Patent Publication Number: US-4147800-A

Title: Pediculicidal toxicants

Description:
BACKGROUND OF THE INVENTION 
     There are only a relatively few pediculicides which are commercially available today. The most popular pediculicidal toxicants are Lindane (gamma benzene hexachloride), Malathion (S-1,2-dicarbethoxyethyl)-0,0-dimethyl phosphorodithioate), synergized pyrethrins and Cuprex (a combination of tetrahydronaphthalene, copper oleate and acetone, the acetone not asserted to be active). 
     Because of increased concern about the overall safety of some of the known ectoparasitic toxicants, the search for new, safe and effective pediculicides has intensified recently. It has now been discovered that the combination of an aliphatic alcohol and an aliphatic ester is synergistic as a pediculicide. 
     The results achieved in the instant invention are particularly surprising in view of the prior art. For example, one of the preferred ingredients, isopropanol has been used in Great Britain as a solvent for the Lindane and Malathion toxicants for some time. Additionally, investigations of the effect of various solvent system combinations for increasing the penetration of primary toxicants have been made. Wigglesworth, in &#34;Permeability of Insect Cuticle,&#34; Nature, 147, 116 (January 1941), and &#34;Some Notes on the Integument of Insects in Relation to the Entry of Contact Insecticides,&#34; Bull. Ent. Res., 33 205, (1942) describes the effect of oils and mixtures of oil and alcohol on insects including the louse. Hurst, in &#34;Insect Cuticle as an Asymmetrical Membrane,&#34; Nature 147, 338 (March 1941), &#34;Permeability of Insect Cuticle,&#34; Nature, 145, 462 (March 1940) and &#34;Principals of Insecticidal Action as a Guide to Drug Reactivity--Phase Distribution Relationships,&#34; Trans. Faraday Soc. 39, 390 (1943), describes a mixture of kerosene and ethyl alcohol. However, Wigglesworth, Hurst, and others failed to perceive that such solvent systems, appropriately modified, could be used as pediculicides without the addition of a &#34;primary toxicant.&#34; For example, McKim described the combination of a toxicant with a mixture of lower aliphatic alcohol and a hydrocarbon oil in U.S. Pat. No. 2,396,054 (1946). Moreover, both Wigglesworth and Hurst believed desiccation and imbibition were the means by which the polar/apolar combinations caused distress to insects. The findings that the instant pediculicides exhibit high activity in the presence of high percentages of water is therefore particularly surprising. 
     It is the object of this invention to provide new, safe and effective pediculicides and also to provide a safe and effective treatment for the control of ectoparasites such as lice. This and other objects of the invention will become apparent to those skilled in the art from the following detailed description. 
     SUMMARY OF THE INVENTION 
     This invention relates to ectoparasiticidal toxicants and a method of controlling ectoparasites. More particularly, the invention relates to a pediculicidal toxicant composition containing a mixture of an aliphatic or aryl aliphatic alcohol and an aliphatic ester. The invention also relates to the use of such compositions in controlling such ectoparasites. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The pediculicidal toxicant of the instant invention is an admixture of an aliphatic alcohol and an aliphatic ester. The combination is synergistic and retains its high level of activity when diluted in an inert pharmaceutically acceptable carrier, most notably an aqueous carrier. 
     The aliphatic alcohols employed in the instant invention are those somewhat water soluble aliphatic or aryl aliphatic alcohols containing 2 to about 8 carbon atoms and preferably 3 to 5 carbon atoms in the aliphatic moiety. Typical examples include ethyl alcohol, butyl alcohol, propyl alcohol, isopropyl alcohol, pentyl alcohol, tert-pentyl alcohol, hexyl alcohol, octyl alcohol and the like. The carbon atom chain can be either straight or branched and it is preferred that saturated alcohols be employed although unsaturated alcohols can also be used. In the toxicant composition, a single alcohol can be used or various mixtures of the alcohols can be employed. At present, the preferred alcohol is isopropanol. The water soluble aliphatic alcohols are, at best, feebly pediculicidal. In contrast, the aromatic alcohols such as benzyl alcohol, are pediculicidal alone, but are not as effective as aliphatic alcohols in aqueous combination with aliphatic esters. However, when the aryl moiety is separated from the hydroxyl moiety by a sufficient aliphatic chain, as in phenethyl alcohol, they behave like an aliphatic alcohol in this invention. 
