Note: Descriptions are shown in the official language in which they were submitted.
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BODY CAVITY FOAMS
FIELD OF THE INVENTION
[0001] The invention relates to an alcohol-free, foam carrier for delivery of
an active
agent to a mucosal body cavity. More specifically, the invention relates to
foam carriers
suitable for inclusion of poorly soluble, water soluble and oil soluble
therapeutic agents
for delivery and sustained release to the vaginal cavity.
BACKGROUND OF THE INVENTION
[0002] The vaginal cavity, induding the vagina and cervix, provides a unique
site for
delivery of therapeutic agents, both for systemic and local action.
X0003] There are multiple anatomical structures which comprise the internal
and
external female genital tract including the ditoris, labia minora and corpus
spongiosum
(vestibular) erec6le tissue, vagina, peri-urethral glans, urethra, Halban's
fascia, anterior
fornix erogenous zone, pubococcygeus muscle and cervix.
r0004] The vagina consists of a tube of autonomically-innervated smooth muscle
(longitudinal outer, inner circular layer) lined by stratified squamous
epithelium and a
sub-dermal layer rich in capillaries. The vaginal wall consists of an inner
glandular
mucous type stratified squamous cell epithelium supported by a thick lamina
propia.
This epithelium undergoes hormone-related cyclical changes including slight
keratinization of the superticial cells during the menstrual cycle. Deep in
the epithelium
lies the smooth muscles of the muscularis. There is a deeper surrounding
fibrous layer
above the muscularis which provides structural support to the vagina and is
rich is
collagen and elastin to allow for expansion of the. Three sets of skeletal
muscles
surround 'the vagina including the ischiocavernosum, bulbocavernosus,
transverse
perinei and levator ani and pubococcygeus muscles.
[0005] Women are vulnerable to diseases of the genital tract as the lining of
the
vagina is a permeable mucous membrane. Intercourse, lack of lubrication during
intercourse, changes in the cervix during the menstrual cycle, and
asymptomatic
infections fadlitate the transmission of infection to women. Prepubertal girls
and
adolescents are particularly vulnerable because their vaginal and cervical
tissues may be
less mature and are more readily penetrated by organisms (e.g., chlamydia and
gonococcus). Postmenopausal women are more likely than younger women to get
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1~
~ abrasions in the vagina during sexual activity as a result of thinning of
the tissue and
dryness. Women who already have an infection (particularly one that causes
genital
lesions) are more likely to acquire or transmit another STD, including HIV.
Other
biological risks include the use of vaginal douches, which increase the risk
of pelvic
inflammatory disease (PID), and the influence of hormonal contraceptives on
acquiring
or transmitting an STD (e.g., increased risk of chlamydial infection with use
of oral
contraceptives).
[0006] In particular, the cervix is prone to several diseases, such as
cervicitis (an
inflammation of the uterine cervix, usually caused by infection), cancer,
inflammation,
erosion, intraepithelial neoplasia (CIN), polyps, dysplasia, human
papillomavirus (HPV)
infections causing some tumors, condylomas or warts and abnormal pregnancy.
[0007] Several factors must be taken into consideration when developing
therapeutic
delivery systems for the female genital system. These factors include the
vaginal
anatomy, the mucosal surtace, the presence and composition of vaginal fluids
and
secretions, cervical fluids (mucus), cyclic changes and endogenous microflora.
Drug
stability to enzyme activity, which is quite high in vaginal environment, and
is again a
function of menstrual cycle and lifecycle, should also be taken into account.
Topical drug
delivery through the cervix, as needed to treat disorders of the cervix and
uterus also
presents a challenge.
[0008] Vaginal topical formulation should be compatible with daily activities,
be easy
to administer and provide accurate dosing. Several types of formulations are
known for
delivery to the vaginal cavity. While semi-solid formulations, such as creams,
lotions,
gels and ointments are commonly used, they are often reported to be messy,
require
frequent application and can be difficult to remove after use. Furthermore,
application of
topical gets and creams require several steps of operation. Solid formulations
such as
tablets, suppositories and pessaries also require frequent application, show a
poor
retention in vagina, and exhibit insufficient spreadability.
[0009] Rectal drug administration can be directed to both local and systemic
drug
delivery. It has been effectively used to treat local diseases of the
anorectal area as well
as an alternative to oral administration in the systemic administration of
drugs. Solid
suppositories are the most common dosage form used for rectal drug
administration and
represent the majority of rectal dosage forms; however, creams ointments and
foams are
also being used.
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[0010] Current formulations for rectal administration still have significant
disadvantages. They are difficult to insert through the anal orifice; they are
difficult to
spread throughout the target cavity; and if spreadable, they tend to leak,
causing major
discomfort to the patient. Such negative attributes lead to their very limited
use.
[0011] Thus, new forms are desirable in order to achieve better control and
ease of
application, while maintaining the beneficial properties of such products. A
product for
intravaginal and anorectal application would ideally exhibit the following
properties: (1 )
easy insertion, thus leading to high patient compliance; (2) accurate dosing,
to ensure
effective treatment; (3) expandability, for increased coverage of the target
cavity surface
and cervix; and (4) drip free formulation with good adhesive properties, for
prolonged
drug residence. The duration of the drug inside the vagina or rectum is also
important
for ensuring extended activity.
[0012] Use of emulsions in foam compositions is known. Emulsion systems
provide
a two-phase system including water in one phase and oily components in the
second
phase. Emulsifiers for reducing surface tension and for improving foam
stability are
i~~ncluded in the foam composition. Foams and, in particular, foam emulsions
are
complicated systems which do not form under all circumstances. Slight shifts
in foam
emulsion composition, such as by the addition of active ingredients, may
destabilize the
foam. In the case of oi(-containing foams, high surfactant concentrations are
required to
attain foams of low density and acceptable texture.
[0013] Typical vaginal foam products are aqueous formulations and do not
include
significant levels of an oil-based solvent. For example. a nonoxynol-9-
containing foam
marketed under the trademane DetferK~ foam (Advanced care, 12.5% nonoxynol-9),
EmkoC~ foam (Schering-Plough Healthcare, 12% nonoxynol-9) does not contain any
oily
solvent and has an ingredient list reciting "nonoxynol-9 12.5%, benzoic acid,
cetyl
alcohol, glacial acetic acid, methylparaben, perfume, phosphoric acid,
polyvinyl alcohol,
propellant a-31, propylene glycol, purified water, sodium
carboxymethylceilulose, sorbic
acid, stearamidoethyl diethylamine, stearic acid".
[U014j PGT Publication No. WO 03/053292 discloses drug delivery compositions,
which are suitable for vaginal administration for the treatment of diseases
and disorders
in the urogenital tract. The compositions may be in the form of a tablet,
liquid
suspension or dispersion; dried powder; topical ointment; cream; foam;
suppository; or
aerosol. The drug delivery compositions are administered directly to the
vagina and do
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not require the use of a pressurized canister or other foaming device. The
reference
does not disclose use of hydrophobic or oily solvents.
[0015] US Patent No. 5,759,520 discloses an aqueous foamable composition
having
a delayed foaming action on expulsion from a pressurized container. The
composition
includes (a) a major amount by weight of water; (b) 0.5 to 7.0 weight percent
of a
foaming agent in the form of a water-immiscible liquefied gas; (c) at least
one foam-
stabilizing and emulsifying surfactant; and (d) a water-soluble polymer. A
foaming agent
such as propellant gas forms a foam upon discharge from the container. Water
is used
as the foam vehicle and hydrophobic organic carriers such as oil or emollients
are not
disclosed.
[0016] PCT Publication No. WO 02/00820 discloses a propellant-free foamable
aqueous
composition for use as vaginal or hemorfioidal wipe. The aqueous stable foam
includes
water, at least one surfactant and at least one foam-stabilizing agent. Such
compounds
are storage stable and readily dispensed by a propellantless mechanical pump.
[0017] US Patent No. 5,679,324 pertains to an aerosol foamable fragrance
composition, translucent in its pre-dispensed state, which forms a fast-
breaking foam.
The composition contains a surfactant selected from the group consisting of
ethoxylated
lanolin oil derivatives, propoxylated lanolin oil derivatives, and mixtures
thereof, a
propellant, a fragrance, a thickener, and a cosmetic vehicle (preferably
water) wherein
the ratio of the surfactant to propellant is from about 1:1 to about 1: i 0.
Emollients may
be included, however, being translucent, the composition cannot comprise
significant oil
concentrations (which would make it opaque). Apparently the foam breaks
spontaneously upon discharging from an aerosol container (with no need of any
rubbing
or sheer force application), thus making it impractical for intravaginal
application.
[0018] Additionally, US Patent Nos. 5,536,743 and 5,840,744 relate to a non-
flowing
composition and method for intravaginal treatment of bacterial vaginosis. The
composition contains metronidazole with a buffer system providing an acidic
buffered pH
value in the range of 3.75 to about 4.25. Certain of the compositions
disclosed are
(based on mineral oil or petrolatum. The foam compositions disclosed include
up to 3%
imineral oil as the hydrophobic component of the emulsion.
~[0019] US Patent No. 6,544,530 provides a stable oil-in-glycerin composition
comprising a continuous glycerin phase, at least one vegetable oil, at least
one
biodegradable emulsifier and at least one bioactive essential oil component
for topical,
external use on skin and mucosal. The essential oil is a volatile mixture of
esters,
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aldehydes, alcohols, ketones, and terpenes that possess bioactivity such as
topical anti-
fungal activity, topical anti-bacterial activity, topical anti-parasitic
activity, and topical anti-
viral activity.
[0020] US Patent No. 5,993,846 discloses a method for making an oil-in-water
emulsion having mucoadhesive properties which includes forming a mixture of a
mucoadhesive macromolecule and an aqueous phase; emulsifying the mixture with
a
hydrophobic phase and a surfactant to form an oil-in-water emulsion comprising
a
plurality of submicron particles having a hydrophobic core surrounded by the
surfactant
and the mucoadhesive macromolecule; and providing the emulsion with a final pH
of
between 3 and 8.
[0021] US Patent No. 6,423,323 describes an aqueous foam emulsion. The
composition includes a hydrophobic phase including fatty acids, emulsifiers
and co-
emulsifiers, and an aqueous phase containing hydrophilic moisturizers and
emulsifiers.
An optional ingredient is one or more refatting substances.
(0022] US Pat. No. 6,730,288 teaches a pharmaceutical foam composition
including
(a) an active ingredient; (b) an occlusive agent; (c) an aqueous solvent; and
(d) an
organic cosolvent; wherein the active ingredient is insoluble in water and
insoluble in
both water and the occlusive agent; and wherein there is enough occlusive
agent to form
an occlusive layer on the skin.
SUMMARY OF THE INVENTION
[0023] In some aspects, the present invention provides an easy to use vaginal
delivery system that will be simple to operate with minimal preparation, will
be very
tolerable without having a feeling of foreign matter, will provide accurate
dose
administration, will evenly spread throughout the vaginal cavity surface, will
effectively
reach the cervix, wiH not leak and will retain intravaginally an active agent
for a significant
period of time. In other aspects, the present invention provides a lubricating
vaginal drug
vehicle for moisture replenishing or moisturizing vaginal vehicles. In other
aspects, the
invention provides an improved delivery system for active agents to other body
cavities,
such as the rectum, penile urethra, nasal cavity and ear cavity and to mucosal
surfaces.
[0024] The present invention relates to foam compositions for intra-vaginal
and body
cavity application of a wide range of active ingredients. The compositions
contain at
least one active agent in a biocompatible alcohol-free foamable carrier,
including
oleaginous foams, oil-in-water foams, water-in-oil foams, liposome-based foams
and
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,r
nanoparticle-based foams. These compositions provide long lasting, drip-free,
expandable formulations for drug delivery into body cavities.
