|Numéro de publication||US3216897 A|
|Type de publication||Octroi|
|Date de publication||9 nov. 1965|
|Date de dépôt||2 nov. 1961|
|Date de priorité||2 nov. 1961|
|Numéro de publication||US 3216897 A, US 3216897A, US-A-3216897, US3216897 A, US3216897A|
|Inventeurs||Krantz Jr John C|
|Cessionnaire d'origine||Air Reduction|
|Exporter la citation||BiBTeX, EndNote, RefMan|
|Citations de brevets (10), Référencé par (36), Classifications (7)|
|Liens externes: USPTO, Cession USPTO, Espacenet|
United States Patent 3,216,897 INJECTABLE ANESTHETIC John C. Krantz, Jr., Ruxton, Md., assignor to Air Reduction Company, Incorporated, New York, N.Y., a corporation of New York No Drawing. Filed Nov. 2, 1961, Ser. No. 149,504 13 Claims. (Cl. 16752) This application is a continuation-in-part of application Serial No. 71,144, filed November 23, 1960, now abandoned.
This invention relates to injectable pharmacological compositions and is more particularly concerned with compositions of the character indicated which contain a normally-volatile pharmacological agent, more specifically a volatile anesthetic agent.
Anesthetics are chemical agents which depress vital functions of all types of cells but particularly those of nervous tissue. General anesthetics depress the central nervous system to an extent that the patient loses all sensitivity to pain and undergoes a hiatus of consciousness. General anesthetics are commonly subdivided into volatile compounds which are conventionally administered by the respiratory route, and so-called fixed anesthetics, which are non-volatile compounds and are commonly administered by intrvenous injection.
The introduction of anesthetic agents intravenously has important advantages both for the patient and for the surgeon. Thus, rapidity of induction is an important feature of intravenous anesthesia. Generally, the patient is asleep within thirty seconds and the patient is relieved of the psychic shock often associated with the more potracted induction encountered in inhalation anesthesia. When anesthesia is induced by the intravenous route, the patient appears to fall into a natural sleep and quickly passes into the stage of surgical anesthesia. This method does not cause respiratory distress and the patient experiences little excitement, and there is thus very little tendency to struggle. The post-operative period is particularly free from undesirable effects. Thus, there is essentially no irritation of the respiratory system and this is of great importance when there is a disease of the respiratory tract. The surgeon is additionally benefitted by the fact that intravenous anesthesia permits the anesthesiologist to remove himself from the field of operation and the surgeon is allowed more freedom, and the danger of contamination of the operative field is lessened.
Notwithstanding the problems encountered in known methods for the administration of so-called volatile anesthetic agents, however, and notwithstanding the recognized advantages of intravenous administration, volatile anesthetics have nevertheless continued to be administered by inhalation procedures because it has not heretofore been possible to administer them satisfactorily by the intravenous route. Thus, intravenous injection of anesthetics is conventionally limited to the so-called fixed anesthetics, e.g. the barbiturates such as sodium arnytal (sodium amobarbital), nembutal (pentobarbital sodium) and its thioanalog, sodium S-ethyl-S-isoamyl-2-thiobarbiturate (pentothal sodium), surital sodium (sodium 5- allyl-S-(l-methyl butyl)-2-thio=barbiturate), and the like. Fixed anesthetics, however, require catabolism in the body to terminate their anesthetic action. On the other hand, the volatile anesthetics do not have to be catabolized and the anesthesia which they induce is terminated by excretion of the volatile anesthetic by the lungs in the exhaled air of the patent. Thus, anesthesia by means of the volatile agents is capable of more effective control with respect to depth and termination of anesthesia and hence such agents have continued to be used extensively, notwithstanding the prolbems encountered in 3,216,897 Patented Nov. 9, 1955 their administration by conventional procedures. Intravenous anesthesia is an ideal procedure for the administration of an anesthetic agent and, as indicated above, the volatile anesthetics are ideal agents because they are readily removed from the body by the normal breathing of the patient. In addition, the barbiturates and thiobarbiturates do not provide the necessary degree of re laxation afforded by the volatile anesthetics.
The a dministration of volatile anesthetics or other pharmacological agents intravenously, however, presents the problem of introducing sufficient amounts of the agent as well as the problem of the deleterious effects on the elements of the blood, and other adverse side effects resulting from such injections. Particular problems encountered are hemolysis of the red cells, pulmonary edema, and thrombosis of the veins at the injection site.
There is, therefore, an important need for means whereby volatile anesthetics can be effectively and satisfactorily administered by conventional intravenous anesthesia techniques.
There is also a need for like means of introducing other normally volatile pharmacological agents.
It is, accordingly, an object of the invention to provide an effective method for the introduction of volatile pharmacological agents intravenously.
It is another object of the invention to provide a method of the character indicated which is particularly suitable for the administration of volatile anesthetic agents intravenously.
It is a further object of the present invention to provide compositions containing volatile anesthetic agents and the like, which can be effectively and successfully administered intravenously.
It is another object of the invention to provide compositions of the character indicated which contain suflicient amounts of the active anesthetic agent that relatively small amounts of the total composition are required to obtain desired anesthesia.
It is a still further object of the invention to provide a method of producing anesthesia with volatile anesthetic agents which avoids the disadvantages and drawbacks of the inhalation procedures conventionally employed at the present time.
