U.S. patent application number 12/849108 was filed with the patent office on 2011-02-10 for device for interstitial fluid extraction, production process thereof and analyzing process of interstitial fluid using the device.
This patent application is currently assigned to SYSMEX CORPORATION. Invention is credited to Kei Hagino, Kazuki Isobe, Reona Koike, Junko Kojima, Akihito Takezaki.
Application Number | 20110034787 12/849108 |
Document ID | / |
Family ID | 43066784 |
Filed Date | 2011-02-10 |
United States Patent
Application |
20110034787 |
Kind Code |
A1 |
Hagino; Kei ; et
al. |
February 10, 2011 |
Device for Interstitial Fluid Extraction, Production Process
Thereof and Analyzing Process of Interstitial Fluid Using the
Device
Abstract
A device for interstitial fluid extraction, having a base
material formed from a synthetic resin film, a pressure sensitive
adhesive layer, a hydrogel layer formed from at least one
hydrophilic polymer selected from the group consisting of polyvinyl
alcohol and polyvinyl pyrrolidone, and a release layer, wherein the
hydrogel layer has an area of a size that the pressure sensitive
adhesive layer is exposed from around the hydrogel layer, does
substantially not contain a sodium ion and causes no water
separation.
Inventors: |
Hagino; Kei; (Hyogo, JP)
; Kojima; Junko; (Hyogo, JP) ; Takezaki;
Akihito; (Tokyo, JP) ; Koike; Reona; (Tokyo,
JP) ; Isobe; Kazuki; (Tokyo, JP) |
Correspondence
Address: |
PORTER WRIGHT MORRIS & ARTHUR, LLP;INTELLECTUAL PROPERTY GROUP
41 SOUTH HIGH STREET, 28TH FLOOR
COLUMBUS
OH
43215
US
|
Assignee: |
SYSMEX CORPORATION
Hyogo
JP
NICHIBAN CO., LTD.
Tokyo
JP
|
Family ID: |
43066784 |
Appl. No.: |
12/849108 |
Filed: |
August 3, 2010 |
Current U.S.
Class: |
600/316 ;
156/272.2; 156/60; 600/573 |
Current CPC
Class: |
C08J 3/075 20130101;
A61B 2010/008 20130101; A61B 10/0045 20130101; A61B 5/14514
20130101; A61B 5/1455 20130101; Y10T 156/10 20150115; A61B 5/14532
20130101; A61B 5/14546 20130101 |
Class at
Publication: |
600/316 ;
600/573; 156/60; 156/272.2 |
International
Class: |
A61B 5/00 20060101
A61B005/00; B32B 37/02 20060101 B32B037/02; B29C 65/14 20060101
B29C065/14 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 4, 2009 |
JP |
2009-181883 |
Jun 24, 2010 |
JP |
2010-143752 |
Claims
1. A device for interstitial fluid extraction, comprising a base
material formed from a synthetic resin film; a pressure sensitive
adhesive layer arranged on one surface of the base material; a
hydrogel layer arranged on the surface of the pressure sensitive
adhesive layer and formed from at least one hydrophilic polymer
selected from the group consisting of polyvinyl alcohol and
polyvinyl pyrrolidone; and a release layer covering exposed
surfaces of both pressure sensitive adhesive layer and hydrogel
layer, wherein the hydrogel layer has an area of a size that the
pressure sensitive adhesive layer is exposed from around the
hydrogel layer, does substantially not contain a sodium ion and
causes no water separation when measured according to the measuring
method described in the present description.
2. The device for interstitial fluid extraction according to claim
1, wherein the hydrogel layer further contains an osmotic pressure
control agent composed of at least one compound selected from the
group consisting of potassium chloride, potassium phosphate,
magnesium chloride, magnesium phosphate, calcium chloride, calcium
phosphate, amino acids, urea, acetic acid, ammonia, tricine,
thiamine, riboflavin, nicotinic acid amide, pyridoxine,
cyanocobalamine and ascorbic acid in a proportion that an
osmolarity falls within a range of from 0.05 to 0.94 osmoles.
3. The device for interstitial fluid extraction according to claim
1, wherein the hydrogel layer is formed by irradiating a coating
film of an aqueous solution of the hydrophilic polymer with
radiation to crosslink the hydrophilic polymer.
4. The device for interstitial fluid extraction according to claim
1, wherein the hydrogel layer is obtained by irradiating a coating
film of an aqueous solution of the hydrophilic polymer, said
aqueous solution having a hydrophilic polymer concentration within
a range of from 7 to 30% by weight, containing an osmotic pressure
control agent composed of at least one compound selected from the
group consisting of potassium chloride, potassium phosphate,
magnesium chloride, magnesium phosphate, calcium chloride, calcium
phosphate, amino acids, urea, acetic acid, ammonia, tricine,
thiamine, riboflavin, nicotinic acid amide, pyridoxine,
cyanocobalamine and ascorbic acid in a proportion that an
osmolarity falls within a range of from 0.05 to 0.94 osmoles,
substantially containing no sodium ion, and satisfying, assuming
that the concentration of the hydrophilic polymer is b % by weight,
and the osmolarity of the osmotic pressure control agent is a
osmole(s), the relationship represented by the following expression
(A): a.ltoreq.0.1b-0.6 (A) with radiation selected from the group
consisting of .alpha.-ray, electron beam and .gamma.-ray to
crosslink the hydrophilic polymer.
5. The device for interstitial fluid extraction according to claim
4, wherein the hydrogel layer is obtained by irradiating the
coating film of the aqueous solution of the hydrophilic polymer
with electron beam, whose accelerating voltage is within a range of
from 200 kV to 10 MV and whose irradiation dose is within a range
of from 5 to 20,000 kGy, to crosslink the hydrophilic polymer.
6. The device for interstitial fluid extraction according to claim
1, wherein the hydrophilic polymer is polyvinyl alcohol having a
saponification degree within a range of from 78 to 100 mol % and an
average polymerization degree within a range of from 500 to
4,000.
7. The device for interstitial fluid extraction according to claim
1, wherein the water content in the hydrogel layer is within a
range of from 70 to 95% by weight.
8. The device for interstitial fluid extraction according to claim
1, wherein the swelling rate of the hydrogel layer, which is
obtained by multiplying a value obtained by dividing a weight after
immersing the hydrogel layer in physiological saline for 24 hours
by a weight before the immersion in the physiological saline by
100, is within a range of from 100 to 300%.
9. The device for interstitial fluid extraction according to claim
1, which is used in an analyzing process of an interstitial fluid,
comprising extracting the interstitial fluid in the hydrogel layer
through the skin of a vertebrate subjected to a
permeability-improving treatment, analyzing the interstitial fluid
collected in the hydrogel layer after a predetermined period of
time has elapsed to measure the concentrations of a sodium ion and
glucose contained therein and calculating out a value corresponding
to a glucose concentration in the blood of the vertebrate on the
basis of these measured values.
10. The device for interstitial fluid extraction according to claim
1, wherein the hydrogel layer is arranged directly or through an
intermediate layer composed of a nonwoven fabric or synthetic resin
film on the surface of the pressure sensitive adhesive layer.
11. A production process of a device for interstitial fluid
extraction, comprising providing a base material formed from a
synthetic resin film; arranging a pressure sensitive adhesive layer
on one surface of the base material; arranging a hydrogel layer
formed by irradiating a coating film of an aqueous solution of at
least one hydrophilic polymer selected from the group consisting of
polyvinyl alcohol and polyvinyl pyrrolidone with radiation to
crosslink the hydrophilic polymer on the surface of the pressure
sensitive adhesive layer; and covering exposed surfaces of both
pressure sensitive adhesive layer and hydrogel layer with a release
layer, wherein the hydrogel layer has an area of a size that the
pressure sensitive adhesive layer is exposed from around the
hydrogel layer, does substantially not contain a sodium ion and
causes no water separation when measured according to the measuring
method described in the present description.
12. The production process according to claim 11, wherein in the
step of arranging the hydrogel layer, the hydrogel layer is formed
by irradiating a coating film of an aqueous solution of the
hydrophilic polymer, said aqueous solution having a hydrophilic
polymer concentration within a range of from 7 to 30% by weight,
containing an osmotic pressure control agent composed of at least
one compound selected from the group consisting of potassium
chloride, potassium phosphate, magnesium chloride, magnesium
phosphate, calcium chloride, calcium phosphate, amino acids, urea,
acetic acid, ammonia, tricine, thiamine, riboflavin, nicotinic acid
amide, pyridoxine, cyanocobalamine and ascorbic acid in a
proportion that an osmolarity falls within a range of from 0.05 to
0.94 osmoles, substantially containing no sodium ion, and
satisfying, assuming that the concentration of the hydrophilic
polymer is b % by weight, and the osmolarity of the osmotic
pressure control agent is a osmole(s), the relationship represented
by the following expression (A): a.ltoreq.0.1b-0.6 (A) with
radiation selected from the group consisting of .alpha.-ray,
electron beam and .gamma.-ray to crosslink the hydrophilic polymer,
and the hydrogel layer is then arranged o the surface of the
pressure sensitive adhesive layer.
13. The production process according to claim 12, wherein in the
step of arranging the hydrogel layer, the hydrogel layer is formed
by irradiating the coating film of the aqueous solution of the
hydrophilic polymer with electron beam, whose accelerating voltage
is within a range of from 200 kV to 10 MV and whose irradiation
dose is within a range of from 5 to 20,000 kGy, to crosslink the
hydrophilic polymer, and the hydrogel layer is then arranged o the
surface of the pressure sensitive adhesive layer.
14. An analyzing process of an interstitial fluid, comprising
extracting a interstitial fluid in a hydrogel layer through the
skin of a vertebrate subjected to a permeability-improving
treatment analyzing the interstitial fluid collected in the
hydrogel layer after a predetermined period of time has elapsed to
measure the concentrations of a sodium ion and glucose contained
therein and calculating out a value corresponding to a glucose
concentration in the blood of the vertebrate on the basis of these
measured values, wherein the device for interstitial fluid
extraction according to claim 1 is used.
15. A device for interstitial fluid extraction, by which an
interstitial fluid is extracted in a hydrogel layer through the
skin of a vertebrate subjected to a permeability-improving
treatment on the basis of a difference in osmotic pressure, and
which comprises a base material formed from a synthetic resin film;
a pressure sensitive adhesive layer arranged on one surface of the
base material; a hydrogel layer arranged on the surface of the
pressure sensitive adhesive layer and formed from at least one
hydrophilic polymer selected from the group consisting of polyvinyl
alcohol and polyvinyl pyrrolidone; and a release layer covering
exposed surfaces of both pressure sensitive adhesive layer and
hydrogel layer, wherein the hydrogel layer contains an osmotic
pressure control agent, does substantially not contain a sodium
ion, and satisfies, assuming that the concentration of the
hydrophilic polymer is b % by weight, and the osmolarity of the
osmotic pressure control agent is a osmole(s), the relationship
represented by the following expression (A): a.ltoreq.0.1b-0.6 (A)
(however, 0.05.ltoreq.a.ltoreq.0.94, and 7.ltoreq.b.ltoreq.30).
16. The device for interstitial fluid extraction according to claim
15, wherein the osmotic pressure control agent is at least one
compound selected from the group consisting of potassium chloride,
potassium phosphate, magnesium chloride, magnesium phosphate,
calcium chloride, calcium phosphate, amino acids, urea, acetic
acid, ammonia, tricine, thiamine, riboflavin, nicotinic acid amide,
pyridoxine, cyanocobalamine and ascorbic acid.
17. The device for interstitial fluid extraction according to claim
15, wherein the device for interstitial fluid extraction can
extract the interstitial fluid in the hydrogel layer without
applying any electric energy.
18. The device for interstitial fluid extraction according to claim
15, wherein the hydrogel layer does substantially not contain an
enzyme metabolizing an interstitial fluid component.
Description
TECHNICAL FIELD
[0001] The present invention relates to a device for interstitial
fluid extraction and a production process thereof, and particularly
to a device for interstitial fluid extraction, which has a hydrogel
layer of polyvinyl alcohol (PVA) and/or polyvinyl pyrrolidone (PVP)
through a pressure sensitive adhesive layer on one surface of a
base material and can be used in quantitative analysis of glucose
contained in an interstitial fluid, or the like.
[0002] The present invention also relates to a device for
interstitial fluid extraction, which is used in an analyzing
process of an interstitial fluid, comprising extracting the
interstitial fluid in a hydrogel layer through the skin of a
vertebrate subjected to a permeability-improving treatment,
analyzing the interstitial fluid collected in the hydrogel layer
after a predetermined period of time has elapsed to measure the
concentrations of a sodium ion and glucose contained therein and
calculating out a value corresponding to a glucose concentration in
the blood of the vertebrate on the basis of these measured values,
and an analyzing process of an interstitial fluid using the device
for interstitial fluid extraction.
BACKGROUND ART
[0003] In mammal, blood glucose is a synonym of blood sugar. A
serious diabetic is required to measure a blood glucose
concentration generally 4 to 6 times per day. A general method for
measuring the blood glucose concentration is a method of collecting
a part of the blood of a patient and analyzing it. However, the
analyzing method of frequently collecting the blood greatly burdens
the patient and has a possibility that the patient may be infected
with an infectious disease through the part where the blood has
been collected. Therefore, there is proposed a method of extracting
an interstitial fluid present under the skin of a patient through
the skin and measuring a glucose concentration in the interstitial
fluid collected.
[0004] In the present invention, "tissue" means a combination of
cells gathered for fulfilling a particular role in vivo and
intercellular cements filled therebetween. The tissue of a
vertebrate such as human is generally roughly divided into 4
tissues of an epithelial tissue, a supporting tissue (for example,
fibrous connective tissue, cartilaginous tissue, bone tissue, blood
and lymph), a muscular tissue and a nervous tissue. "Interstitial
fluid" generally means a fluid component (also referred to as
"intercellular fluid") present between cells and becoming an
environment of the cells in the tissue of a vertebrate such as
human.
[0005] For example, WO 96/00110 (Patent Literature 1) proposes an
ion-introducing device having a collecting reserver having ion
conductive hydrogel, first and second ion-introducing electrodes,
and a sensor coming into contact with the collecting reserver, and
adapted for transferring glucose or a glucose metabolite to the
collecting reserver by applying electric energy to percutaneously
monitor a target substance. The ion conductive hydrogel of Patent
Literature 1 is specifically a crosslinked acrylic acid polymer
containing NaCl and NaHCO.sub.3 for applying a high ion
conductivity.
[0006] When a pad composed of the ion conductive hydrogel is struck
on the skin of a subject to apply electric energy thereto, an
interstitial fluid containing glucose is transferred to the pad
through the skin, and the glucose then reacts with a glucose
oxidase contained in the ion conductive hydrogel in the pad to
generate hydrogen peroxide. A current proportional to the
concentration of hydrogen peroxide in the pad is generated in a
sensor operating electrode, and this current gives a signal
interpreted by a system controller to display the concentration of
glucose on a display. Patent Literature 1 describes that when the
actual concentration of blood glucose of the subject is measured,
that concentration can be correlated with the above-described
glucose concentration.
[0007] WO 97/02811 (Patent Literature 2) proposes a hydrogel patch
comprising a hydrophilic compound forming hydrogel in the presence
of water, water in an amount of at most 95% by weight based on the
weight of the hydrogel, an enzyme reacting with glucose and an
electrolyte. This hydrogel patch is also adopted for measuring a
glucose concentration by measuring a current generated by a
reaction of the enzyme with glucose like the ion conductive
hydrogel described in Patent Literature 1 and is such that transfer
of glucose from a subject to the hydrogel patch is also conducted
by an electro-osmotic method.
[0008] Patent Literature 2 exemplifies polyethylene oxide,
polyvinyl alcohol, polyacrylic acid, polyacrylamide
methylpropanesulfonate and polyvinyl pyrrolidone as hydrophilic
compounds forming hydrogel. The hydrogel of Patent Literature 2
contains a chloride ion-containing salt typified by NaCl as the
electrolyte and a glucose oxidase as the enzyme.
[0009] When the ion-introducing device or the hydrogel patch
disclosed in Patent Literature 1 or Patent Literature 2 is used, an
interstitial fluid can be percutaneously extracted by the hydrogel
struck on surface of the skin without collecting blood to determine
the concentration of glucose contained in the interstitial fluid by
analyzing the interstitial fluid collected in the hydrogel after a
predetermined period of time has elapsed. When that concentration
is correlated with a blood glucose concentration measured by
collecting the blood, a value corresponding to the concentration of
glucose in the blood can be obtained.
[0010] However, the ion-introducing device and the hydrogel patch
disclosed in Patent Literatures 1 and 2 both contain a relatively
large amount of a sodium ion in the hydrogel for imparting electric
conductivity to the hydrogel and an enzyme for metabolizing
glucose, such as a glucose oxidase.
[0011] When micropores are formed from the surface of the skin to a
horny layer by applying electric energy like the technique
described in Patent Literatures 1 and 2 for extracting the
interstitial fluid using the hydrogel, the amount of glucose in the
interstitial fluid collected in the hydrogel varies according to
the hole diameter and depth of the micropores, a measured portion
on the skin, and the like. Therefore, a value corresponding to the
concentration of blood sugar glucose in the blood cannot be exactly
obtained by the mere measurement of a glucose concentration in the
interstitial fluid, so that in Patent Literature 1, a processing of
correlating the measured glucose concentration with a blood glucose
concentration measured by actually collecting the blood is
conducted.
Citation List
Patent Literature
Patent Literature 1: WO 96/00110
Patent Literature 2: WO 97/02811
SUMMARY OF INVENTION
Technical Problem
[0012] It is an object of the present invention to provide a device
for interstitial fluid extraction equipped with a hydrogel layer,
by which a value correlated with a blood glucose concentration can
be determined from the concentration of glucose contained in an
interstitial fluid collected without being correlated with a blood
glucose concentration measured by actually collecting the
blood.
[0013] More specifically, a main object of the present invention is
to provide a device for interstitial fluid extraction, which can be
used in an analyzing process of the interstitial fluid, comprising
extracting the interstitial fluid in a hydrogel layer through the
skin of a vertebrate subjected to a permeability-improving
treatment, analyzing the interstitial fluid collected in the
hydrogel layer to measure the concentrations of a sodium ion and
glucose contained therein and calculating out a value corresponding
to a glucose concentration in the blood of the vertebrate on the
basis of these measured values.