[0025] According to one aspect of the present invention, an alcohol-free
foamable
therapeutic composition for application to a body cavity or a mucosal surface
includes:
at least one organic carrier selected from a hydrophobic organic carrier, a
polar
solvent, an emollient and mixtures thereof hydrophobic organic carrier and
mixtures
thereof, at a concentration of about 2% to about 75% by weight;
about 0.2% to about 5% by weight at least one surface-active agent;
about 0.01 % to about 5% by weight at least one polymeric agent, selected from
a
bioadhesive agent, a gelling agent, a film forming agent and a phase change
agent;
at least one active agent at a therapeutically effective concentration; and
a liquefied or compressed gas propellant at a concentration of about 3% to
about
25% by weight of the total composition,
which upon release from an aerosol container provides an expanded foam
suitable for topics! administration.
[0026] According to one embodiment, the composition further includes a foam
adjuvant at a concentration less than about 5% by weight. Water and optional
ingredients added to complete the total mass to 100%. The content of the foam
compositions is presented herein as concentration (percent by weight, %w/w).
[0027) According to one or more embodiments of the present invention, the
solvent
level varies and can be at a level of about 2 to about 5, about 5% to about
20% by
weight, or at a concentration of about 20% to about 75% by weight.
[0028] In another aspect of the present invention, an alcohol free oleaginous
therapeutic foam composition for administration to a body cavity or mucosal
surface
includes:
at least one organic carrier selected from a hydrophobic organic carrier, an
emollient, a polar solvent, and mixtures thereof, at a concentration of about
70% to about
99% by weight;
at least one surface-active agent at a concentration of about 0.2 to about
15%;
at least one polymeric agent, selected from a bioadhesive agent, a gelling
agent,
a film forming agent and a phase change agent at a concentration of about 0.1
% to
about 5% by weight;
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at least one active agent at a therapeutically effective concentration; and
a liquefied or compressed gas propellant at a concentration of about 3% to
about
25% by weight of the total composition,
which upon release from an aerosol container provides an expanded foam
suitable for topical administration.
[0029] Water and optional ingredients are added to complete the total mass to
100%. As used herein "oleaginous foam composition" means a stable foam
composition, or a composition capable of forming a stable foam composition
that
contains a high level of oil or emollient as the hydrophobic organic carrier.
The
hydrophobic organic carrier is included in the oleaginous foam composition at
levels at or
above 70%, and up to about 99% by weight.
(0030] According to one embodiment, at least one of the composition
components,
selected from the group consisting of organic carrier, surface active agent,
foam adjuvant
or polymeric agent can also function as an active agent.
[0031] In another aspect of the present invention, a method of making a
foamable
composition includes selecting at least one active agent; selecting a solvent
that
solubilizes the active agent substantially better than a hydrocarbon solvent
such as
mineral oil or petrolatum, for example, 5 fold better than mineral oil or
petrolatum, or
even 10-fold better than mineral oil or petrolatum; and adjusting the type and
concentration of surfactant and gelling agent, to provide a foamable
composition.
[0032] According to another aspect of the present invention, a method of
treating a
syndrome, disease or disorder of a body cavity or mucosal surface includes
administering an alcohol-free foamable therapeutic composition. The foamable
composition can be an oleaginous foam, an oil-in-water foam, a water-in-oil
foam, a
liposome based foam and a nanoparticle based foam.
[0033] In one or more embodiments of the present invention, the syndrome,
disorder
or disease of the body cavity is a syndrome, disorder or disease of the
vaginal cavity. In
one or more embodiments, the disorder is a microbial disorder including
bacterial
vaginosis, candidiasis, candidal vaginitis and trichomonas vaginitis. In
another
embodiment the microbial disorder is a sexually transmitted disease (STD) such
as
chlamydia, herpes simplex, human immunodeficiency virus (HIV). In another
embodiment the syndrome, disorder or disease of the vaginal cavity is related
to
hormonal or post-menopausal vaginal dryness. In yet another embodiment the
syndrome, disorder or disease is related to the cervix and includes malignant
and benign
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I tumors, dysplasias, human papillomavirus (HPV) or to the vulva and includes
lichen
sclerosus, vulvodynia and other pathologies.
DETAILED DESCRIPTION OF THE INVENTION
(0034] The present invention provides a foamable therapeutic compositions
useful
for delivery of an active agent to a mucosal body cavity. The composition is
dispensed
as a foam providing a stable product that is pleasant and easy to use for high
patient
compliance.
[0035] The foamable therapeutic composition of the present invention is
suitable for
facile administration into the rectum, bladder, the cavity between the uterus
and the
fallopian tubes, the ovaries and other body areas, which may accept topically-
applied
products.
[0036] In one or more embodiments of the present invention, a foamable
composition includes water in one phase and at least one solvent selected from
a
hydrophobic organic carrier, a polar solvent, an emollient and mixtures
thereof in the
second phase. The compositions may be water-in-oil or oii-in-water emulsions.
[0037] Despite the commonly accepted understanding that hydrophobic organic
carriers, polar solvents and emollients are difficult to formulate into a foam-
producing
product and that addition of such solvents interferes with the foam forming
ability of a
surfactant, the present invention has surprisingly identified a series of foam
compositions, which, upon admixing with a liquefied gas propellant in an
aerosol
container, produce a stable foam composition that is suitable for topical and
mucosal
administration to body cavities, such as the vagina, rectum, penile, urethra,
nasal cavity
and ear cavity. Upon discharge from an aerosol container, the composition
forms an
expanded foam, which does not break down immediately upon discharge, and
remains
in the body cavity for an extended time.
[0038] Such compositions, when placed in an aerosol container and combined
with a
liquefied gas propellant, create an emulsion, which, upon release from the
aerosol
container, provides a therapeutically beneficial foam product.
[0039] According to one or more embodiments of the present invention, the
therapeutic foam composition for administration to a body cavity or mucosal
surface
includes at least one solvent selected from a hydrophobic organic carrier, a
polar
solvent, an emollient and mixtures thereof, at a level of about 2% to about
5%, or about
5% to about 10%; or about 10% to about 20%; or about 20% to about 75%; or
about
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i 70% to about 99% by weight. The composition also contains about 0.2% to
about 5% by
weight of a surface-active agent; about 0.01 % to about 5% by weight of a
polymeric
additive selected from a bioadhesive agent, a gelling agent, a film forming
agent and a
phase change agent; at least one active agent at a therapeutically effective
concentration; and a liquefied gas propellant at a concentration of about 3%
to about
25% by weight of the total composition, which upon release from an aerosol
container
provides an expanded foam suitable for topical administration.
[0040] According to one embodiment, the composition further comprises a foam
adjuvant at a concentration less than about 5%.
[0041] Water (to make an emulsion) and optional ingredients are added to
complete
the total mass to 100%. Upon release from an aerosol container, the foamable
composition forms an expanded foam suitable for topical administration.
[0042] In one or more embodiments, the foam composition is formulated as an
emulsion and can be an oil-in-water emulsion or a water-in-oil emulsion. The
choice of
the type of emulsion (oil-in-water or water-in-oil) is made in light of the
nature of the
active agent, so that it is suitable for inGusion of either or both water-
soluble and oii-
soluble active agents. The choice of the type of emulsion is also influenced
by the type
of interaction which is desirable between the composition, the active agent
and the target
tissue.
[0043] In one or more embodiments, the emulsion is a micro-emulsion.
Microemulsions are dispersions of either oil-in-water or water-in-oil, which
are typically
clear, as the droplet diameter is approximately 100 nanometers (nm) or less.
[0044] In one or more embodiments, the foam composition of the present
invention
comprises liposomes.
[0045] In one or more embodiments, the foam composition of the present
invention
comprises nanoparticles, and, for example, the diameter is about 200 nm to
about 400
nm. Nanoparticles are typically introduced as an active agent.
[0046] The foam composition may include a propellant substance in an amount of
about 3% to about 25% by weight, housed in an aerosol container.
[0047] When released, the c~nposition produces a foam, suitable for facile
administration into body orifices and mucosal cavities, including, but not
limited to the the
vagina, the rectum and penile cavities, the urinary tract, bladder, the cavity
between the
uterus and the fallopian tubes, the ova~es and other body areas, which may
accept
topically-applied products .
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~ [0048] It has been surprisingly discovered that the propellant helps provide
a stable
emulsion. The propellant makes up part of the "oil phase° component of
the emulsion,
providing a product with long shelf-life. Thus, admixing the liquid and solid
foam
components with a short chain hydrocarbon propellant, results in a stable
emulsion, that
does not undergo phase separation after stress test, including either exposure
to at least
two freeze and though cycles.
[0049] The terms "therapy" and "treatment' as used herein interchangeably,
cover
any treatment of a disease or disorder, and includes, for example, curing the
disease or
disorder, preventing the disease or disorder from occurring in a subject which
may be
predisposed to the disease but has not yet been diagnosed with the disease or
disorder,
inhibiting the disease or disorder, relieving the disease or disorder,
providing a
prophylactic effect, evolving a beneficial immunological effect; and improving
the quality
of life of a subject afflicted by a disease or disorder.
j0050] In one or more embodiments of the present invention, a therapeutic
product is
provided that includes an active agent in a therapeutically effective
concentration. Active
agents are included in each of the compositions described herein; however, in
some
instances the solvent, which is part of the composition, provides therapeutic
benefit and
thus, can be defined as the at least one active agent. Therapeutic products
are intended
for topical treatment of human and animal disorders of body cavities, or any
other
disorder, that requires topical application of a drug into a body cavity.
[0051] The foamable composition of the present invention can be an emulsion,
or
microemuision, including an aqueous phase and an organic carrier phase. The
organic
carrier is selected from a hydrophobic organic carrier (also termed herein
"hydrophobic
solvent°), an emollient, a polar solvent, and a mixture thereof.
[0052] A "hydrophobic organic carrier» as used herein refers to a material
having
solubility in distilled water at ambient temperature of less than about 1 gm
per 100 m(_,
more preferable less than about 0.5 gm per 100 ml_, and most preferably less
than about
0.1 gm per 100 mL. It is liquid at ambient temperature. The identification of
a
hydrophobic organic carrier or "hydrophobic solvent", as used herein, is not
intended to
characterize the solubitization capabilities of the solvent for any specific
active agent or
any other component of the foamable composition. Rather, such information is
provided
to aid in the identification of materials suitable for use as a hydrophobic
carrier in the
foamable compositions described herein.
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1 [0053] In one or more embodiments, the hydrophobic organic carrier is an
oil, such
as mineral oil. Mineral oil (Chemical Abstracts Service Registry number 8012-
95-1 ) is a
mixture of aliphatic, naphthalenic, and aromatic liquid hydrocarbons that
derive from
petroleum. It is typically liquid; its viscosity is in the range of between
about 35 CST and
about 100 CST (at 40°C), and its pour point (the lowest temperature at
which an oil can
be handled without excessive amounts of wax crystals forming so preventing
flow) is
below 0°C. Term hydrophobic organic carrier does not include thick or
semi-solid
materials, such as white petrolatum, also termed "Vaseline°, which, in
certain
compositions is disadvantageous due to its waxy nature and semi-solid texture.
[0054] According to one or more embodiments, hydrophobic solvents are liquid
oils
originating from vegetable, marine or animal sources. Suitable liquid oil
includes
saturated, unsaturated or polyunsaturated oils. By way of example, the
unsaturated oil
may be olive oil, com oil, soybean oil, canola oil, cottonseed oil, coconut
oil, sesame oil,
sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil, herring
oil, cod-
liver oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose oils or
mixtures
thereof, in any proportion.
