U.S. patent application number 14/430869 was filed with the patent office on 2015-08-27 for device for electrochemically releasing a composition in a controlled manner.
This patent application is currently assigned to SORIN CRM SAS. The applicant listed for this patent is NEUROTECH S.A., SORIN CRM SAS, UNIVERSITE CATHOLIQUE DE LOUVAIN. Invention is credited to Vincent Callegari, Jean Delbeke, Sophie Demoustier-Champagne, Benoit Gerard, Lucas Leprince.
Application Number | 20150238758 14/430869 |
Document ID | / |
Family ID | 46963708 |
Filed Date | 2015-08-27 |
United States Patent
Application |
20150238758 |
Kind Code |
A1 |
Delbeke; Jean ; et
al. |
August 27, 2015 |
DEVICE FOR ELECTROCHEMICALLY RELEASING A COMPOSITION IN A
CONTROLLED MANNER
Abstract
According to a first aspect, the invention relates to a device
(10) for electrochemically releasing a composition and comprising:
one working electrode (30) comprising an electroactive conjugated
polymer (40) containing or doped with said composition, a counter
electrode (50), and a reference electrode (60). The device (10) is
characterized in that it comprises electrical means (95, 100; 320;
165, 180) connected to the working electrode (30) and to the
counter electrode (50) for obtaining at said working electrode (30)
at least one composition releasing sequence (65) with respect to
said reference electrode (60), each composition releasing sequence
(65) comprising: a first voltametric pulse (70), followed by a rest
period (80) during which no current is able to flow through said
working electrode (30), followed by a second voltametric pulse
(90), followed by an intermediate period (160) during which no
current is able to flow through said working electrode (30).
Inventors: |
Delbeke; Jean; (Kraainem,
BE) ; Demoustier-Champagne; Sophie; (Bossiere,
BE) ; Callegari; Vincent; (Louvain-la-Neuve, BE)
; Leprince; Lucas; (Bruxelles, BE) ; Gerard;
Benoit; (Dion-le-Mont, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NEUROTECH S.A.
UNIVERSITE CATHOLIQUE DE LOUVAIN
SORIN CRM SAS |
LOUVAIN -LA-NEUVE
LOUVAIN-LA-NEUVE
CLAMART |
|
BE
BE
FR |
|
|
Assignee: |
SORIN CRM SAS
CLAMART
FR
|
Family ID: |
46963708 |
Appl. No.: |
14/430869 |
Filed: |
September 25, 2012 |
PCT Filed: |
September 25, 2012 |
PCT NO: |
PCT/EP2012/068891 |
371 Date: |
March 24, 2015 |
Current U.S.
Class: |
204/230.2 |
Current CPC
Class: |
A61N 1/04 20130101; A61N
1/05 20130101; A61N 1/306 20130101; A61N 1/32 20130101 |
International
Class: |
A61N 1/30 20060101
A61N001/30 |
Claims
1. A device (10) for a controlled electrochemical release of a
composition and comprising: at least one working electrode (30)
comprising an electroactive conjugated polymer (40) containing or
doped with said composition; a counter electrode (50); a reference
electrode (60); characterized in that said device (10) further
comprises: electrical means (95, 100; 320; 165, 180) connected to
the at least one working electrode (30) and to the counter
electrode (50) for obtaining at said at least one working electrode
(30) at least one composition releasing sequence (65) with respect
to said reference electrode (60), each composition releasing
sequence (65) comprising: a first voltametric pulse (70) for
releasing said composition, having a first voltage, a first
polarity and a first duration, followed by a rest period (80)
during which no current is able to flow through said at least one
working electrode (30), followed by a second voltametric pulse (90)
for replacing said composition with at least one ion, having a
second voltage, a second polarity opposite to said first polarity
and a second duration, followed by an intermediate period (160)
during which no current is able to flow through said at least one
working electrode (30), at the end of which another composition
releasing sequence (65) may be applied.
2-15. (canceled)
Description
FIELD OF THE INVENTION
[0001] According to a first aspect, the invention relates to a
device for a controlled electrochemical release of a composition.
Preferably, this device is implantable. According to a second
aspect, the invention relates to a method for a controlled
electrochemical release of a composition.
DESCRIPTION OF PRIOR ART
[0002] The active control of the release of a composition, in terms
of time, quantity and accuracy of delivery, remains a big
challenge. For example in the case of medical applications, the
strategy of substance local delivery is really promising in
comparison with systemic drug taking. Therefore, controlled release
of a composition or drug has become an important mode of treatment
for various diseases. A release rate of such methods can be
controlled mechanically for example, as it is the case in the U.S.
Pat. No. 6,748,954. Alternatively, electrochemical methods can be
used as explained for instance in the patents U.S. Pat. No.
5,422,246, U.S. Pat. No. 4,585,652 or in the patent application
WO2009/050168. As known by the one skilled in the art,
electrochemical methods typically use an electrode coated with an
electroactive conjugated polymer containing or doped with a
composition. This composition, bound to the polymer, is present as
ionic charge to compensate the charge of the polymeric backbone, so
it ensures the polymer electroneutrality. Upon electrical
stimulation, the composition can be released as the conjugated
polymer can be electrically switched between an oxidized and a
reduced state as an example: the electroactive conjugated polymer
is in an oxidized state when containing the composition, whereas it
passes in a reduced state (by the application of a negative voltage
to the electrode covered by the electroactive conjugated polymer)
when the composition has been released.
[0003] In the U.S. Pat. No. 4,585,652, a polymer (polypyrrole for
instance) containing a composition (glutamate for instance) has
been deposited on an electrode to form a film. A voltage time
square wave was then applied to the film between two limits of
opposite polarity. Hence, the square wave comprises voltametric
pulses of opposite polarity. For a value of a given polarity of
these voltametric pulses, the polymer is reduced and for the other
one, it is oxidized. When the film is reduced, release of the
composition takes place. The system proposed in this patent U.S.
Pat. No. 4,585,652 presents some drawbacks. After a release of a
composition because of the application of a reduction pulse for
instance, this composition can immediately be re-attracted to the
polymer film because of the application of an oxidation pulse that
follows. Hence, the composition cannot efficiently diffuse towards
a zone to be treated. In other words, the system of U.S. Pat. No.
4,585,652 lacks efficiency. Second, the pulses of the potential
time square wave (of positive or negative polarity) have a rather
long duration. In the examples given in this patent, these pulses
are applied between a time equal to or longer than 1 s. When
applied to living tissues, such long voltage pulses can lead to
undesirable activation of excitable tissues close to the electrode
comprising the polymer.
[0004] In the publication entitled "Promoting neurite outgrowth
from spiral ganglion neuron explants using polypyrrole/BDNF-coated
electrodes" by Evans A J et al. and published in J Biomed Mater Res
A. 2009 October; 91(1):241-50, another system is proposed for
delivering a composition contained in a polymer deposited on an
electrode. As shown in FIG. 1(b) of this article, an electrode
covered by a polymer containing a composition is subjected to
biphasic current pulses. Between two current pulse phases, there is
a 25 .mu.s open-circuit pulse interphase gap. Such a gap is not
described in the U.S. Pat. No. 4,585,652. Between biphasic current
pulses, there is a short-circuit phase (having a duration of around
3.78 ms). Such a system does not allow one to have a good and
precise control on the quantity of composition that is released. In
particular, due to typical inhomogeneous ionic concentration, this
short-circuit will allow the release of the composition to go on
according to an uncontrolled manner, when no release of the
composition is normally wanted. Also, there is a `burst` of release
of the composition during the first day, even when no electrical
stimulation is applied as shown in FIG. 2(a) of the above mentioned
paper.