In accordance with the invention, there is provided an intravenously-injectable composition which is an aqueous emulsion containing a volatile pharmacological agent, e.g. a volatile anesthetic, as the dispersed phase. More particularly, the dispersed or discontinuous phase of the emulsion also comprises an oil in which the volatile agent is dissolved. These compositions can be easily and effectively administered by conventional intravenous injection techniques and it has been found that, in the case of such compositions containing a volatile anesthetic, desirable anesthesia can be readily produced and terminated at will with minimal effort on the part of the anesthesiologist, and without requiring any of the complicated apparatus normally utilized in the conventional administration of volatile anesthetic agents. In addition, the compositions are fully tolerated by the body and the adverse effects encountered in prev-ions attempts to administer volatile anesthetic agents intravenously are avoided.
It is a feature of the invention that the recognized advantages of intravenous injection can be realized in the administration of volatile anesthetic agents.
ing the concomitant administration of undesirably large quantities of fluid.
Other objects and features of the invention will be readily apparent from the following detailed description of illustrative embodiments thereof.
The injectable emulsions of this invention comprise water as the continuous phase, which suitably contains glucose, or other suitable agent to render it isotonic, and a discontinuous or dispersed phase composed of an oil and the volatile pharmacological agent, e.g. a volatile anesthetic agent. While satisfactory emulsions can be produced which contain only the above-mentioned components, when prolonged storage stability is desired, the emulsions advantageously also contain a primary emulsifier, and, preferably, a secondary emulsifier or emulsion stabilizer or adjuvant, these components suitably being added before emulsification is effected. More specifically, the oil is present in the amount of 1 to 25 percent volume/volume, preferably 2 to 15 percent volume/ volume, the active pharmacological agent is present in the amount of 2 to 30 percent volume/volume, the isotonic agent is present in the amount of 4 to 5 percent weight/volume, and, when used, the primary emulsifying agent is present in the amount of 0.5 to percent weight/volume, and the secondary emulsifying agent or stabilizer is present in the amount of 0.01 to '1 percent weight/volume, the remainder being water for injection. In general, increased amounts of oil are used with increased amounts of active agent, the two being employed roughly in direct proportions, and the quantity of emulsifying agent, when used, is adjusted accordingly. The amount of the active agent, e.g. the anesthetic, is related to the specific activity or potency of the agent. More potent agents are present in lesser amounts than less potent agents. The potency of volatile pharmacological agents, e.g. anesthetic agents, has been established and can be readily determined in routine manner by an anesthesiologist. The injectable composition is, of course, necessarily compatible with all of the elements of the blood and is, accordingly, of a tonicity substantially similar therewith, the isotonic agent being employed in suitable amounts for this purpose, and advantageously in amounts to render the composition substantially isotonic.
While the invention is generally applicable to all volatile anesthetic agents and other pharmacological agents which are liquid at ordinary room temperature, e.g. 25 C., at atmospheric pressure, which are conveniently referred to as normally-volatile agents, particularly good results have been realized with such volatile agents, e.g. anesthetic agents, having boiling points at atmospheric pressure of 40 to 140 C., preferably about 90 to 120 C. Typical volatile anesthetics which may be formed into intravenously-injectable compositions in accordance with this invention include 2,2-dichloro-1,l-difiuoroethyl methyl ether (CI-ICl CF COCH 2-bromo-2-chloro-1, 1,1-trifluoroethane (CF CHClBr) 2-bromo 1,2-dichloro- 1,1-difluoro-ethane (CF CIOHBrCI), 2-chloro-l;l,2-trifluoroethyl methyl ether (CHFClCF OCH l,1,=2-trifluoro-Z-bromoethyl methyl ether (CHFBrCF OCH 2, 2,2-trifiuorothyl vinyl ether (CF CH OCH=CH and the like. The anesthetic agents contemplated for use in the compositions of this invention, such as those specifically referred to above, and like halogenated ethers and hydrocarbons, are known compounds produced by known methods. For example, the preparation of 2,2- dichloroal,l-difiuoroethyl methyl ether and related compounds is described in British Patent 523,449 and at pages 43 1-2 of vol. 70 of the Journal of the American Chemical Society (1948), the latter also showing the synthesis of 2-chloro-l,1,2-trifiuoroethyl methyl ether. The preparation of 2-bromo-2-chloro-1,1;1-trifluoroethane and related compounds is described in Suckling et al. US. Patent 2,849,502, and Chapman et al. U.S. Patent 2,921,099 also discloses a method for preparing this compound, along With the preparation of 2-bromo-'1,2-dichloiro-.1, l-difiuoroethane. Methods suitable for the production of l,1,2-trifluoro-2-bromoethyl methyl ether and related compounds are shown in Hanford et al. US. Patent 2,409,274 and Miller et al. US. Patent 2,803,665, and Shukys U.S. Patent 2,830,007 describes a method of producing 2,2,2-trifluoroethyl vinyl ether. Other volatile anesthetic agents are similarly produced by known methods and it is to be understood that, while halogenated ethers and halogenated hydrocarbons which are anesthetics, such as those specifically named above, are particularly suitable for administration in the form of emulsions in accordance with this invention, the invention is fully applicable to other volatile anesthetic agents, as well as to other volatile pharmacological agents. A typical volatile non-anesthetic agent which. may be employed, for example, is the convulsant 2,2,2,2,2,2-hexafiuorodiethyl ether, of the formula described in copendiug application Serial No. 39,206, filed June 28, 'l960.
