U.S. patent application number 10/315066 was filed with the patent office on 2003-07-17 for iontophoresis device and drug unit.
This patent application is currently assigned to Hisamitsu Pharmaceutical Co., Inc.. Invention is credited to Higo, Naruhito, Koga, Nobuhiro, Kuribayashi, Mitsuru, Maeda, Hiroyuki.
Application Number | 20030135150 10/315066 |
Document ID | / |
Family ID | 18493999 |
Filed Date | 2003-07-17 |
United States Patent
Application |
20030135150 |
Kind Code |
A1 |
Kuribayashi, Mitsuru ; et
al. |
July 17, 2003 |
Iontophoresis device and drug unit
Abstract
Herein disclosed is an iontophoresis device suitable for
effective use of a drug supported on a drug support. A donor
electrode-printed portion (6) and a reference electrode-printed
portion (7) are arranged on a backing layer (4). The backing layer
is provided with, at the periphery, an adhesive film (3) for fixing
a pharmaceutical preparation to an application site. The both
electrode-printed portions (6), (7) are electrically connected to a
current-generating portion (Ia) through a conductive snap connector
(Id). The drug support (14) is removably joined with a conductive
layer (11) formed on the electrode on the side of the donor
electrode-printed portion (6). The drug support (14) is subjected
to a drug diffusion-inhibitory treatment (30).
Inventors: |
Kuribayashi, Mitsuru;
(Tsukuba-shi, JP) ; Maeda, Hiroyuki; (Tsukuba-shi,
JP) ; Koga, Nobuhiro; (Tsukuba-shi, JP) ;
Higo, Naruhito; (Tsukuba-shi, JP) |
Correspondence
Address: |
TOWNSEND & BANTA
Suite 500
1225 Eye Street, N.W.
Washington
DC
20005
US
|
Assignee: |
Hisamitsu Pharmaceutical Co.,
Inc.
|
Family ID: |
18493999 |
Appl. No.: |
10/315066 |
Filed: |
December 10, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10315066 |
Dec 10, 2002 |
|
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|
09581262 |
Jun 28, 2000 |
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6510341 |
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Current U.S.
Class: |
604/20 |
Current CPC
Class: |
A61N 1/0448
20130101 |
Class at
Publication: |
604/20 |
International
Class: |
A61N 001/30 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 30, 1997 |
JP |
1997-369268 |
Claims
1. An iontophoresis device comprising a drug-dissolving portion
having a function of activating a drug; and a drug unit, which is
subjected to at least one treatment selected from a drug
diffusion-inhibitory treatment and an air-exhausting treatment,
having a drug support removably joined with the drug-dissolving
portion.
2. The iontophoresis device according to claim 1, wherein the drug
diffusion-inhibitory treatment includes a resin member and/or a
thermally compressed portion disposed at the periphery of the drug
support.
3. The iontophoresis device according to claim 1, wherein the
air-exhausting treatment is to form an air vent hole at the
periphery of the drug support.
4. A drug unit comprising a drug support for supporting a drug; a
first cover arranged on one side of the drug support; a second
cover arranged on the other side of the drug support; and a member
for removably fixing the first and second covers to the drug
support.
5. The drug unit according to claim 4, wherein the first cover has
an opening for supplying a drug to the drug support.
6. The drug unit according to claim 4, further comprising a drying
component arranged therein.
7. The drug unit according to claim 4, wherein at least one of the
first and second covers is subjected to a drug
adsorption-inhibitory treatment.
8. The drug unit according to claim 4, wherein the drug support is
subjected to at least one treatment selected from a drug
diffusion-inhibitory treatment and an air-exhausting treatment.
9. The drug unit according to claim 7, wherein the drug
adsorption-inhibitory treatment is a treatment with silicone or
Teflon.
10. The drug unit according to claim 8, wherein the air-exhausting
treatment is a stripe coating treatment of the member.
11. A drug support comprising a porous member, which is subjected
to a drug diffusion-inhibitory treatment and/or an air-exhausting
treatment; and a drug incorporated into the porous member.
12. The drug support according to claim 11, wherein the drug
diffusion-inhibitory treatment is to form a resin member at the
periphery of the porous member.
13. The drug support according to claim 11, wherein the drug
diffusion-inhibitory treatment comprises thermally compressing the
periphery of the porous member to form a thermally compressed
portion.
14. The drug support according to claim 11, wherein the
air-exhausting treatment is to form an air vent hole at the
periphery of the porous member.
Description
TECHNICAL FIELD
[0001] The present invention relates to an iontophoresis device
suitable for the percutaneous administration and the application
through the mucous membranes and in particular to an iontophoresis
device activated upon the practical use.
BACKGROUND ART
[0002] Recently, there have been developed a variety of dosage
forms in the field of pharmaceutical preparations for external use
and the development of dosage forms has gradually become a matter
of great concern. The reason for this is as follows: The
administration of a drug, which may have a local or systemic
pharmacological action, through the skin or the mucous membranes
has many advantages. For instance, the sustained-release effect of
the drug can be expected; such administration is not greatly
influenced by the metabolism due to the first-pass effect in the
liver unlike the oral administration and permits the effective use
of the drug; and drugs accompanied by, for instance, liver
disorders can relatively safely be administered to a patient.
[0003] However, the normal skin naturally has a protective effect
against external stimulations and this makes the absorption and
penetration of a drug through the skin relatively difficult. For
this reason, in the existing circumstances, a drug is not absorbed
in an amount sufficient for ensuring a satisfactory effect even if
the drug is administered to a patient in a dosage form for external
use. Moreover, in the administration method, which makes use of
absorption routes through biological membranes other than the skin,
such as mouth, rectum, oral cavity and nose as well as the
sublingual route, it is difficult to penetrate into or transmit
through the related biological membranes depending on the kinds of
drugs and therefore, there have been known a large number of drugs
having low bioavailability. Accordingly, there has been desired for
the development of an absorption-promoting method, which can
sufficiently enhance the permeability, penetrability and absorbency
of a drug against the skin and other biological membranes, can
ensure a sufficient pharmacological efficacy of the drug and is
substantially free of, for instance, its local and systemic
toxicity and is highly useful and safe.
[0004] As such absorption-promoting methods, there have recently
been known chemically promoting methods, which make use of
absorption-promoting agents, and physically promoting methods in
which iontophoresis or phonophoresis techniques are employed. Among
these, the iontophoresis technique has unexpectedly attracted
special interest recently and has been expected as an
administration method, which can solve the fore going problems.
[0005] The iontophoresis technique is a method for the
administration of a drug by applying an electric voltage to the
skin or a mucous membrane to electrically induce the migration of
an ionic drug and to thus administrate the drug through the skin or
a mucous membrane. In general, an iontophoresis device is provided
with a pair of electrode for iontophoresis, i.e., an anode and a
cathode and the device is so designed that these electrodes are
arranged on or attached to the skin at a predetermined distance
apart from one another and an electric current generated by a
current generator is guided to these electrodes to thus effect
treatments of patients.
[0006] Moreover, this iontophoresis device has a structure which
comprises a combination of these electrodes and a layer, which
stores a drug therein, and a variety of additives for maintaining
the drug efficacy are, if necessary, enclosed in the layer in
addition to a predetermined amount of the effective component in
order to keep a desired blood concentration in the body over a long
period of time.
[0007] It has been a recent tendency to study the administration,
by the iontophoresis, of polypeptide type drugs, which should be
administered in a time control or intermittent type mode.
Originally, the physiologically active peptides and proteins are
decomposed by the digestive juice in the gastrointestinal tracts
and simultaneously hydrolyzed by the hydrolases present on the wall
of the digestive tract. For this reason, it is difficult to improve
the absorption efficiency of these drugs and it is the leading
mainstream in the medical field to administer the drugs not orally,
but through injection. However, the administration through
injection would give a heavy physical burden to a patient and is
not always a treating method of a high compliance. Contrary to
this, the iontophoresis permits the establishment of any absorption
pattern by strictly controlling the electrical charging time and is
an effective percutaneous absorption system which can realize an
effective drug treatment, while taking into consideration the
circadian rhythm, in particular, in the treatment in which an
endogenous compound is supplemented. Therefore, if an iontophoresis
device that permits the administration of drugs by a patient per se
can be developed, it would be possibly to open the way for the home
treatment.
[0008] According to the conventional studies, there have been
proposed a large number of techniques relating to drug supports,
which takes, into consideration, the instability of polypeptide
type drugs to water and the high adsorbing ability thereof. For
instance, Japanese Un-Examined Patent Publication Nos. Hei 2-218375
and Hei 2-206473 disclose drug supports capable of being
electrically communicated with an electrode on the
drug-administration side and capable of being brought into contact
with the skin. As the drug supports of this type, there have been
known, for instance, those constituted by organic members and those
constituted by inorganic members. In addition, as methods for
applying a drug to the drug support, there have been used, for
instance, methods for coating the support with a drug or
impregnating the support with a drug; or methods for applying a
drug by drying or half-drying.
