concentration of benzocaine in solution, especially at temperatures below ordinary room temperature, as may be encountered in the storage, shipping, or use of such preparations.

One of the solvents which has been in commercial use for some years in such preparations is a polyethylene glycol diester formed from mixed coconut oil fatty acids. When this solvent was tried 'in preparations formulated as described in pending application Serial No. 380,945, it was found that a single phase system could not be achieved at normal use temperatures while employing the desired high ratio of the aerosol propellant to the benzocaine solvent. When the propellant is present as a separate phase and is only partial-1y dissolved in the solvent-benzo caine phase, the preparation is rendered less stable, and benzocaine crystals tend to form and collect at the interface. Since the spray nozzles of aerosol containers have small orifices, even a small amount of benzocaine crystals can cause clogging of the nozzle. Under more extreme conditions, as when the temperature is lowered, a substantial portion of the benzocaine can crystallize and settle out in the container. With a system containing two liquid phases or where solid particles of benzocaine are present, it is difiicult to avoid settling of the contents of the aerosol container, and at the very least it is necesshanghai Patented May 30, 1196? sary to shake the container vigorously before applying the preparation. Otherwise, the preparation will be applied in a nonhomogeneous form.

A different but somewhat related problem arises when it is desired to store or use such preparations at temperatures below ordinary room temperature. If the temperature is reduced to a point where a multiple phase system results or where the preparation becomes partially solidified or frozen, the benzocaine is thrown out of solution, and it is dilficult or impossible to get all of the benzocaine back in solution merely by such expedients as warming the aerosol container to room temperature, shaking the container, etc. Such preparations cannot be used at temperatures during winter weather conditions in most of the United States.

It is therefore a principal object of the present invention to provide an improved formulation for an aerosol anesthetic preparation which substantially overcomes the problems and difficulties described above. More specifically, it is an object to provide a nonstinging and nonchilling liquid anesthetic preparation suitable for packaging in an aerosol container which can be formulated as a single phase system, and which is characterized by ease of reconstitution to its single phase state if the preparation is stored at low temperatures and even if the preparation becomes solidified or frozen. In certain embodiments the preparations of this invention are particularly adaptable for use at low temperatures, since the preparations remain as single phase liquid systems down to temperatures as low as 0 F. Further objects and advantages are indicated in the following detailed specification.

This invention is based on the discovery that nonstinging, nonchilling aerosol anesthetic preparations can be prepared While at the same time providing preparations which are single phase systems and which are temperature resistant, being easily reconstitutatable and/or adapted for use at low temperatures. Specifically, it was discovered that the alkyl chain length in the ester groups is critical for achieving these objectives, when the preparation utilizes the propellant mixture described in Serial No. 380,945 and a high concentration of benzocaine. Fatty acids derived from coconut oil are normally regarded as having relatively short alkyl groups, as compared with the fatty acids derived from other naturally occurring fats and oils. For example, a typical analysis of coconut oil shows that it contains from 60 to 65% of fatty acids (principally lauric acid) having chain lengths of C to C and from 35 to 40% of fatty acids (principally myristic acid) having chain lengths of from C to C Nevertheless, during the experimental Work leading to the present invention, it was found that polyethylene glycol diesters formed from mixed coconut oil fatty acids, such as the diester of nonaethylene glycol, failed to produce preparations which could be packed and distributed as essentially single phase systems.

The foregoing problem was not solved until it was discovered that the solvent should be formed of diesters wherein the alkyl groups are composed substantially entirely of C to C chain lengths. More specifically, the polyethylene glycol ester solvent for the benzocaine should contain at least by weight of compounds represented by the formula 0 0 II I! R '(J O(CHZCH20)D C RI wherein n is an integer from 7 to 15 and R and R are alkyls containing from 7 to 11 carbons. Preferably, the solvent is composed substantially entirely to of compounds falling within the above formula.

