Note: Descriptions are shown in the official language in which they were submitted.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
FLUX-ENABLING 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
adhesive
solidifying formulations having a viscosity suitable for application to a skin
surface, and which form a sustained drug-delivering adhesive solidified layer.
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 transdermal) 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
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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
2
example, many semisolid formulations usually contain only volatile solvent(s),
such as water and ethanol, which 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.
Some traditional semisolid formulations may also contain some non-volatile
liquid substances that are chosen or formulated for spreading the formulation
or
improving the aesthetics of the formulation rather than delivering the drug
with
sufficient flux. Drug delivery from those formulations may not be sufficient
or
sustainable. 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 but still outside 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 may 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. In 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,
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
3
optimal transdermal flux can be achieved when the drug is dissolved in certain
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 dermal drug delivery
systems, it would be desirable to provide systems, formulations, and/or
methods
that can i) provide sustained drug delivery over long periods of time; ii) are
not
vulnerable to unintentional removal by contact with clothing, other objects,
or
people for the duration of the application time; iii) can be applied to a skin
area
subject to stretching and expansion without causing discomfort or poor contact
to skin; and/or iv) can be easily removed after application and use.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
4
SUMMARY OF THE INVENTION
Although film-forming technologies have been used in cosmetic and
pharmaceutical preparations, typically, the solvents used in such systems do
not
last very long on skin surface, and thus, are not optimal for sustained-
release
applications. In accordance with this, the inventors of the current invention
recognized that the use of both volatile solvent as well as flux-enabling non-
volatile solvent in the formulation can improve or even optimize sustained
drug
delivery. Thus, it would be advantageous to provide dermal delivery
formulations, systems, and/or methods in the form of adhesive solidifying
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
can be easily removed, such as by peeling or washing with a solvent. In one
embodiment, the adhesive solidifying compositions or formulation, once
solidified, can be cohesive.
In accordance with this, a solidifying 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 having one or more
volatile solvent(s) and a non-volatile solvent system having one or more non-
volatile solvent(s), wherein the non-volatile solvent system comprises at
least
one flux-enabling non-volatile solvent for the drug such that the drug can be
delivered in therapeutically effective amounts over a period of time, even
after
most of the volatile solvent(s) is (are) 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 configured such that when
applied
to the skin surface, the formulation forms a solidified layer after at least a
portion
of the volatile solvent(s) is (are) evaporated, but yet continues to deliver
drug
after substantially solidifying. In certain embodiments, the solidified layer
can be
coherent so that it is peelable from the skin, or is washable from the skin
using a
solvent. In one particular embodiment, the drug can be a sex hormone, and in
another particular embodiment, the drug can be an anti-wart drug, though many
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
other drug types can be used, as described herein. The solidifying agents are
typically polymers that form rigid solids without plasticizing agent
(plasticizer).
Therefore, the non-volatile solvent system has to be a plasticizer to the
solidifying agent.
5 In an alternative embodiment, a method of dermally delivering a drug to,
into, or through the skin can comprise applying a formulation to a skin
surface of
a subject, where the formulation comprises a drug; a solvent vehicle, and a
solidifying agent. The solvent vehicle comprises a volatile solvent system
including one or more volatile solvent, and a non-volatile solvent system
including one or more non-volatile solvent, wherein the non-volatile solvent
system is flux-enabling for the drug. In this embodiment, the formulation can
have a viscosity suitable for application and adhesion to a skin surface prior
to
evaporation of the volatile solvent system, and the formulation can be applied
such that the skin surface forms a solidified layer after at least partial
evaporation of the volatile solvent system. An additional step includes
dermally
delivering the drug from the solidified layer to the subject at
therapeutically
effective rates over a sustained period of time, wherein the drug continues to
be
delivered after the volatile solvent system is substantially evaporated. In
some
embodiments, the solidified layer can be a soft or flexible, coherent,
continuous
solid, and can be removed by peeling.
In another embodiment, a method of preparing a formulation for dermal
drug delivery can comprise steps of selecting a drug suitable for dermal
delivery; selecting or formulating a non-volatile solvent or a mixture of non-
volatile solvents that is flux-enabling for the selected drug, selecting a
solidifying
agent that is compatible with the drug and the non-volatile solvent, selecting
or
formulating a volatile solvent system that is compatible with the drug, the
non-
volatile solvent and the solidifying agent; and formulating all above
ingredients
into a formulation. The formulation can have a viscosity suitable for
application
to a skin surface prior to evaporation of the volatile solvent system, and can
be
applied to the skin surface where it forms a solidified layer after at least a
portion of the volatile solvent system is evaporated. in this embodiment, the
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
6
drug continues to be delivered at a therapeutically effective amount after the
volatile solvent system is substantially evaporated.
In still another embodiment, a solidified layer for delivering a drug can.
comprise a drug, a non-volatile solvent system, and a solidifying agent. The
non-volatile solvent system can include at least one flux-enabling non-
volatile
solvent or a mixture of non-volatile solvents that is/are flux-enabling for
the drug.
The solidified layer can be a soft, coherent solid that is adhered to a body
surface, and while dermally delivering at least a portion of the drug
therefrom,
the solidified layer is at least substantially devoid of water and solvents
more
volatile than water, and wherein the solidified layer is also flux-enabling
for the
drug.
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 the cumulative amount of
diclofenac delivered transdermally across human cadaver skin over time from a
formulation in accordance with embodiments of the present invention where
steady-state delivery is shown over 28 hours.
FIG. 2 is a graphical representation of the cumulative amount of
ropivacaine delivered transdermally across human cadaver skin over time from
a formulation with similar composition in accordance with embodiments of the
present invention, where steady-state delivery is shown over 30 hours.
FIG. 3 is a graphical representation of cumulative amount of testosterone
delivered across a biological membrane in vitro over time from a solidified
adhesive formulation in accordance with embodiments of the present invention,
which is compared to the marketed product (AndroGel).
FIG. 4 is a graphical representation of the cumulative amount of acyclovir
delivered transdermally over time from two separate formulations in accordance
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
7
with embodiments of the present invention, which is 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
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
rnaking it more amenable for getting to, into, or through the skin, and this
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
8
particular form is defined as the physical form favorable for dermal delivery.
For
example the steady state flux of diclofenac sodium from flux enabling non-
volatile solvents is much higher than the steady state flux of diclofenac acid
from
the same flux enabling non-volatile solvents. It is therefore desirable to
evaluate
the flux of the physical forms of a drug from non-volatile solvents to select
a
desirable physical form/non-volatile solvent combination.
The phrases "dermal drug delivery" or "dermal delivery of drug(s)" shall
include both transdermal and topical drug delivery, and includes the delivery
of
drug(s) to, through, or into the skin. "Transdermal delivery" of drug can be
targeted to skin tissues just under the skin, regional tissues or organs under
the
skin, systemic circulation, and/or the central nervous system. "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 epidermat
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 in this patent application 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
9
to be able to provide therapeutically effective flux for a particular drug(s).
For
topically or regionally delivered drugs, a flux enabling non-volatile solvent
system is defined as a non-volatile solvent system which, alone without the
help
of any other ingredients, is capable of delivering therapeutic sufficient
levels of
the drug across, onto or into the subject's skin when the non-volatile solvent
system is saturated with the drug. For systemically targeted drugs, a flux
enabling non-volatile solvent system is a non-volatile solvent system that can
provide therapeutically sufficient daily doses over 24 hours when the non-
volatile solvent system is saturated with the drug and is in full contact with
the
subject's skin with no more than 500 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 sufficient
amount of
time. In reality, it may be difficult to keep a liquid solvent on the skin of
a human
volunteer for an extended period of time. Therefore, an alternative method to
determine whether a solvent system is "flux-enabling" is to measure the in
vitro
drug permeation across the hairless mouse skin or human cadaver skin using
the apparatus and method described in Example 1. This and similar methods
are commonly used by those skilled in the art to evaluate permeability and
feasibility of formulations. Alternatively, whether a non-volatile solvent
system is
flux-enabling can be tested on the skin of a live human subject with means to
maintain the non-volatile solvent system with saturated drug on the skin, and
such means may not be practical for a product. For example, the non-volatile
solvent system with saturated drug can be soaked into an absorbent fabric
material which is then applied on the skin and covered with a protective
membrane. Such a system is not practical as a pharmaceutical product, but is
appropriate for testing whether a non-volatile solvent system has the
intrinsic
ability to provide sufficient drug flux, or whether it is flux-enabling.
It is also noted that once the formulation forms a solidified layer, the
solidified layer can also be "flux enabling" for the drug while some of the
non-
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
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
5 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
10 may affect the ability of a substance to perform its intended task.
Therefore, an
"effective amount," "therapeutically effective amount," or "therapeutically
effective rate(s)" may be dependent in some instances on such biological
factors to some degree. However, for each drug, there is usually a consensus
among those skilled in the art on the range of doses or fluxes that are
sufficient
in most subjects. Further, while the achievement of therapeutic effects may be
measured by a physician or other qualified medical personnel using evaluations
known in the art, it is recognized that individual variation and response to
treatments may make the achievement of therapeutic effects a subjective
decision. The determination of a therapeutically effective amount or delivery
rate is weli virithin the ordinary skill in the art of pharmadeutical 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 delivei- a
sufficient
amount of the drug into the target tissues within a clinically reasonable
amount
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
11
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
effective flux" and may be different in different subjects and or at different
times
for even the same subject. However, for each drug, there is usually a
consensus among the skilled in the art on the range of doses or fluxes that
are
sufficient in most subjects at most times.
The following are estimates of flux for some drugs that are therapeutically
effective or more than sufficient:
Table A - In vitro steady state flux values of various drugs
Estimated
Drug Indication Therapeutically
effective flux*
mc /cm2/h
Ropivacaine** Neuropathic pain 5
Lidocaine Neuropathic pain 30
Acyclovir Herpes simplex virus 3
Ketoprofen Musculoskeletal pain 16
Diclofenac Musculoskeletal pain 1
Clobetasol Dermatitis, psoriasis, 0.05
eczema
Betamethasone Dermatitis, psoriasis, 0.01
eczema
Testosterone Hypogonadal men 0.8
Testosterone Hormone treatment for 0.25
postmenopausal women
lmiquimod Warts, basal cell 0.92
carcinoma
* Flux determined using an in vitro method described in Example 1.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
12
** Estimated flux based on known potency relative to lidocaine.
The therapeutically effective flux values in Table A (with the exception of
ropivacaine) represent the steady state flux values of marketed products
through hairless mouse or human epidermal membrane in an in vitro system
described in Example 1. These values are meant only to be estimates and to
provide a basis of comparison for formulation development and optimization.
The therapeutically effective flux for a selected drug could be very different
for
different diseases to be treated for, different stages of diseases, and
different
individual subjects. It should be noted that the flux listed may be more than
therapeutically effective.
The following examples listed in Table B illustrate screening of non-
volatile solvent's flux enabling ability for some of the drugs specifically
studied.
Experiments were carried out as described in Example 1 below and the results
are further discussed in the subsequent Examples 2-9.