SUMMARY OF THE INVENTION
[0005] According to a first aspect, it is an object of the present
invention to provide a device for electrochemically releasing a
composition with a higher control of the quantity and timing of the
released composition. To this end, the device of the invention
comprises: [0006] at least one working electrode comprising an
electroactive conjugated polymer containing or doped with said
composition; [0007] a counter electrode; [0008] a reference
electrode; characterized in that said device further comprises:
[0009] electrical means connected to the at least one working
electrode and to the counter electrode for obtaining at said at
least one working electrode at least one composition releasing
sequence with respect to said reference electrode, each composition
releasing sequence comprising: [0010] a first voltametric pulse for
releasing said composition, having a first voltage, a first
polarity and a first duration, followed by [0011] a rest period
during which no current is able to flow through said working
electrode, followed by [0012] a second voltametric pulse for
replacing said composition with at least one ion, having a second
voltage, a second polarity opposite to said first polarity and a
second duration, followed by [0013] an intermediate period during
which no current is able to flow through said at least one working
electrode, at the end of which another composition releasing
sequence may be applied. Preferably, the composition that is
released is a therapeutic composition.
[0014] The device of the invention is advantageous in that it
comprises electrical means for applying a controlled signal to the
at least one working electrode such that at least one composition
releasing sequence as defined above can be obtained at the working
electrode with respect to the reference electrode. Such electrical
means allow a higher control of the quantity and timing of the
released composition. Indeed, electrochemical release is determined
by the effective voltage. Hence, the device of the invention is
more precise. The electrical means can comprise for instance a
generator, a battery, a switch or a combination of any of such
elements. The electrical means can comprise any other devices
suitable for obtaining voltametric pulses at the working electrode
with respect to the reference electrode. These electrical means
allow obtaining that no current is able to flow through the working
electrode during the rest period and during an intermediate period
between composition releasing sequences contrary to what is
explained in page 243 of Evans A J et al.'s publication. This
ensures that no activation of the electroactive conjugated polymer
allowing a release of the composition takes place when it is not
desired. Hence, the device of the invention provides a higher
control of the quantity and timing of the released composition. By
using the device of the invention, there is no `burst` of release
of the composition during the first day if no biphasic voltage
pulse is applied to the working electrode. During the rest period,
no current is able to flow through the working electrode. This
allows the composition to diffuse efficiently towards and/or into a
zone to be treated (zone of interest) contrary to the system of
U.S. Pat. No. 4,585,652. Preferably, the device of the invention is
rechargeable. Hence, in such a preferred embodiment, it is possible
to recharge the electroactive conjugated polymer with a
composition.
[0015] Preferably, the electrical means comprise a voltage source
and a switch connected between the working and the counter
electrodes. Preferably, the electrical means comprise a current
source connected between the working and the counter
electrodes.
When a current source is used, its very large internal impedance
(this internal impedance tends to infinity in an ideal case),
ensures that no current is able to flow through the working
electrode when a controller associated with the current source
imposes zero current.
[0016] Preferably, the rest period has a duration comprised between
35 .mu.s and 10 ms. Such a preferred duration allows increasing the
efficiency of the release of the composition.
[0017] Preferably, the device of the invention further comprises
determination means for determining a quantity of flowing
electrical charges through the working electrode during the first
and second voltametric pulses. Then, the device of the invention
allows determining a quantity of composition that is released.
Indeed, the released composition comprises ions in methods of
electrochemical release. Therefore, by determining the quantity of
flowing electrical charges through the working electrode during the
first voltametric pulse, one can determine and control the quantity
of released composition. The determination means can comprise for
instance an ammeter for measuring an electrical current between the
working and the counter electrode during the first and second
voltametric pulse. The determination means can also comprise for
instance a time integrator for determining the first duration of
the first voltametric pulse. Then, by integrating the electrical
current flowing through the working electrode, one can determine
the flowing electrical charges through the working electrode during
the first voltametric pulse, and finally the quantity of
composition that is released during the first duration of the first
voltametric pulse. Hence, in this preferred embodiment, the device
of the invention further allows determining a quantity of released
composition. As an illustrative example, it can be estimated from
the electrochemical equations that 1 ms pulses could release about
1 pg Dexamethasone from a 0.1 mm.sup.2 working electrode at -0.45 V
relative to a silver/silver chloride reference electrode. By
comparing the quantity of flowing electrical charges through the
working electrode during the first and second voltametric pulses,
one can check that electro-neutrality is respected. Such an aspect
is of primary importance for biocompatibility reasons when the
device is implantable according to a preferred embodiment.
[0018] Preferably, the device of the invention further comprises
control means for adapting the first duration of the first
voltametric pulse for allowing the device to release a preset
quantity of composition. Such control means can include for
instance a computer or any control unit. Other devices are
possible. By controlling the first duration of the first
voltametric pulse, it is possible to deliver a preset quantity of
composition.
[0019] Preferably, the device of the invention comprises control
means for automatically determining and adapting the second
duration of the second voltametric pulse from a quantity of flowing
electrical charges through the working electrode during the first
voltametric pulse. This preferred embodiment has the advantage of
allowing a control of the electro-neutrality. Such an aspect is of
primary importance for biocompatibility reasons when the device is
implantable.
Preferably, this quantity of flowing electrical charges through the
working electrode during the first voltametric pulse is determined
by the determination means.
[0020] Preferably, Silver or silver choride are used as a material
for the reference, working and counter electrodes. However, Silver
or silver choride are toxic and are thus preferably not used for
implantable electrodes for in-vivo applications. Preferably, for
implantation applications, biocompatible stable materials such as
platinum, platinum-iridium, platinum coated with iridium, iridium,
gold, chromium, carbon, stainless steel can be used for the
reference, working and counter electrodes. Preferably, these three
electrodes are made of a material such that they are characterized
by a stable electrochemical potential in implanted conditions.
[0021] Preferably, the first polarity of the first voltametric
pulse is negative with respect to the reference electrode when the
composition comprises negatively charged ions. In another preferred
embodiment, the first polarity of the first voltametric pulse is
positive with respect to the reference electrode when the
composition comprises positively charged ions.
[0022] Preferably, the device of the invention is implantable in a
mammal body. Then, the first duration of the first voltametric
pulse is preferably such that it prevents the first voltametric
pulse from inducing a stimulation of nerves and/or living tissues.
Preferably, the first duration of the first voltametric pulse is
equal to or shorter than 1 s. Such a small duration induces that a
small quantity of electric charges is delivered during the first
voltametric pulse. As a consequence, the risk of activating tissues
surrounding the working electrode is avoided or strongly limited
when using the device of the invention in-vivo. In another
preferred embodiment, the device of the invention comprises
stimulation means able to produce at the working electrode an
output appropriate for stimulating nerves or living tissues. Hence,
according to this preferred embodiment, the device of the invention
is able to release a composition and to stimulate nerves or living
tissues. Preferably, said stimulation means are able to produce at
the working electrode an output appropriate for stimulating nerves
or living tissues when the composition is totally released.
