Patent Publication Number: US-4584319-A

Title: Polyoxyethylene derivatives as antipruritic ectoparasiticide

Description:
This is a division of application Ser. No. 429,444, filed Sept. 30, 1982 (now U.S. Pat. No. 4,497,831) which is a division of application Ser. No. 4,299, filed Jan. 17, 1979 (now U.S. Pat. No. 4,372,977) which, in turn, is a continuation of application Ser. No. 802,012, filed May 31, 1977, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     Ectoparasites such as lice and mites cause pruritus or pain in their animal or human hosts. Therapy which simply kills the parasite leaves the host with subcutaneous or intradermal residues which continue to itch for significant time periods after the infestation is extinguished. Furthermore, scratching during and after the episode frequently leads to painful excoriation. 
     It has now been found that certain ethoxylates exhibit insecticidal and/or ovicidal activity. The same boundaries which delimit the insecticidal properties also include compositions which have a valuable degree of topical anesthetic performance. Although chemically unrelated to any of the conventional anesthetic configurations, these ethoxylates demonstrate topical pharmacologic properties which can be variously characterized as analgesic, anesthetic or antiprurtic. 
     V. B. Wigglesworth (Journal of Experimental Biology, 21, 3, 4 p. 97 (1945)) in a study of transpiration through insect cuticles, reported on the moisture loss of Rhodnius nymphs following treatment with various surfactants. He observed that the ethoxylates of ring compounds had very little action, and that the eight mole ethoxylate of cetyl alcohol was the most effective surfactant be tested, the nymphs losing 48% of body weight in 24 hours. Wigglesworth failed to appreciate that this effect could be adapted to killing insects by an action having no counterpart in higher animals. 
     Maxwell and Piper (Journal of Economic Entomology, 61, No. 6, December 1968 p. 1633) explored the lethal activity of a large series of ethoxylates against southern house mosquito pupae. They found activity at high dilutions (in the parts per million range), but contrary to Wigglesworth, they reported greatest activity with some ethoxylates of alkylphenols. 
     In tests against lice and their ova, we have made certain discoveries which were unexpected in light of Maxwell and Piper, and Wigglesworth. We found efficacy only at concentrations several orders of magnitude greater than Maxwell and Piper. Where they reported that short ethylene oxide chain lengths were less effective than 4-6 moles of ethylene oxide, we discovered that the aryl alkyl ethoxylates were best at 1-3 moles of ethylene oxide, and that such compounds were good ovicides but mediocre pediculicides. Certain ethoxylates of aliphatic alcohols were much superior both as insecticides and as ovicides. Moreover, those most effective as toxicants were also found to be most effective as topical anesthetics. 
     The ethoxylates of this invention are well known as surface active agents and have been incorporated in many pharmaceutical and cosmetic preparations as such. For example, polyoxyethylene (4) lauryl ether is 5.5% of a washable coal tar ointment, polyoxyethylene (23) lauryl ether is 8% of an all purpose anionic emulsion for skin application, and a mixture of these two lauryl ethers constitutes 35% of a commercial tar shampoo. 
     Smith (U.S. Pat. No. 2,666,728) teaches the use up to 5% of a nonionic polyethylene oxide ether of aromatic glycols in a composition for destroying lice. Lindner (U.S. Pat. No. 2,898,267) teaches the use of ethoxylates in emulsifiers for acaricidal compositions. 
