NZ613644B2 - Analytical aid with hydrophilic coating containing nanoparticles with silica structure - Google Patents
Analytical aid with hydrophilic coating containing nanoparticles with silica structure Download PDFInfo
- Publication number
- NZ613644B2 NZ613644B2 NZ613644A NZ61364412A NZ613644B2 NZ 613644 B2 NZ613644 B2 NZ 613644B2 NZ 613644 A NZ613644 A NZ 613644A NZ 61364412 A NZ61364412 A NZ 61364412A NZ 613644 B2 NZ613644 B2 NZ 613644B2
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- analytical aid
- nanoparticles
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- 239000011248 coating agent Substances 0.000 title claims abstract description 152
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- FWDBOZPQNFPOLF-UHFFFAOYSA-N ethenyl(triethoxy)silane Chemical compound CCO[Si](OCC)(OCC)C=C FWDBOZPQNFPOLF-UHFFFAOYSA-N 0.000 description 1
- CWAFVXWRGIEBPL-UHFFFAOYSA-N ethoxysilane Chemical compound CCO[SiH3] CWAFVXWRGIEBPL-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N ethylene glycol monomethyl ether Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
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- 125000002883 imidazolyl group Chemical group 0.000 description 1
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- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 238000003780 insertion Methods 0.000 description 1
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- 238000005342 ion exchange Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
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- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 239000007769 metal material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- VHWYCFISAQVCCP-UHFFFAOYSA-N methoxymethanol Chemical compound COCO VHWYCFISAQVCCP-UHFFFAOYSA-N 0.000 description 1
- HLXDKGBELJJMHR-UHFFFAOYSA-N methyl-tri(propan-2-yloxy)silane Chemical compound CC(C)O[Si](C)(OC(C)C)OC(C)C HLXDKGBELJJMHR-UHFFFAOYSA-N 0.000 description 1
- 239000002365 multiple layer Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
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- 125000000962 organic group Chemical group 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002270 phosphoric acid ester group Chemical group 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- NPYPAHLBTDXSSS-UHFFFAOYSA-N potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
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- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- JMHRGKDWGWORNU-UHFFFAOYSA-M sodium;2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate Chemical compound [Na+].CC1=C(CC([O-])=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 JMHRGKDWGWORNU-UHFFFAOYSA-M 0.000 description 1
- 238000004528 spin coating Methods 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CPUDPFPXCZDNGI-UHFFFAOYSA-N triethoxy(methyl)silane Chemical compound CCO[Si](C)(OCC)OCC CPUDPFPXCZDNGI-UHFFFAOYSA-N 0.000 description 1
- MSRJTTSHWYDFIU-UHFFFAOYSA-N triethoxy(octyl)silane Chemical compound CCCCCCCC[Si](OCC)(OCC)OCC MSRJTTSHWYDFIU-UHFFFAOYSA-N 0.000 description 1
- UDUKMRHNZZLJRB-UHFFFAOYSA-N triethoxy-[2-(7-oxabicyclo[4.1.0]heptan-4-yl)ethyl]silane Chemical compound C1C(CC[Si](OCC)(OCC)OCC)CCC2OC21 UDUKMRHNZZLJRB-UHFFFAOYSA-N 0.000 description 1
- JXUKBNICSRJFAP-UHFFFAOYSA-N triethoxy-[3-(oxiran-2-ylmethoxy)propyl]silane Chemical compound CCO[Si](OCC)(OCC)CCCOCC1CO1 JXUKBNICSRJFAP-UHFFFAOYSA-N 0.000 description 1
- DQZNLOXENNXVAD-UHFFFAOYSA-N trimethoxy-[2-(7-oxabicyclo[4.1.0]heptan-4-yl)ethyl]silane Chemical compound C1C(CC[Si](OC)(OC)OC)CCC2OC21 DQZNLOXENNXVAD-UHFFFAOYSA-N 0.000 description 1
- BPSIOYPQMFLKFR-UHFFFAOYSA-N trimethoxy-[3-(oxiran-2-ylmethoxy)propyl]silane Chemical compound CO[Si](OC)(OC)CCCOCC1CO1 BPSIOYPQMFLKFR-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Abstract
Disclosed herein is an analytical aid comprising a surface that is at least partly coated with a hydrophilic coating, said hydrophilic coating containing nanoparticles with a silica structure and an average particle size ranging from 1 to 500 nm, determined according to DIN ISO 22412:2008. Additionally disclosed is a method for producing an analytical aid and sampling device containing the aforementioned analytical aid that is at least partly coated. lly disclosed is a method for producing an analytical aid and sampling device containing the aforementioned analytical aid that is at least partly coated.
Description
Analytical aid with hydrophilic coating containing nanoparticles with silica structure
Field of the invention
The present invention relates to an analytical aid, comprising a surface coated at least
partially with a hydrophilic coating, wherein the hydrophilic coating contains nanoparticles
with silica structure and an average particle size, determined according to DIN ISO
22412:2008 (dynamic light scattering), in the range from 1 to 500 nm. The present
invention further relates to a method of production of an analytical aid, comprising a
surface coated at least partially with a hydrophilic coating containing nanoparticles with
silica structure and an average particle size, determined according to DIN ISO 22412:2008
(dynamic light scattering), in the range from 1 to 500 nm. The present invention also
relates to an analytical aid producible by this method and a sampling device containing the
at least partially coated analytical aid described.
Prior art
A great many analytical aids are described in the prior art, in particular for the rapid and
quantitative analytical determination of constituents of liquid samples, for example in the
form of individual test strips or strip-shaped test materials or in integrated systems, in
which the testing element is a part of a sampling device. For reasons of simplified and
more economical production and component stability, conventional testing elements are as
a rule made of plastic or metal and generally have a comparatively hydrophobic surface,
which is a disadvantage for rapid and uniform wetting of the analytical aid with the liquid,
generally aqueous, samples.
Thus, for example from , sampling devices for collecting body fluids are
known, which have a needle element and are equipped with a testing element, with which
at least one analyte in the body fluid can be detected qualitatively or quantitatively. In this
case the sample of body fluid is transported along the needle element to the testing
element. Since as a rule the site of insertion of the needle element in the skin is disposed at
some distance from the testing element, as a rule the sample of body fluid must travel a
few millimetres along the capillary to reach the testing element. Usually needle elements
made of steel are used, which have a relatively hydrophobic steel surface, and therefore are
not very suitable for transporting the aqueous body fluid.
For the purpose of increasing the flow rate of the body fluid along the needle element, EP
2 025 287 A1 describes modification of the surface of the needle element with a
hydrophilic coating. Non-ionic surfactants, such as polysorbate, are mentioned in particular
as hydrophilic coatings.
Similarly, EP 2 014 727 A1 describes hydrophilizing metal-oxide coatings, for example
AlOOH, TiO , SiO , or the like, wherein these coatings are for example applied and fixed
in the form of discrete particles in suspensions. The use of organic polymer compounds,
for example PVP-PEG, and of water-soluble organic poly-acids and/or salts thereof, for
example PAA or heparin salts, as hydrophilic coating, is also known from the prior art.
For forming a hydrophilic surface of the needle element, a hydrophilization by
physicochemical means is also possible, for example the etching of a steel surface or a
plasma or corona treatment in the sense of creating active metal surfaces. Usually these
effects are temporary and therefore as a rule are only auxiliary measures for preparing the
needle element surface for subsequent coating.
In order to improve the transport of the body fluid along the needle element, in addition a
capillary-active surface structure can be provided, and hydrophilic coating of precisely this
capillary surface structure can be especially advantageous for the speed of transport of the
body fluid along the needle element.
EP 1 887 355 A1 describes a needle element designed as a microfluidic system for the
capillary transport of a liquid and a method of applying a hydrophilic surface coating on
said needle element. Polyacrylic acid, polyacrylate, dextran sulphate and/or chondroitin
sulphate are used as surface coating materials. Especially preferably, a surface structure
formed as a microchannel on the needle element is provided with said hydrophilic surface
coating, to ensure rapid and reliable transport of the body fluid along the needle element.
However, the coating materials described in the prior art often have inadequate stability, in
particular inadequate long-term stability. As reasons for inadequate stability, we may
mention for example insufficient bonding of the coating to the coated surface of the
substrate, which may result in detachment of the coating during the coating process, or
during storage or during use of the substrate, for example when a needle element coated in
this way is inserted into the skin. The hydrophilic coating may also not even be resistant to
longer storage at room temperature or to temperature fluctuations. Moreover, some
compounds display low stability when they are exposed to sterilization conditions and/or
low resistance to gas evolution from packaging.
In particular, instability with respect to packaging materials often means that, for example
in the case of substrates packaged in plastic materials, the hydrophilicity of the coated
surfaces decreases markedly during storage and sufficient hydrophilicity of the substrates
after storage is no longer guaranteed. This loss of hydrophilicity can for example be
explained by adsorption of volatile, as a rule nonpolar, constituents of the packaging
materials.
In order to prevent such loss of hydrophilicity, describes the use of
specific packaging, which contains a loose covering for the hydrophilic coating and/or the
addition of adsorbents in the packaging, to prevent absorption of said volatile constituents
by the hydrophilic coating. However, the packaging proposed in is
complicated, expensive and in particular is disadvantageous for measuring equipment with
automatic operation, which must also provide reliable unpacking of the substrate from the
packaging.
US 20070179373 A1 describes apparatus and methods for collecting a fluid sample. It
discloses inter alia an integrated collection device having an analyte detector and a gradient
means to drive the transport of a sample fluid from a point of contact to a point of
detection. The integrated collection device has a layered structure including multiple
layers. The design features inter alia a first layer and a second layer which forms a surface
layer. A hydrophilic surface is generated by powder coating with fumed silica
nanoparticles.
There is therefore a need for analytical aids with hydrophilic coatings, which have
sufficient stability, in particular sufficient stability even in the presence of volatile, as a
rule nonpolar, constituents of packaging materials.
The problem to be solved by the invention
The present invention is therefore concerned with the problem of providing an analytical
aid with a hydrophilic coating, which has advantageous wetting properties and is
characterized by high stability of the coating.
Disclosure of the invention
According to the invention, this problem is solved by the objects of the independent
claims. Advantageous embodiments are the object of the dependent claims.
Surprisingly, it was found that when nanoparticles with silica structure and an average
particle size, determined according to DIN ISO 22412:2008 (dynamic light scattering), in
the range from 1 to 500 nm are used for coating analytical aids, analytical aids with
especially advantageous properties are produced. The analytical aids so coated are
characterized by advantageous hydrophilicity and wettability. Moreover, high stability of
the coating is provided.
Accordingly, the present invention also relates to an analytical aid, comprising a surface
coated at least partially with a hydrophilic coating, wherein the hydrophilic coating
contains nanoparticles with silica structure and an average particle size, determined
according to DIN ISO 22412:2008 (dynamic light scattering), in the range from 1 to
500 nm, and the nanoparticles comprise groups of structure (I) and/or (II)
Si OR
(I)
(II)
wherein in each of the groups of structure (I), independently of one another, R is selected
from the group consisting of H, a metal-containing ion,
(O) R
R N R m
w x y z
and wherein R , R , R and R , independently of one another, are selected from H and
alkyl,
a b c
and wherein R , R and R , independently of one another, are optionally substituted
residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl,
cycloheteroalkyl, alkenyl and alkoxyalkyl,
and wherein n, m and p, independently of one another, are 0 or 1,
and wherein M is a metal ion and A is a physiologically compatible anion.
