U.S. patent application number 17/667424 was filed with the patent office on 2022-05-26 for topical avermectin formulations and methods for elimination and prophylaxis of susceptible and treatment resistant strains of head lice.
The applicant listed for this patent is ARBOR PHARMACEUTICALS, LLC. Invention is credited to Garry T. Gwozdz, Nicholas Spring.
Application Number | 20220159961 17/667424 |
Document ID | / |
Family ID | 1000006128721 |
Filed Date | 2022-05-26 |
United States Patent
Application |
20220159961 |
Kind Code |
A1 |
Spring; Nicholas ; et
al. |
May 26, 2022 |
Topical Avermectin Formulations and Methods for Elimination and
Prophylaxis of Susceptible and Treatment Resistant Strains of Head
Lice
Abstract
An avermectin-based topical formulation is disclosed which is
useful for prevention and treatment of head lice (Pediculus humanus
capitis). This topical formulation may be formulated as a
shampoo-condition which comprises an effective amount of
avermectin, solubilizers, suspending agents, preservatives,
nonionic surfactants, humectants, a silicone compound, and water.
Also disclosed are methods of using the topical formulations
disclosed within this specification to treat either a susceptible
or treatment-resistant strain of lice, as well as uses in the
manufacture of a medicament for treating or preventing a lice
infestation from a susceptible or treatment-resistant strain in a
human patient.
Inventors: |
Spring; Nicholas;
(Jenkintown, PA) ; Gwozdz; Garry T.; (Bethlehem,
PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARBOR PHARMACEUTICALS, LLC |
Atlanta |
GA |
US |
|
|
Family ID: |
1000006128721 |
Appl. No.: |
17/667424 |
Filed: |
February 8, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15968364 |
May 1, 2018 |
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17667424 |
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14572664 |
Dec 16, 2014 |
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15968364 |
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13116547 |
May 26, 2011 |
8927595 |
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14572664 |
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11871660 |
Oct 12, 2007 |
8791153 |
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13116547 |
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60976259 |
Sep 28, 2007 |
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60851352 |
Oct 12, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A01N 25/04 20130101;
A61K 47/14 20130101; A01N 43/90 20130101; A01N 25/00 20130101; A61K
47/24 20130101; A61K 31/7048 20130101; A61K 47/26 20130101 |
International
Class: |
A01N 43/90 20060101
A01N043/90; A61K 47/26 20060101 A61K047/26; A61K 47/14 20060101
A61K047/14; A61K 47/24 20060101 A61K047/24; A61K 31/7048 20060101
A61K031/7048; A01N 25/00 20060101 A01N025/00; A01N 25/04 20060101
A01N025/04 |
Claims
1. A topical formulation comprising about 0.1% to about 2.0% by
weight ivermectin, at least one solubilizer, at least one
suspending agent, at least one paraben preservative, at least one
non-ionic surfactant, and about 30% to 40% by weight water.
2. The topical formulation of claim 1, comprising about 0.5% by
weight ivermectin.
3. (canceled)
4. The topical formulation of claim 1, wherein said solubilizer is
selected from the group consisting of polysorbate 80, cetyl
acetate, acetylated lanolin alcohol and combinations thereof.
5. The topical formulation of claim 1, wherein the preservative is
selected from the group consisting of methylparaben, propylparaben,
ethylparaben, butylparaben, isobutylparaben, isopropylparaben, or
benzylparaben, sodium salts thereof, and combination thereof.
6. The topical formulation of claim 1, wherein said nonionic
surfactant is selected from the group consisting of oleyl alcohol,
lanolin alcohol, sorbitan tristerate, bees wax, erucyl alcohol,
ricinolyl alcohol, arachidyl alcohol, capryl alcohol, capric
alcohol, behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl
alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol,
palmitoleyl alcohol, linoleyl alcohol, elaidyl alcohol,
elaidolinoleyl alcohol, linolenyl alcohol, elaidolinolenyl alcohol,
glycerine, glyceryl triacetate, sorbitol, xylitol, maltitol,
polydextrose, quillaia, lactic acid, urea, and combinations
thereof.
7. The topical formulation of claim 6, wherein said nonionic
surfactant is selected from the group consisting of oleyl alcohol,
lanolin alcohol, acetylated lanolin alcohol, sorbitan tristearate,
and combinations thereof.
8. The topical formulation of claim 1, further comprising a
conditioner.
9. The topical formulation of claim 8, wherein said conditioner is
selected from the group consisting of cyclomethicone, dimethicone,
hexamethyldisiloxane, octamethyltrisiloxane,
decamethyltetrasiloxane, dodecamethylpentasiloxane,
polydimethylsiloxanes, and combinations thereof.
10. The topical formulation of claim 1, formulated as a cream, gel,
or pomade.
11. The topical formulation of claim 1 prepared according to a
method comprising: (a) preparing a first solution by dissolving
ivermectin in the at least one solubilizer; and (b) adding to the
first solution a second solution comprising the at least one
suspending agent, the at least one paraben preservative, and the at
least one non-ionic surfactant; and (c) dispersing the mixture of
(b) in water.
12. (canceled)
13. A method of treating a head lice infestation in a human patient
comprising topically administering to said patient the topical
formulation of claim 1 in one dosage or multiple dosages.
14. The method of claim 13, wherein said human patient is a
child.
15. The method of claim 13, wherein at least about 60 mL of the
topical formulation is applied to said human patient.
16. The method of claim 13, wherein about 1 mL to about 100 mL of
the topical formulation is applied to said human patient.
17. The method of claim 13, wherein said topical formulation is
left on the scalp for about 1 to about 60 minutes.
18. The method of claim 17, wherein said topical formulation is
left on the scalp for about 3 minutes, about 5 minutes, or about 10
minutes.
19. The method of claim 13 wherein the topical formulation is
administered as a single dose.
20. The method of claim 13 wherein the topical formulation is
administered as an initial dosage with one or two additional
dosages.
21. The topical formulation of claim 1, wherein the at least one
suspending agent comprises a combination of fatty oils and fats.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of and claims priority to
U.S. patent application Ser. No. 13/116,547, filed May 26, 2011;
which is a divisional application of U.S. patent application Ser.
No. 11/871,660, filed Oct. 12, 2007, issued as U.S. Pat. No.
8,791,153; which claims the benefit under 35 U.S.C. .sctn. 119(e)
of U.S. Patent Application No. 60/851,352 filed Oct. 12, 2006 and
U.S. Patent Application No. 60/976,259 filed Sep. 28, 2007, each of
which are incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to topical formulations
containing avermectin for use in the prophylactic and therapeutic
treatment of a head lice infestation in humans. The topical
formulations of the present invention are effective against both
susceptible and treatment resistant strains of head lice. To this
end, the present invention also relates to methods of treating an
infestation of head lice which comprises administering one or
multiple doses of the disclosed topical formulations to a human
patient, wherein the infestation being treated represents a
susceptible and/or treatment-resistant strain of head lice.
BACKGROUND OF THE INVENTION
[0003] Head lice, Pediculus humanus capitis, are parasitic insects
that mainly live and feed in the scalp and neck hairs of human
hosts. A typical infested scalp of a patient with head lice houses
about 20 female lice, which are prolific egg layers over the course
of their 30-day life cycle. These eggs are cemented to the hair
shaft and are commonly called nits. Head lice have a similar
appearance to wingless ants. Like all insects, the parasite has a
body that is constructed of a hard chitinous exoskeleton. The egg
case that surrounds the nits is of similar construction and is
glued to the hair shaft via a cement that is similar in
characteristics to the hair keratin itself. Infections, irritation
and lesions to the scalp are common side effects of head lice
infestation. Head lice infestation is an oft occurring problem in
the United States and is easily spread from direct head-to-head
contact with an infected person's hair and common usage of combs
and clothing. There are between 6 to 12 million annual head lice
infestations in the United States. Grade school children suffer
most from head lice infestations, with one result being an
accumulation of absences from school, where lice outbreaks are
believed to account for 12 million to 24 million missed days a
year. A majority of public schools have instituted a no lice or a
no lice and no-nit policy, forcing absenteeism on children and
maybe forcing working parents to stay at home to look after them.