[0009] In these methods, however, it has been believed that drugs
such as physiologically active peptides or proteins may be adsorbed
on the drug support and accordingly, the rate of transdermal
absorption of the drug is reduced. For this reason, there have also
been proposed many techniques for solving the problem of the
adsorption of drugs on the drug support. For instance, Japanese
Un-Examined Patent Publication No. Hei 6-16535 discloses a
technique comprising the step of coating a porous or capillary
structure made of a non-conductive material with a high molecular
weight protein such as bovine serum albumin, human serum albumin or
gelatin. Moreover, Japanese Un-Examined Patent Publication No. Hei
8-98894 discloses an interface for the iontophoresis device in
which a coating layer of an ionic surfactant is formed on a drug
support material. In addition, Japanese Un-Examined Patent
Publication No. Hei 9-56827 discloses an interface for the
iontophoresis device in which a physiologically active peptide is
deposited on or applied to a thin film having an average pore size
ranging from 0.1 to 15 .mu.m, a porosity ranging from 65 to 90% and
a low protein adsorptivity. Moreover, Japanese Un-Examined Patent
Publication No. Hei 9-77658 discloses a technique comprising the
step of applying a drug onto a hydrophobic area formed on a part of
a hydrophilic film to thus give a transdermally absorbable
pharmaceutical preparation.
[0010] In the conventional techniques, however, the drug support is
in an exposed state and therefore, the drug is lost by any physical
contact and through adsorption on the skin of a patient by any
accidental touch with hands upon the application thereof, even if
the drug in the dried condition is supported on the drug support.
Moreover, when a drug support, which makes use of a porous
hydrophilic film, is used and when a drug solution is supplied to
the drug support or a drug included in the drug support in the
dried condition is re-dissolved, the drug solution diffuses from
the center of the drug support to the periphery thereof due to the
capillary phenomenon. Therefore, such a drug support suffers from a
problem in that the drug solution moves towards an adhesive layer
(for fitting the support to the skin) disposed at the periphery of
the support and the amount of the drug to be used for the treatment
is reduced.
[0011] On the other hand, when it is intended to incorporate, into
a drug support, a drug having a high adsorbing ability and unstable
to moisture, care should be taken not to lose a drug solution due
to the movement thereof to other members during the term extending
from the application of the drug to the completion of the drying.
Otherwise the drug would be lost. It is necessary to prevent any
movement of the drug towards other members during storing the drug
support, or any movement of the drug towards other members during
assemblage (or preparation) of a pharmaceutical preparation
dissolved immediately before the practical use and during usage
(during treatment), for the same reason.
[0012] In addition, it is sometimes observed that when the drug
support is joined to the drug-dissolving portion, the air, which
penetrates into the joint plane, would inhibit uniform dissolution
of the drug and accordingly, the application of the device never
ensures any sufficient drug efficacy. This would likewise be
considered to be a drug loss in a wide sense and such insufficient
dissolution of the drug present in the drug support would inhibit
the effective use of the drug. Moreover, the electrical charging of
the device is non-uniform due to the air penetration and there is
sometimes observed skin stimulations upon practical use. The
inventors of this invention were the first research workers to
experience such a problem during studying and developing an
iontophoresis device and there has never been known any prior art
which refers to this problem.
[0013] Accordingly, it is an object of the present invention to
provide an iontophoresis device suitable for effective use of a
drug incorporated into a drug support as well as a drug unit.
DISCLOSURE OF THE INVENTION
[0014] The foregoing object of the invention can be accomplished by
providing an iontophoresis device which comprises a drug-dissolving
portion having a drug-activation function and a drug support
subjected to a treatment for inhibiting any drug diffusion and/or a
treatment for exhausting air and removably connected to the drug
dissolving portion.
[0015] Thus, if the drug support is subjected to a drug
diffusion-inhibitory treatment, the dissolved drug does not migrate
to other members and the drug may efficiently be used. In addition,
if the drug support is subjected to a treatment for exhausting any
air, any air present is exhausted when the drug-dissolving portion
is joined to the drug support and the drug is uniformly dissolved.
Therefore, the drug can likewise efficiently be used in this
case.
[0016] In this respect, the drug support can be subjected to a drug
diffusion-inhibitory treatment by disposing a resin part or a
thermally compressible portion at the periphery of the drug
support. In addition, the air-exhausting treatment may comprise the
step of forming an air vent hole at the periphery of the drug
support.
[0017] Moreover, the drug support prior to the practical use is
provided in the form housed in a drug unit. This drug unit is
provided with members such as a drug support for accommodating a
drug, a cover placed on one side of the drug support, a cover
placed on the other side of the support and an adhesive for
removably fixing the both covers to the drug support. These covers
also serves as members for protecting the drug support and thus
examples thereof usable herein are liners and caps or lids covering
or put on the drug support. In addition, if necessary, the cover
may be subjected to a drug adsorption-inhibitory processing or a
drying agent for maintaining drugs in the dry condition may be
positioned within the drug unit. Such a construction of the drug
unit permits the protection of the drug support from any touch with
hands and/or any physical contact immediately before the practical
use. In addition, the construction also prevents any transfer of
the drug to other members and can maintain the drug in its dry
state. Thus, the drug support allows the effective use of the drug
accommodated therein.
BRIEF DESCRIPTION OF THE-DRAWINGS
[0018] FIG. 1 is a diagram showing the cross sectional structure of
an iontophoresis device according to the present invention upon its
practical use.
[0019] FIG. 2 is a diagram showing an embodiment of a drug unit in
which (a), (b) and (c) area view of the surface, an internal view
and a cross sectional view of the drug unit, respectively.
[0020] FIG. 3 is a diagram showing another embodiment of a drug
unit in which (a), (b) and (c) are a view of the surface, an
internal view and a cross sectional view of the drug unit,
respectively.
[0021] FIG. 4 is a diagram showing still another embodiment of a
drug unit in which (a), (b) and (c) are a view of the surface, an
internal view and a cross sectional view of the drug unit,
respectively.
[0022] FIG. 5 is a diagram showing a variety of embodiments of the
method for subjecting a drug support to a drug diffusion-inhibitory
treatment, in which (a), (c), (e) and (g) are views of the surface
of the support and (b), (d), (f) and (h) are cross sectional views
thereof.
[0023] FIG. 6 is a diagram showing a variety of embodiments of the
method for subjecting a drug support and an adhesive layer to an
air-exhausting treatment, in which (a), (c), (e) and (g) are views
of the surface of the support and (b), (d), (f) and (h) are cross
sectional views thereof.
[0024] FIG. 7 is a diagram showing an embodiment of the
configuration of a current-generating portion Ia, in which (a), (b)
and (c) are a view of the surface, a view of the back face and a
cross sectional view of the portion, respectively.
[0025] FIG. 8 is a diagram showing an embodiment of the
configuration of an integrated electrode portion Ib, in which (a),
(b), (c) and (d) are a view of the surface, an internal view, a
view of the back face and a cross sectional view of the electrode
portion, respectively.
[0026] FIG. 9 is a diagram showing an embodiment of the
configuration of a conductive snap connector Id, in which (a) and
(b) are a view of the surface and across-sectional view of the
connector, respectively.
[0027] FIG. 10 is a diagram showing an embodiment of the
configuration of an auxiliary stand for assemblage Ie-1, in which
(a) and (b) are a view of the surface and a cross sectional view of
the connector, respectively.
[0028] FIG. 11 is a diagram showing an embodiment of the
configuration of an auxiliary stand for assemblage Ie-2, in which
(a) and (b) are a view of the surface and a cross sectional view of
the connector, respectively.
[0029] FIG. 12 is a diagram showing an embodiment of the method for
assembling an iontophoresis device, which makes use of a drug unit
Ic-1, in which (a) shows the first half of the assembling process
and (b) shows the second half of the assembling process,
respectively.
[0030] FIG. 13 is a diagram showing an embodiment of the method for
assembling an iontophoresis device, which makes use of a drug unit
Ic-2, in which (a) shows the first half of the assembling process
and (b) shows the second half of the assembling process,
respectively.
[0031] FIG. 14 is a graph showing changes, with time, of the
concentration of hPTH (1-34) in the serum observed in Test Example
3.
BEST MODE FOR CARRYING OUT THE INVENTION
[0032] FIG. 1 is a diagram showing the cross sectional structure of
an iontophoresis device according to the present invention upon its
practical use. In this figure, every part is depicted separately to
make, easier, the understanding of these parts, which are in fact
in a laminated relation or come in close contact with one
another.
[0033] In this figure, a donor electrode-printed portion 6 is
positioned on one side of a backing layer 4 and a reference
electrode-printed portion 7 is positioned on the other side of the
layer 4. An adhesive film 3 such as a medical adhesive tape is
disposed on the periphery of the backing layer 4 for securing a
pharmaceutical preparation to an application site. The both
electrode-printed portions, 6, 7 are connected to a
current-generating portion Ia through a conductive snap connector
Id. The donor electrode-printed portion 6 on the backing layer 4 is
provided with a conductive layer 11 (a drug-dissolving portion) on
the donor electrode side, while the reference electrode-printed
portion 7 is provided with a conductive layer 10 on the reference
electrode side. A drug support 14 is removably connected to the
drug-dissolving portion 11. An adhesive layer 13 is formed on a
part of the drug support 14, whereby the drug support 14 is fixed
to the backing layer 4 or the donor electrode-printed portion
6.