In contrast, for example, to the abovementioned US 20070179373 A1, which discloses
only a hydrophilic surface coating with fumed silica nanoparticles, the nanoparticles
provided in accordance with the invention thus comprise groups of structure (I) and/or (II).
The present invention also relates to a method of production of an analytical aid,
comprising a surface that is coated at least partially with a hydrophilic coating, wherein the
method comprises:
(a) providing the analytical aid,
(b) coating the analytical aid by bringing the analytical aid into contact with a mixture
G comprising at least one dispersant and nanoparticles with silica structure, which
have an average particle size, determined according to DIN ISO 22412:2008, in the
range from 1 to 500 nm,
wherein the nanoparticles comprise groups of structure (I) and/or (II)
Si OR
(II)
wherein in each of the groups of structure (I), independently of one another, R is
selected from the group consisting of H, a metal-containing ion,
Si (O) R
and ,
R N R
w x y z
and wherein R , R , R and R , independently of one another, are selected from H
and alkyl,
a b c
and wherein R , R and R , independently of one another, are optionally substituted
residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl,
cycloheteroalkyl, alkenyl and alkoxyalkyl,
and wherein n, m and p, independently of one another, are 0 or 1,
and wherein M is a metal ion and A is a physiologically compatible anion.
(c) drying the analytical aid obtained according to (b), and
(d) optionally sterilizing the analytical aid obtained according to (c),
wherein the bringing into contact in (b) preferably takes place by dip coating and/or spray
coating and/or contact coating, and wherein the analytical aid and/or the surface of the
analytical aid preferably consists at least partially of a metal and/or a metal alloy and/or a
metal oxide and/or a mixed metal oxide and/or a mixed metal oxide.
According to another embodiment, the present invention also relates to the use of
nanoparticles with silica structure and an average particle size, determined according to
DIN ISO 22412:2008 (dynamic light scattering), in the range from 1 to 500 nm as
hydrophilic coating for a surface of an analytical aid, preferably as hydrophilic coating for
a needle element of a sampling device for collecting a body fluid, wherein the
nanoparticles comprise groups of structure (I) and/or (II)
Si OR
(II)
wherein in each of the groups of structure (I), independently of one another, R is selected
from the group consisting of H, a metal-containing ion,
(O) R
R N R m
w x y z
and wherein R , R , R and R , independently of one another, are selected from H and
alkyl,
a b c
and wherein R , R and R , independently of one another, are optionally substituted
residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl,
cycloheteroalkyl, alkenyl and alkoxyalkyl, and wherein n, m and p, independently of one
another, are 0 or 1, and wherein M is a metal ion and A is a physiologically compatible
anion.
Nanoparticles
As already noted, the coating comprises nanoparticles with silica structure and an average
particle size, determined according to DIN ISO 22412:2008 (dynamic light scattering), in
the range from 1 to 500 nm.
Preferably the nanoparticles have a size in the range from 1 to 100 nm, more preferably in
the range from 1 to 50 nm, more preferably in the range from 3 nm to 25 nm, and
especially preferably in the range from 5 to 15 nm.
The nanoparticles preferably have a BET surface area in the range from 100 to 700 m /g.
The coating has preferably an average layer thickness, also referred to as average thickness
or mean thickness hereinbelow, of no more than 500 nm, for example no more than 300
nm. The layer thickness may be measured by common methods, for example by means of a
destructive or a non-destructive method. More specifically, the layer thickness may be
measured by means of an ellipsometer and/or by means of a scanning force microscope
and/or by means of an “alpha stepper”, that is a device which scans a surface of the layer
by means of a stylus, the deflection and/or position of which is recorded. Other
measurement methods are also conceivable. Alternatively or additionally, the average layer
thickness may furthermore also be calculated and/or determined semi-empirically. For
example, the average layer thickness may be determined from a known thickness of the
coating and a coating weight. Thus, for example, calculated average layer thicknesses may
be in the range from 30 nm to 300 nm, in particular in the range from 50 nm to 150 nm.
Fluctuations, for example fluctuations in one or more channels and/or capillaries and/or
fluctuations due to edge effects, need not be taken into account here.
With regard to the structure of the nanoparticles, as noted above, they are nanoparticles
with silica structure, which comprise groups of structure (I) and/or (II)
Si OR
(I)
(II)
Preferably at least a portion of the surface of the nanoparticles is modified with groups of
structure (I) or groups of structure (II), preferably at least with groups of structure (I).
According to a preferred embodiment, the present invention accordingly relates to an
analytical aid, as described above, comprising at least one surface coated at least partially
with a hydrophilic coating, wherein the hydrophilic coating contains nanoparticles with
silica structure, which comprise groups of structure (I). The present invention also relates
to a method of production of an analytical aid, and an analytical aid producible by said
method, wherein the analytical aid is coated in step (b) with a mixture G comprising at
least one dispersant and nanoparticles with silica structure, as described above, wherein the
nanoparticles have groups of structure (I).
Groups of structure (I)
As mentioned above, the residue R is selected from the group consisting of H, a metal-
containing ion,
R N R (O)
R Si
(O) R
w x y z
wherein R , R , R and R , independently of one another, are selected from H and alkyl,
a b c
and wherein R , R and R , independently of one another, are optionally substituted
residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl,
cycloheteroalkyl, alkenyl and alkoxyalkyl, and wherein n, m and p, independently of one
another, are 0 or 1.
When R is H, the silica particles then preferably comprise groups of structure
Si O H
Accordingly, the present invention also relates to an analytical aid, as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure, which comprise groups of
structure
Si O H
The present invention also relates to a method of production of an analytical aid, and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the nanoparticles have groups of structure
Si O H
According to an alternative embodiment, R is a metal-containing ion. In this case the silica
particles therefore preferably contain groups of structure
Si O X
According to a preferred embodiment, X is an alkaline-earth metal containing ion, such as
2+ 2+
Mg or Ca , an alkali metal ion or an aluminium containing ion.
When R is an alkali metal ion, the nanoparticle then preferably comprises groups of
structure
or the structure:
+ + +
Especially preferably, the alkali metal is selected from the group consisting of Li , Na , K
and mixtures thereof. In this context, the term "mixtures thereof" means that in each
individual group of structure
Si O X
+ + +
X , independently of each X contained in each further group of structure Si-O- X
contained in the silicon nanoparticle, is selected from the group consisting of
Si O X
+ + + +
containing X is selected from the group consisting of Li , Na and K , and therefore the
nanoparticles can in each case have several different alkali metal counter-ions. Quite
especially preferably, X is Na .
Accordingly, the present invention also relates to an analytical aid, as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure, which comprise groups of
structure
The present invention also relates to a method of production of an analytical aid and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the nanoparticles have groups of structure
According to an alternative embodiment, R is a cation of the following structure
R N R
w x y z
wherein R , R , R and R , independently of one another, are selected from H and alkyl.
The term "alkyl", as used in the context of the present invention, means linear or branched,
optionally substituted alkyl residues.
w x y z
If R and/or R and/or R and/or R is an alkyl residue, it is preferably an alkyl residue
selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl and
tert.-butyl, preferably methyl.
If R is
R N R
w x y z
then R , R , R and R especially preferably, independently of one another, are selected
w x y z
from H, methyl and ethyl. Especially preferably, R , R , R and R are H.
Accordingly, the present invention also relates to an analytical aid, as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure, which comprise groups of
structure
Si O NH
The present invention also relates to a method of production of an analytical aid, and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the nanoparticles have groups of structure
Si O NH
Said nanoparticles are obtainable for example under the name Ludox AS-30 (Grace,
Aldrich) or Levasil 200N/30%. (EKA).
According to an especially preferred embodiment of the present invention, R is
(O) R
a b c
and wherein R , R and R , independently of one another, are optionally substituted
residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl,
cycloheteroalkyl, alkenyl and alkoxyalkyl, and wherein n, m and p, independently of one
another, are 0 or 1.
According to a preferred embodiment of the invention, R is
Si R
wherein p and n are 1 and m is 0.
Accordingly, the present invention also relates to an analytical aid as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure, which comprise silane-
modified silicon groups of structure
Si Si R
The present invention also relates to a method of production of an analytical aid, and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the nanoparticles have silane-modified silicon groups of
structure
Si O Si R
If the silicon nanoparticles contain silane-modified silicon groups of structure
Si Si R
then the silicon nanoparticles can optionally contain further modification of silane groups,
for example groups of structure
and/or groups of structure
and/or groups of structure
and/or similar branched modifications of silane groups,
a* b* c*
in which R , R and R , independently of one another, are optionally substituted
residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl,
cycloheteroalkyl, alkenyl and alkoxyalkyl.
The term "substituted alkyl residue", as used in the context of the present invention, means
alkyl residues in which at least one H has been replaced with a suitable substituent. A
substituted alkyl residue can contain at least one, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or
12 substituents, wherein, if more than one substituent is present, the substituents present
can be identical or different. With regard to the nature of the substituents, in principle there
are no restrictions, provided that when the nanoparticles are used, a coating with sufficient
hydrophilicity and stability can be provided. The substituents can for example be selected
from the group consisting of epoxy, aryl, alkenyl, alkynyl, halogen, hydroxyl,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate,
phosphoric acid ester, amino, acylamino, alkylcarbonylamino, arylcarbonylamino,
carbamates, carbamides, amidine, nitro, imino, SH, alkylthio, arylthio, thiocarboxylate,
sulphate, alkylsulphinyl, sulphonate, sulphamoyl, sulphonamido, trifluoromethyl, cyano,
azido, aldehyde, keto group, cycloalkyl e.g. cyclopentyl or cyclohexyl, heterocycloalkyl
e.g. morpholino, piperazinyl or piperidinyl, and glycosyl. Especially preferred substituents
are hydroxyl groups, glycosyl groups and phosphoric acid ester groups.
The term "cycloalkyl" means, in the context of the invention, optionally substituted, cyclic
alkyl residues, wherein they can be monocyclic or polycyclic groups. Optionally
substituted cyclohexyl may be mentioned as a preferred example of a cycloalkyl residue.
The term "cycloheteroalkyl", as used in the context of the present invention, means
optionally substituted, cyclic alkyl residues, which have at least one heteroatom, such as O,
N or S in the ring, wherein they can be monocyclic or polycyclic groups.
The terms "substituted cycloalkyl residue" or "cycloheteroalkyl", as used in the context of
the present invention, mean cycloalkyl residues or cycloheteroalkyl residues, in which at
least one H has been replaced with a suitable substituent. A substituted cycloalkyl residue
or cycloheteroalkyl residue can in this case contain at least one, for example 2, 3, 4, 5, 6, 7,
8, 9, 10, 11 or 12 substituents, wherein, if more than one substituent is present, the
substituents present can be identical or different. With regard to the nature of the
substituents, reference is made to the substituents mentioned as examples with respect to
substituted alkyl residues.
The term "aryl”, as used in the context of the present invention, means optionally
substituted, 5- and 6-membered aromatic rings, and substituted or unsubstituted polycyclic
aromatic groups (aryl groups), for example tricyclic or bicyclic aryl groups. Optionally
substituted phenyl groups or naphthyl groups may be mentioned as examples. Polycyclic
aromatic groups can also contain non-aromatic rings.