     The esters employed in the present invention are aliphatic carbocyclic acid esters which contain 4 to about 32 carbon atoms. The preferred materials are esters of aliphatic alcohols of 1 to 8 carbon atoms, preferably 2 to 6 carbon atoms, and fatty acids of 12 to 24 carbon atoms, preferably 12 to 20 carbon atoms. Accordingly, the preferred esters generally contain 13 to 32 carbon atoms and most preferably 14 to 26 carbon atoms. Among the esters which can be employed are ethyl acetate, propyl acetate, methyl laurate, ethyl laurate, propyl laurate, isopropyl laurate, butyl laurate, isobutyl laurate, amyl laurate, isoamyl laurate, methyl stearate, ethyl stearate, propyl stearate, isoamyl stearate, isobutyl stearate, ethyl oleate, propyl oleate, isopropyl oleate, isobutyl oleate, methyl myristate, ethyl myristate, propyl myristate, isopropyl myristate, butyl myristate, isobutyl myristate, amyl myristate, isoamyl myristate, myristyl myristate, and the like. The presently preferred ester is isopropyl myristate. In the pediculicidal toxicants of the instant invention, the ester can be a single compound or a mixture of two or more compounds. 
     The aliphatic esters exhibit good pediculicidal properties when applied in a substantially pure form, i.e., in a concentration of at least 70% or more. Obviously, application of the esters in such a form is somewhat inconvenient and inappropriate. In the present invention, the ester is employed in an amount which is usually less than one half of the total toxicant composition employed. With respect to the total weight of the aliphatic alcohol and aliphatic ester, the weight ratio of the former to the latter is usually about 1.1:1 to 3:1 and preferably about 1.3:1 to 1.7:1. 
     The active pediculicidal toxicant mixture of this invention, the aliphatic alcohol and aliphatic ester, can be used in the form of liquids, powders, lotions, creams, gels or aerosol sprays or foams by formulation with inert pharmaceutically acceptable carriers by procedures well known in the art. Any pharmaceutically acceptable carrier, whether aqueous or non-aqueous, which is inert to the active ingredient mixture can be employed. By inert is meant that the carrier does not have a substantial detrimental effect on the pediculicidal toxicant activity of the alcohol-ester admixture. A significant and surprising advantage of the instant composition is that an aqueous carrier can be employed. The presence of significant amounts of water has obvious economic advantages but, more importantly, water greatly reduces the skin and eye irritation liability to the patient. The Draize test is a recognized procedure for assessment of eye irritation and isopropanol, the preferred alcohol of this invention, has been used for calibration of the test because it causes a high degree of eye damage. The instant compositions, for example containing 25% isopropanol with water and other components, have shown zero Draize irritation. 
     The alcohol-ester admixture is incorporated into the composition used to treat the substrate in need of such treatment, believed to be in need of such treatment, or desired to be prophylactically protected in an effective pediculicidal toxic amount. By such amount is meant the amount which will cause virtually 100% of the lice exposed in the two or four minute immersion test described below to die within 24 hours. It has been found that an effective pediculicidal toxic amount can be obtained when the amount of the aliphatic alcohol in the treating composition is at least about 20 percent by weight and the amount of the aliphatic ester is at least about 15 percent by weight. Obviously, amounts of the alcohol and ester in excess of these minimum amounts can be employed but there appears to be no significant advantage if the percentages are significantly in excess of those stated. It will also be apparent from the foregoing that a liquid carrier can constitute up to about 65 weight percent of the treating composition. Preferably the carrier constitutes about 40-60%. 
     The two or four minute immersion test referred to in the preceding paragraph is carried out as follows. A 50 ml beaker is filled with tap water and allowed to come to room temperature (about 24° C.). Ten young adult male and ten young adult female lice (Pediculus humanus corporis) of the same age group and from the same stock colony are placed on a 2 × 2 cm coarse mesh patch. The sample to be tested, maintained at room temperature, is shaken until homogenous and placed into a 50 ml beaker. The mesh patch is placed into the sample immediately after pouring, allowed to submerge, and after either two or four minutes is removed and immediately plunged into the beaker containing the tap water. The patch is vigorously agitated every ten seconds and after one minute the patch is removed and placed on paper toweling. The lice are then transferred to a 4 × 4 cm black corduroy cloth patch and this point of time is considered 0 hours. Thereafter, the corduroy patch is placed in a petri dish which is covered and stored in a 30° C. holding chamber. 
     The synergistic effect of the alcohol-ester combination can be appreciated from the following results of the four minute immersion test. Six samples were prepared by mixing isopropanol and/or isopropyl myristate with 7 parts by weight of Polysorbate 80, an inert emulsifier, and water q.s. ad. 100%. The results achieved were: 
     