For a review, see Burkhart and Burkhart (2006, Expert Opin. Drug
Saf. 5(1):169-179).
[0004] Treatment for eliminating head lice traditionally included
home remedies such as smearing mayonnaise, olive oil, a hair
pomade, or some heavily viscous material about an infested scalp
coupled with rigorous combing of the hair and meticulous removal of
adult lice, nymphs, and nits. Though these home remedies do not
kill head lice, the prevailing thought is that the viscosity of the
material makes it hard for head lice to roam about the scalp,
making for easy removal. Such home remedies are usually ineffective
at controlling head lice due to the ability of the lice to revive
rapidly once these materials are removed.
[0005] More effective treatments for eliminating head lice involve
massaging the infested scalp with over-the-counter (OTC) topical
creams containing active insecticides. Because of their potential
toxicity to the human host, the use of these topical formulas are
regulated by the FDA. Over-the-counter insecticides typically have
pyrethrins or permethrin as active ingredients.
[0006] Pyrethrins are any one of six naturally occurring
insecticides extracted from the chrysanthemum flower. Along with
its synthetic derivative, permethrin, these molecules act on
susceptible head lice by increasing sodium levels in the nervous
system of the lice. The increased sodium levels cause membrane
depolarization in the nervous system of the head lice, which
eventually leads to spastic paralysis and death of the head
lice.
[0007] When first introduced, both pyrethrin and permethrin were
highly effective at eliminating susceptible lice. In the late
1980's, various formulations of both active ingredients had a high
efficacy for eliminating adult head lice and their nits. However,
recent reports indicate that treatment-resistant strains of head
lice have evolved for Nix.RTM., having 1% permethrin as an active
ingredient, and various Rid.RTM. products, having approximately
0.33% pyrethrin as active ingredients. It comes as no surprise that
strains of treatment-resistant head lice have been identified in
both the United States and Europe due to the similar killing
pathway for both insecticides.
[0008] Prescription products are also currently available and
contain either lindane or malathion as the active ingredient. These
insecticides specifically target the nervous system of the head
lice. The chlorinated hydrocarbon, lindane, is formulated as a
topical shampoo and is prescribed to treat head lice infestations.
Lindane eliminates head lice by effectively slowing the insect's
central nervous system causing paralysis and eventual death.
[0009] The reports of continued effectiveness of lindane for
eliminating head lice is inconsistent at best. Reports on the
efficacy of lindane for treating head lice have been listed from
17% in the U.S. to as high as 61% and 93% in other parts of the
world. However, treating head lice with lindane poses problems for
the human host. Side effects include toxicity to the central
nervous system, convulsions, seizures; and it may be a carcinogen.
Lindane has also been reported to have a slow killing time, and has
poor ovicidal capacities.
[0010] Malathion is also available as a prescription insecticide to
treat head lice infestations (e.g., OVIDE.RTM. an alcohol based
lotion containing 0.5% malathion, terpeneol, dipentene and pine
needle oil in 78% isopropyl alcohol). It is an organophospate that
causes spastic paralysis and death in head lice.
[0011] As noted above, recently there has been an increase in
strains of head lice which show resistance to available OTC and
prescription treatments for head lice infestation. These parasites
have adapted to chemical treatments using pyrethrins, permethrins,
lindane, and malathion. In the US, permethrin resistant lice have
been found in Massachusetts, Idaho, Tex., California and Florida.
Single and dual resistance to pyrethrins/permethrins and malathion
has been broadly reported in Great Britain (see Downs et al., 1999,
Br. J. Dermatology 141:508-511).
[0012] Strains of head lice have been identified worldwide which
are resistant to all currently available topical treatments.
Possible neural damage to the human host prevents raising the
insecticide levels above the current threshold in an attempt to
combat these newer treatment-resistant head lice. One possible way
to address this alarming increase in treatment resistant head lice
would be to develop and introduce a topical pediculicide
formulation which is (i) safe; (ii) effective against head lice
infestation from both susceptible and treatment-resistant strains;
(iii) is convenient for patient use; and, (iv) has not previously
been marketed for such an indication. Such a strategy is disclosed
herein by utilizing an anthelmintic agents derived from
avermectin.
[0013] Avermectin is a natural fermentation product derived from
the soil bacterium Streptomyces avermitilis. Avermectin naturally
occurs as abamectin, a mixture of avermectin isomers containing
>80% avermectin B.sub.la and <20% avermectin B.sub.lb, see
FIGS. 1A and 1B, respectively. Other semi-synthetic forms of
avermectin and mutated forms of Streptomyces avermitilis containing
avermectin, for example doramectin, ivermectin, selamectin, and
eprinomectin have found medicinal uses as well.
[0014] Ivermectin is the synthetic dihydro form of avermectin and
is an effective insecticide. These compounds have been shown to
selectively bind with high affinity to glutamate-gated chloride ion
channels (GluCl channels) as well as .gamma.-aminobutyric acid
(GABA) receptors, thus blocking the chemical transmission across
the nerve synapses which utilize glutamate and GABA, respectively.
This blockage, which occurs in invertebrate nerve and muscle cells,
leads to an increase in the permeability of the cell membrane to
chloride ions with hyperpolarization of the nerve or muscle cell,
resulting in paralysis and death of the parasite.
[0015] The selectivity of ivermectin is attributable to the fact
that some mammals do not have glutamate gated chloride channels and
that the compound has a low affinity for mammalian ligand-gated
chloride channels. In addition, ivermectin does not readily cross
the blood brain barrier in humans. Thus, ivermectin has a
documented history of highly safe and efficacious use in humans and
animals. For example, over 400 million doses of orally formulated
ivermectin have been used for controlling river blindness since
1986.
[0016] Ivermectin is commercially available as STROMECTOL.RTM. for
eradication of Strongyloides stercoralis, which causes
strongyloidiasis, and Onchocerca volvulus, which causes
onchocerciasis. Ivermectin is also available as MECTIZAN.RTM. for
eradication of Onchocerca volvulus and Wuchereria bancrofti.
Ivermectin is usually available as a mixture containing at least
90% 5-O-demethyl-22,23-dihydroavermectin A.sub.la and less than 10%
5-O-demethyl-25-de(1-methylpropyl)-22,23-dihyro-25-(1-methylethyl)
avermectin A.sub.L, generally referred to as
22,23-dihydroavermectin B.sub.la and B.sub.lb, or H.sub.2B.sub.la
and H.sub.2B.sub.lb, respectively, see FIG. 2A and FIG. 2B
respectively.
[0017] Glaziou et al. (1994, Trop. Med. Parasitol. 45: 253-254)
disclose treating humans with a single oral 200 ug/kg dose (n=26).
Oral ivermectin was effective at this concentration against head
lice. A second dose was suggested for prophylaxis, but not as part
of the initial therapeutic regime.
[0018] Youssef et al. (1995, Amer. J. Trop. Med. Hyg.
53(6):652-653) describe a method of topical application of
ivermectin to treat head lice.
[0019] Dunne et al. (1991, Trans. R. Soc. Trop. Med. Hyg.
85:550-551) disclose results from a study wherein ivermectin was
administered as a single oral dose of 100-200 ug/kg to treat head
lice infestation. Positive, but not absolute, results where
reported for this oral dosing regime.
[0020] U.S. Pat. No. 4,199,569, issued Apr. 23, 1980, discloses
ivermectin, which as noted above is a semisynthetic, anthelmintic
agent derived from the avermectins, a class of highly active
broad-spectrum anti-parasitic agents isolated from the fermentation
products of Streptomyces avermitilis.
[0021] U.S. Pat. No. 6,103,248, issued to Burkhart and Burkhart,
disclose a topical formulation for the treatment of head lice which
includes a killing agent, and a lipophilic carrier having a
viscosity within a range of from about 10,000 centipoise to about
85,000 centipoise at 21.degree. C.
[0022] U.S. Pat. No. 6,524,602, also issued to Burkhart and
Burkhart, disclose a topical formulation which includes a
parasiticide and N,O-carboxymethyl-chitosan polymer, and a vehicle
for the parasiticide and polymer.