The term "heteroaryl”, as used in the context of the present invention, means optionally
substituted, 5- and 6-membered aromatic rings, and substituted or unsubstituted polycyclic
aromatic groups, for example tricyclic or bicyclic aryl groups, containing one or more, for
example 1 to 4, such as 1, 2, 3, or 4, heteroatoms in the ring system. If more than one
heteroatom is present in the ring system, the at least two heteroatoms that are present can
be identical or different. The following heteroaryl residues may be mentioned as examples:
benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl,
tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl,
benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, methylene-
dioxyphenylyl, naphthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl,
benzofuranyl, deazapurinyl or indolizinyl.
The term "substituted aryl residue or heteroaryl residue", as used in the context of the
present invention, means aryl residues or heteroaryl residues, in which at least one H has
been replaced with a suitable substituent. A substituted aryl residue or heteroaryl residue
can in this case contain at least one, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12
substituents, wherein, if more than one substituent is present, the substituents present can
be identical or different. With regard to the nature of the substituents, in principle there are
no restrictions, provided that compound M has sufficient hydrophilicity and/or a
sufficiently stable coating can be provided with compound M. The substituents can for
example be selected from the group consisting of aryl, alkenyl, alkynyl, halogen, hydroxyl,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate,
phosphoric acid ester, amino, acylamino, alkylcarbonylamino, arylcarbonylamino,
carbamates, carbamides, amidine, nitro, imino, SH, alkylthio, arylthio, thiocarboxylate,
sulphate, alkylsulphinyl, sulphonate, sulphamoyl, sulphonamido, trifluoromethyl, cyano,
azido, cycloalkyl e.g. cyclopentyl or cyclohexyl, heterocycloalkyl e.g. morpholino,
piperazinyl or piperidinyl, sugar residues and heteroaryl.
The term "alkoxyalkyl" means alkyl residues that comprise one or more –O- groups within
the alkyl chain. The term comprises groups of alkyl-O-alkyl structure and similar
structures, wherein the respective alkyl residues, as described above, can be substituted or
unsubstituted.
The term alkenyl means alkyl residues that have at least one C-C double bond. Regarding
the nature of possible substituents, reference is to be made to the foregoing.
a b c
According to a preferred embodiment of the invention, R , R and R are selected,
independently of one another, from the group consisting of H, optionally substituted alkyl
residues and optionally substituted alkyoxyalkyl residues.
Accordingly, the present invention also relates to an analytical aid, as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure, which comprise groups of
structure (I), wherein R is
(O) R
a b c
and wherein R , R and R , independently of one another, are selected from the group
consisting of H, optionally substituted alkyl residues and optionally substituted
alkyoxyalkyl residues.
The present invention also relates to a method of production of an analytical aid, and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the nanoparticles comprise groups of structure (I), wherein R
is
(O) R
a b c
and wherein R , R and R , independently of one another, are selected from the group
consisting of H, optionally substituted alkyl residues and optionally substituted
alkyloxyalkyl residues.
The following preferred groups may be mentioned as examples of the residues R , R or
Examples of silica nanoparticles modified with groups of structure
Si (O) R
are those that are for example modified with the following silanes: octyltriethoxysilane,
methyltrimethoxysilane, methyltriethoxysilane, methyltriisopropoxysilane, isocyanate
silane, beta-(3,4-epoxycyclohexyl)-ethyl-trimethoxysilane; epoxy-silanes or silanes that
have a glycidoxy- and/or a glycidoxypropyl group, such as gamma-
glycidoxypropyltrimethoxysilane, gamma-glycidoxypropyltriethoxysilane, gamma-
glycidoxypropylmethyldiethoxysilane, 3-glycidoxypropyl-hexyltrimethoxysilane, beta-
(3,4-epoxycyclohexyl)-ethyltriethoxysilane, silanes that contain a vinyl group, such as
vinyltriethoxysilane, anhydride silanes, i.e. silanes that bear a cyclic organic anhydride unit
e.g. succinic anhydride or maleic acid anhydride, and hydrolysis products thereof, and/or
aminosilanes such as 3-aminopropyltri(m)ethoxysilane and di-triaminosilanes.
a b c
Especially preferably, R , R and R , independently of one another, are selected from the
group consisting of H, alkyl and groups of the following formulae:
wherein the alkyl group is more preferably methyl or ethyl, and especially preferably is
ethyl.
Quite especially preferably, p and n are 1 and m = 0 and R and R are methyl or ethyl,
preferably, ethyl, and R is more preferably
Accordingly, the present invention also relates to an analytical aid, as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure, wherein the group of
formula (I) has a structure of formula (Ia) or (Ib):
(Ia) (Ib)
The present invention also relates to a method of production of an analytical aid, and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the group of formula (I) has a structure of formula (Ia) or (Ib):
(Ia) (Ib)
and wherein R and R , independently of one another, are selected from the group
consisting of H and alkyl, preferably H, methyl and ethyl.
Said nanoparticles are obtainable for example under the name Bindzil CC30 or CC301
and CC40 or CC401 (EKA Akzo Nobel).
If the nanoparticles contain groups of formula (I), in which R is
(O) R
then preferably 10 to 50% of all groups R of the groups present in the silicon nanoparticle
Si OR
have the structure of formula
(O) R
.
The remaining 50% to 90% of the groups R contained in the nanoparticle are H and/or a
metal-containing ion and/or
R N R
depending on which counter-ion was used for stabilizing the nanoparticles. Preferably, the
remaining groups R, as described above, are H and/or Na .
Accordingly, the present invention also relates to an analytical aid, as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure, which comprise groups of
structure
Si OR
wherein preferably 5 to 50% of all groups R have a structure of formula
(O) R
The present invention also relates to a method of production of an analytical aid, and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the nanoparticles have groups of structure
Si OR
and wherein preferably 5 to 50% of all groups R have a structure of formula
(O) R
Groups of structure (II)
According to another embodiment of the invention, the silica nanoparticles have,
additionally or alternatively to the groups of formula (I), groups of formula (II)
In particular, the nanoparticles have either groups of formula (I) or groups of formula (II),
i.e. when the nanoparticles have groups of formula (I), preferably they have no groups of
formula (II), and vice versa.
M is a metal, preferably a trivalent metal, more preferably aluminium. Especially
preferably, M is accordingly aluminium or M = Al .
Accordingly, the present invention also relates to an analytical aid, as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure and the nanoparticles
comprise groups of structure (IIa)
Al A
.
The present invention also relates to a method of production of an analytical aid, and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the nanoparticles comprise groups of structure (IIa)
Al A
With regard to the chemical nature of the anion A , there are no restrictions in this respect,
provided that the anion is physiologically compatible and does not falsify the result when
the analytical aid is used. Preferred anions are for example chloride, bromide, iodide,
sulphate, hydrogen sulphate, phosphate and hydrogen phosphate. Especially preferably, A
is chloride.
Accordingly, the present invention also relates to an analytical aid, as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure and the nanoparticles
comprise groups of structure (IIa)
Al Cl
The present invention also relates to a method of production of an analytical aid, and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the nanoparticles comprise groups of structure (IIa)
Al Cl
Nanoparticles containing groups of structure (IIa) are obtained for example by treatment of
nanoparticles with aluminium chloride. Such nanoparticles are obtainable for example as
Bindzil CAT (Akzo Nobel).
Silica structure
The nanoparticles have a silica structure, wherein it is preferably amorphous silica.
Furthermore, in addition to Si and O and the groups R or M , the nanoparticles can have
further foreign atoms. These foreign atoms can be for example Sn, Ti, Zr, Hf, Ge, In, Ga,
P, Al or B. If present, the foreign atoms replace one or more Si atoms in the silica
structure.
According to one embodiment of the invention, the nanoparticles contain aluminium as
foreign ion.
Accordingly, the present invention also relates to an analytical aid, as described above,
comprising a surface coated at least partially with a hydrophilic coating, wherein the
hydrophilic coating contains nanoparticles with silica structure, wherein the silica structure
of the nanoparticles has at least one foreign atom, selected from the group consisting of Sn,
Ti, Zr, Hf, Ge, In, Ga, P, Al and B, preferably wherein the foreign atom is Al.
The present invention also relates to a method of production of an analytical aid, and an
analytical aid producible by said method, wherein the analytical aid is coated in step (b)
with a mixture G comprising at least one dispersant and nanoparticles with silica structure,
as described above, wherein the silica structure of the nanoparticles has at least one foreign
atom, selected from the group consisting of Sn, Ti, Zr, Hf, Ge, In, Ga, P, Al and B,
preferably wherein the foreign atom is Al.
If the silica structure of the nanoparticles contains at least aluminium, then the
nanoparticles contain aluminium preferably in an amount in the range from 0.1 to 10 wt.%,
relative to the total weight of the nanoparticle.
Methods of production of the analytical aid
Regarding the coating of the analytical aid by bringing the analytical aid into contact with
mixture G in step (b) of the method described above, said coating can be carried out by all
methods known by a person skilled in the art. The bringing into contact preferably takes
place by dip coating and/or spray coating and/or contact coating. Alternatively or
additionally, however, numerous other methods may be considered. For example, a method
can be applied, selected from: dip coating, spray coating, spin coating, a pressing process,
a knife process or a dropping process. However, combinations of the stated methods and/or
other methods can basically also be used.
Mixture G
Regarding the mixture used in step (b), G contains, as described above, in addition to
nanoparticles, at least one dispersant. The nanoparticles are preferably dispersed or are in
the form of a colloidal solution in the at least one dispersant.
The at least one dispersant is preferably water.
Mixture G can furthermore contain at least one solvent, for example at least one organic
solvent, preferably a polar organic solvent, more preferably a polar, protic organic solvent,
more preferably an alcohol. According to a preferred embodiment, the at least one organic
solvent is miscible with water. Especially preferably, the at least one organic solvent is a
solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol,
methoxymethanol, methoxyethanol and ethylene glycol. If G contains at least one organic
solvent, the solvent mixture preferably contains at most 50 vol.% of the organic solvent,
more preferably in an amount in the range from 0.1 vol.% to 30 vol.%, more preferably in
the range from 1 vol.% to 20 vol.%, and especially preferably in the range from 1.5 vol.%
to 5 vol.%, relative to the total volume of mixture G.
Accordingly, the present invention also relates to a method of production, as described
above, and an analytical aid, producible or produced by said method, wherein mixture G
furthermore contains at least one solvent in an amount of at most 50 vol.%.
Regarding the amount of nanoparticles in mixture G, mixture G contains the nanoparticles
preferably in an amount in the range from 0.01 wt.% to 5 wt.%, preferably in an amount in
the range from 0.02 wt.% to 3 wt.%, more preferably from 0.05 wt.% to 2 wt.%, relative to
the total weight of mixture G.
Accordingly, the present invention also relates to a method of production of an analytical
aid, as described above, and an analytical aid, producible or produced by this method,
wherein mixture G contains the nanoparticles preferably in an amount in the range from
0.01 wt.% to 5 wt.%, relative to the total weight of mixture G.