(OOSS] Suitable hydrophobic solvents also include polyunsaturated oils
containing
poly-unsaturated fatty acids. In one or more embodiments, the unsaturated
fatty acids
are selected from the group of omega-3 and omega-6 fatty acids. Examples of
such
polyunsaturated fatty acids are linoleic and linolenic acid, gamma-linoleic
acid (Gt~4),
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DNA). Such unsaturated
fatty
acids are known for their skin-conditioning effect, which contribute to the
therapeutic
benefit of the present foamable composition. Thus, the hydrophobic solvent can
include
at least 6% of an oil selected from omega-3 oil, omega-6 oil, and mixtures
thereof. In the
context of the present invention, oils that possess therapeutically-beneficial
properties
are termed 'therapeutically active oil'.
[0056] Another class of hydrophobic solvents is the essential oils, which are
also
considered therapeutically active oi(, which contain active biologically
occurring
molecules and, upon topical application, exert a therapeutic effect, which is
conceivably
synergistic to the beneficial effect of the steroid in the composition.
[0057] Another class of therapeutically active oils includes liquid
hydrophobic plant-
derived oils, which are known to possess therapeutic benefits when applied
topically.
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~ [0058] Silicone oils also may be used and are desirable due to their known
skin
protective and occlusive properties. Suitable silicone oils include non-
volatile silicones,
such as polyalkyl siloxanes, polyaryl siloxanes, polyalkylaryl siloxanes and
polyether
siloxane copolymers, polydimethylsiloxanes (dimethicones) and
poly(dimethylsiloxane)-
(diphenyl-siloxane) copolymers. These are chosen from cyclic or linear
polydimethylsiloxanes containing from about 3 to about 9, preferably from
about 4 to
about 5, silicon atoms. Volatile silicones such as cyclomethicones can also be
used.
Silicone oils are also considered therapeutically active oil, due to their
barrier retaining
and protective properties.
[0059] In one or more embodiments, the hydrophobic carrier includes at least
2% by
weight silicone oil or at least 5% by weight.
[0060] The solvent may be a mixture of two or more of the above hydrophobic
solvents in any proportion.
[0061] A further class of solvents includes "emollients" that have a softening
or
soothing effect, especially when applied to body areas, such as the skin and
mucosal
surfaces. Emollients are not necessarily hydrophobic. Examples of suitable
emollients
include hexyleneglycol, propylene glycol, isostearic acid derivatives,
isopropyl palmitate,
isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, maleated
soybean oil,
octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate,
acetylated lanolin
alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl
linoleate, wheat
germ glycerides, arachidyl propionate, myristyl lactate, decyt oleate,
propylene glycol
ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,
neopentylglycol
dicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate,
myristyl
myristate, triisocetyl citrate, octyl dodecanol, sucrose esters of fatty
acids, octyl
hydroxystearate and mixtures thereof_
[0062] According to one or more embodiments of the present invention, the
hydrophobic organic carrier includes a mixture of a hydrophobic solvent and an
emollient. According to one or more embodiments, the foamabte composition is a
mixture of mineral oil and an emollient in a ratio between 2:8 and 8:2 on a
weight basis.
[0063] A "polar solvent' is an organic solvent, typically soluble in both
water and oil.
Examples of polar solvents include polyols, such as glycerol (glycerin),
propylene glycol,
hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-
terpenes, tri-
terpenes, terpen-ols, limonene, terpene-ol, i-menthol, dioxolane, ethylene
glycol, other
12
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Agent Ref. No.: 113873.127W0
31i
glycots, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide,
methyl
dodecyl sulfoxide, dimethytacetamide, monooieate of ethoxylated glycerides
(with 8 to 10
ethylene oxide units), azone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-
dioxolane, esters, such as isopropyl myristate/palmitate, ethyl acetate, butyl
acetate,
methyl proprionate, capridcaprylic triglycerides, octylmyristate, dodecyl-
myristate;
myristyl alcohol, tauryt alcohol, lauric acid, lauryi lactate ketones; amides,
such as
acetamide oleates such as triolein; various alkanoic acids such as caprylic
acid; lactam
compounds, such as azone; alkanois, such as dialkylamino acetates, and
admixtures
thereof.
[0064] According to one or more embodiments, the polar solvent is a
polyethylene
glycol (PEG) or PEG derivative that is liquid at ambient temperature,
including PEG200
(MW (molecular weight) about 190-210 kD), PEG300 (MW about 285-315 kD), PEG400
(MW about 380-420 kD), PEG600 (MW about 570-630 kD) and higher MW PEGs such
as PEG 4000, PEG 6000 and PEG 10000 and mixtures thereof.
(0065] In one or more embodiments, the solvent is a mixture (emulsion) of a
hydrophobic organic carrier and glycerin, as described, for example, in US
Pat.
No.6,544,530. The ratio of hydrophobic organic carrier to glycerin can range
from about
1:4 to about 4:1, and more preferably from about 1:2 to about 2:1.
[0066] In certain cases, a given solvent can be defined as both emollient and
polar
solvent.
[0067] Certain hydrophobic organic carriers, emollients and polar solvents
possess
high solubitization capacity for pharmaceutical active agents, and are
identified herein as
"'potent solvents". A potent solvent as that term is used herein, is one that
solubilizes a
specific active agent substantially better than mineral oil or petrolatum,
preferably 5 fold
better than mineral oil or petrolatum, and even 10-fold better than mineral
oil or
petrolatum, and even 100-fold better than mineral oil or petrolatum.
[iD068] Thus, in one or more embodiments, a foam composition includes at least
one
active agent in a therapeutically effective concentration and a potent
solvent. In one or
more embodiments, the composition includes at least one active agent in a
therapeutically effective concentration and at least one potent solvent in a
sufficient
amount to substantially solubilize the active agent in the composition. In the
context of
the present invention the term "substantially soluble" means that at least
95°J° of the
active agent has been solubilized, i.e., less than about 5% is present in the
composition
13
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Agent Ref. No.: 113873.127W0
~ in a solid state. In one or more embodiments, the potent solvent is more
than about 40%
or more than about 60% by weight of the total solvent of the composition.
[0069] Examples of active agent/potent solvent combinations include, in a non-
limiting manner:
Betamethasone valerate: Practically insoluble in mineral oil (<0.01 %);
soluble
more than 1 % (wJwj in Glycofurol.
Hydrocortisone butyrate: Practically insoluble in mineral oil (<0.01
°!°); soluble
more than 1 % in Glycofurol.
Metronidazole: Practically insoluble in mineral oil (<0.01 %); soluble more
than 1
in dimethyl isosorbide.
Ketoconazole: Practically insoluble in mineral oil (<0.01 %); soluble more
than 1
in glycofurol, propylene glycol and dimethyl isosorbide.
Mupirocin: Practically insoluble in mineral oil (<0.01%); soluble more than
1°I° in
glycofurol, hexylene glycol, dimethyl isosorbide, propylene glycol and
polyethylene glycol 400 (PEG 400).
Meloxicam, a nonsteroidal anti-inflammatory agent: Practically insoluble in
mineral oil (<0.001%); soluble in propylene glycol: 0.3 mg/mL and in PEG 400:
3.7 mglmL.
Progesterone: Practically insoluble in mineral oil (<0.001°I°);
soluble in PEG 400:
15.3 mg/mL.
[tf070] A non-limiting exemplary list of solvents that can be considered as
potent
sr~lvents includes polyethylene glycol, propylene glycol, hexylene glycol,
butanediols and
isomers thereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, ethyl
caprylate,
dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,
polyvinylpyrrolidone, isosorbide derivatives, such as dimethyl isosorbide,
glycofurol and
ethoxydiglycol (transcutol).
[0071 ] The present invention also provides a method of designing a foamable
composition by selecting at least one active agent, selecting a solvent that
solubilizes the
active agent substantially better than mineral oil or petrolatum, and
adjusting the type
and concentration of surfactant and gelling agent to provide a foamable
composition.
This is particularly useful in fomulating foams incorporating poorly soluble
active agents.
[0072] The use of a potent solvent in a foam composition provides an improved
way
to deliver poorly soluble active agents to a target area. It is known that low
drug
14
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Agent Ref. No.: 113873.127W0
t solubility results in poor bioavailability, leading to decreased
effectiveness of treatment.
Foam compositions according to one or more embodiments of the present
invention for
which the solvent is a potent solvent are unique because the majority of the
active agent
is in solution, rather than in particulate form, resulting in high delivery
and improved
therapy.
[0073] Potent solvents are typically in liquid form. Liquid drug formulations
are
generally disadvantageous, since their usage causes unwanted dripping,
resulting in
inconvenience and inadequate dosing. Unexpectedly, the foams of the present
invention
are drip-free and thereby provide a superior vehicle for such drugs and enable
convenient usage and accurate effective dosing.
[0074] Surface-active agents (surfactants) include any agent linking oil and
water in
the composition in the form of emulsion. A surfactant's hydrophilicllipophilic
balance
(HLB) describes the emulsifier's affinity toward water or oil. The HLB scale
ranges from
i (totally lipophilic) to 20 (totally hydrophilic), with 10 representing an
equal balance of
both characteristics. Lipophilic emulsifiers form water-in-oil (w/o)
emulsions, whereas
hydrophilic surfactants form oil-in-water (o/w) emulsions. The HLB of a blend
of two
emulsifiers equals the weight fraction of emulsifier A times its HLB value
plus the weight
fraction of emulsifier B times its HLB value (weighted average).
[0075] Any surface-active agent or combinations thereof may be used as surface-
active agent. According to one or more embodiments of the present invention,
the
surface-active agent has a hydrophilic lipophilic balance (HLB) between about
9 and
about 14, which is the required HLB (the HLB required to stabilize an O/W
emulsion of a
given oil) of most oils and hydrophobic organic carriers. Thus, in one or more
embodiments, the composition is a single surface active agent having an HLB
value
between about 9 and i 4, and in one or more embodiments, the composition is
more than
one surface active agent and the weighted average of their HLB values is
between about
0 and about 14.
[0076] According to one or more embodiments, the surface-active agent in an
oleaginous composition (hydrophobic organic carriers of 70% or greater) has a
surface-
active agent with an HLB in the range of about 3 to about 9.
[0077] The surface-active agent is selected from anionic, cationic, nonionic,
zwitterionic, amphoteric and ampholytic surfactants, as well as mixtures of
these
surfactants. Such surfactants ace well known to those skilled in the
therapeutic and
cosmetic formulation art. Nonlimiting examples of possible surfactants include
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i polysorbates, such as polyoxyethylene (20) sorbitan monostearate (Tween 60)
and
poly(oxyethylene) (20) sorbitan monooleate (Tween 80); poly(oxyethylene) (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, poly(oxyethylene) palmityl
ether,
polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, brij 38,
brij 52, brij 56
and brij W 1; sucrose esters, partial esters of sorbitol and its anhydrides,
such as sorbitan
monolaurate and sorbitan monolaurate; mono or diglycerides, isoceteth-20,
sodium
methyl cocoyl taurate, sodium methyl oleoyl taurate, sodium lauryl sulfate,
triethanolamine tauryl sulfate and betaines.
[0078] In one or more embodiments of the present invention, the surface-active
agent includes at least a non-ionic surfactant. Ionic surfactants are known to
be
irritants. Therefore, non-ionic surfactants are preferred in applications
including sensitive
tissue such as found in most mucosal tissues, especially when they are
infected or
inflamed. We have surprisingly found that non-ionic surfactants alone provide
foams of
excellent quality, i.e. a score of "E" according to the grading scale
discussed herein
below.
[0079] In one or more embodiments, the surface active agent includes a mixture
of
at least one non-ionic surfactant and at least one ionic surfactant in a ratio
in the range of
about 100:1 to 6:i. In one or more embodiments, the non-ionic to ionic
surfactant ratio is
greater than about 6:1, or greater than about 8:1; or greater than about 14:1,
or greater
than about 16:1, or greater than about 20:1.
[0080] In one or more embodiments of the present invention, a combination of a
non-
ionic surfactant and an ionic surfactant (such as sodium lauryl sulphate and
cocamidopropylbetaiine) is employed, at a ratio of between 1:1 and 20:1, or at
a ratio of
4:1 to 10:1. The resultant foam has a low specific gravity, e.g., less than
0.1 g/ml.