Table B - In vitro steady state flux values of various drugs from non-volatile
solvent systems
Drug Non-Volatile Solvent Average Flux*
mcg/crn2/hr
Betamethasone Oleic acid 0.009 0.003
Dipropionate Sorbitan Monolaurate 0.03 0.02
Clobetasol Propionate Propylene Glycol (PG) 0.0038 0.0004
Light Mineral Oil 0.031 t 0.003
Isostearic acid (ISA) 0.019 0.003
Ropivacaine GI cerol 1.2 t 0.7
Mineral Oil 8.9 0.6
Ketoprofen Pol eth lene glycol 400 5 2
S an 20 15 3
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 B frorn non-volatile solvents
show surprising flux-enabling and non flux-enabling solvents. This information
can be used to guide formulation development.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
13
The term "plasticizing" in relation to flux-enabling non-volatile solvent(s)
is defined as a flux-enabling non-volatile solvent that acts as a plasticizer
for the
solidifying agent. A"plasticizer" is an agent which is capable of increasing
the
percentage elongation of the formulation after the volatile solvent system has
at
least substantially evaporated. Plasticizers also have the capability to
reduce
the brittleness of solidified formulation by making it more flexible and/or
elastic.
For example, propylene glycol is a "flux-enabling, plasticizing non-volatile
solvent" for the drug ketoprofen with polyvinyl alcohol as the selected
solidifying
agent. However, propylene glycol in a formulation of ketoprofen with Gantrez S-
97 or Avalure UR 405 as solidifying agents does not provide the same
plasticizing effect. The combination of propylene glycol and Gantrez S-97 or
Avalure UR 405 is less compatible and results in less desirable formulation
for
topical applications. Therefore, whether a given non-volatile solvent is
"plasticizing" depends on which solidifying agent(s) is selected.
Different drugs often have different matching flux-enabling non-volatile
solvent systems which provide particularly good results. Examples of such are
noted in Table C. Experiments were carried out as described in Example I
below and the results are further discussed in the subsequent Examples 2-9.
Table C - In vitro steady state flux values of various drugs from particularly
high
flux-enabling non-volatile solvent s stems
Drug High flux-enabling non- Avg. Flux*
volatile solvent mc /cmz /h
Ropivacaine ISA 11 2
S an20 26 8
Ketoprofen Propylene glycol (PG) 90 50
Acycolvir ISA + 30% trotamine 7 2
Betamethasone Propylene Glycol
Di ro ionate 0.20 0.07
Clobetasol PG+ISA (Ratio of PG:ISA 0.8 0.2
propionate ranging from 200:1 to 1:1)
Each value represents the mean and st. dev of three determinations.
It should be noted that "flux-enabling non-volatile solvent," "flux-enabling,
plasticizing non-volatile solvent," or "high flux-enabling non-volatile
solvent" can
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
14
be a single chemical substance or a mixture of two or more chemical
substances. For example, the steady state flux value for clobetasol propionate
in Table C is a 9:1 for propylene glycol:isostearic acid mixture that
generated
much higher clobetasol flux than propylene glycol or ISA alone (see Table B).
Therefore, the 9:1 propylene glycol:isostearic acid mixture is a "high flux-
enabling non-volatile solvent" but propylene glycol or isostearic acid alone
is
not.
The term "adhesion" 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.
"Adhesive" when used to describe the solidified layer means the solidified
layer is adhesive to the body 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 human body surface for the desired extended period of time partially depends
on the condition of the body 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 body surface
and
deliver the drug over a sustained period of time for every subject under any
conditions on the body surface. A standard is that it maintains good contact
with
most of the body surface, e.g. 70% of the total area, over the specified
period of
time for most subjects under normal conditions of the body 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
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
5 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.
10 The use of the term "substantially" when referring to the evaporation of
the volatile solvents means that a majority of the volatile solvents which
were
included in the initial formulation have evaporated. Similarly, when a
solidified
layer is said to be "substantially devoid" of volatile solvents, including
water, the
solidified layer has less than 10 wt%, and preferably less than 5 wt%, of the
15 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, or
combinations thereof.
"Non-volatile solvent system" can be a single solvent or mixture of
solvents that are less volatile than water. It can also contain substances
that
are solid or liquid at room temperatures, such as pH or ion-pairing agents.
After
evaporation of the volatile solvent system, most of the non-volatile solvent
system should remain in the solidified layer for an amount of time sufficient
to
dermally delivery a given drug to, into, or through the skin of a subject at a
sufficient flux for a period of time to provide a therapeutic effect. In some
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
16
embodiments, in order to obtain desired permeability for an active drug and/or
compatibility with solidifying agents or other ingredients of the formulation,
a
mixture of two or more non-volatile solvents can be used to form the non-
volatile
solvent system. In one embodiment, the combination of two or more non-
volatile solvents to form a solvent system provides a higher transdermal flux
for
a drug than the flux provided for the drug by each of the non-volatile
solvents
individually. The non-volatile solvent system may also serve as a plasticizer
of
the solidified layer, so that the solidified layer is elastic and flexible.
The term "solvent vehicle" describes compositions that include both a
volatile solvent system and non-volatile solvent system. The volatile solvent
system is chosen so as to evaporate from the adhesive peelable 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, 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.
The term "adhesive" in relation to the solidified layer means it is adhesive
to the skin on which the original formulation was applied, and not
necessarily,
and *preferably not, adhesive on the other side to other objects.
"Adhesive solidifying formulation," "solidifying formulation" or
"formulation" in some embodiments 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
17
formulation can form a peel. Such a 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 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 various aliphatic resins and
aromatic
resins.
25. 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
18
removing by washing the formulations of the present invention are numerous,
but preferably are chosen from commonly acceptable solvents including the
volatile solvents listed herein. Preferred washing solvents do not
significantly
irritate human skin and are generally available to the average subject.
Examples of washing solvents include but are not limited to water, ethanol,
methanol, isopropyl alcohol, acetone, ethyl acetate, propanol, or combinations
thereof. In aspect of the invention the washing solvents can be selected from
the group consisting of water, ethanol, isopropyl alcohol or combinations
thereof. Surfactants can also be used in some embodiments.
An acceptable length of time as it relates 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
19
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.
"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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
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.
5 With these definitions in mind, in accordance with this, 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
having one or inore volatile solvent(s) and a non-volatile solvent system
having
one or more non-volatile solvent(s), wherein the non-volatile solvent system
is
10 flux-enabling for the drug such that the drug can be delivered in
therapeutically
effective amounts over a period of time, even after most of the volatile
solvent(s)
is (are) 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 configured such that when applied to the skin surface, the
formulation
15 forms a solidified layer after at least a portion of the volatile
solvent(s) is (are)
evaporated, but yet continues to deliver drug after substantially solidifying.
In
certain embodiments, the solidified layer can be coherent so that it can be
peeled from the skin in one piece or several large pieces, or is washable from
the skin using a solvent. In one particular embodiment, the drug can be a sex
20 hormone, and in another particular embodiment, the drug can be an anti-wart
drug, though many other drug types can be used, as described herein.
In an alternative embodiment, a method of dermally delivering a drug to,
into, or through the skin can comprise applying a formulation to a skin
surface of
a subject, where the formulation comprises a drug; a solvent vehicle, and a
solidifyihg agent. The solvent vehicle comprises a volatile solvent system
including one or more volatile solvent, and a non-volatile solvent system that
is
flux-enabling for the drug. In this embodiment, the formulation can have a
viscosity suitable for application and adhesion to a skin surface prior to
evaporation of the volatile solvent system, and the formulation can be applied
such that the skin surface forms a solidified layer adhered to the skin after
at
least partial evaporation of the volatile solvent system. An additional step
includes dermally delivering the drug from the solidified layer to the subject
at
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
21
therapeutically effective rates over a sustained period of time, wherein the
drug
continues tb be delivered after the volatile solvent system is substantially
evaporated. In some embodiments, the solidified layer can be a soft or
flexible,
coherent, continuous solid, and can be removed by peeling. 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 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.
In another embodiment, a method of preparing a formulation for dermal
drug delivery can comprise steps of selecting a drug suitable for dermal
delivery; selecting or formulating a non-volatile solvent or a mixture of non-
volatile solvents that is flux-enabling for the selected drug, selecting a
solidifying
agent that is compatible with the drug and the non-volatile solvent, selecting
or
formulating a volatile solvent system that is compatible with the drug, the
non-
volatile solvent and the solidifying agent; and formulating all above
ingredients
into a formulation. The formulation can have a viscosity suitable for
application
to a skin surface prior to evaporation of the volatile solvent system, and can
be
applied to the skin surface where it forms a solidified layer after at least a
portion of the volatile solvent system is evaporated. In this embodiment, the
drug continues to be delivered at a therapeutically effective rate after the
volatile
solvent system is substantially evaporated.
In still another embodiment, a solidified layer for delivering a drug can
comprise a drug, a non-volatile solvent system, and a solidifying agent. The
non-volatile solvent system is flux-enabling for the drug. The solidified
layer can
be a soft, coherent solid that is adhered to a body surface, and while
dermally
delivering at least a portion of the drug therefrom, the solidified layer is
at least
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
22
substantially devoid of water and solvents more volatile than water, e.g., the
solidified layer can be considered substantially devoid of water and solvents
more volatile than water when the solidified layer contains no more than 10
wt%
or even 5 wt% of water and solvents more volatile than water. Additionally,
the
solidified layer is also flux-enabling for the drug. In one embodiment, the
solidified layer can be so coherent and elastic that it can be stretched in at
least
one direction by 5%, or even 10% without breaking, cracking, or separation
from
a skin surface to which the solidified layer is applied, and/or can be
peelable
from the skin.
In some applications, reducing the moisture vapor loss from the skin
surface can be desirable, and a solidified layer with a selected or formulated
non-volatile solvent system that is hydrophobic can help achieve this goal.
Therefore, another embodiment of the current invention is related to a
solidifying
formulation whose solidified layer is capable of providing significant
occlusion
effect (defined as decreasing the moisture vapor loss from body surfaces by at
least about 20%, preferably at least about 40%).
These embodiments exemplify the present invention which is related to
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 can 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, for drug delivery. The solidified layer is
optionally
peelable. A solidified layer thus formed is capable of delivering drug to the
skin,
into the skin, across the skin, etc., over an sustained period of time, e.g.,
hours
to tens of hours, so that most of the drug delivery occurs after the
solidified layer
is formed.
Additionally, the solidified layer typically adheres to the skin, but has a
solidified, minimally or non-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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
23
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
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.
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
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
10 wt% to about 85 wt%, from about 20 wt% to about 50 wt%, and in a preferred
embodiment, at least 20 wt 1o.
The volatile solvent system can also be chosen to be compatible with the
non-volatile solvent, solidifying agent, drug, and any other excipients that
may
be present. For example, polyvinyl alcohol (PVA) is not soluble in ethanol.
Therefore, a volatile solvent which can dissolve PVA needs to be formulated in
the solidified layer. For instance, water can dissolve PVA and can be utilized
as
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
24
a volatile solvent in a solidifying formulation; however the drying time in a
formulation in which water is the only volatile solvent 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 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. 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 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 after the evaporation of the volatile solvent. Thus,
appropriate
solidifying agent/non-volatile solvent selections are desirable in developing
a
viable formulation.
