U.S. patent application number 13/220935 was filed with the patent office on 2012-03-01 for topical gel formulation comprising organophosphate insecticide and preparation thereof.
This patent application is currently assigned to Taro Pharmaceuticals North America, Inc.. Invention is credited to Sandhya Goyal, Subhas Kundu, Daniel Moros, Howard Rutman, Avraham Yacobi.
Application Number | 20120053153 13/220935 |
Document ID | / |
Family ID | 35839589 |
Filed Date | 2012-03-01 |
United States Patent
Application |
20120053153 |
Kind Code |
A1 |
Goyal; Sandhya ; et
al. |
March 1, 2012 |
TOPICAL GEL FORMULATION COMPRISING ORGANOPHOSPHATE INSECTICIDE AND
PREPARATION THEREOF
Abstract
The present invention provides a topical gel pharmaceutical
formulation of insecticide suitable for treating an ectoparasite in
a mammal, comprising: a) about 0.1-10% by weight of an insecticide;
b) at least about 75% by weight of an organic solvent selected from
the group consisting of a lower alkyl alcohol, a ketone, a glycol
and a mixture thereof, wherein the organic solvent contains at
least about 40% by weight of the lower alkyl alcohol; and c) at
least one polymer selected from the group consisting of a
cellulosic polymer, acrylates, methacrylates, and polyvinyl
pyrrolidone. The present gel pharmaceutical formulation preferably
contains malathion and optionally contains isopropyl myristate. The
present invention further provides a process of preparing as well
as a method of treating ectoparasites in a mammal using the
same.
Inventors: |
Goyal; Sandhya; (Ryebrook,
NY) ; Kundu; Subhas; (Tappan, NY) ; Moros;
Daniel; (Larchmont, NY) ; Rutman; Howard; (New
York, NY) ; Yacobi; Avraham; (Englewood, NJ) |
Assignee: |
Taro Pharmaceuticals North America,
Inc.
Grand Cayman
KY
|
Family ID: |
35839589 |
Appl. No.: |
13/220935 |
Filed: |
August 30, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11179719 |
Jul 12, 2005 |
8012498 |
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13220935 |
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60587291 |
Jul 12, 2004 |
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60645781 |
Jan 21, 2005 |
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60646826 |
Jan 25, 2005 |
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Current U.S.
Class: |
514/122 |
Current CPC
Class: |
A01N 25/04 20130101;
A01N 53/00 20130101; A01N 53/00 20130101; A01N 57/14 20130101; A01N
37/02 20130101; A01N 57/12 20130101; A01N 37/02 20130101; A01N
57/16 20130101; A01N 57/14 20130101; A01N 53/00 20130101; A01N
57/12 20130101; A01N 53/00 20130101; A01N 57/16 20130101; A01N
57/16 20130101; A01N 57/14 20130101; A01N 2300/00 20130101; A01N
57/16 20130101; A01N 57/12 20130101; A01N 25/04 20130101; A61P
33/14 20180101; A01N 57/14 20130101; A01N 57/16 20130101; A01N
25/04 20130101; A01N 57/12 20130101; A01N 53/00 20130101; A01N
57/12 20130101; A01N 37/02 20130101; A01N 2300/00 20130101; A01N
31/08 20130101; A01N 2300/00 20130101; A01N 25/04 20130101; A01N
25/04 20130101; A01N 37/02 20130101; A01N 2300/00 20130101; A01N
57/14 20130101; A01N 2300/00 20130101; A01N 31/02 20130101; A01N
25/04 20130101; A01N 25/04 20130101; A01N 2300/00 20130101; A01N
25/04 20130101 |
Class at
Publication: |
514/122 |
International
Class: |
A61K 31/6615 20060101
A61K031/6615; A61P 33/14 20060101 A61P033/14 |
Claims
1-82. (canceled)
83. A topical gel pharmaceutical formulation of insecticide
suitable for treating an ectoparasite in a mammal, comprising: a)
about 0.1-10% by weight of malathion; b) at least about 75% by
weight of a lower alkyl alcohol; and c) about 0.1% to about 10% of
at least one cellulosic polymer, wherein the formulation is free of
added water, and has a viscosity at least about 1000 cps.
84. The topical gel pharmaceutical formulation of claim 83, wherein
the viscosity is at least about 3000 cps.
85. The topical gel pharmaceutical formulation of claim 83, wherein
the viscosity is at least about 5000 cps.
86. The topical gel pharmaceutical formulation of claim 83, wherein
the viscosity is between about 2200 cps and about 5300 cps.
87. The topical gel pharmaceutical formulation of claim 83, wherein
the cellulosic polymer is selected from the group consisting of
hydroxyl ethyl cellulose, hydroxy propyl cellulose, hydroxy propyl
methyl cellulose, methyl cellulose, carboxy methyl cellulose,
sodium carboxy methyl cellulose, and ethyl cellulose.
88. The topical gel pharmaceutical formulation of claim 83, wherein
the cellulosic polymer is hydroxyl propyl cellulose.
89. The topical gel pharmaceutical formulation of claim 83, wherein
the cellulosic polymer is present in the amount of about 0.5% to
about 5%.
90. The topical gel pharmaceutical formulation of claim 83, wherein
the lower alkyl alcohol is selected from ethyl alcohol and
isopropyl alcohol.
91. The topical gel pharmaceutical formulation of claim 83,
comprising about 0.1% to about 5% by weight of malathion.
92. The topical gel pharmaceutical formulation of claim 83, further
comprising a fragrance.
93. The topical gel pharmaceutical formulation of claim 83, further
comprising at least one compound selected from the group consisting
of terpineol, terpene, limonene, dipentene, and pine needle
oil.
94. The topical gel pharmaceutical formulation of claim 93, wherein
the at least one compound is present in the amount of about 0.1% to
about 30%.
95. The topical gel pharmaceutical formulation of claim 93, wherein
the at least one compound is present in the amount of about 10% to
about 20%.
96. The topical gel pharmaceutical formulation of claim 83, further
comprising an antioxidant.
97. The topical gel pharmaceutical formulation of claim 96, wherein
the antioxidant is at least one compound selected from the group
consisting of ascorbic acid, butylated hydroxyl anisole, butylated
hydroxy toluene, propyl gallate, tartaric acid, phosphoric acid,
erythrobic acid, lactic acid, sodium sulfite, sodium bisulfate,
sodium metabisulfite, thioglycolic acid, cysteine hydrochloride and
alpha tocopherol.
98. The topical gel pharmaceutical formulation of claim 96 wherein
the antioxidant is present in the amount of about 0.025% to about
5%.
99. The topical gel pharmaceutical formulation of claim 96, wherein
the antioxidant is present in the amount of about 0.1% to about
1%.
100. A topical gel pharmaceutical formulation of insecticide
suitable for treating an ectoparasite in a mammal, comprising: a)
about 0.1 to about 10% by weight of malathion; b) at least 75% by
weight of a lower alkyl alcohol; and about 0.1% to about 10% of at
least one cellulosic polymer, and wherein the formulation is
essentially free of water, and has a viscosity at least about 1000
cps.
101. The topical gel pharmaceutical formulation of claim 100,
wherein the viscosity is at least about 3000 cps.
102. The topical gel pharmaceutical formulation of claim 98,
wherein the cellulosic polymer is selected from the group
consisting of hydroxyl ethyl cellulose, hydroxy propyl cellulose,
hydroxy propyl methyl cellulose, methyl cellulose, carboxy methyl
cellulose, sodium carboxy methyl cellulose, and ethyl
cellulose.
103. The topical gel pharmaceutical formulation of claim 98,
wherein the cellulosic polymer is hydroxyl propyl cellulose.
104. The topical gel pharmaceutical formulation of claim 98,
further comprising at least one compound selected from the group
consisting of terpineol, terpene, limonene, dipentene, and pine
needle oil.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/179,719, filed Jul. 12, 2005, which claims
the benefit under 35 U.S.C. .sctn.1.119(e) of Provisional
Application Serial Nos. 60/587,291 (filed Jul. 12, 2004),
60/654,781 (filed Jan. 21, 2005) and 60/646,826 (filed Jan. 25,
2005), the disclosure of which is incorporated by reference in its
entirety herein.
FIELD OF THE INVENTION
[0002] The present invention generally relates to the treatment of
ectoparasites such as head lice, body lice, pubic lice and scabies
in a mammal. In particular, the present invention relates to a
topical gel pharmaceutical formulation comprising an
organophosphate insecticide such as malathion that is effective,
safe and has a short application time.
BACKGROUND OF THE INVENTION
[0003] Infection with ectoparasites in humans is common and remains
a major health problem in the U.S. and worldwide. The most common
ectoparasites include head lice, body lice, pubic lice and scabies.
For example, head lice (Pediculus capitis) is a persistent health
problem. Six million school children in United States will become
infected with head lice annually; that is, one out of every four
students in elementary schools (Consumer Reports, February 1998). A
total of about ten million people will be infected when all ages
are accounted. The incidence of head lice is only slightly improved
from the reported incidence in 1940, which was prior to the advent
of insecticides and superior knowledge by the medical
establishment.
[0004] Infestation with head lice in human typically causes itching
and lesion of the scalp, as well as swelling of glands in the neck
or under the arms. A secondary problem is that many schools have
enforced absenteeism if a child has any nits (lice eggs) in their
hair (See, e.g., U.S. Pat. No. 6,103,248). Such a "no-nit" policy
has negative social implications for the child and the parents.
Head lice is becoming a sensitive social issue. Evidence also
strongly supports that head lice could be vectors for systemic
human infections. For example Rickettsiae and Spirochetes are known
to be obtainable from the blood of the host (head lice are blood
suckers like mosquitoes); these organisms multiply in the gut of
the head lice, and are found in high numbers in their feces (See,
e.g., U.S. Pat. No. 6,103,248). Viruses, like the AIDS virus, have
been found in the gut and feces of head lice (See, e.g., U.S. Pat.
No. 6,103,248).
[0005] Body lice are tiny parasitic insects (Pediculus humanus
corporis) that can be spread by close contact with infected people
or clothing. They feed on human blood, lay eggs and deposit their
fecal matter on skin. Infestation with body lice in humans causes
intense itching. When body lice are not feeding on blood, they live
in the seams and folds of clothing. Pubic lice are parasitic
insects found commonly in the genital area, body hair including
hair on the legs, armpit, mustache, eyebrows and eyelashes in
humans, especially in young children.
[0006] Scabies is caused by a tiny mite (called Human Itch mite)
that has infested humans for at least 2,500 years. Scabies can
barely be seen by the human eyes. Dermatologists estimate that more
than 300 million cases of scabies occur worldwide every year. The
condition can strike anyone of any race or age, regardless of
personal hygiene. Within several weeks, the patient develops an
allergic reaction causing severe itching; often intense enough to
keep sufferers awake all night.
[0007] Home remedies for these ectoparasites are largely
ineffective or inconvenient to apply. For example, remedies against
head lice include applying petroleum jelly or mayonnaise on the
scalp. Unfortunately, these treatments are ineffective.