[0023] According to a second aspect, the invention relates to a
method for a controlled electrochemical release of a composition
from at least one working electrode comprising an electroactive
conjugated polymer containing or doped with said composition, said
method comprising the step of imposing between the at least one
working electrode and a counter electrode specific electrical
conditions for obtaining at said at least one working electrode at
least one composition releasing sequence with respect to a
reference electrode, each composition releasing sequence
comprising: [0024] i) a first voltametric pulse for releasing said
composition and having a first voltage, a first duration and a
first polarity, followed by [0025] ii) a rest period during which
no current is able to flow through said working electrode, followed
by [0026] iii) a second voltametric pulse for replacing said
composition with at least one ion, having a second voltage, a
second duration and a second polarity opposite to the first
polarity, followed by [0027] iv) an intermediate period during
which no current is able to flow through said at least one working
electrode, at the end of which another composition releasing
sequence may be applied. Examples of specific electrical conditions
are: an open-circuit configuration between the working and the
counter electrodes during the rest and intermediate periods by
using a switch connected between these two electrodes; imposing
that no current is able to flow through the working electrode
during the rest and intermediate periods by using a current source
with a zero-current setting point during these periods; tuning the
electrical current flowing through the working electrode during
steps i) and iii) in order to obtain the first and the second
voltametric pulses.
[0028] Preferably, a quantity of electrical charges flowing through
said working electrode during step i) is determined. Then, the
quantity of composition that is released can be determined.
More preferably, a quantity of electrical charges flowing through
said working electrode during step iii) is also determined. Then,
electro-neutrality can be checked by comparing the quantity of
electrical charges flowing through the working electrode during
steps i) and iii).
[0029] Preferably, the number of composition releasing sequences is
adapted for releasing a preset quantity of composition. More
preferably, the frequency of composition releasing sequences is
adapted for releasing a quantity of composition at a preset
rate.
SHORT DESCRIPTION OF THE DRAWINGS
[0030] These and further aspects of the invention will be explained
in greater detail by way of example and with reference to the
accompanying drawings in which:
[0031] FIG. 1 schematically shows a preferred embodiment of the
device of the invention where the electrical means comprise a
voltage source and a switch connected between the working and the
counter electrodes;
[0032] FIG. 2 schematically shows another preferred embodiment of
the device of the invention where the electrical means comprise a
current source connected between the working and the counter
electrodes;
[0033] FIG. 3 shows a preferred embodiment for the working
electrode of the device of the invention;
[0034] FIG. 4 shows an example of monomer units for the
electroactive conjugated polymer;
[0035] FIG. 5 shows the principle of electrochemical release (or
redox process) of a composition that is contained in an
electroactive conjugated polymer;
[0036] FIG. 6 shows an example of composition releasing sequence at
the working electrode with respect to the reference electrode for
releasing the composition according to the invention;
[0037] FIG. 7 shows another preferred example of electrical means
for obtaining at least one composition releasing sequence at the
working electrode;
[0038] FIG. 8 shows an example of electronic circuit of a preferred
embodiment of the electrical means;
[0039] FIG. 9 shows a simplified illustration of the circuit
configuration for the device of the invention when the electrical
means comprise a voltage source;
[0040] FIG. 10 shows a simplified illustration of the circuit
configuration of a solution known in the state of the art.
[0041] The figures are not drawn to scale. Generally, identical
components are denoted by the same reference numerals in the
figures.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Definitions
[0042] The term "composition" as used herein is a set composed of
various substances whose quantities are controlled, preferably
biocompatible substances.
[0043] The term "voltametric pulse" as used herein is defined as a
pulse of given voltage and given duration between a working 30 and
a reference 60 electrodes, resulting from a voltage pulse or
current pulse actively applied between working 30 and counter 50
electrodes. The working electrode current is preferably determined
in order to quantify the amount of charges exchanged.
[0044] The term "composition releasing sequence" as used herein has
a first voltametric pulse 70, followed by a rest period 80 during
which no current is able to flow through the working electrode (or
corresponding to a zero current phase through the working electrode
30), followed by a second voltametric pulse 90 of opposite
polarity, followed by a intermediate period 160 during which no
current is able to flow through the working electrode (or
corresponding to a zero current phase through the working electrode
30), until a possible next composition releasing sequence 65.
[0045] The terms `no current is able to flow through the working
electrode` (during the rest and intermediate periods), means that
the current flowing through said working electrode is then equal to
or lower than 100 nA.
[0046] The term `doped` means that there is an interaction, for
instance an ionic or covalent binding, between the electroactive
conjugated polymer 40 and the composition.
[0047] The term `contains` means that the composition is simply
contained in the electroactive conjugated polymer 40: it refers to
the amount of composition that has no direct interaction with the
electroactive conjugated polymer 40.
[0048] The term "electroactive conjugated polymer" 40 refers to a
polymer which has the ability to undergo reversible redox reaction
when a voltage is applied to them. Such conjugated polymers 40 can
be for instance polymers or copolymers based on heterocycle moiety
as monomers, aniline and substituted aniline derivatives,
cyclopentadiene and substituted cyclopentadiene derivatives,
phenylene or substituted phenylene derivatives, pentafulvene and
substituted pentafulvene derivatives, acetylene and substituted
acetylene derivatives, indole and substituted indole derivatives,
carbazole and substituted carbazole derivatives. Such conjugated
polymers can also be compounds based on formula (I) and (II) shown
at FIG. 4, wherein
n is an integer greater than 1, 2, 3, 4, or 5, or ranges from 1 to
1000, 5 000, 10 000, 100 000, 200 000, 500 000 or 1 000 000 or
higher, X is selected from the group consisting of --NR.sup.1--, O,
S, PR.sup.2, SiR.sup.5R.sup.6, Se, AsR.sup.3, BR.sup.4 wherein R
and R' which can be identical or not are independently selected
from the group consisting of, alkyl, aryl, hydroxyl, alkoxy; or R
and R' together with the carbon atoms to which they are attached
form a ring selected from aryl, heteroaryl, cycloalkyl,
heterocyclyl; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are independently selected from the group consisting of
hydrogen, alkyl or aryl group; A and A' can be independently
selected from the group consisting of heterocycle, heterocyclyl,
alkenyl, alkynyl or aromatic ring and wherein A and A' can be
identical or not.
[0049] The term copolymers as used herein refers to polymers
derived from at least two different monomeric species. Copolymers
can be alternating, periodic, statistical, random or block
copolymers.
[0050] The term "alkyl" by itself or as part of another substituent
refers to a hydrocarbyl radical of Formula C.sub.nH.sub.2n+1
wherein n is a number greater than or equal to 1. Generally, alkyl
groups of this invention comprise from 1 to 6 carbon atoms,
preferably from 1 to 4 carbon atoms, more preferably from 1 to 3
carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl
groups may be linear or branched and may be substituted as
indicated herein. When a subscript is used herein following a
carbon atom, the subscript refers to the number of carbon atoms
that the named group may contain. Thus, for example, C.sub.i-4
alkyl means an alkyl of one to four carbon atoms. C.sub.i-6 alkyl
includes all linear, or branched alkyl groups with between 1 and 6
carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl,
butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl
and its isomers, hexyl and its isomers.
