Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TRANSDERMAL DRUG DELIVERY SYSTEMS, DEVICES, AND
METHODS EMPLOYING OPIOID AGONIST AND/OR OPIOID
ANTAGONIST
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit under 35 U.S.C. 119(e) of
U.S. Provisional Patent Application No. 60/722,136 filed September 30,
2005, the contents of which are incorporated herein by reference in their
entirety.
BACKGROUND
Field
This disclosure generally relates to the field of iontophoresis
and, more particularly, to transdermal drug delivery systems, devices, and
methods employing opioid agonist and/or opioid antagonist.
Description of the Related Art
lontophoresis employs an electromotive force and/or current to
transfer an active agent (e.g., a charged substance, an ionized compound,
an ionic a drug, a therapeutic, a bioactive-agent, and the like), to a
biological
interface (e.g., skin, mucus membrane, and the like), by applying an
electrical potential to an electrode proximate an iontophoretic chamber
containing a similarly charged active agent and/or its vehicle.
lontophoresis devices typically include an active electrode
assembly and a counter electrode assembly, each coupled to opposite
poles or terminals of a power source, for example a chemical battery or an
external power source. Each electrode assembly typically includes a
respective electrode element to apply an electromotive force and/or current.
Such electrode elements often comprise a sacrificial element or compound,
for example silver or silver chloride. The active agent may be either cationic
or anionic, and the power source may be configured to apply the appropriate
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voltage polarity based on the polarity of the active agent. lontophoresis may
be advantageously used to enhance or control the delivery rate of the active
agent. The active agent may be stored in a reservoir such as a cavity. See
e.g., U.S. Patent No. 5,395,310. Alternatively, the active agent may be
stored in a reservoir such as a porous structure or a gel. An ion exchange
membrane may be positioned to serve as a polarity selective barrier
between the active agent reservoir and the biological interface. The
membrane, typically only permeable with respect to one particular type of
ion (e.g., a charged active agent), prevents the back flux of the oppositely
charged ions from the skin or mucous membrane.
Commercial acceptance of iontophoresis devices is dependent
on a variety of factors, such as cost to manufacture, shelf life, stability
during
storage, efficiency and/or timeliness of active agent delivery, biological
capability, and/or disposal issues. Furthermore, an iontophoresis device
that is able to deliver an active agent and is effective at inducing analgesia
or aesthesia in a subject is likewise desirable.
The present disclosure is directed to overcome one or more of
the shortcomings set forth above, and provide further related advantages.
BRIEF SUMMARY
In one aspect, the present disclosure is directed to a self-
contained iontophoretic drug delivery system. The system includes at least
one active agent reservoir, an active electrode assembly including at least
one active electrode element, a power source, and a biocompatible backing.
In some embodiments, the system is configured for providing transdermal
delivery of one or more therapeutic active agents to a biological interface of
a subject and inducing analgesia or aesthesia in the subject for a limited
period of time.
The at least one active agent reservoir includes a
pharmaceutical composition for inducing analgesia or anesthesia in the
subject. The pharmaceutical composition for inducing analgesia or
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anesthesia in the subject may include at least one analgesic or anesthetic
active agent in combination with at least one opioid antagonist.
The at least one active electrode element is operable to
provide an electromotive force for driving the pharmaceutical composition
(comprising the at least one analgesic or anesthetic active agent in
combination with the at least one opioid antagonist) for inducing analgesia
or anesthesia in the subject from the at least one active agent reservoir, to
the biological interface of the subject.
The power source is electrically coupleable to the active
electrode assembly, and is operable for supplying an electromotive force to
the active electrode assembly. The biocompatible backing is configured to
encase the at least one active agent reservoir and the active electrode
assembly.
In another aspect, the present disclosure is directed to a
method for systemic treatment of at least one condition associated with
pain, neuropathic pain, acute pain, chronic pain, or cancer pain. The
method includes contacting a location on a biological interface with an
iontophoretic drug delivery device that includes an active electrode
assembly having at least one active agent reservoir. The at least one active
agent reservoir includes a pharmaceutical composition including at least a
therapeutically effective amount of at least one opioid agonist and at least
one opioid antagonist.
The method further includes applying a sufficient amount of
current to the active electrode assembly for transdermally administering a
therapeutically effective amount of the pharmaceutical composition
comprising the therapeutically effective amount of the at least one opioid
agonist and the at least one opioid antagonist.
In another aspect, the present disclosure is directed to a
method of treating opiate dependency and/or eliciting a substantially opiate
free state in a subject in need thereof. The method includes contacting a
location on a biological interface of the subject with an iontophoretic drug
delivery operable for iontophoretically delivering a pharmaceutical
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composition comprising a therapeutically effective amount of at least one
opioid antagonist. The method further includes transdermally delivering a
therapeutically effective amount of the pharmaceutical composition
comprising the therapeutically effective amount of the least one opioid
antagonist.
In another aspect, the present disclosure is directed to a
method of inducing anesthesia, analgesia, or anti-hyperalgesia in a subject.
The method includes positioning an active electrode and a counter electrode
of an iontophoretic delivery device on a biological interface of the subject.
In
some embodiments, the iontophoretic drug delivery device is operable for
iontophoretically delivering a pharmaceutical composition comprising an
effective amount of at least one opioid agonist and at least one opioid
antagonist. The method further includes iontophoretically delivering an
anesthesia inducing, an analgesia inducing, or an anti-hyperalgesia inducing
synergistic amount of a pharmaceutical composition comprising at least one
opioid agonist and at least one opioid antagonist.
In yet another aspect, the present disclosure is directed to a
method of treating opiate agonist-induced narcotic/respiratory depression in
a subject in need thereof. The method includes contacting a location on a
biological interface of the subject with an iontophoretic drug delivery device
operable for iontophoretically delivering a pharmaceutical composition
comprising a therapeutically effective amount of at least one opioid
antagonist. The method further includes transdermally delivering a
therapeutically effective amount of the pharmaceutical composition
comprising the therapeutically effective amount of the least one opioid
antagonist.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
In the drawings, identical reference numbers identify similar
elements or acts. The sizes and relative positions of elements in the
drawings are not necessarily drawn to scale. For example, the shapes of
various elements and angles are not drawn to scale, and some of these
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elements are arbitrarily enlarged and positioned to improve drawing
legibility. Further, the particular shapes of the elements as drawn, are not
intended to convey any information regarding the actual shape of the
particular elements, and have been solely selected for ease of recognition in
the drawings.
Figure 1A is a top, front view of a transdermal drug delivery
system according to one illustrated embodiment.
Figure 1 B is a top, plan view of a transdermal drug delivery
system according to one illustrated embodiment.
Figure 2A is a schematic diagram of the iontophoresis device
of Figures 1A and 1 B comprising an active and counter electrode
assemblies according to one illustrated embodiment.
Figure 2B is a schematic diagram of the iontophoresis device
of Figure 2A positioned on a biological interface, with an optional outer
release liner removed to expose the active agent, according to another
illustrated embodiment.
Figure 2C is a schematic diagram of the iontophoresis device
comprising an active and counter electrode assemblies and a plurality of
microneedles according to one illustrated embodiment.
Figure 3A is a bottom, front view of a plurality of microneedles
in the form of an array according to one illustrated embodiment.
Figure 3B is a bottom, front view of a plurality of microneedles
in the form of one or more arrays according to another illustrated
embodiment.
Figure 4 is a flow diagram of a method for systemic treatment
of at least one condition associated with pain, neuropathic pain, acute pain,
chronic pain, or cancer pain according to one illustrated embodiment.
Figure 5 is a flow diagram of a method of inducing anesthesia,
analgesia, or anti-hyperalgesia in a subject according to one illustrated
embodiment.
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Figure 6 is a flow diagram of a method of treating opiate
dependency and/or eliciting a substantially opiate free state in a subject in
need thereof according to one illustrated embodiment.
Figure 7 is a flow diagram of a method of treating opiate
agonist-induced narcotic/respiratory depression in a subject in need thereof
according to one illustrated embodiment.
Figure 8 is a Time (min) vs. Drug Transported (pg) plot for
hydrorryorphone delivery across human skin according to one illustrated
embodiment.
Figure 9 is a mass spectrum plot for hydromorphone in serum
according to one illustrated embodiment.
Figure 10 is a Time (min) vs. Hydromorphone (ng/ml) plot
showing hydromorphone levels in test animals following iontophoretic
delivery according to one illustrated embodiment.
DETAILED DESCRIPTION
In the following description, certain specific details are
included to provide a thorough understanding of various disclosed
embodiments. One skilled in the relevant art, however, will recognize that
embodiments may be practiced without one or more of these specific
details, or with other methods, components, materials, etc. In other
instances, well-known structures associated with iontophoresis devices
including but not limited to voltage and/or current regulators have not been
shown or described in detail to avoid unnecessarily obscuring descriptions
of the embodiments.
Unless the context requires otherwise, throughout the
specification and claims which follow, the word "comprise" and variations
thereof, such as, "comprises" and "comprising" are to be construed in an
open, inclusive sense, that is as "including, but not limited to."
Reference throughout this specification to "one embodiment,"
or "an embodiment," or "in another embodiment" means that a particular
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referent feature, structure, or characteristic described in connection with
the
embodiment is included in at least one embodiment. Thus, the appearance
of the phrases "in one embodiment," or "in an embodiment," or "in another
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, the
particular features, structures, or characteristics may be combined in any
suitable manner in one or more embodiments.
It should be noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and "the" include plural
referents unless the content clearly dictates otherwise. Thus, for example,
reference to an iontophoresis device including "an electrode element"
includes a single electrode element, or two or more electrode elements. It
should also be noted that the term "or" is generally employed in its sense
including "and/or" unless the content clearly dictates otherwise.
As used herein the term "membrane" means a boundary, a
layer, barrier, or material, which may, or may not be permeable. The term
"membrane" may further refer to an interface. Unless specified otherwise,
membranes may take the form a solid, liquid, or gel, and may or may not
have a distinct lattice, non cross-linked structure, or cross-linked
structure.
As used herein the term "ion selective membrane" means a
membrane that is substantially selective to ions, passing certain ions while
blocking passage of other ions. An ion selective membrane, for example,
may take the form of a charge selective membrane, or may take the form of
a semi-permeable membrane.