[0023] U.S. Pat. No. 7,064,108, issued to Guzzo, et al., discloses
an ivermectin-based topical gel composition comprising a
pharmaceutically acceptable alcohol (30-40%; e.g., propylene
glycol), a pharmaceutically acceptable glycol (30-40%; e.g., ethyl
alcohol), and a pharmaceutically acceptable carrier. Ivermectin is
contemplated at a w/v basis from 0.005 to 1.0%. Additional
additives may include d-limonene, a nonionic surfactant and a
pharmaceutically acceptable viscosifying agent (e.g.,
hydroxypropylcellulose).
[0024] U.S. Pat. No. 5,952,372, issued to William McDaniel,
discloses methods of treating rosacea in humans involving
orally-administered or topically-applied ivermectin. The topical
aspect of the invention suggests a topical formulation with about
2% ivermectin.
[0025] U.S. Pat. Nos. 6,399,652; 6,399,651 and 6,319,945, issued to
L. Dean Parks, disclose methods of treating skin disorders via
application of topical formulations containing ivermectin to treat
acne vulgaris (the '652 patent), a variety of dermatoses (e.g.,
transient acantholytic dermatitis, acne miliaris necrotica, acne
varioliformis, perioral dermatitis, and acneiform eruptions; the
'651 patent) and seborrheic dermatitis (the '945 patent).
[0026] U.S. Pat. No. 6,262,031, issued to Larouche, et al.
discloses an oral formulation of ivermectin to treat a head lice
infestation.
[0027] It is evident that the OTC or prescription products
presently available to the public for treatment or prevention of
head lice each have their own significant drawbacks.
Over-the-counter products such as pyrethrin and permethrin are
presently compromised due to emerging strains of
treatment-resistant head lice. On the other hand, the prescription
products such as lindane and malathion carry recognized health
risks and are also losing effectiveness due to the emergence of
treatment-resistant lice. To this end, there remains a need for a
patient friendly product that is safe and effective in treating
susceptible and/or treatment-resistant head lice. The present
invention addresses and meets this needs by disclosing an
avermectin-based topical formulation and exemplifying an
ivermectin-based topical formulation, and associated methods of
use, which is safe, will appeal to the patient for ease of use and
is shown to be effective against multiple strains of either
susceptible and treatment-resistant head lice.
SUMMARY OF THE INVENTION
[0028] The present invention relates to a topical formulation for
use in the prophylaxis or elimination of head lice (Pediculus
humanus capitis) on a human host, wherein the formulation comprises
a pharmaceutically effective amount of an avermectin compound,
solubilizers, suspending agents, preservatives, non-ionic
surfactants, humectants, and water.
[0029] The present invention also relates to a topical formulation
for use in the prophylaxis or elimination of head lice (Pediculus
humanus capitis) on a human host, wherein the formulation comprises
a pharmaceutically effective amount of ivermectin, solubilizers,
suspending agents, preservatives, nonionic surfactants, humectants,
and water.
[0030] In additional embodiments of the present invention, the
topical avermectin/ivermectin-containing formulation may further
comprise additional beneficial agents; non-limiting examples being
nutrients and vitamins, and the absence of pharmaceutically
accepted glycols.
[0031] The present invention relates to a method of treating a head
lice infestation in a human patient which comprises topically
administering to the patient an avermectin- or ivermectin-based
formulation via one or multiple doses; the strain of head lice
being either a susceptible strain, a treatment-resistant strain, or
any combination of either or both types of strains within a
specific human infestation.
[0032] The present invention also relates to a method of treating a
head lice infestation in a human patient which comprises topically
administering to the patient an avermectin or an ivermectin-based
formulation as disclosed herein by one dose or multiple doses; the
strain of head lice being either a susceptible strain or a
treatment-resistant strain or any combination of either or both
types of strains within a specific human infestation.
[0033] Another aspect of the present invention relates to the use,
in manufacture of a topical medicament for treating or preventing a
head lice infestation from a treatment-resistant strain in a human
patient, of avermectin or ivermectin.
[0034] Another aspect of the present invention relates to the use,
in the manufacture of a medicament for treating or preventing a
head lice infestation from a susceptible or treatment-resistant
strain in a human patient, of a topical formulation according to
the present invention.
[0035] The present invention further relates to a method of
preventing a head lice infestation in a human patient at risk which
comprises topically administering to the human an avermectin- or an
ivermectin-based formulation as disclosed herein by one dose or
multiple doses (preferably a single application) so as to prevent
infestation in the patient at risk (i.e., a human likely to be in
close contact with an infected individual) to a strain of head lice
being either a susceptible strain or a treatment-resistant strain
or any combination of either or both types of strains within a
specific human infestation.
[0036] Therefore, the present invention relates to a method of
eliminating or preventing an infestation of head lice on a human
patient, whether the infecting head lice strain be a susceptible
strain or a treatment resistant strain, which comprises applying
one or multiple doses (applications) of the topical
avermectin-containing formulation, including but not limited to an
exemplified ivermectin-containing formulation, to the individual
for a length of time to allow biologically effective contact
between the active ingredient and the lice.
[0037] The present invention also relates to an avermectin- or
ivermectin-based formulations which is effective against
pediculosis via pubic lice (Phthirus pubis) and body lice
(Pediculus humanis corporis). The formulations of the present
invention may be used `as is` to treat a pubic lice and/or body
lice infestation, or may be altered to provide for a formulation
with the consistency of a cream rinse or lotion that may be applied
to the affected area(s), left on for a period of time as
contemplated herein for treatment of head lice, and then rinsed
off. Multiple dosing may also occur as contemplated herein for
treating head lice with a formulation as disclosed herein.
[0038] Another aspect of the present invention relates to the use,
in manufacture of a topical medicament for treating or preventing a
pubic lice or body lice infestation from a treatment-resistant
strain in a human patient, of avermectin or ivermectin.
[0039] Another aspect of the present invention relates to the use,
in the manufacture of a medicament for treating or preventing a
pubic lice or body lice infestation from a susceptible or
treatment-resistant strain in a human patient, of a topical
formulation according to the present invention.
BRIEF DESCRIPTION OF THE FIGURES
[0040] FIGS. 1A and 1B show the chemical structures of avermectin,
form B.sub.la (1A) and B.sub.lb (1B).
[0041] FIGS. 2A and 2B show the chemical structure for ivermectin,
form B.sub.la (2A) and B.sub.lb (2B).
[0042] FIG. 3 shows log time versus percent mortality of
permethrin-resistant human head lice from the South Florida (SF-HL)
strain following a 10 minute exposure to 1%, 0.5%, and 0.25%
ivermectin formulations.
[0043] FIG. 4 shows log time versus percent mortality of
permethrin-resistant human head lice from the South Florida (SF-HL)
strain treated with a 0.5% ivermectin formulation for 3 minutes, 5
minutes, and 10 minutes.
DETAILED DESCRIPTION OF THE INVENTION
[0044] The present invention relates to an avermectin containing
topical formulation useful as a pediculicidal agent in the
treatment or prevention of an infestation of head lice, where the
infested lice may be either a susceptible or treatment-resistant
strain of Pediculus humanus capitis.
[0045] One embodiment of the present invention relates to an
ivermectin-containing topical formulation useful as a pediculicidal
agent in the treatment or prevention of an infestation of head
lice, particularly where the infested lice may be either a
susceptible or treatment-resistant strain of Pediculus humanus
capitis.
[0046] The avermectin/ivermectin-based formulations of the present
invention address the emerging problem of treatment-resistant head
lice strains by allowing use of a single product which is active in
eliminating or preventing head lice infestations, whether the
infestation represents a susceptible or treatment-resistant strain
of head lice.
[0047] A portion of the current invention is exemplified by an
ivermectin-based formulation in an assay to determine killing
ability against permethrin-resistant head lice. It is well known in
the art that similar treatment regimes are presently utilized to
treat not only a head lice infestation, but also at least an
infestation of pubic lice or body lice. Thus, it will be evident
that avermectin- or ivermectin-based formulations will be effective
in treating not only head lice, but also infestations of the human
body of pubic lice and body lice. Pubic lice (Phthirus pubis, e.g.,
"crabs") are usually found in the pubic area but may also be found
on facial hair, on eyelashes, on eyebrows, in the armpits, on chest
hair, and, rarely, on the scalp.