     It is the object of this invention to provide new, safe and effective toxicants for lice and their ova. 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 and the pain or itch related to infestation. More particularly, the invention relates to the use of certain ethoxylates as toxicants for lice and/or their ova, and for mites, to toxicant compositions containing such ethoxylates and to such ethoxylates as adjunctive therapy to relieve pain or itch. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The toxicants of the instant inventin are certain ethoxylates i.e., certain derivatives of polyoxyethylene [H(OCH 2  CH 2 ) n  OH]. The polyoxyethylene glycols per se have not been found to be pediculicidal or ovicidal. For convenience, the polyoxyethylene will hereinafter be referred to as POE and the number of repeating units (n) will be indicated in parenthesis where applicable. 
     The POE derivatives which exhibit toxicant properties are the alkyl ethers, alkyl esters and block polymers of polyoxypropylene and/or ethylenediamine. Thus, the alkyl or ester moiety, derived from a fatty alcohol or fatty acid respectively, contains 12 to 24 carbon atoms and preferably 12 to 20 carbon atoms. The alkyl moiety is preferably unsubstituted but can, if desired, contain an aryl substituent. The block polymers contain 6 to 100 POE units and 30 to 112 units of polyoxypropylene. 
     It has been observed that the POE alkyl ethers, alkyl esters and block polymers of polyoxypropylene and/or ethylendiamine require an appropriate hydrophilic-lipophilic balance (HLB) for good activity. In general, the HLB can be about 2.5 to 13.5. The alkyl ethers appear to exhibit maximum activity at an HLB in the neighborhood of 9, and the alkyl esters and block polymers at a lower HLB, excepting the alkyl diester, POE (8) dilaurate, having an HLB value of 10. 
     Exemplary of the POE alkyl ethers of the present invention are POE (1) lauryl ether, POE (2) oleyl ether, POE (2) stearyl ether, POE (3) oleyl ether, POE (3) tridecyl ether, POE (4) myristyl ether, POE (5) oleyl ether, POE (6) tridecyl ether, POE (10) oleyl ether, and the like. POE (1) ethylphenyl ether and POE (3) octylphenyl ether are examples of somewhat effective POE aryl alkyl ethers. 
     Typical examples of the POE esters include POE (3) oleate, POE (2) laurate, POE (8) dilaurate, and the like. Typical examples of the block polymers include Poloxamer 401, Poloxamer 181 and the like. 
     One or more of the toxic ethoxylates 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 activity of the active ingredient. 
     The carrier may also be additive or synergistic to the primary active ingredient. 
     The active ethoxylate is incorporated into the toxicant 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 toxicant amount. By such amount is meant the amount which will cause at least 50% 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 ova. The minimum concentration of ethoxylate in the composition required to provide an effective toxic amount varies considerably depending on the particular ethoxylate, the particular inert pharmaceutically acceptable carrier being employed and any other ingredients which are present. Thus, in one case a 10% concentration may suffice, while in other cases, concentrations as high as 30 to 40% may be required to obtain an effective toxic dose. 
     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 temperture (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. Thereafer, 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 nonfertile 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, the results of pediculicidal and ovicidal testing for various toxicants of this invention are set forth. The materials were tested in undiluted form (neat) or in a combination (C) containing 15% (w/w) compound, 25% isopropanol and 60% water. For comparative purposes, results achieved with the unmodified ethoxylate, i.e., polyethylene glycol (PEG) and other ethoxylates not within the scope of this invention are also set forth. 
     
