U.S. patent application number 12/643720 was filed with the patent office on 2010-04-22 for iontophoresis device.
This patent application is currently assigned to TTI ELLEBEAU, INC.. Invention is credited to Hidero Akiyama, Kiyoshi Kanamura, Akihiko Matsumura, Takehiko Matsumura, Mie Minegawa, Mizuo Nakayama, Akihiko Tanioka.
Application Number | 20100100031 12/643720 |
Document ID | / |
Family ID | 36757599 |
Filed Date | 2010-04-22 |
United States Patent
Application |
20100100031 |
Kind Code |
A1 |
Tanioka; Akihiko ; et
al. |
April 22, 2010 |
IONTOPHORESIS DEVICE
Abstract
The present invention provides an iontophoresis device with high
administration efficient of a drug. An iontophoresis device,
including an active electrode structure including: an electrode to
which a positive electrical potential is applied; a drug holding
part for holding a drug solution containing positively charged drug
ions, the drug holding part being placed on a front side of the
electrode; a cellulose-based resin film placed on a front side of
the drug holding part or a complex film composed of a cation
exchange membrane and a cellulose-based resin film placed on a
front side of the cation exchange membrane, the complex film being
placed on a front side of the drug holding part, in which the drug
ions are administered through the cellulose-based resin film.
Inventors: |
Tanioka; Akihiko; (Tokyo,
JP) ; Minegawa; Mie; (Tokyo, JP) ; Kanamura;
Kiyoshi; (Tokyo, JP) ; Matsumura; Akihiko;
(Tokyo, JP) ; Nakayama; Mizuo; (Tokyo, JP)
; Matsumura; Takehiko; (Tokyo, JP) ; Akiyama;
Hidero; (Tokyo, JP) |
Correspondence
Address: |
SEED INTELLECTUAL PROPERTY LAW GROUP PLLC
701 FIFTH AVE, SUITE 5400
SEATTLE
WA
98104
US
|
Assignee: |
TTI ELLEBEAU, INC.
Tokyo
JP
|
Family ID: |
36757599 |
Appl. No.: |
12/643720 |
Filed: |
December 21, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11195364 |
Aug 2, 2005 |
7660626 |
|
|
12643720 |
|
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Current U.S.
Class: |
604/20 |
Current CPC
Class: |
A61N 1/0444 20130101;
A61N 1/0436 20130101; A61N 1/044 20130101 |
Class at
Publication: |
604/20 |
International
Class: |
A61N 1/30 20060101
A61N001/30 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 3, 2005 |
JP |
2005027748 |
Claims
1. An iontophoresis device, comprising an active electrode
structure comprising: an electrode to which a positive electrical
potential is applied; a drug holding part for holding a drug
solution containing positively charged drug ions, the drug holding
part being placed on a front side of the electrode; and a cellulose
resin film selected from the group consisting of regenerated
cellulose, cellulose ester, cellulose ether, and cellulose nitrate
and placed on a front side of the drug holding part, wherein the
positively charged drug ions are administered through the cellulose
resin film.
2. The iontophoresis device according to claim 1, wherein a cation
exchange group is introduced to the cellulose resin film.
3. The iontophoresis device according to claim 1, wherein: the
active electrode structure further comprising an electrolyte
solution holding part for holding an electrolyte solution in
contact with the electrode, and an anion exchange membrane placed
on a front side of the electrolyte solution holding part; and the
drug holding part is placed on a front side of the anion exchange
membrane.
4. The iontophoresis device according to claim 3, further
comprising a counter electrode structure, comprising: a second
electrode to which a negative electrical potential is applied; a
second electrolyte solution holding part for holding an electrolyte
solution in contact with the second electrode; a second cation
exchange membrane placed on a front side of the second electrolyte
solution holding part; a third electrolyte solution holding part
for holding an electrolyte solution, the third electrolyte solution
holding part being placed on a front side of the second cation
exchange membrane; and a second anion exchange membrane placed on a
front side of the third electrolyte solution holding part.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/195,364, filed Aug. 2, 2005, now pending,
which application is incorporated herein by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present disclosure relates to an iontophoresis device
for administering positively charged drug ions to a living body by
an action of a positive electrical potential applied to an active
electrode structure holding the drug ions.
[0004] 2. Description of the Related Art
[0005] An iontophoresis device generally includes an active
electrode structure holding a drug solution whose active ingredient
is dissociated to positive or negative ions (drug ions) and a
counter electrode structure that functions as a counter electrode
of the active electrode structure. The drug ions are administered
to a living body by the application of an electrical potential or
voltage with the same polarity as that of the drug ions to the
active electrode structure under the condition that both the
assemblies are in contact with a biological interface (e.g., skin,
mucus membrane) of the living body (e.g., human being or
animal).
[0006] The charge supplied to the active electrode structure is
consumed by the movement of the drug ions to the living body and
the release of biological counter ions present in the living body
and having a polarity opposite to that of the drug ions) to the
active electrode structure. The biological counter ions typically
released are those having a small molecular weight (e.g., Na.sup.+
and Cl.sup.-) and hence high mobility. Therefore, the transport
number (i.e., ratio of the amount of current contributing to the
movement of the drug ions among the whole current supplied to the
active electrode structure) decreases, which makes it difficult or
impossible to administer a sufficient amount of drug.
[0007] JP 3030517 B, JP 2000-229128 A, JP 2000-229129 A, JP
2000-237326 A, JP 2000-237327 A, JP 2000-237328 A, JP 2000-237329
A, JP 2000-288097 A, JP 2000-288098 A and WO 03/037425 disclose
iontophoresis devices that attempt to solve the above-mentioned
problem.
[0008] More specifically, in each of the iontophoresis devices
described in the above-cited references, an active electrode
structure is composed of an electrode, a drug holding part placed
on a front side (i.e., a side facing to the biological interface
when in use) of the electrode, and an ion-exchange membrane that is
placed on a front side of the drug holding part and selectively
passes ions with the same polarity as that of the drug ions held by
the drug holding part, and the drug ions are administered through
the ion-exchange membrane, whereby the release of biological
counter ions is suppressed in an effort to enhance the transport
number and thus the administration efficiency of the drug.
