Note: Descriptions are shown in the official language in which they were submitted.
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METHODS AND TRANSDERMAL COMPOSITIONS FOR PAIN RELIEF
Field Of The Invention
The present invention is directed to methods and compositions for transdermal
administration. In particular, the present invention is directed to methods
and
compositions for the transdermal administration of an amine containing
compound
having biphasic solubility and/or an agent which enhances the activity of the
amine
containing compound having biphasic solubility, e.g., a muscle relaxant, to
relieve pain.
Background Of The Invention
It is believed that damage to somatic sensory nerves causes a somatic sensory
loss. Such damage can be caused by a variety of means including trauma,
diseases such
as diabetes, herpes zoster and late-stage cancer, chemotherapy, or by a
chemical injury.
It is believed that neural pain circuits rewire themselves, both anatomically
and
biochemically, after nerve injury. In many patients suffering from damage to
somatic
sensory nerves, negative symptoms such as numbness are joined by positive
sensations,
involving a sort of false sensation of pain. The experience can range from
mild
dysesthesia to excruciating pain, rendering some patients unable to work, walk
or do
other daily activities.
In the past, patients were generally treated by administration of analgesics
to
relieve pain. A vast majority of such patients receive doses of these agents
orally.
Unfortunately, in some situations, oral administration of such agents has been
associated
with a variety of side effects, such as liver damage, kidney damage,
gastrointestinal side
effects, addiction, sedation, and/or weight gain which cannot be tolerated
well by the
patient. In other cases, malabsorption of oral preparations have resulted in
subtherapeutic plasma levels. In other cases, the agents have relatively short
plasma
half lives, necessitating inconveniently frequent dosing. In general, oral
delivery
involves a time delay as the analgesic is absorbed via the digestive system
before
entering the bloodstream. A number of agents which have traditionally been
administered orally or by injection have been inappropriate or suboptimal for
some
patients when so-administered. There are a number of medications which, in at
least
some patients, are not tolerated well when orally administered (e.g. which
cause
undesirable gastrointestinal or other side effects) andlor which provide
undesirably high
or low concentrations or delayed concentrations in a target tissue. In some
cases,
dosages which are appropriate for oral administration, upon being distributed
more or
less uniformly throughout the body, are undesirably low in a particular area,
e.g., tissue,
to achieve desired results. Oral or injection administration may result in too
slow or too
rapid increase in blood plasma levels, e.g., may involve an undesirably long
time delay
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as the analgesic is absorbed by the digestive system before entering the
bloodstream, or
may result in a "spike" in blood plasma levels followed by an undesirably low
level,
where a more constant level would be preferable. Some analgesics are
particularly
prone to cause or contribute to kidney or liver damage when administered
orally.
S Although other forms of delivery of pharmaceuticals agents are known, each
has
its drawbacks. Parenteral (i.e., intravenously or intramuscularly injected)
administration
is inconvenient and expensive, and is rarely used outside the hospital.
Inhalation is
believed to be not feasible with many analgesic agents currently in use.
Therefore, there is a need for an analgesic delivery system which provides
effective and
acceptable levels, while preferably avoiding or reducing undesired effects
such as liver
damage or gastrointestinal side effects.
Summary Of The Invention
The present invention provides a transdermal composition for the treatment of
pain in a subject, particularly a human subject. The transdermal composition
for the
treatment of pain in a subject includes an amine containing compound having
biphasic
solubility in an amount effective to treat pain in a subject and a
pharmaceutically
acceptable carrier suitable for transdermal delivery of the amine containing
compound,
e.g., a lecithin organogel carrier. In a preferred embodiment, the transdermal
composition further includes an agent which enhances the activity of the amine
containing compound having biphasic solubility, e.g., a muscle relaxant, such
as
guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and
combinations thereof. Preferably, the agent which enhances the activity of the
amine
containing compound having biphasic solubility, e.g., the muscle relaxant,
also has a
biphasic solubility.
In one embodiment of the present invention, the amine containing compound
having biphasic solubility is an antidepressant compound, such as a tricyclic
antidepressant compound, e.g., doxepin or trimipramine.
In another embodiment of the present invention, the amine containing compound
having biphasic solubility is a sodium channel Mocker, an anti-epileptic
compound, or
an anti-convulsant compound.
Another embodiment of the invention features a transdermal composition which
includes an amine-containing compound as described herein and an anti-
inflammatory
compound, such as a nonsteroidal anti-inflammatory compound, e.g., celecoxib,
etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx~, and
combinations
thereof. Such a composition can further include an agent which enhances the
activity of
the amine containing compound, e.g., a muscle relaxant such as guaifenesin.
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In another aspect, the invention features a transdermal composition for the
treatment of pain in a subject including an amine containing compound having
biphasic
solubility in an amount effective to treat pain in a subject; a muscle
relaxant in an
amount effective to enhance the activity of the amine containing compound
having
biphasic solubility; and a pharmaceutically acceptable carrier suitable for
transdermal
delivery of the amine containing compound having biphasic solubility and the
muscle
relaxant.
In yet another aspect, the invention features a transdermal composition for
the
treatment of pain in a subject including doxepin in an amount effective to
treat pain in a
subject; guaifenesin in an amount effective to enhance the activity of
doxepin; and a
pharmaceutically acceptable carrier suitable for transdermal delivery of the
doxepin and
the guaifenesin.
Other aspects of the invention feature methods for treating pain in a subject
in
which the subject is contacted with a transdermal composition including an
amine
containing compound having biphasic solubility in an amount effective to treat
pain in
the subject; and a pharmaceutically acceptable carrier suitable for
transdermal delivery
of the amine containing compound to thereby treat pain in the subject. In a
preferred
embodiment, the transdermal composition is applied to the skin of the subject.
Another aspect of the invention features a method for selecting a compound
suitable for treating pain in a subject. The method includes transdermally
administering
an amine containing compound having biphasic solubility to a subject; and
determining
whether pain is treated in the subject to thereby select a compound suitable
for treating
pain in a subject. In a preferred embodiment, the method can further include
modeling
the compound using a computer equipped with a three-dimensional chemical
structure
modeling program; and determining whether the three-dimensional chemical
structure of
the compound possesses sufficient characteristics to be useful as a sodium
channel
blocker, thereby selecting a compound suitable for treating pain in a subject.
In another aspect, the invention features a transdermal composition suitable
for
transdermal delivery, which includes a therapeutically effective amount of a
pharmaceutical compound (e.g., a serotonin specific reuptake inhibitor, a mood
stabilizing compound, a dopamine compound, a compound suitable for treating
attention
deficit hyperactivity disorder, a compound suitable for treating hypertension
and
akathisia, an analgesic compound, or a compound used in the treatment of
impotence)
and a pharmaceutically acceptable Garner suitable for transdermal delivery of
the
pharmaceutical compound, e.g., a lecithin organogel carrier.
In yet another aspect, the invention features a transdermal composition for
treatment of pain in a subject which includes a compound capable of blocking
afferent
neuron transmission in an amount effective to block afferent neuron
transmission in a
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subject; and a pharmaceutically acceptable cairier suitable for transdermal
delivery of
the compound.
Other features and advantages of the invention will be apparent from the
following detailed description and claims.
Brief Description Of The Drawings
Figure 1 is an evaluation form used in evaluating an embodiment of the present
invention.
Figure 2 is a table depicting the results from clinical experiments using
compositions of the invention.
Detailed Description Of The Invention
The present invention provides a transdermal composition suitable for
treatment
of pain in a subject. The transdermal composition includes an amine containing
compound having biphasic solubility in an amount effective to treat pain in a
subject;
and a pharmaceutically acceptable carrier suitable for transdermal delivery of
the amine
containing compound having biphasic solubility.
As used herein, the term "subject" includes a mammal, such as a human, a
horse,
a pig, a cow, a mouse, a rat, a rabbit, or a goat. In preferred embodiment,
the subject is a
human.
As used herein, the term "pain" is art recognized and includes a bodily
sensation
elicited by noxious chemical, mechanical, or thermal stimuli, in a subject,
e.g., a
mammal such as a human. The term "pain" includes chronic pain, such as lower
back
pain; pain due to arthritis, e.g., osteoarthritis; joint pain, e.g., knee pain
or carpal tunnel
syndrome; myofascial pain, and neuropathic pain. The term "pain" further
includes
acute pain, such as pain associated with muscle strains and sprains; tooth
pain;
headaches; pain associated with surgery; or pain associated with various forms
of tissue
injury, e.g., inflammation, infection, and ischemia.
As used herein, the term "amine containing compound having biphasic
solubility" includes compounds having at least one amine moiety and having
sufficient
lipid solubility (e.g., solubility in polar solvents such as ethanol,
ethoxydiglycerol,
ethoxydiglycol, chloroform, benzene, and the like) such that the compound
passes
through the stratum corneum, and has sufficient aqueous solubility to be
active in the
aqueous environment of the dermis and the underlying tissue.
Transdermal compositions of the present invention include an amine containing
compound having biphasic solubility in an amount effective to treat pain in a
subject.
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As used herein, the terms "amount effective to treat pain in a subject" and
"effective
amount" are used interchangeably herein and include an amount effective, at
dosages
and for periods of time necessary, to achieve the desired result, e.g.,
sufficient to treat
pain in a subject. An effective amount of an amine containing compound or a
pharmaceutical compound as defined herein may vary according to factors such
as the
disease state, age, and weight of the subject, and the ability of the amine
containing
compound or pharmaceutical compound to elicit a desired response in the
subject.
Dosage regimens may be adjusted to provide the optimum therapeutic response.
An
effective amount is also one in which any toxic or detrimental effects of the
amine
containing compound having biphasic solubility or pharmaceutical compound are
outweighed by the therapeutically beneficial effects.
The transdermal compositions of the invention can further include an agent
which enhances the activity of the amine containing compound having biphasic
solubility. As used herein, an "agent which enhances the activity of the amine
containing compound having biphasic solubility" includes an agent which
enhances the
pharmacological activity of the amine containing compound having biphasic
solubility
(e.g., the ability of the amine containing compound to treat pain), or
enhances the
transdermal delivery of the amine containing compound having biphasic
solubility (e.g.,
the ability of the amine containing compound to cross the stratum corneum), or
enhances both the pharmacological activity and the transdermal delivery of the
amine
containing compound. Examples of agents which enhance the activity of the
amine
containing compound having biphasic solubility, include muscle relaxants,
described in
further detail below.
As used herein, the term "transdermal" composition includes compositions
capable of passing through the stratum corneum of a subject. The term
transdermal
further includes compositions capable of passing through the epidermis of a
subject,
compositions capable of passing through the dermis of a subject, and
compositions
capable of passing through the hypodermis of a subject. In preferred
embodiments, the
term transdermal includes compositions capable of passing through the skin of
a subject
and reaching the underlying tissues and organs.