The oil which is employed in making the compositions of this invention and which functions, at least in part, to dissolve the pharmacological agent, e.g. the anesthetic, and protect the red cells from hemolysis, is suitably any normally-liquid metabolizable, non-toxic, fixed oil, as exemplified by the edible oils such as olive oil, cottonseed oil, corn oil, peanut oil, sesame oil, and the like. While the above-mentioned oils are preferred, it will be understood that other metabolizable, non-toxic fixed oils, whether animal, vegetable, or synthetic, are suitably employed. A typical synthetic oil of this nature is described, for example, in US. Patent 2,728,706.
When emulsifying agents are used, the primary emulsifier is most advantageously a monoor di-glyceride of a fatty acid, or a phosphatide, e.g. lecithin. In the case of a phosphatide, any of the numerous purified commercial phosphatide products suitable for intravenous administration, such as Glidden Lecithin Grade RG, purified, are suitably employed. Thus, the phosphatides for use as primary emulsifiers may be derived from the various known sources of these materials, such as egg yolk, and animal and vegetable tissues, and they may also be produced synthetically. Typical phosphatides are described, for example, in Thurman US. Patent 2,245,537 and Kruse U.S. Patent 2,269,772. The alcohol-soluble portions of the various commercially-available soya phosphatides are also advantageously used, these alcohol-soluble portions or fractions suitably being passed through an adsorbent, e.g. activated carbon, to further purify them. As the monoor di-glycerides, e.g. of long-chain fatty acids, any of the commercial products, such as those sold by the Atlas Powder Co. under the trade name Atmul, may be employed. Particularly suitable is Atmul-SOO. Such products are produced by the known glycerolysis of edible fats or oils, and normally contain as preservatives not more than 0.01% of citric acid and not more than 0.1% of alphatocopherol. Processes of producing monoand diglycerides are described, for example, in Barsky US. Patent 2,509,413, Kester US. Patent 2,523,309, and Kuhrt US. Patent 2,634,279. Typical acids include oleic and stearic acids.
It will be understood, however, that the invention is not necessarily limited to the use of monoor di-glycerides, or phosphatides, e.g. soy bean phosphatides, as emulsifying agents when such agents are employed and, in general, other emulsifying agents which can be tolerated by a living body with impunity upon intravenous injection may be employed. Such toleration can be readily determined by routine test.
When a secondary emulsifying agent or stabilizer is used, preference is given to surface-active agents which are ethylene oxide-polypropylene glycol condensation products such as disclosed in US. Patent 2,674,619, but other surface-active agents which are emulsion stabilizers and which are tolerated by the body with impunity upon intravenous injection can be used, whether ionic or nonionic. A typical example of another class of stabilizers are the fatty acid sulfates which have high lipophilichydrophilic coefiicients, such as sodium lauryl sulfate.
The emulsions of this invention, which are oil-in-water emulsions, are suitably produced in conventional emulsifying apparatus of the type well-known in the pharmaceutical industry, but it is advantageous to have the particle size of the dispersed phase as small as possible, e.g., 0.1 to 5 microns in diameter. For this reason, it is preferred that emulsification be effected in a homogenizer, e.g. a Manton Gaulin homogenizer. To prepare the emulsion, the several components are thoroughly mixed with the water, which may be at room temperature or heated if desired, and the mixture is then passed through the emulsifying apparatus, e.g. the homogenizer. Two or more passes through the machine are generally desirable to insure effective emulsification and minimal particle size. Upon cooling, the composition is ready for immediate use. In practice, however, it is immediately poured into containers, e.g. glass bottles, which are stoppered, sterilized in an autoclave, and then stored until used. Refrigera tion is not necessary. In an alternative procedure, all of the components of the emulsion are sterilized before emulsification and then emulsification is effected under sterile conditions. The emulsion product can then be directly stored in sterilized bottles.
Theemulsified compositions of this invention are suitably administered by the usual techniques for intravenous infusion, viz. a graduated reservoir and a flexible delivery tube provided with a conventional drop meter, with a compression clamp placed over the tubing below the drop meter, the outlet end of the' tube being connected, of course, to the infusion needle. The compositions have sufficient fluidity that pressure apparatus is not ordinarily required and the usual gravity method may be employed. Advantageously, the graduated container is supported about 6 to 8 feet above the floor in accordance with conventional infusion practice. While the amount and rate of administration of the anesthetic composition is, of course, determined by the anesthesiologist in accordance with local conditions, the nature of the surgery to be performed, the condition of the patient, and the like, it has been determined that under average conditions a rate of 3 to 6 ml. per kilogram of body weight per hour is suitable, with a. maximum advisable rate being about 10 ml. per kilogram per hour. The total amount administered will depend upon the duration of the desired anesthesia. Advantageously, the composition is caused to flow into the patient intermittently, rather than continuously, since anesthesia can be more accurately controlled in this manner.
Anesthesia produced with these emulsions is compatible with preanesthetic medication such as morphine, atropine, pentobarbital sodium and secobarbital sodium. For more rapid induction, the thiobarbiturates, such as thiopental sodium, may be used preliminary to the injection of the emulsion.