Preferably mixture G consists essentially of the at least one dispersant and the
nanoparticles with silica structure. "Essentially" means that the mixture has further
constituents, such as impurities, in an amount of at most 1 wt.%, preferably in an amount
of at most 0.1 wt.%.
If the coating in step (b) takes place by dip coating, as described above, the dwell time of
the analytical aid immersed in mixture G is preferably max. 5 minutes, more preferably
max. 2 minutes, more preferably max. 1 minute, for example in the range from 1 s to 30 s.
The method described above for production of the analytical aid additionally comprises,
apart from the steps described above
(c) drying the analytical aid obtained according to (b).
Drying means, in the context of the invention, that dispersant present on the analytical aid
and any other solvent present is removed essentially completely, preferably completely.
Drying can be carried out in a drying cabinet at a predetermined temperature of preferably
to 150 degrees Celsius, especially preferably from 20 to 120 degrees Celsius and quite
especially preferably from 20 to 80 degrees Celsius. Additionally or alternatively to this,
drying can take place by flow of a gas, for example air, through the analytical aid.
Alternatively or additionally to this, drying can also take place by storage of the coated
analytical aid in air or in an inert atmosphere at a temperature in the range from 20 to 150
degrees Celsius, preferably at a temperature in the range from 20 to 80 degrees Celsius,
more preferably at room temperature.
Step (c) can, according to one embodiment of the invention, also include an additional
washing step. In this case the analytical aid obtained according to (b) is first dried, as
described above, the analytical aid is then washed with a solvent or solvent mixture,
preferably with water, wherein washing is preferably carried out for a time of max. 1
minute, for example in the range from 1 s to 30 s. Following this optional washing step, the
analytical aid is preferably dried again, wherein in the second drying step, the solvent or
solvent mixture that was used for washing and is present on the analytical aid, is removed
essentially completely, preferably completely. The drying steps can be carried out in the
same way or differently. Preferably, no washing step is carried out in (c).
The analytical aid obtained according to (c), is preferably sterilized in another step (d).
Sterilization preferably uses irradiation with gamma radiation and/or beta radiation.
Further possibilities that can be employed alternatively or additionally are steam
sterilization and/or autoclaving and/or chemical sterilization, for example with ethylene
oxide (EtO). Generally, for example at least one sterilization method can be used, selected
from the group consisting of: radiation sterilization, in particular with gamma radiation
and/or beta radiation, thermal sterilization, in particular dry thermal sterilization and/or
steam sterilization, chemical sterilization with at least one germicidal medium, in particular
a gaseous and/or liquid germicidal medium.
For example, the analytical aids according to the invention can be packed in suitable
containers, for example plastic bags, wherein packing can be effected for example by heat
sealing. The sterilization according to (d) takes place in particular after packing or heat
sealing of the analytical aids, in particular by irradiation with gamma radiation.
Especially preferably, the analytical aid is treated before step (b) with at least one etchant
and/or plasma.
Accordingly, the present invention also relates to a method, as described above, and an
analytical aid producible or produced by said method, wherein the surface of the analytical
aid to be coated is treated before step (b) with at least one etchant and/or with plasma.
According to one embodiment, the analytical aid can be etched with an etchant before, for
example shortly before step (b). "Shortly before" means, in the context of the present
invention, a time interval preferably not exceeding 12 hours, in particular 8 hours,
especially preferably 1 hour and in particular 10 minutes. Thus, for example a freshly
etched analytical aid is used in step (b). A freshly etched analytical aid means an analytical
aid that has been etched lightly on the surface with an etchant shortly before the treatment
with mixture G. It is freshly etched if the time that elapses between the etching of the
analytical aid and the treatment of the analytical aid with mixture G is preferably max. 0 to
12 hours, especially preferably 0 to 8 hours and quite especially preferably 0 to 4 hours, in
particular even 0 to 1 hour or even not more than 10 minutes. If the respective time limits
are observed, we have a freshly etched analytical aid in the sense of the present invention.
The analytical aid, optionally etched and then optionally washed with water, is kept in this
interval between etching and coating, preferably for example in water, optionally provided
with a stabilizer. Optionally, the analytical aid is dried before step (b). Regarding the
conditions for drying, reference should be made to the foregoing. Etching is preferably
carried out with an etchant that comprises nitric acid or an iron(III) chloride solution and
hydrochloric acid.
If nitric acid is used, preferably 20- to 40-wt.% nitric acid is used, especially preferably 25-
to 35-wt.% and quite especially preferably 30- to 34-wt.% nitric acid.
According to another embodiment, the surface to be coated, optionally the surface etched
as described above, of the analytical aid is treated with plasma shortly before step (b).
Thus, preferably an analytical aid freshly treated with plasma is used in step (b). An
analytical aid freshly treated with plasma means an analytical aid that was treated with
plasma shortly before the treatment with mixture G. It is freshly treated with plasma if the
time interval between treatment of the analytical aid with plasma and treatment of the
analytical aid with mixture G is preferably max. 0 to 12 hours, especially preferably 0 to 8
hours and quite especially preferably 0 to 4 hours, in particular even 0 to 1 hour or even
not more than 10 minutes.
Hydrophilic coating
The term "hydrophilic coating", as used in the context of the present invention, means a
coating whose surface has, in comparison with the uncoated surface of the analytical aid, a
smaller contact angle with water, preferably at least 15° smaller, preferably measured
according to DIN 55660.2. In principle, measurement according to DIN EN 828:1997
would also be suitable. Preferably the surface of the coating has a contact angle with water
of less than 60°, preferably of less than 50°, more preferably of less than 40°, and
especially preferably of less than 30°, preferably measured according to DIN 55660.2 with
DIN EN 828:1997 again also being suitable, in principle.
Regarding the quantity of nanoparticles on the surface of the analytical aid, the analytical
aid is preferably coated with a quantity of nanoparticles in the range from 7.5 µg per mm
of surface area of the analytical aid to 150 ng per mm of surface area of the analytical aid.
Preferably at least 90 wt.%, more preferably at least 95 wt.%, more preferably at least
96 wt.%, more preferably at least 97 wt.%, more preferably at least 98 wt.%, more
preferably at least 99 wt.%, more preferably at least 99.5 wt.%, more preferably at least
99.9 wt.%, more preferably 100 wt.%, of the hydrophilic coating consists of nanoparticles
with silica structure.
In the context of the invention, the coatings can contain mixtures of different nanoparticles.
Preferably the coatings contain only nanoparticles of one structure.
In the context of the invention, the surface of the analytical aid can be coated partially or
completely with the hydrophilic coating. Preferably, the surface that faces the sample when
using the analytical aid is coated at least partially or completely. Preferably at least 80%,
more preferably at least 90%, more preferably at least 95%, more preferably at least 98%,
and especially preferably at least 99% of the surface is coated.
If the analytical aid is for example a needle element, for example with at least one internal
space, in particular at least one cannula and/or at least one capillary, then preferably the
whole surface of the internal space of the needle element is provided with a hydrophilic
coating, and especially preferably at least one capillary-active surface structure from a tip
of the needle element up to an optional contact point of the needle element with at least
one optional testing element, for example with at least one test chemistry for detecting at
least one analyte in a body fluid.
Surface of the analytical aid
Regarding the chemical nature of the analytical aid, its surface preferably consists at least
partially of a metal and/or a metal alloy and/or a metal oxide and/or a metal oxide mixture.
This means that the analytical aid consists per se of a metal and/or a metal alloy and/or a
metal oxide and/or a metal oxide mixture or that the analytical aid is produced at least
partially from another material and this material has been coated at least partially with a
metal and/or a metal alloy and/or a metal oxide and/or a metal oxide mixture.
According to one embodiment, the analytical aid accordingly comprises a coating of metal
and/or a metal alloy and/or a metal oxide and/or a mixed metal oxide and/or a mixed metal
oxide.
The coating of metal and/or a metal alloy and/or a metal oxide and/or a mixed metal oxide
and/or a mixed metal oxide can be applied in any known way, for example by sputtering,
vacuum metallization, galvanic coating or deposition from dissolved metal compounds.
Moreover, several layers of metal and/or a metal alloy and/or a metal oxide and/or a mixed
metal oxide and/or a mixed metal oxide can also be applied.
According to one embodiment of the invention, the analytical aid can, for example in the
case when the analytical aid, as described below, is a testing element or distributing
element, be coated by vacuum metallization, for example with aluminium. The analytical
aid thus obtained is then converted for example by oxidation to a metal oxide and/or a
mixed metal oxide, in particular to boehmite. The oxidation is effected for example with
water, alkali-metal or alkaline-earth metal hydroxides, oxygen, hydrogen peroxide, ozone,
heat in the presence of the oxygen of the air or sulphur compounds. The metallic surface is
in this case at least partially oxidized, for example by the boehmite process with hot water
and/or steam.
If such a coating is applied, then this coating containing metal and/or metal alloy and/or
this coating containing metal oxide and/or mixed metal oxide and/or this coating
containing mixed metal oxide is preferably applied on the analytical aid before step (b).
Accordingly, the present invention also describes a method of production of an analytical
aid, comprising a surface coated at least partially with a hydrophilic coating, and an
analytical aid produced or producible by said method, wherein step (a) of the method
described above comprises:
(a) providing the analytical aid, wherein provision comprises the coating of the
analytical aid with a metal and/or a metal alloy and/or a metal oxide and/or a mixed
metal oxide and/or a mixed metal oxide.
If the analytical aid is a needle element, the analytical aid is preferably not coated with a
metal and/or a metal alloy and/or a metal oxide and/or a mixed metal oxide and/or a mixed
metal oxide.
In the case when the nanoparticles comprise groups of structure (I)
Si OR
in which R is a metal-containing ion, or is
according to a preferred embodiment of the invention the nanoparticles are de-ionized
before step (b). In this de-ionizing, the nanoparticles, containing the groups of structures
are converted to nanoparticles with groups of structure
Si OH
The de-ionizing can generally take place by all methods known by a person skilled in the
art. Preferably the de-ionizing is effected by ion exchange chromatography or by bringing
into contact with an acidic ion exchange material.
The present invention therefore relates to a method of production of an analytical aid, and
an analytical aid producible by said method, the method comprising the following steps:
(a) providing the analytical aid,
(a1) providing nanoparticles with silica structure, which have an average particle size,
determined according to DIN ISO 22412:2008, in the range from 1 to 500 nm,
wherein the nanoparticles have groups
Si OH
by de-ionizing nanoparticles with silica structure, wherein the nanoparticles have
groups of structure
w x y z
wherein R , R , R and R , independently of one another, are selected from H and
alkyl,
(b) coating the analytical aid by bringing the analytical aid into contact with a mixture G
comprising at least one dispersant and the nanoparticles obtained according to (A1)
(c) drying the analytical aid obtained according to (b), and
(d) optionally sterilizing the analytical aid obtained according to (c),
wherein the bringing into contact in (b) preferably takes place by dip coating and/or spray
coating and/or contact coating and/or at least one other of the aforementioned methods, and
wherein the analytical aid and/or the surface of the analytical aid preferably consists at
least partially of a metal and/or a metal alloy and/or a metal oxide and/or a mixed metal
oxide and/or a mixed metal oxide.