As used herein, the term "transdermal delivery" includes delivery of, for
example, a compound through the stratum corneum of a subject. The term
transdermal
delivery further includes delivery of, for example, a compound through the
epidermis of
a subject, delivery of, for example, a compound through the dermis of a
subject, and
delivery of, for example, a compound through the hypodermis of a subject. In
preferred
embodiments, the term transdermal delivery includes delivery of, for example,
a
compound through the skin of a subject to the underlying tissues and organs.
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The present invention further features a transdermal composition for treatment
of
pain in a subject which includes a compound capable of blocking afferent
neuron
transmission in an amount effective to block afferent neuron transmission in a
subject;
and a pharmaceutically acceptable carrier suitable for transdermal delivery of
the
compound.
As used herein, the term "compound capable of blocking afferent neuron
transmission" includes a compound which is capable of blocking the ability of
an
afferent neuron, i.e., a sensory neuron, to carry an impulse toward the
central nervous
system.
Various aspects of the invention are described in further detail in the
following
subsections:
Amine Containing Compounds Having Biphasic Solubility
Amine containing compounds having biphasic solubility for use in the
transdermal compositions of the invention include antidepressant compounds,
antiepileptic compounds, anticonvulsant compounds, and sodium channel
blockers.
As used herein, the term "antidepressant compounds" includes compounds capable
of
alleviating the symptoms of depression. Examples of antidepressant compounds
include
all tricyclic antidepressants (e.g., amitriptyline, dothiepin, or
lofepramine), bupropion
(sold under the trade name Wellbutrin), reboxetine (sold under the trade name
Edronax),
nefazodone (sold under the trade name Serzone) and trazodone (sold under the
trade
name Desyrel). Antidepressant compounds are described in, for example, the
1998
SIGMA catalogue and the "The Merck Index", l2t:h Ed., Budavari et al., eds.,
Merck &
Co., Inc., Rahway, N.J., 1996, the contents of which are incorporated herein
by
reference.
In one embodiment of the present invention, the antidepressant compounds of
the present invention contain a tricyclic moiety. Therefore, in a preferred
embodiment,
a transdermal composition of the present invention includes a tricyclic
antidepressant
compounds. Exemplary tricyclic antidepressants include adinazolam,
amitriptylinoxide,
amoxapine, clomipramine, demexiptiline, dimetacrine, dothiepin, doxepin,
imipramine
N-oxide, iprindole, lofepramine, melitracen, metapramine, noxiptilin,
pizotyline,
propizepine, quinupramine, tianeptine, and trimipramine. A particularly
preferred
tricyclic antidepressant for use in the compositions of the invention is
doxepin.
Tricyclic antidepressant compounds are described in, for example, "Guide to
Clinical Neurology" by J.P. Mohr et al. (Churchill Livingstone, 1995), the
contents of
which are incorporated herein by reference.
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Preferably, the tricyclic antidepressant compound is selected from the group
consisting of doxepin, trimipramine, other tricyclics having biphasic
solubility, and
combinations thereof. When combined with other compounds, such as an agent
which
enhances the activity of the amine containing compound, e.g., a muscle
relaxant, and/or
an anti-inflammatory compound, e.g., a nonsteroidal anti-inflammatory
compound, as
discussed below, the tricyclic antidepressant preferably constitutes from
about 1 % by
weight (% by wt.) to about 30 % by wt. of the total amount of the
pharmaceutical, more
preferably from about 3 % by wt;. to about 15 % by wt., and most preferably
from about
5 % by wt. to about 13 % by wt.
The amine containing,compounds having biphasic solubility used in the
transdermal compositions of the invention further include antiepileptic
compounds. As
used herein, the term "antiepileptic compound" includes compounds capable of
alleviating the symptoms of epilepsy. Exemplary antiepileptic compounds for
use in the
compounds of the invention include lamotrigine, felbamate, and carbamazepine.
Preferably, the antiepileptic compound is selected from the group consisting
of
lamotrigine, felbamate, carbamazepine, and combinations thereof. When combined
with
other compounds, such as an agent which enhances the activity of the amine
containing
compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g.,
a
nonsteroidal anti-inflammatory compound as discussed below, the antiepileptic
compound constitutes from about 1 % by wt. to about 30 % by wt. of the total
amount of
the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by
wt., and
most preferably from about 5 % by wt. to about 15 % by wt. Antiepileptic
compounds
are described in, for example, the 199$ SIGMA catalogue, the "The Merck
Index", l2t:h
Ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, and the
"Guide to
Clinical Neurology" by J.P. Mohr et al. (Churchill Livingstone, 1995) the
contents of
which are incorporated herein by reference.
In another aspect of the present invention, the amine containing compounds
having biphasic solubility of the present invention include anticonvulsant
compounds.
As used herein, the term "anticonvulsant compound" includes compounds capable
of
alleviating the symptoms of convulsion, i.e., the violent involuntary tetanic
contractions
of an entire group of muscles. Exemplary anticonvulsant compounds which for
use in
the compositions of the invention include felbamate, lamotrigine and
carbamazepine.
Preferably, the anticonvulsant compound is selected from the group consisting
of
felbamate, lamotrigine, and combinations thereof. When combined with other
compounds, such as an agent which enhances the activity of the amine
containing
compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g.,
a
nonsteroidal anti-inflammatory compound as discussed below, the anticonvulsant
compound constitutes from about 1 % by wt. to about 30 % by wt. of the total
amount of
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the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by
wt., and
most preferably from about 5 % by wt. to about 15 % by wt. Anticonvulsant
compounds are described in, for example, the 1998 SIGMA catalogue, the "The
Merck
Index", l2t:h Ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J.,
1996, and the
"Guide to Clinical Neurology" by J.P. Mohr et al. (Churchill Livingstone,
1995) the
contents of which are incorporated herein by reference.
In yet another aspect of the present invention, the amine containing compounds
having biphasic solubility of the present invention include adrenergic agonist
compounds. Preferably, the adrenergic agonist compound is tizanidine. When
combined with other compounds, such as a muscle relaxant and/or nonsteroidal
anti-inflammatory compound as discussed below, the adrenergic agonist compound
constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of
the
pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt.,
and most
preferably from about 5 % by wt. to about 15 % by wt. Adrenergic agonist
compounds
1 S are described in, for example, the 1998 SIGMA catalogue, the "The Merck
Index", l2t:h
Ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, and the
"Guide to
Clinical Neurology" by J.P. Mohr et al. (Churchill Livingstone, 1995) the
contents of
which are incorporated herein by reference.
The amine containing compounds having biphasic solubility used in the
transdermal compositions of the invention further include sodium channel
blockers. As
used herein, the term "sodium channel blockers " includes compounds which are
capable of blocking the activity of a sodium channel. Examples of sodium
channel
blockers include tetrodoxin, flecainide, disopyramide, and terfenadine. Sodium
channel
blockers are described in, for example, the 1998 SIGMA catalogue, the "The
Merck
Index", l2t:h Ed.,. Budavari et al., eds., Merck & Co., Inc., Rahway, N.J.,
1996, and the
"Guide to Clinical Neurology" by J.P. Mohr et al. (Churchill Livingstone,
1995) the
contents of which are incorporated herein by reference.
Whenever nerves are damaged, for example, by trauma, by diseases such as
diabetes, herpes zoster, or late-stage cancer, or by chemical injury (e.g., as
an untoward
consequence of agents including the false-nucleoside anti-HIV
pharmaceuticals), neural
pain circuits rewire themselves, anatomically and/or biochemically. Thus,
following an
injury, new sodium channels are formed which is believed to constitute the
basis for
chronic pain development. Through a similar action in the dorsal root ganglia,
chronic
regional pain syndromes may develop. Each time one of these sodium channels
depolarizes, a nerve impulse originates. Because there are so many sodium
channels,
there may be a constant cascade of nerve impulses, causing allodynia, burning
sensations, and/or dysesthesias. It is believed that some chronic pains may be
mediated
through sodium channels in nerve cells. Thus, it is believed that amine
containing
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compounds having biphasic solubility which can block sodium channels may also
be
used in the transdermal compositions of the invention.
In one embodiment of the invention, the amine moiety of the amine containing
compounds having biphasic solubility of the present invention may function
similar to a
sodium ion upon entry into the sodium channel of a nerve cell membrane. A non-
polar
moiety, which is preferably present in the amine containing compound having
biphasic
solubility of the present invention may interact with the nerve cell membrane,
perhaps
through Van der Waals forces. In such cases, it is believed that the presence
of the
non-polar moiety prevents or inhibits a complete uptake of the amine
containing
compound having biphasic solubility through the nerve cell membrane. It is
believed
that one or more these interactions prevent or reduce the amount and/or the
rate of
depolarization and ion exchange involved in stimulus conduction, thereby
decreasing
pain sensation.
The amount of an amine containing compound having biphasic solubility useful
in relieving pain transdermally may be determined by methods known in the art,
and
typically ranges from about 1 mg to about 300 mg per subject per dose,
preferably from
about 5 mg to about 100 mg per subject per dose, and more preferably from
about 10 mg
to about SO mg per subject per dose, depending on a variety of factors
including the
particular amine containing compound having biphasic solubility used, whether
the area
of transdermal application is the site of action, and the intended size of the
site of action.
In a preferred embodiment, the amount of an amine containing compound having
biphasic solubility useful in relieving pain transdermally, is 5, 10, 15, 20,
25, 30, 35, 40,
45, S0, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, 150 mg, 200 mg, 250 mg, or
300 mg
per subject per dose.
Muscle Relaxants
Transdennal compositions of the present invention may also include a muscle
relaxant. As used herein, the term "muscle relaxant" includes compounds which
facilitate or enhance the relaxation of muscles (e.g., provide relief from
muscle spasm)
and, thus, facilitate or enhance the transdermal delivery of the transdermal
compositions
of the invention. Exemplary muscle relaxants include both skeletal muscle
relaxants and
smooth muscle relaxants such as anticholinergics, antispasmodics,
bronchodilators, and
vasodilators. Muscle relaxants are described in, for example, the 1998 SIGMA
catalogue, the "The Merck Index", l2t:h Ed., Budavari et al., eds., Merck &
Co., Inc.,
Rahway, N.J., 1996, pp. THER-1 to THER-28, and the "Guide to Clinical
Neurology"
by J.P. Mohr et al.(Churchill Livingstone, 1995) the contents of which are
incorporated
herein by reference. Preferably, the muscle relaxant is selected from the
group
consisting of guaifenesin, benzodiazepines (e.g., clozapine or diazopam),
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chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, other muscle
relaxants
having biphasic solubility, and combinations thereof. More preferably, the
muscle
relaxant is selected from the group consisting of guaifenesin, chlorzoxazone,
and
combinations thereof. A preferred muscle relaxant for use in the compositions
of the
S invention is guaifenesin.