In the case of volatile pharmacological agents which are not anesthetics, repeated injection is generally not necessary, or even desirable, and in that case a single injection is advantageously employed. For example, in the case of 2,2,2,2,',2',2'-hexafluorodiethyl ether, sufficient of the composition is injected to provide 0.5 to 1.0 gram of the active agent. The amounts of other agents to be injected are readily determined by the physician in accordance with the specific conditions of treatment involved.
The following specific compositions will serve to illustrate the invention but it will be understood that they are exemplary only and not limitative. All of these compositions are in the form of stable oil-in-water emulsions.
6 Example 1 V This example shows the use of a volatile anesthetic agent of high anesthetic potency.
2-bromo-2-ch1oro-1,1,1-trifluoroethane ml 3.5 Cotton seed oil ml 3.0 Lecithin g 4.0 Glucose g 4.2
Water sufiicient to make ml.
Example 2 This example shows the use of a volatile anesthetic agent of lesser anesthetic potency.
2,2-dichloro-1,l-difluoroethyl methyl ether ml 25.0
Corn oil ml 10.0 Lecithin a 2.0 Glucose g 4.2
Water sufficient to make 100.0 ml.
Example 3 This example shows the use of an emulsion stabilizer in combination with the primary emulsifier.
2-bromo-2-chloro-1,1,l-trifluoroethane ml 5.0 Cotton seed oil ml 3.0 Lecithin g 15.0 Ethylene oxide-polypropylene glycol condensate (sold commercially as Pluronic F-68) g 0.25 Glucose g 4.2 Water sufficient to make 100.0 ml.
A corresponding amount of the stabilizer used in Example 3 may also be added to the composition of Example 1 to provide a combination of primary emulsifier and stabilizer.
Example 4 This example shows a composition using the active agent of Example 2, together with a stabilizer.
2,2-dichloro-1,l-difluoroethyl methyl ether ml 3.5 Cotton seed oil ml 3.0 Lecithin (soy bean) g Q 4.0 Ethylene oxide-polypropylene glycol condensate (Pluronic F-68) g 0.25 Dextrose g 4.2
Water sufficient to make 100.0 ml.
Example 5 This example shows the use of another volatile anesthetic agent of high anesthetic potency.
1,1,2 trifluoro-2-bromoethyl methyl ether rn1 3.5 Cornoil ml 3.0 Pluronic F-68 g 0.5 Lecithin g 2.0 Glucose g 4.2
Water sufficient to make 100.0 ml.
The following examples show additional compositions representative of the invention and illustrate the use of Water sufiicient to make 100.0 ml.
Water sufiicient to make 100.0 m1.
Example 11 This example shows an emulsion prepared without the use of an emulsifying agent or emulsion stabilizer.
2,2-dichloro-l,l-difluoroethyl methyl ether ml 35 Cotton seed oil ml 3.5 Dextrose g 4.0
Water sufiicient to make 100.0 ml.
This composition was produced by mixing the anesthetic and the cottonseed oil and adding the mixture to a solution of the dextrose in distilled Water and then adding additional distilled water to produce a total volume of 100.0 ml. This liquid was then passed seven times through a homogenizer and the emulsified product which was produced was a milky uniform emulsion having an average particle size of 4-6 microns. Similar emulsions are readily made with other volatile emulsifying agents.
Example 12 This example shows an emulsion prepared with an emulsion stabilizer.
2,2-dichloro-l,l-difluoroethyl methyl ether ml 3.5 Corn oil ml 3.0 Ethylene oxide-propylene glycol condensate (Pluronic F68) g 0.25 Dextrose g 4.2
Water sufiicient to make 100.0 ml.
Example 13 This example shows an emulsion prepared with a combination of emulsion stabilizers.
2,2-dichloro-1,1=difluoroethy1 methyl ether -ml 3.5 Corn oil ml 3.0 Ethylene oxide-propylene glycol condensate (Pluronic F-68) g 0.25 Dextrose g 4.2 Sodium lauryl sulfate, U.S.P. g 0.01-0.05
Water sufficient to make 100.0 ml.
In the case of the compositions of Examples 11 and 12, it is preferable to employ sterilized components and to emulsify under sterile conditions, for best results. The compositions of the other examples may be prepared in this manner or they may be sterilized after formation.
It has been found that other agents may effectively be incorporated in the emulsion compositions of this invention, with or without an emulsifying agent or emulsion stabilizer. For example, it has been found that small amounts of cholesterol tend to have a beneficial effect upon the anesthetic syndrome. The following example shows the use of cholesterol in a typical composition.
Example 14 2,2-dichloro-1,I-difiuoroethyl methyl ether ml 30.0
Corn oil ml 15.0 Lecithin g 2.0 Glucose g 4.2 Cholesterol g 1.0
Water sufiicient to make 100.0 ml.