As used herein the term "charge selective membrane" means
a membrane that substantially passes and/or substantially blocks ions
based primarily on the polarity or charge carried by the ion. Charge
selective membranes are typically referred to as ion exchange membranes,
and these terms are used interchangeabiy herein and in the claims. Charge
selective or ion exchange membranes may take the form of a cation
exchange membrane, an anion exchange membrane, and/or a bipolar
membrane. A cation exchange membrane substantially permits the
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passage of cations and substantially blocks anions. Examples of
commercially available cation exchange membranes include those available
under the designators NEOSEPTA, CM-1, CM-2, CMX, CMS, and CMB
from Tokuyama Co., Ltd. Conversely, an anion exchange membrane
substantially permits the passage of anions and substantially blocks cations.
Examples of commercially available anion exchange membranes include
those available under the designators NEOSEPTA, AM-1, AM-3, AMX,
AHA, ACH, and ACS also from Tokuyama Co., Ltd.
As used herein and in the claims, the term "bipolar membrane"
means a membrane that is selective to two different charges or polarities.
Unless specified otherwise, a bipolar membrane may take the form of a
unitary membrane structure, a multiple membrane structure, or a laminate.
The unitary membrane structure may include a first portion including cation
ion exchange materials or groups and a second portion opposed to the first
portion, including anion ion exchange materials or groups. The multiple
membrane structure (e.g., two film structure) may include a cation exchange
membrane laminated or otherwise coupled to an anion exchange
membrane. The cation and anion exchange membranes initially start as
distinct structures, and may or may not retain their distinctiveness in the
structure of the resulting bipolar membrane.
As used herein and in the claims, the term "semi-permeable
membrane" means a membrane that is substantially selective based on a
size or molecular weight of the ion. Thus, a semi-permeable membrane
substantially passes ions of a first molecular weight or size, while
substantially blocking passage of ions of a second molecular weight or size,
greater than the first molecular weight or size. In some embodiments, a
semi-permeable membrane may permit the passage of some molecules at a
first rate, and some other molecules at a second rate different from the
first.
In yet further embodiments, the "semi-permeable membrane" may take the
form of a selectively permeable membrane allowing only certain selective
molecules to pass through it.
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As used herein and in the claims, the term "porous membrane"
means a membrane that is not substantially selective with respect to ions at
issue. For example, a porous membrane is one that is not substantially
selective based on polarity, and not substantially selective based on the
molecular weight or size of a subject element or compound.
As used herein and in the claims, the term "gel matrix" means
a type of reservoir, which takes the form of a three dimensional network, a
colloidal suspension of a liquid in a solid, a semi-solid, a cross-linked gel,
a
non cross-linked gel, a jelly-like state, and the like. In some embodiments,
the gel matrix may result from a three dimensional network of entangled
macromolecules (e.g., cylindrical micelles). In some embodiments, a gel
matrix may include hydrogels, organogels, and the like. Hydrogels refer to
three-dimensional network of, for example, cross-linked hydrophilic
polymers in the form of a gel and substantially composed of water.
Hydrogels may have a net positive or negative charge, or may be neutral.
As used herein and in the claims, the term "reservoir" means
any form of mechanism to retain an element, compound, pharmaceutical
composition, active agent, and the like, in a liquid state, solid state,
gaseous
state, mixed state and/or transitional state. For example, unless specified
otherwise, a reservoir may include one or more cavities formed by a
structure, and may include one or more ion exchange membranes, semi-
permeable membranes, porous membranes and/or gels if such are capable
of at least temporarily retaining an element or compound. Typically, a
reservoir serves to retain a biologically active agent prior to the discharge
of
such agent by electromotive force and/or current into the biological
interface. A reservoir may also retain an electrolyte solution.
As used herein and in the claims, the term "active agent"
refers to a compound, molecule, or treatment that elicits a biological
response from any host, animal, vertebrate, or invertebrate, including for
example fish, mammals, amphibians, reptiles, birds, and humans.
Examples of active agents include therapeutic agents, pharmaceutical
agents, pharmaceuticals (e.g., a drug, a therapeutic compound,
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pharmaceutical salts, and the like) non-pharmaceuticals (e.g., cosmetic
substance, and the like), a vaccine, an immunological agent, a local or
general anesthetic or painkiller, an antigen or a protein or peptide such as
insulin, a chemotherapy agent, an anti-tumor agent.
In some embodiments, the term "active agent" further refers to
the active agent, as well as its pharmacologically active salts,
pharmaceutically acceptable salts, prodrugs, metabolites, analogs, and the
like. In some further embodiment, the active agent includes at least one
ionic, cationic, ionizeable, and/or neutral therapeutic drug and/or
pharmaceutical acceptable salts thereof. In yet other embodiments, the
active agent may include one or more "cationic active agents" that are
positively charged, and/or are capable of forming positive charges in
aqueous media. For example, many biologically active agents have
functional groups that are readily convertible to a positive ion or can
dissociate into a positively charged ion and a counter ion in an aqueous
medium. Other active agents may be polarized or polarizable, that is
exhibiting a polarity at one portion relative to another portion. For
instance,
an active agent having an amino group can typically take the form an
ammonium salt in solid state and dissociates into a free ammonium ion
(NH4+) in an aqueous medium of appropriate pH.
The term "active agent" may also refer to electrically neutral
agents, molecules, or compounds capable of being delivered via electro-
osmotic flow. The electrically neutral agents are typically carried by the
flow
of, for example, a solvent during electrophoresis. Selection of the suitable
active agents is therefore within the knowledge of one skilled in the relevant
art.
In some embodiments, one or more active agents may be
selected from analgesics, anesthetics, anesthetics vaccines, antibiotics,
adjuvants, immunological adjuvants, immunogens, tolerogens, allergens,
toll-like receptor agonists, toll-like receptor antagonists, immuno-adjuvants,
immuno-modulators, immuno-response agents, immuno-stimulators,
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specific immuno-stimulators, non-specific immuno-stimulators, and immuno-
suppressants, or combinations thereof.
Non-limiting examples of such active agents include lidocaine,
articaine, and others of the -caine class; morphine, hydromorphone,
fentanyl, oxycodone, hydrocodone, buprenorphine, methadone, and similar
opioid agonists; sumatriptan succinate, zolmitriptan, naratriptan HCI,
rizatriptan benzoate, almotriptan malate, frovatriptan succinate and other 5-
hydroxytryptaminel receptor subtype agonists; resiquimod, imiquidmod, and
similar TLR 7 and 8 agonists and antagonists; domperidone, granisetron
hydrochloride, ondansetron and such anti-emetic drugs; zolpidem tartrate
and similar sleep inducing agents; L-dopa and other anti-Parkinson's
medications; aripiprazole, olanzapine, quetiapine, risperidone, clozapine,
and ziprasidone, as well as other neuroleptica; diabetes drugs such as
exenatide; as well as peptides and proteins for treatment of obesity and
other maladies.
Further non-limiting examples of anesthetic active agents or
pain killers include ambucaine, amethocaine, isobutyl p-aminobenzoate,
amolanone, amoxecaine, amylocaine, aptocaine, azacaine, bencaine,
benoxinate, benzocaine, N,N-dimethylalanylbenzocaine, N,N-
dimethylglycylbenzocaine, glycylbenzocaine, beta-adrenoceptor antagonists
betoxycaine, bumecaine, bupivicaine, levobupivicaine, butacaine,
butamben, butanilicaine, butethamine, butoxycaine, metabutoxycaine,
carbizocaine, carticaine, centbucridine, cepacaine, cetacaine,
chloroprocaine, cocaethylene, cocaine, pseudococaine, cyclomethycaine,
dibucaine, dimethisoquin, dimethocaine, diperodon, dyclonine, ecognine,
ecogonidine, ethyl aminobenzoate, etidocaine, euprocin, fenalcomine,
fomocaine, heptacaine, hexacaine, hexocaine, hexyicaine, ketocaine,
leucinocaine, levoxadrol, lignocaine, lotucaine, marcaine, mepivacaine,
metacaine, methyl chloride, myrtecaine, naepaine, octacaine, orthocaine,
oxethazaine, parenthoxycaine, pentacaine, phenacine, phenol, piperocaine,
piridocaine, polidocanol, polycaine, prilocaine, pramoxine, procaine
(Novocaine ), hydroxyprocaine, propanocaine, proparacaine, propipocaine,
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propoxycaine, pyrrocaine, quatacaine, rhinocaine, risocaine, rodocaine,
ropivacaine, salicyl alcohol, tetracaine, hydroxytetracaine, tolycaine,
trapencaine, tricaine, trimecaine tropacocaine, zolamine, a pharmaceutically
acceptable salt thereof, and mixtures thereof.
As used herein and in the claims, the.term "subject" generally
refers to any host, animal, vertebrate, or invertebrate, and includes fish,
mammals, amphibians, reptiles, birds, and particularly humans.
As used herein and in the claims, the term "agonist" refers to a
compound that can combine with a receptor (e.g., an opioid receptor, Toll-
like receptor, and the like) to produce a cellular response. An agonist may
be a ligand that directly binds to the receptor. Alternatively, an agonist may
combine with a receptor indirectly by forming a complex with another
molecule that directly binds the receptor, or otherwise resulting in the
modification of a compound so that it directly binds to the receptor.
As used herein and in the claims, the term "antagonist" refers
to a compound that can combine with a receptor (e.g., an opioid receptor, a
Toll-like receptor, and the like) to inhibit a cellular response. An
antagonist
may be a ligand that directly binds to the receptor. Aiternatively, an
antagonist may combine with a receptor indirectly by forming a complex with
another molecule that directly binds to the receptor, or otherwise results in
the modification of a compound so that it directly binds to the receptor.
As used herein and in the claims, the term "effective amount"
or "therapeutically effective amount" includes an amount effective at
dosages and for periods of time necessary, to achieve the desired result.
The effective amount of a composition containing a pharmaceutical agent
may vary according to factors such as the disease state, age, gender, and
weight of the subject.