[0014] Another object of the present invention is to provide a
production process of the device for interstitial fluid extraction.
A further object of the present invention is to provide an
analyzing process of an interstitial fluid using the device for
interstitial fluid extraction.
[0015] The present inventors have carried out an extensive
investigation with a view toward achieving the above objects. As a
result, the present inventors have reached a device for
interstitial fluid extraction, in which a pressure sensitive
adhesive layer is arranged on one surface of a base material formed
from a synthetic resin film, a hydrogel layer formed from at least
one hydrophilic polymer selected from the group consisting of
polyvinyl alcohol and polyvinyl pyrrolidone is arranged on the
surface of the pressure sensitive adhesive layer, and a release
layer covering exposed surfaces of both pressure sensitive adhesive
layer and hydrogel layer is provided.
[0016] A part of the pressure sensitive adhesive layer is exposed
from around the hydrogel layer. The hydrogel layer does
substantially not contain a sodium ion. The hydrogel layer causes
no water separation when measured according to the measuring method
(measuring method described in Examples) described in the present
description. The hydrogel layer does substantially not contain an
enzyme metabolizing an interstitial fluid component, such as a
glucose oxidase.
[0017] The hydrogel layer in the device for interstitial fluid
extraction according to the present invention is preferably that
crosslinked by irradiation of radiation because mixing of various
chemical substances attending on adoption of a chemical
crosslinking method is prevented. The hydrogel layer is high in
water content, but separation of water therefrom is not observed.
This fact means that the crosslinking reaction in the hydrogel
layer by irradiation of radiation sufficiently progresses without
being inhibited.
[0018] The hydrogel layer preferably contains an osmotic pressure
control agent for increasing an osmotic pressure to improve the
interstitial fluid extraction efficiency thereof. On the other
hand, an aqueous solution of a hydrophilic polymer containing the
osmotic pressure control agent tends to inhibit the crosslinking
reaction by irradiation of radiation. The present inventors have
found that the concentrations of the hydrophilic polymer and the
osmotic pressure control agent in the aqueous solution of the
hydrophilic polymer are controlled in addition to the use of a
specified compound as the osmotic pressure control agent, whereby
the crosslinking reaction by irradiation of radiation sufficiently
progresses to obtain a hydrogel layer causing no water
separation.
[0019] The concentrations of a sodium ion and glucose in the
interstitial fluid collected in the hydrogel layer can be exactly
measured by means of a biocomponent analysis unit having a
structure suitable for application of the device for interstitial
fluid extraction and an analyzing function. The biocomponent
analysis unit is used, whereby the concentrations of the sodium ion
and glucose in the interstitial fluid can be exactly measured, and
a value corresponding to a blood glucose concentration can be
calculated out on the basis of these measured values to display it.
The present invention has been led to completion on the basis of
these findings.
Solution to Problem
[0020] According to the present invention, there is provided a
device for interstitial fluid extraction, comprising
a base material formed from a synthetic resin film; a pressure
sensitive adhesive layer arranged on one surface of the base
material; a hydrogel layer arranged on the surface of the pressure
sensitive adhesive layer and formed from at least one hydrophilic
polymer selected from the group consisting of polyvinyl alcohol and
polyvinyl pyrrolidone; and a release layer covering exposed
surfaces of both pressure sensitive adhesive layer and hydrogel
layer, wherein the hydrogel layer has an area of a size that the
pressure sensitive adhesive layer is exposed from around the
hydrogel layer, does substantially not contain a sodium ion and
causes no water separation when measured according to the measuring
method described in the present description.
[0021] According to the present invention, there is also provided a
production process of a device for interstitial fluid extraction,
comprising
providing a base material formed from a synthetic resin film;
arranging a pressure sensitive adhesive layer on one surface of the
base material; arranging a hydrogel layer formed by irradiating a
coating film of an aqueous solution of at least one hydrophilic
polymer selected from the group consisting of polyvinyl alcohol and
polyvinyl pyrrolidone with radiation to crosslink the hydrophilic
polymer on the surface of the pressure sensitive adhesive layer;
and covering exposed surfaces of both pressure sensitive adhesive
layer and hydrogel layer with a release layer, wherein the hydrogel
layer has an area of a size that the pressure sensitive adhesive
layer is exposed from around the hydrogel layer, does substantially
not contain a sodium ion and causes no water separation when
measured according to the measuring method described in the present
description.
[0022] According to the present invention, there is further
provided an analyzing process of an interstitial fluid, comprising
extracting the interstitial fluid in a hydrogel layer through the
skin of a vertebrate subjected to a permeability-improving
treatment, analyzing the interstitial fluid collected in the
hydrogel layer after a predetermined period of time has elapsed to
measure the concentrations of a sodium ion and glucose contained
therein and calculating out a value corresponding to a glucose
concentration in the blood of the vertebrate on the basis of these
measured values, wherein the above-described device for
interstitial fluid extraction is used.
[0023] According to the present invention, there is still further
provided a device for interstitial fluid extraction, by which an
interstitial fluid is extracted in a hydrogel layer through the
skin of a vertebrate subjected to a permeability-improving
treatment on the basis of a difference in osmotic pressure, and
which comprises
a base material formed from a synthetic resin film; a pressure
sensitive adhesive layer arranged on one surface of the base
material; a hydrogel layer arranged on the surface of the pressure
sensitive adhesive layer and formed from at least one hydrophilic
polymer selected from the group consisting of polyvinyl alcohol and
polyvinyl pyrrolidone; and a release layer covering exposed
surfaces of both pressure sensitive adhesive layer and hydrogel
layer, wherein the hydrogel layer contains an osmotic pressure
control agent, does substantially not contain a sodium ion, and
satisfies, assuming that the concentration of the hydrophilic
polymer is b % by weight, and the osmolarity of the osmotic
pressure control agent is a osmole(s), the relationship represented
by the following expression (A):
a.ltoreq.0.1b-0.6 (A)
(however, 0.05.ltoreq.a.ltoreq.0.94, and 7.ltoreq.b.ltoreq.30).
ADVANTAGEOUS EFFECTS OF INVENTION
[0024] According to the present invention, there is provided a
device for interstitial fluid extraction, which is easy to be
applied to a skin surface, inhibits irritation to the skin and is
equipped with a hydrogel layer of a hydrophilic polymer capable of
exactly analyzing amounts of a sodium ion and glucose contained in
the interstitial fluid collected.
[0025] In particular, the device for interstitial fluid extraction
according to the present invention can be suitably used in an
analyzing process of an interstitial fluid, comprising extracting
the interstitial fluid in the hydrogel layer through the skin of a
vertebrate, analyzing the interstitial fluid collected in the
hydrogel layer after a predetermined period of time has elapsed to
measure the concentrations of a sodium ion and glucose contained
therein and calculating out a value corresponding to a glucose
concentration in the blood of the vertebrate on the basis of these
measured values.
[0026] According to the present invention, there are also provided
a production process of the device for interstitial fluid
extraction and an analyzing process of an interstitial fluid using
the device for interstitial fluid extraction.
BRIEF DESCRIPTION OF DRAWINGS
[0027] FIG. 1 is a perspective view illustrating the appearance of
an exemplary biocomponent analysis unit which can be used for an
analyzing process of an interstitial fluid according to the present
invention.
[0028] FIG. 2 typically illustrates the construction of a liquid
supply part 14 in the biocomponent analysis unit in FIG. 1.
[0029] FIG. 3 typically illustrates the construction of a liquid
discharge part 15 in the biocomponent analysis unit in FIG. 1.
[0030] FIG. 4 is a perspective view illustrating a state that a
device 50 for interstitial fluid extraction has been stuck on a
cartridge 30 for analysis in the biocomponent analysis unit in FIG.
1.
[0031] FIG. 5a is a plan view illustrating the structure of a
device for interstitial fluid extraction, and FIG. 5b is a
cross-sectional view thereof.
[0032] FIG. 6 is a plan view of a cartridge body 310 for
analysis.
[0033] FIG. 7 is another plan view of the cartridge body 310 for
analysis.
[0034] FIG. 8 is a flow chart explaining an exemplary biocomponent
analyzing process using the biocomponent analysis unit.
[0035] FIG. 9 is a flow chart for explaining the process of Step S7
in FIG. 8.
[0036] FIG. 10 is a typical cross-sectional view for explaining the
operation of the biocomponent analysis unit illustrated in FIG.
1.
[0037] FIG. 11 is a typical cross-sectional view for explaining a
particular operation in the biocomponent analysis unit illustrated
in FIG. 1.
[0038] FIG. 12 is a typical cross-sectional view for explaining a
particular operation in the biocomponent analysis unit illustrated
in FIG. 1.
[0039] FIG. 13 is a typical cross-sectional view for explaining a
particular operation in the biocomponent analysis unit illustrated
in FIG. 1.
[0040] FIG. 14 is a typical cross-sectional view for explaining a
particular operation in the biocomponent analysis unit illustrated
in FIG. 1.
[0041] FIG. 15 is a typical cross-sectional view for explaining a
particular operation in the biocomponent analysis unit illustrated
in FIG. 1.
[0042] FIG. 16 is a typical cross-sectional view for explaining a
particular operation in the biocomponent analysis unit illustrated
in FIG. 1.
[0043] FIG. 17 is a view for illustrating a measuring principle of
a blood sugar AUC value.
[0044] FIG. 18 is another view for illustrating the measuring
principle of the blood sugar AUC value.
[0045] FIG. 19 is a graph illustrating the relationship between the
osmolarity of KCl and the concentration of polyvinyl alcohol in a
case where KCl was used as an osmotic pressure control agent in
relation to whether separation of water from a hydrogel layer
occurred or not.
[0046] FIG. 20 is a graph illustrating the relationship between the
concentration of each of various osmotic pressure control agents of
urea, glycine and KCl and a ratio of a glucose extraction rate.
[0047] FIG. 21 is a graph illustrating the relationship between the
concentration of each of various osmotic pressure control agents of
alanine, proline and KCl and a ratio of a glucose extraction
rate.
DESCRIPTION OF EMBODIMENTS
[0048] The device for interstitial fluid extraction according to
the present invention is intended for an interstitial fluid
extracted and collected through a skin tissue subjected to a
permeability-improving treatment. The skin tissue includes a horny
layer and a mucosal tissue. In many cases, however, the horny layer
becomes an object
[0049] The device for interstitial fluid extraction according to
the present invention can be suitably applied to an analyzing
process of an interstitial fluid, comprising extracting the
interstitial fluid in the hydrogel layer through the skin of a
vertebrate such as human, which has been subjected to a
permeability-improving treatment, analyzing the interstitial fluid
collected in the hydrogel layer to measure the concentrations of a
sodium ion and glucose contained therein and calculating out a
value corresponding to a glucose concentration in the blood of the
vertebrate on the basis of these measured values.
[0050] With respect to the device for interstitial fluid extraction
according to the present invention, the details thereof, including
a biocomponent analysis unit suitable for the analyzing process,
will hereinafter be described.
[0051] FIG. 1 is a perspective view illustrating the appearance of
an exemplary biocomponent analysis unit which can be used for the
analyzing process of the interstitial fluid according to the
present invention. The biocomponent analysis unit 1 is equipped
with an analysis unit body 10 and an analyzing kit 20 as
illustrated in FIG. 1. The analyzing kit 20 is equipped with a
cartridge 30 for analysis and a device 50 for interstitial fluid
extraction. This biocomponent analysis unit 1 is used for obtaining
a value corresponding to a blood glucose concentration by
extracting an interstitial fluid from a subject through the skin
thereof by the device 50 for interstitial fluid extraction and
analyzing concentrations of a sodium ion and glucose in the
interstitial fluid collected in the device for interstitial fluid
extraction after a predetermined period of time.
[0052] More specifically, this biocomponent analysis unit 1 is used
in the following manner. First, micropores are formed in the skin
of a subject as the permeability-improving treatment, and the
device 50 for interstitial fluid extraction is then stuck on the
surface of the skin subjected to the permeability-improving
treatment. Accordingly, the permeability-improving treatment in the
present invention typically means a treatment for forming
micropores in the skin of a vertebrate such as human. The
micropores in the skin having a horny layer are preferably formed
through the horny layer from the viewpoint of improvement in
permeability of an interstitial fluid. The device 50 for
interstitial fluid extraction extracts the interstitial fluid in
the hydrogel layer on the basis of a difference in osmotic
pressure. Therefore, the device 50 for interstitial fluid
extraction can extract the interstitial fluid in the hydrogel layer
without applying any electric energy.
[0053] After a certain period of time has elapsed from the sticking
of the device 50 for interstitial fluid extraction on the surface
of the skin subjected to the permeability-imparting treatment, the
device 50 for interstitial fluid extraction is taken out of the
skin of the subject and stuck on the cartridge 30 for analysis as
illustrated by a dashed line 60 in FIG. 1. The cartridge 30 for
analysis is arranged in a cartridge arranging part 12 of the unit
body 10 as illustrated by a dashed line 70. The unit body 10
executes a prescribed analytical processing for the device 50 for
interstitial fluid extraction stuck on the cartridge 30 for
analysis arranged in the cartridge arranging part 12 to measure
concentrations of glucose and a sodium ion in the interstitial
fluid collected in the device 50 for interstitial fluid extraction
and calculate out a value corresponding to a blood glucose
concentration on the basis of these measured values. When the
extraction time of the device 50 for interstitial fluid extraction
is set to at least 60 minutes, the concentrations of glucose and a
sodium ion in the interstitial fluid collected can be measured to
calculate out a value corresponding to a blood sugar AUC (area
under the curve) value on the basis of these measured values.
[0054] The mechanism of the analysis unit body 10 will hereinafter
be described. As illustrated in FIG. 1, the analysis unit body 10
is equipped with a thick rectangular housing as illustrated in FIG.
1, and a recessed part 11 is formed in a top plate on an upper
surface of the housing. The cartridge arranging part 12 composed of
a recessed part formed deeper than the recessed part 11 is provided
in the recessed part 11. A movable top plate 13 having the same
thickness as the height of a side wall of the recessed part 11 is
joined to the recessed part 11.
[0055] The movable top plate 13 is joined to the side walls of the
recessed part 11 by fitting a support shaft 131 extending
horizontally from the side walls thereof into the side walls of the
recessed part 11. The movable top plate 13 can be received in the
recessed part 11 from the state illustrated in FIG. 1 by being
moved around the support shaft 131 and to the contrary, raised as
illustrated in FIG. 1 from the state received in the recessed part
11. The cartridge arranging part 12 has a size capable of receiving
the cartridge 30 for analysis therein.
[0056] The movable top plate 13 is supported by the support shaft
so as to be biased toward the recessed part 11. Accordingly, the
cartridge 30 for analysis arranged in the cartridge arranging part
12 is pressed from above by the movable top plate 13. An injection
nipple 141 and a discharge nipple 151 provided so as to project
from a bottom surface of the cartridge arranging part 12 also
functions as cushioning members when pressed by the movable top
plate 13 because they are made by a member having flexibility. The
movable top plate 13 presses the cartridge 30 for analysis from
above, whereby close contact of the respective nipples with an
inlet hole and an outlet hole formed in the cartridge 30 for
analysis becomes firmer to reduce the risk of liquid leakage.
[0057] The analysis unit body 10 is equipped with a liquid supply
part 14 and a liquid discharge part 15 in its interior. The liquid
supply part 14 is a mechanism for supplying a liquid to the
cartridge 30 for analysis arranged in the cartridge arranging part
12. The liquid discharge part 15 is a mechanism for discharging the
liquid supplied to the cartridge 30 for analysis as a waste
liquid.
[0058] FIG. 2 typically illustrates the construction of the liquid
supply part 14. As illustrated in FIG. 2, the liquid supply part 14
is equipped with an injection nipple 141, a pump 142 and a recovery
liquid tank 144. The pump 142 and recovery liquid tank 144 are
connected to each other by an upstream-side passage 143. The
recovery liquid tank 144 and injection nipple 141 are connected to
each other by a downstream-side passage 145. The pump 142 and
injection nipple 141 are connected to each other by a bypass
passage 146 bypassing the recovery liquid tank 144.
[0059] An electromagnetic valve V1 is provided at a junction of the
upstream-side passage 143 with the bypass passage 146. An
electromagnetic valve V2 is provided at a junction of the
downstream-side passage 145 with the bypass passage 146. An
electromagnetic valve V3 is provided on a downstream side from the
junction of the downstream-side passage 145 with the bypass passage
146. A passage between the electromagnetic valves V2 and V3 is
linked to a waste liquid passage 147 linking to a waste liquid tank
153 of the liquid discharge part 15.
[0060] The injection nipple 141 is provided at the cartridge
arranging part 12 so as to protrude upward and supports the
cartridge 30 for analysis from below together with the discharge
nipple 151 when the cartridge 30 for analysis has been arranged in
the cartridge arranging part 12. A liquid is injected in the
interior of the cartridge 30 for analysis arranged in the cartridge
arranging part 12 through the injection nipple 141.
[0061] The injection nipple 141 is made by a flexible member such
as rubber. The discharge nipple 151 is also made by the flexible
member likewise, whereby the injection nipple 141 and discharge
nipple 151 can be brought into tight contact with the inlet hole
and outlet hole formed in the cartridge 30 for analysis,
respectively, when the cartridge 30 for analysis has been arranged
in the cartridge arranging part 12, which makes hard to cause
liquid leakage. The pump 142 is driven by a motor to send air
within the passage.
[0062] The recovery liquid tank 144 stores a recovery liquid
(recovery liquid for recovering a biocomponent from the
interstitial fluid collected in the hydrogel layer) injected in the
interior of the cartridge 30 for analysis. If impurities are
contained in the recovery liquid, the impurities affect the
detection of glucose and the sodium ion. Therefore, the recovery
liquid is preferably a liquid substantially containing no impurity.
From such a viewpoint, it is desirable that pure water is stored as
the recovery liquid in the recovery liquid tank 144. The recovery
liquid tank 144 is constructed removably out of the unit body 10.
The supplement of the recovery liquid is conducted by replacing the
recovery tank 144 with new one.
[0063] The electromagnetic valve V1 changes over the connection
between the upstream-side passage 143 and the recovery liquid tank
144 to the connection between the upstream-side passage 143 and the
bypass passage 146 by opening and closing the valve. The
electromagnetic valve V2 changes over the connection between the
recovery liquid tank 144 and the downstream-side passage 145 to the
connection between the bypass passage 146 and the downstream-side
passage 145 by opening and closing the valve. The electromagnetic
valve V3 changes over the opening and closing of the
downstream-side passage 145 by opening and closing the valve.
