Note: Descriptions are shown in the official language in which they were submitted.
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 anes-
thetic 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, 4p. 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
.
:'
.
. :"
: - ~- :
effecti~e 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
ha~ing no counterpart in higher animals.
Maxwell and Piper (Journal of Economic Entomology, 61,
No~ 6, Dec. 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 Wigglèsworth. We found eficacy only at concentrations
se~eral orders o magnitude greater than hlaxwell and Piper.
Where they reported that short ethylene oxide chain lengths
were less effective than 4-6 moles of ethylene oxide, we dis-
covered that the aryl alkyl ethoxylates were best at 1~3 moles
of ethylene oxide, and that such compounds were good o~icides but
mediocre pediculicides. Certain ethoxylates of aliphatic alcohols
were much superior both as insecticides and as ovicides, Moreover,
- thoso most effective as toxicants were also found to be most
,
effective as topical anesthetics.
The ethoxylates of this invention are well known as surface
~ acti~e agents and have been incorporated in many pharmaceutica
.,~ .
and cosmetic preparations as such. For example, polyoxyetnylene
(4) lauryl ether is 5.5% of a washable coal tar ointment, poly-
, ....
?~l oxyethylene (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.
,, ' .
,' ' . ~
. . .
~ -2- ~
Smith ~U.S. 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. 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.
SUM~RY OP THE INVENTION
; This invention relates to ectoparasiticidal toxicants and a
~ethod 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
;I such ethoxylates and to such ethoxylates as adjunctive therapy
to relieve p~in or itch.
~! DESCRIPTION OF THE PREF~RRED EMBODIMENTS
~,`1
The toxicants of the instant invention are certain
ethoxylates i.e., certain deriva~ives o polyoxyethylene
~H(OCH2CH2)nOH], The polyoxyethylene glycols per se have not
been ound to be pediculicidal or ovicidal. For convenience,
the polyoxyethylene will hereinafter be reerred 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
.
:
-3-
... ..., _... ... ., .. _ ...........
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; 10 at a lower HLB, excepting the alkyl diester, POE (8j 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 (l)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
~: B examples of the block polymers include Poloxamer~ 401, Poloxame~tM
;j 181 and the like.
One or more of the toxic ethoxylates of the present
invention can be incorporated into an active toxicant com-
, position 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
;~
.' .
.
~4~
. . . , i . -
,,~ ingredient can be employed. By inert is meant that the carrier
does not have a substantial detrimental effect on the pediculi-
cidal 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 treat- ,
ment, 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 con-
centration of ethoxylate in the composition required to provide
an efective 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
,, 20 be required to obtain an e~fective 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 temperature (about 24C),
Ten young adult male and ten young adult emale lice tpeaiculus
humanus ,corporis) of the same age group and from the same stock
colony are placed on a 2x2 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 immsdiately plunged into the
.
.: .
~ 3~
beaker containing the tap water. The patch is Yigorously agitated
e~ery ten seconds and after one minute the patch is remo~èd and
placed on paper toweling. The lice are then transferred to a
4x4 cm black corduroy cloth patch and this point of time is con-
sidered zero hours. Thereafter, the corduroy patch is placed in
a petri dish which is covered and stored in a 30C holding chamber.
Ovicidal activity: 15 adult, 5 to 10 day old, female
lice (Pediculus humanus corporis) are placed on a 2x2 cm nylon
~¦ mesh patch which is placed in a petri dish, covered and maintained
in an incubator at 30C for 24 hours. The adult lice are then
¦ removed and the number o 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 bea~er. Immediately after the pouring, the
mesh patch is placed into the beaXer, 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 remo~ed and placed on paper
toweling for one minute. The patch is then placed in a petri
dish which is covered and stored in the 30C incubator. Pour-
teen tays 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 (24C) tap water substituted for the
sample to be tested. The results of the tests reported are
. j .
net results.
. .
.
. . .. . . .. ..
.
