Note: Descriptions are shown in the official language in which they were submitted.
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SPRAY-ON FORMULATIONS AND METHODS
FOR DERMAL DELIVERY OF DRUGS
FIELD OF THE INVENTION
The present invention relates generally to systems developed for dermal
delivery of drugs. More particularly, the present invention relates to
adhesive
formulations having a viscosity suitable for sprayable application to a skin
surface, and which form a sustained drug-delivery adhesive solidified layer on
the skin.
BACKGROUND OF THE INVENTION
In general, there are several kinds of transdermal or dermal drug delivery
systems: skin patches, semisolids such as ointments creams and lotions, and
spray-on formulations. Typical drug delivery patches are not elastic and have
fixed shapes and sizes. They work best on skin areas that are relatively flat
and
that do not flex or stretch.
Typical semisolid dosage forms, such as ointments and creams, are
often subject to unintended removal or transfer to other skin surfaces after
being
applied on the skin. The solvent in these semisolid formulations also tends to
evaporate quickly after the application, which may negatively impact drug
delivery rates. In addition, when a semisolid formulation is applied on skin,
it is
typically "rubbed in" which means only a very thin layer of the formulation is
applied on the skin. This limits the amount of the drug that can be applied to
each square centimeter of the skin, making sustained drug delivery difficult.
Spray-on formulations, such as those in pressurized containers or
pumps, contain ingredients of traditional semisolid formulations plus
propellants
and/or diluents. The propellants and diluents improve the ease of application
of
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the formulation. Therefore, besides the method of application, they have
similar
limitations and shortcoming as typical semisolids, as listed above.
In view of the shortcomings of many of the current dermal drug delivery
systems, it would be desirable to provide systems, formulations, and/or
methods
that can i) provide sustained drug delivery over long periods of time; ii) are
not
vulnerable to unintentional removal by contact with clothing, other objects,
or
people for the duration of the application time; iii) can be applied to a skin
area
subject to stretching and expansion without causing discomfort or poor contact
to skin; and/or iv) can be easily removed after application and use.
SUMMARY OF THE INVENTION
The present invention relates to novel formulations that can be applied to
a skin surface by spraying, and which can form a coherent, flexible, and/or
continuous solid layer after the evaporation of the propellant in the
formulation.
Although film-forming technologies have been used in cosmetic and
pharmaceutical preparations, typically, the solvents used in such systems do
not
last very long, and thus, are not optimal for sustained-release applications.
In
accordance with this, it has been recognized that the use of a non-volatile
solvent system, specially selected or formulated for the selected drug and for
the application needs, in the formulation can improve or even optimize
sustained drug delivery. For example, the non-volatile solvent(s) in the
formulations can be formulated or selected stay for the duration of the
application of the drug and serve as vehicle solvent for the drug.
In accordance with this, a spray-on formulation for drug delivery can
comprise a drug, a non-volatile solvent system comprising at least one non-
volatile solvent, a solidifying agent, and a propellant. The formulation can
have
an initial viscosity suitable to be expelled out of a pressurized container or
manual pump container and applied onto a skin surface as a layer, and further,
the formulation can also be capable of forming a solidified layer on the skin
surface after evaporation of at least a portion of the propellant.
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In another embodiment, a method for dermal drug delivery can comprise
spraying onto a skin surface an adhesive, solidifying formulation. The
formulation can comprise a drug, a non-volatile solvent system that is flux-
enabling for the drug, a solidifying agent, and a propellant. The formulation
can
have an initial viscosity suitable to be expelled out of a pressurized
container
and applied onto a skin surface as a layer. Additional steps include
solidifying
the formulation to form a solidified layer on the skin surface by at least
partial
evaporation of the propellant, and dermally delivering the drug from the
solidified layer to the skin surface at a therapeutically effective rate over
a
sustained period of time.
Additional features and advantages of the invention will be apparent from
the following detailed description which illustrate, by way of example,
features of
the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)
Before particular embodiments of the present invention are disclosed and
described, it is to be understood that this invention is not limited to the
particular
process and materials disclosed herein as such may vary to some degree. It is
also to be understood that the terminology used herein is used for the purpose
of describing particular embodiments only and is not intended to be limiting,
as
the scope of the present invention will be defined only by the appended claims
and equivalents thereof.
In describing and claiming the present invention, the following
terminology will be used.
The singular forms "a," "an," and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for exampfe, reference to "a drug"
includes reference to one or more of such compositions.
"Skin" is defined to include human skin (intact, diseased, ulcerous, or
broken), finger and toe nail surfaces, and mucosal surfaces that are usually
at
least partially exposed to air such as lips, genital and anal mucosa, and
nasal
and oral mucosa.
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The term "drug(s)" refers to any bioactive agent that is applied to, into, or
through the skin which is applied for achieving a therapeutic affect. This
includes compositions that are traditionally identified as drugs, as well
other
bioactive agents that are not always considered to be "drugs" in the classic
sense, e.g., peroxides, humectants, emollients, etc., but which can provide a
therapeutic effect for certain conditions. When referring generally to a
"drug," it
is understood that there are various forms of a given drug, and those various
forms are expressly included. In accordance with this, various drug forms
include polymorphs, salts, hydrates, solvates, and cocrystals. For some drugs,
one physical form of a drug may possess better physical-chemical properties
making it more amenable for getting to, into, or through the skin, and this
particular form is defined as the "physical form favorable for dermal
delivery."
For example the steady state flux of diclofenac sodium from flux enabling non-
volatile solvents is much higher than the steady state flux of diclofenac acid
from
the same flux enabling non-volatile solvents. It is therefore desirable to
evaluate
the flux of the physical forms of a drug from non-volatile solvents to select
a
desirable physical form/non-volatile solvent combination.
The phrases "dermal drug delivery" or "dermal delivery of drug(s)" shall
include both transdermal and topical drug delivery, and includes the delivery
of
drug(s) to, through, or into the skin. "Transdermal delivery" of drug can be
targeted to skin tissues just under the skin, regional tissues or organs under
the
skin, systemic circulation, and/or the central nervous system.
The term "flux" such as in the context of "dermal flux" or "transdermal
flux," respectively, refers to the quantity of the drug permeated into or
across
skin per unit area per unit time. A typical unit of flux is microgram per
square
centimeter per hour. One way to measure flux is to place the formulation on a
known skin area of a human volunteer and measure how much drug can
permeate into or across skin within certain time constraints. Various methods
(in vivo methods) might be used for the measurements as well. The method
described in Example 1 or other similar method (in vitro methods) can also be
used to measure flux. Although an in vitro method uses human epidermal
membrane obtained from a cadaver, or freshly separated skin tissue from
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hairless mice rather than measure drug flux across the skin using human
volunteers, it is generally accepted by those skilled in the art that results
from a
properly designed and executed in vitro test can be used to estimate or
predict
the results of an in vivo test with reasonable reliability. Therefore, "flux"
values
5 referenced herein can mean that measured by either in vivo or in vitro
methods.
The term "flux-enabling" with respect to the non-volatile solvent system
(or solidified layer including the same) refers to a non-volatile solvent
system
(including one or more non-volatile solvents) selected or formulated
specifically
to be able to provide therapeutically effective flux for a particular drug(s).
For
topically or regionally delivered drugs, a flux enabling non-volatile solvent
system is defined as a non-volatile solvent system which, alone without the
help
of any other ingredients, is capable of delivering therapeutic sufficient
levels of
the drug across, onto or into the subject's skin when the non-volatile solvent
system is saturated with the drug. For systemically targeted drugs, a flux
enabling non-volatile solvent system is a non-volatile solvent system that can
provide therapeutically sufficient daily doses over 24 hours when the non-
volatile solvent system is saturated with the drug and is in full contact with
the
subject's skin with no more than 500 crn2 contact area. Preferably, the
contact
area for the non-volatile solvent system is no more than 100 cm2. Testing
using
this saturated drug-in-solvent state can be used to measure the maximum flux-
generating ability of a non-volatile solvent system. To determine flux, the
drug
solvent mixture needs to be kept on the skin for a clinically sufficient
amount of
time. In reality, it may be difficult to keep a liquid solvent on the skin of
a human
volunteer for an extended period of time. Therefore, an alternative method to
determine whether a solvent system is "flux-enabling" is to measure the in
vitro
drug permeation across the hairless mouse skin or human cadaver skin using
the apparatus and method described in Example 1. This and similar methods
are commonly used by those skilled in the art to evaluate permeability and
feasibility of formulations. Alternatively, whether a non-volatile solvent
system is
flux-enabling can be tested on the skin of a live human subject with means to
maintain the non-volatile solvent system with saturated drug on the skin, and
such means may not be practical for a product. For example, the non-volatile
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solvent system with saturated drug can be soaked into an absorbent fabric
material which is then applied on the skin and covered with a protective .
membrane. Such a system is not practical as a pharmaceutical product, but is
appropriate for testing whether a non-volatile solvent system has the
intrinsic
ability to provide sufficient drug flux, or whether it is flux-enabling.
It is also noted that once the formulation forms a solidified layer, the
solidified layer can also be "flux enabling" for the drug while some of the
non-
volatile solvents remain in the solidified layer, even after the volatile
solvents
(including water) have been substantially evaporated.