[0048] Body lice (Pediculus humanis corporis) live and lay eggs in
the seams of clothing. The lice are only present on the body when
they feed. Under some conditions, these lice may transmit diseases
such as typhus, relapsing fever, and trench fever. The formulations
of the present invention may be used `as is` to treat a pubic lice
and/or body lice infestation. Of course, the core components of the
disclosed formulation may be altered to provide for a formulation
with the consistency of a cream rinse or lotion that may be applied
to the affected area(s), left on for a period of time as
contemplated for treatment of head lice, and then rinsed off.
Multiple dosing may also occur as contemplated herein for treating
head lice with a formulation as disclosed herein.
[0049] The present invention also relates to a method of treating
or preventing a head lice infestation, whether the infestation be
from a strain of head lice that remains susceptible to current OTC
and prescription pediculicides ("a susceptible strain") or from a
strain that is resistant to one or more available OTC and/or
prescription formulations ("a treatment-resistant" or
"drug-resistant" strain). Thus, one aspect of the invention relates
to a method of treatment or prevention of an infestation of head
lice on a human patient utilizing an avermectin- or
ivermectin-based formulation, whether the infecting head lice
strain may be a susceptible strain or a treatment-resistant
strain.
[0050] This methodology comprises applying one dose or multiple
doses (applications) of the topical avermectin- or
ivermectin-containing formulation to the individual for a length of
time to allow an effective amount of the active ingredient to
contact the infecting lice.
[0051] An additional aspect of this portion of the invention
relates to a method for prophylaxis or elimination of either
susceptible or treatment-resistant head lice using the
avermectin-containing formulation as a shampoo-conditioner, where
the shampoo-conditioner is used twice during about a seven day
period (day 1 and day 7), left on the scalp for 1 to 60 minutes at
each application, and then rinsed with warm water. The
shampoo-conditioner is formulated to leave the hair in good
condition while ridding the scalp of lice.
[0052] Thus, another aspect of the present invention relates to the
use, in manufacture of a topical medicament for treating or
preventing a head lice, pubic lice or body lice infestation from a
treatment-resistant strain in a human patient, of avermectin or
ivermectin. Another aspect of the present invention relates to the
use, in the manufacture of a medicament for treating or preventing
a pubic lice or body lice infestation from a susceptible or
treatment-resistant strain in a human patient, of a topical
formulation according to the various formulations disclosed
herein.
[0053] One central aspect of the present invention is that the
topical formulation will comprise avermectin. Avermectin may be
present at varying concentrations, with an expected range (at a
weight/volume percentage) of from 0.005% to 5.0% (w/v) [i.e., a 1%
avermectin formulation would include 1 gram (g) avermectin per 100
milliliters (ml) (1g/100 ml)] of formulation volume.
[0054] Another contemplated range for an avermectin concentration
would be from about 0.1% to about 2.0% (w/v), which is further
supported in Example 1, where avermectin, in the form of
ivermectin, concentrations of 0.25%, 0.5% and 1.0% were shown to
promote effective killing of a permethrin resistant strain of head
lice.
[0055] Of course, dosing may be varied either by the altering the
avermectin concentration, as noted above, or by increasing the
amount of topical formulation applied to the scalp of the human
patient. It will be evident upon review of this specification, that
while an ivermectin-based formulation is exemplified herein, other
known avermectins beside ivermectin are also contemplated as the
active ingredient which will be useful to practice the present
invention.
[0056] While dosing ranges may vary, it is expected that a single
application (dosage) of an exemplified ivermectin containing
formulation of the present invention would be in the range from
about 1 ml to about 100 ml; with an additional range being from
about 3 ml to about 75 ml.
[0057] In a single embodiment, at least about 60 ml the topical
formulation is applied to totally saturate the roots and to
effectively cover the entire scalp area. It is evident upon review
of this specification that the artisan may vary the ivermectin
concentration and/or volume of the topical formulation to
manipulate the effective amount of ivermectin to be delivered to
the patient's scalp.
[0058] Another aspect of the present invention, as noted above,
relates to multiple doses of the topical avermectin- or
ivermectin-based formulations of the present invention. Multiple
applications will include at least one, two, three or four
additional dosages beyond the initial dose, with one or possibly
two additional doses being most reasonably contemplated.
[0059] The initial dose is most likely in response to an
infestation of head lice, while the additional subsequent dose(s)
are follow up applications to eradicate lice that hatch following
the first dose or lice that have somehow survived the first dosing.
Multiple dosing for a therapeutic regime provides an opportunity to
deliver greater amounts of avermectin spaced over a determined time
frame.
[0060] One aspect of this portion of the invention relates to a
method for prophylaxis or elimination of either susceptible or
treatment-resistant head lice using the avermectin- or ivermectin
containing formulation as a shampoo-conditioner. The
shampoo-conditioner may be used twice during about a seven day
period (day 1 and between about day 5 and day 9), as well as three
or four times (with an initial application on day 1 followed for a
second, third or fourth application at intervals from about 5 days
to about 9 days). At each dosing, the formulation remains in the
scalp for from about 1 minute to 60 minutes or from about 3 minutes
to about 60 minutes, then rinsed with warm water.
[0061] The shampoo-conditioner is formulated to leave the hair in
good condition while ridding the scalp of lice. Therefore, the
present invention relates to a method of treating a head lice
infestation in a human patient which comprises topically
administering to the human a formulation as disclosed herein by one
dose or multiple doses; the strain of head lice being either a
susceptible strain or a treatment-resistant strain.
[0062] Furthermore, the present invention relates to a method of
preventing a head lice infestation in a human patient at risk which
comprises topically administering to the human a formulation as
disclosed herein by one dose or multiple doses (preferably a single
application) so as to prevent infestation in the patient at risk to
a strain of head lice being either a susceptible strain or a
treatment-resistant strain. Thus, methods of the present invention
are useful for preventing head lice infestation in a human
susceptible to such infestation.
[0063] Such an at risk individual would be a human coming into
close contact with an infested individual, such as a family member
or possibly in response to an outbreak within a confined space such
as school or the workplace. Either a single or multiple dosing
regime will be effective, the course of a prophylactic treatment
most likely determined by the severity of the outbreak.
[0064] Thus, the present invention provides a formula for
prophylaxis and elimination of head lice comprising an effective
amount of ivermectin in a shampoo-conditioner. However, the formula
may be delivered in various forms, non-limiting examples being
creams, gels, pomades, and the like. The invention also provides a
method for prophylaxis and elimination of head lice on human hosts
comprising topically massaging said formula in a suitable carrier
onto and about the infected area.
[0065] For the purposes of this invention, the following
non-limiting definitions are used:
[0066] The term "active ingredient", when directed toward the
present invention, refers to an avermectin, including but not
limited its synthetic derivative, ivermectin. Ivermectin may be
utilized as a mixture of over 80% 22,23-dihydroavermectin B.sub.la
and less than 20% 22,23-dihydroavermectin B.sub.lb. As exemplified
herein, ivermectin is a mixture of at least 90%
22,23dihydroavermectin B.sub.la and less than 10%
22,23-dihydroavermectin B.sub.lb.
[0067] The terms "solubilizer" and/or "solubilizer phase" refers to
compound or mixture of compounds in which the ivermectin is
initially dissolved. The solubilizer phase is preferably a mixture
of water miscible organic compounds. By way of example,
solubilizers may include the surfactants polysorbate 80 and cetyl
acetate or other surfactants as more fully described herein.
[0068] The term "suspending agent(s)" refers to organic compounds
that suspend the pre-dissolved ivermectin before being dispersed in
water. Suspending agents include, without limitation, olive oil,
shea butter, coco butter, vegetable oil, and the like.
[0069] The term "preservative(s)" refers to compounds that reduce
the growth of fungus and other bacterial agents. In one embodiment,
preservatives are selected from the compounds in the paraben
family.
[0070] The term "non-ionic surfactant(s)" refers to compounds which
act at the water-air and water-oil interfaces, thereby enhancing
wetting ability, emulsion stabilization, foaming, rheology,
antistatic, lubricity, and surface conditioning properties of the
shampoo-conditioner.
[0071] The term "emollient(s)" refers to compounds that soften and
makes the skin smooth by preventing skin from losing moisture.
[0072] The term "silicone compound" refers to hair conditioning
agents that change the texture, feel, and appearance of human hair.