[0009] In the iontophoresis devices in the above-cited references,
the active electrode structure further includes an electrolyte
solution holding part for holding an electrolyte solution in
contact with the electrode, and an ion-exchange membrane that is
placed on a front side of the electrolyte solution holding part
that selectively passes ions having a polarity opposite to that of
the polarity of the drug ions, and the drug holding part is placed
on a front side of the ion-exchange membrane, in an effort to
prevent the drug ions from being decomposed, by isolating the drug
ions from the electrode and preventing the movement of H.sup.+ or
OH.sup.- ions generated at the electrode to the drug holding part
and the biological interface of a living body.
[0010] Furthermore, JP 2004-188188 A discloses a purported
improvement over the iontophoresis devices disclosed in JP 3030517
B, JP 2000-229128 A, JP 2000-229129 A, JP 2000-237326 A, JP
2000-237327 A, JP 2000-237328 A, JP 2000-237329 A, JP 2000-288097
A, JP 2000-288098 A and WO 03/037425. JP 2004-188188 A teaches that
the administration amount of a drug can be enhanced remarkably by
using an ion-exchange membrane in which a porous film composed of a
material such as polyolefin, vinyl chloride resin, or fluorine
resin is filled with an ion-exchange resin (a resin providing an
ion-exchange function).
[0011] As described above, the iontophoresis device disclosed in JP
2004-188188 A is purported to be the one having the most excellent
administration efficiency of a drug among those which are known at
present. However, further improvements with respect to
administration efficiency of drug delivery are desirable, even as
compared with the iontophoresis device disclosed in JP
2004-188188A.
BRIEF SUMMARY OF THE INVENTION
[0012] In one aspect, an iontophoresis device for administering
positively charged drug ions includes an active electrode structure
having an electrode to which a positive electrical potential or
voltage is applied, a drug holding part for holding a drug solution
containing drug ions, the drug holding part being placed on a front
side of the electrode, and a cellulose-based resin film placed on a
front side of the drug holding part.
[0013] For example, an iontophoresis device for administering a
drug whose active ingredient is dissociated to positive ions in a
solution, may employ a cellulose-based resin film in place of the
ion-exchanged film placed on a front side of the drug holding part
in each of the iontophoresis devices of JP 3030517 B, JP
2000-229128 A, JP 2000-229129 A, JP 2000-237326 A, JP 2000-237327
A, JP 2000-237328 A, JP 2000-237329 A, JP 2000-288097 A, JP
2000-288098 A, WO 03/037425 and JP 2004-188188 A.
[0014] The cellulose-based resin film functions as a cation
exchange membrane. However, the characteristics such as an
ion-exchangeability of the cellulose-based resin film are inferior
to those of generally used cation exchange membranes (e.g., those
illustrated in JP 3030517 B, JP 2000-229128 A, JP 2000-229129 A, JP
2000-237326 A, JP 2000-237327 A, JP 2000-237328 A, JP 2000-237329
A, JP 2000-288097 A, JP 2000-288098 A, WO 03/037425 and JP
2004-188188 A). Accordingly, it has been out of consideration for
those skilled in the art to apply the cellulose-based resin film to
the iontophoresis device.
[0015] In fact, in the study by the inventors of the present
subject matter, the characteristics superior to those of the other
cation exchange membranes have not been confirmed in vitro
evaluation, which is generally performed in an initial stage of
development. However, when evaluation was performed in vivo using a
living body, it has been found that, according to the
above-mentioned iontophoresis device of the present disclosure, the
administration efficiency of a drug (i.e., drug administration
amount per unit time under the same current conditions from a film
surface with the same surface area) is remarkably enhanced,
compared with the iontophoresis device using a cation exchange
resin disclosed in JP 2004-188188 A.
[0016] Herein, examples of the drug whose active ingredient is
dissociated to positive ions may include: an anesthetic agent such
as morphine hydrochloride or lidocaine; a gastrointestinal disease
therapeutic agent such as carnitine chloride; and a skeletal muscle
relaxant such as pancuronium bromide.
[0017] In another aspect, the drug holding part of the active
electrode structure can be configured as a container for holding
the above-mentioned drug solution in a liquid state. The drug
holding part may hold the drug solution in a gelled or gelatinized
form with an appropriate gelling agent. Alternatively, a polymer
carrier or the like impregnated with a drug solution may be used as
the drug holding part.
[0018] The cellulose-based resin film may take the form of a thin
film composed of a cellulose-based resin such as regenerated
cellulose, cellulose ester, cellulose ether, or cellulose nitrate.
Further, a thin film composed of a cellulose-based resin blended or
mixed with other components (resin, plasticizer, cross-linker,
etc.) can also be used as the cellulose-based resin film, as long
as a main component is the cellulose-based resin, and a serious
damage to the administration characteristics (administration
efficiency, biological compatibility, safety, etc.) of a drug,
which impairs the use as an iontophoresis device, is not
caused.
[0019] Furthermore, the cellulose-based resin film may be a porous
film with an appropriate pore size in accordance with the molecular
weight of drug ions to be administered. The average pore diameter
is typically approximately 1 .ANG. to several .mu.m, and it may be
preferable to have a pore size of approximately 1 to 1,000 .ANG.,
and or approximately 1 to 100 .ANG..
[0020] In another aspect, the iontophoresis device uses the active
electrode structure under the condition that it is attached to the
biological interface of a living body. Therefore, it is desired
that the cellulose-based resin film used herein have flexibility
capable of following the expansion/contraction and bending of the
biological interface of the living body and a strength to such a
degree not to be broken with a stress caused by such
expansion/contraction and bending. Generally, when the thickness of
the cellulose-based resin film increases, the strength can be
enhanced, while the flexibility is reduced. Therefore, it is
preferable that an appropriate thickness be selected in conjunction
with the above-mentioned both characteristics in accordance with
the kind of the cellulose-based resin film.
[0021] In a further aspect, the cellulose-based resin film can
incorporate a cation exchange group such as a sulfonic acid group,
a carboxylic acid group, or a phosphonic acid group by the action
of chlorosulfonic acid, chloracetic acid, an inorganic cyclic
triphosphate, or the like. This can further enhance the transport
number of drug ions in the administration of a drug, and further
enhance the administration efficiency of a drug.