The polyethylene glycol portion of the solvent molecule can be conveniently provided by starting with compounds such as Polyethylene Glycol 400 (or Carbowax 400) which are composed predominantly of nonaethylene glycol. As indicated, the number of ethylene glycol groups in the compound may vary from 7 to 15. Optimally from 8 to 10 ethylene glycol groups are present. A mixed polyethylene glycol can be used where the predominate or average chain lengths correspond with the ranges set out. Such polyethylene glycol compounds can be esterified with C to C fatty acids or with mixtures thereof including specifically caprylic, pelargonic, capric, undecanoic, and lauric acids. Specific preferred compounds are polyethylene glycol dicaprylate, dipelargonate, dicaprate, and dilaurate. Other suitable compounds include the caprate caprylate, the laurate caprylate, the caprylate pelargonate, the laurate pelargonate, the laurate caprate, and the caprate pelargonate.

In practicing the present invention, it is desirable that the propellant consist of at least 70% (viz. from 70 to 100%) by weight of dichlorodifluoromethane. From to 30% of trichlorofluoromethane based on the total weight of the propellant can also be included. The utilization of a propellant containing at least 80% (viz. from 80 to 100%) by weight of dichlorodifluoromethane and from 0 to 20% of trichlorofluoromethane is preferred. For example, an optimum formulation comprises 80 to 95% dichlorodifiuoromethane in admixture with to 20% trichlorofluoromethane.

In practicing the present invention, it is desirable to employ at least one part by weight of the propellant (total) per part of the solvent. Preferably, at least 1.5 parts of the propellant are employed per part of solvent. For example, for each part of solvent, from 1.5 to 2.5 parts of propellant can be used.

The solvent solution (excluding the propellant) should contain at least by weight of benzocaine. It will be understood that this is based on the combined weight of the benzocaine and solvent. In certain preferred embodiments, at least by weight of benzocaine is present in the solvent solution. The benzocaine concentration can range up to about 22%. It will be understood of course that the benzocaine can only be employed up to its saturation solubility in the solvent solution, or in the mixture of the solvent solution with the propellant.

This invention is further illustrated by the following specific examples.

Example 1 A single phase, temperature resistant aerosol topical anesthetic is prepared according to the following formulation:

Formulation A: Wt. percent Nonaethylene glycol (Polyethylene Glycol In preparing the formulation, the benzocaine is dissoived in the nonaethylene glycol .dilaurate at room temperature (e.g. 70 F.). The solvent solution is then introduced into the aerosol containers in a manner well known in the art. After the spray nozzle components have been applied and the container closed, the propellant is introduced as a premixed liquid. The containers are then shaken to form a single liquid phase. The preparation is easily reconstitutable if a multiple phase system results from temperature reduction or after the preparation is solidified by freezing.

If desired, small quantities of auxiliary agents may be incorporated in the formula, such as oil-soluble antiseptics like benzethonium chloride, oxyquinoline, oxyquinolinebenzoate, hexachlorophene, etc.

4 Example 2 Another aerosol preparation is produced as described in Example 1, except that the following formulation is used:

Formulation B: Wt. percent Nonaethylene glycol (Polyethylene Glycol 400) caprate caprylate 28.9 Benzocaine 5.8 Dichlorodifiuoromethane 55.4 Trichlorofiuoromethane 9.9

The preparation of Formulation B is particularly useful under relatively cold conditions. The product remains as a single liquid phase in the container down to temperatures as low as 0 F.

Example 3 Additional preparations can be prepared by procedures similar to that used for the preparation of Examples 1 and 2, but utilizing one of the following formulations:

Formulation C: Wt. percent Nonaethylene glycol (Polyethylene Glycol While in the foregoing specification this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to other embodiments and that many of the details described herein can be varied considerably without departing from the basic principles of the invention.

I claim:

1. A liquid anesthetic preparation in an aerosol container, said reparation consisting essentially of a single phase mixture of a liquefied chlorofiuoroalkane propellant and a solution of benzocaine in a polyethylene glycol diester solvent, said propellant being selected from the group consisting of dichlorodifiuoromethane, and mixtures of dichlorodifluoromethane with trichlorofiuoromethane, at least 1.5 parts by weight of said propellant being employed per part of said solvent, said propellant containing at least 70% by weight of dichlorodilluoromethane, said solution of said benzocaine in said solvent containing at least 10% benzocaine by Weight, said solvent consisting essentially of polyethylene glycol diesters at least by weight of which diesters are represented by the formula wherein n is an integer from 7 to 15 and R and R are alkyls containing from 7 to 11 carbons.

