Abstract:
Certain substituted glycine compounds have been found to exhibit strong ovicidal activity, with a good degree of insecticidal activity.

Description:
BACKGROUND OF THE INVENTION 
     Many species of insects encase their ova in protective sheaths which are impregnable to most toxicants. The gestation period of the egg is often relatively long in comparison to the life cycle of the adult forms. Thus, an agent effective only against adults must persist for the lifetime of the developing ovum, or must be re-applied as successive hatchings occur. 
     Highly effective insect ovicides having low toxicity to mammals are quite rare. 
     It has now been found that certain N-acyl sarcosines, i.e., N-acyl-N-methyl glycines, exhibit effective ovicidal activity, often with a useful degree of insecticidal activity. These glycines are well known as surface active agents and have been incorporated in many pharmaceutical and cosmetic preparations as such. For example, tetradecylamine lauroyl sarcosinate has been used in an anti-dandruff preparation and cocoyl sarcosine constitutes greater than 10% of Head and Shoulders shampoo. Cocoyl sarcosine has been used in hair tint shampoos at a pH of 5.5. Dvorokovitz (U.S. Pat. No. 2,890,960) teaches the use of antienzymes including lauryl sarcosinic acid to retard ovideposition in fruit flies. 
     It is the object of this invention to provide new safe and effective toxicants for insects and their ova. The low mammalian toxicity of the subject compositions and methods renders them especially suitable for the treatment of ectoparasitic diseases, such as lice and scabies, in man and animals. In these applications, the ovicidal properties are particularly noteworthy, both for speed of impact and for potency. 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 ovicides and insecticides and the method of controlling insects. More particularly, the invention relates to the use of certain N-acyl-N-methyl glycines as toxicants for ectoparasites and their ova and to toxicant compositions containing such glycines. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The toxicants of the instant invention are those N-acyl-N-methyl glycines in which the acyl moiety contains 12 to 20 carbon atoms, preferably 13 to 20 carbon atoms. Typical examples of the glycines are lauroyl sarcosine (N-lauroyl-N-methyl glycine), oleoyl sarcosine (N-oleoyl-N-methyl glycine) and cocoyl sarcosine (N-cocoyl-N-methyl glycine) and the like. 
     As noted earlier, the glycines of the instant invention are known compounds and have been used as surface active agents in shampoo formulations. Shampoo formulations generally have pHs in excess of 5.5. It has been observed that only the acid form of the sarcosine is active and therefore the pH of the formulation containing the sarcosine must be less than 5.5 for the material to exhibit optimum pediculicidal and ovicidal activity. Accordingly, the prior art shampoos employed the sarcosine as a surfactant in the form in which they were not toxicant, except to the limited extent that the acidic form may have existed in equilibrium with the ionized salt. 
     One or more of the toxic glycines of the present invention can be incorporated into an active toxicant composition which can be in the form of a liquid, powder, lotion, cream, gel or aerosol spray, or foam as the result of formulation with inert pharmaceutically acceptable carriers by procedures well known in the art. Any pharmaceutically acceptable carrier, whether aqueous or not aqueous, which is inert to the active ingredient can be employed. By inert is meant that the carrier does not have a substantial detrimental effect on the pediculicidal or ovicidal toxicant performance of the active ingredient. 
     The active glycines are incorporated into the toxicant composition used to treat the substrate (human or animal) in need of such treatment, believed to be in need of such treatment, or desired to be prophylactically protected in an effective toxicant amount. By such amount is meant the amount which will cause at least 50%, preferably at least 75%, of the ectoparasites exposed in the two minute immersion tests described below to die within 24 hours in the case of lice and within 2 weeks in the case of the ova. The minimum concentration of glycines in the composition required to provide an effective toxic amount varies considerably depending on the particular glycine, the particular inert pharmaceutically acceptable carrier being employed and any other ingredients which are present. Thus, in one case a 5% concentration may suffice, while in other cases, concentrations as high as 30 to 40% may be required to obtain an effective toxic dose. In most instances, however, a concentration of 1 to 15% is sufficient. Higher concentrations may be irritating to the skin or eyes of vertebrates. 
     The instant glycines can also be employed as an adjunct toxicant in a preparation which otherwise exhibits pediculicidal and/or ovicidal activity. In such preparations, the term &#34;effective toxic dose&#34; means that amount which will increase the mortality rate by at least about 20% in the standard immersion tests. 
     The formulation in which the glycine is used must have a pH below about 5.5. It is preferred to maintain the pH above about 2.0 and the preferred pH range is about 3 to 5. The pH can be adjusted by procedures well known in the art, e.g., by using a suitable acid, ion exchange resins, etc. 
     The two minute immersion test referred to above is carried out as follows: 
     Pediculicidal activity: 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 homogeneous and placed into a 50 ml beaker. The mesh patch is placed into the sample immediately after pouring, allowed to submerge, and after two 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 zero hours. Thereafter, the corduroy patch is placed in a petri dish which is covered and stored in a 30° C. holding chamber. 
     Ovicidal activity: 15 adult, 5 to 10 day old, female lice (Pediculus humanus corporis) are placed on a 2 × 2 cm nylon mesh patch which is placed in a petri dish, covered and maintained in an incubator at 30° C. for 24 hours. The adult lice are then removed and the number of plump, viable eggs and shriveled non-fertile eggs on the patch are recorded. The sample to be tested, maintained at room temperature, is shaken until homogeneous and poured into a 50 ml beaker. Immediately after the pouring, the mesh patch is placed into the beaker, allowed to submerge, and after two minutes is removed and immediately plunged into a 50 ml beaker containing tap water at room temperature (about 24° C.). The patch is vigorously agitated every ten seconds and after one minute, the patch is removed and placed on paper toweling for one minute. The patch is then placed in a petri dish which is covered and stored in the 30° C. incubator. Fourteen days following treatment, the number of hatched eggs and the number of shriveled or unhatched eggs is noted. 
     In both the pediculicidal and ovicidal two minute immersion test, controls are run in identical manners to that described with room temperature (24° C.) tap water substituted for the sample to be tested. The results of the tests reported are net results. 
     In the following tables 1 and 2, the results of pediculicidal and ovicidal testing of lauroyl sarcosine is set forth. The sarcosine was tested at various concentrations in a formulation which contained 25% isopropanol and water q.s. ad. 100%. 
     