[0022] In yet a further aspect, a cellulose-based resin film filled
with ion-exchange resin with a cation exchange group introduced
thereto can also be used as the cellulose-based resin film. This
also may enhance the transport number of drug ions in the
administration of a drug, and further increases the administration
efficiency of a drug.
[0023] Such a cellulose-based resin film can, for example, be
obtained by: impregnating a porous thin film body composed of
cellulose-based resin with a monomer composition composed of a
hydrocarbon type monomer having a function group capable of
introducing a cation exchange group, a cross-linkable monomer, and
a polymerization initiator; and allowing chlorosulfonic acid,
chloracetic acid, an inorganic cyclic triphosphate, etc. to act on
the resultant porous thin film body.
[0024] A sulfonic acid group that is a strong acid group is may be
preferable as the cation exchange group to be introduced to the
above-mentioned cellulose-based resin film or ion-exchange
resin.
[0025] Furthermore, each of the above cation exchange groups may be
present as a free acid, or may be present as a salt with alkaline
metal ions such as sodium ions and potassium ions, ammonium ions,
etc.
[0026] In still another aspect, an iontophoresis device may
comprise an active electrode structure having: an electrode to
which a positive electrical potential or voltage is applied; a drug
holding part for holding a drug solution containing positively
charged drug ions, the drug holding part being placed on a front
side of the electrode; and a complex film composed of a cation
exchange membrane and a cellulose-based resin film placed on a
front side of the cation exchange membrane, the complex film being
placed on a front side of the drug holding part, in which the drug
ions are administered through the cellulose-based resin film. This
may further enhance the transport number in the administration of a
drug, and further enhance the administration efficiency of a
drug.
[0027] The complex film as mentioned above can also be used as the
cellulose-based resin film of the previously described
embodiments.
[0028] In this case, it may be preferable to use as the cation
exchange membrane a configuration filled with an ion-exchange resin
in which a cation exchange group is introduced to a porous film
made of a material such as polyolefin, a vinyl chloride resin, or a
fluorine resin. This may further enhance the transport number in
the administration of a drug.
[0029] In the above-mentioned complex film, in order to prevent an
air layer from being present at an interface between the cation
exchange membrane and the cellulose-based resin film, it may be
preferable to bond the interface between them so as to integrate
the cation exchange membrane and the cellulose-based resin
film.
[0030] Examples of a bonding method include adhesion by heat
sealing, ultrasonic bonding, adhesion with an adhesive such as a
cyanoacrylate-type adhesive, and a cross-linking reaction with a
cross-linker such as divinylbenzene. Alternatively, a
cellulose-based resin film is formed on a cation exchange membrane
(e.g., cellulose is regenerated by allowing sulfuric acid to act on
a cellulose copper ammonia solution applied to a cation exchange
membrane), whereby the cation exchange membrane can be bonded to
the cellulose-based resin film.
[0031] Herein, in the case of bonding the cation exchange membrane
to the cellulose-based resin film by the adhesion, cross-linking
reaction, or formation of a cellulose-based resin film on a cation
exchange membrane, it may be preferable to perform bonding under
the condition that at least the surface of a cation exchange
membrane facing the cellulose-based resin film is roughened by an
approach such as embossing, grooving, notching, mechanical
polishing, or chemical polishing. This may enhance the adhesion and
integration of the cation exchange membrane and the cellulose-based
resin film.
[0032] Furthermore, the cation exchange membrane can also be
roughened by mixing an inorganic filler such as calcium carbonate
or magnesium carbonate, or an organic filler such as denatured
polyethylene particles or denatured polyacrylic acid resin
particles, with a resin film constituting the cation exchange
membrane.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0033] 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 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.
[0034] In the accompanying drawings:
[0035] FIG. 1 is a schematic diagram showing a configuration of an
iontophoresis device according to one illustrated embodiment.
[0036] FIG. 2 is a schematic diagram showing a configuration of an
iontophoresis device according to another illustrated
embodiment.
[0037] FIG. 3A is a graph showing a time transition of the
concentration of morphine in the blood before and after the
administration of a drug, when morphine hydrochloride is
administered to a mouse using the iontophoresis device according to
one illustrated embodiment.
[0038] FIG. 3B is a chart showing a pH value (b) of a drug solution
and an electrolyte solution before and after the administration of
a drug, when morphine hydrochloride is administered to a mouse
using the iontophoresis device according to one illustrated
embodiment.
[0039] FIG. 4 is a graph showing a time transition of the
concentration of morphine in the blood, when morphine hydrochloride
is administered to a mouse using a conventional iontophoresis
device.
[0040] FIG. 5 is a schematic diagram showing a configuration of a
test device used for evaluating morphine transfer characteristics
in vitro.
[0041] FIG. 6 is a graph showing evaluation results of morphine
transfer characteristics in a test device equivalent to the
iontophoresis device disclosed herein.
[0042] FIG. 7 is a graph showing evaluation results of morphine
transfer characteristics in a test device equivalent to a
conventional iontophoresis device.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0043] In the following description, certain specific details are
set forth in order to provide a thorough understanding of various
disclosed embodiments. However, one skilled in the relevant art
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, ion exchange membranes,
power sources, voltage and/or current regulators and controllers
have not been shown or described in detail to avoid unnecessarily
obscuring descriptions of the embodiments.
[0044] 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."
[0045] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment. Thus, the appearances of the
phrases "in one embodiment" or "in an embodiment" in various places
throughout this specification are not necessarily all referring to
the same embodiment. Further more, the particular features,
structures, or characteristics may be combined in any suitable
manner in one or more embodiments.
[0046] The headings provided herein are for convenience only and do
not interpret the scope or meaning of the embodiments.
[0047] FIG. 1 shows an iontophoresis device X1, including an active
electrode structure 1, a counter electrode structure 2, and a power
source 3, as main components (members). Reference numeral 4 denotes
a biological interface such as skin or a mucous membrane.