In one embodiment, the silicone compound is cyclomethicone.
[0073] The term "susceptible" or "susceptible strain" refers to a
strain of head lice which is susceptible to one or more available
OTC and/or prescription pediculicides, having active ingredients
selected from the group consisting of pyrethrins, permethrins,
lindane, and malathion where the active ingredient is at least at
the pharmaceutically acceptable treatment concentration allowable
for that respective pediculicide(s) and all or effectively all head
lice are killed at that concentration. In other words, a
susceptible strain is a strain which will be effectively controlled
following treatment with a pharmaceutically acceptable
concentration for that respective pediculicide.
[0074] The term "treatment-resistant" or "drug-resistant" or any
such similar term refers to a strain of head lice which shows
resistance to one or more available OTC and/or prescription
pediculicides having active ingredients selected from the group
including, but not limited to one or more pyrethrins, permethrin,
lindane, and malathion, where the active ingredient is at least at
the pharmaceutically acceptable treatment concentration recommended
or allowed for that respective pediculicide(s) and at least some
head lice survive at that concentration. Pyrethrins which are
approved for use on humans are extracted from the chrysanthum
flower, of which there are six active constituents which are esters
of two carboxylic acids (chrysanthemic acid and pyrethric acid) and
four cyclopentenoles (pyrethrolone, cinerolone, and jasmolone I and
II). So, it is evident that a treatment-resistant strain of lice is
a strain that shows a measurable level of resistance to killing by
a specific pediculicide treatment regime as compared to a
susceptible strain, where all or effectively all of the head lice
will be killed. Such a measure may be made by an art-accepted
assay, for example, as disclosed herein in Example section 1; or
may possibly be determined by other means (e.g., comparative
testing in individuals).
[0075] The present invention is exemplified by, but in no way
limited to, a topical ivermectin-containing formulation as
disclosed in Table 1. This final formulation is in the consistency
of a shampoo-condition and at least comprises an effective amount
of ivermectin, as well as a solubilising agent(s), water, a
suspending agent(s), a surfactant(s), silicone compound(s), and a
preservative(s), in any combination and/or concentration which may
be contemplated by the artisan upon review of this
specification.
[0076] Solubilising Active Ingredient
[0077] FIGS. 1A and 1B show the chemical formula for avermectin,
forms B.sub.la and B.sub.lb. FIGS. 2A and 2B show ivermectin as a
mixture comprising about 90% 22,23-dihydroavermectin B.sub.la and
less than about 10% 22,23-dihydroavermectin B.sub.lb. Ivermectin
may be delivered to a head lice infested scalp by way of an
emulsion based shampoo-conditioner. However, ivermectin is
hydrophobic and is poorly solvated by water. Thus, the active
ingredient should preferably be pre-dissolved in suitable
surfactants to improve the stability of said active ingredients in
water. Preferably, these surfactants are easily soluble in water or
are water miscible.
[0078] In one embodiment, ivermectin is pre-dissolved in a mixture
containing the water miscible organic compounds, e.g. polysorbate
80, cetyl acetate, and acetylated lanolin alcohol. More
specifically, ivermectin is present in the formula at a level of
about 0.05% to 5%, or alternatively from about 0.1% to 2% by
weight, or alternatively from about 0.25% to 1% by weight.
Polysorbate 80 is present in the formula at a level of about 5% to
about 25% by weight, or alternatively from about 10% to 15% by
weight (e.g. about 11.25% to 13.5% by weight). Cetyl acetate is
present in the formula at a level of about 0.5% to 10% by weight,
or alternatively from about 1% to 4% by weight (e.g. about 1.50% to
3.75% by weight). Acetylated lanolin alcohol is present in the
formula at a level of about 0.10% to 3% by weight, or alternatively
from about 0.5% to about 1% by weight (e.g, 0.15% to 0.75% by
weight).
[0079] Having these surface active agents bound to the surfaces of
ivermectin will ensure that the active ingredient will be stable in
the aqueous environment of the shampoo-conditioner. In one
embodiment of the invention ivermectin may be stabilized by
pharmaceutically accepted glycols present in said formula at a
level below 30% by weight, such as, for example, below 25%, or
below 20% or below 15% or below 10% or below 5%. In another
embodiment of the invention said formula does not include any
glycols.
[0080] Suspending Agents
[0081] Once the active ingredient is dissolved in a surfactant
bath, ivermectin is placed in suspending agents. In one embodiment,
a combination of fatty oils and fats serve as suspending agents.
Olive oil is a triacylglyceride, where three fatty acids are
tethered to a glycerol backbone and shea butter is primarily made
of palmitic, stearic, oleic, linoleic, and arachidic fatty acids.
Although these fatty acids have shown to be adequate home remedies
for removal of head lice from the scalp, they do not kill head
lice. Both olive oil and shea butter are viscous materials that
slow the movement of adult lice to better remove them. Also note
that both fatty acids can act as skin moisturizers. In one
embodiment, olive oil is present in the formula at a level of about
20% to 30% by weight, or alternatively from about 25% to 28% by
weight (e.g., about 27.5% by weight). Shea butter is present in the
formula at a level of about 1% to 5% by weight (e.g. about 2% by
weight). Other known suspending agents which may be utilized in the
formulations and related methods include, but are not limited to,
coconut oil, palm oil, cottonseed oil, vegetable oil, soybean oil,
olive oil, peanut oil, corn oil, sunflower oil, safflower oil,
jojoba oil, canola oil, shea butter, cocoa butter, milk fat,
amaranth oil, apricot oil, argan oil, avocado oil, babassu oil, ben
oil, algaroba oil, coriander seed oil, false flax oil, grape seed
oil, hemp oil, kapok seed oil, meadowfoam seed oil, okra seed oil,
perilla seed oil, poppyseed oil, prune kernel oil, pumpkin seed
oil, quinoa oil ramtil oil, rice bran oil, camellia oil, thistle
oil, wheat germ oil and combinations thereof
[0082] Surfactants
[0083] The formulation may be further stabilized by non-ionic
surfactants. In one embodiment of the invention, a fatty alcohol or
a mixture of fatty alcohols serve as surfactants. Apart from
additional stabilization of ivermectin, the non-ionic surfactants
have various purposes in the surface chemistry of said formula,
where said formula is used in a final product comprising a
shampoo-conditioner. In addition to their surface-active
properties, fatty alcohols are emollients that make the skin
smoother and act at the water-air and water-oil interfaces, thereby
enhancing wetting ability, emulsion stabilization, foaming,
rheology, antistatic, lubricity, and surface conditioning
properties of the formula. Suitable non-ionic surfactants include,
without limitations, oleyl alcohol, lanolin alcohol, sorbitan
tristerate, bees wax, erucyl alcohol, ricinolyl alcohol, arachidyl
alcohol, capryl alcohol, capric alcohol, behenyl alcohol, lauryl
alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol,
isostearyl alcohol, oleyl alcohol, palmitoleyl alcohol, linoleyl
alcohol, elaidyl alcohol, elaidolinoleyl alcohol, linolenyl
alcohol, elaidolinolenyl alcohol, glycerine, glyceryl triacetate,
sorbitol, xylitol, maltitol, polydextrose, quillaia, lactic acid,
urea, and combinations thereof.
[0084] In one embodiment of the invention, the fatty alcohols are
oleyl alcohol and lanolin alcohol with combined concentration of
about 10% to 35%, or alternatively about 18% to about 24% by
weight. More specifically, oleyl alcohol is present in the formula
at a level of about 5% to 15% by weight (e.g. about 10% by weight).
Lanolin alcohol is present in the formula at a level of about 3% to
about 15% by weight, or alternatively from about 5% to 10% by
weight (e.g. about 8% by weight).
[0085] Sorbitan tristearate is available commercially as Glycomul
TS (Lonza, Inc.) or SPAN 65 as sold by Merck Schuchardt OHG.
Sorbitan tristearate is a low HLB ester based surfactant and has
many uses in the food and cosmetic industries. The chemical
structure of sorbitan tristearate is defined by a cyclic five
member ether, with hydroxyl groups, and three fatty acid side
chains. Sorbitan tristearate is present in the formula at a level
of about 0.1% to 3% by weight, e.g. about 0.5% by weight.