[0051] The term "aryl" as used herein refers to a polyunsaturated,
aromatic hydrocarbyl group having a single ring (i.e. phenyl) or
multiple aromatic rings fused together (e.g. naphtyl). or linked
covalently, typically containing 5 to 12 atoms; preferably 6 to 10,
wherein at least one ring is aromatic. The aromatic ring may
optionally include one to two additional rings (either cycloalkyl,
heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to
include the partially hydrogenated derivatives of the carbocyclic
systems enumerated herein. Non-limiting examples of aryl comprise
phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-, 3-,
4-, 5-, 6-, 7- or 8-azulenyl, naphthalen-1- or -2-yl, A-, 5-, 6 or
7-indenyl, 1-2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or
5-acenaphtenyl, 1-, 2-, 3-, 4- or 10-phenanthryl, 1- or
2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl,
1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or
5-pyrenyl. The aryl ring can optionally be substituted by one or
more substituent(s). An "optionally substituted aryl" refers to an
aryl having optionally one or more substituent(s) (for example 1 to
5 substituent(s)), for example 1, 2, 3 or 4 substituent(s) at any
available point of attachment selected independently in each
incidence. Unless provided otherwise, non-limiting examples of such
substituents are selected from halogen, hydroxyl, oxo, nitro,
amino, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, alkoxy, aryl,
heteroaryl, arylalkyl, haloalkyl, haloalkoxy, alkoxycarbonyl,
alkylcarbamoyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl,
alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl,
arylcarbonyl, carbamoyl, alkylsulfoxide, alkylcarbamoylamino,
sulfamoyl, N--C.sub.1-4-alkylsulfamoyl or N, N--C.sub.1-4
dialkylsulfamoyl, --SO.sub.2R.sup.C, alkylthio, carboxyl, and the
like, wherein R.sup.C is C.sub.1-4alkyl, haloalkyl,
C.sub.3-6cycloalkyl, C.sub.1-4 alkylsulfonamido or optionally
substituted phenylsulfonamido.
[0052] The term "heteroaryl" as used herein by itself or as part of
another group refers but is not limited to 5 to 12 carbon-atom
aromatic rings or ring systems containing 1 to 2 rings which are
fused together or linked covalently, typically containing 5 to 6
atoms; at least one of which is aromatic in which one or more
carbon atoms in one or more of these rings can be replaced by
oxygen, nitrogen or sulfur atoms where the nitrogen and sulfur
heteroatoms may optionally be oxidized and the nitrogen heteroatoms
may optionally be quaternized. Such rings may be fused to an aryl,
cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples
of such heteroaryl, include: pyrrolyl, furanyl, thiophenyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl,
oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl,
pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl,
imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl,
thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl,
thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl,
indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl,
benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl,
1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl,
1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl,
benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl,
1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl,
purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl,
2-oxopyridin-1(2H)-yl, 6-oxo-pyrudazin-1(6H)-yl,
2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl,
isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.
[0053] The term "cycloalkyl" as used herein is a cyclic alkyl
group, that is to say, a monovalent, saturated, or unsaturated
hydrocarbyl group having 1 or 2 cyclic structure. Cycloalkyl
includes all saturated hydrocarbon groups containing 1 to 2 rings,
including monocyclic or bicyclic groups. Cycloalkyl groups may
comprise 3 or more carbon atoms in the ring and generally,
according to this invention comprise from 3 to 10, more preferably
from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon
atoms. The further rings of multi-ring cycloalkyls may be either
fused, bridged and/or joined through one or more spiro atoms.
Cycloalkyl groups may also be considered to be a subset of
homocyclic rings discussed hereinafter. Examples of cycloalkyl
groups include but are not limited to cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, with cyclopropyl being particularly
preferred. An "optionally substituted cycloalkyl" refers to a
cycloalkyl having optionally one or more substituent(s) (for
example 1 to 3 substituent(s), for example 1, 2 or 3
substituent(s)), selected from those defined above for substituted
alkyl. When the suffix "ene" is used in conjunction with a cyclic
group, this is intended to mean the cyclic group as defined herein
having two single bonds as points of attachment to other
groups.
[0054] The terms "heterocyclyl" or "heterocyclo" as used herein by
itself or as part of another group refer to non-aromatic, fully
saturated or partially unsaturated cyclic groups (for example, 3 to
7 member monocyclic, 7 to 1 1 member bicyclic, or containing a
total of 3 to 10 ring atoms) which have at least one heteroatom in
at least one carbon atom-containing ring. Each ring of the
heterocyclic group containing a heteroatom may have 1, 2, 3 or 4
heteroatoms selected from nitrogen atoms, oxygen atoms and/or
sulfur atoms, where the nitrogen and sulfur heteroatoms may
optionally be oxidized and the nitrogen heteroatoms may optionally
be quaternized. The heterocyclic group may be attached at any
heteroatom or carbon atom of the ring or ring system, where valence
allows. The rings of multi-ring heterocycles may be fused, bridged
and/or joined through one or more spiro atoms. An optionally
substituted heterocyclic refers to a heterocyclic having optionally
one or more substituent(s) (for example 1 to 4 substituent(s), or
for example 1, 2, 3 or 4 substituent(s)), selected from those
defined above for substituted aryl. Non limiting exemplary
heterocyclic groups include aziridinyl, oxiranyl, thiiranyl,
piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl
imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl,
thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl,
3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl,
2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl,
2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl,
3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl,
3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl,
1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl,
2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl,
tetrahydrothiophenyl, tetrahydroquinolinyl,
tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl,
tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl,
thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide,
thiomorpholin-4-ylsulfone, 1, 3-dioxolanyl, 1,4-oxathianyl,
1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolizinyl,
tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and
morpholin-4-yl.
[0055] The term "alkenyl" as used herein refers to an unsaturated
hydrocarbyl group, which may be linear, branched or cyclic,
comprising one or more carbon-carbon double bonds. Alkenyl groups
thus comprise between 2 and 6 carbon atoms, preferably between 2
and 4 carbon atoms, still more preferably between 2 and 3 carbon
atoms. Examples of alkenyl groups are ethenyl, 2-propenyl,
2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its
isomers, 2,4-pentadienyl and the like. An optionally substituted
alkenyl refers to an alkenyl having optionally one or more
substituent(s) (for example 1, 2 or 3 substituent(s), or 1 to 2
substituent(s)), selected from those defined above for substituted
alkyl.
[0056] The term "alkynyl" as used herein, similarly to alkenyl,
refers to a class of monovalent unsaturated hydrocarbyl groups,
wherein the unsaturation arises from the presence of one or more
carbon-carbon triple bonds. Alkynyl groups typically, and
preferably, have the same number of carbon atoms as described above
in relation to alkenyl groups. Non limiting examples of alkynyl
groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl
and its isomers, 2-hexynyl and its isomers and the like. An
optionally substituted alkynyl refers to an alkynyl having
optionally one or more substituent(s) (for example 1 to 4
substituent(s), or 1 to 2 substituent(s)), selected from those
defined above for substituted alkyl.
Preferred Embodiments
[0057] FIG. 1 shows a preferred embodiment of a device 10 according
to a first aspect of the invention. This device 10 comprises a
working electrode 30, a counter electrode 50 and a reference
electrode 60. The working electrode 30 comprises an electroactive
conjugated polymer 40 (not shown in FIG. 1) that contains or that
is doped with a composition. Even if it is preferred to have a
three electrodes configuration (comprising the working 30, counter
50, and reference 60 electrode), one could use the device 10 of the
invention with only two electrodes. In this case, the counter 50
and reference 60 electrodes are identical. Nevertheless, as known
by the one skilled in the art, a reference electrode 60 is
preferably an electrode with zero current. Counter electrode 50 is
sometimes named current drain by the one skilled in the art.