Preferably the muscle relaxant has biphasic solubility. Preferably the muscle
relaxant, when present in the pharmaceutical composition, constitutes from
about 1
by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more
preferably
from about 3 % by wt. to about 20% by wt., and most preferably from about 5 %
by wt.
to about 15 % by wt.
Anti-Inflammatory Compounds
The transdermal compositions of the present invention may also include an
anti-inflammatory compound. As used herein, the term "anti-inflammatory
compound"
1 S includes a compound which is capable of reducing cell migration, caused by
ischemic
and trauma associated events, and therefore reduces edema formation to thereby
provide
pain relief. Preferably, the anti-inflammatory compound is a nonsteroidal
anti-inflammatory compound (i. e., NTHE) including ketoprofen. Anti-
inflammatory
compounds, e.g., NTHEs, are described in, for example, the 1998 SIGMA
catalogue, the
"The Merck Index", l2t:h Ed., Budavari et al., eds., Merck & Co., Inc.,
Rahway, N.J.,
1996, pp. THER-1 to THER-28, and the "Guide to Clinical Neurology" by J.P.
Mohr et
al.(Churchill Livingstone, 1995) the contents of which are incorporated herein
by
reference. Preferably, the NTHE is selected from the group consisting of
celecoxib,
etodolac, mefanamic acid, nabumetone, salsalate, naproxen, Vioxx~, COX-2 NTHEs
having biphasic solubility, and combinations thereof.
More preferably, the NTHE is selected from the group consisting of celecoxib,
etodolac, naproxen, COX-2 NTHEs having biphasic solubility, and combinations
thereof. Preferably, the NTHE has biphasic solubility. The NTHE, when present
in the
transdermal composition, preferably, constitutes from about 1 % by wt, to
about 30
by wt. of the total amount of the pharmaceutical, more preferably from about 3
% by wt.
to about 30 % by wt., and most preferably from about 5 % by wt. to about 30 %
by wt.
Dosa es
The concentration as well as the quantity of the amine containing compounds
having biphasic solubility, the agents which enhance the activity of the amine
containing
compounds, e.g., the muscle relaxants, and the anti-inflammatory compounds can
be
varied independently in order to achieve the desired effect. For example,
higher
concentrations of the amine containing compounds having biphasic solubility,
the
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muscle relaxants, and the anti-inflammatory compounds contained in a dosage
form of
decreased viscosity may result in an analgesic with fast onset and short
duration. High
concentrations of the amine containing compounds having biphasic solubility,
the
muscle relaxants, and the anti-inflammatory compounds contained in a dosage
form of
increased viscosity may result in potent analgesic with fast onset and long
duration.
Low concentrations of the amine containing compounds having biphasic
solubility, the
muscle relaxants, and the anti-inflammatory compounds in a dosage form of
decreased
viscosity may result in mild analgesic with longer onset and short duration.
Low
concentrations of the amine containing compounds having biphasic solubility,
the
muscle relaxants, and the anti-inflammatory compounds contained in a dosage
form of
increased viscosity may have mild analgesic properties with longer onset and
longer
duration. The ability to vary the concentration of the amine containing
compounds
having biphasic solubility, the muscle relaxants, and the anti-inflammatory
compounds
from very low to high of the total composition, combined with the ability to
coat thin
(about 0.1 mm) or thick (about 0.5 mm) enables the practitioner of the
invention to vary
the dosage of the system as needed for particular level of pain and anatomical
sites of
interest. It should be appreciated, however, that onset time as well as
duration of
analgesic effect of the transdermal composition of the present invention will
vary from
subject to subject as well as on the basis of the site of application, and
properties of the
amine containing compounds having biphasic solubility, the muscle relaxants,
and the
anti-inflammatory compounds.
Generally, the concentration of the amine containing compounds having biphasic
solubility, the muscle relaxants; and the anti-inflammatory compounds can
range, on a
weight basis, from about 1 % to about 30 % of the total composition,
preferably from
about 3 % to about 20 %, and more preferably from about 5 % to about 15 %.
Pharmaceutically Acceptable Carriers
The transdermal compositions of the present invention also includes a
pharmaceutically acceptable carrier which is capable of transdermal delivery
of the
amine containing compound having biphasic solubility. As used herein, the term
"pharmaceutically acceptable carrier suitable for transdermal delivery"
includes a carrier
capable of delivering the amine containing compound transdermally as defined
above.
Suitable carriers for transdermal delivery of pharmaceuticals are described in
U.S.
Patent No. 5,446,070, the contents of which are incorporated herein by
reference.
Briefly, pharmaceutically acceptable carriers of the present invention include
any
suitable finite (i. e, solid) or non-finite (i. e., non-solid, such as liquid
or semi-liquid)
carrier including liquids, semi-liquids or solid carriers, such as a
bioadhesive. Thus, the
amine containing compounds having biphasic solubility may be admixed with a
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pharmaceutically acceptable Garner such as a cream, gel, emulsion, lotion,
salve, paste,
plaster, ointment, spray solution, or any other "non-finite" carrier known in
the art of
pharmaceutical delivery. For example, the base of a non-finite carrier may be
lipid
including phospholipids such as lecithins; fatty oils; lanolin; vasoline;
paraffins; glycols;
higher fatty acids; and higher aIcohols.
The term "bioadhesive" as used herein includes an adhesive which attaches to a
biological surface such as skin or mucosal tissue. Preferably, the bioadhesive
of the
present invention is self adhesive in that it attaches to the site of interest
without the
need to reinforce its attachment by way of another adhesive. Suitable
bioadhesive
include natural or synthetic polysaccharides such as cellulose derivatives
including
methylcellulose, cellulose acetate, carboxymethylcellulose,
hydroxyethylcellulose and
the like; pectin; a mixture of sulfated sucrose and aluminum hydroxide;
hydrophilic
polysaccharide gums including natural plant exudates, such as karaya gum,
ghatti gum,
tragacanth gum, xanthan gum, jaraya gum and the like; seed gums including guar
gum,
locust bean gum, psillium seed gum and the like; and lecithins such as Soya
lecithin.
In addition to the above ingredients, compositions of the present invention
may also
include other ingredients such as various pharmaceutically acceptable
additives
available to those skilled in the art. These additives include binders,
stabilizers,
preservatives, flavorings, fragrances, and pigments.
In another embodiment, the pharmaceutically acceptable carrier of the present
invention includes van pen cream (cetyl alcohol, stearyl alcohol, steric acid,
gllycerol
monosterate, isopropyl myristate, soya lecithin, BHT alcohol 95%, simethicone,
sodium
hydroxide 30% solution, polyoxyl stearate, edetate disodium 5%, purified
water, urea).
Other Pharmaceutical Compounds
In another aspect, the invention features a transdermal composition suitable
for
transdermal delivery, which includes a therapeutically effective amount of a
pharmaceutical compound (e.g., a serotonin specific reuptake inhibitor, a mood
stabilizing compound, a dopamine compound, a compound suitable for treating
attention
deficit hyperactivity disorder, a compound suitable for treating hypertension
and
akathisia, an analgesic compound, or a compound used in the treatment of
impotence)
and a pharmaceutically acceptable Garner suitable for transdermal delivery of
the
pharmaceutical compound.
As used herein, the term "pharmaceutical compound" includes compounds
suitable for treating a targeted condition and capable of being delivered in
active form,
in vivo. Examples of pharmaceuticals include drugs, enzymes, chemical
compounds,
combinations of chemical compounds, biological macromolecules and analogs
thereof.
Examples of pharmaceutical compounds are described in detail below.
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In one embodiment of the invention, the pharmaceutical compound is a serotonin
specific reuptake inhibitor (SSRI). SSRIs are commonly prescribed for patients
with
diagnoses of mood disorders, some forms of anxiety disorder (particularly
panic
disorder), obsessive compulsive disorders, some forms of menopausal disorders,
and
eating disorders (especially bulimia nervosa). Examples of such SSRIs include
sertraline (sold under the trade name Zoloft), paroxetine (sold under the
trade name
Paxil), fluoxetine (sold under the trade name Prozac), venlafaxine (sold under
the trade
name Effexor), and fluvoxamine (sold under the trade name Luvox).
In another embodiment of the invention, the pharmaceutical compound is a
mood stabilizing medication, such as carbamazepine (sold under the trade name
Tegretol) and valproic acid (sold under the trade name Depakote). These agents
are used
frequently in psychiatric practice as either augmentation medications (to
render
antidepressants more effective) or as anti-manic medications in the treatment
of bipolar
mood disorder. Mood stabilizing medications are also used in neurologic
practice for the
1 S treatment of seizure disorders and for the treatment of certain pain
disorders.
In yet another embodiment of the invention, the pharmaceutical compound is a
compound used for treating Attention Deficit Hyperactivity Disorder (ADHD),
one
example of which is permoline, sold under the trade name Cylert. Permoline is
a
medication that is used in the treatment of Attention Deficit Hyperactivity
Disorder in
children and adults. It is practically insoluble in water, but soluble in
ethylene glycol and
lipids, making it a good candidate for transdermal administration.
In a further embodiment of the invention, the pharmaceutical compound is a
dopamine compound, used for treating Parkinson's disease, examples of which
are
pergolide, sold under the trade name Permax and bromocriptine mesylate, sold
under the
trade name Parlodel.
In yet another embodiment of the invention, the pharmaceutical compound is a
compound used for treating hypertension and akathisia, one example of which is
propranalol, sold under the trade name Inderal.
In yet a further embodiment of the invention, the pharmaceutical compound is a
compound used in the treatment of impotence such as sildenafil, sold under the
tradename Viagra. It is believed that transdermal administration of sildenafil
may be
useful, for at least some subjects, as compared to oral administration which
has been
found, in at least some situations, to be associated with gastrointestinal
side effects.
Methods For Preparing The Transdermal compositions
Another embodiment of the present invention provides a method for preparing
the above described transdermal compositions, by admixing a therapeutically
effective
amount of the amine containing compound having biphasic solubility, optimally
an
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agent which enhances the activity of the amine containin com and e. '
g ho , g., a muscle
relaxant, optimally an anti-inflammatory compound with the carrier suitable
for
transdermal delivery of the amine containing compound.
In one embodiment of the present invention, a transdermal composition is
prepared by dispersing or dissolving crushed tablets, capsules or other
preparations) of
the amine containing compound having biphasic solubility, the muscle
relaxants, and the
anti-inflammatory compounds, which were intended for oral delivery, in a gel
formed of
Soya lecithin and isopropyl palmitate or isopropyl myristate, alcohol, or
ethoxy diglycol.