2. The anesthetic preparation of claim 1 in which the diesters represented by said formula are nonaethylene glycol diesters having ester groups selected from the group consisting of dilaurate, caprate caprylate, dicaprate, dipelargonate, and mixtures of said diesters.

3. The anesthetic preparation of claim 1 in which the diesters represented by said formula comprise from to 100% by weight of the total polyethylene glycol diesters of said solvent.

4. The anesthetic preparation of claim 3 in which the diesters represented by said formula are nonaethylene glycol diesters having ester groups selected from the group consisting of dilaurate, caprate caprylate, dicaprate, dipelargonate, and mixtures of said diesters.

5. The anesthetic preparation of claim 2 in which said ester groups are dilaurate.

6. The anesthetic preparation of claim 2 in which said ester groups are caprate caprylate.

7. A liquid anesthetic preparation in an aerosol container, said preparation consisting essentially of a single phase mixture of a liquefied chlorofluoroalkane propellant and a solution of benzocaine in a polyethylene glycol diester solvent, said propellant being a mixture of dichlorodifluoromethane with trichlorofluoromethane and containing at least 70% by weight of said dichlorodifluoromethane, from 1.5 to 2.5 parts by weight of said propellant being employed per part of said solvent, said solution of said benzocaine in said solvent containing at least by weight of benzocaine, said solvent consisting essentially of polyethylene glycol diesters at least 90% by Weight of which diesters are represented by the formula:

0 R-i Jo(oHzoHz0).. :-R1 wherein n is an integer from 7 to and R and R are alkyls containing from 7 to 11 carbons.

References Cited UNITED STATES PATENTS 2,457,188 12/1948 Stone 167-52 2,713,019 7/1955 Jefiries 16763 2,801,201 7/1957 Kipnis 167-82 OTHER REFERENCES Carbowax Polyethylene Glycols for Pharmaceuticals and Cosmetics Booklet, Union Carbide Chemicals Company, New York, N.Y., 1962 page 5.

ALBERT T. MEYERS, Primary Examiner. JULIAN S. LEVITT, Examiner. JEROME D. GOLDBERG, Assistant Examiner.

Claims (1)

1. A LIQUID ANESTHETIC PREPARATION IN AN AEROSOL CONTAINTER, SAID PREPARATION CONSISTING ESSENTIALLY OF A SINGLE PHASE MIXTURE OF A LIQUEFIED CHLOROFLUOROALKANE PROPELLANT AND A SOLUTION OF BENZOCAINE IN A POLYETHLENE GLYCOL DIESTER SOLVENT, SAID PROPELLANT BENG SELECTED FROM THE GROUP CONSISTING OF DICHLORODIFLUOROMETHANE, AND MIXTURES OF DICHLORODIFLUOROMETHANE, WITH TRICHLOROFLUOROMETHANE, AT LEAST 1.5 PARTS BY WEIGHT OF SAID PROPELLANT BEING EMPLOYED PER PART OS SAID SOLVENT, SAID PROPELLANT CONTAINING AT LEAST 70% BY WEIGHT OF DICHLORODIFLUOROMETHANE, SAID SOLUTION OF SAID BENZOCAINE IN SAID SOLVENT CONTANING AT LEAST 10% BENZOCAINE BY WEIGHT, SAID SOLVENT CONSISTING ESSENTIALLY OF POLYETHYLENE GLYCOL DIESTERS AT LEAST 90% BY WEIGHT OF WHICH DIESTERS ARE REPRESENTED BY THE FORMULA R-COO-(CH2-CH2)N-CO-R1 WHEREIN N IS AN INTEGER FROM 7 TO 15 AND R AND R1 ARE ALKYLS CONTAINING FROM 7 TO 11 CARBONS.