[0008] Commercial treatments also include applying an insecticide
on the scalp hair. The marketed products (prescription and OTC)
include insecticides such as malathion, gamma benzene hexachloride,
permethrin, pyrethrin, or piperonyl butoxide.
[0009] These pharmaceutically formulated insecticides are
universally admixed in a water based composition such as mousse,
foam, ointment, shampoo, lotion, and cream rinse. U.S. Pat. No.
5,783,202 describes a mousse formulation and European Patent 125471
describes a foaming pesticide. These two formulations are limited
as they break down quickly (e.g., within 2-30 seconds) and risking
the exposure of eyes/ears to the toxic insecticide. In addition,
the generated air bubbles in these formulations may be bigger than
the pores on the cap of the eggs and hence may actually impede the
insecticide activity. U.S. Pat. No. 6,524,602 describes the use of
N,O-carboxymethyl-chitosan polymer to increase the retention of
formulation on skin. The safety of the polymer and how it affects
stability of insecticides have not been established.
[0010] U.S. Pat. No. 6,103,248 describes a thick ointment
preparation containing an insecticide, lipophillic carrier and a
surfactant. The carrier has a viscosity within the range of 10,000
centipoise to about 85,000 centipoise at 21.degree. C. A main
disadvantage associated with such formulations is the presence of
surfactant, which may raise the pH of the formulation thus
affecting the stability of insecticides like malathion which is pH
sensitive. Because of its high viscosity and oily nature, the
formulation is difficult to spread evenly in the hair, and to wash
away from the hair (requires a minimum of two washings). Some head
lice products are available as shampoo; however the efficacy of
such dosage form is uncertain. The shampoo needs to be diluted with
water to 1:20 to 1:30 times for application to the hair which
lowers the efficacy of the insecticide. Head lice have spiracles,
by which the adult lice breathe and the eggs have opercula by which
lice larvae in the eggs exchange oxygen. When lice comes in contact
with water, it grasps hair reflectively and close their breathing
spiracles to avoid being drowned. The opercula in eggs also close
when in contact with water thus making it difficult for shampoos
and other aqueous products containing insecticide difficult to
penetrate and lead to loss in efficacy. Aqueous lotions, shampoos
and cream rinse also have too big a wetting angle for fluid to flow
into the opercula directly. Because of these problems associated
with various formulations, there has been an increasing evidence of
development of resistance against these products.
[0011] Currently marketed Ovide.RTM. Lotion containing malathion,
is the only insecticide, against which the lice has still not
developed resistance. Since its introduction in the mid 1980's,
there are no other commercial malathion preparations other than the
lotion form. The pharmaceutical form of malathion contains 78%
isopropyl alcohol, which functions as a solvent for delivery of
malathion. A major difficulty encountered in applying this lotion
is that it spreads freely on the scalp and hair shafts, thus giving
false appearance of sufficient wetness after application of very
small quantity (i.e., patients get the impression that this
quantity is sufficient). Moreover, the lotion (due to its low
viscosity) may easily run into the eyes, ears and down the
patient's neck causing eye, ear and skin irritation as well as
soiling the clothes. The patient is instructed to apply the lotion
for 8-12 hours and not go near open flame or use a hair dryer
during this time due to higher alcohol content which is
flammable.
[0012] Treatment against ectoparasites further includes applying
permethrin cream (5%), pyrethrin shampoo, lindane (1%) lotion,
crotamiton cream, or oral dosage of ivermectin. Permethrin and
lindane treatment requires applying the drugs from the neck down at
night and washed off in the morning. Reapplication is often
required. Many of these drugs are either toxic to nervous system or
causes allergy. For example, lindane can not be used on infants,
children, pregnant/nursing women, people with seizures or other
neurological diseases. The National Pediculosis (head lice)
Association recently established a database to track "adverse
event" reports related to use of lindane to treat head lice in the
U.S. In the first 24 months, more than 500 events were reported
(County Sanitation Districts 2000). In 1996, in response to a
petition from several public interest groups in the U.S., the Food
and Drug Administration reviewed its regulations and determined
that lindane should be used only as a "treatment of last resort"
for lice and scabies. Lindane 1% shampoo is banned in California
due to environmental problems with lindane in sewage effluent.
Crotamiton cream has allergic activity. Oral dosage of ivermectin
cannot to be used in infants or pregnant women. Antihistamines
often are needed to relieve itching for the treatment.
[0013] Thus, there is a continuing need for a pharmaceutical
formulation containing stable insecticides including
organophosphate insecticides, such as malathion, that are
effective, safe and have a short application time.
SUMMARY OF THE INVENTION
[0014] In one aspect, the present invention provides a topical gel
pharmaceutical formulation comprising an insecticide effective to
exhibit pediculicidal, ovicidal and scabicidal activity, an organic
solvent and a viscosity-modifying polymer.
[0015] In another aspect, the present invention provides a topical
gel pharmaceutical formulation comprising an organophosphate
insecticide (such as malathion) effective to exhibit pediculicidal,
ovicidal and scabicidal activity, an organic solvent and a
viscosity-modifying polymer.
[0016] In another aspect, the present invention provides a topical
gel pharmaceutical formulation optionally containing isopropyl
myristate.
[0017] In another aspect, the present invention provides a process
of preparing a topical gel pharmaceutical formulation, comprising
the steps of: [0018] a) mixing a viscosity-modifying polymer in an
organic solvent to hydrate the polymer in the organic solvent,
[0019] wherein the viscosity-modifying polymer is at least one
polymer selected from the group consisting of a cellulosic polymer,
acrylates, methacrylates, and polyvinyl pyrrolidone, [0020] wherein
the organic solvent is selected from the group consisting of a
lower alkyl alcohol, a ketone, a glycol and a mixture thereof,
[0021] wherein the organic solvent is at least about 75% by weight,
[0022] wherein the organic solvent contains at least about 40% by
weight of the lower alkyl alcohol; and [0023] b) adding about
0.1-10% by weight an insecticide into the polymer mixture to form a
topical gel pharmaceutical formulation.
[0024] In yet another aspect, the present invention provides a
method for treating head lice in a mammal, comprising the step of
topically applying to the mammal in need thereof, a therapeutically
effective amount of the gel pharmaceutical formulation, said gel
pharmaceutical composition comprises an organophosphate insecticide
(such as malathion) exhibiting pediculicidal and ovicidal activity,
an organic solvent and a viscosity-modifying polymer.
BRIEF DESCRIPTION OF THE FIGURES
[0025] FIG. 1 depicts the viscosity of various gel formulations
including Ovide.RTM. lotion.
[0026] FIG. 2 depicts the in vitro efficacy of various gel
formulations in killing lice.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Definitions: As used herein, "insecticide" refers to a
substance used to prevent, destroy, repel, mitigate, or kill
insects; "organophosphate" refers to an organophosphorous compound
that displays anti-cholinesterase activity; "malathion" refers to a
pesticide (CAS # 121-75-5) belonging to the category of
organophosphate insecticide; "mammal" refers to a class of higher
vertebrates comprising man and all other animals that nourish their
young with milk secreted by mammary glands and have the skin more
or less covered with hair; "pediculicidal activity" refers to lice
killing activity; "ovicidal activity" refers to egg (of lice)
killing activity; "scabicidal" refers to scabies mites killing
activity; "HPC" refers to hydroxy propyl cellulose; "cellulosic
polymer" refers to polymers containing cellulose or modified
cellulose and are available in a variety of grades depending upon
the viscosity and extent of crosslinking; "lower alkyl alcohol"
refers to a compound of a general formula ROH where R is linear or
branched C.sub.1-8alkyl group (including substituted) and OH is the
hydroxyl group; "ketone" refers to an organic compound with a
carbonyl group attached to two carbon atoms; "glycol" refers to an
organic compound containing two hydroxyl groups; "ectoparasites"
refers to an organism that lives parasitically on the outside of it
host e.g. insects which live on the skin of cattle like ticks,
lice, fleas; "head lice" refers to Pediculus capitis, that are
small parasitic insects exquisitely adapted to living mainly on the
scalp and neck hairs of their human host; "pubic lice" refers to
small, six-legged creatures that invade the genital hair region and
infest it with their eggs; they can also infest armpit hair and
eyebrows; "body lice" refers to tiny parasitic insects (Pediculus
humanus corporis) that can be spread by close contact with other
people; "scabies" refers to an infestation of the skin with the
microscopic mite Sarcoptes scabei; "therapeutically effective
amount" refers to an amount of drug sufficient to exert the desired
therapeutic effect; "sufficient to kill" refers to amount of a
therapeutically effective agent which is sufficient to kill an
organism; " flash point" refers to the lowest temperature at which
a liquid or a solid gives off enough vapor to form flammable
air-vapor mixture near its surface; "viscosity" refers to a measure
of a fluid's resistance to flow; "viscosity-modifying polymer"
refers to a polymer that changes the viscosity of the formulation,
preferably, a modifying polymer increases the viscosity of the
formulation; "Ovide.RTM." refers to a tradename product having the
malathion as an active ingredient and is marketed by Taro
Pharmaceuticals, NY, USA; "Lindane" refers to a generic name
product having the gamma benzene chloride as an active ingredient
and is marketed by Alpharma, NJ, USA; "Nix.RTM." refers to a
tradename product having permethrin as an active ingredient and is
marketed by Warner-Lambert, Morris Plains, N.J., USA; and "Klucel
HF.RTM." refers to a tradename product having hydroxypropyl
cellulose and is marketed by Hercules Incorporated, Wilmington,
Del.
[0028] Unless otherwise indicated, as expressed in the present
specification as well as in the set of claims as wt/wt, %
(percentage) refers to % wt/wt.
[0029] By employing the present invention, all of the prior art
difficulties and drawbacks are eliminated and a safe, effective gel
formulation containing stable insecticide is attained. As detailed
herein, the present invention provides a gel formulation comprising
an insecticide (such as malathion) which have been uniquely
combined to attain a stable insecticide for highly effective
insecticide activity.
[0030] For purposes of the present invention, a topical gel
formulation is intended to encompass other suitable dosage forms
including cream, foam and the like, so long as the viscosity of the
other dosage forms is similar to that of the gel formulation as
detailed herein.
[0031] Although gel preparation for insecticide has been employed,
we have found surprisingly that a gel formulation for insecticide
having a high alcohol content and substantially aqueous free (i.e.,
not a water-based formulation) is exceedingly better. Traditional
gel preparation often involves the use of an aqueous base (i.e.,
formulation containing water) and a low level of alcohol (i.e.,
usually <10-20% alcohol). Aqueous base formulation that contains
water is found to be unsuitable for insecticide including
organophosphate compounds (e.g., malathion) due to its well-known
property that organophophate compounds are unstable when exposed to
an aqueous environment. Thus, the presence of water in any
formulation renders the organophosphate compounds to be unstable.