[0086] Silicone Compound
[0087] After ivermectin has been pre-dissolved and stabilized by
surfactants, a silicone compound may be added. In one embodiment,
the silicone compound is selected from a group consisting of
volatile silicones, of which cyclomethicone is one. Cyclomethicone
may act as a conditioner in the shampoo-conditioner. It gives a
soft, silky feel to hair and evaporates quickly leaving little
residue. Cyclomethicone is present in the formula at a level of
about 1% to 5% by weight, e.g. about 3% by weight. Thus,
conditioners which may be used include but are in no way limited to
cyclomethicone, dimethicone, hexamethyldisiloxane,
octamethyltrisiloxane, decamethyltetrasiloxane,
dodecamethylpentasiloxane, polydimethylsiloxanes and combinations
thereof
[0088] Preservatives
[0089] In yet another embodiment, the formula of the instant
invention further contains a preservative, protecting the formula
from fungus by chemicals. In one embodiment, the preservative is
chosen from the paraben family. More specifically, the preservative
is selected from methylparaben, propylparaben, or a combination
thereof. In one embodiment, the concentration of the preservative
is about 1% by weight. More specifically, methylparaben is present
in the formula at levels of about 0.01% to 2% by weight (e.g. 0.20%
by weight). Propylparaben is present in the formula at levels of
about 0.01% to 1.0%, or alternatively from about 0.01% to about
0.5% by weight (e.g., 0.05% by weight). Also note that
representative preservatives may include, but are not limited to,
methylparaben, propylparaben, ethylparaben, butylparaben,
isobutylparaben, isopropylparaben, benzylparaben and their sodium
salts thereof
[0090] Water
[0091] The oil mixture containing pre-dissolved ivermectin,
suspending agents, surfactants, a silicone compound and
preservatives is then dispersed in water. In one embodiment, water
is deionized. Water acts as a carrier and may be included as
warranted for any respective formulation. In the exemplified
formulation, water is present in the formula at a level of about
30% to 40% by weight (e.g. 33% by weight). The addition of the oily
mixture with ivermectin to deionized water results in a colloidal
suspension of ivermectin, where micelles form around the ivermectin
and are arranged such that hydrophilic heads of the surfactants are
in contact with the solvent water molecules and the hydrophobic
tails of the surfactants are in contact with ivermectin. This
formulation is especially suitable delivering ivermectin in a
shampoo-conditioner, which gives the shampoo-conditioner a suitable
washout and flow behavior leaving the hair in good condition.
[0092] Specific ivermectin concentrations tested, as shown in
Example 1, include 0.25%, 0.50% and 1.00% ivermectin. This
concentration range, shown in Example 1 to effectively kill
permethrin-resistant head lice, is presented to simply exemplify
the invention and in no way limit the effective range that may be
utilized by the artisan to practice the claimed invention. As noted
above in this Detailed Description of the Invention section, the
artisan may choose an appropriate range of ivermectin (measured as
weight/volume [w/v]) anywhere in the range from about 0.005% to
about 5%.
[0093] Of course, the w/v ratio of the formulation may be adjusted
to take into account differing amounts of ivermectin on a g/l
basis. Adjustments may easily be incorporated with components,
known equivalent components, combination of components, and
respective concentrations to provide for alternative avermectin- or
ivermectin-based formulations for uses disclosed herein.
[0094] Thus, the artisan will be aware that the percentage by
weight of any component may be adjusted to compensate for the
concentration of the active ingredient, the texture of the topical
formulation (e.g., shampoo, cream, gel) and that components may be
added at differing concentrations or may be left out of a
formulation or substituted with an equivalent component so as to
provide for an avermectin- or ivermectin-based topical formulation
which possesses efficacy against treatment-resistant strains of
head, pubic or body lice similar to the exemplified topical
formulation described herein.
TABLE-US-00001 TABLE 1 Ingredient % (by weight) Ivermectin 0.5
Deionized Water 33 Olive Oil USP 27.75 Polysorbate 80 (and) 11.75
Cetyl Acetate (and) 3.0 Acetylated Lanolin Alcohol .25 Oleyl
Alcohol 10 Lanolin Alcohol 8 Cyclomethicone 3 Shea Butter 2
Sorbitan Tristearate 0.5 Methylparaben 0.2 Propylparaben 0.05
[0095] A person of the ordinary skill in the art will appreciate
that other beneficial agents can be added into a formula of the
instant invention. Such beneficial agents include, without
limitation, vitamins, hair dyes, nutrients, anti-dandruff agents
and the like.
[0096] A person of the ordinary skill will have sufficient
expertise to properly select the beneficial agent or the
combination thereof depending on the specific embodiment of the
invention, so that the at least one beneficial agent would not
negate the beneficial aspects of the formula.
[0097] One of ordinary skill in the art would appreciate that the
formulation and method described herein for eliminating treatment
resistant lice is not meant to be a limiting disclosure, but only
gives a preferred embodiment of the invention.
Example 1
Formulation and Testing of Ivermectin Shampoo-conditioner on
Permethrin Resistant Head Lice
[0098] Having described the invention in general terms, the
following specific example is offered for purposes of illustration
and for illustration only, and no intention to limit the invention
is to be inferred therefrom. A pediculicide containing ivermectin
as a topical shampoo-conditioner for eliminating treatment
resistant lice may be prepared as follows.
[0099] Preparing the Formulation
[0100] The formulation shown in Table 1 may be made by the
following non-limiting example. The 0.50% w/v of the active
ingredient (ivermectin) is pre-dissolved in a vessel containing
surfactants, hereinafter Phase A, consisting of 11.75% w/v of
polysorbate 80, 3% w/v of cetyl acetate, and 0.25% w/v of
acetylated lanolin alcohol. Phase A is heated, with mixing, at a
constant temperature of 65.degree. C. until the active ingredient
is completely dissolved in the surfactants. Phase A is then
transferred into a vessel containing Phase B, wherein Phase B
consists of suspending agents, preservatives, non-ionic
surfactants, humectants, and a conditioner agent.
[0101] Phase B may consist of 27.75% w/v of olive oil, 2% w/v of
shea butter, 8% w/v of lanolin alcohol, 3% w/v of cyclomethicone,
0.50% w/v of sorbitan tristearate, 0.20% w/v of methyl paraben, and
0.05% w/v of propyl paraben. Phase B combined with Phase A are
heated, with mixing, at a constant temperature of about 85.degree.
C. until all ingredients are dissolved and/or melted. Concurrently,
Phase C, consisting of water, is heated at a constant temperature
of about 85.degree. C. With vigorous mixing, Phase A/B is slowly
transferred into Phase C. Continue mixing the formulation at or
near room temperature until the desired formulation consistency is
obtained and subsequently package the formulation.
[0102] Formulated Ivermectin Concentrations
[0103] The present invention may be prepared in concentrations of
1%, 0.5%, and 0.25% of ivermectin in a formulation containing
deionized water, olive oil USP, surfactants, shea butter, sorbitan
tristearate, methylparaben, and propylparaben. For comparison
purposes, a Nix.RTM. formulation (Pfizer, Morris Plains, N.J.)
containing 1% permethrin (v/v), an Ovide.RTM. formulation (Medicis,
Phoenix, Ariz.) containing 0.5% malathion (v/v), a non-formulated
ivermectin solution (Chem Service Inc., West Chester, Pa.), a
placebo formulation (ivermectin formulation sans ivermectin) and
distilled, deionized water (ddH2O) are used as positive (Nix.RTM.,
Ovide.RTM. and non-formulated ivermectin), negative (placebo), and
no treatment (ddH2O) controls.
[0104] Selection of Human Head Lice
[0105] The SF-HL strain of permethrin-resistant human head lice
(Pediculus humanus capitis, Phthiraptera:Pediculidae) is collected
from infested children in Plantation and Homestead, Fla. and is
maintained on an in vitro feeding system at the University of
Massachusetts at Amherst, Mass. as described by Yoon et al. (2006).