In further detail, non-volatile solvent(s) that can be used alone or in
combination to form non-volatile solvent systems can be selected from a
variety
of pharmaceutically acceptable liquids, including but not limited to 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
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
5 citrate, or combinations thereof. In a further embodiment the non-volatile
solvent system can include 1,2,6-hexanetriol, alkyltriols, alkyldiols, acetyl
monoglycerides, tocopherol, alkyl dioxolanes, p-propenylanisole, anise oil,
apricot oil, dimethyl isosorbide, alkyl glucoside, benzyl alcohol, bees wax,
benzyl benzoate, butylene glycol, caprylic/capric triglyceride, caramel,
cassia oil,
10 castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa
butter,
cocoglycerides, coriander oil, corn oil, coriander oil, corn syrup, cottonseed
oil,
cresol, cyclomethicone, diacetin, diacetylated monoglycerides, diethanolamine,
dietthylene glycol monoethyl ether, diglycerides, ethylene glycol, eucalyptus
oil,
fat, fatty alcohols, flavors, liquid sugars ginger extract, glycerin, high
fructose
15 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-
20 (octadecyloxy)ethoxy)ethanol, benzyl benzoate, butylated hydroxyanisole,
candelilla wax, carnauba wax, ceteareth-20, cetyl alcohol, polyglyceryl,
dipolyhydroxy stearate, PEG-7 hydrogenated castor oil, diethyl phthalate,
diethyl
sebacate, dimethicone, dimethyl phthalate, PEG Fatty acid esters such as PEG-
stearate, PEG - oleate, PEG- laurate, PEG fatty acid diesters such as PEG-
25 dioleate, PEG- distearate, PEG-castor oil, glyceryl behenate, PEG glycerol
fatty
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, caprylate/caprate, sodium
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
26
pyrrolidone carboxylate, sorbitol, squalene, stear-o-wet, triglycerides, alkyl
aryl
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-dimethylalkylarnides), 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
further embodiment the non-volatile solvent system can include a combination
or mixture of non-volatile solvents set forth in the any of the above
discussed
embodiments.
In addition to these and other considerations, the non-volatile solvent
system can, and preferably should, also serve as plasticizer in the
formulations
of the current invention 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) are irritating to the skin but
are desirable to use to achieve the desired solubility and/or permeability of
the
drug. It 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 gtycol.
. The formulations of the current invention may also contain two or more
non-volatile solvents that independently cannot generate as high flux for a
drug
as when formulated together according to a certain and often experimentally
determined ratio. One possible reason for these initially non or less flux-
enabling
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
27
non-volatile solvents to become more flux-enabling 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 non-volatile solvent
system
that might be more flux-enabling include but are not limited to isostearic
acid
/trolamine, isostearic acid /diisopropyl 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 can 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 welt 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 B) 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-trimethylammonioethyi
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
having a MW similar to Instant Pure-Cote B793 (Grain Processing Corporation),
ethyl cellulose MW greater than 5,000 or MW similar to Aqualon EC N7, N10,
N14, N22, N50, or N100 (Hercules), fish gelatin having a MW 20,000-250,000
(Noriand Products), gelatin, other animal sources with MW greater than 5,000,
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
28
acrylates/octylacrylamide copolymer MW greater than 5,000 or MW similar to
National Starch, and Chemical Dermacryl 79.
In another embodiment the solidifying agent can include ethyl cellulose,
hydroxy ethyl cellulose, hydroxy methyl cellulose, hydroxy propyl cellulose,
hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose,
polyether amides, corn starch, pregelatinized corn starch, polyether amides,
shellac, polyvinyl pyrrolidone, polyisobutylene rubber, polyvinyl acetate
phthalate or combinations thereof. In. a further embodiment the solidifying
agent
can include ammonia methacrylate, carrageenan, cellulose acetate phthalate
aqueous such as CAPNF from Eastman, carboxy polymethylene, cellulose
acetate (microcrystalline), cellulose polymers, divinyl benzene styrene,
ethylene
vinyl acetate, silicone, guar gum, guar rosin, gluten, casein, calcium
caseinate,
ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate,
microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate,
PEG/PVP,
xantham gum, trimethyl siloxysilicate, maleic acid/anhydride colymers,
polacrilin,
poloxamer, polyethylene oxide, poly glactic acid/poly-l-lactic acid, turpene
resin,
locust bean gum, acrylic copolymers, polyurethane dispersions, dextrin,
polyvinyl alcohol-polyethylene glycol co-polymers, methyacrylic acid-ethyl
acrylate copolymers such as BASF's Kollicoat polymers, methacrylic acid and
methacrylate based polymers such as poly(methacrylic acid), or combinations
thereof. In another embodiment, the solidifying agent can include a
combination
of solidifying agents set forth in the any of the above discussed embodiments.
Other polymers may also be suitable as the solidifying agent, depending on the
solvent vehicle components, the drug, and the specific functional requirements
of the given formulation. 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.
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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
29
so that substantially no non-volatile solvent oozes out of the layer, and/or
iii) the
solidified layer formed with the selected non-volatile solvent system and the
solidifying agent has acceptable flexibility, rigidity, tensile strength,
elasticity,
and adhesiveness to skin. The weight ratio of the non-volatile solvent system
to
the solidifying agent(s) can be from about 0.1:1 to about 10:1. In another
aspect, the weight ratio of the non-volatile solvent system to the solidifying
agent can be from about 0.2:1 to about 4:1, and more preferably from about
0.5:1 to about 2:1.
The flexibility and stretchability of a solidified layer, which is optionally
also a peel, can be desirable in some applications. For instance, certain non-
steroidal anti-inflammatory agents (NSAIDs) can be 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 NSAIDs 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
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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
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.
Other benefits of the solidified layers of the present invention include the
5 presence of a physical barrier that can be formed by the material itself. In
some
disease or injury situations, the skin surface is sensitive to the touch of
foreign
objects or vulnerable to infection if contact by foreign objects. In those
situations, the solidified layer can provides physical protection to the skin
surface. For instance, local anesthetic agents and other agents such as
10 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.
15 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 formulation
layer applied to the skin is relatively thick and can contain much more active
20 drug than a typical layer of traditional cream, gel, lotion, ointment,
paste, etc.,
and further, is resistant to unintentional removal. The solidified layer
comprises
a non-volatile solvent system that ,is flux-enabling for the drug so that the
drug
can be delivered over sustained period of time at therapeutically effective
rates.
Further, as the solidified layer remains adhesive to skin and is preferably
25 peelable, easy removal of the solidified layer can occur, may be 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
30 stretched by 5%, or even 10% or greater, in at least one direction without
cracking, breaking, and/or separating form a skin surface to which the layer
is
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
31
applied. Still further, the solidified layer can be configured to
advantageously
deliver drug and protect sensitive skin areas without cracking or breaking.
In one embodiment of the invention, the solidified layer'may be washed
off with a solvent, such as water or ethanol, at the end of the desired drug
delivery. Other solvents which could also be used to wash off the solidified
formulation include but are not limited to the volatile solvents listed
herein. The
ability to be removed by washing is particularly advantageous for certain
applications. For example, if the solidifying formulation is applied to a body
area
with a lot of hair (e.g. an anti genital herpes solidifying formulation
applied on
genital skin area with pubic hair), removal by peeling might cause discomfort
and therefore be undesirable, and hence washing can be a preferred form of
removal in this type of application. In another example, if the solidifying
formulation is applied to a palmar surface, such as the palm of the hand or
the
sole of a foot, the ability for removal by peeling may be secondary
consideration
to a formulation that will adhere to the skin surface. In these cases, a
solidified
layer configured to be easily washed off by water or ethanol may be more
desirable. In washing embodiments, the solvent used to wash off the solidified
layer may dissolve the layer or make it less adhesive to the skin so that it
can be
easily removed from the skin.
As a further note, it is a unique feature that the solidified layers of the
present invention can keep a substantial amount of the non-volatile solvent
system, which is optimized for delivering the drug, on the body surface. This
feature can provide unique advantages over existing products. For example,
Penlac is a product widely used for treating nail fungal infections. It
contains the
drug ciclopirox, volatile solvents (ethyl acetate and isopropyl), and a
polymeric
substance. After being applied on the nail surface, the volatile solvents
quickly
evaporate and the formulation layer solidifies into a hard lacquer. The drug
molecules are immobilized in the hard lacquer layer and are substantially
unavailable for delivery into the nail. As a result, it is believed that the
delivery
of the drug is not sustained over a long period of time. As a result, without
being bound by any particular theory, it is believed that this is at least one
of the
reasons why Penlac, while widely used, has an efficacy rate of only about 10%.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
32
Conversely, in the solidified layer of the present invention, the drug
molecules
are quite mobile in the non-volatile solvent system which is in contact with
the
skin surface, e.g., skin, nail, mucosal, etc., 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 solidifying formulation for treating the same disease. In
another
embodiment, retinoic acid and benzoyl peroxide can be combined in a solidified
layer for treating acne, or alternatively, 1 wt /a clindamycin and 5 wt%
benzoyl
peroxide can be combined in a solidifying formulation for treating acne. In
another embodiment, a retinol solidifying formulation (OTC) can be prepared
for
treating wrinkles, or a lidocaine solidifying formulation can be prepared for
treating back pain. In another embodiment, a zinc oxide solidifying
formulation
(OTC) can be prepared for treating diaper rash (the physical barrier provided
by
the solidified layer against irritating urine and feces is believed to be
beneficial),
or an antihistamine solidified layer can be prepared for treating ailergic
rashes
such as that caused by poison ivy.
Additional applications include delivering drugs for treating certain skin
conditions, e.g., dermatitis, psoriasis, eczema, skin cancer, alopecia,
wrinkles,
viral infections such as cold sore, genital herpes, shingles, etc.,
particularly
those that occur over joints or muscles where a transdermal patch may not be
practical. For example, solidifying formulations containing imiquimod can be
formulated for treating skin cancer, prematurely aged skin, photo-damaged
skin,
common and genital warts, and actinic keratosis. Solidifying formulations
containing antiviral drugs such as acyclovir, penciclovir, famciclovir,
valacyclovir,
steroids, 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 treating soft
tissue
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
33
injury and muscle-skeletal pains such as joint and back pain of various
causes.
As discussed above, patches over these skin areas typically do not have good
contact over sustained period of time, especially for a physically active
subject,
and may cause discomfort. Likewise, traditional semi-solid formulations such
as
creams, lotions, ointments, etc., may prematurely stop the delivery of a drug
due
to the evaporation of solvent and/or unintentional removal of the formulation.
The solidifying formulations of the present invention address the shortcomings
of both of these types of delivery systems.
One embodiment can entail a solidified layer containing a drug from the
class of alpha-2 antagonists which is applied topically to treat neuropathic
pain.
The alpha-2 agonist is gradually released from the formulation to provide pain
relief over a sustained period of time. The formulation can become a coherent,
soft solid after about 5 minutes and remains adhered to the body surface for
the
length of its application, typically hours to tens of hours. The solidified
layer is
easily removed after the intended application without leaving residual
formulation on the skin surface.