[(1081] In one or more embodiments of the present invention, the surface-
active
agent includes mono-, di- and tri-esters of sucrose with food fatty acids
(sucrose esters),
prepared from sucrose and esters of fatty acids or by extraction from sucro-
glycerides.
Suitable sucrose esters include those having high monoester content, which
have higher
HI_B values.
[0082] Unlike prior art foamable compositions, the total surface active agent
required
to obtain a foam that is stable, of low specific gravity and has a fine bubble
structure is
low. This is desirable because lower surface active agent levels, particularly
of ionic
surfactants, reduce skin irritations. Total surface active agent is in the
range of about 0.1
16
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Agent Ref. No.: 113873.127W0
r
to about 5% of the foamable composition, and is typically less than about 2%,
preferably
less than about 1 %.
(0083] It has been unexpectedly found that it is possible to prepare stable
foams with
stabilizing surfactants even in very low concentration of less than about 1 %
which enable
low irritating and low itching vaginal foams. "Stable foam° denotes
shelf life stability of
the emulsion and also a sustainable foam that does not break upon extrusion of
the
package to enable delivery, spreading and expansion of the foam throughout the
entire
vaginal cavity before collapse.
[0084] The foamabfe composition includes a polymeric agent to increase the
durationlresidence time of the composition in the body cavity. The polymeric
agent
serves to stabilize the foam composition and to control drug duration in the
target organ.
[0085] Exemplary polymeric agents, which provide means of controlling duration
are
classified below in a non-limiting manner. In certain cases, a given polymer
can belong
to more than one of the classes provided below.
[0086] Bioadhesion has been defined as the attachment of synthetic or
biological
macromolecules to a biological tissue. The term mucoadhesion refers to the
special
case of bioadhesion where the biological tissue is an epithelium covered by
mucous, for
example such as found in the vagina, gastrointestinal tract and the nasal
cavity.
Mucoadhesive agents are a class of polymeric biomaterials that exhibit the
basic
characteristic of a hydrogel, i.e. swell by absorbing water and interacting by
means of
adhesion with the mucous that covers epithelia.
X0087] Compositions of the present invention may contain a mucoadhesive
macromolecule or polymer in an amount sufficient to confer bioadhesive
properties. The
bioadhesive macromolecule enhances the delivery of biologically active agents
on or
through the target surface. The mucoadhesive macromolecule may be selected
from
acidic synthetic polymers, preferably having at least one acidic group per
four repeating
or monomeric subunit moieties, such as poly(acrylic)- and/or poly(methacrylic)
acid (e.g.,
Carbopo!~, Carbomer~), poly(methylvinyl etherlmaleic anhydride) copolymer, and
their
mixtures and copolymers; acidic synthetically modified natural polymers, such
as
carboxymethylcellulose (CMG); neutral synthetically modified natural polymers,
such as
(hydroxypropyl)methylcellulose; basic amine-bearing polymers such as chitosan;
acidic
polymers obtainable from natural sources, such as alginic acid, hyaluronic
acid, pectin,
gum tragacanth, and karaya gum; and neutral synthetic polymers, such as
polyvinyl
alcohol or their mixtures. An additional group of mucoadhesive polymers
includes
17
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Agent Ref. No.: 113t373.127W0
i
v natural and chemically modified cyclodextrin, especially hydroxypropyl-(3-
cyclodextrin
(HP(iCD). Such polymers may be present as free acids, bases, or salts, usually
in a final
concentration of about 0.01 % to about 0.5% by weight.
[0088] A suitable bioadhesive macromolecule is the family of acrylic acid
polymers
and copolymers, (e.g., CarbopolC~). These polymers contain the general
structure -[CH2-
CH(COOH)--]". Hyaluronic acid and other biologically-derived polymers may be
used.
[0089] Exemplary bioadhesive or mucoadhesive macromolecules have a molecular
weight of at least 50 kDa, or at least 300 kDa, or at least 1,000 kDa. Favored
polymeric
ionizable macromolecules have not less than 2 mole percent acidic groups
(e.g., COOH,
S03H) or basic groups (NH2, NRH, NR2), relative to the number of monomeric
units. The
acidic or basic groups can constitute at least 5 mole percent, or at least 10
mole percent,
or at least 25, at least 50 more percent, or even up to 100 mole percent
relative to the
number of monomeric units of the macromolecule.
[0090] Yet, another group of mucoadhesive agent includes inorganic gelling
agents
such as silicon dioxide (fumed silica), including but not limited to, AEROSIL
200
(DEGUSSA).
[0091] Many mucoadhesive agents are known in the art to also possess gelling
properties.
[0092] A gelling agent controls the residence of a therapeutic composition in
the
target site of treatment by increasing the viscosity of the composition,
thereby limiting the
rate of its clearance from the site. Many gelling agents are known in the art
to possess
mucoadhesive properties.
[Q093] The gelling agent can be a natural gelling agent, a synthetic gelling
agent and
an inorganic gelling agent. Exemplary gelling agents that can be used in
accordance
with one or more embodiments of the present invention include, for example,
naturally-
occurring polymeric materials, such as locust bean gum, sodium alginate,
sodium
caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate,
xanthan gum,
quince seed extract, tragacanth gum, guar gum, starch, chemically modified
starches
and the like, semi-synthetic polymeric materials such as cellulose ethers
(e.g.
hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxy
propylmethyl
cellulose), guar gum, hydroxypropyl guar gum, soluble starch, cationic
celluloses,
cationic guars, and the like, and synthetic polymeric materials, such as
carboxyvinyl
polymers, polyvinylpyrrolidone, polyvinyi alcohol, polyacrylic acid polymers,
polymethacrytic acid polymers, polyvinyl acetate polymers, polyvinyl chloride
polymers,
18
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Agent Ref. No.: 113873.127W0
~ polyvinytidene chloride polymers and the like. Mixtures of the above
compounds are
contemplated.
[0094] Further exemplary gelling agents include the acrylic acid/ethyl
acrylate
copolymers and the carboxyvinyl polymers sold, for example, by the B.F.
Goodrich
Company under the trademark of Carbopol4 resins. These resins consist
essentially of
a colloidal water-soluble polyalkenyl polyether crosslinked polymer of acrylic
acid
crosslinked with from 0.75% to 2% of a crosslinking agent such as polyallyl
sucrose or
polyallyl pentaerythritol. Examples include Carbopol~ 934, CarbopolC~ 940,
CarbopolC~
950, CarbopolC~ 980, CarbopolC~ 951 and Carbopol4 981. CarbopolC~ 934 is a
water-
soluble polymer of acrylic acid crossfinked with about 1 % of a polyallyl
ether of sucrose
having an average of about 5.8 allyl groups for each sucrose molecule.
[0095] Yet, another group of gelling agents includes inorganic gelling agents,
such
as silicone dioxide (fumed silica).
[0096] According to one or more embodiments, the foam composition contains at
least one film forming component. The film forming component may include at
least one
water-insoluble alkyl cellulose or hydroxyatkyl cellulose_ Exemplary alkyl
cellulose or
hydroxyalkyl cellulose polymers include ethyl cellulose, propyl cellulose,
butyl cellulose,
cellulose acetate, hydroxypropyl cellulose, hydroxybutyl cellulose, and
ethylhydroxyethyl
cellulose, alone or in combination. fn addition, a plasticizes or a cross
linking agent may
be used to modify the polymer's characteristics. For example, esters such as
dibutyl or
diethyl phthalate, amides such as diethyldiphenyl urea, vegetable oils, fatty
acids and
alcohols such as oleic and myristyl acid may be used in combination with the
cellulose
derivative.
[0097] In one or more embodiments, the composition of the present invention
includes a phase change polymer, which alters the composition behavior from
fluid-like
prior to administration to solid-like upon contact with the target mucosal
surface. Such
phase change results from external stimuli, such as changes in temperature or
pH and
exposure to specific ions (e.g., Ca++).
[0098] Non-limiting examples of phase change polymers include poly(N-
isopropylamide), Poloxamer 407~ and Smart-GeK~ (Poloxamer + PAA).
[0099] The polymeric agent is present in an amount in the range of about 0.01
% to
about 5.0% by weight of the foam composition. In one or more embodiments, it
is
typically less than about 1 wt% of the foamable composition.
19
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Agent Ref. No.: 113873.127W0
t (0100] A foam adjuvant is optionally included in the foamab(e compositions
of the
present invention to increase the foaming capacity of surfactants and/or to
stabilize the
foam. In one or more embodiments of the present invention, the foam adjuvant
agent
includes fatty alcohols having 15 or more carbons in their carbon chain, such
as cetyl
alcohol and stearyl alcohol (or mixtures thereof). Other examples of fatty
alcohols are
arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), as welt
as alcohvls
with longer carbon chains (up to C50). Fatty alcohols, derived from beeswax
and
including a mixture of alcohols, a majority of which has at least 20 carbon
atoms in their
carbon chain, are especially well suited as foam adjuvant agents. The amount
of the
fatty alcohol required to support the foam system is inversely related to the
length of its
carbon chains.
[0101 ] In one or more embodiments of the present invention, the foam adjuvant
agent includes fatty acids having 16 or more carbons in their carbon chain,
such as
hexadecanoic add (C16) stearic acid (C18), arach(dic acid (C20), behenic acid
(C22),
octacosanoic acid (C28), as wet! as fatty acids with longer carbon chains (up
to C50), or
mixtures thereof. As for fatty alcohols, the amount of fatty acids required to
support the
foam system is inversely related to the length of its carbon chain.
[0102] Optionally, the carbon atom chain of the fatty alcohol or the tatty
acid may
have at least one double bond. A further class of foam adjuvant agent includes
a
branched fatty alcohol or fatty acid. The carbon chain of the fatty acid or
fatty alcohol
also can be substituted with a hydroxyl group, such as 12-hydroxy stearic
acid.
[0103] The foam adjuvant according to one or more embodiments of the present
invention includes a mixture of fatty alcohols, fatty acids and hydroxy fatty
acids and
derivatives thereof in any proportion, providing that the total amount is 0.1
% to 5% (w/w)
of the carrier mass. More preferably, the total amount is 0.4% - 2.5% (w/w) of
the carrier
mass.
[0104] While fatty alcohols and fatty acids serve to stabilize the resultant
foam
composition, they often provide additional therapeutic properties. Long chain
saturated
and mono unsaturated fatty a(cohols, e.g., stearyl alcohol, erycyl alcohol,
arachidyl
alcohol and docosanol have been reported to possess antiviral, anti infective,
anti-
proliferative and anti-inflammatory properties (US Patent No. 4,874,794).
Longer chain
fatty alcohols, e.g., tetraoosanol, hexacosanol, heptacosanol, octacosanol,
triacontanol,
etc. are also known for their metabolism modifying properties and tissue
energizing
properties. Long chain fatty acids have also been reported to possess anti-
infective
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characteristics. Thus, the therapeutic or cosmetic carrier, containing the
foam adjuvant
agent of the present invention provides an extra therapeutic benefit in
comparison with
currently used vehicles, which are inert and non-active.
[0105] Lower alcohols having up to 5 carbon atoms in their carbon chain
skeleton,
such as ethanol, propanof, isopropanol, butanol, iso-butanol, t-butanol and
pentanol, are
considered less desirable solvents or polar solvents due to their skin-
irritating effect.
Thus, the composition is substantially alcohol-free and should comprise less
than about
5% final concentration of Power alcohols, preferably less than about 2%, more
preferably
less than about 1 %.
[0106] The therapeutic foam of the present invention may further optionally
include a
variety of formulation excipients, which are added in order to fine-tune the
consistency of
the formulation, protect the formulation components from degradation and
oxidation and
modify their consistency. Such excipients may be selected, for example, from
stabilizing
agents, antioxidants, humectants, preservatives, colorant and odorant agents
and other
formulation components, used in the art of formulation.