The use of high alcohol content and substantially aqueous-free
formulation as a gel preparation represents an unique and unobvious
departure from prior art teachings.
[0032] One unique aspect of the present invention is that the
insecticide (such as malathion) is stable in the present
formulation. The absence of water maintains the stability of the
insecticide. Alkyl alcohol is maintained at an amount sufficient to
effect the insecticide activity. Alkyl alcohol acts synergistically
with the stable insecticides in the gel formulation to kill the
ectoparasites.
[0033] Optionally, the present formulation may contain isopropyl
myristate. Without being bound by a theory, it is believed that the
presence of isopropyl myristate may enhance the penetration of the
insecticide (such as malathion). Our data indicate that the
presence of isopropyl myristate does not affect the stability of
the gel formulation.
[0034] Another unique aspect of the present invention is that the
gel provides an optimal viscosity such that it avoids the run-over
disadvantages of the lotion. We have found surprisingly that
viscosity-modifying polymer, when prepared in a substantially
aqueous free formulation, provides good viscosity for easy
spreading over the hair/body while maintaining stability for the
insecticide (such as malathion).
[0035] Another yet unique aspect of the present invention is that
the gel provides good retention (by avoiding rapid evaporation) of
high alcohol level within the formulation for effective killing of
lice.
[0036] In accordance with the present invention, malathion is a
preferred insecticide used in the topical gel pharmaceutical
formulation. Malathion is an organophosphate pesticide which
members include methyl parathion, dimethoate and chiorpyrifos.
Malathion was first introduced in the U.S. in 1950 by American
Cyanamid Company. Malathion has a chemical name of
O,O-dimthyl-S-(1,2-di(ethoxycarbonyl)-ethyl) phosphorodithioate and
has a CAS No.121-75-5. U.S. Pat. Nos. 3,352,664, 3,396,223, and
3,515,782 describe the use of malathion in killing pesticides, the
disclosure of these reference is incorporated by reference.
[0037] Conventional processes for preparing malathion are well
known and generally include the two-step process of reacting
phosphorus pentasulfide with methanol in the presence of dioxane,
benzene or toluene to form a solution of crude O,O-
dimethyldithiophosphoric acid (DMDP) and then reacting the solution
with diethyl maleate (See, e.g., U.S. Pat. Nos. 3,463,841 and
4,367,180). In a recently filed application (U.S. Provisional
Application 60/697,010, from which priority was claimed in U.S.
11/427863) entitled "Process for preparing pharmaceutical grade
malathion" (filed on Jul. 6, 2005), we disclosed an improved
malathion composition that has a better impurity profile as well as
a process of preparing a pharmaceutical grade malathion having
>99% purity and an improved impurity profile (i.e., less than
0.1% isomalathion, 0.05% O,O,S-trimethyl phosphorothioate, and 0.1%
methyl malathion). The disclosed process generally involves
reacting a phosphorus sulfide with methanol in an organic solvent
to form O,O-dimethyldithiophosphoric acid; extracting the
O,O-dimethyldithiophosphoric acid in water; and reacting the
O,O-dimethyldithiophosphoric acid in water with diethyl maleate to
form malathion, as exemplified below. The disclosure of this
recently filed application, U.S. Provisional Application
60/697,010, is hereby incorporated by reference in its
entirety.
[0038] Phosphorus pentasulfide (1.4 kg) and toluene (1.4 L) were
combined under nitrogen in a 5-L jacketed glass reactor equipped
with mechanical stirrer, and the resulting suspension was heated
with stirring to about 60.degree. C. Methanol (1.1 L) was added
dropwise over the course of four (4) hours and fifteen (15)
minutes, while maintaining the temperature of the reaction mass at
67.degree. C. or lower. The resulting gaseous H.sub.2S was trapped
using an aqueous solution of sodium hypochlorite/sodium hydroxide.
After complete addition of the methanol, the mixture was stirred at
55-65.degree. C. for an additional one (1) hour.
[0039] The mixture was cooled to a temperature of 22-30.degree. C.
and the mixture was filtered to remove unreacted phosphorus
pentasulfide. Additional toluene (0.3 L) was added to the resulting
filtrate. The mixture was distilled under vacuum (200 mbar) at a
temperature of about 50-60.degree. C. to remove about 600 mL of
toluene.
[0040] The resulting concentrate was cooled to a temperature of
22-30.degree. C. and water (3 kg) was added. The two phases were
mixed for 20 minutes, and then the phases were separated. The
aqueous phase was washed with toluene (0.3 L), and the aqueous
phase again was separated, to provide an aqueous solution of
dimethyldithiophosphoric acid (about 4.22 kg containing about 1.22
kg of dimethyldithiophosphoric acid).
[0041] The aqueous solution of dimethyldithiophosphoric acid was
combined with diethyl maleate (1.33 kg) and hydroquinone (3.3 g),
and the resulting two-phase mixture was heated for 8 h at
53-57.degree. C. under nitrogen atmosphere. The two-phase mixture
was cooled to 22-30.degree. C., and the phases were separated. The
organic phase was washed with water (2.times.1 kg) to afford crude
malathion (1.86 kg) containing at least about 30% (w/w) diethyl
fumarate.
[0042] Sodium bisulfite (1 kg) was dissolved in water (4kg), and
the pH of the solution was adjusted to 6.1-6.3 by addition of 50%
(w/w) sodium hydroxide (0.37 kg). The pH-adjusted solution was
combined with the crude malathion, and the resulting two-phase
mixture was heated at 60-65.degree. C. for 2 hours. The final pH of
the mixture was about 6.8-6.9. The mixture was cooled to
22-30.degree. C. and the phases were separated. The organic phase
was washed with water (1.5 kg), and the phases were separated.
Next, the organic phase was washed with 2.5% (w/w) aqueous sodium
hydroxide (1.5 kg), and the phases were separated. Finally, the
organic phase was washed with water (2.times.1 kg) to afford
malathion (0.94 kg).The purity of the obtained malathion was
determined using HPLC.
[0043] The quantities of known and unknown impurities are listed in
the following table.
TABLE-US-00001 Compound Quantity (% w/w) Diethyl fumarate 0.05
Isomalathion <0.04 (LOD) MeOOSPS 3.5 Malaoxon <0.05 (LOD)
Dimethyl malathion <0.02 (LOD) Methyl malathion <0.03 (LOD)
O, O--Me, Et Malathion analog.sup.1 0.06 Tetraethyl
dithiodisuccinate 0.04 Unknown (RRT = 0.38) 0.05 .sup.1Values of
Limit of Detection and Limit of Quantitation as for malathion were
used, and relative response factor RRF = 1
[0044] These data demonstrate that greater than 99% (w/w) of the
diethyl fumarate was removed from the crude malathion. These data
further demonstrate that the purified malathion contained only
0.04% (w/w) of tetraethyl dithiodisuccinate.
[0045] Water (2.8 kg) was added to the malathion, and the resulting
two-phase mixture was subjected to azeotropic distillation over the
course of four days at a temperature of about 35-50.degree. C. and
a pressure of about 30-60 mbar. Water was added to the mixture at
approximately one-hour intervals to replace the quantity removed by
distillation during that period (about 0.2-0.7 L each time). A
total of about 34.2 L of water was distilled during this process.
The two-phase mixture was cooled to 22-30.degree. C., and the
phases were separated, providing wet pharmaceutical grade malathion
(0.84 kg).
[0046] The purity of the obtained malathion was determined using
HPLC. The quantities of known and unknown impurities are listed in
the following table:
TABLE-US-00002 Compound Quantity (% w/w) Diethyl fumarate <0.01
(LOD) Isomalathion 0.07 MeOOSPS 0.1 Malaoxon <0.05 (LOD)
Dimethyl malathion <0.02 (LOD) Methyl malathion 0.06 Unknown
(RRT = 0.38) 0.05 Malathion purity 99.5
[0047] These data demonstrate that at least 97% (w/w) of the
MeOOSPS was removed. These data further demonstrate that the
purified malathion contained only 0.07% (w/w) of isomalathion.
[0048] The wet pharmaceutical grade malathion was heated at
38-42.degree. C., and air was bubbled through the wet mass for
about 20 hours. Water content was then determined by a Karl Fisher
procedure according to USP Method I <921>, and found to be
0.05% (w/w). The mixture was then cooled to room temperature and
filtered through glass paper, to provide dry pharmaceutical grade
malathion (0.8 kg).
[0049] The purity of the obtained malathion was determined using
HPLC. The quantities of known and unknown impurities are listed in
the following table:
TABLE-US-00003 Compound Quantity (% w/w) MeOOSPO <0.04 (LOD)
MeOS SPO <0.02 (LOD) MeOOSPS 0.1 Malaoxon <0.05 (LOD) Diethyl
fumarate <0.01 (LOD) Dimethyl malathion <0.02 (LOD) Methyl
malathion 0.06 O, O--Me, Et Malathion analog.sup.1 0.08
Isomalathion <0.02 (LOD) Tetraethyl dithiodisuccinate' 0.06
Unknown (RRT = 0.38) 0.04 Total 0.3 .sup.1Values of Limit of
Detection and Limit of Quantitation as for malathion were used, and
relative response factor RRF = 1
[0050] The assay of the obtained malathion was determined using
HPLC, and found to be 99.5% (w/w).
[0051] Two additional batches of pharmaceutical grade malathion
were prepared. The purity of the obtained malathion was determined
using HPLC. The quantities of known and unknown impurities are
listed in the following table:
TABLE-US-00004 Quantity (% w/w) Quantity (% w/w) Compound in Batch
1 in Batch 2 MeOOSPO <0.04 (LOD) <0.04 (LOD) MeOSSPO <0.02
(LOD) <0.02 (LOD) MeOOSPS 0.09 0.09 Malaoxon <0.05 (LOD)
<0.05 (LOD) Diethyl fumarate 0.06 <0.01 (LOD) Dimethyl
malathion <0.02 (LOD) <0.02 (LOD) Methyl malathion 0.08 0.07
O,O--Me,Et Malathion analog.sup.1 0.11 0.09 Isomalathion <0.02
(LOD) <0.02 (LOD) Tetraethyl dithiodisuccinate' 0.08 0.08
Unknown (RRT = 0.38) 0.06 0.05 Total 0.5 0.4 .sup.1Values of Limit
of Detection and Limit of Quantitation as for malathion were used,
and relative response factor RRF = 1.
[0052] In one embodiment, the present invention provides a topical
gel pharmaceutical formulation of insecticide suitable for treating
an ectoparasite in a mammal, comprising: [0053] a) about 0.1-10% by
weight of an insecticide; [0054] b) at least about 75% by weight of
an organic solvent selected from the group consisting of a lower
alkyl alcohol, a ketone, a glycol and a mixture thereof, wherein
the organic solvent contains at least about 40% by weight of the
lower alkyl alcohol; and [0055] c) at least one viscosity-modifying
polymer selected from the group consisting of a cellulosic polymer,
acrylates, methacrylates, and polyvinyl pyrrolidone.