As used herein and in the claims, the term "analgesic" refers to
an agent that lessens, alleviates, reduces, relieves, or extinguishes a neural
sensation in an area of a subject's body. In some embodiments, the neural
sensation relates to pain, in other aspects the neural sensation relates to
discomfort, itching, burning, irritation, tingling, "crawling," tension,
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temperature fluctuations (such as fever), inflammation, aching, or other
neural sensations.
As used herein and in the claims, the term "anesthetic" refers
to an agent that produces a reversible loss of sensation in an area of a
subject's body. In some embodiments, the anesthetic is considered to be a
"local anesthetic" in that it produces a loss of sensation only in one
particular
area of a subject's body.
As one skilled in the relevant art would recognize, some
agents may act as both an analgesic and an anesthetic, depending on the
circumstances and other variables including but not limited to dosage,
method of delivery, medical condition or treatment, and an individual
subject's genetic makeup. Additionally, agents that are typically used for
other purposes may possess local anesthetic or membrane stabilizing
properties under certain circumstances or under particular conditions.
As used herein and in the claims, the term "immunogen" refers
to any agent that elicits an immune response. Examples of an immunogen
include, but are not limited to natural or synthetic (including modified)
peptides, proteins, lipids, oligonucleotides (RNA, DNA, etc.), chemicals, or
other agents.
As used herein and in the claims, the term "allergen" refers to
any agent that elicits an allergic response. Some examples of allergens
include but are not limited to chemicals and plants, drugs (such as
antibiotics, serums), foods (such as milk, wheat, eggs, etc), bacteria,
viruses, other parasites, inhalants (dust, pollen, perfume, smoke), and/or
physical agents (heat, light, friction, radiation). As used herein, an
allergen
may be an immunogen.
As used herein and in the claims, the term "adjuvant" and any
derivations thereof, refers to an agent that modifies the effect of another
agent while having few, if any, direct effect when given by itself. For
example, an adjuvant may increase the potency or efficacy of a
pharmaceutical, or an adjuvant may alter or affect an immune response.
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As used herein and in the claims, the term "opioid" generally
refers to any agent that binds to and/or interacts with opioid receptors.
Among the opioid classes examples include endogenous opioid peptides,
opium alkaloids (e.g., morphine, codeine, and the like), semi-synthetic
opioids (e.g., heroin, oxycodone and the like), synthetic opioids (e.g.,
buprenorphinemeperidine, fentanyl, morphinan, benzomorphan derivatives,
and the like), as well as opioids that have structures unrelated to the opium
alkaioids (e.g., pethidine, methadone, and the like).
As used herein and in the claims, the terms "vehicle," "carrier,"
"pharmaceutically vehicle," "pharmaceutically carrier," "pharmaceutically
acceptable vehicle," or "pharmaceutically acceptable carrier" may be used
interchangeably, and refer to pharmaceutically acceptable solid or liquid,
diluting or encapsulating, filling or carrying agents, which are usually
employed in pharmaceutical industry for making pharmaceutical
compositions. Examples of vehicles include any liquid, gel, salve, cream,
solvent, diluent, fluid ointment base, vesicle, liposomes, nisomes,
ethasomes, transfersomes, virosomes, non ionic surfactant vesicles,
phospholipid surfactant vesicles, micelle, and the like, that is suitable for
use
in contacting a subject.
In some embodiments, the pharmaceutical vehicle may refer
to a composition that includes and/or delivers a pharmacologically active
agent, but is generally considered to be otherwise pharmacologically
inactive. In some other embodiments, the pharmaceutical vehicle may have
some therapeutic effect when applied to a site such as a mucous membrane
or skin, by providing, for example, protection to the site of application from
conditions such as injury, further injury, or exposure to elements.
Accordingly, in some embodiments, the pharmaceutical vehicle may be
used for protection without a pharmacological agent in the formulation.
The headings provided herein are for convenience only and do
not interpret the scope or meaning of the embodiments.
Figures 1A and 1 B show an exemplary iontophoretic drug
delivery system 6 for delivering of one or more active agents to a subject.
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The system 6 includes an iontophoresis device 8 including active and
counter electrode assemblies 12, 14, respectively, and a power source 16.
The active and counter electrode assemblies 12, 14, are electrically
coupleable to the power source 16 to supply an active agent contained in
the active electrode assembly 12, via iontophoresis, to a biological interface
18 (e.g., a portion of skin or mucous membrane). The iontophoresis device
8 may optionally include a biocompatible backing 19. In some
embodiments, the biocompatible backing 19 encases the iontophoresis
devices 8. In some other embodiments, the biocompatible backing 19
physically couples the iontophoresis device 8 to the biological interface 18
of
the subject. In some embodiments, the system 6 is configured for providing
transdermal delivery of one or more therapeutic active agents to a biological
interface of a subject and inducing analgesia or aesthesia in the subject for
a limited period of time.
As shown in Figures 2A and 2B, the active electrode assembly
12 may further comprise, from an interior 20 to an exterior 22 of the active
electrode assembly 12: an active electrode element 24, an electrolyte
reservoir 26 storing an electrolyte 28, an inner ion selective membrane 30,
one or more inner active agent reservoirs 34, storing one or more active
agents 36, an optional outermost ion selective membrane 38 that optionally
caches additional active agents 40, and an optional further active agent 42
carried by an outer surface 44 of the outermost ion selective membrane 38.
The active electrode assembly 12 may further comprise an optional outer
release liner 46.
In some embodiments, the one or more active agent reservoirs
34 are loadable with a vehicle and/or pharmaceutical composition for
transporting, delivering, encapsulating, and/or carrying the one or more
active agents 36, 40, 42. In some embodiments, at least one active agent
reservoir 34 includes a pharmaceutical composition for inducing analgesia
or anesthesia in the subject. The pharmaceutical composition for inducing
analgesia or anesthesia in the subject may include at least one analgesic or
anesthetic active agent in combination with at least one opioid antagonist.
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In some embodiments the pharmaceutical composition includes at least a
therapeutically effective one or more active agents 36, 40, 42 selected from
one or more opioid agonist. In some embodiments, the pharmaceutical
composition includes at least a therapeutically effective one or more active
agents 36, 40, 42 selected from one or more opioid antagonist. In yet some
further embodiments, the pharmaceutical composition includes a
therapeutically effective amount of at least one opioid agonist and at least
one opioid antagonist.
The at least one opioid agonist may be selected from
endogenous opioid peptides, opium alkaloids, semi-synthetic opioids, and
fully synthetic opioids, or analogs or derivatives, or pharmaceutically
acceptable salts or solvates thereof. In some embodiments, the at least one
opioid agonist is selected from (5a,7a,8[i-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-
1-
oxaspiro(4, 5)dec-8-yl]-benzene-acetamide (U69,593)), [D-AIa2,N-Me-
Phe4,Gly5-ol]enkephalin (DAMGO), delta-([D-Pen2,D-Pen5]-enkephalin
(DPDPE)), buprenorphine, codeine, dextromoramide, dihydrocodeine,
fentanyl, heroin, hydrocodone, hydromorphone, meperidine, methadone,
morphine, nicomorphine, opium, oxycodone, oxymorphone, pentazocine,
pethidine, propoxyphene, and tilidine, or analogs or derivatives, or
pharmaceutically acceptable salts or solvates thereof.
The at least one opioid antagonist may be selected from [(-)-
(1 R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorphan]
(MR2266), [aIIyI]2-tyr-alpha-amino-isobutyric acid (Aib)-Aib-Phe-Leu-OH
(ICI-174864), 4-(3-hydroxyphenyl)-34-dimethyl-alpha-phenyl-1-
piperidinepropanol (LY117413), 6(3-Naltrexol, 7-Benzylidenenaltrexone
(BNTX), b-funaltrexamine (b-FNA), cyclazocine, cyclorphan, dezocine,
diprenorphine, levorphanol, meptazinol, methiodide, methyinaltrexone,
nalide, nalmefene, nalmexone, nalorphine, nalorphine dinicotinate,
naloxonazine, naloxone, naltrexone, naltriben (NTB), naltrindole (NTI),
naltrindole isothiocyanate (NTII), N-cyclopropylmethyl-4,14-dimethoxy-
morphinan-6-one (cyprodime), nor-binaltorphimine (nor-BNI), oxilorphan,
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nalbuphine, and trans-3,4-dimethyl-4-phenylpiperides, or analogs or
derivatives, or pharmaceutically acceptable salts or solvates thereof.
In some embodiments, the at least one opioid antagonist is
selected from hydromorphone, or analogs or derivatives, or
pharmaceutically acceptable salts or solvates thereof; and the at least one
opioid antagonist is selected from naloxone, naltrexone, nalmefene,
naloxonazine, NTI, nor-BNI, LY25506, LY9935, LY255582, and LY117413,
or analogs or derivatives, or pharmaceutically acceptable salts or solvates
thereof.
In some embodiments, the at least one opioid antagonist is
selected from hydromorphone, or analogs or derivatives, or
pharmaceutically acceptable salts or solvates thereof; and the at least one
opioid antagonist is selected from naloxone, naltrexone, 6p-naltrexol,
nalmefene, and naloxonazine, or analogs or derivatives, or pharmaceutically
acceptable salts or solvates thereof. In some embodiments, the at least one
opioid antagonist is selected from palladone, Palladone SR, Dilaudid and
hydromorphone hydrochloride; and the at least one opioid antagonist is
selected from Narcan , Trexan , Revex@, Nubian , nalaxone
hydrochloride, naltrexone hydrochloride, nalmefene hydrochloride, and
nulbuphine hydrochloride. In some embodiments, the least one opioid
agonist and at least one opioid antagonist are present in synergistic anti-
hyperalgesic effective amounts.
The pharmaceutical composition may further comprises at
least one active agent selected from vaccines, antibiotics, adjuvants,
immunological adjuvants, immunogens, tolerogens, allergens, toll-like
receptor agonists, and toll-like receptor antagonists, immuno-adjuvants,
immuno-modulators, immuno-response agents, immuno-stimulators,
specific immuno-stimulators, non-specific immuno-stimulators, and immuno-
suppressants, or combinations thereof.
In some embodiments, the pharmaceutical composition may
include a therapeutically effective amount of at least one opioid agonist, at
least one opioid antagonist, and at least one active agent selected from an
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antihistamine drug, a vasoconstrictor drug (e.g., epinephrine, adrenaline,
norepinephrine, and the like), a steroid, and the like.
