U.S. patent application number 16/100432 was filed with the patent office on 2018-12-06 for methods of treatment of anorectal and genital disorders.
The applicant listed for this patent is PeriTech Pharma Ltd.. Invention is credited to Eran Eilat, Evgenia Lozinsky.
Application Number | 20180344743 16/100432 |
Document ID | / |
Family ID | 51488109 |
Filed Date | 2018-12-06 |
United States Patent
Application |
20180344743 |
Kind Code |
A1 |
Lozinsky; Evgenia ; et
al. |
December 6, 2018 |
METHODS OF TREATMENT OF ANORECTAL AND GENITAL DISORDERS
Abstract
A topical anorectal or genital composition includes at least one
film forming ingredient; at least one surfactant; at least one
non-polar volatile siloxane solvent; at least 15% (w/w) water; and
a therapeutically effective concentration of at least one
pharmaceutical agent, wherein the composition is sufficiently
designed to dry within 60 seconds after application to the
anorectal or genital surface to form a dried composition, and
wherein the dried composition forms: a flexible film, wherein the
flexible film closely follows irregularities of the body surface as
well as movement of the body surface, and (ii) a durable film,
wherein the durable film does not crack or flake off and remains
intact for more than 12 hours giving release of the pharmaceutical
agent for an extended period of time.
Inventors: |
Lozinsky; Evgenia;
(Beer-Sheva, IL) ; Eilat; Eran; (Herzliya,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PeriTech Pharma Ltd. |
Herzliya |
|
IL |
|
|
Family ID: |
51488109 |
Appl. No.: |
16/100432 |
Filed: |
August 10, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14203329 |
Mar 10, 2014 |
|
|
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16100432 |
|
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61775598 |
Mar 10, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 17/00 20180101;
A61K 47/20 20130101; A61K 47/24 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/137 20130101; A61K 9/08 20130101;
A61K 31/137 20130101; A61K 31/5375 20130101; A61P 1/00 20180101;
A61K 47/34 20130101; A61K 47/26 20130101; A61K 9/7015 20130101;
A61P 17/10 20180101; A61P 17/04 20180101; A61K 31/535 20130101;
A61K 9/0014 20130101; A61K 45/06 20130101; A61K 9/06 20130101; A61K
9/107 20130101; A61K 9/0031 20130101; A61K 31/5375 20130101 |
International
Class: |
A61K 31/5375 20060101
A61K031/5375; A61K 45/06 20060101 A61K045/06; A61K 31/535 20060101
A61K031/535; A61K 47/24 20060101 A61K047/24; A61K 9/00 20060101
A61K009/00; A61K 9/06 20060101 A61K009/06; A61K 9/107 20060101
A61K009/107; A61K 31/137 20060101 A61K031/137; A61K 9/08 20060101
A61K009/08; A61K 47/20 20060101 A61K047/20; A61K 9/70 20060101
A61K009/70; A61K 47/34 20060101 A61K047/34; A61K 47/26 20060101
A61K047/26 |
Claims
1. A method of treating an anorectal or genital disorder
comprising: topically applying to the anorectal or genital surface
of a subject in need of such treatment a therapeutically effective
amount of a topical anorectal or genital composition comprising:
from 10.0% (w/w) to 30.0% (w/w) of trimethylsiloxysilicate; from
1.0% (w/w) to 5.0% (w/w) of at least one surfactant; from 30.0%
(w/w) to 75.0% (w/w) of at least one non-polar volatile siloxane
solvent; from about 15% (w/w) to about 40% (w/w) of water; and a
therapeutically effective concentration of at least one
pharmaceutical agent, selected from the group consisting of
pramoxine, phenylephrine, hydrocortisone, salicylic acid,
nitroglycerine, sildenafil, nifedipine, diltiazem, verapamil,
procaine, lidocaine, tetracaine, dibucaine, prilocaine, phenacaine,
benzyl alcohol, benzocaine, diperodon, dyclonine, dimethisoquin,
epinephrine, tetrahydrozoline hydrochloride, an amphetamine, an
antihistamine, methylphenidate, mephedrone, oxymetazoline,
pseudoephedrine, psilocybin, ephedrine sulphate, imiquimod,
podophyllin, podophylotoxin, trichloroacetic acid, bichloroacetic
acid, formic acid, fluorouracil, sinecatechins, plant extracts,
acyclovir, penciclovir, famciclovir, docosanol or their salts and
combinations thereof, wherein the composition is sufficiently
designed to dry within 60 seconds after application to the
anorectal or genital surface to form a dried composition, and
wherein the dried composition forms: (i) a flexible film, wherein
the flexible film closely follows irregularities of the surface as
well as movement of the surface, and (ii) a durable film, wherein
the durable film does not crack or flake off and remains intact for
more than 12 hours giving release of the pharmaceutical agent for
an extended period of time.
2. The method of claim 1, comprising topically applying twice
weekly to the anorectal or genital surface of the subject in need
of such treatment the therapeutically effective concentration of
the composition.
3. The method of claim 1, comprising topically applying once daily
to the anorectal or genital surface of the subject in need of such
treatment the therapeutically effective concentration of the
composition.
4. The method of claim 1, wherein, after a period of time post
topical application of the composition, a similar or better
therapeutic effect is observable than a commercially available
composition comprising the same active ingredient(s) in the same
concentrations wherein applied several times daily.
5. The method of claim 1, wherein the genital disorder is genital
warts or herpes.
6. The method of claim 1, wherein the anorectal disorder is anal
warts or herpes.
7. The method of claim 1, wherein the anorectal disorder is
selected from the group consisting of hemorrhoid anal fissures,
anal cracks, anal fistulas, anal abscesses and anal pruritus.
8. The method of claim 1, wherein the composition is in the form of
a gel.
9. The method of claim 1, wherein the composition is in the form of
an oil-in-water emulsion.
10. The method of claim 1, wherein in the composition, the at least
one surfactant is a polysorbate.
11. The method of claim 1, wherein in the composition, the at least
one non-polar volatile siloxane solvent is selected from the group
consisting of methylsiloxane, hexamethyldisiloxane, and
combinations thereof.
12. The method of claim 1, wherein the composition further
comprises an additive selected from the group consisting of a
dimethicone/vinyl dimethicone crosspolymer, a silicone gum blend, a
gelling agent, and a combination thereof.
13. The method of claim 1, wherein the composition further
comprises a buffer to adjust the pH of the composition to a pH of
about 4.2-4.4.
14. The method of claim 1, wherein the composition further
comprises an organosilicone surfactant.
15. The method of claim 1, wherein the composition further
comprises a viscosity modifier.
16. The method of claim 1, wherein the composition comprises: about
25.0% (w/w) of trimethylsiloxysilicate; from about 1.0% (w/w) to
about 5.0% (w/w) of polyoxyethylene sorbitan monooleate; and from
about 30.0% (w/w) to about 50.0% (w/w) of a non-polar volatile
siloxane solvent.
17. The method of claim 1, wherein the genital or anorectal
disorder is anal or genital warts and wherein the composition
comprises 4.0% (w/w) to 5.0% (w/w) imiquimod.
18. The method of claim 1, wherein the genital or anorectal
disorder is anal or genital warts and wherein the composition
comprises 0.5% (w/w) podophyllotoxin.
19. The method of claim 1, wherein the genital or anorectal
disorder is anal or genital warts and wherein the composition
comprises 1.0% (w/w) to 20% (w/w) salicylic acid, 0.1% (w/w) to 10%
(w/w) 5-fluorouracil or a combination thereof.
20. The method of claim 1, wherein the genital or anorectal
disorder is anal or genital herpes and wherein the composition
comprises an antiviral selected from the group consisting of
acyclovir, penciclovir, famciclovir, docosanol and combinations
thereof.
Description
RELATED APPLICATION
[0001] This application is a divisional of U.S. application Ser.
No. 14/203,329, filed Mar. 10, 2014, which claims the benefit of
and priority to U.S. Provisional Application No. 61/775,598, filed
Mar. 10, 2013, which is incorporated herein by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] Anal and genital disorders are widespread and include a
number of different conditions such as anal warts, genital warts,
hemorrhoids, anal fissures, anal cracks, anal fistulas, anal
abscesses, anal pruritus, herpes, other local genital and anorectal
lesions. Topical disorders include common warts. Currently, there
are a number of topically applied formulations for the treatment of
the above conditions, including ointments, creams, gels, lotions,
jellies and pastes, foams, sprays and medicated pads.
SUMMARY OF THE INVENTION
[0003] Topical compositions and methods of treatment of anorectal
and genital disorders are disclosed herein.
[0004] According to aspects illustrated herein, there is provided a
topical anorectal or genital composition that includes at least one
flexible film forming agent; at least one surfactant; at least one
non-polar volatile siloxane solvent; at least 15% (w/w) water; and
a therapeutically effective concentration of at least one
pharmaceutical agent, wherein the composition is sufficiently
designed to dry within 60 seconds after application to an anorectal
or genital surface to form a dried composition, and wherein the
dried composition forms: a flexible film, wherein the flexible film
closely follows irregularities of the surface as well as movement
of the surface, and (ii) a durable film, wherein the durable film
does not crack or flake off and remains intact for more than 12
hours giving release of the pharmaceutical agent for an extended
period of time.
[0005] According to aspects illustrated herein, there is provided a
topical composition that includes from about 10.0% (w/w) to about
30.0% (w/w) of trimethylsiloxysilicate; from about 1.0% (w/w) to
about 5.0% (w/w) of at least one surfactant selected from the group
consisting of sodium lauryl sulfate, alkyl- and alkoxy-dimethicone
copolyol, polysorbate and a combination thereof; from about 30.0%
(w/w) to about 75.0% (w/w) of a non-polar volatile siloxane
solvent; and from about 0.005% (w/w) to about 25.0% (w/w) of a
pharmaceutical agent selected from the group consisting of
pramoxine, phenylephrine, hydrocortisone, salicylic acid,
nitroglycerine, sildenafil, procaine, lidocaine, tetracaine,
dibucaine, prilocaine, phenacaine, benzyl alcohol, benzocaine,
diperodon, dyclonine, dimethisoquin, epinephrine, tetrahydrozoline
hydrochloride, an amphetamine, an antihistamine, methylphenidate,
mephedrone, oxymetazoline, pseudoephedrine, psilocybin, ephedrine
sulphate imiquimod, podophyllin, podophylotoxin, trichloroacetic
acid, bichloroacetic acid, formic acid, fluorouracil,
sinecatechins, plant extracts, or their salts and combinations
thereof, wherein the composition is sufficiently designed to dry
within 60 seconds after application to a genital or anorectal
surface to form a dried composition, and wherein the dried
composition forms: a flexible film, wherein the flexible film
closely follows irregularities of the surface as well as movement
of the surface, and (ii) a durable film, wherein the durable film
does not crack or flake off and remains intact for more than 12
hours giving release of the pharmaceutical agent for an extended
period of time.
[0006] According to some embodiments, if the anorectal or genital
disorder is anal or genital warts, the pharmaceutical agent to be
administered is selected from the group consisting of an
immunomodulator, a cytotoxin, an anti-inflammatory agent, and
combinations thereof.
[0007] Genital warts comprise vaginal warts and penile warts.
[0008] According to additional embodiments, the composition for use
in treating or preventing anal or genital warts comprises about
4.0% (w/w) to about 5.0% (w/w) imiquimod. Alternatively, the
composition comprises about 0.5% (w/w) podophyllotoxin. Further
alternatively, the composition comprises about 1.0% (w/w) to about
20% (w/w) salicylic acid, about 0.1% (w/w) to about 10% (w/w)
5-fluorouracil or a combination thereof.
[0009] According to some embodiments, if the topical disorder is
herpes, the pharmaceutical agent is an antiviral selected from the
group consisting of acyclovir, penciclovir, famciclovir, docosanol
and combinations thereof.
[0010] Herpes is a viral affliction, usually transmitted through
sexual contact.
[0011] Available topical regimens include penciclovir cream, 1%
(applied every 2 hours during waking hours for 4 days) and
acyclovir cream, 5% (applied 5 times a day for 4 days). Docosanol,
a saturated fatty alcohol, is a safe and effective topical
application that has been approved by the United States Food and
Drug Administration for herpes labialis in adults with properly
functioning immune systems.
[0012] All the above treatments are applied topically several times
a day which is a disadvantage. Formulating the above
pharmaceuticals agents in the compositions of the present invention
may lead to improved and speedier healing as well as better patient
compliance.
[0013] According to some embodiments, if the genital disorder is
genital warts, the pharmaceutical agent is selected from the group
consisting of an immunomodulator, a cytotoxin, an anti-inflammatory
agent, and combinations thereof.
[0014] According to additional embodiments, the composition for use
in treating or preventing anal or genital warts comprises about
4.0% (w/w) to about 5% (w/w) imiquimod. Alternatively, the
composition comprises about 0.5% (w/w) podophyllotoxin. Further
alternatively, the composition comprises about 1.0% (w/w) to about
20% (w/w) salicylic acid, about 0.1% (w/w) to about 10% (w/w)
5-fluorouracil or a combination thereof.
[0015] According to a further aspect, the present invention
provides a method of preventing or treating an anorectal or genital
disorder comprising applying the composition of the present
invention to an anorectal or a genital region of a subject in need
of such treatment, thereby preventing or treating the anorectal or
genital disorder.
[0016] According to aspects illustrated herein, there are provided
topical compositions that include at least one flexible film
forming ingredient, at least one surfactant, at least one non-polar
volatile siloxane solvent, and a therapeutically effective
concentration of at least one pharmaceutical agent, wherein the
composition is sufficiently designed to dry within 60 seconds after
application to a genital or anorectal surface to form a dried
composition, and wherein the dried composition forms: (i) a
flexible film, wherein the flexible film closely follows
irregularities of the surface as well as movement of the surface,
and (ii) a durable film, wherein the durable film does not crack or
flake off and remains intact for more than 12 hours giving release
of the pharmaceutical agent for an extended period of time.
[0017] According to aspects illustrated herein, there is provided a
method of preventing or treating an anorectal or a genital disorder
that includes topically applying, once daily to a genital or
anorectal surface of a subject in need of such treatment, a
therapeutically effective amount of a topical composition of the
present invention.
[0018] According to aspects illustrated herein, there is provided a
method of preventing or treating an anorectal or a genital disorder
that includes topically applying, once every other day or twice
weekly to a genital or anorectal surface of a subject in need of
such treatment, a therapeutically effective concentration of a
topical composition of the present invention.
[0019] The above methods of preventing or treating an anorectal or
genital disorder achieve a similar or better therapeutic effect
than commercially available compositions comprising the same active
ingredient(s) in the same concentrations wherein applied several
times daily.
[0020] The topical disorders treated with the compositions of the
present invention include, but are not limited to, hemorrhoids,
anal fissures, anal cracks, anal fistulas, anal abscesses, anal
pruritus, other local anorectal lesions, common warts, genital
warts, anal warts, and herpes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The presently disclosed embodiments will be further
explained with reference to the attached drawings. The drawings
shown are not necessarily to scale, with emphasis instead generally
being placed upon illustrating the principles of the presently
disclosed embodiments.
[0022] FIG. 1 shows hemorrhoidal pain level after treatment with
compositions of the present invention as gel and wipes, as compared
to Preparation H. The data presented are the delta meaning the
change from the previous day for each parameter measured.
[0023] FIG. 2 shows hemorrhoidal itching after treatment with
compositions of the present invention as gel and wipes as compared
to Preparation H. The data presented are the delta meaning the
change from the previous day for each parameter measured.
[0024] FIG. 3 shows hemorrhoidal swelling after treatment with
compositions of the present invention as gel and wipes, as compared
to Preparation H. The data presented are the delta meaning the
change from the previous day for each parameter measured.
[0025] FIG. 4 shows hemorrhoidal bleeding after treatment with
compositions of the present invention as gel and wipes, as compared
to Preparation H. The data presented are the delta meaning the
change from the previous day for each parameter measured.
[0026] FIG. 5 shows hemorrhoidal discomfort after treatment with
compositions of the present invention as gel and wipes, as compared
to Preparation H. The data presented are the delta meaning the
change from the previous day for each parameter measured.
