Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS 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
formulations
including at least two non-volatile solvents, wherein the formulation as a
whole
has a viscosity suitable for application as a layer to a skin surface, and
which
forms a sustained drug-delivering adhesive solidified layer on the skin.
BACKGROUND OF THE INVENTION
Traditional dermal drug delivery systems can generally be classified into
two forms: semisolid formulations and dermal patch dosage forms. Semisolid
formulations are available in a few different forms, including ointments,
creams,
foams, pastes, gels, or lotions and are applied topically to the skin. Dermal
(including transdermat) patch dosage forms also are available in a few
different
forms, including matrix patch configurations and liquid reservoir patch
configurations. In a matrix patch, the active drug is mixed in an adhesive
that is
coated on a backing film. The drug-laced adhesive layer is typically directly
applied onto the skin and serves both as means for affixing the patch to the
skin
and as a reservoir or vehicle for facilitating delivery of the drug.
Conversely, in a
liquid reservoir patch, the drug is typically incorporated into a solvent
system
which is held by a thin bag, which can be a thin flexible container. The thin
bag
can include a permeable or semi-permeable membrane surface that is coated
with an adhesive for affixing the membrane to the skin. The membrane is often
referred to as a rate limiting membrane (although it may not actually be rate
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limiting in the delivery process in all cases) and can control transport of
the drug
from within the thin bag to the skin for dermal delivery.
While patches and semisolid formulations are widely used to deliver
drugs into and through the skin, they both have significant limitations. For
example, most semisolid formulations usually contain solvent(s), such as water
and ethanol, which are volatile and thus evaporate shortly after application.
The
evaporation of such solvents can cause a significant decrease or even
termination of dermal drug delivery, which may not be desirable in many cases.
Additionally, semisolid formulations are often "rubbed into" the skin, which
does
not necessarily mean the drug formulation is actually delivered into the skin.
Instead, this phrase often means that a very thin layer of the drug
formulation is
applied onto the surface of the skin. Such thin layers of traditional
semisolid
formulations applied to the skin may not contain sufficient quantity of active
drug
to achieve sustained delivery over long periods of time. Additionally,
traditional
semisolid formulations are often subject to unintentional removal due to
contact
with objects such as clothing, which may compromise the sustained delivery
and/or undesirably soil clothing. Drugs present in a semisolid formulation
rimay
also be unintentionally delivered to persons who come in contact with a
subject
undergoing treatment with a topical semisolid formulation.
With respect to matrix patches, in order to be delivered appropriately, a
drug should have sufficient solubility in the adhesive, as primarily only
dissolved
drug contributes to the driving force required for skin permeation.
Unfortunately,
solubility in adhesives that is too low does not generate adequate skin
permeation driving force over sustained period of time. ln addition, many
ingredients, e.g., liquid solvents and permeation enhancers, which could be
used to help dissolve the drug or increase the skin permeability, may not be
able to be incorporated into many adhesive matrix systems in sufficient
quantities to be effective. For example, at functional levels, most of these
materials may adversely alter the wear properties of the adhesive. As such,
the
selection and allowable quantities of additives, enhancers, excipients, or the
like
in adhesive-based matrix patches can be limited. To illustrate, for many
drugs,
optimal transdermal flux can be achieved when the drug is dissolved in certain
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liquid solvent systems, but a thin layer of adhesive in a typical matrix patch
often
cannot hold enough appropriate drug and/or additives to be therapeutically
effective. Further, the properties of the adhesives, such as coherence and
tackiness, can also be significantly changed by the presence of liquid
solvents
or enhancers.
Regarding liquid reservoir patches, even if a drug is compatible with a
particular liquid or semisolid solvent system carried by the thin bag of the
patch,
the solvent system still has to be compatible to the adhesive layer coated on
the
permeable or semi-permeable membrane; otherwise the drug may be adversely
affected by the adhesive layer or the drug/solvent system may reduce the
tackiness of the adhesive layer. In addition to these dosage form
considerations, reservoir patches are bulkier and usually are more expensive
to
manufacture than matrix patches.
Another shortcoming of dermal (including transdermal) patches is that
they are usually neither stretchable nor flexible, as the backing film (in
matrix
patches) and the thin fluid bag (in reservoir patches) are typically made of
polyethylene or polyester, both of which are relatively non-stretchable
materials.
If the patch is applied to a skin area that is significantly stretched during
body
movements, such as a joint, separation between the patch and skin may occur
thereby compromising the delivery of the drug. In addition, a'patch present on
a
skin surface may hinder the expansion of the skin during body movements and
cause discomfort. For these additional reasons, patches are not ideal dosage
forms for skin areas subject to expansion, flexing and stretching during body
movements.
In view of the shortcomings of many of the current 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.
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SUMMARY OF THE INVENTION
Although film-forming technologies have been used in cosmetic and
pharmaceutical preparations, typically, the solvents used in such systems
evaporate shortly after application, and thus, are not optimal for sustained-
release applications. In accordance with this, it has been recognized that the
use of multiple non-volatile solvents, multiple volatile solvents, and/or
multiple
solidifying agents in the formulation can often optimize sustained drug
delivery.
In accordance with this, it would be advantageous to provide dermal
delivery formulations, systems, and/or methods in the form of adhesive
compositions or formulations having a viscosity suitable for application to
the
skin surface and which form a drug-delivering solidified layer on the skin
that is
optionally peelable or otherwise easily removable after use. As such, an
adhesive formulation for dermal delivery of a drug can comprise a drug, a
solvent vehicle, and at least one solidifying agent. The solvent vehicle can
comprise a volatile solvent system including at least one volatile solvent and
a
non-volatile solvent system including at least one non-volatile solvents. The
at
least two non-volatile solvents of the non-volatile solvent system can
facilitate
transdermal delivery of the drug at a therapeutically effective rate over a
sustained period of time, even after the non-volatile solvent system is
substantially evaporated from the solidified layer. The formulation can have
viscosity suitable for application to the skin surface prior to evaporation of
at
least one volatile solvent, and can further be formulated such that when
applied
to the skin surface, the formulation forms a solidified layer after at least a
portion
of the volatile solvent system is evaporated. Sustained drug deliGery from the
solidified layer can also occur. The formulation is formulated such that it
has at
least two volatile solvents, at least two non-volatile solvents, at least two
solidifying agents, or combinations thereof.
In an alternative embodiment, a method of dermally delivering a drug can
comprise applying an adhesive formulation to a skin surface of a subject. The
formulation be any formulation as set forth above. Other steps include
solidifying the formulation to form a solidified layer on the skin surface by
at
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least partial evaporation of the volatile solvent system, and dermally
delivering
the drug from the solidified layer to the skin surface at therapeutically
effective
rates over a sustained period of time.
In another embodiment, a solidified layer for delivering a drug can
5 comprise a drug, a non-volatile solvent system including at least one non-
volatile solvents, wherein the non-volatile solvent system is capable of
facilitating the delivery of the drug at therapeutically effective rates over
a
sustained period of time, and at least one solidifying agent. In one
embodiment,
the solidified layer can be stretchable by 5% in one direction without
cracking,
breaking, or separating from a skin surface to which the layer is applied. The
formulation is formulated such that it has at least two non-volatile solvents,
at
least two solidifying agents, or combinations thereof.
Additional features and advantages of the invention will be apparent from
the following detailed description and figures which illustrate, by way of
example, features of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I is a graphical representation of cumulative amount of testosterone
delivered across a biological membrane in vitro over time from a solidified
adhesive formulation and a marketed product (AndroGel) in accordance with
embodiments of the present invention.
FIG. 2 is a graphical representation of the cumulative amount of acyclovir
delivered transdermally over time from two separate formulations in accordance
with embodiments of the present invention compared to the marketed product
Zovirax cream.
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
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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 example, 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.
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
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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. "Topical
delivery"
includes delivery of a drug to a skin tissue, and subsequent absorption into
deeper tissues that may occur.
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 I 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
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
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 effective
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 effective 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
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skin with no more than 500 cm2 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 effective 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
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 effective 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
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"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" 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 in that some of the patient 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/400cm2/10 hour, which equals I
mcg/cm2/hr. By this definition, different drugs have different
"therapeutically
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effective flux. Therapeutically effective flux may also 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.
5 The following are estimates of flux for some drugs that are therapeutically
effective:
Table 1- In vitro steady state flux values of various drugs
Estimated Therapeutically
Drug Indication effective flux*
mc /cm2/h
Ropivacaine** Neuropathic pain 5
Lidocaine Neuropathic pain 30
Ac c(ovir Herpes simplex virus 3
Ketoprofen Musculoskeletal pain 16
Diclofenac Musculoskeletal pain I
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
Imiquimod Warts, basal cell
carcinoma 0'92
* Flux determined using an in vitro method described in Example 1.
10 ** Estimated flux based on known potency relative to lidocaine.
The therapeutically effective flux values in Table 1(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, different
individual subjects, etc. It should be noted that the flux listed may be more
than
therapeutically effective.
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The following examples listed in Table 2 illustrate screening of a 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 2- 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 Monotaurate 0.03 0.02
Clobetasol Propionate Propylene Glycol (PG) 0.0038 0.0004
Light Mineral Oil 0.031 0.003
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 15t3
Acyclovir Pol eth lene I co1400 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 2 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
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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.
Different drugs often have different matching flux-enabling non-volatile
solvent systems which provide particularly good results. Examples of such are
noted in Table 3. Experiments were carried out as described in Example I
below.
Table 3 - In vitro steady state flux values of various drugs from particularly
high
flux-enablin non-volatile solvent systems
Drug High flux-enabling non- Avg. Flux*
volatile solvent mc /cm2/h
Ropivacaine ISA 11 2
S an 20 26 8
Ketoprofen Propylene glycol (PG) 90 50
Acycolvir ISA + 30 /a trolamine 7 2
Betamethasone Propylene Glycol
Di ro ionate 0.20 0.07
Clobetasol PG+ISA (Ratio of PG:ISA
propionate ran in from 200:1 to 1:1 0'8 0'2
* 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
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 3 is a 9:1 for propylene glycol:isostearic acid mixture that
generated
much higher clobetasol flux than propylene glycol or 1SA alone (see Table 2).
Therefore, the 9:1 propylene glycol:isostearic acid mixture is a "high flux-
enabling non-volatile solvent" but propylene glycol or isostearic acid alone
is
not.
The term "adhesion" or "adhesive" when referring to a solidified layer
herein refers 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.
Thus, "adhesive" or the like when used to describe the solidified layer means
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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
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," "elastic," "elasticity," or the like, as used herein
refer
to sufficient elasticity of the solidified layer so that it is not broken if
it is
stretched in at least one direction by up to about 5%,. and often to about 10%
or
even greater. For example, a solidified layer that exhibits acceptably
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
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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.
"Volatile solvent system" can be a single solvent or a mixture of solvents
that are volatile, including water and solvents that are more volatile than
water.
Non-limiting examples of volatile solvents that can be used in the present
invention include iso-amyl acetate, denatured alcohol, methanol, ethanol,
isopropyl alcohol, water, propanol, C4-C6 hydrocarbons, butane, isobutene,
pentane, hexane, acetone, chlorobutanol, ethyl acetate, fluro-chloro-
hydrocarbons, turpentine, methyl ethyl ketone, methyl ether,
hydrofluorocarbons, ethyl ether, 1,1,1,2 tetrafluorethane
1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, and
combinations thereof.
"Non-volatile solvent system" in this invention is defined as a mixture of at
least two solvents that are each less volatile than water. Similarly, a non-
volatile
solvent is defined as a solvent that is less volatile than water. The non-
volatile
solvent system 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 a period of time sufficient to adequately dermally
deliver 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.
The non-volatile solvent system can also serve as a plasticizer of the
solidified layer, so that the solidified layer is elastic and flexible. In one
embodiment, the non-volatile solvent system provides better plasticizing
effects
for the solidifying agents than any single non-volatile solvent of the non-
volatile
solvent system alone. Including multiple non-volatile solvents as part of the
non-volatile solvent system can also provide various other benefits. In some
cases, a single non-volatile solvent may not provide the formulation with
adequate compatibility with other ingredients in the formulation, e.g.
volatile
solvent system or solidifying agent, and/or the ability to generate
therapeutically
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effective flux of the drug. In one aspect of the invention, the non-volatile
solvent
system provides better compatibility with the solidifying agent than any
single
non-volatile solvent of the non-volatile solvent system alone. In another
aspect
of the invention, the non-volatile solvent system provides higher flux than
any
5 single non-volatile solvent of the non-volatile solvent system alone. The
present
invention allows for combinations of two or more non-volatile solvents which
together are able to provide both therapeutically effective drug flux while
maintaining formulation component compatibility.