Effective anesthetics are similarly produced by substituting other volatile anesthetic agents for the agents specifically employed in the foregoing examples, and by substituting other edible oils, other primary emulsifiers, other stabilizers, and other isotonic agents. In Examples 12 and 13, for instance, other anesthetic agents can be substituted for the agent specified and other oils, particularly cottonseed oil, and other stabilizers, may be used. Upon intravenous injection of the anesthetic compositions of this invention, as exemplified in Examples 1 to 14, anesthesia is rapidly and smoothly produced in the subject without discomfiture to him, and the desired plane of anesthesia is readily maintained by controlling the rate of flow of the composition being injected. In typical cases, a rate of flow of 5 to 6 ml./kg./ hr. is effective to produce anesthesia suitable for operative procedures on the head, neck, thorax, extremities and perineum. When only a relatively light plane of anesthesia is desired, the composition may be administered more slowly, for example, at a rate of the order of 3-5 ml./kg./hr. For the deeper relaxation required for intra-abdominal operations, deeper planes of anesthesia are required and this necessitates a somewhat increased rate of flow of about 7 ml./kg./hr. The anesthetic is exhaled by the subjects lungs and, when injection is terminated, recovery is extremely rapid. Depending upon the depth of anesthesia, just before termination of injection, the subject recovers his protective reflexes within 10 to 15 minutes after termination. Full recovery is rapid and smooth and free of excitement, nausea and emesis. Hemolysis of the red cells, pulmonary edema, and thrombosis of the veins are minimal or absent entirely.
The present invention thus provides a method of administering volatile anesthetics which is more precise than the inhalation procedure and it will be apparent that the explosion hazard is eliminated even in the case of explosive anesthetics. In addition, it is a feature of the invention that mixtures of anesthetics may be employed. For example, a minor percentage (e.g. 5-25%) of a rapidly-acting agent can be combined with a major percentage (cg. 75-95%) of a long-acting, slow-inducing agent to constitute the active component of an emulsion suitable for intravenous injection in accordance with this invention. To produce typical compositions of this type, such mixtures of agents can be substituted for the anesthetic component of any of the compositions set forth in Examples 1-12.
Emulsion compositions produced in accordance with this invention have been used successfully in producing anesthesia in both animals and human beings. The following are representative cases of such successful use. Except as otherwise indicated, the anesthetic composition was an emulsion containing 2,2 dichloro 1,1 difiuoroethyl .methyl ether (methoxyflurane) as represented by the composition of Example 4.
In the case of a 33-year-old 60-ki-logram female human who was a candidate for vaginal hysterectomy and anterior and posterior repair, anesthesia was induced with intravenous methoxyflurane emulsion followed by the administration of oxygen by the low-flow circle-absorption technique. Induction of anesthesia was associated with a fall in blood pressure which returned to normal or nearnormal levels shortly thereafter. Respirations were slightly depressed also shortly after the initial injection of the methoxyflurane, but returned to normal levels promptly. An endotracheal catheter was placed in situ approximately minutes after induction under the influence of the relaxation produced by the intravenous emulsion. Approximately minutes after induction, the patient had received 120 cubic centimeters of the emulsion, or roughly 6 cubic centimeters per kilogram per hour. The patient recovered her reflexes fairly promptly after termination of anesthesia. There were no complications related to the use of the intravenous emulsion. Postoperative serum bilirubin and serum transaminase determinations were within normal limits.
In the case of a 9-year-old 40 kilogram husky male child who was a candidate for right inguinal hernia repair and orchiopexy, preliminary medication consisted of 50 milligrams of demerol and 0.4 milligram of scopolamine given intramuscularly approximately one hour prior to induction of anesthesia. Anesthesia was induced with 150 milligrams of surital given intravenously followed by 20 cubic centimeters of the emulsion given in fractional doses over a period of about 6 minutes. Following completion of these injections, a continuous drip of emulsion was administered at a moderately rapid rate so that over a period of two hours and fifteen minutes the patient received a total of 250 cubic centimeters of the emulsion, or approximately 3 cubic centimeters per kilogram per hour. The level of anesthesia became quite light in several instances, necessitating the need for the rapid intravenous infusion on these occasions. Except for this minor complication, the maintenance of anesthesia was quite satisfactory. Because of the avoidance of large intravenous doses initially, there was no fall in blood pressure nor any depression of respirations. The conduct of anesthesia was adjudged satisfactory. There were no postoperative complications relative to the operative procedure or to'the anesthesia.
In the case of a 33-year-old 52-kilograrn female human who was a candidate for cold knife conization and dilitation and curettage of the cervic, preliminary medication consisted of 75 milligrams of demerol, milligrams of phenergan and 0.4 milligram of atropine, given intramuscularly 60 minutes prior to induction of anesthesia. Following the initial use of 25 0 milligrams of intravenous surital, 70 cubic centimeters of the emulsion were administered over a period of 45 minutes, a rate of administration of 1.76 cubic centimeters per kilogram per hour. The level of anesthesia was light. Relaxation was adequate, however, and there were no postoperative complications. Postoperative serum bilirubin and serum transaminase determinations were within normal limits.
In the case of a 15-year-old 45-kilogram female human who was a candidate for an abdominal Pomeroy operation, preliminary medication consisted of demerol 50 milligrams and scopolamine 0.4 milligram given intramuscularly 45 minutes prior to induction of anesthesia. Methoxyflurane anesthesia was induced and maintained by intermittent intravenous injections of the emulsion, a total of 103 cubic centimeters being administered over a 40 minute period, a dosage of 3.4 cubic centimeters per kilogram per hour. There were no operative complications, and anesthesia was adjudged to be adequate. No supplemental muscle relaxants were employed. There was a fall in systolic and diastolic pressure shortly after induction, but the blood pressure soon returned to near preoperative levels with no further depression.