[0064] The liquid supply part 14 is equipped with the
above-described construction, whereby only a predetermined amount
of the recovery liquid stored in the recovery liquid tank 144 can
be sent to the cartridge 30 for analysis by sending air from the
pump 142.
[0065] FIG. 3 typically illustrates the construction of a liquid
discharge part 15. The liquid discharge part 15 is equipped with a
discharge nipple 151, a passage 152 and a waste liquid tank 153.
The discharge nipple 151 is provided at the cartridge arranging
part 12 so as to protrude upward and supports the cartridge 30 for
analysis from below together with the injection nipple 141 when the
cartridge 30 for analysis has been arranged in the cartridge
arranging part 12. The recovery liquid sent from the liquid supply
part 14 is taken in the cartridge 30 for analysis through the
injection nipple 141.
[0066] The waste liquid tank 153 is connected to the discharge
nipple 151 through the passage 152 and stores a waste liquid of the
recovery liquid taken in from the discharge nipple 151. The waste
liquid tank 153 is constructed connectably to the outside of the
unit body 10 so as to enable the waste liquid to be discharged to
the outside of the unit body 10.
[0067] As illustrated in FIG. 1, the unit body 10 is equipped with
a glucose detection part 21, a sodium detection part 22, a display
part 23, an operation part 24 and a control part 25. The glucose
detection part 21 is provided at a back surface (i.e., a surface
facing the cartridge arranging part 12 when the movable top plate
13 is received in the recessed part 11) of the movable top plate
13.
[0068] The glucose detection part 21 is equipped with a light
source 211 for irradiating with light and a light reception part
212 for receiving reflected light of the light irradiated from the
light source 211, whereby the glucose detection part 21 is so
constructed that the cartridge 30 for analysis arranged in the
cartridge arranging part 12 can be irradiated with the light, and
the reflected light from the cartridge 30 for analysis irradiated
can be received. The cartridge 30 for analysis contains reaction
reagents (reactive substances) 330 such as a glucose oxidase and a
pigment reacting with an active oxygen of hydrogen peroxide formed
by the oxidase to develop a color. The glucose detection part 21
detects a change in absorbance by such a chemical reaction of
glucose and the reagents by the reflected light, thereby
quantitatively analyzing glucose.
[0069] The sodium detection part 22 is provided at the bottom
surface of the cartridge arranging part 12. The sodium detection
part 22 is equipped with a rectangular plate-like member 221
provided at the bottom surface of the cartridge arranging part 12,
and a pair of electrodes 222 for measurement of a sodium ion
concentration is provided at the substantial center of this
plate-like member 221. The electrodes 222 for measurement of the
sodium ion concentration include a sodium ion-selective electrode
equipped with a sodium ion selecting membrane and composed of
silver/silver chloride and a silver/silver chloride electrode that
is a counter electrode.
[0070] The plate-like member 221 is covered with a flexible
material and also functions as a cushioning member when the
cartridge 30 for analysis arranged in the cartridge arranging part
12 is pressed by the movable top plate 13. The plate-like member
221 forms a closed space with a recessed part (a first connection
passage, a storage part for sodium detection, and a second
connection passage; see FIGS. 6 and 7 illustrated below) formed in
a lower surface of the cartridge 30 for analysis, and this space
functions as a passage through which the liquid passes. From the
viewpoint of preventing liquid leakage, thus the cartridge 30 for
analysis and the plate-like member 221 preferably comes into tight
contact with each other. In a preferred embodiment, the
construction that the surface of the plate-like member 221 is
covered with a flexible material, and the cartridge 30 for analysis
is pressed from above by the movable top plate 13 can improve the
close contact between the plate-like member 221 and the cartridge
30 for analysis.
[0071] The display part 23 illustrated in FIG. 1 is provided on an
upper surface of the housing of the unit body 10 and constructed
comprising a liquid crystal panel. This display part 23 functions
in such a manner that an operation image is displayed for a user
upon operation, and a measured result is displayed at the time the
measurement has been completed.
[0072] The operation part 24 illustrated in FIG. 1 is provided on
the upper surface of the housing of the unit body 10 and
constructed comprising a plurality of buttons. A user can direct
beginning and shut-down of measurement to the control part 25 by
operating these.
[0073] The control part 25 illustrated in FIG. 1 is provided in the
interior of the unit body 10 and equipped with a control mechanism
composed of CPU, ROM, RAM and the like. CPU reads and executes a
program stored in ROM, thereby controlling the operations of the
respective parts. RAM is used as a developing region of the program
when the program stored in ROM is executed.
[0074] As illustrated in FIG. 1, the analyzing kit 20 is composed
of the cartridge 30 for analysis and the device 50 for interstitial
fluid extraction stuck on the cartridge 30 for analysis. The
analyzing kit 20 is provided separately with the cartridge 30 for
analysis and the device 50 for interstitial fluid extraction before
it is used in the analysis. Upon using in the analysis, the device
50 for interstitial fluid extraction is stuck on the cartridge 30
for analysis.
[0075] FIG. 4 is a perspective view illustrating a state that the
device 50 for interstitial fluid extraction has been stuck on the
cartridge 30 for analysis. As illustrated in FIG. 4, the cartridge
30 for analysis is mainly equipped with a cartridge body 310 and
the reaction reagents 330 to glucose. FIG. 4 illustrates the
cartridge body 310 with its detailed structure omitted.
[0076] The device 50 for interstitial fluid extraction is described
with reference to FIGS. 5a and 5b. FIG. 5a is a plan view
illustrating the structure of the device 50 for interstitial fluid
extraction. In FIG. 5a, a lower surface (a surface coming into
contact with the skin in FIG. 1) of the device 50 for interstitial
fluid extraction is illustrated in an exposed state. In the
following description, a surface of the device 50 for interstitial
fluid extraction, with which the skin comes into contact, is
referred to as a lower surface, and a back surface (opposing
surface) thereof is referred to as an upper surface.
[0077] The device 50 for interstitial fluid extraction is equipped
with the hydrogel layer 501 and a pressure sensitive adhesive film
502 and has a structure that the hydrogel layer 501 is held on the
substantial center of the pressure sensitive adhesive film 502. The
pressure sensitive adhesive film 502 is composed of a base material
and a pressure sensitive adhesive layer.
[0078] The device for interstitial fluid extraction according to
the present invention has a multilayer structure that
a) a base material formed from a synthetic resin film, b) a
pressure sensitive adhesive layer, c) a hydrogel layer formed from
a hydrophilic polymer, and d) a release layer are arranged in this
order.
[0079] When the pressure sensitive adhesive layer is formed from a
pressure sensitive adhesive comprising a hydrophobic polymer as a
base, adhesion between the pressure sensitive adhesive layer and
the hydrogel layer formed from the hydrophilic polymer may be
insufficient in some cases. In such a case, an intermediate layer
formed of a material having good adhesion to both layers may be
arranged between the pressure sensitive adhesive layer and the
hydrogel layer.
[0080] In general, the base material is desirably a synthetic resin
film having flexibility and good resistance to moisture permeation.
In the device for interstitial fluid extraction according to the
present invention, the hydrogel layer has a function of extracting
an interstitial fluid through the skin and collecting the
interstitial fluid extracted over a predetermined period of time.
Therefore, the base material present on the side opposing to the
hydrogel layer is required to have sufficient resistance to
moisture permeation not to vaporize off water in the hydrogel layer
and an interstitial fluid component collected. The base material is
also required to have cushioning property and protective property
for a skin site on which the device for interstitial fluid
extraction is stuck.
[0081] From these points in view, as the synthetic resin film
forming the base material, is preferred, for example, a
polyethylene film, a polypropylene film, a polyester film or a
polyurethane film, and more preferred a polyethylene film, a
polyester film or a polyurethane film. The thickness of the
synthetic resin film is within a range of preferably from 30 to 250
.mu.m, more preferably from 40 to 200 .mu.m, particularly
preferably from 50 to 120 .mu.m.
[0082] Examples of the pressure sensitive adhesive forming the
pressure sensitive adhesive layer include acrylic pressure
sensitive adhesives, rubber-based pressure sensitive adhesives,
silicone-based pressure sensitive adhesives and urethane-based
pressure sensitive adhesives. Since the device for interstitial
fluid extraction according to the present invention is often stuck
on a skin surface over a relatively long period of time, these
pressure sensitive adhesives are preferably little in skin
irritativity. Acrylic pressure sensitive adhesives and rubber-based
pressure sensitive adhesives are preferred from the viewpoint of
little skin irritativity, and acrylic pressure sensitive adhesives
are more preferred.
[0083] The acrylic pressure sensitive adhesive used in the present
invention is an alkyl (meth)acrylate copolymer comprising, as a
main component, an alkyl acrylate or alkyl methacrylate having 1 to
18 carbon atoms, preferably 4 to 12 carbon atoms. Here, the alkyl
(meth)acrylate means an alkyl acrylate or alkyl (meth)acrylate.
[0084] Examples of the alkyl (meth)acrylate include methyl
(meth)acrylate, ethyl (meth)acrylate, n-butyl (meth)acrylate,
isobutyl (meth)acrylate, t-butyl (meth)acrylate, n-hexyl
(meth)acrylate, n-octyl (meth)acrylate, 2-ethylhexyl
(meth)acrylate, isooctyl (meth)acrylate, isononyl (meth)acrylate,
n-decyl (meth)acrylate, isodecyl (meth)acrylate, lauryl
(meth)acrylate and stearyl (meth)acrylate.
[0085] These alkyl (meth)acrylates may be used either singly or in
combination of 2 or more monomers thereof. Among the alkyl
(meth)acrylates, n-butyl (meth)acrylate, 2-ethylhexyl
(meth)acrylate, n-octyl (meth)acrylate, isooctyl (meth)acrylate and
isononyl (meth)acrylate are preferred.
[0086] The alkyl (meth)acrylate copolymer is a copolymer
comprising, as a main monomer component, an alkyl (meth)acrylate,
whereby the copolymer can exhibit properties as the acrylic
pressure sensitive adhesive. The copolymerization proportion of the
alkyl (meth)acrylate is preferably 60 to 90% by weight, more
preferably 65 to 97% by weight, particularly preferably 70 to 96%
by weight.
[0087] As a comonomer copolymerizing with the alkyl (meth)acrylate,
is preferred a vinyl monomer having a functional group. Specific
examples thereof include acrylates having a hydroxyl group, such as
2-hydroxyethyl acrylate, 3-hydroxypropyl acrylate and
4-hydroxybutyl acrylate; vinyl monomers having a carboxyl group,
such as acrylic acid, methacrylic acid, maleic acid, maleic
anhydride, itaconic acid and monobutyl maleate; vinyl monomers
having an amide group, such as acrylamide, dimethylacrylamide,
diethylacrylamide, methacrylamide and N-methylolacrylamide; vinyl
monomers having an amino group, such as dimethylaminoethyl
acrylate; vinyl monomers having an epoxy group, such as glycidyl
acrylate and glycidyl methacrylate; vinyl monomers having a
pyrrolidone ring, such as N-vinylpyrrolidone; and alkoxyalkyl
acrylates such as 2-methoxyethyl acrylate and ethoxyethyl acrylate.
The monomers having the functional group may be used either singly
or in combination of 2 or more monomers thereof. The
copolymerization proportion of the monomer having the functional
group in the alkyl (meth)acrylate copolymer is preferably 1 to 40%
by weight, more preferably 2 to 35% by weight, particularly
preferably 3 to 30% by weight.
[0088] Examples of other comonomers include vinyl esters such as
vinyl acetate; unsaturated nitriles such as acrylonitrile and
methacrylonitrile; and vinyl aromatic compounds such as styrene.
The other comonomers may be used either singly or in combination of
2 or more monomers thereof. The copolymerization proportion of the
other comonomer in the alkyl (meth)acrylate copolymer is preferably
0 to 30% by weight.
[0089] The alkyl (meth)acrylate copolymer can be generally
synthesized by radical-polymerizing the monomers. Examples of a
polymerization process include a solution polymerization process,
an emulsion polymerization process and a bulk polymerization
process. However, the solution polymerization process is preferred
in that good tackiness is easily achieved. Examples of a
polymerization initiator include organic peroxides such as benzoyl
peroxide and lauroyl peroxide; and azo initiators such as
azobisisobutyronitrile. The radical polymerization initiator is
added in a proportion of about 0.1 to 3% by weight based on all the
monomers, and the resultant mixture is stirred for from several
hours to several tens hours at a temperature of about 40 to
90.degree. C. under a nitrogen atmosphere to conduct
copolymerization. In the solution polymerization process, ethyl
acetate, acetone, toluene, or a mixture thereof is commonly used as
a solvent.
[0090] The weight average molecular weight of the acrylic pressure
sensitive adhesive is preferably 300,000 to 1,000,000, more
preferably 450,000 to 650,000. The weight average molecular weight
of the acrylic pressure sensitive adhesive is controlled within the
above range, whereby cohesiveness, adhesive strength, workability
upon mixing with other components, affinity for other components,
and the like can be balanced with one another. The weight average
molecular weight of the acrylic pressure sensitive adhesive is a
value determined in terms of a value of standard polystyrene by gel
permeation chromatography (GPC).
[0091] Various kinds of crosslinking agents may be used for
increasing the cohesive strength of the acrylic pressure sensitive
adhesive. Examples of the crosslinking agents include
polyfunctional isocyanate compounds, polyfunctional epoxy compounds
and polyvalent metal salts. When the crosslinking agent is added to
the acrylic pressure sensitive adhesive, the used proportion
thereof is preferably 0.01 to 3 parts by weight, more preferably
0.02 to 2 parts by weight, particularly preferably 0.03 to 1 part
by weight per 100 parts by weight of the acrylic pressure sensitive
adhesive. If the proportion of the crosslinking agent used is too
low, the effect to increase the cohesive strength becomes little.
If the proportion is too high, the cohesive strength is too
increased.
[0092] Examples of the rubber-based pressure sensitive adhesive
used in the present invention include compositions obtained by
incorporating a tackifying resin, a softner and the like into a
rubber base such as synthetic polyisoprene rubber, polyisobutylene,
styrene-isoprene-styrene block copolymer (SIS),
styrene-butadiene-styrene block copolymer (SBS) or
styrene-ethylene.butylene-styrene block copolymer (SEBS). These
rubber bases may be used either singly or in combination of 2 or
more bases thereof. Among these rubber bases, thermoplastic
elastomers such as SIS, SBS and SEBS are preferred in that
sensitization to the skin is little, and crosslinking points are
present in their molecules, with SIS being particularly
preferred.
[0093] A tackifier is generally incorporated into the rubber-based
pressure sensitive adhesive for increasing adhesive strength. As
examples of the tackifier, may be mentioned C5 petroleum resins, C9
petroleum resins, terpene resins, rosin resins, phenol resins and
xylene resins. The tackifier is used in a proportion of generally
50 to 350 parts by weight, preferably 80 to 300 parts by weight,
more preferably 100 to 250 parts by weight per 100 parts by weight
of the rubber base. The rubber-based pressure sensitive adhesive
may contain a softner such as liquid paraffin, a filler, an
antioxidant, a crosslinking agent, etc. as needed.
[0094] The coating of the pressure sensitive adhesive can be
conducted by a method of coating a base material layer (synthetic
resin film) with a pressure sensitive adhesive solution comprising
an organic solvent or water as a medium by means of a coating
device such as a reverse-roll coater, comma roll coater or bar
coater. The pressure sensitive adhesive solution may be applied on
to a paper base such as woodfree paper or glassine paper treated
with a release agent such as a silicone resin, or a sheet such as a
polyester film and dried to form a pressure sensitive adhesive
layer, and a base material layer (synthetic resin film) may be then
laminated on the pressure sensitive adhesive layer to transfer the
pressure sensitive adhesive layer to one surface of the base
material layer.
[0095] When the rubber-based pressure sensitive adhesive is used,
the rubber-based pressure sensitive adhesive is heated and kneaded
to melt it, and the melt is applied on to the base material layer
(synthetic resin film). A method of applying the melt on to release
paper and laminating the base material layer (synthetic resin film)
on the resultant coating may also be adopted. Upon the coating, an
organic solvent may be used, as needed, to apply a solution
containing the rubber-based pressure sensitive adhesive.
[0096] In this manner, the pressure sensitive adhesive layer is
arranged on one surface of the base material formed from the
synthetic resin film. The thickness of the pressure sensitive
adhesive layer is generally 10 to 250 .mu.m, preferably 15 to 200
.mu.m, more preferably 20 to 150 .mu.m.
[0097] In the present description, a multilayer film having a layer
structure of "synthetic resin film/pressure sensitive adhesive
layer" may be called "pressure sensitive adhesive film" merely. One
surface of the pressure sensitive adhesive film has pressure
sensitive adhesion property because it is a pressure sensitive
adhesive layer, and the other surface does not have the pressure
sensitive adhesion property because it is a synthetic resin film.
As illustrated in FIG. 5b, the pressure sensitive adhesive film 502
has a 2-layer structure of the base material layer 502a composed of
the synthetic resin film and the pressure sensitive adhesive layer
502b.
[0098] The device for interstitial fluid extraction according to
the present invention does desirably not vaporize off water from
the hydrogel layer during sticking on the surface of the skin, to
say nothing of during its storage. Therefore, the area of the
pressure sensitive adhesive film (base material/pressure sensitive
adhesive layer) is preferably larger by 1.2 to 30 times, more
preferably 1.2 to 20 times, particularly preferably 1.5 to 15 times
than the area (area stuck on the pressure sensitive adhesive layer)
of the hydrogel layer. As described above, the area of the hydrogel
layer is smaller than the area of the pressure sensitive adhesive
layer (accordingly, base material/pressure sensitive adhesive
layer), and the pressure sensitive adhesive layer is exposed from
around the hydrogel layer. The device for interstitial fluid
extraction can be brought into strong contact with the surface of
the skin by the exposed surface of the pressure sensitive adhesive
layer to fix it thereto.
[0099] Notches are preferably formed in the pressure sensitive
adhesive film (base material/pressure sensitive adhesive layer) so
as to become marks upon close contact of the device for
interstitial fluid extraction with the surface of the skin. The
notches are formed by triangular or semi-circular cutouts or
projections to make positioning easy. FIG. 5a illustrates a case
where notches each composed of a triangular cutout were formed in
both sides of the pressure sensitive adhesive film.