[0107] Aerosol propellants are used to generate and administer the foamable
composition as a foam. The total composition including propellant, foamable
compositions and optional ingredients is referred to as the foamable carrier.
The
propellant makes up about 3% to about 25 wt% of the foamable carrier. Examples
of
suitable propellants inGude volatile hydrocarbons such as butane, propane,
isobutane or
mixtures thereof, and fluorocarbon gases.
Composition and Foam Physical Characteristics
[0108] The compositions described herein, including water, additional
solvents,
formulation excipients, active agents and propellant creates a stable emulsion
that does
not exhibit full phase separation at ambient temperature for at least a year.
[0109] Yet, another property of a composition is its level of flow, since a
composition
that is not free flowing cannot flow through the dip-tube of the aerosol
container and
create acceptable foam. It has been noted that in the context of the
composition of the
present invention, compositions including semi-solid hydrophobic organic
carriers, e.g.,
white petrolatum, are excessively viscous and demonstrate poor flowability.
[0110] The combination of at feast one surface active agent, at least one
polymeric
agent and optionally at least one foaming adjuvant, according to one or more
embodiments of the invention provides a low specific gravity foam having
superior
expandability, flow properties and sheer breakability (among other
attributes). According
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Agent Ref. No.: 113873.i27W0
to one or more embodiments of the present invention, the total amount of at
least one
surface active agent, at least one polymeric agent and optionally at least one
foaming
adjuvant, in combination does not exceed 8 % (wlw) of foamable composition. In
one or
more embodiments, the combined amounts of at feast one surface active agent,
at least
one polymeric agent and optionally at least one foaming adjuvant is less than
5 % (wlw)
of foam composition. The low solid content improves the flow properties of the
foam,
reduces unpleasant skin residue and reduces the cost of manufacture. As is
demonstrated herein, the foam stability and expandability ace excellent,
despite the low
levels of these components in the foam.
[0111] Expandability is an important feature of a product that is intended to
treat
internal cavities of the body. Thus, in one or more embodiments of the present
invention,
the spedfic gravity of the foam, upon discharge from the foam dispenser is
between
about 0.02 gr/mL and 0.4 gr/mL, or between about 0.04 grlmL and about 0.14
grlmL.
[0112] The following scale for foam quality is used to evaluate foams.
E (excellent): very rich and creamy in appearance, does not show any bubble
structure or shows a very fine (smatf) bubble structure.
G (good): rich and creamy in appearance, very small bubble size, "dulls" more
rapidly than an excellent foam.
FG (fairly good): a moderate amount of creaminess noticeable, bubble structure
is noticeable.
F (fair): very little creaminess noticeable, larger bubble structure than a
"fairly
good" foam.
P (poor): no creaminess noticeable, large bubble structure.
VP (very poor): dry foam, large very dull bubbles, difficult to spread on the
skin.
[U113] Foams that are adequate for topical administration according to the
present
invention have to be of quality grade E or G, upon release from the foam
dispenser.
Smaller bubbles mean more stable foam, which does not collapse spontaneously
immediately upon discharge from the container. The finer foam structure looks
and feels
smoother, thus increasing its usability and appeal.
[U114] In one or more embodiments, the foam compositions are stable for a
prolonged period of time. Thus, the foam composition does not undergo phase
separation following at least two freeze and thaw cycles.
22
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Agent Ref. No.: 113873.127W0
i [0115] Upon discharge from a foam dispenser, e.g., an aerosol can, onto a
mucosal
membrane at about 37°C, the foam expands to reach its designated volume
and stays
stable as a foam for at least 60 seconds, or 2 minutes, or even 3 minutes,
following
application.
Metered dosing
[0116] tn order to provide proper therapy, precise dosing is desired.
According to
one or more embodiments, the foam therapeutic product is adapted for storage
in a foam
dispenser having a metered dose valve for dispensing an accurate dose of drug
in the
form of a foam. The metered dose valve is selected to release a foam in a
volume that is
in the size of the target body cavity to allow effective spreading of the
active agent
throughout the body cavity with substantially minimal overflow.
[0117] In one or more embodiments, the meter dose valve provides a unit dose
of
between about 10 p.L and about 1000 p.L. Assuming a representative foam
density
(specific gravity) of 0.06 glmL, a 10 ~L valve provides a volume of about 0.17
mL of
foam, and a 1000 wL metered dose valve provides about 17 mL of foam. Thus, by
selecting a specific metered dosing valve and adjusting the foam density by
fine tuning
formulation parameters and adjusting the ration between the liquid components
of the
composition and the propellant, one can design an adequate dosage fom~
according to
the speafic target organ cavity
Administration
[0118] One limitation of existing vaginal and rectal dosage form relates to
the
dimensions of the product applicator. In order to administer 5 mL of gel
(which is
required to attain effective coverage of the vaginal surface), an insert
applicator, 10 cm
long and about 1.5 cm thick is employed. It is to be understood that such a
thick
applicator is found repulsive by patients, which leads to poor patient
compliance.
Furthermore, the length of the applicator, which is beyond the natural depth
of a relaxed
'vagina! cavity, makes it difficult for the patient to accurately administer
the composition
into the target organ.
[0119] By contrast, application of a foam composition according to the present
invention is not limited by applicator dimensions. The insert is thin and
thus, it is
acceptable to the patient. The thickness of the aerosol insert can range
between about
0.2 cm and about 1 cm. Likewise, the aerosol insert can be designed in any
length, to fit
the dimensions of the target organ. Thus, the length of a vaginal insert can
range
between about 2 cm and about 10 cm; the length of an insert for the nasal
system or ear
23
CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
canal can be shorter and the insert for rectal administration can be adjusted
according to
the location of the disorder, between about 1 cm and about 20 cm. In one or
more
embodiments, the insert is designed to be flexible, to allow insertion into a
body cavity
that is difficult to access using a non-flexible insert.
Fields of application
[0120] By including an appropriate active agent in the foamable composition,
it is
useful in the therapy and prevention of a variety of disorders of a body
cavity or mucosal
surfaces, including, but not limited to the cranial cavity, the thoracic
cavity, the abdominal
cavity, the ventral cavity, the vagina, the rectum and penile cavities, the
urinary tract,
bladder, the cavity between the uterus and the fallopian tubes, the ovaries,
the nasal
cavity, the mouth, the eye, the ear the peritoneum, the large and small bowel,
the
caecum, bladder, and stomach, and other body cavities or spaces, which may
accept
topically-applied products.
[0121] Exemplary treatable disorders are listed below.
Bacterial, fungal and viral infections
[0122] Bacterial, fungal and viral infections: a variety of anti-infective,
anti-bacterial,
anti-fungal and anti-viral agents can be included in the foam of the present
invention, to
be used for the treatment and / or prevention of diseases, such as chlamydia,
gonorfiea,
hepatitis B, herpes, HIV/AIDS, human papallomavirus (HPV) 8~ genital warts;
syphilis;
bacterial vaginosis, candidiasis, chancroid, granuloma inguinale,
lymphogranloma
venereum, mucopurulent cervicitis (MPG), molluscum contagiosum, nongonococcal
urethritis (NGU), trichomoniasis, and vulvar disorders.
[0123] A variety of active agents, known in the art, can be included in the
foam to be
used for the treatment and / or prevention of diseases such as vulvodynia
(vulvar pain),
yeast infections, genital warts (condyloma) vulvar dystrophy, vulvar
intraepithelial
neoplasia (VIN), invasive cancer of the vulva, contact dermatitis, pelvic
inflammation,
pelvic inflammatory disease (PID), genital cancer and cancer of the cervix,
vulva or
vagina.
Vagina! dryness
(0124] Vaginal dryness is caused by a number of conditions and can be either
an
occasional hassle or a chronic problem. A variety of anti-inflammatory active
agents,
hormones, moisturizing, refatting and lubricating agents and local anesthetic
agents can
be included in the foam of the present invention, to be used for the treatment
and / or
prevention of vaginal dryness.
24
CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
,;A
Dyspareunia
[0125] Dysareunia is pain in the vagina or pelvis experienced during sexual
intercourse. A variety of anti-inflammatory active agents, hormones,
moisturizing,
refatting and lubricating agents and local anesthetic agents can be included
in the foam
of the present invention, to be used for the treatment and / or prevention of
vaginal pain.
Anal and rectal disease, such as anal abscess/fistula, anal cancer, anal
fissure, anal
warts, Crohn's disease , hemorfioids, anal itch, also called pruritus ani,
fecal
incontinence, and polyps of the colon and rectum all may be treated using the
foamable
composition according to one or more embodiments of the invention.
[0126] The foam composition of the present invention, comprising an active
agent
that is known to treat one of said anorectal disorders and administered
rectally, expands
effectively in the rectal cavity and provides optimal coverage of the cavity
surface, for
improved therapeutic results.
HIV and STD treatment and prevention
[0127] When comprising appropriate protective agents, the foam is active
against
HIV infection and other infections {bacterial and fungal), including sexually
transmitted
disease (STD) by creating a protective layer and/or decreasing the frequency
of
transmission. Non-binding examples of protective agents include:
[0128] Negatively charged sulfated polymers, which have been reported to have
anti-HIV-1 activity and are being considered for development as topical
microbicides.
[0129] Dextrin sulphate, a microbicide, which in various laboratory and pre-
clinical
studies, has been shown to block the transfer of HIV virus into mammalian
cells while at
the same time not causing injury to normal cell tissue.
[0130] Cellulose acetate phthalate, which inactivates HIV-1, herpesvirus types
1
{HSV-1 ) and 2 (HSV-2) and the major nonviral STD pathogens; and found
effective in
animal models for vaginal infection by HSV-2 and simian immunodeficiency
virus.
[0131] Several polymers, such as hydroxypropyl methylcellulose phthalate,
carrageenans, naphthalene sulfonate polymer, sodium alginate, and cationic
polymer,
such as chitosan, are insoluble in water and can be solubilized in water by
adjusting the
pH of the environment to about 6 or above, or by the use of appropriate
organic solvents.
Vaginal secretions from healthy, reproductive-age women are characteristically
acidic
(pH values of 3.4 to 6.0). Consequently, the topical application of a
formulation in which
such polymers would be soluble (i.e., pH>_6) would be expected to contribute
to a vaginal
environment which is physiologically undesirable.
CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
[0132] Thus, in one embodiment of present invention, there is an advantage to
an
oily foamable carrier, comprising solvents that solubilize water-insoluble
polymenrs such
as mentioned above. By way of non-limiting example, such solvents include
polyethylene glycol, propylene glycol, hexylene glycol, benzyl alcohol, DMSO,
isosorbide
derivatives, such as dimethyl isosorbide, glycofurol and ethoxydiglycol
(transcutol).
[0133] In one or more embodiments of the present invention, the foam
composition
is useful in the therapy of disorders that respond to transmucosal delivery of
an active
agent. By way of example, such disorders include, which respond to hormone
therapy,
such as hormone replacement therapy, and other systemic disorders, known to be
affected by drugs that are delivered transmucosally.
[0134] The goal of a mucosal vaccine is to induce antigen-specific immune
responses (cellular and humoral) that are detectable at the mucosal surfaces
of the host.
Because many pathogens initiate infection at the mucosal surfaces, pathogen-
specific
mucosal immune responses may provide superior protection against infectious
diseases
than immune responses induced by parenteral vaccines because parenteral
vaccines do
not induce mucosal immunity.