The term "solvent vehicle" describes compositions that include both a
10 volatile solvent system and non-volatile solvent system. The volatile
solvent
system is chosen so as to evaporate from the adhesive formulation quickly to
form a solidified layer, and the non-volatile solvent system is formulated or
chosen to substantially remain as part of the solidified layer after volatile
solvent
system evaporation so as to provide continued delivery of the drug. Typically,
15 the drug can be partially or completely dissolved in the solvent vehicle or
formulation as a whole. Likewise, the drug can also be partially or completely
solubilizable in the non-volatile solvent system once the volatile solvent
system
is evaporated. Formulations in which the drug is only partially dissolved in
the
non-volatile solvent system after the evaporation of the volatile solvent
system
have the potential to maintain longer duration of sustained delivery, as the
undissolved drug can dissolve into the non-volatile solvent system as the
dissolved drug is being depleted from the solidified layer during drug
delivery.
"Adhesive solidifying formulation" or "solidifying formulation" refers 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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16
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 acrylsan
alkyl/octylacrylamido (Dermacryl 79), and/or various aliphatic resins and
aromatic resins.
The terms "washable," "washing" 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,
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methanol, isopropyl alcohol, acetone, ethyl acetate, propanol, and
combinations
thereof. In aspect of the invention the washing solvents can be selected from
the group consisting of water, ethanol, isopropyl alcohol and combinations
thereof. Surfactants can also be used in some embodiments.
An acceptable length of time with respect to "drying time" refers 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 or dried 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 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).
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
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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With these definitions in mind, the present invention is drawn to an
adhesive formulation for dermal delivery of a drug can comprise a drug, a
solvent vehicle, and a solidifying agent. The solvent vehicle can comprise a
volatile solvent system including at least one volatile solvent and a non-
volatile
solvent system including at least two non-volatile solvents. The at least two
non-volatile solvents of the non-volatile solvent system can facilitate
transdermal
delivery of the drug at a therapeutically effective rate over a sustained
period of
time, even after the non-volatile solvent system is substantially evaporated..
The formulation can have viscosity suitable for application to the skin
surface
prior to evaporation of at least one volatile solvent, and can further be
formulated such that when applied to the skin surface, the formulation forms a
solidified layer after at least a portion of the volatile solvent system is .
evaporated. Sustained drug delivery from the solidified layer can also occur.
In an alternative embodiment, a method of dermally delivering a drug can
comprise applying an adhesive solidifying formulation to a skin surface of a
subject. The formulation can comprise a drug, solvent vehicle, and a
solidifying
agent. The solvent vehicle can comprise a volatile solvent system including at
least one volatile solvent, and a non-volatile solvent system including at
least
two non-volatile solvents, wherein the non-volatile solvent system facilitates
dermal delivery of the drug at a therapeutically effective rate over a
sustained
period of time. The formulation can have a viscosity suitable for application
and
adhesion to the skin surface prior to evaporation of the volatile solvent
system
Other steps include solidifying the formulation to form a solidified layer on
the
skin surface by at least partial evaporation of the volatile solvent system;
and
dermally delivering the drug from the solidified layer to the skin surface at
therapeutically effective rates over a sustained period of time.
In another embodiment, a solidified layer for delivering a drug can
comprise a drug, a non-volatile solvent system including at least two non-
volatile
solvents, wherein the non-volatile solvent system is capable of facilitating
the
delivery of the drug at therapeutically effective rates over a sustained
period of
time, and a solidifying agent. The solidified layer can be stretchable by 5%
in at
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least one direction without cracking, breaking, or separating from a skin
surface
to which the layer is applied.
In another embodiment, an adhesive formulation for dermal delivery of a
drug can comprise a drug, a solvent vehicle, and at least two solidifying
agents.
5 The solvent vehicle can include a volatile solvent system including at least
one
volatile solvent, and a non-volatile solvent system including at least one non-
volatile solvent wherein the non-volatile solvent system can be flux-enabling
for
the drug such that the drug can be delivered in therapeutically effective
amounts
even after most of the volatile solvent(s) is(are) evaporated. The formulation
10 can have a viscosity suitable for application and adhesion to a skin
surface prior
to evaporation of the volatile solvent system, and can form a solidified layer
after
at least partial evaporation of the volatile solvent system after skin
application.
The drug can continue to be dermally delivered after the volatile solvent
system
is substantially evaporated.
15 In another embodiment, a method of dermally delivering a drug can
comprise applying an adhesive solidifying formulation to a skin surface of a
subject. The formulation can include a drug, a solvent vehicle, and at least
two
solidifying agents. The solvent vehicle can comprise a volatile solvent system
including at least one volatile solvent, and a non-volatile solvent system
20 including at least one non-volatile solvent. The formulation can have a
viscosity
suitable for application and adhesion to the skin surface prior to evaporation
of
the volatile solvent system. Other steps include solidifying the formulation
to
form a solidified layer on the skin surface by at least partial evaporation of
the
volatile solvent system; and dermally delivering the drug from the solidified
layer
to the skin surface at therapeutically effective rates over a sustained period
of
time.
In another embodiment, a solidified layer for delivering a drug can
comprise a drug, a non-volatile solvent system comprising at least one non-
volatile solvent, and at least two polymeric solidifying agents.
In yet another embodiment, a formulation for dermal delivery of a drug
can comprise a drug, a solvent vehicle, and a solidifying agent. The solvent
vehicle can comprise a volatile solvent system including at least two volatile
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solvents, and a non-volatile solvent system including at least one non-
volatile
solvent. The formulation has a viscosity suitable for application and adhesion
to
a skin surface prior to evaporation of the volatile solvent system wherein the
non-volatile solvent system can be flux-enabling for the drug such that the
drug
can be delivered at a therapeutically effective amount even after most of the
volatile solvent(s) is(are) evaporated. The formulation applied to the skin
surface
can form a solidified layer after at least partial evaporation of the volatile
solvent
system and can further be formulated such that when applied to the skin
surface, the formulation forms a solidified layer after at least a portion of
the
volatile solvents is (are) evaporated, but yet continues to deliver drug after
substantially solidifying. Additionally, the drug can continue to be delivered
after
the volatile solvent system is at least substantially evaporated.
In another embodiment, a method of dermally delivering a drug can
comprise applying an adhesive solidifying formulation to a skin surface of a
subject. The adhesive formulation can comprise a drug, a solvent vehicle, and
a solidifying agent. The solvent vehicle can comprise a volatile solvent
system
including at least two volatile solvent, and a non-volatile solvent system
including at least one non-volatile solvent. The formulation can have a
viscosity
suitable for application and adhesion to the skin surface prior to evaporation
of
the volatile solvent system. Other steps include solidifying the formulation
to
form a solidified layer on the skin surface by at least partial evaporation of
the
volatile solvent system; and dermally delivering the drug from the solidified-
layer
to the skin surface at therapeutically effective rates over a sustained period
of
time.
In further detail, the formulations 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 a period of time sufficient
to
adequately dermally deliver 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. The
non-
volatile solvent system can also serve as a plasticizer of the solidified
layer, so
that the solidified layer is elastic and flexible.
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Thus, these embodiments exemplify the present invention which is
related to novel formulations, methods, and solidified layers that are
typically in
the initial form of semi-solids (including creams, gels, pastes, ointments,
and
other viscous liquids), which cari be easily applied onto the skin as a layer,
and
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 which can be peelable, for drug delivery. A
solidified layer thus formed is capable of delivering drug to the skin, into
the
skin, across the skin, etc., at substantially constant rates, over an
sustained
period of time, e.g., hours to tens of hours, so that most of the active drug
is
delivered after the solidified layer is formed.
Although a solid layer-forming formulation for dermal drug delivery can
use a single solidifying agent, the use of two or more solidifying agents in
the
formulation herein can provide important advantages. This is because in
addition to solidifying,the formulations, the solidifying agent(s) in the
formulation
often impacts component compatibility as well as flexibility and skin
adhesiveness of the solidified layer. Sometimes it takes two or more
solidified
agents to address all these needs. The present invention is related to
solidifying
formulations that use two or more solidified agents to produce better
formulation
properties than any single solidifying agent alone within a given formulation
could accomplish.
Additionally, the solidified layer typically adheres to tlie 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 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, or other joints.
In selecting the various components that can be used, e_g., drug, solvent
vehicle of volatile solvent system and non-volatile solvent system,
solidifying
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23
agent(s), etc., various considerations can occur. For example, the volatile
solvent system can be selected from pharmaceutically or cosmetically
acceptable solvents known in the art. In one embodiment of the present
invention, the volatile solvent system can include ethanol, isopropyl alcohol,
water, dimethyl ether, diethyl ether, butane, propane, isobutene, 1,1,
difluoroethane, 1,1,1,2 tetrafluorethane, 1,1,1,2,3,3,3-heptafluoropropane,
1,1,1,3,3,3 hexafluoropropane, ethyl acetate, acetone or combinations thereof.
In another embodiment of the present invention, the volatile solvent system
can
include iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene,
pentane, hexane, chlorobutanol, turpentine, cytopentasiloxane, cyclomethicone,
methyl ethyl ketone, or combinations thereof. The volatile solvent system can
include a mixture or combination of any of the volatile solvents set forth in
the
embodiments above.
In one embodiment, of the present invention the volatile, solvent system
comprises at least one volatile solvent with a boiling point higher than 20 C
(a
liquid volatile solvent) and at least one volatile solvent with a boiling
point lower
than about 20 C (gaseous volatile solvents). Boiling points refer to boiling
points measured at normal atmospheric pressure. Formulations of the present
invention which have both liquid and gas volatile solvents can have
significantly
shorter drying times than those with only liquid volatile solvents. When a gas
volatile solvent is included in the volatile solvent system, it is often the
case that
concentration of the gas volatile solvent is below the formulations
solubility.
This allows the formulation to be stored in containers for conventional, un-
pressurized semi-solid products. Alternatively, these solvents can be used as
propellants for spray-on formulations. Examples of gas volatile solvents which
may be used in the present invention include but are not limited to ether,
dimethyl ether, diethyl ether, propane, isobutene, diflouroethane, butane,
1,1,1,2 tetraflourethane, 1,1,1,2,3,3,3-heptaflouropropane, and 1,1,1,3,3,3,
hexaflouropropane, and combinations thereof.
Additionally, these volatile solvents should be chosen to be compatible
with the rest of the formulation. It is desirable to use an appropriate weight
percentage of the volatile solvent(s) in the formulation. Too much of the
volatile
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solvent system prolongs the drying time. Too little of the volatile solvent
system
can make it difficult to spread the formulation on the skin. For most
formulations, the weight percentage of the volatile solvent(s) can be from
about
wt% to about 85 wt%, and more preferably from about 20 wt% to about 50
5 wt%. In one aspect of the invention, the volatile solvent system comprises
at
least 10 wt% of the formulation. In another embodiment, the volatile solvent
system comprises at least about 20 wt% of the formulation.
The volatile solvent system can also be chosen to be compatible with the
non-volatile solvent system, solidifying agent, drug, and any other excipients
10 that may be present. For example, polyvinyl alcohol (PVA) is not soluble in
ethanol. Therefore, a volatile solvent which will dissolve PVA needs to be
formulated in the solidified layer. For instance, water will dissolve PVA and
can
be utilized as a volatile solvent in a formulation; however, the drying time
in such
a formulation may be too long to certain applications. Therefore, a second
volatile solvent (e.g., ethanol) can be formulated into the formulation to
reduce
the water content but maintain a sufficient amount of water to keep PVA in
solution and thereby reduce the drying time for the formulation.
The volatile solvent system can be chosen to reduce drying time for the
formulation. Returning to the PVA example above, the use of waterto dissolve
the PVA may result in the drying time in such a formulation may be too long to
certain applications. Therefore, a second volatile solvent (e.g., ethanol) can
be
formulated into the formulation to reduce the water content but maintain a
sufficient amount of water to keep PVA in solution and thereby reduce the
drying time for the formulation.
The volatile solvent can be chosen to improve solubility of a particular
drug form utilized in the formulation. For example, ropivacaine HCI is not
soluble in non-volatile solvents isostearic acid, triacetin, and Span 20.
Therefore, addition of water to the formulation will aid in dissolving the
ropivacaine HCI and with addition of a small amount of base to dissolve the
remaining drug crystals. Complete dissolution of ropivacaine in the
formulation
is advantageous to having to avoid suspending the undissolved drug particles
in
a formulation with a relatively low viscosity that may result in drug
settling.
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For a selected drug or a selected solidifying agent, some volatile solvents
may be better solvents or more compatible than other volatile solvents.
However, some times, the most suitable volatile solvent for a drug is not
compatible with a solidifying agent, and vice versa. In some other situations,
the
5 most suitable volatile solvent for a drug and a solidifying agent evaporates
to
slowly resulting in a drying time that is unacceptable for the application. In
the
above situations, satisfactory compromises may be reached by using a specially
formulated volatile solvent systems that contains two or more volatile
solvents
according to certain ratios (which are often experimentally determined). For
10 example, one solvent can provide acceptable evaporation time, and another
volatile solvent provides improved formulation compatibility.
In one embodiment of the present invention, one of the volatile solvents
of the volatile solvent system can be less volatile than the other. The less
volatile solvent can have better compatibility with the solidifying agent as
15 compared to a more volatile solvent in the solvent system.