[0100] A lead part may be formed at an end of the pressure
sensitive adhesive film (base material/pressure sensitive adhesive
layer). Since the device for interstitial fluid extraction
according to the present invention is generally relatively small,
the lead part is desirably provided for improving visibility and
making the release layer easy to be peeled. The lead part is formed
as a projected piece at the base material. However, the lead part
may be formed by a method, in which no pressure sensitive adhesive
layer is formed at that portion, or a method, in which a film or
pressure sensitive adhesive film is additionally arranged on the
pressure sensitive adhesive layer of that portion to make that
portion noncohesive.
[0101] The lead part is preferably larger because ease of peeling
from the release layer is improved. However, if the lead part is
too large, sealing performance between the pressure sensitive
adhesive film and the release layer is lowered, which forms the
cause that water in the hydrogel layer held between them is
vaporized off. Therefore, the area of the lead part is desirably
controlled to at most 30% of the area of the pressure sensitive
adhesive film. For example, when a pressure sensitive adhesive film
(base material/pressure sensitive adhesive layer) 30 mm long and 30
mm wide is used, the width of the lead part is preferably
controlled within a range of from 2 to 5 mm, preferably from 3 to 4
mm from the end of the pressure sensitive adhesive film. The lead
part may be provided as one piece or two or more pieces, or around
the whole periphery of the pressure sensitive adhesive film. The
lead part may also be colored into various color tones such as
blue.
[0102] The intermediate layer arranged between the pressure
sensitive adhesive layer and the hydrogel layer is an optional
layer and may be provided if necessary. The intermediate layer is a
layer for improving the adhesion between the pressure sensitive
adhesive layer and the hydrogel layer to integrate them. In
particular, when a pressure sensitive adhesive layer formed of a
hydrophobic pressure sensitive adhesive, for example, an acrylic
pressure sensitive adhesive is arranged on one surface of the base
material layer, the intermediate layer is interposed, whereby the
hydrophobic pressure sensitive adhesive layer and the hydrophilic
hydrogel layer can be brought into firm and close contact with each
other. As a material used in the intermediate layer, may be
mentioned various kinds of nonwoven fabrics or films. As the
intermediate layer, is preferred a laminated product of a nonwoven
fabric of polyethylene terephthalate (PET) and a PET film, or a
polyethylene film from the viewpoints of good conformability to the
hydrogel layer and transparency. The polyethylene film is also
preferred from the viewpoint of flexibility. The area (area coming
into contact with the pressure sensitive adhesive layer) of the
intermediate layer is preferably almost equal to the area of the
hydrogel layer.
[0103] The hydrogel layer is arranged directly or through the
intermediate layer on the surface of the pressure sensitive
adhesive layer. The hydrogel layer is a hydrogel layer formed from
at least one hydrophilic polymer selected from the group consisting
of polyvinyl alcohol (hereinafter may be abbreviated as "PVA") and
polyvinyl pyrrolidone (hereinafter may be abbreviated as "PVP").
The hydrophilic polymer forming the hydrogel layer may be PVA alone
or PVP alone or may be a mixture of both polymers. The hydrophilic
polymer is preferably PVA alone or a mixture of PVA and PVP.
[0104] Hydrogel layer can be formed by a method of crosslinking the
hydrophilic polymer in an aqueous solution thereof. The hydrogel
layer can be formed by a method, in which an aqueous solution of
the hydrophilic polymer is applied on to a base to form a coating
film, and the hydrophilic polymer contained in the coating film is
crosslinked. Crosslinking methods of the hydrophilic polymer
include a chemical crosslinking method and a radiation-induced
crosslinking method, and the radiation-induced crosslinking method
is desirably adopted in that various chemical materials are hard to
be mixed as impurities in the hydrogel layer.
[0105] The hydrogel layer arranged in the device for interstitial
fluid extraction according to the present invention does
substantially not contain a sodium ion and causes no water
separation. The hydrogel layer has a function of extracting and
collecting an interstitial fluid through the skin, and this
function can be improved by increasing the osmotic pressure
thereof. Therefore, it is desirable to contain an osmotic pressure
control agent in the aqueous solution of the hydrophilic polymer
upon preparation of the hydrogel layer. An electrolyte such as
sodium chloride (NaCl) has heretofore been used for imparting
electric conductivity to the hydrogel layer, but also acts as an
osmotic pressure control agent.
[0106] However, when a hydrogel layer containing NaCl is used, it
is difficult to exactly determine a minute amount of a sodium ion
in an interstitial fluid extracted and collected through the skin.
In order to extract the interstitial fluid by the hydrogel layer,
it is necessary to form micropores from the surface of the skin to
a horny layer. The glucose concentration in the interstitial fluid
extracted by the hydrogel layer and collected in the hydrogel layer
varies according to the hole diameter, number and depth of the
micropores, a measured portion on the skin, and the like. The
hydrogel layer substantially containing no sodium ion is used,
whereby the condition of the micropores formed in the skin for
extracting the interstitial fluid can be exactly monitored, and the
minute amount of the sodium ion in the interstitial fluid collected
can be exactly determined. In addition, the concentrations of the
sodium ion and glucose in the interstitial fluid can be measured to
exactly measure values corresponding to a blood glucose
concentration and a blood sugar AUC value on the basis of these
measured values.
[0107] Therefore, it is preferred that a sodium ion is
substantially not caused to exist in the hydrogel layer. The
allowable content of the sodium ion in the hydrogel layer of the
present invention is at most 30 ppm, preferably at most 20 ppm,
more preferably at most 10 ppm based on the weight from the
viewpoint of reducing an error upon determination of a blood
glucose concentration from the measured value of the glucose
concentration using the measured value of the sodium ion
concentration described above to at most 5%. The lower limit of the
content of the sodium ion in the hydrogel layer of the present
invention is zero (critical value of measurement). In the present
invention, to substantially contain no sodium ion typically means
that the sodium ion concentration in the hydrogel layer is at most
30 ppm based on the weight.
[0108] It is preferred that a compound (unsugar), which does
substantially not contain a sodium ion and is non-analogous to
glucose that is an object of analysis, is caused to be contained as
an osmotic pressure control agent in the hydrogel layer from the
viewpoint of improving the interstitial fluid extraction
efficiency. From the viewpoint of the safety to the living body, as
such an osmotic pressure control agent, may be used, for example,
an inorganic osmotic pressure control agent such as ammonia,
potassium chloride, potassium phosphate, magnesium chloride,
magnesium phosphate, calcium chloride or calcium phosphate; an
amino acid (organic osmotic pressure control agent) such as
alanine, arginine, asparagine, asparagic acid, cysteine, glutamine,
glutamic acid, glycine, histidine, isoleucine, leucine, lycine,
methionine, phenylalanine, proline, serine, threonine, tryptophan,
tyrosine or valine; a water-soluble vitamin (organic osmotic
pressure control agent) such as thiamine, riboflavin, nicotinic
acid amide, pyridoxine, cyanocobalamine or ascorbic acid; or a
further organic osmotic pressure control agent such as tricine,
urea or acetic acid. Among these osmotic pressure control agents,
at least one compound selected from the group consisting of
potassium chloride, potassium phosphate, magnesium chloride,
magnesium phosphate, calcium chloride, calcium phosphate, amino
acids, urea, acetic acid, ammonia, tricine, thiamine, riboflavin,
nicotinic acid amide, pyridoxine, cyanocobalamine and ascorbic acid
is preferred, and potassium chloride, urea, glycine, alanine and
proline are particularly preferred.
[0109] These compounds are contained in the aqueous solution of the
hydrophilic polymer prior to crosslinking. On the other hand, when
these compounds are contained in the aqueous solution of the
hydrophilic polymer prior to crosslinking, a crosslinking reaction
by irradiation of radiation tends to be inhibited. Therefore, such
an osmotic pressure control agent is preferably contained in the
aqueous solution of the hydrophilic polymer in a proportion that
the osmolarity thereof falls within a range of from 0.05 to 0.94
osmoles.
[0110] The degree of the osmotic pressure does not depend on the
size and nature of a substance making up a solute and depends on
only the number of particles. Such physical nature is called
colligative property. An osmole (Osm) is used as an index
indicating a concentration of a solute paying attention to this
colligative property. The osmole is a unit of osmolarity and is
equal to an osmolarity of a solution equal in osmotic pressure to
an ideal solution of a nondissociative substance, which has a
concentration of 1 mole in solute/1 litter (L) in solvent.
[0111] An actual osmolarity can be determined on the basis of the
sum of concentrations of respective molecules contained in a
solution. Therefore, the osmolarity [mole/L=osmole (Osm)] can be
calculated out on the basis of the concentration (% by weight) of
an osmotic pressure control agent such as potassium chloride (KCl).
In, for example, 10 mM (millimol) of KCl, KCl is dissociated into a
potassium ion and a chloride ion in an aqueous solution thereof, so
that the number of particles becomes twice, and so the osmolarity
thereof is 20 milliosmoles. When 10 mM of dissociative KCl and 5 mM
of nondissociative urea are used in combination, the osmolarity is
25 milliosmoles (10.times.2+5).
[0112] The osmolarity of the osmotic pressure control agent is
within a range of preferably from 0.05 to 0.94 osmoles, more
preferably from 0.10 to 0.90 osmoles, particularly preferably from
0.20 to 0.80 osmoles. If the osmolarity of the osmotic pressure
control agent is too low, the interstitial fluid extraction
efficiency of the hydrogel layer is lowered. If the osmolarity is
too high, the crosslinking reaction of the aqueous solution of the
hydrophilic polymer by irradiation of radiation tends to be
inhibited. However, the extracting function of the device for
interstitial fluid extraction can be developed by controlling the
size of the hydrogel layer, a time stuck on the skin surface, etc.
without using any osmotic pressure control agent.
[0113] The hydrogel layer 501 illustrated in FIG. 5a is mainly
intended to continuously extract an interstitial fluid through
micropores formed in the horny layer by the permeability-improving
treatment to obtain a value corresponding to a blood sugar AUC
value. The glucose concentration is greatly affected by not only a
blood sugar value, but also the size and depth of the micropores
formed. As described above, the amount of the interstitial fluid
collected varies according to the condition of the micropores
provided in the horny layer, so that the mere measurement of the
glucose content in the interstitial fluid collected cannot exactly
calculate out the blood glucose concentration and blood sugar AUC
value. In order to solve this problem, it is effective to normalize
the amount of the interstitial fluid collected by collecting a
sodium ion at the same time as glucose to measure the amount of the
sodium ion. Therefore, the hydrogel layer 501 is desirably one
substantially containing no sodium ion.
[0114] In order to conduct the measurement with high precision,
glucose in an amount more than a measurable lower limit of a
glucose measuring sensor must be collected. When a osmotic pressure
control agent such as KCl is added into the hydrogel layer 501, the
osmotic pressure of the hydrogel layer 501 becomes higher than the
osmotic pressure of an interstitial fluid of a living body, and the
interstitial fluid extraction efficiency becomes high. Therefore,
it is desirable to contain the osmotic pressure control agent such
as KCl in the hydrogel layer. Quite naturally, a hydrogel layer
sufficiently containing water and substantially containing no
sodium ion can extract an interstitial fluid containing glucose
without containing any osmotic pressure control agent.
[0115] Significance of correcting the glucose concentration on the
basis of the sodium ion concentration is described. Glucose is
accumulated in the hydrogel layer in a state contained in the
interstitial fluid. On the other hand, since the amount of the
interstitial fluid exuded from the body varies according to the
condition of the micropores provided in the horny layer, it is
necessary to determine the amount of glucose taking into account
the condition of the micropores formed. Since the sodium ion is
considered to exist at substantially a fixed concentration in the
body, the concentration of the sodium ion accumulated in the
hydrogel layer after a certain extraction time has elapsed becomes
high when, for example, the hole diameter of the micropores is
large, and the concentration becomes low when the hole diameter is
small. In other words, the concentration of the sodium ion in the
interstitial fluid extracted reflects the condition of the
micropores formed.
[0116] The hydrogel layer of the present invention is generally
obtained by crosslinking by irradiation of radiation. According to
the crosslinking by irradiation of radiation, a very clean hydrogel
layer can be obtained because any chemical substance such as a
crosslinking agent is not used unlike the chemical crosslinking.
The crosslinking by irradiation of radiation can be carried out by
a method, in which an aqueous solution of the hydrophilic polymer
is applied on to a base to form a coating film, and the coating
film is irradiated with radiation. When a group of plural rolls is
used to move the base, and the coating of the aqueous solution of
the hydrophilic polymer and the crosslinking by irradiation of
radiation are conducted thereon, a sheet-like hydrogel layer can be
continuously prepared. Therefore, when the crosslinking method by
irradiation of radiation is adopted, the hydrogel layer can be
continuously mass-produced.
[0117] Polyvinyl alcohol (PVA) prior to crosslinking has a
saponification degree within a range of generally from 78 to 100
mol %, preferably from 97 to 100 mol % and an average
polymerization degree within a range of from 500 to 4,000,
preferably from 1,000 to 3,000, more preferably from 1,200 to
2,500. If the saponification degree of PVA is too low, the
crosslinking reaction does not sufficiently progress, and the
interstitial fluid-extracting ability of the resulting hydrogel
layer is lowered. If the average polymerization degree of PVA is
too low, the viscosity of an aqueous solution of such PVA becomes
too low. When the aqueous solution of such PVA is applied on to a
base, such problem that cissing occurs, and the thickness of the
resulting coating film becomes uneven may be caused in some cases.
If the average polymerization degree of PVA is too high, its
solubility in water is lowered, and it is difficult to prepare an
aqueous solution having a moderate concentration.
[0118] When heating and stirring are conducted upon the preparation
of the aqueous solution of PVA, an aqueous solution of PVA having a
moderate concentration can be obtained even when PVA having a high
average polymerization degree is used. However, deterioration by
heat and yellowing are liable to occur. The saponification degree
and average polymerization degree of PVA can be measured according
to the methods known per se in the art. In case of a commercially
available product, a cataloged value (indicated value) may be
used.
[0119] The concentration of PVA in the aqueous solution of PVA is
within a range of preferably from 7 to 30% by weight, more
preferably from 7 to 20% by weight, particularly preferably from
7.5 to 15% by weight. In many cases, the concentration of PVA is
controlled within a range of from 9 to 15% by weight, whereby good
results can be obtained.
[0120] If the concentration of PVA in the aqueous solution of PVA
is too low, cissing occurs, and difficulty is encountered on the
formation of a coating film even in thickness when such an aqueous
solution of PVA is applied on to a base. If the concentration of
PVA is too low, there is a strong tendency for the crosslinking by
irradiation of radiation to be inhibited when an osmotic pressure
control agent (for example, 80 mM of KCl) in an amount necessary
for isotonicity between the hydrogel layer and the human skin is
added into the aqueous solution of PVA, in addition to the
above-described problems.
[0121] If the concentration of PVA in the aqueous solution of PVA
is too high, the viscosity of such aqueous solution of PVA becomes
too high, and so it is necessary to make the viscosity of the
aqueous solution of PVA low by heating the aqueous solution upon
coating. Thus, deterioration by heat and yellowing are liable to
occur. If the concentration of PVA is too high, it is difficult to
obtain hydrogel having a sufficient water content after the
crosslinking by irradiation of radiation, in addition to the
above-described problems.
[0122] Polyvinyl pyrrolidone (PVP) has an average polymerization
degree within a range of from 20,000 to 150,000, preferably from
25,000 to 120,000. The concentration of PVP in the aqueous solution
of PVP is within a range of preferably from 7 to 30% by weight,
more preferably from 7 to 20% by weight, particularly preferably
from 7.5 to 15% by weight. In many cases, the concentration of PVP
is controlled within a range of from 9 to 15% by weight, whereby
good results can be obtained.
[0123] PVP may be used by itself. However, it is preferably used in
combination with PVA. A weight ratio of PVA:PVP is within a range
of generally from 9:1 to 1:9, preferably from 8:2 to 2:8, more
preferably from 8:2 to 5:5.
[0124] In order to form a hydrogel layer with a hydrophilic polymer
composed of PVA and/or PVP, an aqueous solution of the hydrophilic
polymer is applied on to a base, and the resultant coating film is
irradiated with radiation to crosslink the hydrophilic polymer. No
particular limitation is imposed on the base so far as the aqueous
solution of the hydrophilic polymer can be applied thereto to form
a coating film. However, examples thereof include glass and
synthetic resin films. When a radiation-permeable synthetic resin
film is used as the base, the base can be irradiated with radiation
not only from an upper side of the base but also from a lower side
of the base.
[0125] The radiation used in the present invention means
particle-rays such as a-ray (particle-ray of an atomic nucleus of
helium-4 emitted from a radioactive nuclide conducting
.alpha.-disintegration), .beta.-ray (negatron and positron emitted
from an atomic nucleus) and electron ray (electron beam having
almost fixed kinetic energy; generally produced by accelerating
thermoelectrons in vacuum; and ionizing radiations such as
.gamma.-ray (electromagnetic radiation short in wavelength emitted
and absorbed by transition between energy levels of atomic nuclei
or elementary particles, or pair annihilation or pair production of
elementary particles). In the present invention, ultraviolet ray is
not included in the radiation. In the present invention, electron
beam and .gamma.-ray among the radiations are preferred from the
viewpoints of workability and handling ability upon a production
step of the hydrogel layer, with the electron beam being more
preferred.
[0126] The irradiation of the electron beam can be conducted by
means of a general-purpose electron beam irradiation apparatus.
However, to the contrary, the production of the hydrogel layer is
restricted by the characteristics of the electron beam irradiation
apparatus. For example, regarding an absorbed dose at the surface
when a coating film of the aqueous solution of PVA is irradiated
with the electron beam by means of an electron beam irradiation
apparatus, the accelerating voltage of which is 300 kV, as 100%,
the relative dose is attenuated to about 50% at a deep portion of
300 .mu.m. In an electron beam irradiation apparatus, the
accelerating voltage of which is 800 kV, the relative dose is
attenuated to about 30% at a deep portion of 2,500 .mu.m. The
relation between the accelerating voltage and the attenuation of
the relative dose is not a linear proportional relation. When the
relative dose at a deep portion is attenuated, the effect of
crosslinking by irradiation of the electron beam is lowered at this
portion. In order to conduct uniform crosslinking, it is desirable
that the irradiation is conducted at such an accelerating voltage
as to achieve a high relative dose, or the thickness of the coating
film is controlled.