In another embodiment of the present invention, Pluronic gel, formed of
Pluronic such
as Pluronic F 127, potassium sorbate and water is used.
In a particular embodiment of the present invention, a transdermal composition
including a combination of doxepin with guaifenesin is useful for treating
pain. It is
believed that transdermal administration of such combination can be
advantageous, for
at least some patients, as compared to oral administration, because higher
local
1 S pharmaceutical concentrations at the site(s), e.g., of injury, can be
achieved yielding an
improved therapeutic response without systemic side effects such as weight
gain,
drowsiness, gastrointestinal upset and/or other known side effects of these
pharmaceuticals.
Methods For Use
In one embodiment, the invention feature methods for treating pain in a
subject
in which the subject is contacted with a transdermal composition including an
amine
containing compound having biphasic solubility in an amount effective to treat
pain in
the subject; and a pharmaceutically acceptable carrier suitable for
transdermal delivery
of the amine containing compound to thereby treat pain in the subject. In a
preferred
embodiment, the transdermal composition is applied to the skin of the subject
as often as
needed for the alleviation of pain. For example, the transdermal composition
may be
applied daily, weekly, monthly, yearly, for a length of time sufficient to
alleviate pain.
Detailed examples of the preparation are provided below, along with examples
of results obtained from transde; mal administration to human patients.
Preferably, a gel
preparation is applied to the skin at the site or sites of pain. Patients can
be evaluated by
means of a structured evaluation form, e.g., completed at a frequency of at
least one time
per week. Evaluation of patients are for the present symptoms as well as any
side effects
from currently administered medications. "This makes it possible to note
changes on an
ongoing basis.
Compositions of the invention can be self administered doses in the form of a
gel
applied to the skin by the patient, or be implemented by providing a
transdermal
preparation in premeasured doses preferably in connection with an adhesive or
other
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covering or patch so that the dosage may be administered e.g., by placing the
adhesive
patch on the skin of the patient. Although some embodiments of the invention
have been
described in connection with positioning the pharmaceutical gel on the arm of
a patient,
other positioning on the skin of a patient can also be used. Because,
depending on the
formulation, speed or duration of transdermal delivery may vary as function of
skin
location, in one embodiment the location of the skin to which the
pharmaceutical is
applied is selected so as to relatively increase or decrease the delay, speed,
duration, or
rate of delivery of the pharmaceutical, either with respect to a particular
tissue or
systemically.
For example, when a rapid rise in blood serum levels is desired, a placement
which enhances delivery rate, such as behind the ear, can be used. When it is
desired to
enhance dose or delivery rate locally, the transdermal formulation may be
positioned
adjacent the desired treatment area. Membranes or matrices, such as a polymer
matrix,
may be used to limit or control delivery rates. In addition to transdermal gel
or patch
delivery, delivery of the transdermal or aerosol formulation can be achieved,
e.g. by
administration as nose drops, eardrops, eyedrops and/or suppositories.
In one embodiment, medications dispensed in transdermal gel form will be
dispensed in unit doses, such as blister packs. The gel will be extruded from
the blister
pack, and rubbed on the administration site. The dosage will be adjusted by
varying the
number of unit dose applied. This will ensure accurate dosimetry and will
avoid
contamination of the gel.
Methods For Selecting A Compound Suitable For Treating Pain
In a further aspect, the invention features a method for selecting a compound
suitable for treating pain in a subject. The method includes transdermally
administering
an amine containing compound having biphasic solubility to a subject; and
determining
whether pain is treated in the subject to thereby select a compound suitable
for treating
pain in a subject. In a preferred embodiment, the method can further include
modeling
the compound using a computer equipped with a three-dimensional chemical
structure
modeling program (e.g., Molecules-3D Professional Edition, version 2.60,
copyright
1991-1998, Molecular Arts Corp., ~ 1994-1998 WCB/McGraw Hill); and determining
whether the three-dimensional chemical structure of the compound possesses
sufficient
characteristics to be useful as a sodium channel blocker, thereby selecting a
compound
suitable for treating pain in a subject.
The effectiveness of the amine containing compound having biphasic solubility
to treat pain can be tested in vitro or in vivo. An animal model for pain ,
e.g., such as the
one described in Kral M.G. et al. (1999) Pain 81(1-2):15-24 can, for example,
be used
for testing such compounds.
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This invention is further illustrated by the following examples which should
not
be construed as limiting. The contents of all references, patents and
published patent
applications cited throughout this application, as well as the Figures are
incorporated
herein by reference.
EXAMPLES
Example 1
One hundred grams of lecithin soya (granular) and 0.66 grams sorbic acid (NF-
FCC powder) were dispersed in 100 grams (117 milliliters (mL)) of isopropyl
palmitate
NF and allowed to stand overnight. Approximately 220 milliliters of lecithin-
isopropyl
palmitate in a form of a liquid of a syrup consistency was formed.
Example 2
One hundred grams of lecithin soya (granular) and 0.66 grams sorbic acid (NF-
FCC powder) is dispersed in 100 grams (I 17 milliliters) of isopropyl
myristate NF and
allowed to stand overnight. Approximately 220 milliliters of lecithin-
isopropyl myristate
in a form of a liquid of a syrup consistency was formed.
Example 3
A beaker was prepared by measuring to a volume of 100 milliliters. It was
considered important to measure the volume accurately rather than using beaker
markings. An amount of Pluronic F127 NF (20 grams for a 20 percent gel, 30
grams for
a 30 percent gel, 40 grams for a 40 percent gel) was mixed with 0.3 grams
potassium
sorbate NF. Refrigerated purified water was added in an amount sufficient to
bring the
volume to 100 milliliters. When all of the granules had been wet the gel was
refrigerated. Solution took place upon cooling, taking 12 to 24 hours. The
resulting 100
milliliters of Pluronic gel was kept refrigerated, since the gel will solidify
at room
temperature.
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Example 4
Nine grams of carbamazepine in tablet form was ground in mortar and pestle.
4.3
milliliters of ethoxy diglycol was added and mixed to form a creamy paste.
13.2
milliliters of Soya lecithin was added and mixed until smooth. The resulting
24 cc of
solution was put into a 60 cc syringe. About 36 cc Pluronic F 127 gel 20
percent (made
according to Example 3) was placed in another syringe. The material was mixed
well
between syringes to yield 60 cc of carbamazepine organogel having a strength
of 150
milligrams (mg) per milliliter. In some cases, the mixture was run through an
ointment
mill to reduce particle size.
Example 5
Sixty 100 milligram tablets of buproprion were ground and strained to form a
fine powder. The buproprion powder was dissolved in 30 cc purified water,
placed in a
filter and washed with 10 to 20 cc purified water. The filtrate was used to
make a 20
1 S percent Pluronic gel using the procedures from Example 3, substituting
filtrate for an
equivalent volume of water, and stored in a refrigerator. Thirteen milliliters
of Soya
lecithin was mixed with one-half the buproprion Pluronic gel and mixed between
syringes to form a first batch. Thirteen milliliters of soya lecithin was
mixed with the
second half of the buproprion Pluronic gel and mixed between syringes to form
a second
batch. To each batch was added sufficient Pluronic gel F127 (made according to
example 3) to yield a total of two 60 cc batches of buproprion HC 1 organogel
having a
strength of 15 milligrams per milliliter.
Example 6
600 milligrams of fluoxetine HC 1 (in the form of thirty 20 milligram
capsules)
was placed in a beaker and dissolved in approximately 18 cc of 95 percent
ethyl alcohol.
The solution was filtered through a filter funnel using fine filter paper. The
residue was
washed with 95 percent alcohol. The filtrate was heated, maintaining a
temperature less
than 85° C, to evaporate the alcohol to concentrate to 1 to 2
milliliters. 600 milligrams
of isopropyl palmitate was combined with 600 milligrams of Soya lecithin
(granular), set
aside and allowed to liquefy. Upon liquefaction, a thick syrupy consistency
was
obtained. 1.2 grams of the mixture was drawn into a 10 milliliter syringe and
the
alcoholic solution of fluoxetine HC 1 was drawn into another syringe. The two
syringes
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were attached together with a Luer-Luer adapter and the gel was thoroughly
mixed. A 11
of the organogel was then transferred into one syringe and the empty syringe
was
disconnected. Sufficient quantity of 20 percent Pluronic F127 gel (formed as
described
in Example 3) was drawn into the empty syringe to make a total of 6
milliliters when
added to the volume in the other syringe. A Luer-Luer adapter was attached and
the
contents of the two syringes was remixed until a smooth creamy mixture was
obtained.
All the mixture was transferred into one syringe, the empty syringe was
removed and the
Luer-Luer adapter was removed.
A Luer-oral adapter was attached to the mixture and transferred to six I
milliliter
oral syringes, was filled with 1 milliliter of the gel. In this way, each
syringe contained
five 20 milligram doses, or ten 10 milligram doses to yield a total of 60
doses of
fluoxetine in lecithin organogel having a strength of 10 milligrams per 0.1
milliliters.
Example 7
Twelve 250 milligram tablets of nefazadone were crushed in a mortar and pestle
and put through a strainer. 4.8 milliliters of ethoxy diglycol (8 percent) was
added and
mixed. In cases in which all particles were not dissolved, 2 milliliters of
Pluronic were
added and mixed. 13.6 milliliters of soya lecithin were added and mixed. The
resulting
mixture was put into syringes with a Luer adapter and mixed well. Sufficient
Pluronic
F127 gel, prepared according to Example 3, was added to achieve a volume of 60
cc and
mixed well to yield 60 cc of nefazadone organogel having a strength of SO
milligrams
per milliliter.
Example 8
Thirty 40 milligram tablets of paroxetine were crushed and run through a
strainer, discarding green coating material. 4.8 milliliters of ethoxy
diglycol was added
to the powder and mixed in a mortar and pestle. Forty milliliters of Pluronic
F127 gel 20
percent, formed according to Example 3, was added in graduated amounts to the
powder
and mixed until smooth using a spatula. 13.2 milliliters of soya lecithin was
added and
mixed well and the resulting material placed into syringes and sufficient
quantity of
Pluronic gel was added to bring the volume to 60 milliliters. In those such
cases where
particle size of the resulting material was too large, the cream was run
through an
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ointment mill to yield 60 milliliters of paroxetine organogel having a
strength of 20
milligrams per milliliter.
Example 9
Thirty I 00 milligram tablets of sertraline were crushed into a fine powder
and
strained, discarding the yellow coating. Sufficient amount of Platonic F127
gel 20
percent (formed according to Example 3) was added to achieve a volume of 38
milliliters and mixed well in a mortar and pestle until a smooth cream was
achieved.