The pharmaceutical composition may be useful for systemic
treatment of at least one condition associated with pain, neuropathic pain,
acute pain, chronic pain, or cancer pain. In some embodiments, the at least
one condition associated with pain, neuropathic pain, acute pain, chronic
pain, or cancer pain includes cancer; chemotherapy; alcoholism;
amputation; a back, leg, or hip problem; diabetes; a facial nerve problem; an
HIV infection or AIDS; multiple sclerosis; spinal surgery; opiate induced
narcotic/respiratory depression; or detoxification of opiate-dependency.
The onset of acute pain brought on by, for example, injury to a
tissue typically results from the stimulation of special nerve endings called
nociceptors. The nociceptors respond to a variety of stimuli including burns,
cuts, infection, chemical changes, pressure, and many other sensations that
are interpreted as pain by a biological subject. By eliminating the cause of
such nociceptive pain and allowing the healing process to commence, the
tenderness and pain associated with the injury or other stimulus typically
dissipates. Although neuropathic pain is certainly real, the cause may be
difficult to determine.
Neuropathic pain is often described as shooting, stabbing,
burning or searing. As used herein and in the appended claims, such pain
is termed "neuropathic pain." Conditions with which neuropathic pain may
be commonly associated include, but are not limited to, shingles (herpes
zoster virus infection; post-herpetic pain); cancer; chemotherapy;
alcoholism; amputation (e.g., phantom limb syndrome); back, leg, and hip
problems (sciatica); diabetes; facial nerve problems (trigeminal neuralgia);
HIV infection or AIDS; multiple sclerosis; and spinal surgery. Chronic pain
may also occur without any know injury or disease. For example, subjects
may experience pain with no obvious injury or other stimulus. In some other
cases, subjects may experience chronic pain that persist for prolong periods
including months, years, or even decades. Such pain predominantly results
from damage within the peripheral or central nervous system.
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Although the cause of neuropathic pain may be unknown, or
uncontrollable, in one disclosed embodiment a treatment may include
chronic ongoing administration of drugs or other active agents that
ameliorate the pain, such as analgesic active agents, anesthetic active
agents and/or painkillers. Such drugs or other active agents may be
administered passively by application of one or more devices 8 to a
biological interface 18 (e.g., skin or mucous membrane) at or near areas
where a subject is experiencing neuropathic pain. Once the device 8 is in
contact with the biological interface 18, the one or more agents are
deliverable from the device 8 onto or into the biological interface 18 to
exert
its effect in alleviating the pain. Alternatively, one or more agents may
advantageously be actively administered by a device 8 through a biological
interface 18 and tissue into the systemic circulation. Accordingly, the agent
may exert its therapeutic effect locally and more broadly. In one
embodiment, for example, one or more active agents are administered
through area portion of a biological interface from which they may enter the
blood stream and be carried systemically into a capillary bed or other
vasculature of an area experiencing pain (e.g., neuropathic pain and the
like). In certain embodiments, the device for active administration of an
anesthetic or painkiller is an iontophoretic device, as described in detail
herein.
As used herein and in the appended claims, "systemic
circulation" typically refers to movement of blood through the portion of a
cardiovascular system and/or circulatory system that carries oxygenated
blood from the heart to the body and oxygen-depleted blood from the body
back to the heart. Within this portion of the cardiovascular system, blood
may flow through vessels that include, but are not necessarily limited to,
arteries, arterioles, capillaries, venuies, and veins. Systemic circulation,
as
used herein and in the claims, may also refer to movement of fluids through
a lymphatic system, which collects lymph from tissues and returns it to the
cardiovascular circulatory system. Lymph typically originates from blood
plasma that leaks from the cardiovascular system into spaces within tissue.
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"Systemic delivery", as used herein and in the claims, refers to movement of
compounds, such as active agents, from one location to another via
systemic circulation.
Referring to Figures 2A and 2B, the active electrode assembly
12 of the iontophoretic delivery device 8 may further comprise an optional
inner sealing liner (not shown) between two layers of the active electrode
assembly 12, for example, between the inner ion selective membrane 30
and the inner.active agent reservoir 34. The inner sealing liner, if present,
would be removed prior to application of the iontophoretic device to the
biological surface 18. Each of the above elements or structures will be
discussed in detail below.
In some embodiments, the system 6 takes the form of a self-
contained iontophoretic drug delivery system. The system 6 includes at
least one active agent reservoir 34, an active electrode assembly 12
including at least one active electrode element 24, and a power source 16.
The at least one active agent reservoir 34 includes a pharmaceutical
composition for inducing analgesia or anesthesia in the subject. The
pharmaceutical composition for inducing analgesia or anesthesia in the
subject may include at least one analgesic or anesthetic active agent in
combination with at least one opioid antagonist.
The active electrode element 24 is electrically coupled to a first
pole 16a of the power source 16 and positioned in the active electrode
assembly 12 to apply an electromotive force to transport the active agent
36, 40, 42 via various other components of the active electrode assembly
12. Under ordinary use conditions, the magnitude of the applied
electromotive force is generally that required to deliver the one or more
active agents according to a therapeutic effective dosage protocol. In some
embodiments, the magnitude is selected such that it meets or exceeds the
ordinary use operating electrochemical potential of the iontophoresis
delivery device 8. The at least one active electrode element 24 is operable
to provide an electromotive force for driving the pharmaceutical composition
(comprising the at least one analgesic or anesthetic active agent in
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combination with the at least one opioid antagonist) for inducing analgesia
or anesthesia in the subject from the at least one active agent reservoir 34,
to the biological interface 18 of the subject.
The active electrode element 24 may take a variety of forms.
In one embodiment, the active electrode element 24 may advantageously
take the form of a carbon-based active electrode element. Such may, for
example, comprise muitiple layers, for example a polymer matrix comprising
carbon and a conductive sheet comprising carbon fiber or carbon fiber
paper, such as that described in commonly assigned pending Japanese
patent application 2004/317317, filed October 29, 2004. The carbon-based
electrodes are inert electrodes in that they do not themselves undergo or
participate in electrochemical reactions. Thus, an inert electrode distributes
current through the oxidation or reduction of a chemical species capable of
accepting or donating an electron at the potential applied to the system,
(e.g., generating ions by either reduction or oxidation of water). Additional
examples of inert electrodes include stainless steel, gold, platinum,
capacitive carbon, or graphite.
Alternatively, an active electrode of sacrificial conductive
material, such as a chemical compound or amalgam, may also be used. A
sacrificial electrode does not cause electrolysis of water, but would itself
be
oxidized or reduced. Typically, for an anode a metal/metal salt may be
employed. In such case, the metal would oxidize to metal ions, which would
then be precipitated as an insoluble salt. An example of such anode
includes an Ag/AgCl electrode. The reverse reaction takes place at the
cathode in which the metal ion is reduced and the corresponding anion is
released from the surface of the electrode.
The electrolyte reservoir 26 may take a variety of forms
including any structure capable of retaining electrolyte 28, and in some
embodiments may even be the electrolyte 28 itself, for example, where the
electrolyte 28 is in a gel, semi-solid or solid form. For example, the
electrolyte reservoir 26 may take the form of a pouch or other receptacle, a
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membrane with pores, cavities, or interstices, particularly where the
electrolyte 28 is a liquid.
In one embodiment, the electrolyte 28 comprises ionic or
ionizable components in an aqueous medium, which can act to conduct
current towards or away from the active electrode element. Suitable
electrolytes include, for example, aqueous solutions of salts. Preferably, the
electrolyte 28 includes salts of physiological ions, such as, sodium,
potassium, chloride, and phosphate. In some embodiments, the one or
more electrolyte reservoirs 24 including an electrolyte 28 comprising at least
one biologically compatible anti-oxidant selected from ascorbate, fumarate,
lactate, and malate, or salts thereof.
Once an electrical potential is applied, when an inert electrode
element is in use, water is electrolyzed at both the active and counter
electrode assemblies. In certain embodiments, such as when the active
electrode assembly is an anode, water is oxidized. As a result, oxygen is
removed from water while protons (H+) are produced. In one embodiment,
the electrolyte 28 may further comprise an anti-oxidant. In some
embodiments, the anti-oxidant is selected from anti-oxidants that have a
lower potential than that of, for example, water. In such embodiments, the
selected anti-oxidant is consumed rather than having the hydrolysis of water
occur. In some further embodiments, an oxidized form of the anti-oxidant is
used at the cathode and a reduced form of the anti-oxidant is used at the
anode. Examples of biologically compatible anti-oxidants include, but are
not limited to, ascorbic acid (vitamin C), tocopherol (vitamin E), or sodium
citrate.
As noted above, the electrolyte 28 may take the form of an
aqueous solution housed within a reservoir 26, or in the form of a dispersion
in a hydrogel or hydrophilic polymer capable of retaining substantial amount
of water. For instance, a suitable electrolyte may take the form of a solution
of 0.5 M disodium fumarate: 0.5 M polyacrylic acid: 0.15 M anti-oxidant.
The inner ion selective membrane 30 is generally positioned to
separate the electrolyte 28 and the inner active agent reservoir 34, if such a
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membrane is included within the device. The inner ion selective membrane
30 may take the form of a charge selective membrane. For example, when
the active agent 36, 40, 42 comprises a cationic active agent, the inner ion
selective membrane 30 may take the form of an anion exchange membrane,
selective to substantially pass anions and substantially block cations. The
inner ion selective membrane 30 may advantageously prevent transfer of
undesirable elements or compounds between the electrolyte 28 and the
inner active agent reservoir 34. For example, the inner ion selective
membrane 30 may prevent or inhibit the transfer of sodium (Na+) ions from
the electrolyte 28, thereby increasing the transfer rate and/or biological
compatibility of the iontophoresis device 8.
The inner active agent reservoir 34 is generally positioned
between the inner ion selective membrane 30 and the outermost ion
selective membrane 38. The inner active agent reservoir 34 may take a
variety of forms including any structure capable of temporarily retaining
active agent 36. For example, the inner active agent reservoir 34 may take
the form of a pouch or other receptacle, a membrane with pores, cavities, or
interstices, particularly where the active agent 36 is a liquid. The inner
active agent reservoir 34 further may comprise a gel matrix.