~3~ ~:
, , , . ' `:
~n 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 for~
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., poly-
' ethylene 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(OCH2CH2)nOH-
,, ' ' ' , , ' ,
Mortality
Pediculicidal Ovicidal
~.,, - ,
Compound n Neat C Neat C
diethylene glycol 2 0 5 0 S4
;~ PEG 12 lZ 25 35 35 16
PEG 32 32 (1) 20 0(2) 0
PEG 75 75 ~1) 15 0(2) 14
~'' ' ' .
. . ,
1....................................................... .
,, ' , .
, ....
~' '
. "1 , .,
' ' , .
:: .
~ 7
-
~3e~
Table II. Pediculicidal and ovicidal activity for a
series of alkyl ethoxylate ethers.
.
: .
. % ~lortality ~ .
Pediculicidal OvicidaL
Compound HLB NeatC Neat C
POE (1) lauryl ether 3.6 10040 100(3) 100
POE ~2) oleyl ether 4.9 10010 100~3) 100 : :
:~ POE (2) stearyl ether 4.9 100. 40 100 : 33
POE (3) oleyl ether 6.6 10010 100 41
.. . . . .
POE (3).tridecyl ether 8 10020 100 100
POE (4) myristyl ether 8.8 10035 100~3) 100:
POE (5) oleyl ether 8.8 10015 100 8.3
POE (4) lauryl ether 9.5 10030 100 83
POE (6) tridecyl ether 11 10030 100 o
POE (6.5) tridecyl ether- 11.6 100 15 100 34
POE (6) lauryl thioether 11.6 100 20 100 n
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 15.6 ioo 20 100~3) 19
POE (10) lauryl thioether 13.9 15 5 30 0
POE (12) lauryl ether 14.5 . 20 5 100 o
POE (20) isohexadecyl ether 15.7 (1~ o llt2) 2
POE ~23) lauryl ether 16.9 (1) o 69(2) 3
... .~
'~'' ' ,, ' ':
, '
.~, . .
. . .
:. -8- :.
. i
Table III. Pediculicidal and ovicidal activity ~or some
: arylalkyl ethoxylate ethers.
% Mortality
Pediculicidal Ovicidal
Com ound HLB Neat C Neat C
, P
POE (l) octylphenyl ether 3.6 80 lO lOO~3) 66
POB (3) octylphenyl ether 7.8 15 5 82(3) 34
~: POE (lO) nonylphenyl ether 13.420 5 82t3) 0
,,.
.. " :
. Table IV. Pediculicidal and ovicidal activity for
ethoxylate mono and diesters.
. ' ' ' ~'.
... ~ Mortality
' Pediculicidal- Ovicidal
Compound HLB Neat C Neiat, C
POE (2) oleate 3.5 70 75 lOO~3) 14
1 .. 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 ~l) 40 ~l) 23
'~1 POB t4) laurate 8.6 lO 15 14 5.9
~! 20 POE (4) sorbitol
'~! septaoleate 9 5 20 77 21
POE (8) dilaurate lO 80 lO 23 38 ~ -
POE (12) distearate lO.6 (l) 40 (l) 24
?ij
POE (20) stearate 15 (l) o (l) o
POE (lOO) stearate 18.8 (l) o (l) 5
'.' ..
~ ~ .
:. 9
,
...... _ _ -
TABLE V. Pediculicidal and ovicidal activity for
ethoxylate block polymers having the general structure type :
outlined for each section.
i'~'' . ' ' , . .
A) based on structure type
HO(CHCH20)x(cH2cH2o)y(cHc~2o) z
CH3 CH3
; - .
. % ~lortality
Pediculicidal Ovicidal
: . x _y__ z HLB Neat C Neat C
. . . _ .
18 14 18 4.5 10 0 56 4.8
12 . 23 12 8.4 5 0 0 lS
7 22 . 7 10.8 10 0 . O 41
... .
,. . .
B) based on structure type
Ho~cH2cHzo)x(cHcl~2o)y(cH2c~l2o)zH
: CH3 : .
. % ~lortality
::' Pediculicidal Ovicidal
~,
. x _y_ z HLB Neat C Neat C
3 30 . 3 3 10 0 70 0 ~.