Another embodiment involves a solidifying formulation containing
capsaicin which is applied topically to treat neuropathic pain. The capsaicin
is
gradually released from the formulation for treating this pain over a
sustained
period of time. The formulation can become a coherent, soft solid after about
5
minutes and remains adhered to the body 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 a solidifying formulation containing
clobetasol propionate which is applied topically to treat hand dermatitis. The
clobetasol propionate is gradually released from the formulation for treating
dermatitis over a sustained period of time. The formulation can become a
coherent, soft solid after about 7 minutes and remains adhered to the body
surface for the length of its application. The physical barrier also protects
the
compromised skin from potentially harmful substances. It is easily removed any
time after drying without leaving residual formulation on the skin surface.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
34
Another embodiment involves a solidifying formulation containing
clobetasol propionate which is applied topically to treat alopecia. The
clobetasol
propionate is gradually released from the formulation for promoting hair
growth
over a sustained period of time. The formulation can become a coherent, soft
solid after about 5 minutes and remains adhered to the body surface for the
length of its application. It is easily removed any time after drying by
peeling to
showering.
Another embodiment involves solidifying formulations containing tazorac
for treating stretch marks, wrinkles, sebaceous hyperplasia, or seborrheic
keratosis.
In another embodiment, solidifying formulations containing glycerol can
be made so as to provide a protective barrier for fissuring on finger tips.
Still another embodiment can include a solidifying formulation containing
a drug selected from the local anesthetic class such lidocaine and ropivacaine
or the 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/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 about 5-10 minutes and remains adhered to the
body
surface for the length of its application. It is easily removed any time after
drying without leaving residual formulation on the skin surface.
A further embodiment involves a solidifying formulation containing at
least one alpha-2 agonist drug, at least one tricyclic antidepressant agent,
and/or at least one local anesthetic drug which is applied topically to treat
neuropathic pain. The drug(s) are gradually released from the formulation to
provide pain relief over a sustained period of time. The formulation can
become
a coherent, soft solid after 2-10 minutes and remains adhered to the body
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 solidifying formulation containing
drugs capsaicin and a local anesthetic drug which is applied topically to the
skin
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
to provide pain relief. Another embodiment can include a solidifying
formulation
containing the combination of a local anesthetic and a NSAID. In both of the
above embodiments the drugs are gradually released from the formulation to
provide pain relief over a sustained period of time.. The formulation can
become
5 a coherent, soft solid after about 2-10 minutes and remains adhered to the
body
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
10 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
15 to, non-steroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen and
diclofanac, COX-2 selective NSAIDs and agents, COX-3 selective NSAIDs and
agents, local anesthetics such as lidocaine, bupivacaine, ropivacaine, and
tetracaine, steroids such as dexamethasone.
Delivering drugs for the treatment of acne and other skin conditions can
20 also benefit from principles of the present invention, especially when
delivering
drugs having low skin permeability. Currently, topical retinoids, peroxides,
and
antibiotics for treating acne are mostly applied as traditional semisolid gels
or
creams. However, due to the shortcomings as described above, sustained
delivery over many hours is unlikely. For example, clindamycin, benzoyl
25 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
30 delivery of the drug. The formulations of the present invention typically
do not
have this limitation.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
36
In another embodiment, the delivery of drugs for treating neuropathic
pain can also benefit from the methods, systems, and formulations of the
present invention. A patch containing a local -anesthetic agent, such as -
LidodermTM, is widely used for treating neuropathic pain, such as pain caused
by post-herpetic neuralgia. Due to the limitations of the patch as discussed
above, the solidified layers prepared in accordance with the present invention
provide some unique benefits, as well as provide a potentially less expensive
alternative to the use of a patch. Possible drugs delivered for such
applications
include, but are not limited to, local anesthetics such as lidocaine,
prilocaine,
tetracaine, bupivicaine, etidocaine; and other drugs including capsaicin and
alpha-2 agonists such as clonidine, dissociative anesthetics such as ketamine,
tricyclic antidepressants such as amitriptyline.
The solidifying formulations of the present invention can be formulated to
treat a variety of conditions and disease such as musculoskeletal pain,
neuropathic pain, alopecia, skin disease including dermatitis and psoriasis as
well as skin restoration (cosmetic skin treatment), and infections including
viral,
bacterial, and fungal infection. As such the formulations can deliver a wide
ranging number and types of drugs and active agents. In one embodiment the
solidifying formulation can be formulated to include acyclovir, econazole,
miconazole, terbinafine, lidocaine, bupivacaine, ropivacaine, and tetracaine,
amitriptyline, ketanserin, betamethasone dipropionate, triamcinolone
acetonide,
clindamycin, benzoyl peroxide, tretinoin, isotretinoin, clobetasol propionate,
halobetasol propionate, ketoprofen, piroxicam, diclofenac, indomethacin,
imiquimod, salicylic acid, benzoic acid, or combinations thereof
In one embodiment, the formulation can include an antifungal drug such
as amorolfine, butenafine, naftifine, terbinafine, fluconazole, itraconazole,
ketoconazole, posaconazole, ravuconazoie, voriconazole, clotrimazole,
butoconazole , econazole, miconazole, oxiconazole, sulconazole, terconazole,
tioconazole, caspofungin, micafungin, anidulafingin, amphotericin B, AmB,
nystatin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin, toinaftate,
and
undecylenate, or combinations thereof.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
37
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
as clindamycin and benzoyl peroxide, retinol, vitamin A derivatives such as
tazarotene and isotretinoin, cyclosporin, anthralin, vitamin D3,
cholecalciferol,
calcitriol, ca{cipotriol, tacalcitol, calcipotriene, etc.
In yet another embodiment, the delivery of medication for treating warts
and other skin conditions would also benefit from long periods of sustained
drug
delivery. Examples of anti-wart compounds include but are not limited
to:imiquimod, rosiquimod, keratolytic agents: salicylic acid, alpha hydroxy
acids,
sulfur, rescorcinol, urea, benzoyl peroxide, allantoin, tretinoin,
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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
38
of progesterone, norethindrone, norethindroneacetate, desogestrel,
drospirenone, ethynodiol diacetate, norelgestromin, norgestimate,
levonorgestrel, dl-norgestrel, cyproterone acetate, dydrogesterone,
medroxyprogesterone acetate, chlormadinone acetate, megestrol,
promegestone, norethisterone, lynestrenol, gestodene, tibolene, androgens
consisting of testosterone, methyl testosterone, oxandrolone, androstenedione,
dihydrotestosterone, estrogens consisting of estradiol, ethniyl estradiol,
estiol,
estrone, conjugated estrogens, esterified estrogens, estropipate, or
combinations thereof.
Non-sex steroids can also be delivered using the formulations of the
present invention. Examples of such steroids include but are not limited to
betamethasone dipropionate, halobetasol propionate, diflorasone diacetate,
triamcinolone acetonide, desoximethasone, fluocinonide, halcinonide,
mometasone furoate, betamethasone valerate, fluocinonide, fluticasone
propionate, triamcinolone acetonide, fluocinolone acetonide, 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.
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
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 alprazoiam;
N-methyl-D-aspartate (NMDA) antagonists such as ketamine; 5-HT2A receptor
antagonists such as ketanserin; and immune modulators such as tacrolimus and
picrolimus.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
39
A further embodiment involves the following steps: selecting a drug for
dermal delivery, selecting or formulating a flux-enabling or high flux-
enabling
non-volatile solvent system for the selected drug, selecting a solidifying
agent
that is compatible with the non-volatile solvent system and volatile solvent
system, selecting a volatile solvent system that meets a preferred drying time
frame and is compatible with the above ingredients, and formulating above
ingredients into a solidifying formulation that optionally further includes
other
ingredients such as viscosity modifying agent(s), pH modifying agent(s), and
emollients.
Another embodiment involves a method of maintaining a liquid flux-
enabling or high liquid flux-enabling non-volatile solvent on human skin
(including mucosa or nail surfaces) for delivery of a drug into tissues under
the
surfaces, comprising selecting a drug for dermal delivery, selecting or
formulating a flux-enabling or high flux-enabling non-volatile solvent system
for
the selected drug, selecting a solidifying agent that is compatible with the
flux-
enabling or high flux-enabling non-volatile solvent system and volatile
solvent
system, and formulating above ingredients into a solidifying formulation.
Another embodiment involves a method for keeping a liquid flux-
enabling non-volatile solvent system on human skin for delivery of a drug into
the human skin or tissues under the human skin. The method includes applying
to a human skin a layer a formulation comprising a drug, a flux enabling non-
volatile solvent system, a solidifying agent capable of gelling the liquid
flux-
enabling non-volatile solvent system into a soft solid, and a volatile solvent
system that is compatible with the rest of components of the formulation. The
formulation layer is such that the evaporation of at least some of the
volatile
solvent system transforms the formulation from an initial less than solid
state
into a soft-coherent solid layer. The drug in the soft-coherent solid layer is
delivered at therapeutically effective rates for a sustained period of time.
One use of the present invention can be for delivering sex hormones. In
one embodiment, a formulation for dermal delivery of a sex hormone can
include a sex hormone, a solvent vehicle, and a solidifying agent that
contributes to solidification of the formulation applied as a layer on a skin
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
surface upon at least partial evaporation of the volatile solvent system. The
solvent vehicle can include a volatile solvent system inc(uding at least one
volatile solvent, and a non-volatile solvent system including at least one non-
volatile solvent. The formulation can have a viscosity which is suitable for
5 application and adhesion to a skin surface prior to evaporation of the
volatile
solvent system. When applied to a skin surface the formulation forms a
solidified layer after at least partial evaporation of the volatile 'solvent
system.
The sex hormone continues to be delivered therapeutically sufficient rates
even
after the volatile solvent system is at least substantially evaporated.
10 The formulations of the present inventions can also be used in the
treatment and elimination of warts. An antiwart formulation can include an
anti-
wart drug, a solvent vehicle, and a solidifying agent. 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. The
15 formulation can have a viscosity which is suitable for application and
adhesion
to a skin surface prior to evaporation of the volatile solvent system. When
applied to a skin surface the formulation forms a solidified layer after at
least
partial evaporation of the volatile solvent system. The antiwart hormone
continues to-be delivered therapeuticaliy sufficient rates even after the
volatile
20 solvent system is at least substantially evaporated_
In an additional embodiment, a formulation for delivering clobetasol
propionate can include clobetasol propionate, a solvent vehicle, and a
solidifying agent. The solvent vehicle includes a volatile solvent system
including at least one volatile solvent, and a non-volatile solvent system.
The
25 non-volatile solvent system can include propylene glycol and/or a fatty
acid.
The formulation can have a viscosity which is suitable for application and
adhesion to a skin surface prior to evaporation of the volatile solvent
system.
When applied to a skin surface the formulation forms a solidified layer after
at
least partial evaporation of the volatile solvent system. The clobetasol
30 propionate continues to be delivered therapeutically sufficient rates even
after
the volatile solvent system is at least substantially evaporated. The
solidifying
agent can be a protein based solidifying agent.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
41
In another embodiment, a solidifying formulation for delivering
ropivacaine can include ropivacaine, a solvent vehicle, and a solidifying
agent.
The volatile solvent system including at least one volatile solvent and the
non-
volatile solvent system which can comprise solvents such as isostearic acid
span 20, and triacetin. The formulation can have a viscosity which is suitable
for application and adhesion to a skin surface prior to evaporation of the
volatile
solvent system. When applied to a skin surface the formulation forms a
solidified layer after at least partial evaporation of the volatile solvent
system.
Even after the at least a portion of the partial evaporation of the volatile
the
ropivacaine continues to be delivered into or across the skin at a rate of no
less
than 5 mcg/hr/cm2 for at least 6 hours after the volatile solvent system has
at
least substantially evaporated.