[0027] While the above-identified drawings set forth presently
disclosed embodiments, other embodiments are also contemplated, as
noted in the discussion. This disclosure presents illustrative
embodiments by way of representation and not limitation. Numerous
other modifications and embodiments can be devised by those skilled
in the art which fall within the scope and spirit of the principles
of the presently disclosed embodiments.
DETAILED DESCRIPTION OF THE INVENTION
[0028] The present invention provides topical compositions
comprising active pharmaceutical agents and uses thereof for
treating anorectal and genital disorders, including, but not
limited to, hemorrhoids, anal fissures, anal cracks, anal fistulas,
anal abscesses, anal pruritus and other local anorectal lesions,
genital warts, anal warts and herpes.
[0029] The topical compositions of the present invention are
applied to a genital or anorectal surface for the treatment of
genital or anorectal disorders. Topical formulations currently
available for use in the treatment of anorectal or genital
disorders typically comprise polar solvents which enable the
incorporation of the medicaments into the formulation. The major
disadvantage of these currently available topical formulations
comprising polar solvents, e.g. ethanol, is their stinging effect
when applied to the skin or mucosal surface.
[0030] In contrast to currently available topical formulations, the
topical compositions of the present invention comprise an aqueous
phase which allows dissolution and substantially homogeneous
distribution of the pharmaceutical agents. In an embodiment,
addition of water to the topical composition reduces the use of
stinging polar solvents and hence improves the compliancy of the
subject to be treated. It is further disclosed that the topical
compositions of the present invention, upon drying, form a film on
a genital or anorectal mucosal surface and thus provide a
protective coating.
[0031] In addition, the topical compositions of the present
invention, when dried, form a durable film which does not crack or
flake off and remains intact for more than 12 hours giving release
of the pharmaceutical agent for an extended period of time, thus
leading to enhanced healing of the affected areas.
[0032] The sustained or extended release of the pharmaceutical
agent(s) from the compositions of the present invention enables
methods of treatment including less frequent administration (such
as once daily, once every other day or twice weekly) than existing
commercially available products, while achieving similar or better
therapeutic results.
[0033] Further, the topical compositions of the present invention,
when dried, form a flexible film, closely following irregularities
of the body surface as well as movement of the body surface.
[0034] According to an aspect, the present invention provides a
topical anorectal or genital composition that includes: [0035] from
about 10.0% (w/w) to about 30.0% (w/w) of a silicone film forming
agent like trimethylsiloxysilicate; [0036] from about 1.0% (w/w) to
about 5.0% (w/w) of at least one surfactant selected from the group
consisting of sodium lauryl sulfate, alkyl- and alkoxy-dimethicone
copolyol, polysorbate and a combination thereof; [0037] from about
30.0% (w/w) to about 75.0% (w/w) of a non-polar volatile siloxane
solvent; [0038] from about 15.0% (w/w) to about 40% (w/w) of water;
and [0039] from about 0.005% (w/w) to about 25.0% (w/w) of a
pharmaceutical agent selected from the group consisting of
pramoxine, phenylephrine, hydrocortisone, salicylic acid,
nitroglycerine, sildenafil, procaine, lidocaine, tetracaine,
dibucaine, prilocaine, phenacaine, benzyl alcohol, benzocaine,
diperodon, dyclonine, dimethisoquin, epinephrine, tetrahydrozoline
hydrochloride, an amphetamine, an antihistamine, methylphenidate,
mephedrone, oxymetazoline, pseudoephedrine, psilocybin, ephedrine
sulphate imiquimod, podophyllin, podophylotoxin, trichloroacetic
acid, bichloroacetic acid, formic acid, fluorouracil,
sinecatechins, plant extracts, acyclovir, penciclovir, famciclovir,
docosanol or their salts and combinations thereof wherein the
composition is sufficiently designed to dry within 60 seconds after
application to a genital or anorectal surface to form a dried
composition, and wherein the dried composition forms: [0040] (i) a
flexible film, wherein the flexible film closely follows
irregularities of the surface as well as movement of the surface,
and [0041] (ii) a durable film, wherein the durable film does not
crack or flake off and remains intact for more than 12 hours giving
release of the pharmaceutical agent for an extended period of
time.
[0042] According to an aspect, the present invention provides a
topical anorectal or genital composition that includes: [0043] (i)
at least one flexible film forming ingredient, (ii) at least one
surfactant, (iii) at least one non-polar volatile siloxane solvent
(iv) at least 15% (w/w) water, and (v) a therapeutically effective
concentration of at least one pharmaceutical agent, wherein the
composition is sufficiently designed to dry within 60 seconds after
application to a genital or anorectal surface to form a dried
composition, wherein the dried composition forms: (i) a flexible
film, wherein the flexible film closely follows irregularities of
the surface as well as movement of the surface, and (ii) a durable
film, wherein the durable film does not crack or flake off and
remains intact for more than 12 hours giving release of the
pharmaceutical agent for an extended period of time.
[0044] According to an embodiment, a topical composition of the
present invention is in the form of an emulsion. In an embodiment,
the emulsion is an oil-in-water emulsion. The emulsion may be in
the form of a viscous gel (25000-45000 cP) or a liquid whose
viscosity ranges from 1-1.2 cP, close to the viscosity of water.
While the gel is applied to the skin or mucosal surface as such,
the liquid emulsion is mainly used for the preparation of the
wipes.
[0045] The topical compositions of the present invention can be
administered as a gel, a wipe, a towellete, a water-based solution,
a spray or a foam.
[0046] According to one embodiment, the at least one film forming
ingredient is selected from the silicone resin group consisting of
siloxysilicate, silsesquioxane or other silicone polymers.
According to one embodiment, the siloxysilicate is
trimethylsiloxysilicate. According to an additional embodiment, the
silsesquioxane is polymethylsilsesquioxane.
[0047] According to some embodiments, the at least one surfactant
is an anionic surfactant. The anionic surfactant can be selected
from the group consisting of sodium alkyl sulfate, sodium alkyl
sulfonate, sodium alkyl aryl sulfonate, sodium stearate, dioctyl
sodium sulfosuccinate, sodium cholate, and any combination thereof.
According to a certain embodiment, the sodium alkyl sulfate is
sodium lauryl sulfate.
[0048] According to further embodiments, the at least one
surfactant is a nonionic surfactant. The nonionic surfactant can be
selected from the group consisting of organosilicone surfactants,
nonionic organic surfactants and a combination thereof.
[0049] According to some embodiments, the organosilicone surfactant
comprises alkyl- and alkoxy-dimethicone copolyol. According to
further embodiments, the alkyl- and alkoxy-dimethicone copolyol is
cetyl dimethicone copolyol. According to a certain embodiment, the
cetyl dimethicone copolyol is Cetyl PEG/PPG-10/1 Dimethicone.
[0050] According to further embodiments, the nonionic organic
surfactant is selected from the group consisting of polysorbate,
glyceryl stearate, polyoxyethylene (POE) fatty acid ester,
poly(oxyethylene) alkylyl ether, polyethoxylene castor oil
derivative, PEG-6 octanoic/decanoic glycerides, polyoxyethylene
glycerol trioleate, decaglycerol mono/dioleate, and any combination
thereof. The polysorbate can be selected from the group consisting
of polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene
sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan
monostearate (Tween 60) and polyoxyethylene sorbitan monooleate
(Tween 80).
[0051] According to still further embodiments, the at least one
surfactant is a cationic surfactant, an amphoteric surfactant, or a
combination thereof.
[0052] According to additional embodiments, the volatile solvent is
a non-polar volatile siloxane, such as methylsiloxane or a
polydimethylsiloxane. According to some embodiments, the volatile
polydimethylsiloxane is a linear polydimethylsiloxane or a cyclic
polydimethylsiloxane. According to further embodiments, the
volatile polydimethylsiloxane is selected from the group consisting
of hexamethyldisiloxane, heptamethyloctyltrisiloxane
octamethylcyclotetrasiloxane, octamethyltrisiloxane,
decamethylcyclopentasiloxane, decamethyltetrasiloxane,
dodecamethylpentasiloxane, dodecamethylcyclohexasiloxane, and a
combination thereof. According to a certain embodiment, the
volatile polydimethylsiloxane is hexamethyldisiloxane.
[0053] According to further embodiments, the volatile solvent is a
volatile aliphatic hydrocarbon selected from the group consisting
of alkanes, alkenes, alkynes, and mixtures thereof. According to
yet further embodiments, the alkane is selected from the group
consisting of pentane, isooctane, isododecane, isohexadecane and a
combination thereof. According to a certain embodiment, the
volatile aliphatic hydrocarbon is isooctane. According to another
embodiment, the volatile solvent is a combination of a siloxane and
isooctane.
[0054] According to additional embodiments, the pharmaceutical
agent is selected from the group consisting of anesthetic agents,
vasoconstrictors, protectants, an immunomodulator, a cytotoxin,
antipruritic agents, immunomodulators, cytotoxins,
anti-inflammatory agents, muscle relaxants, and a combination
thereof. Each possibility is a separate embodiment of the
invention.
[0055] The anesthetic agent can be selected from the group
consisting of pramoxine, procaine, lidocaine, tetracaine,
dibucaine, prilocaine, phenacaine, benzyl alcohol, benzocaine,
diperodon, dyclonine, dimethisoquin, salts thereof, and a
combination thereof. According to a certain embodiment, the
anesthetic agent is pramoxine. According to some embodiments, the
anesthetic agent is present in the topical composition in an amount
ranging from about 0.15% (w/w) to about 25% (w/w).
[0056] According to further embodiments, the vasoconstrictor is
selected from the group consisting of phenylephrine, phenylephrine
hydrochloride, epinephrine, epinephrine hydrochloride,
tetrahydrozoline hydrochloride an amphetamine, an antihistamine,
methylphenidate, mephedrone, oxymetazoline, pseudoephedrine,
psilocybin, ephedrine sulphate, and a combination thereof.
According to an exemplary embodiment, the vasoconstrictor is
phenylephrine. According to some embodiments, the vasoconstrictor
is present in the topical composition in an amount ranging from
about 0.005% (w/w) to about 2% (w/w).
[0057] According to a certain embodiment, the pharmaceutical
topical composition comprises a combination of pramoxine and
phenylephrine.
[0058] According to further embodiments, the antipruritic agent is
selected from the group comprising corticosteroid, camphor, juniper
tar, menthol and a combination thereof. According to a certain
embodiment, the corticosteroid is hydrocortisone. According to some
embodiments, the antipruritic agent is present in the topical
composition in an amount ranging from about 0.1% (w/w) to about 5%
(w/w).
[0059] According to yet further embodiments, the muscle relaxant is
nifedipine, diltiazem verapamil, nitroglycerin, sildenafil, or a
salt thereof. According to a certain embodiment, the muscle
relaxant is sildenafil citrate. According to some embodiments, the
muscle relaxant is present in the topical composition in an amount
ranging from about 0.1% (w/w) to about 15% (w/w).
[0060] According to still further embodiments, the
anti-inflammatory agent is selected from the group consisting of
salicylic acid, indomethacin, sodium indomethacin trihydrate,
salicylamide, naproxen, colchicine, fenoprofen, sulindac,
diflunisal, diclofenac, indoprofen and sodium salicylamide.
According to still further embodiment, the anti-inflammatory agent
is salicylic acid.
[0061] According to some embodiments, a topical composition of the
present invention can further comprise an astringent, a keratolytic
agent, an antibiotic agent, an antiseptic agent, an antioxidant, a
keratolytic, a protectant, an astringent or a combination thereof.
Each possibility is a separate embodiment of the invention.
[0062] According to some embodiments, a pharmaceutical topical
composition of the present invention can further comprise an
additive/excipient selected from the group consisting of a
dimethicone/vinyl dimethicone crosspolymer, a silicone gum blend, a
gelling agent and a combination thereof. Each possibility is a
separate embodiment of the invention.
[0063] According to a certain embodiment, the dimethicone/vinyl
dimethicone crosspolymer comprises bis-vinyldimethicone,
vinyldimethicone and hydrogen dimethicone.
[0064] According to additional embodiments, the silicone gum blend
comprises a blend of high and low molecular weight silicones.
According to a certain embodiment, the silicone gum blend comprises
cyclopentasiloxane and dimethiconol.
[0065] According to additional embodiments, the gelling agent is a
cellulose derivative. According to a certain embodiment, the
cellulose derivative is hydroxypropyl methyl cellulose. According
to other embodiments, the gelling agent is selected from the group
consisting of carbomer, carbomer copolymers, gelatin, aluminum
monostearate, dextrin, sodium alginate, alginic acid, pectin,
acacia, alginic acid, carrageenan, xanthan, tragacanth, magnesium
aluminum silicate, bentonite, poloxamers, polyvinyl alcohol, and a
combination thereof.
[0066] According to some embodiments, a topical composition
comprises: (i) trimethylsiloxysilicate; (ii) a surfactant selected
from the group consisting of an anionic surfactant, a nonionic
surfactant and a combination thereof; (iii) a volatile solvent
selected from the group consisting of a siloxane such as
methylsiloxane or a polydimethylsiloxane, an aliphatic hydrocarbon,
and a combination thereof, (iv) water; and (v) at least one
pharmaceutical agent selected from the group consisting of an
anesthetic agent, a vasoconstrictor, an antipruritic agent, an
immunomodulator, a cytotoxin, an anti-acne agent, an
anti-inflammatory agent, a muscle relaxant, and a combination
thereof. According to a certain embodiment, the surfactant is an
anionic surfactant. According to some embodiments, the topical
composition further comprises an additive selected from the group
consisting of a dimethicone/vinyl dimethicone crosspolymer, a
silicone gum blend, a gelling agent and a combination thereof.
[0067] According to some embodiments, a topical composition
comprises: (i) about 10% (w/w) to about 40% (w/w) of
trimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 7% (w/w) of
a surfactant selected from the group consisting of sodium lauryl
sulfate, alkyl- and alkoxy-dimethicone copolyol, polysorbate, and a
combination thereof; (iii) about 30% (w/w) to about 80% (w/w) of a
volatile solvent, selected from the group consisting of a siloxane
such as methylsiloxane or a polydimethylsiloxane, volatile
aliphatic hydrocarbon and a combination thereof; (iv) about 20%
(w/w) to about 40% (w/w) of water; and (v) about 0.005% (w/w) to
about 25% (w/w) of at least one pharmaceutical agent, selected from
the group consisting of pramoxine, phenylephrine, hydrocortisone,
salicylic acid, nitroglycerine, sildenafil citrate, and a
combination thereof. According to a certain embodiment, the at
least one surfactant is sodium lauryl sulfate. According to another
embodiment, the surfactant is a combination of sodium lauryl
sulfate and cetyl dimethicone copolyol. According to additional
embodiments, the surfactant is a combination of polysorbate and
cetyl dimethicone copolyol. According to some embodiments, cetyl
dimethicone copolyol is Cetyl PEG/PPG-10/1 Dimethicone. According
to some embodiments, polydimethylsiloxane is hexamethyldisiloxane.
According to additional embodiments, volatile aliphatic hydrocarbon
is isooctane. According to some embodiments, the topical
composition further comprises about 0.2% (w/w) to about 15% (w/w)
of an additive selected from the group consisting of
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
cyclopentasiloxane and dimethiconol; hydroxypropyl methyl
cellulose; and a combination thereof. According to some
embodiments, bis-vinyldimethicone, vinyldimethicone and hydrogen
dimethicone can be present in the topical composition in an amount
ranging from about 5.0% (w/w) to about 15% (w/w). According to
further embodiments, cyclopentasiloxane and dimethiconol can be
present in the topical composition in an amount ranging from about
0.5% (w/w) to about 2.5% (w/w). According to still further
embodiments, hydroxypropyl methyl cellulose can be present in the
topical composition in an amount ranging from about 0.05% (w/w) to
about 5% (w/w).