[0056] Preferably, the insecticide is an organophosphate.
[0057] In accordance with the present invention, organophosphorus
insecticides include, but are not limited to, malathion,
chlorphyrifos, parathion, ethyl-methyl parathion, methyl malathion,
ethion fonofos, acephate, formothion, azamethiphos, azinphos-ethyl,
azinphos-methyl, chlorfenvinphos, cyanophos, danifos,
fensulfothion, tribufos, dimethoate, dioxathion, disulfoton,
endothion, ethion, fenitrothion, ethoprop, chlorethoxyfos,
iprobenfos, isazofos, isofenphos, isoxathion, vamidothion,
methidathion, methyl parathion, mevinphos, morphothion, naled,
fenamiphos, fosmethilan, pyridaphenthion, omethoate, parathion,
phencapton, phenthoate, phorate, phosalone, phosmet, phosnichlor,
phosphamidon, leptophos, phoxim, pirimiphos-methyl,
pirimiphos-ethyl, profenofos, prothidathion, prothoate, piperophos,
tolclofos-methyl, ronnel, cadusafos, sophamide, demeton, demeton I
(thiono isomer), demeton II (thiolo isomer), cyanthoate,
tebupirimfos, terbufos, tetra chlorvinphos, thiometon, prothiofos,
dialifos, trichlorfon and the like.
[0058] Preferably, the organophosphorus insecticides are malathion,
phosmet, parathion, dioxanthion, terbufos and prothiofos.
[0059] More preferably, the organophosphate is malathion.
[0060] Preferably, the insecticide is gamma benzene chloride,
permethrin, pyretlui, piperonyl butoxide, spinosyns, polydimethyl
siloxane or pyrantel pamoate.
[0061] Preferably, the insecticide is present in the amount of
about 0.1% to about 10%. Preferably, the insecticide is present in
the amount of about 0.1% to about 5%. More preferably, the
insecticide is present in the amount of about 0.5%.
[0062] Preferably, the insecticide is malathion. Preferably,
malathion is present in the amount of about 0.1% to about 10%. More
preferably, malathion is present in the amount of about 0.1% to
about 5%. More preferably, malathion is present in the amount of
about 0.5%
[0063] Preferably, the organic solvent is at least one solvent
exemplified to include a lower alkyl alcohol, a ketone, a glycol
and the like.
[0064] Preferably, the organic solvent is present in the amount of
about 1% to about 99%. More preferably, the organic solvent is
present in the amount of about 20% to about 80%. More preferably,
the organic solvent is present in the amount of about 60% to about
80%.
[0065] Preferably, the lower alkyl alcohol is exemplified to
include a C.sub.1-C.sub.8 alcohol and the like, including branch or
linear alcohol. Preferably, the lower alkyl alcohol is ethyl
alcohol or isopropyl alcohol.
[0066] Preferably, the ketone is exemplified to include acetone,
N-methyl pyrrolidone, and the like.
[0067] Preferably, the glycol is exemplified to include propylene
glycol and the like.
[0068] Preferably, the organic solvent is a mixture of a first
solvent selected from the group consisting of ethyl alcohol and
isopropyl alcohol and a second solvent selected from the group
consisting of benzyl alcohol, ketone and glycol, wherein the wt/wt
ratio of the first solvent and the second solvent results in an
increase in the flash point: of the formulation to reduce its
flammability.
[0069] Preferably, the organic solvent is a mixture of ethyl
alcohol and propylene glycol, ethyl alcohol and benzyl alcohol,
ethyl alcohol and N-methyl pyrrolidone.
[0070] Preferably, the organic solvent is a mixture of isopropyl
alcohol and propylene glycol, isopropyl alcohol and benzyl alcohol,
ethyl alcohol and N-methyl pyrrolidone.
[0071] Optionally, the present formulation may contain isopropyl
myristate. Isopropyl myristate may be present in the amount of
about 4% to about 14%. Preferably, isopropyl myristate is present
in the amount of about 8% to about 12%. More preferably, isopropyl
myristate is present in the amount of about 10%.
[0072] Preferably, the cellulosic polymer is exemplified to include
hydroxyl ethyl cellulose, hydroxy propyl cellulose, hydroxy propyl
methyl cellulose, methyl cellulose, carboxy methyl cellulose,
sodium carboxy methyl cellulose, ethyl cellulose and the like. More
preferably, the cellulosic polymer is hydroxyl propyl
cellulose.
[0073] Preferably, the cellulosic polymer is present in the amount
of about 0.1% to about 20%. More preferably, the cellulosic polymer
is present in the amount of about 0.1% to about 10%. More
preferably, the cellulosic polymer is present in the amount of
about 0.5% to about 5%.
[0074] Preferably, the topical gel pharmaceutical formulation may
further contain a fragrance. Preferably, the fragrance is
exemplified to include terpineol, terpenes, pine needle oil and
other natural and synthetic fragrances and the like.
[0075] Preferably, the fragrance is present in the amount of about
0.1% to about 30%. More preferably, the fragrance is present in the
amount of about 5% to about 20%. More preferably, the fragrance is
present in the amount of about 10% to about 20%.
[0076] Preferably, the topical gel pharmaceutical formulation may
further contain an antioxidant. Preferably, the antioxidant is
exemplified to include ascorbic acid, butylated hydroxyl anisole,
butlylated hydroxy toluene, propyl gallate, tartaric acid,
phosphoric acid, erythrobic acid, lactic acid, sodium sulfite,
sodium bisulfate, sodium metabisulfite, thioglycolic acid, cysteine
hydrochloride, alpha tocopherol and the like. The antioxidant may
be present in the salt form.
[0077] Preferably, the antioxidant is present in the amount of
about 0.025% to about 5%. More preferably, the antioxidant is
present in the amount of about 0.1% to about 1%.
[0078] The present topical gel pharmaceutical formulation is
resistant to microbial growth (due to high alcohol content) and
hence does not require the addition of preservatives. However,
formulations containing lower amount of alcohol may be preserved by
adding preservatives that are commonly known to the one skilled in
the art
[0079] Preferably, the topical gel pharmaceutical formulation has a
pH between about 3 to about 10. More preferably, the pH is about 4
to about 7. More preferably, the pH is about 5.
[0080] Preferably, the present pharmaceutical formulation is
present as a gel. Preferably, the present pharmaceutical
formulation has a viscosity of at least about 1,000 centipoise
(cps). More preferably, the topical gel pharmaceutical formulation
has a viscosity of the gel pharmaceutical formulation is at least
about 3,000 cps. Preferably, the viscosity of the present
pharmaceutical formulation does not exceed 50,000 cps.
[0081] In another embodiment, the present invention provides a
topical gel pharmaceutical formulation of insecticide suitable for
treating an ectoparasite in a mammal, comprising: a) about 0.5% by
weight of malathion; b) at least one organic solvent selected from
the group consisting of ethyl alcohol, isopropyl alcohol, propylene
alcohol, benzyl alcohol, and propylene glycol; and c) hydroxyl
propyl cellulose.
[0082] In another embodiment, the present invention provides a
topical gel pharmaceutical formulation of insecticide suitable for
treating an ectoparasite in a mammal, comprising: a) about 0.5% by
weight of malathion; b) at least one organic solvent selected from
the group consisting of ethyl alcohol, isopropyl alcohol, propylene
alcohol, benzyl alcohol, and propylene glycol; c) isopropyl
myristate; and d) hydroxyl propyl cellulose.
[0083] In another embodiment, the present invention provides a
process of preparing a topical gel pharmaceutical formulation of
insecticide, comprising the steps of: [0084] a) mixing a
viscosity-modifying polymer in an organic solvent to hydrate the
polymer in the organic solvent, [0085] wherein the
viscosity-modifying polymer is at least one polymer selected from
the group consisting of a cellulosic polymer, acrylates,
methacrylates, and polyvinyl pyrrolidone, wherein the organic
solvent is selected from the group consisting of a lower alkyl
alcohol, a ketone, [0086] a glycol and a mixture thereof, [0087]
wherein the organic solvent is at least about 75% by weight, [0088]
wherein the organic solvent contains at least about 40% by weight
of the lower alkyl alcohol; and [0089] b) adding about 0.1-10% by
weight an insecticide into the polymer mixture to form a topical
gel pharmaceutical formulation.
[0090] Preferably, the insecticide is an organophosphate. More
preferably, the organophosphorous insecticide is malathion.
[0091] For purposes of the present invention, the ingredient
malathion of the present pharmaceutical formulation is intended to
encompass malathion having a purity of <99%, 99% (i.e.,
commercial source) (technical grade malathion) and malathion having
a purity of >99% (pharmaceutical grade malathion). As stated, in
a separate application (U.S. Provisional Application 60/697,010)
entitled "Process for preparing pharmaceutical grade malathion"
(filed Jul. 6, 2005), we have disclosed a novel and unique
synthesis pathway for preparing a pharmaceutical grade malathion,
which has an improved impurity profile, the disclosure of which is
incorporated herein in its entirety. The pharmaceutical grade
malathion has a purity of >99% and contains less than 0.1%
isomalathion, 0.05% O,O,S-trimethyl phosphorothioate, and 0.1%
methyl malathion.
[0092] In an embodiment, the improved pharmaceutical grade
malathion contains the following impurity profile: <0.02%
isomalathion, <0.04 wt % O,O,S-trimethyl 20 phosphorothioate,
and 0.08% methyl malathion. In addition, the improved
pharmaceutical grade malathion contains <0.02% O,S,S,-trimethyl
phosphorodithioate, 0.09% O,O,S-trimethyl phosphorodithioate ,
<0.05% malaoxon, 0.06% diethyl fumarate, <0.02% dimethyl
malathion, 0.11% O,O-Me,Et malathion analog, and 0.08% tetraethyl
dithiodisuccinate. The prepared pharmaceutical grade malathion may
be conveniently and suitably used in the present gel pharmaceutical
formulation.
[0093] Preferably, the mixing step (i.e., step a) is performed by
heating and stirring. More preferably, the mixing step involves
heating at about 45.degree. C.
[0094] Preferably, the viscosity-modifying polymer is exemplified
to include a cellulosic polymer and the like. Preferably, the
cellulosic polymer is exemplified to include hydroxyl ethyl
cellulose, hydroxy propyl cellulose, hydroxy propyl methyl
cellulose, methyl cellulose, carboxy methyl cellulose, sodium
carboxy methyl cellulose, ethyl cellulose and the like. More
preferably, the cellulosic polymer is hydroxyl propyl
cellulose.
[0095] Preferably, the organic solvent may include one or more
solvent exemplified to include a lower alkyl alcohol, a ketone, a
glycol and the like. More preferably, the lower alkyl alcohol is
exemplified to include a C.sub.1-C.sub.8 alcohol and the like. More
preferably, the lower alkyl alcohol is ethyl alcohol or isopropyl
alcohol.
[0096] Preferably, the ketone is exemplified to include N-methyl
pyrrolidone, acetone and the like.