The phrase "effective amount," "therapeutically effective amount,"
"therapeutically effective rate(s)," or the like, as it relates to a drug,
refers to
sufficient amounts or delivery rates of a drug which achieves any appreciable
level of therapeutic results in treating a condition for which the drug is
being
delivered. It is understood that "appreciable level of therapeutic results"
may or
may not meet any government agencies' efficacy standards for approving the
commercialization of a product. It is understood that various biological
factors
may affect the ability of a substance to perform its intended task. Therefore,
an
"effective amount," "therapeutically effective amount," or "therapeutically
effective rate(s)" may be dependent in some instances on such biological
factors to some degree. However, for each drug, there is usually a consensus
among those skilled in the art on the range of doses or fluxes that are
sufficient
in most subjects. Further, while the achievement of therapeutic effects may be
measured by a physician or other qualified medical personnel using evaluations
known in the art, it is recognized that individual variation and response to
treatments may make the achievement of therapeutic effects a subjective
decision. The determination of a therapeutically effective amount or delivery
rate is well within the ordinary skill in the art of pharmaceutical sciences
and
medicine.
"Therapeutically effective flux" or "therapeutically sufficient flux" is
defined
as the permeation flux of the selected drug that delivers sufficient amount of
drug into or across the skin to be clinically beneficial. "Clinically
beneficial" or
"clinically sufficient" when referring to flux means at some of the patient
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population can obtain some degree of benefit from the drug flux. It does not
necessarily mean that most of the patient population can obtain some degree of
benefit or the benefit is high enough to be deemed "effective" by relevant
government agencies or the medical profession. More specifically, for drugs
that target skin or regional tissues or organs close to the skin surface (such
as
joints, certain muscles, or tissues/organs that are at least partially within
5 cm of
the skin surface), "therapeutically effective flux" refers to the drug flux
that can
deliver a sufficient amount of the drug into the target tissues within a
clinically
reasonable amount of time. For drugs that target the systemic circulation,
"therapeutically effective flux" refers to drug flux that, via clinically
reasonable
skin contact area, can deliver sufficient amounts of the selected drug to
generate clinically beneficial plasma or blood drug concentrations within a
clinically reasonable time. Clinically reasonable skin contact area is defined
as a
size of skin application area that most subjects would accept. Typically, a
skin
contact area of 400 cm2 or less is considered reasonable. Therefore, in order
to
deliver 4000 mcg of a drug to the systemic circulation via a 400 cm2 skin
contact
area over 10 hours, the flux needs to be at least 4000 mcg/400cm2/1 0 hour,
which equals 1 mcg/cm2/hr. By this definition, different drugs have different
"therapeutically effective flux." Therapeutically sufficient flux" may be
different in
different subjects and or at different times for even the same subject.
However,
for each drug, there is usually a consensus among the skilled in the art on
the
range of doses or fluxes that are sufficient in most subjects at most times.
The following are estimates of flux for some drugs that are therapeutically
effective or more than sufficient:
Table A - In vitro steady state flux values of various drugs
Estimated
Drug Indication Therapeutically
sufficient flux*
mc Icm2/h
Ro ivacaine"'* Neuropathic pain 5
Lidocaine Neuropathic pain 30
Acyclovir Herpes simplex virus 3
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Ketoprofen Musculoskeletal pain 16
Diclofenac Musculoskeletal pain 1
Clobetasol Dermatitis, psoriasis, 0.05
eczema
Betamethasone Dermatitis, psoriasis, 0.01
eczema
Testosterone Hypogonadal men, 0.8 [
Testosterone Hormone treatment for 0.25
postmenopausal women
lmiquimod Warts, basal cell .0 92
carcinoma
* Flux determined using an in vitro method described -in Example 1.
** Estimated flux based on known potency relative to lidocaine.
The therapeutically effective flux values in Table A (with the exception of
ropivacaine) represent the steady state flux values of marketed products
through hairless mouse or human epidermal membrane in an in vitro system
described in Example 1. These values are meant only to be estimates and to
provide a basis of comparison for formulation development and optimization.
The therapeutically effective flux for a selected drug could be very different
for
different diseases to be treated for, different stages of diseases, and
different
individual subjects. It should be noted that the flux listed may be more than
therapeutically effective.
The following examples listed in Table B illustrate screening of non-
volatile solvent's flux enabling ability for some of the drugs specifically
studied.
Experiments were carried out as described in Example 1 below and the results
are further discussed in the subsequent Examples 2-9.
Table B - In vitro steady state flux values of various drugs from non-volatile
solvent systems
Drug Non-Volatile Solvent Average Flux*
mcg/cm2/hr
Betamethasone Oleic acid 0.009 0.003
Dipropionate Sorbitan Monolaurate 0.03 0.02
Clobetasol Propionate Pro lene Glycol (PG) 0.0038 0.0004
Light Mineral Oil 0.031 0.003
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Isostearic acid (ISA) 0.019 0.003
Ropivacaine Glycerol 1.2 0.7
Mineral Oil 8.9 0.6
Ketoprofen Pol eth lene glycol 400 5 2
S an20 15 3
Acyclovir Pol eth lene I col400 0
Isostearic acid + 10% 2.7 0_6
trolamine
* Each value represents the mean and st. dev of three determinations.
The in vitro steady state flux values in Table B from non-volatile solvents
show surprising flux-enabling and non flux-enabling solvents. This information
can be used to guide formulation development.
The term "plasticizing" in relation to flux-enabling non-volatile solvent(s)
is defined as a flux-enabling non-volatile solvent that acts as a plasticizer
for the '
solidifying agent. A "plasticizer"is an agent which is capable of increasing
the
percentage elongation of the formulation after the volatile solvent system has
at
least substantially evaporated. Plasticizers also have the capability to
reduce
the brittleness of solidified formulation by making it more flexible and/or
elastic.
For example, propylene glycol is a "flux-enabling, plasticizing non-volatile
solvent" for the drug ketoprofen with polyvinyl alcohol as the selected
solidifying
agent. However, propylene glycol in a formulation of ketoprofen with Gantrez S-
97 or Avalure UR 405 as solidifying agents does not provide the same
plasticizing effect. The combination of propylene glycol and Gantrez S-97 or
Avalure UR 405 is less compatible and results in less desirable formulation
for
topical applications. Therefore, whether a given non-volatile solvent is
"plasticizing" depends on which solidifying agent(s) is selected.
.20 Different drugs often have different matching flux-enabling non-volatile
solvent systems which provide particularly good results. Examples of such are
noted in Table C. Experiments were carried out as described in Example I
below and the results are further discussed in the subsequent Examples 2-9.
Table C - In vitro steady state flux values of various drugs from particularly
high
flux-enabling non-volatile solvent systems
Drug High flux-enabling non- Avg. Flux*
volatile solvent mc /cmz/h
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Ropivacaine ISA 11 2
S an 20 26 8
Ketoprofen Propylene glycol (PG) 90 50
Acycolvir ISA + 30% trolamine 7 2
Betamethasone Propylene Glycol 0.20 0.07
Di ro ionate
Clobetasol PG+ISA (Ratio of PG:ISA 0 8+ 0.2
proplonate ran in from 200:1 to 1:1)
* Each value represents the mean and st. dev of three determinations.
It should be noted that "flux-enabling non-volatile solvent," "flux-enabling,
plasticizing non-volatile solvent," or "high flux-enabling non-volatile
solvent" can
5 be a single chemical substance or a mixture of two or more chemical
substances. For example, the steady state flux value for clobetasol propionate
in Table C is a 9:1 for propylene glycol:isostearic acid mixture that
generated
much higher clobetasol flux than propylene glycol or ISA alone (see Table B).
Therefore, the 9:1 propylene glycol:isostearic acid'mixture is a "high flux-
10 enabling non-volatile solvent" but propylene glycol or isostearic acid
alone is
not.
The term "adhesion" and "adhesive" when referring to a solidified layer
herein refer to sufficient adhesion between the solidified layer and the skin
so
that the layer does not fall off the skin during intended use on most
subjects.
"Adhesive" or the like when used to describe the solidified layer can also
mean
the solidified layer is adhesive to the skin surface to which the initial
formulation
layer was originally applied (before the evaporation of the volatile
solvent(s)). In
one embodiment, it does not mean the solidified layer is adhesive on the
opposing side. In addition, it should be noted that whether a solidified layer
can
adhere to a skin surface for the desired extended period of time partially
depends on the condition of the skin surface. For example, excessively
sweating or oily skin, or oily substances on the skin surface may make the
solidified layer less adhesive to the skin. Therefore, the adhesive solidified
layer
of the current invention may not be able to maintain perfect contact with the
skin
surface and deliver the drug over a sustained period of time for every subject
under any conditions on the skin surface. A standard is that it maintains good
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contact with most of the skin surface, e.g. 70% of the total area, over the
specified period of time for most subjects under normal conditions of the skin
_
surface and external environment.
The terms "flexible," "eiastic," "elasticity," or the like, as used herein
refer
to sufficient flexibility and elasticity of the solidified layer so that it is
not broken
or separate from the skin surface during the intended use. For example, a
solidified layer that exhibits acceptably flexibility, elasticity, and
adhesion to skin
can be attached to human skin over a flexible skin location, e.g., elbow,
finger,
wrist, neck, lower back, lips, knee, etc., and will remain substantially
intact on
the skin upon stretching of the skin. It should be noted that the solidified
layers
of the present invention do not necessarily have to have any elasticity in
some
embodiments.
The term "peelable," when used to describe the solidified layer, means
the solidified layer can be lifted from the skin surface in one large piece or
several large pieces, as opposed to many small pieces or crumbs.