In another aspect of the present invention, it can be beneficial to retain or
delay the volatilization of the volatile solvent system so that the
solidifying
formulation can maintain its desirable wear, and drug delivery properties.
Such
retention can be accomplished by including a volatile solvent retaining
20 substance in the formulation. Volatile solvent retaining substances can
include
water, hygroscopic substances, honey, glycerol, propylene glycol, and the
like.
The non-volatile solvent system can also be chosen or formulated to be
compatible with the solidifying agent, the drug, the volatile solvent, and any
other ingredients that may be present. For example, the solidifying agent can
25 be chosen so that it is dispersible or soluble in the non-volatile solvent
system.
Most non-volatile solvent systems and solvent vehicles 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
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26
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 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. It is not necessary that both the non-volatile
solvents
of the non-volatile solvent system be compatible with the solidifying agent.
In
some embodiments one of the non-volatile solvents of the non-volatile solvent
system can be present to provide compatibility with the solidifying agent
while a
second non-volatile solvent can act as the flux enabling non-volatile solvent.
In further detail, the at least two non-volatile solvents that can be used to
form non-volatile solvent systems can be selected from a variety of
pharmaceutically acceptable liquids. In one embodiment of the present
invention, 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, atkyldiols, 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, cinnamaidehyde,
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
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monoethyl ether, diglycerides, ethylene glycol, eucalyptus oil, fat, fatty
alcohols,
flavors, liquid sugars ginger extract, glycerin, high fructose corn syrup,
hydrogenated castor oil, IP paimitate, 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, polyglyceryi;
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
fatky
acid esters such as PEG 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, 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, ca prylate/cap rate, sodium
pyrrolidone carboxylate, sorbitol, squalene, stear-o-wet, triglycerides, alkyl
aryi
polyether alcohols, polyoxyethylene derivatives of sorbitan-ethers, saturated
polyglycolyzed C8-C10 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 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
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28
further embodiment, the non-volatile solvent system can include a combination
or mixture of non-volatile solvents set forth in any of the above discussed
embodiments.
In addition to these and other considerations, the non-volatile solvent
system, or at least one of the non-volatile solvents in 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 volatile and/or nonvolatile solvent(s) that are irritating to the skin
may be desirable to use to achieve the desired solubility and/or permeability
of
the drug. ft is also 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 volatile solvent is capable of
irritating
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 reducing skin irritation include, but are not limited to,
glycerin,
honey, and propylene glycol.
The feature of two non-volatile solvents in the non-volatile solvent system
enhances the ability of the non-volatile solvent to provide therapeutically
effective flux, while at the same time providing additional important
characteristics which make the solidified formulations superior. As discussed
in
other areas of the application, non-volatile solvents can provide advantageous
benefits such as acting as a plasticizer, improve adhesion, reducing skin
irritation, inhibiting phase separation, and the like. In some embodiments it
may
be desirable to deliver two drugs which do not share a common flux-enabling
non-volatile solvent. In such instances at least on of the at least two non-
volatile
solvents present in the non-volatile solvent system can act to promote the
flux of
one of the drugs while the other non-volatile solvent promotes the flux of the
other drug. In such situations it may be desirable or necessary to include an
additional non-volatile solvent which provides some of the other advantageous
benefits discussed above.
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The two or more non-volatile solvents of the non-volatile solvent system
of the present invention may be such that the non-volatile solvents used
independently are not flux-enabling non-volatile solvents for a drug but when
formulated together become a flux-enabling non-volatile solvent. One possible
reason for these initially non enabling non-volatile solvents to become
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 the
non-volatile solvents 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 an
adequate non-volatile solvent system include but are not limited to isostearic
acid /trolamine, isostearic acid /dilsopropyl amine, oleic acid/trolamine, and
propylene glycol /isostearic acid.
The selection of the solidifying agent can also be carried out in
consideration of the other components present in the adhesive formulation. The
solidifying agent cain be selected or formulated to be compatible to the drug
and
the solvent vehicle (including the volatile solvent(s) and the non-volatile
solvent
system), as well as to provide desired physical properties to the solidified
layer
once it is formed. Depending on the drug, solvent vehicle, 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 8) with a MW
range of 120,000-180,000, dimethylaminoethyl methacrylate-butyl methacrylate-
methyl methacrylate copolymer (Degussa Eudragit E100) with a MW range
of100,000-200,000, ethyl acrylate-methyl methacrylate-trimethyiammonioethy!
methacrylate chloride copolymer with a MW greater than 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
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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, N 10,
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,
5 acrylates/octylacrylamide copolymer MW greater than 5,000 or MW similar to
National Starch, Chemical Dermacryl 79, or combinations thereof.
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,
10 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,
15 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, rnicrocrystalline wax, polyvinyl acetate, PVP ethyl
cellulose,
acrylate, PEG/PVP, xantham gum, trimethyl siloxysilicate, maleic
acid/anhydride
20 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,
methacrylic acid-ethyl acrylate copolymers such as BASF's Kollicoat polymers,
methacrylic acid and methacrylate based polymers such as poly(methacrylic
25 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 vehicle components, the drug, and the specific
functional requirements of the given formulation. Other polymers may also be
30 suitable as the solidifying agent, depending on the solvent vehicle
components,
the drug, and the specific functional requirements of the given formulation.
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In 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. 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 ratio between the non-volatile solvent system and the solidifying agent
can
be from about 0.5:1 to about 2:1.
The use of at least two solidifying agents can provide superior peel
characteristics. Desirable characteristics can include enhanced elasticity,
enhanced skin adhesion, enhanced tensile strength, and the like. In some
embodiments, the combination of the at least two solidifying agents can
provide
a more homogenous formulation with minimal if any phase separation. For
example, in one embodiment, polyvinyl alcohol (PVA) can be used as one of the
solidifying agents in combination with Gantrez. In that combination, the PVA
functions to provide enhanced elasticity while the Gantrez provides enhanced
skin adhesion. In another embodiment, a formulation can be made which
utilizes Eudgragit E-1 00 in combination with PVA as the solidifying agent.
The
formulation has quicker solidifying characteristics and results in a
solidified layer
with enhanced tensile strength.
The thickness of the formulation layer applied on the skin should also be
appropriate for a given formulation and desired drug delivery considerations.
If
the layer is too thin, the amount of the drug may not be sufficient to support
sustained delivery over the desired length of time. If the layer is too thick,
it may
take too long to form a non-messy outer surface of the solidified layer. If
the
drug is very potent and the solidified layer has very high tensile strength, a
layer
as thin as 0.01 mm may be sufficient. If the drug has rather low potency and
the
solidified layer has low tensile strength, a layer as thick as 2-3 mm may be
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desirable. Thus, for most drugs and formulations, the appropriate thickness
can
be from about 0.01 mm to about 3 mm, but more typically, from about 0.05 mm
to about 1 mm.
The flexibility and stretchability of a solidified layer can be desirable in
some applications. In one aspect of the invention, the solidified layer is
coherent, flexible, and continuous. Such flexible and coherent nature can
greatly enhance the ease of use of the formulation. For instance, certain non-
steroidal anti-inflammatory agents (NSAIDs) can be applied directly over
joints
and muscles 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 NSAfDs into joints and/or muscles, the
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 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. For instance,
if
the formulation is applied on a small facial area overnight for treating acne,
a
subject would experience minimal discomfort and formulation-skin separation
even if the solidified layer is not stretchable, as facial skin usually is not
stretched very much during a sleep cycle.
A further feature of a formulation prepared in accordance with
= 25 embodiments of the present invention is related to drying time. If a
formulation
dries too quickly, the user may not have sufficient time to spread the
formulation
into a thin layer on the skin surface before the formulation is solidified,
leading to
poor skin contact. If the 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 longer than about 15 seconds but shorter than about 15 minutes, and
preferably from about 0.5 minutes to about 5 minutes.
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Other benefits of the solidified layers of the present invention include the
presence of a physical barrier that can be formed by the material itself. 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.
These and other advantage can be summarized in the following non-
limiting list of benefits, as follows. The solidified layers of the present
invention
can be prepared in an initial form that is easy to apply as a semisolid dosage
form. Additionally, upon volatile solvent system evaporation, the resulting
solidified layer is relatively thick and can contain much more active drug
than a
typical layer of traditional cream, gel, lotion, ointment, paste, etc., and
further, is
not as subjeat to unintentional removal. Further, as the solidified layer
remains
adhesive and optionally peelable, easy removal of the solidified layer can
occur,
usually 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 solidified layer is applied. Still further, the solidified layer can
be
formulated to advantageously deliver drug and protect sensitive skin areas
without cracking or breaking. Generally, the solidified layers made using the
formulations of the present invention can be soft and coherent solids that are
peelable from a skin surface as a single piece or as only a few large pieces
relative to the application size. In other embodiments, the solidified layer
can be
removable by use of a solvent, such as water, alcohol, surfactant, or mixture
thereof.
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
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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 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 including bupivacaine, lidocaine, or
ropivacaine,
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 solidified layer 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% clindamycin and 5 wt% benzoyl
peroxide can be combined in a solidified layer 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, or an antihistamine solidified layer can be
prepared for treating allergic rashes such as poison ivy.
Additional applications include delivering drugs for treating certain skin
conditions, e.g., dermatitis, psoriasis, eczema, skin cancer, 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, common and genital warts, and actinic keratosis. Solidifying
formulations containing antiviral drugs such as acyclovir, penciclovir,
famciclovir,
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valacyclovir, steroids, 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
5 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
10 stop the delivery of a drug due to the evaporation of solvent and/or
unintentional
removal of the formulation. The solidified adhesive formulations of the
present
invention address the shortcomings of both of these types of delivery systems.
A further embodiment involves a formulation containing at least one
alpha-2 agonist drug, at least one tricyclic antidepressant agent, and/or at
least
15 one local anesthetic drug which is applied topically to treat neuropathic
pain.
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
after 2-5 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
20 formulation on the skin surface.
Another embodiment involves a 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 after 2-5 minutes and remains
25 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.
Another embodiment involves solidifying formulations containing tazorac
for treating stretch marks, wrinkles, sebaceous hyperplasia, seborrheic
keratosis. In another embodiment, solidifying formulations containing glycerol
30 can be made so as to provide a protective barrier for fissuring on finger
tips.
Still another embodiment can include a formulation containing a drug
selected from the local anesthetic class such lidocaine and ropivacaine or the
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like, or NSAID class, such as ketoprofen, piroxicam, diclofenac, indomethacin,
or the like, which is applied topically to treat symptoms of back pain, muscle
tension, or myofascial pain or a combination thereof. The local anesthetic
and/or NSAID is gradually released from the formulation to provide pain relief
over a sustained period of time. The formulation can become a coherent, soft
solid after about 2-5 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.
A similar embodiment can include a formulation containing drugs
capsaicin and a local anesthetic drug which is applied topically to the skin
to
provide pain relief. Another embodiment can include a 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 after 2-4 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
that treat 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
diclofanec, COX-2 selective NSAIDs and agents, COX-3 selective NSAIDs and
agents, local anesthetics such as lidocaine, bupivacaine, ropivacaine, and
tetracaine, 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
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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.
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 and diabetes induced neuropathic pain. 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 other drugs including capsaicin and alpha-2 agonists such as clonidine,
dissociative anesthetics such as ketamine, tricyclic antidepressants such as
amitriptyline,.
As set forth in part above, 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, bupivacalne,
ropivacaine, and tetracaine, amitriptyline, ketanserin, betamethasone
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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, tolnaftate,
and
undecylenate, or combinations thereof.
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 tetracaine; 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
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as clindamycin and benzoyl peroxide, retinol, vitamin A derivatives such as
tazarotene and isotretinoin, cyclosporin, anthralin, vitamin D3,
cholecalciferol,
calcitriol, calcipotriol, tacalcitol, calcipotriene, or combinations thereof.
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,
trichloroacetic
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
of progesterone, norethindrone, norethindroneacetate, desogestrel,
drospirenone, ethynodiol diacetate, norelgestromin, norgestimate,
levonorgestrel, dl-norgestrei, cyproterone acetate, dydrogesterone,
medroxyprogesterone acetate, chlormadinone acetate, megestrol,
promegestone, norethisterone, lynestrenal, gestodene, tibolene, androgens
consisting of testosterone, methyl testosterone, oxandrolone, androstenedione,
dihydrotestosterone. estrogens consisting of estradiol, ethniyi 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, flurandrenolide,
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.
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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 tripelennamine. These agents
5 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;
10 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
methods of the current invention include humectants, emollients, and other
skin
care compounds.
15 EXAMPLES
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
20 invention. Numerous modifications. and alternative compositions, methods,
and
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
25 further detail in connection with what are presently deemed to be the most
practical and preferred embodiments of the invention.
Example I
Hairless mouse skin (HMS) or human epidermal membrane (HEM) is
30 used as the modelmembrane for the in vitro flux studies described in
herein.