         ______________________________________                                    
                       % Dead                                             
______________________________________                                    
42w %    of 95% isopropanol  7.5                                          
         in inert vehicle                                                 
15w %    of isopropyl myristate                                           
                             5                                            
         in inert vehicle                                                 
42w %    of 95% isopropanol, and                                          
15w %    of isopropyl myristate                                           
                             100                                          
         in inert vehicle                                                 
20w %    of 95% isopropanol and                                           
15w %    of isopropyl myristate                                           
                             75                                           
         in inert vehicle                                                 
42w %    of 95% isopropanol and                                           
10w %    of isopropyl myristate                                           
                             60                                           
         in inert vehicle                                                 
25w %    of isopropanol and                                               
15w %    of isopropyl myristate                                           
                             100                                          
         in inert vehicle                                                 
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     The synergistic effect of the present invention can also be appreciated from the sole FIGURE which is a graph of lice mortality versus concentration in the two minute immersion test described above. Several test compositions were used each containing 7 weight percent of Polysorbate 80 (an inert surfactant) and water q.s. ad. 100%. Curve 2 represents the test composition containing varying concentrations of isopropyl myristate and curve 1 represents the test compositions containing varying concentrations of isopropyl alcohol. It will be noted that the compositions containing only the isopropyl alcohol up to 95% never achieved a percent mortality in excess of 15% (at 100% concentration, mortality was 65%) and it required not less than 70% of the isopropyl myristate to achieve a 100% mortality. Curve 3 represents the results achieved with test compositions containing 15% isopropyl myristate and varying percentages of isopropyl alcohol. 100% mortality was achieved in this two minute test when the isopropyl alcohol concentration reached 30 weight percent. 
     Other examples of alcohol-ester combinations which can be used within the context of the instant invention include butanol and ethyl stearate, pentanol and methyl laurate, octanol and isobutyl oleate, ethanol and myristyl myristate, ethanol and butanol and isopropyl myristate, isopropyl alcohol and ethyl stearate and isopropyl myristate, ethanol and butanol and ethyl stearate and isobutyl oleate and the like. 
     Various alcohol-ester combinations were evaluated in the two minute immersion test described above. The results are set forth in the following tables. It will be appreciated that the mortality results set forth represent only the particular material tested and should not be interpreted to mean that other concentrations, are not pediculicidal. 
     In Table I, the results of the testing using aliphatic monoesters undiluted or in a combination containing 25% isopropanol (IPA) and 60% aqueous carrier are set forth. 
     