This material was placed into syringes and mixed between the syringes to
obtain a
compact cream. 13.2 milliliters of soya lecithin was added and mixed well
between the
syringes using about 20 pumps. Sufficient quantity of Platonic F127 gel 20
percent was
added to yield 60 milliliters of sertraline gel having a strength of 1 S
milligrams per
milliliter.
Example 10
Venlafaxine hydrochloride has a solubility in water of 572 mg/mL (adjusted to
ionic strength of 0.2 M with sodium chloride). Forty-five 100 milligram
tablets of
venlafaxine were crushed and put through a strainer. The powder was dissolved
in 1 S cc
purified water, the solution placed into a filter and washed with 10 cc
purified water.
The filtrate was used to make a 20 percent Platonic gel using the procedures
of Example
3 (substituting the filtrate for an equivalent amount of water) and placed
into a
refrigerator overnight. 13.2 milliliters of soya lecithin were drawn into a
syringe with a
Luer loc. The venlafaxine Platonic gel was drawn into another syringe coupled
to the
first syringe and mixed well. Sufficient Platonic F127 gel was added to
achieve a
volume of 60 cc with a strength of 75 mg. per cc.
Example 11
15 grams of sodium valproate (Depakote) was ground in mortar and pestle. 4 mL
of ethoxy diglycol was added and mixed well to form a creamy paste. 19.8 mL of
soya
lecithin was added and mixed until smooth. The resulting 24 cc of solution was
put into
2 syringes with a Luer Loc and mixed well. The mixture was divided so that
half is in
each syringe. Using another 60 cc syringe, Platonic 30% gel was added to each
to bring
each syringe to a volume of 45 mL.
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Example 12
PCT/US99/14653
Paroxetine hydrochloride has a solubility in water of 5.4 mg/mL. Paroxetine
(Paxil) gel was prepared, according to the procedures of example 8. A dosage
of 40 mg
per day was self administered by a 59 year old male patient by application to
the skin,
for a period of at least 1 hour. No skin irritation was reported. After 210
days, blood was
drawn and blood serum level of Paxil was determined to be 0 nanograms (ng) per
mL,
while typical reference levels are 49 t 26 ng/mL, indicating possible poor
absorption or
lab error. Clinical evaluation of the patient over a 210 day period of such
transdermal
administration indicated benefit to patient without GI side effects similar to
that noted
with oral preparation.
Example 13
Sertraline hydrochloride is slightly soluble in water and isopropyl alcohol
and
sparingly soluble in ethanol. Sertraline (Zoloft) gel was prepared, according
to the
procedures of example 9. A dosage of 100 mg per day was self administered by a
54
year old female patient by application to the skin, for a period of at least 1
hour. No skin
irritation was reported. After 19 days, blood was drawn and blood serum level
of Zoloft
was determined to be 5 ng/mL, while typical reference levels are 30-200 mg/mL
indicating possible limited absorption or lab error.
Example 14
Fluoxetine hydrochloride has a solubility in water of 14 mg/mL. Fluoxetine
(Prozac) gel was prepared, according to the procedures of example 6. A dosage
of 20 mg
per day was self administered by a 54 year old female patient by application
to the skin,
for a period of at least 1 hour. No skin irritation was reported. After 7
days, blood was
drawn and blood serum level of fluoxetine was determined to be 45 ng/ml, while
the
plasma level of the primary active metabolite norfluoxetin was also 45 ng/ml.
There was
evidence of patient benefit from the clinical evaluation.
Ex~ple 1$
Carbamazepine is practically insoluble in water and soluble in alcohol and in
acetone. Carbamazepine (Tegretol) gel was prepared, according to the
procedures of
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example 4. A dosage of 400 mg per day was self administered by a 55 year old
male
patient by application to the skin, for a period of at least I hour. No skin
irritation was
reported. After 120 days, blood was drawn and blood serum level of Tegretol
was
determined to be 4.6 micrograms (~,g) per mL, while typical therapeutic levels
are 4-10
l l~g/mL indicating good absorption. There were no GI side effects and the
patient
demonstrated clinical improvement.
Example 16
Carbamazepine (Tegretol) gel was prepared, according to the procedures of
example 4. A dosage of 200 mg per day was self administered by a 53 year old
male
patient by application to the skin, for a period of at least 1 hour. No skin
irritation was
reported. After 60 days, blood was drawn and blood serum level of Tegretol was
determined to be 10.8 pg/mL, while typical therapeutic levels are 4-10 I
lpg/mL
indicating excellent absorption. There were no GI side effects and the patient
demonstrated clinical improvement.
Example 17
Sertraline (Zoloft) gel was prepared, according to the procedures of example
9.
A dosage of 50 mg per day was self administered by a 53 year old male patient
by
application to the skin, for a period of at least I hour. No skin irritation
was reported.
After 63 days, blood was drawn and blood serum level of Zoloft was determined
to be
23 ng/mL, while typical reference levels are 30-200 mg/mL. The patient
demonstrated a
good clinical response without GI side effects.
Example 18
Carbamazepine (Tegretol) gel was prepared, according to the procedures of
example 4. A dosage of 200 mg per day was self administered by a 47 year old
male
patient by application to the skin, for a period of at least 1 hour. No skin
irritation was
reported. After 91 days, blood was drawn and blood serum level of Tegretol was
determined to be less than 0.5 ~g/mL, while typical therapeutic levels are 4-
10 ~g/mL,
indicating poor absorption, lab error, or patient non-compliance.
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Example 19
Buproprion is highly soluble in water. Buproprion (Wellbutrin) gel was
prepared, according to the procedures of example 5. A dosage of 100 mg per day
was
selfadministered by a 47 year old male patient by application to the skin, for
a period of
at least 1 hour. No skin irritation was reported. After 44 days, blood was
drawn and
blood serum level of Wellbutrin was determined to be less than 0.5 ng/mL,
while typical
therapeutic levels are 10-30 indicating poor absorption, lab error, or patient
non-
compliance.
Example 2p
Fluoxetine gel was prepared, according to the procedures of example 6..
Typically, a total daily adult dosage of fluoxetine as applied to the skin
according to the
present invention is between about 20mg and 200 mg, more preferably between
about
120 mg and about 200 mg. Dosages for non-adults and/or non-human mammals may
1 S need to be adjusted, e.g. proportionally to body weight. A dosage of 20-60
mg per day
was self administered by 5 patients, including that of example 13 and also
including a
44 year old male patient, a 53 year old female patient, a 47 year old male
patient and a
36 year old female patient by application to the skin, for a period of at
least 1 hour. No
skin
irritation or gastrointestinal side effects were reported. Clinical evaluation
of the patients
over a 30-180 day period of such transdermal administration indicated a
clinical
response ranging from complete remission of symptoms to moderate improvement.
Example 21
Fluoxetine gel was prepared, according to the procedures of example 6. A
dosage of 80-160 mg per day was self administered by a SO year old female by
application to the skin, for a period of at least 1 hour. No skin irritation
was reported.
After 7 days at the 80 mg dosage level blood was drawn and the blood serum of
fluoxetine was determined to be 34 ng/mL fluoxetine and 25 ng/mL
norfluoxetine, while
typical reference levels are 50-480 ng/mL, indicating good absorption. There
was
evidence of patient benefit from the clinical evaluation. The dosage was then
increased
to 160 mg per day and administered by the same method. After 7 days at the 160
mg
dosage level blood was drawn and the blood serum level of fluoxetine was
determined
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to be 90 ng/mL fluoxetine and 25 ng/mL norfluoxetine, indicating good
absorption.
There was evidence of increased patient benefit at this higher dosage Level
which
correlated positively with the higher plasma level. The patient has been
receiving the
medication continuously for a period of 5 months.
Example 22
Fluoxetine gel was prepared, according to the procedures of example 6. A
dosage of 80-160 mg/day was self administered by a 38 year old female by
application
to the skin, for a period of at least 1 hour. No skin irritation was reported.
After 7 days at
the 80 mg dosage level, blood was drawn and the blood serum level of
fluoxetine was
determined to be 25 ng/mL of fluoxetine and 25 ng/mL norfluoxetine. There was
evidence of patient benefit from the clinical evaluation. The dosage was then
increased
to 160 mg per day and administered by the same method.
Example 23
Sertraline (Zoloft) gel was prepared, according to the procedures of example
9.
A dosage of 50-200 mg per day was self administered by 6 patients, including
those of
examples 12 and 16 and also including a 60 year old male patient, a 53 year
old male
patient, a 48 year old male patient, a 38 year old male patient and a 47 year
old male
patient, by application to the skin, for a period of at least 1 hour. No skin
irritation or
gastrointestinal side effects were reported. Clinical evaluation of the
patients over a 7-90
day period of such transdermal administration indicated responses ranging from
complete resolution of depression to no noticeable response.
ZS Example 24
Carbamazepine (Tegretol) gel was prepared, according to the procedures of
example 4. A dosage of 200-400 mg per day was self administered by 6 patients,
including those of examples 14, 15 and 17, and also including a 48 year old
female
patient, a 48 year old male patient and a 54 year old female patient, by
application to the
skin, for a period of at least 1 hour. No skin irritation or gastrointestinal
side effects
were reported. The clinical evaluation of the patients over a 30-300 day
period of such
transdermal administration indicated responses ranging from moderate
improvement to
no positive clinical response.
23
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Example 25
PCT/US99/14653
Paroxetine (Paxil) gel was prepared, according to the procedures of example 8.
A
dosage of 20 mg per day was self administered by the patient of example 12 as
well as
by a 15 year old female patient by application to the skin, for a period of at
least 1 hour.
No skin irritation was reported. Clinical evaluation of the patients over a 30-
210 day
period of such transdermal administration indicated equivocal clinical
improvement of
the depression which may (or may not) have been related to the transdermally
administered Paxil.
Example 26
Five 150 mg tablets of amitriptyline were crushed and run through a strainer.
The
powder was put into syringes with a Luer Loc and mixed well with 2 mL ethoxy
diglycol. About 6 mL Pluronic Gel 20% was added and mixed well. 6.6 mL Soya
Lecithin was added and mixed well. This mixture was thinned to 30-mL total
volume
with Pluronic Gel 20% and mixed well. The resulting mixture having a strength
of 25
mg/mL was placed in appropriate dispensing device.
Example 27
Amitriptyline (Elavil) gel was prepared, according to the procedure of example
26. A dosage of 25 mg per day was self administered by a 47 year old male
patient.
Administration was by application to the skin, for a period of at least 1
hour. No skin
irritation or gastrointestinal side effects were reported. Clinical evaluation
of the patients
over a 100 day period of such transdermal administration indicated an
apparently good
clinical response, comparable to that achieved with oral medication.
Example 2-g
Trazodone (Desyrel) gel was prepared, according to a procedure similar to that
of example 7. A dosage of SO-150 mg per day was self administered by 2
patients,
including a 36 year old female patient and a 47 year old male patient.