Freshly separated epidermis removed from the abdomen of a hairless mouse is
mounted carefully between the donor and receiver chambers of a Franz
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diffusion cell. The receiver chamber is filled with pH 7.4 phosphate buffered
saline (PBS). The experiment is initiated by placing test formulations on the
stratum corneum (SC) of the skin sample. Franz cells are placed in a heating
block maintained at 37 C and the HMS temperature is maintained at 35 C. At
predetermined time intervals, 800 L aliquots are withdrawn and replaced with
fresh PBS solution. Skin flux ( g/cm2/h) is determined from the steady-state
slope of a plot of the cumulative amount of permeation versus time. It is to
be
noted that human cadaver skin can be used as the model membrane for the in
vitro flux studies as well. The mounting of the skin and the sampling
techniques
used as the same as described above for the HMS studies.
Examgle 2
Human cadaver skin is used as a membrane to select a non-volatile
solvent for clobetasol propionate. In vitro methodology is described in
Example
1. About 200mcL of 0.1 %(w/w) solution of clobetasol in various non-volatile
solvents is added to the donor compartment of Franz cells. Results obtained
after LC analysis are shown in Table 4.
Table 4 - Non volatile solvents for clobetasol propionate
Non-volatile solvent system Skin Flux*
n /cm /h
Propylene Glycol 3.8 0.4
Glycerol 7.0 4.1
Light Mineral Oil 31.2 3.4
Isostearic Acid (ISA) 19.4 3.2
Ethyl Oleate 19.4 1.6
Olive Oil 13.6 3.3
Propylene Glycol/ISA (9:1) 764.7 193.9
* Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 6-28 hours. If the
experiment was continued it is anticipated the steady state would
continue.
All the neat non-volatile solutions studied have an average flux of less
than 40 ng/cm2/hr over the 30 hour time period. Propylene glycol and glycerol
have the lowest permeation for clobetasol propionate. A mixture of propylene
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glycol and isostearic acid at a weight ratio of 9:1 have significantly higher
flux
than either of the solvents alone or with the other solvents tested. The
average
flux is 20 times higher than that with light mineral oil which is the best non-
mixed
solvent. Hence, for clobetasol propionate, propylene glycol/isostearic acid
combination is a good candidate for a non-volatile solvent system.
Examples 3-8
Adhesive formulations containing 0.05% (w/w) clobetasol propionate with
propylene glycol and isostearic acid as non volatile solutions and various
solidifying agents are prepared. The formulations are prepared from the
ingredients as shown in Table 5.
Table 5- Solidif in formulation com onents
Percent Percent Percent Percent Percent
Example Polymer Polymer Ethanol Propylene Isostearic Water
Gi col Acid
3 Polyvinyl 20 30 19.6 0.4 30
Alcohol
4 Shellac 50 30 19.6 0.4 0
5 Dermacryl 65.76 21.16 12.76 0.26 0
79
6 Eudragit 50 30 19.6 0.40 0
E100
7 Eudragit 50 30 19.6 0.40 0
RLPO
8 Gantrez 14.3 57.1 28 0.6 0
S97
Each of the compositions shown above are studied for flux of clobetasol
propionate as shown in Table 6 as follows:
Table 6 - Steady state flux of Clobetasol propionate through human
cadaver skin at 35 C
Formulation Skin Flux*
n /cm2/h
Exam le3 87.8 21.4
Example 4 9.7 2.4
Exam le5 8.9 0.8
Exam le6 3.2 1.7
Example 7 20.2 18.6
Exam le 8 147.5 38.8
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~ Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
piots. The linear region was observed to be between 6-28 hours. If the
experiment was continued it is anticipated the steady state would
continue.
As seen from Table 6 formulation described in Example 3 that contains
polyvinyl alcohol as solidifying agent has high flux of clobetasol propionate.
Polyvinyl alcohol is known to form stretchable films and it is likely that
this
formulation will have acceptable wear properties. The toughness of the
resulting
film can be modified by adding appropriate plasticizers if needed. Tackiness
can
also be modified by adding appropriate amounts of tackifier or by adding
appropriate amounts of another solidifying agent such as Dermacryl 79.
Regarding formulation described in Example 8, a higher percentage of
ethanol is needed to dissolve the polymer. However, the solidifying agent used
in Example 8 provides the highest flux of clobetasol propionate among the
solidifying agents studied. The wear properties of this formulation can be
modified by adding appropriate levels of other ingredients including but not
limited to plasticizers, tackifiers, non-volatile solvents and or solidifying
agents.
Example 9
Formulations of acyclovir in various non-volatile solvent systems are
evaluated. Excess acyclovir is present. The permeation of acyctovir from the
test formulations through HMS is presented in Table 7 below.
Table 7
Non-volatile solvent system Skin Flux*
mc /cm /h
lsostearic acid 0.1 0.09
lsostearic acid + 10% trolamine 2.7 t 0.6
Isostearic acid + 30% trolamine 7 2
Olive oil 0.3 0.2
Olive oil + 19 % trolamine 3 3
Olive oil + 30% trolamine 0.3 0.2
Oleic acid 0.4 0.3
Oleic acid +10% trolamine 3.7 0.5
Oleic acid + 30% trolamine 14 5
Eth I oleate 0,2 0,2
Ethyl oleate + 10% trolamine 0.2 0.2
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* Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 4-8 hours. If
experimental conditions allowed, the steady-state delivery would likely
continue well beyond 8 hours.
Steady state flux of acyclovir from the above non-volatile solvents are
obtained by placing 200 mcL on the stratum corneum side (donor) of hairless
mouse skin. The in vitro studies are carried out as described in Example 1.
The surprising result showed the polyethylene glycol 400, span 80, ethyl
oleate,
or ethyl oleate plus trolamine are not flux-enabling solvents for acyclovir
(e.g.,
steady state flux values significantly less than the steady state flux of
acyclovir
in the marketed product noted in Table 2, where the flux was about
3mcg/cm2/h). However, the combination of isostearic acid and trolamine or
oleic acid and increasing amounts of trolamine are flux-enabling solvents for
acyclovir. As can be seen, the highest flux was achieved using 30% trolamine
with oleic acid as the non-volatile solvent system.
Examples 10-13
Prototype solidifying formulations are prepared as follows. Several
acyclovir solidifying formulations are prepared in accordance with embodiments
of the present invention in accordance with Table 8, as follows:
Table 8
Example 10 11 12 13
% b wei ht
Ethanol 21 25 28 29.5
Eudragit RL-PO 15 18 20 21.0
Isostearic Acid 31 36 39 42.0
Trolamine 30 18 10 4.7
Ac ciovir 3 3 3 2.8
In Examples 10-13, the compositions in Table 6 are prepared as follows.
Eudragit RL-PO and ethanol are combined in a glass jar and heated with
stirring
until the RL-PO is dissolved. The isostearic acid and trolamine is added to
the
RL-PO/ethanol mixture and the mixture is vigorously stirred. Once a uniform
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mixture is obtained, acyclovir is added to the mixture and the formulation is
vigorously mixed.
Examples 14-15
5 Prototype peel formulations are prepared as follows. Several acyclovir
solidifying formulations are prepared in accordance with embodiments of the
present invention in accordance with Table 9, as follows:
Table 9
Example 14 15
-% b weight
Ethanol 26 21
Eudragit RL-PO 44 15
-Isostearic Acid 26 31
Diiso ro anol Amine 2 --
Neutrol TE Polyol -- 30
Acyclovir 2 3
10 The compositions of Examples 14 and 15 as shown in Table 8 are prepared as
follows. Eudragit RL-PO and ethanol are combined in a glass jar and heated
with stirring until the RL-PO is dissolved. The isostearic acid and
diisopropanol
amine or Neutrol TE Polyol (BASF) is added -to the RL-PO/ethanol mixture and
the mixture is vigorously stirred. Once a uniform mixture is obtained,
acyclovir
15 is added to the mixture and the formulation is vigorously mixed.
Examples 16-17
Prototype solidifying formulations are prepared as follows. Several
acyclovir solidifying formulations are prepared in accordance with embodiments
20 of the present invention in accordance with Table 10, as follows:
Table 10
Example 16 17
% by wei ht
Ethanol 59.6 58
EC-N7 19.9 --
EC-N 100 -- 19
Trolamine 7.6 9
Isostearic Acid 7.7 9
Acyclovir 5.2 5
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In Examples 16-17 the compositions in Table 10 are prepared as follows. Ethyl
cellulose ECN7 or ethyl cellulose ECN 100 and ethanol are combined in a glass
jar and heated with stirring until the solid cellulose is dissolved. The
isostearic
acid and trolamine is added to the cellulose/ethanol mixture and the mixture
is
vigorously stirred. Once a uniform mixture is obtained, acyclovir is added to
the
mixture and the formulation is vigorously mixed.
Example 18
The formulations of Examples 10-17 are tested in a hairless mouse skin
(HMS) in vitro model described in Example 1. Table 11 shows data obtained
using the experimental process outlined above.
Table 11 - Steady-state flux J of Acyclovir throu h HMS
Formulation J* Ratio to
(pg/cm?/h) Control
Exam le 10 12 5 6
Exam le 11 19 1 8
Exam le 12 8 1 4
Example 13 1 1 0.5
Example 14 0.7 0.3 0.35
Exam le 15 1 0.9 0.5
Exam le 16 2 1 1
Exam le 17 19 7 8
Zovirax Cream 2 0.4 1
* Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 4-8 hours. If
experimental conditions allowed the steady state flux would extend
beyond the 8 hours measured.
The formulations of the invention shown above generally provide for
significant
penetration of the active ingredient, and further, the formulations of
Examples
10-12 and 17 are found to be much greater in permeability than the marketed
product Zovirax Cream. The quantity of acyclovir that permeated across the
HMS stratum corneum over time for Examples 10, 11, and Zovirax Cream are
shown in FIG. 2. Each value shown indicates the mean SD of at least three
experiments.
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Examples 10-13 show the impact of the trolamine to isostearic acid (ISA)
ratio on acyclovir flux enhancement. The optimal ISA:trolamine ratio is 1:1 to
2:1 and ratio greater than 4:1 show a significant decrease in the acyclovir
skin
flux. Additions of diisopropanol amine and Neutrol in place of trolamine
(Examples 14 and 15 in the formulation show a significant decrease in
acyclovir
flux values. This may be due to a specific chemical interaction between
trolamine and ISA creating an environment within the formulation which
facilitates higher skin flux. Examples 16 and 17 utilize a different
solidifying
agent to evaluate the impact of the solidifying agent on acyclovir flux.
Surprisingly, Example 16 shows a significant decrease in acyclovir skin flux,
but
Example 17, which differed from Example 16 only by the molecular weight of the
solidifying agent, shows no impact on acyclovir skin flux compared to a
similar
ISA:trolamine ratio in Example 10.
As can be seen from FIG. 2, Examples 10 and 11 show sustained
delivery of acyclovir up to 8 hours, it is reasonable to assume based on the
drug
load and the continued presence of the non volatile solvent that the delivery
of
acyclovir would continue at the reported flux values for as long as the
subject
desires to leave the solidifying formulation affixed to the skin.
Examples 19-21
Prototype solidifying formulations are prepared as follows. Several
solidifying formulations are prepared in accordance with embodiments of the
present invention in accordance with Table 12, as follows:
Table 12
Example 19 20 21
% by weight
Volatile Solvents
Ethanol 25 24 43
Water 22
Solidi in a ents
Eudragit RL-PO 18 40
Pol vin I Alcohol 14
Non-volatile solvents
Glycerol 12 14
Propylene Glycol 4
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Pol eth lene glycol 6
Isostearic Acid 36 13
Trolamine 18 4
Dru
Acyclovir 3
Ropivacaine 3
Testosterone 1
Solidifying formulations of Examples 19-21 are prepared in the following
manner:
= The solidifying agents are dissolved in the volatile solvent (e.g., dissolve
polyvinyl alcohol in water, Eudragit polymers in ethanol),
= The non-volatile solvent is mixed with the solidifying agent/volatile
solvent
mixture.
= The resulting solution is vigorously mixed well for several minutes.
= The drug is then added and the solidifying formulation is mixed again for
several minutes.
In all the Examples noted above, the flux-enabling non-volatile
solvent/solidifying agentlvolatile solvent combination is compatible as
evidenced
by a homogeneous, single phase system that exhibited appropriate drying time,
and provided a stretchable solidified layer and steady state flux for the drug
(see
Example 22 below).
Example 22
The formulations of the examples are tested in a hairless mouse skin
(HMS) or HEM in vitro model described in Example 1. Table 13 shows data
obtained using the experimental process outlined above.
Table 13 - Steady-state flux (J) *
Formulation (pg/CM21h)
Example 19 19 1***
Example 20 32 2***
Exam le 21 4 1***
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* Skin flux measurements represent the mean and standard
deviation of three determinations.
** Data gathered using human epidermal membrane.
***Flux measurements reported were determined from the linear
region of the cumulative amount versus time plots. The linear region was
observed to be between 4-8 hours. If experimental conditions allowed,
the steady-state delivery would likely continue well beyond 8 hours.
****Flux measurements reported were determined from the linear
region of the cumulative amount versus time plots. The linear region was
observed to be between 6-28 hours. If the experiment was continued it is
anticipated the steady state would continue.