[0048] The active electrode structure 1 includes an electrode 11
electrically coupleable to a positive pole of the power source 3,
an electrolyte solution holding part 12 for holding an electrolyte
solution in contact with or proximate the electrode 11, an anion
exchange membrane 13 placed on a front side of the electrolyte
solution holding part 12, a drug holding part 14 placed on a front
side of the anion exchange membrane 13, and a cellulose-based resin
film 15 placed on a front side of the drug holding part 14. The
entire active electrode structure 1 is housed in a cover or a
container 16 composed of a material, for example, a resin film or a
plastic.
[0049] On the other hand, the counter electrode structure 2
includes an electrode 21 connected to a negative pole of the power
source 3, an electrolyte solution holding part 22 for holding an
electrolyte solution in contact with or proximate the electrode 21,
a cation exchange membrane 23 placed on a front side of the
electrolyte solution holding part 22, an electrolyte solution
holding part 24 placed on a front side of the cation exchange
membrane 23, and an anion exchange membrane 25 placed on a front
side of the electrolyte solution holding part 24. The entire
counter electrode structure 2 is housed in a cover or a container
26 composed of a material, for example, a resin film or a
plastic.
[0050] In the iontophoresis device X1, those which are made of any
conductive material can be used as the electrodes 11 and 21 without
any particular limit. In particular, a counter electrode composed
of carbon, platinum, or the like may be preferred, and a carbon
electrode free from the elution of metal ions and the transfer
thereof to a living body may be more preferred.
[0051] However, an active electrode such as a silver/silver
chloride couple electrode in which the electrode 11 is made of
silver and the electrode 21 is made of silver chloride can also be
adopted.
[0052] For example, in the case of using the silver/silver chloride
couple electrode, in the electrode 11 that is a positive pole, a
silver electrode and chlorine ions (Cl.sup.-) easily react with
each other to generate insoluble AgCl as represented by
Ag.sup.+Cl.sup.-.fwdarw.AgCl+e.sup.-, and in the electrode 21 that
is a negative pole, chlorine ions (Cl.sup.-) are eluted from a
silver chloride electrode. Consequently, the following effects may
be obtained: the electrolysis of water is suppressed, and the rapid
acidification based on H.sup.+ ions at the positive pole, and the
rapid basification based on OH.sup.- ions at the negative pole can
be prevented.
[0053] In contrast, in the active electrode structure 1 and the
counter electrode structure 2 in the iontophoresis device X1 in
FIG. 1, owing to the function of the anion exchange membrane 13 and
the cation exchange membrane 23, the rapid acidification based on
H.sup.+ ions in the electrolyte solution holding part 12 and the
rapid basification based on OH.sup.- ions in the electrolyte
solution holding part 22 may be suppressed. Therefore, an
inexpensive carbon electrode free from the elution of metal ions
can be advantageously used in place of the active electrode such as
a silver/silver chloride couple electrode.
[0054] Furthermore, the electrolyte solution holding parts 12, 22,
and 24 in the iontophoresis device X1 in FIG. 1 hold an electrolyte
solution so as to maintain the conductivity. Phosphate buffered
saline, physiological saline, etc. can be used as the electrolyte
solution typically.
[0055] Furthermore, in order to more effectively prevent the
generation of gas caused by the electrolytic reaction of water and
the increase in a conductive resistance caused by the generation of
gas, or the change in pH caused by the electrolytic reaction of
water, an electrolyte that is more readily oxidized or reduced
(i.e., oxidation at the positive pole and the reduction at the
negative pole) than the electrolytic reaction of water can be added
to the electrolyte solution holding parts 12 and 22. In terms of
the biological safety and economic efficiency (e.g., low cost and
easy availability), for example, an inorganic compound such as
ferrous sulfate or ferric sulfate, a medical agent such as ascorbic
acid (vitamin C) or sodium ascorbate, and an organic acid such as
lactic acid, oxalic acid, malic acid, succinic acid, or fumaric
acid and/or a salt thereof may be preferred. Alternatively, a
combination of those substances (for example, 1:1 mixed aqueous
solution containing 1 mol (M) of lactic acid and 1 mol (M) of
sodium fumarate) can also be used.
[0056] The electrolyte solution holding parts 12, 22, and 24 may
hold the above-mentioned electrolyte solution in a liquid state.
However, the electrolyte solution holding parts 12, 22, and 24 may
be configured by impregnating a water-absorbing thin film carrier
made of a polymer material or the like with the above-mentioned
electrolyte solution, thereby enhancing the ease of handling
thereof. The same thin film carrier as that can be used in the drug
holding part 14 can be used as the thin film carrier described
herein. Therefore, the detail thereof will be described in the
following description regarding the drug holding part 14.
[0057] The drug holding part 14 in the iontophoresis device X1
according to this embodiment holds at least an aqueous solution of
a drug whose active ingredient is dissociated to positive drug ions
by the dissolution, as a drug solution.
[0058] Herein, the drug holding part 14 may hold a drug solution in
a liquid state. However, it is also possible to impregnate such a
water-absorbing thin film carrier as described below with a drug
solution so as to enhance the ease of handling thereof.
[0059] Examples of a material that can be used for the
water-absorbing thin film carrier in this case include a hydrogel
body of acrylic resin (acrylhydrogel film), segmented polyurethane
gel film, and/or an ion conductive porous sheet for forming a gel
solid electrolyte. By impregnating the above aqueous solution at an
impregnation ratio of 20 to 60%, a high transport number (high drug
delivery property), e.g., 70 to 80% may be obtained.
[0060] The impregnation ratio in the present specification is
represented by % by weight (i.e., 100.times.(W-D)/D[%] where D is a
weight in a dry state and W is a weight after impregnation). The
impregnation ratio should be measured immediately after the
impregnation with an aqueous solution to eliminate a chronological
influence.
[0061] Furthermore, the transport number refers to the ratio of the
amount of current contributing to the transfer of particular ions
among the whole current flowing through the electrolyte solution.
In the present specification, the transport number is used in terms
of that regarding drug ions, i.e., the ratio of a current
contributing to the transfer of drug ions among the whole currents
supplied to the active electrode structure.