The term "sustained" relates to therapeutically effective rates of dermal
drug delivery for a continuous period of time of at least 30 minutes, and in
some
embodiments, periods of time of at least about 2 hours, 4 hours, 8 hours, 12
hours, 24 hours, or longer.
The use of the term "substantially" when referring to the evaporation of
the volatile solvents means that a majority of the volatile solvents which
were
included in the initial formulation have evaporated. Similarly, when a
solidified
layer is said to be "substantially devoid" of volatile solvents, including
water, the
solidified layer has less than 10 wt%, and preferably less than 5 wt%, of the
volatile solvents in the solidified layer as a whole.
The term "propellant" refers to a solvent which has a boiling point less
than 20 C and which can generate adequate pressure in a closed container at
temperatures above 20 C to expel the formulations of the present invention
from the container. The propellant can be in dissolved in rest of the
formulation,
exist as a separate phase (separated or suspended) in the rest of the
formulation, or exist in a separate enclosure (bag in can types) or
compartment.
When the propellant is maintained in a separate phase or compartment from the
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rest of the formulation, it can be mixed with the other components of the
formulation prior to application to a skin surface, such as by shaking,
inverting,
agitation, or other manual or mechanical mixing methods.
"Volatile solvent system" refers to a single solvent or combination of
solvents that are volatile, including water and solvents that are more
volatile
than water, but which have a boiling point which is greater than 25 C.
"Non-volatile solvent system" can be a single solvent or mixture of
solvents that are less volatile than water. It can also contain substances
that
are solid or liquid at room temperatures, such as pH or ion-pairing agents.
After
evaporation of the volatile solvent system, most of the non-volatile solvent
system should remain in the solidified layer for an amount of time sufficient
to
dermally delivery a given drug to, into, or through the skin of a subject at a
sufficient flux for a period of time to provide a therapeutic effect. In some
embodiments, in order to obtain desired permeability for an active drug and/or
compatibility with solidifying agents or other ingredients of the formulation,
a
mixture of two or more non-volatile solvents can be used to form the non-
volatile
solvent system. In one embodiment, the combination of two or more non-
volatile solvents to form a solvent system provides a higher transdermal flux
for
a drug than the flux provided for the drug by each of the non-volatile
solvents
individually. The non-volatile solvent system may also serve as a plasticizer
of
the solidified layer, so that the solidified layer is elastic and flexible.
"Adhesive solidifying formulation" or "solidifying formulation," "sprayable
solidifying formulation", and the like, are used interchangeably and refer to
a
composition that has a viscosity suitable for application to a skin surface
prior to
evaporation of its volatile solvent(s), and which can become a solidified
layer
after evaporation of at least a portion of the volatile solvent(s). The
solidified
layer, once formed, can be very durable. In one embodiment, once solidified on
a skin surface, the formulation can form a peel. The peel can be a soft,
coherent solid that can be removed by peeling large pieces from the skin
relative to the size of the applied formulation, and often, can be peeled from
the
skin as a single piece. The application viscosity is typically more viscous
than a
water-like liquid, but less viscous than a soft solid. Examples of preferred
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viscosities include materials that have consistencies similar to pastes, gels,
ointments, and the like, e.g., viscous liquids that flow but are not subject
to
spilling. Thus, when a composition is said to have a viscosity "suitable for
application" to a skin surface, this means the composition has a viscosity
that is
high enough so that the composition does not substantially run off the skin
after
being applied to skin, but also has a low enough viscosity so that it can be
easily spread onto the skin. A viscosity range that meets this definition can
be
from about 100 cP to about 3,000,000 cP (centipoises), and more preferably
from about 1,000 cP to about 1,000,000 cP.
In some embodiments of the present invention, it may be desirable to add
an additional agent or substance to the formulation so as to provide enhanced
or increased adhesive characteristics. The additional adhesive agent or
substance can be an additional non-volatile solvent or an additional
solidifying
agent_ Non-limiting examples of substances which might be used as additional
adhesion enhancing agents include copolymers of methylvinyl ether and maleic
anhydride (Gantrez polymers), polyethylene glycol and polyvinyl pyrrolidone,
gelatin, low molecular weight polyisobutylene rubber, copolymer of acryisan
alkyl/octylacrylamido (Dermacryl 79), and various aliphatic resins and
aromatic
resins.
The terms "washable" or "removed by washing" when used with respect
to the adhesive formulations of the present invention refers to the ability of
the
adhesive formulation to be removed by the application of a washing solvent
using a normal or medium amount of washing force. The required force to
remove the formulations by washing should not cause significant skin
irritation
or abrasion. Generally, gentle washing force accompanied by the application of
an appropriate washing solvent is sufficient to remove the adhesive
formulations
disclosed herein. The solvents which can be used for removing by washing the
formulations of the present invention are numerous, but preferably are chosen
from commonly acceptable solvents including the volatile solvents listed
herein.
Preferred washing solvents do not significantly irritate human skin and are
generally available to the average subject. Examples of washing solvents
include but are not limited to water, ethanol, methanol, isopropyl alcohol,
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acetone, ethyl acetate, propanol, or combinations thereof. In aspect of the
invention the washing solvents can be selected from the group consisting of
water, ethanol, isopropyl alcohol or combinations thereof. Surfactants can
also
be used in some embodiments.
The term "drying time" or "acceptable length of time" refer to the time it
takes for the formulation to form a non-messy solidified surface after
application
on skin under standard skin and ambient conditions, and with standard testing
procedure. It is noted that the word "drying time" in this application does
not
mean the time it takes to completely evaporate off the volatile solvent(s).
Instead, it means the time it takes to form the non-messy solidified surface
as
described above.
"Standard skin" is defined as dry, healthy human skin with a surface
temperature of between about 30 C to about 36 C. Standard ambient
conditions are defined by the temperature range of from 20 C to 25 C and a
relative humidity range of from 20% to 80%. The term "standard skin" in no way
limits the types of skin or skin conditions on which the formulations of the
present invention can be used. The formulations of the present invention can
be used to treat all types of "skin," including undamaged (standard skin),
diseased skin, or damaged skin: Although skin conditions having different
characteristics can be treated using the formulations of the present
invention,
the use of the term "standard skin" is used merely as a standard to test the
compositions of the varying embodiments of the present invention. As a
practical matter, formulations that perform well (e.g., solidify, provide
therapeutically effective flux, etc.) on standard skin can also perform well
diseased or damaged skin.
The "standard testing procedure" or "standard testing condition" is as
follows: To standard skin at standard ambient conditions is applied an
approximately 0.1 mm layer of the adhesive solidifying formulation and the
drying time is measured. The drying time is defined as the time it takes for
the
formulation to form a non-messy surface such that the formulation does not
lose
mass by adhesion to a piece of 100% cotton cloth pressed onto the formulation
surface with a pressure of between about 5 and about 10 g/cm2 for 5 seconds.
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"Solidified layer" describes the solidified layer of an adhesive solidifying
formulation after at least a portion of the volatile solvent system has
evaporated.
The solidified layer remains adhered to the skin, and is preferably capable of
maintaining good contact with the subject's skin for substantially the entire
5 duration of application under standard skin and ambient conditions. The
solidified layer also preferably exhibits sufficient tensile strength so that
it can be
peeled off the skin at the end of the application in one piece or several
large
pieces (as opposed to a layer with weak tensile strength that breaks into many
small pieces or crumbles when removed from the skin).
10 As used herein, a plurality of drugs, compounds, and/or solvents may be
presented in a common list for convenience. However, these lists should be
construed as though each member of the list is individually identified as a
separate and unique member. Thus, no individual member of_such list should
be construed as a de facto equivalent of any other member of the same list
15 solely based on their presentation in a common group without indications to
the
contrary.
Concentrations, amounts, and other numerical data may be expressed or
presented herein in a range format. It is to be understood that such a range
format is used merely for convenience and brevity and thus should be
interpreted flexibly to include not only the numerical values explicitly
recited as
the limits of the range, but also to include all the individual numerical
values or
sub-ranges encompassed within that range as if each numerical value and sub-
range is explicitly recited. As an illustration, a numerical range of "about
0.01 to
2.0 mm" should be interpreted to include not only the explicitly recited
values of
about 0.01 mm to about 2.0 mm, but also include individual values and sub-
ranges within the indicated range. Thus, included in this numerical range are
individual values such as 0.5, 0.7, and 1.5, and sub-ranges such as from 0.5
to
1.7, 0.7 to 1.5, and from 1.0 to 1.5, etc. This same principle applies to
ranges
reciting only one numerical value. Furthermore, such an interpretation should
apply regardless of the breadth of the range or the characteristics being
described.
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In accordance with this, a spray-on formulation for drug delivery can
comprise a drug, a non-votatile solvent system comprising at least one non-
volatile solvent, a solidifying agent, and a propellant. The formulation can
have
an initial viscosity suitable to be expelled out of a pressurized container or
manual pump container and applied onto a skin surface as a layer, and further,
the formulation can also be capable of forming a solidified layer on the skin
surface after evaporation of at least a portion of the propellant.
In another embodiment, a method for dermal drug delivery can comprise
spraying onto a skin surface an adhesive, solidifying formulation. The
formulation can comprise a drug, a non-volatile solvent system that is flux-
enabling for the drug, a solidifying agent, and a propellant. The formulation
can
have an initial viscosity suitable to be expelled out of a pressurized
container
and applied onto a skin surface as a layer. Additional steps include
solidifying
the formulation to form a solidified layer on the skin surface by at least
partial
evaporation of the propellant, and dermally delivering the drug from the
solidified layer to the skin surface at a therapeutically effective rate over
a
sustained period of time.