Administration
was by application to the skin, for a period of at least I hour. No skin
irritation or
gastrointestinal side effects were reported. Clinical evaluation of the
patients over a
24
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PCT/US99/14653
42-90 day period of such transdermal administration indicated a good to
excellent
clinical response.
Example 29
Venlafaxine (Effexor) gel was prepared, according to a procedure similar to
that
of example 9. A dosage of I 50-225 mg per day was self administered by 2
patients,
including a 54 year old female patient and a 55 year oId male patient.
Administration
was by application to the skin, for a period of at least 1 hour. No skin
irritation or
gastrointestinal side effects were reported. Clinical evaluation of the
patients over a 15--
165 day period of such transdermal administration indicated a response ranging
from no
clinical improvement to mild clinical improvement.
Example 30
Propranolol (Inderal) gel was prepared, according to a procedure similar to
that
of example 8 to produce a gel having a strength of 40 mg of propranalol per mL
of gel.
A dosage of 80 mg per day was self administered by 2 patients, including a 36
year old
female patient and a 47 year old male patient. Administration was by
application to the
skin, for a period of at least 1 hour. No skin irritation or gastrointestinal
side effects
were reported. Clinical evaluation of the patients over a I 00 day period of
such
transdermal administration indicated results comparable to those achieved with
oral
medication.
Example 31
Buproprion (Wellbutrin) gel was prepared, according to a procedure described
in
example S. A dosage of 150-200 mg per day was self administered by 3 patients,
including that of example I 8, and also including a 38 year old male patient
and a 53 year
old female patient. Administration was by application to the skin, for a
period of at least
1 hour. No skin irritation or gastrointestinal side effects were reported.
Clinical
evaluation of the patients over a 5-45 day period of such transdermal
administration
indicated equivocal results.
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Example 32
Valproic acid (Depakote) gel was prepared, according to a procedure similar to
that of example 4. A dosage of 1000 mg per day was self administered by a 38
year old
male patient. Administration was by application to the skin, for a period of
at least I
hour. No skin irntation or gastrointestinal side effects were reported.
Clinical evaluation
of the patients over a 30 day period of such transdermal administration
indicated results
comparable to those achieved with oral medication.
Example 33
r
Valproic acid (Depakote) gel was prepared according to the procedure of
example 1 I . A dosage of 500-1000 mg was self administered by two male
patients, ages
41 and 49. Administration was by application to the skin, for a period of at
least one
hour. Significant skin irritation occurred with one patient, but no
gastrointestinal side
effects were reported. Clinical evaluation of the patients over a period of
two months
1 S revealed improvement, but upon longer term follow-up it appeared that
other factors
may have been responsible. After 28 days, blood was drawn and a serum valproic
acid
level of 26 pg/mL was obtained for the 49 year old patient (while taking 250
mg twice
daily), with a therapeutic reference range of 50-150 pg/mL. This indicated
poor to fair
absorption, and the dosage was raised to 500 mg twice daily, with a further
improvement in clinical response. The 41 year old patient reported a good
clinical
response to an initial dosage of 250 mg administered twice daily, but a serum
valproic
acid level of only 1 pg/mL was obtained. The dosage was increased to S00 mg
twice
daily, and a similar serum valproic acid level was obtained. The disparity
between the
clinical response and the plasma level might be explained either by laboratory
error or
placebo effect.
Example 34
A gel containing reboxetine (sold under the trade name Edronax) is prepared
according to a procedure similar to that described in example S but using
reboxetine in
place of boproprion. The resulting mixture will be self administered by
patients by
application to the skin for a period of at least I hour. No skin irritation or
gastrointestinal
side effects are expected. Clinical evaluation of patients over a 5-45 day
period of such
transdermal administration is expected to indicate a good response to
treatment.
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Example 35
Nefazodone (Serzone) gel was prepared, according to a procedure described in
example 7. A dosage of 100 mg per day was self administered by a 61 year old
(male,
female) patient. Administration was by application to the skin, for a period
of at least 1
hour. No skin irntation or gastrointestinal side effects were reported.
Clinical evaluation
of the patients over a 21 day period of such transdermal administration
indicated a good
response to treatment.
Example 36
I gram of permoline tablets are crushed in a mortar and then dissolved in
propylene glycol, just sufficient to effect dissolution. 3 mL of propylene
glycol or 95%
ethyl alcohol is added to form a paste. 6.6 mL soya lecithin is added to the
mixture in
the mortar. The mixture is placed in two syringes with a Luer Loc and mixed
thoroughly. Each syringe is filled to 30 mL Pluronic F127 20% gel and mixed
between
syringes to produce a mixture having a strength of 33 mg/mL. The mixture is
put in an
appropriate dispensing device.
Example 37
A 16-year-old female with an established diagnosis of Attention Deficit
Disorder
had been treated successfully with oral pemoline (Cylert) for about 6 months.
To
potentially decrease the risk of liver damage associated with long-term use,
permoline
prepared according to the procedure of example 36 will be administered
transdermally,
by application to the skin in the post auricular region for a period of at
least one hour, at
two sites, twice daily. No skin irritation is expected. The clinical results
are expected to
be comparable to those obtained with the oral medication, although the dosage
may have
to be adjusted upwards to achieve adequate plasma levels, and more time may be
required to achieve satisfactory plasma levels.
For psychiatric patients, some have received two or more
psychopharmaceuticals, and in some cases, two or more of the above examples
describe
different evaluations for the same period of administration of a
psychopharmaceutical
agent.
27
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Of the patients who have received prescriptions for one or more of the
medications as described in the examples above, each had previously
demonstrated a
significant intolerance to oral administration of one or more medications,
prior to
instituting transdermal administration. The laboratory measures of plasma
blood levels
described above for transdermally administered fluoxetine and carbamazepine
are
believed to demonstrate good absorption transdermally using lecithin organogel
matrix
as the vehicle. Valproic acid and sertraline do not appear to be absorbed well
or reliably.
Valproic acid appears to cause skin irritation in some patients necessitating
discontinuation. Both the Laboratory measure of Buproprion and the patient
clinical
responses indicated poor or equivocal absorptions and results. Patient
tolerance of
transdermal administration has been good to excellent. Patients in the example
above
who suffered very severe GI side effects using oral preparations were more
tolerant of
the inconvenience of rubbing on the gel than were patients who had experienced
only
mild to moderate side effects. In general, more highly motivated and
treatment-compliant patients also had a higher rate of sustained compliance.
Patients in the examples above were evaluated by means of a structured
evaluation form depicted in Fig. 1, which was completed at a frequency of at
least one
time per week for each patient receiving transdermal medication according to
the
present invention. The patients were evaluated both for all present
psychiatric symptoms
as well as any side effects from currently-administered medications. In
general, it is
believed that patients with the most clear cut and uncomplicated diagnosis of
major
depression experienced the best results. In general, patients with severe
personality
disorders or with concealed substance abuse disorders did less well.
Example 38
1800 mg of gabapentin in powder form is dissolved with 1 mL propylene glycol
in syringes with a Luer Loc. 6.6 mL of Soya lecithin is added and mixed
thoroughly
between syringes. The resulting material is placed in a device for dispensing
measured
amounts.
Example 39
Gabapentin mixtures of 2% and 4% will be prepared by substituting 1200 mg
gabapentin or 600 mg gabapentin in place of 1800 mg gabapentin, in example 38.
28
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Example 40
PCT/CTS99/14653
Gabapentin, prepared according to Example 38 or 39, will be combined with
either 3% or 5% Lidocaine in varying ratios.
Example 41
4% gabapentin, prepared according to Example 38 or 39, will be combined with
7% carbamazepine and 7% amitriptyline.
Example 42
2% gabapentin, prepared according to Example 38 or 39, will be combined with
2% carbamazepine and 1 % Piroxicam, which is expected to yield better
penetration into
muscle tissue.
Example 43
Gabapentin, prepared according to Example 38 or 39, in concentrations ranging
from 2%-6% will be combined with clonidine in concentrations between .2% and
.3%.
Example 44
A 56-year-old woman had painful upper and lower extremity spasms as a result
of spastic quadriparesis resulting from an injury. Oral gabapentin, an
anticonvulsant, had
been administered previously, but had caused a "drugged" feeling, one of the
commonly
reported side effects with this agent. It was believed that use of transdermal
gabapentin
might provide local relief by achieving high local tissue concentrations near
the site of
administration without correspondingly elevated blood plasma levels. It is
known that
other anticonvulsants, such as carbamazepine, are useful in reducing
neurogenic pain.
Gabapentin's solubility in water exceeds 10%, making systemic absorption less
likely.
Gabapentin prepared according to the procedure of example 38 was self
administered by
application to the skin in the area of pain. The patient reported moderate
relief of spasms
over a period of one week, with no systemic side effects and no report of skin
irritation.
29
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PCT/US99/14653
Example 45
Six grams of amitriptyline powder was placed in 40 milliliters of Platonic
FI27
33% gel and placed under refrigeration to dissolve. Two milliliters of ethoxy
diglycol
was added to 4.8 grams of carbamazepine and mixed to form a smooth paste. 16.4
grams
of Soya lecithin was added to the resulting paste and mixed well. The
dissolved
amitriptyline composition was added to the carbamazepine composition and
sufficient
Platonic F 127 20% was added to make I20 milliliters and the resulting
composition was
mixed well to yield a composition having 5% amitriptyline and 4%
carbamazepine.
Example 46
6 grams of doxepin was added to 20 milliliters Platonic 33% F127 and put into
a
refrigerator to dissolve. 24 grams of ketoprofen and 12 grams of guaifenesin
was added
to I 0 milliliters of 95% alcohol and mixed well. 26.4 milliliters of Soya
lecithin was
added and mixed well and the doxepin composition was mixed with the
ketoprofen/
I S guaifenesin composition. The resulting mixture was added to sufficient
Platonic 33% to
yield I20 milliliters. The resulting composition was mixed well to yield a
composition
having about 20% ketoprofen, 5% doxepin and 10% guaifenesin.
Example 47
6 grams of doxepin was added to 26 milliliters Platonic 33% and refrigerated
to
dissolve. 2 milliliters ethoxy diglycol was added 4.8 grams carbamazepine and
mixed.
The resultant mixture was added to 24 grams ketoprofen and six milliliters
alcohol and
the result was mixed well. 26.4 milliliters Soya lecithin was added to the
ketoprofen
composition and mixed well. The doxepin composition was mixed with the
carbamazepine/ ketoprofen composition and sufficient Platonic 33% was added to
yield
120 milliliters. The resultant composition was mixed well to yield a
composition having
about 20% ketoprofen, 4% carbamazepine and S% doxepin.
