Abstract:
A new anesthetic composition comprising a specified mixture of acepromazine or its pharmaceutically acceptable salts and midaflur is disclosed. This composition induces a useful surgical plane of anesthesia in mammals while substantially reducing troublesome side effects encountered with the use of midaflur by itself.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This application is a continuation-in-part of Ser. No. 787,643, filed Apr. 14, 1977, and now abandoned. 
    
    
     This invention deals with a new and improved anesthetic composition for mammals. More specifically, this composition comprises a specified mixture of acepromazine or its pharmaceutically acceptable salts and midaflur. The novel compositions described herein reduce or eliminate side effects, such as involuntary leg movements and vocalization during their use in inducing anesthesia. 
     2. Prior Art 
     U.S. Pat. No. 3,567,831 and U.S. Pat. No. 3,459,766, incorporated herein by reference, both disclose 3-imidazoline 4-amino-2,2,5,5, tetrakis (trifluoromethyl) which is the chemical name for the compound generically known as midaflur. The compounds in these patents are described as having a depressing effect upon the central nervous system and the ability to decrease muscle tone. These properties are described as useful in causing relaxation in general anesthesia. 
     A paper entitled, &#34;The Pharmacology and Toxicology of Midaflur&#34; by R. Clark et al appearing in Toxicology and Applied Pharmacology 18,917-943 (1971) also describes the above-mentioned properties. 
     U.S. Pat. No. 3,330,826, incorporated herein by reference, describes acepromazine and its corresponding salts and describes these compounds as having local anesthetic properties equal or greater than those of chlorpromazine. 
     SUMMARY OF THE INVENTION 
     It has now been discovered that when midaflur is administered intravenously it induces a surgical plane of general anesthesia in mammals. However, troublesome side effects frequently occur during the induction period as well as the period of surgical anesthesia. It has now been found that when acepromazine or its pharmaceutically acceptable salts is administered with midaflur, side effects are reduced or eliminated. The amount of acepromazine or its pharmaceutically acceptable salts necessary to reduce or eliminate side effects varies from about 0.025 mg/kg to about 6.0 mg/kg of mammal body weight. The preferred range is from about 0.05 mg/kg to about 2.5 mg/kg. The ratio of midaflur to acepromazine or its pharmaceutically acceptable salts is from about two hundred to one to about one to one. The preferred ratio is from about one hundred to one to about two to one. 
     DESCRIPTION OF THE INVENTION 
     For purposes of this application the following terms will have the following meaning: 
     Induction Time--In all animal species with the exception of horses, this refers to the time from injection to the first time the pedal reflex was abolished or the first time the animal did not show any indication of a pain response (pigs and sheep only). In horses, the induction time refers to the time from injection to the first time the animal was in a position of lateral recumbancy. 
     Surgical Plane--For all species with the exception of horses, the surgical plane was defined as the time from injection until the last recorded time the pedal reflex was abolished or the animals showed no indication of a pain response (pigs and sheep only). In horses, the surgical plane was the time from injection to the last recorded time the animal was in lateral recumbancy. 
     Recovery Time--For all animal species, the recovery time was defined as the first time the animal stood after injection. 
     In addition to acepromazine or their pharmaceutically acceptable salts being used to eliminate the side effects of midaflur; chloropromazine, promazine, decamethonium bromide, d-tubocurarine chloride, diazepam or their pharmaceutically acceptable salts can be used to reduce or eliminate the side effects of midaflur. In a preferred embodiment of this invention the maleate salt of acepromazine is employed with midaflur. Electroencephalographic data indicates that acepromazine maleate potentiates midaflur&#39;s ability to depress brain activity. 
     The minimum effective dose of the preferred formulation of midaflur/acepromazine maleate in several animal species is as follows: 
     Dogs and Cats about 4.0/0.04 mg/kg of body weight 
     Sheep about 2.0/0.02 mg/kg of body weight 
     Horse about 1.0/0.01 mg/kg of body weight 
     Pigs about 1.5/0.015 mg/kg of body weight 
     When this preferred formulation is administered to small animals such as dogs and cats the concentration of midaflur/acepromazine maleate is about 10.0-20.0/0.2-0.4 mg/ml. Higher concentrations per ml would be utilized for larger animal use. 
     The compositions of this invention can be prepared by dissolving midaflur and acepromazine or its pharmaceutically acceptable salts in an appropriate solvent such as ethyl alcohol. Propylene glycol can be used in combination with ethyl alcohol. Water can also be added to these solvents. The compositions of this invention can be administered intravenously, intramuscularly, intraperitoneally and subcutaneously. For best results the compositions of this invention are administered intravenously to mammals. Examples of mammals on which the formulation of this invention have been used successfully include dogs, sheep, horses, pigs, cats and primates. The following examples illustrate the advantages of a midaflur-acepromazine maleate anesthetic composition over the individual components. 
    