[0068] According to some embodiments, a topical composition
comprises: (i) about 20% (w/w) trimethylsiloxysilicate; (ii) about
3.0% (w/w) sodium lauryl sulfate; (iii) about 267% (w/w)
hexamethyldisiloxane and 20% (w/w) isooctane; (iv) about 30% (w/w)
water; and (v) about 1% (w/w) pramoxine as the pharmaceutical
agent. Alternatively, the pharmaceutical agent is phenylephrine in
an amount of about 0.05% (w/w). Further alternatively, the
pharmaceutical agent is a combination of about 1% (w/w) pramoxine
and about 0.25% (w/w) phenylephrine. Still further alternatively,
the pharmaceutical agent is hydrocortisone in an amount of about 1%
(w/w), or salicylic acid in an amount of about 1-20% (w/w), or
nitroglycerine in an amount of about 0.2% (w/w) to about 0.5%
(w/w), or sildenafil citrate in an amount of about 10%, or
nifedipine in an amount of about 0.1% (w/w) to about 5% (w/w) or
diltiazem in an amount of about 0.1-5% w/w, or verapamil in an
amount of about 0.1% (w/w) to about 5.0% (w/w) or a combination
thereof.
[0069] According to a certain embodiment, a topical composition
comprises: (i) about 20% (w/w) trimethylsiloxysilicate; (ii) about
3.0% (w/w) sodium lauryl sulfate; (iii) about 26% (w/w)
hexamethyldisiloxane and 20% (w/w) isooctane; (iv) about 30% (w/w)
water; (v) about 1% (w/w) pramoxine; and (vi) about 0.05% (w/w)
phenylephrine.
[0070] According to further embodiments, a topical composition
comprises: (i) about 20% (w/w) trimethylsiloxysilicate; (ii) about
1.5% (w/w) sodium lauryl sulfate; (iii) about 4% (w/w) Cetyl
PEG/PFG-10/1 Dimethicone (iv) about 24% (w/w) hexamethyldisiloxane
and 20% (w/w) isooctane; (v) about 30% (w/w) water; and (vi) about
1% (w/w) pramoxine as the pharmaceutical agent. Alternatively, the
pharmaceutical agent is phenylephrine in an amount of about 0.25%
(w/w). Further alternatively, the pharmaceutical agent is a
combination of about 1% (w/w) pramoxine and about 0.25% (w/w)
phenylephrine. Still further alternatively, the pharmaceutical
agent is hydrocortisone in an amount of about 1% (w/w), yet further
alternatively the pharmaceutical agent is imiquimod in an amount of
about 4.0% (w/w) to about 5.0% (w/w), or podophyllotoxin in an
amount of about 0.5% (w/w), or 5-fluorouracil in an amount of about
0.1% (w/w) to about 10% (w/w), or salicylic acid in an amount of
about 1.0% (w/w) to about 20% (w/w), or nitroglycerine in an amount
of about 0.2% (w/w) to about 0.5% (w/w), or sildenafil citrate in
an amount of about 10% (w/w), or nifedipine in an amount of about
0.1% (w/w) to about 5% (w/w) or diltiazem in an amount of about
0.1% (w/w) to about 5.0% (w/w), or verapamil in an amount of about
0.1% (w/w) to about 5.0% (w/w) or a combination thereof.
[0071] According to still further embodiments, a topical
composition comprises: (i) about 20% (w/w) trimethylsiloxysilicate;
(ii) about 1.5% (w/w) Tween 80; (iii) about 4% (w/w) Cetyl
PEG/PPG-10/1 Dimethicone (iv) about 24% (w/w) hexamethyldisiloxane
and 20% (w/w) isooctane; (v) about 30% (w/w) water; and (vi) about
1% (w/w) pramoxine as the pharmaceutical agent. Alternatively, the
pharmaceutical agent is phenylephrine in an amount of about 0.25%
(w/w). Further alternatively, the pharmaceutical agent is a
combination of about 1% (w/w) pramoxine and about 0.25% (w/w)
phenylephrine. Still further alternatively, the pharmaceutical
agent is hydrocortisone in an amount of about 1% (w/w), or
salicylic acid in an amount of about 1.0% (w/w) to about 20% (w/w),
or nitroglycerine in an amount of about 0.2% (w/w) to about 0.5%
(w/w), or sildenafil citrate in an amount of about 10% (w/w), or
nifedipine in an amount of about 0.1% (w/w) to about 5.0% (w/w) or
diltiazem in an amount of about 0.1% (w/w) to about 5.0% (w/w), or
verapamil in an amount of about 0.1% (w/w) to about 5.0% (w/w0 or a
combination thereof.
[0072] According to some embodiments, the pH of a topical
composition of the present invention is from about 3.5 to about 5.
According to other embodiments, the pH of a topical composition of
the present invention is from about 4.0 to about 4.6. According to
additional embodiments, the pH of a topical composition of the
present invention is from about 4.2 to about 4.4. According to some
embodiments, the pH is maintained using citrate buffer.
[0073] According to another aspect, the present invention provides
a method of treating or preventing a topical disorder, the method
comprising the step of topically applying to the skin or mucosal
surface a mucosal surface of a subject in need of such treatment a
therapeutically effective amount of a topical composition of the
present invention.
[0074] According to some embodiments, the topical disorder is
selected from the group consisting of hemorrhoids, anal fissures,
anal cracks, anal fistulas, anal abscesses and anal pruritus
dermatitis, acne, rosacea, onychomycosis, pityriasis, actinic
keratosis, eczema, erythema, urticaria, common warts, genital
warts, anal warts and herpes.
[0075] According to a certain embodiment, the topical disorder is
an anorectal disorder selected from hemorrhoids, fissure and anal
pruritus.
[0076] According to a certain embodiment, the topical disorder is
genital warts, anal warts and herpes.
[0077] According to a certain embodiment, the topical disorder is
acne or rosacea.
[0078] According to additional embodiments, if the anorectal
disorder is hemorrhoids, the pharmaceutical agent is an anesthetic
agent, a vasoconstrictor, or a combination thereof. According to a
certain embodiment, the topical composition for use in treating or
preventing hemorrhoids comprises a combination of about 1% (w/w)
pramoxine and about 0.25% (w/w) phenylephrine.
[0079] According to some embodiments, if the anorectal disorder is
anal pruritus, the topical composition for use in treating or
preventing anal pruritus comprises an antipruritic agent. According
to a certain embodiment, the antipruritic agent is hydrocortisone
in an amount of about 1% w/w hydrocortisone.
[0080] According to some embodiments, if the anorectal disorder is
anal fissures, the pharmaceutical agent to be administered is a
muscle relaxant. According to an exemplary embodiment, the topical
composition comprises about 0.1% (w/w) to about 0.5% (w/w)
nifedipine, or about 0.2% (w/w) to about 0.5% (w/w) nitroglycerine,
or about 10% (w/w) sildenafil citrate or diltiazem in an amount of
about 0.1% (w/w) to about 5.0% (w/w), or verapamil in an amount of
about 0.1% (w/w) to about 5.0% (w/w).
[0081] According to one embodiment, the subject to be treated is a
human being. According to another embodiment, the subject to be
treated is an animal.
[0082] According to yet another aspect, the present invention
provides a kit comprising a topical composition of the present
invention, a container-applicator device suitable for storage and
application of the composition to the genital or anorectal region,
and instructions for administering the topical composition to a
subject in need thereof.
[0083] According to some embodiments, the container-applicator
device is selected from the group consisting of a single use wipe,
a syringe, a dropper, a spray dispenser, a swab, a compressible
bottle or tube, a spatula, a suppository insertion tube, an
extrusion tube, a pump dispenser, a pressurized dispenser and an
inflatable member.
[0084] According to another aspect, the present invention provides
a topical composition for use in treating or preventing an
anorectal or genital disorder.
[0085] Other objects, features and advantages of the present
invention will become clear from the following description and
claims.
[0086] A topical composition of the present invention comprises at
least one film forming agent, at least one surfactant, at least one
non-polar volatile solvent, water and at least one pharmaceutically
active agent. One such film forming agent may be a silicone resin.
The topical composition can further comprise additives, such as
dimethicone/vinyl dimethicone crosspolymers, silicone gum blends
and gelling agents.
[0087] The term "film forming agent" or "film forming ingredient"
or "film former", as used herein, means an inactive ingredient such
as a silicone resin that after dissolution in at least one solvent
and application on a substrate leaves a film on the substrate to
which it is applied, for example once the at least one solvent
evaporates, absorbs and/or dissipates on the substrate.
[0088] The anorectal disorders have a unique feature which is only
shared with topical use on skin and joints. Anal fissure (a tear in
the anus) and hemorrhoids both extend significantly during
defecation, which causes reopening of the anal fissure, bleeding,
itching and pain. Therefore, flexible films possess a distinct
advantage for the treatment of anorectal disorders such as anal
fissure and hemorrhoids, providing a better protection of the
wound, and reduction of bleeding, itching and pain during extension
that occurs during defecation.
[0089] Silicone resins, such as polydimethylsiloxane and
polymethylsilsesquioxane have a unique semi-organic structure and
are flexible.
[0090] While using film forming agents in the instant invention, it
is desirable to use such flexible film forming agents and formulate
them in such compositions which produce flexible and durable films.
In an embodiment, there are provided flexible and durable film
forming compositions, providing beneficial therapeutic effects like
reduced bleeding, pain and itching.
[0091] The durability and flexibility of the films formed from the
compositions of the present invention on drying were investigated
by applying the composition L of Table 2, Example 3 on the elbow,
neck and internal part of the arm of a patient. Shortly thereafter
(about 20 seconds) the composition dried and left a thin film on
the skin. The films were examined after 12, 18 and 24 hrs for
durability and flexibility. During this period the patient carried
out their usual daily activities and took one shower.
[0092] It was found that the films remained intact after 12, 18 and
24 hrs. The films did not fall off the body surface and did not
crack or flake off. It was found that the films remained flexible
after 12, 18 and 24 hrs. The films closely followed the patient's
skin irregularities as well as skin movement throughout the day
during normal activity. The skin under the film was slightly pale,
which shows the vasoconstrictor phenylephrine was still active
after 24 hrs. After 24 hrs, the film was removed from the skin and
tested by high performance liquid chromatography (HPLC), whereupon
significant amounts of the two actives (pramoxine and
phenylephrine) were found in the film despite the extended period
of time.
[0093] The film formed on the skin or mucosal surface allows the
tissues to "breathe", which is beneficial because of the extended
period of time the film stays on the tissues.
[0094] The compositions of the instant invention dry relatively
fast after application on the skin or mucosal surface between 5
seconds and 1 minute to form a durable and elastic film.
[0095] The film formed on the substrate is substantially dry, which
means it contains less than 10% volatiles. In an embodiment, the
dried film contains less than 5% volatiles. In an embodiment, the
dried film contains less than 2% volatiles. The important aspect of
the substantially dry films of this invention, whatever the
percentage of volatiles left, is that they feel dry to touch and do
not soil, stain or otherwise absorb into the underwear.
[0096] Most of the commercially available topical formulations are
in the form of cream, ointment, enema, suppositories or other forms
of administration which leave on the anus and rectum a greasy
deposit which is very problematic, because of the potential of
staining, soiling or otherwise absorbing into the underwear.
[0097] In an embodiment, there are provided non-soiling
compositions, affording convenience for the patient, improving
patient compliance and avoiding embarrassment.
[0098] Commercially available anorectal products and compositions
are usually applied several times daily and before each
defecation.
[0099] Thus, for example, Preparation H.RTM. Maximum Strength,
containing phenylephrine HCl 0.25% and Pramoxine HCl 1% is applied
"up to 4 times daily, especially at night, in the morning or after
each bowel movement".
[0100] It has been surprisingly found that compositions of the
instant invention may be administered less often than commercial
products containing the same pharmaceutically active agents in the
same concentrations.
[0101] Thus, in a comparative clinical study, composition PP-110
(see Example 8) of the instant invention containing HCl 0.25% and
Pramoxine HCl 1% (the same pharmaceutical actives in the same
concentrations as Preparation H.RTM.) showed comparable or superior
results compared to the Preparation-H arm in one or both of PP-110
arms. This includes pain, itching, swelling, bleeding and
discomfort, and was achieved even though PP-110 was applied once
daily and Preparation-H was applied 4 times per day. It is believed
that, as a result, the patient is exposed to a much lower dose of
the active pharmaceutical ingredient(s).
[0102] Without wishing to be bound by theory, the inclusion of the
active pharmaceutical in the flexible film seems to have a
long-acting or sustained release effect, achieving comparable or
superior results compared to similar commercial products, while
exposing the patient to smaller amounts of the active
pharmaceutical ingredient(s).
[0103] In an embodiment, there are provided anorectal or genital
compositions achieving a similar or better therapeutic effect than
a commercially available composition comprising the same active
pharmaceutical agent(s) in the same concentrations wherein applied
several times daily.
[0104] In an embodiment, there are provided once daily anorectal or
genital topical compositions comprising: [0105] (i) at least one
flexible film forming ingredient; [0106] (ii) at least one
surfactant; [0107] (iii) at least one non-polar volatile solvent;
[0108] (iv) at least 15% (w/w) water; and [0109] (v) a
therapeutically effective concentration of at least one
pharmaceutical agent, [0110] wherein the composition is
sufficiently designed to dry within 60 seconds after application to
a mucosal surface of an anorectal or genital region to form a dried
composition, wherein the dried composition forms: (i) a flexible
film, wherein the flexible film closely follows irregularities of
the mucosal surface as well as movement of the mucosal surface, and
(ii) a durable film, wherein the durable film does not crack or
flake off and remains intact for more than 12 hours giving release
of the pharmaceutical agent for an extended period of time. The
dried film in non-soiling.
[0111] The above compositions may be topically administered even
less often than once daily, such as once every other day or twice
weekly.
[0112] In an embodiment, there are provided once daily anorectal or
genital topical compositions comprising: [0113] (i) at least one
flexible film forming ingredient; [0114] (ii) at least one
surfactant; [0115] (iii) at least one non-polar volatile solvent;
[0116] (iv) at least 15% (w/w) water; [0117] (v) at least one
viscosity modifier; and [0118] (vi) a therapeutically effective
concentration of at least one pharmaceutical agent, [0119] wherein
the composition is sufficiently designed to dry within 60 seconds
after application to a mucosal surface of an anorectal or genital
region to form a dried composition, wherein the dried composition
forms: (i) a flexible film, wherein the flexible film closely
follows irregularities of the mucosal surface as well as movement
of the mucosal surface, and (ii) a durable film, wherein the
durable film does not crack or flake off and remains intact for
more than 12 hours giving release of the pharmaceutical agent for
an extended period of time. The dried film in non-soiling.
[0120] In an embodiment there is provided a method of treatment of
anorectal or genital disorders, the method comprising the step of
topically applying once daily, or once every other day or twice
weekly to an anorectal or genital region of a subject in need of
such treatment, a therapeutically effective concentration of a
topical composition of the present invention.
[0121] The selection of the inactive pharmaceutical ingredients and
their concentration has an impact on the therapeutic effect of the
compositions, so that extensive experimentation was needed until
the optimal compositions were developed. Thus, for example, low
concentrations of water result in incomplete solubilization of the
active(s) and high-water concentrations lead to slow rate of
drying.
[0122] It has been surprisingly found that when a topical
composition of the present invention is formulated for use as a
wipe, the addition of inactive ingredients like Pemulen.RTM., have
a profound effect on the viscosity of the compositions, lowering
the viscosity even at concentrations below 0.1% (w/w). Therefore,
Pemulen.RTM. may be included in the composition for the wipes,
which requires a lower viscosity.
[0123] In an embodiment, the film forming agents used in the
compositions of the present invention are non-polymerizable and
therefore, unlike the polymerizable agents are less sensitive to
moisture, more stable and more suitable for repeated use.
[0124] The term "volatile solvent", as used herein, means that the
solvent has a measurable vapor pressure. Suitable volatile solvents
are non-polar solvents.
[0125] Some of the film forming agents according to the present
invention are silicone resins. The non-limiting examples of
silicone resins useful in the compositions of the invention are
siloxysilicates, silsesquioxanes (usually denoted as T-resins) and
a combination thereof. One non-limiting example of a siloxysilicate
in accordance with the present invention is
trimethylsiloxysilicate, which may be represented by the following
formula:
[(CH3)3-Si--O]x-(SiO4/2)y
[0126] wherein x and y may, for example, range from 50 to 80. Such
siloxysilicates are commercially available from General Electric
and Dow Corning under the trade name Resin MQ.RTM.. One
non-limiting example of silsesquioxane is polymethylsilsesquioxane.