[0127] The irradiation dose of the electron beam is preferably
selected from a range of from 5 to 20,000 kGy. An optimum value of
the irradiation dose of the electron beam greatly varies depending
on the accelerating voltage, properties of a subject to be
irradiated, etc. For example, when electron beam of 200 kV in
accelerating voltage is irradiated at an irradiation dose of 40
kGy, and .gamma.-ray is then irradiated at 25 kGy, a good hydrogel
layer can be formed.
[0128] The irradiation dose relates to a crosslinking density of
the hydrogel layer. The larger the irradiation dose, the higher the
crosslinking degree. It is preferable that electron beam, whose
accelerating voltage is within a range of from 200 kV to 10 MV and
whose irradiation dose is within a range of from 5 to 20,000 kGy,
is irradiated to conduct crosslinking. The irradiation dose is
preferably 15 to 3,000 kGy, more preferably 20 to 2,000 kGy when
the accelerating voltage is 200 to 800 kV, and the thickness of the
coating film is of the order of 70 to 500 .mu.m though it varies
according to the accelerating voltage and the thickness of the
coating film. The irradiation of the electron beam is generally
conducted under an atmosphere of an inert gas such as nitrogen for
avoiding the generation of ozone and improving the reaction
efficiency.
[0129] When the thickness of the coating film of the aqueous
solution of the hydrophilic polymer is great, it is possible to
raise the accelerating voltage or increase the irradiation dose.
When a process, in which an aqueous solution of a hydrophilic
polymer is applied on to a base, the coating film formed is
irradiated with radiation to conduct crosslinking, a coating film
of a new aqueous solution of the hydrophilic polymer is then formed
on the hydrogel layer obtained by the crosslinking, and this
coating film is irradiated with the radiation, is adopted necessary
times, a hydrogel layer having a desired total thickness can be
formed.
[0130] When at least one osmotic pressure control agent selected
from group consisting of potassium chloride, urea, glycine, alanine
and proline is used, the relationship between the concentration of
the hydrophilic polymer and the osmolarity of the osmotic pressure
control agent is preferably controlled in such a manner that the
crosslinking reaction by the irradiation of radiation is not
inhibited. Whether the crosslinking reaction of the coating film of
the aqueous solution of the hydrophilic polymer is inhibited or not
can be judged by whether a water separation phenomenon is observed
in the resulting hydrogel layer or not. When no water separation is
observed in the hydrogel layer, it can be judged that a sufficient
crosslinking reaction occurs.
[0131] Whether a water separation phenomenon occurs in the hydrogel
layer or not can be judged by placing a hydrogel layer cut out into
a size 7 mm wide, 12 mm long and 700 .mu.m thick on a polyester
film held in a flat state for 1 minute in a thermohygrostat of
23.degree. C. in temperature and 55% in relative humidity and
observing whether water separation is observed at the surface of
the hydrogel layer and around it or not. The fact that no water
separation is observed in the hydrogel layer means that the
crosslinking reaction by the irradiation of radiation is not
inhibited.
[0132] The relationship between the concentration of the
hydrophilic polymer and the osmolarity of the osmotic pressure
control agent is preferably controlled as the reference that no
water separation is observed in the hydrogel layer. More
specifically, an aqueous solution of a hydrophilic polymer prepared
by controlling the concentration of the hydrophilic polymer within
a range of from 7 to 30% by weight and containing at least one
osmotic pressure control agent selected from group consisting of
potassium chloride, urea, glycine, alanine and proline in a
proportion that the osmolarity thereof falls within a range of from
0.05 to 0.94 osmoles in such a manner that a sodium ion is
substantially not contained is used. Supposing that the
concentration of the hydrophilic polymer is b % by weight, and the
osmolarity of the osmotic pressure control agent is a osmoles, a
coating film of an aqueous solution of the hydrophilic polymer,
which satisfies the relationship represented by the following
relational expression (A)
a.ltoreq.0.1b-0.6 (A),
is irradiated with the radiation to conduct crosslinking, whereby a
hydrogel layer free of inhibition of the crosslinking reaction can
be formed. As the radiation, may be used one radiation selected
from the group consisting of .alpha.-ray, .beta.-ray and
.gamma.-ray.
[0133] FIG. 19 is a graph prepared on the basis of experimental
data obtained by Examples 1 to 9 and Comparative Examples 1 to 4 in
the present description. An abscissa of this graph indicates a
concentration (b % by weight) of PVA in an aqueous solution of PVA,
and an ordinate indicates an osmolarity (a osmoles) calculated out
from the concentration (% by weight) of KCl. A case where no water
separation was observed in the hydrogel layer obtained by
irradiation of radiation (i.e., a case where the crosslinking
reaction by the irradiation of the radiation is sufficient) and a
case where water separation was observed are distinguished by an
oblique line. A lower side of this oblique line indicates a region
satisfying the relational expression (A). The concentration (b) of
PVA is within a range of from 7 to 30% by weight, and the
osmolarity (a) of KCl is within a range of from 0.05 to 0.94
osmoles.
[0134] Urea, glycine, alanine and proline are evaluated as being
substantially equivalent to KCl from the viewpoint of the function
as the osmotic pressure control agent for the hydrogel layer of the
present invention. This fact is apparent from experimental results
in FIGS. 20 and 21. FIG. 20 is a graph illustrating the
relationship between the osmolarity (osmoles) of each of potassium
chloride (KCl), urea and glycine and an interstitial fluid
extraction-accelerating effect. FIG. 21 is a graph illustrating the
relationship between the osmolarity (osmoles) of each of potassium
chloride (KCl), alanine and proline and an interstitial fluid
extraction-accelerating effect.
[0135] The amount of the interstitial fluid extracted can be
indicated by taking the amount of glucose percutaneously collected
in a reserver as an index. Micropores extending to the horny layer
were formed in the skin of a human upper arm, and a reserver
(specifically, using a gel reserver formed from a PVA gel layer
substantially containing no Na and having a size of 7 mm.times.12
mm and a base material layer of a PE film and a size of 28
mm.times.28 mm) was placed thereon. The extraction of the
interstitial fluid was conducted according to the following
procedure for evaluating the above-described 3 kinds of osmotic
pressure control agents as to the interstitial fluid
extraction-accelerating effect.
[0136] Procedure 1: Water (hereinafter may be referred to as "RO
water") purified by reverse osmosis and having, the osmolarity of
which is substantially zero, is put in a reserver to conduct
extraction of an interstitial fluid over a predetermined period of
time.
[0137] Procedure 2: Solutions of various osmolarities (for example,
0.3, 0.6, 1.2, 2.5 and 5.0 osmoles) are filled in the reserver by
turns to conduct extraction of an interstitial fluid over a
predetermined period of time.
[0138] Procedure 3: Lastly, RO water is put in the reserver to
conduct extraction of an interstitial fluid over a predetermined
period of time.
[0139] The concentration of glucose in the interstitial fluid
collected in the reserver is measured by an enzyme method using a
well-known glucose oxidase. The total amount (unit=ng) of glucose
contained in the reserver is calculated out from the measured value
of the glucose concentration. This total amount of glucose is
divided by the extraction time (unit=min) to calculate out a
glucose extraction rate (unit=ng/min). Supposing that the glucose
extraction rate at each osmolarity of the osmotic pressure control
agent is x, and an average value of the glucose extraction rates
when RO water was used in Procedures 1 and 2 is y, the interstitial
fluid extraction-accelerating effect of each osmotic pressure
control agent can be calculated out by the following expression
(B)
Interstitial fluid extraction-accelerating effect=x/y (B)
[0140] As apparent from the results illustrated in FIG. 20, it is
understood that urea and glycine exhibit substantially the same
interstitial fluid extraction-accelerating effect as KCl.
Accordingly, it can be understood that low-molecular organic
compounds such as urea and glycine, which have the same effect as
KCl, may also be used as the osmotic pressure control agent in
place of KCl. As apparent from the results illustrated in FIG. 21,
it is understood that alanine and proline exhibit substantially the
same interstitial fluid extraction-accelerating effect as KCl.
Accordingly, it can be understood that low-molecular organic
compounds such as alanine and proline, which have the same effect
as KCl, may also be used as the osmotic pressure control agent in
place of KCl.
[0141] A better interstitial fluid extraction efficiency is
exhibited as the water content in the hydrogel layer becomes
higher. On the other hand, it is not preferable that the water
content in the hydrogel layer is made excessively high from the
viewpoints of suitability of the device for interstitial fluid
extraction according to the present invention for the skin surface,
releasability from the skin surface, physical strength upon
measurement, etc. The water content in the hydrogel layer is within
a range of preferably from 70 to 95% by weight, more preferably
from 80 to 93% by weight, particularly preferably from 84 to 92% by
weight.
[0142] In order to efficiently extract glucose and a sodium ion in
the interstitial fluid, the swelling rate of the hydrogel layer is
preferably controlled within a range of from 100 to 300%. The
swelling rate of the hydrogel layer is a numerical value obtained
by multiplying a value obtained by dividing a weight after
immersing the hydrogel layer in physiological saline for 24 hours
by a weight before the immersion in the physiological saline by
100.
[0143] It is effective that no sodium ion is substantially present
in the hydrogel layer before the extraction of the interstitial
fluid for conducting the measurement of interstitial fluid
extracts. Therefore, the hydrogel layer is formed with a material
substantially containing no sodium ion. When PVA is prepared, PVA
can be generally obtained by saponifying polyvinyl acetate obtained
by polymerizing a vinyl acetate monomer with a salt such as sodium
chloride. Therefore, hydrogel of PVA obtained by dissolving
commercially available PVA in an aqueous solution and crosslinking
the resultant aqueous solution by irradiation of radiation
generally comes to contain a sodium ion. Besides, when a
significant amount of a sodium ion is contained in the hydrogel
layer by some cause, the hydrogel layer is immersed in the aqueous
solution used in the preparation of the PVA solution, and stirring
is conducted, whereby the content of the sodium ion in the hydrogel
layer can be reduced.
[0144] In order to impart flexibility to the hydrogel layer, a
plasticizer such as glycerol, polyglycerol, polyethylene glycol
(PEG) or polypropylene glycol (PPG) may be contained in the aqueous
solution of the hydrophilic polymer in the production step of the
hydrogel layer. Pharmacologically active substances such as an
antibacterial agent may also be contained in the hydrogel layer in
such a proportion that the crosslinking by the irradiation of the
radiation is not inhibited. When an enzyme metabolizing an
interstitial fluid component, such as a glucose oxidase, is
contained in the hydrogel layer, it is difficult to stably collect
the interstitial fluid component. Therefore, it is preferable that
the hydrogel layer used in the present invention does substantially
not contain an enzyme reacting with glucose, such as a glucose
oxidase.
[0145] The thickness of the hydrogel layer is within a range of
generally from 50 .mu.m to 1.5 mm, preferably from 100 .mu.m to 1
mm, more preferably from 300 to 900 .mu.m. If the thickness of the
hydrogel layer is too large, stress against the skin upon
application of the device for interstitial fluid extraction becomes
large, so that such inconveniences that a pressed trace is left on
a portion where the hydrogel layer has come into contact with the
skin, and a gap is made between the release layer and the pressure
sensitive adhesive film (base material/pressure sensitive adhesive
layer) to vaporize off water in the hydrogel layer are liable to
occur. If the thickness of the hydrogel layer is too small, a back
flow of glucose extracted occurs, and an interstitial fluid
containing glucose in an amount necessary for analysis cannot be
sufficiently collected.
[0146] In order to provide a hydrogel layer having a desired
thickness, it is also possible to multi-layer the hydrogel layer.
The multi-layering of the hydrogel layer can be achieved by
adopting a method of laminating a plurality of hydrogel layers or a
method, in which a hydrogel layer is formed by irradiating a
coating film of an aqueous solution of a hydrophilic polymer with
radiation in a step of irradiating with radiation, an aqueous
solution of a hydrophilic polymer is then applied on to the
hydrogel layer to form a coating film, and this coating film is
irradiated with radiation. In the latter method, the process is
repeated at least twice, whereby a multilayer hydrogel layer with
each hydrogel layer uniformly crosslinked can be formed.
[0147] A portion of the hydrogel layer, with which the skin surface
comes into contact, may be suitably changed according to a
measuring instrument. However, it is generally preferable that its
long side is 5 to 15 mm, and its short side is 3 to 10 mm When the
area (area of micropores) of a portion punctured by micro-needles
is regarded as 100%, a contact area of the hydrogel layer with the
skin is controlled to 50 to 200%, preferably 100 to 200% so as to
cover the punctured portion.
[0148] The hydrogel layer is arranged on the substantial center of
the pressure sensitive adhesive film (base material/pressure
sensitive adhesive layer). The hydrogel layer desirably is desired
to have good anchoring property so as to be held on the pressure
sensitive adhesive film until the extraction of the interstitial
fluid is completed. On the other hand, it is desired that the
hydrogel layer can be easily peeled from the skin surface after
completion of the extraction.
[0149] Examples of the release layer includes paper bases such as
woodfree paper and glassine paper treated with a release agent such
as a silicone resin, and sheets such as polyester films. As the
release layer, may be used that used as release paper or release
liner in the technical field of pressure sensitive adhesive tapes.
Exposed surfaces of both pressure sensitive adhesive layer (exposed
surface of the pressure sensitive adhesive layer) and hydrogel
layer are covered with the release layer.
[0150] The device for interstitial fluid extraction according to
the present invention has an area of a size that the pressure
sensitive adhesive layer is exposed from around the hydrogel layer.
The area of the hydrogel layer is equal to an area coming into
contact with the skin surface. As described above, the device for
interstitial fluid extraction according to the present invention
can be caused to easily adhere to the skin by the construction that
an adhesive surface capable of adhering to the skin is provided
around the hydrogel layer, so that the device can be fixed to a
desired skin surface without using a fitting device such as a belt,
whereby the device for interstitial fluid extraction can relieve a
burden to a user.
[0151] The pressure sensitive adhesive film 502 illustrated in FIG.
5a has a lower surface (pressure sensitive adhesive layer) having
pressure sensitive adhesion property and an upper surface (base
material layer composed of a synthetic resin film) having no
pressure sensitive adhesion property and has a nature that water is
not permeated. The pressure sensitive adhesive film 502 typically
has a substantially square shape of a size of 28 mm.times.28 mm.
The lower surface having pressure sensitive adhesion property has
pressure sensitive adhesion property to a subject and the cartridge
body 310. The hydrogel layer 501 is held on the substantial center
of the pressure sensitive adhesive film 502 by adhering to the
lower surface of the pressure sensitive adhesive film 502.
[0152] The pressure sensitive adhesive film 502 has a surface
(pressure sensitive adhesive layer) having pressure sensitive
adhesion property, whereby the hydrogel layer 501 can be held
thereon, and the film can adhere to the skin in a state that the
hydrogel layer 501 has been held. The pressure sensitive adhesive
film 502 is composed of a material that water is not permeated,
whereby vaporizing-off of water contained in the hydrogel layer 501
and water in the interstitial fluid collected can be prevented.
Therefore, the area coming into contact with the skin can be
prevented from being changed by vaporization of water in the
hydrogel layer 501 during the collection of the interstitial fluid
by the hydrogel layer 501, and so scattering of interstitial fluid
extraction efficiency can be prevented.
[0153] The pressure sensitive adhesive film 502 has an area of the
above-described size, whereby an opening in a gel receiving part
311 (see FIG. 6) can be blocked in such a manner that a liquid does
not leak from the opening when the device for interstitial fluid
extraction has been arranged in the gel receiving part 311 of the
cartridge body 310. Notches 505, 505 for positioning upon sticking
on the skin surface may be provided in the pressure sensitive
adhesive film 502. A lead part (not illustrated) may also be
provided at the pressure sensitive adhesive film 502.
[0154] FIG. 5b is a cross-sectional view illustrating a state of
the device 50 for interstitial fluid extraction before use. The
pressure sensitive adhesive film 502 is composed of a base material
layer 502a formed from a synthetic resin film and a pressure
sensitive adhesive layer 502b. The pressure sensitive adhesive film
502 is caused to adhere to a release layer 503 by an exposed
surface of the pressure sensitive adhesive layer 502b in the state
before use. The release layer 503 is so constructed that the
hydrogel layer 501 and the pressure sensitive adhesive layer 502b
present around it are exposed when the release layer is peeled upon
use. The device for interstitial fluid extraction, from which the
release layer 503 has been removed, is brought into close contact
to the skin surface by the surface of the hydrogel layer 501 and
the exposed surface of the pressure sensitive adhesive layer
502b.
[0155] The structure and function of the cartridge 30 for analysis
will be described in more detail. As illustrated in FIG. 4, the
cartridge 30 for analysis is equipped with a cartridge body 310 and
reaction reagents 330 to glucose. The reaction reagents 330 include
reaction reagents such as an enzyme [for example, glucose oxidase
(abbreviated as "GOD")], which becomes a catalyst for glucose, an
enzyme [peroxidase (abbreviated as "POD")], which becomes a
catalyst for hydrogen peroxide (H.sub.2O.sub.2), and a coloring
pigment, tetramethylbenzidine (3,3',5,5'-tetramethylbenzidine),
reacting with an active oxygen (O*) formed from H.sub.2O.sub.2 by
the presence of POD. The reaction reagents 330 to glucose have size
and shape fittable into a reagent holding part 314 (FIG. 6)
provided in the cartridge body 310.
[0156] The cartridge body 310 is a rectangular plate formed from a
synthetic resin such as an acrylic resin colored by a pigment into,
for example, black. The cartridge body 310 is formed of, for
example, a rectangular plate 24 mm long, 56 mm wide and 3 mm thick,
and the reaction reagents 330 to glucose are fitted into a recessed
part (reagent holding part 314 in FIG. 6) formed in the surface
thereof. A recessed part (gel receiving part 311 in FIG. 6) for
receiving the hydrogel layer 501 of the device 50 for interstitial
fluid extraction is formed in the surface of the cartridge body
310. The device 50 for interstitial fluid extraction is caused to
adhere to the surface of the cartridge body 310 by the pressure
sensitive adhesive layer while the hydrogel layer 501 is being
received in the recessed part. A surface (an exposed surface in
FIG. 4) of the cartridge body 310, to which the device 50 for
interstitial fluid extraction adheres, is referred to as an upper
surface, and a back surface thereof is referred to as a lower
surface. The structure of the cartridge body 310 will hereinafter
be described in more detail with reference to FIGS. 6 and 7.