    
     EXAMPLE 1 
     Two 20 mg/ml midaflur formulations were prepared in the manner essentially described below. These two formulations were prepared with the following components: 
     
         ______________________________________Midaflur Formulations#1 -   20.0 mg/ml  1500 mg midaflur  q.s. to 75.0 ml with 50% ethanol#2 -   20.0 mg/ml  800 mg midaflur dissolved in 16.0 ml of 100% ethanol  q.s. to 40.0 ml with sterile distilled water______________________________________ 
    
     Both of these formulations were administered intravenously at various doses to dogs. The results are summarized in Table I which appears on the following page: 
     
                                           TABLE I__________________________________________________________________________DOGSTHE EFFECT OF VARIOUS CONCENTRATIONS OF MIDAFLUR I.V. ON INDUCTION TIME,SURGICAL PLANE, RECOVERY TIME AND SIDE EFFECTS__________________________________________________________________________Formulation No.        2   2   1  2  2   1  1  2  2  1   1   1   1   1Dose (mg/kg)  2.0             2.0                5.8                    6.0                       6.0                           8.0                              8.0                                 8.0                                    8.0                                       9.0                                          12.0                                              12.0                                                  16.0                                                      16.0Concentration (mg/ml)        20.0            20.0                20.0                   20.0                      20.0                          20.0                             20.0                                20.0                                   20.0                                      20.0                                          20.0                                              20.0                                                  20.0                                                      20.0Induction Time (min)        --  --  8  4-6                      --  2  4  4  -- 6   2    3  3   2Surgical Plane (min)        None            None                22 45 None                           77                              43                                &lt;23                                   ?   28 &lt;120                                              32  &lt;32  180Recovery (min)        &gt;30 14  74 60 20  240                             285                                 45                                   &gt;85                                      140 165 &gt;270                                                   62 &gt;210Side EffectsA. Running Movements        a   a   2  3  a   1  1  3  Yes                                      0   3   3   1   3B. Vocalization        a   a   0  1  a   1  1  3  Yes                                      0   0   1   1   1Emesis       No  No  No No No  Yes                             Yes                                No No Yes No  No  No  No__________________________________________________________________________ a = not applicable Side effects refer to those side effects that occur from induction time until the end of the surgical plane where:  0 = none  1 = minimal, occurred during less than 1/4 of the surgical plane  2 = moderate, occurred during 1/4 to 1/2 of the surgical plane  3 = maximal, occurred during greater than 1/2 of the surgical plane 
    
     As can be seen from the preceding table, ten of the fourteen dogs tested experienced running movements during the surgical plane, vocalization occurred with eight of the fourteen dogs at least 50 minutes after injection. Therefore, while midaflur does induce a surgical plane of anesthesia in dogs, there are troublesome side effects that do occur which limits the use of midaflur as an anesthetic. 
     EXAMPLE 2 
     Four different formulations (5-8) containing midaflur and acepromazine maleate were prepared. Additionally, Formulation 2, described in Example 1, was administered simultaneously in various dose levels via a &#34;Y&#34; shaped tube with each of two acepromazine maleate formulations having a concentration of 5 mg/ml (Formulation 3) and 10 mg/ml (Formulation 4) respectively. The preparation and components of Formulations 3 through 8 are represented below: 
     
         ______________________________________Acepromazine Maleate Formulation#3 - 5.0 mg/ml5.0 ml of a preserved pH adjusted aqueous AcepromazineMaleate Injectable Formulation (10.0 mg/ml)plus5.0 ml of sterile distilled waterAcepromazine Maleate Injectable Formulation#4 - 10.0 mg/ml of a preserved pH adjusted aqueousinjectable formulation.______________________________________ 
    
     
         ______________________________________ Midaflur/Acepromazine Maleate Formulations______________________________________#5 -      75.0/37.5 mg/ml     7.500 g midaflur     3.750 g acepromazine maleate     35.0 ml absolute alcohol     35.0 ml propylene glycol     q.s. to 100.0 ml with distilled water______________________________________ 
    
     Vehicle system (for Midaflur/Acepromazine Maleate formulation Nos. 6, 7, and 8) 
     A stock solution consisting of equal parts of: 
     propylene glycol 
     ethyl alcohol 
     distilled water 
     