Using the composition described in Example 11, a male dog, weighing 7.6 kilograms, put to sleep with 5.5 ml. of sodium pentothal solution, was maintained at a light level of anesthesia by the slow injection of the emulsion through the jugular vein. The heart rate was followed and was noticed to change from 116 to 144. The respiration rate changed from 20 to 48. The degree of anesthesia was followed by the eye lid reflexes. After minutes of smooth anesthesia, injection of the emulsion (total of 22 ml. used) was discontinued. In 5 minutes the dog was lifting its own head and in ten minutes the dog was walking around in good health.
A second dog, a female weighing 8.6 kg. responded in the same way and used a total of 33 ml. of emulsion for the 30-minute period of anesthesia.
While, as mentioned above, the present invention makes possible the administration of volatile pharmacologicallyactive agents, such as anesthetics, by intravenous injection, it is one of the advantages of the invention that the intravenously-injectable compositions can be readily used in conjunction with the conventional closed-cycle breathing apparatus that is commonly employed in the administration of volatile anesthetics, if the anesthesiologist should feel that such a system is advantageous under particular operating conditions. In such case, the intravenous injection is generally stopped and the patient merely rebreathes the volatile anesthetic which he has exhaled, along with oxygen. A typical closed-cycle system is shown, for example, in Hay US. Patent 2,864,363. Generally, additional anesthetic is not introduced into the closed cycle system and, when desired, intravenous injection can be resumed at will. There is, therefore, complete flexibility in the techniques available to the anesthesiologist when he employs the compositions and the methods of this invention.
It will further be understood that, while the compositions of the present invention provide a particularly effective solution to the problem of administering volatile anesthetic agents intravenously, as explained above, they may also, as mentioned, be employed for administering other pharmacological agents, such as convulsants, sedatives, tranquilizers, and the like, particularly such agents which are normally volatile. The following examples of injectable emulsions in which the active agent is the convulsant 2,2,2,2,2,2'-hexafiuorodiethyl ether are representative of this aspect of the invention.
Example 15 2,2,2,2,2',2-hexafluorodiethyl ether ml 5.0 Corn oil ml 3.0 Lecithin (soy bean) g 4.0 Ethylene oxide-polypropylene glycol condensate (Pluronic F-68) g 0.25 Dextrose g 4.2 Water sufficient to make 100.0 ml.
Example 16 2,2,2,2',2',2,-hexafluorodiethyl ether ml 3.5 Cottonseed oil ml 3.0 Atmul-SOO g 0.5 Glucose g 4.2
Water suflicient to make 100.0 ml.
In like manner, injectable emulsions embodying features of the present invention can be prepared with other normally volatile pharmacological agents which are effective to evoke desirable therapeutic elfects but which are not miscible with blood for intravenous administration.
Since the compositions of this invention are used for intravenous injection it will, of course, be understood that each component must be in a relatively pure, pharmaceutically acceptable form free from toxic contaminants. Thus, the water employed is sterile, and the various other liquid and solid components are suitably purified by conventional techniques to free them from any toxic materials. The active agents, e.g. the anesthetic agents, if not readily available in pharmaceutically-acceptable form, are advantageously purified by washing with water and washing with an aqueous solution of a mineral acid, e.g. hydrochloric acid, followed by a further Wash with water and with an aqueous solution of caustic alkali. The washed material is dried and is then fractionally distilled. If the active agent tends to polymerize when exposed to heat, it is advantageously admixed with a small amount, e.g. 0.01% by weight, of an alkaline agent as a stabilizer, such as phenyl-alpha-naphthylamine. Typical stabilizers and purification procedures suitably used when required are described, for example, in Shukys US. patent 2,830,007.
It will be understood, therefore, that various changes and modifications may be made in the embodiments described without departing from the invention as defined in the appended claims, and it is intended, therefore, that all matter contained in the foregoing description shall be interpreted as illustrative only and not as limitative of the invention.
1. An intravenously-injectable anesthetic composition comprising an oil-in-water emulsion containing a metabolizable, nontoxic, fixed oil as the oil phase and 21 normally-volatile anesthetic dissolved in said oil phase.
2. An intravenously-injectable anestheic composition comprising an oil-in-water emusion containing a normally-volatile anestheic having a boiling point at atmospheric pressure of at least 40 C., a metabolizable, nontoxic, fixed oil, and an emulsifying agent.
3. An intravenously-injectable anesthetic composition comprising an oil-in-water emulsion containing a normally-volatile anesthetic having a boiling point at atmospheric pressure of at least 40 C., a metabolizable, nontoxic, fixed oil and an emulsifying agent, said emulsifying agent being a member of the group consisting of phosphatides, ethylene oxide-polypropylene glycol condensation products and monoand di-glycerides of fatty acids.
4. An intravenously-injectable anestheic composition comprising an oil-in-water emulsion containing 2 to 25 volume/volume of a normally-volatile anesthetic having a boiling point at atmospheric pressure of about 40 to 140 C. and 1 to 25 volume/ volume of a metabolizable, nontoxic, fixed oil.
5. An intravenously-injectable anesthetic composition comprising an oil-in-water emulsion containing 2 to 25% volume/volume of a normally-volatile anesthetic having a boiling point at atmospheric pressure of about 90 to 120 C., 1 to 25% volume/volume of a metabolizable, non-toxic, fixed oil and 1 to weight/volume of an emulsifying agent.