[0058] In the preferred embodiment shown in FIG. 1, electrical
means for obtaining at the working electrode 30 at least one
composition releasing sequence 65 comprise a voltage source 95 and
a switch 100 connected between the working 30 and the counter 50
electrodes. As shown in FIG. 1, the voltage source 95 is preferably
adjusted through a controller 300 so that the voltage between
working 30 and reference 60, measured by amplifier 310, reaches the
preset level of the voltametric pulses (70 and 90). Preferably, an
ammeter 110 connected to the controller 300 allows one to measure
the electric current flowing through the working electrode 30, and
so the delivered quantity of electric charges during the first 70
and/or second 90 voltamectric pulses. Preferably, the controller
300 is able to control the switch 100 and the electric charges
balance between first 70 and second 90 voltametric pulses. The
switch 100 allows imposing that no current is able to flow through
the working electrode 30 during the rest period 80 and during an
intermediate period 160 between two composition releasing sequences
65.
[0059] FIG. 2 schematically shows another preferred embodiment of
the device 10 of the invention when the electrical means comprise a
current source 320 for obtaining at the working electrode 30 the at
least one composition releasing sequence 65. In this case, the
controller 300 continuously adjusts the electrical current provided
by the current source 320 in order to induce an electric voltage
between the working 30 and the reference electrode 60 that follows
a desired preset voltametric pulse amplitude and duration. In this
case, no switch 100 is necessary. As shown in FIG. 2, the electric
voltage between the working 30 and the reference 60 electrodes is
preferably provided to a controller 300 by the intermediate of an
amplifier 310. The controller 300 and the current source 320 are
able to impose that no current is able to flow through the working
electrodes 30 (in particular during the rest 80 and the
intermediate 160 periods) as a current source has a very large
internal impedance (this internal impedance tends to infinity for
an ideal current source when current output is set to zero). Hence,
the controller 300 and the current source 320 allow obtaining rest
80 and intermediate 160 periods during which no current is able to
flow through the working electrode 30.
[0060] Upon electrical stimulation of the working electrode 30, the
composition can be released. The working electrode 30 is
electrically connected to electrical means capable of charging and
discharging the electroactive conjugated polymer 40. More
precisely, these electrical means are able to apply a controlled
signal to the working electrode 30 in order to obtain at the
working electrode 30 at least one composition releasing sequence 65
with respect to the reference electrode 60. In the simplified
illustrations of FIGS. 1 and 2, these electrical means are
represented by either (FIG. 1) a voltage source 95 and a switch 100
that are connected in series to the working electrode 30, either
(FIG. 2) a current source 320. Preferably, these electrical means
are coupled to a controller 300. The voltage source 95 is also
electrically connected to the counter electrode 50 in the example
shown in FIG. 1. Preferably, the device 10 of the invention also
includes determination means 110. These determination means 110 are
able to determine a quantity of flowing electrical charges between
the working 30 and the counter 50 electrode during the first
voltametric pulse 70. Preferably, the determination means 110 are
also able to determine a quantity of flowing electrical charges
between the working 30 and the counter 50 electrodes during the
second voltametric pulse 90. Preferably, the determination means
110 comprise an ammeter, for measuring an electrical current
between the working 30 and the counter 50 electrodes, and a time
integrator for determining the first duration of the first
voltametric pulse 70. Preferably, such a time integrator is also
able to determine the second duration of the second voltametric
pulse 90. In a preferred embodiment, the three electrodes (30, 50
and 60) are in contact with a physiological medium such as spinal
fluid, lymph, nerve, muscle or any other tissue as an example. In a
preferred use, the three electrodes (30, 50 and 60) are implanted
in a mammal body for releasing a composition in vivo. Preferably,
the working electrode 30 is coated with the electroactive
conjugated polymer 40 and the working 30, counter 50 and reference
60 electrodes are made of platinum or of any biocompatible noble
metal or metal combination that can provide a stable potential
reference in a mammal body. In a preferred embodiment, the working
electrode 30 comprises nanoscopic sized electrically conducting
surface microstructures 140 coated by the electroactive conjugated
polymer 40 containing the composition as shown in FIG. 3.
[0061] Electrochemical release of a composition is notably
described in the patent application WO2009/050168 and is known by
the one skilled in the art. In a preferred embodiment, the
electroactive conjugated polymers 40 are based on heterocycle
moiety as monomers such as pyrrole and substituted pyrrole
derivatives, furan and substituted furan derivatives, thiophene and
substituted thiophene derivatives, phosphole and substituted
phosphole derivatives, silole and substituted silole derivatives,
arsole and substituted arsole derivatives, borole and substituted
borole derivatives, selenole and substituted selenole derivatives
or aniline and substituted aniline derivatives. In a preferred
embodiment, the conjugated polymers are based on pyrrole and
substituted pyrrole derivatives. This list in not exhaustive.
Electroactive conjugated polymer 40 can also be a compound based on
formula (I) and (II) of FIG. 4.
[0062] The electroactive conjugated polymer 40 of the device 10 of
the invention may also be combined with or doped with a composition
such as for example a therapeutic composition or a drug, which,
according to the invention, shall be locally released upon further
electrical stimulation. The composition may comprise natural
compounds, or biological molecules of interest. Natural compounds
may be vitamins. Biological molecules may be nucleic acids such as
nucleotides, oligonucleotides, antisense oligonucleotides, DNA, RNA
and mRNA; amino acids and natural, synthetic and recombinant
proteins, glycoproteins, polypeptides, peptides, enzymes;
antibodies, hormones, cytokines and growth factors. The composition
may comprise chemical molecules. Preferably, the composition
comprises one or more anticancer drugs, antipsychotic,
antiparkinsonian agents, antiepileptic agents, antimigraine agents.
The electroactive conjugated polymer 40 of the device 10 of the
invention is preferably doped with a composition or drug that can
be locally released upon further electrical stimulation. The
composition may comprise bioactive molecules of interest including,
for example, nutritional substances such as vitamins; active
compounds such as anticancer drugs, antipsychotic, antiparkinsonian
agents, antiepileptic agents, antimigraine agents; nucleic acids
such as nucleotides, oligonucleotides, antisense oligonucleotides,
DNA, RNA and mRNA; amino acids and natural, synthetic and
recombinant proteins, glycoproteins, polypeptides, peptides,
enzymes; antibodies, hormones, cytokines and growth factors.
Preferably, the composition comprises one or more antiinflammatory
agents. More preferably, the composition comprises one or more
anti-TNF-alpha agents such as adalimumab, infliximab, etanercept,
certolizumab pegol, and golimumab; one or more steroidal
anti-inflammatory agents such as dexamethasone disodium; one or
more non-steroidal anti-inflammatory agents like aceclofenac,
acemetacin, aspirin, celecoxib, dexibuprofen, dexketoprofen,
diclofenac, diflunisal, etodolac, etoricoxib, fenbrufen,
fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen,
ketorolac trometamol, lumiracoxib, mefanamic acid, meloxicam,
nabumetone, naproxen, nimesulide, oxaprozin, parecoxib,
phenylbutazone, piroxicam, proglumetacin, sulindac, tenoxicam, and
tiaprofenic acid.
[0063] FIG. 5 schematically shows the principle of electrochemical
release (or redox process) of a composition that is contained in an
electroactive conjugated polymer 40. More precisely, FIG. 5 depicts
the redox process at the basis of release of a composition (A-),
where polypyrrole (electroactive conjugated polymer 40) in an
oxidized conductive form 120 is shown converting to polypyrrole in
a neutral form 130 after electrical stimulation. `A-` represents
hydrated ions (the composition) and `x` the oxidation state of
pyrrole unit in polypyrrole. In the example shown in FIG. 5,
release of the composition is induced by reduction of the
electroactive conjugated polymer 40.