[0034] The iontophoresis device having such a structure discussed
above is adhered to, for instance, the skin 40 upon the practical
use thereof, as shown in FIG. 1. At this stage, the drug, which is
in a dry condition and supported on the drug support 14, is
dissolved in the water supplied from the drug-dissolving portion
11. Since the periphery of the drug support 14 is subjected to a
drug diffusion-inhibitory treatment 30, the drug remains at a
desired position on the drug support 14 without causing any
migration towards other members. Moreover, the air is removed from
the joined region between the drug-dissolving portion 11 and the
drug support 14 since the drug support 14 has been subjected to an
air-exhausting treatment (not shown). Then a power supply for the
current-generating portion Ia is switched on to thus put the
iontophoresis device in operation.
[0035] In this respect, the drug support 14 is accommodated in the
drug unit prior to the practical use as will be detailed below and
thus separated from the drug-dissolving portion 11. Accordingly,
even if the drug support comprises a drug (such as physiologically
active peptides) whose stability to water is insufficient, it is
not necessary to be anxious about decomposition of the drug with
time due to the moisture present in the drug-dissolving
portion.
[0036] The drug dissolved in the water supplied from the
drug-dissolving portion never migrates to other members of the
device since the periphery of the drug support is subjected to a
drug diffusion-inhibitory treatment. In addition, any air does not
penetrate into the joined region between the drug-dissolving
portion and the drug support because of the air-exhausting
treatment and therefore, the drug can uniformly be dissolved in the
water originated from the drug-dissolving portion. Thus, the drug
accommodated in the drug support can efficiently be used.
[0037] We will now explain, in detail, Examples of drug units, in
which such a drug support 14 is accommodated. Detailed structures
of other portions and methods for assembling the device will be
described below.
(EXAMPLE 1)
[0038] FIG. 2 is a diagram showing an embodiment of a drug unit in
which (a), (b) and (c) area view of the surface, an internal view
and a cross sectional view of the drug unit, respectively. The drug
unit (Ic-1) according to this Example is formed by sandwiching a
porous drug support 14 between a liner 17 on the electrode side and
a liner 12 on the skin side. In this connection, the liner 17 on
the electrode side is provided with a perforation for folding the
liner, while the liner 12 on the skin side is provided with two
insertion openings 15 for a conductive snap connector as will be
explained below and a perforation 16 for pulling out the liner
after the completion of the assemblage. Either of these liners
herein used may be a film having low drug-adsorptive properties
such as polyethylene terephthalate. The drug is adhered to and
supported by the drug support 14 by a method comprising the steps
of, for instance, spraying or impregnating the support with a drug
solution through an opening 18 for the application of the solution.
In this respect, a cover for sealing may close the opening 18 for
the application of a drug solution after the application of the
drug in order to maintain the periphery of the drug support 14
under the dry condition. Moreover, Adhesive layers 13 are disposed
on both sides of the periphery of the drug support in order to
adhere the electrode portion to the skin and the coated pattern of
the adhesive layer 13 is a stripe coating for ensuring the air
exhaustion. In this connection, the side of each liner 12, 17,
which comes in contact with the drug support 14, is subjected to a
treatment 12', 17' with silicone in order to prevent any drug
adsorption and to improve the peeling ability thereof. Moreover,
the liners are also subjected to a drug diffusion-inhibitory
treatment 30 to prevent any spreading of the drug solution towards
the adhesive layer.
(EXAMPLE 2)
[0039] FIG. 3 is a diagram showing another embodiment of a drug
unit in which (a), (b) and (c) are a view of the surface, an
internal view and a cross sectional view of the drug unit,
respectively. Sandwiching a porous drug support 14 between a liner
17 on the electrode side and a liner 12 on the skin side forms the
drug unit (Ic-2) according to this embodiment. The liner 17 is
provided with an opening 18 for the application of a drug solution.
In addition, the side, of the drug support 14, of each liner 12, 17
is subjected to a treatment 12', 17' with silicone to prevent any
drug adsorption and adhesive layers 13 are disposed on the both
sides of the drug support 14. In this respect, Example 2 is
identical to Example 1. However, Example 2 is substantially
different from Example 1 in that both of the liners are fabricated
and designed in such a manner that they do not come in direct
contact with the drug support 14. A drying agent 19 (such as a
patch type-drying agent) is disposed on the inner side of the
fabricated liner 12.
(EXAMPLE 3)
[0040] FIG. 4 is a diagram showing still another embodiment of a
drug unit in which (a), (b) and (c) are a view of the surface, an
internal view and a cross sectional view of the drug unit,
respectively. In the drug unit (Ic-3) according to this Example,
The configuration of the unit is identical to those disclosed in
Examples 1 and 2 except that the structure of the liner differs
from those used in Examples 1 and 2. The liner of this Example is
constituted by an integrally molded liner 20 and divided into a
molded portion and a flat portion, which border across a folding
axis 23. In other words, the liner is designed such that the drug
support is sandwiched between the molded and flat portions upon
storing the same. In addition, a fixing terminal 22 and an opening
21 for inserting the fixing terminal are formed as a member for
fixing the liner after sandwiching the drug support. Moreover, the
integrally molded liner 20 comprises a conventional plastic film
and a dry component-containing layer 20' laminated with the film so
that the interior of the drug unit is maintained in its dry
condition. In principle, this Example does not require the use of
any drying agent, but a drying agent may be used in
combination.
(EXAMPLE 4)
[0041] FIG. 5 is a diagram showing a variety of embodiments of the
method for subjecting a drug support to a drug diffusion-inhibitory
treatment. In this Example, the drug support 14 is composed of a
porous film material. In this figure, (a), (c), (e) and (g) are
views of the surface of the support and (b), (d), (f) and (h) are
cross sectional views thereof.
[0042] In an embodiment Ma-1, the diffusion-inhibitory treatment 30
comprises, as shown in FIGS. 5(a) and (b), the step of partially
applying a thermosetting water-repellent resin (such as a silicone
resin) to a region adjacent to the interior of the adhesive layer
13 of the drug support 14 or printing the region with the resin to
thus close the pores.
[0043] In an embodiment Ma-2, the drug support 14 is treated by the
same method described above, as shown in FIGS. 5(c) and (d). In
this case, however, the drug support is further entirely subjected
to a diffusion-inhibitory treatment 30 in a mesh-like pattern in
order to uniformly disperse a drug solution on the drug support
14.
[0044] In an embodiment Ma-3, the diffusion-inhibitory treatment 30
comprises the step of partially subjecting the drug support 14 to a
thermal compression treatment, as shown in FIGS. 5(e) and (f), to
thus eliminate any pores of the support. In this Example,
unevenness is simultaneously imparted to the porous film material
during the treatment. According to this Example, any diffusion of
the drug solution can be prevented by the elimination of the pores
and the formation of unevenness by the thermal compression
treatment.
[0045] In an embodiment Ma-4, the diffusion-inhibitory treatment 30
comprises, as shown in FIGS. 5(g) and (h) the combination of a
partial compression treatment of the drug support 14 and a method
comprising cutting through, for instance, a perforation. In this
case, the perforation is formed on the exterior of the thermally
compressed portion corresponding to a non-conductive region.
[0046] The shape and width of the pattern formed by the
diffusion-inhibitory treatment 30 are not restricted to any
specific one. The pattern is desirably a circular shape having a
width ranging from 0.5 to 1.5 mm. In this Example, 4 embodiments of
the diffusion-inhibitory treatment have been described, but the
treatment is not restricted to these specific embodiments and the
treating methods and the processed patterns may arbitrarily be
combined or changed.
(EXAMPLE 5)
[0047] FIG. 6 is a diagram showing a variety of embodiments of the
method for subjecting a drug support 14 and an adhesive layer 13 to
an air-exhausting treatment, in which (a), (c), (e) and (g) are
views of the surface of the support and adhesive layer; and (b),
(d), (f) and (h) are cross sectional views thereof.
[0048] In an embodiment Mb-1 the adhesive layer 13 positioned in a
region adjacent to the exterior of a region of the drug support 14
subjected to a diffusion-inhibitory treatment 30 (thermal
compression) is subjected to an air-exhausting treatment 31 such as
a stripe coating, as shown in FIGS. 6(a) and (b).
[0049] In an embodiment Mb-2, four air-exhausting holes, as regions
subjected to an air-exhausting treatment 31, are formed between the
region subjected to the diffusion-inhibitory treatment 30 (thermal
compression) and the adhesive layer and further the adhesive layer
13 is subjected to a stripe coating treatment for air-exhaustion,
as shown in FIGS. 6(c) an (d). A desired effect can be expected by
forming at least two holes, as such air-exhausting holes, having a
diameter of 1 mm or less.
[0050] In an embodiment Mb-3, four air-exhausting holes are formed
within the region subjected to the diffusion-inhibitory treatment
30 (thermal compression treatment), as regions subjected to an
air-exhausting treatment 31 and uncoated portions 32 for
air-exhaustion are formed on the adhesive layer 13, as shown in
FIGS. 6(e) and (f).