Trimethylsiloxysilicate and polymethylsilsesquioxane are widely
used in cosmetic industry due to their film forming properties, as
described, for example, in U.S. Pat. Nos. 7,879,316 and 7,879,346
and U.S. Patent Application Publication No. 2005/0201961. The
present invention discloses for the first time the use of
trimethylsiloxysilicate for therapeutic applications, inter alia,
for treatment of anorectal or genital disorders.
Trimethylsiloxysilicate is soluble in the volatile solvent of a
topical composition of the present invention. The amount of the
silicone resin film forming agent in the composition is determined
based on the desired adhesion properties of the dried film to the
target surface. The amount depends, inter alia, on the target
surface, the condition to be treated, and the amount of composition
ingredients. The amount of the silicone resin film forming agent
further defines the viscosity of the topical composition. The
amount of the silicone resin film forming agent in the composition
typically ranges from about 10% to 40% w/w. The term "about" as
used herein denotes .+-.10% of the value indicated.
[0127] In an embodiment, the volatile solvent useful for dissolving
the silicone resin is chosen from volatile silicone or volatile
aliphatic hydrocarbon. In an embodiment, water solubility of the
volatile solvent is less than about 0.1%. According to some
embodiments, the volatile silicone solvent is a linear or cyclic
polydimethylsiloxane, having from 2 to 9 silicon atoms, these
silicones being optionally substituted with alkyl or alkoxy groups
of 1 to 10 carbon atoms. The non-limiting examples of a siloxane
such as methylsiloxane or a polydimethylsiloxane in accordance with
the present invention are hexamethyldisiloxane,
heptamethyloctyltrisiloxane octamethylcyclotetrasiloxane,
octamethyltrisiloxane, decamethylcyclopentasiloxane,
decamethyltetrasiloxane, dodecamethylpentasiloxane,
dodecamethylcyclohexasiloxane, and mixtures thereof. A suitable
polydimethylsiloxane used in the compositions is
hexamethyldisiloxane.
[0128] The volatile solvent can further comprise a volatile
aliphatic hydrocarbon. The aliphatic hydrocarbon in accordance with
the present invention may be any aliphatic hydrocarbon, including
an alkane, a mixture of alkanes, an alkene, a mixture of alkenes,
an alkyne, a mixture of alkynes, an ester or a mixture thereof. In
an embodiment, the aliphatic hydrocarbon is an alkane such as
pentane, isooctane, isododecane, isohexadecane or a mixture
thereof. According to a certain embodiment, the aliphatic
hydrocarbon is isooctane. The volatile ester useful for dissolving
the film former may be a branched ester, such as isohexyl or
isodecyl neopentanoate and mixture thereof.
[0129] The volatile solvent may comprise a volatile silicone, a
volatile aliphatic hydrocarbon or a mixture thereof. According to a
certain embodiment, the volatile solvent comprises methylsilozane
or a hexamethyldisiloxane and isooctane.
[0130] According to some embodiments, the presence of water in a
topical composition of the present invention allows dissolution of
the pharmaceutically active agents, which are not soluble in the
non-polar volatile solvents used for dissolving the film-former,
thus avoiding the need to use polar solvents. As the
pharmaceutically active agents are completely dissolved in the
compositions of the present invention and do not precipitate or
crystallize on drying, the resulting essentially dry films
comprising the active(s) are clear, transparent and not "white
films".
[0131] The emulsion can be a water-in-oil or oil-in-water emulsion.
According to exemplary embodiments, a topical composition of the
present invention is an oil-in-water emulsion, wherein the aqueous
phase includes the pharmaceutical agents dissolved therein and the
oil phase includes the film forming agent dissolved in the volatile
solvent. The oil-in-water emulsion allows the film former and the
pharmaceutical active agents to be homogeneously dispersed in the
topical composition. The stable emulsion provides fine dispersion
of the emulsion ingredients in the topical composition, in the
container-applicator device and upon the application to the target
surface, such that once the volatile solvent and water evaporate
both the film former and the pharmaceutical active ingredients
remain finely dispersed on the target surface. The stable emulsion
prevents clamping, floating and/or precipitation of the polar
active ingredients in the non-polar volatile solvents. The presence
of the aqueous phase in the topical composition further obviates
the use of polar solvents, formerly required to dissolve and
disperse pharmaceutical active ingredients in silicone based liquid
bandages.
[0132] The amount of the volatile solvent and water affects the
viscosity and evaporation time of the topical composition when
applied to a target surface. The amount of the volatile solvent and
water is determined so as to adjust the viscosity and evaporation
time to desired values. The amount of volatile solvent and water
further affects the morphology of the silicone/water emulsion. The
amount of the volatile solvent can be adjusted to obtain the
desired emulsion type. The amount of the volatile solvent in the
composition typically ranges from about 30% to about 80% w/w. The
amount of water can be adjusted to obtain the desired emulsion
type. The amount of water in the composition typically ranges from
about 20% (w/w) to about 40% (w/w).
[0133] The topical compositions of the present invention further
comprise at least one surfactant. Addition of the surfactant allows
mixing of the silicone and the aqueous phases, producing a
silicone/water emulsion. Addition of the surfactant further allows
the emulsion stabilization. As described hereinabove, the obtained
emulsion may be an oil-in-water emulsion, wherein the aqueous phase
includes dissolved pharmaceutical ingredients and finely dispersed
volatile solvent phase, containing the dissolved film former.
[0134] The surfactant is selected from the group consisting of an
anionic surfactant, a non-ionic surfactant, selected from
organosilicone surfactant or nonionic organic surfactant, a
cationic surfactant, an amphoteric surfactant and a combination
thereof. Each possibility is a separate embodiment of the
invention.
[0135] The anionic surfactants usable in the compositions of the
present invention include sodium alkyl sulfates, such as, but not
limited to sodium lauryl sulfate; sodium alkyl sulfonates; sodium
alkyl aryl sulfonates, such as sodium dodecyl benzene sulfonate and
the like; sodium stearate; dioctyl sodium sulfosuccinate; sodium
cholate; and a combination thereof.
[0136] Examples of suitable organosisilicone surfactants include,
but are not limited to dimethicone copolyols such as: alkoxy
dimethicone copolyols, alkyl and alkoxy-dimethicone copolyols,
silicones having pendant hydrophilic moieties such as linear
silicones having pendant polyether groups, branched polyether and
alkyl modified silicones, branched polyglycerin and alkyl modified
silicones. A suitable dimethicone copolyol is cetyl dimethicone
copolyol, such as Cetyl PEG/PPG-10/1 Dimethicone sold under the
name Abil EM-90. Other suitable dimethicone copolyols include
branched polyether and alkyl modified silicones such as Lauryl
PEG-9 Polydimethylsiloxyethyl Dimethicone sold under the name
KF-6038, and branched polyglycerin and alkyl modified silicones
such as Lauryl Polyglyceryl-3 Polydimethylsiloxyethyl Dimethicone
sold under the name KF-6105. Additional dimethicone copolyols
useful in the compositions of the present invention include
bis-PEG/PPG-14/dimethicone copolyol sold under the name Abil EM-97
and the polyglyceryl-4 isostearate/cetyl dimethicone copolyol/hexyl
laurate mixture sold under the name Abil WE 09. Another suitable
dimethicone copolyol is PEG-9 Polydimethylsiloxyethyl Dimethicone
sold under the name KF-6028. Abil EM-90, Abil EM-97 and. Abil WE 09
are available from Evonik Goldschmidt GmbH of Essen, Germany.
KF-6038 are KF-6105 are available from Shin-Etsu Silicones of
Akron, Ohio.
[0137] Non-limiting examples of possible non-ionic organic
surfactants include polysorbates, such as polyoxyethylene sorbitan
monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate
(Tween 40), polyoxyethylene sorbitan monostearate (Tween 60) and
polyoxyethylene sorbitan monooleate (Tween 80); glyceryl stearate;
polyoxyethylene (POE) fatty acid esters, such as Myrj 45, Myrj 49,
Myrj 52 and Myrj 59; poly(oxyethylene) alkylyl ethers, such as
poly(oxyethylene) cetyl ether (Brij 52, Brij 56, Brij 58),
poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl
ether, polyethylene glycol cetyl ether, and the like;
polyethoxylene castor oil derivatives, such as Cremophor EL, ELP
and RH 40; PEG-6 octanoic/decanoic glycerides, such as Softigen 767
and the like; polyoxyethylene glycerol trioleate, such as but not
limited to Tagat TO; decaglycerol mono/dioleate, such as Caprol
PGE860 and the like; and a combination thereof. The nonionic
organic surfactants may further comprise sorbitan fatty acid
esters, such as sorbitan monolaurate (Span 20), sorbitan
monopalmitate (Span 40), sorbitan monooleate (Span 80), sorbitan
monostearate (Span 60); mono/diglycerides of octanoic/dectanoic
acids, such as but not limited to Imwitor-742, Imwitor-308, and a
combination thereof.
[0138] Non-limiting examples of possible cationic surfactants
include phosphatides, such as phosphatidyl choline and the like;
quaternary ammonium cationic surfactants, such as
hexadecyltrimethyl ammonium bromide and the like; pyrimidinium
cationic surfactants, such as, but not limited to dodecyl
pyridinium chloride; and a combination thereof.
[0139] The amphoteric surfactant may include lecithine, N-dodecyl
alanine, cocamidopropyl amino betaine or a combination thereof.
[0140] The type and the amount of surfactant may be determined so
as to obtain the Hydrophile-Liphophile Balance (HLB) of the
surfactant or the surfactant mixture suitable for the oil-in-water
systems.
[0141] According to some embodiments, the surfactant used in the
compositions of the present invention is an anionic surfactant.
According to additional embodiments, the surfactant may further
comprise nonionic surfactant. The nonionic surfactant may be
selected from the group consisting of nonionic organic surfactant,
organosilicone surfactant and a combination thereof. According to
other embodiments, the surfactant in the compositions of the
present invention is a nonionic surfactant.
[0142] According to an embodiment, the surfactant is sodium alkyl
sulfate, such as sodium lauryl sulfate. According to other
embodiments, the surfactant is a combination of sodium alkyl
sulfate and alkyl and alkoxy-dimethicone copolyol, for example,
sodium lauryl sulfate and Cetyl PEG/PPG-10/1 Dimethicone. According
to other embodiments, the surfactant is selected from
polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene
sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan
monostearate (Tween 60), polyoxyethylene sorbitan monooleate (Tween
80) or any mixture thereof. According to further embodiments, the
silicone surfactant is a combination of polysorbate alkyl and
alkoxy-dimethicone copolyol, for example, polyoxyethylene sorbitan
monooleate (Tween 80) and Cetyl PEG/PPG-10/1 Dimethicone.
[0143] A topical composition of the present invention may further
comprise an additive selected from the group consisting of
dimethicone/vinyldimethicone crosspolymers, silicone gum blends,
gelling agents, and a combination thereof.
[0144] The dimethicone/vinyldimethicone crosspolymer is available,
for example, from Dow Corning as Dow Corning 9506 Cosmetic Powder.
According to other embodiments, the dimethicone/vinyldimethicone
crosspolymer can be present in the compositions of the present
invention in a form of two-part silicone elastomer. Without being
bound to any mechanism of action, the addition of two-part silicone
elastomers to the topical composition can provide enhanced film
adhesion onto the target surface and can allow reduction of skin
strain, which may be caused by the silicone resin. The two-part
silicone elastomers form a crosspolymer network by addition
reaction, upon mixing the two parts, enhancing the composition
adhesive properties. One part of the two-part silicone elastomer
usually contains vinyl endblocked silicone polymer and a catalyst
suitable for promoting the addition reaction and another part
contains vinyl endblocked silicone polymer and silicone polymer
carrying SiH groups. These two parts are stored separately before
use and the crosslinking reaction starts upon mixing the two parts
in a defined ratio. The ratio of the two parts is usually 50:50 and
the crosslinking reaction may proceed at room temperature
(25.+-.5.degree. C.). The two-part silicone elastomers may comprise
dimethicone, hydrogen dimethicone, vinyldimethicone,
bis-vinyldimethicon and phenyltrimethicone. According to a certain
embodiment, the topical composition of the present invention
comprises bis-vinyldimethicone as the first part of the two-part
silicone elastomers and vinyldimethicone and hydrogen dimethicone
as the second part. The first part can further contain a platinum
catalyst. The bis-vinyldimethicone, vinyldimethicone and hydrogen
dimethicone are available, for example, from KCC as SM9010.TM. or
SM9020.TM.. The amount of the dimethicone/vinyldimethicone in the
composition may be in a range from about 5% (w/w) to about 15%
(w/w).
[0145] The topical compositions of the present invention may
further comprise a silicone gum blend. Without being bound to any
mechanism of action, the addition of the silicone gum blend
provides enhancement of silkiness of the film. Silicone gum blend
may be a blend of a high molecular weight and a low molecular
weight silicone. In an embodiment, the average molecular weight of
the high molecular weight silicone is 100,000 or greater. In an
embodiment, the average molecular weight of the low molecular
weight silicone is 10,000 or less. High molecular and low molecular
weight silicones may comprise dimethicone and/or dimethiconol. The
non-limiting examples of a silicone gum blend are
cyclopentasiloxane and dimethiconol, and cyclotetrasiloxane and
cyclopentasiloxane and dimethiconol. The cyclopentasiloxane and
dimethiconol blends are available, for example, from KCC as
SF9902E.TM. or from Momentive as Silsoft 1215 Dimethicone.TM.. The
amount of the silicone gum blend in the composition may be in a
range from about 0.5% (w/w) to about 2.5% (w/w).
[0146] The gelling agent increases the aqueous phase viscosity when
introduced in said aqueous phase. Without being bound to any
mechanism of action, the topical composition in form of a gel
comprises pharmaceutical agents primordially dissolved in the
aqueous phase of the emulsion, finely dispersed in the continuous
jelly phase and the silicone resin, primordially dissolved in the
volatile solvent and finely dispersed in the aqueous phase of the
emulsion, dispersed in the continuous jelly phase of the topical
composition.
[0147] The gelling agent useful in a topical composition of the
present invention may comprise hydroxypropyl cellulose,
hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl
cellulose, ethyl cellulose, carboxymethyl cellulose, carbomer,
carbomer copolymers, gelatin, aluminum monostearate, dextrin,
sodium alginate, alginic acid, pectin, acacia, alginic acid,
carrageenan, xanthan, tragacanth, magnesium aluminum silicate
(Veegum.RTM.), bentonite, poloxamers (Pluronics.RTM.), polyvinyl
alcohol, or mixtures thereof. Each possibility is a separate
embodiment of the invention. Suitable gelling agents are cellulose
derivatives. According to one embodiment, the gelling agent is
hydropropyl methylcellulose. According to some embodiments, the
gelling agent is not soluble is the volatile solvent and/or in the
silicone oil phase of the emulsion. The amount of the gelling agent
in the composition may be in a range from about 0.05% (w/w) to
about 5% (w/w).
[0148] According to some embodiments, the pH is maintained in the
range from about 3.5 to about 5, or from about 4.0 to about 4.6, or
from about 4.2 to about 4.4 using an appropriate buffering system.
The non-limiting examples of the weak acids suitable for buffering
the compositions of the present invention include citric acid,
citric acid monohydrate, boric acid, and phosphoric acid. Examples
of some acid salts which can be used in the buffering systems of
the compositions of the present invention include, but are not
limited to, sodium citrate, sodium citrate dihydrate, monopotassium
phosphate, and disodium phosphate.
[0149] Upon application of a topical composition to the genital or
anorectal area, the volatile solvent and water evaporate, leaving
an adhered, dry film which includes at least one pharmaceutically
active agent. The dried film is elastic and durable. It is to be
appreciated that the compositions of the present invention are
devoid of polar solvents required for dissolving active
ingredients, thus providing non-stinging topical compositions that
have a comfortable feel when applying on the anorectal or genital
surface.
[0150] The emulsions of the instant invention possess the advantage
of reduced stinging effect in comparison with non-aqueous or polar
compositions.
[0151] In an embodiment, the compositions of the instant invention
are essentially non-stinging.
[0152] In an embodiment, the compositions of the present invention
are devoid of acrylates. The adhesiveness of the compositions does
not require acrylates.