                       TABLE I                                                     
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                         15% Ester, 25% IPA,                              
Esters         100% Ester                                                 
                         60% aqueous carrier                              
______________________________________                                    
Ethyl Acetate  100       95                                               
Ethyl Cyanoacetate                                                        
               0         5                                                
Butyl Acetate  100       95                                               
Ethyl Acetoacetate                                                        
               0         5                                                
Ethyl 4-Chlorobutyrate                                                    
               80        5                                                
Butyl Lactate  25        85                                               
Ethyl Levulinate                                                          
               5         0                                                
Ethyl Caproate 100       100                                              
Ethyl Caprylate                                                           
               100       100                                              
Methyl Caprate 100       100                                              
Ethyl Caprate  100       100                                              
Methyl Laurate 100       100                                              
Ethyl Laurate  100       100                                              
Methyl Myristate                                                          
               95        100                                              
Isopropyl Laurate                                                         
               100       100                                              
Lauryl Lactate 100       100                                              
Isopropyl Myristate                                                       
               100       100                                              
Methyl Palmitate                                                          
               *         90                                               
Butyl Myristate                                                           
               100       100                                              
Isononyl Isononanoate                                                     
               100       100                                              
Isopropyl Palmitate                                                       
               95        100                                              
Cetyl Lactate  *         100                                              
Isopropyl Linoleate                                                       
               85        35                                               
Isopropyl Isosterate                                                      
               100       100                                              
Butyl Stearate 80        95                                               
2-Ethylhexyl Palmitate                                                    
               100       100                                              
Decyl Oleate   70        100                                              
Myristyl Myristate                                                        
               **        100                                              
______________________________________                                    
 *solid - could not be tested at 100%                                     
 **solidified upon contact with rinse.                                    
 
    
     The foregoing results show that the aliphatic monoesters containing 4 to 28 carbon atoms are potent pediculicides and when combined with 25 weight percent isopropanol and 60% aqueous carrier are highly pediculicidal. The presence of various functional groups such as the 2-nitrile, 3-or 4-keto, 2-hydroxy, 4-chloro and unsaturation in the acid moiety of the ester reduces pediculicidal activity. Reduction in activity, however, can be offset by extension of the chain length as shown by the activity of the combinations of lauryl lactate, cetyl lactate, and decyl oleate. 
     In Table II, various aliphatic alcohols were evaluated alone, in aqueous solution, and in solution with 15 weight percent of isopropyl myristate (IPM) and 60% aqueous carrier. 
     
                       TABLE II                                                    
______________________________________                                    
                                  25% Alcohol                             
         100%     15% IPM, 25% Alcohol,                                   
                                  75% aqueous                             
Alcohol  Alcohol  60% aqueous carrier                                     
                                  carrier                                 
______________________________________                                    
Methanol 0        0               0                                       
Ethanol  45       0               0                                       
iso-Propanol                                                              
         65       100             0                                       
n-Propanol                                                                
         70       100             0                                       
iso-Butanol                                                               
         95       100             40                                      
sec-Butanol                                                               
         95       100             0                                       
t-Butanol                                                                 
         80       100             0                                       
n-Butanol                                                                 
         100      100             20                                      
iso-Pentanol                                                              
         100      100             55                                      
n-Pentanol                                                                
         100      100             10                                      
n-Hexanol                                                                 
         100      100             5                                       
n-Octanol                                                                 
         100      40              10                                      
n-Decanol                                                                 
         100      60              20                                      
n-Dodecanol                                                               
         100      45              10                                      
Hexadecanol                                                               
         100      35              40                                      
Oleyl                                                                     
Alcohol  100      0               0                                       
______________________________________                                    
 
    
     In Table III, 5 aliphatic diesters are set forth. 
     
                       TABLE III                                                   
______________________________________                                    
                          15% Ester, 25% IPA,                             
Diester        100% Ester 60% aqueous carrier                             
______________________________________                                    
Diethyl Oxalate                                                           
                20         5                                              
Diisopropyl Adipate                                                       
               100        40                                              
Dimethyl Sebicate                                                         
               100         5                                              
Dimethyl Brassylate                                                       
               100        95                                              
Di-n-hexyl Azelate                                                        
                85        20                                              
______________________________________                                    
 
    
     In Table IV, the results achieved using aryl mono and diesters are set forth. 
     
                       TABLE IV                                                    
______________________________________                                    
                          15% Ester, 25% IPA                              
Aryl Ester     100% Ester 60% aqueous carrier                             
______________________________________                                    
Benzyl Benzoate                                                           
               95          5                                              
Diethyl Phthalate                                                         
                0          5                                              
Dibutyl Phthalate                                                         
               60         10                                              
Dioctyl Phthalate                                                         
               40         10                                              
______________________________________                                    
 
    
     The mortalities achieved using 2 aryl alkyl alcohols are set forth in Table V. 
     