Accordingly, the present invention preferably also relates to an analytical aid, as described
above, comprising a surface coated at least partially with a hydrophilic coating, wherein
the hydrophilic coating contains nanoparticles with silica structure, wherein the
nanoparticles contain groups of structure
Si OH
Analytical aid:
The term "analytical aid", as used in the context of the present invention, generally means
an element, by means of which or with the aid of which at least one property of at least one
sample can be determined. Basically, in this respect any analytical aids may be considered,
for example rigid analytical aids or also deformable analytical aids. The analytical aid can
in particular consist completely or partially of a material selected from the group consisting
of a metal, a metal oxide, a paper, a ceramic, a plastic and a textile material such as for
example cellulose or synthetic fibres. Combinations of the aforementioned materials and/or
other materials are also conceivable.
In particular, the analytical aid can be an analytical aid for qualitative and/or quantitative
analysis of samples.
The sample can in particular be a liquid or gaseous sample. Especially preferably the
sample comprises at least one body fluid or portions thereof, in particular blood or blood
constituents, interstitial fluid, saliva or urine.
The at least one property can basically be any chemical, physical or biological property.
Especially preferably, the at least one property comprises a concentration of at least one
analyte in the sample, in particular of at least one metabolite, for example glucose, lactate
or cholesterol.
Especially preferably, the analytical aid is therefore an analytical aid that can be used in the
context of detecting at least one analyte in a liquid, in particular a body fluid. In particular,
the analytical aid can be an analytical aid that can be used during sampling, for example
when collecting a sample of a body fluid, and/or during analysis of the sample, for
example in the detection of at least one analyte in a body fluid. In particular, the analytical
aid can accordingly be an analytical aid or a part of an analytical aid for qualitative and/or
quantitative analysis of blood and/or interstitial fluid.
Especially preferably, the analytical aid is suitable for measuring and/or for the qualitative
and/or quantitative detection of at least one analyte of the body fluid, for example of the
blood and/or of the interstitial fluid, for example sugar, preferably glucose, lipids,
metabolic products, e.g. urea or uric acid, proteins, peptides and salts, or other constituents
of the blood or of the interstitial fluid. At least one analyte to be detected can be for
example at least one metabolite, for example blood glucose, lactate, cholesterol or other
metabolites.
Regarding the nature of the analytical aid, all analytical aids known by a person skilled in
the art are included. Preferably the analytical aid is selected from the group consisting of a
needle element, a testing element for detecting at least one analyte in a liquid, and
optionally a distributing element for distributing a sample of a body fluid that has been
collected.
Testing element
"Testing element" means, in the context of the present invention, all carrier-bound
elements for detecting at least one analyte in a liquid. A testing element can in principle be
intended for detecting at least one analyte for medical or non-medical purposes. These
carrier-bound testing elements preferably comprise one or more layers, containing at least
one detection reagent for detecting the at least one particular analyte of interest. Preferably
these detection reagents are incorporated in corresponding layers of a carrier. Bringing the
testing element and in particular the detection reagent in contact with the liquid leads, in
the presence of the at least one analyte to be detected, which can also be called the target
analyte, to a detectable change, for example of a physical and/or chemical nature, for
example with formation of covalent, non-covalent or complex bonds between the detection
reagent and the target analyte. This preferably leads to a measurable signal, for example an
electrical signal and/or a colour change, preferably to a measurable optical signal, which
can for example be evaluated visually or by means of equipment, for example by reflection
photometry or fluorescence photometry.
Regarding the outward appearance of the testing element, all outward appearances familiar
to a person skilled in the art are included in the context of the invention. In particular the
testing element can be a test strip, a test tape or a test disk. Without restriction of further,
alternatively or additionally usable embodiments, in particular flat, strip-shaped testing
elements, i.e. test strips, are described in the following.
In addition to the at least one detection reagent, which can carry out at least one analyte-
specific reaction, the testing element, in particular at least one test field of the testing
element, can contain further substances, for example carriers, excipients, pigments, fillers,
buffer substances or similar. In the following, no distinction will be made between further
substances that also participate in the reaction for detecting the analyte, and the actual
detection reagent. In particular, the detection reagent can comprise an enzymatic detection
reagent. As examples of glucose-specific enzymatic detection reagents of this kind, we
may mention oxidoreductase enzymes (e.g. GlucDOR/PQQ), dehydrogenase enzymes,
oxidase enzymes or similar enzymes, for example glucose oxidase (GOD) or glucose
dehydrogenase.
The at least one detectable reaction is, as already noted, preferably an optically detectable
reaction. However, other types of reactions are basically possible. In particular, it can be a
reaction in which, if the at least one target analyte is present, at least one detection
substance is formed. Several detection substances can also be formed and/or used, which
can be detected individually, in groups or all of them. Detection substances are thus
substances that form as a result of the at least one detection reaction and/or take place in
the at least one detection reaction and are detectable. Based on the at least one detection
substance that is detected, for example the at least one analyte can be detected
quantitatively and/or qualitatively. However, detections and/or detection substances are
also possible, for which detection of the at least one detection substance is not used or is
not only used for detection of the analyte, but alternatively for example for determining the
volume layer of the sample thickness above the test field, as will be described below.
Preferably, the test chemistry described above for the detection of at least one target
analyte with at least one detection reagent is not sensitive to the hydrophilic coating. This
ensures that if traces of the hydrophilic coating become detached when using the analytical
aid, the testing element can be contaminated without affecting the test chemistry.
Therefore, owing to the insensitivity of the test chemistry to the coating, the test for
detection of the target analyte is not, or is only insignificantly, falsified by traces of the
compound of formula (I) or degradation products thereof. Preferably, during use for
determination, essentially no, more preferably no, proportion of the hydrophilic coating
becomes detached from the analytical aid.
Regarding the structure of the testing element, this has preferably at least one carrier
element, in particular a carrier strip. This carrier element can comprise for example a
plastic material, a ceramic material, a paper material, a composite material or similar. The
test field can then be applied on this carrier element. The carrier element can be used for
providing a mechanically supporting function for the testing element, for example to
enable the testing element to be held during sample application and/or during a
measurement. The at least one hydrophilic coating can for example be applied completely
or partially on the carrier element and/or in particular on the test chemistry and/or on one
or more other elements of the testing element.
The carrier element can for example comprise at least one film element, in particular at
least one plastic film. The film element preferably has a closed surface, which preferably is
essentially impermeable to the sample. Preferably the film element is of non-porous
design, has a non-porous surface or has pores with an average pore radius of not more than
μm, preferably of not more than 1 µm. Therefore the film element differs for example
from conventional network-like materials, for example spreading networks. Generally the
carrier element and/or the carrier surface can have at least one material that is essentially
impermeable to the sample.
Distributing element
A distributing element is to be understood, in the context of the invention, as a device with
which a sample received, in particular a liquid sample, can be distributed over a two-
dimensional distribution region and/or a three-dimensional distribution volume. In
particular, for uniform, extensive and rapid distribution of the sample to be analysed,
preferably small blood samples, the distributing element can preferably be arranged on
testing elements, for example test strips, in particular glucose test strips.
The distributing element can in particular be selected from the group consisting of a
capillary structure, a membrane, a network, in particular a spreading network. Preferably,
in the context of the invention, the distributing element is a spreading network. A
membrane is to be understood, in the context of the present invention, as a porous element,
for example a porous film or porous layer, which is arranged in order to take up the sample
and distribute it preferably laterally, i.e. parallel to a plane of the film or layer. In particular
the membrane can comprise at least one porous plastic film. The term "spreading network"
is to be understood, in the context of the present invention, expressly as a generic term for
all filament structures suitable for purposes of spreading or distribution or transfer. This
includes, among others, textiles, knitted fabrics and fleeces. The term "filament" comprises
both mono- and poly-filaments of uniform or non-uniform material basis and
dimensioning. It should be mentioned that sample transfer preferably takes place through
the filament structure.
According to a preferred embodiment, the membrane and/or the spreading network lie on
at least one layer of a testing element, for example a detection layer of the testing element,
containing the at least one detection reagent, and/or a separating layer, containing at least
one reflecting pigment and/or at least one substance that is arranged for separating sample
constituents, for example red blood cells. The sample liquid applied can thus be led for
example by the spreading network envisaged according to the invention, by capillary
action to the layer containing the at least one detection reagent and, at the points of contact
of the spreading network and detection layer, can be spread or distributed, also by capillary
forces, on the detection layer. The spreading network therefore serves preferably as an aid
for undirected (isotropic) two-dimensional distribution of a liquid sample at the target
location, namely on the at least one layer containing the at least one detection reagent. The
desired intermediate storage and superficial spreading of the sample only occur in
interaction with the spreading network, with the spreading network demarcating, with
respect to the detection layer, a large number of varying capillary-active interstices or
capillary gaps, which owing to the surface contour of the filaments and the spatial
arrangement thereof, are largely undirected overall.
As described above, the surface of the analytical aid preferably comprises a metal and/or a
metal alloy and/or a metal oxide and/or a mixed metal oxide. Accordingly, the analytical
aid, according to a preferred embodiment, is a distributing element comprising a surface
consisting of a metal and/or a metal alloy and/or a metal oxide and/or a mixed metal oxide.
Preferably, in the context of the invention, the analytical aid is a distributing element, for
example a spreading network, which can be coated with a metal and/or a metal alloy and/or
a metal oxide and/or a mixed metal oxide, as described above.
Accordingly, the present invention also relates to an analytical aid, wherein the analytical
aid is a spreading network, optionally coated with a metal and/or a metal alloy and/or a
metal oxide and/or a mixed metal oxide.
Needle element
According to an alternative preferred embodiment, the analytical aid is a needle element or
comprises said needle element. In this case, a needle element can basically be any element
with a tip or blade, which is arranged for producing an opening in a portion of a user's skin.
For example, a lancet, a cannula, in particular a hollow cannula, an at least partially open
hollow cannula, a microcutter or the like, a capillary, in particular a capillary gap, can be
used as the needle element.
If the needle element is a lancet, the lancet can in particular comprise a so-called
microsampler, i.e. an element that has both a tip and/or blade for producing a puncture and
at least one capillary channel for taking up the sample. Furthermore, the microsampler can
optionally have at least one testing element for detecting at least one analyte in the sample.
In general, the needle element can have at least one capillary-active surface structure,
which is also simply called capillary structure in the following and which need not
necessarily be arranged completely on a surface of the needle element. In particular the
capillary structure can have at least one capillary channel and/or at least one capillary
trough. Owing to the capillary action of the surface structure, the body fluid flowing from
the puncture site can be taken up by the capillary structure and for example be transported
to a testing element arranged on the needle element. The capillary structure can provide a
receiving volume, for example for receiving an amount of body fluid required for one or
more tests. Said surface structure can be formed by at least one capillary trough running
parallel and/or at least partially transversely to the longitudinal axis of the needle element.
In the case of capillary troughs running parallel to the longitudinal axis of the needle
element, a number of said capillary troughs from 2 to 6, in particular 2 or 3, is preferred.
However, it is also possible, for example, for up to 10 capillary troughs to be formed on the
needle element. In the case for example of a hollow cannula, the capillary structure is
formed by the hollow shape of the cannula.
In particular the possibility of targeted uptake and/or targeted transport of body fluid out of
or from the puncture site is advantageous in the design of said capillary structures. For
example, transport can take place to at least one testing element, for example to at least one
testing element arranged on or arrangeable on the needle element or to the needle element.