[0051] In an embodiment Mb-4, a notch is formed on the adhesive
layer 13, which has been subjected to a stripe coating as an
air-exhausting treatment 31, through the drug support 14, as shown
in FIGS. 6(g) and (h). In this embodiment, the effect of
air-exhaustion through the adhesive layer 13 is further improved.
In any case, the regions subjected to the air-exhausting treatment
are formed such that the conductive portion containing a drug
solution is electrically isolated and therefore, there is not any
possibility of causing a leakage of electricity through the
regions, which have been subjected to such an air-exhausting
treatment.
[0052] In case where the adhesive layer 13 is subjected to the
foregoing pattern coating (intermittent coating, stripe coating,
intermittent stripe coating), the width of the intermittent pattern
is not restricted to any particular range insofar as a good balance
between the adhesive force and air-permeability is established, but
it is desirably ranges from 0.1 to 20 mm. It is also possible to
make a cut such as a perforation, in addition to the foregoing
methods. The shape of the cut is not restricted to any particular
one. However, a circular perforation is desirably formed, which has
a width ranging from 0.5 to 2 mm. In this Example, four embodiments
are illustrated as a method for subjecting the drug support 14 to
an air-exhausting treatment, but the present invention is not
restricted to these embodiments. More specifically, the treating
methods and the processed patterns may arbitrarily be combined or
changed.
[0053] We will hereunder explain, in detail, materials or the like
of each part of the drug unit as shown in FIGS. 2 to 6.
[0054] The adhesive layer 13 may be formed using adhesives used for
forming an adhesive film 3 as will be detailed below. This layer
can be formed by pattern coating (intermittent coating, stripe
coating, intermittent-stripe coating) and the layer desirably has a
structure, through which air easily passes. The width of the
intermittent pattern formed by the pattern coating is not
restricted to any particular range insofar as a good balance
between the adhesive force and air-permeability is established, but
it is desirably ranges from 0.1 to 20 mm.
[0055] The drug support 14 may support a drug consisting of a
physiologically active substance and may be formed from any
material insofar as the drug may pass through the material. In case
where the drug is a physiologically active substance or a protein,
a hydrophilic porous material may be used for forming the support
14 and the material can support drugs in dry states and has low
adsorptivity. The hydrophilic film formed from such a hydrophilic
porous material includes a thin film having high wettability by
water such as a hydrophilized hydrophobic (or water-repellent)
polymer thin film or a hydrophilic substance-containing hydrophilic
polymer film.
[0056] Examples of hydrophilized hydrophobic polymer thin films are
thin films formed from hydrophilized fluoroplastics (such as
hydrophilic DURAPORE available from Millipore Company and
hydrophilic poly(tetrafluoroethylene) available from Toyo Roshi
Co., Ltd.), thin films such as those formed from hydrophilic
polyther sulfone (such as Supor available from German Science
Company) and hydrophilized cellulose derivatives (such as
hydrophilized cellulose monoacetate and hydrophilized cellulose
triacetate).
[0057] Examples of hydrophilic substance-containing hydrophilic
polymer thin films include a variety of polymers obtained by adding
appropriate surfactants and impregnating therewith and then drying,
for instance, hydrophilized cellulose acetate films (such as
Asymmetric Ultra Filter available from sartorius Company and
cellulose acetate type ones available from Toyo Roshi Co., Ltd.),
hydrophilized polycarbonate films (such as Isopore Membranes
available from Nihon Millipore Ltd.), hydrophilized poly
(tetrafluoroethylene) films (such as Omnipore Membranes available
from Millipore Company), hydrophilized polysulfone films (such as
HT Tuffryn available from Gelman Sciences Inc.) and hydrophilized
nonwoven fabrics (such as films obtained by coating polyester
nonwoven fabrics with cellulose acetate (e.g., coated type
membranes available from Toyo Roshi Co., Ltd.)) The hydrophilic
films also include, for instance, nylon films (such as BIODYNE
available from Nihon PALL Ltd.).
[0058] Incidentally, drugs unstable to water should desirably be
included in or adhered to the drug support in their dry state in
order to improve the stability of these drugs and to inhibit any
leakage and deterioration thereof. On the other hand, in case of
drugs stable to water, they may be supported on the drug support in
their gel-like conditions. In such a gel-like drug support,
suitably used herein are water-soluble polymers and hydrogel
thereof. A method for preparing such a gel-like drug support
comprises the step of mixing and kneading a gelling agent such as a
water-soluble polymer and a drug solution. Moreover, the electrical
conductivity of the gel-like drug support can be enhanced by
addition of an electrolyte such as sodium chloride, potassium
chloride, sodium carbonate, phosphoric acid or sodium citrate; or a
pH-buffering agent such as acetic acid, sodium acetate, phosphoric
acid, sodium phosphate, citric acid or sodium citrate. Moreover,
the kneaded mixture is formed into a product to such an extent that
it has a self shape-maintainability and then spreaded into a sheet
or a film. If the kneaded mixture has an insufficient self
shape-maintainability, a mesh-like support maybe incorporated into
the gel. The thickness of the gel layer desirably ranges from 0.1
to 2 mm and particularly preferably 0.3 to 0.8 mm. If it is too
thin, the gel strength is considerably low, while if it is too
thick, the movement of the drug is inhibited and accordingly, the
rate of drug absorption is reduced.
[0059] In the present invention, the drug unit is provided therein
with a protective member, which is designed to permit the
arrangement of a drying agent 19. The role of the protective member
is to store a drug unstable to water in its dry state and to thus
improve the storage stability thereof. Further, the protective
member serves to protect the drug support from any external impact.
The protective member is specifically a liner such as those
described above and a product obtained by molding and processing a
film. The drying agent is arranged in the drug unit without coming
in close contact with the drug support.
[0060] The liners 12, 17 as the protective members may be any
oneinsofarastheyareformedfromawater-impermeablematerial, but are
desirably those capable of being processed through molding (such as
thermal molding and vacuummolding). Examples of such
water-impermeable materials usable herein are aluminum foils,
polyester films, polypropylene films and polyethylene films as well
as laminated films thereof. In addition, it is desirable to use
these materials after subjecting them to an adsorption-inhibitory
treatment such as a treatment with silicone or Teflon. This
treatment would facilitate the peeling off thereof from the
adhesive layer.
[0061] As the drying agent 19, there may be used a patch type one
and this is positioned on the inside of the protective member. The
drying agents are not limited to any particular one insofar as they
do not adversely affect the efficacy of the drug and examples
thereof preferably used herein are those having strong drying
ability and strong hygroscopicity or an ability of absorbing
moisture within a short period of time, such as silica gel, alumina
and zeolite. Moreover, the drying agent in the form of particles or
powder may be packed in, for instance, paper or nonwoven fabrics or
enclosed in a container. Preferably, the drying agent or package
thereof is provided with an adhesive layer for the installation
thereof.
[0062] Moreover, the use of a plastic film laminated with a drying
component-containing layer, as a protective member, permits the
maintenance of the interior of the drug unit in the dry condition.
Examples of the drying components usable herein are those, which
may adversely affect the drugs (the lique faction of the drying
components due to their deliquescence) and thus cannot be used in
the package of the drying agents, such as calcium chloride,
magnesium sulfate, aluminum oxide and barium oxide, not to speak of
the components of the drying agents listed above. Moreover, the
drying component-containing layer may be a product obtained by
mixing and kneading the foregoing drying components with, for
instance, a thermoplastic resin and then molding the resulting
blend into films and may be used alone or after laminating them
with the protective member, upon the practical use. Examples of
such thermoplastic resins are polyethylene, polypropylene,
polycarbonate, polyamide, ethylene-vinyl acetate copolymer,
ethylene-methyl acrylate copolymer, polyvinyl chloride,
polystyrene, polyester terephthalate and polyvinylidene chloride.
These thermoplastic resins may be used alone or in any
combination.
[0063] In case where the drug is decomposed through oxidation, a
deoxygenation agent may simultaneously be enclosed or incorporated
into the drug unit in addition to the foregoing drying
component.
[0064] Drugs usable here in are any medicine used in any
therapeutic field, which is soluble or dispersible in water and, in
particular, physiologically active substances having a molecular
weight ranging from 1.times.10.sup.2 to 1.times.10.sup.6 can widely
be used in the present invention. Examples of drugs are narcotics,
analgesics, anorexics, anthelmintics, drugs for asthma,
anticonvulsants, antidiarrheals, antineoplastic agents, drugs for
Parkinson's diseases, antipruritics, sympatholytic agents, xanthine
derivatives, drugs for angiocardiac diseases such as calcium
channel blockers, antipyretics, .beta.-blockers, antiarrhythmic
agents, hypotensive drugs, diuretics, vasodilators for blood
vessels including systemic, coronary, peripheral and cerebral
vessels, drugs for hemicrania, drugs for drunkness and motion
sickness, antiemetics, central nervous system stimulants, drugs for
cough and common cold, decogestants, diagnostics, drugs for
hormonotherapy, parasympatholytic agents, parasympathomimetic
agents, psychostimulants, sedatives, tranquilizers,
anti-inflammatory agents, anti-arthritic agents, anti-spasmodics,
antidepressants, drugs for treating psychosis, drugs for treating
dizziness, anti-anxiety agents, narcotic antagonists, carcinostatic
agents, hypnotics, immunosuppressors, muscle relaxants, antiviral
agents, antibiotics, anorexics, antiemetics, anti-cholinergic
agents, antihistamic agents, contraceptives, antithrombotic agents,
bone-absorption suppressors and osteogenesis-promoting agents.