         ______________________________________#6 -      37.5/37.5 mg/ml     1.875 g midaflur     1.875 g acepromazine maleate     q.s. to 50.0 ml with vehicle system#7 -      37.5/18.75 mg/ml     3.750 g midaflur     1.875 g acepromazine maleate     q.s. to 100.0 ml with vehicle system#8 -      10.0/5.0 mg/ml     2.500 g midaflur     1.250 g acepromazine maleate     q.s. to 250.0 ml with vehicle system______________________________________ 
    
     All of the above formulations described in Example 2 were administered intravenously at various doses to dogs. The results are summarized in Table II. 
     From Table II, it can be seen that side effects were reduced or eliminated when acepromazine maleate was administered intravenously with midaflur. A dose response with acepromazine maleate was noted wherein, by the criteria used in Example 2, a dose of 1.1 mg/kg was less effective and doses of 3.0 and 6.0 mg/kg were more effective. No differences in the elimination of side effects were noted between the 3.0 and 6.0 mg/kg doses of acepromazine maleate. 
     
         TABLE II  DOGS THE EFFECT OF VARIOUS CONCENTRATIONS OF MIDAFLUR/ACEPROMAZINE MALEATE I.V. ON INDUCTION TIME, SURGICAL PLANE, RECOVERY TIME AND SIDE EFFECTS   Formulation No. 2,3 2,3  2,3 2,3 2,3 2,3  2,3 2,3 2,3 2,3 2,3 2,3 2,3 2,3 2,3 2,3 2,3 Midaflur  Dose (mg/kg) 2.0 2.0  4.0 4.0  4.0 4.0  6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0  Concentration (mg/ml) 20.0 20.0  20.0 20.0 20.0 20.0  20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Acepromazine Maleate  Dose (mg/kg) 1.1 1.1  1.1 1.1 0.75 1.1  1.1 1.1 1.1 1.65 1.65 1.65 1.65 2.0 2.0 2.0 2.0  Concentration (mg/ml) 5.0 5.0  5.0 5.0  5.0 5.0  5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Induction Time (min) 2 2  2 2 2-4 2  2 2 2 2 2 2 2 2 2 2 2 Surgical Plane (min) 30 20  45 45 ≈45 30  80 60 80 40 40 60 100 45 30 45 45 Recovery (min) 45 26  55 65 75 75  103 129 160 137 145 210 145 120 92 102 120 Side Effects  A. Running Movements 1 1  0 0 1 0  3 0 1 02 0 1 0 0 0 0  B. Vocalization 1 0  0 1 0 1  1 0 0 1 0 0 0 0 0 0 0 Formulation No. 2,3 2,3 2,3 2,3 2,4 2,4 2,4 2,4 2,4 2,4 7 7 7 7 7 7 7 7 7 Midaflur  Dose (mg/kg)  6.0  6.0  6.0  6.0  6.0  6.0  6.0  6.0  6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0  Concentration (mg/ml) 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 Acepromazine Maleate  Dose (mg/kg) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0   Concentration (mg/ml) 5.0 5.0 5.0 5.0 10.0 10.0 10.0 10.0 10.0 10.0 18.75 18.75 18.75 18.75 18.75 18.75 18.75 18.75 18.75 Induction Time (min) 2 2 2 2 2 2 2 2 2 2-10 2 2 2 2 2 2 5 2 4 Surgical Plane (min) 30 30 60 30150 60 75 45 60 ≈45 60 75 60 30 30 45 45 30 75 Recovery (min) 148 118 125 115 205 124 140 135 185 145 280 &gt;420 150 254 231 &gt;452 185 &gt;450 &gt;463 Side Effects  A. Running Movements 0 0 0 0 0 1 0 0 1 0 0 0 1 0 0 0 0 0 0  B. Vocalization 0 0 0 0 1 1 0 0 0 0 0 1 0 0 0 0 0 0 0Formulation No. 5 5 5 5 5 5 6 6 6 6 6 6 5 5 6 6 7 7 7 Midaflur  Dose (mg/kg) 6.0 6.0 6.0  6.0  6.0  6.0  6.0  6.0  6.0  6.0  6.0  6.0  6.0 6.0  6.0 6.0 6.0 6.0 6.0  Concentration (mg/ml) 75.0 75.0 75.0 75.0 75.0 75.0 37.5 37.5 37.5 37.5 37.5 37.5 75.0 75.037.5 37.5 37.5 37.5 37.5 Acepromazine Maleate  Dose (mg/kg) 3.0 3.0 3.0 3.0  3.0  3.0  6.0  6.0 6.0  6.0  6.0  6.0  3.0  3.0 6.0  6.0 3.0 3.0 3.0  Concentration (mg/ml) 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 18.75 18.75 18.75 Induction Time (min) 7 2 2  2  2  2  2  2  2  2  2  2 2-4 2 2-5 2 22 2 Surgical Plane (min) 45 30 60 35  30 10 75 30 45 30 60 90 ≈10 30 ≈10 20 45 60 45 Recovery (min) 249 231 372 &gt;402 313 &gt;390 &gt;390 &gt;360 120 405 &gt;450 259 135 150 123 90 122 333 262 Side Effects  A. Running Movements 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  B. Vocalization 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 Formulation No. 7 7 7 8 8 8 8 8 8 7 7 5 8 8 8 8 8 8 Midaflur  Dose (mg/kg)  6.0  6.0 6.0  6.0  6.0 6.0  6.0 6.0  6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0  6.0  6.0  Concentration (mg/ml) 37.5 37.5 37.5 10.0 10.0 10.0 10.0 10.0 10.0 37.5 37.5 75.0 10.0 10.0 10.0 10.0 10.0 10.0 Acepromazine Maleate  Dose (mg/kg) 3.0  3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0  Concentration (mg/ml) 18.75 18.75 18.75 5.0 5.0 5.0 5.0 5.0 5.0 18.75 18.75 37.5 5.0 5.0 5.0 5.0 5.0 5.0 Induction Time (min)  2 2 2 2-10 2 2  2 2  2 4 2 3 2 2 1 3 1-5  2 Surgical Plane (min) 75 120 45 ≈30 ≈30 30 60 30 30 30 30 60 45 45 45 75 ≈120 30 Recovery (min) &gt;420 &gt;420 254 &gt;420 &gt;420 235 &gt;410 225 &gt;400 145 222 363 115 311 309 344  333 &gt;325 Side Effects  A. Running Movements 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0  B. Vocalization 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0    Formulation No. 2,3 2,3 2,4 2,4 2,4 2,4 2,4  Midaflur  Dose (mg/kg) 8.0 8.0 8.0 8.0 8.0 8.0 8.0  Concentration (mg/ml) 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Acepromazine Maleate  Dose (mg/kg) 1.1 1.1 2.5 2.5 2.5 2.5 2.5  Concentration (mg/ml) 5.0 5.0 10.0 10.0 10.0 10.0 10.0 Induction Time (min) 2 4 2 2 2 2 2 Surgical Plane (min) 150 75 60 75 120 75 60 Recovery (min) 300 283 167 175 200 195 105 Side Effects  A. Running Movements 2 0 0 0 1 11 Side effects refer to those side effects that occur from induction time until the end of the surgical plane where:  0 = none  1 = minimal, occurred during less than 1/4 of the surgical plane  2 = moderate, occurred during 1/4 to 1/2 of the surgical plane  3 = maximal, occurred during greater than 1/2 of the surgical plane 
    