[0062] Herein, the above-mentioned acrylhydrogel film (for example,
available from Sun Contact Lens Co., Ltd.) is a gel body having a
three-dimensional network structure (i.e., cross-linking
structure). When an electrolyte solution that is a dispersion
medium is added to the acrylhydrogel film, the acrylhydrogel film
becomes a polymer adsorbent having ion conductivity. Furthermore,
the relationship between the impregnation ratio of the
acrylhydrogel film and the transport number can be adjusted by
controlling the size of the three-dimensional network structure and
the kind and ratio of a monomer constituting a resin. The
acrylhydrogel film with an impregnation ratio of 30 to 40% and a
transport number of 70 to 80% can be prepared from
2-hydroxyethylmethacrylate and ethyleneglycol dimethacrylate
(monomer ratio 98 to 99.5:0.5 to 2), and it is confirmed that the
impregnation ratio and transport number are almost the same in a
range of an ordinary thickness of 0.1 to 1 mm.
[0063] Furthermore, the segmented polyurethane gel film has, as
segments, polyethylene glycol (PEG) and polypropylene glycol (PPG),
and can be synthesized from a monomer and diisocyanate constituting
these segments. The segmented polyurethane gel film has a
three-dimensional structure cross-linked by a urethane bond, and
the impregnation ratio, transport number, and adhesion strength of
the gel film can be easily adjusted by controlling the size of a
network, and the kind and ratio of a monomer in the same way as in
the acrylhydrogel film. When water that is a dispersion medium and
an electrolyte (alkaline metal salt, etc.) are added to the
segmented polyurethane gel film (porous gel film), oxygen in an
ether connecting part of polyether forming a segment and an
alkaline metal salt form a complex, and ions of the metal salt move
to oxygen in a subsequent blank ether connecting part when a
current flows, whereby the conductivity is expressed.
[0064] As the ion conductive porous sheet for forming a gel solid
electrolyte, for example, there is the one disclosed in JP
11-273452 A. This porous sheet is based on an acrylonitrile
copolymer, and a porous polymer with a porosity of 20 to 80%. More
specifically, this porous sheet is based on an acrylonitrile
copolymer with a porosity of 20 to 80% containing 50 mol % or more
(preferably 70 to 98 mol %) of acrylonitrile. The acrylonitrile gel
solid electrolytic sheet (solid-state battery) is prepared by
impregnating an acrylonitrile copolymer sheet soluble in a
non-aqueous solvent and having a porosity of 20 to 80%, with a
non-aqueous solvent containing an electrolyte, followed by gelling,
and a gel body includes a gel to a hard film.
[0065] In terms of the ion conductivity, safety, and the like, it
may be preferable to compose the acrylonitrile copolymer sheet
soluble in a non-aqueous solvent of an acrylonitrile/C1 to C4 alkyl
(meth)acrylate copolymer, an acrylonitrile/vinylacetate copolymer,
an acrylonitrile/styrene copolymer, an acrylonitrile/vinylidene
chloride copolymer, or the like. The copolymer sheet is made porous
by an ordinary method such as a wet (dry) paper making method, a
needlepunching method that is a kind of a non-woven fabric
producing method, a water-jet method, drawing perforation of a
melt-extruded sheet, or perforation by solvent extraction. Among
the above-mentioned ion conductive porous sheets of an
acrylonitrile copolymer used in a solid-state battery, a gel body
(a gel to a hard film) holding the above-mentioned aqueous solution
in a three-dimensional network of a polymer chain and in which the
above-mentioned impregnation ratio and transport number are
achieved is useful as a thin film carrier used in the drug holding
part 14 or the electrolyte solution holding parts 12, 22, and
24.
[0066] Regarding the conditions for impregnating the
above-mentioned thin film carrier with a drug solution or an
electrolyte solution, the optimum conditions may be determined in
terms of the impregnation amount, impregnation speed, and the like.
For example, an impregnation condition of 30 minutes at 40.degree.
C. may be selected.
[0067] An ion-exchange membrane carrying an ion-exchange resin
having an anion exchange function in a base, for example, NEOSEPTA,
AM-1, AM-3, AMX, AHA, ACH, ACS, ALE04-2, AIP-21, produced by
Tokuyama Co., Ltd. can be used as the anion exchange membrane
(ion-exchange membrane having characteristics of selectively
passing negative ions) 13 and 25 in the iontophoresis device X1
according to this embodiment. An ion-exchange membrane carrying an
ion-exchange resin having a cation exchange function in a base, for
example, NEOSEPTA, CM-1, CM-2, CMX, CMS, CMB, CLE04-2, produced by
Tokuyama Co., Ltd. can be used as the cation exchange membrane
(ion-exchange membrane having characteristics of selectively
passing positive ions) 23. In particular, a cation exchange
membrane in which a part or an entirety of a pore of a porous film
is filled with an ion-exchange resin having a cation exchange
function, or an anion exchange membrane filled with an ion-exchange
resin having an anion exchange function can be used preferably.
[0068] Herein, a fluorine type resin with an ion-exchange group
introduced to a perfluorocarbon skeleton or a hydrocarbon type
resin containing a resin that is not fluorinated as a skeleton can
be used as the above-mentioned ion-exchange resin. In view of the
convenience of a production process, a hydrocarbon type
ion-exchange resin is preferable. Furthermore, although the filling
ratio of the ion-exchange resin is also related to the porosity of
the porous film, the filling ratio is generally 5 to 95% by mass,
in particular, approximately 10 to 90% by mass, and may be
preferred to be approximately 20 to 60% by mass.
[0069] Furthermore, there is no particular limit to an ion-exchange
group of the above-mentioned ion-exchange resin, as long as it is a
functional group generating a group having negative or positive
charge in an aqueous solution. As specific examples of the
functional group to be such an ion-exchange group, those of a
cation exchange group include a sulfonic acid group, a carboxylic
acid group, and a phosphonic acid group. Those acid groups may be
present in the form of a free acid or a salt. Examples of a counter
cation in the case of a salt include alkaline metal cations such as
sodium ions and potassium ions, and ammonium ions. Of those cation
exchange groups, generally, a sulfonic acid group that is a strong
acidic group is particularly preferable. Furthermore, examples of
the anion exchange group include primary to tertiary amino groups,
a quaternary ammonium group, a pyridyl group, an imidazole group, a
quaternary pyridinium group, and a quaternary imidazolium group.