Example 48
.15 grams sildenafil was crushed and strained and dissolved in S milliliters
Platonic 20% F127 and mixed between syringes. 2.2 milliliters of Soya lecithin
was
added and mixed. Sufficient Platonic 20% was added to yield I O milliliters
and the
CA 02335837 2000-12-21
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PCT/US99/14653
resultant composition was mixed well to yield a composition having the
strength of
about 15 milligrams per milliliter.
Example 49
A mixture of Sildenafil 15 mg/ml was applied to the penis and scrotum of a 51
year old male. An immediate and strong erection resulted with sexual
stimulation,
without any irritation or burning. It is believed the composition will possess
the
therapeutic results claimed for orally administered Sildenafil, without any
time delay,
without any systemic GI side effects, and possibly without the degree of drug
interaction
with nitrates used in cardiac disease. It is believed that this will
contribute both to the
convenience of use of the pharmaceutical and to its safety.
Example SO
Compositions according the examples 45 through 47, 53, 55 were transdermally
1 S applied to numerous patients, for the purpose of treating pain including
as described in
other examples herein, with the results summarized in Table I below. The
meaning of
certain entries in Table I is indicated in Table II below. Blank results
indicate no
treatment at the pertinent site for this patient. Where a given line of Table
I shows more
than one site, one "best" (greatest pain relief) result if shown in bold.
31
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CA 02335837 2000-12-21
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CA 02335837 2000-12-21
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CA 02335837 2000-12-21
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CA 02335837 2000-12-21
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36
CA 02335837 2000-12-21
WO 00/00120 PCT/US99/14653
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37
CA 02335837 2000-12-21
WO 00/00120 PCT/US99/14653
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38
CA 02335837 2000-12-21
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TABLE II
Gender: 1 = male 2 = female
Surgery: I = one or more surgeries 2 = no surgeries
Pain: I = mild 2 = moderate 3 = severe-sufficient to
produce observed tears
Duration: length of treatment trial in weeks
Result: 0 = no benefit
1 = mild benefit
2 = moderate benefit (greater than 25% pain reduction)
3 = major benefit (greater than 40-45% pain reduction)
4 = almost complete relief (greater than 80% pain reduction)
1 S Certain results drawn from the information of Table I are summarized in
Table III and
IV.
Table III - Percent reported pain relief
Site N (NumberNone Mild Mild- moderateMajor Total
of data moderate
points)
Wrist 13 16.7 33.3 8.3 41.7
Shoulder14 7.1 21.4 14.3 42.9 7.1 7.1
Elbow S 40 20 20 20
Back 25 24 32 8 28 8
Arm 7 28.6 14.3 14.3 28.6 14.3
Neck 11 9.1 18.2 45.5 9.1 18.2
Knee 13 15.4 46.2 15.4 7.7 15.4
39
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Table IV (percent reported pain relief)
N None Mild Mild- moderateMajor Total
moderate
Best result without36 16.7 36.1 8.3 27.8 8.3 2.8
tricyclic
Best result with 20 10 10 20 35 1 S I 0
any tricyclic
Either tricyclic 7 I 4.3 14.3 42.9 14.3 14.3
-sole agent
Best result with 25 16 44 4 28 8
ketoprofen
gabapentin piroxicam
Best result without43 I 8.6 32.6 14 23.3 7 4.7
doxepin --
Best result with 13 7.7 7.7 53.8 23.1 7.7
doxepin
Example 51
A 51 year old female administered a composition prepared according to example
46, containing 20% ketoprofen, S% doxepin, and 10% guaifenesin to her back for
a
period of 2 weeks. She reported moderate pain relief, lasting several hours,
after each
application. She reported no skin irritation nor any other side effects. Oral
medications
had produced no relief, and had caused significant GI side effects.
Example 52
A 34 year old man administered a composition containing 20% ketoprofen, 4%
carbamazepine, and 5% doxepin to a very severely scarred wrist that had
undergone 4
surgeries for carpet tunnel syndrome. He reported moderate pain relief,
lasting for
several hours after each application. No other treatment, including opiate
oral pain
1 S medication, had been effective in providing even minor pain relief.
Example 53
24 grams ketoprofen and sufficient guaifenesin to result in a 10% final
guaifenesin concentration, was mixed well with 10 milliliters 95% alcohol.
1200 mg
gabapentin was dissolved in one ml propylene glycol in a syringe with a luer
loc. 26.4
ml of soya lecithin was added to the ketoprofen-guaifenesin-alcohol mixture
and mixed
well. The resulting mixture was added to the gabapentin-propylene glycol
mixture and
mixed well. 4.8 gm of carbamazepine was combined with the resultant
combination and
mixed well to form a smooth paste. The resulting paste was combined with the
ketoprofen-guaifenesin-alcoholgabapentin mixture and mixed well with
sufficient
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pluronic to yield 120 ml of a composition containing ketoprofen 20%,
carbamazepine
4%, gabapentin 4%, guaifenesin 10%.
Example 54
A 58 year old female with damage to her cervical spinal cord with a resultant
spastic quadreparesis reported moderate relief of both pain and muscle spasms
when she
applied a mixture prepared generally according to example 53, containing
ketoprofen
20%, carbamazepine 4%, gabapentin 4%, guaifenesin I O% for a period of 8 weeks
to
her back and hip. She had been unable to tolerate both oral carbamazepine and
oral
gabapentin because of systemic side effects, including skin rash with the
carbamazepine
and dizziness and sedation with the gabapentin. She experienced no skin
irritation nor
other side effects with the transdermal formulation.
Example 5 S
Six grams of doxepin powder combined with 26 milliliters pluronic and placed
in the refrigerator until dissolved. 1200 mg gabapentin was mixed with 1 ml
propylene
glycol and placed in a syringe with luer lock. 6.6 ml of soya lecithin was
added and
mixed well between syringes. 24 gm of ketoprofen and 8 milliliters alcohol was
mixed
well between two syringes with luer loc. The doxepin mixture was mixed well
with the
gabapentin mixture and subsequently the ketoprofen mixture was added and mixed
well.
Sufficient pluronic 20% (about 54 ml) was added to yield 60 ml of a
composition having
about 20% ketoprofen, 4% weight percent gabapentin and 5% weight percent
doxepin.
Example 56
A 57 year old female applied a mixture, prepared generally according to
example
55, containing ketoprofen 20%, gabapentin 4%, and doxepin S% for a period of 8
weeks
to her neck and reported major relief. She applied the same mixture to her
shoulder and
reported moderate relief. A mixture that substituted piroxicam for the doxepin
produced
only mild shoulder relief.
Example 57
A 35 year old man with a history of knee injury with vascular compromise and 3
surgeries applied a mixture, prepared generally according to example 45,
containing 4%
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carbamazepine and 5% amitriptyline to his knee, and reported mild to moderate
pain
relief, without skin irritation nor other side effects.
Example 57A
S A 41 year old woman with history of back surgery applied a mixture, prepared
generally according to example 45, containing 4% carbamazepine and 5%
gabapentin to
her back for a period of 2 weeks. She reported mild pain relief.
Example 58
A 53 year old man with a history of two total bilateral knee replacements
applied
a mixture, prepared generally according to example 45, containing 4%
carbamazepine
and 5% amitriptyline to both knees for a period of 4 weeks. He reported no
pain relief.
Example 58A
A 54 year old man with a history of 7 back surgeries applied a mixture,
prepared
generally according to example 45, containing 4% carbamazepine and 5%
amitriptyline
to his hack for a period of 2 weeks. He reported mild to moderate pain relief,
over and
above that he was receiving from a transdermal opiate medication (Duragesic).
He
reported no side effects, and specifically no skin irritation.
Example 59
A 38 year old man with a history of shoulder strain applied a mixture,
prepared
generally according to example 45, containing 4% carbamazepine and 5%
amitriptyline
to his shoulder for a period of 2 weeks. He reported mild to moderate pain
relief, and
reported no skin irritation nor other side effects.
Example 61
Sufficient carbamazepine and gabapentin was added to a combination of Soya
lecithin and pluronic to yield a lecithin organogel having about 4%
carbamazepine and
5% gabapentin.
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Example 62
A 42 year old woman with a history of 3 back surgeries and cervical
degenerative disc disease applied a mixture, prepared according to example 61,
containing 4% carbamazepine and S% gabapentin to her neck and reported total
relief of
pain. She reported no side effects, and no skin irritation. She noted the
complete and
rapid resolution of a migraine like headache at the same time. Administration
of the
same mixture to her arm and her wrist, affected by a diagnosed condition of
reflex
sympathetic dystrophy, yielded moderate pain relief.
Example 63
3.6 grams gabapentin was dissolved with 5.4 ml ethoxy diglycol using a mortar
and pestle. 9.6 grams ketoprofen and 2.7 grams piroxicam were added and the
resultant
composition mixed well. 19.8 milliliters soya lecithin was added and resultant
mixture
mixed well and added to a sufficient quantity of 20% pluronic gel to yield 90
milliliters
of a composition having about 10 percent ketoprofen, 4% gabapentin and 3%
piroxicam.
Example 64
3.6 grams gabapentin was dissolved with 5.4 ml ethoxy diglycol using a mortar
and pestle. 9 grams ketoprofen and 0.9 grams piroxicam were added and mixed
well.
19.8 milliliters soya lecithin was added to the resultant mixture and mixed
well.
Sufficient amount of pluronic gel 20% was added to yield 90 milliliters of a
composition
having approximately 10% ketoprofen, 4% gabapentin and 1% prioxicam.
Example 65
12 g doxepin was mixed with 50 ml Pluronic F 127 33% and placed in a
refrigerator to dissolve. 12 g gabapentin was dissolved in 9 ml ethoxy
diglycol and
mixed to form a smooth paste. 52.8 ml of soya lecithin was added and mixed
well. The
doxepin/Pluronic mixture was added and mixed well. Sufficient quantity of
Pluronic F
127 20% was added to produce 240 ml of a composition having about 5 wt%
gabapentin
and 5 wt% doxepin.
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Example 66
A 36 year old man with a knee injury involving joint surface damage and
vascular comprise applied a mixture, prepared generally according to Example
65 to his
knee several times per day. He reported moderate to major (40%) relief of pain
that
persisted for 4 to 6 hours. An earlier trial of carbamazepine-amitriptyline
gel produced
no relief when.applied to his knee.
Example 67
6 gm doxepin was mixed with 18 ml of Pluronic 33% to and placed in a
refrigerator to dissolve. 6 gm gabapentin was ground in a mortar and pestle to
a fine
powder, added to 6 ml ethoxy diglycol and mixed to form a smooth paste. 12 gm
guaifenesin was added and mixed well. 26.4 ml soya lecithin was added and
mixed well.