                       TABLE 1
______________________________________
Pediculicidal and ovicidal activity for
ethoxylate alcohols having a general structure type
H(OCH.sub.2 CH.sub.2).sub.n OH.
                % Mortality
                Pediculicidal
                          Ovicidal
Compound     n        Neat   C      Neat C
______________________________________
diethylene glycol
              2        0      5      0   54
PEG 12       12       25     35     35   16
PEG 32       32       (1)    20     0(2)  0
PEG 75       75       (1)    15     0(2) 14
______________________________________
 
    
     
                       TABLE II
______________________________________
Pediculicidal and ovicidal activity for a
series of alkyl ethoxylate ethers
                  % Mortality
                  Pedi-
                  culicidal
                          Ovicidal
Compound         HLB    Neat    C   Neat  C
______________________________________
POE  (1)    lauryl ether 3.6  100   40  100(3)
                                              100
POE  (2)    oleyl ether  4.9  100   10  100(3)
                                              100
POE  (2)    stearyl ether
                         4.9  100   40  100    33
POE  (3)    oleyl ether  6.6  100   10  100    41
POE  (3)    tridecyl ether
                         8    100   20  100   100
POE  (4)    myristyl ether
                         8.8  100   35  100(3)
                                              100
POE  (5)    oleyl ether  8.8  100   15  100   8.3
POE  (4)    lauryl ether 9.5  100   30  100    83
POE  (6)    tridecyl ether
                         11   100   30  100    0
POE  (6.5)  tridecyl ether
                         11.6 100   15  100    34
POE  (6)    lauryl thioether
                         11.6 100   20  100    0
POE  (10)   oleyl ether  12.4 100   10   5     68
POE  (7)    lauryl ether 12.5 100(4)
                                     0  100(4)
                                               36
POE  (8)    lauryl thioether
                         13.4  75   20   67    0
POE  (9)    lauryl ether 13.6 100   20  100(3)
                                               19
POE  (10)   lauryl thioether
                         13.9  15    5   30    0
POE  (12)   lauryl ether 14.5  20    5  100    0
POE  (20)   isohexadecyl ether
                         15.7 (1)    0  11(2)  2
POE  (23)   lauryl ether 16.9 (1)    0  69(2)  3
______________________________________
 
    
     
                       TABLE III
______________________________________
Pediculicidal and ovicidal activity for some
arylalkyl ethoxylate ethers.
                  % Mortality
                  Pediculicidal
                           Ovicidal
Compound         HLB    Neat    C    Neat  C
______________________________________
POE  (1)    octylphenyl ether
                         3.6  80    10   100(3)
                                               66
POE  (3)    octylphenyl ether
                         7.8  15    5     82(3)
                                               34
POE  (10)   nonylphenyl ether
                         13.4 20    5     82(3)
                                                0
______________________________________
 
    
     
                       TABLE IV
______________________________________
Pediculicidal and ovicidal activity for
ethoxylate mono and diesters
                % Mortality
                Pediculicidal
                         Ovicidal
Compound      HLB     Neat   C     Neat  C
______________________________________
POE  (2)    oleate    3.5   70   75    100(3)
                                             14
POE  (2)    laurate   6.0   25   20    100(3)
                                             6.5
POE  (8)    dioleate  7.2   40    0    7.3   28
POE  (2)    laurate   7.4   95   55    100(3)
                                             8.3
POE  (8)    distearate
                      7.8   (1)  40    (1)   23
POE  (4)    laurate   8.6   10   15     14   5.9
POE  (4)    sorbitol  9      5   20     77   21
            septaoleate
POE  (8)    dilaurate 10    80   10     23   38
POE  (12)   distearate
                      10.6  (1)  40    (1)   24
POE  (20)   stearate  15    (1)   0    (1)   0
POE  (100)  stearate  18.8  (1)   0    (1)   5
______________________________________
 
    
     
                       TABLE V
______________________________________
Pediculicidal and ovicidal activity for
ethoxylate block polymers having the general structure type
outlined for each section.
               % Mortality
               Pediculicidal
                          Ovicidal
x    y       z      HLB    Neat C      Neat   C
______________________________________
(A) based on structure type
 ##STR1##
18   14      18     4.5    10   0       56    4.8
12   23      12     8.4     5   0       0     15
 7   22       7     10.8   10   0       0     41
(B) based on structure type
 ##STR2##
 3   30       3     3      10   0       70    0
13   67      13     4      --   10      0(2)  1.2
 6   67       6     5      55   0       80    84
 8   30       8     7       0   50      8.4   0
21   67      21     8      (1)  10      0(2)  4.5
13   30      13     15      5   20      0     17
38   54      38     15     (1)  0       0(2)  19
122  47      122    27.5   (1)  40       (1)  4.5
(C) based on structure type
 ##STR3##
18    2             2       5   20      79    0
12    2             3      45   0       73(3) 11
21    7             3.5    30   0      100(3) 53
26    8             5       5   0      100(3) 49
13    4             7       0   20      58    0
26   24             13     85   0       --    20
 8    7             16      0   20      0     28
______________________________________
 
    
     Notes to Tables I-V 
     (1) Solid--could not be tested at 100% 
     (2) 50% (w/w) in ethanol 
     (3) pad noted to be coated with compound at conclusion of test 
     (4) 90% (w/w) in water 
     The pediculicidal activity of various compounds set forth in Table II as a function of concentration was determined in a diluted system containing 25% isopropanol and water q.s. The results are shown in Table VI. 
     