Examples of a counter anion in those anion exchange groups include
halogen ions such as chlorine ions and hydroxy ions. Of those anion
exchange groups, generally, a quaternary ammonium group and a
quaternary pyridinium group that are strong basic groups are used
preferably.
[0070] Furthermore, a film shape or a sheet shape having a number
of small holes passing from front to back sides are used as the
above-mentioned porous film without any particular limit. In order
to satisfy both the high strength and the flexibility, the porous
film may be made of a thermoplastic resin.
[0071] Examples of the thermoplastic resins constituting the porous
film include, without limitation: polyolefin resins such as
homopolymers or copolymers of .alpha.-olefins such as ethylene,
propylene, 1-butene, 1-pentene, 1-hexene, 3-methyl-1-butene,
4-methyl-1-pentene, and 5-methyl-1-heptene; vinyl chloride resins
such as polyvinyl chloride, vinyl chloride-vinyl acetate
copolymers, vinyl chloride-vinylidene chloride copolymers, and
vinyl chloride-olefin copolymers; fluorine resins such as
polytetrafluoroethylene, polychlorotrifluoroethylene,
polyvinylidene fluoride, tetrafluoroethylene-hexafluoropropylene
copolymers, tetrafluoroethylene-perfluoroalkyl vinylether
copolymers, and tetrafluoroethylene-ethylene copolymers; polyamide
resins such as nylon 6 and nylon 66; and those which are made from
polyamide resins. Polyolefin resins may be preferable as they are
superior in mechanical strength, flexibility, chemical stability,
and chemical resistance, and have good compatibility with
ion-exchange resins. As the polyolefin resins, polyethylene and
polypropylene may be particularly preferable and polyethylene may
be most preferable.
[0072] There is no particular limit to the property of the
above-mentioned porous film made of the thermoplastic resin.
However, the average pore diameter of pores of approximately 0.005
to 5.0 .mu.m may be preferred, while approximately 0.01 to 2.0
.mu.m may be more preferred, and approximately 0.02 to 0.2 .mu.m
may be most preferred since the porous film having such an average
pore diameter is likely to be a thin ion-exchange membrane having
excellent strength and a low electric resistance. The average pore
diameter in the present specification refers to an average flow
pore diameter measured in accordance with a bubble point method
(JIS K3832-1990). Similarly, the porosity of the porous film of
approximately 20 to 95% may be preferred, while approximately 30 to
90% may be more preferred, and approximately 30 to 60% may be most
preferred. Furthermore, the thickness of the porous film may of
approximately 5 to 140 .mu.m, approximately 10 to 120 .mu.m may be
even more preferred, and approximately 15 to 55 .mu.m may be most
preferred. Usually, an anion exchange membrane or a cation exchange
membrane using such a porous film has a thickness of the porous
film with +0 to 20 .mu.m.
[0073] The cellulose-based resin film 15 used in the iontophoresis
device X1 according to this embodiment can be constituted by
cellulose-based resins such as regenerated cellulose manufactured
by a method such as a cuprammonium process or a tertiary amineoxide
process, cellulose esters (e.g., cellulose acetate, cellulose
propionate, or cellulose acetate butyrate), cellulose ethers (e.g.,
hydroxyethyl cellulose or hydroxypropyl cellulose) or
nitrocellulose. A porous thin film of cellulose-based resins having
an average pore diameter of approximately 1 .ANG. to a few .mu.m
may be preferred, approximately 1 to 1,000 .ANG. may be more
preferred, and around 1 to 100 .ANG. may be particularly preferred,
and a thickness of approximately 10 to 200 .mu.m may be preferred,
and approximately 20 to 50 .mu.m may be particularly preferred.
[0074] A cation exchange group such as a sulfonic acid group, a
carboxylic acid group, or a phosphonic acid group can be introduced
to the above-mentioned cellulose-based resin film by allowing
chlorosulfonic acid, chloroacetic acid, inorganic cyclic
triphosphate, or the like to act on the cellulose-based resin film.
By using a cellulose-based resin film with such a cation exchange
group introduced thereto as the cellulose-based resin film 15, the
administration efficiency of a drug can be enhanced further.
[0075] Alternatively, a porous thin film made of the
above-mentioned cellulose-based resin in which pores are filled
with a cation exchange resin can also be used for the
cellulose-based resin film 15.
[0076] The cellulose-based resin film filled with a cation exchange
resin can be obtained by: impregnating the above-mentioned porous
thin film made of a cellulose-based resin with a monomer
composition composed of a hydrocarbon type monomer having a
functional group capable of introducing a cation exchange group, a
cross-linkable monomer, and a polymerization initiator;
polymerizing them under appropriate reaction conditions; and
allowing chlorosulfonic acid, chloracetic acid, an inorganic cyclic
triphosphate, or the like to act on the resultant porous thin
film.
[0077] Examples of the hydrocarbon-type monomer having a functional
group capable of introducing a cation exchange group include
aromatic vinyl compounds such as styrene, .alpha.-methylstyrene,
3-methylstyrene, 4-methylstyrene, 2,4-dimethylstyrene,
p-tert-butylstyrene, .alpha.-halogenated styrene, and
vinylnaphthalene and each one or more of them can be used. Examples
of an available cross-linkable monomer include: polyfunctional
vinyl compounds such as divinylbenzenes, divinyl sulfone,
butadiene, chloroprene, divinylbiphenyl, and trivinylbenzene; and
polyfunctional methacrylic acid derivatives such as trimethylol
methane trimethacrylate, methylenebis acrylamide, and hexamethylene
methacrylamide. Examples of an available polymerization initiator
include octanoyl peroxide, lauroyl peroxide,
t-butylperoxy-2-ethylhexanoate, benzoyl peroxide, t-butyl
peroxyisobutyrate, t-butyl peroxylaurate, t-hexyl peroxybenzoate,
and di-t-butylperoxide.
[0078] In addition to the above components, other hydrocarbon-type
monomers which are copolymerizable with the above hydrocarbon-type
monomers and cross-linkable monomers, or plasticizers may be added
as required. Examples of the other monomers which may be used
include acrylonitrile, acrolein, and methylvinylketone. Further,
examples of the plasticizers which may be used include dibutyl
phthalate, dioctyl phthalate, dimethyl isophthalate,
dibutyladipate, triethylcitrate, acetyltributylcitrate,
dibutylsebacate, and dibenzylether.