The doxepin/Pluronic mixture was added and mixed well. Sufficient quantity of
Pluronic gel (25.2 ml of 33% Pluronic, although 30% or 20% Pluronic can be
used), was
added to produce 120 ml of a composition having about 5 wt% gabapentin, about
5 wt%
doxepin and about 10 wt% guaifenesin.
Example 68
A 55 yeas old woman with a back and shoulder injury sustained as a nursing
care
provider applied a mixture, prepared generally according to Example b7, to her
back
three times per day for a period of two weeks and achieved major relief. She
applied the
same mixture to her hip and leg and reported moderate to major relief. A
mixture
containing only doxepin provided only moderate relief to her back, and mild to
moderate relief to her hip and leg. A mixture that contained only ketoprofen,
gabapentin
and piroxicam provided only mild relief to her back.
Example 69
A 59 year old woman with cervical and back strain applied a mixture, prepared
generally according to example 51, but without steps involving ketoprofen)
containing
about 5 wt % doxepin and about 10 wt% guaifenesin, to her neck for a period of
two
weeks, two to four times per day, and achieved total relief. She applied the
same mixture
to her back and achieved major to total relief.
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Example 70
4.S gm of doxepin HCI was dissolved using 2.S ml 9S% alcohol and mixed well
between syringes. It is also possible to mix the doxepin with S ml Platonic
20% and
place in a refrigerator to dissolve. Sufficient quantity of 20% Platonic F 127
was added
S to produce 90 ml of a composition having about S wt% doxepin. Preferably
this and
other disclosed compositions are protected from light.
Example 71
A 61 year old man with injuries to his back, neck and arm applied a mixture
(prepared generally according to Example 70) to his neck four times per day
and
achieved major relief. He applied the same mixture to his elbow and achieved
moderate
relief.
Example 72
1 S A formulation of 7% antidepressant and about 10% muscle relaxant was
prepared by dissolving 3.1 S g of trimipramine and 4.5 g of guaifenesin in a
mixer jar
using 2.7 mL of ethoxy diglycol. About 9.9 mL of soya lecithin was added and
the
mixture was mixed well. Sufficient quantity of Platonic F 127 NF (20%) to make
total
volume of about 45 mL was added and mixed well.
Example 73
A gel formulation of 30% NTHE was prepared from 36 g of celecoxib, 7.2 mL
of ethoxy diglycol, 26.4 mL of Soya lecithin and sufficient quantity of
Platonic F 127 NF
(20%) to make total volume of 120 mL.
2S
Example 74
A gel formulation containing about 7% antidepressant and about 13% muscle
relaxant was prepared from 14.4 g of doxepin, 31.2 g of guaifenesin, 12 mL of
ethoxy
diglycol, 52.8 mL of soya lecithin and sufficient quantity of Platonic F127 NF
(33%) to
make total volume of 240 mL.
Example 7S
A gel formulation containing S% antiepileptic was prepared from 6 g of
lamotrigine, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient
quantity of
3S Platonic F127 NF (33%) to make total volume of 120 mL.
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Example 76
A gel formulation containing 10% adrenergic agonist was prepared from 12 g of
crushed tizanidine, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and
sufficient
quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
Example 7?
A gel formulation containing 10% muscle relaxant was prepared from 12 g of
crushed metaxalone, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and
sufficient
quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
Example 78
A gel formulation containing I 0% muscle relaxant was prepared from 12 g of
crushed carisoprodol, 6 mL of ethoxy diglycol, 26.4 mL of Soya lecithin and
sufficient
quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
Example 79
A gel formulation containing 10% methocarbamol was prepared from 12 g of
crushed methocarbamol, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and
sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
Example 80
A gel formulation containing 10% muscle relaxant was prepared from 12 g of
crushed dantrolene sodium, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin
and
sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
Example 81
A gel formulation containing 7% antidepressant, 10% muscle relaxant was
prepared from 8.4 g of crushed doxepin, 12 g of chlorzoxazone, 6 mL of ethoxy
diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF
(33%) to
make total volume of 120 mL.
Example 82
A series of experiments in human subjects were performed using various
combinations of pharmaceuticals. The results are indicated in Figure 2.
Values of pain relief as rated by the patients are provided for each body part
for
which the medication was administered. The scale used in Figure 2, is as
follows:
0 - None no benefit or equivocal benefit
1 - Mild less than 15% pain reduction
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1.5 - Mlld-moderate 15-25%pain reduction
2.0 - Moderate 25-33%pain reduction
2.5 - Moderate-major 33-45%pain reduction
3.0 - Major 45-60%pain reduction
3.5 Major-total 60-80%pain reduction
-
4.0 - Total greaterhan 80% pain
t reduction
For each body part and for each percentage composition of each compounded
medication, the individual ratings as well as a mean, which is the statistical
mean of the
values given according to the scale listed above, are provided. For example, 3
patients
were administered doxepin 5% to their back, and the mean level of relief was
2.333. By
contrast, 13 patients received the 5%/10% doxepin-guaifenesin combination, and
their
mean level of pain relief was 2.885. Results for 7/10 and 10/10 compositions
of doxepin
guaifenesin are also given, and the mean for the entire sample of dox-guai in
all
combinations is provided at the end of the section, namely 2.722.
The abbreviations used in Figure 2 are as follows:
Abbreviations Generic Pharmaceutical names
c-dox-gu carbamazepine doxepin guaifenesin
c-gab-do carbamazepine gabapentin doxepin
carb carbamazepine
carb-ami carbamazepine amitriptyline
carb-gab carbamazepine gabapentin
dox doxepin
dox-chl doxepin chlorzoxazone
dox-guai doxepin guaifenesin
g-dox-gu gabapentin doxepin guaifenesin
gab-dox gabapentin doxepin
k-ca-dox ketoprofen carbamazepine doxepin
k-car-pi ketoprofen carbamazepine piroxicam
k-dox-ch ketoprofen doxepin chlorozoxazone
k-dox-gu ketoprofen doxepin guaifenesin
k-dox-pi ketoprofen doxepin piroxicam
k-g-do-g ketoprofen gabapentin doxepin guaifenesin
k-gab ketoprofen gabapentin
k-gab-ami ketoprofen gabapentin amitriptyline
k-gab-do ketoprofen gabapentin doxepin
k-gab-gu ketoprofen gabapentin guaifenesin
k-gab-pi ketoprofen gabapentin piroxicam
k-pi ketoprofen piroxicam
la-li-gu lamotrigine lidocaine guaifenesin
lam-chl lamotrigine chlorzoxazone
n-dox-ch naproxen doxepin chlorzoxazone
naproxen naproxen
tri-chl trimipramine chlorzoxazone
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Based on the results described herein, doxepin appears to be an effective pain
relief medication when administered transdermally and appears to be
substantially free
of side effects when administered transdermally as described herein.
Doxepin appears to provide about three times the positive response rate
compared to at least some other pharmaceutical agents described herein,
regardless of
whether such other pharmaceutical agents are administered singly or in
combination.
Doxepin appears to be substantially more effective than amitriptyline as a
pain, e.g.,
neuropathic pain agent when administered transdermally. This appears to be
true
regardless of whether doxepin is administered as a single agent or is
administered in
combination with other pharmaceuticals as described herein.
Carbamazepine appears to provide positive effects as a pain, e.g., neuropathic
pain agent, at least in properly selected patients. Carbamazepine appears to
cause a rash
in at least some patients, requiring its discontinuation.
These side effects appear similar to those that are noted for oral
administration of
carbamazepine. Gabapentin appears to be free of side effects when administered
transdermally. Although some patients appear to derive some benefit from a
combination of transdermally administered ketoprofen, gabapentin, and
prioxicam, the
effect appears to be relatively weak compared to the effect provided by
doxepin.
Guaifenesin appears to provide benefit as an adjunctive treatment, of painful
spasticity. For the patient population described herein, amitriptyline
appeared to offer
limited pain relief when administered transdermally. It appears that combining
gabapentin with doxepin may offer some additional benefit. The addition of
guaifenesin to doxepin may be of particular value when painful spasticity is
present.
In view of the above, the invention provides treatment to patients for whom
oral
delivery is suboptimal, such as patients who experience gastrointestinal or
other side
effects, patients who experience poor absorption for orally delivered
pharmaceuticals
and/or patients who benefit from delivery over an extended period or a
relatively rapid
delivery or higher rate of increase of plasma levels. The present invention
achieves
delivery of therapeutic amounts of pharmaceuticals, for at least some patient
populations, substantially without skin irritation, gastrointestinal or other
side effects
associated with orally-delivered pharmaceuticals, especially
psychopharmaceuticals, and
yields clinical benefits comparable to or greater than those received by
patients to whom
corresponding pharmaceuticals were administered orally. In view of the above
reasons,
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particularly effective pain medications are those described in examples 65,
67, 69 and
70.
A number of variations and modifications of the invention can also be used. It
is
believed that blood plasma levels may be increased by providing for two or
more
transdermal applications per day and/or applying a transdermal composition to
two or
more sites.
In at least one case, application of a Prozac gel formulation twice daily
appeared
to approximately double the plasma level. It is believed that an approach such
as
applying a Prozac gel formulation twice daily to two sites will yield middle
range
therapeutic levels of about 140-250 ng/ml. At least partially on the basis of
the results
described herein for fluoxetine, it is believed olanzapine (sold under the
trade name
Zyprexa) or a fluoxetine/olanzapine mixture in a lecithin organogel will prove
useful.
Other types of psychotropic or psychopharmaceutical medications for which the
described transdermal delivery may be used including psychostimulant
medications.
One example of a psychostimulant medication is Methylphenidate (sold under the
trade
name Ritalin) used in the treatment of attention deficit hyperactivity
disorder (ADHD).
Methylphenidate typically has a 2-4 hour duration of action necessitating
frequent
dosing of a patient which is particularly difficult to accomplish with
children in school.
It is believed that by using transdermal administration, it will be possible
to achieve an
extension of effective dosing throughout the day, eliminating the need for
frequent oral
medication administration. It is believed that transdermal administration will
also
eliminate peaks and valleys of blood plasma levels which, it is believed, will
be more
clinically effective. It is believed similar results will be obtained with
other
pharmaceuticals, for example, Dextroamphetamine (under the trade name
Dexedrine)
although it is believed the need is less acute since a time release "spansule"
form of the
medication is available which typically has a 5-6 hour duration of action.
Another group
of psychotropic medications which, it is believed, will benefit from
transdermal delivery
includes antipsychotic medication such as those used in the treatment in
schizophrenia.
Embodiments of the invention include, but are not necessarily limited to, use
by
patients with enteric absorption deficits.
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Equivalents
Those skilled in the art will recognize, or be able to ascertain using no more
than
routine experimentation, many equivalents to the specific embodiments of the
invention
described herein. Such equivalents are intended to be encompassed by the
following
claims.