However, the present invention is not restricted to these specific
drugs listed above. These drugs may be used alone or in any
combination.
[0065] Specific examples of these drugs include steroids such as
estradiol, progesterone, norgestrel, levonorgestrel, norethindrone,
medroxy-progesterone acetate, testosterone and esters thereof;
nitro group-containing compounds and derivatives such as
nitroglycerin and isosorbide dinitrates, nicotine,
chlorpheniramine, terfenadine, triprolidine and hydrocortisone;
oxicam derivatives such as piroxicam; acetic acid or propionic acid
derivatives such as indometacin, flurbiprofen, felbinac and
diclofenac, ketoprofen; mucopolysaccharides such as thiomucase,
buprenorphine, fentanyl, naloxone, codeine, lidocaine,
dihydroergotamine, pizotyline, salbutamol and terbutaline;
prostaglandins such as misoprostol, enprostil, omeprazole and
imipramine; benzamides such as metoclopramine, scopolamine and
clonidine; dihydropyridines such as nifedipine, verapamil,
ephedrine, pindolol, metoprolol, spironolactone, nicardipine HCl
and calcitriol; thiazides such as hydrochlorothiazide and
flunarizine; sydnone imines such as molsidomine; sulfated
polysaccharides such as heparin fractions and proteins; and
peptides such as insulin and homologues thereof; calcitonins and
homologues such as elcatonin, protamin and glucagone; globulins,
angiotensin I, angiotensin II, angiotensin III, lypressin,
vasopressin, somatostatin and homologues thereof; growth hormones
and oxytocin; as well as, if necessary, pharmaceutically acceptable
salts thereof with acids or bases. Preferred are, for instance,
narcotics, hormones, proteins, analgesics, or other low molecular
weight cations. More preferably, examples of drugs include peptides
or polypeptides such as insulin, calcitonin, calcitonin-related
genetic peptides, vasopressin, desmopressin, protirelin (TRH),
adrenocorticotropic hormones (ACTH), luteinizing hormone-release
hormones (LH-RH), growth hormone-release hormones (GRH), nerve
growth factors (NGF) and other release factors, angiotensins,
parathyroid hormones (PTH), luteinizing hormones (LH), serumal
gonadotropin, hypophyseal hormones (such as HGH, HMG, HCG), growth
hormones, somatostatin, somatomedin, glucagon, oxytocin, gastrin,
secretin, endorphin, enkephalin, endothelin, cholecystokinin,
neurotensin, interferon, interleukin, transferrin, erythropoietin,
superoxide dismutase (SOD), filgrastim (G-CSF),
vasoactive-intestinal-pol- ypeptides (VIP), muramyldipeptides,
corticotropin, urogastrone and atrial sodium uragogue peptides
(h-ANP). However, the present invention is not restricted to these
specific drugs a tall. Among these, particularly preferred are
peptide hormones. It is also possible to optionally use
adsorption-inhibitory agents such as benzalkonium chloride, BSA
(bovine serum albumin) and monolauric acid.
[0066] In the present invention, at least one of the foregoing
drugs and salts thereof may be supported on the drug support. In
addition, the amount of the drug is determined depending on a
particular drug in such a manner that, upon administration thereof
to a patient, a predetermined effective blood concentration is
maintained over an effective period of time and the size of the
iontophoresis device as well as the area of the drug-delivery
surface thereof are determined in proportion thereto.
[0067] We will now explain, in detail below, the structures of
parts other than the drug unit detailed above.
[0068] FIG. 7 is a diagram showing an embodiment of the
configuration of a current-generating portion Ia, in which (a), (b)
and (c) are a view of the surface, a view of the back face and a
cross sectional view of the current-generating portion,
respectively. The current-generating portion Ia is a plastic molded
body having therein a built-in current-control circuit. A
current-control switch 1 is arranged on the current-generating
portion, while a female electrode terminal 2 (one each of the
terminal on the sides of the anode and cathode) is arranged below
the current-generating portion. This current-generating portion Ia
is preferably designed such that no physical burden due to the size
and weight thereof is given to a patient.
[0069] More specifically, the current-generating portion is
constituted by a self-oscillator circuit provided with a built-in
small-sized cell, an appropriate high voltage-generating circuit
connected to the oscillator circuit and a control circuit for
operating and controlling these circuits. It is also possible to
incorporate a BOLUS button for temporarily increasing the injection
rate for a drug into the current-generating portion. This is quite
useful function when an analgesic is administered to a patient and
the patient desires for a temporary increase in the dose thereof in
proportion to the degree of his pains.
[0070] Moreover, the control circuit is, for instance, designed in
such a manner that the circuit permits the manual on/off switching
in order to allow the on-demand medication regime and the on/off
switching at a period adapted for the biological circadian rhythm
and the pattern at intervals of 24 hours. In addition, the control
circuit may be equipped with a built-in microprocessor and
therefore, the circuit permits the modification of the level of the
current and the wave form such as pulses and sinusoidal waves to be
applied over a predetermined time. Moreover, the control circuit
may comprise a biosensor or a certain kind of feedback system for
monitoring the biosignals emitted by a patient, evaluating the
treating method and adjusting the amount of the drug to be
administered to the patient in response to the results of the
evaluation. It is also possible to incorporate one or more programs
predetermined by the maker of the drug, a physician or a patient
into the control circuit.
[0071] FIG. 8 is a diagram showing an embodiment of the
configuration of an integrated electrode portion Ib, in which (a),
(b), (c) and (d) are a view of the surface, an internal view, a
view of the back face and a cross sectional view of the electrode
portion, respectively. The integrated electrode portion Ib has a
backing layer 4 consisting of a film of a polyester or a polyolefin
such as polypropylene, or a molded body of such a film laminated
with an aluminum layer. Printed electrode portions 6, 7 are
arranged on the molded backing layer 4 and they are formed by
printing silver (on the anode side) and silver chloride (on the
cathode side). Moreover, two insertion openings 5 (one each of the
opening on the sides of the anode and cathode) for conductive snap
connectors are positioned on the printed electrode portion at the
center of the backing layer.
[0072] Conductive layers 10, 11 are formed on the integrated
electrode portion Ib in such a manner that they are adjacent to the
printed electrode portions 6, 7 and the material used for forming
these layers is a water-retentive material such as a nonwoven
fabric or a hydrophilic polymer, which comprises an electrolyte. In
this respect, the conductive layer 11 on the donor side (in this
Example, the layer on the anode side) also serves as a moisture
supply source for the drug accommodated in the drug unit (Ic-1),
upon activation. Moreover, the conductive layers are packaged with
a water-impermeable cover material 9 through easily peeled heat
seal in order to prevent any moisture evaporation during storage.
Further an adhesive film 3 such as a medical adhesive tape is
applied onto the periphery of the backing layer 4 for the purpose
of fixing the pharmaceutical preparation to a drug-application site
and a liner 8 is fitted to the adhesive film during storage.
[0073] Incidentally, the integrated electrode portion Ib may have a
known electrode structure. For instance, usable herein are
materials such as platinum black, titanium, carbon, aluminum, iron,
lead, carbon-containing conductive rubber and conductive resins,
with platinum electrodes, silver electrodes, silver chloride
electrodes or the like being particularly desirable.
[0074] The foregoing cover material 9 is not restricted to any
particular one in so far as it is formed from a water-impermeable
material. For instance, the cover material is formed from a film
laminated with an aluminum layer. If a highly sealed condition by
heat sealing is required, the cover material is laminated with a
plurality of films such as those described above in connection with
the liner or it is coated with another polymer resin. This makes
the peeling off of the cover material easy. For instance, there can
be used an easily peelable laminate film. It is desirable that the
laminate film have a peel strength at 180 degrees of 2000 g or
less.
[0075] A pressure-sensitive adhesive is used as an adhesive
material for the adhesive film 3 (the adhesive layer 13 at the
periphery of the drug support). Any pressure-sensitive adhesive may
be used herein inasmuch as they can maintain the iontophoresis
device on the surface of the skin or mucous membrane of a patient,
while the device is brought into close contact therewith, they have
an adhesive force sufficient for ensuring good adhesion of the drug
support to the drug-dissolving portion and they are physiologically
acceptable for the skin. Specific examples thereof are acrylic
adhesives comprising homopolymers or copolymers of alkyl acrylates
whose alkyl moiety has 4 to 18 carbon atoms, such as acrylic acid,
methyl acrylate, ethyl acrylate, 2-ethylhexyl acrylate, isooctyl
acrylate, decyl acrylate, lauryl acrylate and stearyl acrylate;
methacrylic adhesives comprising homopolymers or copolymers of
alkyl methacrylates whose alkyl moiety has 4 to 18 carbon atoms,
such as methyl methacrylate, ethyl methacrylate, butyl
methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate,
decyl methacrylate, lauryl methacrylate and stearyl methacrylate;
silicone type adhesives such as those comprising polyorganosiloxane
and polydimethyl-siloxane; and rubber type adhesives such as those
comprising natural rubber, polyisobutylene, polyvinyl ether,
polyurethane, polyisobutylene, polybutadiene,
styrene-butadienecopolymer, styrene-isoprene copolymer and
styrene-isoprene-styrene block copolymer. Moreover, the adhesive
material may, if necessary, comprise a tackifier and a softening
agent.