Optionally, an outermost ion selective membrane 38 is
positioned generally opposed across the active electrode assembly 12 from
the active electrode element 24. The outermost membrane 38 may, as in
the embodiment illustrated in Figures 2A and 2B, take the form of an ion
exchange membrane having pores 48 (only one called out in Figures 2A
and 2B for sake of clarity of illustration) of the ion selective membrane 38
including ion exchange material or groups 50 (only three called out in
Figures 2A and 2B for sake of clarity of illustration). Under the influence of
an electromotive force or current, the ion exchange material or groups 50
selectively substantially passes ions of the same polarity as active agent 36,
40, while substantially blocking ions of the opposite polarity. Thus, the
outermost ion exchange membrane 38 is charge selective. Where the
active agent 36, 40, 42 is a cation (e.g., lidocaine), the outermost ion
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selective membrane 38 may take the form of a cation exchange membrane,
thus allowing the passage of the cationic active agent while blocking the
back flux of the anions present in the biological interface, such as skin.
The outermost ion selective membrane 38 may optionally
cache active agent 40. Without being limited by theory, the ion exchange
groups or material 50 temporarily retains ions of the same polarity as the
polarity of the active agent in the absence of electromotive force or current
and substantially releases those ions when replaced with substitutive ions of
like polarity or charge under the influence of an electromotive force or
current.
Alternatively, the outermost ion selective membrane 38 may
take the form of semi-permeable or microporous membrane which is
selective by size. In some embodiments, such a semi-permeable
membrane may advantageously cache active agent 40, for example by
employing the removably releasable outer release liner to retain the active
agent 40 until the outer release liner is removed prior to use.
The outermost ion selective membrane 38 may be optionally
preloaded with the additional active agent 40, such as ionized or ionizable
drugs or therapeutic agents and/or polarized or polarizable drugs or
therapeutic agents. Where the outermost ion selective membrane 38 is an
ion exchange membrane, a substantial amount of active agent 40 may bond
to ion exchange groups 50 in the pores, cavities or interstices 48 of the
outermost ion selective membrane 38.
The active agent 42 that fails to bond to the ion exchange
groups of material 50 may adhere to the outer surface 44 of the outermost
ion selective membrane 38 as the further active agent 42. Alternatively, or
additionally, the further active agent 42 may be positively deposited on
and/or adhered to at least a portion of the outer surface 44 of the outermost
ion selective membrane 38, for example, by spraying, flooding, coating,
electrostatically, vapor deposition, and/or otherwise. In some embodiments,
the further active agent 42 may sufficiently cover the outer surface 44 and/or
be of sufficient thickness to form a distinct layer 52. In other embodiments,
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the further active agent 42 may not be sufficient in volume, thickness, or
coverage as to constitute a layer in a conventional sense of such term.
The active agent 42 may be deposited in a variety of highly
concentrated forms such as, for example, solid form, nearly saturated
solution form, or gel form. If in solid form, a source of hydration may be
provided, either integrated into the active electrode assembly 12, or applied
from the exterior thereof just prior to use.
In some embodiments, the active agent 36, additional active
agent 40, and/or further active agent 42 may be identical or similar
compositions or elements. In other embodiments, the active agent 36,
additional active agent 40, and/or further active agent 42 may be different
compositions or elements from one another. Thus, a first type of active
agent may be stored in the inner active agent reservoir 34, while a second
type of active agent may be cached in the outermost ion selective
membrane 38. In such an embodiment, either the first type or the second
type of active agent may be deposited on the outer surface 44 of the
outermost ion selective membrane 38 as the further active agent 42.
Alternatively, a mix of the first and the second types of active agent may be
deposited on the outer surface 44 of the outermost ion selective membrane
38 as the further active agent 42. As a further alternative, a third type of
active agent composition or element may be deposited on the outer surface
44 of the outermost ion selective membrane 38 as the further active agent
42. In another embodiment, a first type of active agent may be stored in the
inner active agent reservoir 34 as the active agent 36 and cached in the
outermost ion selective membrane 38 as the additional active agent 40,
while a second type of active agent may be deposited on the outer surface
44 of the outermost ion selective membrane 38 as the further active agent
42. Typically, in embodiments where one or more different active agents
are employed, the active agents 36, 40, 42 will all be of common polarity to
prevent the active agents 36, 40, 42 from competing with one another.
Other combinations are possible.
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The outer release liner may generally be positioned overlying
or covering further active agent 42 carried by the outer surface 44 of the
outermost ion selective membrane 38. The outer release liner may protect
the further active agent 42 and/or outermost ion selective membrane 38
during storage, prior to application of an electromotive force or current. The
outer release liner may be a selectively releasable liner made of waterproof
material, such as release liners commonly associated with pressure
sensitive adhesives.
An interface-coupling medium (not shown) may be employed
between the electrode assembly and the biological interface 18. The
interface-coupling medium may take, for example, the form of an adhesive
and/or gel. The gel may take, for the form of a hydrating gel. Selection of
suitable bioadhesive gels is within the knowledge of one skilled in the
relevant art.
In the embodiment illustrated in Figures 2A and 2B, the
counter electrode assembly 14 comprises, from an interior 64 to an exterior
66 of the counter electrode assembly 14: a counter electrode element 68,
an electrolyte reservoir 70 storing an electrolyte 72, an inner ion selective
membrane 74, an optional buffer reservoir 76 storing buffer material 78, an
optional outermost ion selective membrane 80, and an optional outer
release liner (not shown).
The counter electrode element 68 is electrically coupled to a
second pole 16b of the power source 16, the second pole 16b having an
opposite polarity to the first pole 16a. In one embodiment, the counter
electrode element 68 is an inert electrode. For example, the counter
electrode element 68 may take the form of the carbon-based electrode
element discussed above.
The electrolyte reservoir 70 may take a variety of forms
including any structure capable of retaining electrolyte 72, and in some
embodiments may even be the electrolyte 72 itself, for example, where the
electrolyte 72 is in a gel, semi-solid or solid form. For example, the
electrolyte reservoir 70 may take the form of a pouch or other receptacle, or
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a membrane with pores, cavities, or interstices, particularly where the
electrolyte 72 is a liquid.
The electrolyte 72 is generally positioned between the counter
electrode element 68 and the outermost ion selective membrane 80,
proximate the counter electrode element 68. As described above, the
electrolyte 72 may provide ions or donate charges to prevent or inhibit the
formation of gas bubbles (e.g., hydrogen or oxygen, depending on the
polarity of the electrode) on the counter electrode element 68 and may
prevent or inhibit the formation of acids or bases or neutralize the same,
which may enhance efficiency and/or reduce the potential for irritation of the
biological interface 18.
The inner ion selective membrane 74 is positioned between
and/or to separate, the electrolyte 72 from the buffer material 78. The inner
ion selective membrane 74 may take the form of a charge selective
membrane, such as the illustrated ion exchange membrane that
substantially allows passage of ions of a first polarity or charge while
substantially blocking passage of ions or charge of a second, opposite
polarity. The inner ion selective membrane 74 will typically pass ions of
opposite polarity or charge to those passed by the outermost ion selective
membrane 80 while substantially blocking ions of like polarity or charge.
Alternatively, the inner ion selective membrane 74 may take the form of a
semi-permeable or microporous membrane that is selective based on size.
The inner ion selective membrane 74 may prevent transfer of
undesirable elements or compounds into the buffer material 78. For
example, the inner ion selective membrane 74 may prevent or inhibit the
transfer of hydroxy (OH-) or chloride (Cl-) ions from the electrolyte 72 into
the buffer material 78.
The optional buffer reservoir 76 is generally disposed between
the electrolyte reservoir and the outermost ion selective membrane 80. The
buffer reservoir 76 may take a variety of forms capable of temporarily
retaining the buffer material 78. For example, the buffer reservoir 76 may
take the form of a cavity, a porous membrane, or a gel. The buffer material
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78 may supply ions for transfer through the outermost ion selective
membrane 42 to the biological interface 18. Consequently, the buffer
material 78 may comprise, for example, a salt (e.g., NaCI).
The outermost ion selective membrane 80 of the counter
electrode assembly 14 may take a variety of forms. For example, the
outermost ion selective membrane 80 may take the form of a charge
selective ion exchange membrane. Typically, the outermost ion selective
membrane 80 of the counter electrode assembly 14 is selective to ions with
a charge or polarity opposite to that of the outermost ion selective
membrane 38 of the active electrode assembly 12. The outermost ion
selective membrane 80 is therefore an anion exchange membrane, which
substantially passes anions and blocks cations, thereby prevents the back
flux of the cations from the biological interface. Examples of suitable ion
exchange membranes include the previously discussed membranes.
Alternatively, the outermost ion selective membrane 80 may
take the form of a semi-permeable membrane that substantially passes
and/or blocks ions based on size or molecular weight of the ion.
The outer release liner (not shown) may generally be
positioned overlying or covering an outer surface 84 of the outermost ion
selective membrane 80. The outer release liner may protect the outermost
ion selective membrane 80 during storage, prior to application of an
electromotive force or current. The outer release liner may be a selectively
releasable liner made of waterproof material, such as release liners
commonly associated with pressure sensitive adhesives. In some
embodiments, the outer release liner may be coextensive with the outer
release liner (not shown) of the active electrode assembly 12.
The iontophoresis device 8 may further comprise an inert
molding material 86 adjacent exposed sides of the various other structures
forming the active and counter electrode assemblies 12, 14. The molding
material 86 may advantageously provide environmental protection to the
various structures of the active and counter electrode assemblies 12, 14.
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Enveloping the active and counter electrode assemblies 12, 14 is a housing
material 90.
As best seen in Figure 2B, the active and counter electrode
assemblies 12, 14 are positioned on the biological interface 18. Positioning
on the biological interface may close the circuit, allowing electromotive
force
to be applied and/or current to flow from one pole 16a of the power source
16 to the other pole 16b, via the active electrode assembly, biological
interface 18 and counter electrode assembly 14.
In use, the outermost active electrode ion selective membrane
38 may be placed directly in contact with the biological interface 18.