In another embodiment, a solidifying formulation for delivering imiquimod
can include imiquimod, a solvent vehicle, and a solidifying agent. The
volatile
solvent system including at least one volatile solvent, and the non-volatile
solvent system can comprise solvents such as isostearic acid span 20, and
triacetin. The formulation can have a viscosity which is suitable for
application
and adhesion to a skin surface prior to evaporation of the volatile solvent
system. When applied to a skin surface the formulation forms a solidified
layer
after at least partial evaporation of the volatile solvent system. Even after
the at
least a portion of the partial evaporation of the volatile the ropivacaine
continues
to be delivered into or across the skin at a rate of no less than 5 mcg/hr/cm2
for
at least 6 hours after the volatile solvent system has at least substantially
evaporated.
in another embodiment, a solidifying formulation for delivering imiquimod
can include imiquimod, a solvent vehicle, and a solidifying agent. The
volatile
solvent system including at least one volatile solvent and the non-volatile
solvent system can comprise solvents such as isostearic acid span 20, and
triacetin. The formulation can have a viscosity which is suitable for
application
and adhesion to a skin surface prior to evaporation of the volatile solvent
system. When applied to a skin surface the formulation forms a solidified
layer
after at least partial evaporation of the volatile solvent system. Even after
the at
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
42
least a portion of the partial evaporation of the volatile the imiquimod
continues
to be delivered into or across the skin at a rate of no less than 0.8
mcg/hr/cm2
for at least 6 hours after the volatile solvent system has at least
substantially
evaporated.
In another embodiment, a solidifying formulation for delivering ketoprofen
can include ketoprofen, a solvent vehicle, and a solidifying agent. The
volatile
solvent system includes a volatile solvent system including at least one
volatile
solvent and a non-volatile solvent system comprising glycerol and propylene
glycol. The formulation can have a viscosity which is suitable for application
and adhesion to a skin surface prior to evaporation of the volatile solvent
system. When applied to a skin surface the formulation forms a solidified
layer
after at least partial evaporation of the volatile solvent system. Even after
the at
least a portion of the partial evaporation of the volatile the ketoprofen
continues
to be delivered across the skin at a rate of no less than 10 mcg/hr/cmZfor at
least 6 hours after the volatile solvent system has at least substantially
evaporated.
Other drugs that can be delivered using the formulations and methods
of the current invention include humectants, emollients, and other skin care
compounds.
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
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
further detail in connection with what are presently deemed to be the most
practical and preferred embodiments of the invention.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
43
Example I
Hairless mouse skin (HMS) or human epidermal membrane (HEM) is
used as the model membranes as noted for the in vitro flux studies described
in
herein. Hairless mouse skin (HMS) is used as the model membrane 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 diffusion cell. The receiver chamber is
filled
with pH 7.4 phosphate buffered saline (PBS). The experiment is initiated by
placing test formulations (of Examples 2-5) 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.
Example 2
Human cadaver skin is used as membrane to select "flux-enabling"
non-volatile solvent for betamethasone dipropionate. About 200 mcL of
saturated solutions of BDP in various solvents are added to the donor
compartment of the Franz cells. In vitro analysis as described in Example 1 is
used to determine the steady state flux of BDP. In vitro methodology used is
described in Example 1. Active enzymes in the skin convert betamethasone
dipropionate to betamethasone. The steady state flux values reported in Table
1 are quantified using external betamethasone standards and are reported as
amount of betamethasone permeating per unit area and time.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
44
Table 1- Non-volatile solvents for betamethasone di ro ionate
Non-volatile solvent system Skin F12 x*
n /c /h
Propylene Glycol 195.3 68.5
Triacetin 4.6 2.8
Light Mineral Oil 11.2 3.1
Oleic Acid 8.8 3.3
Sorbitan Monolaurate 30.0 15.9
Labrasol 12.2 6.0
* 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.
As seen from the results, triacetin, labrasol, oleic acid, and light mineral
oil have flux values close to the estimated therapeutically effective flux of
10
ng/cm2lhr. Addition of solidifying agents and other components could possible
decrease the flux and hence the above mentioned non-volatile solvents may not
be an ideal choice as "flux-enabling" solvents. However, sorbitan monolaurate
has 3 times higher flux than one possible therapeutic level and hence has
better
chances to be a "flux-enabling" solvent. Its compatibility with various
solidifying
agents would determine the appropriate levels at which it can be used.
Additionally, propylene glycol has 19 times higher flux than therapeutic level
needed, and hence provides significantly higher flux than other non-volatile
solvent systems tested. The ability of a non-volatile solvent to generate a
flux
much higher than just barely "enabling" can be advantageous as the
incorporation of other necessary or desired ingredients into the formulation
tends to decrease the flux, and it may allow achieving the desired therapeutic
effect with relatively low drug concentrations in the formulation, which tend
to
make the formulation less expensive and safer.
Example 3
Formulations of clobetasol propionate in various non-volatile solvent
systems are evaluated. All solvents have 0.1 %(w/w) clobetasol propionate.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
The permeation of clobetasol from the test formulations through HEM is
presented in Table 2 below.
Table 2 - Non volatile solvents for clobetasol ro ionate
Non-volatile solvent system Skin FI2 x*
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 GI col/ISA (9:1) 764.7 193.9
5 * 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
10 continue.
Human cadaver skin is used as a membrane to select "flux-enabling" solvent for
clobetasol propionate. In vitro methodology is described in Example 1. About
200 mcl of 0.1 %(w/w) solution of clobetasol in various non-volatile solvents
is
15 added to the donor compartment of Franz cells. Results obtained after LC
analysis are shown in Table 2. All the neat non-volatile solutions studied
herein
have an average flux of less than 50 ng/cm2/hr over a 30 hour time period.
Propylene glycol and glycerol have the lowest permeation for clobetasol
propionate. This result is surprising considering that betamethasone
20 dipropionate which is similar in structure to clobetasol propionate has
good flux
with propylene glycol. The solvent system which is a mixture of propylene
glycol and isostearic acid at a weight ratio of 9:1 has significantly higher
flux
than either of the solvents alone or the other solvents tested. The average
flux
is 20 times higher than light mineral oil which appears to be the best non-
mixed
25 solvent. Hence, for clobetasol propionate, the propylene glycol/isostearic
acid
provided the highest flux for a non-volatile solvent system. Among the non-
volatile solvents listed in Table 2, only 9:1 propylene glycol:ISA is
considered to
be flux enabling. In this example, flux enabling non-volatile solvent system
is
not a pure, single substance, but rather a mixture of two or more substances
at
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
46
a flux-enabling ratio. This being stated, other ratios or substance
combinations
may be used to generate a flux-enabling non-volatile solvent system.
Examples 4-9
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 3.
Table 3 - Salidi in formulation com onents
Percent Percent
Percent Percent Precen#
Example Polymer Polymer Ethanol Propylene Isostearic Water
GI col Acid
4 Polyvinyl 20 30 19.6 0.4 30
Alcohol
5 Shellac 50 30 19.6 0.4 0
6 Dermacryl 65.76 21.16 12.76 0.26 0
79
7 Eudragit 50 30 19.6 0.40 0
E100
8 Eudragit 50 30 19.6 0.40 0
RLPO
9 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 4 as follows:
Table 4 - Steady state flux of Clobetasol propionate through human
cadaver skin at 35 C
Formulation Skin Flux*
n /cm /h
Exam le4 87.8 21.4
Example 5 9.7 2.4
Exam le6 8.9 0.8
Exam le 7 3.2 1.7
Example 8 20.2 18.6
Example 9 147.5 38.8
* 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
47
experiment was continued it is anticipated the steady state would
continue.
As seen from Table 4 formulation described in Example 4 that contains
polyvinyl alcohol as a solidifying agent has high flux of clobetasol
propionate.
Polyvinyl alcohol is known to form stretchable solidified layers and it is
likely that
this formulation will have acceptable wear properties. The toughness of the
resulting solidified layer can be modified by adding appropriate plasticizers
if
needed (the non-volatile solvent system itself can serve as a plasticizer).
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 9, a higher percentage of
ethanol is needed to dissolve the polymer. However, the solidifying agent used
in Example 9 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 10
Formulations of acyclovir in various non-volatile solvent systems are
evaluated. Excess acyclovir is present.
The permeation of acyclovir from the test formulations through HMS is
presented in Table 5 below.
Table 5
Non-volatile solvent system Sfcin Fluzx*
mc /cm !h
Isostearic Acid 0.1 0.09
lsostearic Acid + 10% Trolamine 2.7 0.6
Isostearic Acid + 30% Trolamine 7 2
Olive Oil 0.3 0.2
Olive Oil + 11 % 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
Oieic Acid + 30% Trolamine 14 -~ 5
Ethyl Oleate 0.2 0.2
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
48
Ethyl Oleate + 10% Trolamine 0.2 0.2
* 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.
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 1, where the flux was about
3mcg/cm2/h). However, the combination of isostearic acid and trolamine or
oteic 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 11-14
Prototype formulations are prepared as follows. Several acyclovir
solidifying formulations are prepared in accordance with embodiments of the
present invention in accordance with Table 6, as follows:
Table 6
Example 11 12 13 14
% by 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
Acyclovir 3 3 3 2.8
In Examples 11-14, 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
49
mixture is obtained, acyclovir is added to the mixture and the formulation is
vigorously mixed.
Examples 15-16
Prototype formulations are prepared as follows. Several acyclovir
solidifying formulations are prepared in accordance with embodiments of the
present invention in accordance with Table 7, as follows:
Table 7
Example 15 16
% 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
The compositions of Examples 15 and 16 as shown in Table 3 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-POlethanol 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.
Examples 17-18
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 8, as follows:
Table 8
Example 17 18
% by wei ht
Ethanol 59.6 58
Ethyl Cellulose --
(EC) N7 19.9
Ethyl Cellulose. 19
EC N 100 --
Trolamine 7.6 9
Isostearic Acid 7.7 9
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
Acyclovir 5.2 5
In Examples 17-18 the compositions in Table 8 are prepared as follows. Ethyl
cellulose (EC)N7 or EC N100 from Aqualon and ethanol are combined in a
glass jar and heated with stirring until the solid cellulose is dissolved. The
5 isostearic acid and trolamine is added to the celluiose/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 19
10 The formulations of Examples 11-18 are tested in a hairless mouse skin
(HMS) in vitro model described in Example 1. Table 9 shows data obtained
using the experimental process outlined above.
Table 9-- Stead -state flux (J) of Ac clovir through HMS
Formulation J* Ratio to
(pg/cm2/h) Control
Exam le 11 12 5 6
Exam le 12 19 1 8
Exam le 13 8 1 4
Example 14 1 1 0.5
Example 15 0.7 0.3 0.35
Example 16 1 0.9 0.5
Exam fe 17 2 1 1
Exam le 18 19 7 8
Zovirax Cream 2 0.4 1
15 * 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
20 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
11-13 and 18 are found to be much greater in permeability than the marketed
25 product Zovirax Cream. The quantity of acyclovir that permeated across the
HMS stratum corneum over time for Examples 11, 12, and Zovirax Cream are
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
51
shown in FIG. 4. Each value shown indicates the mean SD of at least three
experiments.