[0076] These adhesive materials are first mixed in a mixing machine
such as a kneader or a mixer and then spreaded on a support film,
before the practical use. In addition, in case of the adhesive
layer 13 for the periphery of the drug support, the adhesive
materials are used according to, for instance, a method comprising
the step of directly and partially applying them to the drug
support; or a method comprising the steps of spreading them on a
thermoplastic support film and then fixing the support film to the
drug support through heat seal. If the drug support has
insufficient flatness, the latter method is preferably used and the
resulting adhesive layer permits the inhibition of any penetration
of air upon activation of a drug present in the drug support. In
this connection, materials for the support film usable herein may
be those for the backing layer 4 as will be detailed below, but it
is important to select and use materials free of any interaction
with the drug and/or free of any adsorption of the drug. Moreover,
in case of the adhesive film 3, preferably used herein are foams of
synthetic resins, which have high gas permeability and which are
quite agreeable to the touch. On the other hand, incase of the
adhesive layer 13 for the periphery of the drug support, preferred
are polyolefinic films having a low melting point.
[0077] A material for the backing layer 4 herein used may be an
effective component-impermeable material. Examples thereof are
films, sheets and foams of synthetic resins such as polyethylene,
polypropylene, polyethylene terephthalate, polyvinylchloride,
polyvinylidenechloride, plasticized vinyl acetate copolymer,
plasticized vinyl acetate-vinyl chloride copolymer, polyamide,
cellophane, cellulose acetate, ethyl cellulose, polyester,
polycarbonate, polystyrene, polyurethane, polybutadiene, polyimide,
poly-acrylonitrile, polyisoprene, polystyrene derivatives,
ethylene-vinyl acetate copolymer, ethylene-polyvinyl alcohol
copolymer, fluoroplastics, acrylic resins and epoxy resins, which
may be used alone or in the form of a laminate of at least two of
them.
[0078] In addition, the films, sheets, foams or the like of these
synthetic resins may be laminated with metal foils such as aluminum
and tin foils; nonwoven fabrics and synthetic paper or may be
covered with deposited aluminum layers and ceramic coatings.
Moreover, if closed package by, for instance, heat sealing is
required, they may be laminated with a heat-sealable material.
[0079] The electrode portion may be deposited on the backing layer
by, for instance, a method comprising the steps of mixing an
electrode material with, for instance, a print ink for electric
wirings, applying the print ink to a material for the backing layer
and then drying the same; a method comprising the steps of
spreading an electrode material and then fixing the material to the
backing layer; a method comprising the step of depositing an
electrode material onto the backing layer; or a method in which the
electrode portion is formed by photo-etching an electrode material
applied onto the backing layer. In addition, an insulating layer
may additionally be applied onto a part of the printed electrode
layer, which may come in contact with the skin of a patient.
[0080] The conductive layer may simply comprise water or may
comprise at least one member selected from the group consisting of
soft porous materials such as ion-exchangeable polymers, foaming
materials and sponge and water-absorptive polymers. Moreover, the
conductive layer may comprise an electrolyte such as sodium
chloride, potassium chloride, sodium carbonate, phosphoric acid or
sodium citrate; or a ph-buffering agent such as acetic acid, sodium
acetate, phosphoric acid, sodium phosphate, citric acid or sodium
citrate, for the improvement of the electric conductivity
thereof.
[0081] Specific examples of the preferably used conductive layers
in general include nonwoven fabric, paper, gauze, absorbent
wadding, polyethylene or polypropylene having open cells, polyvinyl
acetate, porous films and foams of, for instance, polyolefin foams,
polyamide foams and polyurethane, natural polysaccharides such as
karaya gum, tragacanth gum, xanthane gum, starches, gum arabic,
locust bean gum, gellan gum, guar gum and carrageenan; gelatin,
pectin, agar, sodium alginate or poly vinyl alcohol and partially
saponified products thereof; polyvinylformal, polyvinylmethylether
and copolymers thereof; polyvinyl pyrrolidone and copolymers
thereof; aqueous or water-soluble cellulose derivatives such as
sodium carboxy-methyl cellulose, methyl cellulose, hydroxyethyl
cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose,
hydroxypropyl cellulose and cellulose acetate phthalate;
carboxyvinyl polymer, polyacrylamide and poly-acrylamide
derivatives, casein, albumin, chitin, chitosan, polyacrylic acid,
sodium polyacrylate, poly-HEMA, poly-HEMA derivatives,
methoxyethylene-maleic acid anhydride copolymer, N-vinyl acetamide,
N-vinyl acetamide and acrylic acid and/or acrylic acid salt
copolymers, as well as crosslinked products thereof, water-soluble
polymers optionally plasticized with, for instance,
ethyleneglycolorglycerin and hydrogels thereof. However, the
present invention is not restricted to these specific ones. In
addition, the foregoing materials may be used in any combination of
at least two of them. Moreover, it is also possible to use, if
necessary, benzalkonium chloride BSA (bovine serum albumin) and
adsorption-inhibitory agent such as monolauric acid.
[0082] Furthermore, the conductive layer may also comprise an
ion-exchangeable polymer for the removal of ions competitive with a
desired drug. Such ion-exchangeable polymers usable herein are
appropriately selected from anion-exchange polymers,
cation-exchange polymers and ampholytic ion-exchange polymer,
depending on the ionic properties of each particular drug. In
addition, the ion-exchangeable polymer may be incorporated into the
conductive layer by, for instance, a method comprising the step of
dispersing fine powder of anion-exchangeable polymer in the
foregoing polymer to thus form the mixture in a gel-like form or a
method, which makes use of a product of such an ion-exchangeable
polymer previously formed into a film, but the present invention is
not restricted to these methods at all.
[0083] The capacity of the conductive layer on the donor electrode
side (drug-dissolving portion) is not particularly restricted to a
specific range, but depends on, for instance, the size of the
electrode portion and the optimumamount of water required for
dissolving a drug accommodated in the drug support, or the water
content of the absorptive member of the drug-dissolving portion. In
this respect, however, if the amount of water is too large, it may
cause leakage of the drug-dissolving liquid, while if it is too
small, the drug present in the drug support cannot completely be
dissolved and the drug efficacy is correspondingly reduced.
Therefore, the amount of water is desirably on the order of the
maximum water absorption of the drug support. If a hydrogel is used
in the drug-dissolving portion, the syneresis thereof particularly
preferably ranges from 10 to 100 mg/cm.sup.2. Moreover, the
hydrogel should have such a gel strength that the gel is never
broken during the assemblage of the device and during the
application thereof to the skin and therefore, the hydrogel
desirably has a gel strength ranging from 400 to 1500
g/cm.sup.2.
[0084] The amount of water required for dissolving a drug present
in the drug support is, in advance, controlled in the
drug-dissolving portion. Thus, a precise amount of water can
certainly and rapidly be supplied to the drug support at any time
upon the practical use and this makes the therapeutic effect
accurate. Moreover, this can also simplify the treating operations
and reduce the treating time.
[0085] FIG. 9 is a diagram showing an embodiment of the
configuration of a conductive snap connector Id, in which (a) and
(b) are a view of the surface and a cross sectional view of the
connector, respectively. This connector Id is provided with two
electrode terminals 25 (male) on an electrode terminal-fixing table
24 and they are designed in such a manner that they can be
connected to the electrode terminals 2 (female) of the
current-generating portion Ia, after the assemblage of the
device.
[0086] The current-generating portion is connected to the electrode
portion such that the latter is sandwiched in between the electrode
terminal on the current-generating portion side and that on the
conductive snap connector side. The electrode terminal on the
conductive snap connector side comes in contact with the printed
electrode portion (either of the anode and cathode) of the
electrode portion due to the connection. Accordingly, the
current-generating portion and the electrode portion can
electrically be charged and the electrical connection can thus be
established.
[0087] In addition, if they are connected, while inserting the drug
unit in between the current-generating portion and the electrode
portion upon the assemblage of the device, the electrode terminal
also serves as a means for mechanical connection for the purpose of
positioning or aligning the electrode portion with the drug unit.
Thus, the connection of the current-generating portion to the
conductive snap connector through the electrode terminals is quite
important as a means for assembling the device.