[0157] FIGS. 6 and 7 are plan views of the cartridge body 310. In
FIG. 6, the structures of the upper surface and lower surface of
the cartridge body 310 are illustrated by a solid line and a broken
line, respectively. In FIG. 7, the structures of the lower surface
and upper surface of the cartridge body 310 are illustrated by a
solid line and a broken line, respectively.
[0158] As illustrated in FIGS. 6 and 7, the cartridge body 310 is
provided with a gel receiving part 311, inlet hole 312,
upstream-side connection hole 313, reaction reagent holding part
314, storage part 317 for glucose detection, downstream-side
connection hole 315 and discharge hole 316 as structures visible
from the upper surface. The cartridge body 310 is provided with a
first connection passage 321, storage part 322 for sodium detection
and second connection passage 323 as structures visible from the
lower surface. These respective parts are recessed parts or
through-holes. Therefore, the cartridge body 310 can be produced by
integrally molding a synthetic resin by injection molding or the
like.
[0159] The cartridge body 310 forms one passage from the inlet hole
312 to the discharge hole 316 when arranged in the cartridge
arranging part 12 of the analysis unit body 10. The inlet hole 312
is a circular hole extending through from the upper surface of the
cartridge body 310 to the lower surface thereof, and the diameter
thereof can be set to, for example, 0.7 mm The inlet hole 312 is
provided in such a manner that the injection nipple 141 provided in
the cartridge arranging part 12 is located just under the hole in a
vertical direction when the cartridge body 310 has been arranged in
the cartridge arranging part 12 of the analysis unit body 10,
whereby the recovery liquid is injected into the gel receiving part
311 through the inlet hole 312 when the cartridge body 310 has been
arranged in the cartridge arranging part 12.
[0160] The gel receiving part 311 is a rectangular recessed part
formed in the upper surface of the cartridge body 310 and has a
size of, for example, 14 mm (long side).times.9 mm (short
side).times.2 mm (depth). The inlet hole 312 is provided in a
bottom surface of gel receiving part 311. The gel receiving part
311 has, for example, such a size as described above, whereby the
hydrogel layer 501 held by the device 50 for interstitial fluid
extraction and having a size of 12 mm (long side).times.7 mm (short
side).times.0.7 mm (thickness) can be received.
[0161] The hydrogel layer 501 held by the device 50 for
interstitial fluid extraction is received in the gel receiving part
311. Specifically, the device 50 for interstitial fluid extraction
is arranged in the gel receiving part 311, whereby the pressure
sensitive adhesive film 502 of the device 50 for interstitial fluid
extraction adheres to a peripheral edge of the gel receiving part
311, and the hydrogel layer 501 held thereby is received in the gel
receiving part 311 in a state dangled in a midair.
[0162] A stepped part 318 recessed deeper than the bottom surface
of the gel receiving part 311 and the upstream-side connection hole
313 are provided at the bottom surface of the gel receiving part
311 and at a position on a diagonal line of the inlet hole 312. The
upstream-side connection hole 313 is composed of a circular hole
extending through from the upper surface of the cartridge body 310
to the lower surface thereof and having a diameter of, for example,
1.5 mm
[0163] As illustrated in FIG. 7, the upstream-side connection hole
313 is opened in the bottom surface of the first connection passage
321 composed of a groove formed in the lower surface and having a
depth of, for example, about 0.5 mm. The first connection passage
321 extends horizontally in a direction of the long side of the
cartridge body 310 and is linked to the storage part 322 for sodium
detection formed at the substantial center of the lower surface of
the cartridge body 310.
[0164] The storage part 322 for sodium detection is composed of a
circular groove having a depth of, for example, about 1.5 mm. The
storage part 322 for sodium detection is provided so as to be
located just above the sodium detection part 22 provided at the
bottom surface of the cartridge arranging part 12 in a vertical
direction when the cartridge body 310 has been arranged in the
cartridge arranging part 12 of the analysis unit body 10. More
specifically, the storage part 322 for sodium detection is provided
in such a manner that the electrodes 222 for measurement of the
sodium ion concentration of the sodium detection part 22 are
located at a space surrounded by the plate-like member 221 and the
storage part 322 for sodium detection.
[0165] The storage part 322 for sodium detection is linked to the
second connection passage 323 composed of a groove having a depth
of, for example, about 0.5 mm. The second connection passage 323
extends horizontally in a direction of the short side of the
cartridge body 310 through a stepped part from the storage part 322
for sodium detection as an initial point, then turns its direction
by 90.degree. to extend horizontally in a direction of the long
side, and further turns its direction by about 45.degree. inward to
extend horizontally. The downstream-side connection hole 315 is
formed at the bottom of the distal end of the second connection
passage 323. The downstream-side connection hole 315 is composed of
a circular hole extending through from the upper surface of the
cartridge body 310 to the lower surface thereof and having a
diameter of, for example 0.7 mm.
[0166] As illustrated in FIG. 6, the reagent holding part 314 is
provided at the upper surface of the cartridge body 310. The
reagent holding part 314 is composed of a recessed part formed in
the upper surface of the cartridge body 310 and having a depth of,
for example, about 1 mm. The reagent holding part 314 is shaped
into a substantially rectangular form long in the long side
direction of the cartridge body 310.
[0167] The storage part 317 for glucose detection composed of a
groove formed deeper than the reagent holding part 314 is provided
at the reagent holding part 314. The downstream-side connection
hole 315 is opened in the bottom surface of this storage part 317
for glucose detection. The storage part 317 for glucose detection
is composed of a groove having a depth of about 1.5 mm from the
bottom surface of the reagent holding part 314. The storage part
317 for glucose detection extends horizontally in a direction of
the short side of the cartridge body 310 from a position where the
downstream-side connection hole 315 is opened as an initial point,
then turns its direction by 90.degree. to extend horizontally in a
direction of the long side, further turns its direction by
90.degree. inward to extend horizontally in the short side
direction, and then further turns its direction by 90.degree. to
extend horizontally in the long side direction. The discharge hole
316 is formed at the distal end of the storage part 317 for glucose
detection.
[0168] The discharge hole 316 is a circular hole extending through
from the upper surface of the cartridge body 310 to the lower
surface thereof and having a diameter of, for example, 0.7 mm. The
discharge hole 316 is provided in such a manner that the discharge
nipple 151 provided in the cartridge arranging part 12 is located
just under the hole in a vertical direction when the cartridge body
310 has been arranged in the cartridge arranging part 12 of the
analysis unit body 10, whereby the recovery liquid is discharged
from the discharge nipple 151 through the discharge hole 316 when
the cartridge body 310 has been arranged in the cartridge arranging
part 12.
[0169] The inlet hole 312 is linked to the upstream-side connection
hole 313 through the gel receiving part 311. The upstream-side
connection hole 313 is linked to the downstream-side connection
hole 315 through the first connection passage 321, the storage part
322 for sodium detection and the second connection passage 323.
More specifically, the upstream-side connection hole 313 is linked
to the downstream-side connection hole 315 in the lower surface
through a series of grooves having a depth and a width, which
permit a liquid passing through between a horizontal plane and the
lower surface of the cartridge body 310 when the cartridge body 310
is placed on the horizontal plane. The downstream-side connection
hole 315 is linked to the discharge hole 316 through the storage
part 317 for glucose detection. Therefore, the cartridge body 310
forms one passage from the inlet hole 312 to the discharge hole 316
when placed on the horizontal plane.
[0170] The function of the cartridge 30 for analysis will
hereinafter be described together with the operation of the
analysis unit body 10. FIG. 8 is a flow chart illustrating a
biocomponent analyzing process using a biocomponent analysis unit
according to this embodiment. In Step S1, a subject is subjected to
a pretreatment of a site, from which an interstitial fluid is
collected, more specifically, alcohol washing. Substances (sweat,
dust, etc.) attached to the skin, which form disturbance factors of
analysis, are removed by the alcohol washing.
[0171] In Step S2, micropores are formed in the collection site
washed with alcohol as a permeability-improving treatment. The
micropores are holes extending through the horny layer of the skin
and having such a depth as may extend up to a boundary between the
interior of the epidermis and the dermis, but does not extend up to
a deep site of the dermis. The treatment for forming such
micropores can be conducted by means of, for example, the fine hole
forming device described in US2007/0233011 A1. The extraction and
collection of an interstitial fluid from the subcutaneous tissue
can be thereby accelerated without being followed by bleeding.
[0172] In Step S3, the device 50 for interstitial fluid extraction
is stuck on the collection site in which the micropores have been
formed. More specifically, the hydrogel layer 501 contained in the
device 50 for interstitial fluid extraction is brought into contact
with the skin in such a manner that the skin site, in which the
micropores have been formed, is covered with the hydrogel layer
501. The pressure sensitive adhesive film 502 holding the hydrogel
layer 501 is caused to adhere to around the skin site in which the
micropores have been formed. The device 50 for interstitial fluid
extraction is left to stand for a predetermined period of time of
at least 120 minutes in a state stuck on the skin in this manner to
extract an interstitial fluid exuded from the skin, in which the
micropores have been formed, and collect it in the hydrogel layer
501.
[0173] After the predetermined period of time has elapsed after the
device 50 for interstitial fluid extraction was stuck on the skin,
the process is advanced to Step S4 to take the device 50 for
interstitial fluid extraction out of the skin.
[0174] In Step S5, the device 50 for interstitial fluid extraction
taken out of the skin is stuck on the cartridge 30 for
analysis.
[0175] In Step S6, the cartridge 30 for analysis, on which the
device 50 for interstitial fluid extraction has been stuck, is
arranged in the cartridge arranging part 12 of the analysis unit
body 10. The cartridge 30 for analysis is arranged in such a manner
that the storage part 322 for sodium detection faces the bottom
surface of the cartridge arranging part 12. After the cartridge 30
for analysis has been arranged in the analysis unit body 10, the
movable top plate 13 of the analysis unit body 10 is closed. Since
the movable top plate 13 is biased toward a direction to be closed,
the cartridge 30 for analysis arranged in the cartridge arranging
part 12 is pressed from above by the movable top plate 13 in a
state surrounded by the injection nipple 141, the discharge nipple
151, the sodium detection part 22 and the movable top plate 13.
[0176] In Step S7, analysis of a biocomponent is conducted on the
basis of the interstitial fluid collected. Specifically, a user
operates the operation part 24 of the analysis unit body 10 in a
state that the cartridge 30 for analysis has been arranged in the
cartridge arranging part 12 to direct beginning of analysis of the
biocomponent to the control part 25. The control part 25, to which
the beginning of analysis has been directed, execute a
predetermined program, thereby conducting the analysis of the
biocomponent. The analysis of the biocomponent includes analysis of
a glucose concentration by cooperation of the glucose detection
part 21 and the control part 25, and analysis of a sodium ion
concentration by cooperation of the sodium detection part 22 and
the control part 25.
[0177] After the analysis of the biocomponent by the analysis unit
body 10 has been completed, analytical results are displayed on the
display part 23. In Step S8, the subject confirms the analytical
results displayed on the display part 23, thereby completing a
series of analyzing steps.
[0178] FIG. 9 is a flow chart for explaining the process of Step S7
in FIG. 8. A program for realizing the step shown herein is stored
in ROM contained in the control part 25. CPU of the control part 25
executes the program stored in ROM, thereby executing the step
shown in this flow chart.
[0179] FIG. 10 to FIG. 16 are typical cross-sectional views for
explaining the operation of the biocomponent analysis unit
according to this embodiment, and the flow of a recovery liquid is
illustrated with time in order of these drawings. These drawings
illustrate a state that the cartridge 30 for analysis has been
arranged in the cartridge arranging part 12, the recovery liquid is
indicated by black, and the flow of air sent by the pump 142 is
indicated by an arrow. The operating principle of the analysis unit
is described on the basis of FIG. 9, and FIGS. 10 to 16.
[0180] In Step S71 of FIG. 9, the control part 25 judges whether
direction about the beginning of analysis by the user has been
accepted or not. When the control part 25 judges that the direction
about the beginning of analysis has been accepted ("YES" in Step
S71), the process is advanced to Step S72. When the control part 25
judges that the direction about the beginning of analysis has not
been accepted ("NO" in Step S71), the process is returned to Step
S71.
[0181] In Step S72, the control part 25 executes a process of
injecting a recovery liquid for recovering a biocomponent in the
interstitial fluid collected in the hydrogel layer 501.
Specifically, the control part 25 executes a process of controlling
the electromagnetic valve V1 to connect the upstream-side passage
143 to the pump 142, controlling the electromagnetic valve V2 to
connect the pump 142 to the downstream-side passage 145 and
controlling the electromagnetic valve V3 to shut down the
connection between the downstream-side passage 145 and the
injection nipple 141. The control part 25 then executes a process
of sending air to the passages by driving the pump 142 by a motor
(not illustrated). The recovery liquid stored in the recovery
liquid tank 144 is thereby pressed out to the downstream-side
passage 145 and the waste liquid passage 147 to fill the passage
from the electromagnetic valve V2 to the electromagnetic valve V3
with the recovery liquid pressed out (see FIGS. 2, 10 and 11).
[0182] After the control part 25 has stopped the drive of the pump
142, the control part 25 executes a process of controlling the
electromagnetic valve V1 to connect the upstream-side passage 143
to the bypass passage 146, controlling the electromagnetic valve V2
to connect the bypass passage 146 to the downstream-side passage
145 and controlling the electromagnetic valve V3 to open the
connection between the downstream-side passage 145 and the
injection nipple 141. A series of passages from the pump 142 to the
injection nipple 141 through the bypass passage 146 is thereby
formed.
[0183] The control part 25 executes a process of driving the pump
142 again to send air to the passages. The air sent from the pump
142 is thereby passed through the upstream-side passage 143, the
bypass passage 146 and the downstream-side passage 145 and send to
the injection nipple 141. At the time the opening and closing of
the electromagnetic valves V2 and V3 have been changed over, the
passage from the electromagnetic valve V2 to the electromagnetic
valve V3 is filled with a predetermined amount of the recovery
liquid. The air is sent from the pump 142, whereby the
predetermined amount of the recovery liquid stored between the
electromagnetic valve V2 and the electromagnetic valve V3 is
pressed out toward the injection nipple 141, and the recovery
liquid flowed in the waste liquid passage 147 is pressed out toward
the waste liquid tank 153 (see FIG. 12).
[0184] The injection nipple 141 is arranged so as to link to the
inlet hole 312 of the cartridge 30 for analysis arranged in the
cartridge arranging part 12. The recovery liquid sent toward the
injection nipple 141 is injected into the gel receiving part 311
through the injection nipple 141 and the inlet hole 312.
[0185] When the recovery liquid is injected into the gel receiving
part 311, the gel receiving part 311 is being filled with the
recovery liquid. If the recovery liquid is transferred toward the
upstream-side connection hole 313 from the inlet hole 312 at the
shortest distance, the recovery liquid is first held by the stepped
part 318 due to surface tension before leaked out of the
upstream-side connection hole 313 because the periphery of the
upstream-side connection hole 313 is surrounded by the stepped part
318 higher by a step than the opening face of the upstream-side
connection hole 313. Therefore, the recovery liquid is pressurized
in a direction spreading in the gel receiving part 311 rather than
a direction leaking out of the upstream-side connection hole 313 so
far as a pressure higher than the surface tension applied to the
stepped part 318 is not applied. Accordingly, the recovery liquid
injected spreads in the whole of the gel receiving part 311 without
leaking out of the upstream-side connection hole 313 (see FIG. 12).
Lowering of analytical precision caused by filling the gel
receiving part 311 with the recovery liquid in an uneven state can
be thereby prevented.
[0186] When all the predetermined amount of the recovery liquid is
injected into the gel receiving part 311, the hydrogel layer 501 is
embedded in the recovery liquid (see FIG. 13). The control part 25
temporally stops the drive of the pump 142 at the time the
injection of the predetermined amount of the recovery liquid has
been completed. Even when the drive of the pump 142 is stopped, the
recovery liquid does not flow backward because an air pressure is
applied to the liquid facing the inlet hole 312 from a lower side.
Since the passage is maintained at a certain air pressure by
stopping the drive of the pump 142, the recovery liquid filled in
the gel receiving part 311 is held in a state stored in the gel
receiving part 311 without leaking out of the upstream-side
connection hole 313.
[0187] In Step S73 of FIG. 9, the control part 25 judges whether a
predetermined period of time (for example, 10 minutes) has elapsed
from the completion of the injection of the recovery liquid or not.
When the control part 25 judges that the predetermined period of
time has elapsed ("YES" in Step S73), the process is advanced to
Step S74. When the control part 25 judges that the predetermined
period of time has not elapsed ("NO" in Step S73), the process is
returned to repeat the process of S73 until the predetermined
period of time has elapsed.
[0188] The hydrogel layer 501 is left to stand for the
predetermined period of time in a state embedded in the recovery
liquid in this manner, whereby the interstitial fluid collected in
the hydrogel layer 501 sufficiently diffuses into the recovery
liquid.
[0189] In Step S74 of FIG. 9, the control part 25 executes a
process of transferring the recovery liquid stored in the gel
receiving part 311 to the storage part 322 for sodium detection and
the storage part 317 for glucose detection. Specifically, the
control part 25 controls the pump 142 in such a manner that air of
the same volume as the gel receiving part 311 is sent to the gel
receiving part 311. When the air is sent to the gel receiving part
311, a pressure higher than the surface tension is applied to the
liquid facing the upstream-side connection hole 313, and the
recovery liquid stored in the gel receiving part 311 is caused to
flow out to the first connection passage 321 through the
upstream-side connection hole 313.
[0190] When the air is further sent to the gel receiving part 311,
the recovery liquid flowed out to the first connection passage 321
reaches the storage part 322 for sodium detection to fill the
storage part 322 for sodium detection with the recovery liquid.
When the air is still further sent to the gel receiving part 311,
the recovery liquid reaches the storage part 317 for glucose
detection through the downstream-side connection hole 315. The
recovery liquid sent to the storage part 317 for glucose detection
comes into contact with the reaction reagents 330 to glucose held
by the reagent holding part 314 (see FIG. 14).
[0191] The construction that the recovery liquid stored in the gel
receiving part 311 is sent to a position different from the gel
receiving part 311 is adopted, whereby the recovery liquid is
agitated. Therefore, even if the biocomponent transferred into the
gel receiving part 311 unevenly diffuses into the recovery liquid,
the concentration distribution of the biocomponent in the recovery
liquid can be made even by agitating the recovery liquid.