Thus, these embodiments exemplify the present invention which is
related to novel formulations, methods, and solidified layers. The
formulations
are sprayable onto skin surfaces, form solidified layers that can quickly
(from 15
seconds to about 4 minutes under standard skin and ambient conditions) to
moderately quickly (from about 4 to about 15 minutes under standard skin and
ambient conditions) change into a solidified layer, e.g., a coherent and soft
solid
layer that is optionally peelable, for drug delivery. The solidified layer
thus
formed is capable of delivering drug to the skin, into the skin, or across the
skin,
etc., at a therapeutically effective rate over a sustained period of time,
e.g., 30
minutes to tens of hours, so that most of the active drug that is delivered to
the
subject is delivered after the solidified layer is formed.
Additionally, the solidified layer formed by the formulations of the present
invention typically adheres to the skin, but has a solidified, minimally-
adhering,
outer surface which is formed relatively soon after application and which does
not substantially transfer to or otherwise soil clothing or other objects that
a
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17
subject is wearing or that the solidified layer may inadvertently contact. The
solidified layer can also be formulated such that it is highly flexible and
stretchable, and thus capable of maintaining good contact with a skin surface,
even if the skin is stretched during body movement, such as at a knee, finger,
elbow, other joints, lips, etc.
To use the spray-on solidifying formulations of the present invention, the
user sprays the formulation on the skin surface. The formulation forms a thin,
wet layer on the skin surface. When the propellant (and the optional volatile
solvent(s)) evaporates, the formulation solidifies into a thin, non-rigid,
coherent,
flexible, continuous, and/or preferably elastic solid layer. This solid layer
has
sufficient adhesion to the skin surface so that it can maintain good contact
with
the skin surface for the desired length of time, typically hours to tens of
hours.
Since the non-volatile solvent system does not evaporate and is designed to
provide sufficient flux across the skin surface for the drug, the drug can be
delivered from the solidified layer into or across the skin surface
continuously for
a sustained period of time or substantially for the entire duration of the
application period.
In selecting the various components that can be used, e.g., drug, non-
volatile solvent system, solidifying agent(s), propellant etc., various
considerations may be applicable. For example, the propellant can be selected
from pharmaceutically or cosmetically acceptable solvents known in the art to
be useful for pressurized spray-on applications. Examples of propellants which
can be used include hydrofluorocarbons, hydrochiorofluorocarbon, ethers or
alkanes. More specifically, they include but are not limited to propane,
butane,
isobutane, pentane, isopentane, diethyl ether, dimethyl ether, 1,1 .
difluoroethane, 1,1,1,2 tetrafluorethane, 1,1,1,2,3,3,3-heptafluoropropane,
1,1,1,3,3,3 hexafluoropropane, vinyl chloride, compressed carbon dioxide,
compressed nitrogen, or combinations thereof. The propellant can be in
dissolved in the formulation, exist as a separate phase or as a suspended
phase in the rest of the formulation, exist in a separate enclosure (bag in
can
types), or exist in a separate compartment and be mixed with the rest of the
formulation to provide the propulsion at the application time.. For most
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formulations, the weight percentage of the propellant can be from about 4 wt%
to about 90 wt%, and more preferably from about 10 wt% to about 60 wt%.
Some embodiments of the present invention can also comprise a volatile
solvent. Examples of volatile solvents which can be used include, but are not
limited to, iso-amyl acetate, denatured alcohol, methanol, propanol,
chiorobutanol, turpentine, cytopentasiloxane, cyclomethicone, methyl ethyl
ketone, ethanol, isopropyl alcohol, water, ethyl acetate, acetone, or
combinations thereof. When included in the formulations, these volatile
solvents
should be chosen to be compatible with the rest of the formulation. When used,
it is desirable that an appropriate weight percentage of the volatile
solvent(s) be
present in the formulation. Too much of the volatile solvent system prolongs
the
drying time.
The non-volatile solvent system,can also be chosen or formulated to be
compatible with the solidifying agent, the drug, the propellant, and any other
ingredients that may be present. For example, the solidifying agent can be
chosen so that it is dispersible or soluble in the non-volatile solvent
system..
Most non-volatile solvent systems as a whole will be formulated appropriately
after experimentation. For instance, certain drugs have good solubility in
poly
ethylene glycol (PEG) having a molecular weight of 400 (PEG 400, non-volatile
solvent) but poor solubility in glycerol (non-volatile solvent) and water
(volatile
solvent). However, PEG 400 cannot effectively dissolve poly vinyl alcohol
(PVA), and thus, is not very compatible alone with PVA, a solidifying agent.
In
order to dissolve sufficient amount of an active drug and use PVA as a
solidifying agent at the same time, a non-solvent system including PEG 400 and
glycerol (compatible with PVA) in an appropriate ratio can be formulated,
achieving a compatibility compromise. As a further example of compatibility,
non-volatile solvent/solidifying agent incompatibility is observed when Span
20
is formulated into a solidifying formulation containing PVA. With this
combination, Span 20 can separate out of the formulation and form an oily
layer
on the surface of the solidified layer. Thus, appropriate solidifying
agent/non-
volatile solvent selections are desirable in developing a viable formulation
and
compatible combinations.
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In further detail, non-volatile solvent(s) that can be used alone or in
combination to form non-volatile solvent systems can be selected from a
variety
of pharmaceutically acceptable liquids. In one embodiment, the non-volatile
solvent system can include glycerol, propylene glycol, isostearic acid, oleic
acid,
propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate,
sorbitan monooleate, sorbitan monopalmitate, butanol, or combinations thereof.
In another embodiment, the non-volatile solvent system can include benzoic
acid, butyl alcohol, dibutyl sebecate, diglycerides, dipropylene glycol,
eugenol,
fatty acids such as coconut oil, fish oil, palm oil, grape seed oil, isopropyl
myristate, mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan
fatty acid
surfactants, triethyl citrate, or combinations thereof. In a further
embodiment,
the non-volatile solvent system can include 1,2,6-hexanetriol, alkyltriols,
alkyldiols, acetyl monoglycerides, tocopherol, alkyl dioxolanes, p-
propenylanisole, anise oil, apricot oil, dimethyl isosorbide, alkyl glucoside,
benzyl alcohol, bees wax, benzyl benzoate, butylene glycol, caprylic/capric
triglyceride, caramel, cassia oil, castor oil, cinnamaldehyde, cinnamon oil,
clove
oil, coconut oil, cocoa butter, cocoglycerides, coriander oil, corn oil,
coriander
oil, corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin,
diacetylated
monoglycerides, diethanolamine, dietthylene glycol monoethyl ether,
diglycerides, ethylene glycol, eucalyptus oil, fat, fatty alcohols, flavors,
liquid
sugars ginger extract, glycerin, high fructose corn syrup, hydrogenated castor
oil, IP palrnitate, lemon oil, lime oil, limonene, milk, monoacetin,
monoglycerides, nutmeg oil, octyldodecanol, olive alcohol, orange oil, palm
oil,
peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle
oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable
oil,
vegetable shortening, vinyl acetate, wax, 2-(2-(octadecyloxy)ethoxy)ethanol,
benzyl benzoate, butylated hydroxyanisole, candelilla wax, carnauba wax,
ceteareth-20, cetyl alcohol, polyglyceryl, dipolyhydroxy stearate, PEG-7
hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone,
dimethyl phthalate, PEG Fatty acid esters such as PEG-.stearate, PEG - oleate,
PEG- laurate, PEG fatty acid diesters such as PEG-dioleate, PEG-distearate,
PEG-castor oil, glyceryl behenate, PEG glycerol fatty acid esters such as PEG
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glyceryl laurate, PEG glyceryl stearate, PEG glyceryl oleate, hexylene
glycerol,
lanolin, lauric diethanolamide, lauryl lactate, lauryl sulfate, medronic acid,
methacrylic acid, multisterol extract, myristyl alcohol, neutral oil, PEG-
octyl
phenyl ether, PEG -alkyl ethers such as PEG-cetyl ether, PEG-stearyl ether,
5 PEG- sorbitan fatty acid esters such as PEG-sorbitan diisosterate, PEG-
sorbitan
monostearate, propylene glycol fatty acid esters such as propylene glycol
stearate, propylene glycol, caprylate/caprate, sodium pyrrolidone carboxylate,
sorbitol, squalene, stear-o-wet, triglycerides, alkyl aryl polyether alcohols,
polyoxyethylene derivatives of sorbitan-ethers, saturated polyglycolyzed C8-
C10
10 glycerides, N-methyl pyrrolidone, honey, polyoxyethylated glycerides,
dimethyl
sulfoxide, azone and related compounds, dimethylformamide, N-methyl
formamaide, fatty acid esters, fatty alcohol ethers, alkyl-amides (N,N-
dimethylalkylamides), N-methyl pyrrolidone related compounds, ethyl oleate,
polyglycerized fatty acids, glycerol monooleate, glyceryl monomyristate,
glycerol
15 esters of fatty acids, silk amino acids, PPG-3 benzyl ether myristate, Di-
PPG2
myreth 10-adipate, honeyquat, sodium pyroglutamic acid, abyssinica oil,
dimethicone, macadamia nut oil, limnanthes alba seed oil, cetearyl alcohol,
PEG-50 shea butter, shea butter, aloe vera juice, phenyl trimethicone,
hydrolyzed wheat protein, or combinations thereof. In yet a further
embodiment,
20 the non-volatile solvent system can include a combination or mixture of non-
volatile solvents set forth in the any of the above discussed embodiments.