[0135] In the context of the present invention, the term immunization or
vaccination
refers to administering a preparation that contains an infectious agent or its
components,
which is able to stimulate an immune response that will protect a person from
illness due
to that agent. Such vaccines are expected be capable of preventing the
transmission or
limiting the severity of sexually-transmitted infections, such as HIV and
other infectious
disease. Vaccines are usually administered in conjunction with an adjuvant- a
substznce
that is used in a vaccine to improve the immune response so that less vaccine
is needed
to produce a non-specific stimulator of the immune response. There are several
types of
adjuvants, including, for example, minerals such as aluminum hydroxide,
aluminum
phosphate and calcium phosphate, oil emulsions, products from bacteria (their
synthetic
derivatives as well as liposomes) or gram-negative bacteria, endotoxins,
cholesterol,
fatty acids, aliphatic amines, paraffinic and vegetable oils.
[0136] The foam composition of the present invention, comprising an immunizing
agent, and optionally an adjuvant and administered onto the mucosal tissue of
a body
cavity, expands effectively in said cavity and provides optimal coverage of
the cavity
surface, for improved therapeutic results.
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Agent Ref. No.: 113873.127W0
r
Post-surgical adhesions treatment and prevention
[0137] Adhesions are scars that form abnormal connections between tissue
surfaces. Post-surgical adhesion formation is a natural consequence of
surgery, resulting
when tissue repairs itself following incision, cauterization, suturing, or
other means of
trauma. When comprising appropriate protective agents, the foam is suitable
for the
treatment or prevention of post surgical adhesions. The use of foam is
particularly
advantageous because foam can expand in the body cavity and penetrate into
hidden
areas that cannot be reached by any other alternative means of administration.
Hormonal therapy
[0138] The foamable composition of the present invention is suitable for
administering a hormone to a mucosal membrane or a body cavity, in order to
deliver the
hormone into the tissue of the target organ, in any disorder that responds to
treatment
with a hormone. Topically applied hormones can also be useful in
contraception, when
administered in foam, using a metered dose unit.
Active Agents
[0139] The composition of the present invention comprises at least one active
agent,
also referred to as "drug(s)"_ The at least one active agent may consist of a
single drug
or a combination of drugs that can be dissolved in the water phase or the
hydrophobic
phase of the carrier composition. Examples of such drugs are antibiotic,
antibacterial,
antifungal, antiviral, antiinflammatory, anesthetic, analgesic, antiallergic,
corticosteroid
and antiproliferative medications and mixtures thereof at any proportion. The
concentration of drugs may be adopted to exert a therapeutic effect on a
disease when
applied to an afflicted area.
[0140] One important class of drugs comprises antibacterial agents. It is well
known
that bacterial infections are involved in a variety of superficial disorders
of mucosal
membranes and body cavities.
(0141] In one or more embodiments, the antibiotic agent is selected from the
classes
consisting of beta-lactam antibiotics, aminoglycosides, ansa-type antibiotics,
anthraquinones, azoles, glycopeptides, macrolides, nucleosides, antibiotic
peptides,
antibiotic polyenes, antibiotic poiyethers, quinolones, antibiotic steroids,
sulfonamides,
tetracycline, antibiotic metals, including silver, copper, zinc, mercury, tin,
lead, bismuth,
cadmium, chromium and ions and complexes thereof, oxidizing agents and
substances
that release free radicals and/or active oxygen, cationic antimicrobial
agents,quaternary
27
CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
X
ammonium compounds, biguanides, triguanides, bisbiguanides and analogs and
polymers thereof and naturally occurring antibiotic compounds.
[0142] An antibacterial drug can be active against gram positive and gram-
negative
bacteria, protozoa, aerobic bacteria and anaerobic bacteria.
[0143] By way of example, the antibacterial drugs are selected from
chloramphenicol, beta-lactam antibiotics, aminoglycosides, ansa-type
antibiotics,
anthraquinones, azoles, glycopeptides, macrolides, nucleosides, antibiotic
peptides,
antibiotic polyenes, antibiotic polyethers, quinolones, antibiotic steroids,
sulfonamides,
tetracycline, antibiotic metals, including silver, copper, zinc, mercury, tin,
lead, bismuth,
cadmium, chromium and ions and complexes thereof, oxidizing agents and
substances
that release free radicals and/or active oxygen, cationic antimicrobial
agents,quaternary
ammonium compounds, biguanides, triguanides, bisbiguanides and analogs and
polymers thereof and naturally occurring antibiotic compounds, metronidazlole
and its
derivatives and analogs, dicarboxylic acids, such as azelaic acid, slicylates,
cyclosporines and any combination thereof at a therapeutically effective
concentration.
(0144] Another group of antibacterial agents which have broad spectrum
activity
comprises strong oxidants and free radical liberating compounds, such as
oxygen,
hydrogen peroxide, benzoyl peroxide, elemental halogen species, as well as
oxygenated
halogen species, bleaching agents (e.g., sodium, calcium or magnesium
hypochloride
and the like), perchlorite species, iodine, iodate, and benzoyl peroxide.
Organic oxidizing
agents are also included in the definition of "oxidizing agent" according to
the present
invention, such as quinones. Such agents possess a potent broad spectrum
activity
[0145] Antibacterial compositions according to the present invention are
selected to
treat infections of an afflicted organ. The composition of the present
invention,
comprising a hydrophobic component, would facilitate an enhanced rate of
penetration.
Furthermore, the intrinsic antibacterial and antiinflammatory effects of the
foam adjuvant
agents, i.e., fatty alcohols and acids, provides a combined effect for better
therapeutic
response to treatment.
[0146] Fungal infections are another object of treatment using the composition
of the
present invention. Fungal infection of the vaginal cavity is one of the most
common
disorders seen in gynecological practice. Candidiasis is an infection caused
by the yeast
like fungus Candida albicans or occasionally other species of candida.
Clinical
syndromes of candidiasis include: (a) oral candidiasis (oral thrush); (b)
candidiasis of the
skin and genital mucous membrane; and (c) candida paronychia, which inflicts
the nail.
28
CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
~r
[0147] The therapeutic composition may comprise an antifungal drug, which is
active
against dermatophytes and candida, selected from the group of, but not limited
to azoles,
diazoles, triazoles, miconazole, fluconazole, ketoconazole, clotrimazole,
itraconazole
griseofulvin, ciclopirox, amorolfine, terbinafine, Amphotericin B, potassium
iodide,
flucytosine (5FC) and any combination thereof at a therapeutically effective
concentration. According to one preferred embodiment the active agent is
metronidazole.
[0148] The composition of the present invention is particularly beneficial in
the case
of viral infections including herpes simplex Type 1 virus. Molluscs are small
viral growths
that appear singly or in groups on the face, trunk, lower abdomen, pelvis,
inner thighs, or
penis_ Warts are a common, benign skin tumor caused by viral infection. HPV
(Human
Papillomavirus) is a common genital disease.
29
CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
[0149] Viral infections are currently treated with various antiviral agents,
as
summarized in the following table:
Drug Viruses Chemical
Type
Nucleoside
Vidarabine Herpesviruses
analogue
Nucleoside
cyclovir Herpes simplex
(HSV)
analogue
CytomegalovirusNucleoside
Gancyclovir
(CMV) analogue
Nucleoside-analog reverse transcriptase
inhibitors
Nucleoside
(NRTI): AZT (Zidovudine), ddl (Didanosine),Retroviruses
ddC (HIV)
analogue
(Zalcitabine), d4T (Stavudine),
3TC (Lamivudine)
Non-nucleoside reverse ~transcriptase Nucleoside
inhibitors
Retroviruses
(HIV)
(NNRTI): Nevirapine, Delavirdine analogue
Protease Inhibitors: Saquinavir, Peptide
Ritonavir, Indinavir,
HIV
Nelfinavir analogue
Broad spectrum:
HCV,
Triazole
Ribavirin HSV, measles,
carboxamide
mumps, Lassa
fever
mantadine / Rimantadine Influenza A Tricyclic
strains amine
Interferons Hepatitis B Protein
and C
[0150] Any of the above antiviral agents, in a therapeutically effective
concentration,
can be incorporated in the foam composition of the present invention. The
composition of
the present invention, which comprises a hydrophobic organic carrier, would
facilitate an
enhanced rate of penetration and better topical distribution of any of the
above listed
antiviral drugs. Furthermore, the intrinsic antiviral effects of the foam
adjuvant agents,
i.e., fatty alcohols and acids, provides a combined effect that should result
in a better
therapeutic response to treatment.
[0157] In one or more embodiments, the active agent is a steroid, selected
from the
following groups.
CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
i. a compound containing a cyclopenta[ajphenanthrene skeleton;
ii. a compound, containing a cyclopenta[a]phenanthrene skeleton carrying one
or
more functional groups selected from halogens, alkyl groups, aryl groups,
benzyl
groups, carboxy groups and alkoxy groups;
0
H
(57j
3a~7a~.12a-Ttiydmxy 5~-cMles~a 24-al
!i1. orctnlaldehyde(fromclabcacidj
iv. a steroid compound, selected from the families of (a) cardanolides, (b)
bufanolides, (c) spirostans, (d) furostans, (e) steroid alkaloids, (f) a
steroid
lactone, (g) an oxo-steroid, (h) a steroid-alcohol and (i) a steroid-amine;
v. a steroid compound, where one or more of the cyclopenta[a]phenanthrene
rings
is contracted by loss of an unsubstituted methylene group;
vi. a steroid compound, where one or more of the cyclopenta[a]phenanthrene
rings
is expandeded by indusion of a methylene group;
vii. a compound, containing a cyclopenta[a]phenanthrene skeleton and a
carbocyclic or heterocyctic ring component fused to it;
viii. an anti-inflammatory steroid;
ix. a steroid possessing immunomodulating and/or anti-inflammatory properties;
x. a steroid, selected from the group of low-potency anti-inflammatory
steroids,
medium potency anti-inflammatory steroids and high potency anti-inflammatory
steroids;
xi. an anti-inflammatory steroid, selected from the group consisting of
hydrocortisone, hydrocortisone acetate, desonide, betamethasone valerate,
clobetasone-17-butyrate, flucinonide, fluocinolone acetonide, alcometasone
dipropionate, mometasone furoate, prednicarbate, triamcinolone acetonide,
betamethasone-17-benzoate, methylprednisolone aceponate, betamethasone
dipropionate, haldnonide, triamcinolone acetonide, halobetasol, clobetasol-17-
propionate;
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Agent Ref. No.: 113873.127W0
xii. a steroid hormone;
xiii. a steroid hormone, selected from the group consisting of an androgen, an
estrogen and a progestogen
xiv. an androgen, selected from the group consisting of testosterone,
testosterone
cipionate, testosterone decanoate, testosterone enantate, testosterone
isocaproate, testosterone phenylpropionate, testosterone propionate,
testosterone undecylate, 5a-dihydrotestosterone, dehydroepiandrosterone (also
termed prasterone and DHEA), androstenedione, androstanediol, androsterone,
androstenolone, prasterone enantate, prasterone sodium sulfate, ormeloxifene,
mesterolone, fluoxymesterone, methyltestosterone, gestrinone, delmadinone,
delmadinone acetate, chlormadinone, chlormadinone acetate, danazol and
testolactone;
xv. an estrogen selected from the group consisting of estradiol, estradiol
benzoate,
estradiol cipionate, estradiol dipropionate, estradiol enantate, estradiol
hexahydrobenzoate, estradiol phenylpropionate, estradiol valerate,
polyestradiol
phosphate, estriol, estriol sodium succinate, estriol succinate, polyestriol
phosphate, quinestradol, ethinylestradiol, estrapronicate, mestranol,
estrapronicate and equilin;
xvi. a progestogen, selected from the group consisting of progesterone,
norethisterone, norethisterone acetate, norethisterone enantate,
medroxyprogesterone acetate, delmadinone acetate, flugestone acetate,
dydrogesterone, desogestrel, norgestrel, levonorgestrel, dydrogesterone,
gestodene, chlormadinone acetate, dienogest, drospirenone, lynestrenol,
tybolone, cyproterone acetate, megestrol acetate, nomegestrol acetate;
xvii. an inhibitor of a steroid hormone;
xviii. an inhibitor of a steroid hormone, selected from the group consisting
of inhibitors
are finasteride, dutasteride and spironolactone;
xix. a vitamin D;
xx. a vitamin D, selected from the group consisting of cholecalciferol, 25-
hydroxycholecalciferol, 1 a,25-dihydroxycholecalciferol, ergocalciferol, 1
a,25-
dihydroxyergocalciferol, 22,23-dihydroergocalciferol, 1,24,25-
trihydroxycholecalciferol, previtamin D3, tachysterol3 (also termed
tacalciol),
32
CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
Isovitamin D3, dihydrotachysterol3, (1 S~-hydroxycalciol, (24Fi)-
hydroxycalcidiol,
25-fluorocalciol, ercalcidiol, ertacalciol, (5!7-Isocalciol, 22,23-
Dihydroercalciol,
(245-methylcalcivl, (5E)-(105-10,19-Dihydroercalcioi, (245-Ethylcalciol and
(22~-(24F~-Ethyl-22,23-didehydrocalciol; and
xxi. a phytosteroid or a phytosterol.