[0192] In Step S75 of FIG. 9, the control part 25 executes a
process of stopping the drive of the pump 142 and measuring a
sodium concentration.
[0193] As illustrated in FIG. 14, the sodium detection part 22
provided at the bottom surface of the cartridge arranging part 12
forms a closed space with the storage part 322 for sodium detection
provided at the lower surface of the cartridge 30 for analysis. The
sodium detection part 22 is equipped with the electrodes 222 for
measurement of a sodium ion concentration provided so as to be
exposed to the surface. When the recovery liquid is stored in the
storage part 322 for sodium detection, the electrodes 222 for
measurement of a sodium ion concentration are in a state completely
immersed in the recovery liquid stored. In this state, the control
part 25 apply a fixed current to the electrodes 222 for measurement
of a sodium ion concentration to acquire a voltage value and to
obtain a sodium ion concentration "C.sub.Na" on the basis of the
thus-obtained voltage value and a calibration curve stored in the
control part 25 in advance.
[0194] In Step S76 of FIG. 9, the control part 25 executes a
process of measuring a glucose concentration. The light source 211
and the light reception part 212 are provided at the surface of the
movable top plate 13, which faces the cartridge 30 for analysis. As
illustrated in FIG. 14, the reaction reagents 330 to glucose are
held in the reagent holding part 314 of the cartridge body 310. The
reaction reagents 330 are immersed in the recovery liquid. Glucose
transferred into the recovery liquid undergoes the following
chemical reactions with GOD, H.sub.2O.sub.2, POD and the coloring
pigment contained in the reaction reagents 330. As a result, the
reaction reagents 330 change a color.
Glucose+O.sub.2+H.sub.2O.fwdarw.(Catalysis by GOD).fwdarw.Gluconic
acid+H.sub.2O.sub.2H.sub.2O.sub.2+Coloring
pigment.fwdarw.(Catalysis by POD).fwdarw.2H.sub.2O+Coloring
pigment
(oxidation, coloring)
[0195] As apparent from the above reaction formulae, the degree of
coloring of the coloring pigment is proportional to the amount of
glucose. Thus, the degree of color change of the coloring pigment
is optically detected, whereby the glucose concentration can be
obtained.
[0196] In this embodiment, the glucose detection part is so
constructed that the reaction reagents 330 are irradiated with
light of a wavelength high in absorption efficiency by a color
after color change of the coloring pigment from the light source
211. The light reception part 212 is so constructed that reflected
light of the light irradiated by the light source 211 is received.
The control part 25 acquires a glucose concentration "C.sub.Glc" on
the basis of a difference in quantity between the quantity of light
received by the light reception part 212 before coloring of the
coloring pigment and the quantity of light received by the light
reception part 212 after coloring of the coloring pigment.
[0197] In Step S77 of FIG. 9, the control part 25 executes a
process of sending the recovery liquid stored in the cartridge 30
for analysis to the liquid discharge part 15. Specifically, the
control part 25 executes a process of sending air to the storage
part 322 for sodium detection and the storage part 317 for glucose
detection by driving the pump 142 again. The air send presses out
the recovery liquid toward the passage 152 through the discharge
nipple 151 (see FIG. 15). The recovery liquid pressed out is stored
in the waste liquid tank 153 through the passage 152 (see FIG.
16).
[0198] In Step S78 of FIG. 9, the control part 25 applies the
resultant sodium ion concentration "C.sub.Na" and glucose
concentration "C.sub.Glc" to the following equation (1) to acquire
blood sugar AUC and stores the blood sugar AUC thus obtained in
ROM.
[Numerical Formula 1]
AUC=(C.sub.Glc.times.E+F).times.t/(C.sub.Na.times.G+H) (1)
[0199] In the equation, t is a time required to collect an
interstitial fluid, and in this embodiment, t is set to 60 minutes
temporarily. E, F, G and H are constants.
[0200] In Step S79 of FIG. 9, the control part 25 displays the
blood sugar AUC obtained in Step S78 on the display part 23 and
advances the process to Step 8
[0201] A measuring principle of a measuring method of a blood sugar
AUC value is described with reference to FIGS. 17 and 18. In
general, the glucose concentration [IG(t)] in an interstitial fluid
exhibits good followability for the glucose concentration [BG(t)]
in the blood, and it is known that the glucose concentration
[IG(t)] in the interstitial fluid and the glucose concentration
[BG(t)] have strong correlation. The glucose concentration [IG(t)]
in the interstitial fluid can be represented by the following
equation (2) using a constant .alpha..
[Numeral Formula 2]
BG(t)=.alpha..times.IG(t) (2)
[0202] When the hydrogel layer 501 is fitted on the skin surface of
a living body to collect an interstitial fluid from the living body
through the skin as illustrated in FIG. 17, the amount of glucose
collected per unit time is regarded as a glucose collecting rate
[J.sub.glc], and a glucose collecting rate at a certain time t is
regarded as [J.sub.glc(t)]. At this time, J.sub.glc(t) is
represented as a product of a glucose concentration IG(t) in the
interstitial fluid at the time t and a glucose permeability
[P.sub.glc] as shown in the following equation (3).
[Numeral Formula 3]
J.sub.glc(t)=P.sub.glc.times.IG(t) (3)
[0203] The glucose permeability [P.sub.glc] is a coefficient
indicating the permeability to glucose through the skin, and the
amount of glucose collected from the skin per unit time becomes
large as the glucose permeability [P.sub.glc] is high.
[0204] Here, a case where the collection is conducted for a
predetermined period of time is considered. With respect to the
left side of the equation (3), J.sub.glc(t) is integrated over a
time T, and the integrated value thereof becomes a total amount
[M.sub.glc(T)] of glucose collected in the hydrogel layer 501 from
the living body within the time T. This relation is shown in the
following equation (4).
[Numeral Formula 4]
M.sub.glc(T)=.intg.J.sub.glc(t) (4)
[0205] For example, when the glucose collecting rate [J.sub.glc(t)]
is 10 ng/min, the total amount [M.sub.glc] of glucose collected in
the hydrogel layer for the time T=60 min is 10 ng/min.times.60
min=600 ng.
[0206] On the other hand, with respect to the right side of the
equation (3), the glucose concentration [IG(t)] in the interstitial
fluid is integrated over the time T, and the integrated value
thereof becomes an area {area under the curve, AUC [IG(t)]} of a
figure (a hatched portion) defined by the graph of the glucose
concentration [IG(t)] for the time T as illustrated in FIG. 18.
This relation is shown in the following equation (5).
[Numeral Formula 5]
AUC[IG(t)]=.intg.IG(t) (5)
[0207] Since there is correlation between IG(t) and BG(t) as shown
in the equation (5), there is also correlation between the area
under the curve, AUC [IG(t)] and the area under the curve, AUC
[BG(t)]. Accordingly, the relation between the area under the
curve, AUC [BG(t)] and the area under the curve, AUC [IG(t)] is
represented by the following equation (6) using the constant
.alpha..
[Numeral Formula 6]
AUC[BG(t)]=.alpha..times.AUC[IG(t)] (6)
[0208] Here, when integration over the time T is considered, the
following equation (7) is established from the equations (3) and
(4).
[Numeral Formula 7]
M.sub.glc(T)=.intg.P.sub.glc.times.IG(t) (7)
[0209] The following equation (8) is established from the equations
(5) and (7).
[Numeral Formula 8]
M.sub.glc(T)=P.sub.glc.times.AUC[IG(t)] (8)
[0210] From the equations (6) and (8), M.sub.glc(T) is represented
by the following equation (9) using AUC[BG(T)].
[Numeral Formula 9]
M.sub.glc(T)=(P.sub.glc/.alpha.).times.AUC[BG(T)] (9)
[0211] AUC[BG(T)] can be acquired from the total amount
[M.sub.glc(T)] of glucose stored in the hydrogel layer 501 (see
FIG. 17) within the time T, the permeability (glucose permeability
[P.sub.glc]) to glucose through the skin at the time T and the
constant .alpha. according to the equation (9). Since the glucose
concentration in the blood is almost equal to the glucose
concentration in the interstitial fluid, .alpha. may be regarded as
1.
[0212] The principle of calculating out the blood sugar AUC value
will hereinafter be described on the basis of the equation (1). The
area under the blood sugar concentration-time curve AUC[IG(T)]
determined from the glucose concentration in the interstitial fluid
can be determined by the following equation (10) from the equation
(9).
[Numeral Formula 10]
AUC[IG(T)]=M.sub.glc(T)/P.sub.glc (10)
[0213] M.sub.glc(T) is the amount of glucose stored in the hydrogel
layer 501 within the time T. The amount of glucose stored is
proportional to the glucose concentration [C.sub.glc] in the
recovery liquid at the time glucose has been transferred to the
recovery liquid from the hydrogel layer 501 so far as the volume of
the recovery liquid is fixed. Accordingly, M.sub.glc(T) can be
represented by the following equation (11) using the constants E
and F.
[Numeral Formula 11]
M.sub.glc(T)=C.sub.glc.times.E+F (11)
[0214] P.sub.glc indicates ease of collecting the interstitial
fluid. The amount of the interstitial fluid collected varies
according to the condition of the skin. The amount of glucose
contained in the interstitial fluid varies depending on the blood
sugar value. Accordingly, the amount of the interstitial fluid
collected must be grasped. The sodium ion concentration within the
body is presumed to be constant unlike glucose. When the amount of
the sodium ion contained in the interstitial fluid collected is
great, it is considered that the condition of the skin is in a
state easy to collect the interstitial fluid. When the amount of
the sodium ion collected is small on the other hand, it is
considered that the condition of the skin is in a state hard to
collect the interstitial fluid.
[0215] From this fact, the ease [P.sub.glc] of collecting the
interstitial fluid can be represented by the following equation
(12) using a sodium ion collecting rate J.
[Numeral Formula 12]
P.sub.glc=J.times.G+H (12)
[0216] Since the collecting rate J is a concentration of the sodium
ion collected from the living body per unit time, the rate is
represented by a value obtained by multiplying the concentration
[C.sub.Na] of the sodium ion transferred from the hydrogel layer
501 by 1/t. Accordingly, the following equation (13) is
established.
[Numeral Formula 13]
J=C.sub.Na.times.1/t (13)
[0217] The following equation (14) is established from the
equations (10) to (13).
[Numeral Formula 14]
AUC[IG(T)]=(C.sub.glc.times.E+F)/(C.sub.Na.times.1/t).times.G+H
(14)
[0218] The right side of this equation (14) is rearranged, thereby
giving
[Numeral Formula 15]
AUC=(C.sub.Glc.times.E+F).times.t/(C.sub.Na.times.G+H) (1)
[0219] Thus, the equation (1) is drawn.
[0220] The analyzing process adaptable in the present invention
comprises 3 steps of a step of forming fine passes (micropores) for
interstitial fluid extraction in the skin; a step of sticking a
hydrogel layer on the skin to extract an interstitial fluid; and a
step of peeling the hydrogel layer stuck on the skin to assay and
analyze interstitial fluid components (glucose and sodium ion)
collected in the hydrogel layer.
[0221] The formation of the micropores that is the first step is
conducted by pressing a micro-needle array, in which a plurality of
fine projections having a height of, for example, 0.3 mm has be
formed or worked, against the skin surface using a device for the
exclusive use of the skin. At this time, it is necessary to clarify
a position of the skin where the micropores have been formed. Thus,
the exclusive device for forming the micropores is equipped with a
mechanism for positioning. A tape is stuck on a portion of the
device, with which the skin comes into contact, in advance. When
the device is separated from the skin after the formation of the
micropores, this tape for positioning is separated from the device
and left on the skin. The position of the micropores formed on the
skin can be specified by the tape left on the skin.
[0222] As the second step, the hydrogel layer is stuck on the skin
surface matching to the tape for positioning left on the skin. The
stuck state is held for 1 to 3 hours to extract and collect an
interstitial fluid.
[0223] After a predetermined period of time has elapsed, analysis
of interstitial fluid components that is the third step is
conducted. The hydrogel layer is taken out of the skin and set in
an exclusive device. This device is composed of a sodium ion
measuring part and a glucose measuring part, and a value
corresponding to a blood sugar AUC value can be determined from
measured results thereof.
[0224] As apparent from the specific example of the biocomponent
analysis unit, the analyzing process thereof and the analyzing
principle thereof, the device for interstitial fluid extraction
according to the present invention can be used in an analyzing
process of the interstitial fluid, comprising extracting the
interstitial fluid in the hydrogel layer through the skin of a
vertebrate, analyzing the interstitial fluid collected in the
hydrogel layer after a predetermined period of time has elapsed to
measure the concentrations of a sodium ion and glucose contained
therein and calculating out a value corresponding to a blood sugar
AUC value in the blood of the vertebrate on the basis of these
measured values.
[0225] Biocomponents are recovered from the interstitial fluid
collected in the hydrogel layer using the recovery liquid and
submitted for analyses of a sodium ion concentration and a glucose
concentration. The analyses of the respective components can be
conducted according to the above-described analyzing process.
Accordingly, according to the present invention, there can be
provided an analyzing process of an interstitial fluid comprising
using the device for interstitial fluid extraction of the present
invention in the analyzing process.
EXAMPLES
[0226] The present invention will hereinafter be described more
specifically by Examples and Comparative Examples. Measuring
methods or evaluating methods of various physical properties and
properties are as follows.
1. Content of Sodium Ion
[0227] The content of a sodium ion in an aqueous solution of PVA
used for preparation of a hydrogel layer was measured by an atomic
absorption spectrometry. The sodium ion contained in the aqueous
solution of PVA remains as it is.
2. Evaluation of Hydrogel Layer
[0228] The mechanical strength, hardness, resistance to water
separation, water content and swelling rate of PVA hydrogel layers
prepared in Examples and Comparative Examples were evaluated
according to the following respective methods. The evaluation of
these physical properties and properties was made in a
thermohygrostat of 23.degree. C. in temperature and 50% in relative
humidity unless expressly noted.
(1) Mechanical Strength
[0229] A PVA hydrogel layer was cut into a size 7 mm wide, 12 mm
long and 700 .mu.m thick to prepare a sample. The sample was left
at rest on a plane. More specifically, after the PVA hydrogel
sample was left to stand for 1 minute on a polyester film left at
rest in a flat state, whether change in shape by gravity occurred
or not, and the hydrogel was disintegrated when the surface thereof
was pressed by a finger, or not was observed to evaluate the sample
as to mechanical strength according to the following standard.
Three samples (n=3) of each hydrogel layer were evaluated, and a
major evaluation result thereof is shown.
A: No change in shape by gravity occurred, and the gel was not
disintegrated even when pressed by a finger. B: No change in shape
by gravity occurred, but the gel was disintegrated when pressed by
a finger. C: The shape of the gel was changed by gravity.
(2) Hardness
[0230] A PVA hydrogel layer was cut into a size 7 mm wide, 12 mm
long and 700 .mu.m thick to prepare a sample. The hardness of the
sample was determined by measuring a penetration at 3 points on the
surface of the gel by a micro-rubber hardness meter MD-1
manufactured by KOBUNSHI KEIKI CO., LTD. Three samples (n=3) of
each hydrogel layer were evaluated to determine an average value
thereof.
(3) Resistance to Water Separation
[0231] A PVA hydrogel layer was cut into a size 7 mm wide, 12 mm
long and 700 .mu.m thick to prepare a sample. After the PVA
hydrogel sample was left to stand for 1 minute on a polyester film
left at rest in a flat state, the condition of water separation was
evaluated according to the following standard. Three samples (n=3)
of each hydrogel layer were evaluated, and a major evaluation
result thereof is shown.
A: No water separation was observed. B: Water separation was
somewhat observed on the surface of the gel. C: Water separation
was clearly observed around the gel.
(4) Water Content (% by Weight)
[0232] A PVA hydrogel layer was cut into a size 3 cm wide, 3 cm
long and 700 .mu.m thick to prepare a sample. The sample was placed
on an aluminum pan, the weight of which was measured in advance, to
measure the weight of the sample together with the pan. Thereafter,
the sample was dried for 3 hours in a thermostat of 105.degree. C.
to measure the weight after the drying. The water content (% by
weight) was determined by finding the weight (a) of the sample
before the test and the weight (b) of the sample after the drying
(both, g) to find the water contend (% by weight) in accordance
with the following equation:
Water content(% by weight)=[(a-b)/a].times.100.
Three samples (n=3) of each hydrogel layer were evaluated to
determine an average value thereof.
(5) Swelling Rate (%)
[0233] A PVA hydrogel layer was cut into a size 3 cm wide, 3 cm
long and 700 .mu.m thick to prepare a sample. A value obtained by
dividing the weight of the sample after immersing it in
physiological saline for 24 hours by the weight of the sample
before the immersion in the physiological saline was found, and the
value was multiplied by 100. Three samples (n=3) of each hydrogel
layer were evaluated to determine an average value thereof.
3. Evaluation of Device for Interstitial Fluid Extraction
[0234] Devices for interstitial fluid extraction prepared in
Examples and Comparative Examples were evaluated as to respective
items of adhesion property to the surface of the skin, pain upon
peeling, adhesive deposit (adhesive residue) and irritation to the
skin (irritation index).
(1) Adhesion Property to the Skin
[0235] A device for interstitial fluid extraction was stuck on the
skin surface of a human forearm for 3 hours. At this time, the
stack state of the device for interstitial fluid extraction on the
skin surface and whether the hydrogel layer was separated from the
base material layer or not were observed to evaluate the device
according to the following standard (n=30).
A: The hydrogel layer and pressure sensitive adhesive layer
remained adhering to the skin surface all over the surface even
after the sticking for 3 hours, no vaporization of water from the
hydrogel layer occurred, and the separation of the base material
from the hydrogel layer is also not observed. B: Peeling from the
skin surface was partly observed in 2 to 5 samples among 30
samples. C: Peeling from the skin surface was partly observed in at
least 6 samples among 30 samples.
(2) Pain Upon Peeling
[0236] A device for interstitial fluid extraction was stuck on the
skin surface of a forearm of each of 10 healthy adult persons for 3
hours. Thereafter, the device for interstitial fluid extraction was
peeled from the skin surface to conduct hearing as to the degree of
pain at this time. The pain upon peeling was evaluated according to
the following standard.