In addition to these and other considerations, the non-volatile solvent
system can also serve as plasticizer in the adhesive formulation so that when
the solidified layer is formed, the layer is flexible, stretchable, and/or
otherwise
"skin friendly."
Certain ingredients in the formulations may be irritating to the skin may
be desirable to use to achieve the desired solubility and/or permeability of
the
drug. In those cases, it is desirable to add compounds that are both capable
of
preventing or reducing skin irritation and are compatible with the
formulation.
For example, in a formulation where the propellant is irritating to the skin,
it
would be helpful to use a non-volatile solvent that is capable of reducing
skin
irritation. Examples of solvents that are known to be capable of preventing or
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21
reducing skin irritation include, but are not limited to, glycerin, honey,
and/or
propylene glycol.
The formulations of the present invention may also contain two or more
non-volatile solvents that independently are not flux-enabling rion-volatile
solvents for a drug, but when formulated together become flux enabling non-
volatile solvents as part of a system. One possible reason that these
initially
non-flux-enabling non-volatile solvents become flux-enabling non-volatile
solvents when formulated together may be due to the optimization of the
ionization state of the drug to a physical form which has higher flux, or
alternatively, the non-volatile solvents together act in some other
synergistic
manner. One further benefit of the mixing of the non-volatile solvents is that
it
may optimize the pH of the formulation or the skin tissues under the
formulation
layer to minimize irritation. Examples of suitable combinations of non-
volatile
solvents that result in adequate non-volatile solvent systems for certain
drugs
include, but are not limited to, isostearic acid /trolamine, isostearic
acid/diisopropyl amine, oleic acid/trolamine, propylene glycol /isostearic
acid.
The selection of the solidifying agent(s) can also be carried out in
consideration of the other components present in the adhesive formulation. The
solidifying agent can be selected or formulated to be compatible to the drug
and
the propellants and the non-volatile solvent system (and optionally, other
volatile
solvents that are not propellants), as well as to provide desired physical
properties to the solidified layer once it is formed. Depending on the drug,
solvent, and/or other components that may be present, the solidifying agent
can
be selected from a variety of agents. In one embodiment, the 'solidifying
agent
can include polyvinyl alcohol with a MW range of 20,000-70,000 (Amresco),
esters of polyvinylmethylether/maleic anhydride copolymer (ISP Gantrez ES-
425 and Gantrez ES-225) with a MW range of 80,000-160,000, neutral
copolymer of butyl methacrylate and methyl methacrylate (Degussa Plastoid B)
with a MW range of 120,000-180,000, dimethylaminoethyl methacrylate-butyl
methacrylate-methyl methacrylate copolymer (Degussa Eudragit E100) with a
MW range of 100,000-200,000, ethyl acrylate-methyl methacrylate-
trimethylammonioethyl methacrylate chloride copolymer with a MW greater than
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5,000 or similar MW to Eudragit RLPO (Degussa), Zein (prolamine) with a MW
greater than 5,000 such as Zein with a MW around 35,000 (Freeman
industries), pregelatinized starch having a MW similar to Instant Pure-Cote
B793
(Grain Processing Corporation), ethyl cellulose MW greater than 5,000 or MW
similar to Aqualon EC N7, N10, N14, N22, N50 , or N100 (Hercules), fish
gelatin
having a MW 20,000-250,000 (Noriand Products), gelatin, other animal sources
with MW greater than 5,000, acrylates/octylacrylamide copolymer MW greater
than 5,000 or MW similar to National Starch, and Chemical Dermacryl 79.
In another embodiment, the solidifying agent can include ethyl cellulose,
hydroxy ethyl cellulose, hydroxy methyl cellulose, hydroxy propyl cellulose,
hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose,
polyether amides, corn starch, pregelatinized corn starch, polyether amides,
shellac, polyvinyl pyrrolidone, polyisobutylene rubber, polyvinyl acetate
phthalate or combinations thereof. In a further embodiment the solidifying
agent
can include ammonia methacrylate, carrageenan, cellulose acetate phthalate
aqueous such as CAPNF from Eastman, carboxy polymethylene, cellulose
acetate (microcrystalline), cellulose polymers, divinyl benzene styrene,
ethylene
vinyl acetate, silicone, guar gum, guar rosin, gluten, casein, calcium
caseinate,
ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate,
microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate,
PEG/PVP,
xantham gum, trimethyl siloxysilicate, maleic acid/anhydride colymers,
polacrilin,
poloxamer, polyethylene oxide, poly glactic acid/poly-l-lactic acid, turpene
resin,
locust bean gum, acrylic copolymers, polyurethane dispersions, dextrin,
polyvinyl alcohol-polyethylene glycol co-polymers, methyacrylic acid-ethyl
acrylate copolymers such as BASF's Kollicoat polymers, methacrylic acid and
methacrylate based polymers such as poly(methacrylic acid), or combinations
thereof. In another embodiment, the solidifying agent can include a
combination
of solidifying agents set forth in the any of the above discussed embodiments.
Other polymers may also be suitable as the solidifying agent, depending on the
solvent(s), the drug, and the specific functional requirements of the given
formulation. Other polymers may also be suitable as the solidifying agent,
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23
depending on the solvent(s), the drug, and the specific functional
requirements
of the given formulation.
!n one embodiment, the non-volatile solvent system and the solidifying
agent(s) should be compatible with each other. Compatibility can be defined as
i) the solidifying agent does not substantially negatively influence the
function of
the non-volatile solvent system, except for some reduction of flux; ii) the
solidifying agent can hold the non-volatile solvent system in the solidified
layer
so that substantially no non-volatile solvent oozes out of the layer, and/or
iii) the
solidified layer formed with the selected non-volatile solvent system and the
solidifying agent has acceptable flexibility, rigidity, tensile strength,
elasticity,
and adhesiveness to skin. The weight ratio of the non-volatile solvent system
to
the solidifying agent(s) can be from about 0.1:1 to about 10:1. In another
aspect, the weight ratio of the non-volatile solvent system to the solidifying
agent can be from about 0.2:1 to about 4:1, and more preferably from about
0.5:1 to about 2:1.
The flexibility and stretchability of a solidified layer, which is optionally
also a peel, can be desirable in some applications. For instance, certain non-
steroidal anti-inflammatory agents (NSAIDs) can be sprayed directly over
joints
and muscles to form a solidified layer for transdermal delivery into joints
and
muscles. However, skin areas over joints and certain muscle groups are often
significantly stretched during body movements. Such movement prevents non-
stretchable patches from maintaining good skin contact. Lotions, ointments,
creams, gels, foams, pastes, or the like also may not be suitable for use for
the
reasons cited above. As such, in transdermal delivery of NSAIDs into joints
and/or muscles, the sprayable solidifying formulations of the present
invention
can offer unique advantages and benefits. It should be pointed out that
although good stretchability can be desirable in some applications, the
sprayable solidifying formulations of the present invention do not always need
to
be stretchable, as certain applications of the present invention do not
necessarily benefit from this property.
A further feature of a formulation prepared in accordance with
embodiments of the present invention is related to-drying time. If the
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formulation dries too slowly, the subject may have to wait a long time before
resuming normal activities (e.g. putting clothing on) that may remove un-
solidified formulation. Thus, it is desirable for the drying time to be
shorter than
about 15 minutes, preferably shorter than 3 minutes, and most preferably
shorter than 1 minute.
Other benefits of the solidified layers of the present invention include the
presence of a physical barrier that can be formed by the solidified layer
itself. In
some disease or injury situations, the skin surface is sensitive to the touch
of
foreign objects or vulnerable to infection if contact by foreign objects. In
those
situations, the solidified layer can provides physical protection to the skin
surface. For instance, local anesthetic agents and other agents such as
clonidine may be delivered topically for treating pain related to neuropathy,
such
as diabetic neuropathic pain. Since many of such subjects feel tremendous
pain, even when their skin area is only gently touched, the physical barrier
of the
solidified layer can prevent or minimize pain caused by accidental contact
with
objects or others.
Another advantage of the sprayable formulations of the present invention
is that they can be applied to a skin surface without the need to touch or rub
the
skin surface. For example, as noted above, subjects experiencing neuropathic
pain often feel pain even when the skin area is only gently touched, such as
with an applicator. Sprayable application of the solidifying formulation
allows for
the application of medicated formulation without the need to touch or rub the
skin. For instance, a spray-on solidified formulation of a corticosteroid for
treating alopecia can be applied easier than a traditional semi-solid
formulation
onto a scalp area that has some hair. Another example in which spray
application can be beneficial is in damaged or infected skin. Subjects having
damaged or infected skin or tissue may not be able to withstand the pain
associated with non-spray-on formulations. Additionally, when a formulation
requires the subject to physically touch the damaged or infected skin, the
risk of
a new or increased infection is also increased.