[0097] Preferably, the glycol is exemplified to include propylene
glycol, hexylene glycol and the like.
[0098] Preferably, the process may further comprise the step of
adding a fragnance.
[0099] More preferably, the fragrance is least one compound
exemplified to include terpineol, terpenes, pine needle oil, other
natural and synthetic fragrances and the like.
[0100] Preferably, the process may further comprises the step of
adding an antioxidant. More preferably, the antioxidant is at least
one compound exemplified to include ascorbic acid, butylated
hydroxyl anisole, butlylated hydroxy toluene, propyl gallate,
tartaric acid, phosphoric acid, erythrobic acid, lactic acid,
sodium sulfite, sodium bisulfate, sodium metabisulfite,
thioglycolic acid, cysteine hydrochloride, alpha tocopherol and the
like. Antioxidant may be present in salt forms. Preferably, the
salt form of antioxidant is exemplified to include ascorbic acid,
tartaric acid, phosphoric acid, erythrobic acid, lactic acid and
the like.
[0101] In another embodiment, the present invention provides a
method for treating an ectoparasite in a mammal, comprising the
step of topically applying to a mammal a therapeutically effective
amount of the topical gel pharmaceutical formulation, said
formulation comprises: a) about 0.1-10% by weight of an
insecticide; b) at least about 75% by weight of an organic solvent
selected from the group consisting of a lower alkyl alcohol, a
ketone, a glycol and a mixture thereof, wherein the organic solvent
contains at least about 40% by weight of the lower alkyl alcohol;
and c) at least one viscosity-modifying polymer selected from the
group consisting of a cellulosic polymer, acrylates, methacrylates,
and polyvinyl pyrrolidone.
[0102] In another embodiment, the present invention provides a
method for treating an ectoparasite in a mammal, comprising the
step of topically applying to a mammal a therapeutically effective
amount of the topical gel pharmaceutical formulation, said
formulation comprises: a) about 0.1-10% by weight of an
insecticide; b) at least about 75% by weight of an organic solvent
selected from the group consisting of a lower alkyl alcohol, a
ketone, a glycol and a mixture thereof, wherein the organic solvent
contains at least about 40% by weight of the lower alkyl alcohol;
c) isopropyl myristate; and d) at least one viscosity-modifying
polymer selected from the group consisting of a cellulosic polymer,
acrylates, methacrylates, and polyvinyl pyrrolidone.
[0103] In another embodiment, the present invention provides a
method for treating an ectoparasite in a mammal, comprising the
step of topically applying to a mammal a therapeutically effective
amount of the topical gel pharmaceutical formulation, said
formulation comprises: a) about 0.5% by weight of malathion; b) at
least about 75% by weight of an organic solvent selected from the
group consisting of ethyl alcohol, isopropyl alcohol, benzyl
alcohol, and propylene glycol, wherein the organic solvent contains
at least about 40% by weight of ethyl alcohol or isopropyl alcohol;
and c) hydroxyl propyl cellulose.
[0104] In another embodiment, the present invention provides a
method for treating ectoparasites in a mammal, comprising the steps
of: topically applying to a mammal a therapeutically effective
amount of the topical gel pharmaceutical formulation, said gel
pharmaceutical formulation comprises: malathion, ethyl alcohol
and/or isopropyl alcohol, hydroxyl propyl cellulose. Optionally,
the gel pharmaceutical formulation may contain isopropyl myristate.
Optionally, the gel pharmaceutical formulation may also contain a
fragrance and/or an antioxidant.
[0105] In another embodiment, the present invention provides a
method for treating ectoparasites in a mammal, comprising the steps
of: topically applying to a mammal a therapeutically effective
amount of the topical gel pharmaceutical formulation, said gel
pharmaceutical formulation comprises 0.5% by weight malathion, 78%
by weight isopropyl alcohol, 1.0% by weight hydroxyl propyl
cellulose. Optionally, the gel pharmaceutical formulation may
contain 10% by weight dipentene, 10.1% by weight terpineol and
0.25% by weight pine needle oil.
[0106] Preferably, the present gel pharmaceutical formulation is
highly effective in killing ectoparasites in a mammal Preferably,
the mammal is a human.
[0107] Preferably, the present pharmaceutical formulation of
insecticide is a gel. Other suitable dosage forms include cream,
foam and the like, insofar as the viscosity of these dosage forms
is similar to that of the gel formulation.
[0108] Optionally, the present pharmaceutical formulation may be
stored in a single compartment after the insecticide is mixed with
the base formulation. Alternatively, the present pharmaceutical
formulation may be stored in a multi-compartment dispensing system.
For example, the insecticide may be stored in a first compartment;
and the viscosity-modifying polymer in organic solvent (e.g.,
cellulosic polymer in isopropyl alcohol) may be conveniently stored
in a second compartment. In accordance with the present invention,
the first and second compartments may be separately stored.
Preferably, the first and second compartments are stored under
air-tight condition. Before use, a final composition is prepared by
mixing the insecticide in the first compartment with the
viscosity-modifying polymer in organic solvent (e.g., isopropyl
alcohol) in the second compartment. Conveniently, the mixing of the
individual compartments may occur in the dispensing system
immediately prior to use. It is believed that such
multi-compartment dispensing system avoid further possible
degradation of insecticides (e.g., malathion) due to exposure to
water and thus is believed to enhance the stability and shelf-life.
Multi-compartment dispensing system may be stored without
refrigeration.
[0109] The present gel pharmaceutical formulation is safe.
Preferably, the gel pharmaceutical formulation is effective to kill
head lice, body lice, pubic lice or treat scabies. Exemplified head
lice include Pediculis capitis and the like. Exemplified body lice
include Pediculus humanus and the like. Exemplified pubic lice
include Pthiris pubis and the like. Exemplified scabies mite
include Sarcoptes scabiei and the like.
[0110] Preferably, the gel pharmaceutical formulation is applied to
the mammal for a time sufficient to kill the ectoparasites.
Preferably, the topical gel is applied for about 15 minutes.
Preferably, the topical gel is applied for about 30 minutes.
Preferably, the topical gel is applied for about 60 minutes.
Preferably, the topical gel is applied for about 90 minutes.
[0111] Preferably, the topical gel pharmaceutical formulation is
applied so that the hair (or the body) is totally saturated with
it. Preferably, the gel pharmaceutical formulation may be applied
more than once, if required. Preferably, the gel pharmaceutical
formulation may be applied a second time after 6 days to about 10
days after the first application. More preferably, the gel
pharmaceutical formulation may be applied 7 days after the first
application.
[0112] The present pharmaceutical formulation is in a gel form
suitable for topical administration. The characteristics of the
topical gel pharmaceutical composition allow the formulation to be
applied with ease without dripping into eye, ear and neck or
causing eye irritation along with a short application time. The
present pharmaceutical formulation may encompass suitable dosage
forms other than gel, such as cream or form, as long as they have
similar Viscosity as compared to that of the gel form.
[0113] The present topical gel pharmaceutical formulation is to be
applied to totally saturate the scalp hair/the body. Preferably,
the topical gel pharmaceutical formulation is applied to the
hair/the body in the amount of about 50 grams. This will reduce the
problem with current commercial compositions in which people are
not sufficiently saturating their hair/the body with insecticide.
By totally saturating the hair/the body, all the hair from the root
to the tips will be inundated with the insecticide, and thereby
eliminating the possibility of resistance developing.
[0114] The present topical gel pharmaceutical formulation may be
applied for a short duration of time (e.g., 5 minutes to 2 hours)
as compared to other commercial products instructed to have
application time of 8-12 hours or overnight. The present topical
gel pharmaceutical formulation is sufficient viscous enough to stay
on the hair (or the body) but does not run off. The topical gel
thus stays in contact with ectoparasites (such as lice and eggs)
long enough to kill them.
[0115] Without wishing to be bound by theory, it is believed that
the viscosity-modifying polymer provides a better vehicle to
deliver an insecticide such as malathion so as to effectively kill
the parasites such as head lice. It is further believed that the
polymer provides an optimal viscosity, which permits sufficient
exposure for the malathion to be exposed to the parasites. Head
lice or scabies live on the surface of the scalp, the scalp hair
and body respectively. The polymeric gel formulation provides a
"depot" effect, keeping the insecticide on the surface of scalp, on
the hair and the body by forming a thin film that washes away
easily when rinsed with shampoo. This film allows insecticide to be
in intimate contact with hair and body thus increasing the
retention of the treatment on the hair and the outside surface of
scalp and body. This reduces the absorption of treatment into the
skin, which may cause neurotoxocity and which is a major
disadvantage associated with some marketed products for treatment
of head lice or scabies such as lindane shampoo.
[0116] Without further wishing to be bound by theory, the alkyl
alcohol in the present formulation is maintained at an amount
sufficient to effect the insecticide effect. Alkyl alcohol effects
optimal killing of ectoparasites by serving as a vehicle to deliver
the insecticide into the ectoparasite's body. Alkyl alcohol may
provide osmotic force to dehydrate the ectoparasites and weaken
them, rendering them more susceptible to the insecticide. Alkyl
alcohol may also act synergistically with the insecticides in
killing the ectoparasites.
[0117] Without further wishing to be bound by theory, it is
believed that alkyl alcohol effects optimal killing of
ectoparasites by opening up spiracles on the ectoparasites or 30
opercula on their eggs and hence permits sufficient delivery of the
insecticides.
[0118] The viscosity-modifying polymer, when prepared in a high
alkyl alcohol solvent system (i.e., non-aqueous system), permits
the gel to attain optimal viscosity to prevent easy run-over of the
formulation, which is in contrast to that of lotion where the
run-over poses major disadvantages. The present gel formulation
also prevents rapid evaporation of alkyl alcohol, which is found to
be essential in ectoparasite killing.
[0119] Without further wishing to be bound by theory, it is
believed that inclusion of isopropyl myristate may enhance the
penetration of the insecticides (such as malathion) and provide
effective killing of the ectoparasites.
[0120] The present invention is illustrated by means of the
following examples representative of the pharmaceutical
formulations included in the present invention, which should not be
considered as restrictions of the scope of the same.
EXAMPLE 1
Topical Gel Pharmaceutical Formulation Containing Malathion
TABLE-US-00005 [0121] GEL FORMULA (% W/W) INGREDIENTS (Formulation
No. 1) Organophosphate (Malathion) 0.525 Hydroxy propyl cellulose
(Klucel HF .RTM.) 1.0 Fragrance 0.5 Isopropyl Alcohol 48 Propylene
Glycol 39.725 Dipentene -- Temineol 10 Pine Needle Oil 0.25
[0122] The formulation (example 1) was prepared in the following
manner
[0123] a) propylene glycol and isopropyl alcohol was mixed;
[0124] b) Klucel HF.RTM. was added to this solution and the mixture
was stirred;
[0125] c) the mixture was heated to 45.degree. C. and the
temperature was maintained for 1 hour to allow the polymer to
hydrate with continuous stirring;
[0126] d) the mixture was cooled to room temperature;
[0127] e) prepared terpineol (by warming to about 35.degree. C. to
melt) and added to the mixture;
[0128] f) malathion, fragrance & pine needle oil was weighed
and dissolved in isopropyl alcohol (5%) (antioxidant, preservative
may be added at this stage);
[0129] g) the dissolved malathion mixture (f) was added to
terpineol mixture (e); and added to the mixture (d);
[0130] h) continued to mix for some time to achieve uniform
distribution of drug and hydration of the polymer.