                       Table 1______________________________________Pediculicidal Activity     Concentration. %                  Mortality, %______________________________________Acid       1              0       2              5       3              5       4              5       5              20       6              75       7              90       8              100Sodium Salt       30             5       40             0       50             5       60             5       70             5       80*            0       90*            0______________________________________ *isopropanol level was zero in these samples. 
    
     
                       Table 2______________________________________Ovicidal Activity     Concentration, %                  Mortality, %______________________________________Acid       1              82       2              62       3              96       4              100       5              100       6              100       7              100       8              100       9              100       10             100Sodium Salt       30             0       40             20       50             12       60             38       70             0       80*            34       90*            77______________________________________ *isopropanol level was zero in these samples. 
    
     Tables 1 and 2 illustrate that when the sarcosine is used in the form of sodium salt, i.e., at an approximately neutral pH, the formulations are not strongly pediculicidal or ovicidal. 
     The pediculicidal and ovicidal activity of oleoyl sarcosine as a function of concentration was determined in a formulation which contained 25% isopropanol and water q.s. ad. 100%. The results are shown in table 3. 
     
                       Table 3______________________________________         Mortality, %Concentration, %           Pediculicidal                        Ovicidal______________________________________1               40             772               75           1003               75           1004               55           1005               65           1006               100          1007               95           1008               100          100______________________________________ 
    
     The pediculicidal and ovicidal activity of cocoyl sarcosine was determined as a function of concentration in a system containing 25% isopropanol and water q.s. ad. 100%. The results are shown in Table 4. 
     
                       Table 4______________________________________         Mortality, %Concentration, %           Pediculicidal                        Ovicidal______________________________________1                5           1002                5            933               15           1004               10           1005               35           1006               50           1007               40           1008               40           1009               75           100 10             80           100 12             70           -- 15              100         --______________________________________ 
    
     The sarcosines may be used in formulations other than those used to determine the data set forth in the foregoing tables. For example, a composition containing 50% stearoyl sarcosine and 50% ethanol has an activity of 80% in the standard ovicidal testing described before. Similarly, a formulation containing 15% stearoyl sarcoside, 25% isopropanol, 7% Tween 80 and 53% water exhibits 100% activity in both the pediculicidal and ovicidal tests hereinberfore described. 
     Some typical formulations are set forth below and the amounts recited are percentages by weight: 
     
         ______________________________________Clear liquid suitable for mechanical sprayapplication or inunction isopropanol                40 lauroyl sarcosine          10 water                      60Clear liquid shampoo isopropanol                25 cocoyl sarcosine           4 triethanolamine lauryl sulfate                    20 water                      51Powder pyrophyllite               94 oleoyl sarcosine           6Quick breaking aerosol foam mono and diglycerides from the glycerides of edible fats  8 isopropanol                25 lauroyl sarcosine          8 glycerin                   3 water                      48 isobutane                  8Ovicidal aerosol spray cocoyl sarcosine           1 isopropanol                25 water                      64 isobutane                  10Ovicidal liquid suitable for mechanicalspray application or inunction oleoyl sarcosine           2 isopropanol                35 water                      63Gel isopropanol                25 oleoyl sarcosine           7 xanthan gum                2 acetic acid, 1N            10 water                      56Cream cetyl alcohol              3.0 cocyl sarcosine            14.0 glyceryl monostearate      8.0 sorbitan monostearate      8.0 isopropanol                25.0 xanthan gum                0.3 water                      41.7______________________________________ 
    
     The ovicidal aerosol spray and the ovicidal liquid are primarily ovicidal; all other formulations are both insecticidal and ovicidal. 
     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 to limit it. Throughout this specification and claims, all temperatures are in degrees Centigrade and all parts and percentages are by weight unless otherwise indicated.