6. An intravenously-injectable anesthetic composition comprising an oil-in-water emulsion containing 2 to volume/volume of a normally-volatile anesthetic having a boiling point at atmospheric pressure at least 40 C., l to 25% volume/volume of a metabolizable, non-toxic, fixed oil and 1 to 15% weight/ volume of an emulsifying agent, said emulsifying agent being a member selected from the group consisting of phosphatides, ethylene oxidepolypropylene glycol condensation products and monoand di-glycerides of fatty acids.
7. An intravenously-injectable anesthetic composition comprising an oil-in-water emulsion containing 2 to 25 volume/volume of a normally-volatile anesthetic, 1 to 25% volume/volume of a metabolizable, non-toxic, fixed oil and 1 to 15% weight/volume of an emulsifying agent, said emulsifying agent being a soy bean phosphatide, said oil and said anesthetic being in the dispersed phase and said anesthetic being dissolved in said oil.
8. An intravenously injectable composition comprising an oil-in-water emulsion containing a metabolizable, nontoxic fixed oil as the oil phase and 2,2,2,2,2,2-hexafluorodiethyl ether dissolved in said oil phase.
9. A method of producing anesthesia in animal and human subjects which comprises intravenously. injecting into said subject to be anesthetized an aqueous emulsion containing a normally-volatile anesthetic having a boiling point at atmospheric pressure of at least 40 C. dispersed therein.
10. A method of inducing anesthesia in animal and human subjects which comprises intravenously injecting into said subject an aqueous emulsion containing 2,2- dichloro-1,1-difluoroethyl methyl ether as the dispersed phase.
11. A method of inducing and maintaining anesthesia in animal and human subjects by administering to said subject a noncatabolized anesthetic which comprises directly injecting into the blood stream of said subject a volatile anesthetic contained as the dispersed phase in an aqueous emulsion, allowing the anesthetic to be eliminated from the subjects body by excretion through the lungs of the subject during breathing, and controlling the rate of injection of said anesthetic to produce a desired depth of anesthesia.
12. A method of anesthetizing animal and human subjects which comprises intravenously injecting into said subject an oil-water emulsion containing said anesthetic in the dispersed oil phase in an aqueous medium.
13. A method of anesthetizing animal and human subjects which comprises intravenously injecting into said subject an emulsion containing said anesthetic in a waterinsoluble carrier compatible with said anesthetic and etfective to protect the red cells from hemolysis, said anesthetic and said carrier being present in the dispersed phase in an aqueous medium.
References Cited by the Examiner UNITED STATES PATENTS 2,830,007 4/58 Shukys 16752 2,870,019 1/59 Meyer 16766 2,945,869 7/60 Meyer 16766 2,953,496 9/60 Phillips 16766 2,972,565 2/ 61 Zilversmit 16766 2,977,283 3/61 Meyer 16766 3,004,892 10/61 Hainsworth 16766 3,044,931 7/ 62 Holstius 16766 FOREIGN PATENTS 530,438 9/56 Canada. 523,449 7/40 Great Britain.
OTHER REFERENCES Cole: J. Am. Med. Assoc., vol. 166, No. 9, pp. 1042- 1043, 1958.
Gabel: Am. J. of Vet. Research, vol. 22, July 1961, pp. 720730, citing Adams, Intravenous Anesthesia, P. B. Hoeber Inc., New York, 1944, pp. 64.
Gwathmey: Anesthesia, 2nd ed. 1924, Macmillan Co., page 629, Krantz and Carr, Pharmacologic Principles of Medical Practice, The Williams and Wilkins Co., 1954, pp. 427430. 19Lever: J. of Invest. Derm., vol. 28, No. 4, pp. 317-320,
Zilversmit: J. Lab. and Clin. Med, vol. 48, No. 3, pp. 386-391, 1956.
JULIAN S. LEVITT, Primary Examiner.
MORRIS O. WOLK, LEWIS GOTTS, Examiners.