EXAMPLE 2
Topical Gel Pharmaceutical Formulation Containing Malathion
TABLE-US-00006 [0131] GEL FORMULA (% W/W) INGREDIENTS (Formulation
No. 2) Organophosphate (Malathion) 0.525 Hydroxyl propyl cellulose
(Klucel HF .RTM.) 1.0 Fragrance -- Isopropyl Alcohol 78 Propylene
Glycol -- Dipentene 10 Temineol 10.225 Pine Needle Oil 0.25
[0132] The formulation (example 2) was prepared in the following
manner:
[0133] a) isopropyl alcohol was weighed
[0134] b) Klucel HF.RTM. was added and the mixture was stirred;
[0135] c) the mixture was heated to 45.degree. C. and the
temperature was maintained for 1 hour to allow the polymer to
hydrate with continuous stirring;
[0136] d) the mixture was cooled to room temperature;
[0137] e) prepared Terpineol (by warming to about 35.degree. C. to
melt) and added to the mixture; i) malathion, dipentene & pine
needle oil were weighed and dissolved in isopropyl alcohol (5%)
(antioxidant, preservative may be added at this stage);
[0138] f) the dissolved malathion mixture (f) was added to
terpineol mixture (e); and added to the mixture (d);
[0139] g) continued to mix (g) for some time to achieve uniform
distribution of drug and hydration of the polymer.
[0140] Without wishing to be bound by theory, it is believed that
the amount of isopropyl alcohol, propylene glycol used in the
pharmaceutical formulation may be varied so as to render the gel
less flammable.
[0141] Alternatively limited amount of water or other solvents may
be added to the formulation as illustrated in the following
examples.
EXAMPLE 3
Further Topical Gel Formulations of Malathion
[0142] Several topical gel pharmaceutical formulations (#3-14)
containing malathion were prepared and the respective ingredients
are presented in Table 1. A combination, of a variety of solvents,
antioxidants, fragrance were prepared and evaluated for physical,
chemical properties and their efficacy in killing lice in vitro.
(See, Table 2).
EXAMPLE 4
Topical Gel Formulation of Malathion Containing Isopropyl
Myristate
[0143] Optionally, topical gel pharmaceutical formulation of
malathion may contain isopropyl myristate. The following table
illustrates such gel formulation (formulation #15).
TABLE-US-00007 GEL FORMULA (% W/W) INGREDIENTS (Formulation No. 26)
Organophosphate (Malathion) 0.654 Hydroxyl propyl cellulose (Klucel
HF .RTM.) 1.0 Fragrance 0.5 Isopropyl Alcohol 48 Propylene Glycol
10 Dipentene 29.6 Temineol 10.0 Pine Needle Oil 0.25
[0144] The formulation #15 (example 4) was prepared in the
following manner
[0145] a) propylene glycol and isopropyl alcohol (80% of total
quantity required) were mixed;
[0146] b) Klucel HF was added and the mixture was stirred;
[0147] c) the mixture was then heated to and maintained at
40.degree. C. for 1 hour to allow the polymer to hydrate with
continuous stirring;
[0148] d) allowed the mixture to cool to room temperature;
[0149] e) prepared terpineol (by warming to about 35.degree. C. to
melt);
[0150] f) malathion, fragrance and pine needle oil were weighed and
dissolved in isopropyl alcohol (10% of the total quantity
required);
[0151] g) the dissolved malathion mixture and terpineol were added
to the polymer mixture;
[0152] h) isopropyl myristate was weighed and added to the polymer
mixture;
[0153] i) made up the weight of the mixture with remaining
isopropyl alcohol and stirring for some more time to allow complete
hydration of the polymer.
EXAMPLE 5
Viscosity Measurement
[0154] Physical property (i.e., viscosity) of the prepared topical
gel pharmaceutical formulations was evaluated. The viscosity
measurement was conducted using Brookfield viscometer (model No. RV
DV III). The viscosity was measured at 50 rpm using Helipath
spindle T-C at 25.degree.. An average of five reading was
calculated and was presented. The degree of variation among the
readings was found to be minimal. The viscosity values are
expressed in cps.
[0155] FIG. 1 depicts the viscosity values (expressed in cps) in a
log scale. As shown in FIG. 1, all the gel formulations have
viscosity values at least about 3,000 cps. Formulations 1 and 2
have viscosity values of about 5,000 cps. In comparison, Ovide.RTM.
lotion, which is a liquid, has a low viscosity value of about 2
cps.
EXAMPLE 6
In Vitro Insecticide Activity
[0156] The prepared topical gel pharmaceutical formulations
containing insecticide were evaluated for pediculicidal activity
using an in vitro lice model. The prepared formulations are
compared against several commercial products including Lindane
Shampoo, Nix.RTM. cream rinse and Ovide.RTM. lotion.
[0157] The in vitro pediculicidal lice study was conducted as
follow. Head lice (Pediculus capitis) were collected from the heads
of infested human individuals. Ten lice, including male and female
adults and nymphs were distributed evenly between test samples and
control. The lice were placed in a sterile petri dish (15.times.60
mm) which contained five centimeter (5 cm) diameter cotton towel
disks. The disks containing the test/control substance were
dampened with filtered or distilled water to prevent dehydration of
the cloth.
[0158] Lice specimens in each petri dish were examined with a
10.times. hand lens by the investigator for viability, intact legs
and antennae. The following parameters were observed and
recorded.
[0159] 1) Behavior: Unsteady gait, stumbling, disorientation,
convulsions, tremors, hyperexcitability and response to light,
warmth and carbon dioxide.
[0160] 2) Physical Signs: Bloating, dehydration, extrusion of
gonads in males, excretion of blood meal, signs of peripheral nerve
discharges, CNS toxicity, including tremors and twitching etc.
[0161] 3) Incapacitation: Inability to walk, only occasional
tremors or twitching of legs or antennae. This is a stage that lice
rarely or never recover. At this stage they are described as
moribund.
[0162] 4) Death: When all movement of limbs, antennae and
peristalsis of gut ceases. The definition of death in lice exposed
to toxicants is difficult to determine In many instances,
individual lice may show no sign of life except an occasional
twitch of an antenna or claw. Translated to a clinical situation,
they are harmless, cannot feed, infest another person, or lay
eggs.
[0163] These parameters were monitored up to 3 hours. The gel
pharmaceutical formulations containing malathion showed excellent
pediculicidal activity against head lice (Pediculus capitis). All
the formulations exhibited 100% kill rate in one hour indicating
the efficacy at shorter application time. As shown in FIG. 2, the
present formulations (#3-12) exhibit good insecticide activity
towards the head lice, reaching >80% killing activity by about
60 minutes. Note that the commercial pesticide preparations are
less effective. While Nix.RTM. cream rinse reaches its 80% killing
at about 120 minutes, the Lidane shampoo is totally ineffective
during the 180 minutes period. The results are summarized in Table
2.
EXAMPLE 7
Stability Studies for Malathion Formulations (Formulation #
1-14)
[0164] Stability of the topical gel pharmaceutical formulations was
tested in humidity chambers at various conditions. The results are
summarized in Tables 3A, 3B, 3C, 3D, 3E and 3F.
[0165] Various formulations were evaluated at different conditions
(i.e., 4.degree. C., 25.degree. C./60% relative humidity,
30.degree. C/60% relative humidity and 40.degree. C./75% relative
humidity). The stability data indicate that the formulations are
stable and meet the regulatory requirements.
EXAMPLE 8
Stability Studies for Malathion Formulation Containing Isopropyl
Myristate (Formulation # 15)
[0166] Stability of the topical gel pharmaceutical formulation
(containing isopropyl myristate) was tested in humidity chambers at
various conditions (i.e., 30.degree. C./60% relative humidity,
40.degree. C./75% relative humidity for 1-3 months). The results
are summarized in Table 3 G.
[0167] The stability data indicate that the formulation containing
isopropyl myristate (formulation #15) has the similar stability
profile as the formulations without isopropyl myristate (i.e.,
formulations # 1-14). Thus, optional addition of isopropyl
myristate may enhance the efficacy of the formulation (e.g., by
enhancing the penetration of malathion), without adversely
affecting the stability of the gel formulation.
EXAMPLE 9
Further Topical Gel Formulations of Different Organophosphate
Insecticides
[0168] Several topical gel pharmaceutical formulations (#16-20)
containing various organophosphate were prepared and the respective
ingredients are presented in following table.
TABLE-US-00008 Formulation Quantity (% w/w) Nos. Ingredients (per
100 grams) 16 Phosmet 0.6 -- -- -- -- 17 Parathion -- 0.6 -- -- --
18 Dioxathion -- -- 0.6 -- -- 19 Terbufos -- -- -- 0.6 -- 20
Prothiofos -- -- -- -- 0.6 16-20 Klucel 1.0 1.0 1.0 1.0 1.0 HF
.RTM. 16-20 Isopropyl 78 78 78 78 78 alcohol 16-20 Limonene 10.0
10.0 10.0 10.0 10.0 16-20 Pine 0.25 0.25 0.25 0.25 0.25 Needle Oil
16-20 Terpineol 10.096 10.096 10.096 10.096 10.096
[0169] The formulations #16-20 (example 9) was prepared in the
following manner:
[0170] a) isopropyl alcohol (80% of total quantity required) was
weighed;
[0171] b) Klucel HF.RTM. was added and the mixture was stirred;
[0172] c) the mixture was heated to 40.degree. C. and the
temperature was maintained for 1 hour to allow the polymer to
hydrate with continuous stirring;
[0173] d) the mixture was cooled to room temperature;
[0174] e) prepared terpineol (by warming to about 35.degree. C. to
melt) and added to the mixture;
[0175] f) organophosphate insecticidal agent, limonene, fragrance
and pine needle oil were weighed and dissolved in isopropyl alcohol
(10% of the total quantity required);
[0176] g) the organophosphate insecticidal dissolved mixture and
terpineol were added to the polymer mixture; and
[0177] h) made up the weight of the mixture remaining isopropyl
alcohol and stirring for some more time to allow complete hydration
of the polymer.
EXAMPLE 10
Physical Characterization of Formulations Containing Various
Organophosphate Insecticidals
[0178] The following table summarizes the physical characterization
of various 5 organophosphate gels.