[0088] In respect of the modes of the connection of the
current-generating portion to the electrode portion, the device may
be operated in a cordless mode or a remote control mode using a
cord. In case of the former, a small-sized current-generating
portion is directly connected to the electrode portion when it is
intended to carry out an easy and quick treatment. Besides, in case
of the latter, the current-generating portion is connected to the
electrode portion through an exclusive connecting cord when it is
intended to carry out a treatment while operating the
current-generating portion at hand. In this connection, connection
means are fitted to the both sides of the connecting cord for the
purpose of connecting the current-generating portion to the
conductive snap connector. In this embodiment, electrode terminals
(both anode and cathode terminals) are incorporated into a plastic
molded body so that it serves to connect the terminals, to each
other, of the current-generating portion and the conductive snap
connector. In this respect, the connection means is not restricted
to an electrode terminal and the shape and the connection mode
thereof maybe arbitrarily be changed. Preferably, the connection
means on the conductive snap connector side has such a structure
that the drug portion and the electrode portion are in line with
each other and they can firmly maintain a desired arrangement.
[0089] FIG. 10 is a diagram showing an embodiment of the
configuration of an auxiliary stand for assemblage Ie-1, in which
(a) and (b) are a view of the surface and a cross sectional view of
the connector, respectively. The auxiliary stand Ie-1 for
assemblage is designed in such a manner that it possesses a space
27 for accommodating the electrode portion, whose shape corresponds
to that of the backing layer 4 of the electrode portion and that it
has two rods 26 used for positioning upon the assemblage of the
device. Materials for the auxiliary stand for assemblage are not
restricted to any specific one insofar as they are selected from
those capable of being shaped and/or processed, such as paper,
metals, wood and plastic films (such as polypropylene, Teflon and
polyvinyl chloride films), but preferred are plastic film shaving
high shape-retentionability and a thickness of 0.5 mm or more.
[0090] This auxiliary stand for assemblage is devised to make,
easy, the operations required when a patient assemble this device.
In this embodiment, the stand is provided with a space 27 for
accommodating the electrode portion, whose shape corresponds to
that of the backing layer 4 of the electrode portion and therefore,
the electrode portion can be disposed on the precise position on
the auxiliary stand. The electrode-accommodating space 27 is also
important in that it can prevent any damage of the electrode
portion possibly encountered when the device is assembled.
[0091] In addition, the auxiliary stand may be provided with
alignment rods 26. The alignment rod 26 makes it easy to align the
electrode portion with the drug unit upon the assemblage of the
device and is effective for eliminating the occurrence of any
artificial error.
[0092] FIG. 11 is a diagram showing an embodiment of the
configuration of an auxiliary stand Ie-2 for assemblage, in which
(a) and (b) are a view of the surface and a cross sectional view of
the connector, respectively. The auxiliary stand Ie-2 for
assemblage is designed so as to have a space 29 for accommodating
the current-generating portion, whose shape is in conformity with
that of the current-generating portion Ia. The space 29 is provided
with a means 28 for fixing the current-generating portion to the
auxiliary stand Ie-2.
[0093] In this connection, the auxiliary stand for assemblage may
have a structure combined with those described above depending on
the shape and the procedures for assemblage of the device, and the
shape thereof can further be modified. Materials for the auxiliary
stand are not restricted to any specific one insofar as they are
selected from those capable of being shaped and/or processed, such
as paper, metals, wood and plastic films (such as polypropylene,
Teflon and polyvinyl chloride films), but preferred are plastic
films having a high shape-retention ability and a thickness of 0.5
mm or more.
[0094] FIG. 12 is a diagram showing an embodiment of the method for
assembling an iontophoresis device, which makes use of a drug unit
Ic-1 according to the embodiment 1, in which (a) shows the first
half of the assembling process and (b) shows the second half of the
assembling process, respectively.
[0095] A current-generating portion Ia is incorporated into a space
29 for accommodating the current-generating portion on an auxiliary
stand Ie-2 for assemblage so that an electrode terminal 2 (female)
looks upward as indicated by an arrow .quadrature. in FIG. 12(a)
and fixed to the stand by means 28 for fixing. Then an electrode
portion Ib is disposed while it coincides with a recess of the
auxiliary stand Ie-2 as indicated by an arrow .quadrature. in FIG.
12(a) and thereafter a cover material 9 of the electrode portion Ib
is peeled off to thus expose a drug-dissolving portion 11 as
indicated by an arrow .quadrature. in FIG. 12(a). Subsequently, the
electrode portion Ib is brought into contact with a drug unit Ic-1
using a conductive snap connector Id as indicated by arrows
.quadrature. and .quadrature. in FIG. 12(a) in such a manner that
they are in line with each other and thereafter a liner 17 of the
drug unit Ic-1 on the electrode portion side (which has been folded
along a perforation) is peeled off as indicated by an arrow
.quadrature. in FIG. 12(a). At the same time, a drug support 14 of
the drug unit is connected to the drug-dissolving portion 11 of the
integrated electrode portion as shown by an arrow .quadrature. in
FIG. 12(a), whereby the moisture present in the drug-dissolving
portion 11 penetrates into the drug support 14 and the drug present
therein is thus dissolved.
[0096] Thereafter a liner 12 of the drug unit on the skin side is
pulled out from the conductive snap connector Id as indicated by an
arrow .quadrature. in FIG. 12(b), then a liner 8 for an adhesive
film is peeled off immediately before the application of the device
as indicated by an arrow .quadrature. in FIG. 12(b) and finally the
device is detached from the auxiliary stand. Thus, the
iontophoresis device can be applied to an application site without
any pre-treatment to thus initiate the treatment of a patient. The
iontophoresis device according to this embodiment permits the
inhibition of any movement of the drug and the drug-dissolving
liquid towards the peripheral regions and the prevention of the
occurrence of any non-uniform, electrically charged state due to
air-admixture.
[0097] FIG. 13 is a diagram showing an embodiment of the method for
assembling an iontophoresis device, which makes use of a drug unit
Ic-2 according to Example 2 of the present invention, in which (a)
shows the first half of the assembling process and (b) shows the
second half of the assembling process, respectively.
[0098] An electrode portion is positioned on an auxiliary stand
Ie-1 using an alignment rod 26 of the stand as indicated by an
arrow .quadrature. in FIG. 13(a) and then a cover material 9 of the
electrode portion Ib-1 is peeled off to thus expose a
drug-dissolving portion 11, as indicated by an arrow .quadrature.
in FIG. 13(a). Further a liner 17 of the drug unit Ic-2 on the
electrode portion side is peeled off, as indicated by an arrow
.quadrature. in this figure. Thereafter, the electrode portion Ib-1
is brought into contact with the drug unit Ic-2 while they are in
line with one another, as indicated by an arrow .quadrature. in the
same figure to thus join the drug support 14 of the drug unit and
the drug-dissolving portion 11 of the integrated electrode portion,
as indicated by an arrow .quadrature. in this figure. Thus, the
moisture present in the drug-dissolving portion 11 penetrates into
the drug support 14 and the drug present therein is correspondingly
dissolved. Subsequently, the pharmaceutical preparation is removed
from the auxiliary stand Ie-1.
[0099] Then, after joining a conductive snap connector Id and a
current-generating portion Ia as indicated by an arrow .quadrature.
in FIG. 13(b) and a liner 12 of the drug unit on the skin side is
peeled off immediately before the application thereof as shown by
an arrow .quadrature. in the same figure, a liner 8 for an adhesive
film is peeled off as indicated by an arrow .quadrature. in this
figure. Thus, the iontophoresis device can be fitted to an
application site without any pre-treatment and accordingly, a
treatment of a patient can be initiated. The assemblage of the
device according to the procedures described above would permit the
inhibition of any movement of the drug and the drug-dissolving
liquid towards the peripheral regions and the prevention of the
occurrence of any non-uniform, electrically charged state due to
air-admixture. Moreover, the use of a molded liner likewise permits
the inhibition of any adsorption of the drug solution onto the
liner. Moreover, in this embodiment, a drying agent can be
positioned within the drug unit and therefore, the device of the
present invention permits the miniaturization of packages and the
improvement in stability of the drug to be incorporated into the
device.
(TEST EXAMPLE 1)
[0100] Experiments on Drug Adsorption on Drug Protective Member
upon Assemblage of Device
[0101] In this Test Example, the drug units of Examples 1 and 2 and
Comparative Example 1 were inspected for the amounts of drugs
adsorbed on the protective members when the drug units were
activated. In this respect, the drug units and the electrode
portions used herein and the device of Comparative Example 1 were
as follows:
[0102] Drug Unit
[0103] Human parathyroid hormone (hPTH (1-34), 400 .mu.g per sheet
of drug support) was supported on a drug support (hydrophilic
DURAPORE, average pore size: 5 .mu.m; porosity: 70%; effective
surface area: 2.5 cm 2) in its dry condition to thus give each drug
unit.
[0104] On the other hand, the drug unit of Comparative Example 1
had a structure identical to that of Example 1, except that a
protective member (liner 17 on the electrode portion side, liner 12
on the skin side) free of any adsorption-inhibitory treatment was
used.
[0105] Electrode Portion
[0106] There was introduced 1.5 g of a 1.5% agar gel containing a
citric acid buffering solution (33 mM, pH 5) into a conductive
layer (drug-dissolving portion) adjacent to 2.5 cm.sup.2 of a donor
electrode (silver-printed portion) and 1.0 g of sodium
chloride-containing polyvinyl alcohol (UF-250G available from
Unitika, Ltd.) was introduced into a reference electrode (silver
chloride-printed portion) to thus give an electrode portion.