|Brevet cité||Date de dépôt||Date de publication||Déposant||Titre|
|US2830007 *||27 mai 1953||8 avr. 1958||Air Reduction||Trifluoroethyl vinyl ether compositions and methods for preparing and using the same|
|US2870019 *||16 sept. 1954||20 janv. 1959||Upjohn Co||Therapeutic composition|
|US2945869 *||30 avr. 1956||19 juil. 1960||Upjohn Co||Phosphatide emulsifying agent and process of preparing same|
|US2953496 *||2 déc. 1958||20 sept. 1960||Upjohn Co||Vitamin emulsion|
|US2972565 *||4 avr. 1958||21 févr. 1961||Univ Tennessee Res Corp||Fat composition|
|US2977283 *||5 sept. 1957||28 mars 1961||Upjohn Co||Therapeutic intravenous fat compositions|
|US3004892 *||27 mars 1959||17 oct. 1961||Baxter Don Inc||Fat emulsion and process of producing same|
|US3044931 *||12 févr. 1960||17 juil. 1962||Geigy Chem Corp||Aryloxy acetic acid amides: process for parenteral application|
|CA530438A *||18 sept. 1956||Armour & Co||Stable intravenous fat emulsions|
|GB523449A *||Titre non disponible|
|Brevet citant||Date de dépôt||Date de publication||Déposant||Titre|
|US3449504 *||3 oct. 1966||10 juin 1969||Air Reduction||1,1,2 - trifluoro - 2 - bromoethyl difluoromethyl ether as an inhalant anesthetic agent|
|US3476860 *||8 déc. 1966||4 nov. 1969||Air Reduction||Halomethyl fluoroisopropyl ethers as anesthetic agents|
|US3527811 *||12 juin 1968||8 sept. 1970||Air Reduction||1,1,2 - trifluoro - 2 - bromoethyl difluoromethyl ether and its methods of preparation|
|US3527813 *||4 sept. 1968||8 sept. 1970||Air Reduction||1,1,2 - trifluoro - 2 - chloroethyl difluoromethyl ether and its method of preparation|
|US3609196 *||2 mars 1970||28 sept. 1971||Air Reduction||Ether compounds|
|US3883665 *||8 déc. 1966||13 mai 1975||Airco Inc||Fluorinated isopropyl derivatives as inhalation anesthesias|
|US4005190 *||2 avr. 1975||25 janv. 1977||J. Pfrimmer & Co.||Infusion solution for parenteral feeding|
|US4073943 *||12 mars 1976||14 févr. 1978||Apoteksvarucentralen Vitrum Ab||Method of enhancing the administration of pharmalogically active agents|
|US4153636 *||17 janv. 1977||8 mai 1979||The Dow Chemical Company||Deuterated analogues of methoxyflurane useful as an anesthetic|
|US4168308 *||23 nov. 1977||18 sept. 1979||Apoteksvarucentralen Vitrum Ab||Composition for enhancing the administration of pharmacologically active agents|
|US4281020 *||11 févr. 1980||28 juil. 1981||The Dow Chemical Company||Deuterated analogues of methoxyflurane useful as an anesthetic|
|US4622219 *||17 juin 1983||11 nov. 1986||Haynes Duncan H||Method of inducing local anesthesia using microdroplets of a general anesthetic|
|US4676979 *||24 oct. 1985||30 juin 1987||Eastern Virginia Medical Authority/Med. Ctr. Hosp.||Method of protecting animals against ionizing radiation|
|US6576264||17 oct. 1996||10 juin 2003||Skyepharma Canada Inc.||Insoluble drug delivery|
|US6634576||29 août 2001||21 oct. 2003||Rtp Pharma Inc.||Milled particles|
|US6682761||20 avr. 2001||27 janv. 2004||Rtp Pharma, Inc.||Water-insoluble drug particle process|
|US6974593||9 juin 2003||13 déc. 2005||Jagotec Ag||Insoluble drug delivery|
|US7041705||26 mars 2001||9 mai 2006||Jagotec Ag||Injectable aqueous dispersions of propofol|
|US7097849||18 août 1999||29 août 2006||Jagotec Ag||Injectable aqueous dispersions of propofol|
|US7255877||31 mars 1999||14 août 2007||Jagotec Ag||Fenofibrate microparticles|
|US7816409 *||20 août 2004||19 oct. 2010||Cristalia Productos Quimicos Farmaceuticos Ltda||Stable pharmaceutical composition of fluoroether compound for anesthetic use method for stabilizing a fluoroether compound, use of stabilizer agent for precluding the degradation of a fluoroether compound|
|US7939105||19 nov. 1999||10 mai 2011||Jagotec Ag||Process for preparing a rapidly dispersing solid drug dosage form|
|US7939106||23 mai 2003||10 mai 2011||Jagotec Ag||Process for preparing a rapidly dispersing solid drug dosage form|
|US8206746||30 sept. 2002||26 juin 2012||Jagotec Ag||Microparticles of water-insoluble substances|
|US8415329||9 avr. 2013||Jagotec Ag||Thermoprotected compositions and process for terminal steam sterilization of microparticle preparations|
|US8586094||2 mai 2003||19 nov. 2013||Jagotec Ag||Coated tablets|
|US8703202||24 juil. 2006||22 avr. 2014||Jagotec Ag||Coated tablets|
|US9125953||14 janv. 2011||8 sept. 2015||Sapiotec Gmbh||Halogenated ether complex|
|US20030013693 *||22 avr. 2002||16 janv. 2003||Rtp Pharma Inc.||Method and composition for treatment of inflammatory conditions|
|US20040018229 *||9 juin 2003||29 janv. 2004||Henriksen Inge B.||Insoluble drug delivery|
|US20040086571 *||17 mars 2003||6 mai 2004||Skyepharma Canada Inc.||Fibrate-statin combinations with reduced fed-fasted effects|
|US20060228383 *||20 août 2004||12 oct. 2006||Cristalia Productos Quimicos Farmaceuticos Ltda||Stable pharmaceutical composition of fluoroether compound for anesthetic use method for stabilizing a fluoroether compound, use of stabilizer agent for precluding the degradation of a fluoroether compound|
|USRE32393 *||14 août 1984||7 avr. 1987||Kabivitrum Ab||Composition for enhancing the administration of pharmacologically active agents|
|DE1792410A1 *||29 août 1968||11 nov. 1971||Vitrum Apoteksvar||Pharmakologische Komposition und Verfahren zu ihrer Herstellung|
|EP2345427A1 *||14 janv. 2010||20 juil. 2011||SapioTec GmbH||Fluoran complex|
|WO2011086146A1 *||14 janv. 2011||21 juil. 2011||Sapiotec Gmbh||Halogenated ether complex|
|Classification aux États-Unis||514/722, 568/683, 568/684, 568/685|