13 67 13 4 _ 10 ~t2) 1.2
6 67 6 5 55 0 80 . 84
. 8 30 8 7 0 50 8.4 O
21 67 . 21 8 (1) 10 0~2) 4.5
, 13 30 13 15 5 20 0 . 17
~' 38 5~ 38 15 (1) 0(2) 19
122 47 122 27.5 (1) 40 ~1) 4.5
:~ .
.
-10 -
.
;
.-.
~' : ' ' -- '; ~
.. . .
C) based on structure type
C~13 C~13
H(ocH2cH2)y~ocH2cH)x / (CHcH2o)x(cl{2cH2o)yH
NC11 CH N
C~13 / \ CH3
H(ocH2cH2)y(oc~l2cHlx (C~CH20)x(CH2CH20)yH
% ~1ortality
. . Pediculicidal Ovicidal
x y HLB Neat C Neat C
_
18 2 2 5 20 79 0
;:. 12 2 3 ~5 0 73(3)ll
21 7 3.5 30 0 l00(3)53
.
26 .8 . 5 5 . 0 . l00(3)49
13 4 7 0 : 20 58 O
,; . .
~`i 26 24 13 85 0 - 20
., 8 7 16 0 20 0 28
, . ' ' ' ' ' ",
Notes to Tables I-V
(l) solid - could not be tested at 100%
. (2) 50% (w/w) in ethanol
(3) pad noted to be coated ~Yith 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.
-11 - -
.
-,
TABLE VI
': Concentration, %~w/w) Mortality, $
,' A. POE ~1) lauryl ether HLB = 3.6 -
. 20 80
- 85
. SO . 95
'
B. POE (2) oleyl ether HLB - 4.9
IO 10 30 ~ ~
. 15 10 . ~ ~.
~
~ 20 35 `
.
! 30 15 :
.
^ 40 20
C. POE (2) stearyl ether HLB ~ 4.9
' 10 o
: 15 40
. 20 30 50
i .
100
: 50 100
,'' ' ' ' ' I .
'' ' , .
-12- 1
. .. .. 1~
.: ' - ~
~, .
D. POE (3) oleyl ether HLB- 6,6
. 70
` 100 .
100
E. POE t3) tridecyl ether HLB = 8 -
. 15 . 20
` : .95
100
i `. 100
,;! .
F. POE ~4) myristyl ether HLB ~ 8
, 10 75
. 90
100
~ 40 100
100
,:
G. POE (4) lauryl ether HLB = 9.5
,
. 40 85
~: . 50 60
.,. , . - .
~ -13-
~ ~. .
: : :
.3~
il. POE (6) tridecyl ether HLB = 11
~-~ 30 75
. 35
. '
- I . POE (6 . 5) tridecyl ether HLB = 11. 6
0 20 25
~, J. POE (7) Iauryl ether HLB = 12 . 5
; 15 . 0
; 20 10
. 35
', , ' ',
K. POE t9) lauryl ether ~ILB = 13 . 6
lS 20
~5:
.
lS
: 40 25
. 60 . 50
-14 -
. . . . . .
P~-
L. POE (12) lauryl ether HLB = 14.5
. 0
. 15
.
: 70 45
M. POE (23) lauryl ether HLB = 16.9
. . 0
0
;~ 10 30 . 0
0
. 0
.: , .
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,
'
. . ' ' . '
, ..
, . .
~,,
-15-
' ','
:, , . :
TABLE VII
Concentration, % (w/w) ~lortality,
A. POE (Z) oleyl ether ~ILB = 4.9 .
O :~
. . 10 10 ' .
100
. . 100
100
100 100 , ' '
.
B, POE (4) lauryl ether HLB - 9.5
. S
' 5 , . ..
lS 45
100 -
100
100
100 ' ' 100
.
The ovicidal activity of various compounds set forth
in Table II as a unction of concentration was determined
in a diluted system containing 25~ isopropanol and water q.s.
The results are shown in lable VIII.
-16-
'~
~3E. `~3
TABLE VIII
.
- . Concentration, ~ tw/w) ~ ~lortality -
A. POE (1) lauryl ether ~ILB = 3.6
100 ~ .
3 100
100
7 100
9 100
',:
B. POE t3) tridecyl ether HLB = 8
. lq ' 10 100
. 15 100
20 100
100
, . 40 100
.