Acyclovir, ropivacaine, and testosterone have surprisingly higher steady state
flux values when the flux-enabling non-volatile solvent is incorporated into
the
solidifying formulation. It is speculated that the higher flux values may be
the
result of contributions of the volatile solvent or the solidifying agent
impacting
the chemical environment (e.g., increasing solubility) of the drug in the
solidifying formulation resulting in higher flux values. Conversely,
ketoprofen
and diclofenac have lower steady state flux values when the enabling non-
volatile solvent is incorporated into the solidifying formulation. This could
be the
result of the volatile solvent system or solidifying agent having the opposite
impact on the chemical environment (e.g., decreasing solubility, physical
interactions between drug and solidifying formulation) resulting in lower flux
values. The steady state flux value for imiquimod is unchanged when
comparing the solidifying formulation with the flux-enabling non-volatile
solvent
flux values.
Example 23
A formulation with the following composition: 10.4% polyvinyl alcohol,
10.4% polyethylene glycol 400, 10.4% polyvinyl pyrrolidone K-90, 10.4%
glycerol, 27.1 % water, and 31.3% ethanol was applied onto a human skin
surface at an elbow joint and a finger joint, resulting in a thin,
transparent,
flexible, and stretchable solidified layer. After a few minutes of evaporation
of
the volatile solvents (ethanol and water), a solidified layer that was
peetable was
formed. The non-volatile solvent system of polyethylene glycol and glycerol
acts
a plasticizer in the formulation. The stretchable solidified layer had good
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adhesion to the skin and did not separate from the skin on joints when bent,
and
could easily be peeled away from the skin.
Examples 24-26
5 Three formulations similar to the formulation in Example 27 (replacing
ropivacaine base with ropivacaine HCI) are applied on the stratum corneum side
of freshly separated hairless mouse skin. The in vitro flux is determined for
each formulation as outlined in Example 1. The formulation compositions are
noted in Table 14 below.
10 Table 14
Example 24 25 26
% b wei ht
PVA 15 15 15
Water 23 23 23
Eth lcellulose N-100 11 11 11
Ethanol 33 33 33
San20 11
Pol eth lene Glycol 400 11
Tween 40 11
Tromethamine 4 4 4
Ropivacaine HCI 3 3 3
Avg. Flux* (mcg/cm2/h) 15 1 4.7 3.4
0.3 0.7
* Flux values represent the mean and standard deviation of three
determinations. Flux measurements reported were determined from the
linear region of the cumulative amount versus time plots. The linear
region was observed to be between 4-9 hours. If the experiment was
15 continued it is anticipated the steady state would continue.
Since all three formulations have the exact same compositions of
solidifying agent, volatile solvents, and flux-enabling non-volatile solvent.
The
only difference is which flux-enabling non-volatile solvent is used it is
20 reasonable to conclude that for ropivacaine HCI that Span 20, polyethylene
glycol 400, and Tween 40 qualify as flux-enabling non-volatile solvents.
Addition of tromethamine and Span 20 in example 30 produced a flexible
coherent solid that was much less brittle than a formulation containing no non-
volatile solvents.
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Examples 27-31
A solidifying formulation for dermal delivery of imiquimod is prepared
which includes a specified amount of imiquimod in an excipient mixture to form
an adhesive formulation in accordance with embodiments of the present
invention. The solidifying formulations contained the following components:
Table 15 - Imi uimod peelable formulation ingredients
Example
Ingredients*
27 28 29 30 31
PVA 12 21.5
Plastoid B** 22.7 21.1 21
Pemulen TR-2 0.3 0.3
Water 62.7 34.4 2.8
lso ro anol 42.5 42.5 41.7
ISA (Isostearic 19 35.2 9.2 28.2 27.8
Acid)
S an20 8.5
Trolamine 2 3.6 6.1
Triacetin 4.2 4.2 4.2
Imiguimod 4 5 4 4 5.3
* Ingredients are noted as weight percent.
** Polymer from Degussa
These formulations are applied to HMS skin as described in Example 1, and the
imiquimod flux is measured. A summary of the results from in vitro flux
studies
carried out with the formulations in Examples 27-31 are listed in Table 16.
Table 16 - Steady-state flux of imiquimod through hairless mouse skin
from various adhesive formulations at 35 C
Average flux Ratio to
Formulation mc /cm2lh* Control**
Example 27 0.7 0.09 0.7
Example 28 0.52 0.06 0.6
Example 29 0.40 0.08 0.4
Exam le30 0.5 0.1 0.5
Exam le31 0.8 0.1 0.9
Aldara (control) 0.92 0.02
The flux values represent the mean and SD of three determinations
** Ratio to control calculated by dividing the flux value for each Example
by the flux value for Aldara control flux.
Regarding the formulation described in Examples 27 and 28, water is used as
the volatile solvent, and the ISA, trolamine mixture is used as the non-
volatile
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solvent system. Through experimentation, it is determined that ISA and Span
20 provide the appropriate solubility for the drug, however, these non-
volatile
solvents are hydrophobic and not compatible with the volatile solvent system
used to dissolve the solidifying agent PVA. An emulsifier Pemulen TR-2 was
used to emulsify the non-volatile solvents into the water phase. Further, in
this
embodiment, ISA and trolamine act as a plasticizer in the peelable formulation
after the water (volatile solvent) has evaporated. The steady state flux of
formulation Examples 27 and 28 demonstrate the importance of the amount of
non-volatile solvent in added to the formulation in dictating the flux-
generating
power of the entire formulation. Formulation Examples 29-31 utilize a
different
solidifying agent which is compatible in a non-aqueous volatile solvent system
(isopropanol). The selection of non-volatile solvent system ISA/triacetin or
ISA/Span 20/trolamine/triacetin combination showed no change in the in vitro
flux. The increase in vitro flux is shown to be influenced by an increase in
the
amount of imiquimod present in the formulation. At imiquimod levels above 4%
the drug is saturated in the solidifying formulation. The increase in vitro
flux as
a function of increased drug addition (Examples 30 and 31) may be due to the
increased solubility of drug in the solidified formulation once the volatile
solvent
is evaporated off.
Example 29 demonstrated comparable imiquimod flux to the other
formulation Examples, but the importance of the non-volatile solvent system
and
solidifying agent compatibility necessitated the removal of trolamine because
this non-volatile solvent negatively influenced the function of the Plastoid B
polymer.
Example 32-35
A solidifying formulation for dermal delivery of imiquimod is prepared
which includes a specified amount of imiquimod in an excipient mixture to form
an adhesive formulation in accordance with embodiments of the present
invention. The solidifying formulations contained the following components:
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Table 17 - Imiquimod formulation ingredients
Exam le
ingredients*
32 33 34 35
PVA 10.1
Plastoid B** 17.5
Eudragit RL 16.2 24.8
PO
Pemulen 0.3
TR-2
Water 52.9
Iso ro anol 35.1
Ethanol 32.4 38.6
ISA 16.8 23.4 23.1 27.6
(Isostearic
Acid)
Salicylic 15.2 16.4 16.2
Acid
Trolamine 1.7
Triacetin 3.5 3.5 4.1
Imi uimod .3.0 4.1 4.0 4.8
* Ingredients are noted as weight percent.
** Polymer from Degussa
These formulations are applied to HMS skin as described in Example 1, and the
imiquimod flux is measured. A summary of the results from in vitro flux
studies
carried out with the formulations in Examples 32-35 are listed in Table 18.
Table 18 - Steady-state flux of Imiquimod through hairless mouse skin
from various adhesive formulations at 35 C
Formulation Average flux Ratio to
mc /cmZ/h* Control**
Example 32 1 1 . 1.1
Example 33 4.5 0.4 5
Example 34 3.8 0.5 4.2
Example 35 0.8 0.2 0.9
Aldara 0.9 0.02 1
* The flux values represent the mean and SD of three determinations
** Ratio to control calculated by dividing the flux value for each Example
by the flux value for Aldara control flux.
In vitro flux of Examples 32-35 is substantially increased compared to the
Aldara control. The reason for the improved in vitro flux values is attributed
to
the addition of salicylic acid. Improved in vitro flux of imiquimod in
Examples
32-35 is thought to be due to an ion pair interaction between imiquimod and
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salicylic acid. The ion pair mechanism is thought that the lipophilicity of
the
counter ion (salicylic acid) improves the flux of imiquimod across the stratum
corneum because it makes imiquimod less 'comfortable' in the formulation.
Comparison of the flux of Examples 32-34 show that the selection of the
polymer and/or volatile solvents will impact the flux of imiquimod. Example 32
contains PVA and water, one or both of these elements may contribute to an
unfavorable medium in which the ion pair can form resulting in a negligible
increase in imiquimod flux versus the Aldara control.
Example 36 To demonstrate the ability of the solidified formulations to reduce
the
transepidermal water loss (TEWL) the following experiment was conducted.
A placebo PVA formulation was applied to the top of the hand and the
TEWL was measured on a site immediately adjacent to the solidified layer and
on top of the solidified layer. The TEWL measurement of the site covered by
the solidified layer was 33% lower than the untreated skin site.
Placebo Plastoid B formulation similar to the formulation described in
Example 5 was applied to the top of the hand and the TEWL was measured on
a side immediately adjacent to the solidified layer and on top of the
solidified
layer. The TEWL measurement on the site covered by the solidified layer was
30% lower than the untreated skin site.
Examples 37-38
A solidifying formulation for dermal delivery of ropivacaine is prepared
which includes a specified amount of ropivacaine in an excipient mixture to
form
an adhesive formulation in accordance with embodiments of the present
invention. The solidifying formulations contained the following components:
Table 19 Ropivacaine formulation ingredients.
Ingredients* Examples
37 38
Eudragit RL-100 39.6% 39.6%
Ethanol 23.7% 23.6%
ISA Isostearic Acid 13.5% 13.5%
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PG (Propylene G! col 7.9% 4.0%
Trolamine 4.0% 4.0%
Glycerol 7.9% 11.9%
Ropivacaine 3.4% 3.4%
* Ingredients are noted as weight percent.
These formulations are applied to HMS skin as described in Example 1, and the-
ropivacaine flux is measured. A summary of the results from in vitro flux
studies
5 carried out with the formulations in Examples 37 and 38 is listed in Table
20.
Table 20 - Steady-state flux of Ropivacaine through hairless mouse skin
from various adhesive formulations at 35 C
Formulation Average flux
mc /cmz/h
Example 37 36 5
Example 38 32 2
* The flux values represent the mean and SD of three
10 determinations
Regarding the formulation described in Examples 37 and 38, ethanol is used as
the volatile solvent, and the ISA, glycerol, trolamine, and PG mixture is used
as
the non-volatile solvent system. Through experimentation, it is determined
that
15 ISA and propylene glycol used together to provide the appropriate
solubility for
the drug, while being compatible with the Eudragit RL-1 00 solidifying agent.
Further, in this embodiment, ISA, PG and glycerol serve as a plasticizer in
the
peelable formulation after the ethanol (volatile solvent) has evaporated. The
steady state flux of ropivacaine from formulation Examples 37 and 38
20 demonstrate the importance of the non-volatile solvent in dictating the
flux-
generating power of the entire formulation.
Example 39
A formulation for dermal delivery of lidocaine is prepared which includes
25 a saturated amount of lidocaine in an excipient mixture to form an adhesive
formulation in accordance with embodiments of the present invention. The
solidifying formulation is prepared from the ingredients as shown in Table 26.
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Table 21 - Lidocaine formulation com onents
Ingredients* Example
39
PVA 11.7
Eud ra it E-100** 11.7
PVP-K90 5.8
GI cerol 8.8
PEG-400 8.8
Water 23.8
Ethanol 23.8
Lidocaine 5.6
*Ingredients are noted as weight percent.
** from Rohm & Haas.
Table 22 Steady-state flux of Lidocaine through hairless mouse skin
from various adhesive formulations at 35 C
Formulation Average flux
mc /cm2/h*
Example 39 47 3
The adhesive formulation of lidocaine formulation in the present example
has similar physical properties to the formulations in examples noted above.
The transdermal flux across hairless mouse skin is acceptable and steady-state
delivery is maintained over 8 hours.
Examples 40-43
A formulation for dermal delivery of amitriptyline and a combination of
amitripyline and ketamine is prepared which includes an excipient mixture to
form an adhesive formulation in accordance with embodiments of the present
invention_ The solidifying formulation is prepared from the ingredients as
shown
in Table 23.
Table 23 - Amitriptyline and Amitriptyline/Ketamine formulation
components.
Exam le
ingredients*
40 41 42 43
Iso ro anol 50.3 48.6 50.8 49.8
Water 2.7 2.6 2.7 2.7
Isostearic Acid 6.2 6.1 6.3 6.2
Triiso ro anolamine 7.5 7.3 7.5 7.4
Triacetin 2.9 2.8 2.9 2.8
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S an2O 5.7 5.5 5.8 5.6
Plastoid B** 21.7 21.1 22 21.5
Amitri t line 2 4
Ketamine 1 2 2 4
*Ingredients are noted as weight percent.