                       TABLE V                                                     
______________________________________                                    
                        15% IPM, 25% Alcohol                              
Alcohol     100% Alcohol                                                  
                        60% aqueous carrier                               
______________________________________                                    
Benzyl alcohol                                                            
             90          75                                               
Phenethyl alcohol                                                         
            100         100                                               
______________________________________                                    
 
    
     As noted above, the pediculicidal compositions of this invention can be formulated into a variety of end use forms. Typical formulations are set forth below in which IPA represents isopropyl alcohol, IPM represents isopropyl myristate, and the amounts set forth are percentages by weight. 
     Clear liquid pediculicide, suitable for mechanical spray application or inunction 
     
         ______________________________________                                    
        IPA            65                                                 
        IPM            10                                                 
        Water          25                                                 
______________________________________                                    
 
    
     Pediculicidal Shampoo, clear liquid 
     
         ______________________________________                                    
       IPA              25                                                
       IPM              15                                                
       Triethanolamine                                                    
       lauryl sulfate   20                                                
       Water            40                                                
______________________________________                                    
 
    
     Pediculicidal Aerosol Fast Breaking Foam 
     
         ______________________________________                                    
       IPA              25                                                
       IPM              15                                                
       Mono and Digly-                                                    
       cerides of Edible                                                  
       Fats or Oils      5                                                
       Water            42                                                
       Glycerine         3                                                
       Isobutane        10                                                
______________________________________                                    
 
    
     Pediculicidal Aerosol Spray 
     
         ______________________________________                                    
        IPA            65                                                 
        IPM            10                                                 
        Isobutane      10                                                 
        Water          15                                                 
______________________________________                                    
 
    
     Pediculicidal Aerosol Spray 
     
         ______________________________________                                    
       IPA             25                                                 
       IPM             15                                                 
       Isobutane       15                                                 
       Water           40                                                 
       Polysorbate 80   5                                                 
______________________________________                                    
 
    
     Pediculicidal Gel 
     
         ______________________________________                                    
       IPA              25.0                                              
       IPM              15.0                                              
       Carbopol 940     0.5                                               
       Triethanolamine  0.38                                              
       Water            59.22                                             
______________________________________                                    
 
    
     Pediculicidal Powder* 
     
         ______________________________________                                    
        Pyrophyllite   90.0                                               
        IPA            6.5                                                
        IPM            3.5                                                
______________________________________                                    
 *In a dry inert carrier formulation, the carrier can range up to about   
 95%.                                                                     
 
    
     Pediculicidal Lotion 
     
         ______________________________________                                    
Triethanolamine Stearate  20                                              
Cetyl Alcohol              5                                              
IPA                       25                                              
IPM                       15                                              
Water                     35                                              
______________________________________                                    
 
    
     Pediculicidal Stick 
     
         ______________________________________                                    
       Sodium Stearate  60                                                
       IPA              25                                                
       IPM              15                                                
______________________________________                                    
 
    
     Pediculicidal Lotion 
     
         ______________________________________                                    
Ethanol                   50.0                                            
Sodium carboxymethylcellulose                                             
                          0.2                                             
Carbopol 941              0.2                                             
IPM                       15.0                                            
Triethanolamine           0.2                                             
Acetylated polyoxyethylated                                               
(10) lanolin              3.0                                             
Water                     31.4                                            
______________________________________                                    
 
    
     Pediculicidal Lotion 
     
         ______________________________________                                    
Polyoxyethylene (10)                                                      
cetyl ether             3.0                                               
Talc                    1.5                                               
Carbopol 941            0.3                                               
Triethanolamine         0.3                                               
Ethyl alcohol           40.0                                              
IPM                     15.0                                              
Water                   39.9                                              
______________________________________                                    
 
    
     Various changes and modifications can be made in the instant invention without departing from the spirit and scope thereof. The various embodiments disclosed herein were for the purpose of further illustrating the invention but were not intended as limiting. Throughout this specification and claims, all temperatures are in degrees centigrade and all parts and percentages are by weight unless otherwise indicated.