[0152] According to another embodiment according to the present invention the
at
least one active agent is an antiinflammatory or antiallergic agent. An
antiinflammatory or
antiallergic agent can be selected from the group of corticosteroids (as
listed above),
non-steroidal antiinflammatory drugs (NSAIDs), anti-histamines,
immunosuppressants
and any combination thereof at a therapeutically effective concentration.
[0153] Since corticosteroid drugs are typically hydrophobic, the carrier of
the present
invention, comprising a hydrophobic organic carrier, is most suitable as a
vehicle to
facilitate better topical distribution and an enhanced rate of penetration of
any of the
above listed drugs. Furthermore, the intrinsic antiviral, antibacterial and
antiinflammatory
effects of the foam adjuvant agents, i.e., fatty alcohols and acids, provides
a combined
effect that should result in a better therapeutic response to treatment.
[0154] Antihistaminic agents may comprise, among other options,
diphenhydramine,
doxepin, phrilamine maleate, chlorpheniramine, tripelennamine, phenothiazines,
promethazine hydrochloride and dimethindene maleate. These drugs, as well as
additional antihistamines can also be incorporated in the composition of the
present
invention.
[0155] A second class of anti-inflammatory agents, which is useful in the foam
of the
present invention, includes the nonsteroidal anti-inflammatory agents
(NSAIDs). The
variety of compounds encompassed by this group is well-known to those skilled
in the
art. Specific non-steroidal anti-inflammatory agents useful in the composition
invention
include, but are not limited to: oxicams, such as piroxicam, isoxicam,
tenoxicam,
sudoxicam; salicyiates, such as salicylic acid, ethyl salicylate, methyl
salycilate, aspirin,
disaicid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal;
acetic acid
derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac,
tolmetin, isoxepac,
furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac,
oxepinac,
felbinac, and ketorolac; fenamates, such as mefenamic, meclofenamic,
flufenamic,
niflumic, and tolfenamic acids; propionic acid derivatives, such as ibuprofen,
naproxen,
benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen,
pirprofen,
carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen,
alminoprofen, and
33
CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
tiaprofenic; and pyrazoles, such as phenylbutazone, oxyphenbutazone,
feprazone,
azapropazone, and trimethazone.
[0156] Any further steroidal and nonsteroidal compounds, having the capacity
to
prevent, alleviate the symptoms of, treat or cure inflammation processes, are
generally
included, as possible anti-inflammatory agents, according to the present
invention.
[0157] The therapeutic foam composition of the present invention may also
comprise
an antiinflammatory or antiallergic agent, wherein said agent reduces the
occurrence of
pro-inflammatory cytokines or inhibits the effect of pro-inflammatory
cytokines.
[0158] Mixtures of such anti-inflammatory agents may also be employed, as well
as
the dermatologically acceptable salts, esters, amides, prodrugs and
derivatives of these
agents.
(0159] The compositions of the present invention may contain a safe and
effective
amount of a topical anesthetic. Examples of local anesthetic drugs include
benzocaine,
lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine,
tetracaine,
dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine, phenol, and
therapeutically acceptable salts thereof. Mixtures of such anesthetic agents
may be
synergistically beneficial.
(0160] Anti cancer agents can also be used according to the present invention
as the
drug of choice for treating for example vaginal, cervical and rectal
malignancies. In
certain cases, topical cytotoxic and antiproliferative drugs are used to treat
or prevent
such cancers, including 5-fluorouracil, also called 5-FU. 5-FU, as well as any
other anti-
cancer agents, know in the art of cancer medicine, can be incorporated in the
foam at
therapeutically effective levels.
[0161] A preferred family of anticancer drugs, suitable for usage in the foam
of the
present formulation comprises antiestrogens, such as tamoxifen. Tamoxifen
blocks the
effects of the hormone estrogen in the body.
[0162] A safe and effective amount of an anti-oxidant/radical scavenger may be
added to the compositions of the present invention, preferably from about 0.1
% to about
10% (w/w), more preferably from about 1 % to about 5% (w/w), of the
composition.
[0163] Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) and
its
salts, ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g.,
magnesium ascorbyl
phosphate, sodium ascorbyl phosphate, ascorbyl sorbate), tocopherol (vitamin
E),
tocopheroi sorbate, tocopherol acetate, other esters of tocopherol, butylated
hydroxy
benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-
carboxylic acid
34
CA 02565754 2006-10-30
Agent Ref. No.: i 13873.12TWO
(commercially available under the tradename Trolox~), gallic acid and its
alkyl esters,
especially propyl gallate, uric acid and its salts and alkyl esters, sorbic
acid and its salts,
lipoic acid, amines (e.g., N,N-diethylhydroxylamine, amino-guanidine),
sulfhydryl
compounds (e.g., glutathione), dihydroxy fumaric acid and its salts, lycine
pidolate,
arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine,
methionine,
proline, superoxide dismutase, silymarin, tea extracts, grape skin/seed
extracts, melanin,
and rosemary extracts may be used.
[0164] The foam of the present invention is suitable for delivering cell and
tissue
protecting and revitalizing anti-oxidants/radical scavengers. Polyunsaturated
fatty acids,
containing omega-3 and omega-6 fatty acids (e.g., linoleic and linolenic acid,
gamma-
linoleic acid (Gt~4), eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DNA) are
beneficial in the treatment of inflammation conditions. Likewise, emollients
and silicone
oils exert moisture-retaining and protective effects on the target tissue.
Thus, in a
preferred embodiment, a tissue protective foam is provided, wherein the
hydrophobic
organic carrier comprises in full or in part, a solvent, selected from the
group of
emollients, silicone oil and oils, rich in unsaturated fatty acids, thus,
affording a
synergistic therapeutic effect of the anti-oxidants/radical scavenger agent
and the vehicle
components.
[0165] Active agents, which are known in the art of pharmacology to treat
mucosal
irritations and inhibit inflammation, can be beneficially incorporated in the
foam of the
present invention.
[0166] Examples of such active agents include chamomile extract (matricaria
recutitia), cucumber distillate (cucumis sativus), lavender water (lavendula
angustifolia),
rose water {rosa damascena), witch hazel (hamamelis virginiana), allantoin,
bisabolol,
rosehip oil, calendula oil, azulaene, menthol and camphor.
(0167] There are several potential uses of the foam, particularly the silicone-
oil
based foam, as a lubricating foam. Typical examples are moisture protection
foam and
antifriction foam. For such purposes, the foam can be used in its basic
composition
(without additional formulation aids and active ingredients), or with the
addition of such
additives.
(0168] According to one embodiment, the at least one active agent is selected
from
the group of solvent, surface active agent, foam adjuvant and polymeric agent.
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Agent Ref. No.: 113873.127W0
Penetratiion enhancers
[0169] A penetration enhancer or permeation enhancer is an agent used to
increase
the permeability of tissue to a pharmacologically active agent to increase the
rate at
which the drug diffuses through the skin and enters the tissues and
bloodstream. A
chemical penetration enhancer increases skin permeability by reversibly
altering the
physiochemical nature of the tissue to reduce its diffusional resistance.
According to
one or more embodiments of the present invention a penetration enhancer is
incorporated into the foam composition.
[0170] Examples of penetration enhancers, according to the present invention
include: polyols, such as propylene glycol, hexylene glycol, diethylene
glycol, propylene
glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen-ols, limonene,
terpene-ol, 1-
menthol, dioxolane, ethylene glycol, other glycols, and glycerol; sulfoxides,
such as
dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide,
dimethylacetamide; monooleate of ethoxylated glycerides (with 8 to 10 ethylene
oxide
units); Azone (1-dodecyiazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane;
esters, such
as isopropyl myristate/palmitate, ethyl acetate, butyl acetate, methyl
proprionate,
capric%aprylic triglycerides, octylmyristate, dodecyl-myristate; myristyl
alcohol, lauryl
alcohol, lauric acid, lauryl lactate ketones; amides, such as acetamide
oleates such as
triolein; various surfactants, such as sodium lauryi sulfate; various alkanoic
acids such as
caprylic acid; lactam compounds, such as atone; alkanols, such as oleyl
alcohol;
dialkylamino acetates, and admixtures thereof.
[0171] Lower alcohols, such as ethanol, propanol, isopropanol, butanol, iso-
butanol,
t-butanol and pentanol are less desirable penetration enhancers according to
the present
invention, due to their irritation properties.
[0172] Yet, another preferred class of penetration enhancers in the
cyclodextrines
and related compounds. Cyclodextrins are structurally related cyclic
oligomaltoses
which form a new group of therapeutic excipients.
(0173] The invention is described with reference to the following examples.
This
invention is not limited to these examples and experiments. Many variations
will suggest
themselves and are within the full intended scope of the appended claims.
[0174] Example 1 - General Procedure for Preparing Foam Composition.
[0175] Aqueous Phase: At least one polymeric agent and at least one surface-
active
agent are dissolved in water, with agitation. The solution is warmed to about
50°C to
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CA 02565754 2006-10-30
Agent Ref. No.: 113873.127W0
about 70°C. Water soluble therapeutic active ingredients and optional
water soluble
ingredients are added with agitation to the Aqueous Phase mixture.
[0176] Oil Phase: At least one hydrophobic organic carrier is heated to same
above
temperature. Foam adjuvant agent is added to preheated hydrophobic organic
carrier.
Oil soluble therapeutic active agent or agents and optional oil soluble
formulation
ingredients are added with agitation to the Hydrophobic Phase mixture.
j0177] The warm Hydrophobic Phase is gradually poured into the warm Aqueous
Phase, with agitation, followed by Ultraturax or Silverson homogenization. The
mixture
is allowed to cool down to ambient temperature. In case of heat sensitive
active
ingredients, the active ingredient is added with agitation to the mixture
after cooling to
ambient temperature. The mixture, at ambient temperature, is added to an
aerosol
container, the container is sealed and appropriate amount of propellant (about
3% to
about 25 w% of the composition mass) is added under pressure into the
container.
[0178] Example 2 -Emulsion Foam Carrier Composition for vaginal and rectal
treatment
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Agent Ref. No.: 113873.127W0
[0179] The ingredients listed in the table below are combined to form a
foamable
emulsion composition.