** from DeGussa.
The ingredients listed above are combined according to the following
procedure.
The drug(s), water, and triisopropanolamine are combined in a glass jar and
mixed until the drug is dissolved. Then the isostearic acid, triacetin, Span
20,
and isopropanol are added to the formulation and mixed well. The polymer
Plastoid B is added last and heated to about 60 C until the Plastoid B is
completely dissolved. Once the polymer solution cooled to room temperature,
the formulation is stirred vigorously for 2-3 minutes.
The formulations in Table 10 are applied to HMS according to Example 1,
and the flux of amitriptyline and/or ketamine was measured. The results are
summarized in Table 24:
Table 24 - Steady-state flux of Amitriptyline and Amitriptyline/Ketamine
through
hairless mouse skin from various adhesive formulations at 35 C
Average Average
amitriptyline
Formulation ketamine flux
mcg cm2/h* mcg/cm2/h*
Exam Ie 40 3 1 15 t 4
Exam le41 7.6 0.2 33 6
Exam le 42 3 1
Example 43 8.2 0.7
The non-volatile solvent systems in the adhesive formulations of
amitriptyline and amitriptyline/ketamine were found to exhibit the best
compatibility when triacetin was used as the plastizing solvent. For example,
when propylene glycol was used in place of triacetin the examples noted above
the formulation turned into a soft solid in the storage container in about 12
hours. Replacing propylene glycol with trolamine resulted in a clear, flowable
formulation with viscosity low enough so that is can be spread on a skin
surface..
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Examples 44-47
A formulation for dermal delivery of ropivacaine is prepared which
includes an excipient mixture to form an adhesive formulation in accordance
with embodiments of the present invention. The solidifying formulation is
prepared from the ingredients as shown in Table 25.
Table 25 - Ropivacaine HCI formulation components.
Exam le
Ingredients*
44 45 46 47
Ropivacaine HCI 0.31 0.31 0.31 0.31
Iso ro anol 2 2 2.2 2
Water 0.125 0.125 0.125 0.125
Isostearic Acid 0.36 0.66 0.41 0
Triiso ro anolamine 0.31 0.34 0.34 0.34
Triacetin 0.17 0.19 0 0.19
Span 20 0.34 0 0.37 0.66
Plastoid B** 1 1 1 1
*Ingredients are noted as parts by weight.
** from Degussa.
The ingredients listed above are combined according to the following
procedure.
The ropivacaine HCI, water, and triisopropanolamine are combined in a glass
jar
and mixed until the drug is dissolved. Then the isostearic acid, triacetin,
Span
20, and isopropanol are added to the formulation and mixed well. The polymer
Plastoid B is added last and heated to about 60 C until the Plastoid B is
completely dissolved. Once the polymer solution cooled to room temperature,
the formulation is stirred vigorously for 2-3 minutes.
The formulations in Table 25 are applied to HMS according to Example 1,
and the flux of ropivacaine was measured. The results are summarized in Table
26:
Table 26 - Steady-state flux of Ropivacaine HCI through hairless mouse skin
from various adhesive formulations at 35 C
Formulation Average flux
mc /cm /h
Exa m le 44 56 2
Example 45 39 6
Example 46 31 6
Exam pie 47 37 9
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The flux in each of Examples 44-47 shows the importance of the triacetin,
isostearic acid, Span 20 combination in the formulation. In Examples 45-47
formulations were made without Span 20, triacetin, and isostearic acid
respectively. The in vitro flux of ropivacaine was impacted. The synergistic
combination of the flux-enabling non volatile solvent system is important in
obtaining the maximum in vitro flux of ropivacaine.
Example 48
This formulation has the following ingredients in the indicated weight
parts:
Table 27
Ethyl Dermacryl Isostearic
PVA Water cellulose 79 Ethanol Acid Glycerol Ropivacaine
N-7 (National (ISA)
A ualon Starch)
1 1.5 0.25 0.35 0.85 0.8 0.35 0.3
In this formulation, polyvinyl alcohol (USP grade, from Amresco) is a
solidifying
agent, ethyl cellulose and Dermacryl 79 are auxiliary solidifying agents.
Isostearic acid and glycerol form the non-volatile solvent system while
ethanol
and water form the volatile solvent system. Ropivacaine is the drug.
Procedures of making the formulation:
1. Ropvicaine is mixed with ISA.
2. Ethyl cellulose and Dermacryl 79 are dissolved in ethanol.
3. PVA is dissolved in water at temperature of about 60-70 C.
4. All of the above mixtures are combined together in one container and
glycerol is added and the whole mixture is mixed well.
The resulting formulation is a viscous fluid. When a layer of about 0.1 mm
thick
is applied on skin, a non-tacky surface is formed in less than 2 minutes.
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Examples 49-50
Anti-fungal solidifying formulations are prepared and a qualitative
assessment of the solidified layer's flexibility and viscosity are evaluated.
The
formulation components are presented in Table 28 below.
5
Table 28
Example 49 50
Com onents Parts b Weight
Eudragit RL-PO 3.8 4.2
lsostearic Acid 2 2.2
Ethanol 5.3 3.8
Neutrol TE Polyol I I
Econazole 0.09 0.1
The solidifying formulation in Example 49 has a low viscosity that was lower
than may be desirable for application on a nail or skin surface. The time to
form
10 a solidified layer with this formulation is longer than the desired drying
time. The
formulation in Example 50 had an increase in the amount of solidifying agent
(Eudgragit RL-PO) and decrease in amount of ethanol, which improves the
viscosity and drying time. Example 50 has a viscosity suitable for application
and an improved drying time.
Example 51
A solidifying formulation was prepared in accordance with Table 29, as
follows:
Table 29 - Solidi in formulation for sex steroids
!n redient % by weight
Ethanol 43
Water 22
Pol vin I Alcohol 14
Glycerol 14
Polyethylene 6
Glycol
Testosterone 1
The ingredients of Table 29 were combined as follows:
= The solidifying agent is dissolved in the volatile solvent (i.e. dissolve
polyvinyl alcohol in water).
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= The flux enabling non-volatile solvent is mixed with the solidifying
agent/volatile solvent mixture:
= The resulting solution is vigorously mixed well for several minutes.
= Drug is then added and the solidifying formulation is mixed again for
several minutes.
Example 52
The formulation prepared in Example 51 was tested for Skin Flux, as set
forth in Table 30 below.
Table 30 - Peel-forming formulation for sex steroids
System Skin Fluzx*
mc /cm /h
Exam le 51 4 1
AndroGel 6 2
*Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 4-8 hours. If
experimental conditions allowed, the steady-state delivery would likely
continue well beyond 8 hours.
AndroGel, currently marked product, is applied directly on the hairless
mouse skin and the flux determinations are made as outlined in Example 1.
The steady state flux data is shown in FIG 1. It should be noted, the steady-
state flux value reported in Table 3 is determined using the linear region
between 2-6 hours. As can be seen from FIG. 1, the in vitro flux of
testosterone
from AndroGel substantially decreases beyond 6 hours. This may be due in
part to the evaporation of the volatile solvent which may act as the main
vehicle
for delivery. The formulation in Example 51 will deliver a steady-state amount
of
testosterone for at least 9 hours.
Example 53
A stretchable adhesive formulation for transdermal delivery of ketoprofen
(which is suitable for delivery via skin for treating inflammation or pain of
joints
and muscles) is prepared which includes saturated amount of ketoprofen in an
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excipient mixture (more ketoprofen than that can be dissolved in the excipient
mixture) to form an adhesive formulation, some of which is prepared in
accordance with embodiments of the present invention. The excipient mixture,
which is a viscous and transparent fluid, is prepared using the ingredients as
shown in Table 31.
Table 31 - Ketoprofen formulation components
Example
Ingredients*
53
PVA Pol in i Alcohol) 10.4
PEG-400 Pol eth lene G{ col 10.4
PVP-K90 Pol in I P rrolidone 10.4
Glycerol 10.4
Water 27.1
Ethanol 31.3
Keto rofen saturated
* Ingredients are noted as % by weight.
The compositions of Example 53 were studied for flux of ketoprofen, as shown
in Table 32, as follows:
Table 32 - Steady-state flux of Ketoprofen through hairless mouse skin
from the adhesive formulation of Example 52 at 35 C
Formulation Average flux
mc Icm2/h*
Example 53 8 3
* Skin flux measurement represents the mean and standard
deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 4-8 hours. If
experimental conditions allowed the steady state flux would extend
beyond the 8 hours measured.
Regarding formulation described in Example 53, ethanol and water formed the
volatile solvent system, while a 1:1 mixture of, glycerol and PEG 400 formed
the
non-volatile solvent system. Through experimentation, it is determined that
PEG 400 is a slightly better solvent than glycerol for ketoprofen, while
glycerol is
much more compatible with PVA than PEG 400. Thus, the non-volatile solvent
system of glycerol and PEG 400 are used together to provide a non-volatile
solvent system for the drug, while being reasonably compatible with PVA. In
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additional detail with respect to the formulation in Example 53, PVA and PVP
act as the solidifying agents. Further, in this embodiment, glycerol and PEG
400 also serve as plasticizers in the adhesive formulation formed after the
evaporation of the volatile solvents. Without the presence of glycerol and PEG
400, a solidified layer formed by PVA and PVP alone would be rigid and non-
stretchable.
Example 54
A formulation similar to the formulation of Example 53 composition (with
no ketoprofen) is applied onto a human skin surface at an elbow joint and a
finger joint, resulting in a thin, transparent, flexible, and stretchable
solidified
layer. After a few minutes of evaporation of the volatile solvents (ethanol
and
water), a solidified layer is formed. The stretchable solidified layer has
good
adhesion to the skin and does not separate from the skin on joints when bent,
and can easily be peeled away from the skin.
Example 55
A stretchable adhesive formulation for transdermal delivery of ketoprofen
(which is suitable for delivery via skin on joints and muscles) is prepared
which
includes saturated amount of ketoprofen in an excipient mixture (more
ketoprofen than that can be dissolved in the excipient mixture) to form an
adhesive formulation, some of which are prepared in accordance with
embodiments of the present invention. The excipient mixture, which is a
viscous and transparent fluid, is prepared using the ingredients as shown in
Table 33.
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Table 33
ingredients* FORMULATIONS
A B C
PVA (Celvol 502 MW 10,000) 24.4
PVA (Amresco MW 31,000-
50, 000 24.4
PVA (Celvol 523 MW 125,000) 41.7
Water 33.4 33.4 58.3
Ethanol 8.9 8.9
PG 17.8 17.8
Glycerol 11.1 11.1
Gantrez ES 425 4.4 4.4
Ingredients are noted in weight percent.
Formulations A and B are prepared in the following manner:
= PVA (solidifying agent) is dissolved in water.
= The flux adequate non-volatile solvent (glycerol, PG) is mixed together
with the solidifying agentlvolatile solvent mixture.
= Then ethanol, and Gantrez ES 425 is added to the mixture.
= The resulting solution is vigorously mixed for several minutes.
Preparation of the PVA in water solution in Formulation C was not
feasible for this molecular weight of PVA at the percentages noted.
Formulation
C demonstrates that the correct polymer molecular weight for PVA is important
to obtain the desired formulation properties.
Formulations A and B are placed on the skin of human volunteers. After
a period of several hours, long enough for the volatile solvent to evaporate,
the
solidified layers were removed by the volunteers and the peelability
properties
were evaluated. In all instances the volunteers reported that formulation
example A could not be removed in one or two pieces, but was removed in
numerous small pieces. Formulation example B removed in one or two pieces.
The brittle nature of formulation A is attributed to the lower molecular
weight
PVA sample (Ceivol). Low molecular weight PVA does not possess the same
cohesive strength as higher molecular weight PVA material (Amresco) due to
the reduced size of the polymer chain leading to a reduction in the degree of
cross linking and physical interactions between individual PVA polymer chains.
The reduced PVA chain interactions lead to a weakened solidified layer that is
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unable to withstand the mechanical forces the solidified layer is subjected to
upon removal.
Example 56-57
5 A stretchable adhesive formulation for transdermal delivery of ketoprofen
(which is suitable for delivery via skin on joints and muscles) was evaluated
which includes a placebo excipient mixture which will form an adhesive
formulation, some of which are prepared in accordance with embodiments of the
present invention. The excipient mixture, which is a viscous and transparent
10 fluid, is prepared using the ingredients as shown in Table 34.
Table 34
Examples
(ngredients*
56 57
PVA (Amresco MW 31,000-
50,000) 20.41 21.28
Water 30.61 27.66
Ethanol 20.41 21.28
PG 20.41 21.28
Glycerol 6.12 6.38
Gantrez S97 2.04 2.137d
* Ingredients are noted in weight percent.
Solidifying formulations in Examples 56 and 57 are prepared in the following
manner:
15 = PVA (solidifying agent) is dissolved in water.
= The flux adequate non-volatile solvent (glycerol, PG) is mixed together
with the solidifying agent/volatile solvent mixture.
= Then ethanol, and Gantrez S97 is added to the mixture.