[0153] Pharmaceutical Agents
[0154] The compositions of the present invention further comprise
at least one pharmaceutically active agent, such as an anesthetic
agent, a vasoconstrictor, an antipruritic agent, an
anti-inflammatory agent, a muscle relaxant, an astringent, a
keratolytic agent, an immunomodulator, a cytotoxin, an antibiotic
agent, an antiseptic agent, an anti-acne agent or a combination
thereof. Each possibility is a separate embodiment of the
invention. Additional pharmaceutical active agents include for
example, analgesics, antimicrobial agents and botanical products or
extracts. The compositions of the present invention may further
comprise antioxidants. The compositions may further contain one or
more protectant active ingredients, excipients and carriers.
Pharmaceutically and dermatologically acceptable excipients and
carriers as are known in the art may be included in the
composition, in particular for maintaining the stability and
sterility of the composition, and for promoting delivery, release
and/or application of the active agent(s) to the body surface to
which the composition is applied.
[0155] It is to be understood that the compositions may contain
more than one active agent, and/or may be suitable for use in
treating different anorectal or genital disorders. The
pharmaceutically active agent and the dosage thereof is dependent
upon, for example, the particular condition to be treated and the
age of the subject. In an exemplified embodiment, the composition
comprises an anesthetic agent and a vasoconstrictor. Anesthetic
agents include, but are not limited to, pramoxine, procaine,
lidocaine, tetracaine, dibucaine, prilocaine, phenacaine, benzyl
alcohol, benzocaine, diperodon, dyclonine, dimethisoquin and
combinations thereof. Exemplary anesthetic agent is pramoxine.
Pharmaceutically acceptable salts of the aforementioned anesthetic
agents may also be included in the composition of the invention.
Suitable amounts of such anesthetic agents in the composition may
be readily ascertained by one of ordinary skill in the art, and may
range, for example, from about 0.15% (w/w) to about 25% (w/w). In a
particular embodiment, the anesthetic agent is pramoxine HCl or
lidocaine. In a particular embodiment, the composition of the
invention comprises pramoxine HCl at a concentration of 1% w/w
based on the total weight of the composition.
[0156] Vasoconstrictors which are suitable for use in the invention
include amphetamines, antihistamines, methylphenidate, mephedrone,
oxymetazoline, phenylephrine, pseudoephedrine, psilocybin,
phenylephrine hydrochloride, ephedrine sulphate, epinephrine,
epinephrine hydrochloride, tetrahydrozoline hydrochloride, and
combinations thereof. Suitable amounts of such vasoconstrictor
agents in the composition may be readily ascertained by one of
ordinary skill in the art, and may range, for example, from about
0.005% (w/w) to about 2.0% (w/w). Exemplary vasoconstrictor agent
is phenylephrine HCl. In a particular embodiment, the composition
of the invention comprises phenylephrine HCl at a concentration of
about 0.25% (w/w) based on the total weight of the composition.
[0157] Antipruritic agents which are suitable for use in the
invention include corticosteroids, camphor, juniper tar and
menthol. The non-limiting examples of corticosteroids include
hydrocortisone, fluocinolone, flurandrenolide, triamcinolone,
fluticasone, and desonide. Antipruritic agents may further comprise
corticosteroids such as tetrahydrocortisol, prednisone;
prednisolone, fludrocortisone, 11-desoxycortisol, cortisone,
corticosterone, paramethasone, betamethasone, dexamethasone,
desoxycorticosterone acetate, desoxycorticosterone pivalate,
fludrocortisone acetate, cortisol acetate, cortisol cypionate,
cortisol sodium phosphate, cortisol sodium succinate,
beclopmethasone dipropionate, betamethasone, betamethasone sodium
phosphate and acetate, betamethasone dipropionate, betamethasone
valerate, betamethasone benzoate, cortisone acetate, dexamethasone,
dexamethasone sodium phosphate, dexamethasone acetate,
fuprednisolone, meprednisone, methylprednisolone,
methylprednisolone acetate, methylprednisolone sodium succinate,
paramethasone acetate, prednisolone, prednisolone acetate,
prednisolone sodium phosphate, prednisolone sodium succinate,
prednisolone tebutate, prednisone, triamcinolone acetonide,
triamcinolone diacetate, triamcinolone hexacotonide,
desoximetasone, flumethasone pivalate, fluocinolone acetonide,
fluocinonide, fluorometholone, halcinonide, and medrysone. Suitable
amounts of antipruritic agents in the composition may be readily
ascertained by one of ordinary skill in the art, and may range, for
example, from about 0.1% (w/w) to about 5.0% (w/w).
[0158] Anti-inflammatory agents include salicylic acid,
indomethacin, sodium indomethacin trihydrate, salicylamide,
naproxen, colchicine, fenoprofen, sulindac, diflunisal, diclofenac,
indoprofen and sodium salicylamide.
[0159] Muscle relaxants which are suitable for use in the invention
include nitroglycerin, nifedipine, dilatiazem, verapamil,
amlodopine, sildenafil, tizanidine, and baclofen, or salts thereof
including, but not limited to, sildenafil citrate. Suitable amounts
of such muscle relaxants in the composition may be readily
ascertained by one of ordinary skill in the art, and may range, for
example, from about 0.1% (w/w) to about 15% (w/w).
[0160] Anti-acne agents are selected from the group comprising
adapalene, benzoyl peroxide, tazarotene, azelaic acid, and
clindamycin.
[0161] A topical composition of the present invention may further
include an astringent. As used herein, an "astringent" refers to a
substance that causes tissue (e.g., a hemorrhoidal) to contract and
can optionally arrest secretion or control bleeding from tissue.
Astringents which are suitable for use in the invention include,
e.g., alum, tannic acid, calamine, witch hazel, zinc oxide, or a
combination thereof. Suitable amounts of such astringents in the
composition may be readily ascertained by one of ordinary skill in
the art, and may range, for example, from about 2.0% (w/w) to about
50% (w/w).
[0162] A topical composition of the present invention may further
include a keratolytic agent. As used herein, a "keratolytic agent"
refers to a substance that causes desquamation (loosening) and
debridement or sloughing of the surface cells of the epidermis. The
keratolytic agent used in the compositions of the present invention
are typically pharmaceutically acceptable for topical use in
humans. Suitable keratolytic agents include, but are not limited
to, alcloxa, resorcinol, or a combination thereof. Suitable amounts
of such keratolytic agents in the composition may be readily
ascertained by one of ordinary skill in the art, and may range, for
example, from about 0.1% (w/w) to about 5% (w/w).
[0163] Antibiotics for use in the invention are typically those
suitable for topical application. The antibiotic(s) may be
classified in one or more of the following groups: penicillins,
cephalosporins, carbepenems, beta-lactam antibiotics,
aminoglycosides, amphenicols, ansamycins, macrolides, lincosamides,
glycopeptides, polypeptides, tetracylines, chloramphenicol,
quinolones, fucidins, sulfonamides, sulfones, nitrofurans,
diaminopyrimidines, trimethoprims, rifamycins, oxalines,
streptogramins, lipopeptides, ketolides, polyenes, azoles, and
echinocandins.
[0164] Specific examples of antibiotics which are suitable for use
in the invention include: amikacin, aminosidine, paromomycin,
chloramphenicol, ciprofloxacin, clindamycin, coli
stimethate-sodium, colistin, enfuvirtid, enoxacin, erythromycin,
flucloxacillin, fosfomycin, fusafungin, gentamicin, levofloxacin,
linezolid, mefloquin, metronidazol, mezlocillin, moxifloxacin,
mupirocin, norfloxacin, ofloxacin, oxacillin, penicillin G,
penicillin V, phenoxymethylpenicillin,
phenoxymethylpenicillin-benzathin, pipemidinic acid, piperacillin,
piperacillin+tazobactam, proguanil, propicillin, pyrimethamine,
retapamulin, rifaximin, roxithromycin, sodium sulfacetamide,
sulbactam, sulbactam+ampicillin, sulfadiazine, spiramycin,
sultamicillin, tazobactam+piperacillin, teicoplanin, telithromycin,
tigecyclin, vancomycin and combinations thereof.
[0165] Antiseptics which are suitable for use in the invention
include, e.g., triclosan, phenoxy isopropanol, chlorhexidine
gluconate, povidone iodine, and any combination thereof.
[0166] Antioxidative compounds may also be included in the
composition, in particular the antioxidative compounds collectively
termed catechins. These include for example, epicatechin,
epicatechin gallate, epigallocatechin gallate, and gallocatechin,
as well as stereoisomers and enantiomers of these compounds and
combinations thereof. Such compounds may be provided as synthetic
compounds or in the forms of mixtures as components of plant
extracts, in particular green tea extracts. Botanical products and
extracts include those derived from peppermint, ginger horseradish,
yarrow, chamomile, rosemary, capsicum, aloe vera, tea tree oil
(melaleuca oil), among many others.
[0167] A topical composition of the present invention may further
include protectant active ingredients. The protectant active
ingredients can be selected from the group consisting of aluminum
hydroxide gel, cocoa butter, aqueous solution of glycerin, hard
fat, kaolin, lanolin, mineral oil, petrolatum, topical starch,
white petrolatum, cod liver, shark liver oil, and a combination
thereof. The protectant active ingredient and the dosage thereof is
dependent upon, for example, the particular condition to be treated
and the pharmaceutical active agents present in the
composition.
[0168] A topical composition of the present invention may include
one or more of the following additional ingredients: emulsifiers
(e.g. anionic, cationic or nonionic), chelating agents, colorants,
emollients, fragrances, humectants, lubricants, moisturizers,
preservatives, skin penetration enhancers, stabilizers, thickeners,
and viscosity modifiers.
[0169] Formulations
[0170] According to an embodiment, a topical composition of the
present invention comprises: trimethylsiloxysilicate; at least one
surfactant selected from the group consisting of sodium lauryl
sulfate, alkyl- and alkoxy-dimethicone copolyol, polysorbate and a
combination thereof; a non-polar volatile siloxane solvent, at
least 15% (w/w) water, and a pharmaceutical agent selected from the
group consisting of pramoxine, phenylephrine, hydrocortisone,
salicylic acid, nitroglycerine, sildenafil, or their salts and
combinations thereof. In an embodiment, the water is present in the
composition from about 15% (w/w) to about 40% (w/w). In an
embodiment, the water is part of a buffer to adjust the pH of the
composition to a pH of about 4.2-4.4. In an embodiment, the
composition further comprises a viscosity modifier.
[0171] According to an embodiment, a topical composition of the
present invention comprises: from about 10.0% (w/w) to about 30.0%
(w/w) of trimethylsiloxysilicate; from about 1.0% (w/w) to about
5.0% (w/w) of at least one surfactant selected from the group
consisting of sodium lauryl sulfate, alkyl- and alkoxy-dimethicone
copolyol, polysorbate and a combination thereof; from about 30.0%
(w/w) to about 75.0% (w/w) of a non-polar volatile siloxane
solvent, at least 15% (w/w) water, and from about 0.005% (w/w) to
about 25.0% (w/w) of a pharmaceutical agent selected from the group
consisting of pramoxine, phenylephrine, hydrocortisone, salicylic
acid, nitroglycerine, sildenafil, or their salts and combinations
thereof. In an embodiment, the water is present in the composition
from about 15% (w/w) to about 40% (w/w). In an embodiment, the
composition further comprises a buffer to adjust the pH of the
composition to a pH of about 4.2-4.4. In an embodiment, the
composition further comprises a viscosity modifier.
[0172] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) an anionic surfactant; (iii) a volatile
solvent, (iv) water; and (v) at least one pharmaceutical agent.
[0173] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) an anionic surfactant; (iii) a nonionic
surfactant, (iv) a volatile solvent, (v) water; and (vi) at least
one pharmaceutical agent.
[0174] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) a nonionic surfactant; (iii) a volatile
solvent, (iv) water; and (v) at least one pharmaceutical agent.
[0175] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) an anionic surfactant; (iii) a volatile
solvent, (iv) water; (v) gelling agent; and (vi) at least one
pharmaceutical agent.
[0176] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) an anionic surfactant; (iii) a nonionic
surfactant, (iv) a volatile solvent, (v) water; (vi) gelling agent;
and (vii) at least one pharmaceutical agent.
[0177] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) a nonionic surfactant; (iii) a volatile
solvent, (iv) water; (v) gelling agent; and (vi) at least one
pharmaceutical agent.
[0178] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium alkyl sulfate; (iii) a volatile solvent, selected from the
group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic hydrocarbon and a combination thereof; (iv) water; and
(v) at least one pharmaceutical agent.
[0179] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium lauryl sulfate; (iii) a volatile solvent, selected from the
group consisting of methylsiloxane, hexamethyldisiloxane, isooctane
and a combination thereof; (iv) water; and (v) at least one
pharmaceutical agent.
[0180] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium alkyl sulfate; (iii) alkyl- and alkoxy-dimethicone copolyol;
(iv) a volatile solvent, selected from the group consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination thereof; (v) water; and (vi) at least one
pharmaceutical agent.
[0181] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium lauryl sulfate; (iii) Cetyl PEG/PPG-10/1 Dimethicone; (iv) a
volatile solvent, selected from the group consisting of
methylsiloxane, hexamethyldisiloxane, isooctane and a combination
thereof; (v) water; and (vi) at least one pharmaceutical agent.
[0182] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
polysorbate; (iii) alkyl- and alkoxy-dimethicone copolyol; (iv) a
volatile solvent, selected from the group consisting of
methylsiloxane, polydimethylsiloxane, aliphatic hydrocarbon and a
combination thereof; (v) water; and (vi) at least one
pharmaceutical agent.
[0183] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
Tween 80; (iii) Cetyl PEG/PPG-10/1 Dimethicone; (iv) a volatile
solvent, selected from the group consisting of methylsiloxane,
hexamethyldisiloxane, isooctane and a combination thereof; (v)
water; and (vi) at least one pharmaceutical agent.
[0184] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium alkyl sulfate; (iii) a volatile solvent, selected from the
group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic hydrocarbon and a combination thereof; (iv) water; (v)
cellulose derivatives at least one pharmaceutical agent.
[0185] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium lauryl sulfate; (iii) a volatile solvent, selected from the
group consisting of methylsiloxane, hexamethyldisiloxane, isooctane
and a combination thereof; (iv) water; (v) hydroxypropyl methyl
cellulose; and (vi) at least one pharmaceutical agent.
[0186] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) a surfactant; (iii) a volatile solvent,
(iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; and (vii) a silicone gum
blend.
[0187] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) a surfactant; (iii) a volatile solvent,
(iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; (vii) a silicone gum
blend; and (ix) a gelling agent.
[0188] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) anionic surfactant; (iii) a volatile
solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; and (vii) a silicone gum
blend.
[0189] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) anionic surfactant; (iii) a volatile
solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; (vii) a silicone gum
blend; and (ix) a gelling agent.
[0190] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent; (ii) anionic surfactant; (iii) nonionic surfactant; (iv) a
volatile solvent, (v) water; (vi) at least one pharmaceutical
agent; (vii) a dimethicone/vinyldimethicone crosspolymer; and
(viii) a silicone gum blend.
[0191] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) anionic surfactant; (Iii) nonionic
surfactant; (iv) a volatile solvent, (v) water; (vi) at least one
pharmaceutical agent; (vii) a dimethicone/vinyldimethicone
crosspolymer; (viii) a silicone gum blend; and (ix) a gelling
agent.
[0192] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) nonionic surfactant; (iii) a volatile
solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; and (vii) a silicone gum
blend.
[0193] According to an embodiment, a topical composition of the
present invention comprises: (i) a silicone resin film forming
agent comprising siloxysilicate, silsesquioxane, or a derivative or
a combination thereof; (ii) nonionic surfactant; (iii) a volatile
solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; (vii) a silicone gum
blend; and (ix) a gelling agent.
[0194] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium alkyl sulfate; (iii) a volatile solvent, selected from the
group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic hydrocarbon and a combination thereof; (iv) water; (v) at
least one pharmaceutical agent; (vi) bis-vinyldimethicone,
vinyldimethicone and hydrogen dimethicone; and (vii) dimethiconol
and silicone oil blend.