C. POE (4~ ~yristyl ether HLB = 8.8
, : 10 27
.; , . ,
: 15 100
100
.
92
.20 40 100
100
i; . .
D. .POE (6) tridecyl ether HLB = 11
;~ . 10 0
',. , 15 , O'
- 16
4~
: 40 14
, 50 3
.
-17- -
.
^ ~ ~ ,.
. . .' .. ' ~ ' .
,, .
-
E. POE (12) lauryl ether HLB - 14.5 ~:
0
O
0.2
' 50 ' 5 ~ ,
60 , 2
O
:~,
F. POE ~23) lauryl ether HLB = 16.9
lQ 20 10 . .
" , . SO ' . O .
. '`' ' '' . ':
Table IX reflects the resulting pediculicidal and
.
ovicidal activity of a 15~ (w/w) concentration of POE t4)
lauryl ether with variation af isopropanol. and water content . ..
., .
TABLE rx
% ~ortality
% w/w isopropanol % w/w water Pediculicidal Ovicidal
~ . 25 60 30 83
.: 20 65 30 21 ,
19
S 80 95 100
, .. . .
~ 1 84 20 100 . ,
: 0 85 45 10
.
. ~ .
-18-
-
.
: .
.
~ s can be seen from Table IX, the 15% concentration of
POE (4) lauryl ether exhibited synergistic pediculicidal
activity when the isopropanol ~as about l-S~.
The most efective toxicants o~ 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. ~ Clin. ~led. 15:239, 1929). In
contrast, POE (23) lauryl ether did not exhibit any activity
in the same test. In general, the preerred alkyl ethers
exhibit anesthetic, analgesic or antipruritic activity at
concentrations o at least 1~ and are preferably employed for
this purpose at about 1-10~.
The miticidal acti~ity 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 de-
pression slide containing te~ adult mixed sex mites, Psorop~es
equi var. cuniculi. The slide is positioned at a distance of
ten inches horizontally and four inches below the activator o~
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 sha~en until homogeneous and placed in
the mechanical pump spray device. The primed activator is de-
pressed 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 co~sidered zero hours. The covered slide is then held at
room temperature for 24 hours. .liscroscopic observations ar~
noted at 0, 1, 3, and 24 hours post treatment. Controls are
,
-19-
. , . ... , . . . . = . .. .. . ... . .. .. . . ... . . ..
- . ~
3~
run in an identical manner as that ~escribed using water or the
diluting a~ent, and net mortality results are reported.
Table X shows the miticidal activity of a 50~ twJw)
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 ~orth and the amounts recited
are, percentages by weight:
.. . . .
, Liquid pediculicids and ovicide suitable ~or mechanicsl '
'" spray application or inunction.
POE (8) dilaurate 15
,, 20 Isopropanol 60 ,Water 25 , ,
:
Liquid pediculicide and ouicide shampoo '~
POE (4) lauryl ether 26.0
, , POE (23) lauryl ether 7.7
,~ Isopropanol 7.7
Benzalkonium chloride 0.2
Water 58.4
-20-
~, . ~ -- , . ., -
-
Ovicidal powder
: POE (3) tridecyl ether 3 - .
Pyrophyllite . 97
.
Pediculicidal and ovicidal powder
: POE tl) 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 t4) lauryl ether 20
. Water 72
~: . Isobutane 8
.
Pediculicidal and ovicidal gel
POE (2) oleyl ether 15.0
Isopropanol 25.0
Carbomer 940 (7'r~de~ar~) 0 5
. ~ ,~ . . .
.~. Triethanolamine 0.38
Water 59.12
: , .
~"' , '' .
~'~ ' . .
-21 :
....... ,.. ,,,, , ~
lL13~
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.
: ~'
~: . ,
.''' ' ' .. . .
.''' . ' ', , . , ~. ~
.
,. ' , . ' . :' ' '~'
: '
., '
. . ~ .
. , . .
'. . '
;~ ' .
.'' , ,' . . .
.. , , .
':' '' ' '
,' .
; ' ' . .
. . -22-
.
~,. . ,