TABLE-US-00009 Physical Characteristics Phosmet Gel Parathion Gel
Dioxathion Gel Terbufos Gel Prothiofos Gel Appearance Colorless,
slight hazy, Colorless, slight hazy, Colorless, slight hazy,
Colorless, slight hazy, Colorless, slight hazy, pleasant smelling
gel pleasant smelling gel pleasant smelling gel pleasant smelling
gel pleasant smelling gel Viscosity (cps) 3,565 3,865 3,677 3,573
3,709
[0179] An evaluation of the physical characteristics of the
prepared gel formulations containing various organophosphates
indicates that these prepared gels share similar physical
characteristics (e.g., appearance and viscosity). These data
further support that other organophosphate insecticides similarly
may be prepared in the gel formulation and share physical
characteristics as well. Furthermore, it is reasonably to expect
that they also exhibit similar in vitro and in vivo efficacy as
that exhibited by malathion preparation.
EXAMPLE 11
Further Topical Gel Formulations of Different Insecticides
[0180] Several topical gel pharmaceutical formulations (#21-23)
containing various insecticides were prepared and the respective
ingredients are presented in following table.
TABLE-US-00010 Formulation Quantity (% w/w) Nos. Ingredients (per
100 grams) 21 Piperonyl 0.6 -- -- butoxide 22 Permethrin -- 0.6 --
23 Pyrethrin and -- -- 0.6 pyrethroid 21-23 Klucel HF .RTM. 1.0 1.0
1.0 21-23 Isopropyl 78 78 78 alcohol 21-23 Limonene 10.0 10.0 10.0
21-23 Pine Needle Oil 0.25 0.25 0.25 21-23 Terpineol 10.096 10.096
10.096
[0181] The formulations #21-23 (example 11) was prepared in the
following manner
[0182] a) isopropyl alcohol (80% of total quantity required) was
weighed;
[0183] b) Klucel HF.RTM. was added and the mixture was stirred;
[0184] c) the mixture was heated to 40.degree. C. and the
temperature was maintained for 1 hour to allow the polymer to
hydrate with continuous stirring;
[0185] d) the mixture was cooled to room temperature;
[0186] e) prepared terpineol (by warming to about 35.degree. C. to
melt) and added to the mixture;
[0187] f) the insecticidal agent, limonene, fragrance and pine
needle oil were weighed and dissolved in isopropyl alcohol (10% of
the total quantity required);
[0188] g) the insecticidal dissolved mixture and terpineol were
added to the polymer mixture; and
[0189] h) made up the weight of the mixture remaining isopropyl
alcohol and stirring for some more time to allow complete hydration
of the polymer.
EXAMPLE 12
Physical Characterization of Formulations Containing Different
Insecticidals
[0190] The following table summarizes the physical characterization
of different insecticidal gels.
TABLE-US-00011 Pyrethrin and Physical Piperonyl pyrethroid
Characteristics butoxide Gel Permethrin Gel mixture Gel Appearance
Colorless, slight Colorless, slight Colorless, slight hazy,
pleasant hazy, pleasant hazy, pleasant smelling gel smelling gel
smelling gel Viscosity (cps) 3,745 3,752 3,473
[0191] An evaluation of the physical characteristics of the
prepared gel formulations containing different insecticides
indicates that these prepared gels share similar physical
characteristics (e.g., appearance and viscosity). These data
further support that the different insecticides similarly may be
prepared in the gel formulation and share physical characteristics
as well. Furthermore, it is reasonable to expect that they also
exhibit similar in vitro and in vivo efficacy as that exhibited by
malathion preparation.
EXAMPLE 13
Clinical Studies
[0192] Clinical Protocol The following clinical study was performed
to compare the effectiveness and time of treatment for various
malathion preparations. Specifically, one objective of the clinical
study was to determine whether a 30-minute, 60 minute or 90 minute
application of 0.5% malathion gel is as effective, or more
effective, than the FDA approved 8-12 hour application of
OVIDE.RTM. Lotion or the standard 10 minute application of NIX for
the treatment of head lice. The 0.5% malathion gel composition
(formulation no. 26) used in the clinical trial was:
TABLE-US-00012 GEL FORMULA (% W/W) INGREDIENTS (Formulation No. 15)
Organophosphate (Malathion) 0.5 Hydroxy propyl cellulose (Klucel HF
.RTM.) 1.0 Fragrance -- Isopropyl Alcohol 78 Propylene Glycol --
Dipentene 10 Temineol 10.1 Pine Needle Oil 0.25
[0193] Another objective of the clinical study was to determine the
effects of various treatment times with the malathion gel (e.g.,
30, 60 or 90 minutes) on the effectiveness of the malathion
gel.
[0194] Study was performed in Florida, USA and participants were
visually screened for the presence of live lice and viable nits.
Inclusion criteria required a minimum of 3 live lice and 10 viable
nits. Those family members who qualified for the study were asked
to sign an informed consent after receiving an explanation of the
procedures, risks, benefits and alternatives. Subjects were
examined by the medical staff to ensure they met all other
inclusion criteria.
[0195] A total of 174 subjects (mostly children) met the
eligibility criteria and they were assigned a study number and
randomized by household into one of five study groups:
[0196] 1) 30 minute 0.5% malathion gel (Group A);
[0197] 2) 60 minute 0.5% malathion gel (Group B);
[0198] 3) 90 minute 0.5% malathion gel (Group C);
[0199] 4) 8-12 hour OVIDE.RTM. treatment group (Group D); and
[0200] 5) 10 minute application of NIX.RTM. Creme rinse (Group
E).
[0201] Pediculicidal efficacy was established by the presence or
absence of live lice. Ovicidal activity was assessed by visual
examination of subjects with a lighted magnifier and also by the
stage of nymphs or presence of adults at the 1 week and two week
follow-ups.
[0202] All subjects were treated at Day 1. At Day 8 (.+-.1),
subjects were re-evaluated for efficacy. Anyone with live lice was
retreated with the same product and time as Day 1. At Day 15 (.+-.2
days), subjects did not receive treatment, but were shampooed, and
examined. All subjects who were lice free at both Day 8 and 15,
were considered a Treatment Success. Those who had live lice at Day
8, but not on Day 15, returned for a final follow up at Day 22
(.+-.3) to determine if they were a Treatment Success or
Failure.
[0203] The staff in charge of visual screening, informed consent,
medical history and shampooing did not know to which group subjects
were assigned. Similarly, the investigators that evaluated the
safety and efficacy of subjects using test materials at the 1-week
and 2-week visits, did not take part in the treatment applications
and did not know which treatment was applied. Thus, this study was
investigator blinded.
[0204] Data for each subject collected during the study period was
entered into a case report form. Data from the case report form was
statistically analyzed
RESULTS
[0205] Study Subjects: Age
TABLE-US-00013 Age Group Number of subjects % 2-6 50 29% 7-12 70
41% >12 51 30% Total 171 100%
[0206] Study Subjects: Gender Distribution
TABLE-US-00014 A B C D E Total Male 10 9 6 3 0 28 % Male 19% 22%
17% 10% 0% 16% Female 43 32 29 26 13 143 % Female 81% 78% 83% 90%
100% 84%
[0207] PEDICULICIDAL EFFICACY
[0208] In the per protocol population there was a statistically
significant difference between the overall success rate for each
malathion gel treatment and that for NIX.RTM. (see "Overall
Efficacy" Table below). Similar results were seen in the
intention-to-treat population (with last observation carried
forward) indicating that the exclusion of 10 patients with protocol
violations did not alter the observed outcomes. When combining the
three gel treatment groups (30, 60, and 90 min), the overall
success rate was 97% in both the per protocol and
intention-to-treat populations. The lower one-sided 90% confidence
limits for the gel vs. OVIDE.RTM. differences were -7.4 (per
protocol) and -7.0 (intention-to-treat).
[0209] Overall Efficacy
TABLE-US-00015 A B C D E % Success % Success % Success % Success %
Success n (n) n (n) n (n) n (n) n (n) One 33 100% 24 92% 23 96% 19
100% 3 100% Treatment (33) (22) (22) (19) (3) Two 19 95%* 16 100%*
9 100%* 9 100%* 7 29% Treatments (18) (16) (9) (9) (2) 98%* 95%*
97%* 100%* 50% Overall 52 (51) 40 (38) 32 (31) 28 (28) 10 (5)
*Statistically significant difference from NIX .RTM. using Fishers
exact test (two-sided).
[0210] Overall Efficacy (All gels combined)
TABLE-US-00016 All Gels N % Success (n) One Treatment 80 96% (77)
Two Treatments 44 98% (43) Overall 124 97%* (120) *Statistically
significant from NIT .RTM. using Fishers exact text
(two-sided).
[0211] Effect of Treatment Time
[0212] A comparison of the individual treatment groups shows that
efficacy rates for the malathion gel were not significantly
affected by treatment time. Efficacy rates were 98% for the
30-minute treatment, 95% for the 60-minute treatment and 97% for
the 90-minute treatment. Each of these cure rates was statistically
significantly superior to the NIX.RTM. control group. Based on
these cure rates, it is conclude that treatment times of about 30
minutes is effective and 60 minute and 90 minute treatments achieve
the same therapeutic efficacy.
[0213] Retreatment
[0214] On the second visit (Day 8) live lice were found on 35%
(44/124) of the combined malathion gel subjects, 32% (9/28) of the
OVIDE.RTM. subjects, and 70% (7/10) of the NIX.RTM. subjects. Using
Fisher's exact test, the need for re-treatment rate for the
combined gel group was significantly different from that of the
NIX.RTM. group (p=0.0006) and not significantly different from that
of the OVIDE.RTM. group.
[0215] At the end of 3 weeks 98% of the subjects (51/52) treated
with a 0.5% malathion gel were lice free and 100% of subjects (28)
treated with OVIDE.RTM. for eight hours were lice free. This result
includes the subjects that received a second treatment.
[0216] In conclusion, the present clinical study clearly shows that
a 30, 60, or 90-minute application of 0.5% malathion gel is highly
effective in killing head lice (Pediculus capitis). Malathion gel
is surprisingly found to be as effective as the eight hour
treatment application for OVIDE.RTM.. The 98% cure rate of the
30-minute application of 0.5% malathion gel demonstrated that there
is no statistically significant difference between the 0.5%
malathion gel and the eight hour application of OVIDE.RTM..
[0217] The disclosures of the cited publications are incorporated
herein in their entireties by reference. It is to be understood,
however, that the scope of the present invention is not to be
limited to the specific embodiments described above. The invention
may be practiced other than as particularly described and still be
within the scope of the accompanying claims.