The testing element can be arranged fixed to the needle element and/or the capillary
structure, but it can also be mounted movably to these, for example so that after uptake of
the body fluid into the capillary structure, the testing element is moved towards the
capillary structure. Advantageously, the hydrophilic coating and/or a plasma treatment
and/or formation of nano- and microstructures at least in the capillary troughs, but also on
the whole surface, additionally contribute to the capillary action.
Hydrophilic coating of the needle element can be complete or also partial. Preferably the
whole surface of the needle element is provided with a hydrophilic coating, and especially
preferably the at least one capillary-active surface structure from the tip of the needle
element to the needle element/testing element contact point.
If for example a body fluid is taken up with the needle element, the body fluid is preferably
transported along the needle element within 30-1000 ms per millimetre of transport
distance from the puncture site to the testing element, especially preferably within 40-700
ms/mm of transport distance and quite especially preferably within 40-400 ms/mm of
transport distance. The term transport distance means the distance that is travelled,
preferably can be travelled as a maximum, in the needle element by the sample that is
taken up. The total transport distance can for example have a length from 0.5 mm to
mm, in particular 1 mm to 5 mm. For example, the transport distance can be a total
length of a capillary, for example a capillary gap, in the needle element. Alternatively or
additionally, the term transport distance can also refer to the length of the needle element
from a tip to a discharge opening, for example in the case of a cannula. At least one testing
element with at least one test chemistry for detecting the analyte can be provided, which
can be completely or partially a constituent of the needle element, but which can also be
formed completely or partially separately from the needle element. If the testing element is
not a constituent of the needle element, transfer of the body fluid from the needle element
can also take place with a time delay after uptake of the body fluid by the needle element.
Until this transfer, for example a further period of time can elapse, for example a period
from 0.5 s to 5 s after commencement of puncture and/or after retraction of the needle
element from the body tissue, in particular a period from 1 s to 2 s.
Preferably the analytical aid is a needle element of a sampling device for collecting a body
fluid.
Accordingly, the present invention also relates to an analytical aid, as described above,
wherein the analytical aid is a needle element of a sampling device for collecting a body
fluid. The present invention further relates to a method of production of an analytical aid,
as described above, and an analytical aid, producible or produced by this method, wherein
the analytical aid is a needle element of a sampling device for collecting a body fluid.
The present invention further relates to a sampling device for collecting a body fluid. A
sampling device is generally to be understood as a device that is arranged for taking up a
sample for the purpose of an analysis. Preferably, moreover, the sampling device is also
arranged for generating the sample, for example by making a puncture and/or cut in a skin
surface, for example using at least one needle element. Alternatively or additionally, the
sampling device can also be arranged for detecting at least one analyte in the sample, for
example by means of at least one testing element, for example according to one or more of
the embodiments described above.
The sampling device comprises at least one analytical aid with at least one surface coated
at least partially with a hydrophilic coating, according to one or more of the embodiments
described above, with the proviso that the analytical aid is selected from the group
consisting of a needle element and a testing element. With respect to the possible
embodiments of the needle element and/or of the testing element, reference may be made
to the above description and to the embodiments described hereunder. The needle element
can in particular comprise at least one microsampler, which is provided completely or
partially with the at least one coating, in particular in the region of a capillary structure.
The testing element can in particular comprise at least one distributing element provided
with the hydrophilic coating, preferably at least one spreading network provided with the
hydrophilic coating, which can for example be located on at least one test field of the
testing element.
The sampling device can thus, as described above, have at least one needle element for
taking a sample of a body fluid and/or at least one testing element, with which at least one
analyte in the respective body fluid can be detected qualitatively and/or quantitatively. The
testing element can in particular be connected to the needle element, so that the body fluid
can travel from the needle element to the testing element, for example a sample application
point or a sample application surface of the testing element. Alternatively or additionally,
however, the testing element can also be arranged as a separate testing element or can be
applied in some other way in or on the sampling device, for example in at least one
chamber, in which for example the needle element can also be located. A transfer
mechanism can be provided, which transfers the body fluid taken up by the needle element
to the testing element. This can take place for example in that, by means of an actuator or
some other mechanism, the needle element with the body fluid is brought closer to the
testing element, so that the body fluid is transferred at least partially from the needle
element to the testing element, for example a test field of the testing element. For example,
for this purpose the needle element and/or at least one capillary structure of the needle
element can be placed on the test field. However, other embodiments are also possible. So
that the body fluid can pass from the capillary-active surface structure into the testing
element, the testing element is preferably to be constructed, at a connecting point between
testing element and surface structure, so that the body fluid is transferred by suction from
the surface structure into the testing element. For this, it is desirable for the testing element
to be provided with a capillary-active component, e.g. an absorbent fleece or a fibre
bundle, whose capillary action is greater than the capillarity of the surface structure.
Alternatively or additionally, however, it can also simply be designed so that the capillary
is brought into contact with the chemistry, for example by placing the capillary on the
chemistry, optionally also with application of pressure. Moreover, contact should be
ensured between the surface structure of the cannula and the capillary-active component of
the testing element.
Moreover, the sampling device can have at least one sensor. This sensor can for example
be of electrochemical and/or optical design. In the case of an electrochemical sensor,
through catalytic action of the test chemistry, a substance of the body fluid that is to be
determined can be reacted and this reaction can be measured electrochemically, whereas in
the case of an optical sensor, a product of reaction of the test chemistry with a substance
contained in the body fluid is irradiated with light of a defined wavelength and for example
a degree of absorption of this light and/or a degree of reflection of the light and/or the
fluorescence of the sample are measured.
Furthermore, the sampling device can be equipped with a conducting element, in particular
an electrical conducting element. In the case of an electrochemical sensor, this conducting
element can be a metal layer applied on a plastic film, and/or a metal foil or a metal wire,
which is optionally injected into the respective component, e.g. by an injection moulding
process. The conducting element can also be formed from conductive plastic or in some
other way, for example by means of conductive ink. The sampling device can also have at
least one electrical and/or optical contact point, via which the sampling device can be
coupled to peripheral equipment. Thus, the sampling device can be supplied with current
via an electrical contact point and information can be transferred via said electrical contact
point. Light can be transferred between peripheral equipment and the sampling device via
an optical contact point. In the case of an optical sensor, said sampling device can be
equipped both with an electrical and with an optical contact point.
Preferably, the sampling device can be designed completely or partially as a disposable
article and/or a multi-use article, wherein in the case of a disposable article, the sampling
device is disposed of after a single use, whereas in the case of a multi-use article, multiple
use is intended. Magazining of one or more sampling devices and/or of parts thereof is also
conceivable, similar for example to the magazining of lancets in lancing aids, for example
by storing several sampling devices as a whole in a magazine and/or wherein a sampling
device contains for example several testing elements and/or several needle elements in
magazined form.
As described above, the analytical aid, preferably the needle element and/or the testing
element, can be produced at least partially from a metal and/or a metal alloy and/or a metal
oxide and/or a mixed metal oxide and/or a mixed metal oxide. Moreover, the material of
the needle element and/or of the testing element should be inert, in particular with respect
to the body fluid to be sampled, and biocompatible, and mechanically strong as well as
easy to sterilize. Preferably, the needle element can be made of surgical steel, wherein said
surgical steel can be provided with a coating of metal oxides. Alternatively or additionally
to a metallic material, the needle element can, however, completely or partially, also be
produced in another material or comprise another material, for example a plastic material
and/or a ceramic material. In particular, embodiments are also included within the scope of
the invention, in which the needle element per se, as described above, is coated with a
metal and/or a metal alloy and/or a metal oxide and/or a mixed metal oxide and/or a mixed
metal oxide, and the hydrophilic coating is applied on this surface, for example a surface of
this coating.
The analytical aid according to the invention and the methods according to the invention
have a multiplicity of advantages over known analytical aids and methods. Thus, we
surprisingly found the hydrophilic coating with nanoparticles of the kind described above
firstly to result in surface properties with excellent hydrophilicity. Secondly, the coating
surprisingly is distinguished by good long-term stability, thereby making it possible to
ensure stable storage over a relatively long period of time. More specifically, the
hydrophilic properties of the coating can be shown to be impaired only marginally, if at all,
even by direct or indirect contact with various materials of the analytical aid, such as
plastic materials, adhesives or metals for example. In addition, strain due to sterilization,
for example radiation strain caused by β rays and/or γ rays and/or strain due to chemical
disinfectants such as ethylene oxide, for example, also do not or only marginally impair the
hydrophilic properties of the coating. As a result, a long-term stability of 6-12 months or
more can be achieved without problem, while the hydrophilic surface properties are
maintained.
Moreover, the coating used according to the invention, is extremely resistant to
contaminations and itself does not contaminate a collected sample, for example.
Accordingly, the analytical aid may optionally also be used multiple times. More
specifically, a coating employed according to the invention may be employed in capillary
elements and/or channels of the analytical aid, with these elements having long-lasting
hydrophilicity due to the coating according to the invention.
Moreover, the coating used according to the invention can be prepared in a simple and
reliable manner, for example by using the method of the invention according to one or
more of the developments described above or the embodiments to be described in more
detail below. More specifically, the surface coating can be applied, for example, from an
aqueous solution and/or an aqueous dispersion. An application method of this kind can
easily be carried out.
The following embodiments are especially preferred in the context of the invention:
1. Analytical aid, comprising a surface coated at least partially with a hydrophilic
coating, wherein the hydrophilic coating contains nanoparticles with silica structure
and an average particle size, determined according to DIN ISO 22412:2008, in the
range from 1 to 500 nm and the nanoparticles comprise groups of structure (I) and/or
(II)
Si OR
(II)
wherein in each of the groups of structure (I), independently of one another, R is
selected from the group consisting of H, a metal-containing ion,
R N R
R (O) R
w x y z
and wherein R , R , R and R , independently of one another, are selected from H
and alkyl,
a b c
and wherein R , R and R , independently of one another, are optionally substituted
residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl,
cycloheteroalkyl, alkenyl and alkoxyalkyl,
and wherein n, m and p, independently of one another, are 0 or 1,
and wherein M is a metal ion and A is a physiologically compatible anion.
2. Analytical aid according to embodiment 1, wherein R is selected from the group
consisting of H, an alkaline-earth metal ion, an alkali metal ion,
R N R
R (O) R
and wherein M = Al .
3. Analytical aid according to embodiment 1 or 2, wherein the hydrophilic coating
comprises nanoparticles with silica structure, which comprise groups of structure (I),
and wherein R = H.
4. Analytical aid according to embodiment 1 or 2, wherein the hydrophilic coating
comprises nanoparticles with silica structure, which comprise groups of structure
wherein alkali metal is preferably a sodium ion or a potassium ion, and quite
especially preferably is Na .
. Analytical aid according to embodiment 1 or 2, wherein the hydrophilic coating
contains nanoparticles with silica structure, which have groups of structure (I), with
R = NH .
6. Analytical aid according to embodiment 1 or 2, wherein the hydrophilic coating
contains nanoparticles with silica structure, which have groups of structure (I),
wherein R has the following structure
Si R
7. Analytical aid according to one of the embodiments 1 to 6, wherein the silica
structure of the nanoparticles has at least one foreign atom, selected from the group
consisting of Sn, Ti, Zr, Hf, Ge, In, Ga, P, Al or B, preferably wherein the foreign
atom is Al.