[0079] A battery, a voltage stabilizer, a current stabilizer
(galvano device), a voltage/current stabilizer, or the like can be
used as the power source 3 in the iontophoresis device. It may be
preferable to use a current stabilizer that is operated under safe
voltage conditions in which an arbitrary current can be adjusted in
a range of approximately 0.01 to 1.0 mA, while approximately 0.01
to 0.5 mA, specifically, at approximately 50V or less may be
preferred and approximately 30 V or less may be even more
preferred.
[0080] The iontophoresis device X1 according to this embodiment has
remarkably higher administration efficiency of a drug than that of
a conventional iontophoresis device using a cation exchange
membrane in place of the cellulose-based resin film 15, as
described later in examples.
[0081] FIG. 2 illustrates a configuration of an iontophoresis
device X2 according to another embodiment.
[0082] As shown in FIG. 2, the iontophoresis device X2 has the same
configuration as that of the above-mentioned iontophoresis device
X1, except that a complex film 17 made of a cation exchange
membrane 17a placed on a front side of the drug holding part 14 and
a cellulose-based resin film 17b placed on a front side of the
cation exchange membrane 17a is provided, in place of the
cellulose-based resin film 15.
[0083] The same cation exchange membrane as that described with
respect to the cation exchange membrane 23 can be used as the
cation exchange membrane 17a of the complex film 17. The same
cellulose-based resin film as that described with respect to the
cellulose-based resin film 15 can be used as the cellulose-based
resin film 17b.
[0084] In order to prevent an air layer from being present at an
interface between the cation exchange membrane 17a and the
cellulose-based resin film 17b, it may be preferable that the
complex film 17 be formed by bonding the interface between the
cation exchange membrane 17a and the cellulose-based resin film 17b
by heat sealing, ultrasonic bonding, adhesion with an adhesive,
chemical bonding with a cross-linker, or formation of the
cellulose-based resin film 17b on the cation exchange membrane 17a.
In the case of bonding by means of the adhesion, chemical bonding,
or the like, in order to make the integration and adhesion of the
bonding satisfactory, it may be preferable to use the
cellulose-based resin film 17b in which at least the connection
side surface is roughened by an approach such as embossing,
grooving, notching, mechanical polishing, or chemical polishing, or
by mixing an inorganic filler such as calcium carbonate or
magnesium carbonate and an organic filler such as denatured
polyethylene particles or denatured polyacrylic acid resin
particles with a cellulose-based resin.
[0085] The condition of heat sealing and ultrasonic bonding, the
kind and adhesion condition of an adhesive, the kind and
cross-linking condition of a cross-linker, and the like can be
appropriately determined depending upon the kind of the cation
exchange membrane 17a (mainly, the kind of a porous resin film used
in the cation exchange membrane 17a) and the kind of the
cellulose-based resin film 17b. The connection herein may prevent
the administration efficiency of a drug from decreasing due to the
presence of an air layer at the interface between the cation
exchange membrane 17a and the cellulose-based resin film 17b.
Therefore, the bonding should be sufficiently strong such that the
interface will not be peeled off due to the expansion/contraction
and bending of the skin while the iontophoresis device is
mounted.
[0086] In the iontophoresis device X2 according to this embodiment,
the ion-exchange ability of the complex film 17 is enhanced by the
cation exchange membrane 17a, so that the transport number in the
administration of a drug can be increased, and the administration
efficiency of a drug comparable to or higher than that of the
iontophoresis device X1 can be obtained.
Example 1
In Vivo Test 1
[0087] Using a C57BL/6 mouse (male) of 20 to 24 weekly age as a
test animal, an administration test of morphine hydrochloride in
the above-mentioned iontophoresis device X1 was performed.
[0088] NEOSEPTA ALE04-2 produced by Tokuyama Co., Ltd. was used as
each of the anion exchange membranes 13 and 25 of the iontophoresis
device X1. NEOSEPTA CLE04-02 produced by Tokuyama Co., Ltd. was
used as the cation exchange membrane 23. A regenerated cellulose
dialysis membrane UC8-32-25 (average pore diameter: 50 .ANG.,
transmission molecular weight (MWCO): about 14,000, film thickness:
50 .mu.m) of 99% .alpha.-cellulose obtained from Viskase Sales Co.
(Illinois in the US) was used as the cellulose-based resin film 15.
50 mg/mL of morphine hydrochloride was used as a drug solution of
the drug holding part 14. A 7:1 mixed solution of 0.7 mol/L sodium
fumarate aqueous solution and 0.7 mol/L lactic acid aqueous
solution was used as an electrolyte solution of the electrolyte
solution holding parts 12, 22, and 24. The effective area of the
active electrode structure 1 (area of a film surface of the
cellulose-based resin film 15 through which a drug is administered
(see the reference S in FIG. 1) was 2.23 cm.sup.2.
[0089] The drug was administered under the condition that the
active electrode structure 1 and the counter electrode structure 2
were brought into contact with different sites of the shaved
abdomen of the mouse, and a constant current was allowed to flow
continuously at 0.45 mA/cm.sup.2 for 120 minutes.
[0090] FIG. 3A shows the transition of the concentration of
morphine in the blood of the mouse during the passage of a current
under the above-mentioned conditions, and FIG. 3B shows the pH
values of the electrolyte solution of the electrolyte solution
holding parts 12, 22, and 24, and the drug solution of the drug
holding part 14 before the commencement of the passage of a current
and after the completion thereof.
Comparative Example 1
In Vivo Test 2
[0091] Using an iontophoresis device with the same configuration as
that of the iontophoresis device X1 of Example 1 except for using a
cation exchange membrane (NEOSEPTA CLE04-2 produced by Tokuyama
Co., Ltd.) in place of the cellulose-based resin film 15, morphine
hydrochloride was administered to the mouse under the same
conditions as those of Example 1.
[0092] Here, NEOSEPTA ALE04-2 that is an anion exchange membrane
and CLE04-2 that is a cation exchange membrane are ion-exchange
membranes each having a configuration in which a pore of a porous
film is filled with an ion-exchange resin. Therefore the
iontophoresis device used in Comparative Example 1 has the same
configuration as that of the iontophoresis device of JP 2004-188188
A that is considered to exhibit the highest administration
efficiency of a drug in the prior art.