[0195] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium alkyl sulfate; (iii) a volatile solvent, selected from the
group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic hydrocarbon and a combination thereof; (iv) water; (v) at
least one pharmaceutical agent; (vi) bis-vinyldimethicone,
vinyldimethicone and hydrogen dimethicone; (vii) dimethiconol and
silicone oil blend; and (iv) cellulose derivative.
[0196] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium alkyl sulfate; (iii) alkyl- and alkoxy-dimethicone copolyol;
(iv) a volatile solvent, selected from the group consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination thereof; (v) water; (vi) at least one pharmaceutical
agent; (vii) bis-vinyldimethicone, vinyldimethicone and hydrogen
dimethicone; and (viii) dimethiconol and silicone oil blend.
[0197] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium alkyl sulfate; (iii) alkyl- and alkoxy-dimethicone copolyol;
(iv) a volatile solvent, selected from the group consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination thereof; (v) water; (vi) at least one pharmaceutical
agent; (vii) bis-vinyldimethicone, vinyldimethicone and hydrogen
dimethicone; (viii) dimethiconol and silicone oil blend; and (ix)
cellulose derivative.
[0198] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
polysorbate; (iii) alkyl- and alkoxy-dimethicone copolyol; (iv) a
volatile solvent, selected from the group consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination thereof; (v) water; (vi) at least one pharmaceutical
agent; (vii) bis-vinyldimethicone, vinyldimethicone and hydrogen
dimethicone; and (viii) dimethiconol and silicone oil blend.
[0199] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
polysorbate; (iii) alkyl- and alkoxy-dimethicone copolyol; (iv) a
volatile solvent, selected from the group consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination thereof; (v) water; (vi) at least one pharmaceutical
agent; (vii) bis-vinyldimethicone, vinyldimethicone and hydrogen
dimethicone; (viii) dimethiconol and silicone oil blend; and (ix)
cellulose derivative.
[0200] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium lauryl sulfate; (iii) a volatile solvent, selected from the
group consisting of methylsiloxane, hexamethyldisiloxane, isooctane
and a combination thereof; (iv) water; (v) at least one
pharmaceutical agent, selected from the group consisting of an
anesthetic agent, a vasoconstrictor, an antipruritic agent, an
immunomodulator, a cytotoxin, an anti-inflammatory agent, a muscle
relaxant, and a combination thereof; (vi) bis-vinyldimethicone,
vinyldimethicone and hydrogen dimethicone; and (vii)
cyclopentasiloxane and dimethiconol.
[0201] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium lauryl sulfate; (iii) a volatile solvent, selected from the
group consisting of methylsiloxane, hexamethyldisiloxane, isooctane
and a combination thereof; (iv) water; (v) at least one
pharmaceutical agent, selected from the group consisting of an
anesthetic agent, a vasoconstrictor, an antipruritic agent, an
immunomodulator, a cytotoxin, an anti-inflammatory agent, a muscle
relaxant, and a combination thereof; (vi) bis-vinyldimethicone,
vinyldimethicone and hydrogen dimethicone; (vii) cyclopentasiloxane
and dimethiconol; and (iv) hydroxypropyl methyl cellulose.
[0202] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium lauryl sulfate; (iii) Cetyl PECK/PPCA-10/1 Dimethicone; (iv)
a volatile solvent, selected from the group consisting of
methylsiloxane, hexamethyldisiloxane, isooctane and a combination
thereof; (v) water; (vi) at least one pharmaceutical agent selected
from the group consisting of an anesthetic agent, a
vasoconstrictor, an antipruritic agent, an anti-inflammatory agent,
a muscle relaxant, or a combination thereof; (vii)
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
and (viii) cyclopentasiloxane and dimethiconol.
[0203] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
sodium lauryl sulfate; (iii) Cetyl PEG/PPG-10/1 Dimethicone; (iv) a
volatile solvent, selected from the group consisting of
hexamethyldisiloxane, isooctane and a combination thereof; (v)
water; (vi) at least one pharmaceutical agent selected from the
group consisting of an anesthetic agent, a vasoconstrictor, an
immunomodulator, a cytotoxin, an antipruritic agent, an
anti-inflammatory agent, a muscle relaxant, or a combination
thereof; (vii) bis-vinyldimethicone, vinyldimethicone and hydrogen
dimethicone; (viii) cyclopentasiloxane and dimethiconol; and (ix)
hydroxypropyl methyl cellulose.
[0204] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
Tween 80; (iii) Cetyl PEG/PPG-10/1 Dimethicone; (iv) a volatile
solvent, selected from the group consisting of methylsiloxane,
hexamethyldisiloxane, isooctane and a combination thereof; (v)
water; (vi) at least one pharmaceutical agent selected from the
group consisting of an anesthetic agent, a vasoconstrictor, an
antipruritic agent, an anti-inflammatory agent, a muscle relaxant,
an immunomodulator, a cytotoxin, or a combination thereof; (vii)
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
and (viii) cyclopentasiloxane and dimethiconol.
[0205] According to an embodiment, a topical composition of the
present invention comprises: (i) trimethylsiloxysilicate; (ii)
Tween 80; (iii) Cetyl PEG/PPG-10/1 Dimethicone; (iv) a volatile
solvent, selected from the group consisting of methylsiloxane,
hexamethyldisiloxane, isooctane and a combination thereof; (v)
water; (vi) at least one pharmaceutical agent selected from the
group consisting of an anesthetic agent, a vasoconstrictor, an
antipruritic agent, an anti-inflammatory agent, a muscle relaxant,
an immunomodulator, a cytotoxin, or a combination thereof; (vii)
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
(viii) cyclopentasiloxane and dimethiconol; and (ix) hydroxypropyl
methyl cellulose.
[0206] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10-40% (w/w) of a silicone
resin film forming agent comprising siloxysilicate, silsesquioxane,
or a derivative or a combination thereof; (ii) about 0.5% (w/w) to
about 7% (w/w) of a surfactant; (iii) about 30% (w/w) to about 80%
(w/w) of a volatile solvent; (iv) about 20% (w/w) to about 40%
(w/w) of water; and (v) about 0.005% (w/w) to about 25% (w/w) of at
least one pharmaceutical agent.
[0207] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5% (w/w) to about 2.5% (w/w) of an anionic surfactant;
(iii) about 30% (w/w) to about 80% (w/w) of a volatile solvent;
(iv) about 15$ (w/w) to about 40% (w/w) of water; and (v) about
0.005% (w/w) to about 25% (w/w) of at least one pharmaceutical
agent.
[0208] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5% (w/w) to about 2.5% (w/w) of an anionic surfactant;
(iii) about 30% (w/w) to about 80% (w/w) of a volatile solvent;
(iv) about 20% (w/w) to about 40% (w/w) of water; (v) about 0.005%
(w/w) to about 25% (w/w) of at least one pharmaceutical agent; and
(vi) about 0.05% (w/w) to about 5.0% (w/w) gelling agent.
[0209] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5% (w/w) to about 2.5% (w/w) of an anionic surfactant;
(iii) about 2% (w/w) to about 7% (w/w) of a nonionic surfactant;
(iv) about 30% (w/w) to about 50% (w/w) of a volatile solvent; (v)
about 25% (w/w) to about 40% (w/w) of water; and (vi) about 0.005%
(w/w) to about 25% (w/w) of at least one pharmaceutical agent.
[0210] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5% (w/w) to about 2.5% (w/w) of an anionic surfactant;
(iii) about 2% (w/w) to about 7% (w/w) of a nonionic surfactant;
(iv) about 30% (w/w) to about 80% (w/w) of a volatile solvent; (v)
about 20% (w/w) to about 40% (w/w) of water; (vi) about 0.005%
(w/w) to about 25% (w/w) of at least one pharmaceutical agent and
(vii) about 0.05% (w/w) to about 5.0% (w/w) gelling agent.
[0211] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10$ (w/w) to about 40% (w/w)
of a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5% (w/w) to about 7.0% (w/w) of a nonionic surfactant;
(iii) about 30% (w/w) to about 80% (w/w) of a volatile solvent;
(iv) about 20% (w/w) to about 40% (w/w) of water; and (v) about
0.005% (w/w) to about 25% (w/w) of at least one pharmaceutical
agent.
[0212] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5% (w/w) to about 7.0% (w/w) of a nonionic surfactant;
(iii) about 30% (w/w) to about 80% (w/w) of a volatile solvent;
(iv) about 20% (w/w) to about 40% (w/w) of water; (v) about 0.005%
(w/w) to about 25% (w/w) of at least one pharmaceutical agent; and
(vi) about 0.05% (w/w) to about 5% (w/w) gelling agent.
[0213] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of trimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5%
(w/w) of sodium alkyl sulfate; (iii) about 30% (w/w) to about 80%
(w/w) of a volatile solvent, selected from the group consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination thereof; (iv) about 15% (w/w) to about 40% (w/w) of
water; (v) about 0.005% (w/w) to about 25% (w/w) of at least one
pharmaceutical agent, selected from the group consisting of an
anesthetic agent, a vasoconstrictor, an antipruritic agent, an
anti-inflammatory agent, a muscle relaxant, or a combination
thereof; (vi) about 5.0% (w/w) to about 15% (w/w)
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
and (vii) about 0.5% (w/w) to about 2.5% (w/w) dimethiconol and
silicone oil blend.
[0214] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of trimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5%
(w/w) of sodium alkyl sulfate; (iii) about 30% (w/w) to about 80%
(w/w) of a volatile solvent, selected from the group consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination thereof; (iv) about 15% (w/w) to about 40% (w/w) of
water; (v) about 0.005% (w/w) to about 25% (w/w) of at least one
pharmaceutical agent, selected from the group consisting of an
anesthetic agent, a vasoconstrictor, an antipruritic agent, an
anti-inflammatory agent, a muscle relaxant, or a combination
thereof; (vi) about 5.0% (w/w) to about 15% (w/w)
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
(vii) about 0.5% (w/w) to about 2.5% (w/w) dimethiconol and
silicone oil blend; and (viii) about 0.05% (w/w) to about 5.0%
(w/w) cellulose derivative.
[0215] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of trimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5%
(w/w) of sodium alkyl sulfate; (iii) about 2.0% (w/w) to about 7%
(w/w) of alkyl- and alkoxy-dimethicone copolyol; (iv) about 30%
(w/w) to about 80% (w/w) of a volatile solvent, selected from the
group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic hydrocarbon and a combination thereof; (v) about 15%
(w/w) to about 40% (w/w) of water; (vi) about 0.005% (w/w) to about
25% (w/w) of at least one pharmaceutical agent, selected from the
group consisting of an anesthetic agent, a vasoconstrictor, an
antipruritic agent, an anti-inflammatory agent, a muscle relaxant,
or a combination thereof; (vii) about 5.0% (w/w) to about 15% (w/w)
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
and (viii) about 0.5% (w/w) to about 2.5% (w/w) dimethiconol and
silicone oil blend.
[0216] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of trimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5%
(w/w) of sodium alkyl sulfate; (iii) about 2.0% (w/w) to about 7%
(w/w) of alkyl- and alkoxy-dimethicone copolyol; (iv) about 30%
(w/w) to about 80% (w/w) of a volatile solvent, selected from the
group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic hydrocarbon and a combination thereof; (v) about 15%
(w/w) to about 40% (w/w) of water; (vi) about 0.005% (w/w) to about
25% (w/w) of at least one pharmaceutical agent, selected from the
group consisting of an anesthetic agent, a vasoconstrictor, an
antipruritic agent, an anti-inflammatory agent, a muscle relaxant,
or a combination thereof; (vii) about 5.0% (w/w) to about 15% (w/w)
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
(viii) about 0.5% (w/w) to about 2.5% (w/w) dimethiconol and
silicone oil blend and (viii) about 0.05% (w/w) to about 5% (w/w)
cellulose derivative.
[0217] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of trimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5%
(w/w) of polysorbate; (iii) about 2.0% (w/w) to about 7% (w/w) of
alkyl- and alkoxy-dimethicone copolyol; (iv) about 30% (w/w) to
about 80% (w/w) of a volatile solvent, selected from the group
consisting of methylsiloxane, a polydimethylsiloxane, aliphatic
hydrocarbon and a combination thereof; (v) about 15% (w/w) to about
40% (w/w) of water; (vi) about 0.005% (w/w) to about 25% (w/w) of
at least one pharmaceutical agent, selected from the group
consisting of an anesthetic agent, a vasoconstrictor, an
antipruritic agent, an immunomodulator, a muscle relaxant, or a
combination thereof; (vii) about 5.0% (w/w) to about 15% (w/w)
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
and (viii) about 0.5% (w/w) to about 2.5% (w/w) dimethiconol and
silicone oil blend.
[0218] According to an embodiment, a topical composition of the
present invention comprises: (i) about 10% (w/w) to about 40% (w/w)
of trimethylsiloxysilicate; (ii) about 0.5% (w/w) to about 2.5%
(w/w) of polysorbate; (iii) about 2.0% (w/w) to about 7.0% (w/w) of
alkyl- and alkoxy-dimethicone copolyol; (iv) about 30% (w/w) to
about 80% (w/w) of a volatile solvent, selected from the group
consisting of methylsiloxane, a polydimethylsiloxane, aliphatic
hydrocarbon and a combination thereof; (v) about 15.0% (w/w) to
about 40% (w/w) of water; (vi) about 0.005% (w/w) to about 25%
(w/w) of at least one pharmaceutical agent, selected from the group
consisting of an anesthetic agent, a vasoconstrictor, an
antipruritic agent, a keratolytic, a protectant, an
anti-inflammatory agent, an astringent, a muscle relaxant, or a
combination thereof; (vii) about 5.0% (w/w) to about 15% (w/w)
bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;
(viii) about 0.5% (w/w) to about 2.5% (w/w) dimethiconol and
silicone oil blend and (viii) about 0.05% (w/w) to about 5% (w/w)
cellulose derivative.
[0219] According to an embodiment, a topical composition of the
present invention comprises: (i) about 15% (w/w)
trimethylsiloxysilicate; (ii) about 3% (w/w) sodium lauryl sulfate;
(iii) about 22% (w/w) hexamethyldisiloxane and 21% (w/w) isooctane;
(iv) about 27% (w/w) water or citrate buffer or a combination
thereof; (v) about 1% (w/w) pramoxine; (vi) about 0.25% (w/w)
phenylephrine; (vii) about 5% (w/w) bis-vinyldimethicone and 5%
(w/w) vinyldimethicone and hydrogen dimethicone; and (viii) about
1% (w/w) cyclopentasiloxane and dimethiconol.
[0220] According to an embodiment, a topical composition of the
present invention comprises: (i) about 15% (w/w)
trimethylsiloxysilicate; (ii) about 3% (w/w) sodium lauryl sulfate;
(iii) about 22% (w/w) hexamethyldisiloxane and 21% (w/w) isooctane;
(iv) about 27% (w/w) water or citrate buffer or a combination
thereof; (v) about 1% (w/w) pramoxine; (vi) about 0.25% (w/w)
phenylephrine; (vii) about 5% (w/w) bis-vinyldimethicone and 5%
(w/w) vinyldimethicone and hydrogen dimethicone; (viii) about 1%
(w/w) cyclopentasiloxane and dimethiconol; and (ix) about 0.5%
(w/w) hydroxypropyl methyl cellulose.
[0221] According to an embodiment, a topical composition of the
present invention comprises: (i) about 15% (w/w)
trimethylsiloxysilicate; (ii) about 1.5% (w/w) sodium lauryl
sulfate; (iii) about 4% (w/w) Cetyl PEG/PPG-10/1 Dimethicone; (iv)
about 22% (w/w) hexamethyldisiloxane and 21% (w/w) isooctane; (v)
about 25% (w/w) water; (vi) about 1% (w/w) pramoxine; (vii) about
0.25% (w/w) phenylephrine; (viii) about 5% (w/w)
bis-vinyldimethicone and 5% (w/w) vinyldimethicone and hydrogen
dimethicone; and (ix) about 1% (w/w) cyclopentasiloxane and
dimethiconol.