Alternatively, an interface-coupling medium (not shown) may be employed
between the outermost active electrode ion selective membrane 22 and the
biological interface 18. The interface-coupling medium may take, for
example, the form of an adhesive and/or gel. The gel may take, for
example, the form of a hydrating gel or a hydrogel. If used, the interface-
coupling medium should be permeable by the active agent 36, 40, 42.
In some embodiments, the power source 16 is selected to
provide sufficient voltage, current, and/or duration to ensure delivery of the
one or more active agents 36, 40, 42 from the reservoir 34 and across a
biological interface (e.g., a membrane) to impart the desired physiological
effect. The power source 16 may take the form of one or more chemical
battery cells, super- or ultra-capacitors, fuel cells, secondary cells, thin
film
secondary cells, button cells, lithium ion cells, zinc air cells, nickel metal
hydride cells, and the like. The power source 16 may, for example, provide
a voltage of 12.8 V DC, with tolerance of 0.8 V DC, and a current of 0.3 mA.
The power source 16 may be selectively, electrically coupled to the active
and counter electrode assemblies 12, 14 via a control circuit, for example,
via carbon fiber ribbons. The iontophoresis device 8 may include discrete
and/or integrated circuit elements to control the voltage, current, and/or
power delivered to the electrode assemblies 12, 14. For example, the
iontophoresis device 8 may include a diode to provide a constant current to
the electrode elements 24, 68.
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As suggested above, the one or more active agents 36, 40, 42
may take the form of one or more ionic, cationic, ionizeable, and/or neutral
drugs or other therapeutic agents. Consequently, the poles or terminals of
the power source 16 and the selectivity of the -outermost ion selective
membranes 38, 80 and inner ion selective membranes 30, 74 are selected
accordingly.
During iontophoresis, the electromotive force across the
electrode assemblies, as described, leads to a migration of charged active
agent molecules, as well as ions and other charged components, through
the biological interface into the biological tissue. This migration may lead
to
an accumulation of active agents, ions, and/or other charged components
within the biological tissue beyond the interface. During iontophoresis, in
addition to the migration of charged molecules in response to repulsive
forces, there is also an electroosmotic flow of solvent (e.g., water) through
the electrodes and the biological interface into the tissue. In certain
embodiments, the electroosmotic solvent flow enhances migration of both
charged and uncharged molecules. Enhanced migration via electroosmotic
solvent flow may occur particularly with increasing size of the molecule.
In certain embodiments, the active agent may be a higher
molecular weight molecule. In certain aspects, the molecule may be a polar
polyelectrolyte. In certain other aspects, the molecule may be lipophilic. In
certain embodiments, such molecules may be charged, may have a low net
charge, or may be uncharged under the conditions within the active
electrode. In certain aspects, such active agents may migrate poorly under
the iontophoretic repulsive forces, in contrast to the migration of small more
highly charged active agents under the influence of these forces. These
higher molecular weight active agents may thus be carried through the
biological interface into the underlying tissues primarily via electroosmotic
solvent flow. In certain embodiments, the high molecular weight
polyelectrolytic active agents may be proteins, polypeptides, or nucleic
acids. In other embodiments, the active agent may be mixed with another
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agent to form a complex capable of being transported across the biological
interface via one of the motive methods described above.
In some embodiments, the transdermal drug delivery system 6
includes an iontophoretic drug delivery device 8 for providing transdermal
delivery of one or more therapeutic active agents 36, 40, 42 to a biological
interface 18. The delivery device 8 includes active electrode assembly 12
including at least one active agent reservoir and at least one active
electrode element operable to provide an electromotive force to drive an
active agent from the at least one active agent reservoir. The delivery
device 8 may include a counter electrode assembly 14 including at least one
counter electrode element 68, and a power source 16 electrically coupled to
the at least one active and the at least one counter electrode elements 20,
68. In some embodiments, the iontophoretic drug delivery 8 may further
include one or more active agents 36, 40, 42 loaded in the at least one
active agent reservoir 34.
As shown in Figure 2C, the delivery device 8 may further
include a substrate 10 including a plurality of microneedies 17 in fluidic
communication with the active electrode assembly 12, and positioned
between the active electrode assembly 12 and the biological interface 18.
The substrate 10 may be positioned between the active electrode assembly
12 and the biological interface 18. In some embodiments, the at least one
active electrode element 20 is operable to provide an electromotive force to
drive an active agent 36, 40, 42 from the at least one active agent reservoir
34, through the plurality of microneedles 17, and to the biological interface
18.
As shown in Figures 3A and 3B, the substrate 10 includes a
first side 102 and a second side 104 opposing the first side 102. The first
side 102 of the substrate 10 includes a plurality of microneedies 17
projecting outwardly from the first side 102. The microneedles 17 may be
individually provided or formed as part of one or more arrays. In some
embodiments, the microneedles 17 are integrally formed from the substrate
10. The microneedies 17 may take a solid and permeable form, a solid and
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semi-permeable form, and/or a solid and non-permeable form. In some
other embodiments, solid, non-permeable, microneedles may further
comprise grooves along their outer surfaces for aiding the transdermal
delivery of one or more active agents. In some other embodiments, the
microneedies 17 may take the form of hollow microneedles. In some
embodiments, the hollow microneedies may be filled with ion exchange
material, ion selective materials, permeable materials, semi-permeable
materials, solid materials, and the like.
The microneedies 17 are used, for example, to deliver a
variety of pharmaceutical compositions, molecules, compounds, active
agents, and the like to a living body via a biological interface, such as skin
or
mucous membrane. In certain embodiments, pharmaceutical compositions,
molecules, compounds, active agents, and the like may be delivered into or
through the biological interface. For example, in delivering pharmaceutical
compositions, molecules, compounds, active agents, and the like via the
skin, the length of the microneedle 17, either individually or in arrays 100a,
100b, and/or the depth of insertion may be used to control whether
administration of a pharmaceutical compositions, molecules, compounds,
active agents, and the like is only into the epidermis, through the epidermis
to the dermis, or subcutaneous. In certain embodiments, the microneedle
17 may be useful for delivering high-molecular weight active agents, such as
those comprising proteins, peptides and/or nucleic acids, and corresponding
compositions thereof. In certain embodiments, for example, wherein the
fluid is an ionic solution, the microneedies 17 can provide electrical
continuity between the power source 16 and the tips of the microneedies 17.
In some embodiments, the microneedles 17, either individually or in arrays
100a, 100b, may be used to dispense, deliver, and/or sample fluids through
hollow apertures, through the solid permeable or semi permeable materials,
or via external grooves. The microneedles 17 may further be used to
dispense, deliver, and/or sample pharmaceutical compositions, molecules,
compounds, active agents, and the like by iontophoretic methods, as
disclosed herein.
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Accordingly, in certain embodiments, for example, a plurality of
microneedles 17 in an array 100a, 100b may advantageously be formed on
an outermost biological interface-contacting surface of a transdermal drug
delivery system 6. In some embodiments, the pharmaceutical compositions,
molecules, compounds, active agents, and the like delivered or sampled by
such a system 6 may comprise, for example, high-molecular weight active
agents, such as proteins, peptides, and/or nucleic acids.
In some embodiments, a plurality of microneedles 17 may take
the form of a microneedle array 100a, 100b. The microneedle array 100a,
100b may be arranged in a variety of configurations and patterns including,
for example, a rectangle, a square, a circle (as shown in Figure 3A), a
triangle, a polygon, a regular or irregular shapes, and the like. The
microneedles 17 and the microneedle arrays 100a, 100b may be
manufactured from a variety of materials, including ceramics, elastomers,
epoxy photoresist, glass, glass polymers, glass/polymer materials, metals
(e.g., chromium, cobalt, gold, molybdenum, nickel, stainless steel, titanium,
tungsten steel, and the like), molded plastics, polymers, biodegradable
polymers, non-biodegradable polymers, organic polymers, inorganic
polymers, silicon, silicon dioxide, polysilicon, silicon rubbers, silicon-
based
organic polymers, superconducting materials (e.g., superconductor wafers,
and the like), and the like, as well as combinations, composites, and/or
alloys thereof. Techniques for fabricating the microneedies 17 are well
known in the art and include, for example, electro-deposition, electro-
deposition onto laser-drilled polymer molds, laser cutting and electro-
polishing, laser micromachining, surface micro-machining, soft lithography,
x-ray lithography, LIGA techniques (e.g., X-ray lithography, electroplating,
and molding), injection molding, conventional silicon-based fabrication
methods (e.g., inductively coupled plasma etching, wet etching, isotropic
and anisotropic etching, isotropic silicon etching, anisotropic silicon
etching,
anisotropic GaAs etching, deep reactive ion etching, silicon isotropic
etching, silicon bulk micromachining, and the like), complementary-
symmetry/metal-oxide semiconductor (CMOS) technology, deep x-ray
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exposure techniques, and the like. See for example, U.S. Patent Nos.
6,256,533; 6,312,612; 6,334,856; 6,379,324; 6,451,240; 6,471,903;
6,503,231; 6,511,463; 6,533,949; 6,565,532; 6,603,987; 6,611,707;
6,663,820; 6,767,341; 6,790,372; 6,815,360; 6,881,203; 6,908,453; and
6,939,311. Some or all of the teachings therein may be applied to
microneedle devices, their manufacture, and their use in iontophoretic
applications. In some techniques, the physical characteristics of the
microneedles 17 depend on, for example, the anodization conditions (e.g.,
current density, etching time, HF concentration, temperature, bias settings,
and the like) as well as substrate properties (e.g., doping density, doping
orientation, and the like).
The microneedles 17 may be sized and shaped to penetrate
the outer layers of skin to increase its permeability and transdermal
transport of pharmaceutical compositions, molecules, compounds, active
agents, and the like. In some embodiments, the microneedles 17 are sized
and shaped with an appropriate geometry and sufficient strength to insert
into a biological interface (e.g., the skin or mucous membrane on a subject,
and the like), and thereby increase a trans-interface (e.g., transdermal)
transport of pharmaceutical compositions, molecules, compounds, active
agents, and the like.
Figure 4 shows an exemplary method 400 for systemic
treatment of at least one condition associated with pain, neuropathic pain,
acute pain, chronic pain, or cancer pain.