= The resulting solution is vigorously mixed for several minutes.
20 Formulations above were applied on the forearms of study volunteers
and the drying time was assessed by placing a piece of cotton to the
application
site and then applying a 5 gram weight on the cotton. The cotton and weight
was removed after 5 seconds. This procedure was started approximately 3 - 4
minutes after application and at 10 to 60 second intervals thereafter until
the
25 cotton was removed without lifting the solidified layer from the skin or
leaving
residue behind. The time when this observation is made is defined as the
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drying time for the solidifying formulation. The results of the study are
summarized in Table 35 below.
Table 35
Example D in Time rnin
56 7.0
57 6.5
The amount of water in the formulation did not significantly influence the
time for the formulation to dry. However, it was noted during the study that
the
formulation was difficult to expel from the sample tube. After approximately 4
weeks after the formulation in Examples 56 and 57 were made the sample
tubes were retrieved and were evaluated for ease of dispensing the
formuiation.
It was noted that the formulation was impossible to expel from the tube.
lnterpolymer complexation between Gantrez S-97 and PVA through electrostatic
interactions, hydrophobic interactions, hydrogen bonding, or Van der Waals
interactions is hypothesized to be the reason(s) for the observed thickening.
Moreover, the extent of this interaction may be dependent on the
stoichiometric
ratio of the two polymers.
Example 58-61
A stretchable adhesive formulation for transdermal delivery of ketoprofen
(which is suitable for delivery via skin on joints and muscles) was evaluated
which includes an excipient mixture which will form an adhesive fcirmulation,
some of which are prepared in accordance with embodiments of the present
invention. The excipient mixture, which is a viscous and transparent fluid, is
prepared using the ingredients as shown in Table 36.
30
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Table 36
Examples
ingredients*
58 59 60 61
PVA (Amresco MW 22.1 24.4 22.1 21.1
31,000-50,000
Water 26.6 29.2 30.9 33.8
Ethanol 12.6 4.2 8.4 8.2
Butanol 0.4 0.5 0.4 0.4
PG 19.9 21.9 17.7 16.9
Glycerol 8.8 9.7 11 10.6
Gantrez ES 425 4.6 5.1 4.4 4.0
Ketoprofen 5.0 5.0 5.1 5.0
* Ingredients are noted in weight percent.
Solidifying formulations in Examples 58-61 are prepared in the following
manner:
= PVA (solidifying agent) is dissolved in water.
= The flux adequate non-volatile solvent (glycerol, PG) is mixed together
with the solidifying agent/volatile solvent mixture.
= Then ethanol, and Gantrez ES 425 is added to the mixture.
= The resulting solution is vigorously mixed for several minutes.
= After mixing, ketoprofen is added and the final mixture is vigorously
mixed again for several minutes.
Formulations noted above were placed in laminate packaging tubes and
stored at 25 C/60% RH and 40 C/ 75% RH conditions until pulled for testing.
Physical testing was performed on each formulation. Examples 57-59 have
been studied the longest and the resulting viscosity increase necessitated the
desire to study the viscosity of Example 60. Table 37 summarizes the data
generated on each formulation.
Table 37
Example Viscosity*
Storage Cond. cPs
T=0 2 weeks 4 weeks 8 weeks 12 weeks 16 weeks
58 96000 670000 >2500000 Not
C/60% RH measured
58 96000 500000 587500 2320000
40 C/75% RH
59 168500 204500
25 C/60% RH 251000 >2500000
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59
40 C/75% RH 168500 215000 217500 >2500000
60 23000 -- 25000 36250 76250 57500
25 C/60% RH
40 C/75% RH 23000 -- 31000 40000 243500 164500
61 11250 13750
25 C/60% RH
61
40 C/75% RH 11250 17500
* Viscosity measured using a RVDV 1+ viscometer at 0.5 rpm.
Examples 58 and 59 had the lowest water content of the four
formulations and within 4 weeks of storage attained high viscosity values. The
5 only difference between Examples 58 and 59 is the amount of ethanol in the
formulations. It was hypothesized that reducing the level of ethanol may
reduce
the physical thickening of the formulation due to an incompatibility between
the
PVA and ethanol. The viscosity data show that the higher ethanol formulation
(Example 58) had lower initial viscosity, but over the 4 weeks storage the
10 viscosity of both Examples 58 and 59 attained viscosity values that were
too
high for a viable formulation. Another hypothesis for the formulation
thickening
is that PVA is not compatible in high concentrations when dissolved in water.
Additional formulations with higher water content were prepared to determine
if
an optimal water amount would keep the formulation from thickening up over
15 time. Example 60 viscosity after 16 weeks has not reached the viscosity
values
of the initial viscosity values of Examples 58 and 59.
Placebo versions of the formulations above were applied on study
volunteers and the drying time was assessed by placing a piece of cotton to
the
application site and then applying a 5 gram weight on the cotton. The cotton
20 and weight was removed after 5 seconds. This procedure was started *
approximately 3- 4 minutes after application and at 10 to 60 second intervals
thereafter until the cotton was removed without lifting the solidified layer
or
leaving residue behind. The results of the study are summarized in Table 38
below.
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Table 38
Example Drying Time (min)*
58 4 rnin 49 sec
59 5 min 41 sec
60 4 min 27 sec
61. 5 min 1 sec
* average dry time value from 12 study subjects.
The presence of ethanol as a second volatile solvent appears to significantly
reduce the time to dry. In data not shown a local anesthetic formulation
containing only water as the vofatile solvent and a ratio of water to PVA of
2:1
has a drying time of >15 minutes. Optimizing the ratio and the presence of an
additional volatile solvent in formulations containing water significantly
reduce
the drying time. It is hypothesized that the additional volatile solvent, in
this
case ethanol, will hydrogen bond with the water and vvater will escape with
the
ethanol when evaporating off the skin thereby forming a solidified layer.
Examale 62-63
A stretchable adhesive formulation for transdermal delivery of ketoprofen
(vvhich is suitable for delivery via skin for treating inflammation or pain of
joints
and muscles) is prepared which includes ketoprofen in an excipient mixture to
form an adhesive formulation, some of which is prepared in accordance with
embodiments of the present invention. The solidifying formulation is prepared
from the ingredients as shown in Table 39.
Table 39 - Ketoprofen solidif in formulation com onents
Ingredients* Example Example
62 63
PVA 22.1 18.9
Water 30.9 37.9
Fumed Silicia 3.0
Glycerol 11.1 9.5
Propylene glycol 17.7 15.2
Gantrez ES-425 4.4 3.8
Ethanol 8.8 7.6
Ketoprofen 5.0 4.2
*Ingredients are noted as weight percent.
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Table 40 - Steady-state flux of ketoprofen through hairless mouse skin
from an adhesive solidi in formulations at 35 C
Formulation Average flux
mc /cmZ/h*
Example 62 25 t 6
Example 63 27 2
* Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
5 determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 4-8 hours. If
experimental conditions allowed the steady state flux would extend
beyond the 8 hours measured.
Example 64-66
Placebo formulations containing Gantrez ES 425 as an adhesive polymer
were prepared for wear studies by volunteers. The formulations are shown as
examples in Table 41. All the formulations have polyvinyl alcohol as a
solidifying
agent to provide tensile strength to the solidifying formulation. The amount
of
propylene glycol in the formulations was decreased from 19.6% (w/w) to 8.7%
(w/w), and the amount of glycerol was increased by the same amount to keep
the total non-volatile ratio constant. Keeping the non-volatile ratio constant
is
important as it determines the drying time and the duration of delivery. The
placebo formulations are worn on the palms of hand and percentage adherence
of the solidified layer formed after evaporation of volatile solvents was
observed
after 5-6 hours.
Table 41: Placebo formulations (%w/w ingredients)
Ingredient Example Example Example
64 65 66
Polyvinyl Alcohol 21.7% 21.7% 21.7%
Water 32.6% 32.6% 32.6%
Glycerol 8.7% 13.0% 19.6%
Propylene Glycol 't g 6% 15.2% 8.7%
Gantrez ES 425 4.3% 4.3% 4.3%
Oleic acid 4.3% 4.3% 4.3%
Ethanol 8.7% 8.7% 8.7%
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Wear study results on 3 volunteers show that 70-80% of solidified layer as
described in Example 64 stayed on palms after a duration of 5-6 hours.
However, greater than 90% of solidified layer as shown in Example 66 stayed
on palms of the volunteers. These examples demonstrate that glycerol is a
better plasticizer that propylene glycol for the polyvinyl alcohol polymer. It
also
shows that the ratio of non-volatile solvent is critical in selecting the
formulation
for treatment of hand dermatitis.
Examples 67-68
Adhesive formulations containing 0.05% (w/w) clobetasol propionate and
0.15% (w/w) clobetasol propionate with polyvinyl alcohol as solidifying
polymer
are prepared for in-vitro flux evaluation. Propylene glycol and oleic acid are
the
non volatile solvents selected for facilitation of clobetasol propionate
delivery. As
shown in Example 66, glycerol is added as the non volatile solvent for its
plasticizing properties. Ratios of ingredients used in the two formulations
are
shown in Table 42.
Table 42: Clobetasol Propionate solidifying formulations*
Ingredient Example Example
67 68
Polyvinyl Alcohol 22.7% 22.7%
Water 34.1% 34.0%
Glycerol 17.3% 17.2%
Propylene Glycol 7.7% 7.7%
Gantrez ES 425 4.5% 4.5%
Oleic acid 4.5% 4.5%
Ethanol 9.1% 9.1%
Clobetasol Propionate 0.05% 0.15%
* Numbers do not add to 100% because of rounding in the second decimal.
Both of the compositions shown above are studied for flux of clobetasol
propionate on cadaver skin from three donors. The permeation results are as
shown in Table 43. Commercial clobetasol ointment (0.05% w/w) was used as a
control formulation.
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Table 43 - Steady state flux of clobetasol propionate through human
cadaver skin at 35 C
Control Example 68
Skin Donor Example 67 *
~ J* (ng/ cm2/h)
) cm /h
cm /hj , ~ng)
Donor 1 22.4 2.1 8.8 1.9 29.2 8.2
Donor2 20.012.5 7.6t2.5 18.5 6.4
Donor3 35.0 4.7 19.3 5.9 24.8 7.7
Mean +/- SD (n=3 25.8 7.5 11.9 6.5 24.2 8.0
donors)
* Skin flux measurements represent the mean and standard deviation of
three determinations. Flux measurements reported are determined from the
linear region of the cumulative amount versus time plots. The linear region
are
observed to be between 6-28 hours. If the experiment is continued, it is
anticipated the steady state would continue.
As seen from Table 43 formulation described in Example 67 that contained
polyvinyl alcohol as a solidifying agent and 0.05% clobetasol propionate had
46% flux of clobetasol propionate when compared to the control formulation.
Increasing the clobetasol propionate concentration drug concentration to 0.15%
(w/w) increased the steady state flux and the flux values were 94% of the
control formulation. It is expected that longer duration of application with
the
solidifying formulation would increase cumulative delivery in-vivo resulting
in
effective treatment of dermatitis.
Example 69
Adhesive formulations containing 0.05% (w/w) clobetasol propionate with
gelatin as solidifying agent are prepared for in-vitro flux evaluation.
Propylene
glycol, isostearic acid, and oleic acid are used as non-volatile solvents to
facilitate delivery of clobetasol. Talc is added as a filler to reduce the
drying time
the formulation. Ratio of ingredients used in the formulation is shown in
Table
44.
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Table 44: Clobetasol Propionate formulations*
Ingredient Example
69
Fish Gelatin 29.4%
Water 22.0%
Ethanol 14.7%
Propylene Glycol 17.6%
lsostearic acid 2.2%
Oleic acid 2.2%
Talc 11.8%
Clobetasol Propionate 0.05%
* Numbers do not add to 100% because of rounding in the second decimal.
Unlike the polyvinyl based formulations shown in previous examples, the fish
gelatin based formulation shown in Example 44 is a water washable formulation
and can be easily removed by subjects suffering from hand dermatitis. Steady
state flux across human cadaver skin from 3 donors with formulation as
described in Example 69 is compared to the commercial clobetasol ointment.
The permeation results are shown in Table 45.
Table 45 - Steady state flux of clobetasof propionate through human
cadaver skin at 35 C
Control Example
Skin Donor J* gng/ 69 J'" (ng/
cm /h) cm2/h)
Donor 1 39.2 9.2 46.1 t
14.3
Donor 2 35.6 2.1 52.9
22.3
Donor3 35.6 5.7 79.7
18.4
Mean +/- SD (n=3 36.8 5.8 59.6 t
donors) 22.3
*Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported are
determined from the linear region of the cumulative amount versus time
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plots. The linear region are observed to be between 6-28 hours. If the
experiment is continued, it is anticipated the steady state would continue.
As seen from Table 45, formulation described in Example 69 has 62% higher
steady state flux when compared to the commercial ointment. Higher steady
state flux would result is expected to reduce inflammation in difficult to
treat
dermatitis and psoriasis cases.