Lice are maintained without a human host on the in vitro rearing
system from about 24 to about 36 generations. Permethrin-resistant
SF-HL are selected periodically using 1% permethrin-treated filter
papers (Yoon et al. 2006). Filter papers (35 mm diameter, Whatman
No. 1) are immersed into 1% permethrin dissolved in acetone (w/v)
for 10 seconds and is air dried in a dark fumehood from about 20 to
about 30 minutes. Mixed developmental stages (first instars to
adult) are placed on the treated filter paper and exposed for about
5 hours. Surviving lice are transferred back into the feeding
system. The SF-HL strain are susceptible to Ovide.RTM. (0.5%
malathion), but resistant to Nix.RTM. (1% permethirn) and
cross-resistant to DDT treatments. (Moon et al. 2003).
[0106] Bioassays
[0107] Mortality bioassays are performed to compare lethal time to
50% mortality values (LT50) between the ivermectin formulations,
Nix.RTM., and Ovide.RTM.. Experimental lice are newly hatched first
instars (less than 24 hours old). The lice are randomly taken from
the in vitro rearing system, where the lice take an overnight blood
meal. Lice (about 30 lice/treatment) are placed on an individual
hair tuft (about 300 strands, about 4 cm in length) using sterile
forceps, and the treatment is gently rubbed into the hair until
saturation occurs.
[0108] After a 10 minute exposure period, the hair tuft with lice
are washed sequentially in three separate water baths, containing
about 10 ml of ddH2O for about 5 seconds each. The washed hair tuft
with lice is blotted onto stacks of filter paper and air dried for
about 5 minutes. Any lice dislodged during treatment or washing are
placed back onto the treated hair tuft. After drying, the treated
hair tuft with lice is examined under a dissecting microscope and
the number of dead lice is recorded.
[0109] A louse is considered dead if it can not right itself when
inverted and when its legs have ceased all movements when probed.
Treated hair tufts with lice are then placed onto the feeding
membrane in the in vitro rearing system and are maintained at
31.degree. C. and 75% humidity. The numbers of dead lice are
reassessed at 10 minute intervals until a greater than 90%
mortality is achieved. The timing for mortality begins immediately
following the 10 minute exposure period. Because of this, mortality
is not assessed during the washing and drying intervals (about 5
minutes). Log time versus logit percent mortality regression lines
are generated to determine LT.sub.50 and LT.sub.95 values and
maximum log-likelihood ratio tests are performed to test the
equality (slope and intercept) of the regression lines (p<0.05,
Polo PC, LeOra Software, 1987).
[0110] To determine whether ivermectin in formulation performs
better than ivermectin alone, blood-fed lice are placed onto 0.5%
(w/v) ivermectin formulation-treated hair tufts as described above.
Blood-fed lice are also placed onto hair tufts that are treated
with 0.5% ivermectin in acetone (acetone is allowed to volatilize
in a fumehood for about 1 hour prior to transferring lice to the
treated hair tuft), washed, and transferred to the in vitro rearing
system as described above.
[0111] SF-HL Lice Mortality Response to Ivermectin Formulations
[0112] The mortality responses of the SF-HL lice strain following a
10 minute exposure to all three ivermectin formulations (1%, 0.5%,
and 0.25%) are significantly different compared to SF-HL lice
exposed only to ddH2O (.chi.2=90.1, df=2, P<0.001; .chi.2=199.5,
df=2, P<0.001, .chi.2=213.5, df=2, P<0.001), respectively
(FIG. 3). At the LT.sub.50 and LT.sub.95 following a 10 minute
exposure, the 1% ivermectin formulation is 426 and 491 times faster
than the ddH2O treatments, respectively (Table 2).
TABLE-US-00002 TABLE 2 Comparison of median lethal time (LT.sub.50
and LT.sub.95, following exposures of the SF-HL lice strain to the
ivermectin formulations). Slope values are determined from log time
versus logit mortality regression lines, which are obtained using
the hair tuft bioassay of the permethrin-resistant (SF-HL) and
permethrin-susceptible (EC-HL) head louse populations. Populations
are treated with the formulations, Nix .RTM., and Ovide .RTM..
Reject null Treatment LT.sub.50 (CL).sup.a LT.sub.95 (CL).sup.a
Slope hypothesis.sup.b 1% 50.4 88.0 12.1 .+-. 1.7 + (46.5-54.1)
(78.7-104.5) 0.5% 58.1 130.4 8.4 .+-. 1.0 + (52.9-63.0)
(113.8-158.7) 0.5% (5 min 93.7 196.7 8.5 .+-. 1.1 + exposure)
(82.9-103.6) (168.8-249.1) 0.5% (3 min 204.7 426.4 10.5 .+-. 1.5 +
exposure) (176.7-236.8) (359.3-556.7) 0.25% 119.3 208.9 12.1 .+-.
1.5 + (112.7-125.9) (189.2-241.5) 0.5% (non- 221.8 419.4 10.6 .+-.
1.5 + formulated) (204.5-238.5) (363.9-532.5) Placebo 4.8 days 24
days 3.3 .+-. 0.4 + (formulation (3.6-6.2) sans ivermectin) Nix
.RTM. 4.3 days >15 days 2.1 .+-. 0.17 + (3.9-4.8) Nix .RTM.
177.7 357.0 9.7 .+-. 1.8 + (EC-HL) .sup.d (126.1-223.3)
(282.7-628.6) ddH2O 14.9 days 30 days 3.1 .+-. 0.5 + (12.0-18.8)
Ovide .RTM..sup.e <5.0 <5.0 + .sup.aCL, 95% confidence
interval limit. .sup.bThe null hypothesis tests for equality of the
slope and intercept of the regressions (p < 0.05) (see maximum
log-likelihood ratio test in text). .sup.cNIX .RTM. LT.sub.50
values for SF-HL and EC-HL are from historical data previously
determined using the same experimental bioassay (Moon et al. 2006).
.sup.d EC-HL are permethrin-susceptible lice collected from Kuna
Indians in Ecuador. .sup.eLT.sub.50 and LT.sub.95 values following
Ovide.RTM. treatments are estimated times since log time versus
logit mortality responses curves were not generated given the fast
response times (see methods section).
[0113] At the LT.sub.50 and LT.sub.95 following a 10 minute
exposure, the 0.5% ivermectin formulation is 369 and 331 times
faster than the ddH2O treatments, respectively, and the 0.25%
ivermectin formulation is 180 and 207 times faster than the ddH2O
treatments, respectively (Table 2). The mortality response to the
non-formulated 0.5% ivermectin treatment is significantly different
compared to ddH2O (.chi.2=168.1, df=2, P<0.001) (FIG. 1). At the
LT.sub.50 and LT.sub.95 following a 10 minute exposure,
non-formulated 0.5% ivermectin is 96.7 and 103.0 times faster than
ddH2O treatment, respectively (Table 2).
[0114] Ivermectin as Compared to Placebo
[0115] The mortality responses for all three of the ivermectin
formulations are significantly different compared to the placebo
formulation (.chi.2=157.5, df=2, P<0.001; .chi.2=178.8, df=2,
P<0.001; .chi.2=190.0, df=2, P<0.001, respectively). At the
LT.sub.50 and LT.sub.95 following a 10 minute exposure, the 1%
ivermectin formulation is 137 and 393 times faster than placebo
formulation, respectively (Table 2). At the LT.sub.50 and LT.sub.95
following a 10 minute exposure, the 0.5% ivermectin formulation is
119 and 265 times faster than the placebo formulation,
respectively. At the LT.sub.50 and LT.sub.95 following a 10 minute
exposure, the 0.25% ivermectin formulation is 58 and 165 times
faster than the placebo formulation, respectively (Table 2).
[0116] The mortality response to non-formulated 0.5% ivermectin is
significantly different compared to the placebo formulation
(.chi.2=143.8 df=2, P<0.001). At the LT.sub.50 and LT.sub.95
following a 10 minute exposure, non-formulated 0.5% ivermectin is
31.2 and 82.4 times faster than placebo treatment, respectively
(Table 2).
[0117] Ivermectin as Compared to Nix.RTM.
[0118] The mortality responses for all three of the ivermectin
formulations are significantly different compared to the Nix.RTM.