At 402, the method includes contacting a location on a
biological interface 18 with an iontophoretic drug delivery device 8 that
includes an active electrode assembly 12 having at least one active agent
reservoir 34. The at least one active agent reservoir 34 includes a
pharmaceutical composition including at least a therapeutically effective
amount of at least one opioid agonist and at least one opioid antagonist.
In some embodiments, the at least one opioid agonist is
selected from endogenous opioid peptides, opium alkaloids, semi-synthetic
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opioids, and fully synthetic opioids, or analogs or derivatives, or
pharmaceutically acceptable salts or solvates thereof.
In some embodiments, the at least one opioid agonist is
selected from (5a,7a,8(3-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,
5)dec-8-yl]-benzene-acetamide (U69, 593)), [D-Ala2, N-Me-Phe4,Gly5-
ol]enkephalin (DAMGO), delta-([D-Pen2,D-Pen5]-enkephalin (DPDPE)),
buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, heroin,
hydrocodone, hydromorphone, meperidine, methadone, morphine,
nicomorphine, opium, oxycodone, oxymorphone, pentazocine, pethidine,
propoxyphene, and tilidine, or analogs or derivatives, or pharmaceutically
acceptable salts or solvates thereof.
In some embodiments, the at least one opioid antagonist is
selected from [(-)-(1 R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-
benzomorphan] (MR2266), [allyl]2-tyr-alpha-amino-isobutyric acid (Aib)-Aib-
Phe-Leu-OH (ICI-174864), 4-(3-hydroxyphenyl)-34-dimethyl-alpha-phenyl-l-
piperidinepropanol (LY117413), 6(3-Naltrexol, 7-Benzylidenenaltrexone
(BNTX), b-funaltrexamine (b-FNA), cyclazocine, cyclorphan, dezocine,
diprenorphine, levorphanol, meptazinol, methiodide, methylnaltrexone,
nalide, nalmefene, nalmexone, nalorphine, nalorphine dinicotinate,
naloxonazine, naloxone, naltrexone, naltriben (NTB), naltrindole (NTI),
naltrindole isothiocyanate (NTII), N-cyclopropylmethyl-4,14-dimethoxy-
morphinan-6-one (cyprodime), nor-binaltorphimine (nor-BNI), oxllorphan,
nalbuphine, and trans-3,4-dimethyl-4-phenylpiperides, or analogs or
derivatives, or pharmaceutically acceptable salts or solvates thereof.
In some embodiments, the at least one opioid antagonist is
selected from hydromorphone, or analogs or derivatives, or
pharmaceutically acceptable salts or solvates thereof; and the at least one
opioid antagonist is selected from naloxone, naltrexone, nalmefene,
naloxonazine, NTI, nor-BNI, LY25506, LY9935, LY255582, and LY117413,
or analogs or derivatives, or pharmaceutically acceptable salts or solvates
thereof.
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In some embodiments, the at least one opioid antagonist is
selected from hydromorphone, or analogs or derivatives, or
pharmaceutically acceptable salts or solvates thereof; and the at least one
opioid antagonist is selected from naloxone, naltrexone, 6(3-naltrexol,
nalmefene, and naloxonazine, or analogs or derivatives, or pharmaceutically
acceptable salts or solvates thereof. In some embodiments, the at least one
opioid antagonist is selected from palladone, Palladone SR, Dilaudid and
hydromorphone hydrochloride; and the at least one opioid antagonist is
selected from Narcan@), TrexanO, Revex@, Nubian , nalaxone
hydrochloride, naltrexone hydrochloride, nalmefene hydrochloride, and
nulbuphine hydrochloride.
In yet some further embodiments, the least one opioid agonist
and at least one opioid antagonist are present in synergistic anti-
hyperalgesic effective amounts.
In some embodiments, the at least one condition associated
with pain, neuropathic pain, acute pain, chronic pain, or cancer pain
includes: cancer; chemotherapy; alcoholism; amputation (e.g., phantom
limb syndrome); a back, leg, or hip problem (sciatica); diabetes; a facial
nerve problem (trigeminal neuralgia); an HIV infection or AIDS; multiple
sclerosis; spinal surgery; opiate induced narcotic/respiratory depression; or
detoxification of opiate-dependency.
In some embodiments, the pharmaceutical composition further
comprises at least one active agent selected from vaccines, antibiotics,
adjuvants, immunological adjuvants, immunogens, tolerogens, allergens,
toll-like receptor agonists, and toll-like receptor antagonists, immuno-
adjuvants, immuno-modulators, immuno-response agents, immuno-
stimulators, specific immuno-stimulators, non-specific immuno-stimulators,
and immuno-suppressants, or combinations thereof.
At 404, the method further includes applying a sufficient
amount of current to the active electrode assembly 12 for transdermally
administering a therapeutically effective amount of the pharmaceutical
composition comprising the therapeutically effective amount of the at least
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one opioid agonist and the at least one opioid antagonist. In some
embodiments, applying a sufficient amount of current to the active electrode
assembly 12 comprises providing a sufficient voltage and current for a time
interval, to the to the active electrode assembly 12, for delivering a
therapeutically effective amount of the pharmaceutical composition
comprising the therapeutically effective amount of the at least one opioid
agonist and the at least one opioid antagonist, from the at least one active
agent reservoir 34 to the location on the biological interface 18. In some
embodiments, appiying a sufficient amount of current comprises providing a
sufficient voltage and current for a time interval to the active electrode
assembly 12 to substantially achieve sustained-delivery or controlled-
delivery of the pharmaceutical composition comprising the therapeutically
effective amount of the at least one opioid agonist and the at least one
opioid antagonist, over an extended period of time, so as to produce
anesthesthetic, analgesic, or anti-hyperalgesic therapy in a subject.
Figure 5 shows an exemplary method 500 of inducing
anesthesia, analgesia, or anti-hyperalgesia in a subject.
At 502, the method includes positioning an active electrode
and a counter electrode of an iontophoretic delivery device on a biological
interface of the subject. In some embodiments, the iontophoretic drug
delivery device 8 is operable for iontophoretically delivering a
pharmaceutical composition comprising an effective amount of at least one
opioid agonist and at least one opioid antagonist.
At 504, the method further includes iontophoretically delivering
an anesthesia inducing, an analgesia inducing, or an anti-hyperalgesia
inducing synergistic amount of a pharmaceutical composition comprising at
least one opioid agonist and at least one opioid antagonist.
Figure 6 shows an exemplary method 600 of treating opiate
dependency and/or eliciting a substantially opiate free state in a subject in
need thereof.
At, 602, the method includes contacting a location on a
biological interface 18 of the subject with an iontophoretic drug delivery 8
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operable for iontophoretically delivering a pharmaceutical composition
comprising a therapeutically effective amount of at least one opioid
antagonist.
At, 604, the method further includes transdermally delivering a
therapeutically effective amount of the pharmaceutical composition
comprising the therapeutically effective amount of the least one opioid
antagonist.
At, 606, the method further includes providing sufficient
voltage and current to deliver the therapeutically effective amount of the
pharmaceutical composition comprising the therapeutically effective amount
of the least one opioid antagonist to the location on the biological interface
18 of the subject, so as to eliciting the substantially opiate free state.
Figure 7 shows an exemplary method 600 of method of
treating opiate agonist-induced narcotic/respiratory depression in a subject
in need thereof.
At 702, the method includes contacting a location on a
biological interface 18 of the subject with an iontophoretic drug delivery
device 8 operable for iontophoretically delivering a pharmaceutical
composition comprising a therapeutically effective amount of at least one
opioid antagonist.
At 704, the method further includes transdermally delivering a
therapeutically effective amount of the pharmaceutical composition
comprising the therapeutically effective amount of the least one opioid
antagonist.
Figure 8 shows a Time (min) vs. Drug Transported (pg) plot for
hydromorphone delivery across human skin according to one illustrated
embodiment. A Franz cell setup using dermatomed human skin as the
barrier to the center chamber was used to demonstrate transport across
human skin in a benchtop setting. Hydromorphone was diluted in water at
1 mg/ml and placed in contact with the anodal side of an iontophoresis
delivery device 8. A 0.33 mA/cm2 current density was applied to the cell and
time points taken as demonstrated in the Time (min) vs. Drug Transported
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(pg) plot. Samples were analyzed for the presence of hydromorphone and
plotted as a function of time.
As shown in Figure 9, mass spectrum analysis was performed
on guinea pig serum samples following iontophoretic delivery of
hydromorphone according to one illustrated embodiment. 250 pl of plasma
were combined with 1.25 ml of borate buffer (11 g sodium borate and 6.5 g
boric acid per liter of water) at pH=8.9. 5 ng of internal standard
(hydromorphone-d6) were added and mixed. SPE tubes (Varian Inc.
Harbor City, CA) were prepared by washing with 2 mi of methanol followed
by 2 ml of deionized water. The samples were applied and pulled through
under vacuum. SPE tubes were then washed with 2 ml of deionized water,
2 ml of 10 mM ammonium acetate pH = 4, and 2 ml of methanol. The SPE
tubes were then dried under high vacuum for 5 minutes. Material was
eluted with 2 ml of 80:20:2 methylene chloride:isopropyl alcohol:ammonium
hydroxide. The eluant was evaporated at 40 C under a stream of air. The
residue was then reconstituted in 75 pl of HPLC mobile phase and injected
onto an HPLC column. HPLC-MS is an Agilent Technologies (Palo Alto,
CA.) 1100 series including binary pump, degassing module, autosampler,
column compartment, and mass spectrometer. The column was a Zorbax
SB-C18 150 mm x 2.1 mm x 5 p (Agilent Technologies, Palo Alto, CA.). The
column was maintained at 30 C. The mobile phase consisted of 91:9 10
mM ammonium acetate pH = 4:acetonitrile. The flow rate was 0.25 mI/min.
The mass spectrometer was operated in the ESI+ mode using selected ion
monitoring (SIM) for maximum sensitivity. Ions monitored were m/z 286 for
hydromorphone and m/z 292 for hydromorphone-d6. The lower limit of
quantization of this assay is 0.2 ng/ml and the lower limit of detection is
0.1 ng/ml based upon a 0.25 ml sample size.