A: At least 8 persons stated that no pain was felt, or a light pain
was felt. B: One to 3 persons stated that a pain was felt. C: At
least 4 persons stated that a pain was felt.
(3) Adhesive Deposit
[0237] Three devices for interstitial fluid extraction were stuck
on the skin surface of a forearm of each of 10 healthy adult
persons for 3 hours. Thereafter, the devices for interstitial fluid
extraction were peeled from the skin surface to observe whether the
pressure sensitive adhesive (adhesive) remained on the skin surface
at this time or not (n=30). The adhesive deposit was evaluated
according to the following standard.
A: No adhesive deposit was observed at all, or adhesive deposit was
scarcely observed. B: Adhesive deposit was observed in 1 to 5
devices. C: Adhesive deposit was observed in at least 6
devices.
(4) Skin Irritation Index
[0238] Three devices for interstitial fluid extraction were stuck
on the skin surface of a forearm of each of 10 healthy adult
persons for 24 hours. Thereafter, the devices for interstitial
fluid extraction were peeled from the skin surface. The skin
irritation at the sites where the specimens were stuck after 1 hour
and 24 hours from the peeling was evaluated according to the
following standard (n=30)
[0239] The following -, .+-., +, ++, +++ and ++++ were weighted as
0, 0.5, 1, 2, 3 and 4, respectively, to determine a skin irritation
index by multiply an average value of the evaluated results of each
subject by 100 in accordance with the following equation.
Judgment Standard
[0240] -: No irritation, .+-.: Light erythema,
+: Erythema,
[0241] ++: Erythema+edema, +++: Erythema+edema+papule, ++++:
Erythema+edema+papule, serous papule, vesicle.
Skin irritation index=(Sum total of marks/the number of
subjects).times.100
[0242] The skin irritation index means "little irritation" for
about 10, "strong irritation" for about 30 and "strongest
irritation" for 50 or higher.
4. Interference in Measured Value by Sodium Ion (Na.sup.+)
[0243] Whether a sodium ion contained in a hydrogel layer
interfered in a measured value in the measurement of a value
corresponding to a blood sugar AUC value or not was evaluated
according to the following method.
[0244] A hydrogel layer was cut into a size 7 mm wide, 12 mm long
and 0.7 mm thick to prepare a sample. This sample was immersed for
at least 16 hours in 1,600 .mu.l of purified water. A sodium ion
concentration in the water, in which the sample had been immersed,
was then measured by an ion chromatograph to convert it into a
concentration of a sodium ion contained in the gel. Incidentally,
in this conversion, assumption that the concentration of the sodium
ion in the gel and the sodium ion concentration in the water
reaches an equilibrium state is used. When the sodium ion
concentration determined by the conversion is 30 ppm or less, the
sodium ion is considered not to interfere in the measured
value.
Example 1
1. Preparation of PVA Hydrogel Layer
[0245] Completely saponified PVA (average polymerization degree:
2,000) and potassium chloride (KCl) were added into distilled water
of about 25.degree. C., the distilled water was heated at a rate of
about 10.degree. C./min while it was being agitated by a mixer, and
agitation was conducted for 1 hour at about 95.degree. C. to
prepare an aqueous solution of PVA having a PVA concentration of
14.3% by weight and a KCl concentration of 0.5% by weight.
[0246] This aqueous solution of PVA was sent to a storage tank, the
internal temperature of which was set to 60.degree. C., and left at
rest for 3 hours to conduct defoaming. After the defoaming, this
aqueous solution of PVA was applied on to a polyethylene film
having a thickness of 35 .mu.m and subjected to matting by means of
a knife coater so as to give a thickness of 350 .mu.m. A coating
film thus formed was irradiated from above with electron beam of
300 kV in accelerating voltage at an irradiation dose of 40 kGy to
crosslink PVA, thereby forming a PVA hydrogel layer. A
silicone-treated polyethylene phthalate (PET) film was laminated as
process paper on the hydrogel layer.
[0247] Thereafter, the aqueous solution of PVA was applied on to
the hydrogel layer (first hydrogel layer), from which the process
paper had been peeled, so as to give a total thickness of 700
.mu.m, thereby foaming a coating film. This coating film was
irradiated from above with the electron beam under the same
conditions as described above to form a hydrogel layer (second
hydrogel layer). In this manner, a PVA hydrogel layer having a
thickness of 700 .mu.m with the first and second hydrogel layers
integrated was prepared. The PVA hydrogel layer was then cut into a
moderate size and immersed for 30 minutes in an isotonic aqueous
solution of 40.degree. C. to the KCl concentration in the PVA
solution before the irradiation of the electron beam. This process
was repeated 3 times to obtain a PVA hydrogel layer of the present
invention, which did substantially not contain a sodium ion.
2. Production of Device for Interstitial Fluid Extraction
[0248] An acrylic pressure sensitive adhesive was applied on to one
surface of a base material of a polyethylene (PE) film having a
thickness of 80 .mu.m by a comma roll so as to give a coating
weight of about 35 g/m.sup.2 and dried to form a multilayer film
having a layer structure of base material layer/pressure sensitive
adhesive layer. Polyester film process paper subjected to a
releasing treatment was laminated on the surface of the pressure
sensitive adhesive layer of the multilayer film, and the resultant
laminate was aged for 72 hours at ordinary temperature. The acrylic
pressure sensitive adhesive is such that an alkyl acrylate
copolymer of 96% by weight of isononyl acrylate and 4% by weight of
acrylic acid is used as a base, and 0.03 parts by weight of an
epoxy crosslinking agent is contained in 100 parts by weight of the
copolymer.
[0249] The multilayer film was die-cut into a substantial square of
28 mm.times.28 mm, the corners of which were rounded, in such a
manner that a V-shaped notch is formed in each of the opposite
sides thereof, thereby preparing a pressure sensitive adhesive
film. On the other hand, the hydrogel layer prepared above was
die-cut into a rectangle 7 mm wide and 12 mm long to prepare a
hydrogel layer for interstitial fluid extraction of a size 7 mm
wide, 12 mm long and 700 .mu.m thick. The hydrogel layer for
interstitial fluid extraction was arranged on the central portion
of the surface on the pressure sensitive adhesive layer side of the
pressure sensitive adhesive film, and an exposed surface of the
pressure sensitive adhesive layer and the surface of the hydrogel
layer were then covered with a polyester film subjected to a
releasing treatment to form a release layer. A device for
interstitial fluid extraction having the same layer structure as
that illustrated in FIGS. 5a and 5b was thereby obtained. The
construction and properties of the device for interstitial fluid
extraction are shown in Table 1.
Example 2
[0250] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 1 except that the KCl concentration in the aqueous solution
of PVA was changed to 3.0% by weight from 0.5% by weight. The
results are shown in Table 1.
Example 3
[0251] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 1 except that the PVA concentration and KCl concentration
in the aqueous solution of PVA were changed to 12.0% by weight from
14.3% by weight and to 2.0% by weight from 0.5% by weight,
respectively, and the irradiation dose was changed to 60 kGy from
40 kGy. The results are shown in Table 1.
Example 4
[0252] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 1 except that the PVA concentration in the aqueous solution
of PVA was changed to 10.0% by weight from 14.3% by weight. The
results are shown in Table 1.
Example 5
[0253] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 4 except that regarding the conditions for the irradiation
of the electron beam upon the preparation of the PVA hydrogel
layer, the accelerating voltage and irradiation dose were changed
to 4.8 MV from 300 kV and to 20 kGy from 40 kGy, respectively. The
results are shown in Table 1.
Example 6
[0254] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 1 except that the PVA concentration in the aqueous solution
of PVA was changed to 9.1% by weight from 14.3% by weight. The
results are shown in Table 1.
Example 7
[0255] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 1 except that the PVA concentration in the aqueous solution
of PVA was changed to 7.7% by weight from 14.3% by weight. The
results are shown in Table 1.
Example 8
[0256] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 4 except that the PVA was changed to completely saponified
PVA having an average polymerization degree of 1,700. The results
are shown in Table 1.
Example 9
[0257] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 8 except that regarding the conditions for the irradiation
of the electron beam upon the preparation of the PVA hydrogel
layer, the accelerating voltage and irradiation dose were changed
to 4.8 MV from 300 kV and to 20 kGy from 40 kGy, respectively. The
results are shown in Table 1.
Comparative Example 1
[0258] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 1 except that the PVA concentration and KCl concentration
in the aqueous solution of PVA were changed to 9.1% by weight from
14.3% by weight and to 3.0% by weight from 0.5% by weight,
respectively. The results are shown in Table 2.
Comparative Example 2
[0259] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 1 except that the PVA concentration and KCl concentration
in the aqueous solution of PVA were changed to 7.7% by weight from
14.3% by weight and to 0.8% by weight from 0.5% by weight,
respectively. The results are shown in Table 2.
Comparative Example 3
[0260] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 1 except that the PVA concentration and KCl concentration
in the aqueous solution of PVA were changed to 7.7% by weight from
14.3% by weight and to 1.5% by weight from 0.5% by weight,
respectively. The results are shown in Table 2.
Comparative Example 4
[0261] A PVA hydrogel layer and a device for interstitial fluid
extraction were prepared according to the same process as in
Example 1 except that the PVA concentration and KCl concentration
in the aqueous solution of PVA were changed to 7.7% by weight from
14.3% by weight and to 3.0% by weight from 0.5% by weight,
respectively. The results are shown in Table 2.
Comparative Example 5
[0262] The PVA was changed to completely saponified PVA having an
average polymerization degree of 1,750. In addition, the PVA
concentration and KCl concentration in the aqueous solution of PVA
were changed to 28.0% by weight from 14.3% by weight and to 0% by
weight from 0.5% by weight, respectively. Further, the irradiation
dose was changed to 60 kGy from 40 kGy. A PVA hydrogel layer and a
device for interstitial fluid extraction were prepared according to
the same process as in Example 1 except for these changed points.
The results are shown in Table 2.
Comparative Example 6
[0263] The PVA was changed to completely saponified PVA having an
average polymerization degree of 2,200. In addition, the PVA
concentration and KCl concentration in the aqueous solution of PVA
were changed to 16.0% by weight from 14.3% by weight and to 0% by
weight from 0.5% by weight, respectively. Further, the irradiation
dose was changed to 60 kGy from 40 kGy. A PVA hydrogel layer and a
device for interstitial fluid extraction were prepared according to
the same process as in Example 1 except for these changed points.
The results are shown in Table 2.
TABLE-US-00001 TABLE 1 Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex.. 5 Ex. 6 Ex. 7
Ex. 8 Ex. 9 PVA (% by weight) 14.3 14.3 12.0 10.0 10.0 9.1 7.7 10.0
10.0 KCl (% by weight) 0.5 3.0 2.0 0.5 0.5 0.5 0.5 0.5 0.5
Polymerization degree of 2000 2000 2000 2000 2000 2000 2000 1700
1700 PVA Amount of Na.sup.+ <10 ppm <10 ppm <10 ppm <10
ppm <10 ppm <10 ppm <10 ppm <10 ppm <10 ppm
Conditions for irradiation of EB Accelerating voltage 300 kV 300 kV
300 kV 300 kV 4.8 MV 300 kV 300 kV 300 kV 4.8 MV Irradiation dose
40 kGy 40 kGy 60 kGy 40 kGy 20 kGy 40 kGy 40 kGy 40 kGy 20 kGy
Thickness (.mu.m) 700 700 700 700 700 700 700 700 700 Mechanical
strength A A A A A A A A A Hardness 17 17 20 17 8 17 17 17 17
Resistance to water separation A A A A A A A A A Water content (%)
86.3 84.7 86.3 88.8 88.8 90.9 91.9 88.4 88.8 Swelling rate (%) 140
140 130 170 220 170 180 130 230 Adhesion property to skin A A A A A
A A A A Pain upon peeling A A A A A A A A A Adhesive deposit A A A
A A A A A A Skin irritation index -- -- Gel part: -- -- -- -- -- --
10.3 Tape part: 19.3 Interference in measured None None None None
None None None None None value by Na.sup.+
TABLE-US-00002 TABLE 2 Comp. Ex. 1 Comp. Ex. 2 Comp. Ex. 3 Comp.
Ex. 4 Comp. Ex.. 5 Comp. Ex. 6 PVA (% by weight) 9.1 7.7 7.7 7.7
28.0 16.0 KCl (% by weight) 3.0 0.8 1.5 3.0 0 0 Polymerization
degree of PVA 2000 2000 2000 2000 1750 2200 Amount of Na.sup.+
<10 ppm <10 ppm <10 ppm <10 ppm 300 ppm 50 ppm
Conditions for irradiation of EB Accelerating voltage 300 kV 300 kV
300 kV 300 kV 300 kV 300 kV Irradiation dose 40 kGy 40 kGy 40 kGy
40 kGy 60 kGy 60 kGy Thickness (.mu.m) 700 700 700 700 700 700
Mechanical strength A A A B A A Hardness -- -- -- -- 20 20
Resistance to water separation B B B C A A Water content (%) 87.9
91.9 91.9 88.9 83.8 83.0 Swelling rate (%) -- -- -- -- 130 130
Adhesion property to skin B B B C A A Pain upon peeling A A A A A A
Adhesive deposit A A A A A A Skin irritation index -- -- -- -- --
-- Interference in measured value None None None None Occurred
Occurred by Na.sup.+
<Consideration>
[0264] The devices for interstitial fluid extraction according to
the present invention are such that the hydrogel layer formed from
the hydrophilic polymer has an area of a size that the pressure
sensitive adhesive layer is exposed from around the hydrogel layer,
contains at most 30 ppm of a sodium ion and causes no water
separation (Examples 1 to 3). Therefore, the devices for
interstitial fluid extraction according to the present invention
are easy to be applied to a skin surface, inhibit irritation to the
skin and can exactly analyze the concentrations of a sodium ion and
glucose contained in the interstitial fluid collected.
[0265] Accordingly, the use of the device for interstitial fluid
extraction according to the present invention permits extracting
the interstitial fluid in the hydrogel layer through the skin of a
vertebrate, analyzing the interstitial fluid collected in the
hydrogel layer after a predetermined period of time has elapsed to
measure the concentrations of a sodium ion and glucose contained
therein and determining a value corresponding to the blood sugar
AUC value in the blood of the vertebrate on the basis of these
measured values.
[0266] On the other hand, the device for interstitial fluid
extraction using the hydrogel layer in which water separation is
observed (Comparative Examples 1 to 4), are difficult to stably
extract and collect an interstitial fluid due to the water
separation and also insufficient in adhesion to the skin
surface.
[0267] The devices for interstitial fluid extraction using the
hydrogel layer containing a relatively large amount of a sodium ion
(Comparative Examples 5 and 6) cannot exactly and stably measure a
value corresponding to the blood sugar AUC value because the sodium
ion interferes with the measured value.
[0268] With respect to the preparation of these devices for
interstitial fluid extraction of Examples and Comparative Examples,
the concentration (% by weight) of PVA in the aqueous solution of
PVA used in the preparation of the hydrogel layer and the
osmolarity (osmole) of KCl were plotted in FIG. 19. A case where no
water separation is observed and a case where water separation is
observed can be distinguished by an oblique line on the basis of
the resistance to water separation (whether water separation is
observed or not). The case where no water separation is observed in
the hydrogel layer means that the crosslinking of the hydrogel
layer by irradiation of radiation is sufficient, and thus this
hydrogel layer exhibits excellent performance as the hydrogel layer
of the device for interstitial fluid extraction.
[0269] From FIG. 19, it is understood that when assuming that the
concentration of the hydrophilic polymer is b % by weight, and the
osmolarity of KCl is a osmole(s), an aqueous solution of PVA
satisfying the following expression (A):
a.ltoreq.0.1b-0.6 (A)
is used, a hydrogel layer free of water separation, even and
sufficient in crosslinking by irradiation by radiation and
exhibiting excellent properties is obtained. However, a is 0.05 to
0.94 osmoles, and b is 7 to 30% by weight.
[0270] FIG. 20 illustrates the results that interstitial fluid
extraction rate-accelerating effects on the same skin surface in
various osmolarities (osmoles) of solvents respectively using urea,
glycine and KCl were determined. From the results in FIG. 20, it is
understood that the interstitial fluid extraction rate-accelerating
effects of urea and glycine are equivalent to KCl. From these
results, it is apparent that urea and glycine can be used as the
osmotic pressure control agent within an osmolarity range of from
0.05 to 0.94 osmoles in place of KCl.
[0271] FIG. 21 illustrates the results that interstitial fluid
extraction rate-accelerating effects on the same skin surface in
various osmolarities (osmoles) of solvents respectively using
alanine, proline and KCl were determined. From the results in FIG.
21, it is understood that the interstitial fluid extraction
rate-accelerating effects of alanine and proline are equivalent to
KCl. From these results, it is apparent that alanine and proline
can be used as the osmotic pressure control agent within an
osmolarity range of from 0.05 to 0.94 osmoles in place of KCl.
INDUSTRIAL APPLICABILITY
[0272] The devices for interstitial fluid extraction according to
the present invention can be used in an analyzing process of an
interstitial fluid, comprising extracting the interstitial fluid in
the hydrogel layer through the skin of a vertebrate, analyzing the
interstitial fluid collected in the hydrogel layer after a
predetermined period of time has elapsed to measure the
concentrations of a sodium ion and glucose contained therein and
calculating out a value corresponding to a blood sugar AUC value in
the blood of the vertebrate on the basis of these measured
values.
REFERENCE SIGNS LIST
[0273] 1 Biocomponent analysis unit [0274] 10 Analysis unit body
[0275] 20 Analyzing kit [0276] 30 Cartridge for analysis [0277] 50
Device for interstitial fluid extraction [0278] 11 Recessed part
[0279] 12 Cartridge arranging part [0280] 13 Movable top plate
[0281] 14 Liquid supply part [0282] 15 Liquid discharge part [0283]
21 Glucose detection part [0284] 22 Sodium detection part [0285] 23
Display part [0286] 24 Operation part [0287] 25 Control part [0288]
310 Cartridge body [0289] 311 Gel receiving part [0290] 317 Storage
part for glucose detection [0291] 322 Storage part for sodium
detection [0292] 330 Reaction reagents to glucose [0293] 501
Hydrogel layer [0294] 502 Pressure sensitive adhesive film [0295]
502a Base material [0296] 502b Pressure sensitive adhesive layer
[0297] 503 Release layer
* * * * *