8. Analytical aid according to one of the embodiments 1 to 7, wherein the nanoparticles
have an average particle size in the range from 1 to 100 nm, more preferably in the
range from 1 to 50 nm, more preferably in the range from 3 nm to 25 nm, and
especially preferably in the range from 5 to 15 nm.
9. Analytical aid according to one of the embodiments 1 to 8, wherein 10 to 40% of all
groups R are
Si (O) R
.
. Analytical aid according to one of the embodiments 1 to 9, wherein the group of
formula (I) has a structure of formula (Ia) or (Ib):
(Ia) (Ib)
wherein R and R , independently of one another, are selected from the group
consisting of H and alkyl.
11. Analytical aid according to one of the embodiments 1 to 10, wherein the hydrophilic
coating consists of the nanoparticles with silica structure.
12. Analytical aid according to one of the embodiments 1 to 11, wherein the surface of
the analytical aid coated at least partially with the hydrophilic coating consists at
least partially of a metal and/or a metal alloy and/or a metal oxide and/or a mixed
metal oxide.
13. Analytical aid according to one of the embodiments 1 to 12, wherein the
nanoparticles have an average particle size in the range from 1 to 100 nm and
wherein the hydrophilic coating has a thickness, in particular on average a thickness,
in the region of max. 500 nm, preferably of max. 300 nm and especially of max.
100 nm.
14. Analytical aid according to one of the embodiments 1 to 14, wherein the surface of
the hydrophilic coating has a contact angle with water of less than 60°, preferably
measured according to DIN 55660.2.
. Analytical aid according to one of the embodiments 1 to 15, wherein the analytical
aid is selected from the group consisting of a needle element, in particular a lancet, a
capillary, in particular a capillary gap, a cannula, a testing element for detecting at
least one analyte in a body fluid and a distributing element for distributing a sample
of a body fluid that has been collected, in particular a spreading network, optionally
coated with a metal and/or a metal alloy and/or a metal oxide and/or a mixed metal
oxide, or a plastic film, optionally coated with a metal and/or a metal alloy and/or a
metal oxide and/or a mixed metal oxide.
16. Analytical aid according to one of the embodiments 1 to 16, wherein the analytical
aid is a needle element (112) of a sampling device (110) for taking a sample of body
fluid.
17. Method of production of an analytical aid, comprising a surface that is coated at least
partially with a hydrophilic coating, wherein the method comprises:
(a) providing the analytical aid,
(b) coating the analytical aid by bringing the analytical aid into contact with a
mixture G comprising at least one dispersant and nanoparticles with silica
structure, which have an average particle size, determined according to DIN ISO
22412:2008, in the range from 1 to 500 nm,
wherein the nanoparticles comprise groups of structure (I) and/or (II)
Si OR
(II)
wherein in each of the groups of structure (I), independently of one another, R is
selected from the group consisting of H, a metal-containing ion,
R N R (O)
R Si
(O) R
w x y z
and wherein R , R , R and R , independently of one another, are selected from
H and alkyl,
a b c
and wherein R , R and R , independently of one another, are optionally
substituted residues, selected from the group consisting of H, alkyl, aryl,
heteroaryl, cycloalkyl, cycloheteroalkyl, alkenyl and alkoxyalkyl,
and wherein n, m and p, independently of one another, are 0 or 1,
and wherein M is a metal ion and A is a physiologically compatible anion,
(c) drying the analytical aid obtained according to (b), and
(d) optionally sterilizing the analytical aid obtained according to (c),
wherein the bringing into contact in (b) preferably takes place by dip coating and/or
spray coating and/or contact coating, and wherein the analytical aid and/or the
surface of the analytical aid preferably consists at least partially of a metal and/or a
metal alloy and/or a metal oxide and/or a mixed metal oxide and/or a mixed metal
oxide.
18. Method according to embodiment 17, wherein the surface of the analytical aid to be
coated is treated before step (b) with at least one etchant and/or with plasma or
corona.
19. Method according to embodiment 17 or 18, wherein the at least one dispersant is
water and wherein mixture G preferably has a pH in the range from 2 to 10.
. Method according to one of the embodiments 17 to 19, wherein the nanoparticles
comprise groups of structure (I), and wherein 10 to 40% of all groups R are
(O) R
21. Analytical aid, producible or produced by a method according to one of the
embodiments 17 to 20.
22. Analytical aid according to embodiment 21, wherein the analytical aid is a needle
element of a sampling device for collecting a body fluid.
23. Sampling device (110) for taking a sample of body fluid, containing at least one
analytical aid according to one of the preceding embodiments relevant to an
analytical aid, with the proviso that the analytical aid is selected from the group
consisting of a needle element (112) and a testing element.
24. Use of nanoparticles with silica structure and an average particle size, determined
according to DIN ISO 22412:2008, in the range from 1 to 500 nm as hydrophilic
coating (122) for a surface of an analytical aid, preferably as hydrophilic coating
(122) for a needle element (112) of a sampling device (110) for taking a sample of
body fluid, wherein the nanoparticles comprise groups of structure (I) and/or (II)
Si OR
(II)
wherein in each of the groups of structure (I), independently of one another, R is
selected from the group consisting of H, a metal-containing ion,
R N R
R Si
(O) R
w x y z
and wherein R , R , R and R , independently of one another, are selected from H
and alkyl,
a b c
and wherein R , R and R , independently of one another, are optionally substituted
residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl,
cycloheteroalkyl, alkenyl and alkoxyalkyl,
and wherein n, m and p, independently of one another, are 0 or 1,
and wherein M is a metal ion and A is a physiologically compatible anion.
Brief description of the drawings
Further details and features of the invention can be seen from the following description of
preferred examples, in particular in conjunction with the subclaims. The respective features
can be realized just in themselves or several in combination with one another. The
invention is not limited to the examples.
Fig. 1 shows an example of a sampling device.
Examples
Fig. 1 is a highly schematic sectional side view of an example of a possible sampling
device 110 according to the invention. The invention can, however, also be applied to a
large number of other types of sampling devices and analytical aids.
The sampling device 110 comprises a needle element 112, shown schematically in Fig. 1,
with a tip 114, which on movement of the needle element 112 in a puncturing direction
116 pierces a portion of a user's skin. The movement of the needle element 112 can for
example be driven by an optional actuator 118 of the sampling device 110, which is shown
schematically in Fig. 1 and which can be arranged in various ways known by a person
skilled in the art. The actuator 118 can bring about a forward movement of the needle
element 112 in the puncturing direction 116 and optionally also a backward movement of
the needle element 112 against the puncturing direction.
The needle element 112 can, in the example shown or also in other examples, in addition
optionally comprise at least one capillary-active surface structure in the form of for
example a capillary structure 120, for example at least one capillary gap, which can in
particular extend parallel to the puncturing direction 116. Other embodiments of the
capillary structure 120 are also possible. The capillary structure 120 can for example serve
for taking up and/or for transporting a sample of the body fluid in a sampling operation,
when the needle element 112 penetrates into a body tissue. For example, transporting or
taking-up of the sample can take place by capillary forces.
The needle element 112 further comprises at least one hydrophilic coating 122, preferably
in the region of the capillary structure 120. Possible embodiments of this hydrophilic
coating 122 and possible methods and examples of production thereof are explained in
more detail below.
The sampling device 110 can further comprise at least one testing element 124, for
example with at least one test chemistry, for detecting at least one analyte in the body fluid.
For example, this testing element comprises at least one test field, thus at least one area
coated with the test chemistry. In Fig. 1, the testing element 124 is shown symbolically as
testing element 124, formed separately from the needle element 112, and which can be
arranged for example in or on a housing 126 of the sampling device 110, for example a
magazine housing. For example, after a sample is taken up, the needle element 112 with
the capillary structure 120 can be brought closer to the testing element 124, in order to
transfer a sample of the body fluid or a portion thereof from the capillary structure 120 to
the testing element 124. For this purpose, for example in the sampling device 110, an
actuator 128 can be provided, which moves the needle element 112 or a part thereof, after
sample uptake, in a direction of movement 130 towards the testing element 124.
Alternatively or additionally, however, there are also other possibilities for transferring the
body fluid from the capillary structure 120 and/or from the needle element 112 to the
testing element 124, for example by passing the needle element 112, during a backward
movement after sample collection, along a suitable path past the testing element 124. Once
again, however, it is also possible, alternatively or additionally, to integrate the optional
testing element completely or partially in the needle element 112, for example at one end
of the capillary structure 120.
Various examples relating to the production of hydrophilically coated analytical aids are
explained below.
Examples:
Example 1: Coating of the capillaries and verification of the shelf lives of hydrophilizing
agents
Materials used:
- capillaries with cross-sections of 120x80 µm
- Makrolon 2458 (Bayer) granules coating materials:
1. Ar plasma
2. Heparin
3. Carbopol 971PNF (Na salt of a partially crosslinked high-molecular polyacrylic
acid) (commercially available for example from Lubrizol)
4. Mega 8 (octanoyl-N-methylglucamide) (commercially available for example from
Dojindo)
. DONS (dioctylsodium succinate) (commercially available for example from Cytec
Industries B.V.)
6. PVA 28-99 (polyvinyl alcohol) (commercially available for example from Fluka)
7. PVP K15 (polyvinyl pyrrolidone) (commercially available for example from
Aldrich)
8. Bindzil CC30 (nano-silica dispersion) (Akzo Nobel)
9. Ludox AM-30 (nano-silica dispersion) (commercially available for example from
Aldrich)
. Ludox AS-30 (nano-silica dispersion) (commercially available for example from
Aldrich)
11. Bindzil 2034DI (nano-silica dispersion) (commercially available for example from
Akzo Nobel or EKA)
12. CMC (carboxymethyl cellulose, MW = 700 000 g/mol, degree of substitution DS
0.9) (commercially available for example from Aldrich)
13. Bindzil CC301 (nano-silica dispersion) (Akzo Nobel)
14. Bindzil CC401 (nano-silica dispersion) (Akzo Nobel)
. Bindzil 33/360 (nano-silica dispersion) (Akzo Nobel)
General specification 1(a) for coating capillaries
Coating is effected by allowing the aqueous dispersions or solutions of the coating
materials to flow purely by capillary forces into the capillaries with cross-sections of
120x80 µm, until the capillaries are completely filled (approx. 35 nanolitres). Then the
coating is dried briefly with an air blower at room temperature or by heating to 140°C.
Prior to coating, the capillaries are made wettable by a plasma treatment.
General specification 1(b) for plasma treatment of the capillaries
The capillaries are treated for 30 s in a plasma stove (manufacturer: Plateg) at 50 mbar
argon pressure and 400 W microwave power.
General specification 1(c) for sterilization
Sterilization is effected by treatment with beta radiation, 25 kGy.
Example 1.1 Shelf lives of hydrophilizing agents in the presence of Makrolon
The shelf lives of the various hydrophilizing agents in the presence of volatile constituents
of packaging materials were verified for the example of Makrolon as such a material, by
in each case heat-sealing 6 capillaries coated according to general specification 1(a), which
were treated with plasma prior to coating according to general specification 1(b), with in
each case 4 g of granules of Makrolon 2458 or without granules, in a PET bag and storing
them for the specified time. Unless stated otherwise, all bags were sterilized with 25kGy
beta radiation. The time for filling on a length of 4 mm was measured. The measurement
was carried out with heparin-blood, HK 44. The results are presented in Table 1.