[0064] FIG. 6 shows an example of composition releasing sequence 65
that can be obtained at the working electrode 30 for releasing the
composition according to the invention. More precisely, FIG. 6
shows the time evolution of the electrical potential of the working
electrode 30 during a composition releasing sequence 65 with
respect to the electrical potential of the reference electrode 60
(the abscissa T in FIG. 6 stands for time). Hence, a zero value of
the electrical potential 150 is equal to the electrical potential
150 of the reference electrode 60 in this figure. In the example
shown in FIG. 6, it is assumed that the first 70 and second 90
voltametric pulses have a square shape. Other shapes are
nevertheless possible: as an example, pulses having triangular
shapes can be used. The first 70 and second 90 voltametric pulses
are separated by a rest period 80 during which the electrical
voltage of the working electrode 30 with respect to the reference
electrode 60 is unknown. A composition releasing sequence 65
finally comprises an intermediate period 160 at the end of which
another composition releasing sequence 65 may be applied. Both rest
80 and intermediate 160 periods correspond to time durations during
which no current is able to flow through the working electrode 30
and to time durations where electrical potential of the working
electrode 30 is unknown and not actively applied.
[0065] During the first duration of the first voltametric pulse 70,
the composition included in the electroactive conjugated polymer 40
is released. In the example of FIG. 6, it is assumed that a
reduction of the electroactive conjugated polymer 40 allows a
release of the composition. Hence, the voltage applied to the
working electrode 30 during the first voltametric pulse 70 is
negative with respect to the reference electrode 60. A release of a
composition included in an electroactive conjugated polymer 40
after its oxidation (positive first voltametric pulse 70 in this
case) is nevertheless possible for some compounds. In both cases,
the applied voltage is optimized for an efficient release of the
target compound or composition. After the release of the
composition, it is desired not to re-attract it towards the working
electrode 30 such that it can diffuse towards and/or into a zone of
interest. Therefore, according to the invention, the composition
releasing sequence 65 comprises a rest period 80 before a second
voltametric pulse 90 is applied. During this second voltametric
pulse 90, ions of the composition having diffused towards a
targeted zone are replaced by others, but similarly charged, ions
that are attracted towards the working electrode 30 because of the
application of the second voltametric pulse 90. The voltage of this
second voltametric pulse 90 is optimized for efficient replacement
of the composition by a selected ion in the surrounding solution.
When the three electrodes (30, 50, and 60) are implanted in living
tissues, the ions allowing an efficient replacement of the
composition are often chloride ions.
[0066] The durations of the first voltametric pulse 70, of the rest
period 80, of the second voltametric pulse 90 and of the
intermediate period 160 can be different. During the first
voltametric pulse 70, the electroactive conjugated polymer 40 is
reduced (negative voltage of the first voltametric pulse 70) or
oxidized (positive voltage of the first voltametric pulse 70)
depending on its electrochemical properties. Preferably, the first
voltametric pulse 70 has a first duration equal to or shorter than
1 s. For example, for in vivo applications using electrode contacts
of about 0.5 mm.sup.2, when an electrical current of 100 .mu.A is
measured during the first voltametric pulse 70, flowing through the
working 30 electrode, the first duration of the first voltametric
pulse 70 is preferably chosen equal to or shorter than 100 .mu.s.
That means that the corresponding amount of delivered electrical
charges is lower than or equal to 10 nC. Such a low value does not
normally induce a stimulation of surrounding nerves or living
tissues. In fact, if it is desired to prevent any stimulation of
tissues surrounding the working electrode 30 during the first
voltametric pulse 70, the quantity of delivered electric charges
during this first voltametric pulse 70 should be kept lower than 65
nC. The optimal duration of the rest period 80 depends on the used
electroactive conjugated polymer 40 and composition, and on
environment in contact with the working electrode 30. Preferably,
the rest period 80 is shorter than 10 ms but longer than 35 .mu.s.
During this rest period 80, the composition can diffuse in a
targeted zone (living tissues as an example). Preferably, the
second duration of the second voltametric pulse 90 is automatically
determined from the quantity of flowing electrical charges between
the working 30 and counter 50 electrodes during the first
voltametric pulse 70 that is determined by the determination means
110. It is preferably desired to recover during the second
voltametric pulse 90 the same amount of electric charges as the
quantity of electrical charges delivered during the first
voltametric pulse 70. Preferably, the duration of the second
voltametric pulse 90 is equal or lower than 1 s. Preferably, an
electrical current flowing through the working electrode 30 is
measured during the second voltametric pulse 90 so that same
electric charge as delivered electric charge during the first
voltametric pulse 70 is recovered.
[0067] The magnitude of the voltage applied to the working
electrode 30 during the first voltametric pulse 70 depends on the
optimal voltage allowing an efficient release of the composition
included in the electroactive conjugated polymer 40. Such a value
can be determined by observing the oxydo-reduction peaks of the
electroactive conjugated polymer 40 measured with a cyclic
voltametry method as an example. Generally, the magnitude of the
voltage at the working electrode 30 with respect to the reference
electrode 60 during the first voltametric pulse 70 is comprised
between -1 V and 0 V for most electroactive conjugated polymers 40.
Preferably, such a magnitude is equal to -0.45 V referred to
Silver/Silver Chloride or -0.61 V referred to Platinum for
Dexamethasone loaded Polypyrrole. When a reduction process of the
electroactive conjugated polymer 40 allows a release of a
composition, the voltage applied at the working electrode 30 with
respect to the reference electrode 60 during the first voltametric
pulse 70 is negative. This allows a release of a composition that
comprises negative ions. Then, the second voltametric pulse 90 has
a positive polarity. The voltage magnitude of the second
voltametric pulse 90 preferably corresponds to the electrochemical
potential of the replacement ions (Chloride for instance). The
magnitude of the second voltametric pulse 90 is preferably chosen
such that maximum oxidation (or reduction) of the electroactive
conjugated polymer 40 takes place during this second voltametric
pulse 90. When the electroactive conjugated polymer 40 is
Dexamethasone loaded polypyrrole, such a magnitude is preferably
chosen between 0 V and 1 V. More preferably, this magnitude is
equal to 0.3 V referred to silver/silver chloride or 0.14 V
referred to platinum. When the composition comprises positive ions,
the first polarity of the first voltametric pulse 70 is positive
with respect to the reference electrode 60. The second voltametric
pulse 90 has then a negative polarity preferably corresponding to
the electrochemical potential of the replacement ions (potassium
for instance).
[0068] As explained in the previous paragraph, the voltage to apply
during the first voltametric pulse 70 is predetermined by the
composition to release and by the electroactive conjugated polymer
40; the electric current between the working 30 and counter 50
electrodes during same first voltametric pulse 70 depends on the
impedance between these two electrodes that cannot be adjusted.
Thus, the duration of the first voltametric pulse 70 is used to
control the amount of delivered electrical charges during the first
voltametric pulse 70. For in vivo applications, this amount is
chosen to be less than a threshold (around 65 nC typically)
corresponding to a possible stimulation of tissues surrounding the
working electrode 30. The quantity of composition that is released
is directly proportional to the duration of the first voltametric
pulse 70, i.e to the electric charges that are delivered at the
working electrode 30.