VersionVersionVersionVersion
Ingredient
No.1 No.2 No.3 No.4
Hydrophobic MCT oil 30 - 15 12
organic carrierIPM - 30 - 12
Foam adjuvant Stearyl Alcohol 1.0 1.0 1.0 1.0
GMS 1.0 1.0 1.0 1.0
S
rf
ti
ve
u PEG S-40 3 3 3 3
ace-ac
agent
Polysorbate-60 1 1 1 1
Xanthan Gum 0.3 0.3 -- --
Polymeric agentMethocel ELV15 0.4 0.4 -- --
Natrosol - - 1.5 1.5
Antioxidant 0.2 0.2 0.2 0.2
Other Ingredients
Preservatives 1.0 1.0 1.0 1.0
Propellant* Propane/butane 8.0 8.0 8.0 8.0
Water Water To 100 To 100 To 100 To 100
Foam Specific
ND ND ND 0.06
gravity (gr/ml_)
[0180] The liquefied or gas propellant can be added at a concentration of
about 3%
to about 25%. The compositions use only non-ionic surface active agents, and
the total
amount of surface active agent, foam adjuvants and polymeric agent ranged from
1.4 to
2.1 % (w/w). The foam of this example is useful as a carrier of active agents,
as
exemplified in examples below. It is also useful as lubricating foam, for
various purposes.
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Agent Ref. No.: 113873.127W0
[0181] Example 3 - Further mixed Oil Foam Carrier Composition for vaginal and
rectal treatment
(0182] The ingredients listed in the table below are combined to form a
foamable
emulsion composition.
Version Version
Ingredient No. No.
~ 2
-25% Oil 12.5%
Oil
Mineral oil 10.2 5.6
Hydrophobic organic Isopropyl myristate 5.0 2.5
carrier
MCT oil 7.0 3.8
Foam adjuvant agent Stearyl Alcohol 2.0 2.0
Brij 72 2.5 2.5
Surface-active agent Brij 721 1.0 1.0
Cocoa amido propyl 0.5 0:5
betaine
Xanthan Gum 0.3 -
Polymeric agent Natrosol - 0.3
Methocel ELV15 0.5 --
Propellant* Propane/butane 6.0 6.0
Water Water To 100 To 100
[0183] The liquefied or gas propellant can be added at a concentration of
about 3%
to about 25%. The foams of this example have a non-ionic surface active agent
to ionic
surface active agent ratio (w/w) of 20:1 and 14:1 for versions 1 and 2,
respectively. Total
amounts of surface active agent foam adjuvant and polymeric agent is in the
range of
about 1.75 to about 3.5 % (w/w).
[0184] The compositions are useful as carriers of active therapeutic active
ingredients, as exemplified in examples below. It is also useful as
lubricating foam, for
various purposes.
[0185] The following examples, representing optional drug-containing foams,
are
prototype formulations, which have not been optimized for stability and inter-
component
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Agent Ref. No.: 113873.127W0
compatibility. Such optimization is a customary need, which can be done, using
means,
known to those skilled in the art of therapeutic formulation
{0186] Example 4 - Antibacterial Foam Composition for vaginal vactinosis and
other
vaginal and rectal infections
w/w % w/w % w/w
Met~onidazole 1.00 - -
Clindamycin - 2.00 2.00
Mineral oil 6.00 6.00 6.00
Mineral oil 6.00 6.00 6.00
Isopropyl myristate 6.00 6.00 6.00
Glyceryl monostearate 1.00 1.00 1.00
Stearyl alcohol 1.00 1.00 1.00
Xantan gum 0.30 0.30 0.30
Methocel K100M 0.30 0.30 0.30
Tween 60 1.00 1.00 1.00
MYRJ 52 3.00 3.00 3.00
Cocoamidopropylbetaine 0.50 0.50 -
Parabens (phenoxy ethanol and
methyl, ethyl 0.80 0.80 0.80
and propyl hydroxy benzoate mixture)
Propellant
Propane/butane x 10.00 10.00 10.00
Water to 100.0 to 100.0 to 100.0
[0187] The liquefied or gas propellant can be added at a concentration of
about 3%
to about 25%. The foams of this example have a non-ionic surface active agent
to ionic
surface active agent ratio ranging from about 20:1 to about 6:1. In one
version, no ionic
surface active agent was present.
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Agent Ref. No.: i 13873.127W0
[0188] Example 5 - AntifunQal Foam Composition
Version
Version Version 3 Version
ngredient 1 2 4
"Econazole
"Miconazole""Clotrimazole"~ "Nystatin"
Carrier Ingredients% w/w % w/w % w/w % w/w
~i Mineral oil 30 -- -- 10
',, Isopropyl myristate- 30 - 10
I MCT oil -- 30 10
I
Stearyl Alcohol 2.0 2.0 2.0 2.0
Myrj 40 - - 0.8 -
GMS 2.0 2.0 2.0 2.0
Natrosol 1.0 1.0 1.0 1.0
Active Ingredients
Miconazole 1 - - -
Clotrimazole - 2 - -
Econazole - - 1
Nystatin 100,000
Unitslgr
Propellant* 10.0 10.0 10.0 10.0
Propane/butane
Water To 100 To 100 To 100 To 100
[0189] The liquefied or gas propellant can be added at a concentration of
about 3%
to about 25%. The foams of this example have a non-ionic surface active agent
to ionic
surface active agent ratio ranging from about 16:1 to about 6:1. Total surface
active
agent, foam adjuvant and polymeric agent ranges from 2.05 to 3.5% (w/w). They
are
useful in the treatment of fungal and yeast infections.
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Agent Ref. No.: 113873.127V1/0
[0190] Example 6 - Corticosteroid Foam Composition
w/w % w/w % w/w % w/w % w/w
Mineral oil 5.60 5.60 5.60 5.60 5.60
Isopropyl myrlstate 5.60 5.60 5.60 5.60 5.60
Glyceryl monostearate0.45 0.45 1.00 1.00 1.00
Stearyl alcohol 0.85 0.85 0.85 0.85 0.85
Myrj 52 2.60 2.60 2.60 2.60 2.60
Xantan gum 0.26 - - -
Methocel K100M 0.26 - - -
Chitosan 1.00 - -
Hyaluronic acid - - 0.50 0.50
Avicel CL611 - 2.00 2.00 2.00 2.00
TWEEN 80 0.90 0.90 0.90 0.90 0.90
Cocoamidopropyl betaine0.41 0.41 0.41 0.41 0.41
Betametasoae valerate0.12 - 0.12 0.12 -
Hydrocortisone butyrate- 0.10 - 0.10
Propylene glycol 3.00 3.00 3.00 3.00 3.00
Parabens (phenoxy
ethanol and methyl,
ethyl .8 .8 .8 .8 .8
and propyl hydroxy
benzoate mixture)
Propellant
12.00 12.00 12.00 12.00 12.00
Propane/butane*
Water To 100 To 100 To 100 To 100 To 100
[0191] The liquefied or gas propellant can be added at a concentration of
about 3%
to about 25%. The foams of this example have a non-ionic surfactant to ionic
surfactant
ratio ranging from about 20:1 to about 14:1. Total surface active agent, foam
adjuvant
and polymeric agent ranged from about 2% to about 3_5% (w/w).
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Agent Ref. No.: 113873.12TWO
[0192] Example 7 - Antiviral Foam Composition
Version 1 Version 2 Version 3
~~ Ingredient
"Acyclovir" "Acyclovi~' "a-Interferon"
i
Carrier Ingredients % w/w % w/w % w/w
Mineral oil 48.4 11.0 5.4
Isopropyl myristate 5.0 2.5
j MCT oil 7.0 3.5
', Stearyl Alcohol 0.7 0.4 0.2
' Water To 100 To 100 To 100
Sucrose ester SP70 0.8 0.8 0.8
Distilled monoglyceride 1.2 0.6
Sodium lauryl sulphate0.05 0.1 0.1
Xanthan Gum 0.2 0.3 0.3
Methocel ELV 15 0.2 0.6 0.6
Active Ingredients
Acyclovi r 5 5 -
a-Interferon - 105 IU/g
Propellant* 6.0 6.0 10.0
Propane/butane
[0193] The liquid is added at a concentration of about 3% to about 25%. The
foam
of this example has a non-ionic surfactant to ionic surfactant ration ranging
from 20:1 to
14:1. Total surface active agent, foaming adjuvant and polymeric agent ranged
from
about 2% to about 3.5% (w/w).
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Agent Ref. No.: 113873.127W0
[0194] Example 8. Compositions consisting of corticosteroids, antifunctal and
antiviral agents
Ingredient % w/w % w/w % w/w % w/w
Betamethasone valerate 0.1
Ketoconazole 2.0 2.0
AcyGovir 5.0
Caprylic/Capric Triglycerides60.9 60.0 59.0 56.0
Propylene glycol 10.0 10.0 5.0
Hexylene glycol 10.0
Potent solvent -- -- -- 5.0
Lecithin 10.0 10.0 10.0 10.0
Stearyl alcohol 5.0 5.0 5.0 5.0
Glyceryl monostearate 2.0 2.0 2.0 2.0
PVP K90 2.0 2.0 2.0 2.0
Preservative 0.3 0.3 0.3 0.3
Propellant
10.0 12.0 12.0 10.0
~ Propane/butane
Purified water** ~ TO 100 TO 100 TO 100 TO 100
~ ~ ~
j0195] The liquefied or gas propellant can be added at a concentration of
about 3%
to about 25%. Water content in these compositions was about 10%
[0196] Example 9 - Comparative Tolerability and Acceptability Study of a
Placebo
Foam Composition Vs. a Conventional Gel
[0197] Four patients compared the use of the foam preparation of Example 4,
Version 2, with a conventional intravaginal gel preparation (Metrogel Vaginal,
3M). They
were asked to describe their feeling about the application of each of the
products and to
give their general rating for each of the products on a scale of 0-3 (0 =
poor; 1=barely
acceptable; 2=acceptable and 3=excellent).
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Agent Ref. No.: 113873.127W0
[0198] As demonstrated in the following table, the foam preparation obtained
higher
rates in all aspects of the test.
Property Foam Preparation MetroGel Vaginal
Mean Rating Mean Rating
Ease of preparation prior2~8 0.6
to
administration
Ease of insertion 2. 1.2
Comfort upon insertion 2.0 1.2
Ease of dosing 2.0 1.5
Lack of dripping 2.0 1.3
Ease of removal 2.2 1.6
I
I, Comfort upon removal 1.9 1.3
Overall rating 2.2 1.3
[0199] Example 10: Animal model for drop administration and duration
[0200] The composition of Example 4, Version 2 was prepared, with the addition
of
0.2% methylene blue as coloring agent. A female sheep was administered intra-
vaginally
one dose of the foam (metered dose, 50 ~.L). The vagina and cervix were
observed by
colposcopy and recorded photographically. The insertion was very easy. Foam
expanded effectively and vaginal cavity and cervix area were fully covered.
Fifteen
minutes after treatment, the vagina was swabbed. Colposcopy revealed that the
entire
vaginal cavity and cervix area were still covered by the blue pigment. There
was no
overflow of the foam and no dripping after administration. No signs of
irritation were
observed.
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Agent Ref. No.: 113873.127W0
[0201 ] Example 11 - Very low surfactants formulation
w/w ~ % % w/w % w/w
w/w
Mineral oil 20.00 20.00 30.00
Isopropyl palmitate 15.00
MCT oil 15.00
Glyceryl monostearate 1.00 1.00
Sucrose ester and Sorbitan
stearate 0.20 0.20 0.20 0.20
(Arlatone 2121 )
Pemulen TRi 00.20
Pemulen TR2 00.20 00.20
Methocel K100 00.30 00.30 00.30 00.30
Xantan Gum
TW EEN 80 11.00
TEA 00.10 Ø10 00.10
Propellant 112.00 112.00 112.00 112.00
Water To 100 To 100 To 100 To 100
[0202] The formulations of Example 11 are made stable with unexpectedly low
surfactant concentration making them highly non irritating and of lower
itching potential
for conditions of damaged infected or diseased condition vaginal mucous.
[0203] Although various embodiments that incorporate the teachings of the
present
invention have been shown and in detail herein, those skilled in the art can
readily
devise many other varied embodiments that incorporate these teachings. All
references
mentioned herein are incorporated by reference.
What is claimed is:
46