[0222] According to an embodiment, a topical composition of the
present invention comprises: (i) about 15% (w/w)
trimethylsiloxysilicate; (ii) about 1.5% (w/w) sodium lauryl
sulfate; (iii) about 4% (w/w) Cetyl PEG/PPG-10/1 Dimethicone; (iv)
about 18% (w/w) hexamethyldisiloxane and 19% (w/w) isooctane; (v)
about 30% (w/w) water; (vi) about 1% (w/w) pramoxine; (vii) about
0.25% (w/w) phenylephrine; (viii) about 5% (w/w)
bis-vinyldimethicone and 5% (w/w) vinyldimethicone and hydrogen
dimethicone; (ix) about 1% (w/w) cyclopentasiloxane and
dimethiconol; and (x) about 0.5% (w/w) hydroxypropyl methyl
cellulose.
[0223] According to an embodiment, a topical composition of the
present invention comprises: (i) about 15% (w/w)
trimethylsiloxysilicate; (ii) about 1.5% (w/w) Tween 80; (iii)
about 4% (w/w) Cetyl PEG/PPG-10/1 Dimethicone; (iv) about 22% (w/w)
hexamethyldisiloxane and 21% (w/w) isooctane; (v) about 25% (w/w)
water; (vi) about 1% (w/w) pramoxine; (vii) about 0.25% (w/w)
phenylephrine; (viii) about 5% (w/w) bis-vinyldimethicone and 5%
(w/w) vinyldimethicone and hydrogen dimethicone; and (ix) about 1%
(w/w) cyclopentasiloxane and dimethiconol.
[0224] According to an embodiment, a topical composition of the
present invention comprises: (i) about 15% (w/w)
trimethylsiloxysilicate; (ii) about 1.5% (w/w) Tween 80; (iii)
about 4% (w/w) Cetyl PECK/EPG-10/1 Dimethicone; (iv) about 18%
(w/w) hexamethyldisiloxane and 19% (w/w) isooctane; (v) about 30%
(w/w) water; (vi) about 1% (w/w) pramoxine; (vii) about 0.25% (w/w)
phenylephrine; (viii) about 5% (w/w) bis-vinyldimethicone and 5%
(w/w) vinyldimethicone and hydrogen dimethicone; (ix) about 1%
(w/w) cyclopentasiloxane and dimethiconol; and (x) about 0.5% (w/w)
hydroxypropyl methyl cellulose.
[0225] According to an embodiment, a topical composition of the
present invention in the form of a gel (see composition L in Table
2), comprises: (i) about 25% (w/w) trimethylsiloxysilicate, (ii)
about 43% (w/w) methylsiloxane, (iii) about 4% (w/w) Cetyl
PEG/PPG-10/1 Dimethicone, (iv) about 1.5% (w/w) Tween 80, (v) about
25% (w/w) water, (vi) about 1% (w/w) pramoxine hydrochloride, (vii)
about 0.25% (w/w) phenylephrine hydrochloride, and (viii) about
0.6% (w/w) Hydroxyethylcellulose (Natrosol HHX).
[0226] According to an embodiment, a topical composition of the
present invention (see composition H1 in Table 1, Example 1 in the
form of an oil-in-water emulsion liquid) comprises: (i) about 25%
(w/w) trimethylsiloxysilicate, (ii) about 38% (w/w) methylsiloxane
(0.54 cP), (iii) about 4% (w/w) Cetyl PEG/PPG-10/1 Dimethicone,
(iv) about 3% (w/w) Tween 80, (v) about 30% (w/w) acetate buffer pH
4.4, (vi) about 1% (w/w) pramoxine HCl, and (vii) about 0.25% (w/w)
phenylephrine HCl.
[0227] According to an embodiment, a topical composition of the
present invention (see composition H2 in Table 1, Example 1 in the
form of an oil-in-water emulsion liquid) comprises: (i) about 15%
(w/w) trimethylsiloxysilicate, (ii) about 47% (w/w) methylsiloxane
(0.54 cP), (iii) about 4% (w/w) Cetyl PEG/PPG-10/1 Dimethicone,
(iv) about 3% (w/w) Tween 80, (v) about 20% (w/w) acetate buffer pH
4.4, (vi) about 1% (w/w) pramoxine HCl, (vii) about 0.25% (w/w)
phenylephrine HCl, and (viii) about 0.01% (w/w) to about 0.1% (w/w)
Pemulen TR-1.
[0228] Containers and Applicators
[0229] The compositions for use in the present invention are
generally stored in a container-applicator device for use in a
single dose application (e.g., a wipe or a swab in a disposable
container) or for use in repeated applications to the anus and
rectum. Single dose applicators include those having breakable or
removable seals that prevent moisture, including atmospheric
moisture, from contacting the formulation.
[0230] In an embodiment of the invention, a topical water-based
composition is in the form of a pre-packaged towelette/wipe. The
wipe substrate is typically uniformly impregnated with the topical
water-based composition. According to an embodiment, the topical
water-based composition is in a liquid form, when applied to the
wipe. According to an embodiment, the topical water-based
composition is in a gel form, when applied to a wipe. The wipe
provides the user with a single dose of sterile medication. The
topical composition is transferred to the body surface upon
contacting the wipe with the target surface.
[0231] The design of wipes is well known to those of skill in the
art. Each wipe is generally packaged as a single-use sealed unit.
The wipe is formed of woven or non-woven fabric, cloth or tissue
substrate and the impregnated wipe may be sealed into an enveloping
sachet or pocket. In an embodiment, the sachet or pocket is formed
by sandwiching a folded and impregnated wipe between two sheets of
an aluminum foil/polyethylene film laminate. The sheets of laminate
may comprise folded over portions of a single sheet of such
material.
[0232] A container-applicator may further comprise two parts: (1) a
storage area or reservoir which holds the composition and protects
it from air, water and contaminants; and (2) the applicator which
generally comprises a specially shaped tip designed to aid in
application of the composition to the anorectal and/or genital
area. In particular embodiments, the applicator is an element
integral to the container, for example, an elongated insertion tube
extending from a reservoir. Alternately, the storage area and the
applicator may be separate components, such as a tube reservoir and
a separately supplied dropper. In yet other embodiments, the
container and the applicator may be supplied as separate elements
which are connected during use, for example via compatible male and
female connectors respectively provided on the container and the
applicator or vice versa.
[0233] For repeated and intermittent usage, minimal exposure to
atmospheric moisture is required. This can be achieved by devices
having very narrow applicator outlets and low initial dead space.
One applicator for such repeated intermittent use may, for example,
dispense the composition in a controlled drop wise manner, as
described for example in U.S. Pat. No. 4,958,748.
[0234] Still another container-applicator device comprises a brush
or solid paddle applicator wherein the topical composition is
"painted" onto the surface requiring treatment.
[0235] The container-applicator device for repeated and
intermittent usage may comprise a container suitable for
non-sterile storage of the composition, and an applicator suitable
for metered dispensing of the composition after opening of the
applicator. In particular embodiments, the applicator is
characterized as having a resealable opening of no more than about
0.05 square inch (0.323 square centimeters) so as to permit the
metered dispersement of the composition from the applicator and
which is capable of multiple administrations of the composition,
and is further characterized as having resealing means such as a
cap which either tightly mates with the applicator or which screws
onto the applicator. The opening may be at the terminus of an
elongated and tapered tube-like member suitable for insertion into
the anal canal and accessing internal hemorrhoids. Suitable
openings of the applicator are about 0.001 to about 0.01 square
inch (about 0.00645 to about 0.0645 square centimeters).
[0236] In an embodiment, the walls of the container-applicator
device are made of a pliable material, so that upon application of
pressure onto the walls, the walls depress sufficiently to force
the composition in the container into the applicator and through
the opening. In another embodiment, the composition is released
from the applicator by gravity feed methods well known in the art.
Such methods do not require application of pressure to the walls of
the container.
[0237] In an embodiment, the applicator is manufactured with its
opening covered by a metal foil or other similar construction which
closes this opening until the device is ready for use. The opening
is then reinstated by use of a pin or similar device which
punctures the covering.
[0238] Such devices for intermittent use enable multiple uses of
the topical composition at different points in time by the same
individual.
[0239] In container-applicator devices suitable for repeated
intermittent uses, the topical composition is stored at ambient
conditions and is selected to be bacteriostatic (see, for example,
U.S. Pat. No. 3,527,224). When the selected composition is
bacteriostatic, prolonged storage at ambient conditions can be
achieved without regard to the sterility of the formulation because
there is no adverse buildup of bacteria during storage.
[0240] The reservoir of the container-applicator device may be both
air-tight and water-tight, and keeps the media within free from
contaminants. The reservoir may contain a desiccant material to
keep the media free of water. Reservoirs may be of any shape,
although shapes which provide for a smooth internal flow of media,
such as cylindrical or conical shapes, are typically suitable. The
size of the reservoir may vary within a wide range, but is
typically slightly larger than the volume of composition which will
be placed inside the reservoir to minimize the amount of gas within
the reservoir. The reservoir may be made from any of a variety of
medical grade materials, such as plastics, excluding glass.
Pharmaceutical agents of the topical composition suffer from caking
when stored in glass reservoir. The reservoir may be rigid,
collapsible, or compressible. Use of a compressible or collapsible
reservoir allows the user to have greater control over the rate at
which the composition is expressed, as exertion of pressure on a
compressible or collapsible reservoir would place a force on the on
the composition causing it to flow at a faster rate than it would
in the absence of such pressure. The compressible or collapsible
reservoir design is especially suitable for the topical composition
in the form of gel, for which the force of gravity may not be
strong enough to cause a flow through an applicator sufficient to
treat hemorrhoids or fissures. Collapsible reservoirs which retain
their collapsed shape have the additional advantage of reducing the
amount of air which enters the reservoir following use. This
advantage of collapsible containers is of greater importance in
multiple-use (reusable) devices, wherein media is typically kept
relatively free of potential contaminants between uses.
[0241] Applicator tips can be of any of a number of shapes, sizes,
and configurations. They may be fairly rigid and may be made out of
any material which is compatible with the media formulation, for
example plastic, excluding glass. The choice of a proper applicator
tip for a given application will depend on factors such as the
viscosity of the composition, the desired application rate of the
composition, the nature of the anorectal or genital disorder, and
its severity.
[0242] The container-applicators of the present invention may be
either single-use or multiple-use devices. A container or reservoir
containing enough topical composition for multiple applications may
be configured to accommodate replaceable tips. In such an
embodiment, at the place whereon the replaceable tips connect with
the reservoir, the reservoir would typically have a means such as a
valve, septum or sealing gasket which allows the reservoir to be
sealed in the absence of an applicator tip. Placing an applicator
tip on the reservoir would cause the valve to open, allowing
composition to flow out from the reservoir. In this manner, one
reservoir containing enough composition for several applications
could be used over a period of hours, days or weeks. This
embodiment would also allow the user to use one reservoir with
applicator tips of varying shapes and sizes chosen to best
accommodate the anorectal or genital disorder during the healing
process.
[0243] Uses
[0244] Disorders of the anorectal or genital region are commonly
encountered among the general population, but are often
inadequately unaddressed, since many patients delay or fail to seek
medical attention due to embarrassment. Furthermore, many
medications for such conditions fail to provide adequate relief and
healing. In addition, many medications which are intended for
treatment of conditions such as hemorrhoids, herpes, genital warts,
anal warts may be difficult to self-administer, and are
unsatisfactory due to their uncomfortable sensation after
application.
[0245] The present invention provides compositions which are useful
for effectively treating a variety of anorectal disorders including
hemorrhoids, anal fissures, anal cracks, anal fistulas, anal
abscesses, and anal pruritus, wherein the compositions provide
enhanced therapeutic efficacy and are associated with improved
patient compliance, as compared to prior art compositions. The
provided compositions may be useful for simultaneously treating a
number of anorectal disorders.
[0246] Hemorrhoids (also known as piles) form part of the normal
human anatomy of the anal canal, but may become pathological when
swollen or inflamed. In their physiological state they act as
cushions composed of arterio-venous channels and connective tissue
that aid the passage of stool. The symptoms of pathological
hemorrhoids include rectal bleeding, tenderness and pain in the
anorectal area.
[0247] Pathological hemorrhoids are typically classified as
external or internal, which are differentiated via their position
with respect to the dentate line. External hemorrhoids occur
outside the anal verge (the distal end of the anal canal) as
varicosities of the veins draining the territory of the inferior
rectal arteries, which are branches of the internal pudendal
artery. External hemorrhoids are frequently painful, and are often
accompanied by swelling, skin irritation and itching. External
hemorrhoids are prone to thrombosis, which may occur if the vein
ruptures and/or a blood clot develops.
[0248] Internal hemorrhoids occur within the rectum as varicosities
of veins draining the territory of branches of the superior rectal
arteries. As this area lacks pain receptors, internal hemorrhoids
are often painless and affected individuals may be unaware of their
occurrence. Internal hemorrhoids may however, bleed when irritated.
Untreated internal hemorrhoids can lead to the more sever
conditions of prolapsed or strangulated hemorrhoids. Prolapsed
hemorrhoids are severely distended such that they are extruded
outside the anus. If the anal sphincter muscle goes into spasm and
traps a prolapsed hemorrhoid outside the anal opening, the supply
of blood is cut off, and the hemorrhoid becomes a strangulated
hemorrhoid.
[0249] Internal hemorrhoids can be further graded by the degree of
prolapse, in which Grade I is characterized by the absence of
prolapse; Grade II is characterized by prolapse upon defecation but
which reduce spontaneously; Grade III is characterized by prolapse
upon defecation, which may be manually reduced; and Grade IV is
characterized by prolapse which cannot be manually reduced.
[0250] An anal fissure is a crack or tear in the skin of the anal
canal. Acute cases may be associated with severe periodic pain
after defecation, while chronic cases are associated with less
intense pain. Anal fissures usually extend from the anal opening
and are usually located posteriorly in the midline. Fissure depth
may be superficial or extend down to the underlying sphincter
muscle. Most anal fissures are due to stretching of the anal mucosa
beyond their capability. A common cause of non-healing chronic
fissures is spasm of the internal anal sphincter muscle, resulting
in impaired blood supply to the anal mucosa. The result is a
non-healing ulcer, which may become infected by fecal bacteria.
[0251] Non-surgical conventional treatments for acute and chronic
anal fissures are generally those used for hemorrhoids. Topically
applied medications used for relaxation of the sphincter muscle
include nitroglycerine, nifedipine, diltiazem, verapamil,
sildenafil citrate, and/or lidocaine. Surgical treatment procedures
such as anal stretch (Lord's operation) or lateral sphincterotomy
are aimed to decrease sphincter spasm. Another approach involves
injection of botulinum toxin into the anal sphincter.
[0252] Anorectal or perianal abscess (also known as anal/rectal
abscess, perianal/perirectal abscess) is an abscess occurring
adjacent to the anus, due to infection at one of the anal crypts of
Morgagni. Most cases are sporadic, although individuals with
diabetes mellitus or Crohn's disease, or those undergoing chronic
steroid treatment have increased risk and incidence. The condition
is generally treated by surgery to drain the infection, followed by
oral administration of antibiotics and possibly topical treatments.
Anal abscess often leads to an anal fistula, which is the
development of an infected channel within a gland between the anal
canal and external skin near the anus or rectum. This condition
also requires surgical treatment generally followed by
administration of antibiotics.
[0253] Anal pruritus (also known as pruritus ani or anusitis) is an
irritation of the skin at the anus, associated with intensive urge
to scratch the affected area. The condition may be idiopathic, or
associated with various factors or co-existing conditions,
including occult or overt fecal soiling, ingestion of certain
foods, bacterial or fungal infection, hemorrhoids or additional
co-existing anorectal disorders, and dermatological conditions, in
particular allergic contact dermatitis or psoriasis. Treatment
measures include enhanced hygiene, antibiotics or antifungal
medications when infections are present, various creams and
ointments, generally containing local anesthetics,
vasoconstrictors, protectants or combinations thereof, and topical
steroids. The composition is applied to areas of the anal canal or
rectum affected by hemorrhoids, fissures, fistulae, cracks, warts
or pruritus, under conditions suitable for film formation of the
composition so as to form a protective coating and typically under
non-sterile conditions. In general, sufficient amounts of topical
composition are employed to cover the entire affected mucosal
surface area. In an embodiment, the coating is extended by at least
about 1 centimeter and by at least about 5 centimeters beyond the
affected surface area.