[0069] FIG. 7 shows another example of electrical means for
obtaining at the working electrode 30 at least one composition
releasing sequence 65 such the one shown in FIG. 6. A control unit
170 such as a computer is able to send instructions and electric
power from a battery 165 to an electronic housing 180 through a USB
cable 190 as an example. The electronic housing 180 has a set of
inputs 210 and a set of outputs 220. These outputs 220 are
connected to the working 30, counter 50 and reference 60 electrodes
through cables 200. Preferably, these cables 200 are shielded
cables. When the control unit 170 is a computer, it preferably
comprises a software module comprising processing data such as the
voltage to apply during the first voltametric pulse 70 to have an
optimal release of the composition, the optimal duration of the
rest period 80 to have maximum diffusion for different compositions
and the optimal second voltametric pulse 90 to restore the
electroactive conjugated polymers 40 by preferably replacing the
composition by suitable different ions. This software module
preferably also comprises instructions for controlling a switch 100
for instance in order to produce the composition releasing sequence
65. In a preferred embodiment, the device 10 is implantable and can
be implanted for instance in a mammal body. The control unit 170 is
preferably a microprocessor that can function autonomously. In
still another preferred embodiment, the implant can be miniaturized
to the extreme such that the electrodes 30, 50, and 60 are
controlled and powered by telemetry through the skin. In such an
embodiment, the control unit 170 and the battery 165 are not
implanted and the USB cable 190 does not exist. The reduced
implanted electronic housing 180 would then be integrated with the
electrodes 30, 50, and 60. In a preferred embodiment, in case the
device 10 is implantable, it features a battery-based power source
with either a primary cell or rechargeable battery. Programmed data
(for instance pulse characteristics and regimen) can be either
preset or wirelessly transmitted to the device 10 through a skin of
a mammal body and the device 10 preferably features a small local
microprocessor to process the data. The device electronics,
ultra-low power and compact, is then preferably encapsulated in a
biocompatible material with some proper means to connect to the
three electrodes (30, 50, 60).
[0070] FIG. 8 shows a preferred example of electronic circuit of
the electronic housing 180 for the preferred embodiment shown in
FIG. 7. The working electrode 30 is connected to the output 225,
and the counter electrode 50 is connected to output 228 that is
connected to ground 230. Input 215 allows measuring the electric
potential of the working electrode 30. It the example shown in FIG.
8, it is assumed that there are two reference electrodes 60. For
biocompatible reasons, it is preferred to use titanium or platinum
for the reference electrode 60 as an example. However, such an
electrode can present a varying electric potential because of
various physical effects, such as a variation in temperature. By
using two reference electrodes 60 and by comparing the stability of
their electric potential (thanks to inputs 216 and 217), one can
calculate an ideal reference potential from the variable reference
electrode 60 potential. Such two or more reference electrodes are
connected to outputs 226 and 227 of FIG. 8. Inputs 216 and 217 are
preferably connected to a control unit 170 to check the electric
potential of these two reference electrodes 60. The switch 100 of
FIG. 8 is controlled by a digital input 211. In FIG. 8 the switch
100 is assumed to be an optocoupler (or optoisolator). This switch
100 is closed during the first 70 and second 90 voltametric pulses,
whereas it is open during the rest period 80 and during the
intermediate period 160 between two composition releasing sequences
65. When the switch 100 is open, there is zero current flow through
the working electrode 30 (or said in an equivalent manner, no
current is able to flow through the working electrode 30). Hence,
the switch 100 allows imposing that no current is able to flow
through the working 30 electrode during the rest period 80 and
during the intermediate period 160 between two composition
releasing sequences 65. An analog input 214 allows fixing the
voltage values of the first 70 and second 90 voltametric pulses
with respect to the reference electrode 60. For the composition
releasing sequences 65 shown in FIG. 6, this voltage value is
negative (respectively positive) during the first 70 (respectively
second 90) voltametric pulse. As shown in FIG. 8, there are also an
operational amplifier 255 and different resistors 240, 245, and
250. Preferably, the resistors 240 and 245 have an electric
resistance of 1 kOhm. Preferably, the resistor 250 has an electric
resistance of 100 Ohms. By measuring the difference between the
electrical potentials of inputs 213 and 212, one can deduce the
electrical current flowing through the output 225 when the switch
100 is closed (as the value of the resistor 240 is known). As an
alternative of the situation described in FIG. 8, the electrical
current that is delivered can be measured on a resistor inserted
between 228 and 230. In this case, the measurement would be
referred to the ground but this is only possible when a single drug
releasing channel is used because multiple channel systems would
use a common counter electrode 50. A measure of this electric
current flowing during the first voltametric pulse 70 is important
because this measurement should allow one to determine the duration
of the second voltametric pulse 90. Indeed, as an electric current
is a measure of the number of electric charges carried per unit
time, it is then possible to deduce the number of electric charges
delivered if one knows the electric current flowing through the
working electrode 30 and the duration during which such a current
flows. This is done by time integration of this electric current
during the first duration of the first voltametric pulse 70.
Knowing the number of electric charges delivered during the first
voltametric pulse 70, one has to adapt the second duration of the
second voltametric pulse 90 so that the amount of electric charges
recovered during the second voltametric pulse 90 compensates the
quantity of electric charges delivered during the first voltametric
pulse 70.
[0071] As illustrated in FIG. 8, during the intermediate period 160
between two composition releasing sequences 65, the electrical
circuit imposes that no current is able to flow through the working
electrode 30 connected to output 225. Such a configuration is
different from the solution proposed in FIG. 1 of the article
entitled "Promoting neurite outgrowth from spiral ganglion neuron
explants using polypyrrole/BDNF-coated electrodes" by Evans A J et
al. and published in J Biomed Mater Res A. 2009 October;
91(1):241-50. In this publication, the intermediate period between
two biphasic current pulses correspond to a short-circuit phase.
FIG. 9 presents a simplified view of the circuit configuration for
the invention when the electrical means comprise a voltage source
95, whereas FIG. 10 presents a simplified view of the circuit
configuration for the solution proposed in afore-mentioned
publication. These figures are only shown for explaining the
differences between the invention and the set-up of Evans A J et
al's article when a a voltage source 95 is used for the device 10
of the invention. Hence, these figures do not relate to real
circuit implementations. The circuits on the left parts correspond
to the periods during which voltage (FIG. 9) or current (FIG. 10)
pulses takes place at the working electrode 30. The circuits on the
right parts correspond to the intermediate periods during which no
pulse is applied to the working electrode 30. In FIG. 10, the
electrodes 30 and 50 are connected to a current source 260 and
during the intermediate period, there is a short-circuit
configuration as explained in page 243 of the afore-mentioned
article. The solution proposed in the invention and as illustrated
in FIG. 9 allows a better control of release of a composition
compared to the solution proposed in the afore-mentioned
publication, notably allowing avoiding such a release when it is
not desired (passive release) thanks to imposing zero current
through the working electrode 30 as illustrated in the right part
of FIG. 9. For the device 10 of the invention, an open-circuit
configuration (zero current) is indeed imposed during the rest
period 80 as well as during an intermediate period 160 between two
composition releasing sequences 65. Hence, even if electrical
charges have been accumulated in a living tissue for instance, the
open-circuit configuration (zero current) (imposed by the switch
100 in the example shown in FIG. 9) prevents these charges from
flowing during the rest period 80 as well as during an intermediate
period 160 through the working electrode 30.
[0072] As explained above, in a preferred embodiment, the
electrodes 30, 50, 60, the switch 100, and a voltage source 95 are
implanted in a human or animal body. Biocompatible wires then
connect this voltage source 95 to the working electrode 30 via the
switch 100. In such an embodiment, the switch 100 can be remotely
activated so that the release of a composition can be initiated or
interrupted without the need of surgical procedures. A control unit
170 and electronic housing 180 are also preferably implanted is
such a case.