Examples 11-14 show the impact of the trolamine to isostearic acid (ISA)
ratio on acyclovir flux enhancement. The optimal ISA:troiamine 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 15 and 16) 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 17 and 18 utilize a different
solidifying
agent to evaluate the impact of the solidifying agent on acyclovir flux.
Surprisingly, Example 17 shows a significant decrease in acyclovir skin flux,
but
Example 18, which differed from Example 17 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 11.
As can be seen from FIG. 4, Examples 11 and 12 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 solidified formulation affixed to the skin.
Example 20
A solidifying formulation similar to Example 12 (with no acyclovir) is
applied onto a human skin surface, resulting in a thin, transparent, flexible,
and
stretchable solidified layer. After a few minutes of evaporation of the
volatile
solvent (ethanol), a solidified adhesive layer that is peelable is formed. The
stretchable solidified layer has good adhesion to the skin and did not
separate
from the skin, and could easily be peeled away from the skin. The absence of
acyclovir has minimal to impact on the physical and wear properties of the
formulation and soft, coherent solid because it is present at such low
concentration, when present.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
52
Example 21
Solidifying formulations of ketoprofen in various non-volatile solvent
systems are evaluated. Excess ketoprofen is present.
The permeation of ketoprofen from the test formulations through HMS is
presented in Table 10 below.
Table 10
Non-volatile solvent system Skin Flux*
mc /cm2/h
Glycerol 2t9
Pol eth lene Glycol 400 5 2
S an20 15 3
Propylene Glycol 90 50
Oleic Acid 180 20
* 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 ketoprofen 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.
From Table 10, the non-volatile solvents glycerol and polyethylene glycol 400
had low steady state flux values and would not be considered "flux-enabling."
Span 20 maybe considered flux-enabling, and propylene glycol or oleic acid
provided the highest flux and are considered flux-enabling non-volatile
solvent
systems. Assessment of flux-enabling solvents is based on the estimated
therapeutically effective flux of ketoprofen (16mcg/cm2/h in Table A). Steady
state flux values of a drug from the non-volatile solvent that are below the
therapeutically effective flux (Table A) are not considered flux-enabling
while
steady state flux values of a drug from a non-volatile solvent above the
therapeutically effective flux value is considered flux-enabling.
Example 22
Solidifying formulations of ropivacaine in various non-volatile solvent
systems are evaluated. Excess ropivacaine is present. The permeation of
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
53
ropivacaine from the test formulations through HMS is presented in Table 11
below.
Table 11
Skin Flux*
Non-volatile solvent system mc /crn2lh
Glycerol 1.2 0.7
Tween20 2.4 0.1
Mineral Oil 8.9 0.6
ISA (Isostearic Acid) 11 2
S an20 26 8
* 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 ropivacaine base 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.
From Table 11, the non-volatile solvents glycerol, and Tween 20 had low steady
state flux values and would not be considered "flux-enabling". However,
mineral
oil and isostearic acid are flux-enabling solvents and are good candidates for
evaluation with solidifying agents and volatile solvents to design an
acceptable
solidified formulation. Surprisingly Span 20 has much higher steady state flux
values and would qualify as a highly flux-enabling solvent. Steady state flux
values of a drug from the non-volatile solvent that are below the
therapeutically
effective flux (Table A) are not considered flux-enabling white steady state
flux
values of a drug from a non-volatile solvent above the therapeutically
effective
flux value is considered flux-enabling.
Example 23
Solidifying formulations of diclofenac sodium (obtained from Spectrum) in
various non-volatile solvent systems are evaluated. Excess diclofenac sodium
is present. The permeation of diclodenac sodium from the test formulations
through HMS is presented in Table 12 below.
Table 12
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
54
Non-volatile solvent system Skin Fluzx*
mc /cm /h
Glycerol 1.7 t 0.3
Iso ro l Myristate 13 3
Ethyl Oleate 14 t 4
Propylene Glycol 30 30
S an20 98 20
* 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 diclofenac sodium 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.
From Table 12, the non-volatile solvent glycerol has a steady state flux value
comparable to the estimated therapeutic steady state flux value and maybe
considered a flux-enabling solvent. However, the steady state flux values of
isopropyl myristate, ethyl oleate, propylene glycol, and Span 20 are at least
10
times the flux value reported for glycerol. These non-volatile solvents are
considered flux-enabling solvents.
Example 24
Solidifying formulations of diclofenac acid in various non-volatile solvent
systems are evaluated. Excess diclofenac acid is present. The permeation of
diclofenac from the test formulations through HMS is presented in Table 13
below.
Tab1e 13
Non-volatile solvent system Skin Flu~x*
mc /cm /h
Glycerol 0
Iso ro ( Myristate 8+ 3
Ethyl Oleate 7 3
Propylene Glycol 5 2
S an20 3 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
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.
5 Steady state flux of diclofenac acid 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.
From Table 13, the non-volatile solvent glycerol has no reported steady state
flux value and is not considered a viable non-volatile solvent candidate.
10 However, the steady state flux values of isopropyl myristate, ethyl oleate,
propylene glycol, and Span 20 are no more than 10 times the flux value
reported for currently available marketed products, and as such, could be
considered flux-enabling solvents. It should be noted that the steady state
flux
values for diclofenac acid from each of the above non-volatile solvents are
much
15 lower than the steady state flux values obtained with diclofenac sodium.
Therefore, if therapeutically effective flux values need to be increased,
utilizing a
flux-enabling non-volatile solvent and the salt form of diclofenac would
likely
yield higher steady state flux values than using the acid form of diclofenac.
20 Example 25
Solidifying formulations of testosterone in various non-volatile solvent
systems are evaluated. Excess testosterone is present.
The permeation of testosterone from the test formulations through HMS is
presented in Table 14 below.
25 Table 14
Non-volatile solvent system Skin FI 2x*
mc /cm /h
Tween 60 0
S an20 1.4 0.2
Po! eth lene Glycol 400 1.2 0.1
Isostearic Acid 2.6 0.1
Propylene Glycol 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
30 4-8 hours. If experimental conditions allowed, the steady-state
delivery would likely continue well beyond 8 hours.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
56
Steady state flux of testosterone 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.
From Table 14, the non-volatile solvent Tween 60 (Polyoxyethylene sorbitan
mono-stearate) have no reported steady state flux value and is not considered
a
viable non-volatile solvent candidate. However, the steady state flux values
of
Span 20, polyethylene glycol 400, isostearic acid, and propylene glycol have
steady state flux values comparable to currently available marketed products
(Table A), and thus, could be considered flux-enabling solvents. However,
although all the non-volatile solvents except for Tween 60 are flux-enabling,
propylene glycol may be better for a practical formulation because the high
flux
generated by it means the same amount of drug can be delivered with smaller
skin contact area.
Example 26
Solidifying formulations of hydromorphone HCI in various non-volatile
solvent systems are evaluated. Excess hydromorphone HCI is present. The
permeation of hydromorphone HCI from the test formulations through HMS is
presented in Table 15 below.
Table 15
Non-volatile solvent system Skin Fluzx*
mc /cm /h
Propylene Glycol 2 0.8
Isostearic Acid 3 3
Ethyl Oleate 40 16
* 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 hydromorphone 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.
From Table 15, the non-volatile solvents propylene glycol and isostearic acid
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
57
may qualify as flux-enabling solvents (based on an estimated therapeutically
effective flux for hydromorphone is 2 mcg/cm2/h). Clearly, the steady state
flux
value of hydromorphone from ethyl oleate is much higher and would qualify as a
high flux-enabling solvent.
Example 27
Solidifying formulations of hydromorphone in various non-volatile solvent
systems are evaluated. Excess hydromorphone is present. The permeation of
hydromorphone from the test formulations through HMS is presented in Table
16 below.
Table 16
Non-volatile solvent system Skin Fluzx*
mc /cm /h
Propylene Glycol 1 I
Isostearic Acid 7 2
Ethyl Oteate 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.
Steady state flux of hydromorphone from the above non-volatile solvents
are obtained by placing 200 pL on the stratum corneum side (donor) of hairless
mouse skin. The in vitro studies are carried out as described in Example 1.
From Table 16, the non-volatile solvent propylene glycol may qualify as flux-
enabling solvents (based on an estimated therapeutically effective flux for
hydromorphone is 2 pg/cm2/h). The steady state flux value of hydromorphone
from isostearic acid and ethyl oleate would also qualify as flux-enabling
solvents.
Examples 28-32
Prototype solidifying formulations are prepared as follows. Several
formulations are prepared in accordance with embodiments of the present
invention in accordance with Table 17, as follows:
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
58
Table 17
Example 28 29 30 37 32
% by weight
Volatile Solvents
Ethanol 25 21 24 18.5 43
Water 32 28 22
Solidi in a ents
Eudra it RL-PO 18 40
Eudragit E-100 18.5
Pol in I Alcohol 21 18.5 14
Non-volatile solvents
Glycerol 12 14
Propylene Glycol 21 4
Pol eth lene Glycol 6
Isostearic Acid 36 13
San20 11
Trolamine 18 4
D ru
Acyclovir 3
Ketoprofen 5
Ropivacaine 3
Diclofenac Na 5.5
Testosterone 1
Solidifying formulations of Examples 28-32 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 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 solidified layer and steady state flux for the drug
(see
Example 33 below).
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
59
Examples 33
The formulations of the examples are tested in a hairless mouse skin
(HMS) or HEM in vitro model described in Example 1. Table 18 shows data
obtained using the experimental process outlined above.
Table 18 - Steady-state flux (J)
*
Formulation /cm2/h
Example 28 19 1***
Example 29 35 20***
Example 30 32 2***
Example 31** 5 2****
Example 32 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
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-eriabling non-volatile solvent is incorporated into
the
solidifying formulations. 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
solidified
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 formulations. 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 formulation) resulting in lower flux values.
FIGS_ 1 and 2 provide a graphical representation of the cumulative
amount of diclofenac and ropivacaine, respectively, delivered transdermally
across human cadaver skin. The formulations tested were similar to those
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
described in Examples 30 and 31. In these particularly embodiments, steady-
state delivery is shown over 28 hours, and over 30 hours, repsectively.
Example 34
5 A solidifying 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
10 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.
15 Examples 35-37
Three formulations similar to the formulation in Example 36 (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
20 noted in Table 19 below.
Table 19
Example 35 36 37
% 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 I co1400 11
Tween 40 11
Tromethamine 4 4 4
Ropivacaine HCI 3 3 3
Avg. Flux* (mcg/cm /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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
61
linear region of the cumulative amount versus time plots. The linear
region was observed to be between 6-31 hours. If the experiment was
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
reasonable to conclude that for ropivacaine HCI that Span 20, polyethylene
glycol 400, and Tween 40 qualify as flux-enabling non-volatile solvents.
Examples 38-42
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 20 - Imi uimod eelable formulation ingredients
Ingredients* Example
38 39 40 41 42
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
Iso ro anol 42.5 42.5 41.7
ISA (Isostearic Acid) 19 35.2 9.2 28.2 27.8
S an20 8.5
Trolamine 2 3.6 6.1
Triacetin 4.2 4.2 4.2
Imi uimod 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 38-42 are listed in Table 21.