The spray-on formulations can provide other important advantages over
currently available "spray formulations" or "semi-solid" formulations. When
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compared to other spray-on formulations, the solidified layers of the present
invention formed from the spray-on solidifying formulations can hold a higher
amount of drug for more sustained delivery. When compared to the traditional
semi-solid formulations, the sprayable solidified formulations of the present
5 invention can be easier to apply or can be applied without touching the skin
surface with an application device such as a spatula. The skin surfaces to
which
the formulations of the current invention can be applied include but are not
limited to skin, mucosal surfaces of the lip, genitals, and anus, nail
surface,
wound surface, bed sore surface, and diabetes-induced ulcerous skin surface.
10 The present invention provides a convenient means of applying a
solidifying formulation in combination with liquefied propellants to readily
form a
uniform solidified layer which will remain in intimate contact with the site
of
application, and provide active drug delivery. This requires applying
sufficient
quantities of the formulation per unit area of the skin surface so that the
15 solidified layer can contain sufficient amount of the drug. For most drugs
the
solidified layer needs to be at least 0.01 mm thick, and preferably at least
0.05
mm thick.
These and other advantage can be summarized in the following non-
limiting list of benefits. The formulation can be readily sprayed onto a skin
20 surface without the need to touch the surface which could cause pain or
infection of the area. The solidified layer comprises a non-volatile solvent
system that is flux-enabling for the drug so that the drug can be delivered
over
sustained period of time at therapeutically effective rates. Further, as the
solidified layer remains adhesive to skin and is preferably peelable, easy
25 removal of the solidified layer can occur, and may occur without the aid of
a
solvent or surfactant. In some embodiments, the adhesion to skin and
elasticity
of the material is such that the solidified layer will not separate from the
skin
upon skin stretching at highly stretchable skin areas, such as over joints and
muscles. For example, in one embodiment, the solidified layer can be stretched
by 5%, or even 10% or greater, in at least one direction without cracking,
breaking, and/or separating form a skin surface to which the layer is applied.
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Still further, the solidified layer can be formulated to advantageously
deliver drug
and protect sensitive skin areas.
In one embodiment of the invention, the solidified layer may be washed
off with a solvent, such as water or ethanol, at the end of the desired drug
delivery. Other solvents which could also be used to wash off the solidified
formulation include but are not limited to the volatile solvents listed
herein. The
ability to be removed by washing is particularly advantageous for certain
applications. For example, if the solidifying formulation is applied to a skin
surface with a lot of hair (e.g. an anti genital herpes solidifying
formulation
applied on genital skin area with pubic hair), removal by peeling might cause
discomfort and therefore be undesirable, and hence washing can be a preferred
form of removal in this type of application. In another example, if the
solidifying
formulation is sprayed onto a palmar surface, such as the palm of the hand or
the sole of a foot, the ability for removal by peeling may be secondary
consideration to a formulation that will adhere to the skin surface. In these
cases, a solidified layer formulated to be easily washed off by water or
ethanol
can be more desirable. In washing embodiments, the solvent used to wash off
the solidified layer may dissolve the layer or make it less adhesive to the
skin so
that it can be easily removed from the skin. This being stated, it is noted
that
the solidified layers can be both peelable and washable in some embodiments.
In another embodiment, a solidifying formulation has a viscosity such that
it may be dispensed from a container (aerosol or pump-spray) with a metered
dose or volumetric control such that a controlled amount of the solidifying
formulation is dispensed. The formulation comprises the components as
described in the embodiments described above. Controlling the amount of
formulation dispensed can avoid under-dosing or overdosing that may lead to
undesirable therapeutic effect and/or adverse side effects.
In another embodiment of the present invention, a system having two
components includes a solidifying formulation with viscosity such that it may
be
dispensed from a pressurized container, and a pressurized container. The
formulation comprises a solidifying agent, at least one non-volatile solvent,
a
drug, a propellant, and optionally a volatile solvent system. Once the
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formulation is sprayed onto a skin surface and after the evaporation of the
propellant and the optional volatile solvent(s), the formulation will form a
drug-
delivering solidified layer on the skin that can be easily removed after use.
In
this and other embodiments, shortly before use, the aerosol container
containing the formulation and the propellant can be shaken to mix the
propellant and the rest of the formulation into a temporary suspension which
has
the appropriate viscosity to be sprayed on a skin surface. Once applied and
after the evaporation of the propellant and the optional volatile solvent(s),
the
formulation forms a drug-delivering solidified layer on the skin that can be
easily
removed after use. Alternatively, the pressurized container can include a
mechanism which causes the propellant to mix with the rest of the formulation
to
form a mixture that is expelled from the container onto a skin surface. Once
applied and after the evaporation of the propellant and the optional volatile
solvent(s), the formulation forms a drug-delivering solidified layer on the
skin
that can be easily removed after use.
In another embodiment, a solidifying formulation has a viscosity such that
it may be dispensed from a manual pump-spray container or a conventional
pump spray container. The formulation includes a solidifying agent, a non-
volatile solvent system, a drug, and optionally a volatile solvent(s). The
drug
formulation has the appropriate viscosity such that it can easily be expelled
from
the manual pump-spray container and applied to the skin surface. Once applied
the formulation will form a drug-delivering solidified layer on the skin
surface that
can be easily removed after use.
As a further note, it is a unique feature of the solidified layers of the
present invention that they can keep a substantial amount of the non-volatile
solvent system, which is optimized for delivering the drug, on the skin
surface.
This feature can provide unique advantages over existing products. For
example, in some semi-solid formulations, upon application to a skin surface,
the volatile solvents quickly evaporate and the formulation layer solidifies
into a
hard lacquer-like layer. The drug molecules are immobilized in the hard
lacquer
layer and are substantially unavailable for delivery into the skin surface. As
a
result, it is believed that the delivery of the drug is not sustained.over a
long
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period of time. In contrast to this type of formulation, the solidified layers
formed
using the formulations of the present invention keep the drug molecules quite
mobile in the non-volatile solvent system which is in contact with the skin
surface, thus ensuring sustained delivery.
Specific examples of applications that can benefit from the systems,
formulations, and methods of the present invention are as follows. In one
embodiment, a solidified layer can include bupivacaine, lidocaine, tetracaine,
and/or ropivacaine, and can be formulated for treating diabetic and post
herpetic
neuralgia. Alternatively, dibucanine and an alpha-2 agonist such as clonidine
can be formulated in a solidifying formulation for treating the same disease.
In
another embodiment, retinoic acid and benzoyl peroxide can be combined in a
solidified layer for treating acne, or alternatively, 1 wt% clindarnycin and 5
wt%
benzoyl peroxide can alternatively be combined in a solidifying formulation
for
treating acne. In another embodiment, a retinol solidifying formulation (OTC)
can be prepared for treating wrinkles, or a lidocaine solidifying formulation
can
be prepared for treating back pain. In another embodiment, a zinc oxide
solidifying formulation (OTC) can be prepared for treating diaper rash (the
physical barrier provided by the solidified layer against irritating urine and
feces
is believed to be beneficial), or an antihistamine solidified layer can be
prepared
for treating allergic rashes such as that caused by poison ivy.
Additional applications include delivering drugs for treating certain skin
conditions, e.g., dermatitis, psoriasis, eczema, skin cancer, alopecia,
wrinkles,
viral infections such as cold sore, genital herpes, shingles, etc.,
particularly
those that occur over joints or muscles where a transdermal patch may not be
practical. For example, solidifying formulations containing imiquimod can be
formulated for treating skin cancer, prematurely aged skin, photo-damaged
skin,
common and genital warts, and actinic keratosis. Solidifying formulations
containing antiviral drugs such as acyclovir, penciclovir, famciclovir,
valacyclovir,
steroids, and/or behenyl alcohol can be formulated for treating herpes viral
infections such as cold sores on the face and genital areas. Solidifying
formulations containing non-steroidal anti-inflammatory drugs (NSAIDs),
capsaicin, alpha-2 agonists, and/or nerve growth factors can be formulated for
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treating soft tissue injury and muscle-skeletal pains such as joint and back
pain
of various causes. As discussed above, patches over these skin areas typically
do not have good contact over sustained period of time, especially for a
physically active subject, and may cause discomfort. Likewise, traditional
semi-
solid formulations such as creams, lotions, ointments, etc., may prematurely
stop the delivery of a drug due to the evaporation of solvent and/or
unintentional
removal of the formulation. The solidifying formulations of the present
invention
address the shortcomings of both of these types of delivery systems.
One embodiment can entail a solidified layer containing a drug from the
class of alpha-2 antagonists which is applied topically to treat neuropathic
pain.
The alpha-2 agonist is gradually released from the formulation to provide pain
relief over a sustained period of time. The formulation can become a coherent,
soft solid within about 5 minutes and remains adhered to the skin surface for
the
length of its application, typically hours to tens of hours. The solidified
layer is
easily removed after the intended application without leaving residual
formulation on the skin surface.
Another embodiment involves a solidifying formulation containing
capsaicin which is applied topically to treat neuropathic pain. The capsaicin
is
gradually released from the formulation for treating this pain over a
sustained
period of time. The formulation can become a coherent, soft solid within about
5
minutes and remains adhered to the skin surface for the length of its
application.
It can be easily removed any time after drying without leaving residual
formulation on the skin surface.
Another embodiment involves a solidifying formulation containing
clobetasol propionate which is applied topically to treat hand dermatitis. The
clobetasol propionate is gradually released from the formulation for treating
dermatitis over a sustained period of time. The formulation can become a
coherent, soft solid within about 3 minutes and remains adhered to the skin
surface for the length of its application. The physical barrier also protects
the
compromised skin from potentially harmful substances. It is easily removed any
time after drying without leaving residual formulation on the skin surface.