[0073] In another preferred embodiment, the device 10 comprises
several working electrodes 30 for delivering a same composition at
different places or for delivering different types of composition.
In the latter case, the different working electrodes 30 are
preferably controlled separately, and the controlled signals
applied to them are preferably adjusted to allow an optimal release
of the corresponding composition. In such an embodiment, the device
10 can comprise only one counter electrode 50 if each channel has
an independent current measuring resistor 240, for example as
represented in FIG. 8. One or more reference electrodes 60 can be
used.
[0074] Preferably, the first duration of the first voltametric
pulse is such that it prevents said first voltametric pulse from
inducing a stimulation of nerves and/or living tissues. In another
preferred embodiment, the electrical means for obtaining at the
working electrode 30 the at least one composition releasing
sequence 65 are also able to produce at the working electrode 30 an
output appropriate for stimulating nerves or living tissues. Then,
the device 10 of the invention can be used both for delivering a
composition and for stimulating nerves or living tissues. In this
last preferred embodiment, the electrical means are able to produce
at the working electrode 30 an output appropriate for stimulating
nerves or living tissues preferably when the composition is totally
released. However, in other preferred embodiments, stimulations of
nerves or living tissues could take place concurrently to the
release of the composition. Preferably, the same voltage 95 or
current 260 sources and the same controller 300 and same control
unit 170 are used for delivering the composition and for
stimulation nerves or living tissues when the device 10 of the
invention is used both for delivering a composition and for
stimulating nerves or living tissues. However, the device 10 could
comprise specific stimulation means for producing at the working
electrode 30 an output appropriate for stimulating nerves or living
tissues; that means that specific stimulation means, different from
the electrical means used for lectrochemically releasing a
composition, could be used in this preferred embodiment.
PREFERRED EXPERIMENTAL DETAILS
a) Preparation of the Working Electrode 30
[0075] The working electrode 30 is preferably electrochemically
prepared. The elaboration consists in coating a thin polymer film
on the said working electrode 30, which contains at least one
surface made of metal. For that, a classical three electrode set up
is used. The working electrode 30, a reference electrode 60, and a
counter-electrode 50 are immersed in a solution containing the
monomer and an electrolytic salt comprising at least the
composition to release. The polymer coating on the working
electrode 30 is preferably made by oxidizing the monomer. During
the polymerization, the composition is incorporated within the
polymer as counter-ion.
b) In-Vitro Composition Release
[0076] The active release of the composition from the working
electrode 30 coated with the polymer is then electrochemically
performed. For that, a classical three electrode set up is used.
The working electrode 30, a reference electrode 60, and a counter
electrode 50 are immersed in saline bath as electrolytic bath to
approximate in-vivo conditions. Voltage cycles are then preferably
applied to the working electrode 30.
c) In-Vitro Release Monitoring
[0077] Monitoring the release is preferably carried out by removal
of the electrolytic solution, using a method of characterization
depending upon the nature of the composition.
[0078] According to a second aspect, the invention relates to a
method a method for a controlled electrochemical release of a
composition from at least one working electrode 30 comprising an
electroactive conjugated polymer 40 containing or doped with said
composition, said method comprising the step of imposing between
the at least one working electrode 30 and a counter electrode 50
specific electrical conditions for obtaining at said at least one
working electrode 30 at least one composition releasing sequence 65
with respect to a reference electrode 60, each composition
releasing sequence 65 comprising: [0079] i) a first voltametric
pulse 70 for releasing said composition and having a first voltage,
a first duration and a first polarity, followed by [0080] ii) a
rest period 80 during which no current is able to flow through said
working electrode 30, followed by [0081] iii) a second voltametric
pulse 90 for replacing said composition with at least one ion,
having a second voltage, a second duration and a second polarity
opposite to the first polarity, followed by [0082] iv) an
intermediate period 160 during which no current is able to flow
through said at least one working electrode 30, at the end of which
another composition releasing sequence 65 may be applied.
Preferably, a quantity of electrical charges flowing through said
working electrode 30 during step i) is determined. More preferably,
a quantity of electrical charges flowing through said working
electrode 30 during step iii) is determined.
[0083] Preferably, the number of composition releasing sequences 65
is adapted for releasing a preset quantity of composition. More
preferably, the frequency of composition releasing sequences 65 is
adapted for releasing a quantity of composition at a preset
rate.
[0084] The present invention has been described in terms of
specific embodiments, which are illustrative of the invention and
not to be construed as limiting. More generally, it will be
appreciated by persons skilled in the art that the present
invention is not limited by what has been particularly shown and/or
described hereinabove. The invention resides in each and every
novel characteristic feature and each and every combination of
characteristic features. Reference numerals in the claims do not
limit their protective scope. Use of the verbs "to comprise", "to
include", "to be composed of", or any other variant, as well as
their respective conjugations, does not exclude the presence of
elements other than those stated. Use of the article "a", "an" or
"the" preceding an element does not exclude the presence of a
plurality of such elements.
[0085] Summarized, the invention may also be described as follows.
According to a first aspect, the invention relates to a device 10
for electrochemically releasing a composition and comprising: one
working electrode 30 comprising an electroactive conjugated polymer
40 containing or doped with said composition, a counter electrode
50, and a reference electrode 60. The device 10 of the invention is
characterized in that it comprises electrical means (95, 100; 320;
165, 180) connected to the working electrode 30 and to the counter
electrode 50 for obtaining at said working electrode 30 at least
one composition releasing sequence 65 with respect to said
reference electrode 60, each composition releasing sequence 65
comprising: a first voltametric pulse 70, followed by a rest period
80 during which no current is able to flow through said working
electrode 30, followed by a second voltametric pulse 90, followed
by an intermediate period 160 during which no current is able to
flow through said working electrode 30. According to a second
aspect, the invention relates to a method for electrochemically
releasing a composition.
[0086] The following numerals have been used: [0087] "10" The
device of the invention [0088] "30" The working electrode [0089]
"40" The electroactive conjugated polymer [0090] "50" The counter
electrode [0091] "55" Amplifier [0092] "60" The reference electrode
[0093] "65" Composition releasing sequence [0094] "70" The first
voltametric pulse during which the composition is released [0095]
"80" The rest period between the voltametric pulses [0096] "90" The
second voltametric pulse during which the composition is replaced
[0097] "95" Voltage source [0098] "100" Switch [0099] "110" Means
for measuring an electric current between the working electrode
[0100] "30" and the counter "50" electrode [0101] "120" Polypyrrole
oxidized conductive form [0102] "130" Polypyrrole neutral form
[0103] "140" Nanoscopic sized electrically conducting surface
microstructures [0104] "160" Intermediate rest period [0105] "165"
Battery [0106] "170" Control unit (ex: Computer) [0107] "180"
Electronic housing [0108] "190" USB cable [0109] "200" Cables
[0110] "210" ("211" to "217") Electronic housing inputs [0111]
"220" ("225" to "228") Electronic housing outputs [0112] "230"
Ground [0113] "240" Resistor [0114] "245" Resistor [0115] "250"
Resistor [0116] "255" Operational amplifier [0117] "260" Current
source [0118] "300" Controller [0119] "310" Amplifier [0120] "320"
Current source
[0121] These numerals cannot be interpreted as limiting and are
mentioned for information purpose only.
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