(.chi.2=211.8, df=2, P<0.001; .chi.2=244.0, df=2, P<0.001;
.chi.2=244.0, df=2, P<0.001), respectively (FIG. 3). At the
LT.sub.50 and LT.sub.95 following a 10 minute exposure, the 1%
ivermectin formulation is 123 and 245 times faster than Nix.RTM.,
respectively (Table 2). At the LT.sub.50 and LT.sub.95 following a
10 minute exposure, the 0.5% ivermectin formulation is 107 and 166
times faster than Nix.RTM., respectively. At the LT.sub.50 and
LT.sub.95 following a 10 minute exposure, the 0.25% ivermectin
formulation is 52 and 103 times faster than Nix.RTM., respectively
(Table 2). The mortality response to non-formulated 0.5% ivermectin
is significantly different compared to Nix.RTM. (.chi.2=180.6 df=2,
P<0.001). At the LT.sub.50 and LT.sub.95 following a 10 minute
exposure, non-formulated 0.5% ivermectin is 27.9 and 51.5 times
faster than Nix.RTM., respectively (Table 2).
[0119] The mortality responses for all three of the ivermectin
formulations are significantly different compared to non-formulated
0.5% ivermectin (.chi.2=143.8, df=2, P<0.001; .chi.2=153.2,
df=2, P<0.001; .chi.2=100.3, df=2, P<0.001, respectively
(FIG. 3). At the LT.sub.50 and LT.sub.95 following a 10 minute
exposure, the 1% ivermectin formulation is 4.4 and 4.8 times faster
than non-formulated 0.5% ivermectin (Table 2). At the LT.sub.50 and
LT.sub.95 following a 10 minute exposure, the 0.5% ivermectin
formulation is 3.8 and 3.2 times faster than the 0.5%
non-formulated ivermectin, respectively. At the LT.sub.50 and
LT.sub.95 following a 10 minute exposure, the 0.25% ivermectin
formulation is 1.9 and 2.0 times faster than non-formulated 0.5%
ivermectin, respectively (Table 2).
[0120] Mortality Response of I..sup.96 Ivermectin Formulation as
Compared to 0.5% and 0.25% Ivermectin Formulations
[0121] The mortality response for the 1% ivermectin formulation is
significantly different from that produced by the 0.5% and the
0.25% formulations following 10 minute exposures (.chi.2=11.5,
df=2, P=0.003, .chi.2=134.8, df=2, P=0.001, respectively) (FIG. 3).
At the LT.sub.50 and LT.sub.95 following a 10 minute exposure, the
1% ivermectin formulation is 1.2 and 1.5 times faster than the 0.5%
ivermectin formulation, respectively (Table 1). At the LT.sub.50
and LT.sub.95 following a 10 minute exposure, the 1% ivermectin
formulation is 2.4 and 2.4 times faster than the 0.25% ivermectin
formulation, respectively (Table 2).
[0122] The mortality response for the 0.5% ivermectin formulation
is significantly different than that produced by the 0.25%
formulation following a 10 minute exposure (.chi.2=121.5, df=2,
P<0.001) (FIG. 1). At the LT.sub.50 and LT.sub.95 following a 10
minute exposure, the 0.5% ivermectin formulation is 2.0 and 1.6
times faster than the 0.25% ivermectin formulation, respectively
(Table 2).
[0123] Mortality Response Following 5 and 3 Minute Exposure of the
1.96 and 0.5% Ivermectin Formulations
[0124] The mortality response for the 1% ivermectin formulation
following a 10 minute exposure is significantly different compared
to the 0.5% ivermectin formulation with a 5 minute exposure and the
0.5% ivermectin formulation with a 3 minute exposure (.chi.2=80.6,
df=2, P<0.001, .chi.2=163.3, df=2, P<0.001), respectively. At
the LT.sub.50 and LT.sub.95, the 1.0% ivermectin formulation
following a 10 minute exposure is 1.9 and 2.2 times faster than the
0.5% ivermectin formulation with a 5 minute exposure, respectively
(Table 2).
[0125] At the LT.sub.50 and LT.sub.95, the 1.0% ivermectin
formulation following a 10 minute exposure is 4.1 and 4.9 times
faster than the 0.5% ivermectin formulation with a 3 minute
exposure, respectively (Table 2). The mortality response for the
0.5% ivermectin formulation following a 10 minute exposure is
significantly different compared to the 0.5% formulation with a 5
minute exposure and the 0.5% ivermectin formulation with a 3 minute
exposure (.chi.2=55.1, df=2, P<0.001, .chi.2=175.2, df=2,
P<0.001), respectively. At the LT.sub.50 and LT.sub.95, the 0.5%
ivermectin formulation with a 10 minute exposure is 1.6 and 1.5
times faster than the 0.5% ivermectin formulation with a 5 minute
exposure, respectively (Table 2). At the LT.sub.50 and LT.sub.95,
the 0.5% ivermectin formulation following a 5 minute exposure is
3.5 and 3.3 times faster than the 0.5% ivermectin formulation with
a 3 minute exposure, respectively (Table 2).
[0126] The mortality response for the 0.25% ivermectin formulation
following a 10 minute exposure is significantly different from that
produced by the 0.5% formulation with a 5 minute exposure and the
0.5% ivermectin formulation with a 3 minute exposure (.chi.2=25.6,
df=2, P<0.001, .chi.2=95.0, df=2, P<0.001), respectively
(FIG. 3). At the LT.sub.50 and LT95, the 0.25% ivermectin
formulation following a 10 minute exposure is 1.3 and 1.1 times
slower than the 0.5% ivermectin formulation with a 5 minute
exposure, respectively (Table 2). At the LT.sub.50 and LT95, the
0.25% ivermectin formulation following a 10 minute exposure is 1.7
and 2.0 times faster than the 0.5% formulation with a 3 minute
exposure, respectively (Table 2).
[0127] The mortality response for the 0.5% formulation with a 5
minute exposure is significantly different compared to the 0.5%
formulation with a 3 minute exposure (.chi.2=118.8, df=2,
P<0.001). At the LT.sub.50 and LT.sub.95, the 0.5% formulation
with a 5 min exposure is 2.2 and 2.2 times faster than the 0.5%
formulation with a 3 min exposure, respectively (Table 1).
[0128] Ivermectin Formulation Results Summary
[0129] Treatments with 1%, 0.5% and 0.25% ivermectin formulations
result in a significantly faster mortality response than treatments
with placebo or ddH2O, indicating that the present invention is
pediculicidal on permethrin-resistant head lice. Ivermectin
formulations have a faster mortality response than Nix.RTM.
treatments indicating that the ivermectin formulation of the
present invention is a faster acting pediculicide. The 1%
ivermectin formulation works significantly faster than its 0.5%
formulation and the 0.5% formulation works significantly faster
than its 0.25% formulation.
[0130] The 0.5% ivermectin formulation with a 10 minute exposure
works significantly faster than the 0.5% formulation with a 5
minute exposure and both are significantly faster than the 0.5%
formulation with a 3 minute exposure.
[0131] However, the non-formulated 0.5% ivermectin solution is 3.2
to 3.8 times slower at killing SF-HL than the 0.5% ivermectin
formulation of the present invention. The exact reason for the
superior killing power of ivermectin in formulation may be due to
the increased penetration, or increased transfer, of the active
ingredient residues to louse cuticles.
[0132] Nix.RTM. is not 100% effective at killing treated SF-HL
using the hair tuft bioassay system (Moon et al. 2006). All
ivermectin formulations disclosed herein kills 100% of SF-HL
lice.
[0133] Development of Lice on Substrates Treated with
Ivermectin
[0134] A nit of head lice normally undergoes a 7-9 day incubation
before hatching as a baby nymph. It looks like an adult head louse,
but is smaller. Nymphs mature into adults about 7 days after
hatching. To live, the nymph must feed on blood. It metamorphoses 3
times before it reaches the adult stage.
[0135] During the experiments, including those described above, it
was observed that the eggs incubated on substrates treated with the
compositions of the instant invention were able to hatch into first
instar nymphs but then all died. It is indirectly ovicidal. This
mode of action is different from the mode of action of permethrin.
It was also observed that but the nymphs died almost immediately
after hatching. Therefore, these observations demonstrate that the
compositions of the instant penetrates the egg and the invention
are efficient at least for 7-9 days (i.e., the time needed for
incubation of the eggs)
[0136] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description. Such modifications are intended to fall
within the scope of the appended claims.
* * * * *