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Another embodiment involves a solidifying formulation containing
clobetasol propionate which is applied topically to treat alopecia. The
clobetasol
propionate is gradually released from the formulation for promoting hair
growth
over a sustained period of time. The formulation can become a coherent, soft
5 solid within about 5 minutes and remains adhered to the skin surface for the
length of its application. It is easily removed any time after drying by
peeling to
showering.
Another embodiment involves sprayable solidifying formulations
containing tazorac for treating stretch marks, wrinkles, sebaceous
hyperplasia,
10 or seborrheic keratosis.
In another embodiment, solidifying formulations containing glycerol can
be made so as to provide a protective barrier for fissuring on finger tips.
Still another embodiment can include a solidifying formulation containing
a drug selected from the local anesthetic class, including lidocaine and
15 ropivacaine, or the like, or NSAID class, such as ketoprofen, piroxicam,
diclofenac, indomethacin, or the like. These drugs can be applied topically to
treat symptoms of back pain, muscle tension, and/or myofascial pain. The local
anesthetic and/or NSAID is/are gradually released from the formulation to
provide pain relief over a sustained period of time. The formulation can
become
20 a coherent, soft solid within about 3 minutes and remain adhered to the
skin
surface for the length of its application. It is easily removed any time after
drying without leaving residual formulation on the skin surface.
A further embodiment involves a solidifying formulation containing at
least one alpha-2 agonist drug, at least one tricyclic antidepressant agent,
25 and/or at least one local anesthetic drug which is applied topically to
treat
neuropathic pain. The drug(s) are gradually released from the formulation to
provide pain relief over a sustained period of time. The formulation can
become
a coherent, soft solid within about 3 minutes and rerriains adhered to the
skin
surface for the length of its application. It can be easily removed any time
after
30 drying without leaving residual formulation on the skin surface.
A similar embodiment can include a solidifying formulation containing
drugs capsaicin and a local anesthetic drug which is applied topically to the
skin
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to provide pain relief. Another embodiment can include a solidifying
formulation
containing the combination of a local anesthetic and a NSAID. In both of the
above embodiments the drugs are gradually released from the formulation to
provide pain relief over a sustained period of time. The formulation can
become
a coherent, soft solid within about 3 minutes and remains adhered to the skin
surface for the length of its application. It is easily removed any time after
drying without leaving residual formulation on the skin surface.
In another embodiment, solidifying formulations for the delivery of drugs
useful for treating the causes or symptoms of diseases involving joints and
muscles can also benefit from the systems, formulations, and methods of the
present invention. Such diseases that may be applicable include, but not
limited
to, osteoarthritis (OA), rheumatoid arthritis (RA), joint and skeletal pain of
various other causes, myofascial pain, muscular pain, and sports injuries.
Drugs or drug classes that can be used for such applications include, but are
not limited to, non-steroidal anti-inflammatory drugs (NSAIDs) such as
ketoprofen and diclofanac, COX-2 selective NSAIDs and agents, COX-3
selective NSAIDs and agents, local anesthetics such as lidocaine, bupivacaine,
ropivacaine, and tetracaine, and steroids such as dexamethasone.
Delivering drugs for the treatment of acne and other skin conditions can
also benefit from principles of the present invention, especially when
delivering
drugs having low skin permeability. Currently, topical retinoids, peroxides,
and
antibiotics for treating acne are mostly applied as traditional semisolid gels
or
creams. However, due to the shortcomings as described above, sustained
delivery over many hours is unlikely. For example, clindamycin, benzoyl
peroxide, and erythromycin may be efficacious only if sufficient quantities
are
delivered into hair follicles. However, a traditional semisolid formulation,
such
as the popular acne medicine benzaclin gel, typically loses most of its
solvent
(water in the case of benzaclin) within a few minutes after the application.
This
short period of a few minutes likely substantially compromises the sustained
delivery of the drug. The formulations of the present invention typically do
not
have this limitation.
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In another embodiment, the delivery of drugs for treating neuropathic
pain can also benefit from the methods, systems, and formulations of the
present invention. A patch containing a local anesthetic agent, such as
LidodermTM, is widely used for treating neuropathic pain, such as pain caused
by post-herpetic neuralgia. Due to the limitations of the patch as discussed
above, the solidified layers prepared in accordance with the present invention
provide some unique benefits, as well as provide a potentially less expensive
alternative to the use of a patch. Possible drugs delivered for such
applications
include, but are not limited to, local anesthetics such as lidocaine,
prilocaine,
tetracaine, bupivicaine, etidocaine; and/or other drugs including capsaicin
and
alpha-2 agonists such as clonidine, dissociative anesthetics such as ketamine,
and/or tricyclic antidepressants such as amitriptyline,.
The solidifying formulations of the present invention can be formulated to
treat a variety of conditions and disease such as musculoskeletal pain,
neuropathic pain, alopecia, skin disease including dermatitis and psoriasis as
well as skin restoration (cosmetic skin treatment), and infections including
viral,
bacterial, and fungal infection. As such the formulations can deliver a wide
ranging number and types of drugs and active agents. In one embodiment, the
solidifying formulation can be formulated to include acyclovir, econazole,
miconazole, terbinafine, lidocaine, bupivacaine, ropivacaine, and tetracaine,
amitriptyline, ketanserin, betamethasone dipropionate, triamcinolone
acetonide,
clindamycin, benzoyl peroxide, tretinoin, Isotretinoin, clobetasol propionate,
halobetasol propionate, ketoprofen, piroxicam, diclofenac, indomethacin,
imiquimod, salicylic acid, benzoic acid, or combinations thereof
In another embodiment, the formulation can include an antifungal drug
such as amorolfine, butenafine, naftifine, terbinafine, fluconazole,
itraconazole,
ketoconazole, posaconazole, ravuconazole, voriconazole, clotrimazole,
butoconazole , econazole, miconazole, oxiconazole, sulconazole, terconazole,
tioconazole, caspofungin, micafungin, anidulafingin, amphotericin B, AmB,
nystatin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin, toinaftate,
and
undecylenate, or combinations thereof.
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In another embodiment, the formulation can include an antifungal drug
such as acyclovir, penciclovir, famciclovir, valacyclovir, behenyl alcohol,
trifluridine, idoxuridine, cidofovir, gancyclovir, podofilox,
podophyllotoxin,ribavirin, abacavir, delavirdine, didanosine, efavirenz,
lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir,
indinavir,
nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir,
ribavirin,
rimantadine, zanamivir, or combinations thereof.
When the formulation is intended to provide antibacterial treatment, it can
be formulated to include an antibacterial drug such as erythromycin,
clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B,
quinolones such as ciproflaxin, or combinations thereof.
When the formulation is intended to relieve pain, particularly neuropathic
pain, the formulation can include a local anesthetic such as lidocaine,
bupivacaine, ropivacaine, and/or tetracaine; and/or an alpha-2 agonists such
as
clonidine. When the formulation is intended to treat pain associated with
inflammation, it can be formulated to include an non-steroidal anti-
inflammatory
drug such as ketoprofen, piroxicam, diclofenac, indomethacin, COX inhibitors
general COX inhibitors, COX-2 selective inhibitors, COX-3 selective
inhibitors,
or combinations thereof.
In another embodiment, the formulation can be formulated to treat skin
disorders or blemishes by including active agents such as anti-acne drugs such
as clindamycin and benzoyl peroxide, retinol, vitamin A derivatives such as
tazarotene and isotretinoin, cyclosporin, anthralin, vitamin D3,
cholecalciferol,
calcitriol, cafcipotriol, tacalcitol, calcipotriene, etc.
In yet another embodiment, the delivery of medication for treating warts
and other skin conditions would also benefit from long periods of sustained
drug
delivery. Examples of anti-wart compounds include but are not limited
to:imiquimod, rosiquimod, keratolytic agents: salicylic acid, alpha hydroxy
acids,
sulfur, rescorcinol, urea, benzoyl peroxide, allantoin, tretinoin,
trichioroacetic
acid, lactic acid, benzoic acid, or combinations thereof.
A further embodiment involves the use of the solidifying formulations for
the delivery of sex steroids including, but not limited to, progestagens
consisting
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of progesterone, norethindrone, norethindroneacetate, desogestrel,
drospirenone, ethynodiol diacetate, norelgestromin, norgestimate,
levonorgestrel, dl-norgestrel, cyproterone acetate, dydrogesterone,
medroxyprogesterone acetate, chlormadinone acetate, megestrol,
promegestone, norethisterone, lynestrenol, gestodene, tibolene, androgens
consisting of testosterone, methyl testosterone, oxandrolone, androstenedione,
dihydrotestosterone, estrogens consisting of estradiol, ethniyl estradiol,
estiol,
estrone, conjugated estrogens, esterified estrogens, estropipate, or
combinations thereof.
Non-sex steroids can also be delivered using the formulations of the
present invention. Examples of such steroids include, but are not limited to,
betamethasone dipropionate, halobetasol propionate, diflorasone diacetate,
triamcinolone acetonide, desoximethasone, fluocinonide, halcinonide,
mometasone furoate., betamethasone valerate, fluocinonide, fluticasone
propionate, triamcinolone acetonide, fluocinolone acetonide, flurandrenofide,
desonide, hydrocortisone butyrate, hydrocortisone valerate, alclometasone
dipropionate, flumethasone pivolate, hydrocortisone, hydrocortisone acetate,
or
combinations thereof.