Table 21 - Steady-state flux of imiquimod through hairless mouse skin
from various adhesive peel-forming formulations at 35 C
Average flux Ratio to
Formulation mc /cm2/h* Control**
Exam le 38 0.7 0.09 0.7
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
62
Example 39 0.52 t 0.06 0.6
Example 40 0.40 0.08 0.4
Example 41 0.5 0.1 0.5
Example 42 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 38 and 39, water is used as
the volatile solvent, and the ISA, trolamine mixture is used as the non-
volatile
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 38 and 39 demonstrate the value of the amount of non-
volatile solvent in added to the formulation in dictating the flux-generating
power
of the entire formulation. Formulation Examples 41 and 42 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 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 peel formulation. The increase in in vitro flux
as a
function of increased drug addition (Examples 41 and 42) may be due to the
increased solubility of drug in the solidified peel formulation once the
volatile
solvent is evaporated off.
Example 38 demonstrates comparable imiquimod flux to the other
formulation examples, and the value of the non-volatile solvent system and
solidifying agent compatibility caused by the removal of trolamine because
this
non-volatile solvent negatively influenced the function of the Plastoid B
polymer.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
63
Example 43-46
A solidifying formula,tion 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 peel formulations contained the following components:
Table 22 - fmi uimod eelable formulation ingredients
Exam le
Ingredients*
43 44 45 46
PVA 10.1
Plastoid B** 17.5
Eudra it RL PO 16.2 24.8
Pemulen TR-2 0.3
Water 52.9
Iso ro anol 35.1
Ethanol 32.4 38.6
ISA Isostearic Acid) 16.8 23.4 23.1 27.6
Sa[ic lic Acid 15.2 16.4 16.2
Trolamine 1.7
Triacetin 3.5 3.5 4.1
Imiguimod 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 43-46 are listed in Table 23.
Table 23 - Steady-state flux of imiquimod through hairless mouse skin
from various adhesive peelable formulations at 35 C
Formulation Average flux Ratio to
mc /cm2/h* Control**
Example 43 1 1 1.1
Example 44 4.5 0.4 5
Example 45 3.8 0.5 4.2
Example 46 0.8 0.2 0.9
L
Aidara 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.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
64
In vitro flux of Examples 43-46 is substantially increased compared to the
Aldara
control. The reason for the improved in vitro flux values maybe attributed to
the
addition of salicylic acid. Improved in vitro flux of imiquimod in Examples 43-
46
is thought to be due to an ion pair interaction between imiquimod and
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. Another
reason for the improved flux due to salicylic acid is that it acts as a
penetration
enhancer. Comparison of the flux of Examples 43-45 shows that the selection
of the polymer and/or volatile solvents will impact the flux of imiquimod.
Examples 47-48
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 solidifying formulation in accordance with embodiments of the
present invention. The peel formulations contain the following components:
Table 24 Ropivacaine peelable formulation ingredients
Ingredients* Examples
47 48
Eudragit RL-100 39.6% 39.6%
Ethanol 23.7% 23.6%
ISA Isostearic Acid) 13.5% 13.5%
PG (Propylene GI 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
carried out with the formulations in Examples 47 and 48 is listed in Table 25.
Table 25 - Steady-state flux of ropivacaine through hairless mouse skin
from various adhesive peelable formulations at 35 C
Average flux
L Formulation mc /cm2lh*
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
Example 47 36 5
Example 48 32 2
* The flux values represent the mean and SD of three
determinations
Regarding the formulation described in Examples 47 and 48, ethanol is used as
5 the volatile solvent, and the ISA, glycerol, and PG mixture is used as the
non-
volatile solvent system. Through experimentation, it is determined that ISA
and
propylene glycol used together to provide the appropriate solubility for the
drug,
while being compatible with the Eudragit RL-100 solidifying agent. Further, in
this embodiment, ISA, PG and glycerol serve as a plasticizer in the peelable
10 formulation after the ethanol (volatile solvent) has evaporated. The steady
state
flux of ropivacaine from formulation Examples 47 and 48 demonstrate the
importance of the non-volatile solvent in dictating the flux-generating power
of
the entire formulation.
15 Example 49
The effect of solubility on permeation, compatibility between the non-
volatile solvent system and the solidifying agent is shown in this example.
Ropivacaine base solubility in isostearic acid (ISA) is experimentally
determined
to be slightly above 1:4, meaning I gram ropivacaine base can completely
20 dissolve in 4 gram isostearic acid. In one experiment, two solutions are
made:
Solution A includes I part ropivacaine base and 4 parts isostearic acid.
Solution B includes 1 part ropivacaine base, 4 parts isostearic acid, and 1
part
trolamine. (all parts are in weight). All ropivacaine in Solution A is
dissolved, but
only a portion of ropivacaine in solution B is dissolved. The transdermal flux
25 across hairless mouse skin generated by the solutions is measured by a
typical
Franz Cell system, with the following results:
Table 26 - Flux across hairless mouse skin, in vitro, in /hr/cm2
Cell1 CelI2 Cell 3 Avera e
Solution A 13.1 9.9 9.1 10.7
Solution B 43.2 35.0 50.0 42.7
30 As can be seen, the flux generated by Solution B is about 4 times that of
Solution A. These results demonstrate that the addition of the ion-paring
agent
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
66
trolamine significantly increases the transdermal flux. However, the attempt
to
incorporate this system into a poly vinyl alcohol (PVA) based peel formulation
failed because the PVA in the formulation acted as a strong pH buffer that
inhibited the effect of trolamine. Addition of more trolamine, in atternpt to
over-
power the pH buffer capacity of PVA, caused the loss of the desired
solidifying
property of PVA (in other words, a non-volatile solvent system containing ISA
and too much trolamine is not compatible with PVA). When PVA is replaced by
another solidifying agent, Eudragit RL 100 (Rohm & Haas), the effect of
trolamine is not inhibited and formulations capable of generating fluxes
around
30 Ng/hr/cm2 were obtained. A by product of the addition of trolamine, ISA,
and
Eudragit RL 100 is that a precipitate forms from the ionic interaction of the
three
components. The latter example produced a better formulation in terms of flux
and wear properties, but the precipitation still demonstrates the need for
improvement. In an effort to eliminate the ionic interaction between non-
volatile
solvent and solidifying agent the trolamine, ISA mixture was added to Plastoid
B
polymer in isopropanol. However, in this instance the trolamine was found to
be
incompatible with the Plastoid B polymer and the base was changed to
triisopropanolamine. This combination eliminated the precipitate formed when
the Eudragit RL 100 polymer was used and produced a clear formulation that
was capable of generated flux values around 30 ug/hr/cm2. This demonstrates
the importance of compatibility between the non-volatile solvent system and
the
solidifying agent.
Example 50
A solidifying formulation for dermal delivery of ropivacaine is prepared
from the following ingredients:
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
67
Table 27 - Ropivacaine solidi in formulation components
Ingredients* Example
56
Ropivacaine HCI 0.096
Eudragit RL-100 1.0
Ethanol 0.7
Isostearic Acid 0.34
Glycerol 0.3
Propylene GI col 0.1
Trolamine 0.15
*Ingredients are noted as parts by weight.
The ingredients listed above are combined according to the following
procedure.
The Eudragit RL-1 00 and ethanol are combined in a glass jar and heated to
about 60 C until the Eudragit RL-100 is completely dissolved. Once the
Eudragit solution cooled to room temperature, the appropriate amount of
ropivacaine HCI is added and mixed thoroughly for 1 minute. To this solution,
isostearic acid (ISA) is added and the mixture is stirred vigorously for 2-3
minutes. One hour later, the solution is vigorously mixed again for 2-3
minutes.
To this solution, glycerol, propylene glycol, and trolamine are added in
sequential order. After addition of each ingredient the solution is stirred
for 1
minute.
Additionally, the formulation prepared in accordance with this examples
was applied to HMS as described in Example 1, and the ropivacaine flux was
measured. A summary of the results is listed in Table 28, as follows:
Table 28 - Steady-state flux of ropivacaine through hairless mouse skin
from various adhesive peelable formulations at 35 C
Formulation Average flux
mcg/cm2/h*
Example 49 43 4
* The flux values represent the mean and SD of three
determinations
The ropivacaine peel formulations prepared in accordance with Example 6
possessed acceptable application properties, e.g., ease of removal of peel
from
the sample tube, ease of spreading on intended skin application site, etc.,
and
forms a solidified film in 2-3 minutes after being applied to normal human
skin
surface as a thin layer with a thickness of about 0.1 mm. The solidified
peelable
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
68
layer becomes more easily peelable in 2 hours, and the peel remains affixed to
the skin surface without any unintended removal of the peel for at least 12
hours. At the end of intended use, the peel is easily removed in one
continuous
piece.
Example 51
A solidifying formulation for dermal delivery of lidocaine is prepared which
includes a saturated amount of lidocaine in an excipient mixture to form an
adhesive peelable formulation in accordance with embodiments of the present
invention. The peel formulation is prepared from the ingredients as shown in
Table 29.
Table 29 - Lidocaine solidi in formulation components
Exam le
Ingredients*
51
PVA 11.7
Eud ra it E-100** 11.7
PVP-K90 5.8
Glycerol 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 30 - Steady-state flux of lidocaine through hairless mouse skin
from various adhesive solidifying formulations at 35 C
Formulation Average flux
mc /cm2/h*
Example 51 47 3
The adhesive peelable 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.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
69
Examples 52-55
A solidifying formulation for dermal delivery of amitriptyline and a
combination of amitripyline and ketamine is prepared which includes an
excipient mixture to form an adhesive peelable formulation in accordance with
embodiments of the present invention. The peel formulation is prepared from
the ingredients as shown in Table 31.
Table 31 - Amitriptyline and amitriptyline/ketamine solidifying formulation
components
Example
tngredients*
52 53 54 55
lso 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
S an20 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 31 are applied to HMS according to EXample 1,
and the flux of amitriptyline and/or ketamine was measured. The results are
summarized in Table 32:
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
Table 32 - Steady-state flux of amitriptyline and amitriptyline/ketamine
through
hairless mouse skin from various adhesive solidi in formulations at 35 C
Average Average
amitriptyline
Formulation flux ketamine flux
mc /cm2/h* mcg/cm2lh*
Example 52 3 1 15 4
Example 53 7.6 0.2 38 6
Exam le54 3 1
Example 55 8.2 0.7
The adhesive peelable formulation of amitriptyline and
5 amitriptyline/ketamine formulations in the present examples have similar
physical properties to the formulations in examples noted above. The
transdermal flux is proportional to the amount of drug added into the
formulation.
10 Examples 56-59
A solidifying formulation for dermal delivery of ropivacaine is prepared
which includes an excipient mixture to form an adhesive peelable formulation
in
accordance with embodiments of the present invention. The peel formulation is
prepared from the ingredients as shown in Table 33.
Table 33 - Ro ivacaine HCI solidif in formulation components
Example
Ingredients*
56 57 58 59
Ro ivacaine 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
S a n 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
71
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 33 are applied to HMS according to Example 1,
and the flux of ropivacaine was measured. The results are summarized in Table
34:
Table 34 - Steady-state flux of ropivacaine HCI through hairless mouse skin
from various adhesive solidifying formulations at 35 C
Formulation Average flux
mc /cm2/h*
Example 56 56 2
Example 57 39 6
Example 58 31 6
Example 59 37 9
The flux of Examples 56-59 show the importance of the triacetin, isostearic
acid,
Span 20 combination in the formulation. In Examples 56-59 formulations were
made without Span 20, triacetin, and isostearic acid respectively. The in
vitro
flux of ropivacaine was impacted. The synergistic combination of the non
volatile solvents is an important in obtaining the maximum in vitro flux of
ropivacaine.