                       TABLE VI
______________________________________
Concentration, % (w/w)    Mortality, %
______________________________________
A.  POE (1)    lauryl ether
                           HLB = 3.6
               10                   55
               15                   40
               20                   80
               30                   85
               40                   80
               50                   95
B.  POE (2)    oleyl ether HLB = 4.9
               10                   30
               15                   10
               20                   35
               30                   15
               40                   20
               50                   35
C.  POE (2)    stearyl ether
                           HLB = 4.9
               10                    0
               15                   40
               20                   80
               30                   50
               40                   100
               50                   100
D.  POE (3)    oleyl ether HLB = 6.6
               15                   10
               20                   15
               30                   60
               40                   70
               50                   100
               60                   100
E.  POE (3)    tridecyl ether
                           HLB = 8
               10                   25
               15                   20
               20                   95
               30                   95
               40                   100
               50                   100
F.  POE (4)    myristyl ether
                           HLB = 8
               10                   75
               15                   35
               20                   90
               30                   100
               40                   100
               50                   100
G.  POE (4)    lauryl ether
                           HLB = 9.5
               10                   15
               15                   30
               20                   55
               30                   80
               40                   85
               50                   60
H.  POE (6)    tridecyl ether
                           HLB = 11
               10                   40
               15                   30
               20                   65
               30                   75
               40                   35
               50                   55
I   POE (6.5)  tridecyl ether
                           HLB = 11.6
               15                   15
               20                   25
               30                    5
               40                   35
               50                   30
               60                   60
J.  POE (7)    lauryl ether
                           HLB = 12.5
               15                    0
               20                   10
               30                   20
               40                   20
               50                   35
               60                   40
K.  POE (9)    lauryl ether
                           HLB = 13.6
               15                   20
               20                   25
               30                   15
               40                   25
               50                   70
               60                   50 15 -L. POE (12) lauryl ether HLB =
                                    14.5
               15           5
               40                    0
               50                   15
               60                   30
               70                   45
M.  POE (23)   lauryl ether
                           HLB = 16.9
               15                    0
               20                    0
               30                    0
               40                    0
               50                    0
               60                    5
______________________________________
 
    
     The pediculicidal activity of two ethoxylated alkyl ethers as a function of concentration when diluted with water was determined and the results are set forth in Table VII. 
     
                       TABLE VII
______________________________________
Concentration, % (w/w)  Mortality, %
______________________________________
A.    POE (2)  oleyl ether
                          HLB = 4.9
                5                  0
                10                 10
                20                 35
                30                 90
                40                100
                60                100
                80                100
               100                100
B.    POE (4)  lauryl ether
                          HLB = 9.5
                5                  5
                10                 5
                15                 45
                20                100
                80                100
                90                100
               100                100
______________________________________
 
    
     The ovicidal activity of various compounds set forth in Table II as a function of concentration was determined in a diluted system containing 25% isopropanol and water q.s. The results are shown in Table VIII. 
     
                       TABLE VIII
______________________________________
Concentration, % (w/w)   % Mortality
______________________________________
A.  POE (1)   lauryl ether
                          HLB = 3.6
               1                   100
               3                   100
               5                   100
               7                   100
               9                   100
B.  POE (3)   tridecyl ether
                          HLB = 8
              10                   100
              15                   100
              20                   100
              30                   100
              40                   100
C.  POE (4)   myristyl ether
                          HLB = 8.8
              10                    27
              15                   100
              20                   100
              30                    92
              40                   100
              50                   100
D.  POE (6)   tridecyl ether
                          HLB = 11
              10                    0
              15                    0
              20                    16
              30                    44
              40                    14
              50                    3
E.  POE (12)  lauryl ether
                          HLB = 14.5
              15                    0
              30                    0
              40                   0.2
              50                    5
              60                    2
              70                    0
F.  POE (23)  lauryl ether
                          HLB = 16.9
              15                    3
              20                    10
              30                    4
              40                    5
              50                    0
              60                    5
______________________________________
 