A further embodiment involves controlled delivery of nicotine for treating
nicotine dependence among smokers and persons addicted to nicotine.
Formulations of the present invention would be a cost effective way of
delivering
therapeutic amounts of nicotine transdermally.
Another embodiment involves using the formulation to deliver anti-
histamine agents such as diphenhydramine and/or tripelennamine. These
agents would reduce itching by blocking the histamine that causes the itch and
also provide relief by providing topical analgesia.
Other drugs which can be delivered using the solidifying formulations of
the present invention include, but are not limited to, tricyclic anti-
depressants
such as amitriptyline; anticonvulsants such as carbamazepine and alprazolam;
N-methyl-D-aspartate (NMDA) antagonists such as ketamine; 5-HT2A receptor
antagonists such as ketanserin; and immune modulators such as tacrolimus and
picrolimus. Other drugs that can be delivered using the formulations and
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methods of the current invention include humectants, emollients, and other
skin
care compounds.
EXAMPLES
5
The following examples illustrate the embodiments of the invention that
are presently best known. However, it is to be understood that the following
are
only exemplary or illustrative of the application of the principles of the
present
invention. Numerous modifications and alternative compositions, methods, and
10 systems may be devised by those skilled in the art without departing from
the
spirit and scope of the present invention. The appended claims are intended to
cover such modifications and arrangements. Thus, while the present invention
has been described above with particularity, the following examples provide
further detail in connection with what are presently deemed to be the most
15 practical and preferred embodiments of the invention.
Example 1
A pressurized container filled with a sprayable solidifying formulation for
delivering a drug is prepared which includes a drug (e.g., ketoprofen,
20 testosterone, etc.), a solidifying agents of polyvinyl alcohol (31,000-
50,000 Mw)
(Amresco) and esters of polyvinylmethylether/maleic anhydride copolymer
(80,000-160,000 Mw) (Gantrez ES-425), a non-volatile solvent system of
propylene glycol and glycerol, and a volatile solvent system of water and
ethanol. The propellant includes at least one of: propane, butane, isobutane,
25 pentane, isopentane, fluro-chloro-hydrocarbons, diethyl ether, dimethyl
ether,
1,1 difluoroethane, 1,1,1,2 tetrafluorethane, 1,1,1,2,3,3,3-
heptafluoropropane,
1,1,1,3,3,3 hexafluoropropane, vinyl chloride, compressed carbon dioxide,
compressed nitrogen, or a combination thereof. By adding a sufficient
concentration of the propellant, the container becomes inherently pressurized.
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Example 2
A subject sprays the solidifying formulation prepared similarly as in
Example 1 from a pressurized container on an ankle suffering from pain or
inflammation caused by an injury or arthritis. The solidifying formulation
quickly
solidifies into a soft, coherent, and elastic solid layer after the
evaporation of the
propellant and the volatile solvent(s), and remains in intimate contact with
the
skin site until removal by the subject. The solidified layer delivers a
therapeutically effective amount of ketoprofen across the skin and into the
ankle
tissues over at least 2 hours, and preferably at least 8 hours, to control
pain and
inflammation. The non-volatile solvent(s) also keeps the solidified layer
soft,
coherent, and elastic, as well as provides a flux-enabling solvent in the
solidified
layer to continuously deliver the ketoprofen through the skin in the absence
of
water or more volatile solvents and propellants. At the end of the intended
application period, the solidified layer can be lifted from the skin due to
its good
cohesion.
Example 3
A subject sprays a solidifying formulation containing testosterone
prepared similarly as in Example 1 from a pressurized container on his upper
arm, shoulders or abdomen area. The solidifying formulation quickly solidifies
into a solid layer after the evaporation of the propellant. The solid layer is
soft,
coherent, elastic, and remains in intimate contact with the skin site until it
is
removed. The solidified layer delivers therapeutically effective amounts of
testosterone across the skin and into the subject's systemic circulation over
a
period of at least 6 hours. The non-volatile sotvent serves as the vehicle for
delivering testosterone and also keeps the solidified layer soft, coherent and
elastic, as well as provides a flux-enabling solvent in the solidified layer
to
continuously deliver the testosterone through the skin in the absence of water
or
more volatile solvents and propellants. At the end of the intended application
period, the solidified layer can be removed from the skin due as a single
large
piece or as several large pieces due to its good cohesion.
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Example 4
A subject sprays solidifying formulation containing tetracaine from a
pressurized container onto a skin site of a subject experiencing neuropathic
pain. The solidifying formulation includes tetracaine base, a solidifying
agent of
Plastoid B (neutral copolymer of butyl methacrylate and methyl methacrylate
with a 120,000-180,000 Mw range), a non-volatile solvent system of mineral oil
and isostearic acid, Gantrez ES-425 (esters of polyvinylmethylether/maleic
anhydride copolymer a 80,000-160,000 Mw range for increased adhesion
between the solidified layer and the skin), and propellants of dimethyl ether.
After a layer of.the formulation is sprayed on the skin, the propellant
evaporates
quickly and the formulation solidifies into a soft, coherent, and flexible
solid
layer. The solidified layer delivers tetracaine into the skin and controls the
neuropathic pain for a sustained period of time.
Example 5
A subject sprays solidifying formulation containing ropivacaine from an
aerosol container onto a skin suffering from neuropathic pain. The solidifying
formulation includes ropivacaine base, a solidifying agent Plastoid B (neutral
copolymer of butyl methacrylate and methyl methacrylate with a 120,000-
180,000 Mw range), a non-volatile solvent system including at least one of
tetrahydroxypropyl ethylenediamine, triacetin, span 20, and isostearic acid.
The
formulation also includes dimethyl ether as a propellant. After a layer of the
formulation is sprayed on the skin, the propellant evaporates quickly and the
formulation solidifies into a soft, coherent, and flexible solid layer.
Ropivacaine
is delivered from the solidified layer into the skin over sustained period of
time
for treating the neuropathic pain.
Example 6
A subject sprays solidifying formulation containing clobetasol propionate
from a pressurized container onto a scalp area where the subject is suffering
from alopecia. Although the scalp area is being treated for alopecia, it has
some hair, and the spray-on formulation makes the application easier than
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applying a cream, ointment, or a non-sprayable solidifying formulation. The
solidifying formulation includes clobetasol propionate, a solidifying agent of
fish
gelatin, a non-volatile solvent system of propylene glycol and isostearic
acid,
fumed silica as a filler (optional), and a fluorocarbon or dimethyl ether as a
propellant. After a layer of the formulation is sprayed on the skin, the
propellant
evaporates quickly and the formulation solidifies into a soft, coherent, and
flexible solid layer. A therapeutically effective amount of clobetasol
propionate is
delivered from this layer into the scalp surface over at least 6 hours for
promoting hair growth. After the intended application, the formulation can be
washed off in a shower or head wash, as the solidified layer is soluble in
water.
Example 7
A subject sprays a solidifying formulation containing clobetasol
propionate from a pressurized container onto a palm skin area where the,
subject is suffering from hand dermatitis. The formulation is similar to that
in
Example 6. After a layer of the formulation is sprayed on the skin, the
propellant
evaporates quickly and the formulation solidifies into a soft, coherent, and
flexible solid layer. Clobetasol propionate is delivered in from this
solidified layer
into the palm skin surface over at least 2 hours for suppressing the hand
dermatitis. The solidified layer is adhesive to the skin and also acts as a
physical barrier to protect the skin from external substances that can cause
or
aggravate the dermatitis.
Example 8
A subject sprays a solidifying formulation containing an antibiotic agent
from a pressurized container onto a skin area of bed sore or diabetes-induced
ulcer. The formulation includes an antibiotic, solidifying agent of polyvinyl
alcohol, a non-volatile solvent system of glycerol, and a propellant of
1,1,1,2,3,3,3-heptafluoropropane (propellant). After a layer of the
formulation is
sprayed on the skin, the propellant evaporates quickly and the formulation
solidifies into a soft, coherent, and flexible solid layer. The antibiotic
agent is
delivered at therapeutically effective rates from this layer into the
compromised
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skin surface over at least 2 hours for treating or preventing infection. The
solidified layer is adhesive to the skin surface and also acts as a physical
barrier
to protect the compromised skin area from external pathogens and touch by
external objects that can cause pain.
Example 9
A subject sprays solidifying formulation containing clobetasol propionate
from an aerosol container onto a skin area where the subject is suffering from
psoriasis. The formulation includes the clobetasol propionate, a solidifying
agent
of polyvinyl alcohol, a non-volatile solvent system of glycerol, propylene
glycol,
and oleic acid, Gantrez ES-425 (esters of polyvinylmethylether/maleic
anhydride
copolymer with a 80,000-160,000 Mw range for increased adhesion between
the solidified layer and the skin), and a hydrofluorocarbon as a propellant.
After
a layer of the formulation is sprayed on the skin, the propellant evaporates
quickly and the formulation solidifies into a soft, coherent, and flexible
solid
layer. Clobetasol propionate is delivered from this layer into the psoriatic
skin
surface over at least 2 hours, and preferably over at least 6 hours, for
suppressing the psoriasis.
While the invention has been described with reference to certain
preferred embodiments, those skilled in the art will appreciate that various
modifications, changes, omissions, and substitutions can be made without
departing from the spirit of the invention. It is therefore intended that the
invention be limited only by the scope of the appended claims.