Table 1
Material Concentration of directly after sterilized sterilized sterilized
the solution/ sterilization 8 days / 8 days / 21 days /
dispersion used [in 75°C 75°C 75°C
water] without with with
Makrolon Makrolon Makrolon
(w/w)
Ar-plasma* -- < 300 ms does not does not --
fill fill
(without
sterilization)
Heparin* 0.05% -- 300 ms does not --
fill
Carbopol 0.1% -- 450 ms 625 ms approx.
971PNF* 2100 ms
Mega 8* 0.05% does not fill does not does not --
fill fill
DONS* 0.05% does not fill does not does not --
fill fill
PVA 28-99* 0.05% approx. 2000 > 2500 approx. --
ms ms 2000 ms
PVP K15* 0.05% -- 545 ms 680 ms --
Bindzil CC30 0.5% -- 225 ms 200 ms 210 ms
Ludox AM-30 0.5% -- 342 ms 400 ms 320 ms
Ludox AS-30 0.5% -- 270 ms 240 ms 260 ms
Bindzil 2034DI 0.5% -- 305 ms 240 ms 300 ms
* not according to the invention
The results provide evidence that the coatings according to the invention, even after
storage in PET bags in the presence of Makrolon, permit a filling time of less than 400 ms
for 4 mm length at a cross-section of 120x80 µm.
Example 1.2 Shelf lives of hydrophilizing agents in the presence of Zylar
The shelf lives of the various hydrophilizing agents in the presence of volatile constituents
of packaging materials were also verified for the example of Zylar , which contains a
higher proportion of volatile substances compared with Makrolon, by storing in each case
6 capillaries coated according to general specification 1(a), which were treated with plasma
prior to coating according to general specification 1(b), together with injection mouldings
in the material Zylar 220 (MBS copolymer, manufacturer: Ineos-Nova, approx. 1.5 mm
thick, weight 4 g). The time for filling on a length of 4 mm was measured. Measurement
was carried out with heparin-blood, HK 44. The results are presented in Table 2.
Table 2
Material Concentration Directly after 1 week 75°C 2 weeks 75°C
silica in water sterilization, with with Zylar with Zylar 220
w/w Zylar 220 220
Bindzil CC301 0.5% <300 <500 <700
Bindzil CC30 0.5% <300 <500 <700
Bindzil CC401 0.5% <300 <500 <700
Ludox AS-30 0.5% <300 No filling No filling
Ludox AM-30 0.5% <300 No filling No filling
Bindzil 30/360 0.5% <300 No filling No filling
In the presence of Zylar, the coatings with silica nanoparticles modified by organic groups
display advantages over the silica nanoparticles with no organic modifications.
Example 1.3: Comparative example: Shelf lives of hydrophilizing agents in the
presence of Zylar with non-inventive coating:
By way of a comparative example for comparing coatings according to the invention with
non-inventive coatings, the exemplary embodiment described in Example 1.2 was repeated
once more with non-inventive coatings. The coating material applied here comprised
mixtures of carboxymethyl cellulose with DONS, that is coatings which are described in
EP 2 014 727 A1. The coating involved firstly preparing an aqueous solution of said
carboxymethyl cellulose, to which the appropriate amount of DONS was added. The
aqueous solution obtained was used for coating according to general specification 1(a).
The shelf lives of the particular mixtures of CMC and DONS in the presence of volatile
constituents of packaging materials were again determined for the example of Zylar,
according to Example 1.2.
The results are presented in Table 3.
Table 3
Material (mass ratio) Concentration in Directly after 1 week 75°C with
water w/w sterilization, with Zylar 220
Zylar 220
CMC/DONS 0.05 % <300 No filling
(20:1)
CMC/DONS 0.05 % <300 No filling
(10:1)
In the presence of Zylar, the capillaries having the coatings with CMC and DONS did not
fill anymore even after one week.
Reference numbers
110 sampling device
112 needle element
114 tip
116 puncturing direction
118 actuator
120 capillary structure
122 hydrophilic coating
124 testing element
126 housing
128 actuator
130 direction of movement
Claims (25)
1. Analytical aid, comprising a surface coated at least partially with a hydrophilic coating, wherein the hydrophilic coating contains nanoparticles with silica structure and an average particle size, determined according to DIN ISO 22412:2008, in the range from 1 to 500 nm and the nanoparticles comprise groups of structure (I) or (II) Si OR 15 (II) wherein in each of the groups of structure (I), independently of one another, R is selected from the group consisting of H, a metal-containing ion, R N R R (O) R w x y z and wherein R , R , R and R , independently of one another, are selected from H and alkyl, a b c and wherein R , R and R , independently of one another, are optionally substituted residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, alkenyl and alkoxyalkyl, 25 and wherein n, m and p, independently of one another, are 0 or 1, and wherein M is a metal ion and A is a physiologically compatible anion.
2. Analytical aid according to Claim 1, wherein R is selected from the group consisting of H, an alkaline-earth metal ion, an alkali metal ion, R N R (O) R and wherein M = Al .
3. Analytical aid according to Claim 1 or 2, wherein the silica structure of the nanoparticles has at least one foreign atom, selected from the group consisting of Sn, 10 Ti, Zr, Ge, In, Ga, Al and B, preferably wherein the foreign atom is Al.
4. Analytical aid according to one of Claims 1 to 3, wherein the nanoparticles have an average particle size in the range from 1 to 100 nm, preferably in the range from 1 to 50 nm, more preferably in the range from 3 nm to 20 nm.
5. Analytical aid according to one of Claims 1 to 4, wherein 10 to 40% of all groups R (O) R
6. Analytical aid according to Claim 4, wherein the group of formula (I) has a structure 25 of formula (Ia) or (Ib): 30 (Ia) (Ib) (Ia) (Ib) wherein R and R , independently of one another, are selected from the group consisting of H and alkyl.
7. Analytical aid according to one of Claims 1 to 5, wherein the hydrophilic coating consists of the nanoparticles with silica structure.
8. Analytical aid according to one of Claims 1 to 7, wherein the surface of the 10 analytical aid, coated at least partially with the hydrophilic coating, consists at least partially of a metal and/or a metal alloy and/or a metal oxide and/or a mixed metal oxide.
9. Analytical aid according to one of Claims 1 to 7, wherein the nanoparticles have an 15 average particle size in the range from 1 to 100 nm and wherein the hydrophilic coating has a thickness, in particular an average thickness, in the region of max. 500 nm, preferably of max. 300 nm and especially of max. 100 nm.
10. Analytical aid according to one of Claims 1 to 9, wherein the surface of the 20 hydrophilic coating has a contact angle with water of less than 50°, preferably measured according to DIN 55660.2.
11. Analytical aid according to one of Claims 1 to 10, wherein the analytical aid is selected from the group consisting of a needle element, in particular a lancet, a 25 capillary, in particular a capillary gap, a cannula, a testing element for detecting at least one analyte in a body fluid and a distributing element for distributing a sample of a body fluid that has been collected, in particular a spreading network, optionally coated with a metal and/or a metal alloy and/or a metal oxide and/or a mixed metal oxide, or a plastic film, optionally coated with a metal and/or a metal alloy and/or a 30 metal oxide and/or a mixed metal oxide.
12. Analytical aid according to one of Claims 1 to 11, wherein the analytical aid is a needle element of a sampling device for taking a sample of body fluid.
13. Method of production of an analytical aid, comprising a surface that is coated at least partially with a hydrophilic coating, wherein the method comprises: (a) providing the analytical aid, (b) coating the analytical aid by bringing the analytical aid into contact with a mixture G comprising at least one dispersant and nanoparticles with silica structure, which have an average particle size, determined according to DIN ISO 22412:2008, in the range from 1 to 500 nm, wherein the nanoparticles comprise groups of structure (I) or (II) Si OR (II) wherein in each of the groups of structure (I), independently of one another, R is selected from the group consisting of H, a metal-containing ion, R N R R Si (O) R w x y z and wherein R , R , R and R , independently of one another, are selected from H and alkyl, a b c and wherein R , R and R , independently of one another, are optionally 25 substituted residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, alkenyl and alkoxyalkyl, and wherein n, m and p, independently of one another, are 0 or 1, and wherein M is a metal ion and A is a physiologically compatible anion, 5 (c) drying the analytical aid obtained according to (b), and (d) optionally sterilizing the analytical aid obtained according to (c), wherein the bringing into contact in (b) preferably takes place by dip coating and/or 10 spray coating and/or contact coating, and wherein the analytical aid and/or the surface of the analytical aid preferably consists at least partially of a metal and/or a metal alloy and/or a metal oxide and/or a mixed metal oxide and/or a mixed metal oxide. 15
14. Method according to Claim 13, wherein the surface of the analytical aid to be coated is treated before step (b) with at least one etchant and/or with plasma.
15. Method according to Claim 13 or 14, wherein the at least one dispersant is water and wherein mixture G preferably has a pH in the range from 2 to 10.
16. Method according to one of Claims 13 to 15, wherein the nanoparticles comprise groups of structure (I), and wherein 10 to 40% of all groups R are (O) R
17. Analytical aid, producible or produced by a method according to one of Claims 13 to 35 16. 18. Analytical aid according to Claim 17, wherein the analytical aid is a needle element of a sampling device for collecting a body fluid.
18. Analytical aid according to Claim 17, wherein the analytical aid is a needle element of a sampling device for collecting a body fluid.
19. Sampling device for taking a sample of body fluid, containing at least one analytical 5 aid according to one of the preceding claims referring to an analytical aid, with the proviso that the analytical aid is selected from the group consisting of a needle element and a testing element.
20. Use of nanoparticles with silica structure and an average particle size, determined 10 according to DIN ISO 22412:2008, in the range from 1 to 500 nm as hydrophilic coating for a surface of an analytical aid, more preferably as hydrophilic coating for a needle element of a sampling device for taking a sample of body fluid, wherein the nanoparticles comprise groups of structure (I) or (II) Si OR (II) 20 wherein in each of the groups of structure (I), independently of one another, R is selected from the group consisting of H, a metal-containing ion, R NR R (O) R w x y z and wherein R , R , R and R , independently of one another, are selected from H and alkyl, a b c and wherein R , R and R , independently of one another, are optionally substituted residues, selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, alkenyl and alkoxyalkyl, 5 and wherein n, m and p, independently of one another, are 0 or 1, and wherein M is a metal ion and A is a physiologically compatible anion.
21. An analytical aid according to claim 1 substantially as herein described or 10 exemplified.
22. A method according to claim 13 substantially as herein described or exemplified.
23. An analytical aid according to claim 17 substantially as herein described or 15 exemplified.
24. A sampling device according to claim 19 substantially as herein described or exemplified. 20
25. A use according to claim 20 substantially as herein described or exemplified.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11159172 | 2011-03-22 | ||
EP11159172.3 | 2011-03-22 | ||
PCT/EP2012/054993 WO2012126945A1 (en) | 2011-03-22 | 2012-03-21 | Analytical aid with hydrophilic coating that contains nanoparticles with a silicon dioxide structure |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ613644A NZ613644A (en) | 2015-01-30 |
NZ613644B2 true NZ613644B2 (en) | 2015-05-01 |
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