[0093] FIG. 4 shows the transition of the concentration of morphine
in the blood of the mouse during the passage of a current in
Comparative Example 1.
Reference Example 1
In Vitro Test 1
[0094] A test device having a configuration equivalent to that of
the iontophoresis device X1 used in Example 1 was produced, and a
constant current was allowed to flow continuously at 0.45
mA/cm.sup.2 for 120 minutes.
[0095] FIG. 5 illustrates the configuration of the test device. In
FIG. 5, Reference numerals 11 and 21 denote electrodes. Reference
numerals 13 and 25 denote anion exchange membranes (i.e., NEOSEPTA
ALE04-2 produced by Tokuyama Co., Ltd.). Reference numeral 23
denotes a cation exchange membrane (i.e., NEOSEPTA CLE04-2 produced
by Tokuyama Co., Ltd.). Reference numeral 15 denotes a
cellulose-based resin film (i.e., dialysis membrane UC8-32-25
produced by Viskase Sales Co.). Reference numeral 4 denotes the
skin collected from a mouse. An A-chamber, a D-chamber and an
E-chamber are filled with a mixed solution (7:1) of 0.7 mol/L
sodium fumarate aqueous solution and 0.7 mol/L lactic acid aqueous
solution as an electrolyte solution. A B-chamber is filled with 50
mg/mL of morphine hydrochloride as a drug solution. A C-chamber is
filled with physiological saline.
[0096] FIG. 6 shows the transition of the concentration of morphine
in the C-chamber during the passage of a current in Reference
Example 1.
Comparative Reference Example 1
In Vitro Test 2
[0097] Using the same test device as that of Reference Example 1
except for using a cation exchange membrane (i.e., NEOSEPTA CLE04-2
produced by Tokuyama Co., Ltd.) in place of the cellulose-based
resin film 15 in FIG. 5, which has an equivalent configuration to
the iontophoresis device used in Comparative Example 1, a constant
current was allowed to flow continuously at 0.45 mA/cm.sup.2 for
120 minutes.
[0098] FIG. 7 shows the transition of the concentration of morphine
in the C-chamber during the passage of a current in Comparative
Reference Example 1.
[0099] As is apparent from the comparison between FIG. 3A and FIG.
4, the iontophoresis device, employing the cellulose-based resin
film 15, may administer morphine at efficiency of approximately 5
to 10 times or more, even as compared with the iontophoresis device
having the configuration of Comparative Example 1 in which the
administration efficiency of a drug has been conventionally
considered to be highest.
[0100] Furthermore, as shown in FIG. 3B, in the electrolyte
solution in the electrolyte solution holding parts 12, 22, and 24
and the drug solution of the drug holding part 14 of the
iontophoresis device, employing the cellulose-based resin film 15,
the pH values hardly changed before and after the passage of a
current. Thus, it is understood that the biological compatibility,
safety and stability of the administration of a drug may be
ensured.
[0101] Furthermore, as shown in FIGS. 6 and 7, in the in vitro
test, the transfer speed of morphine in the test device (Reference
Example 1) with the cellulose-based resin film 15 was inferior by
about tens of percentages to that of the test device (Comparative
Reference Example 1) with the conventional configuration.
[0102] In the technical field of iontophoresis, the evaluation and
study in vitro are generally performed without using a living body
in a stage of selecting the material of a member of a device and
the like. As described above, the effect of using a cellulose-based
resin film can only be confirmed by the evaluation in vivo, and can
not be confirmed by the evaluation in vitro, and this fact is
considered to be a proof of the difficulty in constituting the
present invention.
[0103] The present invention has been described with reference to
the illustrated embodiments. The present invention is not limited
thereto, and various alterations can be made within the scope of
the claims.
[0104] For example, in the above embodiment, the case has been
described where the active electrode structure includes the
electrolyte solution holding part 12 and the anion exchange
membrane 13, in addition to the electrode 11, the drug holding part
14, and the cellulose-based resin film 15 (or the complex film 17).
However, the electrolyte solution holding part 12 and the
ion-exchange membrane 13 can also be omitted. In this case,
although the function of suppressing the decomposition of a drug in
the vicinity of the electrode 11, the movement of H.sup.+ ions to
the skin interface, the function of suppressing the variation in pH
at the skin interface caused by the movement of H.sup.+ ions, and
the like cannot be achieved to such a degree as that in the
above-mentioned embodiment, the administration efficiency of a drug
to a living body may be achieved similarly, and such an
iontophoresis device is also included in the scope of the present
invention.
[0105] Similarly, regarding the counter electrode structure, the
cation exchange membrane 23 and the electrolyte solution holding
part 24, or the anion exchange membrane 25 in addition to the
cation exchange membrane 23 and the electrolyte solution holding
part 24 can be omitted. In this case, although the performance of
suppressing the change in pH in a contact surface of the counter
electrode structure 2 with respect to the skin 4 cannot be achieved
to such a degree as that in the above-mentioned embodiment, the
administration efficiency of a drug to a living body may be
achieved similarly, and such an iontophoresis device is also
included in the scope of the present invention.
[0106] Alternatively, it is also possible that the counter
electrode structure 2 is not provided in the iontophoresis device,
and for example, under the condition that the active electrode
structure is brought into contact with the biological interface of
a living body and a part of the living body is brought into contact
with a ground such as an electrical coupling to earth, a drug is
administered by applying an electrical potential or voltage to the
active electrode structure. Such an iontophoresis device may also
similarly enhance the administration efficiency of a drug to a
living body and is included in the scope of the present
invention.
[0107] Furthermore, in the above embodiment, the case has been
described where the active electrode structure, the counter
electrode structure, and the power source are configured
separately. It is also possible that those elements are
incorporated in a single casing or an entire device incorporating
them is formed in a sheet shape or a patch shape, whereby the
handling thereof is enhanced, and such an iontophoresis device is
also included in the scope of the present invention.
[0108] All of the above 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.
[0109] From the foregoing it will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims.
* * * * *