TABLE-US-00017 TABLE 1 Further Topical Gel Formulations
(Formulation Nos. 3-14) 3 4 5 6 7 8 9 10 11 12 13 14 Ingredients %
w/w (per 100 gm) Malathion 0.525 0.525 0.525 0.525 0.525 0.525
0.525 0.525 0.525 0.525 0.525 0.525 Klucel HF .RTM. 1.0 1.0 1.0 1.0
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Fragrance 0.5 0.5 0.5 0.5 0.5 0.5
0.5 0.5 -- -- 0.5 0.5 Benzyl Alcohol 5.0 5.0 5.0 5.0 -- -- 5.0 5.0
-- -- 5.0 Ethyl Alcohol 20.0 40 20 -- -- -- 20 -- -- -- 20
Isopropyl -- -- 20 40 78 78 25 25 78.0 78.0 20 78 alcohol Propylene
72.975 52.975 52.975 52.975 19.9775 -- 47.775 47.775 -- -- 52.911
19.911 Glycol BHA -- -- -- -- 0.1 0.1 0.1 0.1 -- 0.1 -- -- BHT --
-- -- -- 0.1 0.1 0.1 0.1 -- 0.1 -- -- N-Methyl- -- -- -- -- --
19.775 -- 20 -- -- -- -- 2Pyrrolidone Limonene -- -- -- -- -- -- --
-- 10.0 10 -- -- Terpineol -- -- -- -- -- -- -- -- 10.225 10.025 --
-- Pine needle oil -- -- -- -- -- -- -- -- 0.25 0.28 -- --
Tocopherol 0.064 0.064
TABLE-US-00018 TABLE 2 In Vitro Insecticide Activity (Lice Killing
Model) % Lice Dead Topical Topical Topical Topical Topical Topical
Topical Topical Topical Gel Gel Gel Gel Gel Gel Gel Gel Gel Formu-
Formu- Formu- Formu- Formu- Formu- Formu- Formu- Formu- Nix .RTM.
Exposure lation lation lation lation lation lation lation lation
lation Lindane .RTM. Cream OVIDE .RTM. Time No. 3 No. 4 No. 5 No. 6
No. 7 No. 8 No. 9 No. 10 No. 12 Shampoo Rinse Lotion 10 min 0 0 10
3 70 67 3 0 73 0 7 13 20 min 3 20 63 30 100 73 37 67 93 0 13 73 30
min 40 57 90 70 100 87 87 80 100 0 13 93 1 Hour 87 100 100 100 100
100 93 90 100 0 43 100 2 Hour 100 100 100 100 100 100 100 100 100 3
87 100 3 Hour 100 100 100 100 100 100 100 100 100 10 93 100
TABLE-US-00019 TABLE 3 A Stability of Topical Gel Pharmaceutical
Formulation Containing Organophosphate (Malathion) Stability
Formulation Nos. Condition Time 3 4 5 6 Description Initial Slight
Hazy color less Slight Hazy color less Slight Hazy colorless Slight
Hazy color less viscous gel viscous gel viscous gel viscous gel
4.degree. C. 3M NC NC NC NC 25.degree. C. 3M NC NC NC NC 30.degree.
C. A. NC NC NC NC 30.degree. C. B. NC NC NC NC 30.degree. C. C. NC
NC NC NC Assay (%) Initial 106.25 107.6 105.9 104.2 4.degree. C. 3M
103.7 103.8 104.7 102.3 25.degree. C. 3M 96.45 97.5 98.45 95.7
30.degree. C. 1M 96.65 98.85 100.1 97.35 30.degree. C. 2M 95.1 94.3
94.2 94.8 30.degree. C. 3M 91.1 90.55 92.7 91.1 Viscosity Initial
5296 3412 3608 4064 25.degree. C. 3M 5176 3164 3612 3840 30.degree.
C. 1M 4952 3200 3676 4060 30.degree. C. 2M 5172 3212 3496 4028
30.degree. C. 3M 4712 3140 3448 3604 NC--No Change M represents
month(s) A represents 1 month; B represents 2 months; and C
represents 3 months
TABLE-US-00020 TABLE 3 B Stability of Topical Gel Pharmaceutical
Formulation Containing Organophosphate (Malathion) Stability
Formulation Nos. Parameter Condition Time 7 8 9 10 Description
Initial Slight Hazy color less Slight Hazy color less Slight Hazy
color less Slight Hazy color less viscous gel viscous gel viscous
gel viscous gel 4.degree. C. 3M NC NC NC NC 25.degree. C. 3M NC NC
NC NC 30.degree. C. D. NC NC NC NC 30.degree. C. E. NC NC NC NC
30.degree. C. F. NC NC NC NC Assay (%) Initial 106.2 105.6 102.6
100.2 4.degree. C. 3M 106.53 105.1 105 101.13 25.degree. C. 3M
106.7 101.5 100.8 95.1 30.degree. C. 1M 99.8 98.4 98.8 93.3
30.degree. C. 2M NA 96.65 99.6 92.25 30.degree. C. 3M NA 102.1 99.4
NA Viscosity Initial 2916 2260 3228 3592 4.degree. C. 3M 2824 2228
3204 3696 25.degree. C. 3M 2964 2316 3289 4048 30.degree. C. 1M
2940 2204 3556 3820 30.degree. C. 2M 3380 2264 3220 3800 30.degree.
C. 3M 3324 2404 3212 4312 NC--No Change NA--Not analyzed D
represents 1 month; E represents 2 months; and F represents 3
months
TABLE-US-00021 TABLE 3C Stability of Topical Gel Pharmaceutical
Formulation Containing Organophosphate (Malathion) Stability
Formulation No. Parameter Condition Time 11 12 Description Initial
Slight Hazy color Slight Hazy color less viscous gel less viscous
gel 4.degree. C. 3 M NC NC 25.degree. C. 3 M NC NC 30.degree. C. G.
NC NC 30.degree. C. H. NC NC 30.degree. C. I. NC NC 40.degree. C. 1
M NC NC 40.degree. C. 2 M NC NC 40.degree. C. 3 M NC NC Assay (%)
Initial 105.2 107.4 4.degree. C. 3 M 109.0 110.03 25.degree. C. 3 M
105.7 107.9 25.degree. C. 6 M 104.87 30.degree. C. 1 M 105.8 108.75
30.degree. C. 2 M 109.1 108.85 30.degree. C. 3 M 104.5 107.7
30.degree. C. 6 M 101.90 NA 40.degree. C. 1 M 97.7 103 40.degree.
C. 2 M 95.65 NA 40.degree. C. 3 M 93.5 95.27 Content of 4.degree.
C. 3 M 98.4 NA Isopropyl 30.degree. C. 3 M 95.5 NA Alcohol (%)
40.degree. C. 3 M 96.4 NA NC--No Change NA--Not Analyzed G
represents 1 month; H represents 2 months; and I represents 3
months
TABLE-US-00022 TABLE 3D Stability of Topical Gel Pharmaceutical
Formulation Containing Organophosphate (Malathion) Stability
Formulation No. Parameter Condition Time 14 Description Initial
Slight Hazy color less viscous gel 25.degree. C. 3 M NC 30.degree.
C. J. NC 30.degree. C. K. NC 30.degree. C. L. NC 40.degree. C. 1 M
NC 40.degree. C. 2 M NC 40.degree. C. 3 M NC Assay (%) Initial
104.8 25.degree. C. 3 M 97.5 30.degree. C. 1 M 105.6 30.degree. C.
2 M 100.6 30.degree. C. 3 M 95.9 40.degree. C. 1 M 100.9 40.degree.
C. 2 M 94.7 40.degree. C. 3 M 93.0 Viscosity Initial 3060
25.degree. C. 3 M 4376 30.degree. C. 1 M 2960 30.degree. C. 2 M
3084 30.degree. C. 3 M 4404 40.degree. C. 1 M 3044 40.degree. C. 2
M 3128 40.degree. C. 3 M 4352 NC--No Change J represents 1 month; K
represents 2 months; and L represents 3 months
TABLE-US-00023 TABLE 3E Stability of Topical Gel Pharmaceutical
Formulation Containing Organophosphate (Malathion) Stability
Formulation No. Parameter Condition Time 1 Description Initial
Slight Hazy, colorless, viscous gel 25.degree. C. 3 M NC 30.degree.
C. M. NC 30.degree. C. N. NC 30.degree. C. O. NC Assay (%) Initial
103.9 25.degree. C. 3 M 101.2 30.degree. C. 1 M 102.9 30.degree. C.
2 M 105.53 30.degree. C. 3 M 101.8 Viscosity Initial 5225
25.degree. C. 3 M 4540 30.degree. C. 1 M 4378 30.degree. C. 2 M
4092 30.degree. C. 3 M 3660 Content of 4.degree. C. 3 M 98.9
Isopropyl 25.degree. C. 3 M 96.7 alcohol (%) 30.degree. C. 3 M 96.6
NC--No Change M represents 1 month; N represents 2 months; and O
represents 3 months
TABLE-US-00024 TABLE 3F Stability of Topical Gel Pharmaceutical
Formulation Containing Organophosphate (Malathion) Stability
Formulation No. Parameter Condition Time 2 Description Initial
Slight Hazy color less viscous gel 25.degree. C. 3 M NC 30.degree.
C. P. NC 30.degree. C. Q. NC 30.degree. C. R. NC 40.degree. C. 1 M
NC 40.degree. C. 2 M Light yellow, viscous gel 40.degree. C. 3 M
Yellow, viscous gel Assay (%) Initial 104.15 25.degree. C. 3 M
103.05 30.degree. C. 1 M 103.1 30.degree. C. 2 M 102.3 30.degree.
C. 3 M 100.21 40.degree. C. 1 M 99.7 40.degree. C. 2 M 97.24
40.degree. C. 3 M 94.38 Content of 4.degree. C. 1 M 99.0 Isopropyl
30.degree. C. 1 M 97.8 Alcohol (%) 40.degree. C. 1 M 96.0 NC--No
Change P represents 1 month; Q represents 2 months; and R
represents 3 months
TABLE-US-00025 TABLE 3G Stability of Topical Gel Pharmaceutical
Formulation Containing Isopropyl Myristate Stability Formulation
No. Parameter Condition Time 15 Description Initial Slight Hazy
color less viscous gel with pleasant smell 30.degree. C. 1 M Slight
Hazy color less viscous gel with pleasant smell 30.degree. C. 2 M
Slight Hazy color less viscous gel with pleasant smell 30.degree.
C. 3 M Sample on stability 40.degree. C. 1 M Slight Hazy color less
viscous gel with pleasant smell 40.degree. C. 2 M Slight Hazy color
less viscous gel with pleasant smell 40.degree. C. 3 M Sample on
stability Assay (%) Initial 107.48 30.degree. C. 1 M 105.87
30.degree. C. 2 M 105.66 30.degree. C. 3 M Sample on stability
40.degree. C. 1 M 102.67 40.degree. C. 2 M 100.02 40.degree. C. 3 M
Sample on stability Viscosity Initial 4,477 (cps) 30.degree. C. 1 M
4,896 30.degree. C. 2 M 4,931 30.degree. C. 3 M Sample on stability
40.degree. C. 1 M 4,067 40.degree. C. 2 M 3,844 40.degree. C. 3 M
Sample on stability IPA Initial 99.05 content (%) 30.degree. C. 1 M
98.65 30.degree. C. 2 M 97.9 30.degree. C. 3 M Sample on stability
40.degree. C. 1 M 96.3 40.degree. C. 2 M 96.6 40.degree. C. 3 M
Sample on stability
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