Example 70
Adhesive formulations containing 0.05% (w/w) clobetasol propionate with
gelatin as solidifying polymer are prepared for in-vitro flux evaluation.
Propylene
glycol, and isostearic acid are used as non-volatile solvents to facilitate
delivery
of clobetasol. Fumed silica is added as a filler to reduce the drying time the
formulation. Ratio of ingredients used in the formulation is shown in Table
46.
Table 46: Clobetasol Propionate formulations*
Ingredient Example 70
Fish Gelatin 32.2%
Water 24.2%
Ethanol 16.1%
Propylene Glycol 19.3%
Isostearic acid 4.8%
Fumed Silica 3.2%
Clobetasol Propionate 0.05%
* Numbers do not add to 100% because of rounding in the second decimal.
The fish gelatin based formulation shown in Example 70 is a water washable
formulation and can be easily removed by subjects suffering from hand
dermatitis. Steady state flux across human cadaver skin from 4 donors with
formulation as described in Example 70 is compared to the commercial
clobetasol ointment. The permeation results are shown in Table 47.
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Table 47 - Steady state flux of clobetasol propionate through human
cadaver skin at 35 C
Skin Donor Control Exampte70
J* (ng/ cm /h J n/ cm z /h
Donor 1 28.2 7.8 20.7 12.8
Donor2 30.1 14.9 30.6 13.8
Donor 3 36.2 6.2 93.4 7.5
Donor 4 33.6 3.9 101.4 8.5
Mean +/- SD n=3 donors 32.0 8.5 61.5 38.9
*Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported are
5 determined from the linear region of the cumulative amount versus time
plots. The linear region are observed to be between 6-28 hours. If the
experiment is continued, it is anticipated the steady state would continue.
10 As seen from Table 47, on an average, formulation described in Example 70
has at-least similar or better steady state flux when to compared to the
steady
state flux with the commercial ointment. Unlike talc used in Example 69, fumed
silica had a low density and is expected to have a less potential to separate
from the formulation.
Examples 71-73
Solidifying formulations for dermal delivery of ropivacaine HCI are
prepared which include excipient mixtures in accordance with embodiments of
the present invention. The formulations are prepared from the ingredients as
shown in Table 48.
Table 48 - Ropivacaine HCI solidi in formulation com onents.
Ingredients* Example
71 72 73
Ropivacaine HCI 6.9 6.5 6.6
Iso ro anol 50.7 45.8 45.9
Water 5.5 5.2 5.2
lsostearic Acid 6.3 6.6 6.6
Triethylamine 3.0
Diiso ro anolamine 3-9
Cetyl alcohol 3.3 3.9
Triacetin 2.9 2.6 2.6
S an20 5.8 5.2 5.2
Plastoid B** 21.9 20.9 21.0
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*Ingredients are noted as weight percent.
** from Degussa.
The ingredients listed above are combined according to the following
procedure.
The ropivacaine HCI, water, and the amine base (triethylamine or
diisopropanolamine) are combined in a glass jar and mixed until the drug is
dissolved. Then the isostearic acid, triacetin, Span 20, and cetyl alcohol
(Examples 72 and 73) or isopropanol (Example 71) is added to the formulation
and mixed well. The polymer Plastoid B is added last and heated to about 60
C until the Plastoid B is completely dissolved. Once the polymer solution
cooled to room temperature, the formulation is stirred vigorously for 2-3
minutes.
The formulations in Table 48 are applied to HMS -according to Example 1,
and the flux of ropivacaine was measured. The results are summarized in Table
49:
Table 49 - Steady-state flux of ropivacaine hcl through hairless mouse skin
from
various adhesive solidif in g formulations at 35 C
Formulation Average flux
mc /cm 21h*
71 96 14
72 61 2
73 70 7
Example 74
A prototype peel is prepared in accordance with Table 50 as follows:
Table 50
Example 74
% by weight
Plastoid B 21.3
Iso ro ! Alcohol 48.4
Water 2.5
Isostearic Acid 18.2
Trolamine 6.6
Acyclovir 3.0
The formulation was prepared by mixing Plastoid B in isopropyl alcohol until
the
polymer dissolved, then the remaining components were added and the mixture
vigorously stirred until a uniform mixture was obtained.
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Example 74 illustrates the necessity of an appropriate selection of a non-
volatile solvent and a solidifying agent. After mixing the formulation of
Example
74 together, the formulation turned from a flowable solution into two distinct
layers: a soft solid and a liquid layer. The formulation in this state is not
spreadable on the skin surface. An incompatibility between trolamine and the
Plastoid B polymer is suggested because of the hydrophilic nature of the
trolamine and the hydrophobic nature of the polymer resulted in the trolamine
being squeezed out of the formulation.
Examples 75-77
Prototype peel formulations are prepared as follows. Several peel
formulations are prepared in accordance with embodiments of the present
invention in accordance with Table 51, as follows:
Table 51
Example 75 76 77
Volatile Solvents
Ethanol 21 18.5 43
Water 32 28 22
Solidi in a ents
Eudra it E-100 18.5
Pol vin I Alcohol 21 18.5 14
Non-volatile solvents
GI cerol 14
Propylene Glycol 21
Pol eth lene Glycol 6
San20 11
rug
Ketoprofen 5
Diclofenac Na 5.5
Testosterone 1
Peel formulations of Examples 75-77 are prepared in the following manner:
= The solidifying agents are dissolved in the volatile solvent (e.g., dissolve
polyvinyl alcohol in water, Eudragit polymers in ethanol),
= The non-volatile solvent is mixed with the solidifying agent/volatile
solvent
mixture.
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= The resulting solution is vigorously mixed well for several minutes.
= The drug is then added and the peel formulation is mixed again for
several minutes.
In all the Examples noted above, the flux-enabling non-volatile
solvent/solidifying agent/volatile solvent combination is compatible as
evidenced
by a homogeneous, single phase system that exhibited appropriate drying time,
and provided a stretchable peel and steady state flux for the drug (see
Example
78 below).
The use of a volatile solvent system of water and ethanol at the
percentages in Examples 75-77 is an attempt to achieve a balance between
drying time and compatibility with the other ingredients (namely PVA in these
examples) in the formulations. Addition of ethanol is thought to reduce the
drying time for the formulation due to ethanol/water interactions resulting in
an
increased evaporation rate of the volatile solvents, and enough water is
present
to ensure compatibility of PVA in the formulations. This is an example of
using a
two-member solvent system to successfully achieve an acceptable compromise
between compatibility with the solidifying agent and the drying time.
Example 78
The formulations of the Examples are tested in a hairless mouse skin
(HMS) or human epidermal membrane (HEM) in vitro model described in
Example 1. Table 52 shows data obtained using the experimental process
outlined above.
Table 52 - Steady-state flux (J)
*
Formulation J*
Example 75 35 :t 20***
Example 76** 5 2****
Example 77 4 1***
* Skin flux measurements represent the mean and standard
deviation of three determinations.
** Data gathered using human epidermal membrane.
***Flux measurements reported were determined from the linear
region of the cumulative amount versus time plots. The linear region was
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observed to be between 4-8 hours. If experimental conditions allowed,
the steady-state delivery would likely continue well beyond 8 hours.
*'Flux measurements reported were determined from the linear
region of the cumulative amount versus time plots. The linear region was
observed to be between 6-28 hours. If the experiment was continued it is
anticipated the steady state would continue.
In all cases in Table 52, the flux enabling non-volatile solvents in the
formulation
resulted in therapeutically effective flux for each of the formulations
studied.
Example 79
A placebo formulation with the following composition: 10.4% polyvinyl
alcohol, 10.4% polyethylene glycol 400, 10.4% polyvinyl pyrrolidone K-90,
10.4% glycerol, 27.1 % water, and 31.3% ethanol was applied onto a human
skin surface at an elbow joint and a finger joint, resulting in a thin,
transparent,
flexible, and stretchable film. After a few minutes of evaporation of the
volatile
solvents (ethanol and water), a solidified layer that was peelable was formed.
The stretchable solidified layer had good adhesion to the skin and did not
separate from the skin on joints when bent, and could easily be peeled away
from the skin.
Examples 80-82
Prototype peels are prepared as follows. Several acyclovir peel
formulations are prepared in accordance with embodiments of the present
invention in accordance with Table 53 as follows:
Table 53
Example 80 81 82
% by weight
Plastoid B 10 10
Eudragit RL-100 10
Iso ro l Alcohol 57 57
Ethanol 57
Water
Isostearic Acid 9 9 9
Trolamine 9 9 9
Eth Icellulose EC-N7 10
Eth Icellulose EC-N 100 10 10
Ac clovir 5 5 5
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The formulation was prepared by mixing Plastoid B in isopropyl alcohol until
the
polymer dissolved, then the remaining components were added and the mixture
vigorously stirred until a uniform mixture was obtained.
5 Examples 80 and 81 show the importance of an additional polymer to
solve the trolamine/polymer incompatibility. Addition of ethylcellulose (N7
and
N100) to the formulation reduced the amount of Plastoid B polymer to a level
that is compatible with trolamine. The resulting formulation produced a
thickened, easily spreadable formulation. The formulation in Example 82
10 exhibited precipitation, but the thickening due to addition of the N100
ethylcellulose will prevent the settling of the precipitation.
Example 83
The formulations of Examples 80-72 are tested in a hairless mouse skin
15 (HMS) in vitro model described in Example 1. Table 54 shows data obtained
using the experimental process outlined above.
Table 54 - Steady-state flux (J) of Acyclovir through HMS
Formulation . J* Ratio to
(pg/cm2/h) Control
Example 80 4.0 0.8 6.7
Example 81 4 1 6.7
Exam le 82 13 6 21.7
Zovirax Cream 0.6 0.3 1
* Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
20 determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 4-8 hours. If
experimental conditions allowed the steady state flux would extend
beyond the 8 hours measured.
25 Steady-state flux variations of acyclovir through HMS from various lots of
mice
are expected. For this reason a control (Zovirax cream) is run with each
Example formulation. The ratio to control column in Tables 53 and 54 can be
compared to evaluate the improvement of the Example formulation over the
control.
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The formulations of the invention shown above generally provide for
significant penetration of the active ingredient, and further, the
formulations of
Examples 80-82 are found to be much greater in permeability than the marketed
product Zovirax Cream.
Examples 71-82 show similar in vitro flux increase (based on ratio to
control) over the Zovirax control. Addition of ethylcellulose to the
formulations in
Examples 81-83 may increase the occlusion due to the addition of the
hydrophobic polymers.
Examples 84
Prototype peel formulations are prepared as follows. Several peel
formulations are prepared in= accordance with embodiments of the present
invention in accordance with Table 55, as follows:
Table 55
Example 84
% by weight
Volatile Solvents
Ethanol 18.5
Water 28
Solidi in agents
Eudragit E-100 18.5
Pol in I Alcohol 18.5
Non-volatile solvents
S an 20 11
Drug
Diclofenac Na 5.5
The peel formulation of Example 84 is prepared in the following manner:
= The solidifying agents are dissolved in the volatile solvent (e.g., dissolve
polyvinyl alcohol in water, Eudragit polymers in ethanol),
= The non-volatile solvent is mixed with the solidifying agents/volatile
solvent mixture.
= The resulting solution is vigorously mixed well for several minutes.
= The drug is then added and the peel formulation is mixed again for
several minutes.
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In the example noted above, the flux-enabling non-volatile
solvent/solidifying agents/volatile solvent combination is compatible as
evidenced by a homogeneous, single phase system that exhibited appropriate
drying time, and provided a stretchable peel and steady state flux for the
drug
(see Example 85 below).
Addition of Eudragit E-100 polymer into the formulation in Example 84
increases adhesion to the skin surface prior to the evaporation of its
volatile
solvent(s). The PVA polymer in the formulation provides a solidified layer
with
high tensile strength that allows it to remain in one piece on the skin
surface
during the intended time of application. The combination of these two polymers
provides a solidified layer with flexibility and adhesion to the skin that
does not
separate from the skin (sites include skin covering joints) and can easily be
peeled away from the skin
Example 85
The formulations of the Examples are tested in a hairless mouse skin
(HMS) or HEM in vitro model described in Example 1. Table 56 shows data
obtained using the experimental process outlined above.
Table 56 - Stead -state flux (J)
*
Formulation /cma/h
Example 85** 5 2***
* Skin flux measurements represent the mean and standard
deviation of three determinations.
** Data gathered using human epidermal membrane.
***Flux measurements reported were determined from the linear
region of the cumulative amount versus time plots. The linear region was
observed to be between 6-28 hours. If the experiment was continued it is
anticipated the steady state would continue.
Diclofenac have lower steady state flux values when the enabling non-volatile
solvent is incorporated into the peel formulation. This could be the result of
the
volatile solvent system or the solidifying agents having the opposite impact
on
the chemical environment (e.g., decreasing solubility, physical interactions
between drug and peel formulation) resulting in lower flux values. The steady
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state flux value for imiquimod is unchanged when comparing the peel
formulation with the flux-enabling non-volatile solvent flux values.
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.