[0107] Procedures of Experiment
[0108] After assembling the drug unit and the electrode portion
according to the method for assemblage described in Embodiments 1
and 2, the liner of the drug unit on the skin side was peeled off
after one minute from the assemblage, the drug adsorbed on the unit
was extracted with 1 ml of a 0.5 mM acetic acid buffering solution
(containing 0.9% sodium chloride and 0.01% of benzalkonium
chloride; pH 4) and then the amount of the drug adsorbed on the
liner on the skin side was determined by the (reverse phase) high
performance liquid chromatography. (n=4). Incidentally, the
assemblage in Comparative Example 1 was carried out according to
the assemblage method used in Example 1. The results thus obtained
are summarized in the following Table 1.
1 TABLE 1 Shape of Adsorption- Protective Inhibitory Amt. of Drug
Member Material Treatment Adsorbed (%) Example 1 Flat Liner
Polyethylene Treatment 0.10 .+-. 0.13 terephthalate with Silicone
Example 2 Molded Polypropylene Treatment Not Detected Liner with
Silicone Comparative Flat Liner Polyethylene -- 3.57 .+-. 1.89
Example 1 terephthalate
[0109] The data listed in Table 1 clearly indicate that about 4% of
the drug is adsorbed on the liner on the skin side in Comparative
Example 1, while almost no drugs are adsorbed on the liners on the
skin side upon the assemblage, in Examples 1 and 2 which make use
of the protective members subjected to the adsorption-inhibitory
treatment. Moreover, it was also confirmed that the use of a molded
liner as a protective member permitted further reduction of the
influence of the liner on the drug support. In addition, a drug
solution was applied to the drug support through an opening for the
application of a drug solution and then dried to examine the loss
in the drug content. (Test results were not given). As a result,
there was not observed any loss in the drug content for both
Examples 1 and 2. In other words, a drug solution can be applied
after the arrangement of a protective member and therefore, any
drug loss during preparation (due to exogenous factors) can be
prevented.
(TEST EXAMPLE 2)
[0110] Test on Inhibition of Diffusion of Drug Solution After
Assemblage of Device
[0111] In this Test Example, the drug units of Example 2 and
Comparative Example 2 were inspected for the amount of a drug,
which diffused from a drug support to the periphery thereof when
the units were activated. In this respect, the drug units and the
electrode portions used herein and the device of Comparative
Example 2 were as follows:
[0112] Drug Unit
[0113] The drug units of Example 2 and Comparative Example 2 used
herein were identical to that used in Example 1. In this respect,
however, the unit of Example 2 was subjected to a drug
diffusion-inhibitory treatment while that of Comparative Example 2
was free of such a treatment.
[0114] Electrode Portion
[0115] The electrode portions used in this Test Example were the
same as that used in Example 1.
[0116] Procedures of Experiment
[0117] After assembling the drug unit and the electrode portion
according to the method for assemblage used in Embodiment 2, the
drug unit was peeled off after 5 minutes and 15 minutes from the
assemblage, followed by drying. After the drying, the drug unit
(drug support) was divided into the exterior and the interior along
the portion subjected to the diffusion-inhibitory treatment as a
boundary to thus determine the amount of the drug diffused to the
exterior of the portion subjected to the diffusion-inhibitory
treatment (non-conductive portion). The amount of the drug was
determined by extracting the drug adsorbed on each sample with 1 ml
of a 0.5 mM acetic acid buffering solution (containing 0.9% sodium
chloride and 0.01% of benzalkonium chloride; pH 4) and then
subjecting the resulting extract to the (reverse phase) high
performance liquid chromatography. (n=3). The results thus obtained
are summarized in the following Table 2.
2TABLE 2 Diffusion- Amt. of Amt. of Inhibitory Processing Diffused
Drug Diffused Drug Treatment Mode (5 min) (15 min) Example 2 Yes
Thermal Not Detected 0.20 .+-. 0.40 .mu.g Compres- (0.05 .+-.
0.10%) sion (Ma-1) Compara- No -- 200.33 .+-. 7.08 183.99 .+-.
31.43 tive (55.37 .+-. 1.96%) (50.85 .+-. 8.69%) Example 2
[0118] It was confirmed, from the data listed in Table 2, that
about 50% of the drug was found to diffuse to the non-conductive
portion in Comparative Example 2 and that almost no drug diffused
to the non-conductive portion and the drug was maintained within
the effective area in Example 2. The results clearly indicate that,
in a device free of any diffusion-inhibitory treatment, a reduced
amount of the drug is practically used in the treatment of a
patient after the assemblage of the device and therefore, a desired
drug efficacy cannot be expected. In other words, these results
suggest that the diffusion-inhibitory treatment is quite
effective.
(TEST EXAMPLE 3)
[0119] Determination of Blood Concentration of hPTH (1-34)
[0120] In this Test Example, the drug units of Examples 1 and 2 and
Comparative Example 3 were activated, then practically used and
thereafter the concentrations of hPTH (1-34) in the sera were
determined. In this connection, the drug units and the electrode
portions herein used and the device of Comparative Example 3 were
as follows:
[0121] Drug Unit
[0122] Human parathyroid hormone (hPTH (1-34), 400 .mu.g per sheet
of drug support) was supported on a drug support (hydrophilic
DURAPORE, average pore size: 5 .mu.m; porosity: 70%; effective
surface area: 2.5 cm.sup.2) in its dry condition to thus give each
drug unit. As will be seen from Table 3, the drug units of Examples
1 and 2 herein used were subjected to a drug diffusion-inhibitory
treatment (Ma-1) and an air-exhausting treatment (Mb-1, Mb-2). On
the other hand, the drug unit of Comparative Example 3 was
subjected to a drug diffusion-inhibitory treatment (Ma-1), but was
free of any air-exhausting treatment.
3 TABLE 3 Shape of Adsorption- Diffusion- Air- Protective
Inhibitory Inhibitory Exhausting Member Treatment Treatment
Treatment Example 1 Flat Liner Treatment Yes (Ma-1) Yes (Mb-1) with
Silicone Example 2 Molded Liner -- Yes (Ma-1) Yes (Mb-2)
Comparative Flat Liner Treatment Yes (Ma-1) -- Example 3 with
Silicone
[0123] Electrode Portion
[0124] The electrode portion herein used was identical to that used
in Test Example 1.
[0125] Procedures of Experiment
[0126] SD rats (male, 6-week-old) were anesthetized with urethane
and hairs on the abdominal skin was removed (hairclipper-shaver).
Then each drug unit was activated according to the assemblage
method used in Example 1 or 2 and subsequently the resulting device
was fitted to the abdomen of the SD rat and the electrical charging
thereof was initiated. The electrical charging was carried out
using a 0.25 mA DC pulse current having a frequency of 40 kHz and
an on/off ratio (3/7) and continued over 60 minutes. Blood samples
were intrajugularly collected after the elapse of predetermined
times, followed by centrifugation thereof to give each
corresponding sample of the serum. The concentrations (pg/ml) of
hPTH (1-34) in the sera were determined by the
radioimmunoassay.
[0127] The results thus obtained are plotted on FIG. 14 and FIG. 14
is accordingly a graph showing changes, with time, of the
concentration of hPTH (1-34) in the serum observed in Test Example
3. (n=4). When the samples of this Test Example were activated, it
was confirmed, in Examples 1 and 2, that the air in the device was
removed and the drug-dissolving portion was evenly and uniformly
brought into contact with the drug support. On the other hand, air
remained in the device and it was never removed even when the
device was applied to the skin, in the device of Comparative
Example. The experimental results obtained using these samples
indicate that the blood concentration observed in Comparative
Example 3 is generally lower than those observed in Examples 1 and
2 and widely varies. In other words, it would be concluded that the
blood concentration is greatly affected by the presence of air in
the device. Accordingly, these results clearly suggest that the
air-exhausting treatment is quite effective.
[0128] As has been discussed above in detail, the iontophoresis
device according to the present invention comprises a drug support
subjected to a drug solution-diffusion-inhibitory treatment and
therefore, the device suitably permits the prevention of any drug
loss during producing, storing, assembling and using (treating a
patient) the device. The device accordingly permits the reduction
of any possibility of producing substandard products during
manufacture, the improvement of the drug in the long-term stability
during storage and the inhibition of any leakage of a drug solution
and/or any migration thereof during application. Moreover, the drug
unit is subjected to an air-exhausting treatment as a means for
eliminating any puddle of air in the device encountered when the
device is assembled and therefore, the device allows the uniform
dissolution of the drug and the uniform electrical charging of the
device. Further, the device is designed in such a manner that a
drying component may be disposed within the drug unit and
accordingly, the long-term stability of the drug can be improved
and the manufacturing process can be simplified. The foregoing
indicates that the iontophoresis device according to the present
invention permits accurate supply of water required for the
dissolution of the drug to the drug support, which has been stored
under highly stable environment and also permits the prevention of
any loss of the resulting drug solution. Consequently, the device
of the present invention has high biological availability.
INDUSTRIAL APPLICABILITY
[0129] The iontophoresis device and the drug unit according to the
present invention are useful for effective use of a drug
incorporated into a drug support and are suitably used for
iontophoresis in the medical field.
* * * * *