    
     Table IX reflects the resulting pediculicidal and ovicidal activity of a 15% (w/w) concentration of POE (4) lauryl ether with variation of isopropanol and water content 
     
                       TABLE IX
______________________________________
                  % Mortality
% w/w isopropanol
            % w/w water Pediculicidal
                                    Ovicidal
______________________________________
25          60          30          83
20          65          30          21
15          70          15          19
10          75          15          15
 5          80          95          100
 1          84          20          100
 0          85          45          10
______________________________________
 
    
     As can be seen from Table IX, the 15% concentration of POE (4) lauryl ether exhibited synergistic pediculicidal activity when the isopropanol was about 1-5%. 
     The most effective toxicants of this invention have also been found to exhibit topical anesthetic activity. Thus, for example, one drop of 5% aqueous POE (4) lauryl ether caused an onset of corneal anesthetic action in about 5-8 minutes with a duration of about 0.5-4 hours (average four tests was two hours) in a modified Cole and Rose rabbit eye iritiation test (J. Lab. &amp; Clin. Med. 15:239, 1929). In contrast, POE (23) lauryl ether did not exhibit any activity in the same test. In general, the preferred alkyl ethers exhibit anesthetic, analgesic or antipruritic activity at concentrations of at least 1% and are preferably employed for this purpose at about 1-10%. 
     The miticidal activity of some of the instant toxicants was determined as follows. Into a one cubic foot chamber, held at room temperature, is placed a covered microscope depression slide containing ten adult mixed sex mites, Psoroptes equi var. cuniculi. The slide is positioned at a distance of ten inches horizontally and four inches below the activator of a mechanical spray device and uncovered. The mechanical pump spray device delivers 50 micrograms of sample per depression of the activator. The sample to be tested, maintained at room temperature, is shaken until homogeneous and placed in the mechanical pump spray device. The primed activator is depressed twice, releasing 100 micrograms of spray mist into the closed chamber. The mist is allowed to settle and the slide containing the mites is removed and covered. This point of time is considered zero hours. The covered slide is then held at room temperature for 24 hours. Microscopic observations are noted at 0, 1, 3, and 24 hours post treatment. Controls are run in an identical manner as that described using water or the diluting agent, and net mortality results are reported. 
     Table X shows the miticidal activity of a 50% (w/w) concentration of the named compounds in isopropanol. 
     
                       TABLE X
______________________________________
Compound         HLB    Miticidal Activity, %
______________________________________
POE (1)  lauryl ether
                     3.6    100
POE (2)  oleyl ether 4.9     80
POE (4)  myristyl ether
                     8.8    100
POE (4)  lauryl ether
                     9.5    100
POE (6)  tridecyl ether
                     11      90
POE (10) oleyl ether 12.4   100
POE (12) lauryl ether
                     14.5   100
______________________________________
 
    
     As noted, various end use formulations can be prepared. Some typical formulations are set forth and the amounts recited are percentages by weight: 
     Liquid pediculicide and ovicide suitable for mechanical spray application or inunction. 
     
         ______________________________________
POE (8) dilaurate            15
Isopropanol                  60
Water                        25
Liquid pediculicide and ovicide shampoo
POE (4) lauryl ether         26.0
POE (23) lauryl ether        7.7
Isopropanol                  7.7
Benzalkonium chloride        0.2
Water                        58.4
Ovicidal powder
POE (3) tridecyl ether       3
Pyrophyllite                 97
Pediculicidal and ovicidal powder
POE (1) lauryl ether         10
Prophyllite                  90
Pediculicidal Stick
POE (2) oleyl ether          15.0
Sodium stearate              8.0
Sorbitol                     3.5
Isopropanol                  25.0
Ethanol                      39.0
Water                        9.5
Pediculicidal and ovicidal quick breaking aerosol foam
POE (4) lauryl ether         20
Water                        72
Isobutane                    8
Pediculicidal and ovicidal gel
POE (2) oleyl ether          15.0
Isopropanol                  25.0
Carbomer 940                 0.5
Triethanolamine              0.38
Water                        59.12
______________________________________
 
    
     As noted, 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 made 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.