[0254] The term "therapeutically effective amount" as used herein
means an amount of the pharmaceutical agent which is sufficient to
provide a beneficial effect to the subject to which the
pharmaceutical agent is administered. More specifically, a
therapeutically effective amount means an amount of the
pharmaceutical agent effective to alleviate or ameliorate the
symptoms of an anorectal or genital disorder of the subject being
treated.
[0255] As the anorectal or genital disorders are treated with
compositions of certain fixed concentrations, reference is made
herein to "therapeutically effective concentration".
[0256] After an initial layer of topical composition has been
applied and the solvent has evaporated, providing an initial dried
film coating, a second layer may be applied over the initial film.
Additional amounts of topical composition can be applied as
needed.
[0257] In an embodiment, a topical composition is employed to form
a coating of less than about 0.5 mm thick. In an embodiment, a
topical composition is employed to form a coating of at least about
0.1 mm thick. Such coatings can be formed by applying, for example,
about 0.02 ml of topical composition per square centimeter of
affected surface area.
[0258] In general, the particular length of time required for film
formation will vary depending on factors such as the amount of
composition applied, the temperature of the rectal or anal mucosal
area, the moisture content of the rectal or anal, the surface area
for composition application, and the like. However, in an
embodiment, film formation is generally complete within about 10 to
about 60 seconds. During this period, the person to whom
application of the topical composition has been made may minimize
actions and body movements thus allowing the composition to form a
dried film coating.
[0259] The topical compositions of the present invention typically
act at temperatures between room temperature (20.degree. C.) and
body temperature (37.degree. C.). The dried films are conformable
and comfortable and may be elastic and flexible, and do not
irritate the skin and mucous membrane during the application and in
use after drying. The dried films are typically substantially
painless and easily removable substantially without pain. The dried
films formed from the topical compositions are also typically
substantially non-water sensitive and waterproof. The dried films
formed from the topical compositions comprise finely-dispersed
pharmaceutical ingredients, which can be gradually released to the
adhesion area.
[0260] The compositions of the present invention are applicable to
both human patients and to non-human mammalian subjects such as in
veterinary use, for example for treatment of canine, feline,
equine, bovine, porcine and primate species.
[0261] The foregoing description of the specific embodiments will
so fully reveal the general nature of the invention that others
can, by applying current knowledge, readily modify and/or adapt for
various applications such specific embodiments without undue
experimentation and without departing from the generic concept,
and, therefore, such adaptations and modifications should and are
intended to be comprehended within the meaning and range of
equivalents of the disclosed embodiments. It is to be understood
that the phraseology or terminology employed herein is for the
purpose of description and not of limitation. The means, materials,
and steps for carrying out various disclosed functions may take a
variety of alternative forms without departing from the
invention.
[0262] The following examples illustrate certain embodiments of the
invention but are not meant to limit the scope of the claims in any
way. The following examples are put forth so as to provide those of
ordinary skill in the art with a complete disclosure and
description of how to make and use the described invention, and are
not intended to limit the scope of what the inventors regard as
their invention nor are they intended to represent that the
experiments below are all or the only experiments performed.
Efforts have been made to ensure accuracy with respect to numbers
used (e.g. amounts, temperature, etc.) but some experimental errors
and deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, molecular weight is weight average
molecular weight, temperature is in degrees Centigrade, and
pressure is at or near atmospheric.
Example 1
[0263] Table 1 summarizes various embodiments of topical
compositions of the present invention in the form of an
oil-in-water emulsion liquid prepared for use in treating
hemorrhoids.
TABLE-US-00001 TABLE 1 g per 100 g product Ingredient A B C D E F G
H H1 H2 Trimethylsiloxysilicate 15 15 15 15 20 20 13 15 25 25
Hexamethyldisiloxane 22 22 22 22 24 26 18 43 Isooctane 21 21 21
22.5 20 20 17 Methylsiloxane 38.25 46.74 (0.65 cP) Cetyl PEG/PPG- 4
4 4 4 4 4 4 4 10/1 Dimethicone Tween 80 1.5 1.5 1.5 1.5 1.5 3 Tween
20 2 Sodium Lauryl 1.5 3 3 Sulfate Water 25 24.5 25 25 30 30 35 25
Acetate Buffer 30 20 pH 4.4 Pramoxine HCl 1 1 1 1 1 1 1 1 1 1
Phenylephrine 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 HCl
Bis- 5 5 5 5 5 5 vinyldimethicone Vinyldimethicone 5 5 5 5 5 5 and
hydrogen dimethicone Cyclopentasiloxane 1 1 1 1 1 1 and dimethicone
blend Pemulen TR-1 0.01
Example 2
[0264] Composition H1 of Example 1 was prepared as follows:
[0265] Trimethylsiloxysilicate powder was dissolved in
methylsiloxane at room temperature. Cetyl PEG/PPG-10/1 Dimethicone
was added to solution of trimethylsiloxysilicate. Pramoxine and
phenylephrine were dissolved in water. The pH of the aqueous
solution was adjusted to 4.2-4.4 by acetate buffer. Tween 80 was
added to the aqueous solution. The trimethylsiloxysilicate solution
was combined with the aqueous solution and mixed by means of a
homogenizer at room temperature.
[0266] The obtained topical liquid solution was applied to a wipe
substrate and sealed to provide a sealed package of single-use wipe
impregnated with the topical liquid composition. The composition is
applied using single use wipe, wiping the anal region of an adult
subject suffering from external hemorrhoids.
Example 3
[0267] Table 2 summarizes various embodiments of topical
compositions of the present invention in the form of a gel for
treatment of hemorrhoids.
TABLE-US-00002 TABLE 2 g per 100 g product Ingredient I J K L
Trimethylsiloxysilicate 15 17 20 25 Hexamethyldisiloxane 18 18 21
Methylsiloxane (0.65 cP) 42.65 Isooctane 19 20 22 Cetyl
PEG/PPG-10/1 4 4 4 Dimethicone Tween 80 1.5 1.5 1.5 Sodium Lauryl
Sulfate 3 Water 30 30 30 25 Pramoxine HCl 1 1 1 1 Phenylephrine HCl
0.25 0.25 0.25 0.25 Bis-vinyldimethicone 5 5 Vinyldimethicone and 5
5 hydrogen dimethicone Cyclopentasiloxane and 1 1 dimethicone blend
Hydroxypropyl 0.5 0.5 0.5 methylcellulose Hydroxyethylcellulose 0.6
(Natrosol HHX)
Example 4
[0268] Composition L was prepared as follows:
[0269] Trimethylsiloxysilicate powder was dissolved at RT in
methylsiloxane. Silicon Surfactant Cetyl PEG/PPG-10/1 Dimethicone
was added to a solution of Trimethylsiloxysilicate. Pramoxine and
phenylephrine were dissolved in water. The pH of the aqueous
solution was adjusted to 4.2-4.4 by an acetate buffer. Tween 80 was
added to the aqueous solution with slow mixing to avoid bubbling.
Hydroxyethylcellulose (Natrosol HHX) was dispersed in the aqueous
phase under intensive mixing and heating up to 70 deg C. After the
mixture was formed, the mixing was continued until it cooled to
room temperature. The trimethylsiloxysilicate solution was combined
with the aqueous solution and mixed in a homogenizer at room
temperature. Upon dissolution of hydroxypropyl methylcellulose in
the aqueous phase, whereupon a viscous gel was formed.
[0270] The viscous topical gel composition obtained had a viscosity
ranging from 25000-45000 cP.
Example 5
[0271] A female patient aged 42 applied the gel composition L of
Table 2, Example 3 on the elbow, neck and internal part of the arm.
Shortly thereafter (about 20 seconds) the composition dried and
left a thin film on the skin.
[0272] The films were examined after 12, 18 and 24 hrs for
durability and flexibility. During this period the patient carried
out their usual daily activities and took one shower.
[0273] It was found that the films were durable and remained intact
after 12, 18 and 24 hrs. The films did not fall off the body
surface and did not crack or flake off. It was found that the films
remained flexible after 12, 18 and 24 hrs. The films closely
followed the patient's skin irregularities as well as skin movement
throughout the day during normal activity. The skin under the film
was slightly pale, which shows the vasoconstrictor phenylephrine
was still active after 24 hrs. After 24 hrs, the film was removed
from the skin and tested by high performance liquid chromatography
(HPLC), whereupon significant amounts of the two actives (pramoxine
and phenylephrine) were found in the film despite the extended
period of time.
Example 6 (Prophetic)--Durability of Films Obtained on Drying of
the Compositions of the Present Disclosure
[0274] A test will be conducted to assess durability of dried films
of the present disclosure. The model will be based on the principle
that efficacious films provide a physical barrier between the skin
and the external environment. Therefore, the film should also
prevent wash-off and wear-off of a harmless inert marker substance.
Activated carbon powder (ACP) is one such marker.
[0275] Film performance will be assessed by randomly applying films
of the present disclosure over uniformly made ACP prepared sites on
the backs of healthy adult subjects, and measuring the amount of
ACP remaining on those sites over a wear period (e.g., one-day
period, two-day period, three-day period or more). Subjects will go
about normal daily activities and will be asked to shower once per
day and avoid excessive physical activity or prolonged water
exposure. On a daily basis, standardized digital photographs will
be taken of the test sites and used to monitor the amount of ACP
remaining using computer-assisted image analysis. The amount of
marker stain (ACP) remaining after 1, 2, and 3 days of wear will be
used as a measure of film effectiveness. The more stain remaining,
the more effective the film at protecting the test site. The
results can be presented as a chart of mean.+-.SEM durability
expresses as a percentage of the original ACP marker on Day 0.
Example 7 (Prophetic)--Flexibility of Films Obtained on Drying of
the Compositions of the Present Disclosure
[0276] A test will be conducted to assess flexibility of dried
films of the present disclosure. The films will be prepared on
synthetic skin and bent over three sized mandrel bend rods (1/2'',
1/4'', 1/8'') based on ASTM method D4338-97. Multiple data points
will be collected for each film. Whether or not the film cracked
during the bending process will be recorded.
[0277] A tattoo practice skin (synthetic skin) coated with a film
of the present disclosure. The skin will be folded to form an
inverted U-shaped angle over the mandrel maintaining intimate
contact with the upper surface of the film. Using a fresh specimen
for each test, the test will be repeated with progressively smaller
diameter mandrels.
[0278] Procedure: [0279] 1) Film will be applied onto tattoo
practice skin with a dimension of 2.times.4 inches. [0280] 2) The
test films and the test apparatus will be stored at the test
conditions for 24 hours. [0281] 3) The tests will be run in the
same environment used to condition the test films and test
apparatus. [0282] 4) The largest diameter mandrel will be
positioned in the horizontal operating position in the test frame.
[0283] 5) The test film will be grasped between the thumb and
forefinger of one hand, with the longest dimensions between the
fingers. For low-temperature testing, a cotton work glove can be
used to insulate the test film from the warm fingers. [0284] 6) A
flat steel (or other support structure) of the test film will be
laid tangentially at right angles to the longitudinal axis of the
test mandrel. [0285] 7) The test film will be folded with the lower
surface opposite to the mandrel to form an inverted U-shaped angle
over the mandrel maintaining intimate contact with the mandrel.
[0286] 8) Any fracture, crazing, or cracking of the film, observed
with the naked eye, will be recorded. [0287] 9) A fresh film will
be folded onto the next smaller diameter mandrel. [0288] 10) The
test will be repeated a number of times, using fresh films, on
three mandrels with different diameters. [0289] 11) Flexibility of
the films will be determined by the ability of the films to not
crack when subjected to bending.
Example 8--Efficacy of Compositions of the Present Invention in the
Treatment of Hemorrhoids
[0290] Background:
[0291] In a randomized clinical study, patients were divided into 3
groups and received either PP-110 gel (composition L in Table 2),
PP-110 wipes (composition H1 in Table 1) or Preparation-H.RTM.
cream as a comparator. PP-110 was applied once daily, while
Preparation-H was applied 4 times a day, as indicated.
[0292] All patients were asked to record parameters such as pain,
bleeding, itching, swelling, discomfort, and mucus discharge over a
period of 14 days while using the assigned treatment. For most
parameters, patients were asked to choose between 0=none, 1=mild,
2=moderate and 3=significant for each day. The only exception was
pain, where they were asked to select a pain level between 1=none
to 10=maximal.
[0293] Results:
[0294] Based on the first 32 patients who completed the protocol (9
of them with PP-110 gel, 11 with PP-110 wipes, and 12 with
Preparation-H cream), the following interim results were
obtained:
[0295] Pain:
[0296] Reported pain, throughout the 14 days of treatment for
PP-110 (gel or wipes) was reduced compared to reported pain in the
Preparation-H arm, even though PP-110 was used once daily and
Preparation-H was used 4 times per day. FIG. 1 shows hemorrhoidal
pain level after treatment with compositions of the present
invention as gel and wipes, as compared to Preparation H. The data
presented are the delta meaning the change from the previous day
for each parameter measured.
[0297] Itching:
[0298] Itching, throughout the 14 days of treatment for PP-110 (gel
or wipes) was significantly reduced compared to reported itching in
the Preparation-H arm. FIG. 2 shows hemorrhoidal itching after
treatment with compositions of the present invention as gel and
wipes as compared to Preparation H. The data presented are the
delta meaning the change from the previous day for each parameter
measured.
[0299] Swelling:
[0300] For swelling values for the PP-110 gel and wipe arms
throughout the 14 days of treatment were significantly reduced
compared to reported swelling in the Preparation-H arm. FIG. 3
shows hemorrhoidal swelling after treatment with compositions of
the present invention as gel and wipes, as compared to Preparation
H. The data presented are the delta meaning the change from the
previous day for each parameter measured.
[0301] Bleeding:
[0302] PP-110 gel patients and Preparation-H patients showed
similar bleeding results throughout the 14 days. PP-110 wipe
patients were slightly behind in the first 7 days of treatment, but
caught on after that. FIG. 4 shows hemorrhoidal bleeding after
treatment with compositions of the present invention as gel and
wipes, as compared to Preparation H. The data presented are the
delta meaning the change from the previous day for each parameter
measured.
[0303] Discomfort:
[0304] Results of all 3 arms with respect to discomfort were
comparable, even though PP-110 patients used the product once daily
and Preparation-H patients--4 times a day. FIG. 5 shows
hemorrhoidal discomfort after treatment with compositions of the
present invention as gel and wipes, as compared to Preparation
H.
[0305] Summary:
[0306] In all clinical parameters one or both of PP-110 arms showed
comparable or superior results compared to the Preparation-H arm.
This includes pain, itching, swelling, bleeding and discomfort, and
was achieved even though PP-110 was applied once daily and
Preparation-H was applied 4 times per day. The data presented are
the delta meaning the change from the previous day for each
parameter measured.
Example 9--Liquid Compositions with Pemulen TR-1 for the
Preparation of Wipes
[0307] Composition H2 of Table 1 in Example 1 was prepared
similarly to composition H1, with added Pemulen TR-1:
[0308] Trimethylsiloxysilicate powder was dissolved in
methylsiloxane at room temperature. Cetyl PEG/PPG-10/1 Dimethicone
was added to solution of trimethylsiloxy silicate. Pramoxine and
phenylephrine were dissolved in water. The pH of the aqueous
solution was adjusted to 4.2-4.4 by acetate buffer. Tween 80 was
added to the aqueous solution. The trimethylsiloxysilicate solution
was combined with the aqueous solution and mixed by means of a
homogenizer at room temperature.
[0309] A topical liquid composition was obtained, whose viscosity
ranges from 1-1.2 cP, close to the viscosity of water.
[0310] The obtained topical liquid composition was applied to a
wipe substrate and sealed to provide a sealed package of single-use
wipe impregnated with the topical liquid composition. The
composition is applied using single use wipe, wiping the anal
region of an adult subject suffering from external hemorrhoids.
[0311] All patents, patent applications, and published references
cited herein are hereby incorporated by reference in their
entirety. It will be appreciated that several of the
above-disclosed and other features and functions, or alternatives
thereof, may be desirably combined into many other different
systems or application. Various presently unforeseen or
unanticipated alternatives, modifications, variations, or
improvements therein may be subsequently made by those skilled in
the art.
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