     EXAMPLE 3 
     Eight different formulations (9-16) containing midaflur and acepromazine maleate were prepared. The preparation and components of Formulations 9 through 16 are represented below: 
     Formulation 
     
         ______________________________________9.   Midaflur 10.0 mg/mlAcepromazine maleate 5.0 mg/mlIn a vehicle system consisting of equal parts of ethanol,propylene glycol, and distilled water. Filter sterilized.10.  Midaflur 10.0 mg/mlAcepromazine maleate 1.0 mg/mlIn a vehicle system consisting of equal parts of ethanol,propylene glycol, and distilled water. Filter sterilized.11.  Midaflur 20.0 mg/mlAcepromazine maleate 2.0 mg/mlIn a vehicle system consisting of equal parts of ethanol,propylene glycol, and distilled water. Filter sterilized.12.  Midaflur 20.0 mg/mlAcepromazine maleate 0.40 mg/ml J - In a vehicle system consistingof equal parts of ethanol,propylene glycol, and distilled water. Filter sterilized.13.  Midaflur 10.0 mg/mlAcepromazine maleate 0.20 mg/mlIn a vehicle system consisting of equal parts of ethanol,propylene glycol, and distilled water. FIlter sterilized.14.  Midaflur 20.0 mg/mlAcepromazine maleate 0.20 mg/mlIn a vehicle system consisting of equal parts of ethanol,propylene glycol, and distilled water. Filter sterilized.15.  Midaflur 10.0 mg/mlAcepromazine maleate 0.10 mg/mlIn a vehicle system consising of equal parts of ethanol,propylene glycol, and distilled water. FIlter sterilized.16.  Midaflur 20.0 mg/mlAcepromazine maleate 0.10 mg/mlIn a vehicle system consisting of equal parts of ethanol,propylene glycol, and distilled water. Filter sterilized.______________________________________ 
    