Example 60
This solidifying formulation has the following ingredients in the indicated
weight parts:
Table 35
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.
lsostearic acid and glycerol form the non-volatile solvent system while
ethanol
and water form the volatile solvent system. Ropivacaine is the drug.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
72
Procedures of making the formulation:
1. Ropivacaine 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.
Examples 61-62
Anti-fungal solidifying formulations are prepared and a qualitative
assessment of peel flexibility and viscosity are evaluated. The formulation
components are presented in Table 36 below.
Table 36
Example 61 62
Components Parts b Weight
Eudragit RL-PO 3.8 4.2
lsostearic Acid 2 2.2
Ethanol 5.3 3.8
Neutrol TE Pol of I I
Econazole 0.09 0.1
The peel formulation in Example 61 has a low viscosity that was lower than may
be desirable for application on a nail or skin surface. The time to form a
solidified peel with this formulation is longer than the desired drying time.
The
formulation in Example 62 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 62 has a viscosity suitable for application
and an improved drying time.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
73
Example 63 _
A solidifying formulation was prepared in accordance with Table 37, as
follows:
Table 37 - Peel-forming formulation for sex steroids
Ingredient % by weight
Ethanol 43
Water 22
Pol vin l Alcohol 14
Glycerol 14
Pol eth lene Glycol 6
Testosterone 1
The ingredients of Table 37 were combined as follows:
= The solidifying agent is dissolved in the volatile solvent (i.e. dissolve
polyvinyl alcohol in water).
= 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 peel formulation is mixed again for several
minutes.
Example 64
The formulation prepared in Example 63 was tested for skin flux, as set
forth in Table 38 below.
Tabte 38 - Peel-forming formulation for sex steroids
System Skin Flux*
mc /cm2/h
Example 63 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 cumul'ative 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.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
74
The steady state flux data is shown in FIG 3. It should be noted, the steady-
state flux value reported in Table 38 is determined using the linear region
between 2-6 hours. As can be seen from FIG. 3, 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 solidifying formulation in Example 63 will deliver a steady-
state
amount of testosterone for at least 9 hours.
Examples 65-68
A stretchable adhesive solidifying 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 excipient mixture (more ketoprofen than that can be dissolved
in the excipient mixture) to form an adhesive peelable 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 39.
Table 39 - Ketoprofen solidi in formulation components
Ingredients* Examples
65 66 67 68
PVA oI in I alcohol 10.4 21.4 21.1 21.2
PEG-400 (Polyethylene 10.4 10.8 2.9 18.6
GI col
PVP-K90 (Polyvinyl 10.4 0.0 0.0 0.0
P rroiidone
Glycerol 10.4 10.8 19.0 2.9
Water 27.1 57.0 57.0 57.3
Ethanol 31.3 0 0 0
Ketoprofen saturated saturated saturated saturated
* Ingredients are noted as % by weight.
Each of the compositions of Examples 65-68 were studied for flux of
ketoprofen,
as shown in Table 40, as follows:
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
Table 40 - Steady-state flux of ketoprofen through hairless mouse skin
from various adhesive eelable formulations at 35 C
Formulation Average flux
mc /cm2/h*
Example 72 8 3
Example 73 21 6
Example 74 3 I
Example 75 1 0.4
* 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.
10 Regarding formulation described in Example 65, 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
15 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
additional detail with respect to the formulation in Example 65, PVA and PVP
act as the solidifying agents. Further, in this embodiment, glycerol and PEG
400 also serve as plasticizers in the adhesive peelable formulation formed
after
20 the evaporation of the volatile solvents. Without the presence of glycerol
and
PEG 400, a film formed by PVA and PVP alone would be rigid and non-
stretchable.
Regarding the formulation of Example 66, the adhesive peelable
formation formed has similar physical properties as that of Example 65, though
25 the transdermal flux across hairless mouse skin is higher. This suggests
that
the solidifying agent, 1:1 PVA:PVP-K-90 in Example 65 and pure PVA in
Example 66, have an impact on permeation.
The formulation in Example 67 delivers less ketoprofen than the
formulations of Examples 65 or 66. The formulation of Example 68 delivers
30 much less ketoprofen than the formulations in Examples 65 and 66. One
possiblek reason for the reduced flux is believed to be the reduced permeation
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
76
driving force caused by the high concentration of PEG 400 in the non-volatile
solvent system, which resulted in too high of solubility for ketoprofen.
The only significant difference among the formulations in Examples 66,
67, and 68, respectively, is with respect to the non-volatile solvent system,
or
more specifically, the PEG 400:glycerol weight ratio. These results reflect
the
impact of the non-volatile solvent system on skin flux.
Example 69
A stretchable adhesive solidifying formulation for transdermal delivery of
lidocaine is prepared which includes saturated amount of lidocaine in an
excipient mixture to form an adhesive solidifying formulation in accordance
with
embodiments of the present invention. The formulation is prepared from the
ingredients as shown in Table 41.
Table 41 - Lidocaine solidif in formulation components
Ingredients* Example
69
PVA 1
Eud ra it E-100** I
PVP-K90 0.5
G! cero! 0.75
PEG-400 0.75
Water 2
Ethanol 2
Lidocaine 0.48
*Ingredients are noted as parts by weight.
** from Rohm & Haas.
Table 42 - Steady-state flux of lidocaine through hairless mouse skin
from an adhesive solidif in formulations at 35 C
P Formulation Average flux
mc /cm2/h*
Example 69 47 3
* 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.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
77
The adhesive solidifying formulation of lidocaine in the present example
has similar physical properties to the formulations in Examples 65-68. The
transdermal flux across hairless mouse skin is acceptable and steady-state
delivery is maintained over 8 hours.
Example 70
A formulation similar to the formulation of Example 65 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
film. After a
few minutes of evaporation of the volatile solvents (ethanol and water), a
solidified peelable layer is formed. The stretchable film 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 71-73
A stretchable adhesive solidifying 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 peelable 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 43.
Table 43
Ingredients* Examples
71 72 73
Eu ra it RL-PO 28.06 27.7 27.5
Ethanol 40.07 39.5 39.5
GI cerol 27.40 13.9
Pol eth lene Glycol 400 (PEG) 13.9 28.
Keto rofen 4.5 5 5
Peel formulations of Examples 71-73 are prepared in the following manner:
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
78
= The solidifying agents are dissolved in the volatile solvent (i.e., dissolve
Eudragit polymers in ethanol).
= The flux adequate non-volatile solvent (glycerol, PEG) is mixed together
with the solidifying agent/volatile solvent mixture.
= The resulting solution is vigorously mixed for several minutes.
= Drug is then added and the formulation is mixed again for several
minutes.
Example 74
The formulations prepared in accordance with Example 71-73 are applied
to HMS as described in Example 1, and the ketoprofen flux is measured. A
summary of the results is listed in Table 44, as follows:
Table 44 - Stead -state flux of keto rofen through hairless mouse skin
Formulation Average flux
mc Icm2/h*
Exam ie71 15 7
Example 72 10 3
Example 73 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 ketoprofen formulations prepared in accordance with Examples 71-72
possessed acceptable solidified layer properties (e.g., formed a solidified
layer
in 2-3 minutes). With Example 73, the ketoprofen peel does not form a
solidified
layer 30 minutes after application. This demonstrates that order to obtain
desired flux and wear properties in a peel formulation, a delicate balance
between solidifying agents, non-volatile solvents, and volatile solvents is
evaluated and considered in developing a formulation.
Example 75
A stretchable adhesive solidifying formulation for transdermal delivery of
ketoprofen (which is suitable for delivery via skin on joints and muscles) is
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
79
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 peelable 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 45.
Table 45
FORMULATIONS
Ingredients* 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 agent/volatile 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
peels were removed by the volunteers and the peetability 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
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
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
5 and physical interactions between individual PVA polymer chains. The reduced
PVA chain interactions lead to a weakened peel that is unable to withstand the
mechanical forces the peel is subjected to upon removal.
Example 76
10 A stretchable adhesive solidifying 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
peelable formulation, some of which are prepared in accordance with
embodiments of the present invention. The excipient mixture, which is a
15 viscous and transparent fluid, is prepared using the ingredients as shown
in
Table 46.
Table 46
FORMULATIONS
Ingredients*
D E F G
PVA (Amresco MW 31,000-50,000) 22.1 24.4 22.1 21.1
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.
20 Peel formulations in formulations D-G 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.
25 0 The resulting solution is vigorously mixed for several minutes.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
81
= 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. Formulations D-F have
been studied the longest and the resulting viscosity increase necessitated the
desire to study the viscosity of formulation G. Table 47 summarizes the data
generated on each formulation.
Table 47
Formulation Viscosity*
Storage
Cond. cPs
T=0 weeks 4 weeks 8 weeks weeks weeks
25 C/60% RH 96000 670000 >2500000 measured
40 C/75% RH 96000 500000 587500 2320000
25 C/60% RH 168500 204500 251000 .>2500000
E 168500 215000 217500 >2500000
40 C/75% RH
F 23000 -- 25000 36250 76250 57500
25 C/60% RH
40 C/75% RH 23000 -- 31000 40000 243500 164500
25 CI 0% RH 11250 13750
G 11250 17500
40 C/75% RH
* Viscosity measured using a RVDV 1+ viscometer at 0.5 rpm.
Formulations D and E of this example had the lowest water content of the
four formulations and within 4 weeks of storage attained high viscosity
values.
The only difference between formulations 1 and 2 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 (formulation D) had lower initial viscosity, but over the 4 weeks
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
82
storage the viscosity of both formulation D and E 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 time. Formulation F viscosity after 16 weeks has not
reached the viscosity values of the initial viscosity values of formulations I
and
2.
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
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 peel or leaving
residue
behind. The results of the study are summarized in Table 48 below.
Table 48
Formulation D in Time (min)*
D 4 min 49 sec
E 5 min 41 sec
F 4 min 27 sec
G 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 volatile 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 water
will
escape with the ethanol when evaporating off the skin thereby forming a
solidified peel.
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
83
Examples 77-79
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 49.
Table 49 - Ro ivacaine HCI solidi in formulation com onents
Ingredients* Example
77 78 79
Ro ivacaine HCI 6.9 6.5 6.6
Iso ro anol 50.7 45.8 45.9
Water 5.5 5.2 5.2
Isostearic Acid 6.3 6.6 6.6
Trieth lamine 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
*Ingredients are noted as weight percent.
** from Degussa.
The ingredients listed above are combined according to the foliowing
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 78 and 79) or isopropanol (Example 77) 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 49 are applied to HMS according to Example 1,
and the flux of ropivacaine was measured. The results are summarized in Table
50:
CA 02633472 2008-06-13
WO 2007/070695 PCT/US2006/048061
84
Table 50 - Steady-state flux of ropivacaine HCI through hairless mouse skin
from various adhesive solidif in formulations at 35 C
Formulation Average flux
mc /cm2/h*
77 96 14
78 61 2
79 70 7
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.