Figure 10 shows a Time (min) vs. Hydromorphone (ng/ml) plot
of a Guinea pig in vivo experiment according to one illustrated embodiment.
For the electrode, a carbon on polyethylene film base was used. The
backing material of the patch was from 3M (polyolefin closed cell foam
medical backing, product # 9773). The reservoir material was polyester
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fabric (Textile Development Associates, #PETNF322.3030), 17 mm
diameter, and 2 mm nominal thickness. The disks were specially treated by
saturating with a 2% wt/v solution of hydroxypropyl cellulose (Kiucel, MF
Pharm, Hercules Corp.) and dried in a convection oven. The delivery
solution was prepared by dissolving 21 mg of hydromorphone HCI (Sigma
Chemical Co., Lot # 024K1167) into 10 mL of buffer solution containing
0.155 M Na Ascorbate, pH 4.55) to give a final concentration of 2.1 mg/mL.
(Sodium Ascorbate USP, Spectrum Chemical Co., Product # S1349, Lot #
UH0989 and Ascorbic Acid USP, Spectrum Chemical Co., Product #AS105,
Lot # U10026). The counter electrode solution was 0.5 M Disodium
Fumarate (Fluka, Product # 47970, Lot # 443411/1). All buffer and drug
solution were made on the same day of the experiment. The patch was
made by placing the screen-printed electrode (TTI) onto a backing of the
backing material. Over this, two layers of the backing material with 17 mm
holes punched to cover the carbon electrode were placed. Into the holes,
the HPC-treated reservoir disks were placed. An aliquot (325 pL) of either
the drug or the counter solution was placed on the appropriate reservoir and
allowed to hydrate the coated polyester fabric. (In the case of the control
patches, the ascorbate buffer solution alone was used in the delivery side.)
After hydration (-2 min), the release paper of the foam backing material was
removed and the reservoir disk was covered by a protective hydrophilic
membrane. Another release paper liner (3M) was then placed over the
reservoirs until use.
The patches were powered by 8-channel
potentiostat/gaivanostat (Solartron Analytical Model 1480) running Cell Test
software (Solartron Analytical) for instrument control and data acquisition.
The drug delivery electrode was connected to the anode (+) and the counter
electrode was connected to the cathode (-). Current was delivered under a
controlled current protocol at 1 mA (patch area 2.27 cm2, current density
0.44 mA/cmZ) for 45 min duration. The instrument captured the total voltage
drop across the patch reflecting the sum of the voltages (resistance to
current passage) across each electrode, the skin at both interfaces and the
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underlying tissue. Samples were collected at the indicated time points and
analyzed as shown in Figure 10.
The above description of illustrated embodiments, including
what is described in the Abstract, is not intended to be exhaustive or to
limit
the claims to the precise forms disclosed. Although specific embodiments
and examples are described herein for illustrative purposes, various
equivalent modifications can be made without departing from the spirit and
scope of the disclosure, as will be recognized by those skilled in the
relevant
art. The teachings provided herein can be applied to other agent delivery
systems and devices, not necessarily the exemplary iontophoresis active
agent system and devices generally described above. For instance, some
embodiments may include additional structure. For exampie, some
embodiments may include a control circuit or subsystem to control a
voltage, current, or power applied to the active and counter electrode
elements 20, 68. Also for example, some embodiments may include an
interface layer interposed between the outermost active electrode ion
selective membrane 22 and the biologicai interface 18. Some embodiments
may comprise additional ion selective membranes, ion exchange
membranes, semi-permeable membranes and/or porous membranes, as
well as additional reservoirs for electrolytes and/or buffers.
Various electrically conductive hydrogels have been known
and used in the medical field to provide an electrical interface to the skin
of
a subject or within a device to couple electrical stimulus into the subject.
Hydrogels hydrate the skin, thus protecting against burning due to electrical
stimulation through the hydrogel, while swelling the skin and allowing more
efficient transfer of an active component. Examples of such hydrogels are
disclosed in U.S. Patents 6,803,420; 6,576,712; 6,908,681; 6,596,401;
6,329,488; 6,197,324; 5,290,585; 6,797,276; 5,800,685; 5,660,178;
5,573,668; 5,536,768; 5,489,624; 5,362,420; 5,338,490; and 5,240995,
herein incorporated in their entirety by reference. Further examples of such
hydrogels are disclosed in U.S. Patent applications 2004/166147;
2004/105834; and 2004/247655, herein incorporated in their entirety by
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reference. Product brand names of various hydrogels and hydrogel sheets
include CorplexTM by Corium, TegagelTM by 3M, PuraMatrixTM by BD;
VigilonTM by Bard; ClearSiteTM by Conmed Corporation; FlexiGelTM by
Smith & Nephew; Derma-GeITM by Medline; Nu-GeITM by Johnson &
Johnson; and CuragelTM by Kendall, or acrylhydrogel films available from
Sun Contact Lens Co., Ltd.
In certain embodiments, compounds or compositions can be
delivered by an iontophoresis device comprising an active electrode
assembly and a counter electrode assembly, electrically coupled to a power
source to deliver an active agent to, into, or through a biological interface.
The active electrode assembly includes the following: a first electrode
member connected to a positive electrode of the power source; an active
agent reservoir having a drug solution that is in contact with the first
electrode member and to which is applied a voltage via the first electrode
member; a biological interface contact member, which may be a
microneedle array and is placed against the forward surface of the active
agent reservoir; and a first cover or container that accommodates these
members. The counter electrode assembly includes the following: a
second electrode member connected to a negative electrode of the voltage
source; a second electrolyte holding part that holds an electrolyte that is in
contact with the second electrode member and to which voltage is applied
via the second electrode member; and a second cover or container that
accommodates these members.
In certain other embodiments, compounds or compositions
can be delivered by an iontophoresis device comprising an active electrode
assembly and a counter electrode assembly, electrically coupled to a power
source to deliver an active agent to, into, or through a biological interface.
The active electrode assembly includes the following: a first electrode
member connected to a positive electrode of the voltage source; a first
electrolyte reservoir having an electrolyte that is in contact with the first
electrode member and to which is applied a voltage via the first electrode
member; a first anion-exchange membrane that is placed on the forward
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surface of the first electrolyte holding part; an active agent reservoir that
is
placed against the forward surface of the first anion-exchange membrane; a
biological interface contacting member, which may be a microneedle array
and is placed against the forward surface of the active agent reservoir; and
a first cover or container that accommodates these members. The counter
electrode assembly includes the following: a second electrode member
connected to a negative electrode of the voltage source; a second
electrolyte holding part having an electrolyte that is in contact with the
second electrode member and to which is applied a voltage via the second
electrode member; a cation-exchange membrane that is placed on the
forward surface of the second electrolyte reservoir; a third electrolyte
reservoir that is placed against the forward surface of the cation-exchange
membrane and holds an electrolyte to which a voltage is applied from the
second electrode member via the second electrolyte holding part and the
cation-exchange membrane; a second anion-exchange membrane placed
against the forward surface of the third electrolyte reservoir; and a second
cover or container that accommodates these members.
The various embodiments described above can be combined
to provide further embodiments. All of the U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification and/or listed in the Application Data Sheet are incorporated
herein by reference, in their entirety, including but not limited to:
Japanese patent application Serial No. H03-86002, filed March 27, 1991,
having Japanese Publication No. H04-297277, issued on March 3, 2000 as
Japanese Patent No. 3040517;
Japanese patent application Serial No. 11-033076, filed February 10, 1999,
having Japanese Publication No. 2000-229128;
Japanese patent application Serial No. 11-033765, filed February 12, 1999,
having Japanese Publication No. 2000-229129;
Japanese patent application Serial No. 11-041415, filed February 19, 1999,
having Japanese Publication No. 2000-237326;
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Japanese patent application Serial No. 11-041416, filed February 19, 1999,
having Japanese Publication No. 2000-237327;
Japanese patent application Serial No. 11-042752, filed February 22, 1999,
having Japanese Publication No. 2000-237328;
Japanese patent application Serial No. 11-042753, filed February 22, 1999,
having Japanese Publication No. 2000-237329;
Japanese patent application Serial No. 11-099008, filed April 6, 1999,
having Japanese Publication No. 2000-288098;
Japanese patent application Serial No. 11-099009, filed April 6, 1999,
having Japanese Publication No. 2000-288097;
PCT patent application WO 2002JP4696, filed May 15, 2002, having PCT
Publication No W003037425;
U.S. patent application Serial No. 10/488970, filed March 9, 2004;
Japanese patent application 2004/317317, filed October 29, 2004;
U.S. provisional patent application Serial No. 60/627,952, filed November
16, 2004;
Japanese patent application Serial No. 2004-347814, filed November 30,
2004;
Japanese patent application Serial No. 2004-357313, filed December 9,
2004;
Japanese patent application Serial No. 2005-027748, filed February 3,
2005;
Japanese patent application Serial No. 2005-081220, filed March 22, 2005;
U.S. Provisional Patent Application No. 60/722,136 filed September 30,
2005;
U.S. Provisional Patent Application No. 60/754,688 filed December 29,
2005;
U.S. Provisional Patent Application No. 60/755,199 filed December 30,
2005; and
U.S. Provisional Patent Application No. 60/755,401 filed December 30,
2005.
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As one skill in the relevant art would readily appreciate, the
present disclosure comprises methods of treating a subject by any of the
compositions and/or methods described herein.
Aspects of the various embodiments can be modified, if
necessary, to employ systems, circuits and concepts of the various patents,
applications and publications to provide yet further embodiments, including
those patents and applications identified herein. While some embodiments
may include all of the membranes, reservoirs and other structures discussed
above, other embodiments may omit some of the membranes, reservoirs, or
other structures. Still other embodiments may employ additional ones of the
membranes, reservoirs, and structures generally described above. Even
further embodiments may omit some of the membranes, reservoirs and
structures described above while employing additional ones of the
membranes, reservoirs and structures generally described above.
These and other changes can be made in light of the above-
detailed description. In general, in the following claims, the terms used
should not be construed to be limiting to the specific embodiments disclosed
in the specification and the claims, but should be construed to include all
systems, devices and/or methods that operate in accordance with the
claims. Accordingly, the invention is not limited by the disclosure, but
instead its scope is to be determined entirely by the following claims.