     All of the above formulations described in Example 3 were administered intraveneously at various doses to dogs. 
     The number of dogs tested with each formulation is as follows: 
     
         ______________________________________Formulation   Number of Dogs______________________________________9             1410,11         2312,13         6114,15         2016            10______________________________________ 
    
     The results are summarized in Tables III and IV. Tables III and IV show that the side effects were reduced or eliminated when acepromazine maleate was administered intraveneously with midaflur at ratios as low as two hundred to one. A dose response with acepromazine maleate was noted with doses ranging from 0.025 mg/kg to 2.5 mg/kg. 
     
                                           TABLE III__________________________________________________________________________THE EFFECT OF VARIOUS MIDAFLUR/ACEPROMAZINE MALEATEDOSES ON INDUCTION TIME, SURGICAL PLANE, AND RECOVERYTIME WHEN ADMINISTERED I.V. TO DOGS__________________________________________________________________________FORMULATION NUMBER  9   10,11                       12,13                           14,15                               16RATIO OF MIDAFLUR/ACEPROMAZINE MALEATE               2/1 10/1                       50/1                           100/1                               200/1MIDAFLUR DOSE (MG/KG)            5.0 5.0 5.0 5.0 5.0ACEPROMAZINE MALEATE DOSE (MG/KG)            2.5 0.5 0.1 0.05                               0.025INDUCTION TIME (Mean) (minutes)          2.0 2.4 3.0 3.0 2.9SURGICAL PLANE (Mean) (minutes)          51.9                    35.5.sup.(a)                       32.1                           27.9                               30.0RECOVERY TIME (Mean) (minutes)          175.3                   128.0.sup.(b)                       129.5.sup.(b)                           85.0.sup.(c)                               65.9.sup.(c)__________________________________________________________________________ .sup.a = Two of the 23 dogs did not attain a surgical plane. .sup.b = Does not include 1 dog with a 5-24 hour recovery time. .sup.c = Does not include 2 dogs with a 5-24 hour recovery time. 
    
     
                                           TABLE IV__________________________________________________________________________THE EFFECT OF VARIOUS MIDAFLUR/ACEPROMAZINE MALEATE DOSES ON SIDEEFFECTS DURING INDUCTION (I), SURGICAL PLANE (SP),AND RECOVERY (R) WHEN ADMINISTERED I.V. TO DOGS__________________________________________________________________________FORMULATION NO.     9      10,11  12,13 14,15 16RATIO OF MIDAFLUR/ACEPROMAZINE MALEATE               2/1    10/1   50/1  100/1 200/1MIDAFLUR DOSE (MG/KG)            5.0    5.0    5.0   5.0   5.0ACEPROMAZINE MALEATE (MG/KG)            2.5    0.5    0.1   0.05  0.025__________________________________________________________________________STAGES OF ANESTHESIA               I SP R I SP R I SP                                 R I SP                                       R I SP                                             R__________________________________________________________________________SIDE EFFECTS (% of dogsaffected)RUNNING MOVEMENTS None               57                 100                    50                      43                        76 29                             61                               74                                 23                                   45                                     50                                       10                                         40                                           40                                             10 Not Significant.sup.(a)               43                  0 43                      48                        24 62                             28                               25                                 70                                   25                                     50                                       75                                         40                                           60                                             70 Significant.sup.(b)                0                  0 14                      33                         0 19                             16                                0                                 18                                   50                                     10                                       45                                         60                                           20                                             40VOCALIZATION None               79                 100                    64                      86                        100                           86                             75                               98                                 70                                   75                                     95                                       90                                         60                                           90                                             80 Not Significant.sup.(c)               14                  0 36                      10                         0 10                             20                                2                                 20                                   20                                      5                                        5                                         30                                           10                                             10 Significant.sup.(d)                7                  0  7                       5                         0 10                              5                                0                                 16                                    5                                      0                                        5                                         10                                            0                                             10__________________________________________________________________________ .sup.(a) = Running movements that are not signigicant are muscle twitches and slight running movements. .sup.(b) = Running movements that are significant are moderate and strong running movements. .sup.(c) = Vocalization that is not significant is quiet vocalization. .sup.(d) = Vocalization that is significant is loud vocalization.